NCCC - Melanoma Assessment and Management of Melanoma, 2015

DRAFT FOR CONSULTATION
3 Melanoma:
4 assessment and management of
5 melanoma
6
9 Evidence Review
10
11
12
13
14
15 Developed for NICE by the National Collaborating Centre for Cancer
16
17
18 ©2015 National Collaborating Centre for Cancer

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Melanoma: DRAFT evidence review (January 2015) Page 1 of 886

1 Contents
2 1. Communication and Support ................................................................................................ 5
3 Review question: What are the specific information needs of people with melanoma and their
4 carers at different milestones/points in the patient pathway?...................................................... 5
5 Review question: What are the specific support needs of people with melanoma and their
6 carers at different milestones/points in the patient pathway?...................................................... 5
7 Review question: What are the most effective ways of meeting the patients information needs?
8 ........................................................................................................................................................ 5
9 Review question: What are the most effective ways of meeting the patients support needs? .... 5
10 2. Diagnosing Melanoma ........................................................................................................ 85
11 2.1 Dermoscopy and other visualisation techniques ................................................................ 85
12 Review question: To what extent can the diagnostic accuracy of, history-taking and visual
13 examination for the clinical identification of melanoma be improved by dermoscopy or/and
14 new visualisation techniques? ...................................................................................................... 85
15 2.2 Photography................................................................................................................... 125
16 Review question: Is photography an effective method of detecting progression of pigmented
17 lesions, including dermoscopy pictures? .................................................................................... 125
18 2.3 Borderline and Spitzoid melanocytic lesions? .................................................................. 141
19 Review question: What is the best approach to resolving clinico-pathological diagnostic
20 uncertainty for borderline or spitzoid melanocytic lesions? ...................................................... 141
21 2.4 Tumour samples for genetic testing................................................................................. 224
22 Review question: What is the most appropriate tumour sample (primary or secondary) on
23 which to carry out genetic testing to identify people who might benefit from targeted
24 therapies? ................................................................................................................................... 224
25 2.5 Genetic testing in stage I-III melanoma ............................................................................ 259
26 Review question: What is the role of genetic testing of the tumour at diagnosis for a person
27 with early stage [I-III] melanoma? .............................................................................................. 259
28 3. Staging of Melanoma ........................................................................................................ 262
29 Review question: What is the most effective method of accurately staging melanoma in
30 patients with clinicopathological stage IA melanoma? .............................................................. 262
32 patients with clinicopathological stage IB-IIC melanoma? ......................................................... 262
34 patients with clinicopathological stage III melanoma?............................................................... 262
36 patients with clinicopathological stage IV melanoma? .............................................................. 262
37 Economic Evidence Summary ..................................................................................................... 384

1 4. Stage 0-II melanoma ......................................................................................................... 397

2 4.1 Surgical Management ..................................................................................................... 397
3 Review question: What is the most effective surgical treatment for stage 0-II melanoma to
4 achieve clear margins and improved patient outcomes? ........................................................... 397
5 4.2 The use of imiquimod in stage 0 melanoma and skin metastases ..................................... 434
6 Review question: How effective is imiquimod in the treatment of stage 0 melanoma and skin
7 metastases? ................................................................................................................................ 434
8 5. Stage III Melanoma ........................................................................................................... 458
9 5.1 Surgical Management ..................................................................................................... 458
10 Review question: What is the most effective surgical treatment for stage III melanoma? ....... 458
11 5.2 Adjuvant radiotherapy .................................................................................................... 539
12 Review question: What is the effectiveness of adjuvant radiotherapy to the resected lymph
13 node basin for stage III melanoma in people who have undergone curative resection? .......... 539
14 5.3 In transit metastases ...................................................................................................... 568
15 Review question: What is the most effective treatment for in transit melanoma metastases (for
16 example, surgery, isolated limb infusion, isolated limb perfusion, palliative radiotherapy,
17 cryotherapy, electro-chemotherapy or the laser)? .................................................................... 568
18 6. Stage IV Melanoma........................................................................................................... 612
19 6.1 Localised treatments for metastatic stage IV melanoma .................................................. 612
20 Review question: How effective is surgery, ablative treatments or stereotactic radiotherapy for
21 people with stage IV melanoma with oligometastatic disease? ................................................ 612
22 6.2 Localised treatment for brain metastases ........................................................................ 654
23 Review question: What is the effectiveness of local treatment using surgery or radiotherapy
24 compared with systemic drug therapy or supportive care in the management of brain
25 metastases in people with stage IV melanoma? ........................................................................ 654
26 6.3 The role of systemic anticancer therapy .......................................................................... 687
27 Review question: What is the effectiveness of systemic anticancer therapy compared with
28 supportive care in the treatment (first and second line) of patients with stage IV metastatic
29 melanoma? ................................................................................................................................. 687
31 7. Follow-up ......................................................................................................................... 718
32 7.1 Frequency and duration of follow-up? ............................................................................. 718
33 Review question: In asymptomatic patients who have undergone treatment with curative intent
34 for melanoma, what is the optimal method, frequency and duration of follow-up? ................ 718
36 7.2 Brain Imaging ................................................................................................................. 795

1 Review question: In patients with melanoma who are undergoing body imaging as part of
2 follow-up and who have no neurological signs or symptoms, should brain imaging be included?
3 .................................................................................................................................................... 795
4 Review question: Where imaging is indicated, is CT or MRI the most appropriate method of
5 imaging for brain metastasis as part of follow-up for asymptomatic patients?......................... 803
6 8. Other management issues during follow-up ...................................................................... 808
7 8.1 Managing suboptimal vitamin D levels ............................................................................ 808
8 Review question: How should sub-optimal vitamin D levels be managed in people with
9 melanoma (including supplements and monitoring)? ................................................................ 808
10 8.2 Concurrent Drug Therapies ............................................................................................. 848
11 Review question: What is the most effective approach to the management of risks to patients
12 associated with concurrent drug therapies used to treat other conditions, which may affect the
13 prognosis from melanoma (for example, immunosuppressants, levadopa, metformin, HRT,
14 COCP)? ........................................................................................................................................ 848
15 Appendix ................................................................................................................................. 881
16 Health Economic Search Strategies ............................................................................................ 881
17 Excluded Health Economic Studies ............................................................................................. 882
18
19
20
21

2 1. Communication and Support

3 Review question: What are the specific information needs of people with melanoma and
4 their carers at different milestones/points in the patient pathway?
5 Review question: What are the specific support needs of people with melanoma and their
6 carers at different milestones/points in the patient pathway?
7 Review question: What are the most effective ways of meeting the patients information
8 needs?
9 Review question: What are the most effective ways of meeting the patients support
10 needs?
11
12 Background
13 High quality, appropriate and clear individualised information, at different points in the patients
14 pathway, may empower patients/carers to participate in the clinical decision making with regards to
15 treatment, including risks/ benefits and may positively impact on physical and psychosocial
16 wellbeing. Needs may differ in various age groups. Some patients / carers may want to know all
17 information available, while others may wish to know little or nothing, this highlights the need for
18 individualised information assessment/ prescription, needs may change during the pathway.
19 The emotional impact of cancer diagnosis can be significant, however psycho-social support needs
20 vary from patient to patient, and may be associated with treatment morbidity. Holistic needs
21 assessment (HNA) is a tool which is currently used to measure patient needs and opens up
22 communication between patient/carer and healthcare professionals. It can help HCP to recognise
23 and effectively treat depression and other symptoms of stress, or refer patients to available
24 resources.
25 Question in PICO Format
Population Intervention Outcomes

 People with Melanoma Specific information needs of people with Health Related
 Carers of people with melanoma and their carers at different Quality of Life
melanoma milestones/points in the patient pathway? Patient
Stage: satisfaction
 0-Ia Different age groups? Treatment
 Ib – IIIa decision making
 IIIb – IIIc Cultural groups? Patient reported
 IV outcomes
26
27 How will the information be searched?
Searches:

Can we apply date limits to the search (Please Date limit of 1980 to be applied
provide information on any date limits we can
apply to the searches for this topic. This can
be done for each individual intervention as
appropriate)
Are there any study design filters to be used Any study type including RCT, Systemic reviews, Case
(RCT, systematic review, diagnostic test). reports
List useful search terms. (This can include such  Information cancer patients
information as any alternative names for the  Unmet needs cancer patients
interventions etc)
 psychosocial distress,
 health literacy
 psycho-social support.
2 The Review Strategy
3 Evidence was be identified, assessed and synthesised according to the methods outlined in the
4 Guidelines Manual (2012). Relevant studies were identified through sifting the abstracts and
5 excluding studies clearly not relevant to the PICO. In the case of relevant or potentially relevant
6 studies, the full paper was ordered and reviewed, whereupon studies considered to be not relevant
7 to the topic were excluded. Studies which were identified as relevant were critically appraised and
8 quality assessed using GRADE methodology and NICE checklists. Data relating to the identified
9 outcomes were extracted from the relevant studies. The data were not meta-analysed due to the
10 difference in interventions and populations (in terms of melanoma thicknesses) of the included
11 studies, but were instead summarised per study in tabular form, and further in GRADE tables and
12 evidence statements.
13
14 Search Results
Database name Dates Covered No of references Finish date of

found search
Medline 1946-2014 4681 24/03/2014
Premedline Mar 24 2014 303 25/03/2014
Embase 1947-2014 8894 25/03/2014
Cochrane Library Issue 3, Mar 152 25/03/2014
2014
Web of Science (SCI & SSCI) 1900-2014 6494 25/03/2014
PsycInfo 1806-2014 143 25/03/2014
CINAHL 1979-2014 392 31/03/2014
Total References retrieved (after databases combined, de-duplicated and sifted): 352
& 1 reference added 30/04/2014
15 Medline search strategy (This search strategy is adapted to each database)

16 1. exp Melanoma/
17 2. melanoma$.tw.

1 3. (maligna$ adj1 lentigo$).tw.

2 4. (hutchinson$ adj1 (freckle$ or melano$)).tw.
3 5. dubreuilh.tw.
4 6. LMM.tw.
5 7. or/1-6
6 8. Health Services Accessibility/
7 9. Office Visits/
8 10. Remote Consultation/
9 11. Physician-Patient Relations/
10 12. Nurse-Patient Relations/
11 13. Professional-Patient Relations/
12 14. Professional-Family Relations/
13 15. ((patient* or consumer* or carer* or caregiver* or spouse* or famil* or relati*) adj2 (decision*
14 or choice* or preference* or support* or participat* or educat*)).tw.
15 16. ((personal or interpersonal or individual*) adj2 (decision* or choice* or preference* or support*
16 or participat* or educat*)).tw.
17 17. (information adj2 (aid* or support* or need* or provision or deliver* or material* or
18 resource*)).tw.
19 18. ((patient* or carer* or caregiver* or spouse* or famil* or relati*) adj2 (information or
20 literature)).tw.
21 19. ((web* or print*or electronic*) adj2 (information or resource*)).tw.
22 20. Patient Education as Topic/
23 21. Pamphlets/
24 22. (pamphlet* or leaflet* or booklet* or guide* or sheet* or flyer* or flier*).tw.
25 23. ((electronic or email) adj (report* or support)).tw.
26 24. exp Audiovisual Aids/
27 25. (video* or dvd* or tape* or cd*1 or film*1 or telephone* or phone* or computer* or internet or
28 online or web or electronic).tw.
29 26. exp Internet/
30 27. exp telephone/
31 28. exp hotlines/
32 29. ((hot or help* or tele* or phone) adj (line* or support)).tw.
33 30. Communication/
34 31. (communicat* or talking).tw.
35 32. exp social support/
36 33. exp Self-Help Groups/
37 34. ((inform* or support*) adj2 (tool* or method* or group*)).tw.
38 35. (face* adj face*).tw.
39 36. Psychoeducation/
40 37. Psychotherapy/
41 38. ((psychosocial or psycho*) adj2 (support* or educat* or need*)).tw.
42 39. Stress, Psychological/
43 40. Counseling/
44 41. exp Patient Education/mt [Methods]
45 42. or/8-41

1 43. 7 and 42
2 44. limit 43 to yr="1980 -Current"

1 Screening Results
2 The literature search identified 351 potentially relevant papers of which 19 were ordered. Four
3 systematic reviews (Cornish et al, 2009; Kasparian et al, 2009; Barker et al, 2011 and Rychetnick et al
4 2013) were included and one primary study (Olivera et al, 2013). Additional evidence about patient
5 information and support needs came from the 2012-2013 NHS England Cancer Patient Experience
6 Survey which was sent to all adult patients with a primary diagnosis of cancer who were treated in a
7 hospital as an inpatient or day-case patient between September and November 2012.
8 Evidence statements
9 Information needs
10 Timing of Information
11 In one UK based survey (Stamataki et al, 2014) participants reported feeling there was no standard
12 procedure for when patients were provided with information. Some participants reported getting
13 too much information up front and some participants felt that information was provided too late,
14 particularly in the case of sun protection advice.
15 Information needs at diagnosis

16 In the Cancer Patient Experience Survey (2012-2013), despite scoring highly in comparison to other
17 cancers, around 15% of patients with melanoma felt they were not given clear information about
18 their cancer or test results.
19 A UK based study (Stamataki et al, 2014) found that patients felt they could not comprehend the
20 information provided about their prognosis or stage and this contributed to feelings of anxiety and
21 uncertainty for the future.
22 Information needs during treatment

23 In the Cancer Patient Experience Survey (2012-2013) the experience of patients with melanoma
24 ranked the lowest amongst cancer types for being given written information about side effects (68%)
25 and being told they could get free prescriptions (56%).
26 Information needs during follow up

27 Follow up was an important source of information about sun-related behaviours (Rychetnik et al,
28 2013) – the clinic doctor, books & magazines and the clinic nurse being the main sources. Some
29 patients reported a lack of confidence in skin self examination in Olivera (2013).
30 In the Cancer Patient Experience Survey (2012-2013) 13% of patients with melanoma felt they were
31 not given clear information about what to do post discharge.
32 In a UK based study (Stamataki et al, 2014) patients reported a strong desire for more detailed
33 information on sun protection. They reported feeling that the information provided was not detailed
34 enough and did not cover issues such as travelling to hot countries, type of sunscreen and frequency
35 of sunscreen application.
36 Source of Information
37 In a survey of melanoma survivors (Hamilton et al, 2014) 90% of patients (n=28) had used the
38 internet as a source of melanoma information. 69% of patients chose melanoma websites based on

1 top hits returned by searches; 42% chose websites from a known reputable source and 15% chose
2 websites based on recommendations from doctors or health care providers.
3 52% of internet users reported that internet use affected their specialist consultation by helping
4 their decision making while 37% felt it did not influence their decision making and 7% considered it
5 to make their decision more difficult (Hamilton et al, 2014).
6 Ease of access was considered the main strength of the internet (74%) followed by the volume and
7 detail of information (52%) , discussion of different perspectives/options (37%) and anonymity (7%)
8 though 54% of users reported that available information was difficult to understand (Hamilton et al,
9 2014)
10 Support needs
11 General support needs

12 There was consistent evidence that around 20% to 30% of patients with melanoma experience
13 clinically significant levels of distress (Cornish, Kaspariain 2009; Rychetnik, 2013). Rychetnik (2013)
14 reported that around half of patients surveyed would be interested in professional emotional
15 support, preferably from their doctor rather than a psychiatrist or psychologist.
16 In the Cancer Patient Experience Survey (2012-2013) around 25% of patients with melanoma felt
17 that emotional support was insufficient from hospital and G.P. practice staff. In the survey 85% of
18 melanoma patients said that hospital staff gave them information about support groups but only
19 57% said hospital staff gave them information about financial support.
20 One cross-sectional study carried out in two UK centres (Molassiotis et al, 2014) reported that young
21 patients had higher unmet needs relating to the psychological domain (p<0.001). Participants with
22 lymph node involvement expressed significantly higher levels of unmet needs for physical and daily
23 living (p<0.001), psychological needs (p=0.045), sexual needs (p=0.015) and overall score for needs
24 (p=0.006).
25 Psychological needs were the most common unmet needs particularly fears about cancer spreading
26 (29%) and uncertainty about the future (25.2%).
27 Support needs at diagnosis

28 In a systematic review of qualitative studies, Barker (2011) reported that on receiving a diagnosis of
29 skin cancer individuals experience strong emotional responses including anxiety, shock and panic. In
30 a systematic review of quality of life studies in melanoma, Cornish et al (2009) noted that the
31 immediate period following diagnosis was often associated with impairment in health related quality
32 of life, with patients reporting increased pain, less energy and physical or emotional distress which
33 impaired social functioning.
34 In the Cancer Patient Experience survey 64% of melanoma patients said they were told they could
35 bring a friend with them when they were first told they had cancer; this was the lowest proportion
36 of all the cancer types.

1 During treatment
2 Barker et al (2011) noted that once the initial emotional response to a skin cancer diagnosis had
3 subsided individuals typically expressed satisfaction with their experience of care. Cornish et al.
4 (2009) reported that during this phase patients were more likely to be anxious about disease
5 recurrence than the physical limitations related to melanoma or its treatment.
6 During follow up
7 There was evidence that follow-up was a source of both anxiety and reassurance for patients with
8 melanoma. Psychological distress was reported during follow-up, potentially interfering with
9 adherence to screening and preventative behaviours (Cornish, 2009; Olivera, 2013; Rychetnik, 2013)
10 and some people delayed seeking medical advice for their skin cancer symptoms (Barker, 2011). In
11 the Rychetnik (2013) systematic review around half of surveyed patients said that follow up
12 appointments made them anxious (with clinically significant levels in approximately 20% of patients).
13 This was sometimes accompanied by physical symptoms and sometimes started weeks before the
14 appointment. Overall satisfaction with follow-up, however, was high and receiving good news from
15 physician screenings was reassuring (Olivera, 2013; Rychetnik, 2013).
16

1 Table 1.1. Results of the NHS England 2012-2013 Cancer Patient Experience Survey
Overall Melanoma†
No. Survey question Rank*
(N=68,737) (N=1854)
Seeing your GP
1 Saw GP once or twice before being told had to go to hospital 74% 90% 2
2 Patient thought they were seen as soon as necessary 84% 87% 2
How long was it from the time you first thought something might be wrong
3 with you until you first saw a hospital doctor? (% answering less than 12 94% N.S. N.S.
months)
4 Patient's health got better or remained about the same while waiting 80% 94% 1
Diagnostic tests
5 % answering they've had diagnostic tests for cancer in last 12 months 90% N.R. N.R.
6 Staff gave complete explanation of purpose of test(s) 84% N.S. N.S.
7 Staff explained completely what would be done during test 87% N.S. N.S.
8 Given easy to understand written information about test 88% N.S. N.S.
9 Given complete explanation of test results in understandable way 78% 85% 1
Finding out what was wrong
10 % answering that they were first told by a doctor (incl GP) or nurse 95% N.R. N.R.
11 Patient told they could bring a friend when first told they had cancer 74% 63% 13
12 Patient felt they were told sensitively that they had cancer 84% 88% 1
13 Patient completely understood the explanation of what was wrong 73% 81% 1
14 Patient given written information about the type of cancer they had 71% 81% 1
Deciding best treatment
Patient given a choice of different types of treatment (if more than one
15 85% 88% 3
treatment was suitable)
Patient’s views definitely taken into account by doctors and nurses

16 71% 77% 1
discussing treatment
17 Possible side effects explained in an understandable way 75% 74% 6
18 Patient given written information about side effects 82% 68% 13
Patient definitely told about treatment side effects that could affect them
19 55% 57% 5
in the future
20 Patient definitely involved in decisions about care and treatment 72% 79% 1

Overall Melanoma†
(N=68,737) (N=1854)
Clinical nurse specialist
21 Patient given the name of the CNS in charge of their care 88% 84% 10
22 Patient finds it easy to contact their CNS 75% N.S. N.S.
23 CNS definitely listened carefully the last time spoken to 91% N.S. N.S.
24 Get understandable answers to important questions all/most of the time 91% N.S. N.S.
Support for patients
25 Hospital staff gave information about support groups 82% 85% 2
Hospital staff gave information about impact cancer could have on

26 74% 76% 3
work/education
27 Hospital staff gave information on getting financial help 54% 52% 9
28 Hospital staff told patient they could get free prescriptions 76% 56% 13
Research
29 Patient has seen information about cancer research in the hospital 85% 80% 12
30 Taking part in cancer research discussed with patient 32% 18% 12
31 Patient has taken part in cancer research (% of those who were asked) 64% 60% 11
Operations
32 % ans. they've had an operation in last 12 months 56% N.R. N.R.
33 Staff gave complete explanation of what would be done 87% N.S. N.S.
34 Patient given written information about the operation 74% 68% 7
35 Staff explained how operation had gone in understandable way 77% N.S. N.S.
Hospital doctors
36 % ans. they've stayed overnight for cancer care in last 12 months 67% N.R. N.R.
37 Got understandable answers to important questions all/most of the time 83% N.S. N.S.
38 Patient had confidence and trust in all doctors treating them 85% N.S. N.S.
39 Doctors did not talk in front of patient as if they were not there 83% 88% 2
40 Patient’s family definitely had opportunity to talk to doctor 66% 74% 1
Ward nurses
41 Got understandable answers to important questions all/most of the time 75% N.S. N.S.

Overall Melanoma†
(N=68,737) (N=1854)
42 Patient had confidence and trust in all ward nurses 69% 77% 1
43 Nurses did not talk in front of patient as if they were not there 85% 89% 1
44 Always / nearly always enough nurses on duty 61% 74% 1
Hospital care and treatment
45 Patient did not think hospital staff deliberately misinformed them 89% N.S. N.S.
46 Patient never thought they were given conflicting information 79% 87% 1
47 All staff asked patient what name they preferred to be called by 56% 53% 12
48 Always given enough privacy when discussing condition/treatment 84% N.S. N.S.
49 Always given enough privacy when being examined or treated 94% N.S. N.S.
Patient was able to discuss worries or fears with staff during visit (of those
50 64% N.S. N.S.
with worries or fears)
Hospital staff did everything to help control pain all of the time (of those
51 85% N.S. N.S.
with pain)
52 Always treated with respect and dignity by staff 83% N.S. N.S.
Information before leaving and home support
Given clear written information about what should / should not do post
53 84% 87% 2
discharge
54 Staff told patient who to contact if worried post discharge 94% N.S. N.S.
55 Family definitely given all information needed to help care at home 61% N.S. N.S.
Patient definitely given enough care from health or social services (of those
56 60% 61% 3
who needed it)
Day / outpatient care
Staff definitely did everything to control side effects of radiotherapy (of

57 79% N.S. N.S.
those receiving it)
Staff definitely did everything to control side effects of chemotherapy (of

58 81% N.S. N.S.
those receiving it)
59 Staff definitely did everything they could to help control pain 82% N.S. N.S.
60 Hospital staff definitely gave patient enough emotional support 70% 74% 1
Outpatient appointments
61 % ans. they've had an OP appt with a cancer doctor in last 12 months 94% N.R. N.R.

Overall Melanoma†
(N=68,737) (N=1854)
62 Doctor had the right notes and other documentation with them 96% N.S. N.S.
Care from general practices
63 GP given enough information about patient`s condition and treatment 95% N.S. N.S.
64 Practice staff definitely did everything they could to support patient 68% 76% 1
Overall NHS care
65 Hospital and community staff always worked well together 64% 70% 1
Have you had treatment from any of the following range of therapists for
66 - - -
your cancer?
67 Given the right amount of information about condition and treatment 88% N.S. N.S.
68 Patient offered written assessment and care plan 22% 20% 10
69 Patient did not feel that they were treated as a `set of cancer symptoms` 81% 88% 1
70 Patient`s rating of care `excellent`/ `very good` 88% N.S. N.S.
1 †The survey used a “skin cancer” classification, but ICD10 C44 tumours were excluded, so it is assumed that these were patients with
2 melanoma.
3 *Rank of skin cancer patients in comparison to the 12 other cancer types: breast, colorectal/lower gastro, lung, prostate, brain/CNS,
4 gynaecological, haematological, head & neck, sarcoma, upper gastro, urological and other.
5 Abbreviations: N.R., not reported – results were not analyzed or reported by cancer type; N.S. – although there was some variation
6 between cancer types this was not statistically significant and the figures were not reported by cancer type.

1 References
2 Included studies
3 Barker, J. (2011). The needs and experiences of people with a skin cancer: a systematic review.
4 Joanna Briggs Institute Library of Systematic Reviews, 9, 104-121.
5 Cornish, D., Holterhues, C., van de Poll-Franse, L., Coebergh, J. W., & Nijsten, T. (2009). A systematic
6 review of health-related quality of life in cutaneous melanoma. Annals of Oncology, 20, 51-58.
7 Hamilton, S. N., Scali, E. P., Yu, I., Gusnowski, E., and Ingledew, P. A. Sifting Through It All:
8 Characterizing Melanoma Patients' Utilization of the Internet as an Information Source. Journal of
9 Cancer Education . 1-8-2014.
10 Kasparian, N. A., McLoone, J. K., Butow, P. N., Kasparian, N. A., McLoone, J. K., & Butow, P. N. (2009).
11 Psychological responses and coping strategies among patients with malignant melanoma: a
12 systematic review of the literature. [Review] [67 refs]. Archives of Dermatology, 145, 1415-1427.
13 McLoone, J., Menzies, S., Meiser, B., Mann, G. J., & Kasparian, N. A. (2013). Psycho-educational
14 interventions for melanoma survivors: a systematic review. Psycho-Oncology 27[7], 1444-1456.
15 Molassiotis, A., Brunton, L., Hodgetts, J., Green, A. C., Beesley, V., Mulatero, C., Newton-Bishop, J. A.,
16 and Lorigan, P. Prevalence and correlates of unmet supportive care needs in patients with resected
17 invasive cutaneous melanoma. Annals of Oncology . 31-7-2014. National Cancer Patient Experience
18 Survey 2012-13 National Report. Quality Health (2013).
19 Oliveria, S. A., Shuk, E., Hay, J. L., Heneghan, M., Goulart, J. M., Panageas, K. et al. (2013). Melanoma
20 survivors: health behaviors, surveillance, psychosocial factors, and family concerns. Psycho-
21 Oncology, 22, 106-116.
22 Palesh, O., Aldridge-Gerry, A., Bugos, K., Pickham, D., Chen, J. J., Greco, R., and Swetter, S. M. Health
23 behaviors and needs of melanoma survivors. Supportive Care in Cancer . 31-5-2014.
24 Stamataki, Z., Brunton, L., Lorigan, P., Green, A. C., Newton-Bishop, J., and Molassiotis, A. Assessing
25 the impact of diagnosis and the related supportive care needs in patients with cutaneous melanoma.
26 Supportive Care in Cancer . 5-9-2014
27

Evidence tables
Table 1.2 Study Quality
Barker et al Cornish et al Kasparian, Molassiotis Nicole Palesh et Rychetnik, L Stamataki

(2011) (2009) N. A et al et al (2014) Hamilton al (2014) et al (2013) et al
(2009) et al (2014)
(2014)
The review addresses an Yes Yes Yes Yes
appropriate and clearly
focused question that is
relevant to the review
question
The review collects the type Yes Yes Yes Yes
of studies you consider
relevant to the guidance
review question
The literature search is Yes Yes Yes Yes
sufficiently rigorous to
identify all the relevant
studies
Study quality is assessed and Yes Yes Yes Yes
reported
An adequate description of Yes Yes Yes Yes
the methodology used is
included, and the methods
used are appropriate to the
question
Additional Comments Overall Overall Overall Overall
assessment assessment assessment assessment
of internal of internal of internal of internal
validity. Are validity. Are validity. Are validity. Are

Barker et al Cornish et al Kasparian, Molassiotis Nicole Palesh et Rychetnik, L Stamataki

(2011) (2009) N. A et al et al (2014) Hamilton al (2014) et al (2013) et al
(2009) et al (2014)
(2014)
the results the results the results the results
internally internally internally internally
valid? Yes valid? Yes valid? Yes valid? Yes
Overall Overall Overall Overall

assessment assessment assessment assessment
of external of external of external of external
validity – Are validity – Are validity – Are validity – Are
the results the results the results the results
externally externally externally externally
valid (i.e. valid (i.e. valid (i.e. valid (i.e.
generalisable generalisable generalisable generalisable
to the whole to the whole to the whole to the whole
source source source source
population)? population)? population)? population)?
Partially – Partially – Yes Yes
one of the the included
studies studies cover
included a a range of
minority treatments
(5/18) of so it is
patients with difficult to
melanoma. draw specific
conclusions
about
HRQOL
impairments.

Oliveria, S. A et al (2013
Is a qualitative approach appropriate? Appropriate
Is the study clear in what it seeks to do? Clear
How defensible/rigorous is the research Defensible

design/methodology?
How well was the data collection carried out? Appropriate
Is the context clearly described? Clear
Were the methods reliable? Reliable
Are the data 'rich'? Rich
Is the analysis reliable? Reliable
Are the findings convincing? Convincing
Are the conclusions adequate? Adequate
Was the study approved by an ethics committee? Not reported
Is the role of the researcher clearly described? Clear

Study Aim Setting Population Intervention Comparison Follow-up Outcomes and Results
Barker et al To assess the Systematic 2 qualitative Used the N/A Four categories were distilled from
(2011) needs and review of studies met Joanna Briggs the 12 study findings:
experiences of qualitative the inclusion Institute
adults criteria: one Qualitative 1. On receiving a diagnosis of
studies
following a 2009 study of Assessment skin cancer individuals
diagnosis of 10 men with and Review experience a strong
skin cancer melanoma and approach for
emotional response such as
another 2004 meta-
study of skin synthesis. The anxiety, shock and panic.
cancer (5/18 findings of 2. Individuals develop a range of
had each study mechanisms to help them
melanoma). were cope with a diagnosis of skin
Both were UK extracted – cancer
studies and these were 3. Once the initial emotional
used semi- then organised
response to a diagnosis
structured into categories
interviews to which were subsides, individuals express
needs and finally satisfaction with their
experiences of summarised experience of care
the into 4. Individuals delay seeking
participants. “synthesised medical advice in relation to
findings”.
symptoms associated with
skin cancer often trivialising
their significance
Two findings were synthesised from

the above four categories
1. There should be a strategy to

help clinicians assess and

address the psychosocial
needs of skin cancer patients:
Patients given a diagnosis of
skin cancer experience
extreme emotional responses
and develop specific coping
responses to help them deal
with their emotions
2. There is a need to address the
lack of awareness regarding
symptoms of skin cancer and
promote early detection
through public education:
Individuals delay seeking
medical help but once a
diagnosis is given and the
initial emotional response
subsides patients express
satisfaction with their care
Cornish et al To summarise Systematic Patients with Three studies 20 different measures of HRQOL were
(2009) the available review of cutaneous investigated reported in the 13 studies. Both
literature on quantitative melanoma the effects of a generic measures (EORTCQLQ-30, EQ-
HRQOL in studies specific 5D, SF-36, BSI etc) and specific
melanoma therapy on melanoma measures were reported
HRQOL the (e.g. FACT-M)
others were
studies of Approximately one third of patients
HRQOL in reported clinically significant levels of
melanoma distress. The results indicated that
patients in
there were three distinct periods of

general. HRQOL impairment in melanoma:
diagnosis, treatment and follow-up.
Diagnosis
The immediate period following

diagnosis was often associated with
HRQOL impairment. Patients reported
increased pain, less energy and
physical or emotional distress which
impaired social functioning.
Treatment
During this phase patients were

anxious about disease recurrence:
even more so than the physical
limitations related to melanoma or its
treatment.
Follow-up
Psychological distress was reported

during follow-up, potentially
interfering with adherence to
screening and preventative
behaviours.

Predictors of HRQOL impairment
Factors associated with impaired

HRQOL were: poor physical health,
non-cancer life stresses, low levels of
social support and maladaptive
coping styles.
Kasparian, N. What is the Systematic Melanoma or Three studies 20 different measures of HRQOL were
A et al (2009) prevalence of Review of with a high investigated reported in the 13 studies. Both
psychological quantitative risk of the effects of a generic measures (EORTCQLQ-30, EQ-
studies. developing specific
distress 5D, SF-36, BSI etc) and specific
melanoma. therapy on
among people Included HRQOL the melanoma measures were reported
with studies came others were (e.g. FACT-M)
melanoma or from Australia, studies of
with a high Israel, Sweden, HRQOL in Prevalence of psychological distress
risk of USA, Finland, melanoma (anxiety and depression)
developing Germany, patients in
Croatia, general. When measured using a validated
melanoma? scale approximately 30% of patients
Austria and
The reported levels of psychological
What are the
risk factors for Netherlands. distress indicative of the need for
psychological clinical intervention.
distress in this
population?
Demographic, clinical and

psychosocial predictors of distress
Demographic risk factors: female sex,

younger age group, absence of spouse

or partner, fewer children, lower
education and economic adversity
were all factors associated with
increased reporting of psychological
distress.
Clinical factors: The association

between clinical factors (for example
stage of disease and tumour
thickness) and psychological distress if
unclear. There is some evidence that
patients with greater physical
deterioration or tumours on visible
parts of the body experience greater
distress.
Psychological and social factors:

Patients with melanoma who form
positive or meaningful appraisals of
their cancer experience, have an
active-cognitive coping style and/or
greater social support are more likely
to demonstrate healthy psychological
adjustment.
Molassiotis et To examine Cross-sectional N=455 Questionnaire N/A 82% of the sample were from hospital
al (2014) unmet survey Patients with Assessment A and 18% from hospital B
supportive resected stage

care needs of 2 centres in I-III melanoma Patient needs Response Rates were
patients with the UK diagnosed at were assessed 79% in hospital A (face to face
invasive least months-5 using the recruitment)
melanoma, years Supportive 50% in hospital B (recruitment by
with and previously. Care Needs mail)
without lymph Survey Short Supportive Care Needs (Univariate
node Exclusions Form and the Analysis)
involvement Other Cancers supplementar Moderate and high response needs
<3 months y melanoma were merged with low to give a
post- module. dichotomous score (need versus no
treatment need).
Anxiety and
depression Significantly more patients who were
were assessed divorced/separated/widowed, left
using the school at 14-15, had no qualifications,
Hospital performed manual work or had lymph
Anxiety and node involvement or lymphoedema
Depression had at least one unmet need.
scale
Young patients had higher unmet
Quality of life needs relating to the psychological
was assessed domain (p<0.001).
using the 51 Participants with lymph node
item involvement expressed significantly
Functional higher levels of unmet needs for
Assessment of physical and daily living (p<0.001),
cancer psychological needs (p=0.045), sexual
Therapy- needs (p=0.015) and overall score for
Melanoma needs (p=0.006).
Breslow thickness and time since

diagnosis were not associated with

unmet needs.
Psychological needs were the most

common unmet needs:
Fears about cancer spreading
= 29%
Uncertainty about the future
= 25.2%
There was a low level reported for

melanoma specific needs.
Anxiety, depression and quality of life

Mean HADS scores for anxiety was
5.66 (SD=3.9) and depression was 3.2
(SD=3.2)
29% of patients reported signs of

anxiety:
Borderline=15.6%
Definitive=13.4%
11% reported signs of depression

Borderline = 7.5%
Definitive = 3.4%
Anxiety and depression were

significantly associated with unmet
supportive care needs.
Patients reporting no unmet needs or
needs met had a mean anxiety score
of 4.89 (SD=3.6) compared with a

mean score of 8.98 (SD=4.04) for
patients with unmet needs (p<0.001).
Patients reporting no unmet needs or
needs met had a mean depression
score of 2.59 (SD=2.8) compared with
a mean score of 5.36 (SD=3.45) for
patients with unmet needs (p<0.001).
Quality of life scores were relatively

high overall though patients with
lymph node involvement had
significantly worse quality of life in
relation to physical and emotional
wellbeing (p<0.05) but not for overall
quality of life.
Associations with unmet supportive

care needs (multivariate analysis)
Leaving school aged ≥18 years versus
14-15 years (OR=4.85, 95% CI 2.23-
20.54, p<0.001)
High emotional (OR=0.65, 95% CI

0.58-0.74) and social (OR=0.91, 95%
CI 0.86-0.96) quality of life was
associated with lower odds of unmet
needs
Patients aged >70 had fewer

psychological needs compared to
patients aged <50 (p<0.05).

Patients recording a higher emotional
quality of life were less likely to have
specific psychological (p<0.001),
health systems and information
(p<0.001) and patient care and
support needs (p<0.001).
The predictive power for all logistic

regression models was good
classification rates 0.76-0.85
AUC 0.75-0.82
Regression models showed 2-3fold

greater sensitivity (0.41-0.69) than
the random prediction of having
unmet needs (0.27)
National Questionnaire/ The sample 2012-2013 The survey was sent to all adult
Cancer Patient Survey included 1854 English NHS patients with a primary diagnosis of
Patient patients with Cancer Patient cancer who were treated in a hospital
Experience skin cancer. as an inpatient or day-case patient
Experience
Survey 2012- Patients with between 1st September 2012 and
13 National an ICD code of Survey. 31st November 2012. 116,490 surveys
Report. C44 (other returned. were send out and 68,737 (64%) were
Quality Health malignant
(2013). neoplasms of For full results see Table 1.1 in
the skin) were evidence review
excluded from
the survey –
this means
almost all the
included skin

cancer
patients had
melanomas (a
few may have
had Merkel
cell
carcinoma).
Nicole To provide Retrospective N=62 patients Internet as a N/A 31 questionnaires were completed
Hamilton et al updated Case Series agreed to take source of and returned giving a response rate of
(2014) assessment of part melanoma 50%.
how Single Centre information
melanoma (Canada) 29 patients (93%) reported internet
patients use use and 68% of these patients
the internet as 2010-2013 reported using the internet 1-4 times
a source of a day.
information
and to assess 97% accessed the internet at home
how the 55% accessed the internet at work
internet 100% accessed the internet
impacted themselves and 21% also asked
patients family/friends to access the internet
interactions for them.
with their
oncologists 90% of patients (n=28) had used the
and treatment internet as a source of melanoma
decisions information.
Patients who did not use the internet

as a source of melanoma information
reported being satisfied with the
information provided by health

professionals (n=3), being confused or
overwhelmed by the available
information (n=2) or were not
internet users (n=1).
90% of patients used Google, 11%

used Yahoo, 7% used Bing and 4%
used Microsoft Network.
69% of patients chose melanoma

websites based on top hits returned
by searches
42% chose websites from a known
reputable source
15% chose websites based on
recommendations from doctors or
health care providers
54% viewed 1-5 melanoma sites

39% viewed 6-10 sites
8% viewed more than 10 websites
46% of internet users visited specific

hospital/cancer institute specific
websites
15% visited commercial health or
general knowledge websites for
melanoma information.
38% could not recall the sites they
used
96% sought information on

melanoma treatment
prevention
64% sought information on screening
54% sought information on symptom
management and treatment toxicity
18% sought information on clinical
trials
alternative/complementary therapy
‘melanoma’(75%) and ‘skin cancer’

(36%) were the most common search
terms
25% also used terms specific to
melanoma treatments, 11% searched
for terms relating to symptoms and
11% for melanoma staging.
In evaluating the quality of available

information, 64% compared data
from several websites and 64%
discussed the information with their
family doctor or oncologist.
32% selected information from
academic or government sites.
Only 14% referred to the author
credentials
11% examined the references cited on
the website.
85% of internet users reported the

internet to be a useful source of
melanoma information.
78% of users reported that the
internet improved their
understanding of their diagnosis and
71% felt that it had been influential
on their treatment decisions.
52% of internet users reported that

internet use affected their specialist
consultation by helping their decision
making while 37% felt it did not
influence their decision making and
7% considered it to make their
decision more difficult.
Ease of access was considered the

main strength of the internet (74%)
followed by the volume and detail of
information (52%) , discussion of
different perspectives/options (37%)
and anonymity (7%).
54% of users reported that available

information was difficult to
understand.
Oliveria, S. A What are the Focus Groups 48 patients Thematic text Impact of melanoma on life outlook
et al (2013) experiences of diagnosed analysis of the
and broader health (themes with
melanoma Qualitative with invasive focus group
survivors Study primary transcripts. representative quotes)
regarding melanoma,

surveillance, stages I-III and • Receiving good news from physician
psychosocial 1-10 years
screenings was psychologically
and family since diagnosis
concerns? who were reassuring for survivors.
treated at
Memorial ‘Coming back to the
Sloan
Kettering dermatologist, sort of getting
Cancer Centre that stamp of approval for me
between 1996
and 2005. is always a positive thing. And
Random then afterwards you sort of
sample,
stratified by get—you know, it actually
age. clears your head a little bit. So
I don’t mind coming. Not just
clears your head that, okay,
there’s something on the plus
side, but it clears you of any
potential negative thoughts
and worries.’ (Patient <50
years of age; 1 to <5 years
since diagnosis)
• Melanoma diagnosis prompted

many survivors to assess and

reprioritize life values and develop a
more positive life outlook.
‘In terms of my life, I think it

just made me focus down on
the day-to-day and not be so
overwhelmed with irritations
at work. . . It’s just—it’s like
it’s not that important. The
fact that I’m alive another day
is more important than this.’
(Patient <50 years of age; 1 to
<5 years since diagnosis)
• Receiving melanoma diagnosis

elevated the importance of being
more vigilant and proactive regarding
monitoring one’s health and
interacting with physicians to obtain
good care.
‘So what I should have done

right from the beginning was,
as soon as I saw something
like that, if they’re not real
sure, why not just get it taken
off? And why don’t you
biopsy it or do something? So
that taught me to be real
proactive. If somebody says,
“Well, don’t worry about it,”
I’ll tell you what, if it bothers
me, I’m not going to take that
for an answer anymore. I’m
going to say, “Do something. I
demand it.”’ (Patient ≥50
since diagnosis)
• Receiving a melanoma diagnosis

served to either strengthen or place
stress on survivors’ relationships with
romantic partners.

‘Well I’ve been married to
the same person for 42 years,
and I love him dearly, but he
didn’t do well with my
diagnosis, which was two
years ago. And it was a stage
II, and it was a big—it was a
fairly big deal. But for some
reason he became sick when I
got the diagnosis. It was
almost as though I was
getting more attention than
he was, and this became a
problem just because I sort
of—I guess I’m sort of an
insular person, and when this
happened I sort of turned
inward, and you’re trying to
steel yourself and get through
this, and you just don’t want
to deal with—I don’t want to

deal with other people and
their problems. I need to
focus on this. And it’s a selfish
thing for me, I know that, but
I couldn’t deal with him. I
never took him with me to
the doctor because the first
time I did I came out to the
waiting room and there he is
and he says, “Oh, I feel
awful.” Wait a minute, you
know? I’m the guy with
cancer, and you feel awful? So
this was a problem for
probably the first year.’
(Patient ≥50 years of age; 1 to
Modifications to melanoma risk

reduction behaviours
• Survivors became more conscious of

sun exposure and expanded use of
sun protection measures following
diagnosis.
‘The need for sun protection

is just a part of life.’ (Patient
<50 years of age; 5–10 years
since diagnosis)
• Melanoma survivors sought to

continue outdoor pursuits but used
sun protection.
‘Because I still do the

outdoor stuff. . . my whole
thought process is I’m going
to protect myself to the best I
can, but I’m not going to stop
doing what I want to do
because I just want to do it.’

‘I obviously try to stay out of

the sun. I wear sunscreen
every day on my face. I
garden but I try to stay in the
shade. I wear long sleeve
shirts. I wear hats in the
summer if I know I’m going to
be out, but to be honest with
you, one way that I do
manage this illness is I don’t
cover up completely, because
I don’t want it to overtake my
life.’ (Patient <50 years of age;
5–10 years since diagnosis)
• A majority of survivors were more

likely to engage in regular, consistent
sun protection during the summer

months.
‘But since all my doctors told

me what to do to reduce any
kind of risk—I wear the super
strength sunscreen, put it on
every hour. I’m actually never
in the direct sun at all ever,
but if I am even in the shade I
put the sunscreen on every
hour, wear a hat. I wear long
sleeves, long pants.’ (Patient
≥50 years of age; 1 to <5
years since diagnosis)
• The perception that melanoma is

not a serious cancer and confidence
that dermatologists will identify new
melanomas at an early stage both
minimized the necessity of
establishing consistent sun protection

habits for some survivors.
‘I take precautions I don’t

drastically change my life. If I
go to . . .have my skin
examined twice a year, which
I do now, with someone
who’s very competent. . .They
would spot it very early. So
the risk of it being a serious
matter is minimal, in a way. . .
I don’t see the need to really
radically change things,
except to take precautions.’
Physician screening and skin-self

examination practices
• Survivors regularly visited

dermatologists for screening and that
seeing a dermatologist is an effective
strategy to ensure new melanomas
would be identified early.
‘It’s a way of life’ and
‘it’s a lifetime commitment.’

• Skin-self examination varied

significantly across the sample but
most did not conduct skin self-
examinations on a regular basis.
‘I guess what I mean between

formal and informal is I don’t
formally have a set
schedule.’(Patient<50 years of
age; 1 to <5 years since
diagnosis)

• Survivors believed it is important to
find a dermatologist whom they
perceive to be competent—some
survivors had dermatologists who had
missed their melanoma.
‘And there’s a lot of

ignorance around. Doctor
says something, you think
that’s it. I was very ignorant
with that first melanoma. . .’
• Negative associations with seeing

dermatologists were discomfort and
embarrassment being naked and
anxiety prior to appointments that
the dermatologist may identify a
suspicious area.
‘When I’d first come for the

quarterly check-ups or
whatever, I’d feel a little
tense, realizing that I could
walk out of here with a
different answer, or my life
could change.’ (Patient<50
years of age; 5–10 years since
diagnosis)
• Lack of confidence in ability to

identify a suspicious mole was cited as
a barrier to conducting skin self-
examination, and some survivors
preferred to off-load the
responsibility to the doctor.
‘I don’t check myself. . .But

my skin I don’t check, because
the time I said, “Look at this,
this, and this,” and they’ll say,
“It’s nothing.”’ (Patient ≥50

since diagnosis)
‘But over time I’ve really

come to rely on—same
thing—I really believe that in
some ways I’ve sort of put
some of the responsibility on
my doctors and the
photography—and I have
dysplastic nevus as well—but
I don’t feel like I could ever do
a body check.’ (Patient <50
years of age; 5–10 years since
diagnosis)
Economic issues arising from

diagnosis and treatment
• Melanoma diagnosis elevated the

importance of retaining health care
insurance and purchasing life

insurance for younger survivors.
‘I mean and then what do

you do if you can’t get health
insurance? I’ll have to take a
lousy job that I don’t want to
work at so that I’ll have health
insurance. Yeah, that’s
actually a huge fear for me.’
‘Economically I just think I’ll

find the money somewhere.
That’s not going to be the
issue that I’m going to stress
over.’ (Patient <50 years of
age; 5– 10 years since
diagnosis)
• Economic concerns were far more

prominent for younger melanoma

survivors; financial concerns were not
a major worry for older survivors,
with insurance/Medicare coverage.
‘It (my melanoma diagnosis)

really didn’t hit me until I
went to apply for life
insurance. . .it was the life
insurance that made it hit
home and there was a
difference—I have a history
that affected my life.’ (Patient
<50 years of age; 5–10 years
since diagnosis)
Concerns for family members
• Survivors were aware their

diagnosis increased melanoma risk
(genetic susceptibility) and the need
for family members to be screened,

yet many did not discuss risk
reduction with family members.
‘I wanted to make sure that

they (children) understood
that this wasn’t something
that you worry about for this
summer, that you have to be
concerned about it. I try to
teach them that their whole
life they need to be aware of
the effect the sun can have on
them and take appropriate
measures for it. . .I didn’t
want to scare them or
anything like that, or make
them feel like, “Oh my God, I
can never go outside again.” I
was just kind of like, “Hey,
this is something that can
happen. There’s a hereditary

component, and you’re at risk
because of that,” but I didn’t
make it—I didn’t play the
whole thing up like. . .’
Anxiety post-treatment, concerns

about recurrence, and thoughts
about cancer status
• Some survivors experienced anxiety

if outdoors without sun protection.
‘When I don’t think I’m going

to be out and I end up having
to be out, you get stressed.
Like I’m outside for a half
hour and I’m like, “I’ve got to
get out of the sun. I don’t
have anything on.”’ (Patient

<50 years of age; 1 to <5
• Some survivors minimized their

melanoma diagnosis, regarding
melanoma to be a disease that
develops on the surface of the skin.
‘You said the word cured, and

that’s the last word I would
think about, because I never
thought of me as having
cancer, because skin cancer is
almost outside of you. . .It’s
not like something inside you,
systemic or something. This is
sort of like, okay, it was on my
skin that had to be removed.
That’s not—that was on top
of my skin’ (Patient <50 years
of age; 5–10 years since

diagnosis)
• Perceptions of cancer status and

likelihood of future recurrences
varied.
‘Well, I was surprised when I

got the call, because they said
it was for “survivors,” and I
don’t even consider myself a
survivor. I mean I don’t even
think about it. It happened,
they fixed it and it might
happen again and it might
not.’ (Patient ≥50 years of
age; 1 to <5 years since
diagnosis)
• Diagnosis prompted younger female

survivors to shift their attitudes
toward child-bearing (decision not to
have children because of fear of

recurrence and passing down risk to
children; decision to expand family
size to ‘live more fully’).
‘It’s (hearing about increase

likelihood of getting a new
melanoma if you get
pregnant) a disappointment.
He (doctor) said there are
studies showing that you
can—so you’re actually taking
a personal risk by getting
pregnant, not to mention that
then that’s a period of not
being as vigilant, because I
can’t do some of the screens I
was doing. So it’s sort of just
hard to put at odds having a
family versus taking care of
your own body.’
‘I’m thirty-nine and between

my age and the impact of
getting pregnant with
hormonal levels on
melanoma—I think one of the
things that’s impacted me
most significantly is that I’ve
decided not to get
pregnant.’(Patient <50 years
of age; 1 to <5 years since
diagnosis)
‘I always have little skin stuff.

I have lumps over here and,
you know—I don’t know
which of these things are
things to worry about or not,
so going to him regularly gives
a way to check. . .’ (Patient
<50 years of age; 1 to <5
Palesh et al To investigate Prospective N=160 N/A Sun Protective Practices

(2014) psychosocial Case Series patients Following melanoma diagnosis there
and physical providing was an increase in sun protection
function, long- Single Centre evaluable data practices
term effects, (USA) 71% used sunscreen
support needs Mean age was 73.8% wore protective
and health July 20, 2012- 61.9 years clothing when outdoors
behaviours September 10, (SD=13.5) 73% reduced time in the sum
such as 2012 63% reduced time seeking a
physician Median time tan
follow-up and since diagnosis 27.5% decreased sun bed use
self skin was 77
screening of months (2-400 Long Term Effects
melanoma months) Anxiety was the most prevalent long
survivors term effect (34%) followed by
Median time numbness and tingling (32%),
since forgetfulness (26%), depression and
treatment was sleep problems (23-24%) and fatigue
59 months (0- and pain (17-18%)
336 months)
The majority of patients reported no
changes in physical and psychosocial
domains of vitality, bodily pain,
physical functioning, mental health,
social functioning, emotional health,
body image and sexual functioning
(range 72.5%-88.8%) compared with
symptoms experienced prior to
diagnosis.
A subset of participants experienced

diminished self-perception of body
image (23%) and physical functioning

(15%) and a small group of patients
experienced improvement in
psychosocial function.
Survivor Needs
42.5% of patients requested
additional education about the long-
term effects of melanoma
27.5% wanted information on their
family’s risk of melanoma
32.5% did not require additional help
following melanoma diagnosis
53% of patients requested additional
information specific to melanoma
8% of patients responded that they

would like help beyond the survey
options, specifically help with
treatment advances, screening,
education, symptom relief, financial
support and addressing cosmetic
concern.
42.5% of patients reported negative

changes in at least one domain of
physical and psychosocial function.
It was reported that health providers
did not address these adverse signs or
symptoms 55.9% of the time.
Of the 30% of health providers who
did address the changes, 31% initiated
the conversation with the patient.

Differences in behaviours and

Symptoms by Sex
Sun protection practices, long-term
effects and changes in life quality
measures were comparable between
males and females.
73% of females reported a reduction

in time seeking a tan compared with
54% of males (p=0.01)
Females had an increased perception

of post-operative swelling of the arm
or leg compared with males
(p=0.014).
63.5% of males did not want

additional help following diagnosis
compared with 36.5% of females
(0.032).
There was no difference in

perceptions of anxiety or depression
(p=0.05)
Differences by Education
There were no statistically significant
differences by level of education.
Differences by time since diagnosis

Long term survivors were less likely to

receive routine skin screening every
3-6 months compared with short term
survivors (37% vs. 83%, p<0.001).
Long term survivors were less likely to

receive routine follow up for their
melanoma in the 6 months prior to
survey completion compared with
short term survivors (54% vs. 76%,
p<0.04).
Long term survivors decreased

sunbed use compared with short term
survivors (35% vs. 18%, p<0.02) and
time seeking a tan (74% vs. 48%,
p=0.001).
Short term survivors reported more

numbness/tingling at the surgical site
(p=0.027).
Differences by extent of treatment

Patients who received more extensive
treatment (WLE+) reported greater
fatigue (p=0.001), arm or leg swelling
(p<0.001) and weakness (p=0.001)
compared with patients undergoing
WLE alone.
Patients undergoing WLE+ were more

apt to follow-up recently with their
health care provider when compared

with patients undergoing WLE only
(67% vs. 53% at 3-6 months, p=0.025).
More patients undergoing WLE

reduced their tanning bed usage
WLE+ (40% vs. 23%, p=0.047).
More patients undergoing WLE

wanted information on sun protection
WLE+ (40% vs. 11%, p<0.001).
Rychetnik, L What are Systematic Patients with Post 15 studies included (published before
et al (2013) patient Review of stage I or II treatment April 2010): nine from the patient’s
preferences, quantitative melanoma follow-up perspective, 3 from the clinician’s
and qualitative perspective and 3 from both. 12 were
experiences
studies quantitative and 3 qualitative. Overall
and other the studies were at low risk of bias (as
psychosocial The review assessed using the Effective Public
outcomes included Health Practice Project Quality
associated studies from Assessment Tool).
with follow-up USA, UK,
after surgical Austria, Information needs
Germany and
treatment of Follow up was an important source of
Sweden
stage I or II patient information about sun-related
melanoma? behaviours. The main sources of
What are information were the clinic doctor,
clinician books & magazines and the clinic
preferences nurse. Overall satisfaction with follow
and up was high (both G.P. based and

experiences of hospital based) on the whole patients
providing felt reassured and were able to ask
follow-up after questions at their follow up
surgical
appointments.
treatment of
stage I or II
melanoma?
Support needs
More than half the patients surveyed

were interested in professional
emotional support, and most
preferred to get this from their doctor
rather than a psychiatrist or
psychologist. Requests for support
were also associated with greater
interest in complementary therapies.
Around half of surveyed patients

reported anxiety associated with
follow up appointments (clinically
significant levels in approximately
20% of patients). This was sometimes
accompanied by physical symptoms
and sometimes started weeks before
the appointment. Patients expressed
interest in trialing GP-led follow up.

Patients wanted rapid access to a
specialist if a suspicious lesion was
found.
Approximately half the patients

surveyed managed to adhere to
follow-up schedules. Non adherence
was typically attributed to logistical
problems.
Authors concluded that – patients

experience substantial anxiety
associated with follow-up visits but
overall find it reassuring to have
regular checkups with the chance to
ask questions. Patients also report a
degree of unmet need for emotional
support which they would rather
receive from their doctor than from a
psychologist or psychiatrist.
Stamataki et To investigate Qualitative N=15 patients Questionnaire N/A Four major themes were identified:
al (2014) the impact of Cross sectional included in Emotional effects
melanoma survey analysis Effect on relationships
diagnosis on Functional effects
the supportive 2 specialist Mean age 52 Health system and
care needs of cancer referral years (27-78 information needs
patients with centres (UK) years)
cutaneous Emotional Effects
melanoma

Uncertainty
Uncertainty for the future contributed
to the feelings of anxiety, fear and low
moods of melanoma patients.
Participants expressed feelings of
helplessness and frustration due to
their inability to be proactive
(receiving treatment to reduce risk of
recurrence) and only being reactive
(looking for new moles etc).
Patients reported being over vigilant

and over anxious that any new change
might be indicative of recurrence.
A lack of emotional support from the

health care system resulted in
increased concerns, anxiety and
feelings of helplessness.
Altered Body Image

Some participants reported an altered
body image as a result of melanoma
surgery. Issues reported included
appearance of WLE scar and
lymphoedema
Patients reported a disparity between
pre-surgery expectation and
perceived post surgery appearance of
scar and felt that they had not
properly been prepared for the
appearance of the scar despite

speaking to health professionals prior
to surgery.
There appeared to be disparity

between doctors perceptions of a
healing scar and the language used to
describe a well healing scar compared
with a patient’s perception of their
healing scar which has implications
for how doctors might discuss post-
surgery expectations.
Some participants denied being overly

concerned by their altered body
image while others downplayed their
concern and some patients described
wearing clothes/make-up to hide
their scar.
Some participants described concerns
about how altered body image
affected their confidence and
appearance.
Fear of the Sun

Fear of the sun emerged as a strong
theme with patients reporting
feelings of panic or anxiety that they
were going to burn and fear of the
sun meant that participants had
concerns about living their everyday
life.

There was a strong desire from some
participants to receive more detailed
information on sun protection and
that the information they received
was too general and did not cover
issues such as travelling to hot
countries, type of sunscreen and
frequency of sunscreen application.
Effects on Relationships
Concerns around changes to working
lives included changes to working
relationships or an inability to
perform their job as previously. Some
changes resulted in feelings of
embarrassment or awkwardness
about how their illness impacted their
working lives or a loss of confidence
and higher work related stress.
Some participants reported feeling a
lack of support and understanding
from work colleagues and managers
and felt that this may be due to a lack
of public awareness about melanoma
suggesting a need to increase
campaigns to improve understanding.
Family Relationships
Participants generally felt they had
good support from family members
and friends.
Participants reported being mindful of

not discussing their diagnosis with
family and friends for fear of pushing
their partner away or to protect
family members.
Functional Effects
Patients experienced side effects
including lymphoedema, pain and
fatigue following surgery. These side
effects impacted on participants daily
lives including their ability to carry out
normal daily tasks, take part in sports
or hobbies and caused mood changes.
Patients affected by fatigue felt that it

was an inevitable consequence of
surgery and as a result did not seek
health care support and tried to adapt
their lives to manage their symptoms.
Patients seem to want some

reassurance and emotional support to
help cope with their symptoms
regardless of whether they were
already under the care of a specialist.
Health Care System and Information

Needs
Clarity of Information
Participants reported that they could
not comprehend the information

provided about their prognosis or
stage of melanoma and this
contributed to feelings of anxiety and
uncertainty for the future.
Quality of Information
One participant reported that enough
information was provided by the
Nurse specialist but that access to a
Nurse specialist should have been
available from diagnosis.
Information at the right time

There were differing experiences
regarding access to information at the
right time, Patients reported feeling
there was no standard procedure for
when patients were provided with
information.
Some participants reported getting

too much information up front and
some participants felt that
information was provided too late,
particularly in the case of sun
protection advice.
Some participants expressed anxiety

around the amount of time they had
to wait for their test results.
Time spent with health professionals

Participants expressed
disappointment for not getting the
opportunity to ask questions at clinics
and feeling that doctors were so busy
that they did not want to prolong
their visit by asking questions.
Lack of time with health professionals

to discuss their emotional needs
regarding their melanoma diagnosis
was a strong theme. It was a
particularly important to patients who
avoided speaking to their family
members/partners.
Some participants did not feel they
could access health professionals
between clinic visits or access help or
advice over the phone resulting in a
feeling of abandonment.


Population Intervention Comparator Outcomes
 People with Melanoma Information delivery in Each other Health Related
 Carers of people with different formats Different age groups? Quality of Life
melanoma (digital/written) Cultural groups? Patient
Stage: provided at different satisfaction/exper
 0-Ia milestones/points in the ience
 Ib – IIIa pathway Treatment
 IIIb – IIIc  Clinician decision making
 IV  CNS Patient reported
 Helplines/charit Qol
y organisations
 Support groups
(inc online
support groups)
3 Search Results
found search
Medline 1946-2014 4681 24/03/2014
Premedline Mar 24 2014 303 25/03/2014
Embase 1947-2014 8894 25/03/2014
Cochrane Library Issue 3, Mar 152 25/03/2014

2014
PsycInfo 1806-2014 143 25/03/2014
CINAHL 1979-2014 392 31/03/2014
Total References retrieved (after databases combined, de-duplicated and sifted): 352
& 1 reference added 30/04/2014
5 1. exp Melanoma/
6 2. melanoma$.tw.

1 5. dubreuilh.tw.
2 6. LMM.tw.
3 7. or/1-6
4 8. Health Services Accessibility/
5 9. Office Visits/
6 10. Remote Consultation/
7 11. Physician-Patient Relations/
8 12. Nurse-Patient Relations/
9 13. Professional-Patient Relations/
10 14. Professional-Family Relations/
11 15. ((patient* or consumer* or carer* or caregiver* or spouse* or famil* or relati*) adj2 (decision*
12 or choice* or preference* or support* or participat* or educat*)).tw.
13 16. ((personal or interpersonal or individual*) adj2 (decision* or choice* or preference* or support*
14 or participat* or educat*)).tw.
15 17. (information adj2 (aid* or support* or need* or provision or deliver* or material* or
16 resource*)).tw.
17 18. ((patient* or carer* or caregiver* or spouse* or famil* or relati*) adj2 (information or
18 literature)).tw.
19 19. ((web* or print*or electronic*) adj2 (information or resource*)).tw.
20 20. Patient Education as Topic/
21 21. Pamphlets/
22 22. (pamphlet* or leaflet* or booklet* or guide* or sheet* or flyer* or flier*).tw.
23 23. ((electronic or email) adj (report* or support)).tw.
24 24. exp Audiovisual Aids/
25 25. (video* or dvd* or tape* or cd*1 or film*1 or telephone* or phone* or computer* or internet or
26 online or web or electronic).tw.
27 26. exp Internet/
28 27. exp telephone/
29 28. exp hotlines/
30 29. ((hot or help* or tele* or phone) adj (line* or support)).tw.
31 30. Communication/
32 31. (communicat* or talking).tw.
33 32. exp social support/
34 33. exp Self-Help Groups/
35 34. ((inform* or support*) adj2 (tool* or method* or group*)).tw.
36 35. (face* adj face*).tw.
37 36. Psychoeducation/
38 37. Psychotherapy/
39 38. ((psychosocial or psycho*) adj2 (support* or educat* or need*)).tw.
40 39. Stress, Psychological/
41 40. Counseling/
42 41. exp Patient Education/mt [Methods]
43 42. or/8-41
44 43. 7 and 42

1 Screening Results
2 The literature search identified 351 potentially relevant papers of which 19 were ordered. One
3 systematic review was included (McLoone et al, 2013).

2 Interventions for information

3 Evidence about educational interventions for patients with melanoma came from a systematic
4 review by McLoone et al (2013) which included five randomized controlled trials (RCTs) and five
5 other studies. Most interventions involved a personal or group instruction session from a nurse, GP
6 or dermatologist which was also reinforced by printed information (see Table 1). One study
7 examined whole body photography as an aid to skin self examination (SSE).
8 Educational interventions were typically associated with increased melanoma knowledge, better
9 adherence to SSE and better satisfaction with care, but not in all cases. Purely educational
10 interventions did not appear to affect anxiety, depression or psychosomatic symptoms, in the
11 studies that measured these outcomes.
12 Differences between the interventions used in the studies and the way outcomes were measured
13 makes it difficult to identify the effective components of a successful educational intervention.
14 Interventions for support

15 Evidence from a systematic review of three randomized trials (McLoone et al, 2013; see Table 2)
16 suggests uncertainty about the effectiveness of clinical psychologist or psychiatrist led cognitive
17 behavioural therapy (CBT) for improving psychological well-being among people with melanoma.
18 One qualitative study described a telephone peer-support intervention for people with melanoma,
19 which both the patients and their supporting peers viewed as effective.
20 Combined information and support interventions

21 Three randomized controlled trials evaluated variations on the same combined educational and
22 psychological intervention (McLoone et al, 2013; see Table 3). Each of these studies reported
23 decreases in distress (anxiety, depression, hostility, and mood disturbance). The largest of these
24 trials, however, reported only short-term emotional and physiological benefits, and there were no
25 long term group differences in survival or time to recurrence. In a fourth randomized trial,
26 participants who attended an average of 19 sessions with an oncology counsellor over a period of
27 6 months reported a greater decline in anxiety, hostility and depression than a control group

Table 1.3. Educational Interventions (McLoone et al 2013)
Study Intervention(s) Population Design Follow up Outcomes

Brandberg et A nurse-led, group information 171 stage I melanoma RCT 3 months, 6 Intervention group reported an
al. (1994; session (1.5 h) held prior to the patients. months increase in melanoma-related
1996); patient's first medical visit, plus an knowledge and satisfaction with
the provision of information,
information booklet versus control
compared with controls.
group (standard care). The control No psychological or psychosomatic
group received active intervention differences were reported between
after their first medical visit. groups.
After receiving the intervention,
control group knowledge increased
to equal intervention group levels.
No differences in attitude toward
the program were reported
between those who participated
before or after the first medical
visit.
No psychological or psychosomatic
differences were reported between
groups.
Murchie et al. CSE by a GP (followed-up every 3– 142 melanoma patients RCT 12 months Intervention participants reported
(2010) 6 months), instruction in SSE and a from 17 medical practices. increased satisfaction with care
patient information booklet and greater adherence to patient
guidelines.
(detailing SSE) versus control
No group differences in anxiety or
(standard care). depression were reported at
baseline or post-intervention.
Murchie et al. GPs received 4 h training and a 17 GPs providing follow-up N.R. N.R. GPs qualitatively reported high
(2009) detailed manual on how to conduct care for melanoma patients satisfaction with the intervention
CSE and implement the program and perceived patients to


aforementioned intervention for be highly satisfied also.
patients, versus control (no
additional training).
Berwick et al. Nurse-led educational intervention, 75 individuals at high and Prospective N.R. Knowledge improved post-
(2000) consisting of SSE training, average melanoma risk intervention and was associated
educational reading materials, and with a personal history of
melanoma and increased SSE.
an SSE diary.
Post intervention, the proportion
of participants performing optimal-
frequency SSE almost doubled.
However, of participants who
performed SSE at follow-up, only
29% conducted a full SSE including
difficult to see areas of the body.
Robinson and One, dermatologist-led group 100 individuals with a Prospective 20 minutes Identification of border irregularity,
Turrisi (2006) session, teaching SSE (by the ABCDE personal or family history after colour variation and diameter
rules of discrimination; placing of melanoma. intervention improved with education;
asymmetry and identification of
transparencies of a lesion on the
change did not.
participant's arm to personalize 87% thought the brochure was too
learning; a slide show; a brochure; long (20 min to review) and
and a bookmark). preferred the bookmark.
Border, colour, and the decision to
see a physician improved after
skills training.
Robinson et al. Participants were randomly 130 patients with a RCT 4 months Dyadic learners placed more
(2007; 2009) assigned to receive intervention as a personal/family history of importance on conducting SSE
solo learner or dyadic-partnership. melanoma, or dysplastic monthly, partner assistance and
reported greater self-efficacy for
The ABCDE recognition system and nevi and their cohabitating
conducting SSE than solo learners


SSE training were taught. partners versus control at both post-intervention 4-month
group. (Robinson 2007) follow-up.
Dyadic learners also reviewed SSE
guidelines, examined the skin with
and without their partner, more
174 melanoma patients and frequently, than solo learners.
their partners. (Robinson, The ABCDE illustrated card was
2009) used more by dyadic learners.
Cards stored in bedrooms and
bathrooms were used most
frequently.
Dyadic learners referred to the
card mainly for checking colour
variation, single learners referred
to the card to show their partner
what to check.
Robinson et al. Participants were randomly 40 stage I–II melanoma RCT N.R. Both groups increased partner
(2010) assigned to receive an in-person patients and control group assisted SSE, SSE self-efficacy,
intervention (as previously attitude toward SSE and SSE
knowledge.
mentioned above in Robinson
There were no group differences.
2007;2009) or a workbook Workbooks were referred to more
intervention (39 pages). often than ABCDE cards.
Phelan et al. Nurse-led intervention using a 100 high-risk melanoma RCT 4 months Intervention had no effect on skin
(2003); personalized photo-book containing patients (based on a past cancer knowledge, awareness or
Oliveria et al. whole body digital photography to history of melanoma, SSE self-efficacy. Both groups
reported an increase in the above
(2004); Hay et aid SSE versus control (pamphlet on dysplastic nevus, or skin
variables at 4-month follow-up.
al. (2006) how to conduct and diarize SSE). biopsy) plus control group SSE adherence was significantly
increased in the intervention
group, compared with controls


Participation in the intervention
group was significantly associated
with increased SSE self-efficacy and
adherence to SSE.
Adherence to SSE was more likely if
high self-efficacy and skin cancer
knowledge was reported,
irrespective of intervention
condition.
Uliasz and Patient education in conjunction 111 stage I–II melanoma Retrospective N.R. Melanoma diagnoses after patient
Lebwohl with routine follow-up surveillance patients who developed a study. education were more likely to be in
(2007) by a clinician. second primary melanoma. situ than the initial diagnosis, be
less invasive and less thick.
Identified using the
American Joint Committee
on Cancer database
DiFonzo et al. Patient education in conjunction 82 stage I–II melanoma Retrospective N.R. A second melanoma after patient
(2001) with routine follow-up surveillance patients who developed a study. education and routine follow-up
by a clinician. second primary melanoma. care was more likely to be less
invasive, diagnosed at a lower
Identified using the
stage and less thick.
American Joint Committee
on Cancer database
Abbreviations: ABCDE, Asymmetry, Border, Colour, Diameter, Evolving; CSE, clinical skin examination; RCT, randomized controlled trial; SSE, skin self-examination;

Table 1.4. Psychological Interventions (McLoone et al 2013)
Study Intervention(s) Population Design Follow Outcomes

up
Trask et al. Three weekly 50-min sessions of CBT, versus 48 stage I–III RCT 6 Overall, CBT had no effect on
(2003) standard care. CBT focused on relaxation training, melanoma patients months distress levels.
cognitive challenging, and problem solving. with medium-to-high Anxiety scores were significantly
lower for the CBI group at both
distress 2 months after
2-month and 6-month follow-
initial consultation up.
General health, vitality, social
functioning, and mental health
scores all improved immediately
after the CBT,
However, only general health
scores remained higher with
CBT than the standard care
group at 6-month follow-up.
MacCormack 6–8, individual sessions with a psychologist using a 26 metastatic RCT & N.R. Talking to an objective person
et al. (2001) manualized, CBT program. Sessions were 90 min on melanoma patients, qualitative outside the family was
average, conducted at home or at hospital, held over breast and beneficial; fewer feelings of
isolation and stigmatism and a
a 3-month period. The control condition consisted of gynaecological cancer
greater sense of being heard
relaxation therapy with unstructured ‘chat’ time. patients. and feeling ones situation was
Therapists did not address issues or problems, but normal;
provided empathic listening and reflection of Therapist warmth was
content. supportive;
Individual therapy was
preferred (excluding family
members), although specific
sessions purposely for the
family could have been useful;

Study Intervention(s) Population Design Follow Outcomes

up
Preference for being seen at

home; more structured follow-
up would have been helpful.
Rudy et al. Peer-led, telephone-based social support. Two 88 stage III–IV Qualitative N.R. Helpees became more sensitive
(2001) telephone contacts initiated by the helper, prior to melanoma patients and open to available social
the helpee's 1st and 2nd immunotherapy treatment. receiving treatment support
Helpers and helpees viewed
and ‘helpers’
intervention as effective;
Telephone contact was a
satisfactory substitute for face-
to-face support.
Bares et al. Four weekly 50-min sessions of CBT versus standard 30 stage I–III RCT 9 Distress levels decreased to
(2002) care. CBT focused on relaxation training, cognitive melanoma patients months within ‘normal’ range 5 months
challenging, and problem solving. with medium-to-high post-intervention.
No change in distress for
distress 2 months after
patients receiving standard care
initial consultation. only.
Cost analysis demonstrated an
expense of $402 (standard care)
versus $7.66 (CBI) per unit
decrease in distress.
Abbreviations: CBT: Cognitive behavioural therapy; RCT, randomized controlled trial; N.R. not reported.

Table 1.5. Combined educational and psychological interventions (McLoone et al 2013)
Authors Intervention(s) Population Design Follow Outcomes

(year) up
Boesen et Six, 2.5 h, weekly educational sessions, delivered by 262 melanoma RCT 1 year Intervention reduced fatigue and mood
al. (2005; physician (1–4 months post surgery), based on patients versus disturbance and increased vigour and
2007) manual by Fawzy et al.1995 and included health control. active-behavioural/active-cognitive
coping.
education, coping and problem-solving techniques,
Improvements were only significant at 6-
stress management, and psychological support. month follow-up; there were no
differences between groups at
12 months.
Gordon et Oncology counsellor-led (i.e. psychologists, social 308 breast, lung, RCT & 6 Intervention group reported a greater
al. (1980) workers and psychiatric nurses), versus control and melanoma qualitative months decline in anxiety, hostility and
(standard care). Intervention consisted of patients (n = 107), depression;
Intervention group reported a more
versus control.
Education; medical information relating to ones realistic outlook on life; were more likely
diagnosis, how to live with cancer and dealing with to have returned to their previous work
the medical system. status;
Counselling; reactions and feelings towards ones Intervention group displayed a more
disease. active pattern of time usage.
Environment; consults and service referrals. Daily
contact was made by the same oncology counsellor
while an in-patient and on an as-needs basis post
discharge (11 hospital contacts of 20 min each on
average, eight out-patient contacts of 20 min each
on average, for melanoma patients). Intervention
duration was 6 months.
Fawzy et Six, weekly, 1.5 h, psychiatrist-led, group 68 stage I–II RCT 10 Immediate post therapy
al. (1990; psychotherapy intervention versus control (standard malignant years
1993; care), involving health education; illness-related melanoma Increased vigour and active-behavioural


(year) up
2003) problem-solving skills; stress management; patients, versus coping methods were reported by
psychological support. control group. intervention versus control group.
At 6 months
6 months post-intervention, increased

vigour and decreased depression,
fatigue, confusion and total mood
disturbance were reported by the
intervention group versus controls.
In addition, more active coping styles
and less passive-resignation were
reported by the intervention versus
control group.
At 5 years
The intervention group only showed an

increase in natural killer cell percentages
post intervention, compared with
baseline.
Intervention participants had a
significantly better survival rate, and
there was a trend toward a lower
recurrence rate, 5 years post-
intervention.
When controlling for other risk factors,
intervention participation lowered the
risk of recurrence by more than 2.5-fold
and decreased the risk of death
approximately sevenfold.


(year) up
At 10 years
Survival benefit of intervention was no

longer independently significant,
although significant differences were
present after controlling for other
prognostic factors.
Those with smaller Breslow depths who
were female and who attended the
intervention survived longer.
When controlling for other risk factors,
intervention participation reduced the
risk of death threefold.
Fawzy 6-week program including an educational manual 61 stage I–II RCT 3 At 3 months, the intervention group
(1995) and 3 h total of individual nurse-led psycho- malignant months reported significant reductions in total
education focusing on; health education, stress melanoma mood disturbance, fatigue, and
somatisation compared with the control
management and coping skills. patients, post
group.
surgery, versus Less passive resignation coping
control group. strategies were used by the intervention
group compared with controls.
Use of positive coping strategies did not
increase.
Within-group analysis of change scores
found significant decreases for
somatisation, general distress, anxiety,
fatigue, confusion, vigour, and total
mood disturbance in the intervention
group only.
Abbreviations: RCT, randomized controlled trial; SSE, skin self-examination;

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23 intervention for patients with cutaneous malignant melanoma: a replication study. J Clin Oncol
24 2005;23(6):1270–1277.
25 Fawzy F, Kemeny M, Fawzy N, Elashoff R, Morton D, Cousins N, et al. A structured psychiatric

26 intervention for cancer patients: I. Changes over time and methods of coping in affect of
27 disturbance. Arch Gen Psychiatry 1990;47:720–725.
28 Fawzy FI, Fawzy FI. A short-term psychoeducational intervention for patients newly diagnosed with
29 cancer. Support Care Cancer 1995;3(4):235–238.
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31 qualitative investigation of cancer patients' experiences of psychotherapy. Psycho-Oncology
32 2001;10:52–65.
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34 telephone-based social support intervention for melanoma patients. Health Commun 2001;13:285–
35 305.

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2 intervention with cancer patients. J Consult Clin Psychol 1980;48:743–759.
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4 diagnosed malignant melanoma patients. Cancer Nurs 1995;18:427–438.

Evidence Tables
Study Quality
McCloone et al (2013)
The review addresses an appropriate and clearly Yes
focused question that is relevant to the review
question
The review collects the type of studies you consider Yes
relevant to the guidance review question
The literature search is sufficiently rigorous to identify Yes
all the relevant studies
Study quality is assessed and reported Yes
An adequate description of the methodology used is Yes
included, and the methods used are appropriate to
the question
Additional Comments Overall assessment of internal validity.
Are the results internally valid? Yes
Overall assessment of external validity

– Are the results externally valid (i.e.
generalisable to the whole source
population)? Differences in the
interventions included in the review
mean that it is difficult to generalize.

McCloone et To compare the Systematic review of People with  Psycholo Interventions for education see Table 1.2.
effectiveness and qualitative and melanoma gical
al (2013) quantitative studies intervent
quality of
psychological and ions (for
Australia example Interventions for support see Table 1.3.
educational
cognitive
interventions 16 intervention behaviou
designed for people studies were ral
Combined education see Table 1.4.
with melanoma included ( 12 therapy,
quantitative, 2 psychoth
Authors conclude that interventions in this field vary
qualitative and 2 erapy)
widely, limiting the identification of 'active
mixed; 11 were  Educatio
ingredients' for psychological or behavioural change.
RCTs). The quality of nal
Future intervention studies should ensure sufficient
each included study intervent
information is provided to support program
was evaluated ions
replication and comprehensive assessment of
according to (increasi
program outcomes.
whether the ng
intervention was understa
adequately nding of
reported, whether it the
measured clinically disease
meaningful and
outcomes and possible
whether psycholo
implementation of gical
the intervention response
(practicality) had s)
been assessed. Psycho-educational
interventions (a
combination of the
above)

1 2. Diagnosing Melanoma
2 2.1 Dermoscopy and other visualisation techniques
3 Review question: To what extent can the diagnostic accuracy of, history-taking and visual
4 examination for the clinical identification of melanoma be improved by dermoscopy
5 or/and new visualisation techniques?
6 Background
7 We know that the earlier a melanoma is diagnosed and removed, the more likely the patient is to be
8 cured. Until 20 years or so ago, melanoma was diagnosed based on history and clinical examination
9 alone. In an attempt to improve the accuracy of diagnosing melanoma, various new techniques have
10 been developed which seek to optimise the visualisation of suspicious skin lesions. Dermoscopy
11 (dermatoscopy) is now widely used by specialist dermatologists and some primary care doctors with
12 a particular interest in dermatology. The evidence suggests that this technique can be used in two
13 ways, firstly to aid in the diagnosis of specific lesions, something that requires a lot of experience,
14 and secondly to enable less experienced doctors to use simple algorithms to separate the suspicious
15 from the benign. In the hands of dermatologists there seems to be evidence that dermoscopy can
16 improve diagnostic accuracy, but this may not be the case in less experienced doctors. More recently
17 new technologies seek to replace the clinician by the use of dermoscopic images and artificial
18 intelligence systems (using computer generated algorithms). Such new technologies might be
19 helpful but are associated with the problem of either missing melanomas or unduly raising a
20 patient’s anxiety by being over suspicious of malignancy. What we need to know is whether
21 dermoscopy should be considered an essential tool for those involved in diagnosing melanoma and
22 whether any of the other new techniques, such as artificial intelligence systems and confocal
23 microscopy, might help. Some people are suggesting that the use of teledermatology with ‘store and
24 forward’ images (including dermatoscopic images) can be used effectively to diagnose melanoma
25 but there is debate about this.
26 Question in PICO format

Intervention (Index Comparator (Reference
Population Outcomes
Test) Standard)
Patients with lesions  Dermoscopy  Visual Exam  Histological
suspicious of melanoma  Teledermatology  History Taking confirmation
(e.g. suspicious skin with dermoscopy  Clinical opinion
lesions)  New visualisation
Subgroup Analysis: techniques: (Digital
 Superficial dermoscopy ,
spreading Confocal
melanoma microscopy;
 Nodular Artificial intelligence
melanoma based systems)
 Lentigo maligna
melanoma
 Acral
lentiginous

melanoma
 Desmoplastic
melanoma
 Severely
dysplastic naevi
1

Searches:
Can we apply date limits to the search (Please Most of the studies will be since 1990
appropriate)
Are there any study design filters to be used An initial search was conducted with the SIGN
(RCT, systematic review, diagnostic test). Systematic reviews and RCTs filters added
At the request of the GDG and second search of

prospective studies was conducted with no filter to
be added
List useful search terms. (This can include such Dermoscopy, dermatoscopy, artificial intelligence,
information as any alternative names for the teledermatology, confocal microscopy, dermoscopic
interventions etc) algorithms. Some use dermatoscopy others
dermoscopy
Also should specify dermoscopy of naevi (sometimes

spelt nevi)
Epiluminescence microscopy


1 Search Results
Database name Dates No of references No of references Finish date of
Covered found retrieved search
Medline 1946-2013 465 92 24/06/2013
Premedline 24 Jun 2013 3 0 25/06/2013
Embase 1947-2013 294 77 25/06/2013
Cochrane Library Issue 6 of 12 80 31 25/06/2013

June 2013
Web of Science (SCI & 1900-2013 466 41 25/06/2013

SSCI)
1 new reference added 09/07/2013
Total References retrieved (after de-duplication): 174
2 At the request of the GDG, a second search below was performed to find prospective studies only
3 (see below for Medline filter). The results were downloaded into a reference manager database,
4 deduplicated and sifted.
5 Prospective Studies Search

found search
Medline & Premedline 1946-2013 204 24/07/2013
Embase 1947-2013 266 24/07/2013
Total References retrieved (after de-duplication and sifting in Reference Manager): 251
6 Update Searches
7 For the update search, the same search criteria/filters were applied as initial search
Database name No of references found No of references Finish date of

retrieved search
Medline 59 15 23/09/2014
Premedline 7 4 23/09/2014
Embase 57 9 23/09/2014
Cochrane Library 3 0 23/09/2014
Web of Science (SCI & SSCI) 92 3 23/09/2014

5 records found in Pubmed 23/09/2014
1 Prospective Studies search
Database name Dates Covered No of references No of Finish date of

found references search
retrieved
Medline & Premedline 1946-2013 45 10 23/09/2014
Embase 1947-2013 63 15 23/09/2014
SSCI)

3 1. exp Melanoma/
4 2. melanoma$.tw.
7 5. dubreuilh.tw.
8 6. LMM.tw.
9 7. or/1-6
10 8. Dermoscopy/
11 9. Microscopy, Confocal/
12 10. (dermoscop* or dermatoscop* or epiluminescence or ELM or videodermatoscop* or (incident
13 adj2 microscop*) or (skin adj2 microscop*) or (surface adj microscop*) or (confocal adj
14 microscop*)).tw.
15 11. or/8-10
16 12. ((visual or naked eye) adj (exam* or assess*)).tw.
17 13. (skin adj exam*).tw.
18 14. Physical Examination/
19 15. Photography/
20 16. exp Telemedicine/
21 17. telederm*.tw.
22 18. Algorithms/
23 19. exp Diagnosis, Computer-Assisted/
24 20. exp Image Processing, Computer-Assisted/
25 21. exp Artificial Intelligence/
26 22. artificial intelligence.tw.
27 23. (artificial adj2 network*).tw.
28 24. (neural adj analy*).tw.
29 25. (computer* adj (analy* or diagnos*)).tw.
30 26. or/12-25
31 27. 11 or 26

1 28. 7 and 27
2 Screening Results
Records identified through database Additional records identified through

searching 465 other sources 1
Records after duplicates removed

466
Records screened Records excluded

466 437
Full text articles assessed for eligibility Articles excluded

29 12
Studies included in evidence review :

2 systematic reviews (including 14
studies) and 15 other studies
3
4

1 Study quality
2 Risk of bias and applicability were assessed using QUADAS-2 (see figure 2.1). Figure 2.2 illustrates
3 the setting of the included studies.
4 Figure 2.1. Risk of bias and applicability of the included studies – using QUADAS 2

2 High quality evidence (Vestergaard 2008; Rosendahl, 2011) suggests that dermoscopy is both more
3 sensitive and more specific in classifying lesions as melanoma versus not melanoma than clinical
4 examination with the naked eye alone (see Table 4 and Figure 5).
5 Evidence suggests that reflectance confocal microscopy (Stevenson, 2013) is more sensitive than
6 dermoscopy ((Vestergaard 2008) but less specific in classifying lesions as melanoma versus not
7 melanomas (see Table 4 and Figure 5).
8 There is uncertainty over whether computer aided diagnosis can improve upon the diagnostic
9 accuracy of dermoscopy in classifying lesions as melanoma versus not melanoma. The results from
10 studies of computer aided diagnosis using spectophotometry (Monheit et al 2011; Glud et al 2009)
11 suggest their algorithms were optimised for high sensitivity at the expense of specificity.
12 Studies excluded lesions in sites that were inaccessible to the imaging technique used. In such
13 lesions cases clinical examination with the naked eye would be the only option. There is also a test
14 failure rate associated with computer aided diagnostic algorithms: Perrinaud et al (2007) reported
15 failure rates ranging from 5% to 32% of lesions depending on which system was used.
16 The trade off between sending benign lesions for biopsy/histopathology and the risk of missing
17 melanomas is illustrated in Table 1. This uses a hypothetical cohort of 1000 pigmented skin lesions
18 with a melanoma prevalence of 12%, combined with the diagnostic accuracy data from Table 4.
19 Table 2.1. Illustration of trade off when using tests to select pigmented lesions for biopsy in a
20 cohort of 1000 lesions (assumed 12% melanoma prevalence)
Test Benign lesions selected for Melanomas not selected for biopsy
biopsy (missed)
Naked eye 158/880 (18%) 36/120 (30%)
Dermoscopy 106/880 (12%) 14/120 (12%)
Reflectance confocal 211/880 (24%) 8/120 (7%)
microscopy
Computer aided dermoscopy 132/880 (15%) 26/120 (22%)
Computer aided 625/880 (71%) 4/120 (3%)
spectophotometry
21 There was inconsistent evidence about the accuracy of teledermatoscopy. Some studies report
22 relatively high diagnostic accuracy for classification of melanoma versus not melanoma (Piccolo,
23 2004; Tan, 2010). Warshaw et al (2009), however, reported a significant proportion of melanomas
24 would be mismanaged with potentially serious consequences on the basis of teledermatology (19%
25 for macro images alone, 6% if polarised light dermatoscopy was added, 16% if contact immersion
26 dermatoscopy was added).

1 Figure 2.2. Setting of the included studies in the diagnostic pathway
1. Studies in primary care

Naked eye: Argenziano (2006), Walter (2012), Rosendahl (2011)
Dermoscopy: Argenziano (2006), Rosendahl (2011)
Computer aided diagnosis (CAD) Spectrophotometry: Walter (2012)
Teledermatology: Moreno-Ramirez (2007)
Teledermatoscopy
2. Studies about initial tests in secondary care
Naked eye: Vestergaard Benelli (1999), Bono (2002), Bono (2006), Carli (2003), Carli (2004), Cristofolini
(1994), Dummer (1993), Stanganelli (2000)
Dermoscopy: Benelli (1999), Bono (2002), Bono (2006), Carli (2003), Carli (2004), Cristofolini (1994), Dummer
(1993), Stanganelli (2000)
CAD Dermoscopy: Driesetl (2009), Barzegari (2005), Fueyo-Casado (2009)
Teledermatology/Teledermatoscopy: Warshaw (2009), Piccolo (2004), Tan (2010), Borve (2013)
3. Studies about further tests for equivocal lesions in secondary care
Dermoscopy: Ascierto (2010)
CAD-dermoscopy: Perrinaud (2007)
CAD-spectrophotometry: Ascierto (2010), Glud (2009), Monheit (2011)
Reflectance confocal microscopy: Stevenson (2013)
3

1 Table 2.2. Summary diagnostic accuracy statistics
Test N N Sensitivity*[95% Specificity*[95% PPV† NPV†

studies lesions C.I.] C.I.]
Naked eye clinical 8 5628 70% [58-80%] 82% [57-94%] 35% 95%
examination
Dermoscopy 12 6535 88% [83-91%] 88% [74-95%] 50% 98%
Reflectance confocal 5 910 93% [89-96%] 76% [68-83%] 35% 99%
microscopy
Artificial intelligence 5 1317 78% [67-86%] 85% [78-90%] 41% 97%
using dermoscopy
images
Artificial intelligence 2 1715 97% [91-99%] 29% [4-82%] 16% 99%
using spectrophotometry
images
2 *Using bivariate meta-analysis (Reitsma et al 2005); †Assuming melanoma prevalence of 12% (the average prevalence across the
3 dermoscopy studies).
4 Abbreviations: CI, confidence interval; PPV, positive predictive value; NPV, negative predictive value;
5 Sensitivity and specificity
6 Sensitivity and specificity are measures defined conditional on the disease status. They are
7 calculated as proportions of the number diseased and the number non‐diseased respectively.
8 Sensitivity and specificity values are reported either as proportions (0 to 1) or percentages (0% to
9 100%).
10 The sensitivity of a test is the probability that the index test result will be positive in a person with
11 the disease. The closer the test gets to 100% sensitivity the better it is at identifying people with the
12 disease.
13 The specificity of a test is the probability that the index test result will be negative in a non‐diseased
14 person. The closer the test gets to 100% specificity the better it is at identifying people without the
15 disease.
16 Predictive values
17 Predictive values are measures defined conditional on the index test results. They are calculated as
18 proportions of the total with positive and negative index test results. Predictive values are reported
19 either as proportions (0 to 1) or percentages (0% to 100%)
20 The positive predictive value (PPV) of a test is the proportion of those with a positive test result who
21 have the disease.
22 The negative predictive value (NPV) of a test is the proportion of those with a negative test result
23 who do not have the disease.
24

1 Figure 2.3. Illustration in 1000 patients with lesions if tests are used to select patients for biopsy
2 (using accuracy from table 3 and assuming melanoma prevalence of 12%).
3 TP = true positive (melanomas selected for biopsy), FP = false positive (benign lesions selected for
4 biopsy), TN= true negative (benign lesions not selected for biopsy), FN = false negative (melanomas
5 not selected for biopsy).
Naked eye clinical examination Dermoscopy
Reflectance confocal microscopy CAD dermoscopy
CAD spectrophotometry

1 Figure 2.4. Summary sensitivity and specificity estimates (with 95% confidence regions) and ROC
2 curves for the classification of melanoma versus not melanoma using naked-eye, dermoscopy,
3 reflectance confocal microscopy (RCM) and computer aided diagnosis (CAD) using dermoscopy or
4 spectophotometry.

1 Figure 2.5 Summary sensitivity and specificity estimates (with 95% confidence regions) and SROC
2 curves (bivariate model) for individual melanoma tests

Tables 2.3 to 2.7. Test accuracy data from individual studies
2.3: Naked eye clinical exam (including studies from Vestergaard 2008 systematic review)
Study Test Setting Classification TP FP FN TN SN SP

(%) (%)
Argenziano Naked eye clinical Primary care, patients with skin tumours Melanoma versus not 46 362 39 898 54 71
2006 * examination, by primary or requesting screening melanoma
care physician
Benelli 1999 Naked eye clinical Secondary/tertiary care, patients referred Melanoma versus not 40 71 20 270 67 79
examination by expert with suspicious pigmented skin lesions melanoma
dermatologist
Bono 2002 Naked eye clinical Secondary/tertiary care, patients referred Melanoma versus not 57 56 9 191 86 77
dermatologist
Bono 2006 Naked eye clinical Secondary/tertiary care, patients referred Melanoma versus not 10 16 13 167 43 91
dermatologist
Carli 2003 Naked eye clinical Secondary/tertiary care, patients referred Melanoma versus not 3 40 0 0 100 0
dermatologist
Carli 2004 Naked eye clinical Secondary/tertiary care, patients referred Melanoma versus not 3 44 0 255 100 85
dermatologist
Cristofolini Naked eye clinical Secondary/tertiary care, patients with Melanoma versus not 28 46 5 141 85 75
1994 examination by expert suspicious pigmented skin lesions melanoma
dermatologist scheduled for excision
Dummer Naked eye clinical Secondary/tertiary care, patients referred Melanoma versus not 15 49 8 699 65 93
1993 examination by expert with suspicious pigmented skin lesions melanoma
dermatologist scheduled for excision
Stanganelli Naked eye clinical Secondary/tertiary care, patients referred Melanoma versus not 37 33 18 3284 67 99
2000 examination by expert with suspicious pigmented skin lesions melanoma
dermatologist


(%) (%)
Barzegari Naked eye clinical Clinically suspicious melanocytic skin Melanoma versus not 5 5 1 111 83 96
2005 examination (expert lesions, following naked eye examination. melanoma
dermatologist)
Walter 2012 Naked eye clinical Suspicious pigmented lesion in primary Fast track cancer referral 111 61 5 588 96 91
examination by GP care versus manage in primary
care.
Abbreviations: TP, true positive; FP, false positive; FN, false negative; TN, true negative; SN, sensitivity; SP, specificity.
*Excluded from meta-analysis – due to primary care setting.
2.4: Dermoscopy (including studies from Vestergaard 2008 systematic review)

(%) (%)
Perrinaud Dermoscopy (expert Secondary/tertiary care, clinically suspicious Melanoma or 59 19 1 11 98 37
2007 dermatologist) pigmented lesions, excluding obvious dysplastic nevus
melanomas. versus benign
Ascierto 2010 Dermoscopy Secondary/tertiary care, Clinically suspicious Melanoma versus not 12 24 0 18 100 43
melanocytic lesions selected for excision melanoma
following dermatoscopy
Ascieto 2010 Dermoscopy Secondary/tertiary care, Clinically suspicious Melanoma or 34 4 0 18 100 82
melanocytic lesions selected for excision dysplastic nevus
following dermatoscopy versus benign
Glud 2009 Dermoscopy Secondary/tertiary care, Clinically suspicious Melanoma versus not 11 13 1 58 92 82
melanocytic lesions selected for excision melanoma
following clinical examination.
Driesetl 2009 Dermoscopy (expert Clinically suspicious pigmented lesions in Melanoma versus not 26 120 1 311 96 72
dermatologist) secondary/tertiary care, melanoma
Fueyo- Dermoscopy (general Secondary care, melanocytic skin lesions at first Melanoma versus not 6 10 0 287 100 97
Casado 2009 dermatologist) general dermatology consultation. melanoma
Argenziano Dermoscopy, by primary Primary care, patients with skin tumours or Melanoma versus not 61 318 16 808 79 72
2006* care physician requesting screening melanoma


(%) (%)
Benelli 1999 Dermoscopy by expert Secondary/tertiary care, patients referred with Melanoma versus not 48 37 12 304 80 89
dermatologist suspicious pigmented skin lesions melanoma
Bono 2002 Dermoscopy by expert Secondary/tertiary care, patients referred with Melanoma versus not 60 65 6 182 91 74
Bono 2006 Dermoscopy by expert Secondary/tertiary care, patients referred with Melanoma versus not 19 57 4 126 83 69
Carli 2003 Dermoscopy by expert Secondary/tertiary care, patients referred with Melanoma versus not 3 10 0 30 100 75
Carli 2004 Dermoscopy by expert Secondary/tertiary care, patients referred with Melanoma versus not 2 26 0 283 100 92
Cristofolini Dermoscopy by expert Secondary/tertiary care, patients with Melanoma versus not 29 39 4 148 88 79
1994 dermatologist suspicious pigmented skin lesions scheduled for melanoma
excision
Dummer Dermoscopy by expert Secondary/tertiary care, patients referred with Melanoma versus not 22 10 1 738 96 99
1993 dermatologist suspicious pigmented skin lesions scheduled for melanoma
excision
Rosendahl Dermoscopy in primary Primary care, patients with pigmented skin Melanoma versus not 23 56 6 161 79 74
2011* care skin cancer practice lesions scheduled for excision melanoma
Stanganelli Dermoscopy by expert Secondary/tertiary care, patients referred with Melanoma versus not 51 12 4 3305 93 100
2000 dermatologist suspicious pigmented skin lesions melanoma

2.5: Computer assisted diagnostic systems

Study Test Setting Classification TP FP FN TN Sn Sp
(%) (%)
Perrinaud CAD dermoscopy (operated by Secondary/tertiary care, clinically Melanoma versus not 3 12 1 71 75 86
2007 expert dermatologist) – system I suspicious pigmented lesions (post melanoma
dermoscopy and excluding obvious
melanomas).
Perrinaud CAD dermoscopy (operated by Secondary/tertiary care, clinically Melanoma versus not 1 3 3 77 25 96
2007 expert dermatologist) – system III suspicious pigmented lesions (post melanoma
dermoscopy and excluding obvious
melanomas).
Perrinaud CAD dermoscopy (operated by Secondary/tertiary care, clinically Melanoma or 24 9 35 19 41 68
2007 expert dermatologist – system I suspicious pigmented lesions (post dysplastic nevus
dermoscopy and excluding obvious versus benign
melanomas).
2007 expert dermatologist – system II suspicious pigmented lesions (post dysplastic nevus
melanomas).
2007 expert dermatologist – system III suspicious pigmented lesions (post dysplastic nevus
melanomas).
Ascierto CAD spectrophotometry Secondary/tertiary care, clinically Melanoma or 8 10 4 32 67 76
2010 (Spectroshade) suspicious melanocytic lesions selected dysplastic nevus
for excision following dermatoscopy versus benign
Glud 2009 CAD spectrophotometry (SIAscope Secondary/tertiary care, clinically Melanoma versus not 12 29 0 42 100 59
II – operator unclear) suspicious melanocytic lesions selected melanoma
for excision following clinical
examination.
Driesetl CAD dermoscopy (non-expert Secondary/tertiary care, clinically Melanoma versus not 19 82 8 349 70 81
2009 physicians) suspicious pigmented lesions melanoma.

Barzegari CAD dermoscopy (expert Secondary/tertiary care, clinically Melanoma versus not 5 5 1 111 83 96
2005 dermatologist) suspicious melanocytic skin lesions, melanoma.
following naked eye examination.
Fueyo- CAD dermoscopy (Fotofinder, with Secondary care, melanocytic skin Melanoma versus not 5 46 1 251 83 85
Casado TeachScreen software operated by lesions at first general dermatology melanoma
2009 a general dermatologist) consultation.
Monheit CAD spectrophotometry (MelaFind Secondary/tertiary care, pigmented Melanoma (>1% 172 1300 3 157 98 11
2011 operated by expert dermatologist ) lesions scheduled for selected for likelihood) versus not
excision. melanoma
Walter CAD spectrophotometry Suspicious pigmented lesion in primary Fast track cancer 130 99 2 535 98 84
2012* (MoleMate operated by GP) care referral versus
manage in primary
care.
2.6: Reflectance confocal microscopy (studies from Stevenson 2013 systematic review)
Study Test Setting Classification TP FP FN TN Sn (%) Sp (%)
Curchin 2011 RCM Equivocal lesions – probably post dermoscopy Melanoma versus not melanoma 12 3 1 19 92 86
Guitera 2009 RCM Equivocal lesions – probably post dermoscopy Melanoma versus not melanoma 112 65 11 138 91 68
Guitera 2010 RCM Equivocal lesions – probably post dermoscopy Melanoma versus not melanoma 27 8 2 36 93 82
Langley 2007 RCM Equivocal lesions – probably post dermoscopy Melanoma versus not melanoma 36 15 1 73 97 83
Pellicani 2007 RCM Equivocal lesions – probably post dermoscopy Melanoma versus not melanoma 125 66 11 149 92 69

2.7: Teledermatology or teledermatoscopy
Study Test Setting Classification TP FP FN TN Sn(%) Sp(%)

Moreno- Teledermatology (digital images) Clinically suspicious lesions Refer for a face to 168 88 1 146 99% 62%
Ramirez in primary care face consultation
(2007) or not
Piccolo Teledermatoscopy (not reported Acral lesions in secondary Melanoma or not 5-6 0-6 0-1 65-71 91% 95%
(2004) who acquired images) care melanoma
Tan (2010) Teledermatoscopy (operated by Clinically suspicious lesions Melanoma or not 18 5 0 486 100% 99%
trained melanographer – in secondary care. melanoma
interpreted by dermatologist)
Warshaw Teledermatology (macro digital Lesions selected for biopsy Appropriate Accuracy 70%, 7/36 (19%) melanomas
(2009) images) after clinical and management plan mismanaged with potentially life threatening
dermoscopic exam in consequences
secondary care
Warshaw Teledermatoscopy (macro digital Lesions selected for biopsy Appropriate Accuracy 70%, 3/36 (8%) melanomas mismanaged
(2009) images plus polarized light after clinical and management plan
dermatoscopy) dermoscopic exam in
secondary care
Warshaw Teledermatoscopy (macro digital Lesions selected for biopsy Appropriate Accuracy 74%, 6/36 (17%) melanomas
(2009) images plus contact immersion after clinical and management plan mismanaged
dermatoscopy) dermoscopic exam in
secondary care
Borve Teledermatoscopy (operated by Lesions selected for biopsy Benign versus Accuracy 75% to 80%
(2013) expert dermatologist – interpreted after clinical and malignant
by expert dermatologists) dermoscopic exam in
secondary care

2 References
3 Ascierto, P. A., Palla, M., Ayala, F., De, M., I, Caraco, C., Daponte, A. et al. (2010). The role of spectrophotometry
4 in the diagnosis of melanoma. BMC Dermatology, 10, 5.
5 Barzegari, M., Ghaninezhad, H., Mansoori, P., Taheri, A., Naraghi, Z. S., Asgari, M. et al. (2005). Computer-aided
6 dermoscopy for diagnosis of melanoma. BMC Dermatology, 5, 8.
7 Borve, A., Terstappen, K., Sandberg, C., & Paoli, J. (2013). Mobile teledermoscopy--there's an app for that!
8 Dermatol.Pract Concept., 3, 41-48.
9 Dreiseitl, S., Binder, M., Hable, K., Kittler, H., Dreiseitl, S., Binder, M. et al. (2009). Computer versus human
10 diagnosis of melanoma: evaluation of the feasibility of an automated diagnostic system in a prospective clinical
11 trial. Melanoma Research, 19, 180-184.
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13 (2009). Evaluation of a program for the automatic dermoscopic diagnosis of melanoma in a general dermatology
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15 Glud, M., Gniadecki, R., Drzewiecki, K. T., Glud, M., Gniadecki, R., & Drzewiecki, K. T. (2009). Spectrophotometric
16 intracutaneous analysis versus dermoscopy for the diagnosis of pigmented skin lesions: prospective, double-blind
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20 Moreno-Ramirez, D. (2007). Store-and-forward teledermatology in skin cancer triage: Experience and evaluation
21 of 2009 teleconsultations. Archives of Dermatology, 143, 479-484.
22 Perrinaud, A., Gaide, O., French, L. E., Saurat, J. H., Marghoob, A. A., Braun, R. P. et al. (2007). Can automated
23 dermoscopy image analysis instruments provide added benefit for the dermatologist? A study comparing the
24 results of three systems. British Journal of Dermatology, 157, 926-933.
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28 Rosendahl, C., Tschandl, P., Cameron, A., Kittler, H., Rosendahl, C., Tschandl, P. et al. (2011). Diagnostic accuracy
29 of dermatoscopy for melanocytic and nonmelanocytic pigmented lesions. Journal of the American Academy of
30 Dermatology, 64, 1068-1073.
31 Stevenson, A. D., Mickan, S., Mallett, S., & Ayya, M. (2013). Systematic review of diagnostic accuracy of
32 reflectance confocal microscopy for melanoma diagnosis in patients with clinically equivocal skin lesions.
33 Dermatol.Pract Concept., 3, 19-27. The Stevenson systematic review contains the following five studies:
34 1. Curchin, C. E., Wurm, E. M., Lambie, D. L., Longo, C., Pellacani, G., & Soyer, H. P. (2011). First experiences
35 using reflectance confocal microscopy on equivocal skin lesions in Queensland. Australas.J Dermatol., 52,
36 89-97.
37 2. Guitera, P., Pellacani, G., Longo, C., Seidenari, S., Avramidis, M., & Menzies, S. W. (2009). In vivo
38 reflectance confocal microscopy enhances secondary evaluation of melanocytic lesions. J Invest
39 Dermatol., 129, 131-138.
1 3. Guitera, P., Pellacani, G., Crotty, K. A., Scolyer, R. A., Li, L. X., Bassoli, S. et al. (2010). The impact of in vivo
2 reflectance confocal microscopy on the diagnostic accuracy of lentigo maligna and equivocal pigmented
3 and nonpigmented macules of the face. J Invest Dermatol., 130, 2080-2091
4 4. Pellacani, G., Guitera, P., Longo, C., Avramidis, M., Seidenari, S., & Menzies, S. (2007). The impact of in
5 vivo reflectance confocal microscopy for the diagnostic accuracy of melanoma and equivocal melanocytic
6 lesions. J Invest Dermatol., 127, 2759-2765.
7 5. Langley, R. G., Walsh, N., Sutherland, A. E., Propperova, I., Delaney, L., Morris, S. F. et al. (2007). The
8 diagnostic accuracy of in vivo confocal scanning laser microscopy compared to dermoscopy of benign and
9 malignant melanocytic lesions: a prospective study. Dermatology, 215, 365-372.
10
11 Tan, E., Yung, A., Jameson, M., Oakley, A., Rademaker, M., Tan, E. et al. (2010). Successful triage of patients
12 referred to a skin lesion clinic using teledermoscopy (IMAGE IT trial). British Journal of Dermatology, 162, 803-
13 811.
14 Tomatis S. (2005). Automated melanoma detection with a novel multispectral imaging system: results of a
15 prospective study. Physics in Medicine and Biology, 50, 1675-1687.
16 Vestergaard, M. E. M. (2008). Dermoscopy compared with naked eye examination for the diagnosis of primary
17 melanoma: A meta-analysis of studies performed in a clinical setting. British Journal of Dermatology, 159, 669-
18 676. The Vestergaard systematic review includes the following nine studies:
19 1. Argenziano, G., Puig, S., Zalaudek, I., Sera, F., Corona, R., Alsina, M. et al. (2006). Dermoscopy improves
20 accuracy of primary care physicians to triage lesions suggestive of skin cancer. J Clin Oncol, 24, 1877-
21 1882.
22 2. Benelli, C., Roscetti, E., Pozzo, V. D., Gasparini, G., & Cavicchini, S. (1999). The dermoscopic versus the
23 clinical diagnosis of melanoma. Eur J Dermatol., 9, 470-476.
24 3. Bono, A., Bartoli, C., Cascinelli, N., Lualdi, M., Maurichi, A., Moglia, D. et al. (2002). Melanoma detection.
25 A prospective study comparing diagnosis with the naked eye, dermatoscopy and telespectrophotometry.
26 Dermatology, 205, 362-366.
27 4. Bono, A., Tolomio, E., Trincone, S., Bartoli, C., Tomatis, S., Carbone, A. et al. (2006). Micro-melanoma
28 detection: a clinical study on 206 consecutive cases of pigmented skin lesions with a diameter < or = 3
29 mm. Br J Dermatol., 155, 570-573.
30 5. Carli, P., Mannone, F., De, G., V, Nardini, P., Chiarugi, A., & Giannotti, B. (2003). The problem of false-
31 positive diagnosis in melanoma screening: the impact of dermoscopy. Melanoma Res, 13, 179-182.
32 6. Carli, P., De, G., V, Chiarugi, A., Nardini, P., Weinstock, M. A., Crocetti, E. et al. (2004). Addition of
33 dermoscopy to conventional naked-eye examination in melanoma screening: a randomized study. J Am
34 Acad.Dermatol., 50, 683-689.
35 7. Cristofolini, M., Zumiani, G., Bauer, P., Cristofolini, P., Boi, S., & Micciolo, R. (1994). Dermatoscopy:
36 usefulness in the differential diagnosis of cutaneous pigmentary lesions. Melanoma Res, 4, 391-394.
37 8. Dummer, W., Doehnel, K. A., & Remy, W. (1993). [Videomicroscopy in differential diagnosis of skin
38 tumors and secondary prevention of malignant melanoma]. Hautarzt, 44, 772-776.

1 9. Stanganelli, I., Serafini, M., & Bucch, L. (2000). A cancer-registry-assisted evaluation of the accuracy of
2 digital epiluminescence microscopy associated with clinical examination of pigmented skin lesions.
3 Dermatology, 200, 11-16.
4 Walter, F. M., Morris, H. C., Humphrys, E., Hall, P. N., Prevost, A. T., Burrows, N. et al. (2012). Effect of adding a
5 diagnostic aid to best practice to manage suspicious pigmented lesions in primary care: randomised controlled
6 trial. BMJ, 345, e4110.
7 Warshaw, E. M., Lederle, F. A., Grill, J. P., Gravely, A. A., Bangerter, A. K., Fortier, L. A. et al. (2009). Accuracy of
8 teledermatology for pigmented neoplasms.[Erratum appears in J Am Acad Dermatol. 2010 Feb;62(2):319].
9 Journal of the American Academy of Dermatology, 61, 753-765.
10
11 Excluded Studies
12 M. L. Bafounta, A. Beauchet, P. Aegerter, and P. Saiag. Is dermoscopy (epiluminescence microscopy) useful for
13 the diagnosis of melanoma? Results of a meta-analysis using techniques adapted to the evaluation of diagnostic
14 tests.[comment]. Arch.Dermatol. 137 (10):1343-1350, 2001.
15 Reason: Outdated systematic review
16 R. Bowns. Telemedicine in dermatology: A randomised controlled trial. Health Technology Assessment 10 (43):iii-
17 39, 2006.
18 Reason: not specifically concerned with melanoma
19 A. Blum, H. Luedtke, U. Ellwanger, R. Schwabe, G. Rassner, C. Garbe, A. Blum, H. Luedtke, U. Ellwanger, R.

20 Schwabe, G. Rassner, and C. Garbe. Digital image analysis for diagnosis of cutaneous melanoma. Development of
21 a highly effective computer algorithm based on analysis of 837 melanocytic lesions. [Review] [40 refs].
22 Br.J.Dermatol. 151 (5):1029-1038, 2004.
23 Reason: same group of lesions used to develop the algorithm are also used to validate it
24 Friedman RJ, Gutkowicz-Krusin D, Farber MJ, Warycha M, Schneider-Kels L, Papastathis N, Mihm MC Jr, Googe P,
25 King R, Prieto VG, Kopf AW, Polsky D, Rabinovitz H, Oliviero M, Cognetta A, Rigel DS, Marghoob A, Rivers J, Johr R,
26 Grant-Kels JM, Tsao H. Arch Dermatol. 2008 Apr;144(4):476-82.
27 Reason: Case control diagnostic study comparing digital dermatoscopy with A.I. MelaFind system
28 M. J. Jamora, B. D. Wainwright, S. A. Meehan, J. C. Bystryn, Maria Jasmin Jamora, Brent D. Wainwright, Shane A.
29 Meehan, and Jean Claude Bystryn. Improved identification of potentially dangerous pigmented skin lesions by
30 computerized image analysis. Arch.Dermatol. 139 (2):195-198, 2003.
31 Reason: Looks at A.I. (DermoGenius system) as an add-on test in the follow up of patients with clinically unusual
32 lesions which were not sufficiently unusal to trigger biopsy
33 K. Korotkov, R. Garcia, Computerized analysis of pigmented skin lesions: a review. [Review]. Artif.Intell.Med. 56
34 (2):69-90, 2012.
35 Reason: Expert Review
36 Z. Liu, J. Sun, L. Smith, M. Smith, R. Warr, Zhao Liu, Jiuai Sun, Lyndon Smith, Melvyn Smith, and Robert Warr.
37 Distribution quantification on dermoscopy images for computer-assisted diagnosis of cutaneous melanomas.
38 [Review]. Med.Biol.Eng Comput. 50 (5):503-513, 2012.
39 Reason: not validated with an independent sample
40 May, C. G. (2008). Prospective observational comparative study assessing the role of store and forward
41 teledermatology triage in skin cancer. Clinical and Experimental Dermatology, 33, 736-739.

1 Reason: does not report diagnostic accuracy
2 J. Mayer. Systematic review of the diagnostic accuracy of dermatoscopy in detecting malignant melanoma.
3 [Review] [25 refs]. Med.J.Aust. 167 (4):206-210, 1997.
5 A. M. M. Oakley. Excised skin lesions diagnosed by teledermoscopy. Australas.J.Dermatol. Conference

6 (var.pagings):May, 2010.
7 Reason: Conference Abstract
8 S. M. Rajpara, A. P. Botello, J. Townend, and A. D. Ormerod. Systematic review of dermoscopy and digital
9 dermoscopy/ artificial intelligence for the diagnosis of melanoma. [Review] [95 refs]. Br.J.Dermatol. 161 (3):591-
10 604, 2009.
11 Reason: includes retrospective studies and double counts studies in the meta-analysis
12 B. Rosado, S. Menzies, A. Harbauer, H. Pehamberger, K. Wolff, M. Binder, and H. Kittler. Accuracy of computer
13 diagnosis of melanoma: a quantitative meta-analysis. Arch.Dermatol. 139 (3):361-367, 2003.

Evidence tables
Study Quality
Was a Was a Did the study Were the If a Is the Were the Was there an Did all Did Were all Quality
consecutive case- avoid index test threshold reference reference appropriate patients patients patients
or random control inappropriate results was used, standard standard interval receive a receive the included
sample of design exclusions? interpreted was it pre- likely to results between reference same in the
patients avoided? without specified? correctly interpreted index test(s) standard? reference analysis?
enrolled? knowledge of classify the without and reference standard?
the results of target knowledge of standard?
the reference condition? the results of
standard? the index
test?
Ascierto et al Consecutive Yes only those Yes Not reported Yes Not Reported Not Reported Yes Yes Yes High
(2010) selected for
excision on the Low risk
of bias
basis of
overall
dermoscopy were
included
Barzegari et al Consecutive Yes Yes Unclear Not Reported Yes Not Reported Not reported Yes Yes Yes High
(2005)
Low risk
of bias
overall
Borve et al Consecutive Yes Yes Yes Not reported Yes Yes Not reported Yes Yes Yes High
(2013)
Low risk
of bias
overall
Dreiseitl et al Consecutive Yes Yes Yes Not Reported Yes Yes Not Reported Yes Yes No 458/511 High
(2009) patients
(806/3827 Low risk
lesions) of bias
were overall
missing
follow up
information
and not
included in
the analysis.
Fueyo-Casado Random Yes Yes Yes Not Reported Unclear (no Not Reported Not Reported Yes No Yes Moderate
et al (2009) details given
about Unclear
dermoscopy risk of
follow up) bias
relating
to the
reference

standard? the index
test?
standard
Glud et al Consecutive Yes Lesions selected Yes Not Reported Yes Not reported Not reported Yes Yes Yes High
(2009) for excision based Low
on clinical concerns
overall
examination –
regarding
unclear whether the
this involved potential
dermoscopy risk of
bias
Monheit et al Consecutive Yes Yes (although Yes Not Reported Yes Yes Not Reported Yes Yes Yes High
(2011) there were some
exclusions when Low risk
of bias
digital imaging was
overall
unfeasible)
Moreno- Random Yes Yes Yes Not Reported Unclear – Yes Not Reported Yes No Yes Moderate
Ramirez, D. patients not
(2007) biopsied were Unclear
not followed risk of
up beyond bias
face to face relating
consultation to the
reference
standard
Perrinaud et al Consecutive Yes Yes Yes Not Reported Yes Not reported Not Reported Yes Yes If the High
(2007) computer
diagnosis Low risk
system was of bias
unable to overall
analyse a
lesion – it
was
excluded
from the
analysis
Piccolo et al Unclear Unclear Unclear Yes Not Reported Yes Yes Not Reported Yes Yes Yes Moderate
(2004)
Unclear
risk of

standard? the index
test?
bias
relating
to patient
selection
Rosendahl et al Yes Yes Yes Yes Not reported Yes Unclear Not reported Yes Yes Yes High
(2011)
Stevensonet al. Not reported Yes Yes Not reported Not Reported Yes Not reported Not reported Not reported Not reported Not High
(2013). Reported
Low risk of bias in Low risk of bias Low risk of bias
3/5 studies, in 5/5 studies in 5/5 studies Low risk of
unclear in 2/5 bias in 5/5
studies studies
Tan et al (2010) Consecutive Yes Yes Yes Not Reported Yes No Not Reported Yes No Yes Moderate
Tomatis S. Consecutive Yes Yes The index test Not Reported Yes Not Reported Not Reported Yes Yes 94 images Moderate
(2005) is objective and were
should not be inadequate
influenced by (technical
histopathology failure) –
1391 lesions
were
included in
the analysis.
Vestergaard et Consecutive Yes Yes Yes Not Reported Yes Not reported Not reported No Not reported Yes Moderate
al (2008)
Walter et al Random Yes Yes Yes Not Reported Yes No Not Reported Yes Yes No High
(2012) Low risk
of bias
overall
Warshaw et al Consecutive Yes Yes Yes Not Reported Yes Yes Yes Yes Yes Yes High
(2009)
Low risk
of bias
overall
Study Aim Setting Population Intervention Comparison Follow-up Outcomes and

Results


Results
Ascierto et al Secondary/tertiar 54 melanocytic Dermatoscopy Histopathology See tables 2.3-2.7
(2010) y care, National lesions in 54 (Molemax II) of excised lesion
Cancer Institute patients, 65% classifying lesions
of Naples, Italy female, median age as: very low risk,
41 years (range 19 low risk, medium
to 73 years). risk, high risk and
Inclusion criteria: very high risk
Patients selected Spectrophometry
for surgical excision with computer
of melanocytic assisted diagnosis
lesions, following a (SpectroShade)
screening full body classified lesions as
clinical skin not melanoma,
examination with doubtful
dermoscopy of melanoma,
clinically relevant suspected
lesions. Excision melanoma or
was recommended probable
for all high or very melanoma
high risk lesions
and for lower risk
lesions if there was
cosmetic or
functional
justification.
Exclusion criteria:
Not reported
Barzegari et al Secondary care 122 pigmented skin CAD dermoscopy Histopathology First each lesion
(2005) Dermatology lesions from 91 (microDERM was examined
Department, Razi Iranian patients, dermoscope) using clinically with
Hospital, Tehran, 68% female, mean neural network naked eyes, and
Iran. age 32 years (range classifier to give a then CAD
6 to 94 years). score of 0-10 dermoscopy was
Inclusion criteria: where 10 was used. Finally


Results
pigmented skin highest likelihood lesions were
lesions <15mm in of melanoma. For excised and
diameter, with a the analysis 7.88 examined
clinical naked eye was used as the histologically.
diagnosis of a threshold for
melanocytic lesion, melanoma versus
referred for not melanoma.
diagnostic or Naked eye clinical
cosmetic reasons. diagnosis by expert
Exclusion criteria: dermatologist – for
Not reported (but the analysis the
only excised lesions most likely
are included in the diagnosis was used
analysis). as the diagnostic
category where
there were several
possibilities.
Borve et al Newly referred 62 patients, 39% Teledermatoscopy Histopathologic Patients were
(2013) patients following female, median age – an overview al diagnosis referred from GP
their first not reported, race image of each to dermatologist,
dermoscopic and not reported. lesion plus a following expert
clinical Inclusion criteria: dermoscopic image dermatologist face-
examination in Patients with of each lesion, to-face clinical &
secondary/tertiar suspicious skin taken using a smart dermoscopy
y care lesions requiring phone dermoscopy examination those
(Department of biopsy or excision, system (Fotofinder with lesions
Dermatology, following Handyscope). needing biopsy
Sahlgrenska dermoscopic and Images were were included. The
University clinical transferred using a dermoscopy
Hospital, examination by an web-based images and clinical
Sweden). expert teledermoscopy information were
dermatologist. application forwarded to other
Exclusion criteria: (TeleDermis expert
Age < 18 years, iDoc24). Images dermatologists for
lesions on sites not and relevant the


Results
accessible to the clinical information teledermatoscopy
smart phone were sent to two evaluation. Lesions
dermascope, no expert were excised and
knowledge of dermatologists results of both
Swedish language who classified each tests were
lesion as malignant compared with
versus not histopathology
malignant, and
melanocytic versus Study reports
not melanocytic overall diagnostic
and also to allocate accuracy (cannot
one of 12 primary extract sensitivity
diagnostic and specificity) and
categories to the concordance
lesion. between the face-
Face-to-face – a to-face and
single expert teledermoscopists.
dermatologist
examined the
lesion clinically and
dermatoscopically
and recorded the
same diagnostic
classifications as in
the
teledermatoscopy
above.
Dreiseitl et al Secondary/tertiar 511 patients with CAD dermatoscopy Histopathology All patients had
(2009) y care – 3827 pigmented (using Molemax II in those with clinical exam and
pigmented skin lesions entered the images) – used by excised lesions dermoscopy by an
lesion clinic at the study. 458 patients one of 6 physicians 6 months expert
Dermatology with 3021 lesions (depending on clinical follow dermatologist – the
Department, were included in availability) with 0- up for lesions decision to excise
University of the analysis. 4 years training in that were not lesion was based
Vienna, Austria. Prevalence of dermatology and excised on this. The CAD


Results
2004 melanoma was with no specific dermoscopy was
27/458 (6%). training in also done
Inclusion criteria: dermatoscopy. A
Patients referred neural network
for evaluation of classifier scored
pigmented lesions each lesion as
Exclusion criteria: benign, suspicious
Not reported or melanoma.
Physicians were
free to choose
which lesions to
examine – so not
all lesions were
analysed by the
computer system.
Dermatoscopy
(used by an expert
dermatologist)
diagnosed each
patient as
melanoma or not.
Fueyo-Casado Secondary/tertiar 303 lesions in 39 Dermoscopy Histopathology Patients initially
et al (2009) y care, general patients, 56% (Dermlite Pro) – (decision to had both
dermatology female, mean age done by a panel of biopsy was dermoscopy and
consultancy of a 35 (range 19-71 3 general based on clinical the automated
tertiary teaching years) dermatologists – consensus) analysis
hospital, Oviedo, Inclusion criteria: classified lesions as Short term Moleanalyzer tests.
Spain. 2007 adult patients with requiring excision digital Some lesions were
melanocytic skin at the time of first dermoscopy excised on the
lesions examination or not follow up was basis of clinical
Exclusion criteria: requiring the reference consensus,
non melanocytic immediate standard for discordant index
skin lesions excision. lesions that tests were followed
Automated were not up with
dermoscopy biopsied but dermoscopy. Some


Results
diagnosis had discordant patients had no
(Fotofinder classification reference standard
Moleanalyzer) – between test.
classified lesions as dermoscopy
typical melanocytic and the
lesions, somewhat automated
atypical (and system.
should be re- No reference
examined) or high standard for
probability of being those negative
melanoma. The on both index
first two categories tests.
were considered as
not requiring
excision at the time
of examination.
Glud et al Secondary care – 65 patients (83 Dermoscopy by Histopathology See tables 2.3-2.7
(2009) Departments of lesions), 55% expert
Plastic Surgery female, median age dermatologist–
and Dermatology, 47 years (range classification
Denmark Inclusion criteria: melanoma versus
Patients referred not melanoma
by G.P.s for CAD
excision biopsy of spectrophotometry
pigmented lesions – SIAscope II using
where melanoma Australian
could not be ruled algorithm to
out on clinical classify as “strong
examination. chance of
melanoma” or “not
Exclusion criteria: melanoma”
Not reported
Monheit et al 3 academic and 4 1383 patients with Artificial Dermatopathol Patients received
(2011) community 1831 lesions. 1632 Intelligence ogy – melanoma dermoscopy and


Results
dermatology lesions were algorithm and borderline CAD-
departments in included in (MelaFind) using lesions such as spectrophotometry
the USA. analysis. 162 digital high grade before
lesions were not multispectral dysplastic nevi histopathologic
evaluable due to images to classify and atypical reference standard
unsuccessful atypical lesions as melanocytic
imaging attempts, either positive hyperplasias or
19 lesions were (requiring biopsy to proliferations
missing rule out were defined as
histopathology melanoma) or histologically
information. negative (lesion to positive lesions.
Median age 47 be considered for
years (range 7-97 later evaluation).
years). 46% male Clinical diagnosis
54% female. 98% (with or without
white race. dermoscopy)
Inclusion criteria: dermoscopy was
Patients with at used for 645/1632
least one lesions.
pigmented lesion
scheduled for
complete biopsy
Exclusion criteria:
Allergy to isopropyl
alcohol, lesion less
than 2mm or
greater than 22mm
in diameter, lesion
not accessible to
imaging device,
lesion not
previously
biopsied, skin not
intact, lesion within
1mm of the eye,


Results
lesions on palmar,
plantar or mucosal
surface or under
nails, lesion in an
area of scarring or
containing foreign
matter (e.g.
tattoo).
Moreno- Referral from 1589 patients Teledermatology – Histopathology Patients had

Ramirez, D. primary care (12 received two 2 digital images (a or face-to-face teleconsultation,
(2007) primary care teledermatology panoramic view clinical most had a second
centres) to consultations – a and a close up) examination teleconsultation
secondary care random sample of were taken of each and from these a
(pigmented lesion 403 were included lesion (presumably dermoscopy random sample
and skin cancer in the comparison by the primary care where there were selected for
clinic, University with face-to-face doctor/nurse?) . was no surgery face-to-face
Hospital Virgen consultation. Of Images together consultation –
Macarena, these 403 patients, with clinical these form the
Seville, Spain), 59% were female, information were analysis group.
2004-2005. median age 46 sent electronically Some of these
years. to two patients then had
dermatologists for excision/biopsy as
Inclusion criteria: independent appropriate – in
Patients presenting consultation. The others
to primary care dermatologists
with a lesion classified each See tables 2.3-2.7
fulfilling at least lesion with a
one of the possible primary
following: changes diagnosis and gave
in ABCD criteria, a refer or do-not
symptoms, patient refer decision.
request for surgical
treatment and
concern.


Results
Exclusion criteria:
Not reported
Perrinaud et Secondary/tertiar 102 lesions: 91 3 computer Histopathology Patients were

al (2007) y care – clinically suspicious assisted diagnosis examined clinically
pigmented lesion melanocytic digital dermoscopy & dermoscopically,
and melanoma lesions, 11 non- systems (artificial those with
clinic, melanocytic intelligence): suspicious lesions
Dermatology pigmented lesions. Dermogenius Ultra, (not obviously
Department of Inclusion criteria: Fotofinder and malignant) were
the University Melanocytic lesions Microderm. Results entered into the
Hospital Geneva, judged suspicious of the tests were study. Their lesions
Switzerland by a dermatologist anonymised and were analysed
(based on clinical reported as System using the computer
and dermoscopy I, II and III. assisted systems –
examination). One of the systems those whose lesion
Pigmented non- automatically could be analysed
melanocytic lesions classified lesions were included in
and clinically into the second phase
obvious malignant/suspicio of the study
melanomas were us/benign whereas (comparing
also included. the other two gave dermoscopy and
Exclusion criteria: a probability score computer tests).
clinically obvious for malignancy Lesions were then
melanomas. (requiring the excised and
authors to choose analysed
threshold values histopathologically
for classification)
If the computer
diagnosis system
was unable to
analyse a lesion – it
was excluded from


Results
the analysis
Piccolo et al Secondary/tertiar 77 lesions (71 Teledermatoscopy Histopathology Dermoscopy
(2004) y care melanocytic naevi – dermoscopy images were
(Departments of and 6 melanomas) images plus clinical selected from
Dermatology, Inclusion criteria: information (age, databases of 2
Universities of acral lesions sex of patients and dermatology
Graz, Austria and included in the site of lesion) were departments,
L’Aquila, Italy. databases of 2 sent electronically histopathology
dermatology to 11 information was
departments dermatologists of probably already
Exclusion criteria: varying levels of on file.
Not reported experience.
Clinical images
were not sent.
Rosendahl et Primary care skin 3/466 lesions were Dermoscopy – the Histology See tables 2.3-2.7
al (2011) cancer practice in excluded due to expertise of the
Queensland poor quality observer is not
Australia. dermoscopic reported
images. 463 lesions Naked eye clinical
(389 patients) examination – the
included in the expertise of the
analysis. 33% observer is not
female, mean age reported
57 years. 246
lesions were
melanocytic and
217 were non-
melanocytic.
Inclusion criteria:
pigmented lesions
scheduled for
biopsy
Exclusion criteria:


Results
Not reported
Stevensonet Systematic 909 lesions – Reflectance Histopathology See Tables 2.3-2.7
al. (2013). review of average prevalence confocal of the excised

diagnostic of melanoma was microscopy – no skin lesion or
accuracy of 36.2% (range 29% restriction on long term
reflectance to 39%) algorithm or clinical follow
confocal diagnostic process. up.
Inclusion criteria: 3/5 studies used
Post dermoscopy Patients presenting the Pellacani
and clinical with lesions (2005) algorithm
examination in suspicious for 2/5 used the
secondary/tertiar melanoma Guitera (2010)
y care algorithm
Exclusion criteria: 1 did not use a
Cohort studies, named algorithm
diagnostic
threshold setting
studies
Tan et al Secondary/tertiar 200 patients (491 Face-to-face clinical Histopathology Patients were first
(2010) y care, Waikato lesions) , 63% examination with – in cases where seen by a
Hospital female, 94% dermatoscopy the lesion was melanographer
Dermatology European race, age (done by two excised. who took digital
department, New range 11 to 94 dermatologists Face-to-face images of the skin
Zealand. 2008 years. independently). diagnosis in lesions (panoramic
Inclusion criteria: Each lesion was cases where the and macroscopic)
Patients referred assigned one of 11 lesion was not then dermoscopic
from primary care diagnostic excised. images. The patient
for evaluation of categories. was then seen
skin lesions, Able to Teledermatoscopy face-to-face
give informed – digital images independently by
consent and all electronic two dermatologists
Exclusion criteria: history were who examined


Results
none reported reviewed at least 4 their lesions
weeks after the clinically and with a
clinical hand held
examination by the dermoscope.
same
dermatologists
involved in the
clinical
examination. Each
lesion was assigned
one of 11
diagnostic
categories.
Tomatis S. Secondary / 1359 patients Artificial Histopathology See tables 2.3-2.7
(2005) tertiary care – (1485 cutaneous intelligence
melanoma unit of lesions), 56% analysis of
the National female. 94 images spectrophotometer
Cancer Institute were inadequate – images – the image Spectophotomteric
of Milan, Italy 1391 lesions were data then fed into a images of the
included in the neural network lesions were
analysis. Lesions which classified acquired in vivo
were randomly lesions as before surgery
assigned to train, malignant or
verify or validation benign. 94 images were
samples which inadequate
were used to (technical failure) –
develop, constrain 1391 lesions were
and validate the included in the
index test analysis.
algorithm
respectively.
Inclusion criteria:
pigmented lesions
clinically and/or
dermoscopically


Results
suspicious for
cutaneous
melanoma.
Exclusion criteria:
clearly thick or
large melanomas,
lesions inaccessible
to the imaging
device (for example
interdigital, on
ears, on the nose in
the navel)
Vestergaard Systematic Inclusion criteria: Naked eye Histopathology See Tables 2.3-2.7
et al (2008) Review and Studies comparing examination in 8/9 studies,
Meta-analysis clinical (ABCD(E) rule 6/9 follow up for
examination with studies, no presumed
Mostly secondary and without specified rule 3/9) benign lesions
care (referral dermoscopy that Dermoscopy in 3/9 studies
centres with reported sensitivity (pattern analysis Expert diagnosis
experts) 1/9 and specificity for 5/9, ABCD criteria in 1/9 studies
studies was done both, used a valid 2/9, 7 point (the primary
in primary care reference standard, checklist 2/9, 3 care study)
with non-experts did tests point checklist 1/9)
prospectively
Studies were (without
done in the knowledge of the
period 1990- index test result),
2004, in Italy (7/9 included
studies),
Germany (1 Exclusion criteria:
study) or Spain & Retrospective
Italy (1 study). studies, studies
using only images
of melanoma, non-


Results
English language
Walter et al Clinical setting: 1297 patients with Patients were For referred
(2012) primary care (15 1580 lesions, mean randomised to lesions
general age 45 years, 64% receive either of 2 reference
practices), female, 94% white index tests: standard was
England, 2008- race. Naked eye clinical expert opinion
2010 Inclusion criteria: assessment by GP on
age > 18 years, or nurse appropriateness
suspicious practitioner using of referral by a
pigmented lesion Cambridge histologist or
Exclusion criteria: University NHS dermatologist
unable to give Trust guidelines. For non-
consent or Lesions were referred lesions
considered classified as reference
inappropriate to requiring fast track standard was
refer by the G.P. referral for review by two
suspected skin dermatology
cancer or not. experts on
Naked eye clinical appropriateness
assessment of referral, using
supported by CAD all available
spectrophotometry clinical and
(MoleMate system) imaging data as
by GP or nurse well as the
practitioner using a MoleMate
primary care image where
scoring system. available. All
Lesions were non-referred
classified as patients were
requiring fast track offered a
referral for consultation
suspected skin with the lead
cancer or not. clinician for the
trial, including a


Results
second
photograph, at
3-6 months
after the initial
consultation.
Warshaw et al Secondary/tertiar 542 patients (542 Clinical Histopathology. Patients all had
(2009) y care, index lesions), 96% examination with An independent clinical
Minneapolis male 97% one of 11 staff panel of 3 examination. The
Department Caucasian race. 36 clinic expert teledermatology
Veterans’ Affairs melanomas dermatologists dermatologist took place after
dermatology including tests (not involved in this. Then all index
clinic, USA Inclusion criteria: normally available the index tests) lesions were
patients referred in the clinical agreed the most excised.
from primary care setting (e.g. appropriate
for evaluation of palpation, management
pigmented skin diascopy, plan for each
lesions, who also dermatoscopy). patient
underwent excision The lesion was
of the lesion assigned one of 17
common primary
Exclusion criteria: diagnoses, and up
not reported to 2 differential
diagnoses.
Teledermatology –
one of 3 expert
dermatologists
reviewed the
transmitted digital
photographs
(including
dermatoscopy
images) of the
pigmented lesions.
The lesion was


Results
assigned one of 17
common primary
diagnoses, and up
to 2 differential
diagnoses

1 2.2 Photography
2 Review question: Is photography an effective method of detecting progression of pigmented lesions,
3 including dermoscopy pictures?
4 Background
5 Melanoma typically presents as a new enlarging mole or a change in size shape or colour of an existing mole.
6 Early diagnosis and treatment is associated with better survival.
7 In the absence of screening programmes for melanoma, emphasis might better be directed towards developing
8 tools that enable patients to self monitor their moles, particularly for those patients that have a lot of large
9 unusual looking moles.
10 Assessing change in moles can be difficult both for patients and health care professionals. Monitoring moles by
11 sequential photography could well be helpful particularly if dermoscopic pictures are used in combination with
12 ordinary close up pictures that show clearly the measurements of the mole. Additionally, general photographs of
13 the skin to ‘map’ where moles are on the body might help patients and clinicians to notice when new moles are
14 appearing and growing. The latter is called mole mapping, and mole mapping services are provided on the High
15 Street by a range of private providers, but there is limited access to this service for NHS patients.
16 What we don’t know is whether this type of sequential photography (with or without dermoscopic images) can
17 help us to diagnose melanoma and, in particular, the time intervals that would be used to repeat the
18 photographs (e.g. 6 weeks, 3 months), in order to detect an early melanoma.

Patients/population Intervention Comparison Outcomes
Patients with lesions Photography +/- no photography Stage at diagnosis of
suspicious of dermoscopy melanoma
melanoma (e.g. photographs
suspicious skin Time to diagnosis
lesions)
People with atypical

moles
20 Screening Results
21 465 potentially relevant papers were identified through database searching and an additional 6 were identified
22 through other sources (references in identified papers). Abstracts for these 471 papers were screened for their
23 relevance for the review question and 417 papers were excluded leaving 54 papers to be ordered and the full
24 text screened (figure 1). From these 54 papers 4 were relevant and included in the evidence review and 50
25 papers were excluded (table 4).

1 Figure 2.6. Screening results

searching other sources 6
465

471 417

54 50
Studies included in evidence review

4
2
3 Photographic surveillance of single lesions or the entire body has been proposed to limit the number of
4 unnecessary skin surgeries and to enhance the early detection of melanoma.
5 A number of the assessed papers demonstrated the usefulness of photography as a screening tool (Banky et al
6 2005; Bowns et al 2006; Feit et al 2004; Goodson et al 2010; Kelly et al 1997; Rivers et al 1990; Salerni et al 2012;
7 Wang et al 2004). However these studies did not compare photography with other screening methods and so are
8 not included in the evidence review.
9 There were 4 studies that compared the use of photography as a screening tool in patients with lesions
10 suspicious of melanoma against similar patients that did not have photography; 2 retrospective studies, 1
11 randomized trial and 1 cohort study. The studies looked at the outcomes of thickness of melanoma (which is a
12 marker for stage of disease) or clinical stage of melanoma. None of the studies looked at time to diagnosis. Two
13 studies only had baseline photography, 1 study took photographs yearly and 1 study took photographs at follow
14 up every 6 or 12 months.

2 Thickness of melanoma
3 One randomized controlled trial, one cohort study and two retrospective studies examined the thickness of
4 melanoma in patients that had photography compared to patients that had not had photography. All of the
5 studies found that the melanomas excised were thinner in the photography patients.
6 In the randomized trial (Del Mar et al 1995) over 50 medical practitioners, mostly in general practices, in two
7 cities in Queensland, Australia were recruited into the trial. Practitioners in one city randomized to receive the
8 intervention were provided with an algorithm for clinical management of patients with suspicious moles and a
9 Polaroid instant camera. Pathology reports of all lesions excised during the 2 year intervention period were
10 obtained and analyzed. The median thickness of melanomas excised in the intervention group (photography) was
11 0.50 mm compared with 0.60mm in the control group (no photography).
12 In the cohort study (Drugge et al 2009) an assessment of melanoma thickness was compiled from 6 melanoma
13 biopsy cohorts which had undergone different clinical screening methods. The test cohort included patients who
14 were screened using photography yearly, two cohorts represented melanoma biopsies obtained from separate
15 pathology laboratories and the other 3 cohorts were from outside non-dermatologist physician referrals, patients
16 who were self-refereed and a cohort of patients followed by a dermatologist but without photographic
17 screening. The photography cohort had significantly thinner melanomas (0.13-1.4 mm thinner) compared to the
18 3 other clinical screening groups as well as the 2 pathology laboratory cohorts.
19 In the retrospective study (Salerni et al 2011) clinical and dermoscopic characteristics of 215 melanomas
20 consecutively excised and diagnosed over a 2 year period were analyzed. Melanomas diagnosed in patients in a
21 follow up program (total body photography and digital dermoscopy) were compared with melanomas diagnosed
22 in patients not in the follow up program over a 2 year period and were found to be 1.17mm thinner (mean
23 thickness 0.55mm compared to 1.72mm).
24 In another retrospective study (Rademaker et al 2010) 52 invasive melanomas identified from the Molemap NZ
25 database (which involved whole body photography and sequential digital dermoscopy) were compared to 15839
26 invasive melanomas detected by traditional methods as reported to the new Zealand cancer registry and were
27 found to be 0.20mm thinner (mean thickness 0.67mm compared to 0.87 mm). The study also examined
28 proportions of melanomas at different thicknesses. 69% of melanomas from patients who had photography and
29 52% of melanomas from patients who did not have photography were less than 0.75mm. 2% of melanomas from
30 patients who had photography and 11% of melanomas from patients who did not have photography were thicker
31 than 3mm.
32 Clinical stage of melanoma
33 One randomized controlled trial and one retrospective study examined the stage of melanoma in patients that
34 had photography compared to patients that had not had photography.
35 In the randomized trial (Del Mar et al 1995) it was found that there was no difference in the percentage of
36 invasive melanomas excised (72%) in the intervention group (photography) compared with the control group (no
37 photography).
38 In the retrospective study (Salerni et al 2011) 30% of melanomas were invasive melanomas in the patients that
39 had photography compared with 72% in patients without photography. The study also looked at the melanomas
40 in greater detail and classified them according to the American joint committee on cancer staging system. In
41 patients with photography 70% presented at as stage 0 at diagnosis and 30% at stage IA. No melanomas were

1 diagnosed above this stage. However in patients without photography 27.9% presented at stage 0 at diagnosis,
2 37.6% at stage IA, 12.7% at stage IB, 10.9% as stage II, 8.5% at stage III and 2.4% at stage IV.

1 Grade Table 2.1: Should Photography be used
Quality assessment Summary of findings Importance

No of melanomas excised Effect Quality
No of Design Limitations Inconsistency Indirectness Imprecision Other photography no Relative Absolute
studies considerations photography (95%
CI)
stage of melanoma
2
1 observational serious no serious no serious no serious strong 50 165 - 42% more in
1 association situ LOW
studies inconsistency indirectness imprecision
melanomas
in patients
that had
photography
compared to
those who
did not have
photography.
stage of melanoma
2
1 randomised serious no serious no serious no serious none 114 113 - No difference
trials inconsistency indirectness imprecision in the MODERATE
numbers of
in situ and
invasive
melanomas
between
patients that
had
photography
compared to
those who
did not have
photography.
thickness of melanoma

Quality assessment Summary of findings Importance

No of melanomas excised Effect Quality
No of Design Limitations Inconsistency Indirectness Imprecision Other photography no Relative Absolute
studies considerations photography (95%
CI)
2
3 observational serious no serious no serious no serious strong 118 17846 - Breslow
1 association depth of LOW
studies inconsistency indirectness imprecision
melanoma
was 0.1 – 1.4
mm thinner
in patients
that had
photography
compared to
those who
did not have
photography.
thickness of melanoma
2
1 randomised serious no serious no serious no serious none 114 113 - Median
trials inconsistency indirectness imprecision Breslow MODERATE
depth of
melanoma
was 0.1mm
thinner in
patients that
had
photography
compared to
those who
did not have
photography.
1 1
retrospective cohort study
2 2
bias
3 For the two retrospective studies and one cohort study there is selection bias in that it is high risk patients that are included in screening programs with photography. If these patients are at high risk the practitioner may be more likely to
4 excise the lesion anyway and so we would expect to observe melanomas diagnosed at an earlier stage in this group of patients. The randomised trial is not subject to this bias. However it is not without its own limitations in that there is
5 one city in each arm of the trial - ideally several cities would have been randomised to each arm. Also as the study cannot be blinded and practitioners know they are in the intervention city this could also introduce bias. Furthermore it is
6 possible that the study underestimated the full potential of photography because of the duration of the follow up and review (4-8 weeks) may not have been long enough for the photography to detect morphologic change of atypical
7 moles, given that many melanomas are slow growing.

1 References
2 Included Studies
3 Del Mar CB, Green AC. (1995) Aid to diagnosis of melanoma in primary medical care. BMJ 310(6978):492-5.
4 Drugge RJ, Nguyen C, Drugge ED, Gliga L, Broderick PA, McClain SA, Brown CC. (2009) Melanoma screening with
5 serial whole body photographic change detection using Melanoscan technology. Dermatol Online J. 15(6):1.
6 Rademaker M, Oakley A. (2010) Digital monitoring by whole body photography and sequential digital dermoscopy
7 detects thinner melanomas. J Prim Health Care 2(4):268-72.
8 Salerni G, Lovatto L, Carrera C, Puig S, Malvehy J. (2011) Melanomas detected in a follow-up program compared with
9 melanomas referred to a melanoma unit. Arch Dermatol. 147(5):549-55.
10 Excluded Studies
11 Argenziano,G.. Slow-growing melanoma: A dermoscopy follow-up study. British Journal of Dermatology

12 Reason: Not a study looking at photography.
13 Banky JP, Kelly JW, English DR, Yeatman JM, Dowling JP. (2005) Incidence of new and changed nevi and melanomas
14 detected using baseline images and dermoscopy in patients at high risk for melanoma. Arch Dermatol. 141(8):998-
15 1006.
16 Reason: No comparison with no photography.
17 Bowns,I.R.C.. Telemedicine in dermatology: A randomised controlled trial. Health Technology Assessment

18 Reason: Not relevant to PICO
19 Brown,N. and Brown,N.. Exploration of diagnostic techniques for malignant melanoma: an integrative review.
20 [Review] [36 refs]. Clinical Excellence for Nurse Practitioners
21 Reason: Systematic review of diagnostic techniques (1952-1999):
22 Buhl,T.. Integrating static and dynamic features of melanoma: The DynaMel algorithm. Journal of the American
23 Academy of Dermatology
24 Reason: Not a study looking at photography
25 Carli,P. and de Giorgi,V. and Chiarugi,A. and Nardini,P. and Weinstock,M.A. and Crocetti,E. and Stante,M. and
26 Giannotti,B.. Addition of dermoscopy to conventional naked-eye examination in melanoma screening: a randomized
27 study. Journal of the American Academy of Dermatology
29 Carli,P. and De,Giorgi,V and Giannotti,B.. Why digital follow-up of dermoscopically equivocal pigmented lesions
30 should be discouraged. British Journal of Dermatology
31 Reason: Expert opinion.
32 Coates E.Menzies. Total body photography self-examination in patients at high risk of melanoma. Australasian
33 Journal of Dermatology
34 Reason: Conference report on a case series.
35 Coates E.Moloney. Melanoma detection in high risk patients: A case series. Australasian Journal of Dermatology
36 Reason: Conference abstract.

1 De Giorgi,V. Total body photography versus digital dermoscopic follow-up in the diagnosis of pigmented lesions.
2 Dermatologic Surgery
3 Reason: Expert opinion.
4 Drugge,R.J. and Nguyen,C. and Gliga,L. and Drugge,E.D. and Drugge,Rhett J. and Nguyen,Chi and Gliga,Luciana
5 and Drugge,Elizabeth D.. Clinical pathway for melanoma detection using comprehensive cutaneous analysis with
6 Melanoscan. Dermatology Online Journal
8 English DR, Burton RC, et al. (2003) Evaluation of aid to diagnosis of pigmented skin lesions in general practice:
9 controlled trial randomised by practice. BMJ 327 (7411): 375.
10 Reason: Study does not outcomes in PICO.
11 Feit NE, Dusza SW, Marghoob AA. (2004) Melanomas detected with the aid of total cutaneous photography. Br J
12 Dermatol. 150(4), 706-714.
14 Fikrle,T. and Pizinger,K. and Szakos,H. and Panznerova,P. and Divisova,B. and Pavel,S. and Fikrle,T. and Pizinger,K.
15 and Szakos,H. and Panznerova,P. and Divisova,B. and Pavel,S.. Digital dermatoscopic follow-up of 1027
16 melanocytic lesions in 121 patients at risk of malignant melanoma. Journal of the European Academy of
17 Dermatology & Venereology
19 Goodson,A.G.F.. Comparative analysis of total body and dermatoscopic photographic monitoring of nevi in similar
20 patient populations at risk for cutaneous melanoma. Dermatologic Surgery
21 Reason: No comparison to no photography.
22 Gray,M.. The MoleMap experience 15 years on. Australasian Journal of Dermatology

23 Reason: Conference abstract
24 Guitera,P. and Menzies,S.W. and Guitera,Pascale and Menzies,Scott W.. State of the art of diagnostic technology
25 for early-stage melanoma. [Review]. Expert Review of Anticancer Therapy
27 Guitera-Rovel,P. and Vestergaard,M.E. and Guitera-Rovel,P. and Vestergaard,M.E.. [Diagnosis tools for cutaneous
28 melanoma]. [Review] [58 refs] [French]. Annales de Dermatologie et de Venereologie
29 Reason: Foreign Language
30 Haenssle,H.A.K.. Results from an observational trial: Digital epiluminescence microscopy follow-up of atypical nevi
31 increases the sensitivity and the chance of success of conventional dermoscopy in detecting melanoma. Journal of
32 Investigative Dermatology
33 Reason: Not a study looking at photography,
34 Haenssle,H.A.K.. Selection of patients for long-term surveillance with digital dermoscopy by assessment of
35 melanoma risk factors. Archives of Dermatology
37 Haenssle,H.A.K.. Seven-point checklist for dermatoscopy: Performance during 10 years of prospective surveillance of
38 patients at increased melanoma risk. Journal of the American Academy of Dermatology
1 Hanrahan PF, D'Este CA, Menzies SW, Plummer T, Hersey P. (2002) A randomised trial of skin photography as an aid
2 to screening skin lesions in older males. J Med Screen 9(3):128-32.
3 Reason: No data
4 Hanrahan,P.F. and Hersey,P. and Menzies,S.W. and Watson,A.B. and D'Este,C.A. and Hanrahan,P.F. and Hersey,P.
5 and Menzies,S.W. and Watson,A.B. and D'Este,C.A.. Examination of the ability of people to identify early changes of
6 melanoma in computer-altered pigmented skin lesions. Archives of Dermatology
8 Kacenjar S.Zook. An automated multi-imaging registration method for the detection and quantification of
9 morphological changes across pigmented skin lesions. Pigment Cell and Melanoma Research
11 Kelly JW, Yeatman JM, Regalia C, Mason G, Henham AP. (1997) A high incidence of melanoma found in patients with
12 multiple dysplastic naevi by photographic surveillance. Med J Aust. 167(4), 191-194.
13 Reason: No comparisons with no photography.
14 Kittler,H. and Binder,M.. Follow-up of melanocytic skin lesions with digital dermoscopy: risks and benefits. Archives
15 of Dermatology
16 Reason: Brief Comment
17 Kittler,H. and Pehamberger,H. and Wolff,K. and Binder,M.. Diagnostic accuracy of dermoscopy. Lancet Oncology
19 Korotkov,K. and Garcia,R. and Korotkov,Konstantin and Garcia,Rafael. Computerized analysis of pigmented skin
20 lesions: a review. [Review]. Artificial Intelligence in Medicine
21 Reason: Methodological review
22 Lucas,C.R. and Sanders,L.L. and Murray,J.C. and Myers,S.A. and Hall,R.P. and Grichnik,J.M.. Early melanoma
23 detection: nonuniform dermoscopic features and growth. Journal of the American Academy of Dermatology
25 Macbeth,A.E. and Grindlay,D.J. and Williams,H.C. and Macbeth,A.E. and Grindlay,D.J.C. and Williams,H.C.. What's
26 new in skin cancer? An analysis of guidelines and systematic reviews published in 2008-2009. [Review]. Clinical &
27 Experimental Dermatology
28 Reason: Expert review
29 Mayer,J.. Systematic review of the diagnostic accuracy of dermatoscopy in detecting malignant melanoma. [Review]
30 [25 refs]. Medical Journal of Australia
32 Menzies,S.W.S.. Variables predicting change in benign melanocytic nevi undergoing short-term dermoscopic
33 imaging. Archives of Dermatology
35 Milano,A.Bonifazi. Congenital melanocytic nevus. Clinical and dermoscopic signs of malignancy. European Journal of
36 Pediatric Dermatology
38 Moloney,F.J.G.. Observation of a five year high risk clinic for primary melanoma. Australasian Journal of Dermatology

1 Reason: Abstract
2 NHS Centre for Reviews and Dissemination. Systematic review of the diagnostic accuracy of dermatoscopy in
3 detecting malignant melanoma (Structured abstract). Database of Abstracts of Reviews of Effectiveness
4 Reason: Abstract
5 Oakley,A.M.M.. Excised skin lesions diagnosed by teledermoscopy. Australasian Journal of Dermatology

6 Reason: Abstract
7 Rajpara S.Woo. The role of conventional naked eye examination, dermoscopy and digital dermoscopy follow-up in
8 the management of melanocytic skin lesions: A prospective study. British Journal of Dermatology
9 Reason: Abstract
10 Rajpara,S.M. and Botello,A.P. and Townend,J. and Ormerod,A.D. and Rajpara,S.M. and Botello,A.P. and
11 Townend,J. and Ormerod,A.D.. Systematic review of dermoscopy and digital dermoscopy/ artificial intelligence for
12 the diagnosis of melanoma. [Review] [95 refs]. British Journal of Dermatology
13 Reason: No Photography
14 Rivers JK, Kopf AW, Vinokur AF, Rigel DS, Friedman RJ, Heilman ER, Levenstein M. (1990) Clinical characteristics of
15 malignant melanomas developing in persons with dysplastic nevi. Cancer 65(5), 1232-1236.
16 Reason:No comparisons with no photography.
17 Rubegni,P.Burroni. Objective melanoma progression. Skin Research and Technology

18 Reason: No photography
19 Salerni,G. and Carrera,C. and Lovatto,L. and Marti-Laborda,R.M. et al. Characterization of 1152 lesions excised over
20 10 years using total-body photography and digital dermatoscopy in the surveillance of patients at high risk for
21 melanoma. Journal of the American Academy of Dermatology
23 Salerni,G. and Carrera,C. and Lovatto,L. Et al. Benefits of total body photography and digital dermatoscopy ('two-
24 step method of digital follow-up') in the early diagnosis of melanoma in patients at high risk for melanoma. Journal
25 of the American Academy of Dermatology
26 Reason: No comparison
27 Scope,A. and Dusza,S.W. and Marghoob,A.A. and Satagopan,J.M. and Braga Casagrande,Tavoloni J. and Psaty,E.L.
28 and Weinstock,M.A. and Oliveria,S.A. and Bishop,M. and Geller,A.C. and Halpern,A.C. and Scope,Alon and
29 Dusza,Stephen W. et al. Clinical and dermoscopic stability and volatility of melanocytic nevi in a population-based
30 cohort of children in Framingham school system. Journal of Investigative Dermatology
31 Reason: Not Melanoma
32 Seybold,K.Mertz. An automated change detection image analysis system as an aid in the early identification of skin
33 cancer. Journal of Investigative Dermatology
34 Reason: Abstract
35 Slue,Jr. Total body photography for melanoma surveillance. New York State Journal of Medicine
36 Reason: Review
37 Terushkin,V. and Dusza,S.W. and Scope,A. Et al. Changes observed in slow-growing melanomas during long-term
38 dermoscopic monitoring. British Journal of Dermatology

1 Reason: No photography
2 Vestergaard,M.E. and Menzies,S.W. and Vestergaard,Malene E. and Menzies,Scott W.. Automated diagnostic
3 instruments for cutaneous melanoma. [Review] [20 refs]. Seminars in Cutaneous Medicine & Surgery
4 Reason: No Photography
5 Vyas,R.Oakley. Dermoscopy of fading naevi. British Journal of Dermatology

6 Reason: Abstract
1
7 Wang SQ, Kopf AW, Koenig K, Polsky D, Nudel K, Bart RS. (2004) Detection of melanomas in patients followed up
8 with total cutaneous examinations, total cutaneous photography, and dermoscopy. J Am Acad Dermatol. 50(1), 15-
9 20.
10 Reason: No relevant comparison
11 Xu,L.Kittler. Assessment of growth rate of melanomas based on sequential dermatoscopic images. Melanoma
12 Research
13 Reason: Abstract
14

Evidence Tables
Study Quality
Study Appropriate Appropriat Comparabl Comparabl Patient Treatment Equal Equal Appropria Precise Valid Investigat Quality
Randomisati e e groups e Care Blindin Administra Follow- Treatment te follow- definition method of or blinding
on Concealme at baseline apart from g tor up Completio up length of measuring
nt interventi Blinding n/Loss to outcome outcome
on follow up
Del Yes No No Yes No No Yes Yes No Yes Yes Yes Moderat

Mar e
et al
(2011
)
Study Quality (Cohort Studies)
method of Attempts were groups were comparison Blinding followed comparable comparable appropriate precise Investigators Investigators
allocation to made within comparable at groups up for an for treatment with respect length of definition were kept were kept
treatment the design or baseline received the equal completion to the follow-up of outcome 'blind' to 'blind' to other
length of
groups was analysis to same care availability of participants' important
time
unrelated to balance the apart from the outcome data exposure confounding
potential comparison intervention and prognostic
confounding groups for factors
factors potential
confounders
Drugge et Yes Yes Yes Yes No Yes Yes Yes Yes Yes Yes Yes
al (2009)
Rademaker Yes Unclear No Yes No No Yes Unclear No Yes Yes Yes

et al 2010

Salemi et No Unclear No Yes No Yes Yes Yes No Yes Yes Yes

al (2011)
Study Study Type Population Intervention Comparison Outcomes Results
Del Mar et al randomised trial Over 50 medical practitioners, an algorithm and use of an no algorithm and no - stage of the
1995 instant developing instant developing melanoma
Mostly in general practice, in control intervention
each of two cities in tropical camera camera
Melanomas excised 113 114
Queensland, Australia.
- mean Breslow
depths Level I 26.5% (n=30) 26.3% (n=30)
(photographs only taken at
Control: 1997 excisions (113 baseline – follow up and Level II+ 72.5% (n=82) 72%
melanomas) review in 4-8 weeks)
(n=82)
Intervention:2468 excisions (114
melanomas)
Intervention for 2 years. Median (range) thickness 0.60 0.50
of melanoma mm
(0.20-11.00) (0.10-13.0)
Drugge Cohort study Total number of melanoma Serial scanning cohort (SSC): - Patient self-referral mean Breslow
biosies analysed was 1854. Serial whole body photography (PSR) depths
et al 2009 (Melanoscan®) for the Melanomas
cohort Depth (mm)
detection of melanoma - MD referred (MDR) (n)
Serial scanning cohort (SSC) 16 0.0480
9 years. - Followed by
dermatologist (FBD) Patient self-referral (PSR) 21 0.5528
(photographs: yearly)
- Community MD referred (MDR) 20 0.7285
Control: 1842 melanoma pathology laboratory

excisions (CPL) Followed by dermatologist

49 0.2257
(FBD)
Intervention:16 melanoma - Dermatopathology
excisions laboratory (DPL) Community pathology
24 1.4460
laboratory (CPL)
Dermatopathology
1728 0.1824
laboratory (DPL)
Photographic screening enabled the detection of melanoma at

significantly thinner Breslow depths compared to all other clinical
detection methods.
Rademaker Retrospective analysis 52 invasive melanomas identified self referred whole body Patients diagnosed mean Breslow
et al 2010 from the molemap NZ database photography and sequential through traditional, depths
(over 2 years) and 15839 digital dermoscopy methods as reported Whole body
NZCR registrations
invasive melanomas identified to the photography and
Thickness
from the sequential digital n (%)
(mm)
New Zealand cancer dermoscopy
n (%)
New Zealand cancer registry (photographs only at baseline) registry
<0.75 * 36 (69) 8289 (52)
(over 10 years)
0.76-1.49 11 (21) 3411 (22)
1.5-3.0 4 (8) 2432 (15)
>3.0 1 (2) 1707 (11)
*p=0.02
Patients detected by self-referred whole body photography and

sequential digital dermoscopy had thinner melanomas compared to

patients with melanoma identified by traditional methods.
Average with photography = 0.67mm v 0.87mm without photogpraphy.
Salerni Retrospective analysis 201 patients , 40 of whom were follow-up programs with total- patients referred to a - clinical stage of
included in a follow-up program body photographs and digital melanoma unit the melanoma
et al 2011 and 161 of whom were referred dermoscopy follow-up Referred
for evaluation. program patients
- mean Breslow Stage 0 35 (70%) 46 (27.9%)

Follow up: depths
Melanoma Unit, Barcelona Stage IA 15 (30%) 62 (37.6%)
8 patients yearly,
Stage IB - 21 (12.7%)
32 patients evey 6 months
2 years Stage II - 18 (10.9%)
Stage III - 14 (8.5%)
Control: 165 melanoma excisions Stage IV - 4 (2.4%)
Intervention: 50 melanoma
excisions
follow-up Referred patients

program
Thickness mm 0.55 1.72
Mean (0.25-0.90) (0.25-13.00)

(range)
p=0.001

1 2.3 Borderline and Spitzoid melanocytic lesions?
2 Review question: What is the best approach to resolving clinico-pathological diagnostic uncertainty for
3 borderline or spitzoid melanocytic lesions?
4 Background
5 Melanocytic lesions are difficult in clinical and histopathology practice. Early and reliable diagnosis is very important
6 in the management of such lesions, but it is difficult to achieve, due to various factors. One of the reasons is that
7 there is a number of borderline lesions, which require thorough investigations, and may necessitate extensive
8 workup. These lesions comprise atypical melanocytic proliferations, unusual variations of well-known entities and
9 melanocytic lesion is presenting in unusual age groups. Spitzoid lesions are one of the most important differential
10 diagnostic subgroup for melanoma, especially in the younger age group.
11 Clinico-pathological correlation of the lesions is very important and while currently histopathological diagnosis is the
12 gold standard, significant advancement was made in clinical assessment with the more extensive use of dermoscopy.
13 Current development in the histopathology practice (immunohistochemistry and molecular genetics tests) resulted
14 in more accurate diagnostic methods, which will enable us to achieve more accurate and earlier diagnosis.
15 Distinction between the benign and malignant lesions is important, which is this enables us to direct patient pathway
16 better, avoid unnecessary tests and anxiety of the patients. The borderline melanocytic lesion group causes
17 significant diagnostic difficulty at clinical and histopathology level and while no single test is able to differentiate
18 between these and melanoma, we need to assess new techniques and tool, which are now available. As the clinico-
19 pathological correlation is very important, we should look at the clinical and histopathologic diagnostic methods in
20 combination as well.
21 Question in PICO format:

Clinical assessment & 1. Positive

Clinical assessment Predictive Value
Dermoscopy
2. Negative
Histopathological Immunohistochemistry Predictive Value
Patients presenting examination FISH/molecular genetics testing 3. Sensitivity
with borderline or
4. Specificity
spitzoid melanocytic ?each other 5. Accuracy
lesions
6. Reader
SLNB No SLNB variability/intero
bserver
variability

Searches:
Can we apply date limits to the search (Please No
apply to the searches for this topic. This can Epidemiology data is available from early 80’s
be done for each individual intervention as onwards
appropriate)
Are there any study design filters to be used
Diagnostic Accuracy studies including RCTs if
(RCT, systematic review, diagnostic test). available
If we use study filters, this might limit the scope - the
ones to be considered would be review and
diagnostic test.
List useful search terms. (This can include such Atypical melanocytic, spitzoid, borderline
information as any alternative names for the melanocytic, nevoid, naevoid, melanoma, lentigo
interventions etc) maligna, meltump, stump, uncertain malignant
potential, dysplastic naevus, naevus of special sites,

2 Evidence was be identified, assessed and synthesised according to the methods outlined in the Guidelines Manual
3 (2012). Relevant studies were identified through sifting the abstracts and excluding studies clearly not relevant to
4 the PICO. In the case of relevant or potentially relevant studies, the full paper was ordered and reviewed,
5 whereupon studies considered to be not relevant to the topic were excluded. Studies which were identified as
6 relevant were critically appraised and quality assessed using GRADE methodology and NICE checklists. Data relating
7 to the identified outcomes were extracted from the relevant studies. The data were not meta-analysed due to the
8 difference in interventions and populations (in terms of melanoma thicknesses) of the included studies, but were
9 instead summarised per study in tabular form, and further in GRADE tables and evidence statements.
10 Search Results
Database name Dates Covered No of references No of references Finish date of
found retrieved search
Medline 1946-2013 340 111 16/10/2013
Premedline 15 Oct 2013 40 7 16/10/2013
Embase 1947-2013 532 187 16/10/2013

June 2013
Web of Science (SCI & SSCI) 1900-2013 691 163 23/10/2013
12 1. exp Melanoma/
13 2. melanoma$.tw.
16 5. dubreuilh.tw.
17 6. LMM.tw.
18 7. or/1-6
19 8. "Nevus, Epithelioid and Spindle Cell"/
20 9. (spitz* adj2 (melano* or nevi* or naevi* or nevo* or naevo* or nevu* or naevu* or mole* or lesion* or
21 tumo?r*)).tw.
22 10. (borderline* adj2 (melano* or nevi* or naevi* or nevo* or naevo* or nevu* or naevu* or mole* or lesion* or
23 tumo?r*)).tw.
24 11. (atypical* adj2 (melano* or nevi* or naevi* or nevo* or naevo* or nevu* or naevu* or mole* or lesion* or
25 tumo?r*)).tw.

1 12. (uncertain* adj2 (melano* or nevi* or naevi* or nevo* or naevo* or nevu* or naevu* or mole* or lesion* or
2 tumo?r*)).tw.
3 13. (ambiguous adj2 (melano* or nevi* or naevi* or nevo* or naevo* or nevu* or naevu* or mole* or lesion* or
4 tumo?r*)).tw.
5 14. (dysplastic adj2 (melano* or nevi* or naevi* or nevo* or naevo* or nevu* or naevu* or mole* or lesion* or
6 tumo?r*)).tw.
7 15. (stump or meltump).tw.
8 16. (pigmented adj2 melanocytoma*).tw.
9 17. cutaneous melanocytoma*.tw.
10 18. or/8-17
11 19. 7 and 18
12 20. exp Histological Techniques/
13 21. exp Immunohistochemistry/
14 22. histopathology*.tw.
15 23. immunohistochem*.tw.
16 24. ((fluorescen* or immunofluorescen*) adj2 (test* or techni*)).tw.
17 25. In Situ Hybridization,Fluorescence/
18 26. FISH.tw.
19 27. Molecular Diagnostic Techniques/
20 28. Genetic Testing/
21 29. ((molecular or genetic) adj2 (test* or techni*)).tw.
22 30. Physical examination/
23 31. ((physical or clinical or skin) adj (exam* or assessment*)).tw.
24 32. exp Dermoscopy/
25 33. (dermoscop* or dermatoscop*).tw.
26 34. exp Sentinel Lymph Node Biopsy/
27 35. (sentinel and node* and biops*).tw.
28 36. (SNB or SNLB).tw.
29 37. or/20-36
30 38. 19 and 37
31 39. exp "Sensitivity and Specificity"/
32 40. sensitivity.tw.
33 41. specificity.tw.
34 42. ((pre-test or pretest) adj probability).tw.
35 43. post-test probability.tw.
36 44. predictive value$.tw.
37 45. likelihood ratio$.tw.
38 46. (diagnos* adj accura*).tw.
39 47. *"Predictive Value of Tests"/
40 48. Diagnosis, Differential/
41 49. exp Diagnostic Errors/
42 50. or/39-49
43 51. 38 and 50

1 Screening Results
Records screened after duplicates removed Records excluded

333 165
Additional records identified through

other sources
0
Articles excluded
Full text articles assessed for eligibility 101
(26 articles have been excluded but are awaiting a
124 decision regarding inclusion for the FISH/genetic
intervention)

23
Number of included studies according to each intervention:
 Clinical assessment & Dermoscopy: 2
 Histopathological examination & Immunohistochemistry: 14
o FISH studies: 7
o CGH: 1
o BRAF, NRAS and HRAS genes: 6
 SLNB: 7
2
3 Note. The database contained 334 articles but one article was recorded twice (and ordered twice) with the wrong author information so
4 numbers presented are minus this duplication.
5
6

1 Study Quality
2 Figure 2.7. QUADAS summary for clinical assessment and dermoscopy papers (n=2).
3
4
5 Figure 2.8. QUADAS summary for Immunohistochemistry papers (n=14).
6
7 Figure 2.9. QUADAS summary for sentinel lymph node biopsy papers (n=7).

1 Evidence Statements
2 What is the best approach to resolving clinico-pathological diagnostic uncertainty for borderline or Spitzoid
3 melanocytic lesions?
4 Twenty three low quality studies provided information on diagnostic tests. All studies were retrospective case
5 reviews with very limited information on patient selection.
6 Melanoma versus Melanocytic Nevi/naevus

7 Low quality evidence from two studies suggests that clinical assessment is more sensitive when using dermoscopy
8 for detecting melanoma in populations with melanocytic naevi lesions.
9 Low quality evidence from one study showed that in patients with melanocytic lesions (atypical cellular blue nevi,
10 atypical congenital nevi, atypical desmoplastic nevi, and combined nevi) 44% had a positive sentinel node biopsy.
11 Melanoma versus Spitzoid melanoma

12 Low quality evidence from one study did not identify a genetic test (BRAF Exon 11, 15; NRAS Exon 2, 3; HRAS Exon 2,
13 3) that reliably discriminates between melanoma and Spitzoid melanoma.
14 Low quality evidence from two studies suggests that between 35% and 56% of patients with Spitzoid melanoma will
15 have positive sentinel lymph node biopsies.
16 Melanoma versus Spitz nevi.

17 Low quality evidence from five studies suggests that some genetic tests (FISH, BRAF Exon 15, CGH and NRAS Exon 2)
18 are potentially useful in discriminating between melanoma and Spitz nevi.
19 Melanoma versus Atypical Spitz nevi.

20 Low quality evidence from one study suggests that genetic tests involving BRAF Exon 15 may have a role in
21 discriminating between melanoma and atypical Spitz nevi.
22 Low quality evidence from three studies suggests that between 0% and 47% of patients with atypical Spitz nevi will
23 have positive sentinel lymph node biopsies.
24 Melanoma versus Atypical Spitz tumour

25 Low quality evidence from two studies suggests that genetic tests (FISH and BRAF Exon 15) are potentially useful in
26 discriminating between melanoma and Atypical Spitz tumour.
27 Spitzoid melanoma versus Spitz nevi

28 Low quality evidence from one study suggests that FISH is a potentially useful test in discriminating between Spitzoid
29 melanoma and Spitz nevi.
30 Spitzoid melanoma versus Atypical Spitz nevi

31 Low quality evidence from one study suggests genetic tests involving BRAF Exon 15 may have a role in discriminating
32 Spitzoid melanoma from Atypical Spitz nevi.
33 Low quality evidence from one study suggests that rates of positive sentinel lymph node biopsy of 26% and 35% in
34 patients with Atypical Spitz nevi and Spitzoid melanoma respectively.
35 Spitzoid melanoma versus Atypical spitz tumour

36 Low quality evidence from two studies did not identify a genetic test (FISH; BRAF V600E) that reliably discriminates
37 Spitzoid melanoma from Atypical Spitz tumour.

1 Atypical spitzoid nevomelanocytic versus Typical spitz nevi

2 Low quality evidence from one study did not identify a genetic test (BRAF V600E; NRAS Exon 2) that reliably
3 discriminates Atypical Spitzoid nevomelanocytic from typical spitz nevi.
4 Primary cutaneous melanoma and Spitz nevi

5 Low quality evidence from one study did not identify a genetic test (BRAF V600E; NRAS; HRAS) that reliably
6 discriminates Primary cutaneous melanoma from Spitz nevi.
7 Atypical Spitzoid tumour:

8 Low quality evidence from one study suggests that 28.6% patients with Atypical Spitzoid tumours will have positive
9 sentinel node biopsy.

1 Evidence Summary
2 Table 2.8. Overview of evidence for clinical assessment and dermoscopy (n=2).
Article Lesion/Intervention N Sensitivity Specificity PPV NPV Accuracy

Carli et al. (2004) 3053
Non-users* 50.7 97.3
+
Melanoma (n) 319 Dermoscopy Users 63.9 95.7
Spitz/naevus ( n) 77
Krähn et al. (1998) Correct diagnosis total 80
Clinical 78.8
Dermatoscopical 91.3
Melanoma 39
Clinical 79.4 78 77 80 65
Dermatoscopical 89.8 93 92 90 83
Dysplastic nevi 3
Clinical 0
Dermatoscopical 100
Common nevi 38
Clinical 84.2
Dermatoscopical 92.1
3 Note. Non-users refer to 4 dermatologists from general dermatology clinics where their main activity was clinical assessment without dermoscopy. +Dermoscopy
4 users refer to two dermatologists from pigmented lesion clinics where their main activity was clinical assessment with dermoscopy.
5 Table 2.9. Overview of evidence for sentinel lymph node biopsy (n=7).
Article Lesion type N N SLNB SLNB+ SLNB–

n % n % n %
Caraco et al. (2012) Atypical Spitz nevi 40 40 100 0 0 40 100
Cochran et al. (2010) Melanocytic 33 18 54.5 8 44 10 66
Combined nevi 5 3 60 2 40
Atypical cellular blue nevi 4 2 50 2 50
Atypical congenital nevi 4 2 50 2 50
Atypical desmoplastic nevi 2 1 50 1 50
Hung et al. (2013) Spitzoid melanocytic tumour 40 40 100 12 30 28 70
Atypical spitz tumour 23 6 26.1 17 73.9
Spitzoid melanoma 17 6 35.3 11 64.7
Ludgate et al. (2009) Atypical spitz 57 57 100 27 47.4 30 52.6
Murali et al. (2008) Atypical spitzoid tumour 21 21 100 6 28.6 15 71.4
Urso et al. (2006) Atypical spitz 12 12 100 4 33.3 8 66.7
Paradela et al. (2009) Spitzoid melanoma 38 25 65.8 14 56 8 44

Table 2.10. Overview of evidence for Immunohistochemistry (n=14) according to test (FISH, CGH, individual genetic markers) and outcome (e.g.
melanoma, spitz nevi):
Author Test: FISH Outcome: Disease Sensitivity Specificity PPV NPV Accuracy
DM SMN
Gerami et al. 2011 Positive FISH 7 0 46.7 100 100 65.2 73.3
Negative 8 15
SCMM PSCN
Diaz et al. 2011 Positive FISH 11 1 73.3 93.3 91.7 77.8 83.3
Negative 4 14
M N
Hossain et al. 2011 Positive FISH 112 20 71.8 90.2 84.8 80.8 82.3
Negative 44 185
Martin et al. 2012 Positive FISH 12 0 85.7 100 100 84.6 92
Negative 2 11
M SN
Hossain et al. 2011 Positive FISH 112 3 71.8 94.5 97.4 54.2 77.7
Negative 44 52
Martin et al. 2012 Positive FISH 12 19 85.7 62.7 38.7 94.1 67.7
Negative 2 32
Positive FISH 9 2 90 80 81.8 88.9 85
Negative 1 8
SM SN
Kerl et al. 2012 Positive FISH (Abbott criteria) 21 18 61.8 73.9 53.8 79.7 69.9
Negative 13 51
Positive FISH (Gerami et al. criteria) 22 16 64.7 76.8 57.9 81.5 72.8
Negative 12 53
Positive FISH Combined 24 22 70.6 68.1 52.2 82.5 68.9
Negative 10 47
Requena et al. 2012 Positive FISH (Abbott criteria) 7 0 87.5 100 100 83.3 92.3
Negative 1 5
Positive FISH (Gerami et al. criteria) 8 0 100 100 100 100 100
Negative 0 5
M AST
Massi et al. 2011 Positive FISH 9 6 90 76 60 95 80
Negative 1 19
SM AST
Kerl et al. 2012 Positive FISH (Abbott criteria) 24 47 61.8 47.8 30.9 76.8 51.6
Negative 10 43
Positive FISH (Gerami et al. criteria) 24 54 64.7 40 28.9 75 46.8

Negative 10 36
Positive FISH Combined 24 56 70.6 37.8 30 77.3 46.8
Negative 10 34
Note. DM: Desmoplastic melanoma. SMN: Sclerosing melanocytic nevi. MM/M: Malignant melanoma. SM: Spitzoid melanoma. ASN: Atypical spitz nevi. AST: Atypical spitz tumour.
SN: Spitz nevi.
Author Test: CGH Outcome: Disease Sensitivity specificity PPV NPV Accuracy
Bastian et al. 2003 MM SN 96.2 74.1 94.8 80 92.5
At least one chromosomal aberration 127 7
No aberrations 5 20
Note. MM/M: Malignant melanoma. SN: Spitz nevi.
Author Test: BRAF V600E Outcome: Disease Sensitivity specificity PPV NPV Accuracy
SM AST
Fullen et al. 2006 Positive mutation 2 0 15.4 100 100 38.9 45
Negative 11 7
SM SN
Positive mutation 2 10 15.4 79.2 16.7 77.6 65.6
Negative 11 38
PCM SN
Takata et al. 2007 Positive mutation 11 0 45.8 100 100 48 63.9
Negative 13 12
ASN TSN
Emley et al. 2010 Positive mutation 0 1 0 83.3 0 27.8 26.3
Negative 13 5
Note. PCM: Primary Cutaneous Melanoma. SM: Spitzoid melanoma. ASN: Atypical spitz nevi. AST: Atypical spitz tumour. SN: Spitz nevi. TSN: Typical Spitz nevi.
Author Test: NRAS 1 Outcome: Disease Sensitivity specificity PPV NPV Accuracy
Emley et al. 2010 ASN TSN 33.3 100 100 57.9 65.2
Positive mutation 4 0
Negative 8 11
Note. ASN: Atypical spitz nevi. TSN: Typical Spitz nevi.
Author Test: NRAS 2 Outcome: Disease Sensitivity specificity PPV NPV Accuracy
Emley et al. 2010 ASN TSN 0 100 - 31.6 31.6
Negative 13 6
Note. ASN: Atypical spitz nevi. TSN: Typical Spitz nevi.

Author Test: NRAS Outcome: Disease Sensitivity specificity PPV NPV Accuracy
Takata et al. 2007 PCM SN 33.3 100 100 57.9 65.2
Negative 8 11
Note. PCM: Primary Cutaneous Melanoma. SN: Spitz nevi.
Author Test: HRAS Outcome: Disease Sensitivity specificity PPV NPV Accuracy
Takata et al. 2007 PCM SN 0 100 0 33.3 33.3
Negative 22 11
Note. PCM: Primary Cutaneous Melanoma. SN: Spitz nevi.
Author Test: BRAF Exon 15 Outcome: Disease Sensitivity specificity PPV NPV Accuracy
Van Dijk et al. 2005 MM SM 70 36.1 23.3 81.3 35.3
Negative 3 13
MM ASN 70 100 100 84.2 68.5
Negative 3 16
MM SN 70 100 100 82.4 65.3
Negative 3 14
SM ASN 63.9 100 100 55.2 75
Negative 13 16
Gill et al. 2004 SM SN 0 100 0 52.6 52.6
Negative 9 10
Raskin et al. 2011 M AST 66.7 87.5 50 93.3 84.2
Negative 1 14
M SN 66.7 100 100 88.9 90.1
Negative 1 8
Note. MM/M: Malignant melanoma. SM: Spitzoid melanoma. ASN: Atypical spitz nevi. AST: Atypical spitz tumour. SN: Spitz nevi.
Author Test: BRAF Exon 11 Outcome: Disease Sensitivity specificity PPV NPV Accuracy
Van Dijk et al. 2005 MM SM 0 100 0 89.7 89.7
Negative 3 26

MM ASN 0 100 0 81.3 81.3

Negative 3 13
MM SN 0 100 0 75 75
Negative 3 9
SM ASN 0 100 0 33.3 33.3
Negative 26 13
Gill et al. 2004 SM SN 0 100 0 52.6 52.6
Negative 9 10
Author Test: NRAS Exon 2 Outcome: Disease Sensitivity specificity PPV NPV Accuracy
Negative 7 35
MM ASN 0 100 0 68.2 68.2
Negative 7 15
MM SN 0 100 0 65 65
Negative 7 13
SM ASN 0 100 0 30 30
Negative 35 15
Gill et al. 2004 SM SN 0 100 0 52.6 52.6
Negative 9 10
Raskin et al. 2011 M AST 0 87.5 0 82.4 73.7
Negative 3 14
M SN 0 87.5 0 70 63.6
Negative 1 7
Author Test: NRAS Exon 3 Outcome: Disease Sensitivity specificity PPV NPV Accuracy
Van Dijk et al. 2005 MM SM 28.6 80 22.2 84.8 68.7

Negative 5 28
MM ASN 28.6 100 100 73.7 68.7
Negative 5 14
MM SN 28.6 100 100 73.7 68.7
Negative 5 14
SM ASN 20 100 100 33.3 42.9
Negative 28 14
Gill et al. 2004 SM SN 11.1 100 100 55.6 57.9
Negative 8 10
Author Test: HRAS Exon 2 Outcome: Disease Sensitivity specificity PPV NPV Accuracy
Negative 6 35
MM ASN 0 100 0 72.7 72.7
Negative 6 16
MM SN 0 100 0 68.4 68.4
Negative 6 13
SM ASN 0 100 0 31.4 31.4
Negative 35 16
Gill et al. 2004 SM SN 44.4 40 40 44.4 42.1
Negative 5 4
Raskin et al. 2011 M AST 0 100 0 88.9 88.9
Negative 2 16
M SN 0 87.5 0 77.8 70
Negative 2 7
Author Test: HRAS Exon 3 Outcome: Disease Sensitivity specificity PPV NPV Accuracy
Van Dijk et al. 2005 MM SM 0 100 0 85 85

Negative 6 34
MM ASN 0 88.2 0 71.4 65.2
Negative 6 15
MM SN 0 76.5 0 68.4 56.5
Negative 6 13
SM ASN 0 88.2 0 30.6 29.4
Negative 34 15
Gill et al. 2004 SM SN 11.1 90 50 52.9 52.6
Negative 8 9
Note. MM: Malignant melanoma. SM: Spitzoid melanoma. ASN: Atypical spitz nevi. SN: Spitz nevi.

Figure 2.10. SROC for genetic tests comparing Melanoma (MM) and Spitzoid melanoma (SM).
Figure 2.11 . SROC for genetic tests comparing Melanoma (MM) and Spitz nevi (SN).

Figure 2.12. SROC for genetic tests comparing Melanoma (MM) and Atypical spitz nevi (ASN).
Figure 2.13. SROC for genetic tests comparing Melanoma (M) and Atypical spitz tumour (AST).

Figure 2.14. SROC for genetic tests comparing Spitzoid melanoma (SM) and Spitz nevi (SN).
Figure 2.15. SROC for genetic tests comparing Spitzoid melanoma (SM) and Atypical spitz nevi (ASN).

Figure 2.16. SROC for genetic tests comparing Spitzoid melanoma (SM) and Atypical spitz tumour (AST).
Figure 2.17. SROC for genetic tests comparing Atypical spitzoid nevomelanocytic (ASN) and Typical
spitz nevi (TSN).

Figure 2.18. SROC for genetic tests comparing Primary cutaneous melanoma (PCM) and Spitz nevi (SN).

1 References
2 Included Studies
3 Bastian, BC et al. Classifying melanocytic tumors based on DNA copy number changes. American Journal of Pathology
4 2003; 163(5): 1765-1770.
5 Caraco, C et al. Sentinel lymph node biopsy in atypical Spitz nevi: Is it useful? Ejso 2012; 38(10): 932-935.
6 Carli, P et al. Improvement of malignant/benign ratio in excised melanocytic lesions in the 'dermoscopy era': a
7 retrospective study 1997-2001. British Journal of Dermatology 2004; 150(4): 687-692.
8 Cochran, AJ et al. The role of lymphatic mapping and sentinel node biopsy in the management of atypical and
9 anomalous melanocytic lesions. Journal of Cutaneous Pathology 2010; 37 Suppl 1: 54-59.
10 Diaz, A., Valera, A., Carrera, C., Hakim, S., Aguilera, P., Garcia, A., Palou, J., Puig, S., Malvehy, J., and Alos, L. (2011).
11 Pigmented Spindle Cell Nevus: Clues for Differentiating It From Spindle Cell Malignant Melanoma. A Comprehensive
12 Survey Including Clinicopathologic, Immunohistochemical, and FISH Studies. Note: Mentions key search terms but
13 not spiztoid/spitz.
14 Emley, A et al. Oncogenic BRAF and the tumor suppressor IGFBP7 in the genesis of atypical spitzoid nevomelanocytic
15 proliferations. Journal of Cutaneous Pathology 2010; 37(3): 344-349.
16 Fullen, DR et al. BRAF and NRAS mutations in spitzoid melanocytic lesions. Modern Pathology 2006; 19(10): 1324-
17 1332.
18 Gerami, P et al. Fluorescence in situ hybridization as an ancillary method for the distinction of desmoplastic
19 melanomas from sclerosing melanocytic nevi. Journal of Cutaneous Pathology 2011; 38(4): 329-334.
20 Gill, M et al. Genetic similarities between Spitz nevus and Spitzoid melanoma in children. Cancer 2004; 101(11):
21 2636-2640.
22 Hossain, D. Differential diagnosis of melanomas using fluorescence in situ hybridization (FISH)-melano fish.
23 Laboratory Investigation 2011; Conference(var.pagings): February
24 Hung, T et al. Sentinel lymph node metastasis is not predictive of poor outcome in patients with problematic spitzoid
25 melanocytic tumors. Human Pathology 2013; 44(1): 87-94.
26 Kerl, K., Palmedo, G., Wiesner, T., Mentzel, T., Rutten, A., Scharer, L., Paredes, B., Hantschke, M., Kutzner, H., Kerl,
27 Katrin, Palmedo, Gabriele, Wiesner, Thomas, Mentzel, Thomas, Rutten, Arno, Scharer, Leo, Paredes, Bruno,
28 Hantschke, Markus, and Kutzner, Heinz (2012). A proposal for improving multicolor FISH sensitivity in the diagnosis
29 of malignant melanoma using new combined criteria. Note: Mentions key search terms but not spiztoid/spitz.
30 Krahn, G. Dermatoscopy and high frequency sonography: two useful non-invasive methods to increase preoperative
31 diagnostic accuracy in pigmented skin lesions. Pigment cell research / sponsored by the European Society for
32 Pigment Cell Research and the International Pigment Cell Society 1998; 11(3): 151-154.
33 Ludgate, MW et al. The Atypical Spitz Tumor of Uncertain Biologic Potential A Series of 67 Patients From a Single
34 Institution. Cancer 2009; 115(3): 631-641.
35 Martin, V et al. Presence of cytogenetic abnormalities in Spitz naevi: a diagnostic challenge for fluorescence in-situ
36 hybridization analysis. Histopathology 2012; 60(2): 336-346.
37 Massi, D et al. Atypical Spitzoid melanocytic tumors: A morphological, mutational, and FISH analysis. Journal of the
38 American Academy of Dermatology 2011; 64(5): 919-935.

1 Murali, R et al. Sentinel lymph node biopsy in histologically ambiguous melanocytic tumors with spitzoid features
2 (so-called atypical spitzoid tumors). Annals of Surgical Oncology 2008; 15(1): 302-309.
3 Paradela, S et al. Spitzoid melanoma in children: clinicopathological study and application of immunohistochemistry
4 as an adjunct diagnostic tool. Journal of Cutaneous Pathology 2009; 36(7): 740-752.
5 Raskin, L et al. Copy number variations and clinical outcome in atypical spitz tumors. American Journal of Surgical
6 Pathology 2011; 35(2): 243-252.
7 Requena, C et al. Fluorescence in situ hybridization for the differential diagnosis between Spitz naevus and spitzoid
8 melanoma. Histopathology 2012; 61(5): 899-909.
9 Takata, M. Genetic and epigenetic alterations in the differential diagnosis of malignant melanoma and spitzoid
10 lesion. British Journal of Dermatology 2007; 156(6): 1287-1294.
11 Urso, C et al. Sentinel lymph node biopsy in patients with "atypical Spitz tumors." A report on 12 cases. Human
12 Pathology 2006; 37(7): 816-823.
13 Van Dijk, MCRF, Bernsen, MR, and Ruiter, DJ. Analysis of mutations in B-RAF, N-RAS, and H-RAS genes in the
14 differential diagnosis of Spitz nevus and spitzoid melanoma. American Journal of Surgical Pathology 2005; 29(9):
15 1145-1151.
16 Excluded Studies
17 Alomari, AA. Immunohistochemistry versus mass spectrometry in the detection of the differential expression of
18 vimentin and actin in spitz nevi and spitzoid malignant melanomas. American Journal of Dermatopathology 2013;
19 Conference(var.pagings): e85
20 Reason: Not in PICO.
21 Amin, K et al. Ex vivo dermoscopy of cutaneous biopsies for melanocytic neoplasms: a retrospective review of 517
22 cases with histopathologic correlation. American Journal of Dermatopathology 2012; 34(7): 710-715.
24 Andreassi, L., Perotti, R., Rubegni, P., Burroni, M., Cevenini, G., Biagioli, M., Taddeucci, P., Dell'Eva, G., and Barbini, P.
25 (1999). Digital dermoscopy analysis for the differentiation of atypical nevi and early melanoma - A new quantitative
26 semiology. Note: Mentions key search terms but not spiztoid/spitz.
27 Reason: No intervention comparator.
28 Antonio, J. R., Soubhia, R. M., D'Avila, S. C., Caldas, A. C., Tridico, L. A., Alves, F. T., Antonio, Joao Roberto, Soubhia,
29 Rosa Maria Cordeiro, D'Avila, Solange Correa Garcia Pires, Caldas, Adriana Cristina, Tridico, Livia Arroyo, and Alves,
30 Fernanda Tome (2013). Correlation between dermoscopic and histopathological diagnoses of atypical nevi in a
31 dermatology outpatient clinic of the Medical School of Sao Jose do Rio Preto, SP, Brazil. Note: Mentions key search
32 terms but not spiztoid/spitz.
33 Reason: No intervention comparator (e.g. clinical assessment).
34 Baran, JL and Duncan, LM. Combined Melanocytic Nevi: Histologic Variants and Melanoma Mimics. American Journal
35 of Surgical Pathology 2011; 35(10): 1540-1548.
36 Reason: No comparator.
37 Barnhill, RL. Atypical Spitz nevi/tumors: Lack of consensus for diagnosis, discrimination from melanoma, and
38 prediction of outcome. Human Pathology 1999; 30(5): 513-520.
39 Reason: No comparator, clinical assessment.

1 Berlingeri-Ramos, AC et al. Spitz Nevus in a Hispanic Population: A Clinicopathological Study of 130 Cases. American
2 Journal of Dermatopathology 2010; 32(3): 267-275.
3 Reason: No comparator of interventions.
4 Binder, SW et al. The Histology and Differential-Diagnosis of Spitz Nevus. Seminars in Diagnostic Pathology 1993;
5 10(1): 36-46.
6 Reason: No comparator of interventions.
7 Braun, R. P., Gutkowicz-Krusin, D., Rabinovitz, H., Cognetta, A., Hofmann-Wellenhof, R., Ahlgrimm-Siess, V., Polsky,
8 D., Oliviero, M., Kolm, I., Googe, P., King, R., Prieto, V. G., French, L., Marghoob, A., Mihm, M., Braun, R. P.,
9 Gutkowicz-Krusin, D., Rabinovitz, H., Cognetta, A., Hofmann-Wellenhof, R., Ahlgrimm-Siess, V., Polsky, D., Oliviero,
10 M., Kolm, I., Googe, P., King, R., Prieto, V. G., French, L., Marghoob, A., and Mihm, M. (2012). Agreement of
11 dermatopathologists in the evaluation of clinically difficult melanocytic lesions: how golden is the 'gold standard'?.
12 Note: Mentions key search terms but not spiztoid/spitz.
13 Reason: Assessment of clinical judgements, no comparison to dermoscopy.
14 Broganelli, P. Spitz nevus in adults or spitzoid melanoma? Histologicdermatological correlations. Giornale Italiano di
15 Dermatologia e Venereologia 2003; 138(2): 147-149.
16 Reason: N<10 (n=3) case studies. Italian.
17 Buonaccorsi, JNS. Potential misdiagnosis of atypical benign melanocytic lesion of the thigh: A clinicopathologic study
18 of 41 cases. American Journal of Dermatopathology 2011; Conference(var.pagings): 422-423.
19 Reason: Abstract only.
20 Carli, P., de Giorgi, V., Massi, D. & Giannotti, B. (2000) The role of pattern analysis and the ABCD rule of dermoscopy
21 in the detection of histological atypia in melanocytic naevi. British Journal of Dermatology, 143: 290-297.
22 Reason: No comparison to melanoma.
23 Carrera, C et al. Early Stages of Melanoma on the Limbs of High-risk Patients: Clinical, Dermoscopic, Reflectance
24 Confocal Microscopy and Histopathological Characterization for Improved Recognition. Acta Dermato-Venereologica
25 2011; 91(2): 137-146.
26 Reason: No comparator. Descriptive, no comparison of interventions.
27 Cavalcanti, PG, Scharcanski, J, and Baranoski, GVG. A two-stage approach for discriminating melanocytic skin lesions
28 using standard cameras. Expert Systems with Applications 2013; 40(10): 4054-4064.
30 Cerroni, L et al. Melanocytic Tumors of Uncertain Malignant Potential Results of a Tutorial Held at the XXIX
31 Symposium of the International Society of Dermatopathology in Graz, October 2008. American Journal of Surgical
32 Pathology 2010; 34(3): 314-326.
33 Reason: Description of characteristics. No comparison of interventions.
34 Cesinaro, AM et al. Spitz nevus is relatively frequent in adults - A clinico-pathologic study of 247 cases related to
35 patient's age. American Journal of Dermatopathology 2005; 27(6): 469-475.
36 Reason: Description of characteristics of SN. No comparison of interventions.
37 Chung, LS, Man, YG, and Lupton, GP. WT-1 expression in a spectrum of melanocytic lesions: Implication for
38 differential diagnosis. Journal of Cancer 2010; 1: 120-125.
39 Reason: Results are presented in such a way that outcomes cannot be obtained
40 Clemente, C., Bettio, D., Venci, A., Scopsi, L., Rao, S., Ferrari, A., Piris, A., Mihm, M. C., Jr., Clemente, C., Bettio, D.,
41 Venci, A., Scopsi, L., Rao, S., Ferrari, A., Piris, A., and Mihm, M. C. J. (2009). A fluorescence in situ hybridization (FISH)

1 procedure to assist in differentiating benign from malignant melanocytic lesions. Note: Mentions key search terms
2 but not spiztoid/spitz.
3 Reason: Not in PICO
4 Coates, E. Use of a novel dermoscopic technique in combination with in vivo reflectance confocal microscopy to
5 diagnose amelanotic and hypomelanotic melanoma in a 22 case series. Australasian Journal of Dermatology 2013;
6 Conference(var.pagings): May
7 Reason: Abstract only..
8 Crotty, KA et al. Malignant-Melanoma in Childhood - A Clinicopathological Study of 13 Cases and Comparison with
9 Spitz Nevi. World Journal of Surgery 1992; 16(2): 179-185.
10 Reason: No intervention comparison.
11 De Wit, PE et al. DNA in situ hybridization as a diagnostic tool in the discrimination of melanoma and Spitz naevus.
12 Journal of Pathology 1994; 173(3): 227-233.
13 Reason: Not in PICO..
14 Diaconeasa, A et al. Histopathologic features of Spitzoid lesions in different age groups. Romanian Journal of
15 Morphology & Embryology 2013; 54(1): 51-62.
16 Reason: No comparison, intervention.
17 Diaz, A. Clinicopathologic, immunohistochemical and molecular analysis in the differential diagnosis of reed nevus
18 and spindle cell melanoma. Laboratory Investigation 2011; Conference(var.pagings): February
20 Erdem, O, I. Use of immunohistochemistry (HMB-45,P16 and KI-67) in the diagnosis of spitzoid lesions. Laboratory
21 Investigation 2012; Conference(var.pagings): February
23 Ferrara, G et al. The spectrum of Spitz Nevi - A clinicopathologic study of 83 cases. Archives of Dermatology 2005;
24 141(11): 1381-1387.
26 Gammon, B et al. Enhanced detection of spitzoid melanomas using fluorescence in situ hybridization with 9p21 as an
27 adjunctive probe. American Journal of Surgical Pathology 2012; 36(1): 81-88.
29 Gerami, P et al. A highly specific and discriminatory FISH assay for distinguishing between benign and malignant
30 melanocytic neoplasms. American Journal of Surgical Pathology 2012; 36(6): 808-817.
32 Gerami, P., Jewell, S. S., Morrison, L. E., Blondin, B., Schulz, J., Ruffalo, T., Matushek, P., Legator, M., Jacobson, K.,
33 Dalton, S. R., Charzan, S., Kolaitis, N. A., Guitart, J., Lertsbarapa, T., Boone, S., Leboit, P. E., Bastian, B. C., Gerami,
34 Pedram, Jewell, Susan S., Morrison, Larry E., Blondin, Beth, Schulz, John, Ruffalo, Teresa, Matushek, Paul, Legator,
35 Mona, Jacobson, Kristine, Dalton, Scott R., Charzan, Susan, Kolaitis, Nicholas A., Guitart, Joan, Lertsbarapa, Terakeith,
36 Boone, Susan, Leboit, Philip E., and Bastian, Boris C. (2009). Fluorescence in situ hybridization (FISH) as an ancillary
37 diagnostic tool in the diagnosis of melanoma.[Erratum appears in Am J Surg Pathol. 2010 May;34(5):688].
39 Gerami et al. (2013). Risk assessment for atypical Spitzoid melanocytic neoplasms using FISH to identify
40 chromosomal copy number aberrations. AM J Surg Pathol 2013;37:676-684.
41 Reason: no comparator to melanoma.

1 Gerami et al. (2010). Superficial melanocytic neoplasms with pageoid melanocytosis. A study of interobserver
2 concordance and correlation with FISH. Am J Surg Pathol 2010;34:816-821.
4 Gonzalez, A. Cutaneous melanoma in children and adolescents. JDDG - Journal of the German Society of
5 Dermatology 2013; Conference(var.pagings): July
7 Gonzalez-Campora, R et al. Nucleolar organizer regions in pigmented skin lesions. Value in the differential diagnosis
8 of Spitz nevi. Analytical & Quantitative Cytology & Histology 1991; 13(1): 16-22.
10 Haenssle, H. A., Krueger, U., Vente, C., Thoms, K. M., Bertsch, H. P., Zutt, M., Rosenberger, A., Neumann, C., Emmert,
11 S., Haenssle, Holger A., Krueger, Ullrich, Vente, Claudia, Thoms, Kai Martin, Bertsch, Hans P., Zutt, Markus,
12 Rosenberger, Albert, Neumann, Christine, and Emmert, Steffen (2006). Results from an observational trial: digital
13 epiluminescence microscopy follow-up of atypical nevi increases the sensitivity and the chance of success of
14 conventional dermoscopy in detecting melanoma. Note: Mentions key search terms but not spiztoid/spitz.
16 Hafiji, J et al. The spectrum of spitzoid tumours: A clinical study. Australasian Journal of Dermatology 2012; 53(3):
17 211-215.
18 Reason: No comparative data on interventions.
19 Hantschke, M. Consumption of the epidermis: A diagnostic criterion for the differential diagnosis of melanoma and
20 spitz nevus. American Journal of Surgical Pathology 2004; 28(12): 1621-1625.
21 Reason: Description of characteristics of melanoma and spitz nevus. No intervention comparator.
22 Harvell, JD et al. High-resolution array-based comparative genomic hybridization for distinguishing paraffin-
23 embedded Spitz nevi and melanomas. Diagnostic Molecular Pathology 2004; 13(1): 22-25.
24 Reason: N<10 (n=5) case studies.
25 Harvell, JDM. Spitz's nevi with halo reaction: A histopathologic study of 17 cases. Journal of Cutaneous Pathology
26 1997; 24(10): 611-619.
28 Kashani-Sabet, M et al. A multi-marker assay to distinguish malignant melanomas from benign nevi. Proceedings of
29 the National Academy of Sciences of the United States of America 2009; 106(15): 6268-6272.
31 Kauffman, CLS. Development and validation of a chromogenic RNA in situ hybridization assay for diagnosis of
32 atypical melanocytic nevi and malignant melanoma. Laboratory Investigation 2013; Conference(var.pagings):
33 February
35 Kollipara, R and Singh, V. Atypical spitz nevus and melanoma in children: A clinicopathologic study. Pediatric and
36 Developmental Pathology 2013; Conference(var.pagings): 56-February.
38 Kuzbicki, L. The value of cyclooxygenase-2 expression in differentiating between early melanomas and
39 histopathologically difficult types of benign human skin lesions. Melanoma Research 2012; 22(1): 70-76.
40 Reason: Intervention not currently used in the UK.
41 Langley, RGB. The diagnostic accuracy of in vivo confocal scanning laser microscopy compared to dermoscopy of
42 benign and malignant melanocytic lesions: A prospective study. Dermatology 2007; 215(4): 365-372.

2 Lazova, R et al. Imaging mass spectrometry--a new and promising method to differentiate Spitz nevi from Spitzoid
3 malignant melanomas. American Journal of Dermatopathology 2012; 34(1): 82-90.
5 Mazzarello, V et al. Melanoma versus dysplastic naevi: microtopographic skin study with noninvasive method.
6 Journal of Plastic Reconstructive and Aesthetic Surgery 2006; 59(7): 700-705.
8 Medeiros, AC, I. Epiluminescence microscopy of pigmented skin lesions in southern Brazil: The region with the
9 highest incidence of melanoma. Journal of the American Academy of Dermatology 2011; Conference(var.pagings):
10 AB122
11 Reason: Abstract only
12 Mihic-Probst, D. Absence of BRAF gene mutations differentiates Spitz nevi from malignant melanoma. Anticancer
13 Research 2004; 24(4): 2415-2418.
15 Murali, R. Fluorescence in situ hybridisation in the evaluation of melanocytic tumours. Pigment Cell and Melanoma
16 Research 2010; Conference(var.pagings): 965
18 Niemann, TH and Argenyi, ZB. Immunohistochemical Study of Spitz Nevi and Malignant-Melanoma with Use of
19 Antibody to Proliferating Cell Nuclear Antigen. American Journal of Dermatopathology 1993; 15(5): 441-445.
21 Nojavan, H, Cribier, B, and Mehregan, DR. Desmoplastic Spitz nevus: A histopathological review and comparison with
22 desmoplastic melanoma. Annales de Dermatologie et de Venereologie 2009; 136(10): 689-695.
24 North, J. Fishing for melanoma at UCSF: A review of 804 clinical cases. American Journal of Dermatopathology 2011;
25 Conference(var.pagings): 421
27 Okun, MR and Okun, MR. Silhouette symmetry: an unsupportable histologic criterion for distinguishing Spitz nevi
28 and compound nevi from malignant melanoma. Archives of Pathology & Laboratory Medicine 1997; 121(1): 48-53.
30 Paredes, B and Hardmeier, T. Spitz nevus and Reed nevus: Simulation of melanoma in adults. Pathologe 1998; 19(6):
31 403-411.
33 Pellacani, G et al. In Vivo Confocal Microscopic and Histopathologic Correlations of Dermoscopic Features in 202
34 Melanocytic Lesions. Archives of Dermatology 2008; 144(12): 1597-1608.
36 Pellacani, G et al. Spitz nevi: In vivo confocal microscopic features, dermatoscopic aspects, histopathologic
37 correlates, and diagnostic significance. Journal of the American Academy of Dermatology 2009; 60(2): 236-247.
39 Pizzichetta, MA et al. Negative pigment network: an additional dermoscopic feature for the diagnosis of melanoma.
40 Journal of the American Academy of Dermatology 2013; 68(4): 552-559.

1 Reason: no comparison of interventions.
2 Requena, C et al. Characteristics of spitzoid melanoma and clues for differential diagnosis with spitz nevus. American
3 Journal of Dermatopathology 2012; 34(5): 478-486.
5 Requena, C. Spitz nevus: a clinicopathological study of 349 cases. The American Journal of dermatopathology 2009;
6 31(2): 107-116.
8 Ribe, A et al. S100A6 protein expression is different in Spitz nevi and melanomas. Modern Pathology 2003; 16(5):
9 505-511.
11 Rubegni, P et al. Differentiation between pigmented Spitz naevus and melanoma by digital dermoscopy and stepwise
12 logistic discriminant analysis. Melanoma Research 2001; 11(1): 37-44.
13 Reason: no intervention comparison.
14 Shanks, JH et al. VS38 immunostaining in melanocytic lesions. Journal of Clinical Pathology 1996; 49(3): 205-207.
16 Soura E. Clinical features of spitz nevi in greek population: A retrospective study of 64 cases. JDDG - Journal of the
17 German Society of Dermatology 2013; Conference(var.pagings): July
19 Stanelle, EJB. Clinical experience with atypical spitzoid tumors in patients younger than age 18: Does fluorescence in
20 situ hybridization predict lymph node metastasis? Journal of Clinical Oncology 2012; Conference(var.pagings)
22 Steiner, A et al. Pigmented Spitz Nevi - Improvement of the Diagnostic-Accuracy by Epiluminescence Microscopy.
24 Reason: No comparator to melanoma.
25 Stephens, P. Next-generation sequencing of genomic and cDNA to identify a high frequency of kinase fusions
26 involving ROS1, ALK, RET, NTRK1, and BRAF in Spitz tumors. Journal of Clinical Oncology 2013;
27 Conference(var.pagings)
29 Takata, M. Genome profiling of melanocytic tumors using multiplex ligation-dependent probe amplification (MLPA):
30 Its usefulness as an adjunctive diagnostic tool for melanocytic tumors. Journal of Dermatological Science 2005; 40(1):
31 51-57.
32 Reason: Intervention not currently available in the UK.
33 Takeuchi, M. Pigmented spindle cell nevus and pigmented Spitz nevus--clinical and histopathological study on
34 pigmented Spitz nevus, and its differentiation from early melanoma by fluorescence method and measurement of 5-
35 S-CD level in the lesion. Nippon Hifuka Gakkai zasshi 1990; The Japanese journal of dermatology. 100(11): 1153-
36 1165.
38 van Dijk, MC et al. Allelic imbalance in the diagnosis of benign, atypical and malignant Spitz tumours. Journal of
39 Pathology 2002; 197(2): 170-178.

1 Walsh, N et al. Spitz nevus versus spitzoid malignant melanoma: an evaluation of the current distinguishing
2 histopathologic criteria. Human Pathology 1998; 29(10): 1105-1112.
4 Wang, L. Clinical and histopathological analysis of 16 cases of Spitz nevus. Journal of Clinical Dermatology 2006;
5 35(10): 640-642.
7 Wiesner, T et al. A distinct subset of atypical Spitz tumors is characterized by BRAF mutation and loss of BAP1
8 expression. American Journal of Surgical Pathology 2012; 36(6): 818-830.
9 Reason: No breakdown per melanoma and spitz in the results.
10 Wititsuwannakul, J et al. Neuropilin-2 as a useful marker in the differentiation between Spitzoid malignant
11 melanoma and Spitz nevus. Journal of the American Academy of Dermatology 2013; 68(1): 129-137.
13 Wititsuwannakul, J. Neuropilin-2 (NRP2) as a useful marker in the differential diagnosis of Spitzoid malignant
14 melanoma and Spitz nevus. American Journal of Dermatopathology 2012; Conference(var.pagings): e62
16 Zalaudek, I et al. "White" network in Spitz nevi and early melanomas lacking significant pigmentation. Journal of the
17 American Academy of Dermatology 2013; 69(1): 56-60.
18 Reason: No comparison of interventions.
19 Argenziano, G et al. Dermatoscopic pitfalls in differentiating pigmented Spitz naevi from cutaneous melanomas.
20 British Journal of Dermatology 1999; 141(5): 788-793.
21 Reason Not enough data to extract for the relevant outcomes in PICO.
22 Wettengel, GV et al. Differentiation between Spitz nevi and malignant melanomas by interphase fluorescence in situ
23 hybridization. International Journal of Oncology 1999; 14(6): 1177-1183.
25 Bayer-Garner, IB et al. Vascular endothelial growth factor expression in malignant melanoma: prognostic versus
26 diagnostic usefulness. Modern Pathology 1999; 12(8): 770-774.
28 Bergman, R et al. A comparative immunohistochemical study of MART-1 expression in Spitz nevi, ordinary
29 melanocytic nevi, and malignant melanomas. Journal of the American Academy of Dermatology 2000; 42(3): 496-
30 500.
32 Bergman, R et al. Immunohistochemical study of p53 protein expression in Spitz nevus as compared with other
33 melanocytic lesions. American Journal of Dermatopathology 1995; 17(6): 547-550.
35 Bergman, R. MIB-1 monoclonal antibody to determine proliferative activity of Ki-67 antigen as an adjunct to the
36 histopathologic differential diagnosis of Spitz nevi. Journal of the American Academy of Dermatology 2001; 44(3):
37 500-504.
39 Berk, DR et al. Melanoma and Melanocytic Tumors of Uncertain Malignant Potential in Children, Adolescents and
40 Young Adults-The Stanford Experience 1995-2008. Pediatric Dermatology 2010; 27(3): 244-254.

1 Blokhin, E et al. Immunohistochemical expression of p16 in desmoplastic melanoma. Journal of Cutaneous Pathology
2 2013; 40(9): 796-800.
4 Ferrara, G et al. The impact of molecular morphology techniques on the expert diagnosis in melanocytic skin
5 neoplasms. International Journal of Surgical Pathology 2013; 21(5): 483-492.
7 Garcia-Martin, R. Different protein expressions between Spitz nevus and melanoma. Virchows Archiv 2009;
8 Conference(var.pagings): August
10 Garrido-Ruiz, MC et al. The immunohistochemical profile of Spitz nevi and conventional (non-Spitzoid) melanomas: a
11 baseline study. Modern Pathology 2010; 23(9): 1215-1224.
13 Garrido-Ruiz, MC. Immunohistochemical profile distinguishes Spitz nevi from melanomas. Laboratory Investigation
14 2010; Conference(var.pagings): February
16 George E. Immunohistochemical evaluation of p16INK4A, E-cadherin, and cyclin D1 expression in melanoma and
17 Spitz tumors. American Journal of Clinical Pathology 2010; 133(3): 370-379.
19 Hilliard, NJ et al. p16 expression differentiates between desmoplastic Spitz nevus and desmoplastic melanoma.
20 Journal of Cutaneous Pathology 2009; 36(7): 753-759.
22 Kapur, P et al. Spitz nevi and atypical Spitz nevi/tumors: a histologic and immunohistochemical analysis. Modern
23 Pathology 2005; 18(2): 197-204.
25 King, MS et al. Differentiating spitzoid melanomas from Spitz nevi through CD99 expression. Journal of Cutaneous
26 Pathology 2007; 34(7): 576-580.
28 Le Sache-de Peufeilhoux, L et al. Clinical features of Spitz naevus in children: A retrospective study of 196 cases.
29 Annales de Dermatologie et de Venereologie 2012; 139(6-7): 444-451.
31 Mason, A et al. Expression of p16 alone does not differentiate between Spitz nevi andSpitzoid melanoma. Journal of
32 Cutaneous Pathology 2012; 39(12): 1062-1074.
34 Moore, J. Adoption of FISH for diagnosis of melanoma. Laboratory Investigation 2012; Conference(var.pagings):
35 February
37 Nagasaka, T et al. Cyclin D1 overexpression in Spitz nevi: an immunohistochemical study. American Journal of
38 Dermatopathology 1999; 21(2): 115-120.

1 Pilloni, L et al. The usefulness of c-Kit in the immunohistochemical assessment of melanocytic lesions. European
2 Journal of Histochemistry 2011; 55(2): e20
4 Puri, PK et al. Statistical analysis of the concordance of immunohistochemical stains with the final diagnosis in
5 spitzoid neoplasms. American Journal of Dermatopathology 2011; 33(1): 72-77.
7 Rosner, K et al. WT1 marker is not sufficient for distinguishing between melanoma and melanocytic nevi. Journal of
8 Cutaneous Pathology 2009; 36(10): 1077-1082.
10 Shanks, JH and Banerjee SS. (1996). VS38 immunostaining in melanocytic lesions. J Clin Pathol 1996;49:205-207.
12 Stefanaki, C. Cell cycle and apoptosis regulators in Spitz nevi: Comparison with melanomas and common nevi.
15 Wang, L. Clinical and histopathologic characteristics of desmoplastic Spitz nevus and pigmented spindle cell nevus.
16 Journal of Clinical Dermatology 2008; 37(8): 500-502.
18 Zhang, G., Li, G., Zhang, Guohong, and Li, Gang (2012). Novel multiple markers to distinguish melanoma from
19 dysplastic nevi. Note: Mentions key search terms but not spiztoid/spitz.
21 Zhu, YI and Fitzpatrick, JE. Expression of c-kit (CD117) in Spitz nevus and malignant melanoma. Journal of Cutaneous
22 Pathology 2006; 33(1): 33-37.

Evidence Tables
Evidence tables for the included studies comparing clinical assessment to dermoscopy (N=2):
Carli, P et al. “Improvement of malignant/benign ratio in excised melanocytic lesions in the ‘dermoscopy era’: a retrospective study”. British Journal of
Dermatology (2004) 150: 687-692.
Pub year: 2004 Patient selection Index test Reference standard Flow and timing
Country Italy Inclusion criteria: All histologically Non-users: Clinical Histological All skin lesions were excised and all
confirmed melanocytic lesions assessment (4 examination routinely patients received all index tests. No
consecutively excised at the dermatologists from general made by the same staff information provided regarding the time
Dermosurgery room of the Department dermatology clinics) of pathologists. between index test(s) and reference
of Dermatology of the University of standard.
Florence in the period 1997-2001 were Users: Dermatoscopy (2
retrieved. dermatologists from
Exclusion criteria: patients diagnosed in pigmented lesions clinics)
private practice.
Design, Retrospecti Was a Yes Were the Yes Is the Yes Was Unclear
period ve case consecutive or index test reference there an
review random sample results standard appropria
1997-2001 of patients interpreted likely to te
enrolled? without correctly interval
knowledge classify the between
of the target index
results of condition? test(s)
the and
reference reference
standard? standard
?
N 3053 Was a case- Yes If a Unclear Were the Yes Did all Yes
melanocyti control design threshold reference patients
c lesions avoided? was used, results receive a
Follow- Not Did the study Yes was it pre- interpreted reference
up provided avoid specified? without standard
inappropriate knowledge ?
exclusions? of the Did all Yes
results of patients

the index receive

test? the same
reference
standard
?
Could the Low Could the Low Could the Low Were all Yes
selection of conduct or reference patients
patients have interpretati standard, included
introduced on of the its conduct, in the
bias? index test or its analysis?
have interpretati
introduced on have
bias? introduced
bias?
Funding Not Are there Low Are there High. Not just Are there Low Could the Low
source mentioned concerns that concerns comparing concerns patient
the included that the different that the flow have
patients do not index test, index tests target introduce
match the its conduct, but also the condition d bias?
review or impact of as defined
question? interpretati different by the
on differ diagnostic reference
from the settings standard
review (general does not
question? dermatology match the
clinics versus review
pigmented question?
lesion clinics)
Results N = 3053 histological diagnosed melanocytic lesions.
N = 319 melanomas (10.4%)
N = 77 spitz or reed naevus (2.5%)
Patients attending the PLC were older (38.2 years) compared to those attending the dermatology clinic (36.3 years). Dermoscopy more likely to refer problem
naevi among benign lesions. Overall, 54.1%
Table 1. Outcomes according to total sample for the period 1998-2001.
Sensitivity % Specificity %
Non-users 50.7 97.3

Users 63.9 95.7

Note. Differences in sensitivity and specificity between users and non-users did not reach statistical significance in either the study period as a whole or for each
study year.
Commen No information provided on what a clinical assessment entailed. No sample characteristics provided. Comparing two different settings not just types of index
ts test. Authors state that according to the pattern of referral to their PLC it is presumed that the two diagnostic settings differed in terms of the percentage of
patients with atypical moles and melanoma risk factors examined. Not enough raw data provided by authors to create all outcomes for both melanoma and
problem naevi.
Krähn, G et al. “Dermatoscopy and high frequency sonography: two useful non-invasive methods to increase preoperative diagnostic accuracy in pigmented skin
lesions”. Pigment Cell Research (1998) 11: 151-154.
Country Germany 80 patients with pigmented skin lesions. Clinical assessment Histopathology: All skin lesions were excised and all
All skin lesions excised. Dermatoscopy Malignant melanoma patients received all index tests. No
Inclusion criteria: None provided, unclear Dysplastic nevi information provided regarding the time
how patients were selected. Exclusion Common nevi between index test(s) and reference
criteria: None provided standard.
Design, Monocentr Was a Unclear Were the Yes Is the Yes Was Unclear
period ic, no time consecutive or index test reference there an
period random sample results standard appropria
of patients interpreted likely to te
enrolled? without correctly interval
knowledge classify the between
of the target index
the and
reference reference
standard? standard
?
N 80 Was a case- Yes If a Unclear Were the Yes Did all Yes
control design threshold reference Histologic patients
avoided? was used, results al receive a
Follow- Not Did the study Unclear was it pre- interpreted diagnosis reference
up provided avoid specified? without performe standard
inappropriate knowledge d by at ?
exclusions? of the least two Did all Yes

results of independ patients

the index ent receive
test? dermatop the same
athologist reference
s standard
?
Could the Unclear. No Could the Unclear. Could the Low Were all Yes
selection of information on conduct or Dermatoscopy reference patients
patients have patient selection. interpretati conducted by standard, included
introduced on of the a single its conduct, in the
bias? index test dermatologist or its analysis?
have interpretati
introduced on have
bias? introduced
bias?
Funding Not Are there Low Are there Low Are there Low Could the Low
source mentioned concerns that concerns concerns patient
the included that the that the flow have
patients do not index test, target introduce
match the its conduct, condition d bias?
review or as defined
question? interpretati by the
on differ reference
from the standard
review does not
question? match the
review
question?
Results In all 80 cases the clinical diagnosis of melanocytic lesions could be confirmed histologically.
Table 1. Histopathological accuracy of the clinical and dermatoscopical diagnosis of the total sample and according to diagnosis.
Total sample N=80 Malignant melanoma n=39 Dysplastic nevi n=3 Common nevi n=38
Present Sensitivity % Present Sensitivity % Present Sensitivity % Present Sensitivity %
Positive 63 31 0 32
Clinical diagnosis 78.8 79.4 0 84.2
Negative 17 8 3 6
Dermatoscopical Positive 73 91.3 35 89.8 3 100 35 92.1

diagnosis Negative 7 4 0 3
Table 2. Outcomes according to the malignant melanoma lesions.
Malignant melanoma n=39
Sensitivity % Specificity % PPV % NPV % Accuracy %
Clinical diagnosis 79 78 77 80 65
Dermatoscopical diagnosis 90 93 92 90 83
Commen No information on what the clinical diagnosis entailed. No sample characteristics provided. Authors provide limited data in order to create all outcomes for
ts each diagnosis. Authors acknowledge that the diagnostic accuracy was higher than published data and could be explained by the fact that a monocentric study
was conducted and Dermatoscopy was performed by a single dermatologist.

Evidence tables for the included studies assessing immunohistochemistry FISH/molecular genetics (N=14):
FISH studies (n=7) CGH (n=1):

Gerami, P et al. “Fluorescence in situ hybridization as an ancillary method for the distinction of desmoplastic melanomas from sclerosing melanocytic
nevi”. J Cutan Pathol (2011) 38: 329-334.
Country USA Retrieval of archival data of desmoplastic FISH Histopathologically No information provided regarding the
melanomas and sclerosing melanocytic Four probes targeting Ras- confirmed time between index test(s) and
nevi from two dermatology departments. responsive element-binding unequivocal lesions. reference standard.
Inclusion criteria: Diagnostically protein-1, myeloblastosis, cyclin
unequivocal lesions. Exclusion criteria: D1 or chromosome 11q, and No follow-up data.
Diagnostically controversial or centromeric enumeration probe
ambiguous cases. control for chromosome 6.
Design, Retrospecti Was a consecutive No Were the index Unclear Is the Yes Was there an Unclear
period ve case or random sample test results reference appropriate
review of patients interpreted standard interval between
enrolled? without likely to index test(s) and
knowledge of correctly reference
the results of classify the standard?
the reference target
standard? condition?
N 30 Was a case-control Yes If a threshold Yes Were the Yes Did all patients Yes
design avoided? was used, was it reference receive a
Follow- Not Did the study avoid Yes pre-specified? results reference
interpreted standard?
up provided inappropriate
without Did all patients Yes
exclusions?
knowledge receive the same
of the results reference
of the index standard?
test?
Could the selection Low Could the Low Could the Low Were all patients Yes
of patients have conduct or reference included in the
introduced bias? interpretation standard, its analysis?
of the index test conduct, or
have introduced its
bias? interpretatio

n have
introduced
bias?
Funding Honoraria Are there concerns Low Are there Low Are there Low Could the patient Low
source for that the included concerns that concerns flow have
consultant patients do not the index test, that the introduced bias?
work at match the review its conduct, or target
Abbott question? interpretation condition as
Molecular differ from the defined by
Labs and review the
Neogenom question? reference
ics. IDP standard
Foundation does not
, the match the
Dermatolo review
gy question?
Foundation
and the
American
Cancer
Society.
Abbott
Molecular.
Results Demographic data:
N Female/male Mean age Median age Age range
Total 30 10/20 - - -
Desmoplastic melanoma (DM) 15 2/13 67.6 71 28-92
Sclerotic melanocytic nevi (SMN) 15 8/7 41 40 24-57
FISH Disease Sensitivity specificity PPV NPV Accuracy

DM SMN
Positive FISH 7 0 46.7 100 100 65.2 57
Negative 8 15
Commen
ts

Diaz, A et al. “Pigmented spindle cell nevus: Clues for differentiating it from spindle cell malignant melanoma. A comprehensive survey including
clinicopathologic, immunohistochemical, and FISH studies”. Am J Surg Pathol (2011) 35: 1733-1742.
Country Spain Retrieval of archival data of formalin- FISH Histopathologically No information provided regarding the
fixed, paraffin-embedded samples of 4-colour probe set targeting the examination by 3 time between index test(s) and
pigmented spindle cell nevus (PSCN) and ras responsive element binding blinded reference standard.
spindle cell malignant melanoma (SCMM) protein 1 (RREB1) on 6p25, V- dermatopathologists.
from one hospital clinic. Inclusion myb myeloblastosis viral
criteria: Only cases with complete oncogene homolog (MYB) on
uniformity of opinion of 3 blinded 6q23, cyclin D1 (CCND1) on
dermatopathologists. Exclusion criteria: 11q13, and the chromosome 6
Atypical forms of PSCN. centromeric region (Abbott
Molecular, Des Plaines, IL)
2005-2009 enrolled? without likely to index test(s) and
Follow- Mean: 26 Did the study avoid Yes pre-specified? results reference
up months inappropriate
exclusions?
test?

have introduced its

bias? interpretatio
n have
introduced
bias?
Funding Authors Are there concerns Low Are there Low Are there Low Could the patient Low
source disclosed that the included concerns that concerns flow have
that they patients do not the index test, that the introduced bias?
have no match the review its conduct, or target
significant question? interpretation condition as
relationshi differ from the defined by
p with, or review the
financial question? reference
interest in, standard
any does not
commercia match the
l review
companies question?
pertaining
to this
article
N Female/male Median age Age range
Total 46 30/16 - -
Pigmented spindle cell nevus (PSCN) 22 18/4 22 3-54
Spindle cell malignant melanoma (SCMM) 24 12/12 62 26-90
FISH could be assessed in 30 of 44 cases (15 PSCN and 15 SCMM). The remaining cases were excluded because only <30 nuclei could be assessed properly or
because nuclei did not show signals for all probes.
SCMM PSCN
Positive FISH 11 1 73.3 93.3 91.7 77.8 57.7
Negative 4 14
Commen
ts

Hossain, D et al. “Differential diagnosis of melanomas using fluorescence in situ hybridization (FISH) - MelanoFISH”. Conference(var.pagings): February
2011
Country USA Skin biopsy specimens were FISH Diagnosis No information provided regarding the
retrospectively collected from patients Probes for chromosomes 6, 7, 11 independently time between index test(s) and
with benign diagnosis, dysplastic nevi and 20. confirmed by two reference standard.
spitz nevus and melanoma. Exclusion dermatopathologists.
criteria: Not provided. No follow-up data.
Design, Retrospecti Was a consecutive Unclear Were the index Unclear Is the Yes Was there an Unclear
enrolled? without likely to index test(s) and
N 465 Was a case-control Yes If a threshold Yes Were the Yes Did all patients Unclear
Follow- Not Did the study avoid Unclear pre-specified? results reference
up provided inappropriate
without Did all patients Unclear
exclusions?
test?
Could the selection Unclear Could the Low Could the Low Were all patients Unclear
have introduced its
bias? interpretatio
n have
introduced
bias?

Funding Not Are there concerns Unclear Are there Low Are there Low Could the patient Unclear
source provided that the included concerns that concerns flow have
patients do not the index test, that the introduced bias?
match the review its conduct, or target
question? interpretation condition as
differ from the defined by
review the
question? reference
standard
does not
match the
review
question?
Results Sample:
N
Total 465
Benign nevi ( compound nevus, blue nevus, melanocytic nevus) (N) 205
Dysplastic nevi (clark’s, compound, junctional and residual) (DN) 55
Spitz nevi (SN) 49
Melanoma (M) 156
MelanoFISH
M and DN M and SN M and N DN and SN
Disease
D NP PP NP
M SN N Sen Spe PPV Acc Sen Spe PPV NPV Acc Sen Spe Acc Sen Spe PPV NPV Acc
N V V V
Positive 112 19 3 20
61. 85. 40. 94. 97. 77. 71. 84. 80. 82. 38. 63. 68.
Negativ 18 71.8 69.3 71.8 54.2 90.2 94.5 86.4
44 30 52 2 5 5 5 4 7 8 8 8 3 8 4 3
e 5
DN and N SN and N
90. 48. 90. 74.
38.8 86 91.8 5.5 13 78.1
2 7 2 2
The overall percent agreement between histologic diagnosis (melanoma vs. all others) and MelanoFISH results was 82%.
Commen Abstract of conference presentation so limited information. No demographic information provided. Unclear whether the 465 cases were all the participants
ts included in the analysis.

Martin, V et al. “Presence of cytogenetic abnormalities in Spitz naevi: a diagnostic challenge for fluorescence in-situ hybridization analysis”.
Histopathology (2012) 60: 336-346.
Country Switzerlan Consecutive series of 82 patients with FISH Histological review by No information provided regarding the
d spitz naevi diagnosed between 1990- Four-colour probe set LSI two senior time between index test(s) and
2008. Control group included 11 patients RREB1/LSI MYB/LSI CCND1/CEP6. pathologists with reference standard.
with benign nevi and 14 patients with extensive experience
malignant melanomas. Exclusion criteria: in neoplastic Clinical follow-up available for 49
Spitzoid melanoma, spitz tumours of dermatopathology. patients (of the 51 spitz naevi
uncertain malignant potential and Unequivocal patients).
controversial diagnosis. confirmation of
original diagnosis.
Design, Retrospecti Was a consecutive Yes Were the index Unclear Is the Yes Was there an Unclear
Spitz naevi enrolled? without likely to index test(s) and
only: knowledge of correctly reference
1990-2008 the results of classify the standard?
N 76/107 Was a case-control No. Authors If a threshold Yes Were the Uncle Did all patients Yes
design avoided? included controls. was used, was it reference ar receive a
Unclear if age- pre-specified? results reference
matched. interpreted standard?
Follow- Spitz naevi Did the study avoid Yes without
up only inappropriate knowledge Did all patients Yes
(49/51): exclusions? of the results receive the same
Median: of the index reference
8.18 years test? standard?
Range: 2- Could the selection Unclear Could the Low Could the Low Were all patients No
20 years) of patients have conduct or reference included in the 51/82 spitz naevi
introduced bias? interpretation standard, its analysis? gave analysable
of the index test conduct, or results by FISH
have introduced its
bias? interpretatio
n have

introduced
bias?
Funding Abbott Are there concerns Low Are there Low Are there Low Could the patient Unclear
source Molecular that the included concerns that concerns flow have
provided patients do not the index test, that the introduced bias?
match the review its conduct, or target
question? interpretation condition as
review the
question? reference
standard
does not
match the
review
question?
Results Sample:
N Female/male Mean age Age range
Total 76 - - -
Benign nevi (N) 11 - - -
Spitz naevi (SN) 51 36/15 24 1-65
Malignant melanoma (MM) 14 - - -
FISH
MM and SN MM and N SN and N
Disease
Sensitiv Specific PP Accura Sensitivit Specific Accura Sensitivi Specific Accura
MM SN N NPV PPV NPV PPV NPV
ity ity V cy y ity cy ty ity cy
Positive 12 19 0 38. 84. 25.
85.7 62.7 94.1 67.7 85.7 100 100 92 37.3 100 100 48.4
Negative 2 32 11 7 6 6
Commen Demographic data only available for the spitz naevi group. No information on how the controls were selected. Authors state that the majority (14/19: 74%) of
ts the FISH+ spitz naevi cases were characterised by positivity for two or three of the four diagnostic criteria, thus reducing the risk of misinterpretation.

Kerl, K et al. “A proposal for improving multicolour FISH sensitivity in the diagnosis of malignant melanoma using new combined criteria”. Am J
Dermatopathol (2012) 34: 580-585.
Country Germany Formalin-fixed paraffin-embedded specimens FISH Diagnosis independently No information provided
were selected from the archives and Multicolour FISH probe mix confirmed by regarding the time
consultation files of Dermatopathologie (Abbott) consisting of 4 probes dermatopathologists using between index test(s) and
Friedrichshafen. used for the detection of standard criteria in reference standard.
Inclusion criteria: Not provided. Exclusion amplifications or deletions of conjunction with
criteria: Not provided. RREB1, MYB and CCND1 genes hermatoxylin and eosin (H&E) No follow-up data
The authors present data on all 575 lesions and of centromere 6: RREB1 – stained sections and provided.
according to diagnosis. I selected the spitz (RAS responsive element- immunohistochemical stains
nevus, atypical spitz tumour and Spitzoid binding protein 1 encoding for MelanA, HMB45, p16, p21,
melanoma data only 193/575. gene) on 6p25, MYB phosphohistone H3 serin10,
(myeloblastosis gene) on 6q23, MPM2 and Ki67.
CCND1 (cyclin D1 gene) on
11q13, and CEp6 (centromeric
probe of chromosome 6).
Design, Retrospecti Was a consecutive No Were the Unclear Is the Yes Was there an Unclear
period ve case or random sample index test reference appropriate
review of patients results standard likely interval
enrolled? interpreted to correctly between index
without classify the test(s) and
knowledge of target reference
the results of condition? standard?
the reference
standard?
N 193/575 Was a case-control Yes If a threshold Yes Were the Yes Did all Yes
design avoided? was used, was reference patients
Follow- Not Did the study avoid Yes it pre- results receive a
up provided inappropriate specified? interpreted reference
without standard?
exclusions?
knowledge of Did all Yes
the results of patients
the index test? receive the
same
reference

standard?
Could the selection Low Could the Low Could the Low Were all Yes but
of patients have conduct or reference patients not all
introduced bias? interpretation standard, its included in the reported
of the index conduct, or its analysis? in this
test have interpretation table
introduced have
bias? introduced
bias?
Funding No funding Are there concerns Low Are there Low Are there Low Could the Low
source informatio that the included concerns that concerns that patient flow
n. Authors patients do not the index test, the target have
declared match the review its conduct, or condition as introduced
no conflicts question? interpretation defined by the bias?
of interest. differ from the reference
review standard does
question? not match the
review
question?
Results Sample: N
Total 193
Spitz nevus (SN) 69
Atypical spitz tumour (AST) 90
Spitzoid melanoma (SM) 34
Disease SM and AST SM and SN AST and SN

Sensitiv Specific Accura Sensitiv Specific Accura Sensitivi Specific Accura
SM AST SN PPV NPV PPV NPV PPV NPV
ity ity cy ity ity cy ty ity cy
Positive Abbott 21 47 18 30. 76. 53. 79. 72. 54.
61.8 47.8 51.6 61.8 73.9 69.9 52.2 73.9 61.6
Negative 13 43 51 9 8 8 7 3 3
Positive Gerami 22 54 16 28. 57. 81. 77. 59.
64.7 40 75 46.8 64.7 76.8 72.8 60 76.8 67.3
Negative 12 36 53 9 9 5 1 6
Positive 24 56 22 70.6 37.8 30 77. 46.8 70.6 68.1 52. 82. 68.9 62.2 68.1 71. 58 64.8

Combined 3 2 5 8
Negative 10 34 47
Commen No demographic data provided on sample.
ts
Massi, D et al. “Atypical Spitzoid melanocytic tumors: a morphological, mutational, and FISH analysis”. Dermatopathology (2011) 64: 919-935.
Country Italy Atypical spizoid lesions: Archival FISH For the atypical No information provided regarding the
data from pathology files of three Multicolor FISH DNA kit composed Spitzoid lesions: time between index test(s) and
hospitals (n=38). from LSI RRED1 (6p25) Histopathological reference standard.
SpectrumRed/LSI MYB (6q23) slides independently
Comparator: independent cohort of SpectrumGold/LSI CCND1 (11q13) reviewed and then Clinical follow-up available for 49
unambiguously classified as Spitz SpectrumGreen/CEp6 (6p11.1-q11 re-evaluated on the patients (of the 51 spitz naevi patients).
nevi and unequivocal melanomas Alpha Satellite DNA) SpectrumAgua. multiheaded
(n=20). microscope by 4
pathologists with
Inclusion criteria: Patients whose specific background
tumors measured at least 1mm in in dermatopathology.
thickness. Exclusion criteria: Not For the
provided. unambiguously
classified spitz nevi
and unequivocal
melanomas:
reviewed by at least
two
dermatopathologists
who agreed the
diagnosis.
Design, Retrospec Was a consecutive No Were the index test Unclear Is the reference Yes Was there an Unclear
period tive case or random sample results interpreted standard likely to appropriate
review of patients without knowledge of correctly classify the interval
enrolled? the results of the target condition? between index
reference standard? test(s) and
reference

standard?
N 45/58 Was a case- No If a threshold was Yes Were the reference Yes Did all Yes
control design used, was it pre- results interpreted patients
avoided? specified? without knowledge of receive a
Follow- 8 months Did the study Unclear the results of the reference
up – 13 years avoid index test? standard?
Mean: 4 inappropriate Did all No. The
years 10 exclusions? patients control
months receive the group only
same assessed by
reference 2
standard? dermatopath
ologists
Could the Unclear Could the conduct or Low Could the reference Low Were all No. 13 of the
selection of interpretation of the standard, its conduct, patients AST did not
patients have index test have or its interpretation included in the perform in
introduced bias? introduced bias? have introduced analysis? the FISH
bias? analysis
Funding Supported Are there Low Are there concerns Low Are there concerns Low Could the Low
source in part by concerns that the that the index test, its that the target patient flow
Abbott included patients conduct, or condition as defined have
Molecular do not match the interpretation differ by the reference introduced
Inc. review question? from the review standard does not bias?
ACC/R8.5 question? match the review
research question?
project,
and
Fondazion
e Ente
Cassa di
Risparmio
di Firenze.
Results Sample:
Total 45/58 - - -

Spitz naevi (SN) 10 - - -

Atypical Spitzoid tumours 25/38
21/17 24 1-65
(AST)
Melanoma (M) 10 - - -
Only 25/38 atypical Spitzoid tumours performed in the FISH analysis.
FISH
M and AST M and SN AST and SN
Disease
Acc Acc
S NP Sensitivi Specificit NP Sensitivit Specifi
M AST Sensitivity Specificity PPV urac PPV Accuracy PPV NPV urac
N V ty y V y city
y y
Positive 9 6 2 88. 4
90 76 60 95 80 90 80 81.8 85 24 80 75 29.6
9 0
Negative 1 19 8
Comme Demographic data only available for the atypical Spitzoid tumour group. No information on how the controls were selected.
nts
Requena, C et al. “Fluorescence in situ hybridization for the differential diagnosis between spitz naevus and Spitzoid melanoma”. Histopathology (2012) 61:
899-909.
Country Spain All cases of Spitzoid melanomas treated at FISH Histopathological diagnosis No information provided
one hospital assessed. N= 17. Vysis Melanoma FISH based on histopathological regarding the time between
Comparator: Cases of spitz naevi from Probe Kit (Abbott features (Requena et al., index test(s) and reference
hospital files included. N = 6. Molecular Inc., Des 2012) standard.
Inclusion criteria: Not provided. Exclusion Plaines, IL). Designed to
criteria: Two cases of Spitzoid melanoma detect the copy number
excluded as the original biopsies could not be of RREB1, MYB and
obtained, two because of doubts in the CCND1 genes and of
differential diagnosis and one because the centromere 6 labelled
Spitzoid area accounted for <25% of the with SpectrumRed,
biopsy specimen. N=5. SpectrumGold,
SpectrumGreen and
SpectrumAqua.
Design, Retrospec Was a consecutive No Were the Unclear Is the Yes Was there an Unclear
period tive case or random sample index test reference appropriate
review of patients results standard interval
2008-2011 enrolled? interpreted likely to between index
without correctly test(s) and

knowledge of classify the reference

the results of target standard?
the reference condition?
standard?
N 18 Was a case- No If a threshold Yes Were the Yes Did all patients Yes
control design was used, reference receive a
avoided? was it pre- results reference
Follow- Range: 2- Did the study Yes specified? interpreted standard?
up 82 months avoid without Did all patients Yes
inappropriate knowledge receive the
exclusions? of the same reference
results of standard?
the index
test?
Could the Unclear Could the Low Could the Low Were all No
selection of conduct or reference patients
patients have interpretatio standard, included in the
introduced bias? n of the index its conduct, analysis?
test have or its
introduced interpretati
bias? on have
introduced
bias?
Funding Conselleri Are there Low Are there Low Are there Low Could the Low
source a de concerns that the concerns that concerns patient flow
sanitat of included patients the index that the have
the do not match the test, its target introduced
generalita review question? conduct, or condition as bias?
t interpretatio defined by
valenciana n differ from the
. the review reference
question? standard
does not
match the
review
question?

Results Sample:
Total 18 12/6 - -
Spitz naevi (SN) 6 4/2 - 7-38
Spitzoid Melanoma 12
8/4 - 19-56
(SM)
Only 8/12 Spitzoid melanomas performed in the FISH analysis. 5/6 spitz naevi performed in the FISH analysis.
SM SN
Positive FISH (Abbott criteria) 7 0 87.5 100 100 83.33333 92.3
Negative 1 5
Positive FISH (Gerami et al.
8 0
criteria) 100 100 100 100 100
Negative 0 5
Comme Demographic data only available for the atypical Spitzoid tumour group. No information on how the controls were selected.
nts

Bastian, BC et al. “Classifying melanocytic tumors based on DNA copy number changes”. American Journal of Pathology (2003) 163: 1765-1770.
Country USA and Paraffin-embedded primary invasive DNA extraction and Histopathological diagnosis No information provided
Germany melanomas retrieved from archives at two Comparative Genomic regarding the time between
hospitals. Hybridization (CGH). index test(s) and reference
Inclusion criteria: Cases were required to have standard.
at least one area from which a rather pure Results interpreted blinded
population of tumor cells could be isolated to to the histopathological
yield sufficient amounts of DNA for CGH information.
analysis. Exclusion criteria: Not provided.
Of the 54 benign nevi (27 spitz nevi; 19 blue
nevi; 7 congenital nevi) only the 27 spitz nevi
will be reported.
Design, Retrospecti Was a consecutive No Were the Yes Is the Yes Was there an Unclear
period ve case or random sample index test reference appropriate
review of patients results standard interval
enrolled? interpreted likely to between index
without correctly test(s) and
standard?
N 159/186 Was a case-control Yes If a threshold Yes Were the Yes Did all patients Yes
design avoided? was used, was reference receive a
Follow- Not Did the study avoid Yes it pre- results reference
up provided inappropriate specified? interpreted standard?
exclusions?
knowledge receive the
of the results same reference
test?
Could the selection Low Could the Low Could the Low Were all Yes. But not
of patients have conduct or reference patients presented
introduced bias? interpretation standard, its included in the in this table
of the index conduct, or analysis?

test have its

introduced interpretatio
bias? n have
introduced
bias?
Funding Roma and Are there concerns Low Are there Low Are there Low Could the Low
source Marvin that the included concerns that concerns patient flow
Auerback patients do not the index test, that the have introduced
Melanoma match the review its conduct, or target bias?
Fund question? interpretation condition as
review the
question? reference
standard
does not
match the
review
question?
Results Sample:
N Female/male Mean age
Total 186 89/97 53.7
Benign nevi (blue nevi, congenital nevi) 27 - -
Spitz nevi (SN) 27 - -
Malignant Melanoma (MM) 132 65/67 68
Of the 54 benign nevi (27 spitz nevi; 19 blue nevi; 7 congenital nevi) only the 27 spitz nevi will be reported.
CGH Disease Sensitivity specificity PPV NPV Accuracy
MM SN
At least one chromosomal
127 7 96.2 74.1 94.8 80 92.5
aberration
No aberrations 5 20
Commen CGH findings of 79 cases has been published previously.

ts

BRAF, NRAS and HRAS genes studies (n=6):
Emley, A et al. “Oncogenic BRAF and the tumopr suppressor IGFBP7 in the genesis of atypical spitzoid nevomelanocytic proliferations”. J Cutan Pathol
(2010) 37: 344-349.
Country USA Archival materials between 2006-2008 Immunohistochemistry – Histopathology. No information provided regarding the
with a diagnosis of spitz nevus (n=6) and BRAFV600E gene; NRAS1 Histological evaluation. time between index test(s) and
atypical spitzoid nevomelanocytic gene; NRAS2 gene. Diagnosis re-reviewed and reference standard.
proliferations were retrieved from the DNA was extracted by confirmed by a
pathology files of Skin Pathology proteinase K digestion of dermatopathologist.
Laboratory, Boston University. Inclusion laser capture microdissected
criteria: Not provided. Exclusion criteria: samples per protocol.
Not provided.
review of patients interpreted standard likely interval between
2006-2008 enrolled? without to correctly index test(s) and
standard?
Follow- Not Did the study avoid Yes pre-specified? results reference
up provided. inappropriate interpreted standard?
exclusions?
knowledge of receive the same
the results of reference
the index test? standard?
of the index test conduct, or its
have introduced interpretation
bias? have
introduced

bias?
Funding Not Are there concerns Low Are there Low Are there Low Could the patient Low
source provided. that the included concerns that concerns that flow have
patients do not the index test, the target introduced bias?
match the review its conduct, or condition as
question? interpretation defined by the
differ from the reference
review
question?
N Female/male Mean age Median age Age range
Total 20 15/5 29.6 25.5 3-76
Atypical spitzoid nevomelanocytic 14 Note. *ASN group contains 1 spitzoid
10/4
proliferations* melanoma.
Typical spitz 6 5/1
Gene/antibody BRAF V600E NRAS1 NRAS2

Disease Disease Disease
ASN TSN ASN TSN ASN TSN
Positive mutation 0 1 0 0 0 0
Negative 13 5 13 6 13 6
Sensitivity/specificity 0 83.3 0 100 0 100
PPV/NPV 0 27.8 - 31.6 - 31.6
Accuracy 26.3 31.6 31.6
+
Note. ASN: Atypical spitzoid nevomelanocytic proliferation. TSN: Typical spitz nevus. *No lesional tissue for three cases. No lesional tissue for four cases.
1 spitzoid melanoma recorded – No mutations in any of the genes reported.

Commen Paper also looked at KRAS, IGFBP7 and pERK but these have not been extracted.
ts
Fullen, DR et al. “BRAF and NRAS mutations in spitzoid melanocytic lesions”. Modern Pathology (2006) 19: 1324-1332.

Country USA Archival materials with a diagnosis of Immunohistochemistry – Histopathology. No information provided
spitz nevi, atypical spitz tumor and BRAFV600E gene. Histological evaluation. Reviewed regarding the time between
spitzoid melanomas from the pathology DNA extraction information by three board certified index test(s) and reference
department at the University of presented. dermatopathologists. 12/68 standard.
Michigan. Inclusion criteria: Not patients did not have a full set of
provided. Exclusion criteria: Not diagnostic slides available for
provided. review.
review of patients interpreted standard likely interval
enrolled? without to correctly between index
knowledge of classify the test(s) and
the results of target reference
the reference condition? standard?
standard?
N 68 Was a case-control Yes If a threshold Yes Were the Yes Did all Yes
design avoided? was used, was it reference patients
pre-specified? results receive a
Follow- Not Did the study avoid Yes
interpreted reference
up provided. inappropriate
exclusions? without standard?
same
reference
standard?
Could the selection Low Could the Low Could the Low Were all Yes
of patients have conduct or reference patients
introduced bias? interpretation standard, its included in the
of the index test conduct, or its analysis?
bias? have
introduced
bias?

Funding NCI U01 Are there concerns Low Are there Low Are there Low Could the Low
source CA83180 that the included concerns that concerns that patient flow
(SBG) and patients do not the index test, the target have
NIH T32 match the review its conduct, or condition as introduced
HG00040 question? interpretation defined by the bias?
(JNP), differ from the reference
generous review standard does
gift from question? not match the
Lewis and review
Lillian question?
Becker.
Babcock
Memorial
Trust. Ann
Arbor
Veterans
Affairs
Hosptial.
Total 68 39/29 - 2-60
Spitz nevi 48 24/24 20 2-49
Atypical spitz tumours 7 5/2 24 12-52
Spitzoid melanoma 13 10/3 24 10-60
BRAF V600E
AST and SN SN and SM SM and AST
Disease
Ac
Sensiti Specifi Accura Sensitivit Specificit Accura Sensitivit Specifi cu
SM AST SN PPV NPV PPV NPV PPV NPV
vity city cy y y cy y city ra
cy
Positive
2 0 10*
mutation 0 79.2 0 84.4 69.1 15.4 79.2 16.7 77.6 65.6 15.4 100 100 38.9 45
Negative 11 7 38
Note. SN: Spitz nevi. APT: Atypical spitz tumour. SM: Spitzoid melanoma. * Five out of 10 were classic typical spitz nevi and 5/10 were atypical spitz nevi.

Commen Authors conclude that BRAF mutation status does not reliably distinguish all Spitz nevi from non-spitz nevi and melanomas.
ts

Van Dijk, MCRF et al. “Analysis of Mutations in BRAF, NRAS and HRAS genes in the differential diagnosis of spitz nevus and spitzoid melanoma”. Am J Surg
Pathol (2005) 29: 1145-1151.
Country Netherland Paraffin blocks of 101 spitzoid lesions Immunohistochemistry – Histological evaluation at 2 Some of the lesions received with
s sent for consultation to an expert BRAF exon 15 and exon 11; month intervals with one incomplete clinical information
dermatopathologist obtained from NRAS exon 2 and exon 3; expert pathologist (n=unknown) or with unknown follow-up
hospitals in the Netherlands. HRAS exon 2 and exon 3. unaware of the results of for reasons of privacy (n=44) however all
Inclusion criteria: paraffin blocks DNA extraction information the genetic analysis/index included in the index test.
containing spitzoid lesions (n=96). presented. test.
Exclusion criteria: paraffin blocks that did
not contain a spitzoid lesion (n=5).
review of patients interpreted standard likely interval between
enrolled? without to correctly index test(s) and
standard?
N 96 Was a case-control Yes If a threshold Yes Were the Yes Did all patients No
Follow- 1-88 years Did the study avoid Unclear pre-specified? results reference
up inappropriate
without Did all patients No
exclusions?
knowledge of receive the same
the results of reference
the index test? standard?
Could the selection Unclear Could the Low Could the Low Were all patients No
of the index test conduct, or its
bias? have
introduced

bias?
Funding Dutch Are there concerns Unclear Are there Low Are there Low Could the patient High
source Cancer that the included concerns that concerns that flow have
Society patients do not the index test, the target introduced bias?
match the review its conduct, or condition as
question? interpretation defined by the
review
question?
N No
Mean follow-up
Female/male* Mean age Age range + Recurrence* Metastasis* further
(years)*
events*
+
Total 96 37/28 34.76 1-88 7.4 - - -
Spitz nevus (SN) 14 9/1 27.8 10-43 7.8 (6-16) 0 0 3
Atypical spitz nevus (ASN) 16 8/8 19 1-49 6 (2-9) 0 0 3
Suspected for melanoma 23
7/4 35 13-59 7.6 (4-10) 0 2 14
(SusM)
Spitzoid melanoma (SM) 36 11/13 52 10-88 8.2 (4-12) 0 8 24
Melanoma metastasis 7
2/2 40 26-66 - - - -
(MM)
+
Note. *Missing data in each group. Mean age and follow-up not provided by authors and taken from a mean of the provided sub-groups.

Disease MM and SM MM and SUSM MM and ASN MM and SN

Sus Se Sp PP NP Ac Se Sp PP Ac Se Sp PP NP Ac Se Sp PP NP Ac
MM SM ASN SN NPV
M n e V V c n e V c n e V V c n e V V c
BRAF Positive 7 23 6 0 0 70. 36. 23. 81. 35. 70. 79. 53. 76. 70. 10 10 84. 68. 70. 10 10 82. 65.
88.5
Exon 15 Negative 3 13 23 16 14 0 1 3 3 3 0 3 8 9 0 0 0 2 5 0 0 0 4 3
BRAF Positive 0 0 0 0 0 10 89. 89. 10 87. 10 81. 81. 10 75. 75.

0 0 0 0 87.0 0 0 0 0
Exon 11 Negative 3 26 20 13 9 0 7 7 0 0 0 3 3 0 0 0
NRAS Positive 0 0 1 0 0 10 83. 83. 95. 73. 10 68. 68. 10 65. 65.
0 0 0 0 75.9 0 0 0 0
Exon 2 Negative 7 35 22 15 13 0 3 3 7 3 0 2 2 0 0 0
NRAS Positive 2 7 1 0 0 28. 80. 22. 84. 68. 28. 95. 66. 80. 28. 10 10 73. 68. 28. 10 10 73. 68.
81.5
Exon 3 Negative 5 28 22 14 14 6 0 2 8 7 6 7 7 0 6 0 0 7 7 6 0 0 7 7
HRAS Positive 0 0 0 0 0 10 85. 85. 10 78. 10 72. 72. 10 68. 68.

0 0 0 0 78.6 0 0 0 0
Exon 2 Negative 6 35 22 16 13 0 4 4 0 6 0 7 7 0 4 4
HRAS Positive 0 0 1 2 4 10 85. 85. 95. 75. 88. 71. 65. 76. 68. 56.
0 0 0 0 77.8 0 0 0 0
Exon 3 Negative 6 34 21 15 13 0 0 0 5 0 2 4 2 5 4 5
Note. Any positive mutation has been recorded but paper does breakdown mutation according to type within the gene (e.g. BRAF V600E, V600K, Q61R, Q61K etc.)
SM and ASN
Se Sp PP NP Ac
n e V V c
BRA Positiv
F e 63. 10 10 55.
75
Exon Negati 9 0 0 2
15 ve
BRA Positiv
F e 10 33. 33
0 0
Exon Negati 0 3 .3
11 ve
NRA Positiv
10
S e 0 0 30 30
0
Exon Negati

2 ve
NRA Positiv
S e 10 10 33. 42
20
Exon Negati 0 0 3 .9
3 ve
HRA Positiv
S e 10 31. 31
0 0
Exon Negati 0 4 .4
2 ve
HRA Positiv
S e 88. 30. 29
0 0
Exon Negati 2 6 .4
3 ve
Commen
ts

Gill, M et al. “Genetic similarities between spitz nevus and spitzoid melanoma in Children”. Cancer (2004) 101: 2636-40.
Country USA Formalin-fixed paraffin-embedded tumor Immunohistochemistry – Histopathological re-evaluation No information provided
specimens selected from Spitzoid BRAF exon 15 and exon 11; by two dermatopathologists. regarding the time between
melanoma specimens from children age NRAS exon 2 and exon 3; Presence of metastases for the index test(s) and reference
≤10 years (disease confirmed by the HRAS exon 1 and exon 2. melanoma specimens and standard.
presence of metastases) and from typical DNA extraction information diagnostic criteria previously No follow-up data provided.
spitz nevus specimens obtained from presented. published in Paniago-Pereira et
children age ≤10 years. al. (1978) and Mines et al. (2003)
Exclusion criteria: Not provided. for the spitz nevus.
standard?
N 19 Was a case-control No. Age-matched If a threshold Yes Were the Unclear Did all Yes
design avoided? specimens was used, was it reference patients
Follow- Not Did the study avoid Unclear
up provided. inappropriate interpreted reference
without standard?
exclusions?
same
reference
standard?
Could the selection Unclear Could the Low Could the Low Were all Yes

bias? have
introduced
bias?
Funding Dermatolo Are there concerns High Are there Low Are there Low Could the Low
source gy that the included concerns that concerns that patient flow
foundation patients do not the index test, the target have
and the match the review its conduct, or condition as introduced
Waterbor question? interpretation defined by the bias?
Burn and differ from the reference
Cancer review standard does
Foundation question? not match the
review
question?
Total 19 3/6 6 2-10
Spitz nevi (SN) 10 24/24 20 2-49
Spitzoid melanoma (SM) 9 10/3 24 10-60
Gene/antibody BRAF E11 BRAF E15 NRAS E2 NRAS E3 HRAS E2 HRAS E3

Disease Disease Disease Disease Disease Disease
SM SN SM SN SM SN SM SN SM SN SM SN
Positive mutation 0 0 0 0 0 0 1 0 4 6 1 1
Negative 9 10 9 10 9 10 8 10 5 4 8 9
Sensitivity/specificity 0 100 0 100 0 100 11.1 100 44.4 40 11.1 90
PPV/NPV 0 52.6 0 52.6 0 52.6 100.0 55.6 40.0 44.4 50.0 52.9
Accuracy 52.6 52.6 52.6 57.9 42.1 52.6
Commen Authors conclude that mutation analysis of BRAF, NRAS and HRAS is not useful in differentiating between spitzoid melanoma and spitz nevus in children. The
ts authors changed the diagnosis of some of the SM patients from the original histopathological diagnosis at biopsy by the referring pathologist.

Raskin, L et al. “Copy number variations and clinical outcomes in atypical spitz tumors”. Am J Surg Pathol (2011) 35: 243-252.
Country USA FFPE blocks of AST (collected between Immunohistochemistry – Histopathological diagnosis Large range of follow-up for patients.
1999 and 2009), benign spitz nevi, BRAF exon 5; NRAS exon1 based on previously published Information on clinical and
spitzoid melanoma and a classic and exon 2; HRAS exon 1 criteria by a board-certified histopathological characteristics was
superficial spreading melanoma were and exon 2. DNA extraction dermatopathologist(s) in the missing for the spitz nevi group.
collected. information presented. Michigan melanoma progam
Exclusion criteria: Not provided. with concordance by multiple
dermatopathologists for
equivocal cases.
1999-2009 enrolled? without to correctly between index
standard?
Follow- July 1999 – Did the study avoid Unclear
up January inappropriate interpreted reference
without standard?
2010 exclusions?
same
reference
standard?

bias? have
introduced
bias?
Funding Gifts from Are there concerns Low Are there Low Are there Low Could the Low
source the Becker, that the included concerns that concerns that patient flow
Cooper patients do not the index test, the target have
and Fischer match the review its conduct, or condition as introduced
Funds question? interpretation defined by the bias?
review
question?
Total 27 - - -
Spitz nevi (SN) 8 Data not presented Data not presented Data not presented
Atypical spitz tumour (AST) 16 10/6 23.25 5-65
Melanoma (M) (2 spitzoid, 1 superficial 3
0/3 32 8-59
spreading)
See next page for table of results.
Disease AST and SN SN and M M and AST

Sensiti Specifi Accura Sensiti Specifi Accura Sensiti Specifi Accu
M AST SN PPV NPV PPV NPV PPV NPV
vity city cy vity city cy vity city racy
BRAF Positive 2 2 0
Exon 15 12.5 100 100 36.4 35.3 66.7 100 100 88.9 90.1 66.7 87.5 50 93.3 84.2
Negative 1 14 8
NRAS Positive 0 3 0
Exon 1 18.8 100 100 38.1 36.3 0 100 0 72.7 72.7 0 81.3 0 81.3 68.4
Negative 3 13 8
NRAS Positive 0 2 1
Exon 2 12.5 87.5 0 33.3 31.2 0 87.5 0 70 63.6 0 87.5 0 82.4 73.7
Negative 3 14 7
HRAS Positive 0 1 0
Exon 1 6.7 100 100 33.3 32.8 0 100 0 77.8 77.8 0 93.3 0 87.5 82.4
Negative 2 14 7

HRAS Positive 0 0 1
Exon 2 0 87.5 0 30.4 29.2 0 87.5 0 77.8 70 0 100 0 88.9 88.9
Negative 2 16 7
Note. SN: Spitz nevi. APT: Atypical spitz tumour. SM: Spitzoid melanoma. *Authors state some data for the genetic mutations was not available and therefore totals
do not add up to n for all lesions.
Commen Authors conclude that BRAF mutation status does not reliably distinguish all Spitz nevi from non-spitz nevi and mealnomas.
ts

Takata, M et al. “Genetic and epigenetic alterations in the differential diagnosis of malignant melanoma and spitzoid lesions”. British Journal of Dermatology
(2007) 156: 1287-1294.
Country Japan Paraffin-embedded tissues of primary Immunohistochemistry – Histological evaluation. All slides No information provided regarding the
Cutaneous melanoma, spitz naevus and BRAF codon 600; NRAS reviewed by two pathologists. time between index test(s) and
cases in which the histopathological codon 61; HRAS condon 61. reference standard.
diagnosis was ambiguous retrieved from DNA extraction information
the archives of three hospitals in Japan. presented.
Exclusion criteria: none provided.
standard?
Follow- None Did the study avoid Unclear
exclusions? without standard?
same
reference
standard?
bias? have
introduced
bias?

Funding Cancer Are there concerns Low Are there Low Are there Low Could the Low
source Research that the included concerns that concerns that patient flow
from the patients do not the index test, the target have
Ministry of match the review its conduct, or condition as introduced
Health, question? interpretation defined by the bias?
Labor and differ from the reference
Welfare of review standard does
Japan, question? not match the
Science review
Research question?
from Japan
society for
the
Promotion
of Science.
Total 52 35/17 43.3 2-86
Spitz naevus (SN) 12 8/4 64.2 2-50
Ambiguous lesions (AL) 16 12/4 18.6 2-79
Primary cutaneous melanoma (PCM) 24 15/9 30.6 25-86
+
Note. *Missing data in each group. Mean age and follow-up not provided by authors and taken from a mean of the provided sub-groups.
Disease AL and SN SN and PCM PCM and AL
Sensitivit Specificit Sensitivit Specificit Sensitivit Specificit Accurac
PCM* AL* SN* PPV NPV Accuracy PPV NPV Accuracy PPV NPV
y y y y y y y
BRAF Positive 11 1 0
6.3 100 100 44.4 43.9 45.8 100 100 48 63.9 45.8 93.8 91.7 53.6 65
Negative 13 15 12
NRAS Positive 4 1 0
7.7 100 100 47.8 46.8 33.3 100 100 57.9 65.2 33.3 92.3 80 60 64
Negative 8 12 11
HRAS Positive 0 0 0 100
0 0 47.8 47.8 0 100 0 33.3 33.3 0 100 0 35.3 35.3
Negative 22 12 11
Note. SN: Spitz naevus. AL: Ambiguous lesions. PCM: Primary cutaneous melanoma. * Some lesions were either not examined or no data obtained so the totals for each
gene may not add up to total number of lesions in each subtype.

Evidence tables for the included studies assessing sentinel lymph node biopsy (N=7):
Caraco, C et al. “Sentinel lymph node biopsy in atypical spitz nevi: is it useful?”. EJSO (2012) 38: 932-935.
Country Italy Records from the National Institute of Review of medical records Sentinel lymph node No information provided regarding the
Naples were retrospectively reviewed. and pathology slides by four biopsy time between index test(s) and reference
Inclusion criteria: 40 patients with ASN experienced standard.
who underwent SLNB. dermatopathologists. Each
Exclusion criteria: All cases with uncertain member of the review panel
diagnosis or histological features assessed slides separately
indicative of melanoma [no information without recourse to medical
on how many this was] notes and blinded to each
others’ diagnosis.
4/10 lesions initial
disagreement but consensus
achieved after lengthy
discussion.
Design, Retrospecti Was a consecutive No Were the index Unclear Is the Yes Was Unclear
period ve case or random sample test results reference there an
review of patients interpreted standard likely appropria
2003-2011 enrolled? without to correctly te
knowledge of classify the interval
the results of target between
the reference condition? index
standard? test(s)
and
reference
standard
?
design avoided? was used, was it Diagnosti reference patients
Follow- Mean: 52 Did the study avoid Unclear pre-specified? c results receive a
histomor- interpreted reference
up months inappropriate
phologica without standard
Median: 46 exclusions?
l criteria knowledge of ?

months for ASN the results of Did all Yes

(range: 16- (Barnhill the index test? patients
103) & Hoang, receive
1995) the same
reference
standard
?
Could the selection Unclear Could the Low. Could the Low Were all Yes
of patients have conduct or Used reference patients
introduced bias? interpretation consensu standard, its included
of the index test s opinion conduct, or its in the
have introduced interpretation analysis?
bias? have
introduced
bias?
Funding Disclosed Are there concerns Low Are there Low Are there Low Could the Low
source no financial that the included concerns that concerns that patient
and patients do not the index test, the target flow have
personal match the review its conduct, or condition as introduce
relationshi question? interpretation defined by the d bias?
ps. differ from the reference
review
question?
Results N = 40
Mean age at diagnosis: 33 years (median 32 years, range 11-65 years)
24 women (60%)
16 men (40%)
0/40 sentinel node positivity was recorded. No patients developed nodal involvement during the follow-up. All patients were alive and without evidence of
loco-regional or distant relapse at time of review.
Commen Numbers presented in Table 1 do not match the description in the text regarding follow-up.
ts

Cochran, AJ et al. “The role of lymphatic mapping and sentinel node biopsy in the management of atypical and anomalous melanocytic lesions”. J Cutan
Pathol (2010) 37 (1): 54-59.
Country USA Database of 651 UCLA patients who Unclear. Database included Sentinel lymph node No information provided. No follow-up data
underwent SNB for melanocytic lesions. diagnosed lesions so assume biopsy provided.
Inclusion criteria: Patients who diagnosis made by either/or
underwent SNB for atypical and clinical assessment,
anomalous melanocytic lesions. dermoscopy and/or
Exclusion criteria: Patients who histopathology. No
underwent SNB for all other melanocytic information provided
lesions (n=618)
standard? test(s)
and
reference
standard
?
N 33 Was a case-control Yes If a threshold Unclear Were the Uncle Did all Yes
design avoided? was used, was it reference ar patients
Follow- Not Did the study avoid Unclear pre-specified? results receive a
without standard
exclusions?
knowledge of ?
the results of Did all Yes
the index test? patients
receive
the same
reference
standard
?

Could the selection High. Majority of Could the Unclear Could the Low Were all Yes
of patients have patients were conduct or reference patients
introduced bias? referred to UCLA interpretation standard, its included
with the request of the index test conduct, or its in the
that they be have introduced interpretation analysis?
considered for bias? have
SNB. introduced
bias?
Funding National Are there concerns Unclear Are there Unclear Are there Low Could the Low
source Cancer that the included concerns that concerns that patient
Institute. patients do not the index test, the target flow have
match the review its conduct, or condition as introduce
question? interpretation defined by the d bias?
review
question?
Results No demographic information provided.
Atypical cellular blue Atypical congenital Atypical desmoplastic

Total sample Combined nevi
nevi nevi nevi
N (%) 18 5 (27.8) 4 (22.2) 4 (22.2) 2 (11.1)
SLN+ 8 (44) 3 (60) 2 (50) 2 (50) 1 (50)
SLN- 10 (66) 2 (40) 2 (50) 2 (50) 1 (50)
Note. SLN: sentinel lymph node; +: positive; -: negative.
Authors state they were unaware that any of the patients in the group developed additional ‘metastases’ or died of their disease.
Commen No demographic information of sample. No follow-up data. Potential sampling bias as majority of patients were referred to UCLA with the request that they be
ts considered for SNB.

Hung, T et al. “Sentinel lymph node metastasis is not predictive of poor outcome in patients with problematic spitzoid melanocytic tumors”. Human
Pathology (2013) 44: 87-94.
Country USA Records from the Massachusetts general Case review by 2 or more Sentinel lymph node No information provided regarding the
hospital melanoma center dermatopathologists. biopsy time between index test(s) and reference
Inclusion criteria: 40 patients who standard.
underwent SLNB. 23/40 AST and 17/40
SM.
Exclusion criteria: No information
provided
standard? test(s)
and
reference
standard
?
Follow- Mean: 57 Did the study avoid Unclear
up months inappropriate interpreted reference
without standard
(range: 2- exclusions?
knowledge of ?
144)
receive
the same
reference
standard
?

Could the selection Unclear Could the Unclear Could the Low Were all Yes
introduced bias? interpretation standard, its included
of the index test conduct, or its in the
bias? have
introduced
bias?
Funding Not Are there concerns Low Are there Low Are there Low Could the Low
source mentioned that the included concerns that concerns that patient
patients do not the index test, the target flow have
review
question?
Results N = 40
Total sample AST SM AST SM

N (%) 40 23 (57.5) 17 (42.5) Positive 6 (26.1) 6 (35.3)
SNLB
Mean age 33 27 30 Negative 17 (73.9) 11 (64.7)
Age range 11-65 5-60 9-63
Female (%) 26 (65) 16 (70) 10 (59)
Male (%) 14 (35) 7 (30) 7 (41)
At follow-up (57 months, range 2-144 months) metastases beyond the SLN basin were not observed in any of the 40 patients. One patient developed an in-
transit metastasis 3 years after SLN mapping and remained free of additional metastatic tumour 1 year later.
Commen Some variability in terminology existed over the course of the decade of reported lesions. Tumours considered to be AST were also reported as “atypical spit
ts tumour”, “spitz nevus with atypia”, “borderline Spitz nevus”, “borderline spitz tumour”. Tumours considered to be SM were reported as “spitzoid melanoma”
and melanoma with features of spitz tumour”.

Ludgate, MW et al. “The atypical spitz tumour of uncertain biologic potential”. Cancer (2009) 115(3): 631-641.
Country USA Searched prospectively collected Diagnosis of database Sentinel lymph node N = 57 Wide local excision and SLNB
melanoma database for all cases of lesions rendered by at least biopsy N = 10 Wide local excision only (14.9%):
spitzoid melanocytic proliferations ¼ board-certified Follow-up  6 patients had primary lesions with a
between 1994 and 2007. dermatopathologists (or by depth <1mm with no other adverse
Inclusion criteria: Patients with a a dermatopathologist features
diagnosis of an atypical spitz tumour or outside the institution).  4 patients suitable for SLNB but
spitzoid melanocytic proliferation of received wide local excision only. ¼
uncertain biologic potential. due to age (18 months), ¾ treated at
Exclusion criteria: None provided. different institutions and 2 lost to
follow-up.
Follow-up data available for 65 patients
(range: 7.1-57.3 months)
Design, Retrospecti Was a consecutive No Were the index Yes Is the Yes Was Yes
standard? test(s)
and
reference
standard
?
N 67 Was a case-control Yes If a threshold Unclear Were the Uncle Did all No
design avoided? was used, was it reference ar patients 2 patients treated at an
Follow- SLNB- Did the study avoid Unclear pre-specified? results receive a outside institution did not
up positive inappropriate interpreted reference receive SNLB and were lost
without standard to follow-up
group: 43.8 exclusions?
knowledge of ?
months
the results of Did all No
SLNB-
negative receive
the same

group: 28.6 reference

months standard
?
WLE-only Could the selection Unclear Could the Unclear Could the Low Were all No
group: 32.5 of patients have conduct or reference patients 2 patients treated at an
months introduced bias? interpretation standard, its included outside institution did not
of the index test conduct, or its in the receive SNLB and were lost
have introduced interpretation analysis? to follow-up
bias? have
introduced
bias?
Funding Authors Are there concerns Low Are there Low Are there Low Could the Unclear
source made no that the included concerns that concerns that patient
disclosures patients do not the index test, the target flow have
review
question?
Results N=67, median age 23.7 years (range: 1.7-65 years). 41 female (61.2%) and 26 male (38.8%)
Original lesion was congenital in 4 patients (6.0%). A positive family history of melanoma was present in 8 patients (12%); none was immunosuppressed. 59/67
cases reviewed by 2 or more UM dermatopathologists. Concordant diagnosis was reached in 38 (64%). Of the 21 (36%) cases with discordance, the alternative
diagnoses included atypical spitz nevus in 35% and spitzoid melanoma in 65%.
57 wide local excision and SLNB:
 30 SLNB negative
 27 SLNB positive
o 27 complete lymph node dissection
 26 negative non-sentinel nodes
 1 positive non-sentinel node
Commen
ts

Murali, R et al. “Sentinel lymph node biopsy in histologically ambiguous melanocytic tumours with spitzoid features (so-called atypical spitzoid
tumors)”. Annals of Surgical Oncology (2008) 15(1): 302-309.
Country Australia Databases of the SMU and the All available histopathologic Sentinel lymph node No information provided regarding the
Department of Anatomical Pathology at slides of the primary biopsy time between index test(s) and reference
the Royal Prince Alfred Hospital. tumours and their standard.
Inclusion criteria: Patients whose primary corresponding SLNs
Cutaneous melanocytic lesion was reviewed by four Range of follow-up with some less than 6
reported as “atypical spitz nevus”, pathologists. months.
“atypical spitzoid tumor”, or “spitzoid
tumor of uncertain malignant potential”
and who had undergone SLN biopsy.
Exclusion criteria: None provided.
Design, Retrospecti Was a consecutive Unclear Were the index Unclear Is the Yes Was Unclear. No reported
standard? test(s)
and
reference
standard
?
N 21 Was a case-control Yes If a threshold Yes Were the No Did all Yes
Follow- Mean: Did the study avoid Unclear
up 21.5 inappropriate interpreted reference
months; exclusions? without standard
knowledge of ?
Median:
10.7
months the index test? patients
(range: 1.0- receive
62.1) the same
reference

standard
?
introduced bias? interpretation standard, its included
of the index test conduct, or its in the
bias? have
introduced
bias?
Funding Cancer Are there concerns Low Are there Low Are there Low Could the Low
source institute that the included concerns that concerns that patient
NSW patients do not the index test, the target flow have
Clinical match the review its conduct, or condition as introduce
Research question? interpretation defined by the d bias?
Fellowship differ from the reference
program, review standard does
university question? not match the
of Sydney review
Cancer question?
Research
fund,
Australian
National
Health and
Medical
Research
Council,
Melanoma
Foundation
.
Results N=21, median age 31 years (range: 6-50 years).
Total sample SLN+ SLN- Complete lymph node dissection completed in 5/6
N (%) 21 6 (28.6) 15 (11.4) patients. No further metastasis was identified in the CLND
Mean age Median: 31 15.2 29.9 specimens. All patients remained alive and disease-free

Age range 6-50 6-38 12-50 over a media follow-up period of 10.7 months (mean: 21.5
Female (%) 12 (57.1) 4 (66.7) 7 (46.7) months; range: 1.0-62.1 months)
Male (%) 9 (42.9) 2 (33.3) 8 (53.3)
Commen Authors note that the high SLN-positive rates for atypical spitzoid tumours are likely (at least partly) to be a result of selection bias; the tumours in their study
ts were thick lesions, most being Clark level IV or greater. Large variation in follow-up.
Urso, C et al. “Sentinel lymph node biopsy in patients with “atypical spitz tumours.” A report on 12 cases”. Human Pathology (2006) 37: 816-823.
Country Italy Cases retrieved from the files of S.M Annunziata Unclear. Database Sentinel lymph node No information provided regarding
Hospital of Florence, G. Rummo General Hospital of included diagnosed biopsy the time between index test(s) and
Benevento, and Misericordia e Dolce Hospital of lesions so assume reference standard.
Prato, Italy, over a period of 7 years. diagnosis made by
Inclusion criteria: All cases diagnosed as “atypical spitz either/or clinical Range of follow-up with some less
nevi”, “atypical spitz tumors”, “potentially malignant assessment, than 6 months.
spitz tumors”, “possible malignant spitz tumors” and dermoscopy and/or
“possible spitzoid melanomas”. Tumor had to show histopathology. No
histological features characteristic of spitz nevus information provided
mixed to histological features generally referred to
malignant melanoma, appearing as spindle and/or
epitheliod cell lesion “deviating more or less from the
stereotypical morphology of classic spitz nevi. The
tumor had not a clear-cut diagnosis of benign spitz
nevus or malignant melanoma and the patient
underwent sentinel lymph node biopsy.
Exclusion criteria: None provided.
Design, Retrospecti Was a consecutive No Were the Unclear Is the Yes Was there Unclear
period ve case or random sample index test reference an
review of patients results standard appropriate
enrolled? interpreted likely to interval
without correctly between
knowledge classify the index test(s)
of the results target and
of the condition? reference
reference standard?
standard?

N 12 Was a case-control Yes If a threshold Unclear Were the Unclear Did all Yes
design avoided? was used, reference patients
Follow- Mean 26.3 Did the study avoid No was it pre- results receive a
up months inappropriate specified? interpreted reference
without standard?
Range: 2- exclusions?
knowledge Did all Yes
90
of the patients
results of receive the
the index same
test? reference
standard?
Could the selection Low Could the Unclear Could the Low Were all Yes
introduced bias? interpretatio standard, included in
n of the its conduct, the analysis?
index test or its
have interpretati
introduced on have
bias? introduced
bias?
Funding Not Are there concerns Low Are there Unclear Are there Low Could the Low
source provided. that the included concerns concerns patient flow
patients do not that the that the have
match the review index test, target introduced
question? its conduct, condition bias?
or as defined
interpretatio by the
n differ from reference
the review standard
question? does not
match the
review
question?
Results
Total sample SLN+ SLN-
N (%) 12 4 8

Mean age 23.2 15.3 27.1

Age range 2-48 2-30 11-48
Female (%) 9 (57.1) 2(66.7) 7(46.7)
Male (%) 3 (42.9) 2 (33.3) 1 (53.3)
2/12 patients had a local recurrence after excision of the primary lesion.
Commen Authors note that the presence of melanocyties in a lymph node is not always an evidence of metastatic spread because nevus cell aggregates can be found in
ts lymph nodes.... also lymph node metastases do not necessarily imply capacity of distant metastatic disease, especially if they are minimal. Patients with
atypical spitz tumors should be treated as other melanoma patients, with wide local excision of the primary lesion, sentinel node biopsy and adequate long-
term follow-up.

Paradela, S et al. “Spitzoid melanoma in children: clinicopathological study and application of immunohistochemistry as an adjunct diagnostic tool”. J
Cutan Pathol (2009) 36: 740-752.
Pub year: 2009 Patient selection Index test Reference Flow and timing
standard
Country USA UT-MD Anderson Cancer Center Clinical parameters, Sentinel lymph Average number of days between initial
Inclusion criteria: All cases of SM in children and pathological node biopsy surgery and SLND: 45, SD: 39.2
teenagers younger than 18 years old. parameters, Average number of days between initial
Exclusion criteria: None provided. prognostic indicators, surgery and WLE: 35.1, SD: 19.3
Immunhoistochemical Days between SLND and ELND: 12.3, SD:
parameters, follow-up 9.0
features
Design, Retrospecti Was a consecutive No Were the No Is the Yes Was Yes
period ve or random sample index test reference there an
observatio of patients results standard appropria
nal study enrolled? interprete likely to te
1992-2007 d without correctly interval
knowledg classify the between
e of the target index
the and
reference reference
standard standard
? ?
N 38 Was a case-control Yes If a Yes Were the No Did all No
design avoided? threshold reference patients
Follow- Mean 37.9 Did the study avoid No was used, results receive a
was it interpreted reference
up (SD: 42.1) inappropriate
pre- without standard
exclusions?
specified? knowledge ?
of the Did all No
results of patients
the index receive
test? the same
reference
standard

Could the selection Low Could the Low Could the Low Were all Yes
of patients have conduct reference patients
introduced bias? or standard, included
interpret its conduct, in the
ation of or its analysis?
the index interpretati
test have on have
introduce introduced
d bias? bias?
Funding Not Are there concerns Low Are there Low Are there Low Could the Low
source provided. that the included concerns concerns patient
patients do not that the that the flow have
match the review index target introduce
question? test, its condition d bias?
conduct, as defined
or by the
interpret reference
ation standard
differ does not
from the match the
review review
question? question?
Results All patients had spitzoid melanoma. 15 patients were not entirely treated at the centre, so the authors cannot be certain whether they received treatment
consistent with their protocol.
Total sample SLND sample SLN+ SLN-
N (%) 38 25 (65.8) 14 (56) 8 (44)
Mean age 9.9
SD 12
Female (%) 17 (44.7)
Male (%) 21 (55.3)
In the 14 patients with positive SLN no cases of death detected so far.

Commen
ts

1 2.4 Tumour samples for genetic testing
2 Review question: What is the most appropriate tumour sample (primary or secondary)
3 on which to carry out genetic testing to identify people who might benefit from targeted
4 therapies?
5 Background
6 Genetic testing for malignant melanoma became important with the recent advances in
7 therapy. Different molecular pathways, which are involved in the development of
8 melanoma, can be targeted with specific medicines, and the susceptibility/suitability for
9 these therapies can be assessed by molecular testing.
10 It is important to assess, when it is best to do these tests (at the time of primary diagnosis or
11 when secondaries present) so primary or metastatic tumour blocks are best used for testing.
12 The tumours – including melanoma – change their molecular profile and signalling pathways
13 in response to treatment, therefore accurate and timely information on their genetic
14 features is important.
15 The main genetic tests included now are: BRAF, NRAS and c-kit mutation analysis, however
16 this list is likely to grow in the future. Issues regarding safety included in background.

Patients/population Intervention Comparisons Outcomes
Patients with Genetic testing on Genetic testing on  Diagnostic accuracy
metastatic primary tumour secondary tumour (true positives, true
melanoma who are sample for: sample negatives, false
being considered for  BRAF positives, false
systemic therapy.  NRAS, CKIT Genetic testing on negatives)
multiple tumour  Sample adequacy
samples (diagnostic rate - Size
of tumour/ age/
volume/
pigmentation)
 Morbidity due to
biopsies
18 Search Results
Medline 2002-2013 951 234 11/11/2013
Premedline 2002-2013 254 60 11/11/2013
Embase 2002-2013 1019 237 14/11/2013
Cochrane Library 2002-2013 174 10 14/11/2013


SSCI)
1 Screening Results

Records after duplicates removed 494
Records screened 494 Records excluded 471
Full text articles assessed for eligibility Articles excluded 13

23

10
2
3
4 Risk of bias in the included studies

5 Only one study (Boursault et al, 2013) fully reported the patient sampling strategy: studies typically
6 relied on institutional tumour banks. It was also unclear whether the patients included in the studies
7 had been candidates for chemotherapy. One of the studies (Capper et al, 2012) included only
8 samples from brain metastases. The flow and timing of tests was not well reported in the studies –
9 for example the delay between obtaining the tumour samples and the mutation tests was unclear.
10 Some of the studies used more than one test for genetic mutation – in these cases one of the tests
11 was considered the reference standard (gold standard) test.

1 Figure 2.18. Risk of bias and applicability (QUADAS-2)

2 Concordance between primary and metastatic samples for BRAF mutations

3 Low quality evidence suggests that paired primary and metastatic melanoma tumour samples are
4 discordant for BRAF mutation status in between 5% and 40% of patients.
5 In one study (Yancovitz et al 2012) all patients whose primary tumour sample was BRAF wild type
6 had a BRAF mutant metastatic tumour sample. In the remaining studies between 0% and 45% of
7 patients whose primary tumour sample was BRAF wild type had a BRAF mutant metastatic tumour
8 sample.
9 In one study (Yancovitz et al 2012) all patients whose metastatic tumour sample was BRAF wild type
10 had a BRAF mutant primary tumour sample. In the remaining studies between 0% and 50% of
11 patients whose metastatic tumour sample was BRAF wild type had a BRAF mutant primary tumour
12 sample.
13 Concordance between primary and metastatic samples for NRAS mutations

14 Low quality evidence suggests that paired primary and metastatic melanoma tumour samples are
15 discordant for NRAS mutation status in between 2% and 13% of patients.
16 Between 0% and 11% of patients whose primary tumour sample was NRAS wild type had an NRAS
17 mutant metastatic tumour sample.
18 Between 2% and 6% of patients whose metastatic tumour sample was NRAS wild type had an NRAS
19 mutant primary tumour sample.
20 Concordance between primary and metastatic samples for CKIT mutations

21 Our literature searches identified no studies comparing CKIT mutations in paired primary and
22 metastatic tumour samples.
23 Sample adequacy
24 In two studies comparing paired primary and metastatic tumours samples there was no primary
25 tumour sample available to test in between 11% and 39% of eligible patients (Boursault et al 2013;
26 Heinzerling et al 2013). It was unclear why this was: the delay between obtaining the primary and
27 metastatic tumour samples was not reported in any of the included studies. Colombino et al (2012)
28 reported that DNA sequencing was not possible in 8% of samples due to DNA degradation.
29 Morbidity
30 The morbidity associated with obtaining tumour samples for mutation tests was not reported in any
31 of the included studies

Table 2.11. Concordance between primary and secondary tumour samples for BRAF mutations
Study Technique Gene / Sample Sample BRAF BRAF Concordance between primary and metastatic tumour Morbidity
mutation adequacy adequacy mutation mutation rate samples (per patient)
(primary) (metastasis) rate (metastasis)
(primary)
Boursault High resolution melting BRAF Primary N.R. 54.5% 55.6% Primary tumour Primary tumour N.R.
analysis followed by exon 15 BRAF mutant BRAF wt
(2013) tumour Metastatic
Sanger sequencing samples not tumour BRAF 45 (51.1%) 3 (3.4%)
available for mutant
11/99 (11%) Metastatic
patients
tumour BRAF 1 (1.1%) 39 (44.3%)
wt
Number of paired samples = 88

Discordant samples = 4/88 (4.5%)
Capper Immunohistochemistry BRAF 15/85 (18%)- genetic N.R. 42/76 (55%) Primary tumour Primary tumour N.R.
V600E- BRAF mutant BRAF wt
(2012) analysis was unsuccessful Metastatic
mutant tumour BRAF 6 0
protein mutant
expression Metastatic
tumour BRAF 0 N.R.
wt
Number of paired samples=?

Discordant samples =?
Colombino DNA sequencing BRAF 9/108 (8.3%) sample 43% 48% Primary tumour Primary tumour N.R.
exon 11 BRAF mutant BRAF wt
(2012) inadequacy due to DNA Metastatic
exon 15 degradation. tumour BRAF N.R. 6 (6%)
mutant
Metastatic
tumour BRAF 6 (6%) N.R.
wt
Number of paired samples= 99

Discordant samples =18/99 (18%)
Columbino DNA sequencing BRAF N.R. 49% 51% Primary tumour Primary tumour N.R.
(2013) Metastatic
tumour BRAF N.R. 16 (6.8%)
mutant
Metastatic
tumour BRAF 13 (5.5%) N.R.

(primary)
wt

Discordant samples = 29/236 (12.3%)
Edlundh- Pyrosequencing BRAF The authors report the N.R. N.R. Primary tumour Primary tumour N.R.
Rose (2006) majority of samples were Metastatic
codon 600 successfully analysed tumour BRAF N.R. 0
mutant
Metastatic
tumour BRAF 2 N.R.
wt
Number of paired samples=39?

Heinzerling Pyrosequencing BRAF Primary N.R. 45.5% 51.6% Primary tumour Primary tumour N.R.
V600E BRAF mutant BRAF wt
(2013) tumour Metastatic
samples tumour BRAF 6 (37.5%) 0
missing for mutant
16/41 (39%) Metastatic
of eligible
tumour BRAF 5 (31.25%) 5 (31.25%)
wt
patients Number of paired samples=16
Discordant samples =5/16 (31.3%)
Houben Direct sequencing of PCR BRAF N.R. N.R. 34.2% 41.9% Primary tumour Primary tumour N.R.
products Exon 11 BRAF mutant BRAF wt
(2004) Metastatic
exon 15 tumour BRAF 5 (20.8%) 3 (12.5%)
mutant
Metastatic
tumour BRAF 1 (4.2%) 15 (62.5%)
wt
Number of paired samples=24
Omholt PCR-SSCP sequencing BRAF N.R. N.R. N.R. N.R. Primary tumour Primary tumour N.R.
(2003) Metastatic
exon 11 tumour BRAF N.R. 2 (4%)
mutant
Metastatic
tumour BRAF 0 N.R.
wt

(primary)
Yancovitz BRAF mutant-specific BRAF N.R. N.R. 66.7% 77.7% Primary tumour Primary tumour N.R.
PCR V600E BRAF mutant BRAF wt
(2012) Metastatic
tumour BRAF
10 6
mutant (55.5%) (33.3%)
Metastatic
2
tumour BRAF 0
wt (11.1%)
Discordant samples =8/ 18 (44%)
Yadzi BRAF exon 15 DNA BRAF N.R. N.R. 45% 62% Primary tumour Primary tumour N.R.
sequencing V600E BRAF mutant BRAF wt
(2010) Metastatic
tumour BRAF 6 (30%) 5 (25%)
mutant
Metastatic
tumour BRAF 3 (15%) 6 (30%)
wt
Number of paired samples= 20
Abbreviations: N.R., not reported; wt, wild type;
Table 2.12. Concordance between primary and secondary tumour samples for NRAS mutations
Study Technique Gene / Sample Sample NRAS NRAS mutation Concordance between primary and metastatic tumour Morbidity
mutation adequacy adequacy mutation rate rate (metastasis) samples (per patient)
(primary) (metastasis) (primary)
Colombino DNA Sequencing NRAS 9/108 (8.3%) sample inadequacy due 15% 15% Primary tumour Primary tumour N.R.
(2012) exon 2, exon to DNA degradation. NRAS mutant NRAS wt
3 Metastatic
tumour NRAS N.R. 4 (4%)
mutant
Metastatic
tumour NRAS 1 (1%) N.R.
wt

Columbino DNA sequencing NRAS N.R. 15% 16% Primary tumour Primary tumour N.R.
(2013) exon 2, exon NRAS mutant NRAS wt

3 Metastatic
tumour NRAS N.R. 4 (1.7%)
mutant
Metastatic
tumour NRAS 3 (1.3%) N.R.
wt

Edlundh- Pyrosequencing NRAS The authors report the majority of N.R. N.R. Primary tumour Primary tumour N.R.
Rose (2006) exon 2 samples were successfully analysed NRAS mutant NRAS wt
codon 61 Metastatic
tumour NRAS N.R. 0
mutant
Metastatic
tumour NRAS 2 N.R.
wt
Number of paired samples=39?

Houben Direct sequencing NRAS exon N.R. N.R. 6/24 (25%) 7/24 (29%) Primary tumour Primary tumour N.R.
(2004) of PCR products 1, exon 2 NRAS mutant NRAS wt
Metastatic
tumour NRAS 5 (20.8%) 2 (8.3%)
mutant
Metastatic
tumour NRAS 1 (4.2%) 16 (66.7%)
wt

Omholt PCR-SSCP NRAS N.R. N.R. 28% 38% Primary tumour Primary tumour N.R.
(2002) sequencing exon 2 NRAS mutant NRAS wt
codon 61 Metastatic
tumour NRAS 19 (35.8%) 0
mutant
Metastatic
tumour NRAS 1 (1.9%) 33 (62.3%)
wt

Abbreviations: N.R., not reported; wt, wild type;

1 References
2 Included Studies
3 Boursault, L., Haddad, V., Vergier, B., Cappellen, D., Verdon, S., Bellocq, J. P. et al. (2013). Tumor
4 homogeneity between primary and metastatic sites for BRAF status in metastatic melanoma
5 determined by immunohistochemical and molecular testing. PLoS ONE [Electronic Resource], 8,
6 e70826.
7 Capper, D., Berghoff, A. S., Magerle, M., Ilhan, A., Wohrer, A., Hackl, M. et al. (2012).
8 Immunohistochemical testing of BRAF V600E status in 1,120 tumor tissue samples of patients with
9 brain metastases. Acta Neuropathologica, 123, 223-233.
10 Colombino, M., Capone, M., Lissia, A., Cossu, A., Rubino, C., De, G., V et al. (2012). BRAF/NRAS
11 mutation frequencies among primary tumors and metastases in patients with melanoma. Journal of
12 Clinical Oncology, 30, 2522-2529.
13 Colombino, M., Lissia, A., Capone, M., De, G., V, Massi, D., Stanganelli, I. et al. (2013). Heterogeneous
14 distribution of BRAF/NRAS mutations among Italian patients with advanced melanoma. Journal of
15 Translational Medicine, 11, 202.
16 Edlundh-Rose, E., Egyhazi, S., Omholt, K., Mansson-Brahme, E., Platz, A., Hansson, J. et al. (2006).
17 NRAS and BRAF mutations in melanoma tumours in relation to clinical characteristics: a study based
18 on mutation screening by pyrosequencing. Melanoma Research, 16, 471-478.
19 Heinzerling, L., Baiter, M., Kuhnapfel, S., Schuler, G., Keikavoussi, P., Agaimy, A. et al. (2013).
20 Mutation landscape in melanoma patients clinical implications of heterogeneity of BRAF mutations.
21 Br J Cancer, 109, 2833-2841.
22 Houben, R., Becker, J. C., Kappel, A., Terheyden, P., Brocker, E. B., Goetz, R. et al. (2004). Constitutive
23 activation of the Ras-Raf signaling pathway in metastatic melanoma is associated with poor
24 prognosis. J Carcinog., 3, 6.
25 Omholt, K., Platz, A., Kanter, L., Ringborg, U., & Hansson, J. (2003). NRAS and BRAF mutations arise
26 early during melanoma pathogenesis and are preserved throughout tumor progression. Clin Cancer
27 Res, 9, 6483-6488.
28 Omholt, K., Karsberg, S., Platz, A., Kanter, L., Ringborg, U., & Hansson, J. (2002). Screening of N-ras
29 codon 61 mutations in paired primary and metastatic cutaneous melanomas: mutations occur early
30 and persist throughout tumor progression. Clin Cancer Res, 8, 3468-3474.
31 Yancovitz, M., Litterman, A., Yoon, J., Ng, E., Shapiro, R. L., Berman, R. S. et al. (2012). Intra- and
32 inter-tumor heterogeneity of BRAF(V600E))mutations in primary and metastatic melanoma. PLoS
33 ONE, 7, e29336.
34 Yazdi, A. S., Ghoreschi, K., Sander, C. A., & Rocken, M. (2010). Activation of the mitogen-activated
35 protein kinase pathway in malignant melanoma can occur independently of the BRAF T1799A
36 mutation. European Journal of Dermatology, 20, 575-579.
37

1 Excluded studies
2 Busam, K. J., Hedvat, C., Pulitzer, M., Von, D. A., & Jungbluth, A. A. (2013). Immunohistochemical
3 analysis of BRAF(V600E) expression of primary and metastatic melanoma and comparison with
4 mutation status and melanocyte differentiation antigens of metastatic lesions. American Journal of
5 Surgical Pathology, 37, 413-420. 1.
6 Reason: Does not compare primary versus secondary tumour samples
7 Capper, D., Berghoff, A. S., Von, D. A., & Preusser, M. (2012). Clinical neuropathology practice news
8 2-2012: BRAF V600E testing. Clinical Neuropathology, 31, 64-66.
10 Colombino, M., Capone, M., Maio, M., De, G., V, Cossu, A., Lissia, A. et al. (2011). Mutation
11 frequency in BRAF and NRAS genes among primary tumors and different types of metastasis from
12 melanoma patients. Journal of Clinical Oncology, 29.
14 Culos, K. A. & Cuellar, S. (2013). Novel Targets in the Treatment of Advanced Melanoma: New First-
15 Line Treatment Options. Annals of Pharmacotherapy, 47, 519-526.
17 Czirbesz, K., Plotar, V., Serester, O., & Liszkay, G. (2013). BRAF V600 mutation in malignant
18 melanoma. JDDG - Journal of the German Society of Dermatology, 11, 44-45.
20 Hafner, C., Scheitler, S., Rummele, P., Gantner, S., Landthaler, M., & Klein, C. (2011). Divergent BRAF
21 mutation status of matched primary tumours and metastases in melanoma patients. JDDG - Journal
22 of the German Society of Dermatology, 9, 771.
24 Hocker, T. & Tsao, H. (2007). Ultraviolet radiation and melanoma: a systematic review and analysis
25 of reported sequence variants. [Review] [22 refs]. Human Mutation, 28, 578-588.
27 Lee, J. H., Choi, J. W., & Kim, Y. S. (2011). Frequencies of BRAF and NRAS mutations are different in
28 histological types and sites of origin of cutaneous melanoma: a meta-analysis. British Journal of
29 Dermatology, 164, 776-784.
31 Libra, M., Malaponte, G., Navolanic, P. M., Gangemi, P., Bevelacqua, V., Proietti, L. et al. (2005).
32 Analysis of BRAF mutation in primary and metastatic melanoma. Cell Cycle, 4, 1382-1384.
34 Manca, A., Colombino, M., Capone, M., Lissia, A., Cossu, A., Rubino, C. et al. (2012). Pattern and
35 distribution of BRAF/NRAS and P16CDKN2A mutations among primary an secondary lesions in
36 melanoma patients. Cancer Research, 72.

1 McArthur, G. A., Ribas, A., Chapman, P. B., Flaherty, K. T., Kim, K. B., Puzanov, I. et al. (2011).
2 Molecular analyses from a phase I trial of vemurafenib to study mechanism of action (MOA) and
3 resistance in repeated biopsies from BRAF mutation-positive metastatic melanoma patients (pts).
4 Journal of Clinical Oncology, 29.
6 Meier, F., Niessner, H., Forschner, A., Garbe, C., Bauer, J., & Quintanilla-Martinez, L. (2012). The AKT
7 survival pathway is strongly activated in melanoma brain metastases. JDDG - Journal of the German
8 Society of Dermatology, 10, 676.
10 Palmieri, G., Lissia, A., Cossu, A., Ascierto, P. A., Botti, G., Caraco, C. et al. (2013). Different
11 prevalence of BRAF and NRAS somatic mutations in melanomas according to the patients' origin.
12 Journal of Clinical Oncology, 31.
14 Polsky, D., Tadepalli, J. S., Hafner, S., Chang, G., Fleming, N. H., Shao, Y. et al. (2013). Analysis of
15 plasma-based BRAF and NRAS mutation detection in patients with stage III and IV melanoma. Journal
16 of Clinical Oncology, 31.
18 Pracht, M., Mogha, A., Fautrel, A., Lespagnol, A., Mouchet, N., Le, G. F. et al. (2012). C-kit, B-raf, and
19 N-ras mutations in melanoma subtypes. Journal of Clinical Oncology, 30.
21 Romano, E., Pradervand, S., Paillusson, A., Weber, J., Harshman, K., Muehlethaler, K. et al. (2013).
22 Identification of Multiple Mechanisms of Resistance to Vemurafenib in a Patient with BRAF(V600E)-
23 Mutated Cutaneous Melanoma Successfully Rechallenged after Progression. Clinical Cancer
24 Research, 19, 5749-5757.
25 Reason Does not compare primary versus secondary tumour samples
26 Safaee, A. G., Jafarnejad, S. M., Tan, L., Saeedi, A., & Li, G. (2012). The prognostic value of BRAF
27 mutation in colorectal cancer and melanoma: a systematic review and meta-analysis. [Review]. PLoS
28 ONE [Electronic Resource], 7, e47054.
30 Santos-Briz, A., Godoy, E., Arango, L., Antunez, P., Alcaraz, E., & Fernandez, E. (2013). Should
31 BRAFV600E be tested in primary or metastatic malignant melanoma? Laboratory Investigation, 93,
32 120A.
33 Reason Abstract only
34 Satzger, I., Marks, L., Klages, S., Kerick, M., Ruschoff, J., Middel, P. et al. (2013). BRAFV600 mutations
35 are highly consistent in primary melanomas and matched metastases-an analysis of 160 paired
36 tissue samples by real time PCR and next-generation sequencing. JDDG - Journal of the German
37 Society of Dermatology, 11, 4.

1 Vergier, B., Boursault, L., Haddad, V., Capellen, D., Verdon, S., Bellocq, J.-P. et al. (2013). Tumor
2 homogeneity between primary and metastatic sites for BRAF status in metastatic melanoma
3 determined by immunohistochemical and molecular testing. JDDG - Journal of the German Society of
4 Dermatology, 11, 47.
6 Wang, H., Lee, S., Nigro, C. L., Lattanzio, L., Merlano, M., Monteverde, M. et al. (2012). NT5E (CD73)
7 is epigenetically regulated in malignant melanoma and associated with metastatic site specificity.
8 British Journal of Cancer, 106, 1446-1452.
10

Evidence Tables
Was a Was a Did the study Were the If a Is the Were the Was there Did all Did Were all Quality
consecutive case- avoid index test threshold reference reference an patients patients patients
or random control inappropriate results was used, standard standard appropriate receive a receive included
sample of design exclusions? interpreted was it likely to results interval reference the same in the
patients avoided? without pre- correctly interpreted between standard? reference analysis?
enrolled? knowledge of specified? classify the without index standard?
the results of target knowledge test(s) and
the reference condition? of the reference
standard? results of standard?
the index
test?
Boursault et Consecutive Yes Yes Yes Not Yes Yes Unclear Yes Yes No – High
al (2013) Reported primary
tumour
samples
were not Low risk
available of bias
for 11/99 overall
patients
Not reported Unclear Unclear Not reported Not Yes Not reported Not reported No No No Moderate
Capper reported
(2012)
Unclear
risk of
bias
Consecutive Yes Not reported N/A N/A N/A N/A N/A N/A N/A Unclear High
Colombino
(2012)
Low risk
of bias
overall
Consecutive Yes Unclear N/A N/A N/A N/A N/A N/A N/A Unclear High
Colombino

the index
test?
(2013)
Low risk
of bias
overall
Not reported Unclear Unclear Not reported Not Yes Not reported Not Reported Not reported Not No Moderate
Edlundh-rose reported reported
(2006) Unclear
risk of
bias
Consecutive Yes Yes Yes Not Yes Yes Not reported No (only Yes No High
Hienzerling reported equivocal
(2013) cases)
Low risk
of bias
Not reported Unclear Unclear N/A N/A N/A N/A N/A Unclear Unclear Paired Moderate
Houben samples
(2004) only
available
for 24/86 Unclear
patients – risk of
unclear bias
why this

the index
test?
was.
Not reported Unclear Unclear N/A N/A N/A N/A N/A Unclear Unclear Results are Moderate
Omholt presented
(2002) for 72
patients –
but it is Unclear
unclear risk of
how many bias
others
might have
been
eligible
Not reported Unclear Unclear N/A N/A N/A N/A N/A Unclear Unclear Results are Moderate
Omholt presented
(2003) for 72
patients –
but it is Unclear
unclear risk of
how many bias
others
might have
been
eligible
Not reported Not Not reported Not Reported Not Unclear – Not Reported Not reported Yes Yes Yes Moderate
Yancovitz authors

the index
test?
(2012) reported reported report MS-

PCR as more
sensitive than Unclear
conventional Risk of
sequencing. bias
Not reported Not Not reported N/A Not N/A N/A N/A N/A N/A Yes Moderate
Yadzi (2012) reported Reported
Unclear
Risk of
bias
Boursault Diagnostic N=117 Immunohistochemistry High resolution Origin of metastatic samples

V600E
et al with an anti-BRAF melting analysis
(2013) Inclusion criteria: available antibody followed by
of tumour tissue from Sanger Site Proportion from that site
both primary melanoma sequencing
and metastasis, and Lymph nodes 81/142 (57%)
pathologically confirmed

stage IIIb, IIIc or IV on AJCC Brain 1/142 (<1%)
Exclusion criteria: Patients Skin 45/142 (32%)
without paired primary- Liver 4/142 (3%)

metastasis tissue samples
(N=13), inappropriate Lung 6/142 (4%)
fixation of material (N=5)

Other 5/142 (4%)
Clinical setting:
Secondary/tertiary care,
France, Dermatology Unit In primary tumour samples
Tests for BRAF mutation – in Mutation analysis Mutation analysis

primary tumour samples positive for BRAF negative for BRAF
(wild-type)
BRAF immunostaining 42 0
positive
negative
Sensitivity 93% , Specificity 100%
In metastatic tumour samples (per tumour analysis – some

patients contributed more than one sample)
Tests for BRAF mutation – Mutation analysis Mutation analysis

in metastatic tumour positive for BRAF negative for BRAF (wild-

samples type)
positive
negative
Sensitivity 88%, Specificity 100%
Concordance between primary and metastatic tumour samples

for mutation analysis
Primary tumour Primary tumour

mutation analysis mutation analysis
positive for BRAF negative for BRAF
Metastatic tumour 45 3
mutation analysis
positive for BRAF
Metastatic tumour 1 39
mutation analysis
negative for BRAF
The BRAF status was concordant between the primary and

metastatic samples for 84 patients (95.5%).
Discordant results for BRAF status were observed in 4 patients out

of 88 (4.5%).

Non interpretable results
Primary tumour samples Metastatic tumour

samples
BRAF immunostaining 2/88 (2.3%) 3/142 (2.1%)
5/117 eligible patients had inappropriate fixation of samples – so

they could not be analysed.
Retrospective Inclusion criteria: Age 16 Immunohistochemistry Sequencing Origin of metastatic samples

Capper cohort study or older with histologically using anti-BRAF V600E
(2012) diagnosed brain
metastasis of solid cancer.
Site Proportion from that site
FFPE samples of brain
metastasis, (and primary Brain 76/76 (100%)
tumour or other
metastasis if available)
were retrieved. Samples
from 874 patients were
included, 76 of which had
melanoma.
for BRAF V600E immuno-staining
Exclusion criteria: Primary tumour Primary tumour
Clinical setting: positive for BRAF negative for BRAF

Secondary/tertiary care, Metastatic tumour 6 0

mutation analysis positive
Medical University of
for BRAF
Vienna, Austria
Metastatic tumour 0 N.R.
mutation analysis negative
for BRAF
Primary tumour Metastatic Overall

samples tumour samples
Sequencing N.R. N.R. 15/85 (18%)-

genetic
analysis was
unsuccessful
Retrospective Inclusion criteria: 108 Mutation analysis using N/A Origin of metastatic samples in paired analysis
Colombino Study patients with AJCC stage III automated DNA
(2012) or IV (tumour samples sequencing.
were formalin fixed and
paraffin embedded). 29
Melanoma cell lines Lymph nodes 84/165 (51%)
cultured from primary and
metastatic tumours were

also included for controls. Brain 20/165 12%)
Exclusion criteria: Not Skin 36/165 (22%)

reported
Liver 20/165 (12%)
Clinical setting: Not
reported - (patients were Lung 5/165 (3%)
recruited from a number
of Italian institutions).
for BRAF mutation analysis
Primary tumour mutation Primary tumour

analysis positive for BRAF mutation analysis
negative for BRAF
Metastatic tumour
mutation analysis N.R. 6
positive for BRAF
Metastatic tumour
mutation analysis 6 N.R.
negative for BRAF
99 patients had paired primary and metastatic samples

for NRAS mutation analysis

analysis positive for NRAS mutation analysis

negative for NRAS
Metastatic tumour
positive for NRAS
Metastatic tumour
negative for NRAS
99 patients had paired primary and metastatic samples

Sample inadequacy Not reported Not reported 9/108

– due to DNA (8.3%)
degradation
Diagnostic Study Inclusion criteria: 532 Mutation analysis using N/A

Colombino automated DNA
patients with
(2013) sequencing of NRAS Origin of metastatic samples in paired analysis
histologically proven (exons 2 and 3) and
advanced melanoma

(stage III to IV). 236 BRAF (exon 15).

paired primary –
Site Proportion from Concordance with primary for
metastatic samples that site BRAF/NRAS status
were available from 138
Lymph nodes 120/236 (51%) 90.8%
patients.
Brain 24/236 (10%) 79.2%
Exclusion criteria: Not
reported Skin 52/236 (22%) 71.2%
Visceral 40/236 (17%) 92.5%

Clinical setting: Not
reported - (patients
were recruited from a
number of Italian Concordance between primary and metastatic tumour
institutions) 2008-2013. samples for BRAF mutation analysis

Metastatic tumour
mutation analysis positive N.R. 16
for BRAF
Metastatic tumour
mutation analysis negative 13 N.R.
for BRAF
138 patients provided 236 paired primary and metastatic

samples (some patients had samples from multiple
metastatic sites)

Concordance between primary and metastatic tumour

samples for NRAS mutation analysis

negative for NRAS
Metastatic tumour
positive for NRAS
Metastatic tumour
negative for NRAS
138 patients provided 236 paired primary and metastatic

samples (some patients had samples from multiple
metastatic sites)
Non interpretable results: not reported
Diagnostic Study Inclusion criteria: 219 Mutation analysis using Single strand Origin of metastatic samples
Edlundh- patients with cutaneous pyrosequencing of fresh conformation
rose (2006) melanoma treated at a frozen or formalin-fixed polymorphism
single institution. paraffin embedded nucleotide
samples. sequencing
Not reported Not reported
reported

Clinical setting:
Secondary/tertiary care:
Department of Oncology,
Karolinska University
Hospital, Sweden
for BRAF mutation analysis

Metastatic tumour
positive for BRAF
Metastatic tumour
negative for BRAF
In 2/57 cases the primary tumour sample had a BRAF mutation

but the metastatic sample was wild type.

for NRAS mutation analysis

negative for NRAS
Metastatic tumour
positive for NRAS

Metastatic tumour
negative for NRAS
In 2/57 cases the primary tumour sample had a NRAS mutation

but the metastatic sample was wild type.

Pyrosequencing N.R. N.R. The majority of

samples were
successfully
analysed
Diagnostic Study Inclusion criteria: Pyrosequencing Sanger Origin of metastatic samples

Hienzerlin sequencing (used
Patients with stage IV
g (2013) only in equivocal
melanoma (53
patients). 12 patients cases)
with rare BRAF
Skin 137/256 (54%)
mutations were
excluded. Results only Lymph node 20/256 (8%)
reported for the
Other (including liver, lung and 37/256 (14%)
remaining 41 patients of brain)
these primary tumour
Unknown 62/256 (24%)
samples were missing

for 25 patients: 9 were

unknown primary and
for 16 samples no
longer available. Concordance between primary and metastatic tumour
Exclusion criteria: uveal samples for BRAF mutation analysis (only patients with
melanoma BRAF V600E, V600K or wild-type were included)

Clinical setting: analysis positive for BRAF mutation analysis
Secondary/tertiary care, negative for BRAF
University Hospital
Metastatic tumour
Erlangen, Germany mutation analysis 6 0
positive for BRAF
Metastatic tumour
mutation analysis 5 5
negative for BRAF

Pyrosequencing Primary tumour

samples no longer
available for 16/41
(39%) patients.

Diagnostic Study Inclusion criteria: Paraffin Sequencing N/A Origin of metastatic samples
Houben embedded tumour
(2004) samples from 114 primary
and 86 metastatic
tumours. Paired primary
and metastatic samples N.R. N.R.
were available for 24
patients.
Exclusion criteria: None

reported
Clinical setting: Not for BRAF V599 mutation
reported
Metastatic tumour
positive for BRAF
Metastatic tumour
negative for BRAF

for NRAS 61 mutation

positive for NRAS negative for NRAS
Metastatic tumour
positive for NRAS
Metastatic tumour
negative for NRAS

sequencing N.R. N.R. N.R.
Diagnostic Study Inclusion criteria: PCR single strand N/A Origin of metastatic samples
Omholt Malignant melanoma conformation
(2002) primary tumour samples polymorphism (PCR-
(N=74), metastatic tumour SSCP) sequencing –

samples (N=88). Of these screening for N-ras exon Site Proportion from that site
54 were paired allowing 2 mutations
within patient comparison. Lymph node 50/88 (57%)
Samples were formalin
Skin 37/88 (42%)
fixed and paraffin
embedded. Unknown 1/88 (1%)
Exclusion criteria:
Clinical setting: Concordance between primary and metastatic tumour samples

Secondary/tertiary care, for NRAS codon 61 mutation (per patient analysis)
Department of Oncology,
Karolinska Hospital, Primary tumour Primary tumour
Sweden. mutation analysis mutation analysis
positive for NRAS negative for NRAS
(wild type)
Metastatic tumour
positive for NRAS
Metastatic tumour
mutation analysis
1 33
negative for NRAS
(wild type)

Primary Metastatic Overall

tumour tumour
samples samples
PCR-SSCP N.R. N.R. N.R.
Diagnostic Study Inclusion criteria: PCR single strand N/A Origin of metastatic samples
Omholt Malignant melanoma conformation
(2003) primary tumour samples polymorphism (PCR-
(N=52), metastatic tumour SSCP) sequencing –
samples (N=82). Of these screening for BRAF exon
51 were paired allowing 11 and exon 15 Lymph node 50/88 (57%)
within patient comparison. mutations
Samples were formalin Skin 37/88 (42%)
fixed and paraffin
embedded. Unknown 1/88 (1%)
Exclusion criteria:
Clinical setting: Concordance between primary and metastatic tumour samples

Secondary/tertiary care, for BRAF (per patient analysis, N=51)
Department of Oncology, Primary tumour Primary tumour
Karolinska Hospital, mutation analysis mutation analysis
Sweden. positive for BRAF negative for BRAF (wild
type)
Metastatic tumour N.R. 2

mutation analysis

positive for BRAF
Metastatic tumour
mutation analysis
0 N.R.
negative for BRAF (wild
type)
Primary Metastatic Overall

tumour tumour
samples samples
PCR-SSCP N.R. N.R. N.R.
Diagnostic Study Inclusion criteria Patients Conventional sequencing Mutation specific Origin of metastatic samples
Yancovitz has stage III or IV PCR
(2012) melanoma. 112 tumour
samples were analysed (94
metastatic, 18 primary)
Lymph node 43 (46%)
reported Skin 33 (35%)
Clinical setting: Not Visceral 18 (19%)

reported.

for BRAF V600E mutation

(wild type)
Metastatic tumour
positive for BRAF
Metastatic tumour
mutation analysis
2 0
type)

MS-PCR N.R. N.R. N.R.
Sequencing N.R. N.R. N.R.

Diagnostic Study Inclusion criteria: Sequencing N/A Origin of metastatic samples

Yadzi Malignant melanoma
(2012) (N=20 patients), with both
primary and metastatic
tumour samples. Samples
were formalin fixed N.R. N.R.
paraffin embedded.

reported Concordance between primary and metastatic tumour samples
for BRAF T1799A mutation
Clinical setting:
Secondary/tertiary care, Primary tumour Primary tumour
Germany
(wild type)
Metastatic tumour
positive for BRAF
Metastatic tumour
mutation analysis
3 6
type)


Sequencing N.R. N.R. N.R.

1 2.5 Genetic testing in stage I-III melanoma

2 Review question: What is the role of genetic testing of the tumour at diagnosis for a
3 person with early stage [I-III] melanoma?
4 Background
5 Early stage melanoma includes primary melanomas and melanomas with nodal/in-transit or satellite
6 metastases, but no distant organ metastases present. Detecting genetic abnormalities early may be
7 beneficial for the prevention or at least more effective treatment of distant secondary metastases.
8 We would like to assess if genetic testing is beneficial in early stage disease, or later testing is more
9 suited for the treatment of metastatic disease. It is important to see if the results of early tests can
10 guide treatment.
11 There is no real alternative to genetic testing, but we need to assess its’ usefulness in early disease.
12 The timing of the testing is important, as well as the genetic mutation types, which may have
13 different significance in relation to the melanoma subtypes.

Patients with Genetic testing of No genetic testing  (Rate of stratification
melanoma at stage: tumour at diagnosis at diagnosis for treatment)
Ia  Prognosis estimation
Ib& II  Survival
IIIa  Rate of recurrence
IIIb  Failure to obtain a
IIIc valid mutation test
result
 Treatment delays
 Morbidity
 HRQOL
15

1 Search Results
Medline 2002-2013 864 71 18/11/2013
Premedline 2002-2013 38 4 18/11/2013
Embase 2002-2013 820 53 22/11/2013

SSCI)
2 Screening Results

Records after duplicates removed 113
Records screened 113 Records excluded 112
Full text articles assessed for eligibility 1 Articles excluded 1
Studies included in evidence review 0
3
4

2 Our literature searches identified no studies comparing genetic testing at diagnosis with no genetic
3 testing at diagnosis.
4 References
5 Excluded studies
6 G. J. Mann, G. M. Pupo, A. E. Campain, C. D. Carter, S. J. Schramm, S. Pianova, S. K. Gerega, Silva C.

7 De, K. Lai, J. S. Wilmott, M. Synnott, P. Hersey, R. F. Kefford, J. F. Thompson, Y. H. Yang, and R. A.
8 Scolyer. BRAF mutation, NRAS mutation, and the absence of an immune-related expressed gene
9 profile predict poor outcome in patients with stage III melanoma. J.Invest.Dermatol. 133 (2):509-
10 517, 2013.
11 Reason: Does not compare testing at diagnosis with no testing at diagnosis
12

1 3. Staging of Melanoma
3 patients with clinicopathological stage IA melanoma?
5 patients with clinicopathological stage IB-IIC melanoma?
7 patients with clinicopathological stage III melanoma?
9 patients with clinicopathological stage IV melanoma?
10 Background
11 Skin melanoma is routinely treated with surgical excision. The removed skin melanoma is examined
12 by the pathologist who will review the melanoma under a microscope. The pathologist will comment
13 on the depth of skin penetration commonly called the Breslow thickness. The depth of penetration is
14 an important marker of the aggressive of the tumour. Additional information including whether the
15 melanoma is involving adjacent blood vessels or lymphatics plus whether the tumour has broken
16 through the skin surface, ulceration, also inform patient and clinical team of the chances of cure
17 from surgery and predicts the probability of whether the melanoma will spread to other parts of the
18 body following the initial surgery. Spread of melanoma to local lymph nodes or other parts of the
19 body can occur at any time. Thin melanomas are unlikely to spread and may be followed up
20 clinically. Melanomas that are thicker or demonstrate ulceration or blood vessel or lymphatic
21 infiltration have a high rate of spreading to other parts of the body. These pathological findings
22 together with clinical examination and patient symptoms determine whether further imaging is
23 required. There are many radiological techniques that can be used to image patients. These include
24 SNB, US, CT, MRI, PET-CT and PET-MRI. We have to ask the following questions:
25 1. At what pathological and clinical stage do we image patients?

26 2. When imaging is required, what test do we choose and why?
27 Determining whether melanoma has spread or not informs both patient and clinical team of where
28 the cancer is and allows informed decisions on treatment. Current treatment options available
29 include chemotherapy, radiotherapy, immunotherapy, surgery or tumour ablative techniques.
30 Treatment options for patients whose melanoma has spread to either the local lymph nodes or
31 other parts of the body have rapidly changed within the last few years. Chemotherapy has recently
32 proved to improve survival in selected patients. Additional questions to consider include:
33 3. What imaging technique is optimal in evaluating patient response assessment when

34 receiving chemotherapy agents?
35 4. Can the more modern radiological techniques, including both functional and molecular
36 techniques predict patients that may or may not benefit from chemotherapy?
37 The accuracy of a radiological technique is determined by the number of false negative and false
38 positive results i.e. melanoma disease that we fail to detect on imaging and also findings we think

1 are melanoma that with biopsy, surgical removal or more commonly follow up imaging turn out to
2 be not that of melanoma.

Intervention (Index Comparator (Reference
Population Outcomes
Test) Standard)
Patients with SLNB  Clinical examination 1. True Positives/Negatives

clinicopathological stage IA Ultrasound  Each Other 2. False Positives/Negatives
melanoma 3. Regional recurrence
4. Melanoma specific
Survival (5 & 10 yr)
5. Overall survival (5 & 10
yr)
6. HRQL
7. Adverse events long
term, inc: Lymphoedema
8. Adverse Events short
term surgical
Patients with  Ultrasound ±FNAC  Clinical Exam 1. True Positives/Negatives
clinicopathological stage  Targeted Ultrasound  Each other 2. False Positives/Negatives
IB-IIC melanoma ±FNAC 3. Regional recurrence
 SLNB 4. Melanoma specific
 CT Survival (5 & 10 yr)
 PET-CT 5. Overall survival (5 & 10
 Whole body MRI yr)
 MR-PET 6. Adverse events long
term, inc: Lymphoedema
7. HRQL
term surgical
9. Change to treatment
management
Patients with clinical stage  FNAC±Ultrasound Each other 1. Diagnostic accuracy of
III (palpable nodal disease)  Core biopsy of the nodal disease
melanoma node 2. Diagnostic accuracy for
 CT (whole body, chest, disease outside the nodal
abdo, pelvis) basin
 CT (brain and whole 3. Melanoma specific
body) Survival (5 & 10 yr)
 PET-CT 4. Metastasis free survival
 Whole body MRI 5. Overall survival (5 & 10
 MR-PET yr)
6. HRQL
7. Adverse events long term
term
management
Patients with clinical  CT (whole body, chest, Each other 1. Diagnostic accuracy for
changes suggestive of abdo, pelvis) sites of stage IV disease
stage IV melanoma  CT (brain and whole 2. Melanoma specific
body) Survival (5 & 10 yr)
 PET-CT 3. Metastasis free survival
 Whole body MRI 4. Overall survival (5 & 10

 MR-PET yr)
5. HRQL
6. Adverse events long term
term
management

Searches:
Can we apply date limits to the search (Please Searches were not carried out before 1994 as this
provide information on any date limits we can was when the largest trial began recruiting and the
apply to the searches for this topic? This can GDG considered information before this time to be
be done for each individual intervention as of little use to the review question.
appropriate)
Are there any study design filters to be used No filters were applied to the searches as the
(RCT, systematic review, diagnostic test). outcomes covered both clinical and diagnostic
elements and therefore all available study types
were considered necessary, particularly:
Interventional studies which report the listed

outcomes
Prognostic studies may also be of relevance to this

topic
Diagnostic Accuracy studies including RCTs if

available
List useful search terms. (This can include Post surgical morbidity
such information as any alternative names for Stratification criteria for RCT
the interventions etc) SNB as eligibility criterion for RCT
Prognosis
MSLT1
MSLT2
Peg-INTRON EORTC trial melanoma
1. change in stage
2. change in management
3. clinical impact of diagnostic tests / imaging
4. impact on decision making / treatment plan

3 Relevant studies will be identified through sifting the abstracts and excluding studies clearly not
4 relevant to the PICO. In the case of relevant or potentially relevant studies, the full paper will be
5 ordered and reviewed, whereupon studies considered not to be relevant to the topic will be
6 excluded.
7 Studies which are identified as relevant will be critically appraised and quality assessed using GRADE
8 methodology and NICE checklists. Data relating to the identified outcomes will be extracted from
9 relevant studies.

1 If possible a meta-analysis of available study data will be carried out to provide a more complete
2 picture of the evidence body as a whole.
3 An evidence summary outlining key issues such as volume, applicability and quality of evidence and
4 presenting the key findings from the evidence as it relates to the topic of interest will be produced.
5 Search Results
6 E1

Medline 1946-2014 1556 264 13/01/2014
Premedline Jan 6 2014 79 10 07/01/2014
Embase 1947-2014 2089 355 28/01/2014
Cochrane Library Issue 1, 12 Jan 47 18 14/01/2014

2014

SSCI)
7 Updates
Database name No of references No of references Finish date of

Medline 75 13 07/10/2014
Embase 52 15 07/10/2014
8 E2

Medline 1946-2014 1888 367 05/02/2014
Premedline Feb 4 2014 89 16 05/02/2014
Embase 1947-2014 3197 577 12/02/2014

Cochrane Library Issue 2, Feb 93 26 05/02/2014

2014

SSCI)
1 Updates

Medline 87 26 07/10/2014
Premedline 14 3 07/10/2014
Embase 100 29 07/10/2014
2 E3

Medline 1946-2014 935 197 26/02/2014
Premedline Feb 25 2014 60 12 26/02/2014
Embase 1947-2014 1970 214 06/03/2014

2014

SSCI)
3 Updates

Medline 48 15 07/10/2014
Premedline 11 1 07/10/2014
Embase 69 16 07/10/2014

1 E4

Medline 1946-2014 538 186 10/03/2014
Premedline Mar 07 2014 44 10 10/03/2014
Embase 1947-2014 1428 169 12/03/2014

2014

SSCI)
2 Updates

Medline 38 7 07/10/2014
Embase 58 7 07/10/2014
3 Total references in all databases combined (merged and de-duplicated): 1373
5 E1
6 1. exp Melanoma/
7 2. melanoma$.tw.
10 5. dubreuilh.tw.
11 6. LMM.tw.
12 7. or/1-6
13 8. exp neoplasm staging/
14 9. *cancer staging/
15 10. (stag$ or restag$ or re-stag$ or upstag* or classif* or TNM or stratif*).tw.

1 11. or/8-10
2 12. 7 and 11
4 14. ((sentinel and node) adj biops*).tw.
5 15. (sentinel adj1 lymphadenectom*).tw.
6 16. ((sentinel and node) adj dissect*).tw.
7 17. ((sentinel and node) adj procedure).tw.
8 18. ((sentinel and node) adj detection).tw.
9 19. (SNLB or SNB).tw.
10 20. or/13-19
11 21. exp Physical Examination/
12 22. ((clinical or physical) adj exam*).tw.
13 23. ((clinical or physical) adj assess*).tw.
14 24. *Palpation/
15 25. palpat*.tw.
16 26. or/21-25
17 27. exp Ultrasonography/
18 28. (ultraso* or sonogra* or echogra* or echotomogra*).tw.
19 29. 27 or 28
20 30. 20 or 26 or 29
21 31. 12 and 30
23 E2
24 1. exp Melanoma/
25 2. melanoma$.tw.
26 3. 1 or 2
27 4. exp Neoplasm Staging/
28 5. *Cancer Staging/
30 7. or/4-6
31 8. 3 and 7
35 12. *Palpation/
36 13. palpat*.tw.
37 14. or/9-13
40 17. 15 or 16
41 18. *Diagnostic Imaging/
42 19. exp Radionuclide Imaging/
43 20. (radionuclide adj1 (scan* or imaging)).tw.
44 21. exp Magnetic Resonance Imaging/

1 22. magnet* resonance.tw.

2 23. (MRI or MRI*1 or NMR*1).tw.
3 24. (MR adj (imag* or scan*)).tw.
4 25. (magnet* adj (imag* or scan*)).tw.
5 26. (magneti?ation adj3 imaging).tw.
6 27. (wbmr* or whole body mr*).tw.
7 28. Whole Body Imaging/
8 29. exp Tomography/
9 30. exp Tomography, X-Ray Computed/
10 31. PET*1.tw.
11 32. PET-CT.tw.
12 33. (comput* adj1 tomogra*).tw.
13 34. ((diffusion or planar or echoplanar or functional or nuclear or radionuclide or radioisotope or
14 conventional) adj2 (scan* or imag* or tomogra*)).tw.
15 35. (FDG-PET or FES-PET or 18F-FDG-PET or FLT-PET).tw.
16 36. ((CT or CAT) adj (scan* or imaging or examination)).tw.
17 37. (PET adj (scan* or imaging or examination)).tw.
18 38. positron emission tomograph.tw.
19 39. scintigraph*.tw.
20 40. or/18-39
21 41. exp Biopsy, Fine-Needle/
22 42. (fine needle adj1 (biops* or cytolog*)).tw.
23 43. (FNAC or FNA).tw.
24 44. or/41-43
25 45. 14 or 17 or 40 or 44
26 46. 8 and 45
28 E3
29 1. exp Melanoma/
30 2. melanoma$.tw.
31 3. 1 or 2
35 7. or/4-6
36 8. 3 and 7
40 12. *Palpation/
41 13. palpat*.tw.
42 14. or/9-13

1 17. 15 or 16
2 18. *Diagnostic Imaging/
3 19. exp Radionuclide Imaging/
4 20. (radionuclide adj1 (scan* or imaging)).tw.
15 31. PET*1.tw.
16 32. PET-CT.tw.
25 40. or/18-39
26 41. exp Biopsy, Fine-Needle/
27 42. (fine needle adj1 (biops* or cytolog*)).tw.
28 43. (FNAC or FNA).tw.
29 44. or/41-43
30 45. 14 or 17 or 40 or 44
31 46. 8 and 45
33 E4
34 1. exp Melanoma/
35 2. melanoma$.tw.
36 3. 1 or 2
40 7. or/4-6
41 8. 3 and 7


8 19. PET*1.tw.
9 20. (PET-CT or PETCT).tw.
14 24. (MRPET or MR-PET).tw.
19 29. or/9-28
20 30. 8 and 29
22

1 Screening Results
2 Due to the high degree of overlap between the studies found for each of the individual stages of
3 Melanoma, all four individual databases were combined and sifted as one single search with a total
4 of 1322 references. The database was sifted and studies selected firstly according to which stage
5 they were potentially relevant to and secondly according to whether they related to clinical or
6 diagnostic outcomes.


1353

1353 1024

329 298

31

Table3.1-3.3: Characteristics of included studies
3.1 Diagnostic Meta-Analysis
Study Study Design Population Total Modality Ref. Standard Unit of

included Number of Analysis
Patients
Acland et al Retrospective 54 PET Positive Histology/Disease Scans

(2000) Progression
Acland et al Retrospective 54 PET Histology and clinical follow-up Scans

(2000) mean 25 months (range 22-47
months)
Acland et al Prospective >1mm thick or 50 PET Sentinel node biopsy and clinical Patients
(2001) lymphatic invasion follow-up of up to 13 months
(range 5-26 months)
Agnese et al Retrospective 755 SLNB Histology

(2007)
Aukema et al Retrospective 70 PET Biopsy, clinical follow-up, further Scans

(2010) imaging
Bachter et al Retrospective 256 SLNB Histology

(2001)
Basler et al Retrospective FNAC Histology/Follow-up

(1997)
Bastiaannet Prospective 253 PET Biopsy, clinical follow-up, further Scans

et al (2011) imaging


Patients
Belhocine et Prospective Early stage 21 PET Sentinel node biopsy and clinical Patients
al (2002) melanoma follow-up 12 months
Berk et al Retrospective 274 SLNB Histology

(2005)
Blessing et al Retrospective 19 PET Histopathology or follow-up

(1995)
Blessing et al Retrospective 19 Ultrasound Histopathology or follow-up

(1995)
Blumenthal Retrospective Stage IB-II 60 SLNB Histology

et al (2002)
Borgogoni et Retrospective 385 SLNB Histology

al (2004)
Brady et al Prospective 103 CT Patients

(2006)
Cangiarella Retrospective Clinically 115 FNAC Histology/Follow-up Lymph

et al (2000) suspicious lymph Nodes
nodes
Caraco et al Retrospective 331 SLNB Histology

(2004)


Patients
Cascinelli et Retrospective 1108 SLNB Histology

al (2006)
Cascinelli et Retrospective Stage IB-II 829 SLNB Histology

al (2000)
Cecchi et al Retrospective 111 SLNB Histology

(2006)
Chakera et al Retrospective 243 SLNB Histology

(2004)
Chao et al Retrospective 1183 SLNB Histology

(2002)
Clark et al Retrospective T2-T4 melanoma 64 PET Patients

(2006)
Corrigan et Retrospective 149 SLNB Histology

al (2006)
Crippa et al Prospective Clinical/Instrument 38 PET Lymph node dissection plus Regional

(2000) detected lymph histology Lymph
node metastases Nodes
Dalal et al Retrospective 1046 SLNB Histology

(2007)


Patients
Dalle et al Retrospective FNAC Histology/Follow-up

(2006)
Damian et al Retrospective Stage II-IV 100 PET Clinical exam, scans and/or metastases
(1996) histopathology
De Giorgi et Retrospective 104 SLNB Histology

al (2007)
Doting et al Retrospective Stage I-II 200 SLNB Histology

(2002)
Eigtved et al Prospective 38 PET Histopathology and clinical Patients

(2000) follow-up
Estourgie et Prospective 250 SLNB Histology

al (2003)
Fincher et al Retrospective All stages 198 SLNB Histology

(2003)
Fink et al Prospective >1mm thick with 48 PET Sentinel node biopsy and clinical Patients
(2004) no palpable lymph follow up 12 months
nodes
Finkelstein Prospective Stage IV 18 PET Histopathology and clinical

et al (2004) follow-up (median 24 months)


Patients
Gad et al Retrospective 278 SLNB Histology

(2006)
Gershenwald Retrospective Primary cutaneous 317 SLNB Histology

et al (1998) melanoma
Gipponi et al Retrospective 175 SLNB Histology

(2005)
Gomez- Retrospective 113 SLNB Histology

Rivera et al
(2008)
Hafner et al Prospective All patients with 100 PET Histopathology and clinical
(2004) melanoma follow-up 6 and 12 months
Hafner et al Prospective All patients with 100 Ultrasound Sentinel node biopsy and clinical
(2004) melanoma follow-up 6 months and 12
months
Hafner et al Prospective All patients with 100 US/PET Histopathology and clinical
(2004) melanoma follow-up 6 and 12 months
Hafstrom et Retrospective FNAC Histology/Follow-up

al (1980)
Harlow et al Retrospective Clinically node 336 SLNB Histology

(2001) negative


Patients
melanoma
Havenga et Prospective >1mm thick with 45 PET Regional

al (2003) no palpable lymph Lymph
nodes Nodes
Hershko et al Retrospective 64 SLNB Histology

(2006)
Hinz et al Prospective Any cutaneous 81 Ultrasound

(2011) melanoma
Hocevar et al Retrospective Unclear 57 Ultrasound Histology Patients

(2004)
Horn et al Retrospective Cutaneous 33 PET Biopsy, clinical follow-up, further Patients

(2006) melanoma & imaging
subclinical lymph
node metastases
Kettlewell et Prospective 482 SLNB

al (2006)
Klein et al Prospective Patients with 17 PET Sentinel node biopsy and clinical Scans
(2000) cutaneous follow-up of up to 22 months
melanoma
Klein et al Prospective Patients with 17 PET Clinical follow-up 3-19 months

cutaneous


Patients
(2000) melanoma
Kokoska et al Prospective >1mm thick with 18 PET

(2001) clinically negative
nodes
Koskivuo et Retrospective 305 SLNB Histology

al (2007)
Landi et al Retrospective Stage I-II 455 SLNB Histology

(2000)
Longo et al Prospective ≥1mm 25 PET Sentinel node biopsy and clinical

(2003) follow-up >10 months (range 10-
29)
MacFarlane Prospective Stage II-III 23 PET Lymph node dissection plus Patients
et al (1998) histology
Macripo et Prospective 274 SLNB Histology

al (2004)
Manca et al Retrospective 127 SLNB Histology

(2003)
Mattsson et Retrospective 422 SLNB Histology

al (2008)


Patients
Maubec et al Prospective >4mm thick 25 PET Patients

(2007)
Medina- Retrospective 54 SLNB Histology

Franco et al
(2001)
Moehrle et Retrospective 283 SLNB Histology

al (2004)
Morton et al Retrospective 1599 SLNB Histology

(2003)
Morton et al Retrospective 769 SLNB Histology

(2006)
Murali et al Retrospective Image guided Histology/Follow-up

(2007) FNAC
Murali et al Retrospective Palpation Histology/Follow-up

(2007) guided FNAC
Nowecki et Retrospective 1207 SLNB Histology

al (2006)
Paquet et al Retrospective 24 PET Sentinel Node biopsy and clinical scans

(2000) follow-up of 18 months


Patients
Perry et al Retrospective FNAC Histology/Follow-up

(1986)
Pfannenberg Prospective Stage III/IV 64 PET Lesions

Pfannenberg Prospective Stage III/IV 64 PET-CT Lesions

Pfluger et al Retrospective 50 PET Biopsy, clinical follow-up Scans

(2011)
Reinhardt et Retrospective >0.75mm & Clarks 67 PET Clinical, conventional images Scans
al (2002) level III-IV and/or biopsy. Clinical follow-up
≥6 months
Rex et al Retrospective 240 SLNB Histology

(2005)
Rodriguues Retrospective FNAC Histology/Follow-up

et al (2000)
Roka et al Retrospective 309 SLNB Histology

(2005)
Rossi et al Retrospective All patients with 69 Ultrasound

(2000) melanoma


Patients
Rossi et al Prospective >1mm thick 125 Ultrasound Regional

(2003) cutaneous Lymph
melanoma Nodes
Roulin et al Retrospective 327 SLNB Histology

(2008)
Schmalbach Retrospective 80 SLNB Histology

et al (2003)
Schmid- Prospective Lesions suspicious 22 Ultrasound

Weber et al of metastases
(2004)
Schoegen et Retrospective FNAC Histology/Follow-up

al (1993)
Sibon et al Prospective ≤1mm thick or 131 Ultrasound Histology Regional

(2007) ulcerated Lymph
cutaneous Nodes
melanoma
Starrit et al Prospective All patients with 304 Ultrasound Patients

(2005) melanoma with
histologically
confirmed
metastases


Patients
Stas et al Retrospective patients with 84 PET Clinical, conventional images Lesions

(2002) regional or distant and/or biopsy. Clinical follow-up
recurrence or with ≥12 months
suspected
recurrence on
conventional
screening
Steinart et al Prospective 33 PET ≥ conventional imaging or

(1995) histopathology
Stewart et al Retrospective 178 SLNB Histology

(2005)
Swetter et al Retrospective 104 PET Clinical, conventional images

(2002) and/or biopsy
Teltzrow et Retrospective 106 SLNB Histology

al (2007)
Testori et al Prospective Stage I 88 Ultrasound Histology Regional

(2005) Lymph
Nodes
Testori et al Prospective 1313 SLNB

(2009)
Tyler et al Prospective Clinically evident 95 PET Clinical, conventional images Lesions

stage III lymph and/or biopsy. Clinical follow-up


Patients
(2000) node and/or in ≥6 months

transit metastases
Van Akkooi Retrospective 262 SLNB Histology

et al (2006)
van Rijk et al Prospective Patients with 107 Ultrasound

(2006) cutaneous
melanoma eligible
for SLNB
Veit-Haibach Prospective Any cutaneous 74 PET-CT

Veit-Haibach Prospective Any cutaneous 74 PET-CT

Vereecken et Prospective Intermediate/Poor 43 PET Sentinel node biopsy and clinical Patients
al (2005) prognosis follow-up 6 months
melanoma
Vereecken et Prospective Intermediate/Poor 43 PET Sentinel node biopsy and clinical Lesions
al (2005) prognosis follow-up 6 months
melanoma
Vidal Sicart Retrospective 435 SLNB

et al (2003)


Patients
Voit et al Retrospective Image guided Histology/Follow-up

(2000) FNAC
Voit et al Retrospective Palpation Histology/Follow-up

(2000) guided FNAC
Voit et al Prospective >1mm thick 127 Ultrasound Patients

(2006)
Voit et al Retrospective ≥1.00mm thick 1000 Ultrasound ± Histology Patients

(2014) FNAC ± SLNB
Vucetic et al Retrospective 201 SLNB Histology

(2006)
Vuylsteke et Retrospective 209 SLNB Histology

al (2003)
Wagner et al Prospective Stage I-II 12 PET Lymph node dissection plus

(1997) histology
Wagner et al Prospective Stage I-III 74 PET Sentinel lymph node biopsy and
(1999) follow-up
Wagner et al Retrospective 408 SLNB

(2003)
Wagner et al Prospective >1mm thick early 144 PET Sentinel node biopsy and clinical Regional
(2005) stage melanoma follow-up ≥ 6 months Lymph


Patients
Nodes
Wagner et al Prospective Stage I-II 136 PET Clinical , conventional images

(2005) and/or biopsy
Wagner et al Prospective Stage I-III 136 PET Clinical follow-up median 41.4
(2005) months
Wagner et al Retrospective 46 PET Biopsy, clinical follow-up, further Scans

(2011) imaging
Wagner et al Retrospective Histologically 46 PET-CT Biopsy, clinical follow-up, further Distant

(2011) proven melanoma imaging Metastases
with metastatic
involvement of the
sentinel lymph
node and clinically
exempt of
metastases
Wasserberg Retrospective 250 SLNB Histology

et al (2004)
Yancovitz et Retrospective Stage T1b-3b, 158 PET-CT Scans

al (2007) clinically node
negative and no
distant metastasis


Patients
Yee et al Retrospective 1012 SLNB Histology

(2005)
Zeelen et al Retrospective FNAC Histology/Follow-up

(1990)

Table 3.2 Clinical Outcomes
Study Study Type Population Aim Intervention Comparison Outcomes
Faries et al Randomised N=225 patients To investigate whether Wide local Wide local Acute Toxicity including: Wound
(2010) Controlled Trial who underwent early lymph node dissection excision + SLNB excision + separation, seroma/hematoma,
wide local excision was associated with less + CLND delayed CLND haemorrhage, infection,
with SLNB and morbidity than delayed thrombophlebitis, urinary tract
early complete dissection at the time of infection, pneumonia and cardiac
lymph node clinical recurrence complications
dissection
Chronic Toxicity including

lymphoedema and nerve
dysfunction
Freeman et al Systematic Articles which To determine whether SLN Positive Sentinel Negative Overall Survival
(2013) review and evaluated the risk status provides significant Lymph Node Sentinel
Meta-analysis of overall survival prognostic information in Biopsy Lymph Node
and mortality addition to Breslow Biopsy
according to SLN thickness alone
status in patients
with melanoma.
Harlow et al Prospective N=336 with biopsy To determine the success Sentinel Node N/A Disease Recurrence
(2001) Case Series proven invasive rate of identifying and Biopsy
cutaneous removing sentinel lymph Location of recurrence
melanoma (Clark nodes in melanoma patients
Overall Survival
level II or higher) and to determine the rate of
disease recurrence, location
of recurrence and overall

survival rates for patients
Kettlewell et al Observational N=472 patients To determine whether SLNB N/A Time to Recurrence
2006 Case Series (482 SNB sentinel node status adds
procedures) prognostic information to Death from Melanoma
that gained from measuring
tumour thickness
Kunte et al Prospective N=1049 patients To evaluate the effect of SLNB N/A Disease Free Survival
(2010) Case Series with melanoma tumour characteristics and
stage 1/11 SLN status on disease free Overall Survival
scheduled to survival
undergo SLNB
Moehrle et al Prognostic Case N=283 patients To determine the prognostic Sentinel Lymph N/A Recurrence
(2004) Series Study with sentinel lymph significance of histological Node Biopsy
node biopsy in status of sentinel lymph Disease Free Survival
clinical stage I/II node biopsy in regard to
Survival without distant metastases
between 1996- overall survival, disease free
1999. survival and survival without Overall Survival
distant metastases.
Morton et al Randomised Intervention Arm To determine whether Wide excision of Wide excision Primary Outcomes
(2014) Controlled Trial N=1000 sentinel-node biopsy could primary plus post-
be used to identify patients melanoma plus operative Melanoma specific survival
with clinically occult nodal sentinel-node nodal
metastases and whether biopsy (60%) observation
Control Arm N=661
immediate-completion with immediate (40%) with

lymphadenectomy yielded lymphadenecto lymphadenect Secondary Outcomes

better outcomes than my if omy if nodal
complete lymphadenectomy metastases metastases Disease free survival
performed only when nodal were detected developed
Incidence
recurrence was revealed during
during observation observation Timing
Anatomic distribution of distant

metastases
Morbidity of procedures
Significance of TA90 levels
Incidence of Sentinel Node

Metastases (biopsy) vs. Clinical
metastases (observation)
Accuracy of LM
Voit et al Retrospective To evaluate the N=1,000 Ultrasound ± N/A Disease Free Survival
(2014) Case Series increased FNAC ± SLNB
experience with Melanoma Specific Survival
sentinel lymph
node biopsy as an
addition to US-
FNAC
Wasserberg et Retrospective To determine the N=250 patients with SLNB N/A Wound Complications
al (2004) Case Series incidence and malignant melanoma who
severity of SLNB underwent SLNB between Sensory Complications

related 1994 and 2002. Other Complications

complications over
the long term and
to identify possible
Median age was 56.5 years
risk factors
(range 17-84 years)
Table 3.3 Children and Adolescents
Butter et al Retrospective Case N=12 patients aged To review the experience SLNB Disease free survival
(2005) Series <18 years with with paediatric cutaneous
cutaneous melanoma and SLNB Overall Survival
melanoma
Howman- Retrospective Case N=55 patients aged To assess outcomes in SLNB N/A Overall Survival
Giles et al Series <20 years with young patients undergoing
(2009) stage I-II cutaneous SLNB for intermediate
melanoma thickness localised
melanoma
Pacella et al Retrospective Case N=7 patients aged To determine the clinical SLNB Unclear
(2003) Series between 4-11 years utility of intraoperative
with biopsy proven lymph node mapping and
melanoma or a sentinel lymph node biopsy
borderline
melanocytic lesion
of uncertain

biologic potential.
Raval et al Retrospective N=671 patients To assess the ultisation of SLNB Factors impacting SLNB
(2010) Review aged <18 years SLNB in children with
with invasive melanoma, to determine Lymph node metastases
melanoma the clinicopathological,
socioeconomic or hospital
level factors associated with
SLNB use and to identify
factors associated with
lymph node metastases in
children with melanoma
Roaten et al Retrospective Case N=20 patients aged To determine outcomes and SLNB Adverse events
(2005) Series <21 years complications of children (complications)
undergoing SLNBX and adolescents undergoing
for melanoma or SLNBX
other melanocytic
skin lesions
Toro et al Retrospective Case N=12 patients aged To investigate the use of SLNB Recurrence
(2003) Series <18 years with SLNB in the paediatric
clinically node population focusing on its Adverse Events
negative melanoma diagnostic and therapeutic (complications)
implications

1 Study Quality
2 Diagnostic Outcomes
3 Evidence for the diagnostic outcomes was taken primarily from a number of systematic reviews and
4 supplemented where necessary with data from any other relevant studies. Overall the quality of the
5 evidence for diagnostic outcomes ranged from low to high quality for a number of reasons.
6 There were no randomised trials of any of the diagnostic interventions and as a result the studies
7 included in the meta-analysis were at high risk of bias with the included populations highly selected
8 for SLNB or imaging and in many cases it was unclear whether the intervention was being utilised as
9 part of staging at diagnosis or as part of follow-up and surveillance.
10 Other reasons for downgrading the quality of the evidence were similar across the studies and
11 included unmet quality criteria relating to insufficient reporting of patient withdrawals, intermediate
12 results and selection and training of raters (Xing et al, 2010) Several potential sources of bias with
13 many studies failing to report inclusion and exclusion criteria as well as not reporting sufficient
14 population information. Other possible sources of bias identified included potential review bias
15 resulting from a lack of blinding of test reviewers. In many cases, test results were not blinded for
16 reference test results or index test results and only a small proportion of included studies reported
17 how to deal with indeterminate results (Krug et al, 2008).
18 Figure 3.1 Diagnostic Study Quality
Study quality
80
70
60
50
40
No. Of Studies
30
20
10
0
Not reported High Moderate Low
19
20 Clinical Outcomes
21 One systematic review and meta-analysis, 1 randomised trial and 1 cohort study were identified to
22 inform the clinical outcomes of interest. Evidence was only available for sentinel lymph node biopsy
23 and the quality of the evidence ranged from high to very low as assessed by GRADE.

1 Children and Adolescents
2 Evidence relating to children and adolescents specifically was limited and very low in quality as
3 assessed by GRADE. A total of 5 studies, all retrospective reviews with small sample sizes and looking
4 only at SLNB, provided the evidence for this topic.

2 Diagnostic Outcomes
3 Patients with clinically negative nodes
4 Breslow thickness
5 Evidence from a randomized trial (Morton et al, 2014), a systematic review (Lens et al, 2002) and an
6 observational study (Han et al 2013) shows that in patients undergoing sentinel lymph node biopsy,
7 Breslow thickness is associated with the likelihood of a positive result (see figure 4). In those with a
8 Breslow thickness of 0.75mm or less (Lens et al 2002; Han et al, 2013) the positive sentinel lymph
9 node rate was 1% to 3%. This compares with 6% for those with a Breslow thickness of 0.75mm to
10 1.0mm (Han et al 2013) and 8% for those with a Breslow thickness of 0.75mm to 1.5mm (Lens et al
11 2002).
12 Sentinel lymph node biopsy (SLNB)
13 Meta-analysis of 47 studies indicates a sensitivity and specificity of 86.6% and 100% respectively for
14 SLNB. Clinical stage was I or II where mentioned and it was likely that these SLNB studies only
15 included patients with clinically negative nodes given their relatively low prevalence of positive
16 nodes (ranging from 9% to 41%; see Table 1), compared to the studies of other tests.
17 Imaging (Ultrasound or PET)
18 In patients with clinical stage I melanoma, US had a sensitivity of 49.5% and specificity of 91.9%
19 (from meta-analysis of 3 studies; see Table 1). In patients with clinical stage I-II primary melanoma,
20 PET had a sensitivity of 22.3% and specificity of 94.9% for the detection of regional lymph node
21 metastases (from meta-analysis of 4 studies; see Table 1).
22 Voit et al (2014) used lymphoscintagraphy to target ultrasound at the sentinel node in patients
23 scheduled for SLNB. Any suspicious nodes on US underwent FNAC, with the rationale that patients
24 with positive FNAC could be spared the morbidity of surgical SLNB. The sensitivity of targeted
25 ultrasound and FNAC for lymph node metastasis was 50% with 99% specificity. According to these
26 figures about half of those with positive nodes could avoid surgical SLNB, but the absolute number
27 of patients spared SLNB would depend on the prevalence of lymph node metastasis.
28 Patients with clinically positive nodes
29 FNAC for regional nodes
30 The evidence about FNAC came from studies with relatively a high prevalence of positive nodes
31 (ranging from 48% to 87%; see Table 1), where the patients included were more likely than not to
32 have a positive node. It is assumed that FNAC was used as a targeted test for clinically or
33 radiologically suspicious nodes, rather than as a routine test in all patients. Meta-analysis indicated a
34 sensitivity and specificity of FNAC for the identification of regional lymph node metastasis of 95.7%
35 and 97.8% respectively (12 studies)

1 PET for regional nodes
2 In patients with clinical stage II-III primary melanoma, PET had a sensitivity of 64.7% and specificity
3 of 93.9% for the detection of regional lymph node metastases (3 studies).
4 Imaging for any metastasis (including distant metastasis)
5 Meta-analysis of available data for each modality reported a sensitivity and specificity of PET for the
6 identification of any metastases of 87.4% and 88.6% respectively (5 studies) compared with a
7 sensitivity and specificity of 90.6% and 77.2% for PET-CT (1 study).
8 In patients with clinical stage III-IV primary melanoma, PET had a sensitivity of 70.4% and specificity
9 of 83.7% for the detection of any metastases (1 study).
10 Table 3.4 Diagnostic accuracy of tests for identifying regional nodes
11 FNAC
Stage N studies (N Prevalence Sensitivity (95% Specificity LR+ (95%CI) LR-(95%CI)
data points) CI) (95%CI)
Any 12 (3203) 48% to 95.7% (93.2% to 97.8% (96.1% to 46.5 (24.0 to 0.04 (0.03 to
87% 97.4%) 98.8%) 81.9) 0.07)
I - - - - - -
I,II - - - - - -
II - - - - - -
II,III - - - - - -
III - - - - - -
III,IV - - - - - -
IV - - - - - -
12
13 PET
Stage N studies (N Prevalence Sensitivity (95% Specificity LR+ (95%CI) LR-(95%CI)
data points) CI) (95%CI)
Any 9 (753) 15% to 51.3% (26.3% to 92.4% (86.3% to 6.6 (3.9 to 0.5 (0.3 to
66% 75.6%) 95.9%) 10.7) 0.8)
I - - - - - -
I,II 4 (433) 15% to 22.3% (15.1% to 94.9% (86.6% to 5.2 (1.4 to 0.8 (0.7 to
29% 31.6%) 98.2%) 13.6) 0.9)
II - - - - - -
II,III 3 (175) 29% to 64.7% (8.9% to 93.9% (65.0% to 10.5 (2.6 to 0.4 (0.01 to
66% 97.2%) 99.8%) 28.0) 0.9)
III 1 (83) 46% 73.7% 93.3% 13 0.3
III,IV - - - - - -
IV - - - - - -
14
15 Ultrasound
Stage N studies (N data Prevalence Sensitivity (95% Specificity LR+ (95%CI) LR-(95%CI)
points) CI) (95%CI)
Any 7 (868) 16% to 53.5% (25.7% to 88.0% (81.0% to 4.5 (2.2 to 0.5 (0.2 to
46% 79.3%) 92.7%) 7.6) 0.8)
I 3 (510) 16% to 49.5% (8.9% to 91.9% (87.5% to 6.0 (1.3 to 0.5 (0.1 to
26% 90.8%) 94.8%) 11.3) 1.0)
I,II - - - - - -
II - - - - - -

II,III 1 (97) 27% 7.7% 87.3% 0.8 1.1

III 1 (83) 46% 76.3% 93.3% 13.4 0.3
III,IV - - - - - -
IV - - - - - -
1
2 SLNB
points) CI) (95%CI)
Any 47 (19607) 9% to 41% 86.6% (84.6% to 100% 407 (266 to 0.1 (0.1 to
88.4%)) 598) 0.2)
I - - - - - -
I,II 5 (1766) 16% to 88.7% (76.1% to 100% 460 (104 to 0.1 (0.05 to
25% 95.1%) 1330) 0.2)
II - - - - - -
II,III - - - - - -
III - - - - - -
III,IV - - - - - -
IV - - - - - -
3

1 Figure 3.2 Tests for identifying positive regional nodes

1 Table 3.5. Any metastasis
2 PET
points) CI) (95%CI)
Any 5 (965) 23% to 87.4% (38.9% to 88.6% (77.6% to 7.6 (3.6 to 0.2 (0.02
90% 98.7%) 94.6%) 14.0) 0.7)
I 1 (184) 23% 20.9% 97.2% 8.6 0.8
I,II - - - - - -
II - - - - - -
II,III - - - - - -
III - - - - - -
III,IV 1 (420) 70% 70.4% 83.7% 4.4 0.4
IV - - - - - -
3
4 PET-CT
Stage N studies (N data Prevalence Sensitivity (95% Specificity LR+ LR-
points) CI) (95%CI) (95%CI) (95%CI)
Any 1 (420) 71% 90.6% 77.2% 4.0 0.1
I - - - - - -
I,II - - - - - -
II - - - - - -
II,III - - - - - -
III - - - - - -
III,IV - - - - - -
IV - - - - - -
5
6 Figure 3.3: any metastasis

1 Figure 3.4 Sentinel Node Positivity and Breslow thickness

1 Clinical Outcomes
2 From one moderate quality randomised trial (Morton et al, 2014) comparing sentinel node biopsy
3 with nodal observation in a total of 1661 patients, disease free survival in patients with intermediate
4 thickness melanoma was significantly higher in the biopsy group (HR 0.75 95% CI 0.62-0.94;
5 p=0.001)but there was no significant difference in 10 year melanoma specific survival.
7 with nodal observation in a total of 1661 patients, disease free survival in patients with thick
8 melanoma was significantly higher in the biopsy group (HR 0.7 95% CI 0.5-0.96; p=0.003) and no
9 significant difference was observed between the groups for 10 year melanoma specific survival
11 with nodal observation in a total of 1661 patients, in patients with no nodal metastases (no tumour
12 on biopsy or during clinical observation), no treatment related difference in 10 year melanoma
13 specific survival rates was observed between patients in the biopsy group compared with the
14 observation group for either intermediate or thick melanomas.
15 From one systematic review and meta-analysis (Freeman et al, 2013), pooled results from six studies
16 showed that in patients with tumours ≥4mm, SLN positive patients were more likely to die compared
17 with SLN negative patients (HR=2.42, 95% CI 2.00-2.92).
18 From one low quality, retrospective case series study including 1,000 patients (Voit et al, 2014), 5
19 year Kaplan-Meier estimated melanoma specific survival was 95% for patients with a negative US-
20 FNAC compared with 59% for patients with a postive US-FNAC (p<0.001) and the 5 year Kaplan-
21 Meier estimated disease free survival was 84% for patients with a negative US-FNAC compared with
22 33% for patients with a postive US-FNAC (p<0.001).
23 From one low quality, retrospective case series study including 1,000 patients (Voit et al, 2014), 5
24 year Kaplan-Meier estimated melanoma specific survival per SN tumour burden was 96% for SN
25 negative patients versus 100% for patients with metastases <0.1mm in diameter. 5 year Kaplan-
26 Meier estimated melanoma specific survival for patients with metastases 0.1-1.0mm was 73%
27 (p<0.001). 5 year Kaplan-Meier estimated melanoma specific survival for patients with lesions
28 >1.0mm was 68% (p<0.001), 57% (p<0.001) for patients with a lymph node dissection or unknown
29 SN tumour burden.
30 Corresponding disease free survival estimates were 87% for SN negative patients compared with
31 83% for patients with <0.1mm lesions (p=0.45) versus 49% in patients with lesions 0.1-1.0mm
32 (p<0.001) versus 37% for patients with lesions >1.0mm (p<0.001) versus 33% for LND or unknown SN
33 tumour burden patients (p<0.001).
34 From one high quality randomised trial (Faries et al, 2010) lymphoedema was significantly more
35 common in the delayed CLND group (20.4% vs. 12.4%, p=0.04) lymphoedema was strongly
36 associated with basin site with 9% oedema after axillary dissection and 26.6% oedema after inguinal
37 dissection (p<0.001).

1 Complications related directly to surgery occureed in 62/309 nodal basins and were strongly
2 associated with location of melanoma in the extremities (p=0.0002), specifically sentinel node
3 retrieval from the groin (p=0.001)
4 One retrospective case series study including 250 patients (Wasserberg et al, 2004) reported wound
5 complications in 42/309 basins. Independent factors significantly associated with wound infection
6 included inguinal SLNB (p=0.001) and primary lesion in the extremity (p=0.02)
7 One retrospective case series study including 250 patients (Wasserberg et al, 2004) reported nerve
8 related complications in 14 basins. Age younger than 50 years (p=0.003), axillary site (p=0.04) and
9 number of excised sentinel nodes (>2) (p=0.02) were found to be independent prognostic indicators
10 of sensory/mobility complications.

1 GRADE Table 3.1: What is the most effective method of accurately staging melanoma in patients with clinicopathological stage I-IV melanoma?
Quality assessment Summary of findings

No of patients Effect Quality
No of studies Design Limitations Inconsistency Indirectness Imprecision Other Positive Sentinel Node Negative Sentinel Relative Absolute
considerations Biopsy Node Biopsy (95% CI)
Overall Survival (Freeman et al, 2013)
6 observational serious1 no serious no serious no serious none ?/3935 ?/5435 HR 2.42 (2.00 to 2.92) Very Low
(n=936 breslow depth studies inconsistency3 indirectness imprecision
≥4mm)
No of studies Design Limitations Inconsistency Indirectness Imprecision Other Wide excision of Wide excision plus Relative Absolute Quality
considerations primary melanoma plus post-operative (95% CI)
sentinel-node biopsy nodal observation
with immediate with
lymphadenectomy if lymphadanectomy
metastases were if nodal
detected metastases
developed during
observation
Disease Free Survival (Morton et al, 2014)
1(n=1661) randomised Serious2 no serious no serious no serious none Disease free survival was Intermediate Moderate
trials inconsistency indirectness imprecision significantly higher in thickness HR 0.75
the biopsy group for 95% CI 0.62-0.94
both intermediate
thickness and thick
melanomas Thick melanoma HR
0.7 95% CI 0.5-0.96
No of studies Design Limitations Inconsistency Indirectness Imprecision Other Ultrasound ± FNAC Ultrasound ± Relative Absolute Quality
considerations FNAC + SLNB (95% CI)
Disease Free Survival (Voit et al 2014)

1(n=1000) Observational Serious4 No Inconsistency No Indirectness No Imprecision None 5 year Kaplan-Meier Low
Study estimated disease
free survival was 84%
for patients with a
negative US-FNAC
compared with 33%
for patients with a
postive US-FNAC
No of studies Design Limitations Inconsistency Indirectness Imprecision Other Ultrasound ± FNAC Ultrasound ± Relative Absolute Quality
considerations FNAC + SLNB (95% CI)
Melanoma Specific Survival (Voit et al 2014)
1 (n=1000) Observational Serious4 No Inconsistency No Indirectness No Imprecision None 5 year Kaplan-Meier Low
Study estimated melanoma
specific survival was
95% for patients with
a negative US-FNAC
compared with 59%
for patients with a
postive US-FNAC
No of studies Design Limitations Inconsistency Indirectness Imprecision Other Wide local excision + Wide local Relative Absolute Quality
considerations SLNB + CLND excision + (95% CI)
delayed CLND
Adverse Events (Acute Toxicity) (Faries et al (2010)
1(n=255) RCT None No Inconsistency No Indirectness No Imprecision None lymphoedema was significantly more common - High
in the delayed CLND group (20.4% vs. 12.4%,
p=0.04) lymphoedema was strongly associated
with basin site
No of studies Design Limitations Inconsistency Indirectness Imprecision Other SLNB None Relative Absolute Quality
considerations (95% CI)
Adverse Events (wound/sensory complications) (Wasserberg et al, 2004)

1(n=250) Observational Serious4 No Inconsistency No Indirectness No Imprecision None wound complications reported in 42/309 - Low
Study basins.
nerve related complications reported in 14
basins.
1 1
This was a systematic review and meta-analysis which included 29 cohort studies of which it was possible to include 6 studies in a meta-analysis. 2The was a risk of bias due to selective outcome reporting (the
2 results for the group of patients with thin melanomas were not reported). 3No serious heterogeneity (I2=34%) 4 Retrospective Case Series study 5The study does not report the number of events in each of the groups
3 just the pooled HR for the six studies which indicates that survival is better in the patients with a negative SLNB.
4

1 Children and Adolescents
2 From one retrospective study including 55 patients aged <20 years with stage I-II cutaneous
3 melanoma (Howman-Giles et al; 2009) the SLNB positivity rate was 25% (14/55) and children aged
4 <10 years had a higher SLNB positivity rate than those aged ≥10 years (33% versus 17%)
5 From one retrospective study including 55 patients aged <20 years with stage I-II cutaneous
6 melanoma (Howman-Giles et al; 2009) overall survival was 94.1% for the total population and in the
7 SLNB positive patients overall survival was 79%.
8 From one retrospective study (Toro et al; 2003) including 12 patients aged <18 years with clinically
9 node negative melanoma no complications were reported as a result of SLNB.
10 GRADE Table 3.2: Should Sentinel lymph node biopsy be used for staging of melanoma in children
11 and adolescents?
Quality assessment
No of Design Limitations Inconsistency Indirectness Imprecision Other Quality
studies considerations
Overall Survival
5 observational very no serious no serious serious2 none VERY
1
studies serious inconsistency indirectness LOW
Disease Free Survival

studies serious1 inconsistency indirectness LOW
Adverse Events
studies serious1 inconsistency indirectness LOW
12 1
All studies were retrospective case series studies with very small sample sizes
13 2
Small sample sizes in all of the studies

1 References
2 Included
3 Brent-Roaten et al (2005) Sentinel Lymph Node Biopsy for Melanoma and Other Melanocytic
4 Tumours in Adolescents Journal of Paediatric Surgery 40:232-235
5 Butter et al (2005) Melanoma in Children and the use of sentinel lymph node biopsy Journal of
6 Paediatric Surgery 40:797-800
7 Faries et al (2010) The impact on morbidity and length of stay of early versus delayed complete
8 lymphadenectomy in melanoma: results of the multicentre selective lymphadenectomy trial (I)
9 Annals of Surgical Oncology 17:3324-3329
10 Freeman et al (2013) Prognostic Value of Sentinel Lymph Node Biopsy Compared with that of
11 Breslow Thickness: Implications for Informed Consent in Patients with Invasive Melanoma
12 Dermatologic Surgery 39;12
13 Hafner J et al (2004) Clinical and Laboratory Investigations Baseline Staging in Cutaneous Melanoma
14 British Journal of Dermatology 150;677-686
15 Hall B et al (2013) Fine Needle Aspiration Cytology for the Diagnosis of Metastatic Melanoma
16 American Journal of Clinical Pathology 140;635-642
17 Han D et al (2013) Clinicopathological predictors of sentinel lymph node metastasis in thin

18 melanoma Journal of Clinical Oncology 31;35:4387-4393
19 Hocevar M et al (2004) The Role of preoperative ultrasonography in reducing the numberof sentinel
20 lymph node procedures in melanoma Melanoma Research 14;533-536
21 Howman-Giles et al (2010) Sentinel Lymph Node Biopsy in Paediatric and Adolescent Cutaneous
22 Melanoma Patients Annals of Surgical Oncology 17:138-143
23 Jimenez-Requena F et al (2010) Meta-analysis of the performance of 18F-FDG PET in cutaneous

24 melanoma European Journal of Nuclear and Molecular Imaging 37:284-300
25 Klein M et al (2000) Contribution of Whole Body F-18-FDG-PET and lymphoscintigraphy to the

26 Assessment of Regional and Distant Metastases in Cutaneous Malignant Melanoma Nuklearmedizin
27 39;3:56-61
28 Krug B et al (2008) Role of PET in the initial staging of cutaneous malignant melanoma: systematic
29 review Radiology 249;3:836-844
30 Lens M et al (2002) Tumour thickness as a predictor of occult lymph node metastases in patients
31 with stage I and II melanoma undergoing sentinel lymph node biopsy British Journal of Surgery
32 Maubec E et al (2007) F-18 fluorodeoxy D glucose positron emission tomography scan in the initial
33 evaluation of patientswith a primary melanoma thicker than 4mm Melanoma Research 17;3:147-154
34 Mijnhout S et al (2001) Systematic Review of the Diagnostic Accuracy of 18F-Fluorodeoxyglucose

35 Positron Emission Tomography in Melanoma Patients Cancer 91;8:1530-1542
36 Morton et al (2014) Final trial report of sentinel node biopsy versus nodal observation in melanoma
37 New England Journal of Medicine 370;7:599-609

1 Pacella et al (2003) The Utility of Sentinel Lymph Node Biopsy in Head and Neck Melanoma in the
2 Paediatric Population Plast. Reconstr. Surg 112;1257
3 Paquet P et al (2000) An Appraisal of 18-Fluorodeoxyglucose Positron Emission Tomography for

4 Melanoma Staging Dermatology 200;167-169
5 Raval et al (2010) Use of Sentinel Lymph Node Biopsy for Melanoma in Children and Adolescents
6 Journal of Surgical Oncology 102:634-639
7 Roaten et al (2005) Sentinel Lymph node biopsy for melanoma and other melanocytic tumours in
8 adolescents Journal of Paediatric Surgery 40;232-235
9 Reindhardt M. J. Et al (2002) Value of tumour marker S-100B in Melanoma Patients: A Comparison to

10 18-FDG-PET and clinical data Nuklearmedizin 41;3:143-147
11 Rodriguez-Rivera A et al (2014) Value of positron emission tomography scan in stage III cutaneous
12 melanoma: a systematic review and meta-analysis Surgical Oncology 23;11-16
13 Sibon C et al (2007) The contribution of high resolution ultrasonography in preoperatively detecting

14 sentinel node metastases in melanoma patients Melanoma Research 17;4:233-238
15 Starrit E et al (2005) Ultrasound examination of sentinel nodes in the initial assessment of patients
16 with primary cutaneous melanoma Annals of Surgical Oncology 12;1:18-23
17 Testori A et al (2005) The Role of Ultrasound of Sentinel Nodes in the Pre and Post Operative
18 evaluation of stage I melanoma patients Melanoma Research 15;3:191-198
19 Toro J et al (2003) Sentinel Lymph node biopsy in children and adolescents with malignant
20 melanoma Journal of Paediatric Surgery 38;7:1063-1065
21 Valsecchi M et al (2011) Lymphatic Mapping and Sentinel Lymph Node Biopsy in Patients with
22 Melanoma: A Meta-analysis Journal of Oncology 29;11:1479-1487
23 Voit C et al (2014) Ultrasound guided fine needle aspiration cytology as an addendum to sentinel
24 lymph node biopsy can perfect the staging strategy in melanoma patients European Journal of
25 Cancer 50;2880-2288
26 Wasserberg et al (2004) Sentinel Lymph Node Biopsy (SLNB) for Melanoma is not Complication Free
27 European Journal of Surgical Oncology 30;851-856
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29 Melanoma Patients: A Meta-Analysis Journal of the National Cancer Institute 103;129-142
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31 Melanoma Cancer 110;5:1107-1114
32

Evidence Tables
Study Study Study Populati Stage Subgroup Total Modalit Ref. Unit of Total True False False True
Design Quality on Range Analysis Numb y Standard Analysis Number Positive Positiv Nega Negati
included er of of units e tive ve
Patien
ts
Acland Retrospe High Stage I-III Stage I 54 PET Positive Scans 62 18 5 5 34

et al ctive (taken (<1.5mm/≥1.5mm Histology/
(2000) from /Total); Stage II Disease
(2x2 Jimenez- (Recurrence&sate Progressio
taken Requena llites); Stage III n
from et al, and Stage IV
Jimenez- 2010)
Requena
et al,
2010)
Acland Retrospe High Stage I-IV Melanoma 54 PET Histology Scans 62 18 5 5 34

et al ctive metastases and clinical
(2000) (taken follow-up
(taken from mean 25
from Jimenez- months
Jimenez- Requena (range 22-
Requena et al, 47 months)
et al, 2010)
2010)
Acland Prospecti High >1mm Stage IB- 50 PET Sentinel Patients 50 0 7 8 35

et al ve (taken thick or IIIC node
(2001) from lymphati biopsy and
(2x2 Krug et c clinical

Patien
ts
taken al, 2008) invasion follow-up

from of up to 13
Krug et months
al, 2008) (range 5-26
months)
Agnese Retrospe Moderat Regional Lymph 755 SLNB Histology 739 112 0 30 597
et al ctive e Nodes
(2007)
(taken
(2x2 from
taken Valsecchi
from et al,
Valsecch 2011)
i et al,
2011)
Aukema Retrospe Moderat T1-4N1- 70 PET Biopsy, Scans 70 26 1 4 39

et al ctive e (taken 3M0 clinical
(2010) from follow-up,
Rodrigue further
(2x2 z-Rivera imaging
taken et al,
from 2014)
Rodrigue
z-Rivera

Patien
ts
et al,
2014))
Bachter Retrospe Low Regional Lymph 256 SLNB Histology 253 41 0 1 211
et al ctive Nodes
(2001) (taken
from
(2x2 Valsecchi
taken et al,
from 2011)
Valsecch
i et al,
2011)
Basler et Retrospe Moderat Regional Lymph FNAC Histology/F 24 0 0 26

al (1997) ctive e (taken Nodes ollow-up
(2x2 from Hall
taken et al,
from 2013)
Hall et
al, 2013)
Bastiaan Prospecti Moderat T1-4N1- 253 PET Biopsy, Scans 253 68 12 11 162
net et al ve e 3M0 clinical
(2011) follow-up,
(2x2 (taken further
from

Patien
ts
taken Rodrigue imaging

from z-Rivera
Rodrigue et al,
z-Rivera 2014))
et al,
2014)
Belhocin Prospecti High Early Stage I-II 21 PET Sentinel Patients 21 1 1 5 14

e et al ve (taken stage node
(2002) from melano biopsy and
(2x2 Krug et ma clinical
taken al, 2008) follow-up
from 12 months
Krug et
al, 2008)
Berk et Retrospe Moderat Regional Lymph 274 SLNB Histology 260 39 0 10 211
al (2005) ctive e Nodes
(2x2 (taken
taken from
from Valsecchi
Valsecch et al,
i et al, 2011)
2011)

Patien
ts
Blessing Retrospe Moderat Stage III Regional Lymph 19 PET Histopathol 28 3 10 42

et al ctive e (taken Nodes ogy or
(1995) from follow-up
(2x2 Krug et
taken al, 2008)
from
Krug et
al, 2008)
Blessing Retrospe Moderat Stage III Regional Lymph 19 Ultraso Histopathol 29 3 9 42

et al ctive e (taken Nodes und ogy or
(1995) from follow-up
(2x2 Krug et
taken al, 2008)
from
Krug et
al, 2008)
Blument Retrospe Moderat Stage IB- Stage IB-II Regional Lymph 60 SLNB Histology 60 11 0 0 49
hal et al ctive e II Nodes
(2002)
(taken
(2x2 from
taken Valsecchi
from et al,
Valsecch

Patien
ts
i et al, 2011)
2011)
Borgogo Retrospe Moderat Regional Lymph 385 SLNB Histology 375 75 0 8 292
ni et al ctive e Nodes
(2004)
(taken
(2x2 from
taken Valsecchi
from et al,
Valsecch 2011)
i et al,
2011)
Brady et Prospecti Low Stage IIC- 103 CT Patients 103 30 5 14 54

al (2006) ve IV
(2x2 (Taken
taken from
from Krug et
Krug et al, 2008)
al, 2008)
Cangiare Retrospe Moderat Clinically Regional Lymph 115 FNAC Histology/F Lymph 133 95 0 2 33
lla et al ctive e (taken suspicio Nodes ollow-up Nodes
(2000) from Hall us lymph
(2x2 et al, nodes

Patien
ts
taken 2013)
from
Hall et
al, 2013)
Caraco Retrospe Moderat Regional Lymph 331 SLNB Histology 325 68 0 13 244
et al ctive e Nodes
(2004)
(taken
(2x2 from
taken Valsecchi
from et al,
Valsecch 2011)
i et al,
2011)
Cascinell Retrospe High Regional Lymph 1108 SLNB Histology 1108 176 0 47 885
i et al ctive Nodes
(2006) (taken
from
(2x2 Valsecchi
taken et al,
from 2011)
Valsecch
i et al,
201)

Patien
ts
Cascinell Retrospe Moderat Stage IB- Stage IB-II Regional Lymph 829 SLNB Histology 730 141 0 40 549
i et al ctive e II Nodes
(2000)
(taken
(2x2 from
taken Valsecchi
from et al,
Valsecch 2011)
i et al,
2011)
Cecchi et Retrospe Moderat Regional Lymph 111 SLNB Histology 111 17 0 3 91

(2x2 (taken
taken from
from Valsecchi
Valsecch et al,
i et al, 2011)
2011)
Chakera Retrospe Moderat Regional Lymph 243 SLNB Histology 236 53 0 3 180
et al ctive e Nodes
(2004)
(taken
(2x2 from
taken Valsecchi

Patien
ts
from et al,
Valsecch 2011)
i et al,
2011)
Chao et Retrospe Moderat Regional Lymph 1183 SLNB Histology 1183 233 0 11 939
(2x2 (taken
taken from
from Valsecchi
Valsecch et al,
i et al, 2011)
2011)
Clark et Retrospe Moderat T2-T4 Stage IB- 64 PET Patients 64 2 2 15 45

al (2006) ctive e melano Stage IIIC
(2x2 ma
taken (taken
from from
Krug et Krug et
al, 2008) al, 2008)
Corrigan Retrospe Moderat Regional Lymph 149 SLNB Histology 131 46 0 8 77

et al ctive e Nodes
(2006)
(taken

Patien
ts
(2x2 from
taken Valsecchi
from et al,
Valsecch 2011)
i et al,
2011)
Crippa et Prospecti Moderat Clinical/I Stage IIB- 38 PET Lymph Regional 56 35 3 2 16

al (2000) ve e (taken nstrume IIIC node Lymph
(2x2 from nt dissection Nodes
taken Crippa et detected plus
from al, 2008) lymph histology
Krug et node
al, 2008) metastas
es
Dalal et Retrospe Moderat Regional Lymph 1046 SLNB Histology 1046 164 0 28 854
(2x2 (taken
taken from
from Valsecchi
Valsecch et al,
i et al, 2011)
2011)

Patien
ts
Dalle et Retrospe Moderat Regional Lymph FNAC Histology/F 56 2 1 49

(2x2 from Hall
taken et al,
from 2013)
Hall et
al, 2013)
Damian Retrospe Moderat Stage II- Stage II- Recurrent disease 100 PET Clinical metastas 415 388 28
et al ctive e (taken IV IV exam, es
(1997) from scans
Jimenez- and/or
(2x2 Requena histopathol
taken et al, ogy
from 2010)
Jimenez-
Requena
et al,
2010)
De Retrospe Moderat Regional Lymph 104 SLNB Histology 104 0 6 98

Giorgi et ctive e Nodes
al (2007)
(taken
(2x2 from
taken Valsecchi

Patien
ts
from et al,
Valsecch 2011)
i et al,
2011)
Doting Retrospe Moderat Stage I-II Stage I-II Regional Lymph 200 SLNB Histology 197 48 0 2 147
et al ctive e Nodes
(2002)
(taken
(2x2 from
taken Valsecchi
from et al,
Valsecch 2011)
i et al,
2011)
Eigtved Prospecti Moderat Stage I-II 38 PET Histopathol Patients 38 28 4 1 5

et al ve e(taken ogy and
(2000) from clinical
(2x2 Krug et follow-up
taken al, 2008)
from
Krug et
al, 2008)

Patien
ts
Estourgi Prospecti Moderat Regional Lymph 250 SLNB Histology 250 60 0 7 183
e et al ve e Nodes
(2003)
(taken
(2x2 from
taken Valsecchi
from et al,
Valsecch 2011)
i et al,
2011)
Fincher Retrospe Moderat All Regional Lymph 198 SLNB Histology 198 38 0 1 159
et al ctive e stages Nodes
(2003)
(taken
(2x2 from
taken Valsecchi
from et al,
Valsecch 2011)
i et al,
2011)
Fink et al Prospecti High >1mm Stage IB- 48 PET Sentinel Patients 48 1 0 7 40

(2004) ve (taken thick IIC node
(2x2 from with no biopsy and
taken Jimenez- palpable clinical

Patien
ts
from Requena lymph follow up

Krug et et al, nodes 12 months
al, 2008) 2010)
Finkelste Prospecti High Stage IV Stage IV Melanoma 18 PET Histopathol Lesions 94 38 6 10 40

in et al ve (taken metastasis/Recurr ogy and
(2004) from ent Disease clinical
(2x2 Krug et follow-up
taken al, 2008) (median 24
from months)
Krug et
al, 2008)
Gad et al Retrospe Moderat Regional Lymph 278 SLNB Histology 273 79 0 4 190
(2006) ctive e Nodes
(2x2 (taken
taken from
from Valsecchi
Valsecch et al,
i et al, 2011)
2011)
Gershen Retrospe Moderat Primary Regional Lymph 317 SLNB Histology 295 52 0 7 236
wald et ctive e cutaneo Nodes
al (1998) us
(taken

Patien
ts
(2x2 from melano

taken Valsecchi ma
from et al,
Valsecch 2011)
i et al,
2011)
Gipponi Retrospe Moderat Regional Lymph 175 SLNB Histology 169 38 0 6 125
et al ctive e Nodes
(2005)
(taken
(2x2 from
taken Valsecchi
from et al,
Valsecch 2011)
i et al,
2011)
Gomez- Retrospe Moderat Regional Lymph 113 SLNB Histology 113 23 0 5 85

Rivera et ctive e Nodes
al (2008)
(taken
(2x2 from
taken Valsecchi
from et al,
Valsecch 2011)

Patien
ts
i et al,
2011)
Hafner Prospecti High All Stage II-III Regional Lymph 100 PET Histopathol 101 2 0 24 74
et al ve (taken patients Nodes ogy and
(2004) from with clinical
Jimenez- melano follow-up 6
Requena ma and 12
et al, months
2010)
Hafner Prospecti High All Stage II- Regional Lymph 100 Ultraso Sentinel 101 2 9 24 62
et al ve (taken patients IV Nodes und node
(2004) from with biopsy and
Jimenez- melano clinical
Requena ma follow-up 6
et al, months
2010) and 12
months
Hafner Prospecti High All Stage II-III Regional Lymph 100 US/PET Histopathol 101 3 9 23 62
et al ve patients Nodes ogy and
(2004) with clinical
melano follow-up 6
ma and 12

Patien
ts
months
Hafstro Retrospe Moderat Regional Lymph FNAC Histology/F 45 2 3 37

m et al ctive e (taken Nodes ollow-up
(1980) from Hall
(2x2 et al,
taken 2013)
from
Hall et
al, 2013)
Harlow Retrospe Moderat Clinically Regional Lymph 336 SLNB Histology 329 39 0 12 278
et al ctive e node Nodes
(2001) negative
(taken melano
(2x2 from ma
taken Valsecchi
from et al,
Valsecch 2011)
i et al,
2011)
Havenga Prospecti Moderat >1mm Stage IB- 45 PET Regional 45 2 5 11 27

et al ve e (taken thick IIC Lymph
(2003) from with no Nodes
(2x2 Krug et palpable

Patien
ts
taken al, 2008) lymph

from nodes
Krug et
al, 2008)
Hershko Retrospe Moderat Regional Lymph 64 SLNB Histology 64 5 0 1 58

et al ctive e(taken Nodes
(2006) from
Valsecchi
(2x2 et al,
taken 2011)
from
Valsecch
i et al,
2011)
Hinz et Prospecti Low Any Stage I-IV 81 Ultraso 81 2 3 4 0

al (2011) ve cutaneo und
us
(2x2 melano
taken ma
from
original
publicati
on)

Patien
ts
Hocevar Retrospe Low Unclear Stages IA- Regional Lymph 57 Ultraso Histology Patients 57 10 7 4 36
et al ctive IIIA Nodes und
(2004)
(2x2
table
taken
from
original
publicati
on)
Horn et Retrospe Low- Cutaneo Stage III 33 PET Biopsy, Patients 33 4 5 1 23

al (2006) ctive Moderat us clinical
(2x2 e (taken melano follow-up,
taken from ma & further
from Rodrigue subclinic imaging
Rodrigue z-Rivera al lymph
z-Rivera et al, node
et al, 2014) metastas
2014) es
Kettlewe Prospecti Moderat Regional Lymph 482 SLNB 472 105 0 12 355
ll et al ve e Nodes
(2006)
(taken

Patien
ts
(2x2 from
taken Valsecchi
from et al,
Valsecch 2011)
i et al,
2011)
Klein et Prospecti Moderat Patients Stage I-II Regional Lymph 17 PET Sentinel Scans 20 2 0 1 17
al (2000) ve e (taken with Nodes node
from cutaneo biopsy and
(2x2 Jimenez- us clinical
table Requena melano follow-up
taken et al, ma of up to 22
from 2010) months
original
publicati
on)
Kokoska Prospecti >1mm Stage IB- 18 PET

et al ve thick IIA
(2001) with
clinically
negative
nodes

Patien
ts
Koskivuo Retrospe Moderat Regional Lymph 305 SLNB Histology 297 50 0 5 242
et al ctive e Nodes
(2007)
(taken
(2x2 from
taken Valsecchi
from et al,
Valsecch 2011)
i et al,
2011)
Landi et Retrospe Moderat Stage I-II Stage I-II Regional Lymph 455 SLNB Histology 450 75 0 4 371
(2x2 (taken
taken from
from Valsecchi
Valsecch et al,
i et al, 2011)
2011)
Longo et Prospecti Medium ≥1mm Stage IB- 25 PET Sentinel 2 7

al (2003) ve (taken IIIC node
from biopsy and
(taken Jimenez- clinical
from Requena follow-up
Jimenez-

Patien
ts
Requena et al, >10

et al, 2010) months
2010) (range 10-
29)
MacFarla Prospecti Moderat Stage II- Stage II-III Regional Lymph 23 PET Lymph Patients 22 10 1 2 9
ne et al ve e (taken III Nodes node
(1998) from dissection
(2x2 Jimenez- plus
Jimenez- Requena histology
Requena et al,
et al, 2010)
2010)
Macripo Prospecti Moderat Regional Lymph 274 SLNB Histology 270 46 0 10 214
et al ve e Nodes
(2004)
(taken
(2x2 from
taken Valsecchi
from et al,
Valsecch 2011)
i et al,
2011)

Patien
ts
Manca Retrospe Moderat Regional Lymph 127 SLNB Histology 127 21 0 6 100
et al ctive e Nodes
(2003)
(taken
(2x2 from
taken Valsecchi
from et al,
Valsecch 2011)
i et al,
2011)
Mattsso Retrospe Moderat Regional Lymph 422 SLNB Histology 409 79 0 12 318
n et al ctive e Nodes
(2008)
(taken
(2x2 from
taken Valsecchi
from et al,
Valsecch 2011)
i et al,
2011)
Maubec Prospecti >4mm Stage IIB- None 25 PET Patients 25 1 5 5 14

et al ve thick IV
(2007)

Patien
ts
Medina- Retrospe Moderat Regional Lymph 54 SLNB Histology 35 4 0 1 30

Franco ctive e Nodes
et al
(2001) (taken
from
(2x2 Valsecchi
taken et al,
from 2011)
Valsecch
i et al,
2011)
Moehrle Retrospe Moderat Regional Lymph 283 SLNB Histology 283 38 0 11 234
et al ctive e Nodes
(2004)
(taken
(2x2 from
taken Valsecchi
from et al,
Valsecch 2011)
i et al,
2011)
Morton Retrospe Moderat Regional Lymph 1599 SLNB Histology 1599 322 0 33 1244
et al ctive e Nodes
(2003)
(taken

Patien
ts
(2x2 from
taken Valsecchi
from et al,
Valsecch 2011)
i et al,
2011)
Morton Retrospe High Regional Lymph 769 SLNB Histology 764 122 0 26 616
et al ctive Nodes
(2006) (taken
from
(2x2 Valsecchi
taken et al,
from 2011)
Valsecch
i et al,
2011)
Murali et Retrospe Moderat Regional Lymph Image Histology/F 63 0 3 45

al (2007) ctive e (taken Nodes guided ollow-up
(2x2 from Hall FNAC
taken et al,
from 2013)
Hall et
al, 2013)

Patien
ts
Murali et Retrospe Moderat Regional Lymph Palpatio Histology/F 780 5 30 416

al (2007) ctive e (taken Nodes n ollow-up
(2x2 from Hall guided
taken et al, FNAC
from 2013)
Hall et
al, 2013)
Nowecki Retrospe Moderat Regional Lymph 1207 SLNB Histology 1207 228 0 57 922
et al ctive e Nodes
(2006)
(taken
(2x2 from
taken Valsecchi
from et al,
Valsecch 2011)
i et al,
2011)
Paquet Retrospe Low 24 PET Sentinel scans 28 8 2 3 15

et al ctive Node
(2000) biopsy and
clinical
(2x2 follow-up
table of 18
taken

Patien
ts
from months
original
publicati
on)
Perry et Retrospe Moderat Regional Lymph FNAC Histology/F 160 3 25 65

(2x2 from Hall
taken et al,
from 2013)
Hall et
al, 2013)
Pfannen Prospecti N/R Stage Stage 64 PET Lesions 420 209 20 88 103
berg et ve (missing III/IV III/IV
al (2007) from melano melanom
(2x2 supplem ma a
taken entary
from tables of
Krug et Krug et
al, 2008) al, 2008)
Pfannen Prospecti N/R Stage Stage 64 PET-CT Lesions 420 269 28 28 95

berg et ve (missing III/IV III/IV
al (2007) from melano melanom
(2x2 supplem

Patien
ts
taken entary ma a
from tables of
Krug et Krug et
al, 2008) al, 2008)
Pfluger Retrospe Low- T1-4N1- 50 PET Biopsy, Scans 232 151 6 0 75

et al ctive Moderat 3M0 clinical
(2011) e (taken follow-up
(2x2 from
taken Rodrigue
from z-Rivera
Rodrigue et al
z-Rivera (2014)
et al,
2014)
Reinhard Retrospe Medium >0.75m Regional Lymph 67 PET Clinical, Scans 67 60 2 0 5

t et al ctive m& Nodes/Distant convention
(2002) Clarks Metastases al images
level III- and/or
(2x2 IV biopsy.
table Clinical
taken follow-up
from ≥6 months
original
publicati

Patien
ts
on)
Rex et al Retrospe Moderat Regional Lymph 240 SLNB Histology 240 50 0 8 182
(2x2 (taken
taken from
from Valsecchi
Valsecch et al,
i et al, 2011)
2011)
Rodriguu Retrospe Moderat FNAC Histology/F 85 1 0 12

es et al ctive e (taken ollow-up
(2000) from Hall
(2x2 et al,
taken 2013)
from
Hall et
al, 2013)
Roka et Retrospe Moderat Regional Lymph 309 SLNB Histology 299 69 0 7 223
(2x2 (taken
taken from

Patien
ts
from Valsecchi
Valsecch et al,
i et al, 2011)
2011)
Rossi et Prospecti Low >1mm Stage IA- 125 Ultraso Regional 140 12 0 19 109
al (2003) ve thick IB und Lymph
cutaneo Nodes
(2x2 us
taken melano
from ma
original
publicati
on)
Roulin et Retrospe Moderat Regional Lymph 327 SLNB Histology 327 74 0 7 246
(2x2 (taken
taken from
from Valsecchi
Valsecch et al,
i et al, 2011)
2011)
Schmalb Retrospe Moderat Regional Lymph 80 SLNB Histology 77 14 0 3 60

ach et al

Patien
ts
(2x2 (taken
taken from
from Valsecchi
Valsecch et al,
i et al, 2011)
2011)
Schoege Retrospe Moderat Regional Lymph FNAC Histology/F 217 0 5 91

n et al ctive e (taken Nodes ollow-up
(1993) from Hall
(2x2 et al,
taken 2013)
from
Hall et
al, 2013)
Sibon et Prospecti Low ≤1mm Stage IA- 131 Ultraso Histology Regional 264 10 14 58 182
al (2007) ve thick or IB und Lymph
ulcerate Nodes
(2x2 d
taken cutaneo
from us
original melano
publicati

Patien
ts
on) ma
Starrit et Prospecti Low All All stages None 304 Ultraso Patients 31 5 0 26 0
al (2005) ve patients und with
with histologi
(2x2 melano cally
table ma confirme
from d
original metastas
publicati es
on)
Stewart Retrospe Moderat Regional Lymph 178 SLNB Histology 178 47 0 5 126
et al ctive e Nodes
(2005)
(taken
(2x2 from
taken Valsecchi
from et al,
Valsecch 2011)
i et al,
2011)
Teltzrow Retrospe Moderat Regional Lymph 106 SLNB Histology 94 17 0 8 69

et al ctive e Nodes
(2007)
(taken

Patien
ts
(2x2 from
taken Valsecchi
from et al,
Valsecch 2011)
i et al,
2011)
Testori Prospecti Stage I Regional Lymph 88 Ultraso Histology Regional 106 16 9 1 80

et al ve Nodes und Lymph
(2005) Nodes
(2x2
table
taken
from
original
publicati
on)
Testori Prospecti Moderat Regional Lymph 1313 SLNB 1304 220 0 36 1048
et al ve e Nodes
(2009)
(taken
(2x2 from
taken Valsecchi
from et al,

Patien
ts
Valsecch 2011)
i et al,
2011)
Tyler et Prospecti Moderat Clinically Stage III 95 PET Clinical, Lesions 234 144 39 21 30
al (2000) ve e (taken evident convention
(2x2 from stage III al images
taken Krug et lymph and/or
from al, 2008) node biopsy.
Krug et and/or Clinical
al, 2008) in transit follow-up
metastas ≥6 months
es
Van Retrospe Moderat Regional Lymph 262 SLNB Histology 256 77 0 6 173
Akkooi ctive e Nodes
et al
(2006) (taken
from
(2x2 Valsecchi
taken et al,
from 2011)
Valsecch
i et al,
2011)

Patien
ts
Veit- Prospecti Moderat Any Stage I-IV N-Stage 74 PET-CT 56 48 0 8

Haibach ve e cutaneo
et al us
(2009) melano
ma
(2x2
table
taken
from
original
publicati
on)
Veit- Prospecti Moderat Any Stage I-IV M-Stage 74 PET-CT 56 46 3 7

Haibach ve e cutaneo
et al us
(2009) melano
ma
(2x2
table
taken
from
original

Patien
ts
publicati
on)
Vereeck Prospecti High Interme 43 PET Sentinel Patients 39 4 25 6 4

en et al ve (taken diate/Po node
(2005) from or biopsy and
(2x2 Krug et prognosi clinical
taken al, 2008) s follow-up 6
from melano months
Krug et ma
al, 2008)
Vereeck Prospecti High Interme 43 PET Sentinel Lesions 63 4 39 6 14

en et al ve (taken diate/Po node
(2005) from or biopsy and
(2x2 Krug et prognosi clinical
taken al, 2008) s follow-up 6
from melano months
Krug et ma
al, 2008)
Vidal Retrospe Moderat Regional Lymph 435 SLNB 430 72 0 7 351

Sicart et ctive e Nodes
al (2003)
(taken
(2x2 from

Patien
ts
taken Valsecchi
from et al,
Valsecch 2011)
i et al,
2011)
Voit et al Retrospe Moderat Regional Lymph Image Histology/F 171 0 4 89

(2000) ctive e (taken Nodes guided ollow-up
(2x2 from Hall FNAC
taken et al,
from 2013)
Hall et
al, 2013)
Voit et al Retrospe Moderat Regional Lymph Palpatio Histology/F 319 0 1 115

(2000) ctive e (taken Nodes n ollow-up
(2x2 from Hall guided
taken et al, FNAC
from 2013)
Hall et
al, 2013)
Voit et al Prospecti Moderat >1mm Stage IB- 127 Ultraso Patients 121 27 24 7 63
(2006) ve e thick IV und
(2x2

Patien
ts
taken
from
original
publicati
on)
Vucetic Retrospe Moderat ) Regional Lymph 201 SLNB Histology 200 42 0 1 157
et al ctive e (taken Nodes
(2006) from
Valsecchi
(2x2 et al,
taken 2011
from
Valsecch
i et al,
2011)
Voit et al retrospec Stage I/II Stage I/II - 1000 Lympho Different Patient 1000 106 8 102 784
2014) tive melano scintagr reference
ma aphy- standards
(2x2 ≥1.0mm used
taken Breslow US- (histopatho
from thicknes FNAC logy and
original s cytopathol
publicati ogy)
on)

Patien
ts
Cytology (if
FNAC
positive) or
histopathol
ogy (SLNB)
Vuylstek Retrospe High Regional Lymph 209 SLNB Histology 209 40 0 4 165
e et al ctive Nodes
(2003) (taken
from
(2x2 Valsecchi
taken et al,
from 2011)
Valsecch
i et al,
2011)
Wagner Retrospe Moderat Regional Lymph 408 SLNB 408 85 0 4 319

et al ctive e Nodes
(2003)
(taken
(2x2 from
taken Valsecchi
from et al,
Valsecch 2011)
i et al,

Patien
ts
2011)
Wagner Prospecti Moderat >1mm Stage IB- Regional Lymph 144 PET Sentinel Regional 184 9 4 34 137
et al ve e (taken thick IIC Node node Lymph
(2005) from early biopsy and Nodes
(2x2 Krug et stage clinical
taken al, 2008) melano follow-up ≥
from ma 6 months
Krug et
al, 2008)
Wagner Prospecti Moderat Stage I-II Stage IB- Melanoma 136 PET Clinical , 184 9 4 34 137
et al ve e (taken IIC metastases convention
(2005) from al images
(2x2 Krug et and/or
taken al, 2008) biopsy
from
Krug et
al, 2008)
Wagner Prospecti Moderat Stage I- Stage IB- Recurrent disease 136 PET Clinical 184 9 4 34 137
et al ve e (taken III IIC follow-up
(2005) from median
(2x2 Krug et 41.4
taken al, 2008) months
from

Patien
ts
Krug et
al, 2008)
Wagner Retrospe Low- T1-4N1- 46 PET Biopsy, Scans 46 0 6 5 35

et al ctive Moderat 3M0 clinical
(2011) e (taken follow-up,
(2x2 from further
taken Rodrigue imaging
from z-Rivera
Rodrigue et al,
z-Rivera 2014)
et al,
2014)
Wagner Retrospe Low- Histologi Stage I-IV None 46 PET-CT Biopsy, Distant 46 0 6 5 35
et al ctive Moderat cally clinical Metastas
(2011) e (taken proven follow-up, es
(2x2 from melano further
taken Rodrigue ma with imaging
from z-Rivera metastat
Rodrigue et al, ic
z-Rivera 2014 involvem
et al, ent of
2014) the
sentinel
lymph

Patien
ts
node
and
clinically
exempt
of
metastas
es
Wasserb Retrospe High Regional Lymph 250 SLNB Histology 236 26 0 6 204
erg et al ctive Nodes
(2004) (taken
from
(2x2 Valsecchi
taken et al,
from 2011)
Valsecch
i et al,
2011)
Yancovit Retrospe Low Stage Stage IB- 158 PET-CT Scans 344 1 41 0 328
z et al ctive T1b-3b, IIB
(2007) clinically
node
(2x2 negative
taken and no
from distant

Patien
ts
original metastas
publicati is
on)
Yee et al Retrospe Moderat Regional Lymph 1012 SLNB Histology 991 145 0 22 824
(2x2 (taken
taken from
from Valsecchi
Valsecch et al,
i et al, 2011)
2011)
Zeelen Retrospe Moderat Regional Lymph FNAC Histology/F 76 0 5 42

et al ctive e (taken Nodes ollow-up
(1990) from Hall
(2x2 et al,
taken 2013)
from
Hall et
al, 2013)
Notes:

Jimenez-Requena et al (2010) assessed study quality using a modified version of previously developed criteria which evaluated criteria across 7 dimensions
including, description of study design, description of study population, indications leading to FDG-PET use, technical and image interpretation issues, final
confirmation, sensitivity & specificity data and change in management information.
Valsecchi et al (2011): Quality assessment using Methodological Index for Non-randomised Studies criteria which quantifies study quality on eight items up
to a score of 16 points (0-4 Very Low; 4.5-8 Low; 8.5-12 Moderate; 12.5-16 High)
Hall et al (2013): Study quality assessed using QUADAS-2 checklist

Clinical Outcomes
Systematic Reviews
Study Clearly Includes studies Rigorous Study quality Adequate Quality (GRADE)
focused relevant to literature assessed? description of
Question? review question? search? methodology?
Freeman et al Yes Yes Yes Yes Yes Very Low (due to the
(2013) individual studies all
being cohort studies
and only 6 of the 29
studies included in the
meta-analysis
Randomised Trials
Study Appropriate Appropriat Comparabl Comparabl Patient Treatment Equal Equal Appropria Precise Valid Investiga Quality
Randomisati e e groups e Care Blindin Administra Follow- Treatment te follow- definition method of tor (GRADE)
on Concealme at baseline apart from g tor up Completio up length of measuring blinding
on follow up
Faries Yes Yes Yes Yes N/A N/A Yes No Yes Yes Yes Unclear High
et al
(2010
)
Mort Yes Yes Yes Yes N/A N/A Yes No Yes Yes Yes Unclear Moderate
on et
al

(2014
)
Cohort Studies
Study Appropriate Precise definition Valid method of Investigators blind Investigators blind to Quality
length of follow- of an outcome measuring to participants potential confounders and (GRADE)
up outcomes exposure to prognostic factors?
intervention?
Wasserberg et al Yes Yes Unclear No No Very Low

(2004)
Voit et al (2014) Yes Yes Yes No No Low
Children and Adolescents
intervention?
Butter et al (2005) No Yes No No Unclear Very Low
Howman-Giles et Yes Yes No No Unclear Very Low

al (2009)
Pacella et al No Yes No No Unclear Very Low

(2003)

intervention?
Roaten et al Yes Yes No No Unclear Very Low

(2005)
Toro et al (2003) No Yes No No Unclear Very Low

Clinical Outcomes
Study Study Aim Population Intervention Comparison Outcomes

Type/Setting
Faries et al Prospective To investigate whether early N=225 patients who underwent wide Wide local Wide local Acute Toxicity including: Wound
(2010) Cohort lymph node dissection was local excioson with SLNB and early excision + excision + separation, seroma/hematoma,
(following up associated with less complete lymph node dissection SLNB + CLND delayed CLND haemorrhage, infection,
one arm of a morbidity than delayed thrombophlebitis, urinary tract
randomised dissection at the time of infection, pneumonia and cardiac
trial) clinical recurrence complications
Mean Age was 50 years
Chronic Toxicity including

N=143 patients who underwent wide
lymphoedema and nerve
local excision alone and delayed
dysfunction
complete lymph node dissection.
Median Follow up was 5.1 years in

Mean Age was 54.4 years
the early CLND group and 4.9 years
in the delayed CLND group.
Regional and systemic toxicities

were similar between the two
groups.
Systemic Toxicity


Type/Setting
Low systemic toxicity was reported

in both groups (1 urinary tract
infection, 1 pneumonia, 1 cardiac
complication and 1 case of
thrombophlebitis.
Dysesthesia was reported more in

the early CLND group (5.2% vs.
2.3%) but the difference was not
statistically significant.
Lymphoedema was significantly

more common in the delayed CLND
group (20.4% vs. 12.4%, p=0.04)
and the difference remained
significant when severity was taken
into account p=0.03).
Lymphoedema was strongly

associated with basin site with 9%
oedema after axillary dissection
and 26.6% oedema after inguinal
dissection (p<0.001).


Type/Setting
There was no indication that the

benefit to early CLND in
lymphoedema was limited to either
the axillary or the inguinal basin.
Patients with lymphoedema had a

higher BMI than those without
though the difference was not
statistically significant (27.7% vs.
26.7% p=0.21).
The risk of lymphoedema was

greater in obese patients
compared with non-obese patients
though the difference was not
statistically significant (20% vs.
13.9%, p=0.21).
No difference was observed in the

mean number of nodes evaluated
in patients with lymphoedema
compared with patients without
lymphoedema for either axilla
(mean oedema 19.6, no oedema


Type/Setting
21.2 p=0.61) or for inguinal (mean:

oedema 14.9, no oedema 14.2
p=0.36) basin.
Multivariate analysis identified

basin site (groin versus other) as
the most powerful factor (OR 3.64,
95% CI 1.93-6.86, p<0.001) and
delayed CLND (OR=1.74, 95% CI
0.93-3.25, p=0.083) showed trends
toward and independent adverse
effect on oedema risk.
Length of hospital stay varied

between continents. Mean length
of stay was 2.8 days in the USA,
10.6 days in Europe and 9.5 days in
Australia.
Mean stay for the early CLND was

8.3 days and for delayed CLND was


Type/Setting
9.9 days (p=0.021).
Length of stay was longer for

patients undergoing groin
dissection if the deep basin was
dissected (13.9 days versus 10.2
days, p=0.009).
For patients undergoing superficial
Dissection, length of stay was

longer in the delayed group (9.8
days versus 12.3 days, p=0.48).
Length of stay was directly related

to age but after adjusting for age,
the relationship with timing of
dissection remained significant
(p=0.038).
Freeman et Systematic To determine whether SLN Articles which evaluated the risk of Positive Negative Overall Survival
al (2013) review and status provides significant overall survival and mortality Sentinel Sentinel
Meta-analysis prognostic information in according to SLN statis in patients with Lymph Node Lymph Node
addition to Breslow melanoma. Biopsy Biopsy


Type/Setting
thickness alone All included studies were cohort

studies.
Studies conducted before 1992 were
only used if they included patients
treated after 1992.
A total of 29 studies were included.
4 were rated low quality
Average patient age ranged from 47- 17 were rated moderate quality
70.6 years.
8 were rated high quality
Follow-up ranged from 15-77 months

In patients with thin melanoma
(<1mm) results of the sign test
showed no significant survival
advantage for SLN negative
patients over SLN positive patients
(p>0.99).
In patients with melanomas 1-2mm

thick ) results of the sign test
showed no significant survival
advantage for SLN negative
(p=0.62)


Type/Setting
In patients with melanomas 2-4mm

) results of the sign test showed no
survival advantage for SLN negative
(p=0.25)
In patients with melanoma greater

than 4mm there was a significant
survival advantage for SLN negative
(p=0.004).
Pooled results from six studies

showed that in patients with a
tumour depth ≥4mm, SLN positive
patients were more likely to die
compared with SLN negative
patients (HR=2.42, 95% CI 2.00-
2.92).
Morton et Multicentre To determine whether Intervention Arm N=1000 Wide excision Wide excision Primary Outcomes
al (2014) Randomised sentinel-node biopsy could of primary plus post-
Control Trial be used to identify patients melanoma operative Melanoma specific survival
with clinically occult nodal plus sentinel- nodal


Type/Setting
metastases and whether Control Arm N=661 node biopsy observation

immediate-completion (60%) with (40%) with
lymphadenectomy yielded immediate lymphadenect Secondary Outcomes
better outcomes than lymphadenect omy if nodal
Inclusion Disease free survival
complete lymphadenectomy omy if metastases
performed only when nodal Patients between 18-75 years with metastases developed Incidence
recurrence was revealed invasive melanoma with Clark Level III were detected during
during observation and Breslow Thickness ≥1.00mm or observation Timing
Clark level IV or V with any Breslow
Anatomic distribution of distant
thickness (confirmed by pathology)
metastases
Primary cutaneous melanoma (head,
Morbidity of procedures
neck, trunk, extremity, scalp, palm of
hand, sole of foot or subungal skin Significance of TA90 levels
Biopsy completed no more than 10 Incidence of Sentinel Node

weeks before initial clinic visit and Metastases (biopsy) vs. Clinical
surgery schedule within 3 months of metastases (observation)
the biopsy
Accuracy of LM
Patients with a life expectancy of at
least 10 years from time of diagnosis,
excluding the melanoma diagnosis
Follow-up
Clinical exam, blood testing and

Exclusion chest radiography every 3 months
during the first 2 years, every 4
Prior wide excision of the primary with months during year 3, every 6
a diameter ≥3cm and the shortest months during years 4-5 and then


Type/Setting
margin from the tumour edge to the annually until year 10.
excision edge was measured to be
≥1.5cm; or the patient had an elliptical
excision and a margin beyond the
Survival
tumour edge was ≥1.5cm at the
narrowest margin Thin Melanoma (1.2-1.79mm)
Primary cutaneous melanoma Results not reported due to event

involving eye, ear or mucous infrequency
membranes.
Intermediate thickness (1.8-3.5mm)
Clinical evidence of satellite lesions, in
transit, regional nodal or distant No significant difference in 10 year
metastases melanoma specific survival rates
(HR for death in the biopsy group
Second primary invasive melanoma 0.84, 95% CI 0.64-1.09; p=0.18)
Any type of solid tumour or Disease free survival was

haematologic malignancy in the past 5 significantly higher in the biopsy
years (ex. T1 lesions in the past 5 group (HR 0.75 95% CI 0.62-0.94;
years such as basal cell carcinoma, p=0.001)
squamous cell carcinoma, in situ
carcinoma of the cervix and who have 10 year melanoma specific survival
not received treatment within the rate was significantly higher in
previous 6 months) patients with tumour free sentinel
nodes compared with those with
Prior skin grafts, tissue transfers or sentinel node metastases (HR for
flaps or lymph node dissections that death from melanoma 3.09, 95% CI
may alter the lymphatic drainage 2.12-4.49; p<0.001)
pattern from a primary cutaneous


Type/Setting
melanoma to the adjacent regional Thick Melanoma (>3.5mm)

lymph node basins
No significant difference in the 10
Previous chemotherapy, year melanoma specific survival
immunotherapy or radiation therapy rates (HR for death in the biopsy
group 1.12, 95% CI 0.76-1.67;
Organ transplantation/receiving p=0.56)
immunosuppressive agents as a result
of transplantation Disease free survival was
significantly higher in the biopsy
Oral or parenteral steroids or group (HR 0.7 95% CI 0.5-0.96;
immunosuppressive drugs in the past p=0.003)
6 months
10 year melanoma specific survival
Primary or secondary immune rate was significantly higher in
deficiencies patients with tumour free sentinel
nodes compared with those with
A concurrent medical condition which
sentinel node metastases (HR for
will affect life expectancy
death from melanoma 1.75, 95% CI
Pregnancy 1.07-2.87; p=0.03)
Cannot undergo SLN dissection for any Presence of Nodal Metastases

reason
The frequency of nodal metastasis
across all Breslow thickness was
20.8%
1661 patients underwent
randomisation Intermediate thickness (1.8-3.5mm)
585 patients in the intervention arm 87/500 patients in the observation


Type/Setting
and 391 patients in the control arm group had nodal metastasis at a
completed the trial median of 19.2 months (95% CI,
13.6-24.1).
In total 215 patients were lost to
follow-up, 64% of them from the The estimated 10-year cumulative
intervention arm which possibly incidence of nodal metastasis was
reflects a greater incentive for 19.5%
patients in the observation arm to
continue their follow-up.
Sentinel nodes were identified in

765/770 patients in the biopsy
group and 122 patients had
metastases.
Nodal metastases were detected

during observation in 31/643
patients with tumour free sentinel
nodes
The proportion of patients with

nodal metastases in the biopsy
group was 20% (153/765 patients)
and the estimated 10 year
cumulative incidence was 21.9%.
Thick Melanoma (>3.5mm)
44/117 patients in the observation


Type/Setting
arm had nodal relapse at a median

of 9.2 months (95% CI 6.4-12.2)
and the estimated 10 year
cumulative incidence of nodal
metastasis was 41.4%
Sentinel nodes were identified in

all patients and 57/173 had nodal
metastases.
Nodal metastases were

subsequently detected in 12/116
patients with initially tumour free
nodes.
The proportion of patients with

nodal metastasis in the biopsy
group was 39.9% and the
estimated 10 year cumulative
incidence of nodal metastases was
42%
Survival in patients with nodal

metastases
There was no significant difference


Type/Setting
in the distribution of prognostic

factors between the two treatment
groups with the exception of age
among patients with thick
melanomas.
Intermediate thickness (1.8-3.5mm)
10 year melanoma specific survival

rate was 62.1±4.8% in the biopsy
group compared with 41.5±5.6% in
the observation group in patients
with nodal metastases ( HR for
death from melanoma 0.56, 95% CI
0.37-0.84; p=0.006). This treatment
related difference remained
significant after patients with false
negative sentinel nodes were
included (10 year melanoma
specific survival rate, 56±4.3% in
the biopsy group versus 41.5±5.6%
in the observation group (HR 0.67,
95% CI 0.46-0.97; p=0.04))
In patients with no nodal

metastases (no tumour on biopsy
or during clinical observation), no
treatment related difference in 10


Type/Setting
year melanoma specific survival

rates was observed (88.0±1.4% in
in the observation group; HR for
death from melanoma in the
biopsy group 0.89; p=0.54).
Distant disease free survival was

improved in patients receiving
immediate rather than delayed
lymphadenectomy (HR 0.62, 95% CI
0.42-0.91; p=0.02)
Thick Melanoma (>3.5mm)
No significant treatment related

difference was observed for
patients with thick melanomas; the
10 year melanoma-specific survival
rate was 48±7.0% in the biopsy
group versus 45.8±7.8% in the
observation group (HR 0.92, 95% CI
0.53-1.6; p=0.78)
In patients with no nodal

metastases (no tumour on biopsy
or during clinical observation), no
treatment related difference in 10
year melanoma specific survival
rates was observed (69.8±5.0% in


Type/Setting

in the observation group; HR for
death from melanoma in the
biopsy group 1.18; p=0.61).
No significant difference was

observed in distant disease free
survival for patients treated with
immediate versus delayed
lymphadenectomy (HR 0.96, 95% CI
0.56-1.64, p=0.88)
SLNB+immediate
lymphadenectomy
The estimated treatment effect on

disease free survival was 1.17
(p<0.001) indicating an increase is
survival time by a factor of 3.2.

distant disease free survival was
0.73 (p=0.04) indicating an increase
is survival time by a factor of 2.1

melanoma specific survival was
0.68 (p=0.05) indicating an increase


Type/Setting
is survival time by a factor of 2.0.
Voit et al Retrospective To evaluate the increased N=1,000 patients US-FNAC±SNB Disease Free Survival
(2014) Case Series experience with sentinel
lymph node biopsy as an Melanoma-specific survival
addition to US-FNAC
Inclusion All patients
underwent
Breslow thickness at least 1.00mm or ultrasound Median Follow-up was 53 months
Clark IV/V, ulcerated and/or regressed Patients with (mean=56 months)
suspicious or
malignant SN
Median Age was 62 years (mean=59) findings 208 (21%) of patients had positive
underwent lymph node disease on histology
FNAC
Median Breslow thickness was Patients with

1.57mm (mean=2.58mm) positive FNAC The chance for lymph node
or in whom involvement increased with
ultrasound increasing T-stage: 5% (15/288) for
pattern could T1, 12% (37/308) for T2, 32%
not be verified (73/231) for T3 and 48% (83/173)
underwent for T4 (p<0.001)
SLNB
5 year Kaplan-Meier estimated

melanoma specific survival was
95% for patients with a negative
US-FNAC compared with 59% for


Type/Setting
patients with a postive US-FNAC

(p<0.001).

disease free survival was 84% for
patients with a negative US-FNAC
compared with 33% for patients
with a postive US-FNAC (p<0.001).

melanoma specific survival with
negative Berlin morphology criteria
(no malignant or suspicious
ultrasound findings)was 96% versus
89% for peripheral perfusiononly or
central echo wandering to the rim
(p<0.001).

balloon shape or complete loss of
central echo was 59% (p<0.001)


Type/Setting

negative Berlin morphology criteria
(no malignant or suspicious
ultrasound findings)was 85% versus
74% for peripheral perfusiononly or
central echo wandering to the rim
(p<0.001).

disease specific survival with
balloon shape and/or complete
loss of central echo was 36%
(p<0.001)

melanoma specific survival per SN
tumour burden was 96% for SN
negative patients versus 100% for
patients with metastases <0.1mm
in diameter.


Type/Setting

melanoma specific survival for
patients with metastases 0.1-
1.0mm was 73% (p<0.001)

melanoma specific survival for
patients with lesions >1.0mm was
68% (p<0.001), 57% (p<0.001) for
patients with a lymph node
dissection or unknown SN tumour
burden.
Corresponding disease free survival

estimates were 87% for SN
negative patients compared with
83% for patients with <0.1mm
lesions (p=0.45) versus 49% in
patients with lesions 0.1-1.0mm
(p<0.001) versus 37% for patients
with lesions >1.0mm (p<0.001)
versus 33% for LND or unknown SN
tumour burden patients (p<0.001).


Type/Setting
Wasserberg Retrospective To determine the incidence N=250 patients with malignant SLNB N/A Wound Complications
et al (2004) Case Series and severity of SLNB related melanoma who underwent SLNB
complications over the long between 1994 and 2002. Sensory Complications
term and to identify
Other Complications
possible risk factors
Median age was 56.5 years (range 17-

84 years)
Sentinel node metastasis was a
significant prognostic indicator of
poor outcome compared with
negative sentinel nodes: 5 year
survival rate was 65% versus 89%,
p=0.04).
Complications related directly to

surgery occureed in 62/309 nodal
baisins and were strongly associated
with location of melanoma in the
extrmities (p=0.0002), specifically
sentinel node retrieval from the
groin (p=0.001)
Wound complications were

recorded in 42/309 baisins.
Open drainage was required in 6/16


Type/Setting
casaes.
One severe stroptoccol infection was

recorded
Independent factors significantly

associated with wound infection
included inguinal SLNB (p=0.001)
and primary lesion in the extremity
(p=0.02)
Nerve related complications were

recorded in 14 baisins.
8 patients reported post operative

pain and/or other sensory
disturbances and 6 patients
reported mobility limitations.
Age younger than 50 years

(p=0.003), axillary site (p=0.04) and
number of excised sentinel nodes
(>2) (p=0.02) were found to be
independent prognostic indicators of
sensory/mobility complications.
3 patients had significant oedema of


Type/Setting
the leg and ankle which gradually

resolved in all cases.
Children and Adolescents
Study Study Type Population Setting Aim Intervention Comparison Outcomes
Howman- Retrospective N=55 patients aged <20 Single Melanoma To assess outcomes in SLNB Histology Overall Survival
Giles et al Case Series years with stage I-II Unit (Australia) young patients
(2009) cutaneous melanoma undergoing SLNB for
intermediate thickness
localised melanoma
Median age was 17.1 years SLNB positivity rate was 25%
(range: 3.5-19.8 years) (14/55)
Children aged
<10 years had
Location of primary tumour a higher SLNB
positivity rate
Trunk = 36% than those
aged ≥10
Head and neck = 30%
years (33%
Legs = 18% versus 17%)
Arms = 16% Follow-up information was

available for 51/55 patients

Median follow-up was 60

months (range, 5-143 months)
Overall survival was 94.1%

(48/51 patients)
In the SLNB positive patients

overall survival was 79%
Butter et al Retrospective N=12 patients aged <18 2 Children’s To review the SLNB Disease free survival
(2005) Case Series years with cutaneous hospitals experience with
melanoma (Montreal, paediatric cutaneous Overall Survival
Canada) melanoma and SLNB
Only patients diagnosed after
2000 were offered SLNB (n=5
Mean age at diagnosis was patients) 4/5 patients underwent SLNB
8.5 years
1/5 had thin melanoma (<1mm)
and did not qualify.
Location of primary tumour
Extremity = 7 Mean 2 nodes biopsied per

patient
Trunk = 4

Head and neck = 1 2/4 patients had positive SLNB
2/4 had negative SLNB and

after 17 months follow-up 1
Tumour thickness ranged remains disease free while one
from 0.8-6mm (mean = developed clinically positive
3.5mm) axillary nodes 8 months after
SLNB and died 18 months afer
SLNB.
Clarks Level
Level 1 = 0
In patients who did not undergo
Level 2 = 1 SLNB (n=8), 2 underwent TLND
for clinically palpable nodes; 1
Level 3 = 3 had pathologically negative
nodes and remains alive and
Level 4 = 5
disease free 9 years later.
Level 5 = 1
Roaten et al Retrospective N=20 patients aged <21 To determine SLNB Adverse events (complications)
(2005) Case Series years undergoing SLNBX for outcomes and while 1 died of disease 15
maleanoma or other compications of months after diagnosis.
melanocytic skin lesions children and
adolescents
undergoing SLNBX
Stage I: 3.9 years (n=2)
Stage II: 7.7 years (n=6)

Stage III: 2.6 years (n=4)
Overall survival
Stage I: 100% (2/2)
Stage II: 83% (5/6)
Stage III: 75% (3/4)
Pacella et al Retrospective N=7 patients aged between Melanoma Clinic To determine the SLNB Unclear
(2003) Case Series 4-11 years with biopsy (USA) clinical utliity of
proven melanoma (n=4) or a intraoperative lymph
borderline melanocytic node mapping and
4 patients with positive sentinel
lesion of uncertain biologic sentinel lymph node
nodes underwent therapeutic
potential (n=3). biopsy
lymph node dissection.
Mean age 7.6 years (range

Mean follow up was 14 months
4-11)
94-40 months) and all 7
patients were alive and disease
free.
Tumour thickness ranged
from 2.8mm-8mm
(mean=4.27mm)

Toro et al Retrospective N=12 patients aged <18 To investigate the use SLNB Recurrence
(2003) Case Series years with clinically node of SLNB in the
negative melanoma paediatric population Adverse Events (complications)
focusing on its
diagnostic and
therapeutic 3/12 patients had positive
Mean age 14.1 years (range
implications sentinel node biopsies and
4-18 years)
underwent completion lymph
node dissection.
Tumour thickness 0.36mm –

4.7mm (mean 1.65mm)
One patient had a recurrence
6.1 months after CLND and died
after 7.5 months.
Mean number of SLNs
biopsied = 1.75 per draining
baisin
Median follow-up for the
remaining 11 patients was 11.7
months and all patients were
alive and disease free
No complications were related

to SLNB.

Breslow thickness
Study Study Type Population Setting Aim Outcomes Quality
Han (2013) Retrospective N=1250 patients entered Secondary or To determine factors Unclear how patients
observational into the sentinel lymph tertiary care predictive of sentinel were entered onto the
Tumour thickness SLNB+ N Proportion
study node working group lymph node database or how
database from 1994 to micrometastases ≤0.74mm 9 359 2.5% patients with thin
2012 with melanomas ≤ melanomas were
0.75-1.00 56 891 6.3%
1mm in thickness. selected for SLNB
(criteria differed by
individual investigator as
did techniques and
histopathology).
Lens (2002) Systematic 12 studies of patients Secondary or To determine the Individual study quality
review (N=4218) with stage I or II tertiary care degree to which was not considered in
melanoma who received Breslow thickness this review, otherwise
SLNB; of at least 100 predicts the presence ≤0.75mm 2 199 1.0% the methods were
patients; published 1996 – of sentinel lymph adequate
0.76-1.50 133 1600 8.3%
2001 node
micrometastases 1.51-4.0 433 1904 22.7%
>4.0 183 515 35.5%
Total 751 4218 17.8%
Morton Randomised See clinical outcomes table See clinical See clinical outcomes The trial was not
(2014) trial above outcomes table table above designed to answer this
above question,
≤1.2mm N.R. N.R. N.R.
Data were not reported
for tumour thickness

Study Study Type Population Setting Aim Outcomes Quality
1.2 – 3.5 122 765 15.9% <1.2mm
>3.5 57 173 32.9%

1 Economic Evidence Summary

2  The following databases were searched for economic evidence relevant to the PICO:
3 MEDLINE, EMBASE, COCHRANE, NHS EED. Studies conducted in OECD countries other than
4 the UK were considered (Guidelines Manual 2009).
5  303 possibly relevant papers were identified. Of these, 6 full papers relating to this topic
6 were obtained for appraisal. A further 4 papers was excluded as they were not cost-utility
7 studies. Two papers (Wilson et al (2002) and Morton et al (2009)) were included in the
8 current review of published economic evidence for this topic.
9  Wilson et al was a cost-utility analysis comparing four alternative treatment strategies for
10 patients with stage II melanoma. Two different SLNB followed by tailored interferon
11 treatment strategies and two non SLNB strategies; treat all with low dose IFN or a surgery
12 only.
13  The base case analysis concluded that SLNB followed by treating patients with a positive
14 result with high dose IFN and negative with low dose IFN was the most effective treatment
15 in terms of quality adjusted relapse free life-years (QArfLY). This equated to an ICER of
16 $18,700/QArfLY compared to the surgery only approach and $31,100 compared to only
17 treating patients with a positive SLNB. The treat all approach was deemed not cost-effective
18 as a result of extended dominance.
19  Wilson et al. was deemed only partially applicable to the decision problem that we are
20 evaluating. This is primarily because the study did not consider a UK healthcare setting (USA
21 setting).
22  Very serious limitations were identified with Wilson et al. Most notably, a potential conflict
23 of interest (the study was funded by a manufacturer of IFN), the duration component of the
24 QALYs used relapse free survival as opposed to overall survival and an appropriate time
25 horizon was not used.
26  Morton et al was a cost-utility analysis comparing wide-excision (WEX) alone to SLNB (with
27 CLND for patients with positive SLNBs) alongside WEX in patients with primary melanoma of
28 >1mm in thickness.
29  The base-case concluded that adding SLNB alongside WEX resulted in an incremental cost
30 per QALY of AU$1,923 compared to WEX alone. This ranged from SLNB being both cheaper
31 and more effective to AU$90,959 per QALY during sensitivity analyses. These results were
32 sensitive to the probability of distant metastasis post-intervention, the probability of nodal
33 metastasis post WEX and the cost of WEX, SLNB and delayed CLND.
34  Morton et al was deemed only partially applicable to the decision problem that we are
35 evaluating. This is primarily because the study did not consider a UK setting (Australian
36 healthcare setting).
37  Potentially serious limitations were identified with Morton et al most notably the lack of
38 probabilistic sensitivity analysis.

1  Given the large differences in treatments considered following SLNB the results of the two
2 studies are difficult to compare.
3 Volume of evidence
5 were obtained for appraisal. A further 4 papers were excluded as they were not cost-utility
6 studies. Two papers (Wilson et al (2002) and Morton et al (2009)) were included in the
7 current review of published economic evidence for this topic.
8  Wilson et al was a cost-utility analysis, conducted from a US healthcare payer perspective.

9 The study reported cost-effectiveness results in terms of cost per QArfLY over a five-year
10 time horizon was considered for the analysis.
11  Morton et al was a cost-utility analysis, conducted from an Australian healthcare system

12 perspective. The study reported outcomes in terms of QALYs and considered a lifetime time
13 horizon.
14  No cost-utility evidence was found for non-SLNB strategies of staging patients with
15 melanoma.
16  No cost-utility studies were identified which considered a UK healthcare setting
17
Selection criteria for included evidence:

303  297
possibly relevant papers papers excluded based

identified on title & abstract  Studies that compare costs and
health consequences of
interventions (i.e. true cost-
 effectiveness analyses)
 Studies that included quality of life
6  4 based outcomes as a measure of
effectiveness
full text paper obtained papers excluded based
on full text  Studies conducted in OECD countries
were included
 Studies that presented incremental

results or presented enough
information for incremental results
2 to be derived
papers included in evidence

 Studies that matched the
review population, interventions,
comparators and outcomes specified
in PICO

1 Quality and applicability of the included studies
Applicability
Directly applicable Partially applicable
Minor limitations
Methodological quality
Potentially serious
Morton et al. 2009
limitations
Very serious Wilson et al. 2002

limitations
4  Wilson et al and Morton et al are deemed only partially applicable to the decision problem
5 that we are evaluating. This is primarily because the studies did not consider a UK healthcare
6 setting. Wilson et al also did not express health effect values in terms of quality adjusted life
7 years (QALYs).
8  Very serious limitations were identified with Wilson et al. Most notably, a potential conflict
9 of interest (the study was funded by a manufacturer of IFN), the discounting only of costs
10 and an inappropriately short time horizon.
11  Potentially serious limitations were identified Morton et al most notably the lack of
12 probabilistic sensitivity analysis.
13

1 References
2 1. Wilson LS, Reyes CM, Lu C et al ‘Modelling the cost-effectiveness of sentinel lymph node
3 mapping and adjuvant interferon treatment for stage II melanoma’ Melanoma Research 12.6
4 (2002): p607-618.
5 2. Morton RL, Howard K, Thompson JF ‘The cost-effectiveness of sentinel node biopsy in patients
6 with intermediate thickness primary cutaneous melanoma’ Annals of Surgical Oncology 16.4
7 (2009): p929-940

Evidence Tables
Study Population Comparators Costs Effects Incr costs Incr effects ICER Uncertainty Applicability Limitations
Study 1
Wilson et Hypothetical Treat no one with IFN, $18,400 3.06 Reference One-way Sensitivity Partially Very Serious
al. cohort of surgery and clinical Analysis Applicable Limitations.
2002 patients with observation only. Not conducted Study funded by
Stage II For test and treat some from a UK health manufacturer.
malignant versus surgery and test service
melanoma after and treat appropriately perspective.
surgical excision. versus test and treat Inappropriate time
some horizon.
Reducing the cost of
relapse to $10,000
increased the ICER to
$21,900/QALY and
$35,900/QALY
respectively. Increasing
Test with SLNB. Treat $24,200 3.37 $5,800 0.31 $18,700/QALY the cost of relapse to
patients with a positive $50,000 reduced the
result with high dose IFN ICERs by $14,500/QALY
and those with a negative and $26,100/QALY
low dose IFN (test and respectively
treat appropriately).
Treat all with low dose IFN $30,500 3.48 Extended Sensitivity and specificity
following surgery. dominated of SLNB and the
probability of dose
changing toxicities were
reported to have an
insignificant effect on the
ICER for both
Test with SLNB. Treat $33,800 3.68 $9,600 0.31 $31,100/QALY comparisons.
patients with a positive
result with high dose IFN Probabilistic Sensitivity
and those with a negative Analysis (PSA)
with surgery alone (Test Varying across all
and treat some) variables for test and
treat some versus surgery
the median, 25th and
75th percentiles of the
PSA are $19,605,$10,291
and $36,659 per QALY
respectively.
For test and treat

appropriately versus test

and treat some the
median, 25th and 75th
percentiles $30,229,
$16,766 and $58,823 per
QALY respectively.
Comments: The survival component of the QALY uses relapse free survival and not overall survival.

Study Population Comparators Costs Effects Incr costs1 Incr ICERError! Uncertainty Applicability Limitations
effectsError Bookmark not
! Bookmark defined.
not defined.
Study 2
Morton et Hypothetical WEX AU$23,182 9.90 Reference Increasing the probability Partially Potentially serious
al 2009 cohort of QALYs for distant metastasis Applicable limitations
patients with post WEX to 0.02 or Not conducted Probabilistic
biopsy proven reducing the post from a UK health sensitivity analysis
Melanoma WEX+SLNB probability to service was not
≥1mm 0.01 resulted in perspective. performed.
SLNB+WEX becoming less
costly and more effective
(dominant).
Decreasing post WEX

probability to 0.01
decreases the ICER to
$90,959/QALY whilst
WEX+SLNB AU$24,045 10.34 $863 0.44 $1,983/QALY increasing the WEX+SLNB
QALYs to 0.022 increases the
ICER to $52,436/QALY.
Increasing and decreasing

the probability of nodal
metastasis post WEX to
0.04 and 0.0275 results in
WEX+SLNB becoming
dominant and
$6,273/QALY respectively.
Increasing the cost of

delayed CLND to $27,000
again results in
WEX+SLNB becoming
dominant whilst reducing
the cost to $8,717results
in an ICER of $3,815.
Increasing and decreasing
the costs of WEX+SLNB
between $4,339 and
$9811 results in ICERS of
$397/QALY and
$12,976/QALY.

Study Population Comparators Costs Effects Incr costs1 Incr ICERError! Uncertainty Applicability Limitations
effectsError Bookmark not
! Bookmark defined.
not defined.
Comments:
1
Incremental values in comparison to strategy above except when ruled out through extended dominance.

Primary Design Patient Interventions Outcome measures Results Comments

details characteristics
Study 1
Author: Type of analysis: Base case (1)Treat no one with IFN; Effectiveness (QALY): Funding:
Wilson Cost-Utility (population): surgery and clinical (1)Treat no one with IFN, surgery and 3.06 Roche Global
Year: Hypothetical cohort of observation only. observation only. Development
2002 Model structure: patients with Stage II
Country: Decision Tree malignant melanoma (2) Test first with SLNB. (2)Test first with SLNB. High dose IFN for 3.37 Comments
USA after surgical excision. High dose IFN for positive, surgery only for negative.
Cycle length: positive, surgery only for
N/A Sample size: negative. (3)Treat all with low-dose IFN. 3.48
Each patient modelled
Time horizon: independently (3)Treat all with low- (4)Test first with SLNB. High dose for 3.68
5 years dose IFN. positive, low dose for negative.
Age:
Perspective: Not reported (4)Test first with SLNB.
Health-Care Payer High dose for positive, Total costs:
Gender: low dose for negative. (1)Treat no one with IFN, surgery and $18,400
Source of base-line data: Not reported observation only
The probability of metastasis
was taken from a multicentre Subgroup analysis: (2) Test first with SLNB. High dose IFN $24,200
US trial validating accuracy of None for positive, surgery only for negative.
intraoperative lymphatic
mapping and sentinel (3)Treat all with low-dose adjuvant $30,500
lymphadenectomy for early- interferon(IFN)
stage melanoma.
(4)Test first with SLNB. High dose for $33,800
positive, low dose for negative.
Source of effectiveness data:
Probabilities of relapse free 5 ICER (cost per QALY):
year survival were taken from
four studies, three RCTs and a (2) vs (1) $18,700
narrative review. The three (3) vs (2) Extended
RCTs, comparing interferon- Dominated
alfa-2b were set in Austria, (4) vs (2) $31 100


France and the USA.

Cost per Relapse-Free Year
The specificity of SLNB was
taken from prospective cohort (2) vs (1) $26,000
study in the US (Pu et al, 1999). (3) vs (2) $28,800
Sensitivity was taken from (4) vs (2) $35,700
Reintegn et al (1990) a study of
the order of melanoma nodal
metastases. Uncertainty:
One-way sensitivity analyses

Source of utility data:
Utility values were taken from Cost relapse reduced to $10000
Killbridge et al (2001) who used (2) vs (1) $21,900/QALY
a standard gamble on 107 low (4) vs (2) $35,900/QALY
risk US melanoma patients to
evaluate different toxicities and Cost Relapse Increase to $50000
post-treatment outcomes (2) vs (1) $14,500/QALY
following IFN treatment. The (4) vs (2) $26,100/QALY
valuation of these changes
were by the patient group and Prob. dose–changing toxicities Reported
not the general population. Insignificant
Source of cost data: SLNB Sensitivity 0.82 to1.0 Reported

Resource use for diagnostics SLNB Specificity 0.96 to 1.0 Insignificant
and surgery were taken from a
RCT comparing lymph node Decreasing mean utility to lower level
dissection and adjuvant (2)vs(1) $20,300/QALY
interferon alfa-2b in a US (4)vs(2) $38 ,000/QALY
healthcare setting (Mcmasters
(2001)). Probabilistic sensitivity analysis (PSA)
Costs were taken from All variables (Cost per QALY) ($19605,$10291


th th
medicare fee schedules, (2)vs(1) (Median,25 ,75 ) ,$36659)
average US wholesale prices. All variables (Cost per QALY) ($30229,$16766
th th
Recurrence costs were taken (4)vs(2) (Median,25 ,75 ) ,$58823)
from Medicaid hospice rates
and from a previous economic
evaluation.
Costs for drug treatment and

toxicity were sourced from Tsao
et al (1998) who used a
modelling approach to estimate
direct costs of treating
cutaneous melanoma.
Currency unit:
US$
Cost year:
2001
Discounting:
3% Costs
0% Benefits

Primary details Design Patient Interventions Outcome measures Results Comments

characteristics
Author: Type of analysis: Base case (population): Wide Excision(WEX) Effectiveness (): Funding:
Morton Cost-utility Hypothetical cohort of Life years Not Stated
Year: patients with biopsy proven Wide Excision and SLNB WEX 10.45
2008 Melanoma ≥1mm WEX+SLNB 10.77 Comments
Country: Model structure: Probabilistic
Australia Decision Tree and Markov Sample size: QALYS sensitivity analysis
N/A WEX 9.90 not performed
Cycle length: WEX+SLNB 10.34
1 year Age:
Age=52 Total costs:
Time horizon: WEX $23,182
20 years Gender: WEX+SLNB $24,045
Didn’t differentiate
Perspective: ICER (cost per):
Direct Healthcare Costs. Patient QALY Subgroup analysis: LY $2,770/LY
None QALY $1,983/QALY
Source of base-line data:
Patient characteristics were taken from Uncertainty:
the MSLT-I trial, an Australian RCT
comparing SLNB with nodal Probability of distant metastases post WEX
observation. Increase to 0.2 Dominant
Decrease to 0.1 $90,959/QALY
Source of effectiveness data:
Diagnostic accuracy of SLNB was taken Probability Of distant metastases post SLNB
from the MSLT-I trial. Increase to 0.022
Decrease to 0.01
A literature review was performed to $52,436/QALY
identify transition probabilities. Cost of WEX + SLNB Dominant
Probabilities of recurrence and Increase to $9,811
probability of complications from WEX, Decrease to $4,339
SLNB and “immediate” CLND were $12,976/QALY
taken from MSLT-I. Probability of Nodal Metastasis post WEX $397/QALY
Increase to 0.04
Probabilities of complications from Decrease to 0.0275
immediate CLND and for melanoma
death following distant metastases Cost Delayed CLND (with complications) Dominant
were taken from retrospective studies Increase to $27,000 $6,273/QALY
of US patients. Decrease to $8,717
Source of utility data: Dominant

QALY weights were sourced from the $3,815/QALY

melanoma population or from other

cancers and the general population
when melanoma specific weights were
not available.
Source of cost data:

Costs were obtained from Australian
Refined Diagnosis Related Groups (AR-
DRG) or Australian Medicare Benefits
Schedule (MBS). Resource use was
calculated from 40 consecutive patients
from the MSLT-1 trial.
Currency unit:
Australian Dollars
Cost year:
2007
Discounting:
5% Costs
5% Health Benefits

1 4. Stage 0-II melanoma
2 4.1 Surgical Management
3 Review question: What is the most effective surgical treatment for stage 0-II melanoma to
4 achieve clear margins and improved patient outcomes?
5 Background
6 Wide local excision is the treatment of choice for primary, clinically localised, melanoma. The proper
7 clinical resection margin is based upon the Breslow thickness of the lesion. NCCN guidelines
8 recommend for melanomas 1mm or less, wide excision with a 1cm margin whilst for localised
9 melanomas between 2-4mm thick a 2cm margin is suggested. Thicker melanomas are associated
10 with an increased risk of nodal and distant metastases but there is no perceived advantage in wider
11 excision for melanomas thicker than 4mm.
12 The group needs to critically analyse the evidence supporting these statements and review the
13 effectiveness of the different surgical techniques defined in the intervention aspect of the PICO.
14 Mohs micrographic surgery in relation to melanoma is to be assessed in relation to its outcomes as
15 Mohs determines clear peripheral and deep margins but does not measure the clearance; in contrast
16 to standard excision and pathological techniques.
17 Is it appropriate to adjust clinical resection margins to avoid significant anatomical damage e.g. free
18 facial margins, facial nerve?
19 - Aesthetic and functional outcome of surgical excision and reconstruction. What evidence exists
20 that informs us of the impact of the extent of the excision and/or reconstructive techniques eg
21 flaps, grafts and does this vary at different anatomical sites?
22 - Wide local excision reduces local recurrence rate but has no statistically significant effect on
23 survival. Evidence review as regards the validity of this statement.
24 - Sentinal Lymph node biopsy, a surgical procedure that identifies and removes the lymph
25 node(s) immediately draining the area of the primary tumour for histological analysis, is subject
26 to much debate. Whilst providing valuable prognostic information; completion
27 lymphadenectomy, undertaken when the sentinal node is positive, has not been shown to
28 improve survival. Critical analysis of the benefits of SNLB, taking into account the newer
29 therapies for adjuvant treatment, needs to be assessed and contrasted with the clinical
30 morbidity and mortality of the procedure plus the financial implications.

Patients with stage: Stage 0 Each Other 1. Pathological clear
0  Excision with clinical margin, margins
Ia 2mm, 5mm, 10mm 2. Local Recurrence
Ib  MOHS micrographic surgery 3. Regional recurrence
IIa  Johnsons square technique 4. Melanoma specific
IIb  No treatment Survival (5 & 10 yr)
IIc 5. Overall survival (5 & 10
melanoma Stage Ia yr)
 Excision with clinical margin, 6. HRQL
<1cm, 1cm, 2cm, 3cm, 4cm 7. Detection of micro mets
 MOHS micrographic surgery 8. Adverse events, inc:
Cosmesis & surgical
reconstruction,

Stage Ib-IIc lymphoedema after SNB

 Excision with clinical margin
<1cm, 1cm, 2cm, 3cm, 4cm
Searches:
Can we apply date limits to the search (Please No date limits to be applied to the searches
appropriate)
Are there any study design filters to be used Systemic reviews, RCTs, case series (comparative
(RCT, systematic review, diagnostic test). studies with at least 50 patients in each comparison
group; only for surgical margins below 1 cm, Mohs
micrographic surgery and Johnsons squares)
List useful search terms. (This can include such Post surgical morbidity
information as any alternative names for the Stratification criteria for RCT
interventions etc) SNB as eligibility criterion for RCT
Prognosis
MSLT1
MSLT2
Peg-INTRON EORTC trial melanoma
1. change in stage
2. change in management
3. clinical impact of diagnostic tests / imaging
4. impact on decision making / treatment plan
13 Search Results
Dates No of references No of references Finish date of

Database name Covered found retrieved search
Medline 1946-2014 7537 909 21/05/2014
Premedline May 19 2014 108 32 19/05/2014
Embase 1947-2014 6610 410 22/05/2014
April 2014

1 Update Search
2 For the update search, the same search criteria/filters were applied as initial search with a date limit
3 of May 2014 onwards.

retrieved search
Medline 159 12 09/10/2014
Premedline 15 1 09/10/2014
Embase 104 9 09/10/2014
3 references found in Pubmed 09/10/2014

5 1. exp Melanoma/
6 2. melanoma$.tw.
9 5. dubreuilh.tw.
10 6. LMM.tw.
11 7. or/1-6
12 8. exp Melanoma/su
13 9. surgery.sh,fs.
14 10. Dermatologic Surgical Procedures/
15 11. (excision* or margin* or surger* or resection* or remov* or reconstruct*).tw.
16 12. Reconstructive Surgical Procedures/
17 13. or/8-12
18 14. Mohs Surgery/
19 15. ((micrograph* or moh*) adj3 surg*).tw.
20 16. chemosurg*.tw.
21 17. or/14-16
22 18. (johnson* adj2 (square* or technique* or procedure*)).tw.
23 19. (square adj (technique* or procedure*)).tw.
24 20. (geometric adj2 (technique* or procedure*)).tw.
25 21. *Surgical Flaps/
26 22. or/18-20
28 24. ((sentinel and node) adj biops*).tw.
29 25. (sentinel adj1 lymphadenectom*).tw.
30 26. ((sentinel and node) adj dissect*).tw.
31 27. ((sentinel and node) adj procedure).tw.

1 28. (SNLB or SNB).tw.

2 29. or/23-28
3 30. 13 or 17 or 22 or 29
4 31. 7 and 30
5

1 Screening Results
Reasons for Exclusion

Expert Reviews
Abstract Only
No Comparators
Treatment Comparisons not
relevant to PICO
Population not relevant to PICO
Foreign Language
Quality of the included studies

Systematic review of RCTs (n=2)
Systematic review of combined
study designs (n=0)
Randomized controlled trial (n=6
published in 16 papers)
Prospective cross sectional study
(n=0)
Case Series Studies (n=0)
Qualitative Study (n=0)
3 The evidence relating to the surgical excision margins of 1 cm and above for melanoma consisted of
4 one systematic review (Sladden et al 2009) of five RCTs (Balch et al, 2001; Cascinellli et al, 1998;
5 Cohn-Cedergren et al, 2000; Khayat et al, 2003; Thomas et al, 2004) and an RCT (Gillgren et al, 2011),
6 which was published after the systematic review. No evidence relating to Mohs micrographic
7 surgery, Johnsons squares surgery and excision margins below 1 cm was identified.

Table 4.1: Characteristics of included studies
Outcome Balch et al (2001) Cascinelli et al Cohn-Cedermark et al Gillgren et al Khayat et al (2003) Thomas et al (2004)
(1998) (2000) (2011)
Pathological Not reported Not reported Not reported Not reported Not reported Not reported
clear
margins
st st st st
Local 1 relapse: 2 cm 1 relapse: 1 cm 1 relapse: 1 event: 2 cm 2 cm (1/161 patients), Local or in-transit, as a first or
recurrence (0.4%) = 4 cm (0.9%), (2.6%) = 3 cm (1%), (20 events) = 4 secondary recurrence: 1 cm (37
ns ns 2 cm (0.2%), cm (9 events), HR 5 cm (4/165 patients)* events) = 3 cm (25 events), HR = 1.51
= 2.15 (95% CI (95% CI 0.91-2.51), p = 0.1.
Anytime relapse: 2 cm 5 cm (1%) 0.97-4.77), p =
(2.1%) = 4 cm (2.6%), 0.06
ns
st
Regional 5-year disease-free Regional lymph 1 relapse: Regional skin 2 cm (8.1%), As a first or secondary recurrence: 1
st st
recurrence survival: 2 cm (75%) = nodes as 1 metastasis as 1 cm (149 events) = 3 cm (129 events),
4 cm (80%), p = 0.28 relapse: 2 cm (14%), event: 2 cm (19 5 cm (6.7%)* HR = 1.21 (95% CI 0.96-1.53), p = 0.1.
events) = 4 cm
1 cm (6.9%), 5 cm (12%) (15 events), HR = 3-year loco-regional recurrence: HR =
1.25 (95% CI 0.63- 1.34 (95% CI 1.06-1.71), p = 0.02 for
3 cm (7.8%) 5-year recurrence-free 10-year disease-free 1 cm (i.e., favouring 3 cm)
2.46), p = 0.52
survival: 2 cm (81%; survival: 2 cm (85%) = 5
95% CI 77-84%) = 5 cm Regional lymph cm (83%), p = 0.83. Loco-regional recurrence beyond 3
(83%; 95% CI 80-86%), node recurrence years: HR = 0.69 (95% CI 0.36-1.37), p
4-year actuarial ns. st = 0.3.
as 1 event: 2 cm
disease-free
(100 events) = 4
survival: 1 cm = 3 10-year recurrence-
cm (114 events),
cm, p = 0.66. free survival: 2 cm
HR = 0.88 (95% CI
(71%; 95% CI 66-75%)
8-year actuarial 0.68-1.16), p =
= 5 cm (70%; 95% CI
disease-free 0.37
65-74%), ns
survival: 1 cm
Any locoregional
(81.6%) = 3 cm st
recurrence as 1
(84.4%), p > 0.74.
event: 2 cm (139
events) = 4 cm

(1998) (2000) (2011)
(138 events), HR =
1 (95% CI 0.79-
1.28), p = 0.96
5-year
recurrence-free
survival: 2 cm
(56%; 95% CI 51-
61%) = 4 cm
(56%; 95% CI 51-
61%), p = 0.82
st
Melanoma- Not reported Not reported As first event: 2 cm As 1 event?: Not reported 5-year: 1 cm (128 events) = 3 cm
specific (16%) = 5 cm (13%), (105 events), HR = 1.24 (95% CI 0.96-
survival (5 & relative hazard ratio = 2 cm (134 events) 1.61), p = 0.1.
10 yr) 1.22 (95% VI 0.88-1.69, = 4 cm (138
p = 0.24 events), HR = 0.99
(95% CI 0.78-
1.26), p = 0.95
Overall 2 cm (79.5%) = 4 cm 4-year actuarial Not reported 2 cm (65%; 95% Not reported 1 cm (144 events) = 3 cm (137
survival (5- (83.7%), ns. survival: 1 cm CI 60-69%) = 4 cm events), HR = 1.07 (95% CI 0.85-
year) (96.8%) = 3 cm (65%; 95% CI 60- 1.36), p = 0.6.
(96%), p = 0.58 70%), p = 0.69
Overall 2 cm (70%) = 4 cm 8-year actuarial 2 cm (79%; 95% CI 75- Swedish cohort 2 cm (87%) = 5 cm (86%), Not reported
survival (10- (77%), p = 0.07 survival: 1 cm 82%) = 5 cm (76%; 95% only (N = 644): 2 p = 0.56
year) (89.6%) = 3 cm CI 72-80%), ns cm (50%; 95% CI
(90.3%), p = 0.64 44-56%) = 4 cm
(50%; 95% CI 44-
12-year: 1 cm 56%), p = 0.84
(87.2%) = 3 cm
(85.1%)

(1998) (2000) (2011)
Health- Not reported Not reported 2 cm (N = 70) = 5 cm (N Not reported Not reported - Physical component (PCS), and
2
related = 74), i , ns, on all the mental component (MCS) at 1
quality of life measured EORTC QLQ- month:
C30 functioning
(physical, role, Worse for 3 cm.
emotional, cognitive,
social), symptom - PCS improved significantly faster in
(fatigue, pain, 3 cm than in 1 cm group.
insomnia) and financial
- Psychological distress and attitude
difficulties scales and
towards quality of medical care,
global quality of life;
treatment and illness (both at 1
on the HAD-A (anxiety)
month and overall); MCS overall;
and –D (depression)
vocational role and extended family
scales; and on the IES
relations (both all time points): 1 cm
intrusion and
= 3 cm.
avoidance subscales.
- Domestic and sexual role at 1
month, social role at 1 and 3 months;
perception of scar at all time points:
Worse for 3 cm.
- Perception of scar improved

significantly faster in 3 cm than in 1
cm group.
- HADS-A and B: Similar to MCS

results.
Detection of In-transit metastasis Distant metastasis Distant metastasis as Distant Distant recurrence: Distant metastasis:
st st
micro (at 6-year follow up): 2 as 1 relapse: first event: 2 cm (5%) = metastasis as 1
metastases cm (2.5%) = 4 cm 5 cm (7%), relative event: 2 cm (38 2 cm (2.5%), 2 cm (38 events),
(2.1%), ns. 1 cm (5.6%), hazard ratio = 0.76 events) = 4 cm
(95% VI 0.45-1.28, p = (54 events), HR = 5 cm (6.1%)* 5 cm (30 event)
Distant metastasis (at 3 cm (4.6%) 0.71 (95% CI 0.47-

(1998) (2000) (2011)
6-year follow up): 2 0.29 1.08), p = 0.11
cm (10.9%) = 4 cm
(8.5%), ns.
Adverse Skin grafting rate: 2 Not reported Problems with the Not reported Not reported Surgical complication rates: 1 cm
events (incl, cm (11%) < 4 cm scar: 2 cm (12/70 (7.8%) ≤ 3 cm (13.9%), p = 0.05
cosmesis & (46%), p < 0.001. patients) = 5 cm (18/74
surgical patients), ns
reconstructi Wound infection rate:
on, 2 cm (5.4%) = 4 cm
lymphoedem (4.6%), ns.
a after SNB)
Wound dehiscence
rate: 2 cm (4.6%) = 4
cm (4.2%), ns.
ns = non-significant; HR = hazard ratio; *The authors report that “The type of tumor recurrence and surgery performed were independent on statistical analysis (P =
0.22)” (pages 1943-1944).

2 Surgical excision margins of 1 cm compared to surgical excision margins of ≥3 cm were not

3 associated with differences in local recurrence (2 RCTs, N = 1512; low quality), melanoma-specific
4 survival (1 RCT, N = 900; low quality), 5-year overall survival (2 RCTs, N = 1512; low quality), 10-year
5 overall survival (1 RCT, N = 612; low quality), or distant metastasis (2 RCTs, N = 1512; low quality),
6 whereas there was some suggestion that regional recurrence may be higher in the 1 cm group at 3
7 years, but not later (2 RCTs, N = 1512; low quality), that the surgical complication rate may be lower
8 in the 1 cm group (1 RCTs, N = 900; low quality), and that the two excision margins are associated
9 with slightly different health-related quality-of-life profiles (1 RCT, N = 900; low quality).
10 Surgical excision margins of 2 cm compared to surgical excision margins of 4 cm were not associated
11 with differences in local recurrence (2 RCTs, N = 1399; low quality), regional recurrence (2 RCTs, N =
12 1399; low quality), melanoma-specific survival (1 RCT, N = 929; low quality), 5-year overall survival (2
13 RCTs, N = 1399; low quality), 10-year overall survival (2 RCTs, N = 1399; low quality), distant
14 metastasis (2 RCTs, N = 1399; low quality), or wound infection or dehiscence rates (1 RCT, N = 470;
15 low quality) whereas the skin grating rate was higher in the 4 cm group (46%) than in the 2 cm group
16 (11%, p < 0.0001; 1 RCT, N = 470; low quality).
17 Surgical excision margins of 2 cm compared to surgical excision margins of ≥5 cm were not

18 associated with differences in local recurrence (2 RCTs, N = 1326; low quality), regional recurrence (2
19 RCTs, N = 1326; low quality), melanoma-specific survival (1 RCT, N = 989; low quality), 10-year
20 overall survival (2 RCTs, N = 1326; low quality), health-related quality-of-life (1 RCT, N = 989; low
21 quality), distant metastasis (2 RCTs, N = 1326; low quality), or ‘problems with the scar (1 RCT, N =
22 989; low quality).
23

GRADE Table 4.1 Should excision with 1 cm clinical margin versus excision with ≥3 cm clinical margin
No of Design Limitations Inconsistency Indirectness Imprecision Other Excision with 1 Excision with Results
studies considerations cm clinical margin ≥3 cm clinical
margin
Local recurrence
2 randomised serious2 no serious no serious serious3 none N = 758 N = 754 No significant differences
trials1 inconsistency indirectness LOW
Regional recurrence
2 randomised serious2 no serious no serious serious3 none N = 758 N = 754 No significant differences,
trials1 inconsistency indirectness although one study showed a LOW
higher locoregional recurrence
rate in 1 cm at 3 years.
Melanoma-specific survival
1 randomised serious2 no serious no serious serious3 none N = 453 N = 447 No significant difference
5-year overall survival
1 randomised serious2 no serious no serious serious3 none N = 305 N = 307 No significant differences in 8-,
trials5 inconsistency indirectness or 12-year overall survival LOW
Health-related quality-of-life

1 randomised serious2 no serious no serious serious3 none N = 453 N = 447 Some apparently minor
trials4 inconsistency indirectness differences LOW
Distant metastasis
2 randomised serious2 no serious no serious serious3 none N = 758 N = 754 Appear to be similar
Adverse events
1 randomised serious2 no serious no serious serious3 none N = 453 N = 447 Surgical complication rate: 1
trials4 inconsistency indirectness cm (7.8%) ≤ 3 cm (13.9%), p = LOW
0.05
1
Cascinelli et al (1998), Thomas et al (2004)
2
The included studies were associated with under-reporting of a number of design features that therefore put the studies at unclear risk of bias.
3
Low event rate(s).
4
Thomas et al (2004)
5
Cascinelli et al (1998)
Excision with 2 cm clinical margin versus excision with 4 cm clinical margin
studies considerations cm clinical 4 cm clinical
margin margin
Local recurrence

Regional recurrence
Distant metastasis
Adverse events
1 randomised serious2 no serious no serious serious3 none N = 238 N = 232 Skin grafting rate: 2 cm (11%)
trials5 inconsistency indirectness < 4 cm (46%), p < 0.001; LOW
Wound infection/dehiscence
rate: 2 cm = 4 cm
1
Balch et al (2001), Gillgren et al (2011)
2
3
Low event rate(s).
4
Gillgren et al (2011)
5
Balch et al (2001)

Excision with 2 cm clinical margin versus excision with ≥5 cm clinical margin
studies considerations cm clinical ≥5 cm clinical
margin margin
Local recurrence
Regional recurrence
Health-related quality-of-life
Distant metastasis

Adverse events
1 randomised serious2 no serious no serious serious3 none N = 476 N = 513 Problems with the scar:
trials4 inconsistency indirectness No significant differences LOW
1
Cohn-Cedermark et al (2000), Khayat et al (2003)
2
3
Low event rate(s).
4
Cohn-Cedermark et al (2000)

1 Study Quality
2 All the studies included in the systematic review were RCTs and these were supplemented by an
3 additional RCT (Gillgren 2011) which had been published after the systematic review. The adequacy
4 of the randomisation sequence generation was unclear in all the studies in the systematic review
5 and of low risk in Gillgren et al (2011), whereas allocation concealment was considered adequate in
6 Cohn-Cedermark (2000), Gillgren et al (2011) and Thomas (2004) and unclear in Balch et al (2001),
7 Cascinelli et al (1998) and Khayat et al (2003). Blinding of the outcome assessment was employed for
8 survival in Balch et al (2001), but was unclear in the remaining four studies included in the
9 systematic review and in Gillgren et al (2011). With the exception of Cohn-Cedermark (2000), the
10 remaining studies in the systematic review were at unclear risk of attrition bias as judged by Sladden
11 et al (2009), while Gillgren et al (2011) was at low risk of attrition bias. Sladden et al (2009) rated all
12 the included trials as free of selective reporting, and also reported that it was unclear whether the
13 five included RCTs were at risk of other types of bias. Gillgren et al (2011) did not systematically
14 record adverse events and this omission is the only indication that this study is at risk of outcome
15 reported bias.
16 In summary, due to a lack of reporting in the included RCTs, it is not possible to give an overall rating
17 of the quality of the studies included in this evidence review.
18

1 References
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35 Gillgren, P., et al (2011) 2-cm versus 4-cm surgical excision margins for primary cutaneous melanoma
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4 Thomas JM, et al (2004) (United Kingdom Melanoma Study Group, British Association of Plastic
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10
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13 Clinical & Experimental Dermatology, 36: 334-335.
14 Reason: Same as Sladden 2009
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19 nohs/johnson squares
20 Akhtar, S., Bhat, W., Magdum, A., Stanley, P. R., Akhtar, S., Bhat, W., Magdum, A. & Stanley, P. R. W.
21 (2014) Surgical excision margins for melanoma in situ. Journal of Plastic, Reconstructive & Aesthetic
22 Surgery: JPRAS, 67: 320-323.
23 Reason: not in pico as this retrospective study only reports on histological margins, not clinical
24 margins
25 Aloia, T. A., Gershenwald, J. E., Aloia, T. A. & Gershenwald, J. E. (2005) Management of early-stage
26 cutaneous melanoma. [Review] [228 refs]. Current Problems in Surgery, 42: 460-534.
27 Reason: narrative review
28 An, K. P., Ratner, D., An, K. P. & Ratner, D. (2001) Surgical management of cutaneous malignancies.
29 [Review] [151 refs]. Clinics in Dermatology, 19: 305-320.
31 Anderson, K. W., Baker, S. R., Anderson, K. W. & Baker, S. R. (2003) Management of early lentigo
32 maligna and lentigo maligna melanoma of the head and neck. [Review] [26 refs]. Facial Plastic
33 Surgery Clinics of North America, 11: 93-105.
35 Bachaud, J. M., Shubinski, R., Boussin, G., Chevreau, C., David, J. M., Viraben, R., Bonafe, J. L., Daly,
36 N. J., Bachaud, J. M., Shubinski, R., Boussin, G., Chevreau, C., David, J. M., Viraben, R., Bonafe, J. L. &
37 Daly, N. J. (1992) Stage I cutaneous malignant melanoma: risk factors of loco-regional recurrence
38 after wide local excision and clinical perspectives. European Journal of Surgical Oncology, 18: 442-
39 448.
40 Reason: comparisons not in pico
41 Balch, C. M. & Balch, C. M. (1998) The John Wayne Clinical Research Lecture. Surgical management
42 of melanoma: results of prospective randomized trials. Annals of Surgical Oncology, 5: 301-309.

1 Balch, C. M. & Balch, C. M. (1999) Randomized surgical trials involving elective node dissection for
2 melanoma. Advances in Surgery, 32: 255-270.
4 Balch, C. M., Ross, M. I., Cascinelli, N. & Soong, S. J. (2007) Excision margins for primary cutaneous
5 melanoma - Updated pooled analysis of randomized controlled trials - Invited critique. Archives of
6 Surgery, 142: 891-893.
8 Biran, S., Hochman, A., Walach, N., Biran, S., Hochman, A. & Walach, N. (1973) Malignant melanoma.
9 A survey of 232 cases. Oncology, 28: 331-342.
10 Reason: not comparative study
11 Bosbous, M. W., Dzwierzynski, W. W., Neuburg, M., Bosbous, M. W., Dzwierzynski, W. W. &
12 Neuburg, M. (2009) Staged excision of lentigo maligna and lentigo maligna melanoma: a 10-year
13 experience. Plastic & Reconstructive Surgery, 124: 1947-1955.
15 Breslow, A. & Breslow, A. (1978) The surgical treatment of stage I cutaneous melanoma. [Review]
16 [25 refs]. Cancer Treatment Reviews, 5: 195-198.
18 Bricca, G. M., Brodland, D. G., Ren, D., Zitelli, J. A., Bricca, G. M., Brodland, D. G., Ren, D. & Zitelli, J.
19 A. (2005) Cutaneous head and neck melanoma treated with Mohs micrographic surgery. Journal of
20 the American Academy of Dermatology, 52: 92-100.
21 Reason: retrospective/prospective study with historical controls: not possible to ascertain the type
22 of surgery the historical controls were treated with in terms of surgical margins.
23 Brodland, D. G. & Brodland, D. G. (2000) Reconstruction conundrum #3. Excision and reconstruction
24 of recurrent lentigo maligna melanoma. Dermatologic Surgery, 26: 965-968.
25 Reason: not in pico
26 Brodland, D. G. & Brodland, D. G. (2001) The treatment of nail apparatus melanoma with Mohs
27 micrographic surgery. Dermatologic Surgery, 27: 269-273.
28 Reason: not in pico/not comparative study
29 Bruns, S. D., McGee, J. M., Phillips, J. W., Bruns, S. D., McGee, J. M. & Phillips, J. W. (2002) Current
30 treatment of cutaneous melanoma and the sentinel lymph node. [Review] [23 refs]. Journal -
31 Oklahoma State Medical Association, 95: 332-335.
33 Bub, J. L., Berg, D., Slee, A., Odland, P. B., Bub, J. L., Berg, D., Slee, A. & Odland, P. B. (2004)
34 Management of lentigo maligna and lentigo maligna melanoma with staged excision: a 5-year
35 follow-up. Archives of Dermatology, 140: 552-558.
37 Buker, J. L., Amonette, R. A., Buker, J. L. & Amonette, R. A. (1992) Micrographic surgery. [Review] [14
38 refs]. Clinics in Dermatology, 10: 309-315.
40 Cady, B., Legg, M. A., Redfern, A. B., Cady, B., Legg, M. A. & Redfern, A. B. (1975) Contemporary
41 treatment of malignant melanoma. American Journal of Surgery, 129: 472-482.

1 Cascinelli, N. & Cascinelli, N. (1996) The role of clinical trials in assessing optimal treatment of
2 cutaneous melanoma not extending beyond the regional nodes. [Review] [49 refs]. European Journal
3 of Surgical Oncology, 22: 123-127.
5 Chin-Lenn, L. M. (2013) Comparison of outcomes for malignant melanoma of the face treated using
6 mohs micrographic surgery and wide local excision. Dermatologic Surgery, 39: 1637-1645.
7 Reason: not rct, comparison not in pico (mohs v wle [nos]; retrospective, n = 151
8 Cochran, A. J., Bailly, C., Paul, E., Cochran, A. J., Bailly, C. & Paul, E. (2003) Optimal surgery for
9 cutaneous melanoma requires accurate and complete pathologic information. [Review] [17 refs].
10 Facial Plastic Surgery Clinics of North America, 11: 23-32.
12 Cogrel, O. G. (2011) Control of excision margin by micrographic surgery (the spaghetti technique) of
13 in situ or invasive malignant lentigo: A monocentric study of 20 cases. Nouvelles Dermatologiques,
14 30: 49-50.
15 Reason: foreign language
16 Cohen, L. S. (2006) Mohs micrographic surgery for lentigo maligna and lentigo maligna melanoma
17 using mel-5 immunostaining: University of Minnesota experience: Commentary. Dermatologic
18 Surgery, 32: 696-697.
19 Reason: commentary, no original data
20 Coit, D. G. & Coit, D. G. (1993) The role of surgery in cutaneous malignant melanoma. [Review] [166
21 refs]. Cancer Treatment & Research, 65: 297-334.
23 Demirci, H., Johnson, T. M., Frueh, B. R., Musch, D. C., Fullen, D. R. & Nelson, C. C. (2008)
24 Management of periocular cutaneous melanoma with a staged excision technique and permanent
25 sections the square procedure. Ophthalmology, 115: 2295-2300.
27 Duffy, K. L., Truong, A., Bowen, G. M., Andtbacka, R. H., Hyngstrom, J., Bowles, T., Grossmann, K.,
28 Khong, H., Hyde, M., Florell, S. R., Bowen, A. R., Wada, D., and Grossman, D. Adequacy of 5-mm
29 surgical excision margins for non-lentiginous melanoma in situ. Journal of the American Academy of
30 Dermatology 71[4], 835-838. 2014.
31 Reason: No data
32 Eedy, D. J. & Eedy, D. J. (2003) Surgical treatment of melanoma. [Review] [118 refs]. British Journal of
33 Dermatology, 149: 2-12.
35 Elder, D. E., Guerry, D., Heiberger, R. M., LaRossa, D., Goldman, L. I., Clark, W. H., Jr., Thompson, C. J.,
36 Matozzo, I., Van, H. M., Elder, D. E., Guerry, D., Heiberger, R. M., LaRossa, D., Goldman, L. I., Clark,
37 W. H. J., Thompson, C. J., Matozzo, I. & Van Horn, M. (1983) Optimal resection margin for cutaneous
38 malignant melanoma. Plastic & Reconstructive Surgery, 71: 66-72.
39 Reason: retrospective study, n = 105, only relevant results only describe that all six of the in-transit
40 metastases had minimal excision margins > 30 mm
41 Eldh, J. & Eldh, J. (1979) Excisional biopsy and delayed wide excision versus primary wide excision of
42 malignant melanoma. Scandinavian Journal of Plastic & Reconstructive Surgery, 13: 341-345.
43 Reason: not rct, not mohs/johnsons squares/margin <1 cm,

1 Erickson, C. & Miller, S. J. (2010) Treatment options in melanoma in situ: topical and radiation
2 therapy, excision and Mohs surgery. International Journal of Dermatology, 49: 482-491.
4 Esmaeli, B., Youssef, A., Naderi, A., Ahmadi, M. A., Meyer, D. R., McNab, A., Collaborative Eyelid Skin
5 Melanoma Group., Esmaeli, B., Youssef, A., Naderi, A., Ahmadi, M. A., Meyer, D. R., McNab, A. &
6 Collaborative Eyelid Skin Melanoma Group. (2003) Margins of excision for cutaneous melanoma of
7 the eyelid skin: the Collaborative Eyelid Skin Melanoma Group Report. Ophthalmic Plastic &
8 Reconstructive Surgery, 19: 96-101.
9 Reason: not rct, <50 patients in each group
10 Evans, R. A. & Evans, R. A. (1995) Malignant melanoma: primary surgical management (excision and
11 node dissection) based upon pathology and staging. Cancer, 76: 2384-2385.
13 Furukawa, H., Tsutsumida, A., Yamamoto, Y., Sasaki, S., Sekido, M., Fujimori, H., Sugihara, T.,
14 Furukawa, H., Tsutsumida, A., Yamamoto, Y., Sasaki, S., Sekido, M., Fujimori, H. & Sugihara, T. (2007)
15 Melanoma of thumb: retrospective study for amputation levels, surgical margin and reconstruction.
16 Journal of Plastic, Reconstructive & Aesthetic Surgery: JPRAS, 60: 24-31.
17 Reason: not rct, not mohs/johnson squares, comparison was <=4 cm v >4 cm, retrospective, n = 15
18 Gillgren, P. (2011) A randomized multicentre trial comparing 2 versus 4-cm surgical excision margins
19 for thick (>2 mm) primary cutaneous melanoma. Pigment Cell and Melanoma Research, Conference:
20 1061.
21 Reason: abstract
22 Gillgren, P. (2012) 2-cm and 4-cm surgical excision margins did not differ for survival in cutaneous
23 melanoma > 2 mm thick. Annals of Internal Medicine, 156: JC5-JC7.
24 Reason: comment on gillgren rct
25 Grevey, S. C., Zax, R. H., McCall, M. W., Grevey, S. C., Zax, R. H. & McCall, M. W. (1995) Melanoma
26 and Mohs' micrographic surgery. [Review] [65 refs]. Advances in Dermatology, 10: 175-198.
28 Haigh, P. I., DiFronzo, L. A., McCready, D. R., Haigh, P. I., DiFronzo, L. A. & McCready, D. R. (2003)
29 Optimal excision margins for primary cutaneous melanoma: a systematic review and meta-analysis.
30 [Review] [22 refs]. Canadian Journal of Surgery, 46: 419-426.
31 Reason: systematic review with same studies included as in sladden cochrane review, which is
32 included in current evidence review instead.
33 Harish, V., Bond, J. S., Scolyer, R. A., Haydu, L. E., Saw, R. P., Quinn, M. J., Benger, R. S., Uren, R. F.,
34 Stretch, J. R., Shannon, K. F., Thompson, J. F., Harish, V., Bond, J. S., Scolyer, R. A., Haydu, L. E., Saw,
35 R. P. M., Quinn, M. J., Benger, R. S., Uren, R. F., Stretch, J. R., Shannon, K. F. & Thompson, J. F. (2013)
36 Margins of excision and prognostic factors for cutaneous eyelid melanomas. Journal of Plastic,
37 Reconstructive & Aesthetic Surgery: JPRAS, 66: 1066-1073.
39 Harlan, L. C. L. (2011) Trends in the treatment and survival for local and regional cutaneous
40 melanoma in a US population-based study. Melanoma Research, 21: 547-554.
41 Reason: not rct, comprisons not in pico
42 Hazan, C., Dusza, S. W., Delgado, R., Busam, K. J., Halpern, A. C., Nehal, K. S., Hazan, C., Dusza, S. W.,
43 Delgado, R., Busam, K. J., Halpern, A. C. & Nehal, K. S. (2008) Staged excision for lentigo maligna and
44 lentigo maligna melanoma: A retrospective analysis of 117 cases. Journal of the American Academy

1 of Dermatology, 58: 142-148.

2 Reason: comparison and outcome not in pico
3 Heaton, K. M., Sussman, J. J., Gershenwald, J. E., Lee, J. E., Reintgen, D. S., Mansfield, P. F., Ross, M.
4 I., Heaton, K. M., Sussman, J. J., Gershenwald, J. E., Lee, J. E., Reintgen, D. S., Mansfield, P. F. & Ross,
5 M. I. (1998) Surgical margins and prognostic factors in patients with thick (>4mm) primary
6 melanoma. Annals of Surgical Oncology, 5: 322-328.
7 Reason: not rct, not mohs/johnson squares, comparison was <2 cm v >2 cm, retrospective, n = 278
8 Heenan, P. J., Weeramanthri, T., Holman, C. D., Armstrong, B. K., Heenan, P. J., Weeramanthri, T.,
9 Holman, C. D. & Armstrong, B. K. (1985) Surgical treatment and survival from cutaneous malignant
10 melanoma. Australian & New Zealand Journal of Surgery, 55: 229-234.
11 Reason: comparison not in pico (0-29 mm v 30-59 mm v 60+mm)
12 Hilari, H., Llorca, D., Traves, V., Villanueva, A., Serra-Guillen, C., Requena, C., Llombart, B., Sanmartin,
13 O., Guillen, C., Nagore, E., Hilari, H., Llorca, D., Traves, V., Villanueva, A., Serra-Guillen, C., Requena,
14 C., Llombart, B., Sanmartin, O., Guillen, C. & Nagore, E. (2012) Conventional surgery compared with
15 slow Mohs micrographic surgery in the treatment of lentigo maligna: a retrospective study of 62
16 cases. Actas Dermo-Sifiliograficas, 103: 614-623.
17 Reason: comparison and outcome not in pico
18 Hill, D. C. & Gramp, A. A. (1999) Surgical treatment of lentigo maligna and lentigo maligna
19 melanoma. Australasian Journal of Dermatology, 40: 25-30.
21 Hudson, D. A. & Krige, J. E. J. (1993) Conservative Excision for Cutaneous Melanoma on the Face.
22 European Journal of Plastic Surgery, 16: 12-16.
23 not rct, n < 50 in each group
24 Hudson, L. C. (2012) 1 vs 2 cm surgical excision for 1-2 mm melanomas: Does it matter? Annals of
25 Surgical Oncology, Conference: February.
26 Reason: abstract
27 Hudson, L. E., Maithel, S. K., Carlson, G. W., Rizzo, M., Murray, D. R., Hestley, A. C. & Delman, K. A.
28 (2013) 1 or 2 cm margins of excision for T2 melanomas: do they impact recurrence or survival?
29 Annals of Surgical Oncology, 20: 346-351.
30 Reason: not rct, not mohs/johnson squares/margins <1 cm
31 Huilgol, S. C., Selva, D., Chen, C., Hill, D. C., James, C. L., Gramp, A., Malhotra, R., Huilgol, S. C., Selva,
32 D., Chen, C., Hill, D. C., James, C. L., Gramp, A. & Malhotra, R. (2004) Surgical margins for lentigo
33 maligna and lentigo maligna melanoma: the technique of mapped serial excision. Archives of
34 Dermatology, 140: 1087-1092.
36 Jahn, V., Breuninger, H., Garbe, C. & Moehrle, M. (2006) Melanoma of the ear: prognostic factors
37 and surgical strategies. British Journal of Dermatology, 154: 310-318.
39 Jahn, V., Breuninger, H., Garbe, C., Maassen, M. M., Moehrle, M., Jahn, V., Breuninger, H., Garbe, C.,
40 Maassen, M. M. & Moehrle, M. (2006) Melanoma of the nose: prognostic factors, three-dimensional
41 histology, and surgical strategies. Laryngoscope, 116: 1204-1211.

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6 Jewell, W. R. & Jewell, W. R. (1991) Current status of the surgical treatment of melanoma. [Review]
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29 W., Calderon, W., Murillo, L., Dakin, R. L. & Blois, M. S. (1984) The frequency of local recurrence and
30 microsatellites as a guide to reexcision margins for cutaneous malignant melanoma. Annals of
31 Surgery, 200: 759-763.
32 Reason: not rct, n < 50 in each comparison group
33 Kirkham, N., Newton, J., Thomas, M., Kirkham, N., Newton, J. & Thomas, M. (1993) Malignant
34 melanoma excision margins. Lancet, 341: 184.
35 Reason: letter/comment
36 Krown, S. E. C. (2004) Defining Adequate Surgery for Primary Melanoma. New England Journal of
37 Medicine, 350: 823-825.
38 Reason: editorial
39 Kunishige, J. H., Brodland, D. G., Zitelli, J. A., Kunishige, J. H., Brodland, D. G. & Zitelli, J. A. (2012)
40 Surgical margins for melanoma in situ. Journal of the American Academy of Dermatology, 66: 438-
41 444.

1 Lang, N. P., Stair, J. M., Degges, R. D., Thompson, C., Garner, H., Baker, G. F., Westbrook, K. C., Lang,
2 N. P., Stair, J. M., Degges, R. D., Thompson, C., Garner, H., Baker, G. F. & Westbrook, K. C. (1984)
3 Melanoma today does not require radical surgery. American Journal of Surgery, 148: 723-726.
4 Reason: not rct, not johnsons squares/mohs/margins < 1 cm
5 Lange, J. R. & Lange, J. R. (1997) The surgical management of invasive primary melanoma: an update.
6 [Review] [21 refs]. Maryland Medical Journal, 46: 251-254.
8 Lens, M. B., Dawes, M., Goodacre, T., Bishop, J. A., Lens, M. B., Dawes, M., Goodacre, T. & Bishop, J.
9 A. N. (2002) Excision margins in the treatment of primary cutaneous melanoma: a systematic review
10 of randomized controlled trials comparing narrow vs wide excision. [Review] [21 refs]. Archives of
11 Surgery, 137: 1101-1105.
12 Reason: systematic review with same studies included as in sladden cochrane review, which is
14 Lens, M. B., Nathan, P., Bataille, V., Lens, M. B., Nathan, P. & Bataille, V. (2007) Excision margins for
15 primary cutaneous melanoma: updated pooled analysis of randomized controlled trials. Archives of
16 Surgery, 142: 885-891.
17 Reason: systematic review with same studies inlcuded as in sladden cochrane review, which is
19 Livingstone, E., Windemuth-Kieselbach, C., Eigentler, T. K., Rompel, R., Trefzer, U., Nashan, D.,
20 Rotterdam, S., Ugurel, S., Schadendorf, D., Livingstone, E., Windemuth-Kieselbach, C., Eigentler, T. K.,
21 Rompel, R., Trefzer, U., Nashan, D., Rotterdam, S., Ugurel, S. & Schadendorf, D. (2011) A first
22 prospective population-based analysis investigating the actual practice of melanoma diagnosis,
23 treatment and follow-up. European Journal of Cancer, 47: 1977-1989.
25 Macdonald, C. (2013) The impact on quality of life and reconstructive need of wider excision margins
26 >1 cm for primary cutaneous melanoma. JDDG - Journal of the German Society of Dermatology,
27 Conference: July.
28 Reason: abstract
29 Mansfield, P. F., Lee, J. E., Balch, C. M., Mansfield, P. F., Lee, J. E. & Balch, C. M. (1994) Cutaneous
30 melanoma: current practice and surgical controversies. [Review] [425 refs]. Current Problems in
31 Surgery, 31: 253-374.
33 Margolese, R. G. & Margolese, R. G. (306) Controversy in the surgical management of melanoma.

34 Canadian Journal of Surgery, 26: 303-304.
35 Reason: letter
36 Matter, M. L. (2003) Surgical treatment of malignant melanoma. Medecine et Hygiene, 61: 1088-
37 1097.
39 McCall, M. W., Greenway, H. T., Mohs, F. E., McCall, M. W., Greenway, H. T. & Mohs, F. E. (1981)
40 Mohs' chemosurgery for skin cancer, microscopically controlled excision. [Review] [19 refs]. Journal
41 of the Kentucky Medical Association, 79: 613-616.
43 McKenna, D. B., Lee, R. J., Prescott, R. J., Doherty, V. R., McKenna, D. B., Lee, R. J., Prescott, R. J. &
44 Doherty, V. R. (2004) A retrospective observational study of primary cutaneous malignant melanoma

1 patients treated with excision only compared with excision biopsy followed by wider local excision.
2 British Journal of Dermatology, 150: 523-530.
3 Reason: comparison not in pico
4 McLeod, M., Choudhary, S., Giannakakis, G. & Nouri, K. (2011) Surgical treatments for lentigo
5 maligna: a review. Dermatol.Surg., 37: 1210-1228.
7 Mocellin, S., Pasquali, S., Nitti, D., Mocellin, S., Pasquali, S. & Nitti, D. (2011) The impact of surgery on
8 survival of patients with cutaneous melanoma: revisiting the role of primary tumor excision margins.
9 Annals of Surgery, 253: 238-243.
10 Reason: systematic review with same studies inlcuded as in sladden cochrane review, which is
12 Mosca, P. J., Tyler, D. S., Seigler, H. F., Mosca, P. J., Tyler, D. S. & Seigler, H. F. (2004) Surgical
13 management of cutaneous melanoma: current practice and impact on prognosis. [Review] [128
14 refs]. Advances in Surgery, 38: 85-119.
16 Murphy, M. E., Brodland, D. G., Zitelli, J. A., Murphy, M. E., Brodland, D. G. & Zitelli, J. A. (2008)
17 Definitive surgical treatment of 24 skin cancers not cured by prior imiquimod therapy: a case series.
18 Dermatologic Surgery, 34: 1258-1263.
19 Reason: not in pico, 1/24 patients had melanoma
20 Neades, G. T., Hughes, L. E., Neades, G. T. & Hughes, L. E. (1990) Cure and cosmesis in the
21 management of primary malignant melanoma. [Review] [29 refs]. British Journal of Cancer, 61: 192-
22 194.
23 Reason: editorial
24 Neades, G. T., Orr, D. J., Hughes, L. E., Horgan, K., Neades, G. T., Orr, D. J., Hughes, L. E. & Horgan, K.
25 (1993) Safe margins in the excision of primary cutaneous melanoma. British Journal of Surgery, 80:
26 731-733.
27 Reason: comparisons not in pico (includes mixed margins, i.e., 1 or 2 cm versus 1, 2, or 3-5 cm)
28 Newman, L. (2001) Surgical oncology focusing on minimally invasive surgery, more randomized
29 clinical trials. Journal of the National Cancer Institute, 93: 897-899.
31 Ng, A. K., Jones, W. O., Shaw, J. H., Ng, A. K., Jones, W. O. & Shaw, J. H. (2001) Analysis of local
32 recurrence and optimizing excision margins for cutaneous melanoma. British Journal of Surgery, 88:
33 137-142.
34 Reason: not rct, group size not reported by excision margin per se, but only split by excision margin
35 and lesion thickness with n <50 patients in each group
36 Nguyen, J. T., Bakri, K., Nguyen, E. C., Johnson, C. H., Moran, S. L., Nguyen, J. T., Bakri, K., Nguyen, E.
37 C., Johnson, C. H. & Moran, S. L. (2013) Surgical management of subungual melanoma: mayo clinic
38 experience of 124 cases. Annals of Plastic Surgery, 71: 346-354.
39 Reason: not rct, <50 patients in each group, not sure comparisons in pico
40 O'Rourke, M. G., Altmann, C. R., O'Rourke, M. G. & Altmann, C. R. (1993) Melanoma recurrence after
41 excision. Is a wide margin justified? Annals of Surgery, 217: 2-5.
42 Reason: not rct, comparison not in pico (15 mm or less v > 15 mm), etrospective, n = 187, not
43 mohs/johnson squares

1 Pasquali, S., Haydu, L. E., Scolyer, R. A., Winstanley, J. B., Spillane, A. J., Quinn, M. J., Saw, R. P. M.,
2 Shannon, K. F., Stretch, J. R. & Thompson, J. F. (2013) The Importance of Adequate Primary Tumor
3 Excision Margins and Sentinel Node Biopsy in Achieving Optimal Locoregional Control for Patients
4 With Thick Primary Melanomas. Annals of Surgery, 258: 152-157.
5 Reason: comparison not in pico (16 mm or less v > 16 mm), prospective/retrospective?, n = 632, not
6 mohs/johnson squares
7 Rahim, R., Charlton, F., Husain, A. & Lawrence, C. (2012) Slow Mohs surgery for lentigo maligna: a
8 follow-up study. British Journal of Dermatology, 167: 79.
9 Reason: abstract
10 Reali, U. M. (1991) Stage I cutaneous melanoma: Surgical treatment and follow-up. Rivista Italiana di
11 Chirurgia Plastica, 23: 1-6.
13 Robinson, J. K. & Robinson, J. K. (1994) Margin control for lentigo maligna. Journal of the American
14 Academy of Dermatology, 31: 79-85.
16 Rogers, G. S. & Rogers, G. S. (1989) Narrow versus wide margins in malignant melanoma. Journal of
17 Dermatologic Surgery & Oncology, 15: 33-34.
18 Reason: narrative review of cascinelli rct already included.
19 Rosin, R. D. & Rosin, R. D. (1985) The treatment of malignant melanoma. [Review] [46 refs].
20 European Journal of Surgical Oncology, 11: 111-115.
22 Schreiber, M. M. & Schreiber, M. M. (1981) Primary malignant melanoma of the skin: factors in
23 predicting prognosis and in determining initial surgical treatment. [Review] [47 refs]. Cutis, 27: 494-
24 498.
26 Sladden, M. J. (2012) Sufficiency and Safety of 2-cm Excision Margin for Stage IIA Through Stage IIC
27 Cutaneous Melanoma. Archives of Dermatology, 148: 1197-1198.
28 Reason: comment on Gillgren
29 Smith, A. A., Cole, A. B., Fosko, S. W., Smith, A. A., Cole, A. B. & Fosko, S. W. (2003) Melanoma from
30 the dermatologist's perspective. [Review] [87 refs]. Facial Plastic Surgery Clinics of North America,
31 11: 277-286.
33 Sondak, V. K. Z. (2014) Melanoma: MSLT-1 - Putting sentinel lymph node biopsy into context. Nature
34 Reviews Clinical Oncology, 11: 246-248.
35 Reason: review of Sondak (2014) which is not in pico
36 Stander, S., Assmann, K., Nashan, D., Wigbels, B., Luger, T. & Metze, D. (2000) Modified micrographic
37 surgery for malignant melanomas of the face. Hautarzt, 51: 826-832.
39 Taylor, B. A. H. (1985) A policy of selective excision for primary cutaneous malignant melanoma.
40 European Journal of Surgical Oncology, 11: 7-13.

1 Thomas, J. M. (1993) Width of excision of malignant melanoma of thickness 2 mm or greater. A

2 randomized study - 1 cm vs 3 cm [abstract]. European Journal of Surgical Oncology, 19: 497.
3 Reason: abstract
4 Thomas, J. M. (1994) Randomised trial of width of excision of thick cutaneous malignant melanoma.
5 British Journal of Plastic Surgery, 47: 581-582.
6 Reason: letter
7 Thomas, J. M. N. (2004) Primary tumour excision with a surrounding margin of 3 cm reduced

8 recurrence in melanomas > 2 mm thick. Evidence-Based Medicine, 9: 183.
9 Reason: comment on Thomas 2004
10 Timmons, M. J., Thomas, J. M., Timmons, M. J. & Thomas, J. M. (1993) The width of excision of
11 cutaneous melanoma. [Review] [14 refs]. European Journal of Surgical Oncology, 19: 313-315.
13 Timmons, M. J. & Timmons, M. J. (1997) Selecting surgery for malignant melanoma. [Review] [15
14 refs]. Clinical & Experimental Dermatology, 22: 115-117.
16 Trost, O., Danino, A. M., Dutronc, Y., Dalac, S., Lambert, D., Malka, G., Trost, O., Danino, A. M.,
17 Dutronc, Y., Dalac, S., Lambert, D. & Malka, G. (2003) Is sentinel node biopsy beneficial in melanoma
18 patients? A report on 200 patients with cutaneous melanoma (EJSO 2002; 28: 673--678). European
19 Journal of Surgical Oncology, 29: 699.
20 Reason: letter
21 Tseng, J. F., Tanabe, K. K., Gadd, M. A., Cosimi, A. B., Malt, R. A., Haluska, F. G., Mihm, M. C., Jr.,
22 Sober, A. J., Souba, W. W., Tseng, J. F., Tanabe, K. K., Gadd, M. A., Cosimi, A. B., Malt, R. A., Haluska,
23 F. G., Mihm, M. C. J., Sober, A. J. & Souba, W. W. (1997) Surgical management of primary cutaneous
24 melanomas of the hands and feet. Annals of Surgery, 225: 544-550.
26 Urist, M. M. & Urist, M. M. (1996) Surgical management of primary cutaneous melanoma. [Review]
27 [40 refs]. CA: a Cancer Journal for Clinicians, 46: 217-224.
29 van Akkooi, A. C., Voit, C. A., Verhoef, C., Eggermont, A. M., van Akkooi, A. C. J., Voit, C. A., Verhoef,
30 C. & Eggermont, A. M. M. (2010) Potential cost-effectiveness of US-guided FNAC in melanoma
31 patients as a primary procedure and in follow-up. Annals of Surgical Oncology, 17: 660-662.
32 Reason: letter
33 Veronesi, U., Cascinelli, N., Veronesi, U. & Cascinelli, N. (1985) Margins of of resection of malignant
34 melanomas that are less than the hitherto conventional "wide and deep" margins are not advisable
35 as yet. [Review] [16 refs]. American Journal of Dermatopathology, 7 Suppl: 123-126.
36 Reason: letter/response to other paper
37 Walling, H. W., Scupham, R. K., Bean, A. K., Ceilley, R. I., Walling, H. W., Scupham, R. K., Bean, A. K. &
38 Ceilley, R. I. (2007) Staged excision versus Mohs micrographic surgery for lentigo maligna and lentigo
39 maligna melanoma. Journal of the American Academy of Dermatology, 57: 659-664.
40 Reason: not rct, group sizes = 41 patients for staged excision and 16 patients for mohs, i.e., <50
41 patients per group

1 Wayne, J. D. K. (2010) Recurrence of head and neck melanoma is not affected by reducing margins of
2 wide local excision (WLE). Annals of Surgical Oncology, Conference: February.
3 Reason: abstract
4 Welvaart, K., Hermans, J., Zwaveling, A., Ruiter, D. J., Welvaart, K., Hermans, J., Zwaveling, A. &
5 Ruiter, D. J. (1986) Prognoses and surgical treatment of patients with stage I melanomas of the skin:
6 a retrospective analysis of 211 patients. Journal of Surgical Oncology, 31: 79-86.
7 Reason: not rct, comparisons not in pico, n < 50 in one of the comparison groups
8 Wheatley, K., Wilson, J., Gaunt, P. & Marsden, J. (2013) Are Narrow Surgical Excision Margins for
9 Primary Cutaneous Melanoma Safe? An Updated Systematic Review and Meta-Analysis. Journal der
10 Deutschen Dermatologischen Gesellschaft, 11: 10.
11 Reason: abstract
12 Whitman, E. D. & Whitman, E. D. (2003) Surgical margins in melanoma. [Review] [18 refs]. Facial
13 Plastic Surgery Clinics of North America, 11: 87-91.
15 Wright, E. H., Stanley, P. R., Roy, A., Wright, E. H., Stanley, P. R. W. & Roy, A. (2010) Evaluation of
16 sentinel lymph nodes positive for melanoma for features predictive of non-sentinel nodal disease
17 and patient prognosis: a 49 patient series. Journal of Plastic, Reconstructive & Aesthetic Surgery:
18 JPRAS, 63: e500-e502.
20 Wright, F., Spithoff, K., Easson, A., Murray, C., Toye, J., McCready, D., Petrella, T., Melanoma Disease
21 Site Group of Cancer Care Ontario's Program in Evidence-based Care., Wright, F., Spithoff, K., Easson,
22 A., Murray, C., Toye, J., McCready, D., Petrella, T. & Melanoma Disease Site Group of Cancer Care
23 Ontario's Program in Evidence-based Care. (2011) Primary excision margins and sentinel lymph node
24 biopsy in clinically node-negative melanoma of the trunk or extremities. Clinical Oncology (Royal
25 College of Radiologists), 23: 572-578.
26 Reason: guideline (checked for relevant included studies)
27 Yeung, R. S. & Yeung, R. S. (1993) Recurrent cutaneous melanoma: a surgical perspective. [Review]
28 [129 refs]. Seminars in Oncology, 20: 400-418.
30 Zalla, M. J., Lim, K. K., DiCaudo, D. J. & Gagnot, M. M. (2000) Mohs micrographic excision of
31 melanoma using immunostains. Dermatologic Surgery, 26: 771-784.
33 Zitelli, J. A., Brown, C. & Hanusa, B. H. (1997) Mohs micrographic surgery for the treatment of
34 primary cutaneous melanoma. Journal of the American Academy of Dermatology, 37: 236-245.
35 Exclusion reason: comparative, but only with historical controls
36 Zitelli, J. A. (1998) Mohs micrographic surgery for lentigo maligna and lentigo maligna melanoma: A
37 follow-up study - Commentary. Dermatologic Surgery, 24: 677.
38 Reason: comment
39

Evidence Tables
Study Quality (Systematic Reviews)
Clearly Includes studies Rigorous Study Adequate Quality

focused relevant to literature quality description of
Question? review search? assessed? methodology?
question?
Sladden et al Yes Yes Yes Yes Yes High

(2009)
Study Quality (Randomised Controlled Trials)
Appropria Adequate Groups Based on Groups Participant Individuals Based on Equal Treatment
te method allocation previous three received s receiving administerin previous three length of completion
of compara questions, care blind g care blind questions, what follow-up rates
concealment?
randomisa ble at what is the same care to to treatment is the likely risk between comparable
tion? baseline? likely risk (and, apart treatment allocation? (and, if high, the between the
if high, from allocation? direction) of groups? groups (state
direction) of interventio performance numbers)?
selection bias? n? bias?
Gillgren Yes Yes Yes Low risk Yes Unclear No Unclear risk Yes Yes
et al
(2011)
Availabilit Based on Appropri Precise Valid and Outcome Outcome Based on Quality
y of previous three ate definition of reliable assessors assessors previous five
outcome questions, length of method blind to blind to questions, what

data what is the follow- outcome? used to participant other is the likely risk
comparabl likely risk up? determine s’ exposure important (and, if high,
e between (and, if high, outcome? to confounding direction) of
the groups direction) of interventio and detection bias?
(state attrition bias? n? prognostic
numbers)? factors?
Gillgren Yes Low risk Yes Yes Yes Unclear Unclear Unclear risk Moderate
et al
(2011)
Study characteristics
Study Study Type Aim Population Intervention Comparison Further study details
Sladden Systematic To assess the N=3297 (from 5 Narrow Wide
et al Review of effects of studies including excision excision
(2009) RCTs different patients with margin margin
excision margins cutaneous
for primary melanoma). The
cutaneous five RCTs differed
melanoma. in interventions
and populations
and are therefore
summarised
separately below:

Balch et al (2001): 2 cm margin 4 cm margin - Duration of follow up: 10 years
All patients had - Multicentre, trial conducted in US, Canada, Denmark, South
cutaneous (N = 238) (N = 232) Africa involving 93 surgeons practising in 77 centres.
melanoma of 1-4 - “Excision margins measured with a ruler. Lesions could be excised
mm thickness on with a larger margin in one direction to create elliptical defect,
trunk or limbs, with thus easing closure. Underlying subcutaneous tissue, down to or
no evidence of including the underlying muscular fascia, was incorporated into the
metastatic
melanoma in surgical specimen. Definitive resection was performed within 45
lymph nodes or days after biopsy.”
distant sites, aged - “Local recurrence defined as a biopsy-proven first recurrence
18-81 years within 2 cm of the scar”.
Exclusions:
Previous cancer, -“ ’Each participant was also randomly assigned to receive ELND
chemotherapy, (elective lymph node dissection) or observation of the regional
radiotherapy and lymph nodes with delayed lymph node dissection only if clinically
any other adjunct indicated.’ ’Participants receiving ELND were evenly distributed
to surgery; lentigo
between the two treatment arms involving surgical margins, so any
maligna
survival differences that may result from ELND would not influence
the survival outcome from the surgical margin issue’ “.
(All quotes from Sladden et al 2009, pages 20-21).

Cascinelli et al 1 cm margin ≥3 cm - Duration of follow-up: 12 years
(1998): margin - Multicentre, multinational trial with recruitment from 1980 to
All patients had 1985.
cutaneous (N = 305) (N = 307) - “Wide excision was defined as a cutaneous incision made at least
melanoma with ≤ 2 3 cm from the grossly visible margins of the melanoma or from the
mm thickness on scar if the primary melanoma had already been biopsied; the
trunk or limbs (not excisions had to be 1 to 2 cm wider in the subcutaneous fat
fingers, toes, face); extending to muscle fascia.”
aged ≤ 65 years.
Exclusions: - “Narrow excisions were performed according to the same
Melanoma technique; the only difference was that the cutaneous incisions
satellites, multiple were made 1 cm from the visible margins of the primary
primaries, previous melanoma.”
cancer, impossinle - “The margins were measured by the surgeon at the time of the
regular follow-up, operation. Definite surgical treatment was to be performed within
inadequate 6 weeks of the primary diagnostic procedure”.
histological
documentation, - “The trial was published as 3 reports: 1988, 1991, and 1998
biopsy > 6 weeks
The 1988 paper states that ’local recurrences and in-transit and
before definite
nodal metastases were defined as in the TNM staging system
treatment
(IUAC, 1978)’ ......The 1991 paper states that local recurrence was
defined as cutaneous or subcutaneous nodules in scar or within 1
cm of scar”.
- “Concimitant treatment was permitted with guidelines given for

treatment in the first 5 years of follow-up: 1. Local recurrence to

be removed by wide local excision within 4 weeks of diagnosis;
2. If nodal metastases, standard axillary/inguino-iliac node

dissection within 4 weeks; 3. Adjuvant treatment could be given
for after surgery for nodal metastases (defined pretrial); and
4. Distant metastases to be treated with chemotherapy, in the first

instance, dacarbazine”.
Cohn-Cedermark et 2 cm margin ≥5 cm - Duration of follow-up: 11 years overall survival), 8 years

al (2000): margin (recurrence-free survival)
All patients had - Multicentre trial conducted in Sweden in 5 regional oncologic
cutaneous (N = 476) (N = 513) centres/ 39 clinics (38 hospitals) with recruitment from 1982 to
melanoma with > 1991.
0.8 mm ≤ 2 mm - “Definite surgical treatment was to be performed within 6 weeks
thickness on trunk of the primary diagnostic procedure (i.e. all initially received 2 cm
or extremity (not margin, then those randomised to wide excision received
fingers, feet, face); secondary procedure within 6 weeks)”.
any age. - “Local recurrence was defined as a recurrence in the ’scar or
Exclusions: transplant’. Other forms of recurrence are not defined”.
Melanoma
satellites, - “The standard salvage treatment after locoregional disease
metastatic disease, recurrence was surgery. After repeated locoregional recurrences,
previous cancer some participants were treated with limb perfusion. In the event
of distant dissemination, chemotherapy was given at the discretion
of the respective physician”.
(All quotes from Sladden et al 2009, page 23).

Khayat et al (2003): 2 cm margin ≥5 cm - Duration of follow-up: 16 years
All patients had margin
- Multicentre trial undertaken in Europe.
melanoma with ≤ 2
mm thickness on (N = 167) (N = 170) - “Resection was performed within a month of the initial biopsy (if
trunk, limbs, head needed to obtain the
and neck (not overall 2 or 5 cm margin). Excisions extended down to the muscle
fingers, toes, nails); fascia. Lymph node
TNM stage 1; aged
< 70 years. dissections not performed”.
Exclusions:
- “Local disease recurrence defined as recurrence within 2 cm of
Melanomas arising
the scar”
from melanosis,
lentigo, acral - “In-transit metastases was defined as disease recurrence
lesions. between the primary tumour site
and the regional lymph node”
- “Certain concomitant treatment was permitted. Local or regional

tumours that recurred were removed surgically. Metastatic
tumours were treated with chemotherapy or biochemotherapy”.
- “A second randomisation allocated the participant to either 12

months of adjuvant treatment with Isoprinosine or to no adjuvant
treatment. Participant characteristics, including
surgical margins were balanced between the 2 groups based on

the immunotherapy
randomisation. This second randomisation to receive or not to

receive Isoprinosine did
not appear to affect the outcome of these participants. The

median survival periods with
or without the drug were 190 months and 192 months respectively
(P = 0.9) and the
disease-free survival periods were 149.5 months and 153.3 months

respectively (P = 0.89)”.
Thomas et al 1 cm margin 3 cm margin - Duration of follow-up: 5 years

(2004):
All patients had (N = 453) (N = 447) - Multicentre trial undertaken in UK and Poland, with recruitment
single, primary, from 1993 to 2001
localised cutaneous - “Participating surgeons chose 1 of 2 primary treatment
melanoma with ≥ 2 approaches. The primary tumor could be excised before
mm thickness on randomisation, with either a 1 mm or a 1 cm margin to confirm the
trunk or limbs (not diagnosis and determine the thickness of the lesion. The
palms of hands, participants were then randomly assigned to receive a 1 or 3 cm
soles of feet); aged margin after the 1 mm primary excision or to receive no further
≥ 18 years. treatment or an additional 2 cm margin after the 1 cm primary
Exclusions: excision. The trial surgery was to be performed within 45 days
Previous cancer, after the primary excision, and all excisions were to extend to or
immuno- include the deep fascia. Sentinal lymph node biopsy was not
suppressive performed”.
therapy

- “Local recurrence defined as a recurrence within 2 cm of the scar
or graft.”
- “ In-transit recurrence was defined as a recurrence from beyond

the first 2 cm of the scar or graft to the regional nodes.”
- “All locoregional recurrences were detected clinically and

confirmed by biopsy. “
Gillgren Randomised To assess the All patients had 2 cm margin 4 cm margin - Duration of follow-up: 6.7 years overall, and 11.8 years in the
et al controlled effects of 2 cm cutaneous Swedish cohort.
(2011) trial and 4 cm melanoma with > 2 (N = 470) (N = 459)
excision margins mm thickness, - Multicentre trial undertaken in Sweden, Denmark, Estonia and
for primary clinical stage 2A-C, Norway in 53 hospitals, with recruitment from 1992 to 2004.
cutaneous with clinically - “The primary excision of the tumour could be done either by an
melanoma localised disease excisional biopsy (margin of 1–3 mm) or with a 2-cm margin if
thicker than 2 on trunk or upper cutaneous melanoma was strongly suspected. Thus, patients could
mm. or lower be allocated to receive either no further surgery (those operated
extremities(not on with a 2-cm margin and randomised to the 2-cm group) or to an
hands, foot, head- additional wide local excision with a margin of up to either 2 cm or
neck, anogenital 4 cm. Surgical excisions were to extend to, or include, the deep
region); aged ≤ 75 fascia.... Radical surgery was to be performed within 8 weeks after
years. the date of diagnosis”. (page 1636).
Exclusions:
Previous cancer. - Local recurrence was defined as a recurrence in the scar or

transplant.
- “The time of an event was measured from the date of
randomisation. For calculation of overall survival, the time to death

was used, irrespective of cause. Patients who were diagnosed with
a second cutaneous melanoma during the study were censored
when analysing time to first relapse (recurrence-free survival) but
were included in the overall survival analyses. For recurrence-free
survival, either time to first cutaneous melanoma relapse or time

to cutaneous melanoma-related death was used (whichever
occurred first). Randomised patients with a new, non-lethal malig
nancy other than cutaneous melanoma were still included in the
study, and if a cutaneous melanoma event occurred it was
included in the recurrence-free survival analyses.” (pages 1637-
1638)
- Intention-to-treat analyses performed.
- Adverse events not systematically recorded.

1 4.2 The use of imiquimod in stage 0 melanoma and skin metastases
2 Review question: How effective is imiquimod in the treatment of stage 0 melanoma and
3 skin metastases?
4 Background
5 Stage 0 Melanoma (Melanoma in situ) means the melanoma cells are only in the top surface layer of
6 skin cells (the epidermis) and have not spread into the deeper layers.
7 Currently surgical excision is the treatment of choice but this can be difficult for some patients if
8 1. their stage 0 Melanoma is large

9 2. their stage 0 Melanoma is on a surgically sensitive area such as the face
10 3. the patients themselves have other illnesses which make them a surgical risk
11 4. combination of the above
12 As stage 0 Melanoma is confined to the top surface layer of the skin, we want to ask the question to
13 see if imiquimod cream is as effective as surgery or other treatments such as radiotherapy,
14 cryotherapy, laser treatment or another treatment cream called 5 FU.
15 Imiquimod is a cream that is applied to the skin for about 3 months every day to the stage 0
16 melanoma. It causes redness, irritation and could be sore. The redness and irritation clears up a
17 couple of weeks after the cream is stopped.
18 Imiquimod works by changing the body’s immune response and it is speculated that it can promote
19 an immune response against Melanoma.
20 Another question we want to ask is if imiquimod can be used on melanoma skin metastases. This is
21 when the original melanoma has been treated previously but then has spread to other parts of the
22 skin, or rarely the patient may present with skin metastases and the original melanoma has yet to be
23 found. Often the patient can have multiple skin metastases which makes treatment by surgery
24 difficult. We want to know how good imiquimod is at treating these skin metastases and how it is
25 tolerated by the patients.
26 Review question in PICO format
Population Intervention Comparisons Outcomes

Patients diagnosed Imiquimod:  Surgery  Local control
with melanoma  Radiotherapy  Regional disease
 Three times a  Cryotherapy  Overall survival
Subgroups: week for 6  5FU (1,5 and 10
weeks  Laser years)
 Stage 0  Daily for 5  No treatment  Adverse events
 Skin days out of 7  Cosemesis
metastases for 6 weeks  HRQOL
 Daily for 12
weeks

1 How the information will be searched
Searches: (To be Completed by subgroup lead)
Can we apply date limits to the search Since imiquimod became available, (20 years)
Are there any study design filters to be used RCTs systematic reviews preferred but we may need
(RCT, systematic review, diagnostic test). to consider large case series
List useful search terms. Lentigo maligna, Hutchinson’s freckle, in situ

melanoma, Stage 0 melanoma
Melanoma skin metastases
Imiquimod, aldara
2 The review strategy
What data will we extract and how will we Relevant studies will be identified through sifting
analyse the results? the abstracts and excluding studies clearly not
relevant to the PICO. In the case of relevant or
potentially relevant studies, the full paper will be
ordered and reviewed, whereupon studies
considered to be not relevant to the topic will be
excluded.
Studies which are identified as relevant will be

critically appraised and quality assessed using
GRADE methodology and/or NICE checklists.
Data relating to the identified outcomes will be
extracted from relevant studies.
If possible a meta-analysis of available study data

will be carried out to provide a more complete
picture of the evidence body as a whole.
An evidence summary outlining key issues such

as volume, applicability and quality of evidence
and presenting the key findings from the
evidence as it relates to the topic of interest will
be produced.
List subgroups here and planned statistical

analyses.

1 Search Results

Medline 1946-2013 183 88 03/09/2013
Premedline 30 Aug 2013 10 1 03/09/2013
Embase 1947-2013 368 99 03/09/2013
June 2013
SSCI)
2 Update Search
4 of September 2013 onwards.

Medline 11 4 15/10/2014
Embase 47 16 15/10/2014
6 1. exp Melanoma/
7 2. melanoma$.tw.
10 5. dubreuilh.tw.
11 6. LMM.tw.
12 7. or/1-6
13 8. imiquimod.tw.
14 9. aldara.tw.
15 10. zyclara.tw.
16 11. or/8-10
17 12. 7 and 11
18

1 Screening Results
166 Additional records identified through

Records identified through database other sources
searching 0
166
166 138

28 20

8
2
3

2 Stage 0 melanoma (lentigo maligna)
3 There was no evidence on the relative effectiveness of imiqimod compared with other treatments
4 for people with stage 0 melanoma.
5 Very low quality evidence suggests that when punch biopsy is used to assess treatment success,
6 complete response rates range from 73% to 87% (Buettiker et al 2008; Wong et al 2012 ; Powell et al
7 2009 and Naylor et al 2003) .
8 Very low quality evidence suggests that when wide local excision of the tumour location is used to
9 assess treatment success, complete response rates range from 53% to 64% (Ly et al 2011; Hyde et al
10 2012).
11 Very low quality evidence suggests that inflammation, erythema and irritation of the treatment area
12 are common adverse effects with imiquimod treatment in people with stage 0 melanoma.
13 Imiquimod treatment is stopped due to intolerable toxicity in between 0% and 7% of cases.
14 Melanoma skin metastases
15 There was no evidence on the relative effectiveness of imiqimod compared with other treatments
16 for people with melanoma skin metastases.
17 Very low quality evidence suggests that imiquimod combined with IR-laser (Li et al 2010) or
18 interleukin-2 (Green et al, 2007) can visibly clear some skin metastases in patients with melanoma.
19 Grade 3 adverse events occurred in 25% of patients in Li et al (2010) and 20% of patients in Green et
20 al (2007) required antibiotic treatment for local infections.

GRADE Table 4.2 imiquimod versus surgery, radiotherapy, cryotherapy, 5FU, laser or no treatment for stage 0 melanoma.
Quality assessment No of patients Effect Quality
No of Design Risk of Inconsistency Indirectness Imprecision Other Imiquimod Surgery, Relative Absolute
studies bias considerations Radiotherapy, (95%
Cryotherapy, 5FU, CI)
Laser, No
treatment
Complete treatment response (Buettiker, 2008; Wong, 2012; Powell, 2009; Naylor, 2003; Ly, 2011; Hyde, 2012)
2
6 observational no no serious no serious serious none 154/216 - - - VERY
1
studies serious inconsistency indirectness (71.3%) LOW
risk of
bias
Regional disease - not reported
0 - - - - - none - - - -
Overall survival - not reported
0 - - - - - none - - - -
Treatment discontinued due to intolerable side effects (Powell, 2009; Naylor, 2003; Ly, 2011; Hyde, 2012 )
2
4 observational no no serious no serious serious none 7/167 - - -
1
studies serious inconsistency indirectness (4.2%) VERY
risk of LOW

Laser, No
treatment
bias
Health related quality of life - not reported
0 - - - - - none - - - -
1
Case series and one RCT comparing imiquimod with and without tazarotene
2
Low number of events

GRADE Table 4.3 imiquimod versus surgery, radiotherapy, cryotherapy, 5FU, laser or no treatment for melanoma skin metastases.
Laser, No treatment
Overall mortality (follow-up 21 to 64 months) (Li, 2010)
2 3
1 observational no no serious serious serious none 6/11 - - -
1
studies serious inconsistency (54.5%) VERY
risk of LOW
bias
Complete macroscopic response of treated metastases (per lesion) (Green, 2007)
2 3
1
risk of LOW
bias
Complete macroscopic response of treatment site lesions (per patient) (Li, 2010)
2 3
1
risk of LOW
bias
New metastatic lesions appearing during treatment (Green, 2007)

Laser, No treatment
2 3
1
studies serious inconsistency (70%) VERY
risk of LOW
bias
Treatment discontinued due to intolerable side effects (Green, 2007)
2 3
1
studies serious inconsistency (0%) VERY
risk of LOW
bias
One or more Grade 3 adverse events during treatment (Li, 2010)
2 3
1
risk of LOW
bias
Health related quality of life - not reported
0 - - - - - none - - - -
1
case series
2
Treatment differs to that specified in the PICO for this question: imiquimod was combined with IR-laser (Li, 2010) or interleukin-2 (Green,2007) in the included studies.
3

Table 4.2. Imiquimod in stage 0 melanoma
Study N Imiquimod Assessment of treatment Complete Treatment Treatment stopped due Other toxicities
regimen* response response failure to toxicity
Buettiker 32 Daily for 7 weeks 3mm punch biopsies only in 25/32 (78%) 7/32 (22%) Not reported Telangiectasia 4/12;
(2008) those with residual irritation of treatment area
pigmentation was common
Wong 26 3 times per week 3mm punch biopsies 19/26 (73%) 7/26 (27%) Not reported Inflammation, erythema
(2012) for around 20 and crusting were common
weeks
Powell 48 3 times per week 1 or 2 X 4mm punch 37/48 (77%) 11/48 (23%) 3/48 (6%) Scarring 0/48; cytokine
(2009) for 6 to 10 weeks biopsies, adjacent to release syndrome 0/48
diagnostic biopsy site.
Naylor 30 Daily for 12 weeks 4 X 2mm punch biopsies 26/30 (87%) 4/30 (13%) None – but treatment Irritation of treatment area,
(2003) was paused in 10/30 30/30;
due to toxicity
Severe skin reaction, 10/30;
Infection needing
antibiotics, 5/30;
cytokine release syndrome

2/30
Ly (2011) 38 5 times per week Excision of tumour area 20/38 (53%) 18/38 (47%) 3/43 (7%) Not reported
for 12 weeks with 5mm margin

Study N Imiquimod Assessment of treatment Complete Treatment Treatment stopped due Other toxicities
regimen* response response failure to toxicity
Hyde 42 5 times per week Excision of tumour area 27/42 (64%) 15/42 (36%) 1/46 (2%) Not reported
(2012) for 12 weeks with 2mm margin
*Treatment was usually intensified if there was insufficient inflammatory response

Table 4.3. Imiquimod in melanoma skin metastases
Study N Imiquimod treatment Additional Assessment of Treatment response Treatment Other toxicity
regimen treatments treatment response stopped due to
toxicity
Green 13 (182 Daily for 15 to 53 Interleukin-2 Macroscopic Per lesion: complete response 0/10 Erythema, discharge ,
(2007) lesions) weeks appearance and size 74/182 (41%), partial response mild flu like symptoms,
of lesions (no 18/182 (10%), stable disease 83/182 Infection needing
histology) (29%), progressive disease 33/182 antibiotics, 2/10;
(18%)
Li 11 Twice daily for 2 Infrared laser Macroscopic Best overall response for treated Not reported Grade 3 toxicity in 25%
(2010) weeks before and appearance and size area: complete response 7/11 (64%), of patients; Grade 1-2
after 2 weeks of laser of lesions (no partial response 2/11 (18%), stable toxicity was common
treatment histology) disease 1/11 (9%).

1 References
2 Included Studies
3 Buettiker, U. V., Yawalkar, N. Y., Braathen, L. R., Hunger, R. E., Buettiker, U. V., Yawalkar, N. Y. et al.
4 (2008). Imiquimod treatment of lentigo maligna: an open-label study of 34 primary lesions in 32
5 patients. Archives of Dermatology, 144, 943-945.
6 Green, D. S., Bodman-Smith, M. D., Dalgleish, A. G., Fischer, M. D., Green, D. S., Bodman-Smith, M.
7 D. et al. (2007). Phase I/II study of topical imiquimod and intralesional interleukin-2 in the treatment
8 of accessible metastases in malignant melanoma. British Journal of Dermatology, 156, 337-345.
9 Hyde, M. A., Hadley, M. L., Tristani-Firouzi, P., Goldgar, D., Bowen, G. M., Hyde, M. A. et al. (2012). A
10 randomized trial of the off-label use of imiquimod, 5%, cream with vs without tazarotene, 0.1%, gel
11 for the treatment of lentigo maligna, followed by conservative staged excisions. Archives of
12 Dermatology, 148, 592-596.
13 Li, X., Naylor, M. F., Le, H., Nordquist, R. E., Teague, T. K., Howard, C. A. et al. (2010). Clinical effects
14 of in situ photoimmunotherapy on late-stage melanoma patients: a preliminary study. Cancer
15 Biology & Therapy, 10, 1081-1087.
16 Ly, L., Kelly, J. W., O'Keefe, R., Sutton, T., Dowling, J. P., Swain, S. et al. (2011). Efficacy of imiquimod
17 cream, 5%, for lentigo maligna after complete excision: a study of 43 patients. Archives of
18 Dermatology, 147, 1191-1195.
19 Naylor, M. F., Crowson, N., Kuwahara, R., Teague, K., Garcia, C., Mackinnis, C. et al. (2003).
20 Treatment of lentigo maligna with topical imiquimod. British Journal of Dermatology, 149 Suppl 66,
21 66-70.
22 Powell, A. M., Robson, A. M., Russell-Jones, R., Barlow, R. J. (2009). Imiquimod and lentigo maligna: a
23 search for prognostic features in a clinicopathological study with long-term follow-up. British Journal
24 of Dermatology, 160, 994-998.
25 Wong, J. G., Toole, J. W., Demers, A. A., Musto, G., Wiseman, M. C., Wong, J. G. et al. (2012). Topical
26 5% imiquimod in the treatment of lentigo maligna. Journal of Cutaneous Medicine & Surgery, 16,
27 245-249.
28 Excluded studies
29 Alessi, S. S., Sanches, J. A., de Oliveira, W. R., Messina, M. C., Pimentel, E. R. D., & Neto, C. F. (2009).
30 Treatment of Cutaneous Tumors with Topical 5% Imiquimod Cream. Clinics, 64, 961-966.
31 Reason: patients are already included in another publication
32 Baumgartner, M. (2010). Treatment of lentigo maligna with imiquimod: A follow up of 61 patients.

33 Melanoma Research, Conference, June.
34 Reason: conference abstract only
35 Craythorne, E. & Lawrence, C. (2007). The use of topical imiquimod (Aldara (R)) in the treatment of
36 lentigo maligna of the head and neck. British Journal of Dermatology, 157, 109-110.

1 Reason: Abstract
2 Demirci, H., Shields, C. L., Bianciotto, C. G., Shields, J. A., Demirci, H., Shields, C. L. et al. (2010).
3 Topical imiquimod for periocular lentigo maligna. Ophthalmology, 117, 2424-2429.
4 Reason: <5 patients
5 Ellis, L. Z., Cohen, J. L., High, W., Stewart, L., Ellis, L. Z., Cohen, J. L. et al. (2012). Melanoma in situ
6 treated successfully using imiquimod after nonclearance with surgery: review of the literature.
7 Dermatologic Surgery, 38, 937-946.
8 Reason: Narrative Review
9 Erickson, C., Miller, S. J., Erickson, C., & Miller, S. J. (2010). Treatment options in melanoma in situ:
10 topical and radiation therapy, excision and Mohs surgery. [Review] [79 refs]. International Journal of
11 Dermatology, 49, 482-491.
13 Fleming, C. J., Bryden, A. M., Evans, A., Dawe, R. S., Ibbotson, S. H., Fleming, C. J. et al. (2004). A pilot
14 study of treatment of lentigo maligna with 5% imiquimod cream. British Journal of Dermatology,
15 151, 485-488.
17 Garcia, M. S., Ono, Y., Martinez, S. R., Chen, S. L., Goodarzi, H., Phan, T. et al. (2011). Complete
18 regression of subcutaneous and cutaneous metastatic melanoma with high-dose intralesional
19 interleukin 2 in combination with topical imiquimod and retinoid cream. Melanoma Research, 21,
20 235-243.
22 Haskett, M. (2010). Efficacy of imiquimod 5% cream for lentigo maligna as assessed following
23 complete excision - A study of 43 patients. Pigment Cell and Melanoma Research, Conference, 878.
24 Reason: less than 10 patients in study
25 Kai, A. (2013). Five-year recurrence rate of lentigo maligna after treatment with imiquimod
26 determined using in vivo confocal microscopy. British Journal of Dermatology, Conference, July.
27 Reason: Abstract
28 Kidner, T. B., Morton, D. L., Lee, D. J., Hoban, M., Foshag, L. J., Turner, R. R. et al. (2012). Combined
29 intralesional Bacille Calmette-Guerin (BCG) and topical imiquimod for in-transit melanoma. Journal
30 of Immunotherapy, 35, 716-720.
32 Ly, L. (2010). 5% imiquimod cream is not a first line treatment for lentigo maligna. Australasian
33 Journal of Dermatology, Conference, May.
34 Reason: phase I clinical trial in patients with advanced melanoma or renal cancer, melanoma results
35 not reported separately
36 Mahoney, M. H., Joseph, M. G., Temple, C., Mahoney, M. H., Joseph, M. G., & Temple, C. (2008).
37 Topical imiquimod therapy for lentigo maligna. Annals of Plastic Surgery, 61, 419-424.

1 McLeod, M., Choudhary, S., Giannakakis, G., Nouri, K., McLeod, M., Choudhary, S. et al. (2011).
2 Surgical treatments for lentigo maligna: a review. [Review]. Dermatologic Surgery, 37, 1210-1228.
4 McKenna, J. K., Florell, S. R., Goldman, G. D., & Bowen, G. M. (2006). Lentigo maligna/lentigo maligna
5 melanoma: Current state of diagnosis and treatment. Dermatologic Surgery, 32, 493-504.
6 Reason: Narrative review
7 Missall, T. A. H. (2011). A case series of 14 patients with melanoma in situ, lentiginous type treated
8 with topical imiquimod therapy reveals the need for individualized regimens for successful
9 treatment. Journal of the American Academy of Dermatology, Conference, AB122.
10 Reason: Abstract
11 Murphy, M. E., Brodland, D. G., Zitelli, J. A., Murphy, M. E., Brodland, D. G., & Zitelli, J. A. (2008).
12 Definitive surgical treatment of 24 skin cancers not cured by prior imiquimod therapy: a case series.
13 Dermatologic Surgery, 34, 1258-1263
14 Reason: expert review
15 Powell, A. M., Russell-Jones, R., Barlow, R. J., Powell, A. M., Russell-Jones, R., & Barlow, R. J. (2004).
16 Topical imiquimod immunotherapy in the management of lentigo maligna. Clinical & Experimental
17 Dermatology, 29, 15-21.
18 Reason: Included in a more recent publication
19 Savage, P. & Horton, V. (1996). A phase I clinical trial of imiquimod, an oral interferon inducer,
20 administered daily. British Journal of Cancer, 74, 1482-1486.
21 Reason: surgery in patients not cured by imiquimod treatment
22 Salerno, E. P. W. (2012). Topical imiquimod induces immune activation and regressions of cutaneous
23 melanoma metastases. Journal of Immunotherapy, Conference, 751-752.
24 Reason: Abstract
25

Evidence Tables
Study Quality (randomized trial)
Study Appropriate Appropriat Comparabl Comparabl Patient Treatment Equal Equal Appropria Precise Valid Investigat
Randomisati e e groups e Care Blindin Administra Follow- Treatment te follow- definition method of or blinding
on follow up
Hyde Yes Unclear Unclear Yes No No Yes Unclear Yes Yes Yes No
et al
(2012
)
Study Study Funding Population Intervention Comparison Risk of Outcomes

Type/Setting Source Bias/Applicabi
lity
Buettiker Observational Universtiy of 32 patients (34 Imiquimod 5% None Clearance Mean follow up 17.2 months (range
et al Berne lesions) cream, applied to histologically 5 to 31 months)
(2008) Switzerland pigment areas of LM confirmed in
lesions. 6/32 cases
Histologically
Frequency of only
confirmed facial application in most Partial clinical clearance (residual
lentigo maligna (LM), cases once or twice Applicable to pigmentation): 6/32 (histology
no prior treatment. daily. Duration of the population confirmed complete clearance in
Some patients were treatment, mean 7 of interest but these cases).
immuno- weeks (range 2 to 20 study has no
compromised (exact weeks). comparator. Complete clinical clearance: 25/32
If no inflammatory
figure not reported)
response was seen Recurrence: 1/32
initially, treatment
was intensified or Inflammatory response: severe 4/32


lity
occlusion or , strong 20/32, moderate 5/32, mild
cryotherapy were 3/32, none 0/32
used.
Adverse events: persistent
telangiectasia 4/32, irritation of the
treatment area (occurred but
frequency was not reported).
Green et Observational Fischer 13 (10 completed Nightly application of None None Complete response (lesion became
al (2007) Family Trust treatment with 182 imiquimod 5% Identified impalpable or disappeared)
2003-2005 and the lesions) cream, applied to Partial response (50% reduction in
the largest diameter of the lesion)
Cancer each lesion and a
Stage III-IV Stable disease (<50% reduction to
UK Vaccine 1cm margin of Intervention <20% increase in the largest
melanoma, multiple
Institute. normal skin. After 8 does not diameter)
cutaneous or
weeks, or if match the Progressive disease (20% increase in
subcutaneous
inflammatory PICO the largest diameter)
metastases, median
response was seen, (additional IL-2
age 58.5 years
frequency of treatment
(range 46 to 80
application reduced used), no Compl Parti Stabl Progre
years).
to every other day. comparator ete al e ssive
respon resp disea disease
From weeks 4 to 8
se onse se
interleukin-2 was
injected three times Per 0/10 0/10 1/10 9/10
patient (but
a week every 2 with
weeks (either into new
lesio
the lesion N= 9 or
ns)
systemically N=1)


lity
and from week 8 Per 74/182 18/182 83/182 33/182
lesion* (41%) (10%) (29%) (18%)
onwards injected
three times a week *2% of lesions were not assessable
every 4 weeks. New metastatic lesions appearing
Treatment lasted during the course of treatment:
between 15 and 53 7/10
weeks.
Treatment withdrawal due to
intolerable toxicity: 0/10
Treatment toxicity: All experienced

erythema and/or discharge from a
treated lesion. Several reported mild
flu-like symptoms associated with IL-
2 injections. 1/10 experienced grade
3 rigors associated with IL-2
injection.
Local infection requiring antibiotic

treatment: 2/10
Hyde et Randomised No financial N=90 All visible signs of LM All visible Protocol states 5 months of follow
al (2012) Trial disclosure were removed using signs of LM up after initiation of topical
reported Biopsy confirmed shave excision 1 were treatment.
lentigo maligna, month before topical
2005-2008 removed
mean age 68.2 years treatment. Per protocol analysis of patients
using shave


lity
USA (range 35 to 92 Imiquimod 5% excision 1 completing 3 months of treatment
years) cream, 5 days per month (42/46 for monotherapy, 37/44 for
week for 3 months before combined therapy)
topical
Imiqui Imiqui Relative
treatment mod mod + risk (95%
Imiquimod alone tazarot C.I.)
ene
5% cream, 5
days per Complete
response -
week for 3 no residual
months plus LM on post
0.82
treatment
tazarotene excision of
27/42 29/37 [0.62,
1.09]
0.1% gel 2 tumour
footprint
days per plus 2mm
week for 3 margin
months. Treatment
failure -
1.65
residual LM
15/42 8/37 [0.79,
on post
3.45]
treatment
excision
Withdrawal
0.16
from trial
1/46 6/44 [0.02,
due to
1.27]
toxicity
Li et al Observational Grants from N=11 In situ None Unclear how Complete local response
(2012) American photoimmunotherap patients were (macroscopic disappearance of
2004-2008 Cancer Patients with y, which consisted of selected for treatment site lesions): 8/11
metastatic this study Partial local response (30% or more
Society, NIH three components
incomplete macroscopic reduction


lity
USA and National melanoma. Median applied directly to Intervention of treatment site lesions): 3/11
Natural age 69 years (range the skin metastases: does not Best overall response: complete
Science 46 to 87). Prior topical imiquimod, match the response 7/11, partial response
2/11, and stable disease 1/11.
Foundation treatment was injection of PICO
for China. surgery (N=11), indocyanine green (additional
chemotherapy (N=3), and photothermal laser Grade 3 toxicity: at least one grade 3
radiotherapy (N=3), therapy using a near- treatment adverse event occurred in 25 % of
isolated limb infrared laser. used), no the patients. Rates were fatigue
perfusion (N=2). Treatment cycles comparator. (9%), dyspnoea (9%), nausea (18%),
Performance status lasted 6 weeks, anorexia (18%), skin pain (9%), and
was 0 in all cases patients received cellulitis (9%).
between 1 and 6
cycles of treatment. Grade 4 toxicity: none reported
Grade 1 - 2 toxicity: A wide range of

grade 1 to 2 toxicities were also
reported.
Overall survival: Median survival

was not reached: 12 month overall
survival was 70%
Ly et al Observational Skin Cancer N=43 Imiquimod 5% cream None None Follow-up

(2011) Study Foundation; applied to the lesion identified 16 weeks (according to protocol)
3M Histologically 5 times a week for
confirmed LM of the Applicable to
2004-2009 Pharmaceuti 12 weeks, followed
head or neck, age the population
cals (iNova (4 weeks after end of of interest but Treatment response (histologically


lity
Australia Pharmaceuti range 37 to 90 years imiquimod study has no confirmed clearance of LM): 20/38.
cals) (mean age 69 for treatment) by wide comparator
Treatment failure (histologically
women and 64 for local excision of the
men) LM with a 5mm confirmed persistence of LM): 18/38
margin
Macroscopic clearance of LM did not

completely correlate with
histopathologic clearance:
Complete Incomplete
histologic histologic
clearance clearance
Complete 13 7
macroscopi
c clearance
incomplete 7 11
macroscopi
c clearance
Treatment withdrawal due to

intolerable toxicity: 3/43


lity
Naylor et Observational 3M N=30 (28 completer Daily treatment with None None Complete treatment response
al (2003) Study Pharmaceuti the 12 week imiquimod 5% cream identified (histologically confirmed absence of
cals treatment) applied to the tumour): 26/30
Applicable to Treatment failure (histologically
USA tumour plus a 2cm
Age > 18 years the population confirmed persistent tumour): 2/30
margin. Continued of interest but
(mean 69 years for
for 12 weeks unless study has no Treatment withdrawal: 1/30 (stage
men, 60 for women),
rest periods were comparator 1 melanoma discovered during
lentigo maligna with
required due to treatment)
at least 2cm left to
intolerable irritation
treat after biopsy, no
or impending Treatment rest period needed due
suspected stage 1
ulceration. to toxicity: 10/30
melanoma. Location
Treatment response
of LM was head in Irritation at treatment site : 30/30
was monitored using
26/30, upper
4 2mm punch Severe local skin reactions : 10/30
extremity in 3/30
biopsies at 16 weeks.
and 1/30 on the
Secondary infections requiring
thorax.
antibiotics: 5/30
Cytokine-release syndrome: 2/30
Powell et Retrospective Not reported N=48 Imiquimod 5% None None Treatment response (no clinical or
al (2009) observational applied for 8 hours, 3 identified histological evidence of disease):
study Patients had times per week to 37/48
Applicable to Treatment failure (histological
histologically the clinically affected
the population evidence of persistent LM): 11/48
2001-2006 confirmed facial LM, area plus a 2 cm of interest but
not amenable to margin of normal study has no Residual pigmentation: 8/37 (in
UK simple excision, skin. Treatment was comparator.


lity
32/48 had no prior intensified if treatment responders)
treatment, 16/48 inflammatory
Inflammatory response: , strong or
had persistent response was not
disease following elicited moderate (15/48), mild (18/48),
excision, none were none (15/48)
immunocompromise Discontinuation of treatment due to
d. Age 44-90 years toxicity: 3/48
(mean 70.6 years)
Scarring due to imiquimod: 0/48
Cytokine-release syndrome: 0/48
Wong et Observational Authors N=27 Imiquimod 5% None Not reported Post treatment biopsies were done
al (2012) reported no Patients with applied to the how patients on average 19.9 weeks after
2004-2009 financial histologically affected pigmented were selected treatment, and patients were also
confirmed lentigo for the study
disclosure. areas plus a 10mm followed up every 3 to 6 months
Canada maligna. Imiqimod margin, 3 times per after imiquimod (median follow-up
Applicable to
treatment was week. Mean the population not reported).
primary treatment in duration of of interest but
13/27, secondary treatment was 20.6 study has no
treatment in 12/27 weeks (range 10.1 to comparator.
Treatment success was defined as
and tertiary 33.4 weeks). clinical and histopathological
treatment in 1/27. Treatment was clearance of LM. Treatment failure
Location of LM was individualised - for was residual clinical pigmentation
head/neck in 26/27 example frequency seen by dermoscopy or and
and upper extremity of application could histopathological evidence of
in 1/27 be increase if there


lity
was no inflammatory persistent LM.
response or breaks
could be taken if side
effects became Imiquimod Treatment Treatment
intolerable. Use success failure
Primary 10 3
treatment
Secondary 9 3
treatment
Tertiary 0 1
treatment
Overall 19 7
Treatment toxicity: inflammation,

erythema and crusting were
commonly seen (but no figures
given)

1 5. Stage III Melanoma
2 5.1 Surgical Management
3 Review question: What is the most effective surgical treatment for stage III melanoma?
4 Background
5 In this section we are not discussing the rationale for SNB but what is the most effective way to
6 manage the nodal basin if staged by SNB. The rationale for SNB is a topic being discussed elsewhere.
7 The questions here are
8 a) Most patients with a positive sentinel node biopsy are offered a second operation to
9 remove all the nodes in that area of the body (nodal basin) which is called Completion
10 Lymph Node dissection, (CLND). The question we are asking is what is the benefit to this
11 further surgery and if that surgery is beneficial for all patients.
12 c) Sometimes a positive sentinel node is detected in an unusual site (not in the neck, groin or
13 axilla) which is known as an aberrant node. The question we are asking is what is the most
14 beneficial surgery here?
15 Stage IIIb: Macroscopic disease (melanoma that can be felt as a lump): Data indicate that surgery in
16 the form of Therapeutic Lymph Node Dissection (TLND) is mainly to prevent the melanoma recurring
17 in that site and does little to improve overall survival: The major areas that surgery is undertaken is
18 i) Neck: The question is what form of designated neck dissection (TLND) is most effective
19 for disease in the neck. In what circumstances should removal of the parotid gland be
20 included? How extensive does the surgery have to be?
21 ii) Axilla: It is felt that removal of all the glands in the axilla (Level 3 TLND dissection) is
22 necessary for disease here. Is this the most effective surgery?
23 iii) Groin: This is a major area for discussion. Standard surgery for nodal disease in groin is a
24 groin TLND (removing the nodes in superficial and deep femoral triangle). British Assoc.
25 of Dermatology (BAD)/ British Assoc. of Plastic, Reconstructive and Aesthetic Surgeons
26 (BAPRAS) guidelines exist for indications to extend the surgery above the inguinal
27 ligament into the pelvic retroperitoneal space (ileoinguinal TLND). Is there indication to
28 change these guidelines and is this surgery more effective? Are the side effects of the
29 surgery (the morbidity )greater?
30 iv) Nodes can be found very occasionally in epitrochlear (elbow) and popliteal (knee) fossa.
31 What is the most effective management here? This condition is rare
32 As part of surgery, should surgeons look at the effectiveness of the surgery and the side effects that
33 result such as wound infections. There are different ways of trying to measure this? Taskforce
34 groups have identified the following: a) Numbers of procedures by individual surgeon (NICE
35 recommendation), b) Complications (major and minor),c) Readmission to hospital for complications,
36 d) Mortality figures

1 Stage IIIc: Macroscopic disease with in-transit or locally recurrent disease. The management of the
2 nodal basins are identified above in i, ii and iii.
3 The management of in transit disease is part of the discussion featured in Topic I
4 * Stage IIIa Microscopic disease identified in regional nodes

5 ~ are they all identified by SLNB? What other methods are used? Links with Topic E
6 *Stage IIIb Macroscopic disease
7 ~ Neck Lymph node drainage as defined by levels for surgical clearance. Agree Parotid surgery
8 requires clarification in regard to when and how much.
9 *Both;
10 ~ Morbidity associated with all TLNDs a critical assessment especially when surgery on different
11 levels of nodes (extent of surgery) being compared.

Patients diagnosed 1. Local Recurrence
with stage III 2. Regional
melanoma: recurrence
 Micro Metastatic Micro Metastatic Micro Metastatic nodal disease 3. Melanoma
nodal disease as nodal disease  Clinical observation specific Survival
detected by SLNB  Completion  Clinical follow up using (5 & 10 yr)
(inc. aberrant lymphadenectomy Ultrasound 4. Overall survival
lymph nodes) (5 & 10 yr)
5. HRQL
6. Accurate staging
 Palpable nodal Palpable nodal disease Palpable nodal disease 7. Adverse events
disease (inc  Standard (local)  Extended Lymphadenectomy long term, inc:
aberrant lymph Lymphadenectomy o eg inguinal versus Lymphoedema
nodes) inguinal and iliac 8. Adverse Events
o Eg modified neck short term
vs radical surgical
o Eg excision
aberrant node
versus node and
lymphadenectomy
nearest basin
Searches:
Can we apply date limits to the search The GDG did not feel that it was appropriate to apply any
date limits to the searches for this topic
Are there any study design filters to be used (RCT,

systematic review, diagnostic test).
List useful search terms.
Notes .

1 Search Results
Database name Dates No of No of references Finish date of

Covered references retrieved search
found
Medline 1946-2014 4544 1134 09/06/2014
Premedline June 04 2014 133 25 05/06/2014
Embase 1947-2014 5725 889 12/06/2014

June 2014

SSCI)
Total References retrieved (after initial sift and de-duplication): 1599
2 Update Search
3 For the update search, the same search criteria/filters were applied as initial search with a date limit of June
4 2014 onwards.

Medline 64 19 09/10/2014
Embase 37 5 09/10/2014
6 1. exp Melanoma/
7 2. melanoma$.tw.
8 3. 1 or 2
9 4. (stage iii or stage iiia or stage iiib or stage iiic or stage 3 or stage 3a or stage 3b or stage 3c or
10 spread or metasta* or satellite* or regional or lymph* or palpable or "micro metasta*" or micro-
11 metasta* or micrometasta* or microscopic or macroscopic).tw.
12 5. Lymphatic Metastasis/

1 6. 4 or 5
2 7. 3 and 6
3 8. exp Lymph Node Excision/
4 9. Lymph Nodes/su
5 10. lymphadenectom*.tw.
6 11. CLND.tw.
7 12. TLND.tw.
8 13. ((neck or radical) adj2 (excis* or dissect* or surger* or resect*)).tw.
9 14. ((lymph* or node* or nodal) adj2 (dissect* or remov* or excis* or surger* or resect*)).tw.
10 15. or/8-14
12 17. (ultraso* or sonogra* or echotomogra* or echogra*).tw.
13 18. 16 or 17
14 19. exp Aftercare/
15 20. (follow-up or "follow up" or followup).tw.
16 21. (check-up*1 or check up*1).tw.
17 22. surveillance.tw.
18 23. (aftercare or after-care).tw.
19 24. ((post-treatment or posttreatment) adj1 evaluat*).tw.
20 25. ((post-treatment or posttreatment) adj1 care).tw.
21 26. ((post-treatment or posttreatment) adj1 monitor*).tw.
22 27. or/19-26
23 28. 18 and 27
24 29. Observation/
25 30. Physical Examination/
26 31. (visual adj exam*).tw.
27 32. (skin adj exam*).tw.
28 33. (clinical adj (exam* or observ*)).tw.
29 34. (physical adj exam*).tw.
30 35. or/29-34
31 36. 15 or 28 or 35
32 37. 7 and 36
33
34

1 Screening Results
2
3
Expert Reviews
Abstract Only
No Comparators
Treatment Comparisons not relevant
to PICO

study designs (n=0)
Randomized controlled trial (n=0)
(n=0)

Table 5.1 Characteristics of included studies

Type/Setting
Abbott et al Retrospective To compare short-term N=13 MILND Minimally Open  Adverse Events
(2013) Study outcomes between invasive Inguinal
MILND and OILND N=28 OILND inguinal lymph lymph node
among patients with node dissection
metastatic melanoma dissection
from two institutions.
Bamboat et Retrospective To characterise the 4310 patients Completion Nodal  Recurrence (regional,nodal,
al (2014) Study populations undergoing undergoing wide lymph node observation systemic, regional disease as a
nodal observation (no local excision with dissection compoment of recurrence,
CLND) and CLND; SLNB (CLND) nodal disease as a component
determine the pattern of recurrence, systemic
of initial recurrence N=495 (11%) with a disease as a component of
between no CLND and positive SLN recurrence)
CLND group; determine N=167 underwent  Survival
the melanoma specific nodal observation
survival of both patient N=328 underwent
groups and to immediate
characterise the completion lymph
outcome of no CLND node dissection
patients who
experience a
subsequent isolated
nodal recurrence
deVries et al Retrospective To evaluate morbidity N=66 SLNB + SLNB  Long term morbidity
(2006) Study after inguinal SLNB N=52 SLNB only completion (lymphoedema and range of


Type/Setting
alone and inguinal SLNB N=14 underwent lymphadenect motion of restrictions)
with completion completion omy
inguinal dissection lymphadenectomy
(N=11 superficial +
deep groin dissection
and N=3 superficial
groin dissection)
Egger et al Retrospective To evaluate whether a N=143 patients Inguinal Combined  Overall Survival
(2014) study combined inguinal and Dissection inguinal and  Disease free survival
iliac/obturator N=100 inguinal iliac/obturat
dissection improved dissections or dissection
locoregional disease
control and survival N=34 combined
compared with an inguinal and
inguinal dissection iliac/obturator
alone in the absence of dissection
clinical and radiological
evidence of pelvic
lymph node metastases
Kingham et Retrospective To examine a group of N=313 Complete No lymph Unclear appear to be:
al (2010) Study SLNB positive patients N=271 underwent lymph node node
who underwent CLND dissection dissection
completion lymph node N=42 no CLND  Recurrence
dissection compared o Nodal (recurrences
with those who did SLNB+CLND


Type/Setting
SLNB+salvage in the draining nodal
therapeutic lymph basin from the
node dissection primary lesion)
o Regional (local and
in-transit lesions0
o Systemic disease
(lesions in all other
locations)
 Survival
Kretschmer Retrospective To ivestigate the impact N=104 patients with Ilio-inguinal Inguinal  Local tumour control
et al (2001) Study of inguinal versus ilio- cutaneous dissection dissection  Survival
inguinal node dissection melanoma who
in patients with underwent
palpable groin nodes therapeutic groin
dissection.
N=69 ilio-inguinal
dissection
N=35 superfical
inguinal dissection
Kretschmer Retrospective To investigate survival N=937 SLNB + early SLNB +  Overall Survival
et al (2004) Study outcomes in patients N=314 undergoing excision delayed
with lymphatic early excision excision
metastases who N=623 undergoing


Type/Setting
underwent early or delayed excision
delayed excision of
regional lymph nodes
O’Brien et al Retrospective To evaluate the role and N=175 patients who Therapeutic Elective Neck  Recurrence
(1995) Study efficacy of modified and had 183 neck Neck Dissection  Overall Survival
selective neck dissections Dissection (Selective or
dissections and (Selective, Modified)
adjuvant radiotherapy Radical or
in treating patients with modified)
clinical metastatic Elective
melanoma dissections
were
performed
when
primary
melanoma
thickness
was ≥1.5mm
Singletary et Retrospective To investigate whether N=264 patients Superficial Combined  Survival

al (1992) or not a more N=113 with femoral node ilio-inguinal
conservative approach subsequent regional dissection dissection
would offer and nodal disease
improved survival rate N=151 who initially
or better local and had regional nodal Iliac nodal
regional control. disease dissection for


Type/Setting
patients with
synchronous
primary
melanoma
Femoral nodal
dissection six
weeks later for
patients with
palpable groin
disease
Superficial
femoral
dissection or
combined
ilioinguinal
dissection for
patients who
developed
delayed nodal
metastases.
Smith et al Retrospective To determine whether N=350 patients SLNB SLNB +  Disease Specific Survival


Type/Setting
(2012) Study CLND improves survival N=140 SLNB only completion  Overall Survival
in patients with N=210 SLNB +CLND lymph node
cutaneous melanoma of dissection
the head and neck
Spillane et al Retrospective To establish how timing N=1704 SLNB+Immedi Each Other  Disease Free Survival
(2014) Study of lymphandenectomy ate  Post Recurrence Survival
in the ciourse if the N=502 Immediate completion  Overall Survival
disease related to the completion lymphadenect
interval between the lymphadenectomy omy
diagnosis of the primary (ICL)
tumour and the first
recurrence after N=214 Delayed SLNB+delayed
lymphadenectomy. Completion completion
lymphadenectomy lymphadenect
(DCL) omy
N=709 Delayed
therapeutic
Observation+D
lymphadenectomy
elayed
(DTL)
therapeutic
lymphadenect
N=279 Immediate
omy
therapeutic
lymphadenectomy


Type/Setting
(ITL) Immediate
therapeutic
lymphadenect
omy for
clinically
positive nodes
Van der Retrospective To investigate the N=52 clinically node Completion Superficial  Lymph Node Recurrence
Ploeg et al Study pathological findings, negative patients groin node groin node  Disease Free Survival
(2008) the incidence of lymph with cutaneous dissection dissection
node recurrences and melanoma and a
the disease free survival tumour positive
in clinically node sentinel node biopsy
negative patients with a of the groin
positive sentinel node in
the groin who have N=10 patients who
undergone lymph node did not receive
dissection further dissection
due to small tumour
burden in the
sentinel nodes and
were not included in
the analysis.
Van der Retrospective To evaluate the N=1174 patients CLND No CLND  Disease Specific Survival
ploeg et al Study infulence of immediate with SN positive
(2012) completion lymph node melanoma
dissection (CLND) on N=1113 underwent


Type/Setting
outcome in patients immediate CLND
with SN positive N=61 no CLND
melanoma
Van der Retrospective To evaluate the N=121 patients who Combined Therapeutic  Post operative morbidity
ploeg et al Study experience in patients underwent superficial and superficial  Regional Recurrence (Not
(2011) with clinically evident combined superficial deep dissection defined)
metastatic melanoma to and deep dissection dissection  Preoperative CT scan
the groin who (CGD)  Disease free survival
underwent combined  Overall survival
superficial and deep N=48 patients who
groin dissection versus underwent
inguinal or superficial therapeutic
groin dissection superficial dissection
(SGD) for palpable
metastses to the
groin
Van der Retrospective To compare regional N=2931 in the SLNB+wide Observation  Recurrence
ploeg et al, Study recurrence free survival, observation group local excision + total lymph  Disease fre Survival
2014 distant metastases free node  Distant metastases free
survival and melanoma dissection survival
specific survival of SNB N=2909 in the SLNB for  Melanoma Specific survival
patients with arm recurrence
observation patients in


Type/Setting
a large patient cohort
White et al Retrospective To evaluate the N=37 Radical neck Each Other  Survival
(2009) Study outcome of therapeutic dissection
neck dissection for
melanoma in patients Modified
with head and neck radical
melanoma dissection
Selective
dissection

1 Study Quality
2 All studies in this review were retrospective case series studies assessed as very low quality using
3 GRADE methodology.
4 The primary reason for downgrading evidence was due to the fact that was not always clear from
5 the individual studies which AJCC stage was included and therefore there may be a question mark
6 over the relevance of the populations to this question though due to the nature of the comparisons
7 of interest it is considered that the risk of the populations not being directly relevant was low.
8 Individual studies could not be compared for consistency due to differences in outcome reporting in
9 relation to whether studies reported on regional recurrence or local recurrence. In addition, for
10 some outcomes, there was only a single study available so no comparisons comment can be made
11 on consistency of results in these situations.
12 Not all outcomes of interest were reported in the evidence; there was no evidence relating to
13 ‘quality of life’ or ‘accurate staging’ and the evidence relating to ‘adverse events’ was not
14 comprehensive enough to report on short and long term events separately.
16 Sentinel Lymph node biopsy ± completion lymph node dissection
17 Recurrence (Local and Regional)
18 From one retrospective study with a total of 495 patients with a positive sentinel lymph node, there
19 was no significant difference in median time to recurrence when comparing patients undergoing
20 immediate completion lymph node dissection to patients undergoing nodal observation (9 months
21 versus 12 months, p=0.46) (Bamboat et al, 2014).
22 Regional recurrence rates were not significantly different between the completion lymph node
23 dissection (CLND) group and the observation group (18% versus 16%, p=0.58); however there was a
24 statistically significant difference in nodal recurrence rates (CLND=6% versus No CLND=15%,
25 p=0.002) and in systemic recurrences (CLND=27% versus Observation = 8%, p=<0.001) (Bamboat et
26 al, 2014).
27 From one retrospective study with a total of 313 patients no difference in patterns of first
28 recurrence was observed when comparing patients who had a complete lymph node dissection and
29 those who did not (54% versus 48%) (Kingham et al, 2010).
30 Melanoma Specific Survival
31 From one retrospective study with 1174 patients undergoing sentinel lymph node biopsy there was
32 no significant difference in disease specific survival; 3 year disease specific survival was 74% in
33 patients who did not undergo complete lymph node dissection (n=61) versus 76.9% in patients who
34 underwent CLND (n=1113) while 5 year disease specific survival was 66% for patients not undergoing
35 CLND and 66% for the CLND group (Van der Ploeg, 2012).

1 From one retrospective study including 495 patients with a positive sentinel lymph node, melanoma
2 specific survival for patients who underwent immediate completion lymph node dissection was 36.5
3 months (median) and was not reached for patients undergoing salvage lymph node dissection
4 (p=0.005). Increasing age (p=0.006), tumour thickness (p=0.001) and degree of ulceration (p<0.001)
5 were all associated with higher melanoma specific survival (Bamboat et al, 2014).
6 One retrospective study including a total of 350 patients reported no significant difference between
7 treatment groups (SLNB versus SLNB+CLND) in relation to disease specific survival. Age was
8 significantly associated with an increased risk of death from melanoma in patients <60 years and
9 tumour thickness >2mm was a significant predictor of worse survival in the older age group
10 (HR=3.11, p<0.001) (Smith et al, 2012).
11 Overall Survival
12 From one retrospective study with a total of 937 patients, overall survival was significantly better
13 for patients undergoing sentinel lymph node biopsy and early lymph node excision compared with
14 patients undergoing delayed excision (p=0.002). Estimated 3 year survival was 80.1±2.8% in patients
15 positive SLNB and immediate lymph node dissection compared with 67.6±1.9% in patients
16 undergoing delayed lymph node dissection and estimated 5 year survival was 62.5± 5.5% for
17 SLNB+immediate lymph node dissection and 50.2±5.4% for SLNB + delayed lymph node dissection
18 (Kretschmer et al, 2004).
19 Adverse Events
20 From one retrospective study with a total of 66 patients who underwent sentinel lymph node biopsy
21 with or without completion lymphadenectomy, there were no reported deaths as a result of surgical
22 intervention. There was a significantly higher rate of post surgery complications in the SLNB+groin
23 dissection group when compared with the SLNB only group (p<0.001) (deVries et al, 2006).
24 In one retrospective study with a total of 66 patients, a significant difference in leg volume (measure
25 of lymphodema) was observed with patients undergoing SLNB+groin dissection having a greater
26 volume compared with patients undergoing SLNB only (p<0.001) (deVries et al, 2006).

GRADE Table 5.1: Should patients with microscopic disease detected by SLNB undergo Immediate Lymphadenectomy or Observation?
Quality assessment Summary of findings Quality

No of patients Effect
No of Design Limitations Inconsistency Indirectness Imprecision Other SLNB+Immediate SLNB+Observation Relative Absolute
studies considerations Lymphadenectomy (95% CI)
Recurrence (Bamboat et al, 2014; Kingham et al, 2010)
2 (n=808) observational serious1 no serious no serious no serious none ?/5993 ?/2093 Not Pooled Very
studies inconsistency indirectness2 imprecision Low
Melanoma Specific Survival (van der Ploeg et al, 2012; Bamboat et al 2014; Smith et al, 2012)
3 (n=2019) observational serious1 no serious no serious no serious none ?/16513 ?/3683 Not Pooled Very
studies inconsistency indirectness2 imprecision Low
Overall Survival (Kretschemmer et al, 2004)
1 (n=937) observational serious1 no serious no serious no serious none ?/3143 ?/6233 Estimated 3 year Very
studies inconsistency indirectness2 imprecision survival was 80.1±2.8% Low
in patients positive
SLNB and immediate
lymph node dissection
compared with
67.6±1.9% in patients
undergoing delayed
lymph node dissection
Adverse events (deVries et al, 2006)
1 (n=66) observational serious1 no serious no serious no serious none ?/113 ?/553 There was a Very
studies inconsistency indirectness2 imprecision significantly higher rate Low
of post surgery
complications in the
SLNB+groin dissection
group when compared
with the SLNB only
group (p<0.001) -
1
Not a randomised trial 2 The studies do not clearly specify what AJCC stage included patients have been assigned. 3Event rate is not reported

1 Standard lymphadenectomy versus extended lymphadenectomy for palpable lymph node disease
2 Recurrence (local and regional)
3 From one retrospective study with a total of 104 patients undergoing either Ilio-inguinal dissection
4 or inguinal dissection, the type of operation did not have a significant effect on local control of the
5 dissected lymph node (Kretschemer et al, 2001).
6 From one retrospective study with a total of 169 patients undergoing either combined superficial
7 and deep groin dissection (CGD) or a therapeutic superficial groin dissection (SGD), there was no
8 significant difference overall in rates of recurrence with 74% of CGD patients and 73% SGD patients
9 experiencing recurrence. Regional recurrence rates were more common in the SGD group than in
10 the CGD group thought the difference was not statistically significant (p=0.498) (Van der Ploeg et al,
11 2011).
12 From one retrospective study with a total of 143 patients undergoing either inguinal dissection of a
13 combined inguinal and iliac/obturator dissection, rates of pelvic lymph node recurrence did not
14 differ significantly when considering patients with microscopic disease. For patients with
15 macroscopic disease, pelvic node recurrence rates did not differ significantly (Egger et al, 2014).
17 combined inguinal and iliac/obturator dissection, systemic recurrence was the most common type of
18 recurrence with 43% of patients undergoing inguinal dissection and 48% of patients undergoing
19 combined inguinal and iliac/obturator dissection experiencing systemic recurrences. Systemic
20 recurrences were more common in patients with macroscopic disease than in patients with
21 microscopic disease (Egger et al, 2014).
22 Melanoma Specific Survival
23 From one retrospective study which included 52 patients undergoing completion groin node
24 dissection or superficial groin node dissection, 5 year disease free survival was 53% in the superficial
25 node dissection group compared with 61% in the complete groin dissection group (van der Ploeg et
26 al, 2008).
27 From one retrospective study with a total of 169 patients undergoing either combined superficial
28 and deep groin dissection (CGD) or a therapeutic superficial groin dissection (SGD) no significant
29 difference in disease free survival was observed between the groups. 5 year estimated disease free
30 survival rate was 15.7% in the SGD group and 18.3% in the CGD group. Considering the whole
31 cohort, significant prognostic factors for disease free survival included number of positive superficial
32 nodes (HR=1.6, 95% CI 1.03-2.51, p=0.038) and superficial lymph node ratio (HR=2.33, 95% CI 1.25-
33 4.34, p<0.008) (van der Ploeg et al, 2011).
35 combined inguinal and iliac/obturator dissection, disease free survival was significantly greater in
36 patients with macroscopic disease compared with microscopic disease (p=0.0002) (Egger et al,
37 2014).

1 Overall Survival
2 From one retrospective study which included 52 patients undergoing completion groin node
3 dissection or superficial groin node dissection, 5 year overall survival for patients who underwent
4 only a superficial groin node dissection was 76% (95% CI 62-95%) compared with 80% (95% CI 61-
5 100%) for patients who underwent completion groin node dissection (van der Ploeg et al, 2008).
6 From a retrospective study in which 104 patients underwent either ilio-inguinal dissection or
7 inguinal dissection, 5 year overall survival for the whole cohort was 30.4% and 10 year overall
8 survival for the whole cohort was 18.4% and extent of lymph node dissection did no t have a
9 significant effect on survival (Kretschmer et al, 2001).
10 A second retrospective study in which with a total of 169 patients underwent either combined
11 superficial and deep groin dissection (CGD) or a therapeutic superficial groin dissection (SGD) also
12 reported no significant difference in overall survival when comparing extent of lymph node
13 dissection (van der Ploeg et al, 2011).
14 From one retrospective study comparing patients who underwent femoral nodal dissection for
15 palpable groin disease with patients who underwent an iliac nodal dissection for melanoma
16 metastasis, no significant difference in median overall survival was observed (32.7 months versus
17 39.5 months, p=0.17)and type of groin dissection did not impact survival when stratified by tumour
18 burden (Singletary et al, 1992)
19 From one retrospective study (n=37) comparing patients undergoing radical neck dissection,
20 modified radical dissection or selective dissection, overall survival at 60 months was 33% with no
21 difference observed in survival rates for the 3 different types of dissection (White et al, 1992).
22 Adverse Events
23 From one retrospective study in which 13 patients underwent minimally invasive inguinal lymph
24 node dissection(MILND) and 28 patients underwent open inguinal lymph node dissection (OILND),
25 operative time was significantly longer for MILND patients compared with OILND patients (p=0.003)
26 but length of hospital stay was significantly shorter (p=0.01) and incidence of hospital readmission
27 was higher in the OILND group (21%) than in the MILND group (7%) thought the difference was not
28 significant (p=0.25 . Incidence of wound dehiscence (p=0.07) and infection (p=0.13) were greater in
29 the OILND group compared with the MILND group (Abbot et al, 2013).

GRADE Table 5.2: Should patients with palpable lymph nodes undergo Superficial Lymph Node Dissection or Extended lymphadenectomy?
No of Design Limitations Inconsistency Indirectness Imprecision Other Superficial Lymph Node Extended Relative Absolute Quality
studies considerations Dissection lymphadenectomy (95% CI)
Recurrence (Kretschemer et al, 2001; van der Ploeg et al, 2011; Egger et al, 2014)
3 observational serious1 no serious no serious no serious none ?/1833 ?/4163 Not Pooled4 Very
(n=416) studies inconsistency indirectness2 imprecision Low
Melanoma Specific Survival (van der Ploeg, 2008; van der Ploeg et al, 2011; Egger et al, 2014)
(n=374) studies inconsistency indirectness2 imprecision Low
Overall Survival (van der Ploeg, 2008; van der Ploeg et al, 2011; Kretschemer et al, 2001; Singletary et al, 1992; White et al, 1992)
2
(n=636) studies inconsistency indirectness imprecision Low
Adverse Events (Abbot et al, 2013)

1 (n=41) observational serious3 no serious no serious no serious none Operative time was significantly longer for minimally invasive inguinal lymph node Very
studies inconsistency indirectness2 imprecision dissection patients compared with open inguinal lymph node dissection patients Low
(p=0.003) but length of hospital stay was significantly shorter (p=0.01) and incidence of
hospital readmission was higher in the OILND group
1
Not a randomised trial 2 The studies do not clearly specify what AJCC stage included patients have been assigned. 3Event rate is not reported 4Data were not pooled as the individual studies were
comparing different types and locations of surgical intervention

1 References
2 Included
3 Abbott, A. M., et al (2013) Minimally invasive inguinal lymph node dissection (MILND) for melanoma:
4 experience from two academic centers. Annals of Surgical Oncology 20;1:340-345.
5 Bamboat, Z. M., et al (2014) Observation After a Positive Sentinel Lymph Node Biopsy in Patients
6 with Melanoma. Annals of Surgical Oncology . 16-5-2014.
7 Reason:
8 de Vries, M., et al (2006) Morbidity after inguinal sentinel lymph node biopsy and completion lymph
9 node dissection in patients with cutaneous melanoma. Ejso 32:7:785-789.
10 Egger, M. E., et al (2014) Addition of an Iliac/Obturator Lymph Node Dissection Does Not Improve
11 Nodal Recurrence or Survival in Melanoma. Journal of the American College of Surgeons
12 Kingham, T. P., et al (2010) Outcome of patients with a positive sentinel lymph node who do not
13 undergo completion lymphadenectomy. Annals of Surgical Oncology 17;2: 514-520.
14 Kretschmer, L., et al (2004) Patients with lymphatic metastasis of cutaneous malignant melanoma
15 benefit from sentinel lymphonodectomy and early excision of their nodal disease. European Journal
16 of Cancer 40;2:212-218.
17 Kretschmer, L., et al (2001) Superficial inguinal and radical ilioinguinal lymph node dissection in
18 patients with palpable melanoma metastases to the groin--an analysis of survival and local
19 recurrence. Acta Oncologica 40;1:72-78.
20 O’Brien C. J. Et al (1995) Radical, Modified and Selective Neck Dissection for Cutaneous Malignant
21 Melanoma Head and Neck 17;232-241
22 Singletary, S. E., et al (1992) Surgical management of groin nodal metastases from primary
23 melanoma of the lower extremity. Surgery, Gynecology & Obstetrics 174;3:195-200.
24 Smith, V. A., et al (2012) Completion node dissection in patients with sentinel node-positive
25 melanoma of the head and neck. Otolaryngology - Head & Neck Surgery 146;4:591-599.
26 Spillane, A. J., et al (2014) Patterns of recurrence and survival after lymphadenectomy in melanoma
27 patients: clarifying the effects of timing of surgery and lymph node tumor burden. Annals of Surgical
28 Oncology 21;1:292-299.
29 van der Ploeg, I. M., et al (2008) Tumor-positive sentinel node biopsy of the groin in clinically node-
30 negative melanoma patients: superficial or superficial and deep lymph node dissection? Annals of
31 Surgical Oncology 15;5:1485-1491
32 van der Ploeg, A. P., et al (2011) Therapeutic surgical management of palpable melanoma groin
33 metastases: superficial or combined superficial and deep groin lymph node dissection. Annals of
34 Surgical Oncology 18;12: 3300-3308.
35 van der Ploeg, A. P. T. (2012) Prognosis in patients with sentinel node-positive melanoma without
36 immediate completion lymph node dissection. British Journal of Surgery 99;10:1396-1405.
37 van der Ploeg, A. P., et al (2014) Outcome following sentinel node biopsy plus wide local excision
38 versus wide local excision only for primary cutaneous melanoma: analysis of 5840 patients treated at

1 a single institution. Annals of Surgery 260;1:149-157

2
3 White, N., et al (2009) Lymphadenectomy for melanoma in the clinically N1 neck: radical, modified
4 radical, or selective? Journal of Craniofacial Surgery 20;2:385-388.
5 Excluded Studies
6
7 Aziz, A. I. M. (1995) Malignant melanoma of the vulva: Limited local excision versus radical
8 vulvectomy. Contemporary Reviews in Obstetrics and Gynaecology 7;2:101-105.
10 Baas, P. C., et al (1992) Groin dissection in the treatment of lower-extremity melanoma. Short-term
11 and long-term morbidity. Archives of Surgery 127;3:281-286
12 Reason: No Comparison
13 Badgwell, B., et al (2007) Pelvic lymph node dissection is beneficial in subsets of patients with node-
14 positive melanoma. Annals of Surgical Oncology 14;10:2867-2875.
15 Reason: Population not relevant to PICO (No SLNB)
16 Balch, C. M. and Balch, C. M.(1998) The John Wayne Clinical Research Lecture. Surgical management
17 of melanoma: results of prospective randomized trials. Annals of Surgical Oncology 5;4:301-309.
19 Blazer, D. G., Sondak, V. K., and Sabel, M. S. (2007) Surgical therapy of cutaneous melanoma.
20 Seminars in Oncology 34;3:270-280.
22 Cascinelli, N., et al (1998) Immediate or delayed dissection of regional nodes in patients with
23 melanoma of the trunk: a randomised trial. WHO Melanoma Programme. Lancet 351;9105:793-796.
24 Reason: Population/comparison not relevant to PICO
25 Chan, A. D., et al (2000) Judging the therapeutic value of lymph node dissections for melanoma.
26 Journal of the American College of Surgeons 191;1:16-22.
27 Reason: No Comparative Analysis
28 Clary, B. M., et al (2001) Early recurrence after lymphatic mapping and sentinel node biopsy in
29 patients with primary extremity melanoma: a comparison with elective lymph node dissection.
30 Annals of Surgical Oncology 8;4:328-337.
32 Corsetti, R. L., et al (2000) Thin < or = 1 mm level III and IV melanomas are higher risk lesions for
33 regional failure and warrant sentinel lymph node biopsy. Annals of Surgical Oncology 7;6:456-460.
35 De Stefani, S., et al (2010). Inguinal Lymphadenectomy for Penile Cancer and Melanoma: Our
36 Experience with 22 Cases. Anticancer Research 30;4:1480-1481.
37 Reason: Abstract
38 de Vries, M., et al (2009) Quality of life after axillary or groin sentinel lymph node biopsy, with or
39 without completion lymph node dissection, in patients with cutaneous melanoma. Annals of Surgical
40 Oncology 16;10:2840-2847.
41 Reason: Population not relevant to PICO

1 Egberts, F., et al (2011) Risk evaluation in cutaneous melanoma patients undergoing lymph node
2 dissection: impact of POSSUM. Annals of the Royal College of Surgeons of England 93;7:514-522.
3 Reason: Comparison not relevant to PICO (Palpable nodes versus non-palpable nodes)
4 Essner, R., et al (2006) Surgical management of the groin lymph nodes in melanoma in the era of
5 sentinel lymph node dissection. Archives of Surgery 141;9:877-882.
7 Faries, M. B. Et al (2010) The impact on morbidity and length of stay of early versus delayed
8 complete lymphadenectomy in melanoma: results of the Multicenter Selective Lymphadenectomy
9 Trial (I). Annals of Surgical Oncology 17;12:3324-3329.
10 Reason: Comparison not relevant to PICO
11 Fisher, S. R. and Fisher, Samuel R. (2002) Elective, therapeutic, and delayed lymph node dissection
12 for malignant melanoma of the head and neck: analysis of 1444 patients from 1970 to 1998.
13 Laryngoscope 112;1: 99-110.
14 Reason: Comparison not relevant to PICO (compares stage)
15 Fisher, S. R. and Fisher, S. R. (1989) Cutaneous malignant melanoma of the head and neck.
16 Laryngoscope 99;8:Pt 1:822-836.
18 Fortner, J. G. et al (1964) Results Of Groin Dissection For Malignant Melanoma In 220 Patients.
19 Surgery 55, 485-494. 1964.
21 Gadd, M. A. Coitet al (1992) Recurrence patterns and outcome in 1019 patients undergoing axillary
22 or inguinal lymphadenectomy for melanoma. Archives of Surgery 127;12:1412-1416.
23 Reason: No comparator
24 Geltzeiler, M. Givi. (2011) Regional control of head and neck melanoma with selective neck
25 dissection. Otolaryngology - Head and Neck Surgery Conference[var.pagings]
26 Reason: Abstract
27 Ghussen, F. and Kruger, I. Lymphadenectomy in Patients Suffering from Melanomas of the

28 Extremities - A Prospective-Study on 220 Patients. Aktuelle Chirurgie 23;6:232-235. 1988.
29 Reason:
30 Glumac, N., et al (2012) Inguinal or inguino-iliac/obturator lymph node dissection after positive
31 inguinal sentinel lymph node in patients with cutaneous melanoma. Radiology & Oncology 46;3:
32 258-264.
34 Gumport, S. L. M.(1959)Treatment of 126 cases of malignant melanoma: Long term results. Annals
35 of Surgery 150[6], 989-992.
36 Reason: No Data
37 Hotz, G., et al (1986) Prophylactic Lymph-Node Dissection in the Treatment of Cutaneous Malignant-
38 Melanoma - A Study of Matched Pairs. Hautarzt 37;10:554-559.

1 Hyngstrom, J. R. R. (2011) Prospective assessment of lymphedema following lymph node surgery for
2 melanoma. Annals of Surgical Oncology Conference[var.pagings]
3 Reason: Abstract
4 Ingvar, C. et al (1984) Morbidity following prophylactic and therapeutic lymph node dissection for
5 melanoma--a comparison. Tumori 70;6:529-533.
7 Karakousis, C. P et al (1991). Survival after groin dissection for malignant melanoma. Surgery
8 109;2:119-126.
10 Karakousis, C. P., et al (1983) Lymphedema after groin dissection. American Journal of Surgery
11 145;2:205-208..
12 Reason:No useable data
13 Kelemen, P. R., Wanek, et al (1999) Lymph node biopsy does not impair survival after therapeutic
14 dissection for palpable melanoma metastases. Annals of Surgical Oncology 6;2:139-143.
16 Kretschmer, L., et al (2008) Postoperative morbidity of lymph node excision for cutaneous
17 melanoma-sentinel lymphonodectomy versus complete regional lymph node dissection. Melanoma
18 Research 18;1:16-21.
19 Reason: Comparison not relevant to PICO (palpable versus non-palpable nodes)
20 Kunte, C., et al (2011) Analysis of predictive factors for the outcome of complete lymph node
21 dissection in melanoma patients with metastatic sentinel lymph nodes. Journal of the American
22 Academy of Dermatology 64;4:655-662.
23 Reason:
24 Leiter, U., et al (2010) Sentinel lymph node dissection in primary melanoma reduces subsequent
25 regional lymph node metastasis as well as distant metastasis after nodal involvement. Annals of
26 Surgical Oncology 17;1:129-137.
28 Lens, M. B., et al (2002). Elective lymph node dissection in patients with melanoma: systematic
29 review and meta-analysis of randomized controlled trials. [Review] [20 refs]. Archives of Surgery
30 137;4:458-461.
32 Livingstone E.Windemuth-Kieselbach. (2011) A first prospective population-based analysis

33 investigating the actual practice of melanoma diagnosis, treatment and follow-up. European Journal
34 of Cancer 47;13:1977-1989.
36 Mann, G. B., (1999) Does the extent of operation influence the prognosis in patients with melanoma
37 metastatic to inguinal nodes? Annals of Surgical Oncology 6;3:263-271.
39 Martin, B. M., et al (2014) Oncologic outcomes of patients undergoing videoscopic inguinal

40 lymphadenectomy for metastatic melanoma. Journal of the American College of Surgeons 218;4:,
41 620-626.

1 Milton, G. W. et al (1968) Radical dissection of the inguinal and iliac lymph-nodes for malignant
2 melanoma of the leg. British Journal of Surgery 55;9:641-648
4 Morton, D. L., et al (2007) Can completion lymph node dissection be avoided for a positive sentinel
5 node in melanoma? Annals of Surgical Oncology 14;9:2437-2439.
7 Morton, D. L., et al (2006) Sentinel-node biopsy or nodal observation in melanoma. New England
8 Journal of Medicine 355;13:1307-1317.
9 Reason: Using more recent publication
10 Morton, DL et al (2014) Final trial report of sentinel node biopsy versus nodal observation in
11 melanoma The New England Journal of Medicine 370;7:599-609
12 Reason: Each arm of the trial is relevant to an element of the PICO but the overall comparison is not
13 relevant and the results are not reported in a manner which allows inclusion.
14 Mozzillo, N.(2013) Superficial and deep lymph node dissection for stage III cutaneous melanoma:
15 Clinical outcome and prognostic factors. World Journal of Surgical Oncology 11.
17 Nagaraja, V., et al (2013) Is complete lymph node dissection after a positive sentinel lymph node
18 biopsy for cutaneous melanoma always necessary? A meta-analysis. European Journal of Surgical
19 Oncology 39;7:669-680.
20 Reason: Not relevant to PICO (prognostic)
21 Nagaraja, V. (2012) Is completion lymph node dissection after a positive sentinel lymph node biopsy
22 for cutaneous melanoma always necessary? A meta-analysis and systematic review. Asia-Pacific
23 Journal of Clinical Oncology Conference[var.pagings]
24 Reason: Abstract
25 Neuss, H., et al (2010) Postoperative surgical complications after radical axillary lymph node
26 dissection in melanoma disease result in increased pain. International surgery 95;2:166-171.
28 Neuss, H., et al (2010) Influence of Surgical Complications on the Level of Pain after Radical
29 Inguinal/Iliacal Lymph Node Dissection. Acta Chirurgica Belgica 110;3:308-312.
31 Nowecki, Z. I., et al (2008) The survival benefit to patients with positive sentinel node melanoma
32 after completion lymph node dissection may be limited to the subgroup with a primary lesion
33 Breslow thickness greater than 1.0 and less than or equal to 4 mm (pT2-pT3). Annals of Surgical
34 Oncology 15;8:2223-2234.
36 O'Brien, C. J., et al (1994) Evaluation of 107 therapeutic and elective parotidectomies for cutaneous
37 melanoma. American Journal of Surgery 168;5:400-403.
39 O'Brien, C. J., et al (1995) Radical, modified, and selective neck dissection for cutaneous malignant
40 melanoma. Head & Neck 17;3:232-241.

1 O’Brien, C. J., Gianoutsos, M. P., and Morgan, M. J. (1992) Neck Dissection for Cutaneous Malignant-
2 Melanoma. World Journal of Surgery 16;2:222-226.
3 Reason: Comparisons not relevant to PICO
4 O'Brien, et al (1991) Experience with 998 cutaneous melanomas of the head and neck over 30 years.
5 American Journal of Surgery 162;4:310-314.
7 O'Driscoll, D. O'Leary. (2012) Patterns of metastatic recurrence following inguinal lymph node
8 dissection in melanoma. Irish Journal of Medical Science Conference[var.pagings]
9 Reason: Abstract
10 Pasquali S.Mozzillo. (2013) The extent of radical lymph node dissection influences survival of
11 patients with melanoma. Annals of Surgical Oncology Conference[var.pagings], S116-S117.
12 Reason: Abstract
13 Pasquali, S., et al (2010) Early (sentinel lymph node biopsy-guided) versus delayed
14 lymphadenectomy in melanoma patients with lymph node metastases : personal experience and
15 literature meta-analysis. [Review] [30 refs]. Cancer 116;5:1201-1209.
17 Pilko, G., Besic, N., Zgajnar, J., and Hocevar, M. (2011) Prognostic heterogeneity after the excision of
18 lymph node metastases in patients with cutaneous melanoma. Surgical Oncology-Oxford 20;1:26-34.
19 Reason: Comparison not relevant to PICO (palpable versus non-palpable)
20 Reintgen, D. S. et al (1983) Efficacy of elective lymph node dissection in patients with intermediate
21 thickness primary melanoma. Annals of Surgery 198;3:379-385.
23 Ricard, A. S., et al (2007) Management of lymph nodes in head and neck melanoma: a retrospective
24 study of 25 cases. Revue de Stomatologie et de Chirurgie Maxillo-Faciale 108;6:505-508.
26 Rompel, R. Et al (1995) Elective lymph node dissection in primary malignant melanoma: a matched-
27 pair analysis. Melanoma Research 5;3:189-194.
29 Roses, D. F., Harris, et al (1981). Regional lymph node dissection for malignant melanoma of the
30 extremities. Surgery 89;6: 654-659
32 Rossi, C. R., et al (2014) The number of excised lymph nodes is associated with survival of melanoma
33 patients with lymph node metastasis. Annals of Oncology 25;1:240-246.
35 Rossi, C. R., et al (2014) Number of Excised Lymph Nodes as a Quality Assurance Measure for
36 Lymphadenectomy in Melanoma. JAMA Surgery .
38 Rutkowski, P. Nowecki. (2010) The analysis of the outcomes and factors related to iliac-obturatury
39 involvement in cutaneous melanoma patients after completion lymph node dissection (CLND) due to
40 positive sentinel lymph node (SLN) biopsy and after therapeutic LND (TLND) due to clinically

1 detected inguinal metastases. European Journal of Surgical Oncology Conference[var.pagings], 800.

2 Reason: Abstract
3 Serpell, J. W., et al (2003) Radical lymph node dissection for melanoma. ANZ Journal of Surgery
4 73;5:294-299.
6 Shah, J. P. Et al (1970). Incontinuity versus discontinuous lymph node dissection for malignant
7 melanoma. Cancer 26[3], 610-614.
9 Slingluff, C. L., et al (1994) Surgical management of regional lymph nodes in patients with melanoma.
10 Experience with 4682 patients. Annals of Surgery 219;2:120-130.
11 Reason: No Comparator
12 Spillane, A. (2013)The ideal extent of groin lymphadenectomy for metastatic melanoma to inguinal
13 lymph nodes is still controversial: Feasibility of the proposed ANZMTG eagle FM trial. JDDG - Journal
14 of the German Society of Dermatology Conference[var.pagings]
15 Reason: Abstract
16 Spillane, A. J. H. (2011) Inguinal or ilio-inguinal dissection for metastatic melanoma in groin lymph
17 nodes-a randomized trial is still required. Pigment Cell and Melanoma Research
18 Conference[var.pagings], 1067-1068.
19 Reason:Abstract
20 Spillane, A. J., et al (2008). Defining lower limb lymphedema after inguinal or ilio-inguinal dissection
21 in patients with melanoma using classification and regression tree analysis. Annals of Surgery
22 248;2:286-293.
24 Spillane, A. J. T. (2010) A minimally invasive groin radical lymph node dissection based on two
25 incisions for melanoma: A pilot study. Pigment Cell and Melanoma Research
26 Conference[var.pagings], 975.
27 Reason: Abstract
28 Teymoortash, A. Hoch. (2010) Postoperative morbidity after different types of selective neck
29 dissection. Laryngoscope 120;5: 924-929.
31 Thomas, J. M. H. (2008) Multivariable analysis comparing outcome after sentinel node biopsy or
32 therapeutic lymph node dissection in patients with melanoma (Br J Surg 2007; 94: 1293-1299).
33 British Journal of Surgery 95;5:664.
34 Reason: Comment
35 Trias, M., et al (1998) Extraperitoneal laparoscopically assisted ilioinguinal lymphadenectomy for

36 treatment of malignant melanoma. Archives of Surgery 133;3:272-274.
38 Tsutsumida, A. (2013) Is level I and II dissection adequate for patients with positive axillary sentinel
39 lymph nodes in melanoma. JDDG - Journal of the German Society of Dermatology
40 Conference[var.pagings],
41 Reason: Abstract

1 van Akkooi, A. C., et al (2007) Multivariable analysis comparing outcome after sentinel node biopsy
2 or therapeutic lymph node dissection in patients with melanoma. British Journal of Surgery 94;10
3 1293-1299.
5 van der Ploeg, A. P. T. (2010) Surgical management of palpable melanoma groin metastases: The
6 necessity of deep groin lymph node dissection. Pigment Cell and Melanoma Research
8 Reason: Abstract
9 van der Ploeg, I. M., et al. Evaluation of lymphatic drainage patterns to the groin and implications for
10 the extent of groin dissection in melanoma patients. Annals of Surgical Oncology 16;11:2994-2999.
11 Reason: Outcomes not relevant to PICO
12 Veenstra, H. J., V. (2010) Completion lymph node dissection in melanoma patients with a tumor-
13 positive sentinel node does not increase the rate of localregional recurrences. Annals of Surgical
14 Oncology Conference[var.pagings]
15 Reason: Abstract
16 Vigato E.Dalla Pozza.(2013) Completion lymph node dissection after a positive sentinel node biopsy
17 in malignant melanoma: Necessary or not? A preliminary report. JDDG - Journal of the German
18 Society of Dermatology Conference[var.pagings]
19 Reason: Abstract
20 von Kanel, O. E. C. (2005) One-stage versus two-stage lymph node dissection after investigation of
21 sentinel lymph node in cutaneous melanoma: A comparison of complications, costs, hospitalization
22 times, and operation times. European Journal of Plastic Surgery 27;7:347-350.
24 Wasif, N., Faries, M. B., and Morton, D. L. (2009) Survival in Node-Positive Melanoma Patients
25 Correlates with Extent of Lymph Node Dissection. Annals of Surgical Oncology 16:102-103.
26 Reason:
27 Wevers, K. P., et al (2012) Therapeutic lymph node dissection in melanoma: different prognosis for
28 different macrometastasis sites? Annals of Surgical Oncology 19;12:3913-3918.
30 Wong, S. L., et al (2006) Melanoma patients with positive sentinel nodes who did not undergo
31 completion lymphadenectomy: a multi-institutional study. Annals of Surgical Oncology 13;6:809-816.
33 Yu E.Spillane. (2010) Morbidity rates associated with inguinal sentinel lymph node biopsy and
34 inguinal lymph node dissection. Asia-Pacific Journal of Clinical Oncology Conference[var.pagings],
35 Reason: Abstract

Evidence Tables
Appropriate Precise Valid method of Investigators Investigators blind to Quality

length of follow- definition of an measuring blind to potential confounders (GRADE)
up outcome outcomes participants and prognostic factors?
exposure to
intervention?
Abbott et al Yes (median Yes Yes No No Very Low

(2013) follow-up was
different for
both groups,
however
outcomes were
short-term post-
operative and
survival
outcomes were
not compared
due to this
differencein
follow-up times)
Bamboat et al Yes Yes Yes No No Very Low

(2014)
deVries et al Yes Yes Yes No No Very Low
(2006)
Egger et al Yes Yes Yes No No Very Low
(2014)

O’Brien et al Yes Yes Yes No No Very Low

(2014)
Kingham et al Yes Yes Yes No No Very Low
(2010)
Kretschmer et al Yes Yes Yes No No Very Low
(2001)
Kretschmer et al Yes Yes Yes No No Very Low
(2004)
Singletary et al Yes Yes Yes No No Very Low
(1992)
Smith et al Yes Yes Yes No No Very Low
(2012)
Spillane et al Yes Yes Yes No No Very Low
(2014)
Van der Ploeg et Yes Yes Yes No No Very Low
al (2008)
Van der ploeg et Yes Yes Yes No No Very Low
al (2011)
al (2012)
al (2014)
White et al Yes Yes Yes No No Very Low
(2009)

Study Study Aim Population Intervention Comparison Follow Up Outcomes & Results
Type/Setting
Abbott et Retrospective To compare short- N=13 MILND Minimally Open 5 months for Operative time was significantly longer for
al (2013) Study term outcomes invasive Inguinal MILND MLND compared with OILND (245 mins
between MILND and N=28 OILND inguinal lymph node (median) versus 138 mins, p=0.003)
Data for OILND among lymph node dissection
minimally patients with dissection
invasive inguinal metastatic 13 months for Median blood loss was similar for both
lymph node melanoma from two OILND cohorts (MLND 30cc versus OILND 25 cc,
dissection was institutions. (median) p=0.07) and no blood transfusions were
collected administered.
prospectively
from 2010-2012
Length of hospital stay was significantly

Data relating to
shorter in the MLND cohort compared with
open inguinal
the OILND cohort (1 day versus 2 days,
lymph node
p=0.01)
dissection was
retrospective
and collected
from 2002-2011 Median disease free survival and overall
survival could not be compared due to the
2 tertiary difference in median follow up times.
academic
centres (USA)
Total median number of lymph nodes
pathologically identified in the
lymphadenectomy specimen was

Type/Setting
significantly higher in MILND cases than in
OILND cases (11 nodes versus 8 nodes,
p=0.03).
Infection incidence was reduced in the

MILND cohort compared with the OILND
cohort though the difference was not
statisitically significant (1 versus 8, p=0.13).
5/8 infections in the OILND cohort required

re-admission to hospital.
Incidence of wound dehisence was greater

in the OILND group compared with the
MILND group (4 versus 0, p=0.07)
Incidence of hospital readmission was

higher in the OILND cohort compared with
the MILND cohort (21% versus 7%, p=0.25)
None of the MILND patients developed a

VTE while 2 patients in the OILND group

Type/Setting
developed a postoperative VTE (p=0.32)
Drain duration did not differ between the

MILND group and the OILND group ( 28 days
versus 24 days, p=0.25)
Post-operative seroma rates did not differ

between the MILND group and the OILND
group (38% versus 21%, p=0.26).
Bamboat Retrospective To characterise the 4310 patients Completion Nodal No-CLND=23 The no-CLND group had a greater
et al Study populations undergoing lymph node observation months percentage of patients with groin node
(2014) undergoing nodal wide local dissection (median) involvement (43 versus 36%, p=0.03) and
Single institute observation (no excision with (CLND) fewer with axillary basin involvement (29
(USA) CLND) and CLND; SLNB versus 42%, p=0.03)
determine the CLND=80
pattern of initial N=495 (11%) months
recurrence between with a positive (median) 14% of patients in the no-CLND group had
no CLND and CLND SLN more than one nodal basin invovlement
group; determine N=167 versus 10% in the CLND group.
the melanoma underwent
specific survival of nodal
both patient groups observation
There was no difference in the median
and to characterise N=328
number of lymph nodes examined (N=2,

Type/Setting
the outcome of no underwent p=0.17) or percentage of patients with a
CLND patients who immediate single positive SLN (80% no CLND versus
experience a completion 75% CLND, p=0.23)
subsequent isolated lymph node
nodal recurrence dissection
In 66% of the no-CLND group, the reason for
Exclusions not undergoing CLND was patient decision,
Patients with while in 22% of the cohort the reason was
stage IV physician decision.
disease on
extent of In 4% of the cohort, patient co-mordities
disease work was the cited reason.
up Patients
undergoing
nodal Recurrence
observation
under MLST-II 81 patients (49%) in the no-CLND group and
were excluded 179 patients (55%) undergoing CLND
recurred.
Median time to recurrence was not

significantly different ; 9 months versus 12
months (p=0.46).
Sites of first recurrence: Regional recurrence

rates between the groups: No CLND=16%

Type/Setting
versus CLND 18%, p=0.58
Nodal Recurrence: No CLND=15% versus

CLND 6%, p=0.002
Systemic recurrence: No CLND=8% versus

27% CLND, p=<0.001
Median disease specific survival was not

reached for no CLND versus 110 months in
the CLND group (p=0.09)
Recurrence free survival was significantly

higher in the CLND group (34.5 versus 21
months, p=0.02).
In patients who developed systemic disease

as first recurrence, median disease free
survival was 46 months for the no-CLND
group versus 35 months for the CLND group
(p=0.98).

Type/Setting
Comparing DSS i patients undergoing
immediate CLND with a positive NSLN with
those in the no CLND group who developed
node only recurrence and went on to
salvage lymphadenectomy. Patients
undergoing salvage lymphadenectomy
(n=19) had a more favourable melanoma
specific survival (CLND median DSS=36.5
months versus not reached for salvage LND,
p=0.005)
On multivariable analysis factors associated

with higher melanoma specific survival
included increasing age (p=0.006), tumour
thickness (p=0.001) and ulceration
(p<0.001).
deVries Retrospective To evaluate N=66 SLNB + SLNB 51 months  Long term morbidity (lymphoedema
et al Study morbidity after N=52 SLNB completion (median) (4- and range of motion of restrictions)
(2006) inguinal SLNB alone only lymphadene 94 months)
Patients were and inguinal SLNB N=14 ctomy
treated with completion underwent Complications
between 1995 inguinal dissection completion
and 2003 lymphadenect No patient died as a result of surgical
omy (N=11 intervention.
University superficial +

Type/Setting
Medical Centre, deep groin 3 patients developed complications after
Netherlands dissection and inguinal SLNB
N=3 superficial
groin 4 patients developed wound infection after
dissection) SLNB+groin dissection
Exclusions:
After SLNB alone, there were 3
 Treatment complications versus 7 after SLNB+groin
for local or dissection (p<0.001)
lcoc-
ragional
recurrence
Volume
at the
time of In patients who underwent inguinal SLNB,
the study no volume difference was observed
 Bilateral between patients with primary melanoma
SLNB on the trunk compared with primary
 Undergoin melanoma on the leg (p=0.4)
g follow-
up
elsewhere
Volume differen was observed between
 Pre-
primary closure of the excision wound and
existing
closure with a free skin graft (p=0.044)
functional
limitations
 Previous

Type/Setting
operations A significant volume difference was
on the observed (p<0.001)between patients
extremity undergoing SLNB and patients undergoing
concerned SLNB+groin dissection.
 Pre-
exisiting
volume Functional Outcome
difference
between The average difference in degrees was
the two significantly higher in the SLNB+groin
extremitie dissection group for flexion of the hip
s (p=0.011)
 Severe
comorbidi
ty such as
dementia,
disseminat
ed disease
or patients
receiving
palliative
care
Egger et Retrospective To evaluate whether N=143 Inguinal Combined 39 months  Overall Survival
al (2014) study a combined inguinal patients Dissection inguinal and (median)  Disease free survival
and iliac/obturator iliac/obturat
Population dissection improved N=100 inguinal

Type/Setting
included in the locoregional disease dissections or dissection
Sunbelt clinical control and survival
trial were compared with an N=34 Median number of lymph nodes removed
included along inguinal dissection combined was 11 (2-37).
with patients in alone in the absence inguinal and For inguinal dissection the median number
the University of of clinical and iliac/obturator of lymph nodes removed was 11 (3-33) and
Louisville radiological dissection for combined iliac/obturator dissection the
melanoma evidence of pelvic median number of lymph nodes removed
database. lymph node was 22 (10-51).
metastases
Microscopic Disease
94/134 patients (70%) underwent an iguinal

dissection for microscopic (SLN postive)
disease. 12 of these patients underwent
combined inguinal and iliac/obturator
dissection.
The rate of tumour positive pelvic lymph

nodes when a combined inguinal and
ilia/obturator dissection was performed for
microscopic disease was 25% (3/12).
Recurrence rates in the pelvic lymph nodes

Type/Setting
were similar between inguinal dissection
and combined inguinal and iliac/obturator
dissection (12% versus 17%, p=0.66).
Complication rates were similar between

inguinal dissection and combined inguinal
and iliac/obturator dissection (29% versus
27%, p=0.89).
There was no significant difference in the

rate of lymphoedema between the inguinal
dissection and combined inguinal and
iliac/obturator dissection groups (15.9%
versus 27.3%, p=0.35)
Macroscopic Disease
22/40 patients (55%) with macroscopic

disease underwent a combined inguinal and
iliac/obturator dissection.
The rate of tumour positive pelvic nodes

was 55% (12/22) when combined dissection

Type/Setting
was performed for macroscopic disease.

recurrence rates between inguinal lymph
node dissection and combined dissection
(11% versus 5%).
Complication rates were not significantly

different between the inguinal dissection
group and the combined lymph node
dissection group (33% versus 32%, p=0.92).

rates of lymphoedema between the inguinal
dissection and combined lymph node
dissection group (16.7% versus 9.1%, p
=0.47).
Overall rate of positive pelvic lymph nodes

in all patients undergoing combined inguinal
and iliac/obturator dissection was 44.1%.

Type/Setting
No statistically significant risk factors for

tumour positive pelvic lymph nodes were
identified which could identify patients at
high risk for pelvic lymph node metastases
in patients without a priori clinical
knowledge or radiological evidence of
metastases.
5-year lymph node recurrence-free survival

rate was 77%.
Pelvic node recurrence rates did not differ

significantly between all inguinal dissections
compared with combined inguinal and
iliac/obturator dissection (12% versus 8.9%,
p=0.61).
Inguinal or pelvic node recurrences after

inguinal dissection or combined inguinal and
ilia/obturator dissection were often
associated with systemic recurrences; 60%

Type/Setting
of patients with a nodal recurrence also
suffered systemic recurrence.
Systemic recurrence was the most common

type of recurrence (43% for inguinal
dissection and 48% for combined inguinal
and iliac/obturator dissection).
Systemic recurrences were higher in the

macroscopic group compared with the
microscopic group (40% versus 31%).
There was no difference in pelvic node

recurrence-free survival or disease free
survival for inguinal dissection alone
compared with inguinal and iliac/obturator
dissection when stratified by indication
(microscopic versus macroscopic nodal
disease)
Disease free survival was greater for

microscopic disease (p=0.0002).

Type/Setting
5 year overall survival rates (p=0.0163)
Microscopic disease/Inguinal lymph node

dissection = 72%
Microscopic disease/Inguinal and

Iliac/Obturator lymph node dissection =68%
Macroscopic disease/Inguinal lymph node

dissection=51%
Macroscopic disease/Inguinal and

Iliac/obturator lymph node dissection=44%
No difference in overall survival was

observed when comparing inguinal
dissection with inguinal and iliac/obturator
dissection when stratified by indication.
Kingham Retrospective To examine a group N=313 Complete No lymph No CLND=32 Unclear appear to be:
et al Study of SLNB positive N=271 lymph node node months
(2010) patients who underwent dissection dissection (median)
Patients were underwent CLND  Recurrence
treated completion lymph N=42 no CLND
 Survival
between 1992 node dissection CLND=43

Type/Setting
and 2008 compared with SLNB+CLND months
those who did SLNB+salvage (median)
Netherlands therapeutic There was a statistically significant
Cancer Institute lymph node difference between location of melanoma
dissection in patients who did not undergo CLND
compared with those who did (p<0.01)
Lower extremity: 40% versus 13%
Trunk: 26% versus 45%
Head and Neck: 17% versus 8%
Upper Extremity: 12% versus 32%
There was a statistically significant increase

in patients who did not undergo CLND in
more recent periods (1992-2000 versus
2001-2008).
Patients who did not undergo CLND had

significantly higher median age and a
significant difference between the location

Type/Setting
of melanomas
No difference was observed in the pattern

of first recurrence between patients who
had a CLND and those who did not (CLND
54% versus No CLND 48%)
Median interval recurrence was similar in

the two groups (CLND: 14 months versus
No CLND: 13 months)

location of first recurrence
Median relapse free survival was 35

months for the no –CLND group and 36
months for the CLND group (p=0.63). In
this analysis, patients who did not undergo
CLND but had metastasis on SLNB were
removed (n=5).
Kretschm Retrospective To investigate N=937 SLNB + early SLNB + From primary  Overall Survival
er et al Study survival outcomes in N=314 excision delayed diagnosis 32

Type/Setting
(2004) patients with undergoing excision months
Five clinical lymphatic early excision (median)
centres in metastases who N=623 A significantly higher number of metastatic
Germany underwent early or undergoing 3-94 months lymph nodes were excised in patients with
delayed excision of delayed (range) in DLND compare with patients having ELND
SLNEs were regional lymph excision patients with (2.45±2.35 nodes versus 1.54±1.42 nodes;
performed nodes positive SLN p<0.00001).
between 1993 biopsy
and 2002 Study does not
exclusively Overall survival was significantly better for
DLNDs were include stage 121 months patients with SLND and early diagnosis of
performed III patients (median) lymph node metastases (p=0.002).
between 1983 though it is
4-324 months
and 2002 not clear from
(range) in
the paper
patients with Estimated 3 year overall survival rate was
what the 80.1±2.8% in patients with positive SLNs and
DLND
distribution of 67.6±1.9% in patients with DLND.
stages might
be. 5 year overall survival rates: 62.5±5.5 and
Patients were 50.2 ±5.4%
Inclusions routinely
Patients with monitored at
loco-regional 3 month On multivariate analysis , SLNE was an
cutaneous intervals for independent prognostic factor of overall
metastases the first 2 survival (p=0.000052)
prior to lymph years and
node excision every 6

Type/Setting
months for
Exclusions the next 3
Patients with years and
clinically annually
detectable thereafter.
distant
metastases at
the time of
DLND were
excluded
Kretschm Retrospective To ivestigate the N=104 Ilio-inguinal Inguinal 68 months  Local tumour control
er et al Study impact of inguinal patients with dissection dissection (median)  Survival
(2001) versus ilio-inguinal cutaneous
Patients were node dissection in melanoma
operated on patients with who This was a 28-141 Median interval from the date of
between palpable groin nodes underwent highly months lymphadenectomy to reviewing the data
September 1983 therapeutic selected (range) was 127 months (range 42-177)
and August groin group of
1994 dissection. patients
(elderly Follow-up
University N=69 ilio- Overall 5 year survival was 30.4%
patients wiht closed in
Hospital, inguinal cardiopulmo Overall 10 year survival was 18.4%
March 1998
Germany dissection nary risk
N=35 factors in
superfical particular Patients with only 1-2 nodes had a median
inguinal those with survival of 14 months and a 5 year survival

Type/Setting
dissection small groin of 41.4%
metastases;
some
patients with Patients with more than two involved nodes
very thick or iliac metastases had a median survival of
primary 14 months and a 5 year overall survival of
melanomas 13.9%
or patients
presenting
with lymph
Univariate analysis showed a statistically
node and
significant difference between the two
locoregional
groups (crude relative risk=2.4; 95% CI, 1.5-
cutaneous
3.7, p=0.0006)
metastases)
Extent of lymph node dissection did not

have a significant effect on survival.
There was a significant difference in survival

between patients with superficial and pelvic
nodal involvement compared with patients
with only superficia lymph node metastases
(p=0.008)
In patients undergoing ilioinguinal

Type/Setting
dissections, 34.8% had metastatic
involvement of both superficial and pelvic
nodes. Median survival was 12 months for
these patients, overall 3 year survival rate
was 25% and overall 5 year survival rate was
6.2%
Median survival was 30 months and 5 year

survival rate was 36.7% for patients with
superficial lymph node metastases.
33.6% of patients relapsed into the

dissected lymph node basin.
Median time between inguinal

lymphadenectomy and groin recurrence was
9 months (range 1-34).
Median survival after groin recurrence was

10 months.
Tyoe of operation (inguinal versus

ilioinguinal dissection) did not influence

Type/Setting
local control of the dissected lymph node
basin.
O’Brien Retrospective To evaluate the role N=175 Therapeutic Elective Neck Median Lymph nodes were histologically positive in
et al Study and efficacy of patients who Neck Dissection follow-up 80% of 183 dissection specimens
(1995) modified and had 183 neck Dissection (Selective or time was 42
selective neck dissections (Selective, Modified) months (12-
dissections and Radical or 80 months) A total of 72/75 (43%) therapeutic neck
adjuvant modified) dissections were positive compared with
radiotherapy in Elective 8/108 (8%) elective dissections.
treating patients dissections
with clinical were
metastatic performed A total of 92 patients had a therapeutic or
melanoma when elective parotidectomy with their neck
primary dissection.
melanoma
thickness
was ≥1.5mm
Significant surgical complications occurred
in 16 (9%) patients and there was one post-
operative death.
26 patients received post-operative

radiotherapy following histologically
positive dissections.

Type/Setting
Recurrence of metastatic melanoma

developed in 19/183 dissected necks or
parotids representing a cumulative 5 year
control rate of 86%.
Time to recurrence ranged from 2 months

to 51 months after initial dissection.
15/19 recurrences occurred within 1 year

of lymphadenectomy.
Recurrence rate following histologically

positive dissection was 17% compared with
5% after histologically negative dissections.
Incidence of recurrence was not affected

by the number of positive nodes or
presence of extracapsular spread.
Recurrence in the neck or parotid following

Therapeutic Dissection
n 2 yr Irradia Recurr %
F/U ted ence

Type/Setting
RND 32 29 14 4 14
MRND 15 12 2 0 0
SND 28 22 8 5 23
Paroti 19 17 13 4 24
decto
my
Elective Dissection
n 2 yr Irradia Recurr %
F/U ted ence
RND 2 2 0 0 0
MRND 17 14 1 1 7
SND 89 79 1 4 5
Paroti 73 63 0 1 1.5
decto
my
There were 2 recurrences in the 27 node

positive dissections treated with adjuvant
radiotherapy (7%) compared with 12/53
(23%) recurrences in node dissections

Type/Setting
which did not receive radiotherapy.
At time of follow-up, 52 patients had

developed distant metastases (39 node
positive and 13 node negative).
Median time to development of distant

metastases was 8 months in node positive
patients compared with 22 months among
node negative patients.
Cumulative 5 year survival was 50% and

was significantly higher for patients having
elective dissection compared with
therapeutic dissection (due to the fact that
almost all patients having therapeutic
dissections had histological node
involvement).
5 year survival rate was 61% for node

negative patients and 38% for node
positive patients.

Type/Setting
Patients with 2 or more involved nodes had
similar but poorer survival compared with
patients with <2 involved nodes.
Singletary Retrospective To investigate N=264 Superficial Combined 142 (1-411)  Survival

et al whether or not a patients femoral ilio-inguinal months
(1992) University more conservative N=113 with node dissection (median)
Hospital (USA) approach would subsequent dissection No difference was observed in the survival
offer and improved regional nodal rate of patients who initially had nodal
survival rate or disease metastases and patients who subsequently
better local and N=151 who Iliac nodal developed nodal disease (p=0.12).
regional control. initially had dissection
regional nodal for patients
disease with No significant difference in median overall
synchronous survival time was observed among patients
Patients were primary with superficial femoral or radical groin
treated from melanoma dissection (32.7 months versus 39.5 months,
1948-1987
p=0.17)
Femoral
nodal Type of groin dissection did not affect
dissection six survival when stratified by tumour burden
weeks later (1 positive node, p=0.06; 2 or more nodes,
for patients p=0.16; extra nodal, p=0.13)
with
palpable

Type/Setting
groin disease The majority of tumour relapse from
melanom were distant metastases.
15% of all patients had a recurrence within

Superficial the nodal basin after operation with a
femoral higher proportion occuring in the superficial
dissection or
femoral dissection group than in the radical
combined surgical treatment group though the
ilioinguinal difference was likely related to the extent of
dissection tumour burden than to the extent of
for patients
surgery.
who
developed
delayed
nodal
metastases.
Smith et Retrospective To determine N=350 SLNB SLNB + SLNB = 26  Disease Specific Survival
al (2012) Study whether CLND patients completion months  Overall Survival
improves survival in N=140 SLNB lymph node (median)
Patients treated patients with only dissection
between cutaneous N=210 SLNB
Disease specific survival was analysed in two
January 1998 melanoma of the +CLND SLNB+CLND=2 seperate age groups (patients age <60 years
and December head and neck 4 months and patients ≥60 years) Type of lymph node
2007 (median) procedure was not associated with
improved disease specific survival in either
Exclusions
age group (p=0.56).
No nodal

Type/Setting
metastasis
No SLNB
Missing data Age was signficantly associated with disease
regarding the specific survival with an increased risk of
quantity of death from melanoma in the younger age
examined or group (4.5% per additional year of age at
positive nodes diagnosis, p=0.016).
Tumour thickness .2mm was the only

significant predictor of worse survival in the
older age group (HR=3.11, p<0.001).
Disease specific survival for the whole

cohort did not differ significantly for CLND
patients (log rank p>0.2).
In patients with a poorer prognosis (tumour

>2mm thick and/or ulcerated), CLND did not
significantly affect survival.
For patients with the best prognosis,

survival was statistically different based on

Type/Setting
surgical procedure in both age groups:
CLND was associate with improved survival

in patients age <60 (p=0.039)
CLND was associated with worse survival in

patients aged ≥60 (p=0.023)
In low risk patients who had at least 3 SLN

harvested of which only 1 was positive for
metastasis, CLND significantly reduced the
risk of death from melanoma in patients <60
years (p=0.003)
In patients ≥60 years, CLND was associated

with significantly poorer survival (p=0.028).
Spillane Retrospective To establish how N=1704 SLNB+Immed Each Other 69 months  Disease Free Survival
et al Study timing of iate (median) after  Post Recurrence Survival
(2014) lymphandenectomy N=502 completion melanoma  Overall Survival
Melanoma in the ciourse if the Immediate lymphadene diagnosis
Institute disease related to completion ctomy (95% CI 66-
Australia the interval between lymphadenect 73months)
Recurrence occurred in 48% of all patients
the diagnosis of the omy (ICL)
at a median time of 57 months (95% CI 49-
Patients treated primary tumour and SLNB+delaye

Type/Setting
between 1992 the first recurrence N=214 d completion 65)
and 2010 after Delayed lymphadene
lymphadenectomy. Completion ctomy
lymphadenect Site of First Recurrence
omy (DCL)
Observation Local=3.8%
N=709 +Delayed In-transit=7.4%
Delayed therapeutic
therapeutic lymphadene Nodal=7.3%
lymphadenect ctomy
omy (DTL) Distant metastases=29.5%
N=279
Immediate
Immediate Disease free survival was significantly
therapeutic
therapeutic different between the four treatment
lymphadene
lymphadenect groups (p=0.001)
ctomy for
omy (ITL)
clinically Median disease free survival times
positive (months):
Patients with
nodes
proven single
ICL=68 (95% CI, not reached)
cutaneous
melanoma DCL=48 (95% CI 39-56)
managed with
lymphadenect DTL=82 (95% CI 66-97)
omy before
ITL=16 (95% CI, 14-19)
any other
recurrence

Type/Setting
events
Extranodal spread was the only independent

prognostic factor for all four treamtent
groups (multivariate analysis)
TNM N stage was a signififcant independent

predictor of disease free survival in all
groups apart from the DCL group.
Disease free survival after 5 years was

significantly differnect when comparing ICL
(n=113) and DTL (n=283) groups (p=0.005) a
difference that remained significant after
multivariate analysis. Hazards Ratio=2.57;
95% CI, 1.14-5.85, p=0.023).
TNM N-stage remained a significant

predictor of disease free survival after 5
years:
N2 versus N1: HR 2.20, 95% CI, 1.75-5.88,

Type/Setting
p<0.001
N3 versus N1: HR 3.16, 95% CI 1.69-5.92,

p<0.001
Postrecurrence Survival
In patients who experienced relapse after

lymphadenectomy, median post recurrence
survival for the whole cohort was 9 months
(95% CI 7-10 months).
Median PRS by site (p<0.001):
Local/In-transit= 18 months (95% CI 14-21

months)
Nodal= 18 months (95% CI 11-24 months)
Distant metastases= 7 months (95% CI 6-8

months)
Patients in the ICL group had significantly

longer PRS compared with patients in other

Type/Setting
treatment groups (log rank p<0.001)
PRS times by treatment group
ICL=14 months (95% CI 7.2-10.7)
DCL=8 months (95% CI 6.3-9.7)
DTL=9 months (95% CI 7.2-10.7 months)
ITL= 9 months (95% CI 6.7-11.3 months)
ICL versus DCL p<0.001
ICL versus DTL p<0.001
ICL versus ITL, p<0.001
DCL versus DTL p=0.424
DCL versus ITL p=0.769
DTL versus ITL p=0.179
On multivariate analysis, distant site of first

recurrence was a significant prognostic

Type/Setting
factor for all treatment options except DCL.
Overall Survival
There were 675 deaths due to melanoma

(39.6%) and median survival from time of
primary melanoma diagnosis was 91.7
months (95% CI 80.7-102.9).
Overall survival was significantly differnent

across clinical scenarios (p<0.001)
Median Survival by treatment option
ICL=not reached
DCL=71.1 months (95% CI 45.8-96.4)
DTL=101.3 months (95% CI 86.1-116.0)
ITL=29.2 months (95% CI 22.7-35.8)
Extranodal spread and TNM N stage were

Type/Setting
significantly associated with overall survival.
For patients surviving beyond 5 years,

overall survival was significantly different
when comparing the ICL group and DTL
groups (p=0.012)
TNM N stage was the only predictor of

overall survival in patients surviving >5
years.
N2 versus N1 HR=2.37, 95% CI 1.354.14,

p=0.002
N3 versus N1 HR=4.15, 95% CI 2.387.24,

p<0.001)
Van der Retrospective To investigate the N=52 clinically Completion Superficial 61 months  Lymph Node Recurrence
Ploeg et Study pathological node negative groin node groin node (median)  Disease Free Survival
al (2008) findings, the patients with dissection dissection
Patients incidence of lymph cutaneous
treated node recurrences melanoma and
At 5 years 77% of all patients were alive
between June and the disease free a tumour
(95% CI 62-95%) and 56% were disease
1996 and April survival in clinically positive
free (95% CI 40-80%)
2007 node negative sentinel node

Type/Setting
patients with a biopsy of the
positive sentinel groin
node in the groin 5 year survival for patients who underwent
who have N=10 patients only superficial dissection was 76% (95% CI
undergone lymph who did not 56-100%) and 5 year disease free survival
node dissection receive further was 53% (95% CI 31-90%)
dissection due
to small
tumour 5 year survival for patients who underwent
burden in the combined superficial and deep dissection
sentinel nodes was 80% (95% CI 61-100%) and 5 year
and were not disease free survival was 61% (95% CI 39-
included in the 96%)
analysis.
Van der Retrospective To evaluate the N=121 Combined Therapeutic 20 months  Post operative morbidity
ploeg et Study experience in patients who superficial superficial (median) for  Regional Recurrence
al (2011) patients with underwent and deep dissection all patients  Preoperative CT scan
One University clinically evident combined dissection  Disease free survival
Medical Centre metastatic superficial and  Overall survival
(Netherlands) melanoma to the deep 45 months
groin who dissection (median) for
Surgery was underwent (CGD) survivors. Post-operative Morbidity
carried out combined superficial
between 1991 and deep groin N=48 patients Median hospital stay was 6 days (3-27) for
and 2009 dissection versus who patients with CGD and 6 days (2-32) for
inguinal or underwent patients with SGD.

Type/Setting
superficial groin therapeutic
dissection superficial
dissection There were no significant differences in
(SGD) for post-operative morbidities between CGD
palpable and SGD patients (p>0.05).
metastses to
the groin
There was a trend towards more chronic
Exclusions lymphoedema in the CGD group (25.6%
Patients who versus 14.6%, p=0.154)
underwent
sentinel lymph
node biopsy Recurrence
Adjuvant There no statisitically significant difference

radiotherapy in disease free survival time or time to
was given to regional relapse between SGD and CGD
16 patients patients.
Overall recurrence rate was 73% (90/121)

for SGD patients and 74% (35/48) for CGD
patients.
At the time of last follow-up 67% of CGD

patients and 65% of SGD patients had died.

Type/Setting
Regional recurrence rates were more

common in the SGD group that in CGD
group (21% versus 16%, p=0.498).
Pelvic recurrence rates were 10% in both

groups.
Median time to first recurrence was 7.6

months (1-96) for CGD patients and 6
months (1-42) for SGD patients (p=0.677).
Survival Analysis
There was no significant difference in

disease free survival and overall survival
when comparing CGD patients and SGD
patients.
5 year estimated diseasae free survival rate

was 15.7% for SGD patients and 18.3% for

Type/Setting
CGD patients.
5 year estimated overall survival rate was

28.7% for SGD patients and 33% for CGD
patients.
Univariate Analysis
Number of positive superficial nodes was a

significant prognostic factor for Disease free
survival (HR=1.85, 95% CI 1.21-2.84,
p=0.005) and for overall survival (HR=1.6,
95% CI 1.03-2.51, p=0.038) and (HR=2.36,
95% CI 1.50-3.71, p=0.0005)
Superficial lymph node ratio was a

significant prognostic factor for disease free
survival (HR 2.33, 95% CI 1.25-4.34, p<0.008)
and for overall survival HR=3.16, 95% CI
1.68-5.94, p<0.001).
In SGD patients only, the largest diameter of

Type/Setting
the positive lymph node was significant for
overall survival (HR=3.10, 95% CI 1.07-8.98,
p=0.037)
In CGD patients only, superficial lymph node

ratio (HR=5.9, 95% CI 2.21-15.76, p<0.001);
more than three positive lymph nodes
(HR=2.29, 96% CI 1.34-3.91, p=0.002) and
presence of involved deep lymph nodes
(HR=2.25, 95% CI 1.38-3.66, p=0.001) were
poor prognostic factors for overall survival.
In CGD patients only, superficial lymph node

ratio (HR=4.64, 95% CI 1.70-12.65, p<0.003);
more than three positive lymph nodes
(HR=1.96, 96% CI 1.19-3.22, p=0.008) and
presence of involved deep lymph nodes
(HR=1.61, 95% CI 1.02-2.55, p=0.041) were
poor prognostic factors for disease free
survival.
5-year estimated DFS and OS rates for

positive deep lymph nodes were 9.1% and

Type/Setting
12.5% respectively.
5 year estimated disease free survival rates

for positive superficial lymph nodes only in
CGD patients were 21.5% and 39.7%.
5 year estimated disease free survival rates

for the number of positive lymph nodes was
23.7% for 1, 12.0% for 2-3 and 11.2% for ≥4
invovled nodes.
5 year estimated overall survival rates for

the number of positive superficial lymph
nodes was 23.7% for 1, 12% for 2-3 and
11.2% for ≥4 involved nodes.
5 year estimated overall survival rates for

the number of positive superficial lymph
nodes was 42.6% for 1, 25.8% for 2-3 and
17% for ≥4 involved nodes.
Van der Retrospective To evaluate the N=1174 CLND No CLND 48 (25-70)  Disease Specific Survival
ploeg et Study infulence of patients with months

Type/Setting
al (2012) immediate SN positive (median) in
10 European completion lymph melanoma the no CLND
cancer centres node dissection N=1113 group CLND was not a significant prognostic factor
collaborating in (CLND) on outcome underwent for disease specific survival (HR=0.89, 95% CI
the EORTC in patients with SN immediate 0.58-1.37, p=0.6)
Melanoma positive melanoma CLND 34 (20-60)
Group N=61 no CLND months
(median) in In matched pair analysis CLND did not
Matched pair the CLND significantly influence disease specific
analysis was group survival (HR=0.86, 95% CI0.46-1.61, p=0.64)
carried out with
patients from
the study CLND had no significant influence on
44 months
groupmatched prognosis in any of the models adjusting for
(median) in
with those in prognostic imbalance in baseline factors.
the 61
the control
matched
group according
patients who
to age, breslow
underwent There was a trend towards improved
thickness,
CLND outcome for patients who underwent CLND
tumour
compared with those who did not.
ulceration,
rotterdam Model 1. HR=0.81, 95% CI 0.52-1.25, p=0.34)
criteria, Dewar
criteria, S Model 2. HR=0.82, 95% CI 0.53-1.27,
classification p=0.377)
and RDC
Model 3: HR=0.74, 95% CI0.48-1.16,
criteria.

Type/Setting
p=0.189)
Model 4: HR=0.73, 95% CI, 0.47-1.14,

p=0.169)
Subgroup analyses showed no significant

benefit of CLND after correcting for age,
breslow thickness and tumour ulceration.
3 year disease specific survival was 74% in

patients who did not undergo CLND
compared with 76.9% for patients who did.
5 year disease specific survival was 66% for

patients who did not undergo CLND
compared with 66.9% for those who did.
In the matched pair analysis rates for the 61

patients who underwent CLND were 79%
and 69% (HR=0.86, 95% CI 0.46-1.61,
p=0.64)

Type/Setting
Van der Retrospective To compare regional N=2931 in the SLNB+wide Observation Mean follow There were significant differences in
ploeg et Study recurrence free observation local excision + total lymph up for baseline characteristics between the SNB
al, 2014 survival, distant group node observation and observation groups:
metastases free dissection patients was
survival and for 54.2 months SNB group had younger patients and
melanoma specific recurrence (median, 40 melanomas of a nodular subtype.
N=2909 in the
survival of SNB SLNB arm months) Observation group contained more young
patients with patients and more melanomas less than
observation patients 1mm in thickness, with a lower mitotic rate
in a large patient Mean follow- and located in head and neck sites.
cohort up for SLNB
patients was
53.4 months Recurrence
(median, 44
months)
Site of first recurrence was significantly

different in the two groups (SNB=distant
metastases; Observation=regional node
metastases p<0.001)
Median time to first recurrence was 38

months (range: 1-215 months) for SNB
patients and 31 months (range: 1-223
months) for observation patients

Type/Setting
There were significantly fewer regional

node recurrences in the SNB group
compared with the observation group
(p=0.047)
Tumours <1mm with ulceration, Clark level

IV or V invasion or a mitotic rate of 1 or
more per millimetre square – there were
significantly fewer regional node
recurrences in the SNB group (p=0.047)
Tumours =1mm – There was no significant

difference in regional node recurrence
between the groups
Tumours >1mm thick – there were

significantly more regional node
recurrences in the SNB group compared
with the observation group (p<0.001)

Type/Setting
There was no significant difference
between the groups in the proportion of
distant metastases as first recurrences for
patients with tumours <1mm and 1mm
thick while for tumours >1mm there were
significantly more distant metastases as
first recurrences in the SNB group
(p=0.018).
There were significantly fewer recurrences

of any type in the SNB group compared
with the observation group for patients
with melanoma >1mm (p<0.001).
Disease Free and Distant metastases free

survival
SNB showed improved disease free survival

(p<0.001) but no difference in distant
metastases free survival (univariate
analysis).
In patients with T2 or T3 melanomas (>1.0-

Type/Setting
4.0mm) SNB patients demonstrated
improved DMFS compared with the
observation group (p=0.021).
After adjustment for prognostic factors,

the SNB group had significantly better
disease free survival (HR=1.40, 95% CI
1.23-1.58, p<0.001);
Regional lymph node control (HR=3.23,

95% CI 2.66-3.94, p<0.001) and distant
metastasis free survival for T2 and T3
subgroups (HR=1.23, 95% CI 1.01-1.5,
p=0.041) were significantly better in the
observation group.
Melanoma specific survival
No significant difference in MSS between

the groups (p=0.560)
5 year MSS was 85% for SNB patients and

85.8% for observation.

Type/Setting
MSS was better for patients in the SNB
group with tumours >1mm thick (p=0.012)
and in patients with T2 and T3 melanomas
(>1.0-4mm, p=0.011).
5 year MSS for patients with T2 and T3

melanoma was 86.8% for the SNB group
and 85.3% for the observation group.
No significant difference in overall MSS

when adjusting for known prognostic
factors.
SN positive versus SN Negative
Sentinel node status was an independent

prognostic factor for DFS (HR=3.04, 95% CI
2.50-3.70, p<0.001) and for MSS (HR=2.97,
95% CI, 2.34-3.77, p<0.001).
5 year DFS rate for SN positive patients was

81.4% and 5 year MSS rate was 88.9%
5 year DFS rate for SN negative patients

was 51.2% and 5 year MSS rate was 63.8%.

Type/Setting
SNB with Early CLND versus Observation
with late TLND
394/2909 patients were SN positive and

received CLND.
There were positive non SN in 77 (19.5%)

of patients.
89/2515 (3.5%) patients had regional node

recurrence as first recurrence and
underwent delayed lymphadenectomy.
SN false negative rate was 18.4%.
417 patients in the observation group

recurred in the regional node field and
received a delayed TLND.
Mean number of positive nodes in patients

receiving CLND was 1.69 compared with
2.92 for patients in the observation group
and 2.57 for SN false negative patients at
the time of delayed lymphadenectomy

Type/Setting
(p<0.001).
15.2% of early CLND patients had N3

disease compared with 32.5% in the
observation group and 29.2% in the SN
false negative group (p<0.001).
SN positive patients having early CLND had

significantly better DMFS compared with
observation patients undergoing delayed
LND (Obs HR=1.36, 95% CI 1.08-1.72,
p=0.01).
DMFS was significantly different for the SN

positive group compared with the
observation group for patients with T2 and
T3 melanomas (Obs HR=1.36, 95% CI 1.01-
1.84, p=0.042).
MSS was not significantly influenced by

early CLND or delayed TLND.

Type/Setting
5 year MSS estimates were 64.1% for CLND

patients and 60.5% for TLND patients
(p=0.144).
5 year MSS estimates for T2 and T3 patients

were 68.3% after CLND and 62.7% after
delayed TLND
White et Retrospective To evaluate the N=37 Radical neck Each Other 46 months Overall survival at 60 months was 33% with
al (2009) Study outcome of dissection (mean) no difference observed in survival rates for
therapeutic neck the 3 different types of dissection.
2 Plastic Surgery dissection for Inclusions Modified
Units in melanoma in Patients with a radical
dissection Patients with
University patients with head single invovled less than 18
hospitals in the and neck melanoma node based on Selective months
UK (Coventry clinical or dissection follow-up
and radiological were excluded
Warwickshire investigation
NHS trust and
Birmingham Exclusions
NHS trust) Patients
undergoing
concomitant
deep pelvic

Type/Setting
lymphadanect
omy or
isolated limb
perfusion

1 5.2 Adjuvant radiotherapy
2 Review question: What is the effectiveness of adjuvant radiotherapy to the resected

3 lymph node basin for stage III melanoma in people who have undergone curative
4 resection?

Patients who have  Adjuvant  No Adjuvant 1 Local recurrence
undergone a Radiotherapy to Radiotherapy
curative resection the resected lymph 2 Melanoma specific survival
for stage node basin
III melanoma: 3 Lymphoedema
 Neck
 Axilla 4 Metastases free survival
 Groin
5 Adverse events
6 Overall survival
Searches:
Can we apply date limits to the search (Please

apply to the searches for this topic. This can be
done for each individual intervention as
appropriate)
Are there any study design filters to be used (RCT, There are 1 or 2 RCT but don’t look at Lymphoedema and
systematic review, diagnostic test). therefore it would not be appropriate to apply filters
List useful search terms. (This can include such TROG trial ( Radiotherapy trial) The Lancet Oncology,
information as any alternative names for the Volume 13, Issue 6, Pages 589 - 597, June 2012 Adjuvant
interventions etc) radiotherapy versus observation alone for patients at risk
of lymph-node field relapse after therapeutic
lymphadenectomy for melanoma: a randomised trial

2 Any additional information to be added by subgroup lead
What data will we extract and how will we analyse Relevant studies will be identified through sifting the
the results? abstracts and excluding studies clearly not relevant to
the PICO. In the case of relevant or potentially
relevant studies, the full paper will be ordered and
reviewed, whereupon studies considered to be not
relevant to the topic will be excluded.

critically appraised and quality assessed using GRADE
methodology and/or NICE checklists. Data relating to
the identified outcomes will be extracted from
relevant studies.
If possible a meta-analysis of available study data will

be carried out to provide a more complete picture of
the evidence body as a whole.
An evidence summary outlining key issues such as

volume, applicability and quality of evidence and
presenting the key findings from the evidence as it
relates to the topic of interest will be produced.
List subgroups here and planned statistical analyses.
4 Search Results

Medline 1946-2013 322 53 16/09/2013
Premedline 13 Sep 2013 2 0 16/09/2013
Embase 1947-2013 572 38 16/09/2013

June 2013

SSCI)
5 Update Search


retrieved search
Medline 21 4 10/10/2014
Embase 114 4 10/10/2014

2 1. exp Melanoma/
3 2. melanoma$.tw.
4 3. 1 or 2
5 4. Radiotherapy, Adjuvant/
6 5. (radiotherap* adj adjuvant).tw.
7 6. (adjuvant adj (radiation or irradiation)).tw.
8 7. or/4-6
9 8. exp Surgical Procedures, Operative/
10 9. surgery.fs.
11 10. *Lymph Node Excision/
12 11. (surg* or resect* or operat* or excision* or excised or lymphadenectom* or dissection*).tw.
13 12. or/8-11
14 13. 3 and 7 and 12
15
16 Screening Results

Expert Reviews
Abstract Only
No Comparators
relevant to PICO

study designs (n=0)
(n=0)
17
18

Burmeister et Randomised 248 To assess the effect of adjuvant Adjuvant Observation  Lymph Node field
al (2012) Controlled Trial radiotherapy on lymph-node field radiotherapy of 48 relapse
control in patients who underwent Gy in 20 fractions  Acute toxic effects
therapeutic lymphadenectomy for  Relapse free survival
metastatic melanoma in regional  Overall survival
lymph nodes
Burmeister et Retrospective Case 234 To prospectively evaluate the role Adjuvant None  Late Toxicity
al (2006) Series of post-operative radiation therapy radiotherapy (48 Gy  Relapse
to the nodal basin in patients reference dose in 20
having features which would put daily fractions, 5
them at high risk of recurrence times per week over
4 weeks)
Creagan et al Randomised 56 To assess the role of post-operative Adjuvant Observation  Disease free interval
(1978) Controlled Trial radiation therapy directed to the radiotherapy
regional node area in patients
undergoing lymphadenectomy for
metastatic melanoma
Guadagnolo 130 To evaluate outcomes, specifically Adjuvant No  Overall Survival

Retrospective Case
et al (2014) with respect of adjuvant Radiotherapy radiotherapy  Disease Specific
Series radiotherapy for patients with Survival
desmoplastic melanoma
Strom et al Retrospective 277 To analyse the impact of adjuvant Wide local excision + Wide local  Local Control

(2014) post operative radiotherapy on adjuvant excision alone  Locoregional Control

local recurrence rates in patients radiotherapy  Distant Metastases
with desmoplastic melanoma Rate
 Toxicity

2 One randomised trial with a total of 248 patients (Burmeister et al, 2012) reported a significantly
3 lower risk of lymph-node field relapse in patients treated with radiotherapy compared to patients in
4 the observation arm: HR=0.47 (95% CI, 0.28-0.81) p=0.005. [Low Quality Evidence] A second
5 retrospective cohort study (Strom et al, 2014) reported improved local control in patients treated
6 with adjuvant radiotherapy (HR=0.15, 95% CI 0.06-0.39, p=0.001) and poorer local control was
7 significantly associated with male sex, Clarks level V and positive resection margins [Very Low
8 Quality Evidence]
9 From one retrospective observational study including 130 patients, 5 year actuarial melanoma
10 specific survival was 84% and 10 year actuarial melanoma specific survival was 80% for the whole
11 cohort [Very Low Quality Evidence]
12 From two randomised trials with a total of 304 patients (Burmeister et al, 2012; Creagan et al, 1978)
13 no significant difference in relapse free survival between patients in radiotherapy arm versus the
14 observation arm was reported [Low Quality Evidence]
15 From one randomised trial with a total of 56 patients (Creagan et al, 1978) median disease free
16 survival was 43 months for irradiated patients versus 30 months for surgery alone (p=0.15) [Low
17 Quality Evidence]
18 One randomised trial (Burmeister et al, 2012) reported no statistically significant difference in
19 overall survival for patients receiving adjuvant radiotherapy compared with patients in the
20 observation arm: HR 1.35 (95% CI; 0.94-1.92) p=0.12. [Low Quality Evidence]
21 One prospective case series study followed patients treated with adjuvant radiotherapy for a median
22 of 58.4 months (range 21.2-158 months) and reported that radiotherapy was well tolerated in most
23 patients with lymphoedema being the most significant. 9% of patients with axillary disease and 19%
24 of patients with ilio-inguinal disease experienced grade 3 lymphoedema [Very Low Quality
25 Evidence].
26

GRADE Profile 5.3: Should adjuvant radiotherapy of the resected lymph node basin vs. observation be used in patients with stage III melanoma who have
undergone curative resection ?
No of Design Limitations Inconsistency Indirectness Imprecision Other Adjuvant Observation Relative Absolute
studies considerations Radiotherapy (95%
of the CI)
resected
lymph node
basin
Lymph node field relapse (Burmeister et al, 2012)
1 randomised serious1 no serious no serious serious2 none 20/109 34/108 HR 0.47 152 LOW
trials inconsistency indirectness (18.3%) (31.5%) (0.28 to fewer
0.81) per 1000
(from 51
fewer to
214
fewer)
Local Control (Strom et al, 2014)
1 Observational Very No serious no serious No serious none 36/277 patients failed HR 0.15 VERY
Study Serious3 inconsistency indirectness imprecision locally (details not reported (0.06 to LOW
according to treatment) 0.39)

Melanoma Specific Survival (Guadagnolo et al, 2013)(
1 Observational Serious4 No serious no serious No serious None 5 year actuarial melanoma specific survival 84% VERY
Study inconsistency indirectness imprecision for the whole cohort LOW
10 year actuarial melanoma specific survival 80%

for the whole cohort
Relapse free survival/Disease Free Survival (Burmeister et al, 2012 and Creagan et al, 1978)
2 randomised serious1 no serious no serious Serious4 none 79/149 (53%) 86/155 not not LOW
trials inconsistency indirectness (55.5%) pooled pooled
Lymphoedema (Burmeister et al, 2006)
1 observational Serious55 no serious no serious no serious none Grade 3-4 lymphoedema reported in a total of 19 VERY
studies inconsistency indirectness imprecision patients (Axilla=9%; Inguinal=19%) LOW
Early Adverse Events (surgical) (Burmeister et al, 2012)
1 randomised serious1 no serious no serious serious2 none 19 patients reported grade 3-4 dermatitis resulting LOW
trials inconsistency indirectness from radiotherapy (head&neck n=3; axilla n=10;
ilio-inguinal n=6)
2 patients reported grade 3-4 pain resulting from

radiotherapy to the axilla

Overall Survival (Burmeister et al, 2012)
1 randomised serious1 no serious no serious serious2 none 66/122 55/126 HR 1.35 102 LOW
trials inconsistency indirectness (54.1%) (43.7%) (0.94 to more
1.92) per 1000
(from 20
fewer to
231
more)
Late Toxicity (Burmeister et al, 2006)
1 observational Serious6 no serious no serious no serious none 0/0 (0%) 0/0 (0%) RR 0 (0 0 fewer VERY
studies inconsistency indirectness imprecision to 0) per 1000 LOW
(from 0
fewer to
0 fewer)
0% 0 fewer
per 1000
(from 0
fewer to
0 fewer)
1
There was no blinding in this trial, however it is not possible to blind patients and investigators due to the nature of the comparison
2
There was reduced power in the study due to the number of ineligible patients which were excluded. Analysis was carried out on the intent to treat population.
3
Retrsopective observational study comparing wide local excision + adjuvant radiotherapy with wide local excision alone in which patients receiving adjuvant radiotherapy were highly selected according to clinical
features.
4
Retrospective observational study reporting disease specific survival rates with no confidence intervals or p values
5
There was reduced power in the Burmeister study due to the number of ineligible patients which were excluded. Analysis was carried out on the intent to treat population. The Creagan study was also under
powered and had a high number of ineligible patients which were not analysed. Analysis in the Creagan study was not carried out in the intent to treat population.
6
Prospective observational study with no comparison group

1 Evidence Summaries
2 A single randomised trial (Burmeister et al 2012) comparing adjuvant radiotherapy with observation
3 following therapeutic lymphadenectomy. The trial randomised 250 patients on a 1:1 basis and
4 planned analysis was on intent to treat basis, however 2 patients (1 from each group) withdrew
5 consent soon after randomisation and were excluded. In addition there were 41 major protocol
6 infringements in 31 patients which resulted in investigators carrying out analysis in both the intent
7 to treat population and the eligible population. The results presented in this review are from the
8 intent-to treat population with the quality of the evidence down-graded to reflect the possible
9 impact of the protocol violations on outcomes.
10 The median potential follow up time in the intention to treat population was 40 months (IQR 27-55)
11 and in patients who were not lost to follow up the range was 14-80 months (Burmeister et al 2012).
12 Lymph node field relapse as first relapse occurred in 20/122 (16%) of patients treated with adjuvant
13 radiotherapy versus 40/126 (32%) of patients in the observation arm: HR=0.47 (95% CI 0.28-0.81),
14 p=0.005 (Burmeister et al 2012).
15 In the radiotherapy arm 76/122 (63%) relapsed with melanoma at any site compared with 85/126
16 (68%) in the observation arm. Relapse free survival in the intent to treat population showed no
17 significant difference for patients in the adjuvant radiotherapy arm compared with the observation
18 arm: HR=0.90 (95% CI, 0.66-1.22), p=0.53 (Burmeister et al 2012)
19 There was reportedly no significant difference in time to distant relapse (as a first relapse or any
20 relapse) between the radiotherapy arm and observation arm, though these data are not shown for
21 the intent to treat population (Burmeister et al 2012).
22 Median survival was 32 months in the adjuvant radiotherapy arm compared with 47 months in the
23 observation arm. Although this difference was not statistically significant (HR=1.35 (95% CI 0.94-
24 1.92), p=0.12, there may be some clinical significance to this result (Burmeister et al 2012).
25 Analysis of potential prognostic factors indicated that extranodal spread (none vs. Limited vs.
26 Extensive) was the only independent risk factor for lymph node field relapse: HR=1.77 per degree of
27 spread (95% CI, 1.26-2.49), p=0.001 (Burmeister et al 2012).
28 A second randomised trial (Creagan et al, 1978) compared patients receiving adjuvant radiotherapy
29 following lymphadenectomy for metastatic melanoma with patients undergoing surgery alone. The
30 study included a total of 56 patients, 27 of whom were randomized to receive adjuvant
31 radiotherapy.
32 Median time to recurrence was 20 months for patients treated with radiotherapy versus 9 months
33 for patients treated with surgery alone though the difference was not significant (p=0.07) (Creagan
34 et al, 1978).
35 Median survival in the irradiated group was 33 months versus 22 months for surgery alone though
36 again the difference was not significant (p=0.09) For patients with a single involved node, median
37 survival was 43 months for irradiated patients versus 30 months following surgery alone (p=0.15)
38 (Creagan et al, 1978).

1 A total of 8/27 patients treated with radiotherapy and 6/29 patients treated with surgery alone
2 reported lymphoedema (Creagan et al, 1978).
3 One prospective case series study with a total of 234 patients reported that radiation therapy was
4 generally well tolerated in most patients. Lymphoedema was reported to be the most significant late
5 toxic effect with 9% of patients with axillary disease and 19% of patients with ilio-inguinal disease
6 reporting grade 3 changes, though no patient reported grade 4 disease (Burmeister et al, 2006).
7 The most common grade 1-2 late toxicities included skin changes, subcutaneous changes and
8 lymphoedema (Burmeister et al, 2006).

1 References
2 Included Studies
3 Burmeister BH et al (2012) Adjuvant radiotherapy versus observation alone for patients at risk of
4 lymph node field relapse after therapeutic lymphadanectomy for melanoma: a randomised trial
5 Lancet Oncology 13:589-597
6 Burmeister BH et al (2006) A prospective phase II study of adjuvant postoperative radiation therapy

7 following nodal surgery in malignant melanoma – Trans Tasman Radiation Oncology Group (TROG)
8 Study 96.06 Radiotherapy and Oncology 81: 136-142
9 Creagan, E. T., et al (1978) Adjuvant radiation therapy for regional nodal metastases from malignant
10 melanoma: a randomized, prospective study. Cancer 42;5:2206-2210
11 Guadagnolo, B. A et al (2014) The role of adjuvant radiotherapy in the local management of

12 desmoplastic melanoma. Cancer 120;9:1361-1368. Strom, T., et al (2014) Radiotherapy influences
13 local control in patients with desmoplastic melanoma. Cancer 120;9:1369-1378.
14 Excluded Studies
15 Agrawal, S., et al (2008). Therapeutic lymphadenectomy alone versus adjuvant radiotherapy for
16 regional nodal metastases from melanoma. Journal of Clinical Oncology 26;15.
17 Reason: Abstract Only
18 Agrawal, S., (2009) The benefits of adjuvant radiation therapy after therapeutic lymphadenectomy
19 for clinically advanced, high-risk, lymph node-metastatic melanoma. Cancer 115;24:5836-5844.
20 Reason: Population/Outcomes not relevant to PICO
21 Arora, A et al (2005) Wide excision without radiation for desmoplastic melanoma. Cancer
22 104;7:1462-1467.
23 Reason: No radiotherapy
24 Ballo, M. T., et al Radiotherapy for cutaneous malignant melanoma: rationale and indications.
25 [Review] [65 refs]. Oncology (Williston Park) 18;1:99-107.
27 Ballo, M. T., et al (2002) Sphincter-sparing local excision and adjuvant radiation for anal-rectal
28 melanoma. Journal of Clinical Oncology 20;23: 4555-4558.
30 Ballo, M. T., et al (2002) Adjuvant irradiation for axillary metastases from malignant melanoma.
31 International Journal of Radiation Oncology, Biology, Physics 52;4:964-972.
33 Ballo, M. T., et al (2003). Radiation therapy for malignant melanoma. [Review] [88 refs]. Surgical
34 Clinics of North America 83;2:323-342.

1 Ballo, M. T et al (2003) Adjuvant irradiation for cervical lymph node metastases from melanoma.
2 Cancer 97;7:1789-1796.
4 Ballo, M. T., et al (2004) A critical assessment of adjuvant radiotherapy for inguinal lymph node
5 metastases from melanoma. Annals of Surgical Oncology 11;12:1079-1084.
7 Ballo, M. T., et al (2005) Melanoma metastatic to cervical lymph nodes: Can radiotherapy replace
8 formal dissection after local excision of nodal disease? Head & Neck 27;8:718-721.
9 Reason: No Data
10 Ballo, M. T., et al (2006) Combined-modality therapy for patients with regional nodal metastases
11 from melanoma. International Journal of Radiation Oncology, Biology, Physics 64;1:106-113.
13 Ballo, M. T. G. (2009) Adjuvant radiation therapy for patients with cervical lymph node metastases
14 from malignant melanoma. American Journal of Hematology/ Oncology 8;7
16 Bastiaannet, E., et al (2005) Radiation therapy following lymph node dissection in melanoma
17 patients: treatment, outcome and complications. [Review] [48 refs]. Cancer Treatment Reviews
18 31;1:18-26
20 Beadle, B. M., et al (2009) Radiation therapy field extent for adjuvant treatment of axillary
21 metastases from malignant melanoma. International Journal of Radiation Oncology, Biology, Physics
22 73;5:1376-1382.
24 Berk, L. B. and Berk, Lawrence B.(2008) Radiation therapy as primary and adjuvant treatment for
25 local and regional melanoma. [Review] [48 refs]. Cancer Control 15;3:233-238.
27 Bibault, J. E., et al (2011) Adjuvant radiation therapy in metastatic lymph nodes from melanoma.
28 Radiation Oncology 6;12.
29 Reason: No Data
30 Bigault, O. (2009) Post-operative radiation therapy in the adjuvant setting to assess local control for
31 in-transit melanoma. Journal of Medical Imaging and Radiation Oncology Conference[var.pagings],
33 Burmeister, B. H., et al (1995) Radiation therapy for nodal disease in malignant melanoma. World
34 Journal of Surgery 19;3:369-371.
35 Reason: Not systematic

1 Burmeister, B. H et al (2002) Radiation therapy following nodal surgery for melanoma: an analysis of
2 late toxicity. ANZ Journal of Surgery 72;5:344-348
3 Reason: Population included elsewhere
4 Burmeister, B. H. (2009) Adjuvant radiotherapy improves regional control in melanoma patients

5 after lymphadenectomy: Results of an intergroup randomised trial (TROG 02.01/anzmtg 01.02).
6 Journal of Medical Imaging and Radiation Oncology Conference[var.pagings],
8 Chang, D. T., et al (2006) Adjuvant radiotherapy for cutaneous melanoma: comparing

9 hypofractionation to conventional fractionation. International Journal of Radiation Oncology,
10 Biology, Physics 66;4:1051-1055.
12 Conill, C., et al (2007) Toxicity of combined treatment of adjuvant irradiation and interferon alpha2b
13 in high-risk melanoma patients. Melanoma Research 17;5:304-309.
15 Conill, C et al (2009) Loco-regional control after postoperative radiotherapy for patients with
16 regional nodal metastases from melanoma. Clinical & Translational Oncology: Official Publication of
17 the Federation of Spanish Oncology Societes & of the National Cancer Institute of Mexico 11;10:688-
18 693.
19 Reason: Not Randomised
20 Dhungel, B. (2010) Hypofractionated radiation following surgical resection of malignant melanoma.

21 International Journal of Radiation Oncology Biology Physics Conference[var.pagings], S618-S619.
23 Dzhabarov, F. R., et al (2011) [The usefulness of neo- and adjuvant therapy in the treatment of
24 cutaneous melanoma]. [Russian]. Voprosy Onkologii 57;4:521-524.
26 Fenig, E., et al (1999) Role of radiation therapy in the management of cutaneous malignant
27 melanoma. American Journal of Clinical Oncology 22;2:184-186.
29 Finkelstein, S. E., et al (2008) The Florida melanoma trial I: A prospective multi-center phase I/II trial
30 of post-operative hypofractionated adjuvant radiotherapy with concurrent interferon-alpha in the
31 treatment of advanced stage III melanoma. International Journal of Radiation Oncology Biology
32 Physics 72;1:S108.
34 Foote, M., et al (2012) An innovative approach for locally advanced stage III cutaneous melanoma:
35 radiotherapy, followed by nodal dissection. Melanoma Research 22;3:257-262.

1 Foote, M. C et al (2008) Desmoplastic melanoma: the role of radiotherapy in improving local control.
2 ANZ Journal of Surgery 78;4:273-276.
4 Fox, M. C et al (2013) Management options for metastatic melanoma in the era of novel therapies: a
5 primer for the practicing dermatologist: part I: Management of stage III disease. Journal of the
6 American Academy of Dermatology 68;1:1-9.
8 Fuhrmann, D., et al (2001) Should adjuvant radiotherapy be recommended following resection of

9 regional lymph node metastases of malignant melanomas? British Journal of Dermatology 144[1],
10 66-70. 2001. England.
12 Geere, S. L. B. (2012) Management of loco-regionally recurrent melanoma. Cancer Forum 36[3].

14 Geltzeiler, M. (2011) Regional control of head and neck melanoma with selective neck dissection.
15 Otolaryngology - Head and Neck Surgery Conference[var.pagings],
16 Reason: No relevant data
17 Gibbs, Pet al (2001) Management of primary cutaneous melanoma of the head and neck: The
18 University of Colorado experience and a review of the literature. [Review] [35 refs]. Journal of
20 Reason: No adjuvant radiotherapy
21 Gojkovic-Horvat, A., et al (2012) Adjuvant radiotherapy for palpable melanoma metastases to the
22 groin: when to irradiate? International Journal of Radiation Oncology, Biology, Physics 83;1:310-316.
23 Reason:No Comparator
24 Goldner, G. (2013) [Adjuvant radiotherapy following lymphadenectomy for malignant melanoma

25 significantly improves local control][German]. Strahlentherapie und Onkologie 189;1:95-96.
26 Reason: Check data (likely expert review)
27 Guadagnolo, B. A. and Zagars, G. K. (2009) Adjuvant radiation therapy for high-risk nodal metastases
28 from cutaneous melanoma. Lancet Oncology 10;4:409-416.
30 Guadagnolo, B. A., et al (2010) Role of postoperative irradiation for patients with bilateral cervical
31 nodal metastases from cutaneous melanoma: a critical assessment. Head & Neck 32;6:708-713.
33 Gyorki, D. E., et al (2004) Concurrent adjuvant radiotherapy and interferon-alpha2b for resected high
34 risk stage III melanoma -- a retrospective single centre study. Melanoma Research 14;3:223-230.

1 Hamming-Vrieze, O., et al (2009) Regional control of melanoma neck node metastasis after selective
2 neck dissection with or without adjuvant radiotherapy. Archives of Otolaryngology -- Head & Neck
3 Surgery 135;8:795-800.
5 Hazard, L. J., et al (2002) Combined adjuvant radiation and interferon-alpha 2B therapy in high-risk
6 melanoma patients: the potential for increased radiation toxicity. International Journal of Radiation
7 Oncology, Biology, Physics 52;3:796-800.
9 Henderson, M. A. B.(2009) Adjuvant radiotherapy and regional lymph node field control in
10 melanoma patients after lymphadenectomy: Results of an intergroup randomized trial (ANZMTG
11 01.02/TROG 02.01). Journal of Clinical Oncology Conference[var.pagings], LBA9084.
13 Henderson, M. A. B. (2013) Adjuvant radiotherapy after lymphadenectomy in melanoma patients:

14 Final results of an intergroup randomized trial (ANZMTG 0.1.02/TROG 02.01). Journal of Clinical
15 Oncology Conference[var.pagings].
17 Homsi, J., et al (2007) Melanoma of the anal canal: a case series. Diseases of the Colon & Rectum
18 50;7:1004-1010.
20 Kavanagh, D., et al (2005) Adjuvant therapies in the treatment of stage II and III malignant
21 melanoma. [Review] [89 refs]. Surgeon Journal of the Royal Colleges of Surgeons of Edinburgh &
22 Ireland 3;4:245-256.
24 Kelly, P., et al (2011) Sphincter-sparing local excision and hypofractionated radiation therapy for
25 anorectal melanoma: a 20-year experience. Cancer 117;20:4747-4755.
27 Khan, N., et al (2011) The evolving role of radiation therapy in the management of malignant
28 melanoma. [Review]. International Journal of Radiation Oncology, Biology, Physics 80;3:645-654.
30 Lee, R. J., et al (2000) Nodal basin recurrence following lymph node dissection for melanoma:
31 implications for adjuvant radiotherapy. International Journal of Radiation Oncology, Biology, Physics
32 46;2: 467-474.
33 Reason: No Radiotherapy
34 Mendenhall, W. M., et al (2008) Adjuvant radiotherapy for cutaneous melanoma. [Review] [54 refs].
35 Cancer 112;6:1189-1196.

1 Mendenhall, W. M., et al (2013) Surgery and adjuvant radiotherapy for cutaneous melanoma
2 considered high-risk for local-regional recurrence. American Journal of Otolaryngology 34;4:320-322.
4 Moncrieff, M. D., et al (2008) Adjuvant postoperative radiotherapy to the cervical lymph nodes in
5 cutaneous melanoma: is there any benefit for high-risk patients? Annals of Surgical Oncology
6 15;11:3022-3027.
7 Reason:
8 Moozar, K. L., et al (2003) Anorectal malignant melanoma: treatment with surgery or radiation
9 therapy, or both. Canadian Journal of Surgery 46;5:345-349.
11 Moros, M. L., et al (2004). Primary malignant melanoma of the vagina. Poor response to radical
12 surgery and adjuvant therapy. European Journal of Obstetrics, Gynecology, & Reproductive Biology
13 113;2:248-250.
14 Reason:Single Case
15 O'Brien, C. J., et al (1995) Radical, modified, and selective neck dissection for cutaneous malignant
16 melanoma. Head & Neck 17;3:232-241
18 O'Brien, C. J., et al (1997) Adjuvant radiotherapy following neck dissection and parotidectomy for
19 metastatic malignant melanoma. Head & Neck 19;7:589-594.
21 Phipps, A. R., et al (1992). The Effect of Immediately Preoperative Adjuvant Radiotherapy in the
22 Surgical-Treatment of Primary Cutaneous Malignant-Melanoma. British Journal of Plastic Surgery
23 45;1:30-33.
24 Reason: No data
25 Pinkham, M. B., et al (2013) Stage III melanoma in the axilla: patterns of regional recurrence after
26 surgery with and without adjuvant radiation therapy. International Journal of Radiation Oncology,
27 Biology, Physics 86;4:702-708.
28 Reason: Not randomised
29 Ramakrishnan, A. S. M.(2008) Optimizing local control in anorectal melanoma. Indian Journal of

30 Cancer 45;1:13-19.
32 Rao, N. G., et al (2011) The role of radiation therapy in the management of cutaneous melanoma.
33 [Review]. Surgical Oncology Clinics of North America 20;1:115-131.
35 Ridge, J. A. (2000) Adjuvant radiation after lymph node dissection for melanoma. Annals of Surgical
36 Oncology 7;8:550-551.
37 Reason: No data

1 Shen, P., et al (2000). Is adjuvant radiotherapy necessary after positive lymph node dissection in
2 head and neck melanomas? Annals of Surgical Oncology 7;8:554-559.
4 Sherriff, J. (2012) Adjuvant nodal radiation therapy for malignant melanoma with single region nodal
5 metastasis. Journal of Radiation Oncology 1;4:373-380.
6 Reason: Not primary melanoma
7 Stevens, G., (2000) Locally advanced melanoma: results of postoperative hypofractionated radiation
8 therapy. Cancer 88;1:88-94.
10 Strojan, P., et al (2010) Melanoma metastases to the neck nodes: role of adjuvant irradiation.
11 International Journal of Radiation Oncology, Biology, Physics 77;4:1039-1045. .
13 Strojan, P. (2010) Adjuvant radiotherapy for palpable melanoma metastases to the groin: When if at
14 all to irradiate? Radiotherapy and Oncology Conference[var.pagings],
16 Strom, E. Aet al (1995) Adjuvant radiation therapy after axillary lymphadenectomy for metastatic
17 melanoma: toxicity and local control. Annals of Surgical Oncology 2;5:445-449.
18 Reason: No Data
19 Testori, A., et al (2009) Surgery and radiotherapy in the treatment of cutaneous melanoma. Annals
20 of Oncology 20, 22-29.
22 Van Der Bol, W. (2010) Treatment of clinically positive cervical lymph nodes by local excision and
23 adjuvant radiotherapy in frail and elderly patients with metastatic melanoma. European Journal of
24 Surgical Oncology Conference[var.pagings], 907.
26 Vongtama, R., et al (2003) Efficacy of radiation therapy in the local control of desmoplastic malignant
27 melanoma. Head & Neck 25;6:423-428.
29 Wasif, N., et al (2003). Desmoplastic melanoma - the step-child in the melanoma family? Journal of

Evidence Tables
Study Quality
Appropriate Precise definition Valid method of Investigators blind Investigators blind to Quality
length of follow- of an outcome measuring to participants potential confounders and
up outcomes exposure to prognostic factors? (GRADE)
intervention?
Burmeister et al Unclear Yes Yes No Unclear Low

(2012)
Burmeister et al Yes Yes Yes Unclear Unclear Very Low

(2006)
Creagan et al Unclear Yes Yes Unclear Unclear Low

(1978)
Guadagnolo et Yes Yes Yes Unclear Unclear Very Low

al (2013)
Strom et al Yes Yes Yes Unclear Unclear Low

(2014)
Study Aim Setting Population Intervention Comparison Follow-up Outcomes and results
Burmeister et al Clinical Trial 250 patients Radiotherapy Observation Median follow up was Outcomes
(2012) (48Gy in 20 40 months with patients Primary:
Inclusion criteria: fractions) followed up once every Lymph node field relapse as first relapse
Palpable metastatic lymph 3 months for 2 years and

16 hospitals in node field disease then every 6 months Secondary

Australia, New Complete cervical, axillary until 5 years and then Acute toxic effects
Zealand, the or inguinal annually thereafter. Relapse free survival
lymphadenectomy
Netherlands and Overall survival
High risk of further lymph-
Brazil. node field relapse
ECOG performance status
of 0-1
Aged 18 years or older
Life expectancy in the
absence of melanoma of 2
years or more
Staged by CT scan of
lymph node field, chest
abdomen or pelvis and CT
or MRI of brain
Serum LDH concentration
less than 1.5 the upper
limit of normal
Normal FBC and
biochemistry
Informed consent
Exclusion criteria:
Concurrent or previous
history of local, in transit
or distant relapse
Impalpable (Including
detected by SLNB) lymph
node field relapse
Had cancer previously
(unless diagnosed more
than 5 years before with
estimated risk recurrence
of less than 10%)
Burmeister et al To prospectively 8 centres in N=234 patients Prescribed N/A Median follow-up was Primary
(2006) evaluate the role of Australia and New regimen was 58.4 months (range Late Toxicity
post-operative Zealand Inclusion Criteria 48Gy 21.2-158 months)
radiation therapy to Histologically confirmed reference Secondary
the nodal basin in malignant melanoma dose in 20 Relapse
patients considered involving regional lymph daily

to be at high risk of nodes or extranodal soft fractions, 5 Survival

regional recurrence. tissues in the lymph node times/week
basin. over 4 weeks
Disease limited to the with radiation
area of resection, to commence
completely within 3
macroscopically resected months of
with no evidence of surgery.
distant metastases
ECOG performance status
0-1
Full blood counts and
biochemistry within
normal limits
Exclusion Criteria
None provided
Creagan et al January 1972 to July 82 patients were entered Surgery+Radio Surgery Disease free interval
(1978) 1977 in the study. therapy Survival
A total of 17 patients were
considered to be ineligible
to take part and a further
9 patients were later
excluded for various
reasons leaving a total of
56 patients analysed.
N=27 receiving radiation

and N=29 having surgery
alone
Inclusion criteria:
Biopsy proven melanoma
in regional nodes
associated with primary
lesions on the trunk,
extremities or with

unknown primaries.
No clinical or laboratory
evidence of dissemination
Exclusion criteria:
Previous radiotherapy to
node bearing areas
Concomitant
chemotherapy or
immunotherapy
Guadagnolo et al To evaluate Retrospective Case N=130 patients with non- Adjuvant No adjuvant Median Follow-up for Management of primary lesion using surgery alone
(2013) outcomes, Series metastatic, desmoplastic radiotherapy radiotherapy patients still alive at last was accomplished in 59 patients (45%) and using
specifically with melanoma follow up was 6.6 years surgery and adjuvant radiotherapy in 71 patients
respect of adjuvant (11 months – 24 years) (55%).
radiotherapy for
patients with Single Centre (USA) Median total
desmoplastic Median age 66 years (21- dose was
melanoma 97) 30Gy (30- At time of last follow-up, 53 patients had died for a
60Gy) median survival of 11.8 years.
1985-2009
Median 5 year actuarial overall survival was 69%

fractional
dose was 6Gy 10 year actuarial overall survival was 53%
per fraction
(2-6Gy)
5 year actuarial Disease Specific Survival was 84%
Interval 10 year actuarial disease specific survival was 80%

between
surgery and
radiotherapy
5 year actuarial disease free survival was 72%
ranged from 1
month to 60

months 10 year actuarial disease free survival was 70%

(median 7
months)
Lymph node involvement was a significant predictor of

poor disease specific survival (p<0.0001) as was
(the decision positive/uncertain resection margins (p=0.03) even
to use when adjusting for postoperative radiotherapy.
adjuvant
radiotherapy
was at the
discretion of 35/130 patients (27%) developed disease recurrence
the treating
physician and 19 patients (15%) developed local recurrence for an
practice actuarial local recurrence rate of 17% at 5 years and
patterns beyond.
varied)
Actuarial rate of lymph node recurrence at 5 years was

11% and at 10 years was 14%.
There was no significant difference in lymph node

recurrence between patients with pure and mixed
desmoplastic melanoma (12% versus 11% at 5 years,
p=0.81).
21% of patients developed distant metastases at a

median of 19 months (1.8-103 months) for an actuarial
rate of distant metastases development of 20% at 5
years and 25% at 10 years).
Patients presenting with involved lymph nodes at the

time of diagnosis were at higher risk of distant

metastases than those who did not (p<0.0001).
Median overall survival and disease specific survival

after first recurrence was 20 months.
14/59 (24%) patients who underwent surgery without

adjuvant radiotherapy experienced local recurrence
compared with 5/71 patients (7%) who were treated
with adjuvant radiotherapy.
Factors found to be significant predictors of improved

local control included receipt of post-operative
radiotherapy (p=0.03) and negative resection margins
(p=0.008).
Patients with perineural invasion and who received

postoperative radiotherapy had significantly better
local control compared with those who did not receive
adjuvant radiotherapy (91% versus 63% at 10 years,
p=0.02).
21 patients (16%) experienced surgical complications,

with 11 considered moderate in severity.
10 patients experienced surgical complications which

were considered to be severe.
Actuarial rate of surgical complications was 16% at 5

years and median time to surgical complication was 1

months (0-16 months).
15/71 patients (21%) who received adjuvant

radiotherapy experienced a radiotherapy related
complication at a median time of 19 months (1month-
12.5 years).
Actuarial rates of significant radiotherapy related

complications (moderate-severe) were 18% at 5 years
and 22% at 10 years.
Strom et al (2014) To analyse the Retrospective N=277 patients with Wide local Wide local excision Median follow-up was N=113 patients received post-operative radiotherapy.
impact of adjuvant desmoplastic melanoma excision + alone 43.1 months
post operative adjuvant
radiotherapy on radiotherapy
local recurrence Single Centre (USA) Patients with head and neck tumours, Clark level V or
rates in patients Median age=68 years (16- tumours >4mm in thickness were significantly more
with desmoplastic 96) likely to have received adjuvant radiotherapy.
melanoma
1989-2010 Median Breslow
thickness=3.9mm (0.5-
35mm) 33 patients (12%) had pathologically proven regional
lymph node involvement.
Exclusions
Local Control
Patients presenting with
distant disease or locally 36/277 patients (13%) failed locally – median time to
recurrent disease failure was 14 months (2-113 months)
Patients who declined Adjuvant radiotherapy was associated with improved

surgery or who received

radiotherapy prior to local control (HR=0.15, 95% CI 0.06-0.39, p=0.001)

surgery
Poorer local control was found to be associated with:

Patients with no
treatment records male sex [HR=3.8, 95% CI 1.3-11.2, p=0.01]
Clark level V [HR=2.3, 95% CI 1.0-4.9, p=0.04]
Positive resection margins [HR=6.6, 95% CI 2.8-15.7,

p<0.001]
28/164 (17%) who did not receive adjuvant

radiotherapy developed local recurrence compared
with only 8/113 (7%) of patients who received
adjuvant radiotherapy.
1 year actuarial local control rate with radiotherapy

was 96% and without radiotherapy was 91%
5 year actuarial local control rate with radiotherapy

was 95% and without radiotherapy was 76%
35 patients had a positive resection margin and 237

patients had a negative margin (5 had an unknown
margin status).
10/35 patients (29%) with positive margins developed

local recurrence compared with 24/237 patients (10%)

with negative resection margins (p<0.001)
Positive Resection Margins
22/35 patients received adjuvant radiotherapy
3/22 developed local recurrence compared with 7/13

(54%) of patients who had no adjuvant radiotherapy
(p=0.003).
Negative Resection Margins
89/237 patients received adjuvant radiotherapy
5/89 patients (6%) developed local recurrence

compared with 19/148 (13%) of patients who did not
receive adjuvant radiotherapy.
Patients with negative margins and high risk features,

including a head and neck location, Breslow depth
>4mm or Clark level V tumour had significantly
improved local control with the use of radiotherapy
and a ≥10% difference in the absolute rates of local
control.
Locoregional Control
21/264 patients developed a regional disease

recurrence.

Patients treated with adjuvant radiotherapy had

significantly improved locoregional control [Hr=0.20,
95% CI 0.10-0.40, p<0.001).
40/164 patients (24%) who did not receive

local/regional radiotherapy developed a locoregional
recurrence compared with 15/113 patients (13%) who
did.
Other variables significantly associated with poorer

locoregional control included: age >70 years [HR=2.4,
95% CI 1.3-4.2, p=0.003]
Breslow depth >4mm [HR=2.5, 95% CI, 1.4-4.7,

p=0.003]
Positive Resection Margins [HR=4.6, 95% CI 2.3-9.1,

p<0.001].
Positive resection margins
23% had a locoregional recurrence with radiotherapy

versus 69% without (p=0.002)
Negative Resection Margins
10% experienced a locoregional recurrence with

radiotherapy compared with 20% without (p=0.06).

Patient age >70, Breslow depth >4mm and no

radiotherapy were found to be associated with poorer
locoregional control in patients with negative
resection margins (p<0.05).
In patients with high risk features, variables associated

with significantly improved locoregional control with
adjuvant radiotherapy included male sex and patients
with deeper tumours, pure desmoplasia or perineural
invasion.
Distant Metastasis Rate and Salvage Surgery
63/277 patients developed distant metastases with a

median time from wide local excision of 17 months (2-
121 months)
Toxicity
Common acute side effects included skin erythema,

pain and fatigue
Long term side effects included skin fibrosis,

telangiectasis and skin pigment changes.

1 5.3 In transit metastases
2 Review question: What is the most effective treatment for in transit melanoma
3 metastases (for example, surgery, isolated limb infusion, isolated limb perfusion,
4 palliative radiotherapy, cryotherapy, electro-chemotherapy or the laser)?
5 Background
6 In-transit melanoma are metastases located in the regional dermal and subdermal lymphatics which
7 between >2cm from the excision scar and the regional nodes. The risk of developing in transit
8 metastases is directly related to the stage of the disease. In the absence of extensive disease,
9 surgery is treatment of choice for single or a small number of multiple metastases. Many patients
10 will relapse, and for those with intermittent recurrence of a few metastases the morbidity
11 associated with surgical resection is generally considered acceptable. Increase frequency of relapse
12 or significant number of in transit nodules generally suggests alternative regional or systemic
13 approaches should be considered. There are a wide variety of potential approaches.
14 It will be important to compare the different effectiveness and toxicities of regional methods of
15 treating in transit metastases, and whether certain treatments would be favoured in certain
16 circumstances. In particular it will be important to assess the local control rates compared with
17 morbidity of the intervention. The role of new targeted and immunotherapy in unresectable in
18 transit metastases compared with currently available regional therapies is not well defined
19 compared with current options and is evolving rapidly.

Patients with in-  Surgical excision  Each Other 1. Local Control (partial
transit melanoma  Amputation  Systemic response/complete
metastases:  Isolated limb infusion Chemotherapy response)
 Limb  Isolated limb perfusion (inc. targeted) 2. Melanoma specific
 Not limb  Radiotherapy Survival
(Trunk,  Cryotherapy 3. Overall Survival (5 &
head/neck)  Electrochemotherapy 10yr)
 Number of  Co2 Laser 4. Time to next
lesions/dept  Topical agents (Inc. treatment
h/diameter Imiquimod) 5. Adverse Events
6. HRQL
Notes For each study, report what diagnostics were used if possible
Searches:
Can we apply date limits to the search (Please The GDG did not feel it appropriate to apply any
provide information on any date limits we can date limits to this topic.
appropriate)

Are there any study design filters to be used The GDG did not feel is appropriate to apply any
(RCT, systematic review, diagnostic test). filters to this topic as there will not be randomised
trials available for all comparisons
List useful search terms. (This can include such None given
information as any alternative names for the
interventions etc)
2 Any additional information to be added by subgroup lead
excluded.



be produced.
List subgroups here and planned statistical

analyses.
3 Search Results

Medline 1946-2013 1406 136 24/09/2013
Premedline 16 Sep 2013 14 7 25/09/2013
Embase 1947-2013 342 157 25/09/2013
June 2013


SSCI)
1 Update Search

retrieved search
Medline 12 12 10/10/2014
Embase 49 30 10/10/2014

4 1. exp Melanoma/
5 2. melanoma$.tw.
8 5. dubreuilh.tw.
9 6. LMM.tw.
10 7. or/1-6
11 8. exp Dermatologic Surgical Procedures/
12 9. (excis$ or margin$ or surg$ or remov$ or amputat* or operat* or dissection* or
13 lymphadenectom*).tw.
14 10. Chemotherapy, Cancer, Regional Perfusion/
15 11. Dacarbazine/ or dacarbazine.tw.
16 12. temozolomide.tw.
17 13. (limb* adj (infusion or perfusion)).tw.
18 14. Melphalan/ or melphalan.tw.
19 15. Tumor Necrosis Factor-alpha/
20 16. (tumo?r necrosis factor or tnf-alpha or tnfalpha or cachectin or cachexin).tw.
21 17. Interferons/ or interferon*.tw.
22 18. Injections, Intralesional/
23 19. ((intra lesional or intralesional) adj (therap* or injection*)).tw.
24 20. exp Cryotherapy/
25 21. cryotherap*.tw.
26 22. Electrochemotherapy/
27 23. electrochemo*.tw.
28 24. Electroporation/
29 25. (electropor* or electro - por* or electropermeab* or electro - permeab*).tw.
30 26. Laser Therapy/
31 27. laser.tw.
32 28. imiquimod.tw.
33 29. Administration, Cutaneous/
34 30. Radiotherapy/

1 31. (radiotherap* or radiat* or irradiat*).tw.

2 32. or/8-31
3 33. Neoplasm Metastasis/
4 34. (in-transit adj2 (metasta* or disease*)).tw.
5 35. 33 or 34
6 36. 7 and 35
7 37. 32 and 36
8
9 Screening Results
Expert Reviews
Abstract Only
No Comparators
relevant to PICO

study designs (n=1)
(n=0)
10

Study Study Type Population Aim Intervention Comparison Diagnostics Outcomes

Caraco et al Retrospective N=60 with relapse and To analyse the short and Electrochemotherapy N/R  Response rates
(2013) Case Series refactory cutaneous long term responses of
melanoma or in-transit lesions treated with
disease electrochemotherapy with
intravenous injection of
bleomycin in melanoma
patients with in-transit
disease or distant cutaeous
metasases
Fotopoulos Retrospective N= 33 patients with To investigate the role of Surgical Excision None N/R  Survival
et al (1998) Case Series loco-regional surgical treatment for
recurrence of whom 21 survival in patients with
patients had in-transit loco-regional recurrences
melanoma
Kandamany Observational N=16 patients with Not Clear from the study CO2 laser None N\R  Survival
et al (2009) Case series cutaneous and
superficial melanoma
metastases too
numerous or recurring
too frequently for
surgical excision
Hill et al Observational N=60 patients with To investigate the place of CO2 laser None N\R  Development of
(1993) case series cutaneous and CO2 laser ablation of extraregional
superficial cutaneous or sub- disease
subcutaneous cutaneous deposits of  Overall Survival
metastasis of malignant malignant melanoma
melanoma
Mali et al Systematic N=22 studies with To investigate the Electrochemotherapy Chemotherapy where N\R  Response Rates
(2013) Review and melanoma patients effectiveness of available (Complete and
meta-analysis electrochemotherapy in Partial)
patients with cutaneous
and sub-cutaneous

Study Study Type Population Aim Intervention Comparison Diagnostics Outcomes

tumours
Ricotti et al Prospective, N=30 patients affected To evaluate the efficacy, Electrochemotherapy None N/R  Resposne Rates
(2014) non- by 654 metastatic long-term tolerability and
randomised nodules from long-term efficacy of
study melanoma electrochemotherapy in the
treatment of advanced
cutaneous and
subcutaneous melanoma
Seegenschmi Retrospective N=57 patients with To analyse the 20 year Radiotherapy None N/R  Response Rates
edt et al Case Series stage UICC IIII clincial experience with  Survival
(1999) melanoma of which an radiotherapy treatment
unclear number had in- with respect to different
transit melanoma endpoints and prognostic
factors.
Sharma et al Retrospective N=214 patients with in- To summarise the patterns Hyperthermic Isolated Isolated Limb Infusion PET/CT  Response Rates
(2012) case series transit melanoma of recurrence folling a Limb Perfusion  Recurrence
undergoing either ILI or complete response to HILP  Overall Survival
HILP for the first time and ILI and to evaluate
whether the regional
treatment modality
producing a complate
response influences the
probability and/or timing of
local recurrence or overall
survival

2 Electrochemotherapy
3 One systematic review and meta-analysis (Mali et al, 2013) reported a complete response rate of
4 56.8% and an objective response rate of 80.6% for patients with melanoma who were treated with
5 electrochemotherapy [Very Low]
6 CO2 laser
7 Two observational case series studies with a total of 76 patients and 5059 lesions (Hill et al (1993);
8 Kandamany et al (2009)) reported survival in patients treated with CO2 laser. Overall survival at 12
9 months was 67% (40/60) (Hill et al, 1993) and disease free survival at 12 months was 62.5% (10/16)
10 (Kandamany et al, 2009) [Very Low]
11 Radiotherapy
12 One retrospective case series with a total of 57 patients with stage UICC III, of which a small subset
13 had in-transit melanoma, were treated with radiotherapy (Seegenschmiedt et al, 1999). A total of
14 44% of stage UICC III patients had a complete response while 21% of stage UICC III patients showed
15 progressive disease. [Very Low]
16 Surgical Excision
17 One retrospective case series with a total of 33 patients treated for loco-regional metastases of the
18 lower extremities (Fotopoulos et al, 1998) reported a median disease free survival of 16 months (1-
19 104 months) and median overall survival of 31 months (2-264 months). [Very Low]
20 Isolated limb perfusion versus isolated limb infusion

21 One retrospective case series (Sharma et al; 2012) reported a significantly higher rate of complete
22 response in patients treated with HILP compared with patients treated with ILI (44% versus 28%;
23 p=0.01). [Very Low]
24 At 3-year follow-up following a complete response to treatment; a single retrospective case series
25 (Sharma et al; 2012) reported a recurrence rate of 65% (95% CI 43%-79%) for patients treated with
26 HILP compared with a recurrence rate of 85% (95% CI 53%-94%) for patients treated with ILI. Time to
27 first recurrence was longer for HILP (23 vs. 8 months, p=0.02) [Very Low]
28 In patients achieving complete response to treatment, in field recurrence rates were 44% (95% CI
29 16%-58%) for HILP compared with 56% (95% CI 30&-72%) for ILI. Median time to in field recurrence
30 was not statistically significantly different (HILP 46 months vs. ILI 25 months; p=0.15). [Very Low]
31 In patients achieving complete response to out of field recurrence rate was 44% (95% CI 23%-60%)
32 for HILP compared with 77% (95% CI 51%-89%) for ILI. Time to out field recurrence was longer for
33 HILP (42 versus 14 months, p=0.02) [Very Low]
34 In patients achieving complete response, there was no statistically significant difference in median
35 overall survival between HILP and ILI (100 vs. 39 months, p=0.10). [Very Low]

GRADE Table 5.4: Should surgical excision be used in patients with in transit melanoma?
Quality assessment Summary of Findings Quality
local control
0 no evidence available
Melanoma specific survival

No of Design Limitations Inconsistency Indirectness Imprecision Other Surgical None Relative Absolute Quality
studies considerations Excision (95% CI)
Overall Survival (Fotopoulos et al, 1998)
1 (n=33) observational serious1 no serious serious2 serious3 none /334 No Median overall survival of Very
studies inconsistency comparison 31 months (2-264 Low
months)-
Time to next treatment

Adverse Events
Health Related Quality of Life

1
This is a retrospective case series study with no comparison to surgical excision. 2 Not all patients in the study had in-transit melanoma 3Very small numbers of relevant patients in the study and wide ranges in
survival times 4Event rate not reported
GRADE Table 5.5: Should Amputation be used in patients with in-transit melanoma?
Quality assessment Quality
No of studies Design Limitations Inconsistency Indirectness Imprecision Other considerations
Local Control

Melanoma Specific Survival
Overall Survival
Adverse Events
GRADE Table 5.6: Should cryotherapy be used in patients with in-transit melanoma?
Local Control

Overall Survival
Adverse Events
GRADE Table 5.7: Should Radiotherapy be used in patients with in transit melanoma?

No of studies Design Limitations Inconsistency Indirectness Imprecision Other Radiotherapy Relative Absolute
Local Control (Seegenschmiedt et al, 1999)
1 (n=57; 24 observational serious1 no serious serious2 serious3 none No 44% of stage UICC III Very
patients with studies inconsistency compar patients had a complete Low
in-transit ison response while 21% of
metastases) stage UICC III patients
showed progressive
disease

No of studies Design Limitations Inconsistency Indirectness Imprecision Other Radiotherapy None Relative Absolut Quality
considerations (95% CI) e
Overall Survival (Seegenschmiedt et al, 1999)
1 (n=57; 24 observational serious1 no serious serious serious3 none No Patients with in-transit Very
patients with studies inconsistency Compar metastases* had a Low
in-transit ison median survival of 19
metastases) months; 1 year survival
was 69±17% and 5 year
survival was 32±20%.
Adverse Events

1
This is a retrospective case series study with no comparison to radiotherapy 2The study included patients without in-transit melanoma 3The numbers of patients with in-transit melanoma included in the study was a
small proportion of the total patient numbers 4Study states that N=33 patients had in-transit metastases and n=24 patients had regional lymph node metastases however the table within the study states n=33
patients had regional lymph node metastases and n=24 patients had in-transit metastases. It is not clear which is the correct number of patients for each.
GRADE Table 5.8: Should Imiquimod be used in patients with in-transit melanoma?
Local Control

Overall Survival
Adverse Event
GRADE Table 5.9: Should Electrochemotherapy be used in patients with in transit melanoma?

No of Design Limitations Inconsistency Indirectness Imprecision Other Electrochemot control Relative Absolute
studies considerations herapy (95% CI)
Local Control (Mali et al, 2013)
22 (150 observational serious1 serious2 serious3 serious None No A complete response rate
patients studies Comparison of 56.8% and an objective VERY
with 920 response rate of 80.6% for LOW
tumours) patients with melanoma
who were treated with
electrochemotherapy
Melanoma Specific Survival - not measured
0 - - - - - None -
-
Time to next treatment - not measured
0 - - - - - None -
Adverse Events - not measured
0 - - - - - None -

Health Related Quality of Life - not measured

0 - - - - - None -
1
Studies are not randomised trials, many are retropsective studies and case series with a high risk of bias 2Response to treatment varied widely across the individual studies (0%-100% for compete response) 3The
studies included in the review included patients other than those with in-transit melanoma
GRADE Table 5.10: Should CO2 laser be used in patients with in transit melanoma?

No of studies Design Limitations Inconsistency Indirectness Imprecision Other CO2 laser control Relative Absolute
Local Control (Hill et al, 1993; Kandamany et al, 2009)
2 (76 patients with 5059 observational serious1 no serious serious2 serious3 none No Not Pooled Very Low
lesions) studies inconsistency Comparison
Melanoma Specific Survival - not measured

0 - - - - - none - - -
Time to next treatment - not measured
0 - - - - - none - - -
0 - - - - - none - - -
Health Related Quality of Life - not measured
0 - - - - - none - - -
1
Non-randomised studies with no comparator and small numbers (n=76 patients total) 2 Patients with all stages of Melanoma are included in one of the studies 3 Numbers are too small for precise results to be
obtained
GRADE Table 5.11: Should Isolated Limb Perfusion vs. Isolated Limb Infusion be used in Patients with in-transit melanoma?

No of Design Limitations Inconsistency Indirectness Imprecision Other Isolated Limb Isolated Limb Relative Absolute
studies considerations Perfusion Infusion (95%
CI)
Response Rates (Sharma et al, 2012)
1 (n=214) observational serious1 no serious no serious no serious none ?/813 ?/1333 -complete response Very
studies inconsistency indirectness imprecision rate of 44% for Low
patients receiving
first time
hyperthermic

isolated limb
perfusion (HILP)
compared with a
complete response
rate of 28% for
patients undergoing
first time isolated
limb infusion
3 Year Recurrence Rate (Sharma et al, 2012)
1(n=214) observational serious1 no serious no serious serious2 none ?/813 ?/1333 HILP: 65% (95% CI Very
studies inconsistency indirectness 43-79%) Low
ILI: 85% (95% CI 53-

94%).
Overall Survival (Sharma et al, 2012)
1 (n=214) Observational serious1 no serious no serious serious2 none ?/813 ?/1333 In patients achieving Low
studies inconsistency indirectness complete response,
no statistically
significant
difference in median
overall survival
between HILP and
ILI (100 vs. 39
months)
1
Retrospective analysis of a prospective database 2 Only patients who achieved complete response were evaluated for recurrence resulting in small numbers of patients and events 3Event rate not reported

2 There were a number of interventions of interest in this topic for which no evidence was found including surgical
3 incision, amputation, imiquimod, cryotherapy and immunotherapy. For the remaining interventions the available
4 evidence varied in quantity and quality.
5 Electrochemotherapy
6 One systematic review and meta-analysis investigated the effectiveness of electrochemotherapy in cutaneous or
7 subcutaneous tumours, including melanoma. A total of 22 studies, none of which were randomised trials,
8 reported response rates for melanoma. These studies included all types of melanoma and not just in transit and
9 therefore there are some concerns over the applicability of the data for this topic (Mali et al, 2013). Complete
10 response rate with electrochemotherapy (with either bleomycin or cisplatin) was 56.8% and the objective
11 response rate (CR+PR) was 80.6%.
12 A further two observational studies (Caraco et al, 2013 and Ricotti et al, 2014) reported response rates in
13 patients treated with Electrochemotherapy. Ricotti et al (2014) reported and objective response in 100% of
14 patients (complete response in 20%) while Caraco et al reported and objective response rate of 86.6% for all
15 treated lesions.
16 CO2 Laser
17 Two observational case series studies reported on the use of CO2 laser for the treatment of cutaneous and
18 superficial subcutaneous melanoma (Hill et al (1993) and Kandamany et al (2009)). Neither study was
19 comparative and reported only on the survival of patients treated with CO2 laser with no information on any of
20 the other outcomes of interest.
21 Radiotherapy
22 One retrospective case series investigated the use of radiotherapy for the treatment of melanoma, including 24
23 patients with in-transit melanoma (Seegenschmiedt et al, 1999).
24 A total of 44/57 (77%) patients with stage UICC III melanoma had a local tumour response to radiotherapy with
25 25 complete responses. Five patients showed no change and 8 patients had progressive disease.
26 Patients with in-transit metastases* had a median survival of 19 months; 1 year survival was 69±17% and 5 year
27 survival was 32±20%.
28 *Study states that N=33 patients had in-transit metastases and n=24 patients had regional lymph node
29 metastases however the table within the study states n=33 patients had regional lymph node metastases and
30 n=24 patients had in-transit metastases. It is not clear which is the correct number of patients for each.
31 Surgery
32 One retrospective case series study reported on 33 patients who developed a loco-regional relapse following
33 treatment for primary tumour located on the lower extremity; 21 patients had in-transit metastases (Fotopoulos
34 et al, 1998). Five year disease free survival for the total population was 12% and overall survival was 58%
35 following surgical treatment of metastases.
36 Median disease free survival was reported to be 16 months (1-104 months) and median overall survival was
37 reported to be 31 months (2-264 months).
38 There was a statistically significant difference in median disease free survival for patients undergoing surgery
39 with curative intent compared with those undergoing palliative surgery (p<0.01). In patients who underwent
1 surgery with curative intent (n=25); median disease free survival was 22 months (4-104 months) and in patients
2 who underwent surgery with palliative intent median disease free survival was 5 months (1-24 months)
3 There was a statistically significant difference in median overall survival for patients undergoing surgery with
4 curative intent compared with those undergoing palliative surgery (p<0.02). In patients who underwent surgery
5 with curative intent; median overall survival was 46 months (5-264 months) and in patients who underwent
6 surgery with palliative intent median overall survival was 17 months (5-45 months).
7 Hyperthermic Isolated limb perfusion versus Isolated limb infusion

8 One retrospective case series analysing data from a prospective database reported a complete response rate of
9 44% (36/81) for patients receiving first time hyperthermic isolated limb perfusion (HILP) compared with a
10 complete response rate of 28% (37/133) for patients undergoing first time isolated limb infusion Partial response
11 rates were 9% (7/81) for HILP and 13% (17/133) for ILI and stable disease was reported in 11% for both HILP
12 (9/81) and ILI (15/133) (Sharma et al: 2012).
13 In patients recording a complete response to initial treatment, the recurrence rate at 3 year follow up for HILP
14 was 65% (95% CI 43-79%) compared with 85% (95% CI 53-94%). The in-field recurrence rate was 41% (95% CI 16-
15 58%) for HILP compared with 56% (95% CI 30-72%) for ILI. Outfield recurrence rate was 44% (95% CI 23-60%) for
16 HILP compared with 77% (95% CI 51%-89%) for ILI.
17 The median time to first recurrence was significantly longer in the HILP group compared with the ILI group (23
18 months versus 8 months, p=0.02). Median time to out of field recurrence was significantly longer in the HILP arm
19 (42 versus 14 months, p=0.02) but there was no statistically significant difference in the time to in field
20 recurrence between the two groups (46 versus 25 months, p=0.15).
21 Median survival time was longer in the HILP group, though this did not achieve statistical significance (100 versus
22 39, p=0.010).
23

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39 melanoma. Melanoma Research 18;5:359-364.

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5 Metastases: Experience at Two Canadian Centres. Annals of Surgical Oncology 20;S93-S94.
6 Reason: No data
7 Chun, J. Y., et al (2011). Technique and outcomes of isolated limb infusion for locally advanced malignant
8 melanoma--a radiological perspective. Clinical Radiology 66;12:1175-1180.
9 Reason: N=11 & no comparator
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16 Colombo, G. Et al (2010) Electrochemotherapy. European Surgical Research Conference[var.pagings], 236.

18 Cornett, W. R., et al (2007). Is there any reason to delay introduction of tumor necrosis factor in the management
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20 Reason: Comment
21 Cornett, W. R., et al (2006) Randomized multicenter trial of hyperthermic isolated limb perfusion with melphalan
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25 Da Ponte, P. F. F. (2009) Isolated limb perfusion for melanoma in-transit metastases: A single center experience.
26 Skin Cancer 24;3:91-101.
28 Davar, D., Tarhini et al (2013) Adjuvant immunotherapy of melanoma and development of new approaches using
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30 31;3:237-250.
32 De Cian, F., et al (1996) Conventional isolated hyperthermic antiblastic perfusion in the treatment of recurrent
33 limb melanoma. Anticancer Research 16;4A:2017-2024.
34 Reason: No comparator/n=20 relevant patients
35 De Cian, F., et al (1994) [Isolated hyperthermic antiblastic perfusion in recurrent melanoma of the extremities].
36 [Italian]. Minerva Chirurgica 49;7-8: 681-691.
37 Reason: N=14 relevant patients
38 Defty, C. L. and Marsden, J. R. (2012) Melphalan in regional chemotherapy for locally recurrent metastatic
39 melanoma. Current Topics in Medicinal Chemistry 12;1:53-60.

1 Dehesa, L. A., V. (2009) Experience in the treatment of cutaneous in-transit melanoma metastases and satellitosis
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3 Reason: N=7
4 Deroose, J. P., et al (2012) 20 years experience of TNF-based isolated limb perfusion for in-transit melanoma
5 metastases: TNF dose matters. Annals of Surgical Oncology 19;2:627-635.
7 Deroose, J. P., et al (2011) Long-term outcome of isolated limb perfusion with tumour necrosis factor- for
8 patients with melanoma in-transit metastases. British Journal of Surgery 98;11:1573-1580.
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14 Annales de Dermatologie et de Venereologie 136;11:767-771.
16 Dewar, D. J. and Powell, B. W. E. M.(2003) Sentinel node biopsy in patients with in-transit recurrence of
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18 Reason: Case Reports
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21 Check relevance/data
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26 Di Filippo, F., et al (2006) Hyperthermic isolation limb perfusion with TNFalpha in the treatment of in-transit
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28 Reason: No comparator/Poor Data
29 Dubois, R. W et al (2001) Developing indications for the use of sentinel lymph node biopsy and adjuvant high-
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36 Eggermont, A. M., et al (2003). The role of isolated limb perfusion for melanoma confined to the extremities.
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39 Eggermont, A. M. M.(2003) Current uses of isolated limb perfusion in the clinic and a model system for new
40 strategies. Lancet Oncology 4;7:429-437.
41 Reason:Expert Review
1 Eggermont, A. M. and Eggermont, A. M. (1996) Treatment of melanoma in-transit metastases confined to the
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4 Eroglu, A. (1999) Isolated limb perfusion with cisplatin in malignant melanoma: Turkish experience. Journal of B
5 U.ON.. 4;2:137-142.
6 Reason: N=14 relevant patients (group 2)
7 Elias, E. G. S. (2013) Consequential administration of intralesional (intratumoral) GM-CSF and IL-2 in the
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11 Eton, O et al (1999). Pilot study of intra-arterial cisplatin and intravenous vinblastine and dacarbazine in patients
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18 Farricha, V., V.(2010) Electrochemotherapy: A technique for multiple approaches in the treatment of locally
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20 Reason: No data
21 Feldman, A. L., et al (1999) Management of extremity recurrences after complete responses to isolated limb
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24 Fox, M. C., et al (2013) Management options for metastatic melanoma in the era of novel therapies: a primer for
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26 Dermatology 68;1:1-9.
27 Reason: No data
28 Fraker, D. L. and Fraker, Douglas L.(2004) Management of in-transit melanoma of the extremity with isolated
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37 Furukawa, H. (2012) Tailored excision of in-transit metastatic melanoma based on indocyanine green
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39 Reason: No data
40 Garioch, J. and Moncrieff, M. (2013) Topical Diphencyprone for the Treatment of in Transit Melanoma
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2 Reason: No data
3 Garcia, E. D. S. (1999) Treatment of malignant melanoma. Annals of Pharmacotherapy 33;6:730-738.

5 Garbe, C. Isolated limb perfusion of metastatic malignant melanoma of the extremity worthwhile? European
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11 Gattuso, J. M., Waters, R., and Thomas, J. M. (1990) A Preliminary-Report of Treatment for In-Transit Metastatic
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14 Gaudy, C., et al (2006) Randomized controlled study of electrochemotherapy in the local treatment of skin
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17 Geere, S. L. B. (2012) Management of loco-regionally recurrent melanoma. Cancer Forum 36;3

19 Gerlini, G., et al (2013). Dendritic cells recruitment in melanoma metastasis treated by electrochemotherapy.
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23 Cancer Control 15;3:225-232.
25 Gohl, J., et al (2009). [Malignant melanoma]. [German]. Chirurg 80;6:559-567.

26 Reason: No data
27 Green, D. S., et al (2008) Topical imiquimod and intralesional interleukin-2 increase activated lymphocytes and
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31 Grotz, T. E., et al (2011) In-transit melanoma: an individualized approach. Oncology (Williston.Park) 25;14:1340-
32 1348.
33 Reason: No data
34 Grubbs, E. G., (2004) In-transit melanoma: The role of alkylating-agent resistance in regional therapy. Journal of
35 the American College of Surgeons 199;3:419-427.
37 Grunhagen, D. J., et al (2005) Efficacy of repeat isolated limb perfusions with tumor necrosis factor alpha and
38 melphalan for multiple in-transit metastases in patients with prior isolated limb perfusion failure. Annals of

1 Grunhagen, D. J., et al (2004) One hundred consecutive isolated limb perfusions with TNF-alpha and melphalan in
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4 Grunhagen, D. J., et al (2006) The palliative value of tumor necrosis factor alpha-based isolated limb perfusion in
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13 Hallock, A., et al (2011) Is radiotherapy an effective treatment option for recurrent metastatic malignant
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16 Reason: Single Case
17 Han, D., et al (2011). Minimally invasive intra-arterial regional therapy for metastatic melanoma: isolated limb
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21 Hauschild, A. (2001) Safety margins for the primary surgical excison of malignant melanoma. Proposals based on
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24 Hayes, A. J., et al (2007) Meirion. Isolated limb perfusion with melphalan and tumor necrosis factor alpha for
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27 Hayes, A. J., et al (2004). Management of in-transit metastases from cutaneous malignant melanoma. British
28 Journal of Surgery 91;6: 673-682.
30 Hoekstra, H. J. and Hoekstra, H. J. (2008) The European approach to in-transit melanoma lesions. [Review] [58
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33 Hohenberger, W., et al (1994) [Extremity perfusion in malignant melanoma]. [Review] [31 refs] [German]. Chirurg
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36 Hohenberger, W., Meyer, T., and Gohl, J.(1994) Isolation Perfusion in Malignant-Melanoma. Chirurg 65;3:175-
37 185.
39 Hoekstra, H. J., et al (1993) Toxicity of hyperthermic isolated limb perfusion with cisplatin for recurrent
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1 Hsueh, E. C., et al (1999) Active specific immunotherapy with polyvalent melanoma cell vaccine for patients with
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4 Isolated Limb Perfusion and Isolated Limb Infusion for Malignant Lesions of the Extremities. Current Problems in
5 Surgery 48;6:371-430.2011
6 Reason: No data
7 Jiang, B. S., Beasley, G. M., Speicher, P. J., Mosca, P. J., Morse, M. A., Hanks, B., Salama, A., and Tyler, D. S.
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10 Jones, R. F., et al (1972). Total integumentectomy of the leg for multiple in-transit metastases of melanoma.
11 American Journal of Surgery 123;5:588-590.
12 Reason: No dataJose
13 Kam, P. C. A. and Thompson, J. F. (2010) Isolated limb infusion with melphalan and actinomycin D in melanoma
14 patients: factors predictive of acute regional toxicity. Expert Opinion On Drug Metabolism & Toxicology 6;9:1039-
15 1045.
17 Kandamany, N. and Mahaffey, P. (2008) Carbon dioxide laser ablation for the management of in-transit
18 cutaneous malignant melanoma metastases. Journal of Plastic Reconstructive and Aesthetic Surgery 61;9:1111-
19 1113.
21 Kang, J. C., et al (2005) lymphadenectomy does not increase the incidence of in-transit metastases in primary
22 melanoma. Journal of Clinical Oncology 23;21:4764-4770.
24 Karakousis, C. P., et al (1997). Tourniquet infusion chemotherapy for extremity in-transit lesions in malignant
25 melanoma. Annals of Surgical Oncology 4;6:506-510.
26 Reason: Not relevant to PICO (dose comparison)
27 Keilholz, U., et al (2005). Dacarbazine, cisplatin, and interferon-alfa-2b with or without interleukin-2 in metastatic
28 melanoma: a randomized phase III trial (18951) of the European Organisation for Research and Treatment of
29 Cancer Melanoma Group. Journal of Clinical Oncology 23;27:6747-6755.
31 Kidner, T. B., et al (2012). Combined intralesional Bacille Calmette-Guerin (BCG) and topical imiquimod for in-
32 transit melanoma. Journal of Immunotherapy 35;9:716-720.
34 Kirov, K. (2011) Electro-immunotherapy with BCG of superficial in-transit melanoma metastases. Melanoma
35 Research Conference[var.pagings],
37 Kofler, R. et al (1994) Late metastasis of malignant cutaneous melanoma. Der Hautarzt; Zeitschrift fur
38 Dermatologie, Venerologie, und verwandte Gebiete 45;3:145-148.
39 Reason: N=3
40 Koops, H. S., et al (1998) Prophylactic isolated limb perfusion for localized, high-risk limb melanoma: results of a
41 multicenter randomized phase III trial. European Organization for Research and Treatment of Cancer Malignant
1 Melanoma Cooperative Group Protocol 18832, the World Health Organization Melanoma Program Trial 15, and
2 the North American Perfusion Group Southwest Oncology Group-8593. Journal of Clinical Oncology 16;9:2906-
3 2912.
4 Reason: Not relevant to PICO (Population)
5 Krementz, E. T. and Krementz, E. T. (1986) Lucy Wortham James lecture. Regional perfusion. Current
6 sophistication, what next? Cancer 57;3:416-432.
8 Kretschmer, L., et al (2005) lymphonodectomy does not increase the risk of loco-regional cutaneous metastases
9 of malignant melanomas. European Journal of Cancer 41;4:531-538.
11 Kretschmer, L et al (2005) High incidence of in-transit metastases after sentinel node biopsy in patients with
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14 Kretschmer, L., et al (2002) Locoregional cutaneous metastasis in patients with therapeutic lymph node
15 dissection for malignant melanoma: risk factors and prognostic impact. Melanoma Research 12;5: 499-504.
17 Kretschmer, L., et al (2006) Factors predicting the risk of in-transit recurrence after sentinel lymphonodectomy in
18 patients with cutaneous malignant melanoma. Annals of Surgical Oncology 13;8:1105-1112.
20 Kroon, H. M., Moncrieff, M., Kam, P. C. A., and Thompson, J. F.(2008) Outcomes Following Isolated Limb Infusion
21 for Melanoma. A 14-Year Experience. Annals of Surgical Oncology 15;11:3003-3013.
23 Kroon, H. M. and Thompson, J. F. (2009) Isolated Limb Infusion: A Review. Journal of Surgical Oncology
24 100;2:169-177.
26 Kroon, B. B. R., et al (2008) Isolated limb perfusion for melanoma. Surgical Oncology Clinics of North America
27 17;4:785
28 Reason: No data
29 Kroon, H. M. (2009) Factors predictive of acute regional toxicity after isolated limb infusion with melphalan and
30 actinomycin D in melanoma patients. Annals of Surgical Oncology 16;5:1184-1192.
32 Kroon, H. M., Huismans, A. M., Kam, P. C. A., and Thompson, J. F. Isolated Limb Infusion with Melphalan and
33 Actinomycin D for Melanoma: A Systematic Review. Journal of Surgical Oncology 109[4], 348-351. 2014.
34 Kruijff, S. (2011) Salvage surgery for a giant melanoma on the back. Rare Tumors 3;3:90-91.
36 Lasithiotakis, K., et al (2010) Hyperthermic isolated limb perfusion for recurrent melanomas and soft tissue
37 sarcomas: feasibility and reproducibility in a multi-institutional Hellenic collaborative study. Oncology Reports
38 23;4:1077-1083.

1 Leiter, U., et al (2010) Sentinel lymph node dissection in primary melanoma reduces subsequent regional lymph
2 node metastasis as well as distant metastasis after nodal involvement. Annals of Surgical Oncology 17;1:129-137
4 Lejeune, F. J., et al (1977). Hyperthermic isolation-perfusion with melphalan, a preliminary appraisal of local and
5 general effects in malignant melanoma. Tumori 63;3:289-298.
7 Lejeune, F. J., et al (1983) Objective regression of unexcised melanoma in-transit metastases after hyperthermic
8 isolation perfusion of the limbs with melphalan. Recent Results in Cancer Research 86:268-276.
10 Lejeune, F. J., et al (1998). Clinical applications of TNF-alpha in cancer. [Review] [42 refs]. Current Opinion in
11 Immunology 10;5:573-580.
13 Lejeune, F. J., et al (1980). Efficacy of Isolation-Perfusion of the Limbs with Phenyl Alanin Mustard and
14 Hyperthermia on in Transit Metastasis of Malignant-Melanoma. European Surgical Research 12, 120-121
15 Reason: No data
16 Lejeune, F. J. et al (2000) Treatment of in-transit metastases of melanoma by isolated limb perfusion. Oncologie
17 2;1:85-89.
18 Expert Review
19 Lejeune, F. J. L. Et al (1994) Clinical experience with high-dose tumor necrosis factor alpha in regional therapy of
20 advanced melanoma. Circulatory Shock 43;4:191-197.
22 Lidsky, M. E., (2013) Predicting disease progression after regional therapy for in-transit melanoma. JAMA Surgery
23 148;6:493-498.
25 Lienard, D., et al (1992) In transit metastases of malignant melanoma treated by high dose rTNF alpha in
26 combination with interferon-gamma and melphalan in isolation perfusion. World Journal of Surgery 16;2:234-
27 240.
29 Lienard, D., et al (1993) High-Dose of Rtnf-Alpha, Rifn-Gamma and Melphalan in Isolation Perfusion Produce 90-
30 Percent Complete Response in Melanoma in Transit Metastases. Tumor Necrosis Factor : Molecular and Cellular
31 Biology and Clinical Relevance , 233-238.
32 Lienard, D., et al (1994) Isolated perfusion of the limb with high-dose tumour necrosis factor-alpha (TNF-alpha),
33 interferon-gamma (IFN-gamma) and melphalan for melanoma stage III. Results of a multi-centre pilot study.
34 Melanoma Research ; Suppl 1
36 Lienard, D., et al (1999) Isolated limb perfusion with tumour necrosis factor-alpha and melphalan with or
37 without interferon-gamma for the treatment of in-transit melanoma metastases: a multicentre randomized
38 phase II study. Melanoma Research 9;5: 491-502.
39 Check relevance of comparison

1 Lienard, D., et al (1998) Isolated limb perfusion in primary and recurrent melanoma: indications and results.
2 Seminars in Surgical Oncology 14;3:202-209
4 Lienard, D., et al (1992). High-dose recombinant tumor necrosis factor alpha in combination with interferon
5 gamma and melphalan in isolation perfusion of the limbs for melanoma and sarcoma. Journal of Clinical
6 Oncology 10;1:52-60.
8 Lukacs, L. and Lukacs, L. (1992) Loco-regional renewal of malignant melanomas. I. Local recurrence satellites and
9 in-transit nodes. Acta Chirurgica Hungarica 33;3-4: 325-334.
11 Lyo, V., et al (2012) In-Transit Intramammary Sentinel Lymph Nodes From Malignant Melanoma of the Trunk.
12 Annals of Surgery 255;1: 122-127.
14 Marsden, J. (2010) Management of in-transit limb metastases in melanoma: State of the art. Melanoma Research
15 Conference[var.pagings],
16 Reason: No data
17 Martin-Algarra, S.(2004) Isolated hyperthermic limb perfusion in melanoma. Skin Cancer 19[4], 245-260.
19 Martiniuk, F., et al (2010) TH17 is Involved in the Remarkable Regression of Metastatic Malignant Melanoma to
20 Topical Diphencyprone. Journal of Drugs in Dermatology 9:11:1368-1372.
22 Mattsson, J. (2012) Isolated limb perfusion for sarcoma and melanoma. European Journal of Surgical Oncology
23 Conference[var.pagings], 801
25 McClaine, R. J., et al (2012) Quality of life outcomes after isolated limb infusion. Annals of Surgical Oncology
26 19;5:1373-1378.
28 Mendenhall, W. M., et al (2013) Surgery and adjuvant radiotherapy for cutaneous melanoma considered high-
29 risk for local-regional recurrence. American Journal of Otolaryngology 34;4:320-322.
31 Meyer, T., Gohl, J., Meyer, T., and Gohl, J (2001). [Regional chemotherapy--perfusion of the extremities].
32 [German]. Kongressband/Deutsche Gesellschaft fur Chirurgie 118; 200-204.
34 Mian, R et al (2001) A. Isolated limb infusion for melanoma: a simple alternative to isolated limb perfusion.
35 Canadian Journal of Surgery 44;3:189-192.
36 Reason: N=9/No comparator
37 Minor, D. R. A.(1985) A clinical and pharmacokinetic study of isolated limb perfusion with heat and melphalan for
38 melanoma. Cancer 55;11:2638-2644.

1 Moeller, M. G., et al (2008). Toxicities associated with hyperthermic isolated limb perfusion and isolated limb
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3 Reason: No data
4 Mohs, F. E. (1986) Micrographic surgery for satellites and in-transit metastases of malignant melanoma. Journal
5 of Dermatologic Surgery and Oncology 12;5:471-476
6 N=5
7 Moller, M. G., et al (2009). Electrochemotherapy as an adjunct or alternative to other treatments for

8 unresectable or in-transit melanoma. [Review] [204 refs]. Expert Review of Anticancer Therapy 9;11:1611-1630.
10 Moreno-Ramirez, D., et al (2010) A. Isolated Limb Perfusion for Malignant Melanoma: Systematic Review on
11 Effectiveness and Safety. The Oncologist 15;4:416-427.
13 Moreno-Ramirez, D., et al (2009) [Study and treatment of locally advanced melanoma]. [Review] [48 refs]
14 [Spanish]. Actas Dermo-Sifiliograficas 100;9:767-779.
16 Muchmore, J. H. K. (1986) Isolated perfusion of extremities for metastatic melanoma from an unknown primary
17 lesion. Southern Medical Journal 79;3:288-290.
19 Murali, R. Moncrieff. (2010) The prognostic value of tumor mitotic rate and other clinicopathologic factors in
20 patients with locoregional recurrences of melanoma. Annals of Surgical Oncology 17;11:2992-2999.
22 Nathanson, L., et al (1998). Active specific immunotherapy with polyvalent melanoma cell vaccine (PMCV) in
23 patients with in transit (UICC Stage N2b) melanoma metastases. 17Th International Cancer Congress, Vol 1 and
24 2:439-443.
26 Neto, J. P. D., Mauro, A. C. C., Molina, A. S., Nishinari, K., Zurstrassen, C. E., Costa, O. F., Belfort, F. A., Facure, L.,
27 and Fregnani, J. H. Isolated limb infusion with hyperthermia and chemotherapy for advanced limb malignancy:
28 factors influencing toxicity. Anz Journal of Surgery 84[9], 677-682. 2014.
29 Nooijen, P. T., et al (1998) Complete response of melanoma-in-transit metastasis after isolated limb perfusion
30 with tumor necrosis factor alpha and melphalan without massive tumor necrosis: a clinical and histopathological
31 study of the delayed-type reaction pattern. Cancer Research 58;21:4880-4887
33 Noorda, E. M., et al (2004). Isolated limb perfusion for unresectable melanoma of the extremities. Archives of
34 Surgery 139;11:1237-1242.
36 Noorda, E. M., et al (2004) Isolated limb perfusion prolongs the limb recurrence-free interval after several
37 episodes of excisional surgery for locoregional recurrent melanoma. Annals of Surgical Oncology 11;5: 491-499.
39 Noorda, E. M., et al (2003) Prognostic factors for survival after isolated limb perfusion for malignant melanoma.
40 European Journal of Surgical Oncology 29;10:916-921.
1 Olofsson, R. (2011) Long-term Follow-up of all isolated limb perfusions for in-transit metastasis of malignant
2 melanoma in sweden during 25 years. Annals of Surgical Oncology Conference[var.pagings]
4 Olofsson, R., et al (2013). Melan-A specific CD8+ T lymphocytes after hyperthermic isolated limb perfusion: a
5 pilot study in patients with in-transit metastases of malignant melanoma. International Journal of Hyperthermia
6 29;3:234-238.
8 Olofsson, R., Mattsson, J., and Lindner, P.(2013) Long-term follow-up of 163 consecutive patients treated with
9 isolated limb perfusion for in-transit metastases of malignant melanoma. International Journal of Hyperthermia
10 29;6:551-557.
12 Oni, G.(2009) Spontaneous regression of subcutaneous in-transit malignant melanoma deposits of the lower leg
13 after treatment with the carbon dioxide laser. Clinical and Experimental Dermatology 34;8: e650-e652.
15 Ortin-Perez, J., et al (2008). [In-transit sentinel lymph nodes in malignant melanoma. What is their importance?].
16 [Spanish]. Revista Espanola de Medicina Nuclear 27;6: 424-429.
18 Ozawa, A et al (2012) Immunohistological analysis of in-transit metastasis in a patient with advanced melanoma
19 treated with combination therapy of cytosine guanine dinucleotide oligodeoxynucleotide, dacarbazine and beta-
20 interferon: A case report. Journal of Dermatology 39;12:1035-1037.
22 Pais Costa, S. R. C. (2008) Popliteal lymphadenectomy for treating metastatic melanoma: Case report. Sao Paulo
23 Medical Journal 126[4], 232-235.
25 Pace, M., Gattai, R., Mascitelli, E. M., and Millanta (2011) L. Results of Isolated Lower Limb Perfusion for Loco-
26 Regional Advanced/Recurrent Melanoma Using Borderline True Hyperthermia Plus Additional Bolus of
27 Melphalan. A Critical Analysis of Homogeneous Cases. Journal of Surgical Oncology 104;7:718-723.
29 Padsis, J., et al (2010). Pharmacotherapy of regional melanoma therapy. Expert Opinion on Pharmacotherapy
30 11;1:79-93.
32 Papadia, F., et al (2013) Isolated limb perfusion with the tumor-targeting human monoclonal antibody-cytokine
33 fusion protein L19-TNF plus melphalan and mild hyperthermia in patients with locally advanced extremity
34 melanoma. Journal of Surgical Oncology 107;2:173-179.
36 Pannucci, C. J., et al (2012) The role of full-thickness scalp resection for management of primary scalp melanoma.
37 Annals of Plastic Surgery 69;2:165-168.
39 Pasquali, S., et al (2010) Early (sentinel lymph node biopsy-guided) versus delayed lymphadenectomy in
40 melanoma patients with lymph node metastases: personal experience and literature meta-analysis (Provisional

1 abstract). Cancer 116;5:1201-1209.

3 Paulsen, I. F., Chakera, A. H., Drejoe, J. B., Klyver, H., Dahlstrom, K., Oturai, P. S., Mortensen, J., Hesse, B.,
4 Schmidt, G., Drzewiecki, K., Paulsen, Ida Felbo, Chakera, A. H., Drejoe, Jennifer Berg, Klyver, Helle, Dahlstrom,
5 Karin, Oturai, Peter Sandor, Mortensen, Jann, Hesse, Birger, Schmidt, Grethe, and Drzewiecki, Krzysztof. Tumour
6 response after hyperthermic isolated limb perfusion for locally advanced melanoma. Danish Medical Journal
7 61[1], A4741. 2014.
8 Pawlik, T. M., et al (2005) The risk of in-transit melanoma metastasis depends on tumor biology and not the
9 surgical approach to regional lymph nodes. Journal of Clinical Oncology 23;21:4588-4590.
10 Reason: No data
11 Pawlik, T. M., et al (2005) Predictors and natural history of in-transit melanoma after sentinel lymphadenectomy.
14 Pawlik, T. M., et al (2005). Low risk of in-transit metastasis in patients with cutaneous melanoma undergoing
15 sentinal lymph node biopsy. Journal of Clinical Oncology 23;21:4588-4590.
17 Pfohler, C., et al (2004) Complete remission of cutaneous satellite and in-transit metastases. After intralesional
18 therapy with interleukin-2 in two patients with malignant melanoma. Hautarzt 55;2:171-175.
19 Reason: No data
20 Pilati, P., et al (2004). Hypoxic antiblastic stop-flow limb perfusion: clinical outcome and pharmacokinetic findings
21 of a novel treatment for in transit melanoma metastases. Oncology Reports 12;4:895-901.
22 Reason: N=5
23 Posner, M. C., et al(1995) Hyperthermic isolated limb perfusion with tumor necrosis factor alone for melanoma.
24 The Cancer Journal from Scientific American 1;4:274-280.
25 Reason: N=6
26 Raja, C., et al (2007) Interim analysis of oxicity and response in phase 1 trial of systemic targeted alpha therapy
27 for metastatic melanoma. Cancer Biology & Therapy 6;6:846-852.
29 Raymond, A. K., et al (2011) Current Trends in Regional Therapy for Melanoma: Lessons Learned from 225
30 Regional Chemotherapy Treatments between 1995 and 2010 at a Single Institution. Journal of the American
31 College of Surgeons 213;2:306-316.
33 Read, R. (2013) The role of lymphadenectomy in patients who develop in-transit melanoma metastases. JDDG -
34 Journal of the German Society of Dermatology Conference[var.pagings],
36 Read, R., Haydu et al (2012) In-transit Melanoma Metastases: Incidence, Prognostic Importance and Implications
37 for Patient Staging. Annals of Surgical Oncology 19: S23.
38 Reason: No data
39 Roberts, M. S., et al (2001) Pharmacokinetics and pharmacodynamics of melphalan in isolated limb infusion for
40 recurrent localized limb malignancy. Melanoma Research 11;4: 423-431
41 Reason: No data
1 Robinson, D. W., Jr et al (2012) Health-related quality of life among patients with metastatic melanoma: results
2 from an international phase 2 multicenter study. Melanoma Research 22;1:54-62.
4 Rodriguez-Cuevas, S., et al (2001) Electrochemotherapy in primary and metastatic skin tumors: phase II trial using
5 intralesional bleomycin. Archives of Medical Research 32;4:273-276.
7 Romics, L., et al (2011). Initial experiences with isolated limb perfusion for unresectable melanoma of the limb.
8 Irish Journal of Medical Science 180;2:517-520.
9 Reason: No COmparator
10 Roses, D. F., et al (1983) Local and in-transit metastases following definitive excision for primary cutaneous
11 malignant melanoma. Annals of Surgery 198;1: 65-69.
13 Ross, M. I. and Ross, Merrick I. (2008) Current status of hyperthermic limb perfusion for in-transit melanoma.
14 [Review] [50 refs]. International Journal of Hyperthermia 24;3:205-217.
16 Ross, M. I. (2011) Intralesional therapy: Local/regional control and implications for systemic response. Pigment
17 Cell and Melanoma Research Conference[var.pagings], 1010.
18 Reason: No data
19 Rossi, C. R., et al (2007) A pilot study on TNF based hyperthermic perfusion followed by low-dose TNF in patients
20 with in-transit metastasis from melanoma. Annals of Surgical Oncology 14;2:8-9.
21 Reason: No data
22 Rossi, C. R., et al (2008) TNF-based isolated limb perfusion followed by consolidation biotherapy with systemic
23 low-dose interferon alpha 2b in patients with in-transit melanoma metastases: a pilot trial. Annals of Surgical
24 Oncology 15;4:1218-1223.
26 Rossi, C. R., et al (2010) Long-term results of melphalan-based isolated limb perfusion with or without low-dose
27 TNF for in-transit melanoma metastases. Annals of Surgical Oncology 17;11:3000-3007.
29 Rossi, C. R., et al (2004) Hyperthermic isolated limb perfusion with low-dose tumor necrosis factor-alpha and
30 melphalan for bulky in-transit melanoma metastases. Annals of Surgical Oncology 11;2:173-177.
32 Rossi, C. R., et al (2003) TNF-based limb perfusion for cutaneous melanoma in transit metastases: suggestions for
33 modification of the perfusional schedule.[Erratum appears in J Exp Clin Cancer Res. 2006 Sep;25(3):preceding
34 table of contents Note: Ribello, D [corrected to Rubello, D]]. Journal of Experimental & Clinical Cancer Research
35 22;4 Suppl:103-107.
36 Check relevance
37 Rossi, C. R., et al (2002). Isolated limb perfusion in locally advanced cutaneous melanoma. Seminars in Oncology
38 29;4:400-409.

1 Ruschulte, H.(2013) Anesthesia management of patients undergoing hyperthermic isolated limb perfusion with
2 melphalan for melanoma treatment: An analysis of 17 cases. BMC Anesthesiology 13 ;15
4 Russell-Jones, R. (2004) Completion lymphadenectomy may not increase in-transit disease in malignant
5 melanoma [5]. British Medical Journal 329;7477:1288-1289.
6 Reason: No data
7 Rutkowski, P et al (2006). In transit/local recurrences in melanoma patients after sentinel node biopsy and
8 therapeutic lymph node dissection. European Journal of Cancer 42;2:159-164.
10 Salemi, M., et al (2012) Proapoptotic Genes Are Downregulated in a Patient With Melanoma and Repeated In-
11 Transit Metastases. American Journal of Dermatopathology 34:4:454-455.
13 Salerno, E. P. W. (2012) Topical imiquimod induces immune activation and regressions of cutaneous melanoma
14 metastases. Journal of Immunotherapy Conference[var.pagings], 751-752.
15 Reason:Abstract Only
16 Santillan, A. A., et al (2009) Predictive factors of regional toxicity and serum creatine phosphokinase levels after
17 isolated limb infusion for melanoma: a multi-institutional analysis. Annals of Surgical Oncology 16;9:2570-2578.
19 Savoia, P., et al (2009). Skin metastases of malignant melanoma: a clinical and prognostic survey. Melanoma
20 Research 19;5:321-326.
22 Schlag, P. M., et al (1995). [Isolated extremity perfusion with tumor necrosis factor and melphalan.An option for
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25 Schlag, P. M. and Kettelhack, C. (1995) Isolated Limb Perfusion with Tumor-Necrosis-Factor and Melphalan -
26 Option for Treatment of Satellitosis Or in Transit Metastasis of Malignant-Melanoma. Hautarzt 46[5], 361-362.
28 Schnabel, T. (1992) Radiotherapy and simultaneous intra-arterial dacarbazine infusion in the treatment of in
29 transit metastases of malignant melanoma. Regional Cancer Treatment 4;5-6:258-259.
31 Schneider-Burrus, S. (2009) Operative treatment of malignant melanomas. Onkologe 15;8:750-757

32 Reason: No data
33 Schraffordt Koops, H. (1977) Regional perfusion for recurrent malignant melanoma of the extremities. American
34 Journal of Surgery 133[2], 221-224.
36 Seegenschmiedt, M. H., et al (1999). [Long term results following radiation therapy of locally recurrent and
37 metastatic malignant melanoma]. [German]. Hautarzt 50;8:572-579.
38 Reason: N=24/possible duplicate
39 Seegenschmiedt, M. H., et al (1999) [Locally recurrent and metastatic malignant melanoma. Long-term results
40 and prognostic factors after percutaneous radiotherapy]. [German]. Strahlentherapie und Onkologie 175;9:450-

1 457
3 Sersa, G. (2006) The state-of-the-art of electrochemotherapy before the ESOPE study; advantages and clinical
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5 Reason: No data
6 Shekhel, T., Glick, R. M., and Cranmer, L. D. (2009) In-Transit Metastasis From Melanoma Presenting as
7 Lymphangiectasis: A Case Report. Cutis 84;3:151-158.
9 Sherrill, B. (2013) Q-TWiST analysis comparing ipilimumab/dacarbazine vs placebo/dacarbazine for patients with
10 stage III/IV melanoma. British Journal of Cancer 109;1:8-13
12 Shibata S. (2005) Evaluation of clinical prognosis of stage II and III melanoma patients treated with hyperthermic
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15 Squires, M. H., III and Delman, K. A. (2013) Current treatment of locoregional recurrence of melanoma. Current
16 Oncology Reports 15;5:465-472.
17 Reason: No data
18 Stadler, R et al (2000). Management of regional metastases. [Review] [21 refs]. Clinical & Experimental
19 Dermatology 25;6:490-496.
21 Stehlin, J. S., Jr., et al (1966). Melanomas of the extremities complicated by in-transit metastases. Surgery,
22 Gynecology & Obstetrics 122;1:3-14.
24 Strobbe, L. J. A., et al (1997). Carbon dioxide laser for cutaneous melanoma metastases: indications and
25 limitations. European Journal of Surgical Oncology 23;5:435-438.
27 Suojarvi, N. J., et al (2012) Outcome following local recurrence or in-transit metastases in cutaneous melanoma.
28 Melanoma Research 22;6: 447-453.
30 Suzuki, T. (1995) Two cases of in-transit metastases of malignant melanoma successfully treated with
31 cryosurgery. Skin Cancer 10;1:53-59.
32 N=2
33 Takkenberg, R. B., et al (2005) Palliative isolated limb perfusion for advanced limb disease in stage IV melanoma
34 patients. Journal of Surgical Oncology 91;2:107-111.
36 Tavaniello, B. (2010) Electrochemotherapy for primary or metastatic skin tumours: A single institution
37 experience. European Surgical Research Conference[var.pagings], 237
39 Temple-Oberle, C. F., Byers, B. A., Hurdle, V., Fyfe, A., and Mckinnon, J. G. Intra-Lesional Interleukin-2 Therapy for
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1 Terando, A. M. and Carson, W. E., (2011) III. Individualized local treatment strategies for in-transit melanoma.
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3 Reason: No data
4 Testori, A., et al (2011) Treatment of melanoma metastases in a limb by isolated limb perfusion and isolated limb
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7 Testori, A., et al (2011) Local and intralesional therapy of in-transit melanoma metastases. [Review]. Journal of
8 Surgical Oncology 104[4], 391-396. 2011.
10 Testori, A et al (2012) Alternatives for the treatment of local advanced disease: electrochemotherapy, limb
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12 Reason: No data
13 Testori, A., V. (2012) Treatment of in-transit metastasis: Perfusion (ILP), infusion (IP) and electro-chemotherapy
14 (ECT). European Journal of Surgical Oncology Conference[var.pagings], 739-740.
15 Reason: No data
16 Testori, A., et al (2009) Surgery and radiotherapy in the treatment of cutaneous melanoma. [Review] [99 refs].
17 Annals of Oncology 20;Suppl 6:vi22-vi29.
19 Thirlwell, C. (2008) Melanoma - Part 2: Management. BMJ 337;7682:1345-1348.

21 Tokgoz, S., et al (2012). Factors predicting iliac metastasis and overall survival in malignant melanoma of the
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24 Tsuchida, Y. (1997) Six cases of in-transit metastasis on acral lentiginous melanoma. Japanese Journal of Plastic
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27 Turley, R. S., et al (2011) Regional treatment strategies for in-transit melanoma metastasis. [Review]. Surgical
28 Oncology Clinics of North America 20;1:79-103.
30 Turley, R. S., et al (2012) Bevacizumab-Induced Alterations in Vascular Permeability and Drug Delivery: A Novel
31 Approach to Augment Regional Chemotherapy for In-Transit Melanoma. Clinical Cancer Research 18;12: 3328-
32 3339.
34 Utikal, J. (2006) Complete remission of multiple satellite and in-transit melanoma metastases after sequential
35 treatment with isolated limb perfusion and topical imiquimod [9]. British Journal of Dermatology 155;2:488-491.
36 Reason: Combination treatment not relevant to PICO
37 van Der Veen, A. H., et al (2000). An overview on the use of TNF-alpha: our experience with regional
38 administration and developments towards new opportunities for systemic application. [Review] [116 refs].
39 Anticancer Research 20;5B:3467-3474.

1 Van Etten, B., et al (2004). Repeat isolated limb perfusions (ILP) with tumor necrosis factor-alpha (TNF) and
2 melphalan are highly effective in melanoma patients with multiple in-transit metastases who have failed prior
3 ILPs. Annals of Surgical Oncology 11;2:S77.
5 Vaglini, M., et al (1994). Treatment of in-transit metastases from cutaneous melanoma by isolation perfusion
6 with tumour necrosis factor-alpha (TNF-alpha), melphalan and interferon-gamma (IFN-gamma). Dose-finding
7 experience at the National Cancer Institute of Milan. Melanoma Research 4;Suppl 1:35-38.
9 Vaglini, M., et al (1994). Treatment of primary or relapsing limb cancer by isolation perfusion with high-dose
10 alpha-tumor necrosis factor, gamma-interferon, and melphalan. Cancer 73;2:483-492.
11 Reason: No comparator/Case Reports
12 Vaglini, M., et al (1995) Isolation perfusion in extracorporeal circulation with interleukin-2 and lymphokine-
13 activated killer cells in the treatment of in-transit metastases from limb cutaneous melanoma. Annals of Surgical
14 Oncology 2:1:61-70.
16 Veenstra, H. J et al (2010) Reevaluation of the locoregional recurrence rate in melanoma patients with a positive
17 sentinel node compared to patients with palpable nodal involvement. Annals of Surgical Oncology 17;2:521-526.
19 Vendettuoli, D., et al (2010) Role of surgery in patients with metastases from melanoma. A case report. Annali
20 Italiani di Chirurgia 81;6:453-455.
22 Villani, F., et al (1995) Pulmonary toxicity of alpha tumor necrosis factor in patients treated by isolation perfusion.
23 Journal of Chemotherapy 7;5:452-454.
24 Reason: Poor Data
25 Villani, F., et al (1995) Cardiac and pulmonary effects of alpha tumor necrosis factor administered by isolation
26 perfusion. Tumori 81;3:197-200.
27 Reason: Poor Data (possible duplicate)
28 Von Nida, J. Successful treatment of in-transit melanoma metastases using topical 2-4 dinitrochlorobenzene.
29 Australasian Journal of Dermatology 44;4:277-280.
31 Walther, W. Et al (2007) Phase I trial of non-viral jet injection gene transfer into in transit metastases from
32 melanoma and skin metastases from breast cancer. Human Gene Therapy 18;10:994.
34 Wessels, R. (2010) CO2-laser treatment for cutaneous malignant melanoma metastases. European Journal of
35 Surgical Oncology Conference[var.pagings], 908.
37 Weide, B., Eigentler, T. K., Pflugfelder, A., Zelba, H., Martens, A., Pawelec, G., Giovannoni, L., Ruffini, P. A., Elia, G.,
38 Neri, D., Gutzmer, R., Becker, J. C., and Garbe, C. Intralesional Treatment of Stage III Metastatic Melanoma
39 Patients with L19-IL2 Results in Sustained Clinical and Systemic Immunologic Responses. Cancer Immunology
40 Research 2[7], 668-678. 2014.

1 Weichenthal, M. and Chiarion-Sileni, V. Intermittent intensified high-dose intravenous interferon alpha 2b

2 (IFNa2b) for adjuvant treatment of stage III malignant melanoma: Pooled analysis of two randomized phase III
3 trials (NCT00226408 and ISRCTN75125874) with 980 patients. Journal of Clinical Oncology
4 Conference[var.pagings]. 2013.
5 Weide, B., et al (2013) Prognostic factors of melanoma patients with satellite or in-transit metastasis at the time
6 of stage III diagnosis. PLoS One 8;4: e63137.
8 Weide, B., et al (2010) High Response Rate After Intratumoral Treatment With Interleukin-2 Results From a Phase
9 2 Study in 51 Patients With Metastasized Melanoma. Cancer 116;17:4139-4146.
11 Wolf, I. H et al (2004) Locoregional cutaneous metastases of malignant melanoma and their management.
12 Dermatologic Surgery 30;2 Pt 2:244-247.
14 Wong, J., Chen, Y. A., Fisher, K. J., Beasley, G. M., Tyler, D. S., and Zager, J. S. Resection of Residual Disease after
15 Isolated Limb Infusion (ILI) Is Equivalent to a Complete Response after ILI-Alone in Advanced Extremity
16 Melanoma. Annals of Surgical Oncology 21[2], 650-655. 2014.
17 Wong, J. (2011) A standardized approach to isolated limb infusion for in-transit melanoma on the extremities:
18 Perioperative data and outcomes. Pigment Cell and Melanoma Research Conference[var.pagings], 1072-1073.
20 Wong, J. H., et al (1990). Natural history and selective management of in transit melanoma. Journal of Surgical
21 Oncology 44;3:146-150.
23 Wouters, J., et al (2012) Gene expression changes in melanoma metastases in response to high-dose
24 chemotherapy during isolated limb perfusion. Pigment Cell & Melanoma Research 25;4:454-465.
26 Yao, K. A., et al (2003) Is sentinel lymph node mapping indicated for isolated local and in-transit recurrent
27 melanoma? Annals of Surgery 238;5:743-747. 2003.
29 Zager, J. S., Puleo, C. A., and Sondak, V. K. (2011) What is the Significance of the In Transit or Interval Sentinel
30 Node in Melanoma? Annals of Surgical Oncology 18;12: 3232-3234.
31 Reason: No data
32 Zogakis, T. G., et al (2001) Factors affecting survival after complete response to isolated limb perfusion in
33 patients with in-transit melanoma. Annals of Surgical Oncology 8;10:771-778.
35

Evidence Tables
Study Quality
Appropriate and Type of studies Literature search Study quality is Adequate description of Quality
clearly focused you consider is sufficiently assessed and the methodology
relevant to the rigorous reported (GRADE)
guideline review
question
Mali et al (2013) Yes Yes Yes Yes Yes Very Low
Appropriate Precise Valid method of Investigators Investigators blind to Quality

length of follow- definition of an measuring blind to potential confounders
up outcome outcomes participants and prognostic factors? (GRADE)
exposure to
intervention?
Caraco et al Unclear Yes Yes No No Very Low

(2013)
Fotopoulos et al Unclear Yes Yes No No Very Low

1998
Hill et al (1993) Unclear Yes Yes No No Very Low
Kadamany et al Unclear Yes Yes No No Very Low

(2009)
Ricotti et al Unclear Yes Yes No No Very Low

(2014)
Seegenschmiedt Unclear Yes Yes No No Very Low

et al (1999)

Sharma et al Unclear Yes Yes No No Very Low

2012
Study Aim Population Intervention Comparison Follow-up Outcomes and results
Caraco et al (2013) To analyse the short N=60 with relapse and refactory Electrochemotherap None Median follow-up was 21 patients had recurrent cutaneous disease or in-
and long term cutaneous melanoma or in-transit y 27.5 months (range 6-67 transit disease of the trunk
responses of lesions disease months)
treated with 35 patients had in transit disease of an inferior limb
electrochemotherap
y with intravenous 4 patients had cutaneous disease in the head and neck
injection of area
bleomycin in
melanoma patients
with in-transit
Treatment was well tolerated with the most frequent
disease or distant
side effects being mild pain in 22 patients and myalgia
cutaeous metasases
in 8 patients.
No systemic adverse events were recorded
Necrosis of treated lesions occurred in 18 patients
3 months after Electrochemotherapy, 23 patients

recorded a partial response, 29 recorded a complete
response and 8 recorded no change or progressive
disease.
Objective response rate was 86.6% for all treated

lesions.
13 patients experienced a long lasting response to

Electrochemotherapy after one session and were free
of disease after mean follow-up of 27.5 months.

Fotopoulos et al To investigate the N=33 patients who developed a loco- Surgical Excision None Median observation Survival
1998 role of surgical regional relapse after removal of a time was 31 months (5
treatment for primary tumour located to the lower months -22 years)
extremity. 12 patients had a local
survival in patients
recurrence while 21 had in-transit
with loco-regional metastases.
recurrences In transit was defined as cutaneous or
subcutaneous recurrences occurring
between the scar or skin graft after
surgery for the primary tumour and the
regional lymph nodes (groin).
Median age was 67 years (18-85 years)

and there were 26 females and 7 males.
Hill et al (1993) To investigate the N= 60 patients with cutaneous and Co2 laser None Not reported Development of extraregional disease
place of CO2 laser superficial subcutaneous metastases of
ablation of malignant melanoma. Overall Survival
cutaneous or sub-
cutaneous deposits
of malignant
melanoma
Kadamany et al Not Clear – appears N=16 patients with cutaneous and Co2 laser None Not Reported Survival
(2009) to be effectiveness superficial melanoma metastases too
of CO2 laser numerous or recurring too frequently for
surgical excision
Mali et al (2013) To investigate the N=413 patients with 1894 tumours were Electrochemotherap Chemotherapy (where Not reported Response of individual tumours to a single session of
effectiveness of included in the review. y available) ECT (or control treatment) evaluated according to
electrochemotherap N=150 with 922 tumours patients with WHO or RECIST criteria and classified as complete
y (ECT) in cutaneous melanoma were included in the review response (CR), partial response (PR), no change (NC) or
or subcutaneous (22 studies) progressive disease (PD). Objective Response (CR+PR)
tumour. and No Response (NC+PD) were also evaluated.
Inclusion criteria:
 Studies with information about

single session ECT of cutaneous or
subcutaneous tumours performed
on human patients using bleomycin
or cisplatin administered
intratumorally or intravenously.

 Studies with data for number of

patients and tumours, tumour
response (evaluated at least 4
weeks after treatment)
chemotherapeutic drug, route of
drug administration and tumour
type.
For inclusion in meta-analysis,
 studies with data for control

tumours (i.e. tumours treated with
chemotherapeutic drug or
electroporation pulses only or no
treatment
 studies with data for at least two
different histological types of
tumours
Exclusion criteria:
No specific exclusion criteria given
Ricotti et al (2014) To evaluate the N=30 patients affected by 654 metastatic Electrochemotherap None Median follow-up was First ECT
efficacy, long-term nodules from melanoma y 20 months
tolerability and Average number of lesions treated per patient was
long-term efficacy 21.8 (4-54)
of
electrochemotherap Size of lesion ranged from 0.2cm2-10cm2
y in the treatment
of advanced
cutaneous and
100% of patients recorded an objective response
subcutaneous
(complete or partial)
melanoma
Complete response was achieved in 6 patients (20%)

and partial response was achieved in 24 patients
(80%).
Partial response was 31.09% for patients with 1-25

lesions and 33.85% for patients with >26 lesions.

Partial response was 79.116% for nodules ≥1cm2.
48/63 (76.19%) nodules 1-5cm2 had a partial response
9/9 (100%) nodules 5-10cm2 had a partial response
Following second ECT, PR for nodules sized ≥1cm2 was

73.68%.
PR was reported in 68.75% of nodules 1-5cm2
PR was reported in 100% of nodules >5cm2
PR was achieved in 157/360 (26.9%) of nodules 0.2-

0.5cm2 after first ECT and in 31/157 (19.74%) nodules
after second ECT.
50/360(13.8%) nodules 0.2-0.5cm2 achieved PR on first

ECT and 0 nodules at second ECT.
111/222 (50%) nodules 0.6-1cm2 achieved partial

response after first ECT and 33/111 (29.72%) after
second ECT.
Overall PR rate after first ECT was 32.72% (95% CI 29-

36%) (214/654 nodules).
214 nodules were retreated and overall PR rate was

34.11% (95% CI 28-41%) (73/214).
1 month after second ECT, 581/654 lesions had

achieved complete response.
After median 20 month follow-up, CR was achieved in

9/20 patients and PR in 5/20 surviving patients.
Stable or progressive disease was recorded in 6

patients.
Local tumour control rate at 24 months was 72%.
Seegenschmiedt et To analyse the 20 N=121 patients referred for external Radiotherapy None Response Rates
al (1999) year clincial radiotherapy of which 24 patients were
experience with referred due to in-transit metastases. Survival
radiotherapy
N=57 patients with stage UICC III
treatment with (including the 24 patients with in-transit
respect to different metastases) were referred for
endpoints and radiotherapy to reduce or prevent
prognostic factors. tumour related symptoms and improve
quality of life.
Sharma et al 2012 To summarise the From 1995-2011, N= 214 patients Hyperthermic Isolated Limb Infusion Response Rates
patterns of undergoing HILP or ILI for the first time Isolated Limb Recurrence
recurrence folling a for in transit melanoma; 81 HILPs and 133 Perfusion Survival
ILIs.
complete response
PET-CT was used to evaluate disease status prior to
to HILP and ILI and Inclusion Criteria therapy and to detect local and systemic recurrences.
to evaluate whether Patients with AJCC stage IIIB, IIIC or IV Patients treated from 2005 underwent PET-CT scans
the regional with known outside disease resected prior to regional chemotherapy, every 3 months for a
treatment modality before regional treatment. year and every 6 months thereafter.
producing a Pathological confirmation via punch biopsies, fine
complate response Exclusion Criteria needle aspiration, CT guided biopsies or surgical
None given resections were performed when possible.
influences the
probability and/or
timing of local
recurrence or
overall survival

1 6. Stage IV Melanoma
2 6.1 Localised treatments for metastatic stage IV melanoma
3 Review question: How effective is surgery, ablative treatments or stereotactic radiotherapy for
4 people with stage IV melanoma with oligometastatic disease?
5 Background
6 A wide variety of treatment modalities have been used to treat metastatic melanoma, i.e. a melanoma which is
7 spread through the bloodstream to reach distant sites. The commonest metastatic sites for melanoma to spread
8 to are liver, lungs, brain and bone. Melanoma can also spread to other skin sites giving tumours under the skin at
9 subcutaneous nodules. Unfortunately with melanoma, spread can also occur almost anywhere in the body,
10 including sites that other cancers do not usually spread to, such as the gastrointestinal tract or the heart.
11 All the many local treatments which have been used, and several new approaches are in development or at the
12 clinical trials stage, have in common the aim of removing the melanoma metastases completely, and so reducing
13 the risk of recurrence at that particular site, while reducing to a minimum the side-effects or morbidity of using
14 that particular treatment. Therefore some techniques such as the emerging advanced radiotherapy techniques
15 are more appropriate to use for brain metastasis where the inevitable morbidity of any surgical approach, might
16 be too high a cost for the palliation achieved. In contrast, surgical techniques using surgery, laser ablation or
17 localised electro-chemotherapy would be much more appropriate for the palliation of multiple subcutaneous
18 melanoma metastases, than any of even the new radiotherapy techniques.
19 Surgical management of distant malignant melanoma deposits has been used for hundreds of years but these
20 techniques are still developing with increased use of laser treatments and the development of electro-
21 chemotherapy. Advances in imaging and diagnostic techniques has allowed for more precise surgical intervention
22 improving palliation and decreasing mobility.
23 Stereotactic radiosurgery, introduced in the last two decades allows for the treatment of metastases in a much
24 reduced number of fractions and by being able to deliver highly focused radiation treatments to very precise
25 target areas with much reduced dose to surrounding normal tissues reduces treatment morbidity and the
26 number of patient attendances required for treatment. Other new technologies for treating melanoma
27 metastases include CyberKnife and other Intensity Modulation RadioTherapy approaches.
28 Radiation can also be used by delivering radioactive particles to the melanoma metastases and using different
29 techniques so that these particles are preferentially taken up within the melanoma cells. As well as targeting
30 these metastases individually the tumours blood supply can be compromised by radioembolisation using
31 radioactive agents to block the tumours feeding arterial supply and it also places a decaying radiation source
32 close to the tumour itself.
33 The major challenge with all of these new and not some new techniques is that there are very few comparative
34 trials telling us which modality is best in which particular clinical situation and metastatic site.

Patients with stage IV Surgery Each other Overall Survival (1, 5 &
melanoma: Stereotactic radiotherapy Systemic treatment 10yr)
Image guided ablative Radiotherapy Melanoma specific
With oligometastatic techniques: Symptom control survival
disease Radio frequency ablation Observation alone Metastases free survival

(RFA) Adverse Events
Microwave HRQL
Cryotherapy tumour necrosis
Radiologically guided sometimes called
embolisation complete or incomplete
Chemoembolisation tumour ablation or
primary or secondary
For completeness consider effectiveness rates
adding in the electroporation
‘nano knife’ and HIFU
techniques
1
2

1 Search Results

Medline 1998-2013 1510 519 28/10/2013
Premedline 1998-2013 632 105 29/10/2013
Embase 1998-2013 2671 991 05/11/2013
Web of Science (SCI & SSCI) 1998-2013 4254* 908 08/11/2013
*Database error with Web of Science – giving different search totals
2 Update Search

retrieved search
Medline 200 48 10/10/2014
Premedline 31 11 10/10/2014
Embase 961 127 13/10/2014
4 Abstracts for 1745 papers were screened for their relevance for the review question and 1654 papers were
5 excluded leaving 90 papers to be ordered and the full text screened (figure 1). From these 90 papers 15 were
6 relevant (table 3) and included in the evidence review and 74 papers were excluded (table 4). There were a
7 number of papers which were excluded because they are not specific to melanoma and the studies contain
8 patients with metastases from a range of different primary cancers. It was important to select papers specific to
9 melanoma as the effect of treatments on melanoma metastases may be different to other cancers.
10 From the 15 relevant melanoma studies 7 were concerning brain metastases, 1 examined lung metastases, 1
11 examined adrenal metastases, 2 examined liver metastases, 1 examined abdominal metastases, and 3 studies
12 were not specific to any particular metastasis location but contained a wide range of melanoma patients with
13 various metastases.
14 All 15 studies investigated the effect of surgery, 4 also investigated stereotactic radiotherapy and 1 study
15 identified looked at surgery with or without ablation.

1 Screening Results
2

745

1745 1654

91 74

15
3
4

2 Overall survival
3 The effectiveness of surgery, ablative treatments or stereotactic radiotherapy for people with stage IV melanoma
4 with oligometastatic disease is unclear from the evidence in the 14 included papers.
5 Surgery and/or Stereotactic Radiotherapy

6 Very low quality evidence suggests that patients who receive surgery and/or stereotactic radiotherapy have
7 greater median survival compared to patients who do not receive these treatments (Table 2: grade profiles) but
8 these studies are at high risk of selection bias [Very Low Quality Evidence].
9 Surgery versus No Surgery

10 There were a number of papers comparing survival in patients who received surgery compared to those who did
11 have not surgery for a number of different metastases – brain, lung, adrenal, liver and abdominal. There were
12 also 2 papers that examined this in patient cohorts with a range of different metastases locations. All these
13 papers demonstrated that patients having surgery survived longer than those who did not have surgery [Very
14 Low to Low Quality Evidence].
15 Surgery versus Supportive Care, Chemotherapy, WBRT and chemotherapy and/or WBRT
16 These studies for brain metastases showed that surgery gives better results with regards to overall survival than
17 supportive care, chemotherapy, WBRT and chemotherapy and/or WBRT; STR resulted in longer median overall
18 survival than chemotherapy and WBRT; treatment with STR or surgery resulted in longer median overall survival
19 than WBRT and supportive care. There were 2 studies comparing surgery and STR and they demonstrated little
20 difference in overall survival between these two treatments. One study found that surgery increased survival by
21 0.3 months compared to STR and the other study found that STR increased survival by 1.71 months compared to
22 surgery.
23 Surgery + Ablation versus Ablation alone

24 A single study reported on patients undergoing surgery with ablation or ablation alone and reported a 5 year
25 overall survival rate of 6.6% in the non-surgical group compared with 30% in the surgical group (p<0.001) though
26 outcomes did not differ significantly by type of surgery (resection, ablation, resection with ablation).
27 To what extent the longer median survival associated with surgery and stereotactic radiotherapy is related to the
28 treatment itself or to selection of patients with better performance status is unclear. All 14 studies are
29 retrospective cohort studies and all have a high patient selection bias. Also the studies do not aim to compare
30 treatment modalities but to show that the treatment investigated (usually surgery) in suitable patients can
31 confer a survival advantage - many of the studies compare surgery vs. no surgery, but the no surgery group is
32 made up of patients undergoing a range of different treatments or no treatment at all.
33
34 Adverse Events

1 Two studies provided low quality evidence about adverse events. In Bushbaum et al (2002) radiotherapy for
2 brain metastases (either STR or WBRT) was associated with acute complications (swelling requiring steroid
3 treatment or seizures) in 10/70 patients (14%) but no symptomatic radiation necrosis was reported. Surgery was
4 associated with acute complications requiring hospitalization in 6/25 (24%) patients. These complications
5 included infection, haemorrhage and central nervous system deficits. In Gutman et al (2001) surgery for
6 abdominal metastases was associated with a 14% rate of major complications (sepsis, evisceration or pulmonary
7 embolism) and mortality rate of 3% within 30 days of surgery.
8 Metastases free survival
9 In Bushbaum et al (2002) brain metastases recurred locally in 2/10 patients (20%) treated with local therapy only
10 (surgery or STR) and 4/24 patients (17%) treated with WBRT alone.
11 HRQOL
12 Health related quality of life was not reported although there was low quality evidence from one study (Gutman
13 et al, 2001) that surgery provides better symptom relief in patients with abdominal metastases. 23% of patients
14 treated using surgery were symptom free for at least 1 year compared with a typical symptom free period of 1
15 month in those treated without surgery.
16 Melanoma specific survival
17 No comparative evidence was identified relating to this outcome.
18 Tumour necrosis
19 No comparative evidence was identified relating to this outcome.

GRADE table 6.1: Should surgery vs. no surgery be used for stage IV melanoma with oligometastatic disease?
No of Design Limitations Inconsistency Indirectness Imprecision Other surgery no Relative Absolute

studies considerations surgery (95%
CI)
Overall survival: brain metastases
2 observational very no serious no serious no serious none 163 292 - Overall median survival was 5.4 - 7.7 months longer in patients
studies1 serious2 inconsistency indirectness imprecision that underwent surgery compared to those who did not have VERY
surgery. LOW
Serious adverse events: brain metastases
1 observational very no serious no serious serious none 6/25 10/70 - 90 fewer adverse events per 1000 treated in the non surgery
study1 serious2 inconsistency indirectness imprecision3 (24%) (15%) group – but the types of adverse events were different. VERY
LOW
Overall survival: lung metastases
1 observational very no serious no serious serious none 26 96 - Overall median survival was 27 months longer in patients that
studies1 serious2 inconsistency indirectness imprecision3 underwent surgery compared to those who did not have VERY
surgery. LOW
Overall survival: adrenal metastases
1 observational very no serious no serious serious None 16 163 - Overall median survival was 11 months longer in patients that
surgery. LOW
Overall survival: liver metastases
2 very no serious no serious serious none 39 907 - Overall median survival was 17 - 22 months longer in patients
serious2 inconsistency indirectness imprecision3 that underwent surgery compared to those who did not have VERY
observational surgery. LOW
studies

Overall survival: abdominal metastases
1 observational very no serious no serious serious none 96 155 - Overall median survival was 6 months longer in patients that
surgery. LOW
Serious adverse events: abdominal metastases
1 observational very no serious no serious serious none 13/96 - - Cannot calculate because adverse events were not reported for
studies1 serious2 inconsistency indirectness imprecision3 (14%) the non surgical patients. VERY
LOW
Symptom free at 1 year: abdominal metastases
1 observational very no serious no serious serious none 22/96 - - Symptom free rate at 1 year not reported for non-surgical group
studies1 serious2 inconsistency indirectness imprecision3 (23%) – although authors state that such patients were rarely VERY
symptom free for more than a month. LOW
Overall survival: mixed metastases
observational very no serious no serious no serious none 151 318 - Overall median survival was 12.3 - 13 months longer in patients
studies1 serious2 inconsistency indirectness imprecision that underwent surgery compared to those who did not have VERY
surgery. LOW
1
2
High bias due to patient selection for surgery
3
Low number of events or patients
Grade Table 6.2: Should surgery vs. chemotherapy be used for stage IV melanoma with oligometastatic disease?
No of Design Limitations Inconsistency Indirectness Imprecision Other surgery chemotherapy Relativ Absolute
studie considerations e
s (95%
CI)
Overall survival: brain metastases
2 observational very no serious no serious serious none 42 55 - Overall median survival was 4 - 7 months longer in
studies1 serious2 inconsistency indirectness imprecision3 patients treated with surgery compared to those VERY LOW

treated with chemotherapy.
1
2
Serious risk of bias due to patient selection for treatment
3
Grade Table 6.3: Should surgery vs. supportive care be used for stage IV melanoma with oligometastatic disease?
No of Design Limitations Inconsistency Indirectness Imprecision Other surgery supportive Relative Absolute
studies considerations care (95%
CI)
4 observational very no serious no serious no serious none 120 336 - Overall median survival was 4 - 10 months longer in patients
studies1 serious2 inconsistency indirectness imprecision treated with surgery compared to those that had supportive VERY LOW
care only.
1
retrospective cohort studies
2
serious risk of bias due to patient selection for treatment
Grade Table 6.4: Should surgery vs. stereotactic radiotherapy be used for stage IV melanoma with oligometastatic disease?
No of Design Limitations Inconsistency Indirectness Imprecision Other surgery stereotactic Relative Absolute
studies considerations radiotherapy (95% CI)
2 observational very serious2 no serious no serious serious none 73 43 - Overall median survival was -1.71 – 0.3 months
studies1 inconsistency indirectness imprecision3 longer in patients treated with surgery VERY
compared to those treated with stereotactic LOW
radiotherapy.
1
Retrospective cohort study
2
High risk of bias due to patient selection for treatment

3
Grade Table 6.5: Should surgery vs. WBRT be used for stage IV melanoma with oligometastatic disease?
No of Design Limitations Inconsistency Indirectness Imprecision Other surgery WBRT Relative Absolute
studies considerations (95% CI)
4 observational very serious2 no serious no serious serious none 125 418 - Overall median survival was 4.2 - 9 months longer in
studies1 inconsistency indirectness imprecision3 patients treated with surgery compared to those VERY LOW
treated with WBRT.
1
2
Grade Table 6.6: Should surgery vs. chemotherapy and/or WBRT be used for stage IV melanoma with oligometastatic disease?
No of Design Limitations Inconsistency Indirectness Imprecision Other surgery chemotherapy Relative Absolute
studies considerations and/or WBRT (95% CI)
1 observational very serious2 no serious no serious serious none 32 75 - Overall median survival was 2 months longer in
studies1 inconsistency indirectness imprecision3 patients treated with surgery compared to those VERY LOW
treated with chemotherapy and/or WBRT.
1
2
3
Grade Table 6.7: Should STR vs. chemotherapy be used for stage IV melanoma with oligometastatic disease?

No of Design Limitations Inconsistency Indirectness Imprecision Other STR chemotherapy Relative Absolute
1 observational very no serious no serious serious None 17 38 - Overall median survival was 3.7 months longer in
studies1 serious2 inconsistency indirectness imprecision3 patients treated with STR compared to those treated VERY LOW
with chemotherapy.
1
2
3
Grade Table 6.8: Should STR vs. WBRT be used for stage IV melanoma with oligometastatic disease?
No of Design Limitations Inconsistency Indirectness Imprecision Other STR WBRT Relative Absolute
1 observational very serious2 no serious no serious serious none 17 54 - Overall median survival was 4.8 months longer in patients
studies1 inconsistency indirectness imprecision3 treated with STR compared to those treated with WBRT. VERY LOW
1
2
3
Grade Table 6.9: Should STR or surgery vs. supportive care be used for stage IV melanoma with oligometastatic disease?
No of Design Limitations Inconsistency Indirectness Imprecision Other STR or supportive Relative Absolute
studies considerations surgery care (95% CI)
1 observational very no serious no serious serious none 10 3 - Overall median survival was 3.7 months longer in
studies1 serious2 inconsistency indirectness imprecision3 patients treated with STR or surgery compared to VERY LOW

those that had supportive care only.
1
2
3
Grade Table 6.10: Should STR or surgery vs. WBRT be used for stage IV melanoma with oligometastatic disease?
No of Design Limitations Inconsistency Indirectness Imprecision Other STR or WBRT Relative Absolute
studies considerations surgery (95% CI)
1 observational very serious2 no serious no serious serious none 10 25 - Overall median survival was 2.5 months longer in
studies1 inconsistency indirectness imprecision3 patients treated with STR or surgery compared to those VERY LOW
treated with WBRT.
Recurrence of metastasis at local site: brain metastases
1 observational very serious2 no serious no serious serious none 2/10 4/24 - 30 more recurrences per 1000 treated in the non
study1 inconsistency indirectness imprecision3 (20%) (17%) surgery group VERY LOW
1
2
High bias due to patient treatment selection
3
Grade Table 6.11: Should surgery with or without ablation be used to treat oligometastatic disease
No of Design Limitations Inconsistency Indirectness Imprecision Other Surgery±Ablation No Relative Absolute

studies considerations Surgery (95%
CI)
Overall survival: any metastases

1 observational very no serious no serious no serious none Not reported Not Median overall survival was 8 months in the non surgical
studies1 serious2 inconsistency indirectness imprecision reported group compared with 24.8 months in the non-surgical group. VERY
LOW
5 year overall survival was 6.6% in the non-surgical group
compared with 30% in the surgical group (p<0.001)
Outcomes did not differ significantly by type of surgery

(resection, ablation, resection with ablation)
1
Retrospective Cohort Study
2
High risk of bias due to treatment selection

1 References
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20 Raizer, J. J., Hwu, W.-J., Panageas, K. S., Wilton, A., Baldwin, D. E., Bailey, E., Von, A. C., Lamb, L. A., Alvarado, G.,
21 Bilsky, M. H. & Gutin, P. H. (2008) Brain and leptomeningeal metastases from cutaneous melanoma: Survival
22 outcomes based on clinical features. Neuro-Oncology, 10: 199-207.
23 Ricotti, F., Giuliodori, K., Cataldi, I., Campanati, A., Ganzetti, G., Ricotti, G., and Offidani, A. Electrochemotherapy:
24 an effective local treatment of cutaneous and subcutaneous melanoma metastases. Dermatologic Therapy 27[3],
25 148-152. 2014.
26 Stone, A., Cooper, J., Koenig, K. L., Golfinos, J. G. & Oratz, R. (2004) A comparison of survival rates for treatment
27 of melanoma metastatic to the brain. Cancer Investigation, 22: 492-497.
28 Neuman, H. B., Patel, A., Hanlon, C., Wolchok, J. D., Houghton, A. N. & Coit, D. G. (2007) Stage-IV melanoma and
29 pulmonary metastases: factors predictive of survival. Annals of Surgical Oncology, 14: 2847-2853.
30 Collinson, F. J., Lam, T. K., Bruijn, W. M. J., De Wilt, J. H. W., Lamont, M., Thompson, J. F. & Kefford, R. F. (2008)
31 Long-term survival and occasional regression of distant melanoma metastases after adrenal metastasectomy.
32 Annals of Surgical Oncology, 15: 1741-1749.
33 Rose DM, Essner R, Hughes MD, Tang PC, Bilchik A, Wanek LA et al. (2001) Surgical resection for metastatic
34 melanoma to the liver. Arch Surg 136: 950–955.
35 Chua T, Saxena A, Morris DL. (2010) Surgical metastasectomy in AJCC stage IV M1c melanoma with
36 gastrointestinal and liver metastases. Ann Acad Med Singapore 39: 634–639.
37 Gutman, H., Hess, K. R., Kokotsakis, J. A., Ross, M. I., Guinee, V. F. & Balch, C. M. (2001) Surgery for abdominal
38 metastases of cutaneous melanoma. World Journal of Surgery, 25: 750-758.
39 Meyer, T., Merkel, S., Goehl, J. & Hohenberger, W. (2000) Surgical therapy for distant metastases of malignant
40 melanoma. Cancer, 89: 1983-1991.
41 Ollila, D. W., Hsueh, E. C., Stern, S. L. & Morton, D. L. (1999) Metastasectomy for recurrent stage IV melanoma.
42 Journal of Surgical Oncology, 71: 209-213.
1 Excluded Studies
2 Abuodeh, Y., Tsai, Y., Chinnaiyan, P., Sarangkasiri, S., Jain, S. & Yu, H. M. (2012) Review of patients with brain
3 metastasis treated with fractionated stereotactic radiation therapy to surgical resection cavity. International
4 Journal of Radiation Oncology Biology Physics, 84: S287-S288.
5 Reason: Conference abstract., Mixed population of different cancers including 12 melanomas.
6 Adam, R. & Chiche, L. (2013) Liver metastases from melanoma. Digestive and Liver Disease, 45: S240-S241.
8 Agrawal, S., Yao, T. J. & Coit, D. G. (1999) Surgery for melanoma metastatic to the gastrointestinal tract. Annals of
9 Surgical Oncology, 6: 336-344.
10 Reason: Retrospective study that only looks at 68 of the 7965 patients with melanoma
11 Ahmad, Z. K., Hussain, S., Orusz, S. & Corrie, P. (2010) Single centre retrospective review of melanoma patients
12 receiving whole brain radiotherapy (WBRT) for metastatic disease. Radiotherapy and Oncology, 96: S362-S363.
13 Reason: Conference abstract - poster
14 Ammirati, M., Cobbs, C. S., Linskey, M. E., Paleologos, N. A., Ryken, T. C., Burri, S. H., Asher, A. L., Loeffler, J. S.,
15 Robinson, P. D., Andrews, D. W., Gaspar, L. E., Kondziolka, D., McDermott, M., Mehta, M. P., Mikkelsen, T., Olson,
16 J. J., Patchell, R. A. & Kalkanis, S. N. (2010) The role of retreatment in the management of recurrent/progressive
17 brain metastases: a systematic review and evidence-based clinical practice guideline. Journal of Neuro-Oncology,
18 96: 85-96.
19 Reason: Not specific to melanoma.
20 Aoyama, T., Mastrangelo, M. J., Berd, D., Nathan, F. E., Shields, C. L., Shields, J. A., Rosato, E. L., Rosato, F. E. &
21 Sato, T. (2000) Protracted survival after resection of metastatic uveal melanoma. Cancer, 89: 1561-1568.
22 Reason: Primary uveal melanoma – not to be covered (according to scope).
23 Aubin, J.-M., Rekman, J., Fairfull-Smith, R., Mimeault, R., Balaa, F. & Martel, G. (2012) Hepatic resection for
24 metastatic malignant melanoma: A systematic review. HPB, 14: 411.
26 Aubin, J. M., Rekman, J., Vandenbroucke-Menu, F., Lapointe, R., Fairfull-Smith, R. J., Mimeault, R., Balaa, F. K. &
27 Martel, G. (2013) Systematic review and meta-analysis of liver resection for metastatic melanoma. [Review].
28 British Journal of Surgery, 100: 1138-1147.
30 Ballo, M. T., Bonnen, M. D., Garden, A. S., Myers, J. N., Gershenwald, J. E., Zagars, G. K., Schechter, N. R.,
31 Morrison, W. H., Ross, M. I. & Kian, A. K. (2003) Adjuvant irradiation for cervical lymph node metastases from
32 melanoma. Cancer, 97: 1789-1796.
33 Reason: Not stage IV with oligometastatic disease
34 Ballo, M. T., Garden, A. S., Myers, J. N., Lee, J. E., Diaz, E. M., Jr., Sturgis, E. M., Morrison, W. H., Gershenwald, J.
35 E., Ross, M. I., Weber, R. S. & Ang, K. K. (2005) Melanoma metastatic to cervical lymph nodes: Can radiotherapy
36 replace formal dissection after local excision of nodal disease? Head & Neck, 27: 718-721.
37 Reason: Not stage IV with oligometastatic disease.
38 Banfill, K. E., Bownes, P. J., St Clair, S. E., Loughrey, C. & Hatfield, P. (2012) Stereotactic radiosurgery for the
39 treatment of brain metastases: Impact of cerebral disease burden on survival. British Journal of Neurosurgery, 26:
40 674-678.

1 Reason: Not specific to melanoma
2 Barney, B. M., Olivier, K. R., Wilson, Z. C., Miller, R. C., Macdonald, O. K., Brown, P. D., Foote, R. L. & Markovic, S.
3 N. (2011) Clinical outcomes and toxicity using Stereotactic Body Radiotherapy (SBRT) for stage IV melanoma.
4 International Journal of Radiation Oncology Biology Physics, 81: S687.
6 Bashir, A., Hodge, C. J., Jr., Dababneh, H., Hussain, M., Hahn, S., and Canute, G. W. Impact of the number of
7 metastatic brain lesions on survival after Gamma Knife radiosurgery. Journal of Clinical Neuroscience . 15-7-2014.
9 Beadle, B. M., Guadagnolo, B. A., Ballo, M. T., Lee, J. E., Gershenwald, J. E., Cormier, J. N., Mansfield, P. F., Ross,
10 M. I. & Zagars, G. K. (2009) Radiation Therapy Field Extent for Adjuvant Treatment of Axillary Metastases From
11 Malignant Melanoma. International Journal of Radiation Oncology Biology Physics, 73: 1376-1382.
12 Reason: Not stage IV with oligometastatic disease.
13 Boasberg, P. D., O'Day, S. J., Kristedja, T. S., Martin, M., Wang, H., Deck, R., Shinn, K., Ames, P., Tamar, B. &
14 Petrovich, Z. (2003) Biochemotherapy for metastatic melanoma with limited central nervous system
15 involvement. Oncology, 64: 328-335.
16 Reason: Study looking at effect of biochemotherapy.
17 Brown, R. E., Bower, M. R., Metzger, T. L., Scoggins, C. R., McMasters, K. M., Hahl, M. J., Tatum, C. & Martin, R. C.
18 G. (2011) Hepatectomy after hepatic arterial therapy with either yttrium-90 or drug-eluting bead chemotherapy:
19 Is it safe? HPB, 13: 91-95.
20 Reason: Mixed population of different cancers.
21 Caraco, C., Mozzillo, N., Marone, U., Simeone, E., Benedetto, L., Di, Monta G., Di Cecilia, M. L., Botti, G., Ascierto,
22 P. A., Caraco, Corrado, Mozzillo, Nicola, Marone, Ugo, Simeone, Ester, Benedetto, Lucia, Di Monta, Gianluca, Di
23 Cecilia, Maria Luisa, Botti, Gerardo, and Ascierto, Paolo Antonio. Long-lasting response to electrochemotherapy
24 in melanoma patients with cutaneous metastasis. BMC Cancer 13, 564. 2013.
26 Cashin, R. P., Lui, P., Machado, M., Hemels, M. E., Corey-Lisle, P. K. & Einarson, T. R. (2008) Advanced cutaneous
27 malignant melanoma: a systematic review of economic and quality-of-life studies (DARE structured abstract).
28 Value in Health, 11: 259-271.
29 Reason: Economic and quality of life studies.
30 Chua, T. C., Scolyer, R. A., Kennedy, C. W., Yan, T. D., McCaughan, B. C. & Thompson, J. F. (2012) Surgical
31 management of melanoma lung metastasis: an analysis of survival outcomes in 292 consecutive patients. Annals
32 of Surgical Oncology, 19: 1774-1781.
33 Reason: Not study looking at effectiveness of the treatment.
34 Clarke, J. W., Register, S., McGregor, J. M., Grecula, J. C., Mayr, N. A., Wang, J. Z., Li, K., Gupta, N., Kendra, K. L.,
35 Olencki, T. E., Cavaliere, R., Sarkar, A. & Lo, S. S. (2010) Stereotactic radiosurgery with or without whole brain
36 radiotherapy for patients with a single radioresistant brain metastasis. American Journal of Clinical Oncology, 33:
37 70-74.
38 Reason: Mixed population:
39
40 Connolly, E. P. M. Involved field radiation therapy after surgical resection of solitary brain metastases - Mature
41 results. Neuro-Oncology 15[5], 589-594. 2013.

2 Concalves, M., Passos, A., Moreira, A. & Oliveira, J. (2009) Malignant melanoma brain metastases - A single
3 institution experience. European Journal of Cancer, Supplement, 7: 502.
4 Reason: Conference abstract - poster
5 Conill, C., Valduvieco, I., Domingo-Domenech, J., Arguis, P., Vidal-Sicart, S. & Vilalta, A. (2009) Loco-regional
6 control after postoperative radiotherapy for patients with regional nodal metastases from melanoma. Clinical &
7 translational oncology, 11: 688-693.
8 Reason: Not stage IV with oligometastatic disease
9 Dalrymple-Hay, M. J., Rome, P. D., Kennedy, C., Fulham, M. & McCaughan, B. C. (2002) Pulmonary metastatic
10 melanoma -- the survival benefit associated with positron emission tomography scanning. European Journal of
11 Cardio-Thoracic Surgery, 21: 611-614.
13 Dyer, M. A., Arvold, N. D., Chen, Y. H., Pinnell, N. E., Mitin, T., Lee, E. Q., Hodi, F. S., Ibrahim, N., Weiss, S. E., Kelly,
14 P. J., Floyd, S. R., Mahadevan, A., and Alexander, B. M. The role of whole brain radiation therapy in the
15 management of melanoma brain metastases. Radiation Oncology 9. 2014.
17 Fogarty, G., Morton, R. L., Vardy, J., Nowak, A. K., Mandel, C., Forder, P. M., Hong, A., Hruby, G., Burmeister, B.,
18 Shivalingam, B., Dhillon, H. & Thompson, J. F. (2011) Whole brain radiotherapy after local treatment of brain
19 metastases in melanoma patients--a randomised phase III trial. BMC Cancer, 11: 142.
20 Reason: No results reported
21 Fogarty, G., Vardy, J. & Nowak, A. (2011) Whole brain radiotherapy following local treatment of 1-3 intracranial
22 metastases of melanoma - A phase III trial (Anzmtg 01/07; TROG 08/05). Asia-Pacific Journal of Clinical Oncology,
23 7: 44.
25 Gonzalez-Martinez, J., Hernandez, L., Zamorano, L., Sloan, A., Levin, K., Lo, S., Li, Q. & Diaz, F. (2002) Gamma knife
26 radiosurgery for intracranial metastatic melanoma: a 6-year experience. Journal of Neurosurgery, 97: Suppl-8.
27 Reason: Brief report
28 Hasegawa, T., Kondziolka, D., Flickinger, J. C., Germanwala, A. & Lunsford, L. D. (1026) Brain metastases treated
29 with radiosurgery alone: an alternative to whole brain radiotherapy? Neurosurgery, 52: 1318-1326.
31 Herfarth, K. K., Izwekowa, O., Thilmann, C., et al.. (2003) Linac-based radiosurgery of cerebral melanoma
32 metastases. Analysis of 122 metastases treated in 64 patients. Strahlentherapie und Onkologie, 179: 366-371.
33 Reason: No comparisons
34 Ivanova, D. Single brain metastases: Radiotherapy alone or combined with neurosurgery? Supportive Care in
35 Cancer Conference[var.pagings], June. 2013.
36 Reason: Abstract
37 Jung, E. W., Delly, F., Rakowski, J., Mittal, S., Tang, K., Kim, H. & Jagannathan, J. (2012) Repeated stereotactic
38 radiosurgery for progressive brain metastases from melanoma after initial treatment. International Journal of
39 Radiation Oncology Biology Physics, 84: S629.

1 Kalkanis, S. N., Kondziolka, D., Gaspar, L. E., Burri, S. H., Asher, A. L., Cobbs, C. S., Ammirati, M., Robinson, P. D.,
2 Andrews, D. W., Loeffler, J. S., McDermott, M., Mehta, M. P., Mikkelsen, T., Olson, J. J., Paleologos, N. A.,
3 Patchell, R. A., Ryken, T. C. & Linskey, M. E. (2010) The role of surgical resection in the management of newly
4 diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline. Journal of Neuro-
5 Oncology, 96: 33-43.
7 Kim, J. M., Losina, E., Bono, C. M., Schoenfeld, A. J., Collins, J. E., Katz, J. N. & Harris, M. B. (2012) Clinical outcome
8 of metastatic spinal cord compression treated with surgical excision +/- radiation versus radiation therapy alone:
9 A systematic review of literature. Spine, 37: 78-84.
11 Kim, H., Jung, T. Y., Kim, I. Y., Jung, S., Moon, K. S., Park, S. J., Kim, Hyool, Jung, Tae Young, Kim, In Young, Jung,
12 Shin, Moon, Kyung Sub, and Park, Seung Jin. The usefulness of stereotactic radiosurgery for radioresistant brain
13 metastases. Journal of Korean Neurosurgical Society 54[2], 107-111. 2013.
15 Kis, E., Olah, J., Ocsai, H., Baltas, E., Gyulai, R., Kemeny, L. & Horvath, A. R. (2011) Electrochemotherapy of
16 Cutaneous Metastases of Melanoma-A Case Series Study and Systematic Review of the Evidence. Dermatologic
17 Surgery, 37: 816-824.
18 Reason: Electrochemotherapy not in PICO
19 Koay, E. J., Bucheit, A. D., Jakob, J. A., Hyun, E. D., Settle, S. H., Brown, P. D., Davies, M. A. & Sulman, E. P. (2012)
20 Correlation of BRAF and NRAS mutation status with tumor characteristics and treatment outcomes in melanoma
21 patients with brain metastasis. Journal of Clinical Oncology, 30.
23 Kocher, M., Maarouf, M., Bendel, M., Voges, J., Muller, R. P. & Strum, V. (2004) Linac radiosurgery versus whole
24 brain radiotherapy for brain metastes - A survival comparison based on the RTOG recursive partitioning analysis.
25 Strahlentherapie und Onkologie, 180: 263-267.
27 Lee, D. S., White, D. E., Hurst, R., Rosenberg, S. A. & Yang, J. C. (1998) Patterns of relapse and response to
28 retreatment in patients with metastatic melanoma or renal cell carcinoma who responded to interleukin-2-based
29 immunotherapy. The cancer journal from Scientific American, 4: 86-93.
30 Reason: Mixed population
31 Lee, M. K. J. Is stereotactic radiosurgery under-utilised in the treatment of surgically excisable cerebral

32 metastases? British Journal of Neurosurgery 27[5], 658-661. 2013.
34 Lo, S. S., Clarke, J. W., Grecula, J. C., McGregor, J. M., Mayr, N. A., Cavaliere, R., Kendra, K. L., Gupta, N., Wang, J.
35 Z., Sarkar, A. & Olencki, T. E. (2011) Stereotactic radiosurgery alone for patients with 1-4 radioresistant brain
36 metastases. Medical Oncology, 28: Suppl-44.
38 Lopez, E. Frameless stereotactic radiosurgery for brain metastases using image guided radiotherapy (IGRT).
39 European Journal of Cancer Conference[var.pagings], September. 2013
41 Mali, B., Jarm, T., Snoj, M., Sersa, G., and Miklavcic, D. Antitumor effectiveness of electrochemotherapy: A
42 systematic review and meta-analysis. Ejso 39[1], 4-16. 2013

2 Memon, K., Kuzel, T. M., Vouche, M., Atassi, R., Lewandowski, R. J., and Salem, R. Hepatic yttrium-90
3 radioembolization for metastatic melanoma: a single-center experience. Melanoma Research 24[3], 244-251.
4 2014.
6 Miller, D., Zappala, V., El, H. N., Livingstone, E., Schadendorf, D., Sure, U. & Sandalcioglu, I. E. (2013) Intracerebral
7 metastases of malignant melanoma and their recurrences--a clinical analysis. Clinical Neurology & Neurosurgery,
8 115: 1721-1728.
10 Minniti, G., D'Angelillo, R. M., Scaringi, C., Trodella, L. E., Clarke, E., Matteucci, P., Osti, M. F., Ramella, S., Enrici, R.
11 M., and Trodella, L. Fractionated stereotactic radiosurgery for patients with brain metastases. Journal of Neuro-
12 Oncology 117[2], 295-301. 2014.
14 Morton, D. L., Stern, S. & Elashoff, R. (2011) Surgical resection for melanoma metastatic to distant sites. Annals of
15 Surgical Oncology, 18: S21.
17 Narayana, A., Mathew, M., Tam, M., Kannan, R., Madden, K. M., Golfinos, J. G., Parker, E. C., Ott, P. A. & Pavlick,
18 A. C. (2013) Vemurafenib and radiation therapy in melanoma brain metastases. Journal of Neuro-Oncology, 113:
19 411-416.
20 Reason: Study not relevant to PICO.
21 Nieweg, O. Combination treatment for irresectable melanoma masses. European Journal of Cancer
22 Conference[var.pagings], September. 2013.
23 Reason: Abstract
24 Olson, J. J., Paleologos, N. A., Gaspar, L. E., Robinson, P. D., Morris, R. E., Ammirati, M., Andrews, D. W., Asher, A.
25 L., Burri, S. H., Cobbs, C. S., Kondziolka, D., Linskey, M. E., Loeffler, J. S., McDermott, M., Mehta, M. P., Mikkelsen,
26 T., Patchell, R. A., Ryken, T. C. & Kalkanis, S. N. (2010) The role of emerging and investigational therapies for
27 metastatic brain tumors: a systematic review and evidence-based clinical practice guideline of selected topics
28 (DARE structured abstract). Journal of Neuro-Oncology, 96: 115-142.
29 Reason: No discussion of local treatments.
30 Pennacchioli, E., Gandini, S., Verrecchia, F., Tosti, G., Spadola, G., Baldini, F., Mosconi, M., Ferrucci, P. & Testori,
31 A. (2011) Surgery in stage IV melanoma patients: Results from a single institution. Pigment Cell and Melanoma
32 Research, 24: 1066-1067.
34 Peterson, H. E., Larson, E. W., Fairbanks, R. K., Mackay, A. R., Lamoreaux, W. T., Call, J. A., Carlson, J. D., Ling, B.
35 C., Demakas, J. J., Cooke, B. S., Peressini, B., and Lee, C. M. Gamma knife treatment of brainstem metastases.
36 International Journal of Molecular Science 15[6], 9748-9761. 2014.
38 Pflugfelder, A., Kochs, C., Blum, A., et al. (2001) Malignant melanoma S3-guideline "diagnosis, therapy and follow-
39 up of melanoma". Journal der Deutschen Dermatologischen Gesellschaft, 11: Suppl-116.
40 Reason: Guidelines

1 Plana, M., Pons, V. F., Caminal, J. M., Pera, J., Fernandes, I. C., Perez, F. J., Garcia, D. M., X, Gutierrez, C., Jimenez,
2 L. & Piulats, J. M. (2010) Metastatic uveal melanoma: Is there a role for conventional chemotherapy? A single
3 experience based on 58 patients. Journal of Clinical Oncology, 28.
5 Pollock, B. E., Brown, P. D., Foote, R. L., Stafford, S. L. & Schomberg, P. J. (2003) Properly selected patients with
6 multiple brain metastases may benefit from aggressive treatment of their intracranial disease. [Review] [32 refs].
7 Journal of Neuro-Oncology, 61: 73-80.
9 Pons, F., Plana, M., Caminal, J. M., Pera, J., Fernandes, I., Perez, J., Garcia-Del-Muro, X., Marcoval, J., Penin, R.,
10 Fabra, A. & Piulats, J. M. (2011) Metastatic uveal melanoma: is there a role for conventional chemotherapy? - A
11 single center study based on 58 patients. [Review]. Melanoma Research, 21: 217-222.
12 Reason: Primary uveal melanoma – not to be covered (according to scope)
13 Rades, D., Hornung, D., Blanck, O., Martens, K., Khoa, M. T., Trang, N. T., Huppe, M., Terheyden, P., Gliemroth, J.,
14 and Schild, S. E. Stereotactic radiosurgery for newly diagnosed brain metastases. Strahlentherapie und Onkologie
15 190[9], 786-791. 2014.
17 Rades, D., Sehmisch, L., Huttenlocher, S., Blank, O., Hornung, D., Terheyden, P., Gliemroth, J., and Schild, S. E.
18 Radiosurgery Alone for 1-3 Newly-diagnosed Brain Metastases from Melanoma: Impact of Dose on Treatment
19 Outcomes. Anticancer Research 34[9], 5079-5082. 2014.
21 Rades, D., Hornung, D., Blanck, O., Martens, K., Khoa, M. T., Trang, N. T., Huppe, M., Terheyden, P., Gliemroth, J.,
22 and Schild, S. E. Stereotactic radiosurgery for newly diagnosed brain metastases: comparison of three dose levels.
23 Strahlentherapie und Onkologie 190[9], 786-791. 2014.
25 Rezvi, U. Judicious use of radiosurgery (SRS) may change the ultimate patterns of failure in patients with brain
26 metastasis from melanoma. Neuro-Oncology Conference[var.pagings], November. 2013
27 Reason: Abstract
28 Ricotti, F., Giuliodori, K., Cataldi, I., Campanati, A., Ganzetti, G., Ricotti, G., and Offidani, A. Electrochemotherapy:
29 an effective local treatment of cutaneous and subcutaneous melanoma metastases. Dermatologic Therapy 27[3],
30 148-152. 2014.
32 Richtig, E., Ludwig, R., Kerl, H. & Smolle, J. (2005) Organ- and treatment-specific local response rates to systemic
33 and local treatment modalities in stage IV melanoma. British Journal of Dermatology, 153: 925-931.
34 Reason: Not oligometastatic disease.
35 Rivoire, M., De, C. F., Meeus, P., Gignoux, B., Frering, B. & Kaemmerlen, P. (2000) Cryosurgery as a means to
36 improve surgical treatment of patients with multiple unresectable liver metastases. Anticancer Research, 20:
37 3785-3790.
39 Rutter, C. E., Giesen, E., Yu, J. B., Bindra, R. S., Kluger, H. M. & Chiang, V. L. (2013) Influence of braf and nras
40 mutations on distant intracranial recurrence and survival in metastatic melanoma following radiosurgery.
41 International Journal of Radiation Oncology Biology Physics, 87: S275.

1 Sanki, A., Scolyer, R. A. & Thompson, J. F. (2009) Surgery for melanoma metastases of the gastrointestinal tract:
2 Indications and results. European Journal of Surgical Oncology, 35: 313-319.
3 Reason: NO relevant Comparisons
4 Sasse, A. D., Sasse, E. C., Clark-Luciana, G. O., Ulloa, L. & Clark-Otavio, A. C. (2007) Chemoimmunotherapy versus
5 chemotherapy for metastatic malignant melanoma. Cochrane.Database.of Systematic.Reviews.
6 Reason: No discussion of local treatment.
7 Schneebaum, S. (2011) For patients with distant metastases - Surgery is first choice of treatment. European
8 Journal of Cancer, 47: S14.
10 Sia, J., Paul, E., Dally, M., and Ruben, J. Stereotactic radiosurgery for 318 brain metastases in a single Australian
11 centre: The impact of histology and other factors. Journal of Clinical Neuroscience . 7-10-2014.
13 Solari, N., Spagnolo, F., Ponte, E., Quaglia, A., Lillini, R., Battista, M., Queirolo, P., and Cafiero, F.
14 Electrochemotherapy for the Management of Cutaneous and Subcutaneous Metastasis: A Series of 39 Patients
15 Treated With Palliative Intent. Journal of Surgical Oncology 109[3], 270-274. 2014.
17 Soon, Yu Yang, Tham-Ivan, Weng Keong, Lim, Keith H., Koh, Wee Yao, and Lu, Jiade J. Surgery or radiosurgery plus
18 whole brain radiotherapy versus surgery or radiosurgery alone for brain metastases. Cochrane Database of
19 Systematic Reviews . 2014.
21 Strojan, P., Jancar, B., Cemazar, M., Perme, M. P. & Hocevar, M. (2010) Melanoma Metastases to the Neck
22 Nodes: Role of Adjuvant Irradiation. International Journal of Radiation Oncology Biology Physics, 77: 1039-1045.
24 Tait, I. S., Yong, S. M. & Cuschieri, S. A. (2002) Laparoscopic in situ ablation of liver cancer with cryotherapy and
25 radiofrequency ablation. British Journal of Surgery, 89: 1613-1619.
27 Tauceri, F., Mura, G., Roseano, M., Framarini, M., Ridolfi, L. & Verdecchia, G. M. (2009) Surgery and adjuvant
28 therapies in the treatment of stage IV melanoma: our experience in 84 patients. Langenbecks Archives of Surgery,
29 394: 1079-1084.
30 Reason: No relevant comparison
31 Vecchio, S., Spagnolo, F., Merlo, D. F., Signori, A., Acquati, M., Pronzato, P., and Queirolo, P. The treatment of
32 melanoma brain metastases before the advent of targeted therapies: associations between therapeutic choice,
33 clinical symptoms and outcome with survival. Melanoma Research 24[1], 61-67. 2014.
35 Wang, S., Zhao, Z., Barber, B. & Wagner, V. (2012) Surgery, radiation, and systemic therapies in patients with
36 metastatic melanoma. Value in Health, 15: A232-A233.
38 Wiggenraad, R., Verbeek-de, K. A., Mast, M., Molenaar, R., Kal, H. B., Nijeholt, G., Vecht, C. & Struikmans, H.
39 (2012) Local progression and pseudo progression after single fraction or fractionated stereotactic radiotherapy
40 for large brain metastases. A single centre study. Strahlentherapie und Onkologie, 188: 696-701.
41 Reason: Mixed Population

1 Xing, M., Prajapati, H. J., Dhanasekaran, R., Lawson, D. H., Kokabi, N., Eaton, B. R., and Kim, H. S. Selective
2 Internal Yttrium-90 Radioembolization Therapy (90Y-SIRT) Versus Best Supportive Care in Patients With
3 Unresectable Metastatic Melanoma to the Liver Refractory to Systemic Therapy: Safety and Efficacy Cohort
4 Study. American Journal of Clinical Oncology . 7-8-2014.

Evidence tables
Study Quality
method of Attempts Comparable The Participants Treatment Equal Appropriate Precise Valid method Investigators blind Investigators
allocation to were made at baseline comparison blind to administrators follow up length of definition of of measuring to participants blind to
treatment within the groups treatment blind to follow-up an outcome outcomes exposure to potential
design or allocation treatment intervention? confounders
groups was received the
analysis to allocation and
unrelated to balance the same care
prognostic
potential comparison apart from the factors?
confounding groups for intervention(s)
factors potential studied
confounders
Buchsbaum et No No No No No No No Yes Yes Yes No No
al 2002
Chua et al No No No No No No No Yes Yes Yes No No

2010
Collinson et al No No No No No No No Yes Yes Yes No No
2008
Fife et al 2004 No No No No No No No Yes Yes Yes No No
Gutman et al No No No No No No No Yes Yes Yes No No
2001
Konstadoulakis No No No No No No No Yes Yes Yes No No
et al 2000
Meier et al No No No No No No No Yes Yes Yes No No
2004
Meyer et al., No No No No No No No Yes Yes Yes No No
2000
Neuman et al No No No No No No Yes Yes Yes Yes No No
2007
Ollila et al., No No No No No No Yes Yes Yes Yes No No
1999
Panagiotou et No No No No No No Yes Yes Yes Yes No No
al 2005
Raizer et al No No No No No No Yes Yes Yes Yes No No
2008
Rose et al 2001 No No No No No No Yes Yes Yes Yes No No
Stone et al No No No No No No Yes Yes Yes Yes No No
2004


BRAIN METASTASES
PAPER TYPE OF No. PATIENTS TREATMENT COMPARISONS NOTES

STUDY
Buchsbaum, J. C., Suh, J. H., Lee, S. Retrospectiv 74 Treatment No. median No. Risk of Bias – HIGH.
Y., Chidel, M. A., Greskovich, J. F. e patients survival patients
& Barnett, G. H. (2002) Survival by Patient selection bias.
(months with brain
radiation therapy oncology group ) metastases
recursive partitioning analysis recurrence
class and treatment modality in Survival benefit of
patients with brain metastases Combined 36 8.8 18 combination therapy
from malignant melanoma: a therapy (local + likely due to selection
retrospective study. Cancer, 94: WBRT) bias – clinicians had
2265-2272. selected patients for
Local therapy 10 4.8 2
treatment in a fashion
alone
that correlated with the
(surgery or SRS) RTOG RPA schema.
WBRT alone 25 2.3 4
No treatment 3 1.1 -
Combined vs. other p<0.0001
Treatment HR CI p
No treatment v 7.92 1.680-37.409 0.0089

Combined therapy 8
(local + WBRT)


STUDY
WBRT alone v 2.39 1.161-4.929 0.0180

Combined therapy 2
(local + WBRT)
Local therapy alone 1.44 0.648-3.197 0.3703

0
(surgery or SRS) v
Combined therapy
(local + WBRT)
Acute complications
Complications No.
patients
Surgery (alone 6 (24%) 25

or with WBRT)
WBRT or STR 10 (14%) 70
Radiation: 0 patients symptomatic radiation necrosis
Surgery (alone or with WBRT) – acute complications: 1

infection, 2 haemorrhages, 3 central nervous system
deficits. No long term complications.

STUDY
Fife, K. M., Colman, M. H., Retrospectiv 686 patients, Treatment No. median Risk of Bias – HIGH.
Stevens, G. N., Firth, I. C., Moon, e patients survival
D., Shannon, K. F., Harman, R., As of june Patient selection bias.
(months)
Petersen-Schaefer, K., Zacest, A. 2003 646 had
C., Besser, M., Milton, G. W., died as a surgery and 158 8.9
McCarthy, W. H. & Thompson, J. result of postoperative Median survival was
F. (2004) Determinants of melanoma. radiotherapy dependent on treatment,
outcome in melanoma patients which in turn was
surgery alone 47 8.7
with cerebral metastases. Journal dependent on patient
of Clinical Oncology, 22: 1293- radiotherapy alone 236 3.4 selection.
1300.
supportive care alone 210 2.1 Patients were selected
for active treatment on
the basis of having a
single cerebral
metastasis, cerebral
Treatment HR CI p metastases with no
evidence of metastatic
Surgery v supportive 0.43 0.308- <0.001 disease elsewhere, or a
care 6 0.619 younger age.
Radiotherapy v 0.85 0.698- 0.111

supportive care 1 1.038


STUDY
Surgery and 0.34 0.273- <0.001
radiotherapy v 6 0.439
supportive care
Retrospectiv 136 Treatment No. median 1 year

Konstadoulakis, M. M., Messaris, e patients survival survival Risk of Bias – HIGH.
E., Zografos, G., Androulakis, G. & (months
Karakousis, C. (2000) Prognostic Patient selection bias.
)
factors in malignant melanoma
patients with solitary or multiple surgery 32 5 28.13%
brain metastases. Is there a role Survival was dependent
radiotherapy 75 3 6.67% on treatment, which in
for surgery? Journal of
and/or turn was dependent on
Neurosurgical Sciences, 44: 211-
chemotherapy patient selection.
218.
No treatment 29 1 3.45%
One year survival of patients treated surgically was

significantly better than patients who received
radiotherapy and/or chemotherapy or who had no
treatment. p=0.006.
Meier, S., Baumert, B. G., Maier, Retrospectiv 100 patients Treatment No. median 1 year Risk of Bias – HIGH.
T., Wellis, G., Burg, G., Seifert, B. survival
Patient selection bias.

STUDY
& Dummer, R. (2004) Survival and e patients (months) survival
prognostic factors in patients with
brain metastases from malignant Surgery 37 10.6 31% Survival was dependent
melanoma. Onkologie, 27: 145- on treatment, which in
No surgery 63 2.9 3% turn was dependent on
149.
patient selection.
p<0.0001
Treatment No. median 1 year

patients survival survival
(months)
Radiosurgery 17 10.3 35%
No 83 3.9 9%
radiosurgery
p=0.002

(months)
WBRT/PBRT 54 5.5 19%
No 46 2.6 7%
WBRT/PBRT
p=0.009


STUDY
Treatment HR CI p
WBRT/PBRT 0.45 0.29-0.70 0.0004
surgery 0.30 0.19-0.49 <0.0001
radiosurgery 0.31 0.17-0.55 <0.0001
chemotherapy 0.43 0.27-0.70 0.0006
Panagiotou, I. E., Brountzos, E. N., Retrospectiv 64 Treatment No. median Risk of Bias – HIGH.
Kelekis, D. A., Papathanasiou, M. e patients survival
A. & Bafaloukos, D. I. (2005) Patient selection bias.
(months)
Cerebral metastases of malignant
melanoma: contemporary Surgery followed by 5 12
treatment modalities and survival radiotherapy Survival was dependent
outcome. Neoplasma, 52: 150- on treatment.
158. Temozolomide as first line 17 5
Patient characteristics
treatment and radiotherapy

STUDY
after cerebral disease influenced selection of
progression treatment modality.
radiotherapy alone 28 3
supportive care only 14 2
Surgery vs non surgery groups: p=0.0011
Treatment HR SE p
supportive care only
Surgery/radiotherapy 9.6831 7.0301 0.0053
whole brain irradiation 0.4099 1.1010 0.7097
Temozolomide/ 4.1874 2.2236 0.5497
radiotherapy


STUDY
Retrospectiv Brain
e metastases
Raizer, J. J., Hwu, W.-J., Panageas, from 355 Treatment No. median Risk of Bias – HIGH.
K. S., Wilton, A., Baldwin, D. E., melanoma patients survival
Bailey, E., Von, A. C., Lamb, L. A., Patient selection bias.
patients. (months)
Alvarado, G., Bilsky, M. H. &
Gutin, P. H. (2008) Brain and None 83 2.04
leptomeningeal metastases from Patients treated with
cutaneous melanoma: Survival surgery and RS had the
outcomes based on clinical WBRT alone 100 3.98 longest survival. However
features. Neuro-Oncology, 10: a selection bias most
199-207. certainly contributed to
this result in that patients
RS alone 26 9.87
treated with surgery
Surgery alone 36 8.16 and/or RS likely had a
lower intracranial tumour
WBRT + RS 20 9.44 burden and controlled or
absent extracranal
Surgery + WBRT 58 8.81
disease and were likely
Surgery + RS 20 13.75 healthier overall
compared with patients
Surgery + WBRT + RS 12 10.2 receiving WBRT or
supportive care.
Brain metastasis directed therapies improve survival

compared with supportive care only.
Patients treated with surgery and RS had the longest

survival.


STUDY
Retrospectiv
Stone, A., Cooper, J., Koenig, K. L., e 91 patients Gamma knife stereotactic radiosurgery plus WBRT (n=8) Risk of Bias – HIGH.
Golfinos, J. G. & Oratz, R. (2004) A with brain and patients treated with surgery plus WBRT (n=16)
comparison of survival rates for metastases median survival 10.9 months vs radiation alone (n=59) Patient selection bias.
treatment of melanoma from median survival 3.6 months Patients treated with
metastatic to the brain. Cancer malignant Gamma knife stereotactic
Investigation, 22: 492-497. melanoma radiosurgery or surgery
Treatment No. median plus radiation therapy
patients survival were younger, less likely
(months) to present with
symptoms and presented
Gamma knife stereotactic 8 with fewer metastases to
radiosurgery plus WBRT the brain than patients
10.9
treated with radiation
surgery plus WBRT 16 therapy alone.
WBRT alone 59 3.6

LUNG METASTASES
PAPER TYPE OF No. TREATMENT COMPARISONS NOTES

STUDY PATIENTS
Neuman, H. B., Patel, A., Retrospective 122 Treatment No. patients median 5 year Selection bias.
Hanlon, C., Wolchok, J. D., survival survival Patients undergoing surgery
Houghton, A. N. & Coit, D. (months) were more likely to be
G. (2007) Stage-IV Surgery 26 40 29% younger, have localised
melanoma and pulmonary No surgery 96 13 NR rather than regional disease
metastases: factors (82 systemic prior to presentation with
predictive of survival. therapy; distant metastases and have
Annals of Surgical 14 no treatment) a single metastatic focus.
Oncology, 14: 2847-2853.

ADRENAL METASTASES

STUDY
186 patients
Collinson, F. J., Lam, T. K., Bruijn, Retrospectiv with adrenal Treatment No. median High selection bias.
W. M. J., De Wilt, J. H. W., e gland patients survival
Lamont, M., Thompson, J. F. & metastases Patients were selected
(months)
Kefford, R. F. (2008) Long-term from for surgery on the basis
melanoma. adrenalectomy 23 16 of the extent of the
survival and occasional regression
of distant melanoma metastases disease, the resectability
non surgical 163 5 of any concomitant
after adrenal metastasectomy.
treatment metastases, general
Annals of Surgical Oncology, 15:
fitness and performance
1741-1749. p<0.00001
status.

LIVER METASTASES

STUDY
1750 patients
with hepatic
Rose DM, Essner R, Hughes MD, Retrospectiv metastases, of Treatmen No. median 3 year 5 year High selection bias.
Tang PC, Bilchik A, Wanek LA et al. e whom 34 t patients survival survival survival
(2001) Surgical resection for underwent (months
metastatic melanoma to the liver. exploration )
with intent to Outcomes for all 1750
Arch Surg 136: 950–955. patients with hepatic
resect the Surgical 24 28 41% 29%
metastases metastases not reported.
resection
(24 underwent
hepatic Exploratio 10 4 NR NR
resection (18
n only
complete
resection and
Non- 899 6 NR 4%
6 incomplete)
and 10 operative
underwent treatment
exploration
but not
resection).
23 patients
Chua T, Saxena A, Morris DL. Retrospectiv with Treatment No. median 1 year 3 year High selection bias.
(2010) Surgical metastasectomy in e gastrointestina patients survival survival survival
AJCC stage IV M1c melanoma with l/ liver Patients were deemed
(months
gastrointestinal and liver metastases inappropriate for surgery
)
metastases. Ann Acad Med if their disease was
surgery 15 21 60% 40% considered unresectable,
Singapore 39: 634–639.
or if they had other
No surgery 8 4 NR NR metastatic sites that
(clinical were untreated.
trials/system

ic therapies)

ABDOMINAL METASTASES

STUDY
96 patients underwent 119 laparotomies
Gutman, H., Hess, K. R., Retrospectiv 251 melanoma 51 underwent non-surgical intervention (i.e., endoscopic or Selection bias.
Kokotsakis, J. A., Ross, M. I., e patients who percutaneous procedures)
Guinee, V. F. & Balch, C. M. (2001) developed
Surgery for abdominal metastases intra 116 were treated medically only without any invasive
of cutaneous melanoma. World abdominal procedure.
Journal of Surgery, 25: 750-758. metastases Metastases were from a
wide range of abdomen
Treatment No. median locations e.g., small
patients survival bowel, liver, stomach,
(months) colon, pancreas, etc.
Surgery 96 11
(laparotomy)
non surgical 155 5

treatment
p<0.0001
23% of patients treated with surgery were symptom free

for at least 1 year and 16% remained asymptomatic for
more than 2 years. Patients with non-surgical interventions
only rarely remained asymptomatic for more than 1
month.
Major postoperative complications (septicaemia,

abdominal sepsis, evisceration, pulmonary embolism) in

14% of surgical patients, and 18% had minor complications
(wound infection, deep vein thrombosis, pneumonia). The
mortality rate at 30 days after surgery was 3.2%.

MIXED METASTASES

STUDY
Faries et al (2014) Retrospectiv N=58 patients Surgery + Ablation versus Ablation Only
e considered
candidates for Overall survival and disease free survival were better in the
surgery surgical group compared with the non-surgical group.
(resection with
or without Median OS was 8 months in the non-surgical group
ablation) compared with 24.8 months in the surgical group.
5 year OS rate was 6.6% in the non-surgical group
Represents compared with 30% in the surgical group (p<0.001).
5.4% of total
population of Outcomes did not differ significantly by type of surgery
melanoma (resection, ablation, resection/ablation)
patients with
metastatic Outcomes for patients who underwent concomitant
liver disease resection of extrahepatic metastases were not significantly
worse than those with liver only disease.(p=0.14)
Patients who underwent systemic treatment with disease

stabilisation before surgery had favourable overall and
disease free survival compared with those who did not
(p=0.01).
Overall survival was found to be independently associated

with completeness of surgical treatment [HR=3.4, 95% CI
1.4-8.1, p=0.007) and to stabilisation of disease on
previous systemic therapy [HR=0.38, 95% CI 0.19-0.78,
p=0.008).
Disease free survival was associated with completeness of

surgery [HR=5.1, 95% CI 2-12.9, p=0.0007).

Retrospectiv
Meyer, T., Merkel, S., Goehl, J. & e 444 Treatment No. median 2 year Risk of Bias – HIGH.
Hohenberger, W. (2000) Surgical consecutive patients survival survival
therapy for distant metastases of patients with Patient selection bias.
(months)
malignant melanoma. Cancer, 89: distant
1983-1991. melanoma Surgery with 111 17 36.1%
metastases curative resection
Surgery with 63 6 12.7%

palliative
resection
Conservative 270 4 8.1%

treatment
(systemic
chemotherapy
and/or
immunotherapy
with various drugs
or supportive
care)
Retrospectiv
Ollila, D. W., Hsueh, E. C., Stern, S. e 131 patients Risk of Bias – HIGH.
L. & Morton, D. L. (1999) who
Metastasectomy for recurrent developed Treatment No. median 5 year Patient selection bias.
stage IV melanoma. Journal of recurrent patients survival survival
Surgical Oncology, 71: 209-213. stage IV (months)
melanoma Patients managed non-
complete 40 18.2 20%
operatively had multiple
metastasectomy
brain or liver metastases
and/or involvement of

palliative surgical 43 12.5 7% more than 3 anatomic

procedure sites.
nonsurgical 48 5.9 2.1%

management

1 6.2 Localised treatment for brain metastases
2 Review question: What is the effectiveness of local treatment using surgery or radiotherapy
3 compared with systemic drug therapy or supportive care in the management of brain metastases in
4 people with stage IV melanoma?
5 Background
6 A wide variety of treatment modalities have been used to treat metastatic melanoma, i.e. a melanoma which is
7 spread through the bloodstream to reach distant sites. The commonest metastatic sites for melanoma to spread
8 to are liver, lungs, brain and bone. Melanoma can also spread to other skin sites giving tumours under the skin at
9 subcutaneous nodules. Unfortunately with melanoma, spread can also occur almost anywhere in the body,
10 including sites that other cancers do not usually spread to, such as the gastrointestinal tract or the heart.
11 All the many local treatments which have been used, and several new approaches are in development or at the
12 clinical trials stage, have in common the aim of removing the melanoma metastases completely, and so reducing
13 the risk of recurrence at that particular site, while reducing to a minimum the side-effects or morbidity of using
14 that particular treatment. Therefore some techniques such as the emerging advanced radiotherapy techniques
15 are more appropriate to use for brain metastasis where the inevitable morbidity of any surgical approach, might
16 be too high a cost for the palliation achieved. In contrast, surgical techniques using surgery, laser ablation or
17 localised electro-chemotherapy would be much more appropriate for the palliation of multiple subcutaneous
18 melanoma metastases, than any of even the new radiotherapy techniques.
19 Surgical management of distant malignant melanoma deposits has been used for hundreds of years but these
20 techniques are still developing with increased use of laser treatments and the development of electro-
21 chemotherapy. Advances in imaging and diagnostic techniques has allowed for more precise surgical intervention
22 improving palliation and decreasing mobility.
23 Stereotactic radiosurgery, introduced in the last two decades allows for the treatment of metastases in a much
24 reduced number of fractions and by being able to deliver highly focused radiation treatments to very precise
25 target areas with much reduced dose to surrounding normal tissues reduces treatment morbidity and the
26 number of patient attendances required for treatment. Other new technologies for treating melanoma
27 metastases include CyberKnife and other Intensity Modulation RadioTherapy approaches.
28 Radiation can also be used by delivering radioactive particles to the melanoma metastases and using different
29 techniques so that these particles are preferentially taken up within the melanoma cells. As well as targeting
30 these metastases individually the tumours blood supply can be compromised by radioembolisation using
31 radioactive agents to block the tumours feeding arterial supply and it also places a decaying radiation source
32 close to the tumour itself.
33 The major challenge with all of these new and not some new techniques is that there are very few comparative
34 trials telling us which modality is best in which particular clinical situation and metastatic site.

People with stage IV  Surgery  Each other 1. Symptom

melanoma & brain  Stereotactic  Systemic drug therapy Control
metastases Radiotherapy (chemotherapy 2. Survival (1 yr)
 Whole brain and/or 3. HRQL
radiotherapy immunotherapy) 4. Adverse events
 Supportive Care
2 Search Results
Database name Dates Covered No of No of references Finish date of

references retrieved search
found
Medline 1946-2013 831 419 14/11/2013
Premedline November 19 2013 71 46 20/11/2013
Embase 1974-2013 2084 808 19/11/2013
Cochrane Library As per database 68 18 19/11/2013
3 Update Search
4 For the update search, the same search criteria/filters were applied as initial search with a date limit of
5 November 2013 onwards.

retrieved search
Medline 37 28 14/10/2014
Premedline 10 7 14/10/2014
Embase 361 105 14/10/2014
6 Abstracts for 1112 papers were screened for their relevance for the review question and 1068 papers were
7 excluded leaving 44 papers to be ordered and the full text screened (figure 1). From these 44 papers 12 were
8 relevant (table 3) and included in the evidence review and 32 papers were excluded (table 4). There were a
9 number of papers which were excluded because they are not specific to melanoma and the studies contain
10 patients with brain metastases from a range of different primary cancers. It was important to select papers
11 specific to melanoma as the effect of treatments on melanoma metastases may be different to other cancers.
12

1 Screening Results


1112

1112 1068

44 32

12

2 Overall survival
3 All 12 studies examined the effect of treatment on survival and they all found increased survival in patients who
4 underwent local treatment such as surgery or stereotactic radiotherapy compared to systemic drug therapy
5 and/or supportive care. All 12 studies included a mix of patients with both single and multiple metastases.
6 Two retrospective studies analysed the effect of treatment on patients with single or multiple metastases
7 separately (Katz, 1981; Eigentler et al 2011) and they both found surgery to be associated with a significantly
8 longer survival compared with other treatment modalities for patients with a single brain metastasis. This benefit
9 was no longer detectable when considering patients with multiple brain metastases [Very Low Quality Evidence].
10 The effectiveness of local treatment compared with systemic drug therapy or supportive care in the management
11 of brain metastases in people with stage IV melanoma is unclear from the evidence in the 12 included papers. 11
12 of the studies suggest that local treatment is more effective in terms of increased median survival (Table 2: grade
13 profiles) [Very Low Quality Evidence].
14 Extracting data from the different studies demonstrated that in terms of increased survival surgery gives better
15 results than supportive care, chemotherapy, WBRT and chemotherapy and/or WBRT. There was no difference in
16 overall survival between surgery and STR, however only one study compared these treatments. STR resulted in
17 longer overall survival than chemotherapy and WBRT (there were no studies comparing STR with supportive care
18 or chemotherapy and/or WBRT). WBRT resulted in increased survival compared to supportive care. Whether
19 WBRT gives better results than chemotherapy is uncertain as one study showed that WBRT did result in
20 increased survival compared to chemotherapy, but 2 other studies demonstrated longer survival with
21 chemotherapy than WBRT.
22 In one retrospective study of 157 patients treated with stereotactic radiotherapy with and without WBRT (Dyer
23 et al, 2014), death occurred in 135 patients (92%) with a median overall survival of 7.3 months. On multivariate
24 analysis extensive extracranial metastases [HR=1.78, 95% CI 1.25-2.53, p=0.001] and Karnofsky Performance
25 status 50-80 (versus 90-100) [HR=1.52, 95% CI 1.08-2.15, p=0.02] were associated with poorer survival. The use
26 of up front whole brain radiotherapy was associated with treatment centre (p<0.0001) and multiple brain
27 metastases (p<0.0001) [Very Low Quality Evidence]
28 To what extent the longer median survival associated with local treatment using surgery or radiotherapy
29 compared with systemic drug therapy or supportive care is related to the treatment itself or to selection of
30 patients with better performance status is unclear. All 12 studies are retrospective cohort studies and all have
31 undergone patient selection that is biased toward treating patients with more favourable prognoses with local
32 treatments such as surgery. Prospective studies are required to overcome selection bias and confirm the results
33 observed by these retrospective studies.
34 Symptom control
35 There was very low quality evidence from two studies reporting improvement in neurological symptoms
36 following surgery or radiotherapy. One study found similar rates of improvement in neurological symptoms with
37 50% of patients experiencing improvement in at least 1 neurological symptom following surgery and 54% of
38 patients experiencing improvement after whole brain radiotherapy (Sampson, 1998). Another study found that
39 surgery improved neurological symptoms in 70% patients compared to radiotherapy which improved symptoms
40 in 42% of patients (Katz 1981).
41 Adverse events

1 Very low quality evidence from two studies suggests that serious treatment related adverse events are more
2 likely with surgery than radiotherapy. In Sampson et al (1998) 12/139 (9%) patients treated with surgery had
3 treatment-related serious complications (including death) compared with 2/180 (1%) treated with whole brain
4 radiotherapy. In Katz et al (1981) there was a serious adverse event rate of 1/10 (10%) with surgery compared
5 with 0/52 (0%) in the whole brain radiotherapy group.
6 Health related quality of life
7 This outcome was not reported in the included studies.

8

Grade Table 6.12: Should surgery vs. chemotherapy be used for stage IV melanoma & brain metastases?
studies considerations (95%
CI)
overall survival
3 observational very no serious no serious serious none 94 260 - Overall median survival was 4 - 7 months longer in 
studies1 serious2 inconsistency indirectness imprecision3 patients treated with surgery compared to those VERY
treated with chemotherapy. LOW
1
2
Serious risk of bias due to patient selection for treatment
3
Low event rate or low number of patients
Grade Table 6.13: Should surgery vs. supportive care be used for stage IV melanoma & brain metastases?
No of Design Limitations Inconsistency Indirectness Imprecision Other surgery supportive Relative Absolute
CI)
overall survival
3 observational very no serious no serious serious none 84 253 - Overall median survival was 4 - 10 months longer in 
undergoing supportive care. LOW
1
2
serious risk of bias due to patient selection for treatment
3

Grade Table 6.14: Should surgery vs. stereotactic radiotherapy be used for stage IV melanoma & brain metastases?
No of Design Limitations Inconsistency Indirectness Imprecision Other surgery stereotactic Relative Absolute
studies considerations radiotherapy (95%
CI)
overall survival
1 observational very no serious no serious serious none 37 17 - Overall median survival was 0.3 months longer 
studies1 serious2 inconsistency indirectness imprecision3 in patients treated with surgery compared to VERY
those treated with STR. LOW
1
Retrospective cohort study
2
High bias due to patient selection for treatment
3
Grade table 6.15: Should surgery vs. WBRT be used for stage IV melanoma & brain metastases?
No of Design Limitations Inconsistency Indirectness Imprecision Other surgery WBRT Relative Absolute
CI)
overall survival
5 observational very no serious no serious no serious none 149 527 - Overall median survival was 2.5 – 11.5 months longer 
studies1 serious2 inconsistency indirectness imprecision in patients treated with surgery compared to those VERY
treated with WBRT. LOW
Symptom control (improvement in at least 1 neurological symptom)
2 observational very no serious no serious serious none 149 232 - Symptoms improved in 50 – 70% of patients treated 
studies1 serious2 inconsistency indirectness imprecision3 with surgery compared to 42 -54% of patients treated VERY
with WBRT. LOW
Serious complications

2 observational very no serious no serious serious none 13/149 2/232 - 80 per 1000 more with surgery than with WBRT 
studies1 serious2 inconsistency indirectness imprecision3 (9%) (1%) VERY
LOW
1
2
3
Grade Table 6.16: Should surgery vs. chemotherapy and/or WBRT be used for stage IV melanoma & brain metastases?
studies considerations and/or WBRT (95%
CI)
overall survival
1 observational very no serious no serious serious none 32 75 - Overall median survival was 2 months longer in 
treated with chemotherapy and/or WBRT. LOW
1
2
3
Grade Table 6.17: Should STR vs. chemotherapy be used for stage IV melanoma & brain metastases?
No of Design Limitations Inconsistency Indirectness Imprecision Other STR chemotherapy Relative Absolute
CI)
overall survival
1 observational very no serious no serious serious none 17 38 - Overall median survival was 3.7 months longer in 
studies1 serious2 inconsistency indirectness imprecision3 patients treated with STR compared to those treated VERY
with chemotherapy. LOW

1
2
3
Grade Table 6.18: Should WBRT vs. chemotherapy be used for stage IV melanoma & brain metastases?
No of Design Limitations Inconsistency Indirectness Imprecision Other WBRT chemotherapy Relative Absolute
CI)
overall survival
3 observational very no serious no serious no serious none 262 260 - Overall median survival was 3.7 months longer in patients 
studies1 serious2 inconsistency indirectness imprecision treated with WBRT compared to those treated with VERY
chemotherapy in one study. However, for 2 studies overall LOW
median survival was 1.1 - 2 months longer in patients treated
with chemotherapy compared to those treated with WBRT.
1
2
Grade Table 6.19: Should WBRT vs. supportive care be used for stage IV melanoma & brain metastases?
No of Design Limitations Inconsistency Indirectness Imprecision Other WBRT supportive Relative Absolute
CI)
overall survival
3 observational very no serious no serious no serious none 289 227 - Overall median survival was 1 – 1.3 months longer in 
studies1 serious2 inconsistency indirectness imprecision patients treated with WBRT compared to those VERY
undergoing supportive care. LOW
1
2

Grade Table 6.20: Should WBRT vs. STR be used for stage IV melanoma & brain metastases?
No of Effect Quality
patients
No of Design Limitations Inconsistency Indirectness Imprecision Other WBRT STR Relative Absolute
CI)
overall survival
studies1 serious2 inconsistency indirectness imprecision3 patients treated with STR compared to those treated VERY
with WBRT. LOW
1
2
3
Grade Table 6.21: Should STR or surgery vs. supportive care be used for stage IV melanoma & brain metastases?
No of Design Limitations Inconsistency Indirectness Imprecision Other STR or supportive Relative Absolute
studies considerations surgery care (95%
CI)
overall survival
studies1 serious2 inconsistency indirectness imprecision3 patients treated with STR or surgery compared to VERY
those undergoing supportive care. LOW
1
2
3
Grade Table 6.22: Should STR or surgery vs. WBRT be used for stage IV melanoma & brain metastases?

No of Design Limitations Inconsistency Indirectness Imprecision Other STR or WBRT Relative Absolute
studies considerations surgery (95%
CI)
overall survival
studies1 serious2 inconsistency indirectness imprecision3 patients treated with STR or surgery compared to VERY
those treated with WBRT. LOW
1
2
High bias due to patient treatment selection
3
Grade Table 6.23: Should STR or surgery vs. chemotherapy and/or WBRT be used for stage IV melanoma & brain metastases?
No of Design Limitations Inconsistency Indirectness Imprecision Other STR or chemotherapy Relative Absolute
studies considerations surgery and/or WBRT (95%
CI)
overall survival
1 observational very no serious no serious no serious none 122 92 - Overall median survival was 3 months longer in 
studies1 serious2 inconsistency indirectness imprecision patients treated with STR or surgery compared to VERY
those treated with chemotherapy and/or WBRT. LOW
1
2
Grade Table 6.24: Should STR with or without WBRT be used for stage IV melanoma & brain metastases?

No of Design Limitations Inconsistency Indirectness Imprecision Other STR STR+WBRT Relative Absolute
CI)
overall survival
1 observational very no serious no serious no serious none 147 (numbers not Death occurred in 92% of
studies1 serious2 inconsistency indirectness imprecision reported for each patients with a median VERY
treatment separately) overall survival was 7.3 LOW
months
1
2

1 References
2 Included Studies
3 Bremer, A. M., West, C. R. & Didolkar, M. S. (1978) An evaluation of the surgical management of melanoma of
4 the brain. Journal of Surgical Oncology, 10: 211-219.
5 Buchsbaum, J. C., Suh, J. H., Lee, S. Y., Chidel, M. A., Greskovich, J. F. & Barnett, G. H. (2002) Survival by radiation
6 therapy oncology group recursive partitioning analysis class and treatment modality in patients with brain
7 metastases from malignant melanoma: a retrospective study. Cancer, 94: 2265-2272.
8 Dyer, M. A., Arvold, N. D., Chen, Y. H., Pinnell, N. E., Mitin, T., Lee, E. Q., Hodi, F. S., Ibrahim, N., Weiss, S. E., Kelly,
9 P. J., Floyd, S. R., Mahadevan, A., and Alexander, B. M. The role of whole brain radiation therapy in the
10 management of melanoma brain metastases. Radiation Oncology 9. 2014.
11 Eigentler, T. K., Figl, A., Krex, D., Mohr, P., Mauch, C., Rass, K., Bostroem, A., Heese, O., Koelbl, O., Garbe, C.,
12 Schadendorf, D. & Dermatologic Cooperative Oncology Group and the National Interdisciplinary Working Group
13 on Melanoma (2011) Number of metastases, serum lactate dehydrogenase level, and type of treatment are
14 prognostic factors in patients with brain metastases of malignant melanoma. Cancer, 117: 1697-1703.
15 Fife, K. M., Colman, M. H., Stevens, G. N., Firth, I. C., Moon, D., Shannon, K. F., Harman, R., Petersen-Schaefer, K.,
16 Zacest, A. C., Besser, M., Milton, G. W., McCarthy, W. H. & Thompson, J. F. (2004) Determinants of outcome in
17 melanoma patients with cerebral metastases. Journal of Clinical Oncology, 22: 1293-1300.
18 Katz, H. R. (1981) The relative effectiveness of radiation therapy, corticosteroids, and surgery in the management
19 of melanoma metastatic to the central nervous system. International Journal of Radiation Oncology Biology
20 Physics, 7: 897-906.
21 Konstadoulakis, M. M., Messaris, E., Zografos, G., Androulakis, G. & Karakousis, C. (2000) Prognostic factors in
22 malignant melanoma patients with solitary or multiple brain metastases. Is there a role for surgery? Journal of
23 Neurosurgical Sciences, 44: 211-218.
24 Meier, S., Baumert, B. G., Maier, T., Wellis, G., Burg, G., Seifert, B. & Dummer, R. (2004) Survival and prognostic
25 factors in patients with brain metastases from malignant melanoma. Onkologie, 27: 145-149.
26 Panagiotou, I. E., Brountzos, E. N., Kelekis, D. A., Papathanasiou, M. A. & Bafaloukos, D. I. (2005) Cerebral
27 metastases of malignant melanoma: contemporary treatment modalities and survival outcome. Neoplasma, 52:
28 150-158.
29 Sampson J, Carter J, Friedman A, et al. (1998) Demographics, prognosis and therapy in 702 patients with brain
30 metastases from malignant melanoma. J Neurosurg 88, 11-20.
31 Selek, U., Chang, E. L., Hassenbusch, S. J., III, Shiu, A. S., Lang, F. F., Allen, P., Weinberg, J., Sawaya, R. & Maor, M.
32 H. (2004) Stereotactic radiosurgical treatment in 103 patients for 153 cerebral melanoma metastases.
33 International Journal of Radiation Oncology, Biology, Physics, 59: 1097-1106.
34 Zacest, A. C., Besser, M., Stevens, G., Thompson, J. F., McCarthy, W. H. & Culjak, G. (2002) Surgical management
35 of cerebral metastases from melanoma: outcome in 147 patients treated at a single institution over two decades.
36 Journal of Neurosurgery, 96: 552-558.
37 Excluded Studies
38 Ahmed, K. A., Freilich, J. M., Abuodeh, Y., Figura, N., Patel, N., Sarangkasiri, S., Chinnaiyan, P., Yu, H. H. M., Etame,
39 A. B., and Rao, N. G. Fractionated stereotactic radiotherapy to the post-operative cavity for radioresistant and
40 radiosensitive brain metastases. Journal of Neuro-Oncology 118[1], 179-186. 2014.
42 Anderson, D. & Flynn, K. (1997) Stereotactic radiosurgery for metastases to the brain: a systematic review of
43 published studies of effectiveness (DARE structured abstract). Database of Abstracts of Reviews of Effects., 16

1 Reason: Abstract
2 Bindal, R. K., Sawaya, R., Leavens, M. E. & Lee, J. J. (1993) Surgical-Treatment of Multiple Brain Metastases.
3 Journal of Neurosurgery, 79: 210-216.
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6 systematic review. Cancer Therapy, 7: 188-199.
8 Bottoni, U., Clerico, R., Paolino, G., Ambrifi, M., Corsetti, P. & Calvieri, S. (2013) Predictors and survival in patients
9 with melanoma brain metastases. Medical Oncology, 30: 466.
10 Reason: No Brain Metastases
11 Brady, L. W., Mancall, E. L., Lee, D. K., Neff, L. B., Shockman, A. T., Faust, D. S., Antoniades, J., Prasasvinichai, S.,
12 Torpie, R. J. & Glassburn, J. R. (1974) Predictors and survival in patients with melanoma brain metastases.
13 Radiologia Clinica et Biologica, 43: 40-47.
14 Reason: Not melanoma
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16 institution experience. European Journal of Cancer, Supplement, 7: 502.
17 Reason: Abstract
18 DiBiase, S. J., Chin, L. S. & Ma, L. (2002) Influence of gamma knife radiosurgery on the quality of life in patients
19 with brain metastases. American Journal of Clinical Oncology, 25: 131-134.
21 Eigentler, T. K., Figl, A., Krex, D., Mohr, P., Kurschat, P., Tilgen, W., Bostroem, A., Heese, O., Garbe, C. &
22 Schadendorf, D. (2009) Multicenter study on prognostic factors in 692 patients with brain metastases of
23 malignant melanoma. Journal of Clinical Oncology, 27: 9081.
24 Reason: Abstract
25 Feuvret, L., Vinchon, S., Martin, V., Lamproglou, I., Halley, A., Calugaru, V., Chea, M., Valery, C. A., Simon, J. M.,
26 Mazeron, J. J., Feuvret, L., Vinchon, S., Martin, V., Lamproglou, I., Halley, A., Calugaru, V., Chea, M., Valery, C. A.,
27 Simon, J. M., and Mazeron, J. J. Stereotactic radiotherapy for large solitary brain metastases. Cancer
28 Radiotherapie 18[2], 97-106. 2014.
30 Fogarty, G., Morton, R. L., Vardy, J., Nowak, A. K., Mandel, C., Forder, P. M., Hong, A., Hruby, G., Burmeister, B.,
31 Shivalingam, B., Dhillon, H. & Thompson, J. F. (2011) Whole brain radiotherapy after local treatment of brain
32 metastases in melanoma patients--a randomised phase III trial. BMC Cancer, 11: 142
33 Reason: Study Protocol
34 Jung, E. W., Delly, F., Rakowski, J., Mittal, S., Tang, K., Kim, H. & Jagannathan, J. (2012) Repeated stereotactic
35 radiosurgery for progressive brain metastases from melanoma after initial treatment. International Journal of
36 Radiation Oncology Biology Physics, 84: S629.
37 Reason: Abstract
38 Kalani, M. Y. S., Filippidis, A. S., Kalani, M. A., Sanai, N., Brachman, D., McBride, H. L., Shetter, A. G. & Smith, K. A.
39 (2010) Gamma Knife surgery combined with resection for treatment of a single brain metastasis: preliminary
40 results. Journal of Neurosurgery, 113: 90-96.

1 Kocher, M., Maarouf, M., Bendel, M., Voges, J., Muller, R. P. & Strum, V. (2004) Linac radiosurgery versus whole
2 brain radiotherapy for brain metastes - A survival comparison based on the RTOG recursive partitioning analysis.
3 Strahlentherapie und Onkologie, 180: 263-267.
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6 Melanoma. Tumordiagnostik & Therapie, 14: 138-142.
8 Kreth, F. W., Warnke, P. C. & Ostertag, C. B. (1993) Stereotaxic Interstitial Radiosurgery and Percutaneous
9 Radiotherapy for Treatment of Cerebral Metastases. Nervenarzt, 64: 108-113.
11 Lagerwaard F, Levendag P, Nowak P, et al. (1999) Identification of prognostic factors in patients with brain
12 metastases: A review of 1292 patients. Int J Radiat Oncol Biol Phys 43, 795-803.
14 Lowe, M. C., Cavitt, A., Shelton, J., Crocker, I. R., Pan, L., Lawson, D. H., Carlson, G. W., Delman, K. A. & Rizzo, M.
15 (2010) The role of radio-surgery in patients with metastatic melanoma to the brain. Journal of Clinical Oncology,
16 28.
17 Reason: Abstract
18 Osei-Boateng, K., Venur, V. A., Dahiya, S., Du, L., Garje, R., Elson, P., Chao, S. T. & Ahluwalia, M. S. (2013) Graded
19 prognostic assessment index for melanoma with brain metastases (MBM). Journal of Clinical Oncology, 31.
20 Reason: Abstract
21 Ostertag, C. B. & Kreth, F. W. (1995) Interstitial I-125 Radiosurgery for Cerebral Metastases. British Journal of
22 Neurosurgery, 9: 593-603.
24 Patchell, R. A., Tibbs, P. A., Regine, W. F., Dempsey, R. J., Mohiuddin, M., Kryscio, R. J., Markesbery, W. R., Foon,
25 K. A. & Young, B. (1998) Postoperative radiotherapy in the treatment of single metastases to the brain - A
26 randomized trial. Jama-Journal of the American Medical Association, 280: 1485-1489.
28 Rezvi, U. Judicious use of radiosurgery (SRS) may change the ultimate patterns of failure in patients with brain
29 metastasis from melanoma. Neuro-Oncology Conference[var.pagings], November. 2013.
30 Reason:Abstract
31 Rhomberg, W., Eiter, H., Boehler, F., Saely, C. & Strohal, R. (2005) Combined razoxane and radiotherapy for
32 melanoma brain metastases. A retrospective analysis. Journal of Neuro-Oncology, 74: 295-299.
34 Rutigliano, M. J., Lunsford, L. D., Kondziolka, D., Strauss, M. J., Khanna, V. & Green, M. (1995) The Cost-
35 Effectiveness of Stereotaxic Radiosurgery Versus Surgical Resection in the Treatment of Solitary Metastatic Brain-
36 Tumors. Neurosurgery, 37: 445-453.
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39 metastases: Results of a retrospective study. Onkologie, 24: 246-255.

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10 for the treatment of newly diagnosed multiple brain metastases. Cochrane Database Syst Rev. 2012 Apr
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18 melanoma brain metastases before the advent of targeted therapies: associations between therapeutic choice,
19 clinical symptoms and outcome with survival. Melanoma Research 24[1], 61-67. 2014.
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22 metastatic melanoma. Journal of Clinical Oncology, 30.
23 Reason: Abstract
24 Wiggenraad, R., Verbeek-de, K. A., Kal, H. B., Taphoorn, M., Vissers, T. & Struikmans, H. (2011) Dose-effect
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26 Radiotherapy and Oncology, 98: 292-297.
28

Evidence Tables
Study Qualilty
method of Attempts Comparable The Participants Treatment Equal Appropriate Precise Valid Investigators Investigators
allocation to were made at baseline comparison blind to asministrators follow length of definition method of blind to blind to
treatment within the groups treatment blind to up follow-up of an measuring participants potential
allocation treatment
groups was design or received the outcome outcomes exposure to confounders
allocation
unrelated to analysis to same care intervention? and
potential balance the apart from the prognostic
confounding comparison intervention(s) factors?
factors groups for studied
potential
confounders
Bremer et al No No No No No No Yes Yes Yes Yes No No
1978
Buchsbaum et No No No No No No Yes Yes Yes Yes No No
al 2002
Eigentler et al No No No No No No Yes Yes Yes Yes No No
2011
Fife et al 2004 No No No No No No Yes Yes Yes Yes No No
Katz 1981 No No No No No No Yes Yes Yes Yes No No
Konstadoulakis No No No No No No Yes Yes Yes Yes No No
et al 2000
Meier et al No No No No No No Yes Yes Yes Yes No No
2004
Panagiotou et No No No No No No Yes Yes Yes Yes No No
al 2005
Sampson et al No No No No No No Yes Yes Yes Yes No No
1998
Selek et al No No No No No No Yes Yes Yes Yes No No
2004
Zacest et al No No No No No No Yes Yes Yes Yes No No
2002

PAPER TYPE OF STUDY No. PATIENTS TREATMENT COMPARISONS NOTES
Overall survival Risk of Bias – HIGH.
Bremer, A. M., West, C. R. & Didolkar, M. Retrospective 32 Treatment No. patients median Patient selection bias.
S. (1978) An evaluation of the surgical survival
management of melanoma of the brain. (months)
Journal of Surgical Oncology, 10: 211-219.
Multiple brain Median survival was
metastases: 13 Surgery 19 5-6
Single brain dependent on treatment,
metastases: 19 No surgery 13 1 which in turn was dependent
on patient selection
Intratumor haemorrhage (at autopsy) by surgery

No surgery group contains a
Treatment Intra tumour hemorrhage No. patients mix of patients with different
alternative treatments.
Surgery 10 (53%) 19
No surgery 8 (62%) 13
Intratumor haemorrhage (at autopsy) by chemotherapy
Treatment Intra tumour hemorrhage No. patients
Chemotherapy 13 (62%) 21
No chemotherapy 5 (45%) 11

Buchsbaum, J. C., Suh, J. H., Lee, S. Y., Retrospective 74 Treatment No. median Risk of Bias – HIGH.
Chidel, M. A., Greskovich, J. F. & Barnett, patients survival
G. H. (2002) Survival by radiation therapy (months) Patient selection bias.
oncology group recursive partitioning
Multiple brain
analysis class and treatment modality in metastases: 60 Combined therapy 36 8.8
patients with brain metastases from Single brain (local + WBRT)
metastases: 14 Survival benefit of combination
malignant melanoma: a retrospective
Local therapy alone 10 4.8 therapy likely due to selection
study. Cancer, 94: 2265-2272.
bias – clinicians had selected
(surgery or SRS) patients for treatment in a
fashion that correlated with
WBRT alone 25 2.3 the RTOG RPA schema.
No treatment 3 1.1
Combined vs. other p<0.0001
Treatment HR CI p
No treatment v Combined 7.928 1.680-37.409 0.0089

therapy (local + WBRT)
WBRT alone v Combined 2.392 1.161-4.929 0.0180

Local therapy alone 1.440 0.648-3.197 0.3703
(surgery or SRS) v Combined

Complications:
Radiation: 0 patients symptomatic radiation necrosis
Surgery (alone or with WBRT) – acute complications: 1 infection, 2 haemorrhages, 3 central

nervous system deficits. No long term complications.

Dyer, M. A., Arvold, N. D., Chen, Y. H., Retrospective 147 Stereotactic radiotherapy and WBRT Risk of Bias – HIGH.
Pinnell, N. E., Mitin, T., Lee, E. Q., Hodi, F. Case Series
Stereotactic radiotherapy alone Patient selection bias.
S., Ibrahim, N., Weiss, S. E., Kelly, P. J.,
Floyd, S. R., Mahadevan, A., and
The use of up front whole
Alexander, B. M. The role of whole brain brain radiotherapy was
56 patients had distant failure prior to any local failure
radiation therapy in the management of associated with treatment
20 patients had distant and local failure at the same time centre (p<0.0001) and multiple
melanoma brain metastases. Radiation
brain metastases (p<0.0001)
Oncology 9. 2014. 27 patients had local failure first Median number of brain
metastasis for patients
receiving up front WBRT was 4
(IQR 3-5) and for patients
Distant intracranial progression occurred in 59% of patients stereotactic radiotherapy
alone was 1 (IQR 1-2).
Median time to progression was 4.3 months.
Multivariate Analysis
Age >60 HR=0.64 (0.41-0.99, p=0.05)
>1 brain metastases HR=1.90 (1.18-3.06, p=0.008)
Omission of upfront WBRT HR=2.24 (1.27-3.94, p=0.005)
In patients with multiple brain metastases median time to distant

intracranial progression was 2 months in patients who did not receive
upfront WBRT compared with 6 months in patients who were treated
with upfront WBRT (p=0.003).

Median time to progression in patients with solitary brain metastases

was approximately 5 months in both treatment groups.
Death occurred in 135 patients (92%) with a median overall survival of

7.3 months.
On multivariate analysis extensive extracranial metastases [HR=1.78,

95% CI 1.25-2.53, p=0.001] and Karnofsky Performance status 50-80
(versus 90-100) [HR=1.52, 95% CI 1.08-2.15, p=0.02] were associated
with poorer survival.

Eigentler, T. K., Figl, A., Krex, D., Mohr, P., Retrospective 672 For patients with a single brain metastasis, neurosurgery and STR were Risk of Bias – HIGH.
Mauch, C., Rass, K., Bostroem, A., Heese, both found to be associated with a significantly longer survival
O., Koelbl, O., Garbe, C., Schadendorf, D. compared with other treatment modalities such as WBRT and/or Patient selection bias.
& Dermatologic Cooperative Oncology systemic therapy.
Multiple brain
Group and the National Interdisciplinary metastases: 397
Working Group on Melanoma (2011) Single brain However, this benefit is no longer detectable when considering patients
metastases: 249
Number of metastases, serum lactate with limited disease (<3 metastases)
dehydrogenase level, and type of Median survival was
treatment are prognostic factors in dependent on treatment,
patients with brain metastases of which in turn was dependent
Treatment for single brain metastases:
malignant melanoma. Cancer, 117: 1697- on patient selection
1703. Treatment No. patients median
survival
(months)
STR or surgery 122 9

(complete resection)
WBRT and/or 92 6
chemotherapy
p=0.036
Treatment HR CI p
STR or surgery v WBRT 1.5 1.1-1.9 0.0061

and/or chemotherapy

Treatment for limited brain disease (<3 metastases):
Treatment No. patients median

Fife, K. M., Colman, M. H., Stevens, G. N., Retrospective 686 patients, Treatment No. median Risk of Bias – HIGH.
Firth, I. C., Moon, D., Shannon, K. F., patients survival
Harman, R., Petersen-Schaefer, K., Zacest, As of june 2003 (months) Patient selection bias.
A. C., Besser, M., Milton, G. W., 646 had died as a
McCarthy, W. H. & Thompson, J. F. (2004) result of surgery and postoperative 158 8.9
Determinants of outcome in melanoma melanoma. radiotherapy
Median survival was
patients with cerebral metastases.
surgery alone 47 8.7 dependent on treatment,
Journal of Clinical Oncology, 22: 1293-
which in turn was dependent
1300. Multiple brain
radiotherapy alone 236 3.4 on patient selection.
metastases: 173
Single brain
metastases: 178 supportive care alone 210 2.1 Patients were selected for
active treatment on the basis
of having a single cerebral
metastasis, cerebral
metastases with no evidence
of metastatic disease
Treatment HR CI p elsewhere, or a younger age.
Surgery v supportive care 0.436 0.308-0.619 <0.001
Radiotherapy v supportive 0.851 0.698-1.038 0.111

care
Surgery and radiotherapy v 0.346 0.273-0.439 <0.001

supportive care


Retrospective 63 Surgical excision of solitary brain metastases produces better results

Katz, H. R. (1981) The relative than radiotherapy alone. Risk of Bias – HIGH.
Multiple brain
effectiveness of radiation therapy, metastases: 25
corticosteroids, and surgery in the Single brain Overall survival: Patient selection bias.
management of melanoma metastatic to metastases: 38 Solitary brain metastases:
the central nervous system. International
Journal of Radiation Oncology Biology
(months)
Physics, 7: 897-906.
surgery 8 14.7 50%
radiotherapy 29 3.2 n/a
multiple brain metastases:

Treatment No. patients median 1 year
survival survival
(months)
surgery 2 2 0
radiotherapy 23 2.2 n/a
Improvement in neurological symptoms
Improved after No. patients

treatment
Surgery 7 (70%) 10
WBRT 22 (42%) 52
Life threatening complications or death during treatment or 30 days

Melanoma: DRAFT evidence review (January 2015) post treatment. Page 679 of 886
Complications or No. patients

death
Retrospective 136 Treatment No. median 1 year

Konstadoulakis, M. M., Messaris, E., patients survival survival
Multiple brain
Zografos, G., Androulakis, G. & metastases: 75 (months)
Karakousis, C. (2000) Prognostic factors in Single brain Risk of Bias – HIGH.
metastases: 56 surgery 32 5 28.13%
malignant melanoma patients with
Patient selection bias.
solitary or multiple brain metastases. Is
there a role for surgery? Journal of radiotherapy and/or 75 3 6.67%
Neurosurgical Sciences, 44: 211-218. chemotherapy
Survival was dependent on
No treatment 29 1 3.45%
treatment, which in turn was
dependent on patient
One year survival of patients treated surgically was significantly better selection.
than patients who received radiotherapy and/or chemotherapy or who
had no treatment. p=0.006.
Treatment No. median survival 1 year

patients (months) survival
Meier, S., Baumert, B. G., Maier, T., Retrospective 100 patients Risk of Bias – HIGH.
Wellis, G., Burg, G., Seifert, B. & Dummer, Surgery 37 10.6 31%
R. (2004) Survival and prognostic factors Patient selection bias.
in patients with brain metastases from No surgery 63 2.9 3%
Multiple brain
malignant melanoma. Onkologie, 27: 145- metastases: 56
149. Single brain p<0.0001
metastases: 41 Survival was dependent on
treatment, which in turn was
Treatment No. median survival 1 year selection.
patients (months) survival
Radiosurgery 17 10.3 35%
No radiosurgery 83 3.9 9%

p=0.002
Treatment No. patients median 1 year

survival survival
(months)
WBRT/PBRT 54 5.5 19%
No WBRT/PBRT 46 2.6 7%
p=0.009
Treatment HR CI p
WBRT/PBRT 0.45 0.29-0.70 0.0004
surgery 0.30 0.19-0.49 <0.0001
radiosurgery 0.31 0.17-0.55 <0.0001
chemotherapy 0.43 0.27-0.70 0.0006

Panagiotou, I. E., Brountzos, E. N., Kelekis, Retrospective 64 Treatment No. patients median Risk of Bias – HIGH.
D. A., Papathanasiou, M. A. & Bafaloukos, survival
D. I. (2005) Cerebral metastases of (months) Patient selection bias.
malignant melanoma: contemporary
Multiple brain
treatment modalities and survival metastases: 47 Surgery followed by radiotherapy 5 12
outcome. Neoplasma, 52: 150-158. Single brain
treatment.
Temozolomide as first line 17 5
treatment and radiotherapy after Patient characteristics
cerebral disease progression influenced selection of
treatment modality.
radiotherapy alone 28 3
supportive care only 14 2
Surgery vs non surgery groups: p=0.0011
Treatment HR SE p
supportive care only
Surgery/radiotherapy 9.6831 7.0301 0.0053
whole brain irradiation 0.4099 1.1010 0.7097
Temozolomide/ 4.1874 2.2236 0.5497
radiotherapy

Overall survival
Sampson J, Carter J, Friedman A, et al. Retrospective 702 patients Treatment No. median Risk of Bias – HIGH.
(1998) Demographics, prognosis and patients survival
therapy in 702 patients with brain (months) Patient selection bias.
metastases from malignant melanoma. J
Multiple brain
Neurosurg 88, 11-20. metastases: 234 surgery and postoperative 87 8.9
Single brain radiotherapy
surgery alone 52 6.5 treatment, which in turn was
radiotherapy alone 180 4.0 selection.
systemic palliative 205 1.3

chemotherapy
No treatment 178 n/a
Improvement in neurological symptoms
Improved after No. patients

treatment
Surgery 69 (50%) 139
WBRT 96 (54%) 180
Life threatening complications or death during treatment or 30 days

post treatment.
Complications or No. patients

death
Surgery 12 (9%) 139
WBRT 2(1%) 180
Risk of Bias – HIGH.
Selek, U., Chang, E. L., Hassenbusch, S. J., Retrospective 103 Treatment No. patients median Patient selection bias.
III, Shiu, A. S., Lang, F. F., Allen, P., overall
Weinberg, J., Sawaya, R. & Maor, M. H. survival
(2004) Stereotactic radiosurgical (months)
Multiple brain Patient selection was generally
treatment in 103 patients for 153 cerebral metastases: 42
Single brain SRS alone 61 7.5 biased toward treating patients
melanoma metastases. International
metastases: 61 with more favourable
Journal of Radiation Oncology, Biology,
SRS + initial WBRT 12 3.7 prognoses with initial SRS
Physics, 59: 1097-1106.
alone and reserving WBRT or
Salvage SRS after 30 5.4 surgery for salvage therapy,
whereas patients with more

WBRT advanced metastatic brain

disease were treated with
Initial SRS alone is an effective treatment modality for cerebral WBRT with or without SRS.
melanoma when applied to selected patients with small lesions.
Complications:
Local failure occurred in 20 cases:
SRS alone: 12 tumours
SRS+WBRT: 3 tumours
Salvage SRS after WBRT: 5 tumours
Requiring surgical resection owing to tumour progression, bleeding into lesion, or necrosis.
Zacest, A. C., Besser, M., Stevens, G., Retrospective 147 patients with Treatment No. median Risk of Bias – HIGH.
Thompson, J. F., McCarthy, W. H. & 174 craniotomies patients survival
Culjak, G. (2002) Surgical management of (months) Patient selection bias.
cerebral metastases from melanoma:
outcome in 147 patients treated at a Surgery 9 1
Multiple brain
single institution over two decades. metastases: 23
Surgery/WBRT 102 9 Survival was dependent on
Journal of Neurosurgery, 96: 552-558. Single brain
metastases: 124 treatment, which in turn was
Surgery/WBRT/chemo 33 11 dependent on patient
selection.
Surgery/chemo 3 ?
Repeated craniotomy 24 15
Surgery/WBRT 2 5
/radiosurgery

Postoperative morbidity (not reported by treatment group) included:
4 postoperative hematomas requiring operation
8 wound infections (6 of which required repeated craniotomy)
7 pulmonary emboli
5 deep venous thromboses
4 urinary tract or lung infections

1 6.3 The role of systemic anticancer therapy
2 Review question: What is the effectiveness of systemic anticancer therapy compared with
3 supportive care in the treatment (first and second line) of patients with stage IV
4 metastatic melanoma?
5 Background
6 Systemic therapy is playing an ever more important role in the multidisciplinary management of
7 metastatic melanoma. With the development of new targeted treatments and immune therapies
8 the role of chemotherapy has shifted and selection of the most appropriate therapy must now take
9 into account the mutational status of the tumour, tumour load, pace of disease and treatment
10 availability (see Table 11.1).
11 Table 6.1 Factors determining treatment selection of systemic therapy
Mutation Response Onset of Durable Availability in

rate Action response the UK (July
2013)
Targeted yes high days no BRAF mutated,

treatment(s) 1st or 2nd line
Immunotherapy no low months yes 2nd line
Chemotherapy no low weeks no Any
12 Targeted treatment and immunotherapy have taken over many of the previous traditional roles of
13 chemotherapy, however, it will remain a treatment choice for patients in whom targeted treatments
14 and immunotherapy are not considered options. Targeted treatment is only useful in the presence
15 of a tumour mutation, whilst the onset of actions for immunotherapy is in the order of months
16 which may preclude treatment in patient with high disease burden and/or rapidly progressing
17 disease. At present, immunotherapy with anti-CTLA4 antibodies is only available as second line
18 treatment in Europe and therefore chemotherapy is the treatment of choice in patients with BRAF
19 wild type melanoma. Chemotherapy is also an option where targeted treatment or immunotherapy
20 has failed.
21 Dacarbazine chemotherapy has been the standard of care for over 20 years. Temozolomide is an
22 analogue of dacarbazine also currently also in widespread use, particularly in patients with brain
23 metastases. It will be important to compare dacarbazine with temozolamide in order establish if
24 there is any advantage of temozolamide over dacarbazine in terms of efficacy or toxicity, or if there
25 are any special situations in which one drug would be favoured. Carboplatin and paclitaxel are also
26 used in the UK.
Patients/population Intervention Comparator Outcomes

Patients diagnosed with Dacarbazine Each other Symptom control

stage IV melanoma: Temozolomide Supportive care Overall Survival (1 yr, 2

 Location of Carboplatin yr)
metastases Paclitaxel Median OS
 Age Carboplatin + PFS
 Tumour mutation paclitaxel Response status
Status HRQOL
 Previous systemic Adverse events
therapy
 Performance
status
 AJCC stage 4
subgroup
Searches:
Can we apply date limits to the search (Please The GDG did not feel there were any dates which could be
provide information on any date limits we can applied to these searches.
appropriate)
Are there any study design filters to be used (RCT, Due to the nature of the topic under investigation, the
systematic review, diagnostic test). GDG felt that is was appropriate to limit the evidence to
systematic reviews/meta-analysis and randomized
controlled trials
List useful search terms. (This can include such No additional information to add
interventions etc)
What data will we extract and how will we analyse Relevant studies will be identified through sifting the
the results? abstracts and excluding studies clearly not relevant to
the PICO. In the case of relevant or potentially
relevant studies, the full paper will be ordered and
reviewed, whereupon studies considered to be not
relevant to the topic will be excluded.

critically appraised and quality assessed using GRADE
methodology and/or NICE checklists. Data relating to
the identified outcomes will be extracted from
relevant studies.
If possible a meta-analysis of available study data will

be carried out to provide a more complete picture of

the evidence body as a whole.
An evidence summary outlining key issues such as

volume, applicability and quality of evidence and
presenting the key findings from the evidence as it
relates to the topic of interest will be produced.
List subgroups here and planned statistical analyses. If the data are reported, the GDG would like to
see the effectiveness of treatment according to
the following subgroups:
 Location of metastases
 Age
 Tumour mutation Status
 Previous systemic therapy
 Performance status
 AJCC stage 4 subgroup
1 Search results

Medline 1946-2013 897 224 05/08/2013
Premedline 24 Jun 2013 16 5 06/08/2013
Embase 1947-2013 2260 139 13/08/2013

June 2013

SSCI)
2 Update Search
4 of August 2013 onwards.
Database name No of references found No of Finish date

references of search
retrieved

Medline 36 19 08/10/2014
Embase 157 18 08/10/2014
Pubmed 6 6 08/10/2014
2 1. exp Melanoma/
3 2. melanoma$.tw.
4 3. 1 or 2
5 4. Dacarbazine/
6 5. (dacarbazine or DTIC or deticene or (imidazole adj carboxamide) or dticdome or nsc45388 or nsc-
7 45388 or decarbazine or icdt or biocarbazine).tw.
8 6. 4 or 5
9 7. (temozolomide or temodal or temodar or ccrg81045 or mb39831 or methazolastone or
10 nsc362856 or nsc-362856 or temomedac or temoxol).tw.
11 8. Carboplatin/
12 9. (carboplatin or (cis-diammine adj cyclobutanedicarboxylato adj platinum) or CBDCA or ribocarbo
13 or nealorin or neocarbo or paraplatin or carboplat* or paraplatine or carbosin or carbotec or ercar or
14 JM-8 or JM8 or nsc-241240 or nsc241240 or platinwas or blastocarb).tw.
15 10. 8 or 9
16 11. Paclitaxel/
17 12. (paclitax* or paclitac* or paxene or anzatax or abraxane or nsc125973 or nsc-125973 or 7-epi-
18 taxol or taxol or praxel or paxene or onxol).tw.
19 13. 11 or 12
20 14. 6 or 7 or 10 or 13
21 15. 3 and 14
22
23

1 Screening Results
2
Expert Reviews
Abstract Only
No Comparators
to PICO

study designs (n=0)
(n=0)
3
4
5


Crosby et Systematic No relevant studies To investigate the Systemic Best Supportive Care or  Overall Surviival
al (2013) Review identified for efficiency of systemic Anticancer therapy Placebo  Progression Free
inclusion anticancer therapy for in the form of survival
the treatment of cytotoxic  Quality of Life
metastatic melanoma chemotherapy  Response Rates
with/without  Treatment Morbidity
immunotherapy  Health Economics
Kiebert et Randomise N=305 To provide further Temozolomide Dacarbazine  Health Related

al (2003) d Trial details of the Health Quality of Life
Related Quality of Life
results
Middleton Randomise N=305 To compare the Temozolomide Dacarbazine (n=141)  Overall Survival
et al d Trial effectiveness of (n=146)  Time to progression
(2000) temozolomide versus  Objective Response
dacarbazine for the Rate
treatment of  Quality of Life
metastatic melanoma
Patel et al Randomise N=859 patients To determine whether Temozolomide Dacarbazine (n=430)  Overall Survival
(2011) d Trial randomised an extended schedule (n=429)  Progression Free
and escalated dose of Survival
temozolomide is more  Response to
effective treatment for Treatment
metastatic melanoma  Safety
than standard dose of
dacarbazine


Zimpfer- Randomise N=34 To compare the Paclitaxel Paclitaxel + Carboplatin  Overall Survival
Rechner et d Trial response rate of  Progression Free
al (2003) patients receiving Survival
paclitaxel with and  Response Rates
without carboplatin  Toxicity

2 Systemic Anticancer Therapy versus Best Supportive Care
3 From one Cochrane Review (Crosby et al; 2013) there was no evidence comparing the use of
4 systemic anticancer therapy with best supportive care alone for any of the outcomes of interest
5 (GRADE Profile 1).
6 Dacarbazine versus Temozolomide
7 Evidence from two randomised trials (Middleton et al, 2000 and Patel et al, 2010) suggests similar
8 overall survival for patients treated with temozolomide when compared to those treated with
9 dacarbazine. The pooled hazard ratio (HR) for death from any cause was 0.96 (95% CI 0.84 to 1.09),
10 translating to an absolute improvement in median overall survival of 0.33 months with
11 temozolomide [Moderate].
12 Evidence from two randomised trials (Middleton et al, 2000 and Patel et al, 2010) that patients
13 treated with temozolomide have better progression free survival (PFS) than those treated with
14 dacarbazine . The pooled HR for disease progression was 0.87 (95% CI 0.77 to 0.98) translating to an
15 absolute improvement in median progression free survival of 0.28 months with temozolomide. This
16 hazard ratio combined with the control arm PFS data from Patel et al (2010) suggests 6 month
17 progression free survival of 27% with temozolomide treatment compared to 22% with dacarbazine
18 [Moderate].
19 Two randomised controlled trials (Middleton et al; 2000 & Patel et l; 2011) indicate that there is no
20 significant difference in responses to treatment for patients treated with temozolomide compared
21 with patients treated with dacarbazine (OR for complete response: 1.48 (0.59-3.70); OR for partial
22 response: 1.39 (0.94-2.06)) [Moderate]
23 Two randomised controlled trials (Middleton et al; 2000 & Patel et l; 2011) reported that the rate of
24 Grade 3-4 adverse events ranged from 35%-38% in patients treated with temozolomide compared
25 with 29%-36% for patients treated with dacarbazine [Moderate]
26 Paclitaxel versus Paclitaxel + Carboplatin
27 From one phase II randomised trial with 40 participants (Zimpfer-Rechner et al, 2003), the median
28 overall survival time was 218 days for patients treated with paclitaxel versus 209 days for patients
29 treated with paclitaxel + carboplatin [Low].
30 From one phase II randomised trial with 40 participants (Zimpfer-Rechner et al, 2003), the median
31 progression free survival time was 54 days for patients treated with paclitaxel versus 57 days for
32 patients treated with paclitaxel + carboplatin [Low].
33

GRADE Table 6.25: Should Systemic Anti-cancer treatments (Dacarbazine, Temozolomide, Carboplatin, Paclitaxel, Paclitaxel+Carboplatin) vs. Best
Supportive Care be used in patients with metastatic melanoma?
Quality assessment
Overall Survival - not reported
01 - - - - - none
Progression free survival - not reported
01 - - - - - none
Median Survival - not reported
01 - - - - - none
Response Rates - not reported
01 - - - - - none
Health Related Quality of Life - not reported
01 - - - - - none
Symptom Control - not measured
0 - - - - - none

0 - - - - - none
1
Cochrane Review of RCTs comparing systemic anti-cancer therapy with best supportive care (Crosby et al, 2013)

GRADE Table 6.26: Should Temozolomide vs. Dacarbazine be used in patients with metastatic melanoma?
No of Design Limitations Inconsistenc Indirectness Imprecision Other Temozolo Dacarba Relative Absolute
studies y considerations mide zine (95% CI)
Overall Mortality (Patel et al, 2011; Middleton et al, 2000)
2 randomised Serious,2 no serious no serious no serious none 5854 5794 HR 0.96 Median MODERATE
trials inconsistency indirectness imprecision (0.84- overall
5
1.09) survival 0.33
months
longer with
temozolomid
e (from 0.7
months
shorter to
1.5 months
longer
Disease Progression (Patel et al, 2011; Middleton et al, 2000)
2 randomised serious 2 no serious no serious no serious none 508/585 505/579 HR 0.87 Median MODERATE
trials inconsistency indirectness imprecision (87%) (87%) (0.77- progression
5
0.98) free survival
was 0.28

months
longer with
temozolomid
e (from 1
months
shorter to
0.04 months
longer)
Partial Response (Patel et al, 2011; Middleton et al, 2000)
2 randomised serious1 no serious no serious no serious none 67/557 48/537 OR 1.39 31 more per MODERATE
trials inconsistency indirectness imprecision (12%) (8.9%) (0.94 to 1000 (from 5
2.06) fewer to 79
more)
9.1% 31 more per

1000 (from 5
fewer to 80
more)
Complete Response (Patel et al, 2011; Middleton et al, 2000)
2 randomised Serious1 no serious no serious no serious none 12/557 8/547 OR 1.48 7 more per MODERATE
trials inconsistency indirectness imprecision (2.2%) (1.5%) (0.59 to 1000 (from 6
3.7) fewer to 37
more)
2% 9 more per
1000 (from 8
fewer to 50

more)
3
Health Related Quality of Life (Kiebert et al 2003))
1 randomised serious1, 2 no serious no serious no serious none MODERATE

trials inconsistency indirectness imprecision
Grade 3-4 Adverse Events (Patel et al, 2011; Middleton et al, 2000)
2 randomised Serious1,2 no serious no serious no serious none Rate Rate MODERATE

trials inconsistency indirectness imprecision ranged ranged
from 35%- from
38% in 585 29%-
patients 36% in
579
patients
1
There is a lack of information provided in the methodology to adequately assess factors such as allocation concealment or blinding.
2
Two randomised trials compared temozolomide with dacarbazine however it was not possible to conduct a meta-analysis of the results.
3
This study reports the Health Related Quality outcome measured as part of the Middleton et al, 2000 trial, in more detail. The quality assessment has been based on the information provided both in this publication
and also in the original trial publication.
4
Number of deaths was not reported in Middleton, but hazard ratios were reported so meta-analysis was still possible
5
Patel et al included patients with mucosal melanoma which is not covered by the scope of the guideline. However, as the rates of mucosal melanoma are lower than for other types of melanoma, it was considered
that the numbers of patients in the trial with mucosal melanoma would be low enough as to not impact the results and so the evidence was not downgraded for indirectness.
GRADE Table 6.26: Should Paclitaxel vs. Paclitaxel + Carboplatin be used in patients with metastatic melanoma?

Tumour Response

1 randomised trials serious1 no serious inconsistency no serious indirectness serious2 none

LOW
Overall Survival
LOW
Progression Free Survival
LOW
Toxicity
1 randomised trials serious1 no serious inconsistency no serious indirectness serious2 none LOW
1
Phase II trial - small numbers with no details on method of randomisation
2
A sample size of 242 patients was required to assure statistical significance however the study planned to initially recruit 40 patients in order to evaluate response and as the response rates were <10% in each arm,
recruitment to the trial was stopped early .

2 Systemic Anticancer Treatment versus Best Supportive Care
3 A single Cochrane Review (Crosby et al, 2013) sought to compare a variety of systemic anticancer
4 treatments for metastatic cutaneous melanoma with best supportive care; treatments of interest
5 included cytotoxic chemotherapy and immunotherapy with or without hormone therapy. The review
6 found no randomised trials comparing the effects of systemic therapies for metastatic cutaneous
7 melanoma with best supportive care or placebo.
8 Dacarbazine versus Temozolomide
9 Evidence from two randomised trials (Middleton et al, 2000 and Patel et al, 2010) suggests similar
10 overall survival for patients treated with temozolomide when compared to those treated with
11 dacarbazine. The pooled hazard ratio (HR) for death from any cause was 0.96 (95% CI 0.84 to 1.09)
12 [Moderate].
13 Evidence from two randomised trials (Middleton et al, 2000 and Patel et al, 2010) that patients
14 treated with temozolomide have better progression free survival (PFS) than those treated with
15 dacarbazine . The pooled HR for disease progression was 0.87 (95% CI 0.77 to 0.98). This hazard ratio
16 combined with the control arm PFS data from Patel et al (2010) suggests 6 month progression free
17 survival of 27% with temozolomide treatment compared to 22% with dacarbazine [Moderate].
18 Median overall survival was 9.1 months for patients randomised to temozolomide and 9.4 months
19 for patients in the dacarbazine arm. This compares favourably to a second trial (Middleton et al,
20 2000) in which the median overall survival time was 7.7 months for patients randomised to
21 temozolomide versus 6.4 months for patients randomised to dacarbazine.
22 Figure 6.1: Overall Mortality
Temozolomide Dacarbazine Hazard Ratio Hazard Ratio

Study or Subgroup Events Total Events Total O-E Variance Weight Exp[(O-E) / V], Fixed, 95% CI Exp[(O-E) / V], Fixed, 95% CI
Middleton 2000 (1) 0 156 0 149 -10.1 60.98 27.5% 0.85 [0.66, 1.09]
Patel 2011 320 429 325 430 0 161.16 72.5% 1.00 [0.86, 1.17]
Total (95% CI) 585 579 100.0% 0.96 [0.84, 1.09]

Total events 320 325
Heterogeneity: Chi² = 1.21, df = 1 (P = 0.27); I² = 18%
0.5 0.7 1 1.5 2
Test for overall effect: Z = 0.68 (P = 0.50)
Favours temozolomide Favours dacarbazine
(1) Number of deaths was not reported in this study.

23
24 Figure 6.2: Disease Progression
25

1 Response to treatment was measured in both trials (Middleton et al, 2000; Patel et al, 2011) with a
2 similar rate of response observed for both treatments.
3 Figure 6.3: Complete Response to treatment
Temozolomide Dacarbazine Odds Ratio Odds Ratio

Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI
Middleton 2000e 8 401 4 388 57.4% 1.95 [0.58, 6.54]
Patel 2011 4 156 4 159 42.6% 1.02 [0.25, 4.15]
Total (95% CI) 557 547 100.0% 1.48 [0.59, 3.70]

Total events 12 8
Heterogeneity: Tau² = 0.00; Chi² = 0.47, df = 1 (P = 0.49); I² = 0%
0.01 0.1 1 10 100
Favours [temozolomide] Favours [dacarbazine]
4
5 Figure6. 4: Partial Response to treatment
Temozolomide Dacarbazine Odds Ratio Odds Ratio

Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI
Middleton 2000e 50 401 34 388 72.4% 1.48 [0.94, 2.35]
Patel 2011 17 156 14 149 27.6% 1.18 [0.56, 2.49]
Total (95% CI) 557 537 100.0% 1.39 [0.94, 2.06]

Total events 67 48
Heterogeneity: Tau² = 0.00; Chi² = 0.26, df = 1 (P = 0.61); I² = 0%
0.01 0.1 1 10 100
Favours [Temozolomide] Favours [Dacarbazine]
6
7 Health related quality of life was reported in detail in one study (Kiebert et al, 2003) using a self
8 administered EORTC QLQ-C30 with health related quality of life summarised at weeks 12 and 24 to
9 account for the differences in treatment cycle durations. Baseline health related quality of life scores
10 were available for 251/305 with no significant difference between the treatment groups at baseline
11 observed.
12 At week 12 , HQRL data were available for 50 patients in the temozolomide arm and 31 patients in
13 the dacarbazine arm; patients in the temozolomide arm reported significantly better physical
14 functioning and less fatigue and sleep disturbances compared with patients in the dacarbazine arm
15 and at 24 weeks all subscales with the exception of diarrhoea were better for patients in the
16 temozolomide arm though data were only available for 22 patients in the temozolomide arm and 8
17 patients in the dacarbazine arm.
18 For patients in the temozolomide arm there was a statistically significant improvement in emotional
19 functioning (p≤0.001) at week 12. There were improvements in role, cognitive and social functioning
20 also, however the overall change in global HRQL (all functioning scales) was negligible.
21 For patients in the dacarbazine arm, functioning at week 12 decreased in all functioning scales apart
22 from emotional functioning which showed improvement.
23 Patients in the temozolomide arm reported a reduction in pain, sleep disturbance and appetite loss
24 and increased fatigue, nausea and vomiting, dyspnoea, constipation and diarrhoea.

1 In the dacarbazine arm, patients reported reductions in nausea and vomiting, pain, loss of appetite
2 and diarrhoea and increased fatigue, dyspnoea, sleep disturbance, constipation and financial impact.
3 Paclitaxel vs. Paclitaxel + Carboplatin
4 A single, phase II randomised trial (Zimpfer-Rechner et al, 2003) compared the effectiveness of
5 paclitaxel with and without carboplatin in the treatment of patients with histologically advanced
6 metastatic melanoma. Prior to recruiting the full sample of 242 patients, the study initially recruited
7 40 patients in order to evaluate response to treatment however 6 patients were not included in the
8 analysis due protocol violations (n=4) and not receiving treatment (n=2). The overall response rate in
9 this initial patient sample was <10% in both arms and so recruitment to the study was halted.
10 No major clinical responses to treatment were observed and only 8 patients were classified as stable
11 disease. Following 8 weeks 11/18 patients treated with paclitaxel and 12/16 patients treated with
12 paclitaxel + carboplatin showed evidence of progressive disease.
13 All 34 randomised patients were included in the per protocol analysis and median overall survival
14 time, calculated from treatment initiation to time of death, was similar for both arms (218 days for
15 patients treated with paclitaxel and 209 days for patients treated with paclitaxel + carboplatin).
16 Median progression free survival time was 54 days in the paclitaxel arm and 57 days in the paclitaxel
17 + carboplatin arm.
18 Toxicity, assessed according to the WHO grading system was more pronounced in the paclitaxel +
19 carboplatin arm though overall, toxicity was mild and both treatments were well tolerated.
20 Haematological toxicity, particularly leucopoenia, was frequently observed during the first treatment
21 cycle but less so in the second and third treatment cycles. Overall, grade III/IV leucopoenia was
22 observed in 4/22 administered treatment cycles in the paclitaxel arm and in 6/20 administered
23 cycles in the paclitaxel + carboplatin arm.
24

1 References
2 Included
3 Crosby et al (2013) Systemic treatments for metastatic cutaneous melanoma Cochrane Database of
4 Systematic Reviews
5 Kiebert et al (2003) Health related quality of life in patients with advance metastatic melanoma:
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8 Middleton et al (2000) Randomised phase III study of temozolomide versus dacarbazine in the
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23 vinblastine, temozolomide, interleukin 2, and IFN-alpha 2B in patients with metastatic melanoma.
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1
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5 Blesa, J. M. G (2009). Treatment options for metastatic melanoma. A systematic review. Cancer
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7 Reason: No relevant data reported
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30 review of 41 randomised clinical trials. [Review] [70 refs]. Lancet Oncology 4[12], 748-759.
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33 Reason: Relevant studies already identified and included as appropriate
34 Hellman, K., et al (1990). Phase II study of carboplatin in malignant melanoma. SO: Ann-Oncol
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10 immunotherapy in metastatic melanoma: a meta-analysis of 3273 patients from 20 randomized
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12 Reason: Comparator not relevant to PICO
13 Hodi, F. S et al (2002). Phase II study of paclitaxel and carboplatin for malignant melanoma.
14 American Journal of Clinical Oncology 25[3], 283-286.
16 Jiang, G., Li, R. H., Sun, C., Jia, H. Y., Lei, T. C., and Liu, Y. Q. Efficacy and safety between
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19 Lebbe, C et al (2011) Treatment patterns and outcomes among patients diagnosed with
20 unresectable stage III or IV melanoma in Europe: A retrospective, longitudinal survey (MELODY
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22 Reason: No relevant data can be extracted
23 Lorigan, P et al (2013) Treatment patterns, outcomes, and resource utilisation of patients with
24 metastatic melanoma in the U.K.: the MELODY study. British Journal of Dermatology [Jul 16], epub
25 ahead of print.
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3 Alfa-2b, Dacarbazine, and Interleukin-2. Journal of Dermatological Treatment [Jun 14], epub ahead
4 of print.
5 Reason: Any relevant data included in other studies
6 MacNeil, J. S.(2008) Temozolomide fails to improve survival in EORTC trial. Oncology Report [WINTER
7 2008], 48.
8 Reason: Comment
9 Middleton, M. R et al (2000). Randomized phase III study of temozolomide versus dacarbazine in the
10 treatment of patients with advanced metastatic malignant melanoma.[Erratum appears in J Clin
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13 National Horizon Scanning Centre. Temozolomide (Temodal) for advanced metastatic melanoma:
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16 Reason: No data
17 O'Day, S et al (2007) Subgroup analysis of efficacy and safety analysis of a randomized, double-
18 blinded controlled phase 2 study of STA-4783 in combination with paclitaxel in patients with
19 metastatic melanoma. Archives of Dermatological Research 299[5-6], 294.
21 Paul, M. J., et al (2002) Effect of temozolomide on central nervous system relapse in patients with
22 advanced melanoma. Melanoma Research 12[2], 175-178.
23 Reason: Retrospective non-comparative study
24 Perrin, C., Pracht, M., Talour, K., Adamski, H., Cumin, I., Porneuf, M., Talarmin, M., Mesbah, H.,
25 Audrain, O., Moignet, A., Lefeuvre-Plesse, C., and Lesimple, T. Metastatic melanoma: Results of
26 'classical' second-line treatment with cytotoxic chemotherapies. Journal of Dermatological Treatment
27 25[5], 396-400. 2014.
28 Pflugfelder, A et al (2011) Effectiveness of carboplatin and paclitaxel as first- and second-line

29 treatment in 61 patients with metastatic melanoma. PLoS ONE [Electronic Resource] 6[2], e16882.
31 Quirt, I et al (2007) Temozolomide for the treatment of metastatic melanoma: a systematic review.
32 [Review] [36 refs]. The Oncologist 12[9], 1114-1123.
34 Rietschel, P. Wolchok (2008). Phase II study of extended-dose temozolomide in patients with

35 melanoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology
36 26[14], 2299-2304.

1 Reintgen, D. and Saba, H (1993). Chemotherapy for Stage-4 Melanoma - A 3-Year Experience with
2 Cisplatin, Dtic, Bcnu, and Tamoxifen. Seminars in Surgical Oncology 9[3], 251-255.
4 Rosenberg, S. A., (1999) Prospective randomized trial of the treatment of patients with metastatic
5 melanoma using chemotherapy with cisplatin, dacarbazine, and tamoxifen alone or in combination
6 with interleukin-2 and interferon alfa-2b. Journal of Clinical Oncology 17[3], 968-975.
8 Rusthoven, J. J., et al (1996). Randomized, double-blind, placebo-controlled trial comparing the

9 response rates of carmustine, dacarbazine, and cisplatin with and without tamoxifen in patients with
10 metastatic melanoma. National Cancer Institute of Canada Clinical Trials Group. Journal of Clinical
11 Oncology 14[7], 2083-2090.
12 Reason: Interventions not relevant to PICO
13 Steffens, T. A., et al (1991) A phase II trial of high-dose cisplatin and dacarbazine. Lack of efficacy of
14 high-dose, cisplatin-based therapy for metastatic melanoma. Cancer 68[6], 1230-1237.
16 Rao, R. D et al (2006) Combination of paclitaxel and carboplatin as second-line therapy for patients
17 with metastatic melanoma. Cancer 106[2], 375-382
18 Reason: None comparative study.
19 Robinson, D. W (2012) Health-related quality of life among patients with metastatic melanoma:
20 results from an international phase 2 multicenter study. Melanoma Research 22[1], 54-62.
21 Reason: Treatment comparisons not relevant to PICO
22 Schadendorf, D. Hauschild. (2006) Dose-intensified bi-weekly temozolomide in patients with

23 asymptomatic brain metastases from malignant melanoma: A phase II DeCOG/ADO study. Annals of
24 Oncology 17[10], 1592-1597.
26 Teimouri, F.(2012) Evaluation of the efficacy and side effects of dacarbazine in comparison to
27 temozolomide therapies in treatment of malignant melanoma. a meta-analysis. Value in Health
28 Conference[var.pagings], A411.
29 Reason: Abstract
30 Teimouri, F et al (2013) Efficacy and side effects of dacarbazine in comparison with temozolomide in
31 the treatment of malignant melanoma: a meta-analysis consisting of 1314 patients. Melanoma
32 Research [Jul 20], epub ahead of print.
34 Walker, L et al (2005) Phase II trial of weekly paclitaxel in patients with advanced melanoma.
35 Melanoma Research 15[5], 453-459

1 Yi, J. H et al (2011) Dacarbazine-based chemotherapy as first-line treatment in noncutaneous

2 metastatic melanoma: multicenter, retrospective analysis in Asia. Melanoma Research 21[3], 223-
3 227.
4 Reason: Interventions not relevant to PICO
5 Zhu, W., et al (2014) Temozolomide for treatment of brain metastases: A review of 21 clinical trials.
6 [Review]. World Journal of Clinical Oncology 5;1:19-27

Evidence Tables
Study Quality
Systematic Reviews
Appropriate and clearly Studies relevant to Literature search is Study quality is An adequate description
focused question that is the guideline review sufficiently rigorous to assessed and of the methodology used
relevant to the guideline question identify all the relevant reported is included, and the
review question studies methods used are
appropriate to the
question
Crosby et al Yes Yes Yes Yes Yes
(2013)
Randomised Trials
Study Appropriate Appropriate Comparable Comparable Patient Treatment Equal Equal Appropriate Precise Valid method Investigator
Randomisation Concealment groups at Care apart Blinding Administrato Follow- Treatment follow-up definition of of measuring blinding
baseline from r Blinding up Completion/L length outcome outcome
intervention oss to follow
up
Middleton et al Unclear Unclear Yes Yes No No Unclear Unclear Yes Yes Yes Unclear
(2000)
Patel et al Yes Unclear Yes Yes No No Yes Yes Yes Yes Yes Unclear
(2011)
Kiebert et al Unclear Unclear YEs Yes No No Yes Unclear Unclear Unclear Yes Unclear
(2003)

Zimpfer- Unclear Unclear Yes Unclear No No Yes Yes Unclear Yes Yes Unclear
Rechner et al
(2003)

3 MEDLINE, EMBASE, COCHRANE, NHS EED. Studies conducted in OECD countries other than
4 the UK were considered (Guidelines Manual 2009).
6 were obtained for appraisal. A further 1 paper was excluded as it was not applicable to the
7 PICO. Therefore only one paper (Hillner et al. 2000) was included in the current review of
8 published economic evidence for this topic.
9  The study was a cost-effectiveness analysis of temozolomide (TEM) versus dacarbazine

10 (DTIC) which reported the results in terms of incremental cost per life year gained. Typically
11 papers which do not report quality of life based outcomes are excluded but given the
12 paucity of economic evidence on this topic an exception was made.
13  Hillner et al. is deemed only partially applicable to the decision problem that we are
14 evaluating. This is primarily because the study did not consider a UK setting (US healthcare
15 setting) and did not express health outcomes in terms of quality adjusted life years (QALYs).
16  Very serious limitations were identified with Hillner et al. Most notably, a potential conflict
17 of interest was identified (as the study was funded by the manufacturer of temozolomide)
18 and probabilistic sensitivity analysis (PSA) was not conducted.
19  The base case suggested that treating with TEM over DTIC would cost $36 990 per life-year
20 gained although this varied from temozolomide being dominated (more costly, less
21 effective) to $18 670 per life-year gained when the 2.5% and 97.5% confidence interval
22 estimates for effectiveness were used. No analyses using quality adjusted life-years (QALYs)
23 were presented.
26 were obtained for appraisal. A further 1 paper were excluded as it was not applicable to the
27 PICO. Therefore only one paper (Hillner et al. 2000) was included in the current review of
28 published economic evidence for this topic.
29  Hillner et al was an cost-effectiveness analysis, conducted from a US healthcare payer

30 perspective using effectiveness data from a RCT set in Europe and Australia
31  The study reported cost-effectiveness results in terms of cost per life-year gained. No
32 analyses using quality adjusted life-years (QALYs) were presented.


303  301
 Studies that compare costs and health
possibly relevant papers excluded based on title consequences of interventions were
papers identified & abstract included (i.e. true cost-effectiveness
analyses)
  Studies conducted in OECD countries were

included
 Studies that presented incremental results
2  1
or presented enough information for
full text paper papers excluded based on full incremental results to be derived
obtained text
 Studies that matched the population,
interventions, comparators and outcomes
 specified in PICO
papers included in
evidence review

Applicability
Minor limitations
Potentially serious
limitations
Very serious
Hillner et al. 2000
limitations
2  Hillner et al. is deemed only partially applicable to the decision problem that we are
3 evaluating. This is primarily because the study did not consider a UK setting and did not
4 express health effect values in terms of quality adjusted life years (QALYs).
5  Very serious limitations were identified with Hillner et al. Most notably, a potential conflict
6 of interest was identified (as the study was partially funded by the manufacturer of
7 temozolomide) and probabilistic sensitivity analysis (PSA) was not conducted.
8 References
9 Hillner BE, Agarwala S, Middleton MR. ‘Post hoc economic analysis oftemozolomide versus
10 dacarbazine in the treatment of advanced metastatic melanoma’ Journal of Clinical Oncology 18.7
11 (2000): p1474-80
12

Evidence Tables
Modified GRADE profiles for included economic studies
Hillner et Patients with Intravenous DTIC once a day $3 697 8.6 months Reference One-way Sensitivity Analysis Partially Very Serious
al. advanced, for 5 days with a starting dose mean One-way sensitivity analyses Applicable Limitations.
2000 metastatic of 250mg/m2 repeated every survival were conducted with Not conducted Study funded by
malignant 21 days. incremental cost per life-year from a UK manufacturer.
melanoma who gained ranging from $15 600 health service
are previously to TEM being dominated perspective.
untreated for compared to DTIC PSA not
metastatic conducted.
disease. Threshold Sensitivity Analysis QALY results
Threshold sensitivity analysis not presented
showed that TEM could be (life years only).
increased to $1 805 per
course and still be cost-
effective at a WTP of $50 000
Orally administered TEM once $6 902 9.6 months $3 205 0.087 years $36 990 per
per life-year gained.
a day for 5 days with a starting mean survival Life Year
dose of 200mg/m2 repeated survival gained.
every 28 days.
Comments: Papers which do not report quality of life based outcomes are typically excluded from the review of economic evidence. However, given the paucity of economic evidence on this topic an
exception was made.

Study 1
Author: Type of analysis: Base case (population): 1. Intravenous DTIC once a Effectiveness (Survival months): Funding:
Hillner Cost-effectiveness analysis (CEA) using Patients with advanced, day for 5 days with a starting Unrestricted grant
Year: life years as the effectiveness measure. metastatic malignant dose of 250mg/m2 repeated Mean from Schering-
2000 melanoma who are every 21 days. DTIC (ITT Group) 8.6 Plough
Country: Model structure: previously untreated for TEM (ITT Group) 9.6 Corporation and
USA N/A metastatic disease with a 2. Orally administered TEM Faculty Research
WHO performance status of once a day for 5 days with a Median Award from
Cycle length: either 0,1 or 2. starting dose of 200mg/m2 DTIC (ITT Group) 6.4 American Cancer
N/A repeated every 28 days. TEM (ITT Group) 7.7 Society.
Sample size: DTIC (Eligible Patients) 5.9


Time horizon: DTIC (n=149) TEM (Eligible Patients) 7.9 Comments

Lifetime TEM (n=156) DTIC (Treated Eligible) 5.7
TEM (Treated Eligible) 7.9 DTIC High Cost
Perspective: Age (Median): estimate includes
Base case: US Healthcare Payer DTIC=58.8 years nonmedical costs
Perspective TEM=58.5 years Total costs: i.e. lost wages
Sensitivity Analysis: Societal
Gender (Male): Base Case:
Source of base-line data: DTIC=54% TEM $6 902
TEM=63% DTIC $3 697
Baseline data taken from Middleton et al DTIC High Cost $5 403
(2000) trial described below. Subgroup analysis: DTIC Low Cost $1 717
None Performed 2.5% Lower Limit Increased Survival (-13 days)
Source of effectiveness data: TEM
DTIC $6 902
Effectiveness data was taken from the DTIC High Cost $4 567
Middleton et al trial. This was an open DTIC Low Cost $6 674
label trial conducted at 34 European and 97.5% Upper Limit Increased Survival (76 $2 121
Australian centres comparing days)
intravenous DTIC to TEM. The studied TEM
enrolled 260 patients with final analysis DTIC $6 902
after 210 deaths. The cost-effectiveness DTIC High Cost $2 982
analysis used a difference in mean DTIC Low Cost $4 359
survival of 1.04 months for TEM $444
compared to DTIC. ICER (cost per LY):
TEM versus
Source of utility data: Base Case
DTIC
No health related quality of life DTIC Lower Limit $36 690
weightings were used. DTIC Upper Limit $17 300
$59 830
Source of cost data: 2.5% Lower Limit Increased Survival (-13 days)
DTIC
The price of TEM was estimated based DTIC Lower Limit
on the 1999 Food and Drug DTIC Upper Limit Dominated
Administration approval for treatment of Dominated
adults with refractory anaplastic 97.5% Upper Limit Increased Survival (76 Dominated
astrocytoma. days)
DTIC
Drug costs were taken from 1999 US DTIC Lower Limit
wholesale prices. Insurance DTIC Upper Limit $18 670
reimbursement costs were used for the $12 110
cost of preparation of solution. Uncertainty: $30 750


Costs to family members providing Deterministic Sensitivity Analysis

transportation assistance and emotional TEM price reduced from $1500 to $1000
support were estimated from Hayman et TEM reduced $1000 high cost DTIC
al (1996). ITT median survival used $15 600
Treated eligible population Dominant
Currency unit: $29 590
US$ Threshold Sensitivity Analysis $21 370
Cost per course TEM to be Cost-effective for
Cost year: threshold $50000/LY
Drug costs:1999 $1 805
Other costs not stated.
Discounting:
No discounting performed.

1 7. Follow-up
2 7.1 Frequency and duration of follow-up?
3 Review question: In asymptomatic patients who have undergone treatment with curative
4 intent for melanoma, what is the optimal method, frequency and duration of follow-up?
5 Background
6 After a melanoma is treated, patients have regular checkups. The reason for this is to look for signs
7 of
8 1. melanoma coming back around the scar ( local recurrence)
9 2. melanoma spreading to lymph nodes or other parts of the body
10 3. any new melanomas that may develop
11 At the moment follow up depends on how deep the melanoma was initially and is as follows
12 Stage 0- no follow up after initial treatment and results
13 Stage 1A- 2-4 appointments in 12 months then discharged
14 Stage 1b-2 every 3 months for 3 years then every 6 months for another 2 years
15 Stage 3 and over every 3 months for five years
16 Do any of these things alter the long term outcomes for patients and what do patients prefer?
17 Does follow up make a difference to the outcomes for patients or are we seeing patients too often
18 without making a difference.

Asymptomatic patients  Intensive follow-up  Less intensive follow-up 1. Survival
who have undergone packages (follow packages 2. Stage at recurrence
treatment for melanoma up setting No follow-up (each 3. Time to Recurrence
with curative intent primary/secondary other) 4. Patient preference
care) No imaging 5. HRQL
Stage  HCP – 6. Adverse events
 Ia dermatologists, 7. Cost of imaging
 Ib-II plastic surgeons, 8. Radiation
 III dermatology CNS,
 IV skin cancer CNS,
oncologist,
maxofacial
surgeons, MDT’s,
 Imaging (There are
a variety of ways
we can image for
cancer. 95% of the
time we use CT.
The alternatives are
PET-CT and total
body MRI,
Ultrasound)

Searches:
Are there any study design filters to be used (RCT, All study designs were considered as it was felt that there
systematic review, diagnostic test). would not be much available in the form of randomised
trials. In addition some elements of the question would
require diagnostic studies while other elements would
require more qualitative evidence to inform the outcomes
of interest.
List useful search terms. None provided
Notes Two searches were performed for L1 and L2, one

with follow up terms and one with imaging terms, to
best retrieve possible relevant references for the
asymptomatic population.
The results of Topics L1 and L2 were combined into
one Reference Manager database due to the high
duplication of results between the searches.
2 Search Results
3 Follow-up

Medline 1946-2013 106 25 20/11/2013
Premedline 19 Nov 2013 4 0 20/11/2013
Embase 1947-2013 163 27 20/11/2013
Cochrane Library Issue 11 of 47 2 20/11/2013
November
2013
SSCI)
4 Imaging

Medline 1946-2013 115 27 26/11/2013
Premedline 25 Nov 2013 7 1 26/11/2013
Embase 1947-2013 200 33 26/11/2013
November
2013
SSCI)
5 Total References retrieved (after de-duplication) for L1 and L2 combined: 53

1 Update Search
3 Topic L1 and L2 Follow up
Database name No of references found No of references Finish date of search

retrieved
Medline 4 1 08/10/2014
Embase 22 1 08/10/2014
4 Topic L1 and L2 Imaging
Database name No of references found No of references Finish date of search

retrieved
Medline 4 1 08/10/2014
Embase 32 0 08/10/2014

6 Follow-up
7 1. exp Melanoma/
8 2. melanoma$.tw.
11 5. dubreuilh.tw.
12 6. LMM.tw.
13 7. or/1-6
14 8. (asymptom* or symptomless or no symptoms or no symptom or clinically silent).tw.
15 9. ((absence or absent or without) adj1 (sign*1 or symptom*)).tw.
16 10. Asymptomatic Diseases/
17 11. or/8-10

1 12. 7 and 11
7 18. ((post-treatment or posttreatment) adj1 evaluation*).tw.
9 20. ((post-treatment or posttreatment) adj1 monitoring).tw.
10 21. ((post-treatment or posttreatment) adj1 surveillance).tw.
11 22. or/13-21
12 23. 12 and 22
13
14 Imaging
15 1. exp Melanoma/
16 2. melanoma$.tw.
19 5. dubreuilh.tw.
20 6. LMM.tw.
21 7. or/1-6
25 11. or/8-10
26 12. 7 and 11
28 14. "magnetic resonance imaging".tw.
29 15. (MRI or MR*2 or NMR*1 or MP-MR* or MPMR*).tw.
30 16. ((magnet* or mr*) adj (imaging or exam* or scan* or spectroscop*)).tw.
31 17. diagnostic imaging/
32 18. exp TOMOGRAPHY, X-RAY COMPUTED/
33 19. "comput* tomograph*".tw.
34 20. (comput* adj (axial or assisted) adj tomograph*).tw.
35 21. ((ct or cat) adj scan*).tw.
36 22. exp TOMOGRAPHY, EMISSION-COMPUTED, SINGLE-PHOTON/
37 23. spect.tw.
38 24. "single photon emission computed tomography".tw.
39 25. exp Tomography, Emission-Computed/
40 26. (PET or PET-CT).tw.
41 27. or/13-26
42 28. 12 and 27

1 Screening Results

No Follow-up schedules/information
to PICO
Expert Review
Foreign Language
Single Case Reports

study designs (n=0)
(n=0)

Study Study Design Population Follow-up Protocol Outcomes Comment

Abbott et al Retrospective Case N=34 AJCC stage III who  Clinical exam every 3 months  Detection of All patients were followed up
Series underwent at least one post diagnosis Recurrence for at least 6 months post
annual surveillance PET/CT  Annual PET/CT PET/CT scan
Beasley et al Retrospective Case N=97 patients with stage  Initial 3 month evaluation  Detection of PET CT is the focus for this
Series IIIB-IV melanoma (physical examination) Recurrence study
followed every 3 months for  Survival
1 year and every 6 months
thereafter to determine
progression free survival
 Initial PET-CT within 30 days
of initial treatment, every 3
months for the first year and
every6 months thereafter
Garbe et al (2003) Retrospective Case N=2,008 patients with  Follow up exams every 3  Detection of
Series stage I-IV melanoma at months in the first 5 years metastasis or
diagnosis and every 6 months second primary
thereafter until year 10. melanoma
 Extensive education  Survival
regarding the clinical
characteristics of melanoma
and its metastases, self
examination and recognition
of the signs and symptoms of
recurrence.
 Visits included a complete
history, skin inspection and
clinical examination of the
resection site and lymphatic
drainage areas .
 Abdominal sonography,
chest x-ray and blood tests
every 12 months in stage I-II
disease and every 6 months

in stage III disease.

 Sonographic examination of
the resected tumour scar,
lymphatic drainage area and
regional node regions every
12 months in stage I
melanoma, every 6 months
in stage II melanoma and
every 3-6 months in stage III
melanoma.
Hofmann et al Retrospective Case N=661 patients with stage  Stage I/II patients – physician  Time to
Series I-IV melanoma at visits every 3 months during Recurrence
diagnosis the first 5 years and every 6
months thereafter until end
of year 8 or recurrence
 Annual chest x-ray and
sonography of the abdomen
 Lymph node sonography of
peripheral nodes every 6
months
 Stage III/IV follow-up was
extended by increasing the
frequency of diagnostic
imaging – 6 monthly chest x-
ray and abdominal
sonography and 3 monthly
lymph node sonography.
Kottschade et al Retrospective Case N=106 patients with  Not clearly identified though  Detection of
Series resected stage III-IV the purpose of the review Recurrence
melanoma appears to be PET
Koskivuo et al Retrospective Case N= 30 patients with AJCC  Regular follow-up schedule  Detection of
Series stage IIB-IIIC adult including whole body CT at recurrence
melanoma who were free the time of initial surgery and  Diagnostic
of any clinical signs of clinical exam every 3-6 Accuracy of
metastases months during the first 5 Imaging
years.

 Annual Chest X-Ray and

blood tests
 Secondary CT and physical
exam performed
concurrently with PET
 In addition a whole body
FDG-PET 7-24 months after
primary surgery
Leiter et al (2012) Retrospective Study N=33,384 (stage I-III) Every 3 months during the first 5  Overall Survival
years and every 6 months during  Secondary
years six to ten. Melanoma Free
survival
Follow-up includes:  Recurrence Free
 Whole body skin exam survival
 Lymph node ultrasound 1-2
times a year
 Blood examinations of
tumour marker protein
S100β and lactate
dehydrogenase is patients
with melanoma thickness
≥1mm
Meyers et al Retrospective Case N=118 stage II or SLN  A written copy of the follow-  Time to
(2009) Series positive stage III up schedule was provided to Recurrence
melanoma all patients  Detection of
 Follow-up exam with a Recurrence
health care provider (surgical  Survival
oncologist, dermatologist,
surgical nurse practitioner)
every 3 months for the first 3
years, every 6 months in
years 3-5 and annually to
year ten.
 For patients with stage II
melanoma exam should
include full body

examination of skin and

lymph node basins, annual
blood work, annual chest x-
ray
 For patients with stage III
melanoma follow-up should
additionally include annual
body and brain imaging in
years 1-3
Mooney at al Retrospective Case N=154 stage I-II  No. of visits  Follow up setting
Series  Physical Exam
 Lab tests
 Chest radiographs
Morton et al Case Series N=108 AJCC stage III A/B  Chest X-Ray every 6 months  Time to
with a positive SLNB for 5 years and annually for 5 Recurrence
years thereafter
Murchie et al Randomised Controlled   Patient
Trial Satisfaction
 Guideline
Adherence
Poo-Hwu et al Retrospective Case N=419 patients with stage  Follow-up schedule was  Survival
Series I-III melanoma with dependant on AJCC stage at
pathologically confirmed diagnosis with each visit to
melanoma and no include history taking,
evidence of disease physical exam, compete
following surgery. blood count and liver
function tests.
 Annual Chest X-Ray for stage
I-II and 6 monthly chest X-
Rays for stage III for the first
5 years
 Patients with Stage III had a
baseline CT scan with follow-
up CT scans obtained in 6-12

months in the event of

abnormal findings not clearly
indicative of metastatic
disease
Rinne et al Retrospective Case N=48 patients with high  Chest Radiograph, abdominal  Diagnostic PET is the focus of this study
Series risk melanoma in whom sonography, high res Accuracy of and it appears that patients
PET was performed for re- ultrasound of regional lymph Imaging were followed up using
staging as part of follow- nodes, X-Ray CT of thorax standard techniques and PET
up and abdomen, contrast MRI was additionally carried out in
of the brain patients with suspicious
findings on the standard
follow-up imaging. No data
are presented for the other
imaging modalities.
Romano et al Retrospective study N=340 total  Physical exam every 3  Time and site of
(2010) months for the first 2 years first recurrence
Stage IIIA=95 and every 6 months  Method of
Stage IIIB=155 thereafter (no end time detection
Stage IIIC=90 specified)  Overall Survival
 Follow-up included medical
oncology visits, surgical and
dermatologic visits
 CT scans, CBCs,
comprehensive panels and
lactate dehydrogenase were
obtained before the follow-
up visits

1 Quality of the Evidence
2 Fourteen studies (1 RCT and 13 case series studies) were identified as relevant to this topic. The
3 reported follow-up schedules and protocols were broadly similar across the individual studies in
4 terms of timing of follow-up and components of follow-up, with variation in timing occurring mostly
5 in year one of follow-up depending on the stage of melanoma at diagnosis.
6 Overall quality of the evidence for this topic was considered to be very low on GRADE assessment
7 for all clinical outcomes of interest. For diagnostic outcomes, the quality of evidence was considered
8 to be very low based on assessment using the QUADAS checklist.
10 Follow-up Schedules
11 Follow up schedules varied across the individual studies and within the individual studies depending
12 on the stage at diagnosis of primary melanoma, though all follow-up protocols consisted of clinic
13 visits or physician exams and chest x-ray at regular intervals.
14 Follow up setting
15 One randomised trial assessed the impact of GP led follow-up on patient satisfaction and guideline
16 adherence. The overall findings from the trial suggested that GP lead follow-up improved patient
17 satisfaction and was more guideline compliant than hospital based follow up and that the health
18 status and psychological well-being of patients was not adversely affected (Murchie et al 2010).
19 Patient satisfaction was assessed using a 15 point questionnaire which had been developed for use
20 in a randomised trial of GP-led follow-up for breast cancer patients and was administered at
21 baseline, 3 months, 6 months and 12 months No significant difference in patient satisfaction was
22 observed at baseline though at follow-up there were statistically significant differences between the
23 groups on 6 of the 15 aspects assessed. Members of the intervention group were significantly more
24 likely to think that is was ‘easier to get through by phone if you need to’ and they felt that they could
25 usually see a doctor on the same day if needed and that they would usually be seen by a doctor
26 within 20 minutes of their appointment time. The intervention group also reported feeling that the
27 doctor ‘examines you thoroughly when necessary’ and ‘always prescribes medication if you need it.
28 In addition, patients in the intervention groups were more likely to report being seen by ‘a doctor
29 that knows you well’ (Murchie et al, 2010).
30 Health status and psychological well being was assessed using a SF-36 and the HADS questionnaires
31 and no significant differences were recorded between the groups at baseline or at follow-up
32 (Murchie et al, 2010).
33 In the year before the study, adherence to local guidelines was 84.9% in the intervention group and
34 85.4% in the control group. At follow-up however there was a significant difference in adherence to
35 local guidelines (p=0.02); adherence had increased to 98.1% in the intervention group while
36 adherence decreased in the control group to 80.9% (Murchie et al, 2010).

1 Detection of Recurrence
2 One retrospective study analysed how each first relapse was detected during follow-up in a total of
3 340 patients with stage III melanoma. 62% of local and in-transit recurrences, 49% of nodal
4 recurrences and 37% of systemic recurrences were patient detected. Physical Exam (physician)
5 detected 36% of local and in-transit recurrences, 26% of nodal recurrences and9% of systemic
6 recurrences.
7 37% of patients detected systemic relapse by noticing a new tumour or new symptoms
8 63% of patients had asymptomatic systemic relapse and radiological tests identified recurrence in
9 53% of these patients (CT scans 72%) (Romano et al, 2010).
10 One retrospective case series study reported a sensitivity of 100% for PET in the patient by patient
11 analysis, compared with 84.6% for conventional imaging; overall specificity was 95.5% versus 68.2%.
12 Accuracy of PET was 97.9% versus 77.1. In the lesion by lesion analysis, PET sensitivity was 91.8%
13 compared with 57.5% for conventional imaging, specificity was 94.4% compared with 45% and
14 accuracy was 92.1% compared with 55.7%for conventional imaging % (Rinne et al, 1998).
15 In a retrospective case series study of 106 patients diagnosed with stage III-IV melanoma PET
16 successfully identified an additional 12 cases of asymptomatic recurrences which were amenable to
17 complete surgical resection, representing an additional 25% of cases compared with patients whose
18 follow- up did not include PET (Kottschade et al, 2009).
19 In a retrospective study of 30 stage IIB-IIIC patients, six out of seven recurrences observed were
20 upstaged by FDG PET. Recurrence influenced treatment plans in all cases; three patients underwent
21 surgery with curative intent while four patients with inoperable recurrent disease received
22 chemotherapy and/or interferon (Koskivuo et al, 2007).
23 In a retrospective study following up 118 patients treated for melanoma, no statistically significant
24 difference was observed between patients seeking care for symptomatic recurrence compared with
25 patients whose recurrence was asymptomatic (patient detected, physician detected or detected by
26 routine imaging). (Meyers et al, 2009).
27 Time to Recurrence
28 From two retrospective case series studies (Mooney et al 1998 & Hoffmann et al, 2002) 71%-90.7%
29 of recurrences were recorded in the first 5 years of follow-up.
30 In a retrospective case series with a sample size of 108, there was no significant difference in median
31 time to diagnosis for asymptomatic pulmonary metastases (chest x-ray) and symptomatic pulmonary
32 metastases detected during clinical visits (p=0.30). Median time to diagnosis of pulmonary
33 metastasis was 24 months (95% CI 12-41 months) and median time to the diagnosis of pulmonary
34 disease by clinical follow-up was 16 months (95% CI 10-30 months) (Morton et al, 2009)
35 From one retrospective case series study including 118 patients, median time to recurrence was 14
36 months (2-88 months) and there was no significant difference in time to recurrence when comparing
37 stage II and stage II patients (Meyers et al, 2009).

1 From one retrospective study including 33,384 patients treated for stage I-III primary melanoma and
2 undergoing follow-up, median recurrence free survival time was 44 months (IQR 19-85) and median
3 follow-up time to diagnosis of secondary melanoma was 21 months (IQR 4-61) (Leiter et al, 2012).
4 Survival
5 From one retrospective study with 340 stage III melanoma patients, overall 5-year survival from time
6 of first relapse was 20%, in stage IIIA and IIIB patients and 11% in stage IIIC patients. Regional relapse
7 was associated with longer overall survival than systemic relapse (p<0.001). Symptomatic relapse
8 was associated with shorter survival compared with relapse discovered by physical exam or
9 radiological imaging. RR=2.31, 95% CI=1.68-3.18, p<0.001 (Romano et al, 2010).
10 From one retrospective study (n=33,384) 5 year melanoma specific survival was 91.9% (95% CI 91.5-
11 92.2) and 10 year melanoma specific survival was 87.2% (95% CI 86.6-87.8) (Leiter et al, 2012)
12 From a prospective cohort study of 2,008 patients treated for primary melanoma, early detection of
13 recurrence was associated with a higher survival rate for patients with stage I-II melanoma with a
14 76% overall survival rate at 3 years compared with 38% for late detection (p<0.0001). Early
15 detection was similarly associated with an overall survival rate at 3 years for stage III patients (60%
16 versus 18%; p<0.0001) (Garbe et al, 2003).
17 From one retrospective case series with 154 patients treated for stage I-II, no significant difference
18 in disease-free survival interval (28 months and 23 months respectively, p=0.15) however a
19 statistically significant difference in survival following detection of recurrence was observed. Median
20 disease free survival was 12 months for symptomatic recurrences compared with 24 months for
21 asymptomatic recurrences (p=0.02)
22 5-year overall survival was similar for both groups: 46%±11% for any symptomatic recurrences and
23 47%±12% for any asymptomatic recurrences (p=0.26) (Mooney et al, 1998).
24 From one retrospective case series study with 419 patients treated for stage I-III melanoma, patients
25 with loco-regional recurrences had a better survival rate compared to patients with distant
26 recurrences (median survival was 34 months versus 13 months; p=0.03) (Poo-Hwu et al, 1999).
27 Similarly in a second retrospective case series, following up 118 patients treated for stage II or III
28 melanoma, median survival after recurrence was 22 months for patients with loco-regional disease
29 compared with 7 months for patients with distant recurrence (p<0.0001) (Meyers et al, 2009).
30 From one retrospective case series study with 419 patients treated for stage I-III melanoma, median
31 survival was 27 months compared with 14.5 months for patient detected (symptomatic) recurrences
32 for patients with disease recurrence detected at routine examination (asymptomatic) (p=0.02.
33 controlled for stage, symptomatic versus asymptomatic and local versus distant recurrences) (Poo-
34 Hwu et al, 1999).
35 A second retrospective case series study following up 118 patients treated for stage II or III
36 melanoma, reported no statistically significant difference in survival for patients with a symptomatic
37 recurrence compared with patients who had asymptomatic recurrence (p=0.2) (Meyers et al, 2009)
38 A retrospective case series, following up 118 patients treated for stage II or III melanoma reported
39 no statistically significant different in survival for patients who detected their recurrence compared

1 with patients whose recurrence was physician detected or detected on routine imaging (p=0.6)
2 (Meyers et al, 2009)
3 Diagnostic Efficacy of Imaging
4 From one case series study including 48 patients diagnosed with high risk melanoma and undergoing
5 PET for re-staging; overall sensitivity of PET was 100% compared with 84.6% for conventional
6 imaging, overall specificity was 95.5% versus 68.2%. Accuracy of PET was 97.9% versus 77.1% in the
7 patient by patient analysis. While in the lesion by lesion analysis, PET sensitivity was 91.8%
8 compared with 57.5% for conventional imaging, specificity was 94.4% compared with 45% and
9 accuracy was 92.1% compared with 55.7%for conventional imaging (Rinne et al, 1998).
10 One retrospective case series study including 30 patients with stage IIB-IIIC melanoma, PET
11 sensitivity was 86%, specificity was 96%, positive predictive value was 86% and negative predictive
12 value was 9% for melanoma recurrence (Koskivuo et al, 2007).
13

GRADE Table 7.1: What method, duration and frequency of follow-up should be used in patients
who have undergone treatment for melanoma and who are asymptomatic?
Quality assessment Qualit

No of Design Limitation Inconsistenc Indirectnes Imprecisio Other y
studie s y s n consideration
s s
Time to Recurrence
1 2
6 observationa serious serious no serious no serious none VERY
l studies indirectness imprecision LOW
Detection of recurrence
1 2
Overall Survival
1 2
1
All studies were retrospective reviews
2
Studies varied in their follow-up schedules, protocols and frequencies. Length of follow-up varied across the studies Definitions of
symptomatic and asymptomatic recurrences varied.

Table 7.2: Follow-up protocols for each of the included studies
Follow Up Element Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 onwards

Mooney et al (1998) N=154
Physical Exam 3 monthly 4 monthly 6 monthly 6 monthly 6 monthly Annually
Chest X-Ray 3 monthly 4 monthly 6 monthly 6 monthly 6 monthly Annually
Laboratory Tests 3 monthly 6 monthly 6 monthly 6 monthly 6 monthly Annually
CT Some patients underwent routine CT after first recurrence but no details were provided
PET-CT Not Applicable
MRI Not Applicable
Morton et al (2009) N=108
Physical Exam 6 monthly 6 monthly 6 monthly 6 monthly 6 monthly 6 monthly until year 8, then
annually.
Chest X-Ray 6 monthly 6 monthly 6 monthly 6 monthly 6 monthly 6 monthly until year 8, then
annually.
Laboratory Tests Not Applicable
Chest CT If chest x-ray showed findings suspicious of pulmonary metastases
PET If chest x-ray showed findings suspicious of pulmonary metastases
PET-CT Not Applicable
MRI Not Applicable
Histology If chest x-ray showed findings suspicious of pulmonary metastases
Abbot et al (2011) N=34, stage III
Clinical Exam Every 3 months for at least six months
PET-CT Annually with the first PET-CT scan happening between 12-23 months following diagnosis of stage III disease in asymptomatic patients
Rinne et al (1998) N=48 relevant patients
Chest X-Ray No details Provided
Abdominal Ultrasound No details Provided
High Res ultrasound of No details Provided
regional lymph nodes
X-Ray/CT of the thorax No details Provided
and abdomen
Contrast MRI of the No details Provided
brain
PET-CT Performed within 3 weeks of initial diagnosis

Poo-Hwu et al (1999) N=373

History taking
Stage I 6 monthly 6 monthly 6 monthly Annually Annually Annually
Stage II 4 monthly 4 monthly 4 monthly 6 monthly 6 monthly Annually
Stage III 3 monthly 3 monthly 3 monthly 6 monthly 6 monthly Annually
Physical Exam
Blood counts and liver function tests
Chest X-Ray
Stage I Annually Annually Annually Annually Annually Annually
Stage II Annually Annually Annually Annually Annually Annually
CT scans 6-12 months only if there were abnormal findings initially that were not clearly indicative of metastatic disease
Kottschade et al (2009) N=106
PET/PET CT At least 2 PET scans performed less that 1 year apart as part of regular clinical follow-up (No other details of follow-up protocol have been
provided but included physical exam, CT or MRI scanning and plain film X-ray)
Koskivuo et al (2007) N=30
Whole Body CT A baseline CT scan was taken at the time of initial surgery and a secondary scan and physical exam were performed concurrently with FDG
PET.
Clinical Follow-up Every 3-6 Every 3-6 months Every 3-6 months Every 3-6 months Every 3-6 months Annually
months
Chest X-Ray Every 3-6 Every 3-6 months Every 3-6 months Every 3-6 months Every 3-6 months Annually
months
Blood Tests Every 3-6 Every 3-6 months Every 3-6 months Every 3-6 months Every 3-6 months Annually
months
FDG-PET 7-24 months after primary surgery, independently of the regular follow-up schedule.
Hoffman et al (2002) N=561
Physician Visits 3 monthly 3 monthly 3 monthly 3 monthly 3 monthly Every 6 months until year 8 or
recurrence

Chest X-ray and sonography of the abdomen

Stage I/II Annually Annually Annually Annually Annually Annually
Stage III/IV 6 monthly 6 monthly 6 monthly 6 monthly 6 monthly 6 monthly
Lymph node sonography
Stage I/II 6 monthly 6 monthly 6 monthly 6 monthly 6 monthly 6 monthly
Stage III/IV 3 monthly 3 monthly 3 monthly 3 monthly 3 monthly 3 monthly
Beasley et al (2012) N=97
Physician Visits 3 monthly 6 monthly 6 monthly 6 monthly 6 monthly 6 monthly
PET-CT 3 monthly 6 monthly 6 monthly 6 monthly 6 monthly 6 monthly
Meyers et al (2009) N=118
Clinical Follow Up 3 monthly 3 monthly 6 monthly 6 monthly 6 monthly Annually to year 10
Laboratory Tests)
Stage II Annually Annually Annually Annually Annually Annually
Body and brain imaging (CT of chest abdomen pelvis prior to 2003; whole body PET/CT post 2003; MRI for brain)
Stage III Annually Annually Annually
Murchie et al (2010) N=142
Romano et al (2010) N=340 (stage III)
Medical Oncology Visits 3 monthly 3 monthly 6 monthly 6 monthly 6 monthly
(Physical Exam)
Surgical & 3 monthly 3 monthly 6 monthly 6 monthly 6 monthly
Dermatological Visits
CT scans 3 monthly 3 monthly 6 monthly 6 monthly 6 monthly
Laboratory tests 3 monthly 3 monthly 6 monthly 6 monthly 6 monthly
Leiter et al (2012) N=33.384 (stage I-III)
Physical Exam 3 monthly 3 monthly 3 monthly 3 monthly 3 monthly 6 monthly until 10 years
Lymph node ultrasound 1-2 times a year
Imaging techniques 1-2 times a year
Blood Examinations 1-2 times a year
Garbe et al (2003) N=2008 (all stages)
Physician Visits 3 monthly 3 monthly 3 monthly 3 monthly 3 monthly 6 monthly until 10 years
(including full skin
exam, clinical exam of

scar of primary
resection, lymphatic
drainage areas and all
lymphatic regions)
Abdominal Stage 12 monthly 12 monthly 12 monthly 12 monthly 12 monthly 12 monthly
sonography I-II
and chest X- Stage 6 monthly 6 monthly 6 monthly 6 monthly 6 monthly 6 monthly
Ray III
Blood Tests Stage 12 monthly 12 monthly 12 monthly 12 monthly 12 monthly 12 monthly
I-II
Stage 6 monthly 6 monthly 6 monthly 6 monthly 6 monthly 6 monthly
III
Sonographic Stage I 12 monthly 12 monthly 12 monthly 12 monthly 12 monthly
exam of the Stage 6 monthly 6 monthly 6 monthly 6 monthly 6 monthly
resected II
tumour scar, Stage 3-6 monthly 3-6 monthly 3-6 monthly 3-6 monthly 3-6 monthly
;lymphatic III
drainage area
and regional
node regions

1 Evidence Summary
2 Follow-up Schedules
3 In total, 12 studies reported some details of the follow-up protocol that patients followed after
4 treatment for their primary melanoma. Details reported varied in terms of the timings of the follow-
5 up and the components of follow-up though all protocols were broadly similar in that clinician visits
6 with physical exam and some form of imaging at regular intervals formed the basis for follow-up.
7 Follow up schedule for the cohort included physician visits with chest radiographs every 3 months
8 for the first year following diagnosis, every 4 months during the second year, every 6 months during
9 years 3-5 and annually thereafter. Full blood cell counts and liver function tests were obtained on
10 average, every 3 months in the first year, every 6 months during years 2-5 and annually thereafter.
11 For patients in whom recurrence was detected, surveillance was increased resulting in physician
12 visits every 2-3 months in the first year, every 4 months in the 2-4 years, every 6 months in year five
13 and annually thereafter (Mooney et al, 1998).
14 Patients were followed up every 6 months for seven years and the follow-up schedule included
15 physician exam followed by chest x-ray. For patients with findings suspicious of pulmonary
16 metastases, chest CT was carried out within a week of chest x-ray and PET and fine needle biopsy
17 carried out within a month to confirm findings (Morton et al, 2009).
18 Patients were followed up clinically every 3 months with and surveillance PET-CT annually for the
19 first 36 months of follow-up. All patients in the study have been followed up for at least 6 months
20 following surveillance PET-CT. (Abbot et al, 2011).
21 Patients with stage I disease were followed up every 6 months for the first 3 years and annually
22 thereafter; patients with stage II disease were followed up every 4 months for the first 3 years, 6
23 monthly in year 4 and annually thereafter and patients with stage III disease were followed up every
24 3 months for the first 3 years, 6 monthly in year 4 and 5 and annually thereafter. Follow-up protocol
25 included history taking, physical examination, complete blood counts and liver function tests. Chest
26 x-rays were obtained annually for stage I and II patients and every 6 months for stage III patients and
27 all patients with stage III disease had a baseline CT scan (Poo-Hwu et al, 1999).
28 Standard follow up included chest x-ray, abdominal ultrasound, high resolution ultrasound of the
29 regional lymph nodes, X-ray/CT of the thorax and abdomen, and contrast MRI of the brain. No
30 details were provided regarding the timing of follow-up for patients in this study. PET-CT was used in
31 addition to the standard follow-up methods for the purpose of restaging. And was performed within
32 3 weeks either for the purpose of primary staging or for restaging during follow-up (Rinne et al,
33 1998)
34 A total of 30 patients with stage IIB-IIIC melanoma were followed up regularly with a protocol which
35 included whole body CT at the time of initial surgery and clinical exam every 3-6 months for the first
36 5 years. Follow-up also included annual chest x-ray and blood tests. A whole body PET-CT scan was
37 performed 7-24 months after primary surgery along with a secondary CT and physical exam
38 (Koskivuo et al, 2007).

1 Patients with stage III-IV melanoma were followed up regularly by physical exam, CT or MRI scanning
2 and plain film X-ray. In addition, patients also had at least 2 PET scans performed less than a year
3 apart (Kottschade et al, 2009).
4 One study of 661 patients with stage I-IV melanoma reported a follow-up schedule that was
5 dependent on the stage at diagnosis. All patients had physician visits every 3 months during the first
6 5 years and every 6 months between years 5-8. Stage I-II patients had annual chest x-ray and
7 abdominal sonography and lymph node sonography every 6 months whereas patients with stage III-
8 IV disease the frequency of imaging was increased to 6 months for chest x-ray and 3 months for
9 abdominal sonography and lymph node sonography (Hofmann et al, 2002).
10 97 patients with stage IIIB-IV melanoma were followed-up with an initial 3 month evaluation
11 consisting of physical exam and were subsequently followed every 3 months for 1 year and every 6
12 months thereafter. Patients had a PET-CT scan within 30 days of initial treatment and again every 3
13 months for the first year and every 6 months thereafter (Beasley et al, 2012).
14 118 patients with stage II or III melanoma were followed up with a 3 monthly clinic follow-up for the
15 first three years, 6 monthly visits for years 3-5 and annual visits until year 10. Physical exam included
16 full-body examination of the skin and lymph node basins. For stage II patients, follow-up also
17 included annual laboratory tests and for stage III patients, annual body and brain imaging was
18 carried out in years 1-3 of follow-up. All patients were provided with a written copy of the
19 recommended follow-up schedule and routine follow-up was with a health care provider such as
20 surgical oncologist, dermatologist or surgical nurse practitioner (Meyers et al, 2009).
21 340 patients with stage III melanoma were followed up with 3 monthly medical oncology visits for
22 the first 2 years and 6 monthly thereafter. The study did not specify an end date for follow up of the
23 patients. Follow up also included surgical and dermatological visits and CT scans and laboratory tests
24 prior to clinic visits (Romano et al, 2010).
25 From one retrospective study with 33,384 patients, guidelines recommend follow-up every 3 months
26 during the first 5 years and every 6 months during years six to ten with follow-up to includes whole
27 body skin exam, lymph node ultrasound and blood examinations of tumour marker protein S100β
28 and lactate dehydrogenase is patients with melanoma thickness ≥1mm 1-2 times a year (Leiter et al,
29 2012).
30 One study prospectively followed up 2,008 patients treated for primary melanoma with frequency of
31 follow up exams differing according to stage of melanoma at diagnosis; All patients were followed
32 up every 3 months in the first 5 years and every 6 months thereafter until year 10 and there was a
33 focus on educating patients regarding the clinical characteristics of melanoma and its metastases,
34 self examination and recognition of the signs and symptoms of recurrence. Visits included a
35 complete history, skin inspection and clinical examination of the resection site and lymphatic
36 drainage areas .Abdominal sonography, chest x-ray and blood tests every 12 months in stage I-II
37 disease and every 6 months in stage III disease. Follow-up also included sonographic examination of
38 the resected tumour scar, lymphatic drainage area and regional node regions every 12 months in
39 stage I melanoma, every 6 months in stage II melanoma and every 3-6 months in stage III melanoma
40 (Garbe et al, 2003).

1 Time to Recurrence
2 Early recurrence (within 5 years) occurred in 130 patients while late recurrence (post 5 years)
3 occurred in 24 patients with 88% of symptomatic recurrences and 82% of asymptomatic recurrences
4 occurring early.
5 For asymptomatic patient, the majority of pulmonary first recurrences were found within the first 5
6 years after diagnosis: 18% in years 0-2, 53% in years 3-5 and 29% in years 6-10.
7 Median time between last normal chest radiograph and abnormal chest radiograph indicating
8 recurrent disease was 5 months (1-30 months) (Mooney et al, 1998)
9 There was no significant difference in median time to diagnosis for asymptomatic pulmonary
10 metastases (chest x-ray) and symptomatic pulmonary metastases detected during clinical visits
11 (p=0.30). Median time to diagnosis of pulmonary metastasis was 24 months (95% CI 12-41 months)
12 and median time to the diagnosis of pulmonary disease by clinical follow-up was 16 months (95% CI
13 10-30 months) (Morton et al, 2009)
14 From one retrospective case series study, the median time to detection of recurrence by stage was
15 22 months (2-60.5 months) for stage I; 13.2 months (2.4-71 months) for stage II and 10.6 months
16 (2.3-53.8 months) for stage III (table 12.3)
Stage Recurrences (%) Median time to recurrence between

initial visit and diagnosis (range)
I 9 (5%) 22 months (2-60.5 months)
II 35 (40%) 13.2 months (2.4-71 months)
III 34 (54%) 10.6 months (2.3-53.8 months)
17 Table 7.3: Recurrence by stage (Poo-Hwu et al, 1999)
18 From one retrospective case series study, 12/26 recurrences detected by PET were amenable to
19 surgical resection. One patient elected not to undergo surgery and all 11 patients who had surgery
20 had a subsequent recurrence. Median time to subsequent recurrence was 4.7 months (median
21 follow-up was 1.1 years).
22 32/42 (75%) of recurrences detected by methods other than PET were suitable for resection; all but
23 4 of the 32 patients who underwent resection had a second recurrence. Median time to second
24 recurrence was 5.9 months (Kottschade et al, 2009).
25 In one retrospective case series, 95/127 first relapses were detected in the follow up of patients with
26 75 (77.3%) recurrences observed in the first 3 years. In total, 88 (90.7%) relapses were detected
27 within the first 5 years of follow-up.
28 93 patients with surgically resected loco-regional metastases were enrolled in the follow-up program
29 of whom 60 (64.5%) had a relapse within a median time of 7.8 months (Hoffman et al, 2002)
30 43/118 (36%) patients developed recurrence during the follow-up period (27 stage II and 16 stage III)
31 with a median time to recurrence of 14 months (2-88 months). 38/43 (88%) developed recurrence
32 within 36 months of initial diagnosis. There was no significant difference in time to recurrence when
33 comparing stage II and stage II patients (Meyers et al, 2009).
34 In one retrospective study (n=33,384), recurrences were recorded in 4,999 patients (Stage I=7.1%,
35 Stage II=32.5%, Stage III=51%) and median recurrence free survival time was 44 months (IQR 19-85).

1 10 year recurrence free survival was 78.9% (95% CI 73.1-90.5) for the whole cohort. There was a
2 significant difference in 10 year recurrence free survival according to stage at diagnosis; for stage I it
3 was 89%, for stage II it was 56.9% and for stage III it was 36% (p<0.001) (Leiter et al, 2012).
4 Locoregional recurrence accounted for 37.4%, regional lymph node recurrence accounted for 39.5%
5 and distant metastases for 23% of recurrences (Leiter et al, 2012).
6 Detection of Recurrence
7 One retrospective study analysed how each first relapse was detected during follow-up in a total of
8 340 patients with stage III melanoma. 62% of local and in-transit recurrences, 49% of nodal
9 recurrences and 37% of systemic recurrences were patient detected. Physical Exam (physician)
10 detected 36% of local and in-transit recurrences, 26% of nodal recurrences, 9% of systemic
11 recurrences.
12 37% of patients detected systemic relapse by noticing a new tumour or new symptoms
13 63% of patients had asymptomatic systemic relapse and radiological tests identified recurrence in
14 53% of these patients (CT scans 72%) (Romano et al, 2010).
15 In Stage IIIA, lung and liver were the most common sites of first relapse and 4 patients experienced
16 first relapse to CNS. For Stage IIIB lung and liver were again the most common site of first relapse
17 while 7% experienced first relapse to CNS. In this patient group the majority of relapse occurred by
18 23 months.
19 In Stage IIIC, systemic relapse was evenly distributed among skin/subcutaneous , nodal, lung, liver,
20 brain and bone, 13% of patients experienced first relapse to CNS and the majority of relapse
21 occurred by 18 months.
22 When looking at the site specific risk of relapse, overall 5 year risk of relapse at any site for stage IIIA
23 was 48%, stage IIIB was 71% and for stage IIIC was 85%.
24 One retrospective study estimated the time point after which the site specific risk of first relapse at a
25 given site was ≤5%. In stage IIIA patients, the site specific risk of first relapse dropped to ≤5% at 31
26 months for local/in transit, 24 months for nodal, 32 months for systemic (non-brain) sites.
27 In stage IIIB patients, the site specific risk of first relapse dropped to ≤5% at 22 months for local/in
28 transit, 14 months for nodal, 40 months for systemic (non-brain) sites and in stage IIIC patients, the
29 site specific risk of first relapse dropped to ≤5% at 7 months for local/in transit and 40 months for
30 systemic (non-brain) sites (Romano et al, 2010).
31 In one cohort study (n=2,008 melanoma patients), 71% (n=165) of recurrences were detected and
32 confirmed by a physician during regular follow-up examinations compared with 12% (n=29) detected
33 outside of regular follow-up exams. 13% (n=31) were patient detected and confirmed during regular
34 scheduled follow-up compared with only 3% (n=8) patient detected outside of regular follow-up
35 (Garbe et al, 2003).
36 Symptomatic (patient detected) first recurrence occurred in 89/154 (58%) of cases while
37 asymptomatic (physician detected) first recurrence occurred in 65/154 (42%) of cases
38 Recurrences were detected by physical exam in 72% of cases and of these 57% were detected by the
39 patient or family member while 43% were detected by the physician
40 Constitutional symptoms (pain, weight loss, malaise, neurological symptoms or combination)
41 indicated 17% of recurrences

1 Chest radiograph detected the remaining 11% of recurrences

2 Complete cell counts and liver function tests were never the sole indicator of recurrence
3 Diagnosis of symptomatic disease occurred at 55% of unscheduled visits and 43% of scheduled visits
4 while 2% of the visits unclassified.
5 All asymptomatic recurrences were detected during regularly scheduled follow-up appointments
6 Of the 65 first recurrences detected by physicians, 74% were discovered on physical examination
7 and 26% by chest radiograph.
8 There were 84 second recurrences (55% symptomatic; 36% asymptomatic; 8% unclassified). A total
9 of 53% of asymptomatic recurrences were detected on physical exam, 40% on chest radiograph and
10 7% on CT scan.
11 Chest radiographs detected 30 recurrences in 26 patients (17 first, 12 second and 1 third recurrence)
12 whereas screening chest or abdominal CT detected only 6 recurrences (Mooney et al, 1998).
13 30/108 patients had suspicious or highly probable findings on their chest x-rays however only 11/23
14 had a positive biopsy result giving a sensitivity of 48% (95% CI27%-68%) for serial chest x-rays. It is
15 not clear whether the remaining 7 patients underwent biopsy though from the flow chart it seems 7
16 patients died from their disease (Morton et al, 2009).
17 A total of 78 patients experienced recurrence of which 34 (44%) were developed symptoms which
18 indicated recurrence and 44 (56%) were diagnosed by procedures performed during a scheduled
19 visit (Poo-Hwu et al, 1999).
20 There were 39 loco-regional recurrences of which 20 were detected by the patient.
21 There were 39 distant recurrences of which 25 were detected by the physician
22 Physicians detected 44/78 (56%) of all recurrences and the most common method of detection was
23 history taking or physical examination (25/44). Abnormal chest x-ray detected 8 recurrences while
24 10 recurrences were detected using other imaging methods (CT or MRI) which were obtained due to
25 abnormal findings on the baseline CT scan or due to suspicious findings on physical exam
26 Laboratory results were abnormal in 38 patients at the time of recurrence however there was only 1
27 patient for whom abnormal lab results were the sole indicator of recurrence (Poo-Hwu et al, 1999).
28 A total of 68/106 (64%) patients had recurrences during the course of the study period.
29 Asymptomatic recurrences, detected by PET scanning alone, accounted for 25% of recurrences
30 compared with symptomatic recurrences detected by other methods (Kottschade et al, 2009)
31 32/42 (75%) of recurrences detected by methods other than PET were suitable for resection; all but
32 4 of the 32 patients who underwent resection had a second recurrence. Median time to second
33 recurrence was 5.9 months.
34 PET successfully identified an additional 12 cases of asymptomatic recurrences which were
35 amenable to complete surgical resection, representing an additional 25% of cases compared with
36 patients whose follow- up did not include PET (Kottschade et al, 2009).
37 At initial staging, 2554 imaging procedures were performed in 561 patients yielding 31 metastases
38 (true positive) and 202 false positive results which resulted in further examinations.
39 During follow-up of stage I/II patients, 30 metastases were detected by the patient resulting in early
40 clinic visits while the remaining 45 metastases were detected by the clinician.
41 Patient history and physical examination was the most successful diagnostic tool for both initial
42 staging and follow-up of patients detecting approximately 70% of all relapses compared with lymph

1 node sonography which detected between 15-20%, chest x-ray and sonography of the abdomen
2 which detected less than 10% when used for routine follow-up in stage I/II and stage III patients
3 (Hoffman et al, 2002).
4 Twenty patients with microscopic stage III disease underwent sentinel lymph node biopsy followed
5 by lymph node dissection with a follow-up PET-CT performed annually for a mean follow-up time of
6 35 months (range: 21-54 months). Ten patients (10%) developed recurrences detected on PET-CT
7 and one patient developed a local recurrence which was not picked up on PET-CT.
8 Eight patients underwent a second PET-CT scan and at the time of publication, none had evidence of
9 malignant disease.
10 Fourteen patients developed clinically detectable stage III disease and underwent surveillance PET-
11 CT with a mean follow-up time of 34 months (range: 15-24 months) and four patients were found to
12 have developed recurrences that were first picked up by PET-CT (Abbot et al, 2011).
13 FDG-PET/ CT demonstrated complete response in 19/32 (59%) patients with the remaining patients
14 showing FDG activity but no physical or pathological evidence of disease. An additional 5/64 (8%)
15 were classified as complete responders by FDG-PET/CT however these patients showed persistent
16 disease on physical and/or pathological examination.
17 51 patients were identified as having had out of field disease at a median time after ILI of 212 days
18 (range: 34- 1013). FDG-PET/CT identified a second site of distant disease in 23/51 patients at a
19 median time of 468 days (range: 82-944) (Beasley et al, 2012).
20 Initial recurrence was detected on self-examination in 16 patients who were otherwise

21 asymptomatic, 13 patients developed symptoms which led to the detection of recurrence, 10
22 patients had recurrence detected by the physician during routine follow-up exam, 3 patients had
23 recurrence detected on routine imaging and one patient had high LDH levels which resulted in the
24 detection of regional lymph node basin recurrence No statistically significant difference was
25 observed between patients seeking care for symptomatic recurrence compared with patients whose
26 recurrence was asymptomatic (patient detected, physician detected or detected by routine
27 imaging). (Meyers et al, 2009).
28 Survival
29 Comparing symptomatic and asymptomatic recurrences showed no significant difference in disease-

30 free survival interval (28 months and 23 months respectively, p=0.15) however a statistically
31 significant difference in survival following detection of recurrence was observed. Median disease
32 free survival was 12 months for symptomatic recurrences compared with 24 months for
33 asymptomatic recurrences (p=0.02)
34 5-year overall survival was similar for both groups: 46%±11% for any symptomatic recurrences and
35 47%±12% for any asymptomatic recurrences (p=0.26) (Mooney et al, 1998).
36 Median survival time in patients undergoing surgery (n=9) for pulmonary metastasis was 24 months
37 (95% CI 21-27months) versus 7 months (95% CI 5-9 months) in patients refusing surgery or who
38 were unresectable. The remaining patients received chemotherapy and median survival for these
39 patients was 18 months (95% CI 0-37 months).
40 There was no significant difference in survival between surgical and non-surgical groups (p=0.42)
41 (Mooney et al, 1998).

5-year 10-year 15-year

No Recurrence 92%±2%; 85%±3% 77%±4%
Recurrence 46%±8% 17%±6% 14%±6%
1 Table 7.4 The development of any recurrence significantly affected survival (Mooney et al, 1998).
2 Median survival for symptomatic patients was 36 months (95% CI 18-46 months) compared with 42
3 months (95% CI, 24-84 months) in the asymptomatic group (p=0.53) (Morton et al, 2009)
4 5 year overall survival rates were 95% for stage I, 72% for stage II and 52% for stage III (Poo-Hwu et
5 al, 1999)
6 Patients with loco-regional recurrences had a better survival rate compared to patients with distant
7 recurrences (median survival was 34 months versus 13 months; p=0.03).
8 For patients with disease recurrence detected at routine examination (asymptomatic) median
9 survival was 27 months compared with 14.5 months for patient detected (symptomatic) recurrences
10 (p=0.02. controlled for stage, symptomatic versus asymptomatic and local versus distant
11 recurrences).
12 The estimated 6-month hazard rates for death or recurrence after the date of first visit were 0.0044
13 for stage I, 0.0088 for stage II and 0.0278 for stage III (Poo-Hwu et al, 1999).
14 No difference was observed in survival between patients with symptomatic relapse compared with
15 asymptomatic relapse (p=0.643) however there was a greater number of patients with symptomatic
16 relapse (105 vs. 20) (Hoffman et al, 2002)
17 Median time to progression for complete responders was 2.66 years. 3 year disease free rate was
18 62.2% (95% CI: 40.1%-96.4%) for patients who were classified complete responders by both
19 clinical/pathological examination and FDG-PET/CT compared with only 29.4% (95% CI: 9.9%-87.2%)
20 for the complete responders who had residual FDG-PET/CT activity (Beasley et al, 2012).
21 Median survival after recurrence was 22 months for patients with loco-regional disease compared
22 with 7 months for patients with distant recurrence (p<0.0001).
23 There was no statistically significant difference in survival for patients with a symptomatic
24 recurrence compared with patients who had asymptomatic recurrence (p=0.2)
25 There was no statistically significant different in survival for patients who detected their recurrence
26 compared with patients whose recurrence was physician detected or detected on routine imaging
27 (p=0.6) (Meyers et al, 2009)
28 From one retrospective study (n=33,384), the hazards ratio for first recurrences remained stable in
29 stage IA patients (≤1:125; 1 case/125 persons/year for 10 years). In stage IB an increased HR was
30 observed during the first 36 months (1:37 – 1:40) with overlapping CI after 10 years
31 In stage II there was a decline (1:7 – 1:13) during the first 36 months and decreased to 1:40 after 8
32 years
33 In stage III there was a sharp decline during the first 36 months (1:3 – 1:10) and dropped to 1:30
34 after nine years.
35 From 3 years onwards there was no significant difference between stage II and III
36 The hazard to develop a recurrence decreased significantly with the follow up time for stages I, II, III
37 and IB (p<0.05) but no significant decline was observed for stage IA (p=0.654)

1 The hazard ratio for secondary melanoma decreased from 1:222 – 1:769 after 3 years of follow-up
2 (p=0.049) (Leiter et al, 2012).
3 One cohort study reported that for patients with stage I or II disease at diagnosis, early discovery of
4 melanoma metastasis was beneficial with 76% overall survival rate after 3 years versus 38% survival
5 rate for late detection. Early detection of metastasis was also beneficial for patients with stage III
6 disease at diagnosis, overall survival rate after 3 years for early detection was 60% versus 18% for
7 late detection (Garbe et al, 2003).
8 Diagnostic Efficacy of Imaging
9 PET detected 9 lymph node metastases in 4 patients which had not been picked up by conventional
10 methods (Rinne et al, 1998)
11 PET detected 112 lesions in 48 patients compared with 79 detected by conventional imaging
12 methods. PET was false positive for one lesion compared with conventional imaging which was false
13 positive for 10.
14 PET was false negative for 10 metastases compared with conventional imaging which was false
15 positive for 51 metastases.
16 In the patient by patient analysis, overall sensitivity of PET was 100% compared with 84.6% for
17 conventional imaging, overall specificity was 95.5% versus 68.2%. Accuracy of PET was 97.9% versus
18 77.1%.
19 In the lesion by lesion analysis, PET sensitivity was 91.8% compared with 57.5% for conventional
20 imaging, specificity was 94.4% compared with 45% and accuracy was 92.1% compared with 55.7%for
21 conventional imaging (Rinne et al, 1998).
22 Analysis by different region showed both PET and conventional imaging to have 100% specificity and
23 accuracy for the detection of brain metastases (n=15/15). For neck lymph nodes, sensitivity,
24 specificity and accuracy was 100% for PET compared with 66%, 100% and 84% for conventional
25 imaging.
26 PET had a sensitivity of 69.9%, specificity of 100% and accuracy of 81.1% for the detection of lung
27 metastases compared with 87%, 100% and 91.9% for conventional imaging.
28 For detection of liver metastases, PET had a sensitivity, specificity and accuracy of 100% compared
29 with 60%, 86.6% and 80% for conventional imaging.
30 For imaging of the abdominal lymph nodes, PET had 100% sensitivity, specificity and accuracy
31 compared with conventional imaging which had 83.3% sensitivity, 100% specificity and 94.7%
32 accuracy. PET also showed higher sensitivity (100% vs. 26.6%), specificity (94.4% vs. 77.7%) and
33 accuracy (97% vs. 54.5%) compared with conventional imaging.
34 For peripheral lymph nodes, PET showed higher sensitivity (97.1% vs. 51.4%), specificity (100% vs.
35 92.9%) and accuracy (97.9% vs. 63.3%) compared with conventional imaging (Rinne et al, 1998).
36 There were 7 recurrences observed in the study population and six of them were upstaged by FDG
37 PET. One patient presented with a negative finding at first scanning and was regarded as a false
38 negative after a positive finding on further scanning
39 Recurrence influenced treatment plans in all cases; three patients underwent surgery with curative
40 intent while four patients with inoperable recurrent disease received chemotherapy and/or
41 interferon

1 PET sensitivity was 86%, specificity was 96%, positive predictive value was 86% and negative
2 predictive value was 9% for melanoma recurrence (Koskivuo et al, 2007).
3 At initial staging, imaging procedures detected synchronous metastases in 31/561 patients, 27 of

4 whom were upstaged to stage IIIA/B disease (Hoffman et al, 2002).
5 Overall 5-year survival from time of first relapse was 20%, in stage IIIA and IIIB patients and 11% in
6 stage IIIC patients.
7 Regional relapse was associated with longer overall survival than systemic relapse (p<0.001)
8 Symptomatic relapse was associated with shorter survival compared with relapse discovered by
9 physical exam or radiological imaging. RR=2.31, 95% CI=1.68-3.18, p<0.001
10

1 References
2 Included Studies
3 Abbott, R. A., et al (2011) The role of positron emission tomography with computed tomography in
4 the follow-up of asymptomatic cutaneous malignant melanoma patients with a high risk of disease
5 recurrence. Melanoma Research 21;5:446-449.
6 Beasley, G. M., et al (2012). A multicenter prospective evaluation of the clinical utility of F-18 FDG-
7 PET/CT in patients with AJCC stage IIIB or IIIC extremity melanoma. Annals of Surgery 256;2:350-356.
8 Garbe C. et al (2003) Prospective evaluation of a follow-up schedule in cutaneous melanoma

9 patients: recommendations for an effective follow-up strategy Journal of Clinical Oncology 21;3:520-
10 529
11 Hofmann, U., et al (2002) Primary staging and follow-up in melanoma patients--monocenter

12 evaluation of methods, costs and patient survival. British Journal of Cancer 87;2:151-157
13 Koskivuo, I. O., et al (2007) Whole body positron emission tomography in follow-up of high risk
14 melanoma. Acta Oncologica 46;5:685-690.
15 Kottschade, L. A. S.(2009) Positron emission tomography in early detection of relapse in high-risk

16 melanoma patients: A retrospective review. Community Oncology 6;8:344-347.
17 Leiter U. et al (2012) Hazard rates for recurrent and secondary cutaneous melanoma: an analysis of
18 33,384 patients in the German Central Malignant Melanoma Registry Journal of the American
19 Academy of Dermatology 66:37-45
20 Meyers, M. O., et al (2009) Method of detection of initial recurrence of stage II/III cutaneous
21 melanoma: analysis of the utility of follow-up staging. Annals of Surgical Oncology 16;4:941-
22 947.Murchie et al
23 Mooney, M. M., (1998) Impact on survival by method of recurrence detection in stage I and II
24 cutaneous melanoma. Annals of Surgical Oncology 5:1;54-63.
25 Morton, R. L., Craig, J. C., and Thompson, J. F. (2009) The role of surveillance chest X-rays in the
26 follow-up of high-risk melanoma patients. Annals of Surgical Oncology 16;3:571-577
27 Murchie et al (2010) Patient satisfaction with GP-led melanoma follow-up: a randomised controlled
28 trial British Journal of Cancer 102;1447-1455
29 Poo-Hwu, W. J., Ariyan, S., Lamb, L., Papac, R., Zelterman, D., Hu, G. L., Brown, J., Fischer, D.,
30 Bolognia, J., and Buzaid, A. C. Follow-up recommendations for patients with American Joint
31 Committee on Cancer Stages I-III malignant melanoma. Cancer 86[11], 2252-2258. 1-12-1999.
32 Romano E. Et al (2010) Site and timing of first relapse in stage III melanoma patients: implications for
33 follow-up guidelines Journal of Clinical Oncology 28:3042-3047
34 Rinne, D., Baum, R. P., Hor, G., and Kaufmann, R.(1998) Primary staging and follow-up of high risk
35 melanoma patients with whole-body 18F-fluorodeoxyglucose positron emission tomography: results
36 of a prospective study of 100 patients. Cancer 82:9;1664-1671

1 Excluded Studies
2 Abbott, R. and Harries, M.(2009) Positron-emission tomography with computed tomography

3 (PET/CT) in melanoma follow-up. British Journal of Dermatology Conference[var.pagings].
5 Baker, J. J. M.(2011) Routine restaging PET/CT and detection of recurrence in sentinel lymph node
6 positive stage III melanoma. Annals of Surgical Oncology Conference[var.pagings]
8 Buzaid, A. C. T. (1995) Role of computed tomography in the staging of patients with local-regional
9 metastases of melanoma. Journal of Clinical Oncology 13:8;2104-2108.
10 Reason: No brain metastases data
11 Cromwell, K. D., et al (2012) Variability in melanoma post-treatment surveillance practices by

12 country and physician specialty: a systematic review. Melanoma Research 22;5:376-385
14 Danielsen, M., (2013) Positron emission tomography in the follow-up of cutaneous malignant
15 melanoma patients: a systematic review. [Review]. American Journal of Nuclear Medicine and
16 Molecular Imaging 4;1:17-28.
18 DeRose, E. R., et al (2011) Utility of 3-year torso computed tomography and head imaging in
19 asymptomatic patients with high-risk melanoma. Melanoma Research 21;4:364-369.
21 Kuvshinoff, B. W., Kurtz, C., and Coit, D. G.(1997) Computed tomography in evaluation of patients
22 with stage III melanoma. Annals of Surgical Oncology 4:3;252-258.
24 Francken, A. B., et al (2007) Detection of first relapse in cutaneous melanoma patients: Implications
25 for the formulation of evidence-based follow-up guidelines. Annals of Surgical Oncology 14;6:1924-
26 1933.
28 Miranda, E. P., et al (2004) Routine imaging of asymptomatics melanoma patients with metastasis to
29 sentinel lymph nodes rarely identifies systemic disease. Archives of Surgery 139;8:831-836.
30 Reason: Not a follow-up population
31 Mooney, M. M., et al (1997) Life-long screening of patients with intermediate-thickness cutaneous

32 melanoma for asymptomatic pulmonary recurrences: a cost-effectiveness analysis. Cancer
33 80:6;1052-1064.
35 Orfaniotis, G., et al (2012) Findings of computed tomography in stage IIB and IIC melanoma: a six-
36 year retrospective study in the South-East of Scotland. Journal of Plastic, Reconstructive and
37 Aesthetic Surgery 65;9:1216-1219.
39 Panagiotou, I. E. B. (2001) Evaluation of imaging studies at the initial staging and during follow-up of
40 patients with local-regional malignant melanoma. Journal of B U.ON 64:411-414.

1 Rueth, N. M., et al (2013) Is Surveillance Imaging Effective for Detecting Surgically Treatable
2 Recurrences in Patients With Melanoma? A Comparative Analysis of Stage-Specific Surveillance
3 Strategies. Annals of Surgery [Oct 3], epub ahead of print.
4
5 Romano, E. and Scordo, M. (2009) Characteristics of first relapse in stage III melanoma patients with
6 no evidence of disease (NED): Guidelines for follow-up. Journal of Clinical Oncology
9 Tsao, H., et al (2004) Early detection of asymptomatic pulmonary melanoma metastases by routine
10 chest radiographs is not associated with improved survival. Archives of Dermatology 140;1:67-70.
11 Reason: No brain metastases dataWeiss, M., et al (1995) Utility of follow-up tests for detecting
12 recurrent disease in patients with malignant melanomas. JAMA 274:21;1703-1705.
14

Evidence Tables
Study Quality (Randomised Trials)
Study Appropriate Appropriat Comparabl Comparabl Patient Treatment Equal Equal Appropria Precise Valid Investigat Quality
Randomisati e e groups e Care Blindin Administra Follow- Treatment te follow- definition method of or blinding (GRADE)
on follow up
Murc Yes No Yes Yes No No Yes Yes No Yes Unclear Unclear Moderat
hie et e
al
Appropriate Precise Valid method of Investigators Investigators blind to Risk of Bias Quality
length of definition of an measuring blind to potential confounders
follow-up outcome outcomes participants and prognostic factors?
exposure to
intervention?
Abbot et al Yes Yes Yes No No High Low
Beasley et al Unclear Yes Yes No Unclear High Risk of bias, Low

(2012) particularly in
relation to
population
selection
Garbe et al Unclear Yes Yes No Unclear High Low

(2003)

exposure to
intervention?
Kottschade et al Unclear Yes N/A No No There were several Low
limitations to this
study which may
increase the risk of
bias.
The frequency of
PET scanning was
not uniform with
an average of one
scan every six
months, though
timings varied
individually and all
PET scans were not
performed on the
same scanner.
For some patients,

other methods of
radiographic
surveillance were
interposed
between
scheduled PET

exposure to
intervention?
scans.
Leiter et al Yes Yes Yes No No Retrospective Case Moderate

(2012) Series Study
Meyers et al Unclear Yes Yes No No Retrospective Low

(2009) study with a highly
selected
population (single
institute and all
evaluated by SLNB)
which may not be
reflective of a
wider population
scenario.
Mooney at al Yes Yes Yes N/A N/A Retrospective Low

analysis of medical
records from a
single centre
means this is a
highly selected
population. The
investigators
however state that

exposure to
intervention?
the patient and
tumour
characteristics and
overall survival
rates parallel those
of patients with
local cutaneous
melanoma in the
SEER database
over a comparable
period of time and
consider the
results are
generalisable to
the US population
however whether
this is true for the
UK population is
not clear.
Poo-Hwu et al Unclear Yes Yes No No Patients were Low

followed up for a
minimum of two
years; it is not

exposure to
intervention?
clear whether this
length follow-up is
appropriate to
accurately assess
recurrence. Some
studies suggest
that the majority
of
recurrence/disease
progression occurs
within the first two
years following
treatment for
primary melanoma
however, so this
may be
appropriate. In
fact, in this study,
most recurrences
occurred within
the first two years
(79%) with 47%
occurring in the
first year and 32%

exposure to
intervention?
in the second year.
Romano et al Yes Yes Yes No No Retrospective Low

(2010) Analysis
Study Quality (diagnostic Studies)
Was a Was a Did the study Were the If a Is the Were the Was there Did all Did Were all
sample of design exclusions? interpreted was it
likely to results interval reference the same in the
patients avoided? without pre-
enrolled? knowledge specified? correctly interpreted between standard? reference analysis?
of the classify without index standard?
results of the target knowledge test(s) and
the condition? of the reference
reference results of standard?
standard? the index
test?
Hofmann No Yes Unclear No N/A Unclear Unclear Unclear Unclear Unclear Unclear
et al
Koskivuo Yes Yes Yes Unclear Unclear Unclear Unclear Unclear Unclear Unclear Yes
et al

Morton Yes Yes Yes Yes N/A Yes N/A Yes No Yes Yes
et al
Rinne et Yes Yes Yes Yes N/A Unclear Unclear Unclear Unclear Unclear Unclear
al

Study Aim Study Design Population Follow-up Follow-Up Outcomes and Comment
& Setting Protocol Results
Abbott et To evaluate Retrospective N=34 AJCC stage III who  Clinical exam Patients with  Detection of All PET exams
al the role of Case Series underwent at least one every 3 microscopic Recurrence covered skull
PET?CT as a annual surveillance months post stage 3 disease base to upper
surveillance PET/CT diagnosis Mean follow-up Patients with thigh.
tool in patients  Annual PET/CT time from microscopic stage
with AJCC N=20 patients with diagnosis until 3 disease
stage 3 microscopic stage 3 most recent 2/20 patients
primary disease who underwent clinical review developed
cutaneous sentinel lymph node was 38 months recurrences first
melanoma biopsy followed by lymph (21-54 months) detected on
node dissection. surveillance
Patients with PET/CT
macroscopic
stage 3 disease One patient
developed a local
Mean follow-up recurrence within
time from 1 month which
diagnosis of was not picked up
stage 3 disease PET/CT but was
to most recent picked up on
clinical review clinical review.
was 34 months
(15-52) Patients with
macroscopic stage
3 disease
4/14 patients
developed
recurrences that
were picked up on
PET/CT (3 on
initial PET/CT and

1 on their second
surveillance
PET/CT).
Beasley To compare Retrospective N=97 patients with stage  Initial 3 month Median time  Detection of Highly
et al how response Case Series IIIB-IV melanoma evaluation between the Recurrence selected
to ILI as (physical pre-treatment  Survival population –
assessed by Patients undergoing ILI at examination) scan and first only patients
FDG-PET/CT 2 institutions were followed scan post ILI was undergoing
correlates with included if they had a every 3 117 days (range: isolated limb
clinical and FDG-PET/CT scan within months for 1 45-265). infusion are
pathological 30 days of ILI treatment year and included so
response and and at 3 month intervals every 6 the
to evaluate the for the first year and 6 months population
use of FDG- month intervals thereafter to
PET/CT as a thereafter. determine
surveillance progression
tool for the free survival
detection of  Initial PET-CT
systemic within 30 days
recurrence of initial
treatment,
every 3
months for
the first year
and every6
months
thereafter
Garbe et To determine Retrospective  N=2,008 patients with  Follow up Unclear but all  Detection of Early
al (2003) the Case Series stage I-IV melanoma exams every 3 patients appear metastasis or recurrence
effectiveness at diagnosis months in the to have at least second (metastasis)

of follow-up Patients treated first 5 years 25 months primary was defined
procedures in a between August and every 6 melanoma as organ or
large cohort of 1996 and months  Survival lymph node
patients August 1998 thereafter metastases of
treated for until year 10. Detection of no more than
melanoma for Exclusions  Extensive Recurrence and 2cm in
the early Patients who education second diameter with
detection of had not regarding the less than 10
melanomas
developing previously clinical individual
metastasis undergone characteristics nodes being
 233 disease
observation of of melanoma affected and
recurrences
their disease and its simultaneousl
were detected
and who were metastases, y with an
in 112
referred with self indication for
patients with
suspected examination surgery with
stage I-III
metastasis and curative
melanoma.
Patients who recognition of intent.
 In 39/233
had the signs and
recurrences,
discontinued symptoms of
the patient
previous follow- recurrence.
initially
up and returned  Visits included suspected
with possible a complete recurrence
metastasis history, skin with 31/39
inspection and diagnoses
clinical established
examination during
of the subsequent
resection site follow-up
and lymphatic examinations.
drainage areas
 71% of
.

 Abdominal recurrences
sonography, were detected
chest x-ray and confirmed
and blood on scheduled
tests every 12 follow-up
months in examinations
stage I-II  12% of
disease and recurrences
every 6 were
months in discovered by
stage III physicians not
disease. participating
 Sonographic in the
examination melanoma
of the follow-up
resected schedule who
tumour scar, were
lymphatic consulted for
drainage area other reasons.
and regional  62 newly
node regions developed
every 12 second
months in primaries
stage I were
melanoma, identified in
every 6 46 patients; a
months in single second
stage II primary was
melanoma detected in 36
and every 3-6 patients, 2
months in second

stage III primaries in 6
melanoma. patients and
3-4 second
primaries in 4
patients.
Contribution of
history and
physical
examination
Case history and

physical exam
detected almost
50% of all
recurrences and
80% of metastases
detected on
clinical
examination
consisted of local
recurrences,
satellite or in-
transit metastasis
or regional lymph
node metastasis.

Lymph node
sonography
 3,490 lymph
node
examinations
were carried
out during the
follow-up
period. 5%
revealed a
suspicion of
metastasis
and 9%
required
repeated
sonography.
 <1% of lymph
node
sonography
results in
stage IA were
suggestive of
metastasis
 >20% of
lymph node
sonography
results were

suggestive of
metastasis in
stage IV
patients.
 76% of the
lymph node
sonographies
that were
considered
suspicious for
metastasis
were
confirmed
positive on
further
examination.
Chest x-ray and

abdominal
sonography
 A total of
2,396 chest x-
rays were
performed
with a
suspicion of

metastasis in
only 14
patients (12
confirmed as
true-
positives).
 A total of
2,464
abdominal
scans were
carried out
with only 0.8%
resulting is a
suspicion of
metastasis.
Blood Tests and

Additional
Technical
Investigations
 An additional
4048 technical
investigations
(primarily
blood tests)
were carried
out but were

rarely the first
proof of
metastasis.
 In patients
developing
metastases,
LDH and AP
levels were
found to be
elevated in
16.4% and
12.5% of
patients and
both
percentages
were
significantly
higher than in
patients
without
metastasis
(p<0.0001).
 CT scanning
confirmed
metastasis in
14% of stage II
patients, 23%

in stage III
disease and
40% in stage
IV disease.
Impact on Relapse
Detection
 Almost 50% of
all disease
recurrence
was detected
on physical
exam.
Stage
I=55.6%
Stage
II=51%
Stage
III=48.2%
Stage
IV=13.3%
 Lymph node

sonography
was
responsible
for the
detection of
14% of all
recurrences as
part of routine
follow-up. The
detection rate
was highest
for
recurrences in
stage II
patients
(22.4%)
 Abdominal
sonography
detected only
4% of all
recurrences
Early and Late

detection of
recurrences and

their impact on
overall survival
48% of metastasis
were classified as
early discoveries
and 52% were
classified as late
discoveries.
Rate of detection
of metastasis at
an early stage of
development
varied according
to examination
method used:
Lymph
node
sonograph
y=71%
Clinical
examinati
on=56%

CT
scans=30
%
Chest X-
ray &
Abdomina
l
ultrasoun
d=25%
Patients with
metastasis
detected early and
at later stages
were estimated to
have highly
significant overall
survival rates
(p<0.0001).
In patients with
stage I or II
disease, early
discovery of

melanoma
metastasis was
beneficial with
76% overall
survival rate after
3 years versus
38% survival rate
for late detection.
In stage III
disease, overall
survival rate after
3 years for early
detection was
60% versus 18%
for late detection.
Hofmann To evaluate Retrospective N=661 patients with stage  Stage I/II  Time to 
et al records of Case Series I-IV melanoma at patients – Recurrence
patient with diagnosis physician
stage I-III Single Institute visits every 3
melanoma  630 stage I/II, months during
who had been  27 stage IIIA/B, the first 5
seen and  4 stage IV years and
followed up at patients at the every 6
a single time of first months
institute to diagnosis. thereafter
determine until end of
clinical and year 8 or

cost recurrence
effectiveness  Annual chest
of imaging. x-ray and
sonography of
the abdomen
 Lymph node
sonography of
peripheral
nodes every 6
months
 Stage III/IV
follow-up was
extended by
increasing the
frequency of
diagnostic
imaging – 6
monthly chest
x-ray and
abdominal
sonography
and 3 monthly
lymph node
sonography.
Kottscha Case Series N=106 patients with  Not clearly  Detection of
de et al resected stage III-IV identified Recurrence
melanoma though the
purpose of the
Exclusions: review
Patients did not have appears to be
sufficient time intervals PET

between PET scans.
Koskivuo To determine Case Series N= 30 patients with AJCC  Regular Index Test: PET
et al the clinical stage IIB-IIIC adult follow-up Reference Test:
impact of FDG- Single Institute, melanoma who were free schedule Unclear
PET to detect patients treated of any clinical signs of including
clinically silent between March metastases whole body CT  Detection of
metastases in 2004 and at the time of recurrence
the follow-up November 2005 initial surgery  Diagnostic
of patients and clinical Accuracy of
with high risk exam every 3- Imaging
melanoma. 6 months
during the
first 5 years.
 Annual Chest
X-Ray and
blood tests
 Secondary CT
and physical
exam
performed
concurrently
with PET
 In addition a
whole body
FDG-PET 7-24
months after
primary
surgery
Leiter et Retrospective N=33,384 (stage I-III) every 3 months  Overall
al (2012) Study during the first 5 Survival

years and every 6  Secondary
months during Melanoma
years six to ten. Free survival
 Recurrence
Follow-up Free survival
includes:
 Whole body
skin exam
 Lymph node
ultrasound 1-2
times a year
 Blood
examinations
of tumour
marker
protein S100β
and lactate
dehydrogenas
e is patients
with
melanoma
thickness
≥1mm
Meyers To evaluate Retrospective N=118 stage II or SLN  A written copy Minimum  Time to From 1997-
et al the method of Case Series positive stage III of the follow- follow-up of 2 Recurrence 2003, CT of
(2009) detection of melanoma up schedule years  Detection of the
recurrent Single was provided Recurrence chest/abdome
melanoma in Institution Inclusions to all patients  Survival n/pelvis was
patients with review of Patients who underwent  Follow-up used routinely
stage II-III patients from surgical treatment for exam with a however from
melanoma 1997-2005, AJCC stage II or stage III health care 2003 onwards

who were cutaneous melanoma and provider whole body
initially were evaluated by SLNB (surgical PET/CT scan
evaluated by and underwent routine oncologist, was available
SLNB. follow-up . dermatologist, and became
Does a rigid surgical nurse the imaging
follow-up practitioner) method of
schedule with every 3 choice.
a health care months for
professional the first 3
have any years, every 6
impact on the months in
method of years 3-5 and
detection of annually to
recurrence? year ten.
Does the use  For patients
of imaging in with stage II
stage III melanoma
patients have exam should
any impact on include full
the detection body
of recurrence? examination
of skin and
lymph node
basins, annual
blood work,
annual chest
x-ray
 For patients
with stage III
melanoma
follow-up

should
additionally
include annual
body and
brain imaging
in years 1-3
Mooney Case Series N=154 stage I-II  No. of visits 6.1 years for the  Time to Symptomatic
at al  Physical Exam whole cohort Recurrence recurrence
Medical records ~98% of patients were  Lab tests (median)  Survival was defined
between 1971- seen within 2 months of  Chest as recurrence
1995 from a initial biopsy diagnosis radiographs 7.1 years for Early recurrence detected by a
single and of these: patients alive (within 5 years) patient or
institution in 22% were diagnosed and disease free occurred in 130 family
the United between 1971-1979 at the time of patients while late member while
States 46% were diagnosed the study recurrence (post 5 asymptomatic
between 1980-1989 (median). years) occurred in recurrences
32% were diagnosed 24 patients with were defined
between 1990-1995 55 months for 88% of as those
patients with symptomatic detected by a
AJCC T classification of recurrence recurrences and physician.
local tumours based on (median) 82% of
Breslow thickness (94%) asymptomatic
or Clarks Level (6%) at recurrences
diagnosis was as follows: occurring early.
pTI=29%
pTII=27% For asymptomatic
pTIII=26% patient, the
pT4=7% majority of
pulmonary first
Primary tumours were recurrences were
treated with surgical found within the

excision: wide radical first 5 years after
excision 70%; wide radical diagnosis: 18% in
excision with elective years 0-2, 53% in
lymph node dissection years 3-5 and 29%
22%; others 8%. in years 6-10.
Median time
between last
normal chest
radiograph and
abnormal chest
radiograph
indicating
recurrent disease
was 5 months (1-
30 months)
Symptomatic
(patient detected)
first recurrence
occurred in
89/154 (58%) of
cases while
asymptomatic
(physician
detected) first
recurrence
occurred in
65/154 (42%) of
cases
Recurrences were

detected by
physical exam in
72% of cases and
of these 57% were
detected by the
patient or family
member while
43% were
detected by the
physician
Constitutional
symptoms (pain,
weight loss,
malaise,
neurological
symptoms or
combination)
indicated 17% of
recurrences
Chest radiograph
detected the
remaining 11% of
recurrences
Complete cell
counts and liver
function tests
were never the
sole indicator of
recurrence
Diagnosis of
symptomatic

disease occurred
at 55% of
unscheduled visits
and 43% of
scheduled visits
while 2% of the
visits unclassified.
All asymptomatic
recurrences were
detected during
regularly
scheduled follow-
up appointments
Of the 65 first
recurrences
detected by
physicians, 74%
were discovered
on physical
examination and
26% by chest
radiograph.
There were 84
second
recurrences (55%
symptomatic; 36%
asymptomatic; 8%
unclassified). A
total of 53% of
asymptomatic
recurrences were

detected on
physical exam,
40% on chest
radiograph and
7% on CT scan.
Chest radiographs
detected 30
recurrences in 26
patients (17 first,
12 second and 1
third recurrence)
whereas screening
chest or
abdominal CT
detected only 6
recurrences
Comparing
symptomatic and
asymptomatic
recurrences
showed no
significant
difference in
disease-free
survival interval
(28 months and
23 months
respectively,
p=0.15) however a
statistically

significant
difference in
survival following
detection of
recurrence was
observed. Median
disease free
survival was 12
months for
symptomatic
recurrences
compared with 24
months for
asymptomatic
recurrences
(p=0.02)
5-year overall
survival was
similar for both
groups: 46%±11%
for any
symptomatic
recurrences and
47%±12% for any
asymptomatic
recurrences
(p=0.26)
Morton To evaluate Case Series N=108 AJCC stage III A/B  Chest X-Ray  Time to In some cases
et al the accuracy of with a positive SLNB every 6 Recurrence a biopsy of
(2009) detecting months for 5 suspected
asymptomatic years and There was no lung lesions

pulmonary Exclusions annually for 5 significant was not
metastases by years difference in undertaken if
surveillance  <18 years thereafter median time to widespread
chest x-rays in  evidence of satellite,  Histopatholog diagnosis for metastatic
melanoma in-transit, regional y from fine- asymptomatic disease was
patients with a nodal or distant needle biopsy pulmonary observed on
positive disease at the time of of a lung metastases (chest PET or CT
sentinel lymph SLNB. lesion. x-ray) and scans
node biopsy.  Patients with a history  Patients also symptomatic
of melanoma or had Chest CT pulmonary
previous treatment and PET scans metastases
for melanoma with detected during
chemotherapy or clinical visits
radiotherapy (p=0.30). Median
time to diagnosis
of pulmonary
metastasis was 24
months (95% CI
12-41 months)
and median time
to the diagnosis of
pulmonary
disease by clinical
follow-up was 16
months (95% CI
10-30 months)
30/108 patients
had suspicious or
highly probable
findings on their

chest x-rays
however only
11/23 had a
positive biopsy
result giving a
sensitivity of 48%
(95% CI27%-68%)
for serial chest x-
rays. It is not clear
whether the
remaining 7
patients
underwent biopsy
though from the
flow chart it
seems 7 patients
died from their
disease
Murchie Randomised    Patient 

et al Controlled Trial Satisfaction
 Guideline
Adherence
Poo-Hwu To evaluate Case Series N=419 patients with stage  Follow-up Minimum follow  Survival 
et al the time I-III melanoma with schedule was up of 2 years
interval Single pathologically confirmed dependant on
between initial institution from melanoma and no AJCC stage at
visit and January 1988- evidence of disease diagnosis with
diagnosis of 1994. following surgery. each visit to
recurrence include history
Exclusions: taking,

To determine if  Patients with stage IV physical exam,
recurrence was disease or non- compete
detected cutaneous disease blood count
during a  Patients with and liver
scheduled visit inadequate medical function tests.
by a physician records or follow-up.  Annual Chest
or recognised  In total, 46 patients X-Ray for
by the patient were excluded leaving stage I-II and 6
between visits 373 patients to be monthly chest
by self included in analysis. X-Rays for
examination or  193 (52%) of stage III for
symptoms patients had the first 5
To determine stage I years
which disease (stage  Patients with
procedures 1A=84; stage Stage III had a
identified IIB=109) baseline CT
recurrence in  117 (31%) of scan with
asymptomatic patients had follow-up CT
patients stage II scans
disease (stage obtained in 6-
To determine IIA=85; stage 12 months in
where was the IIB=109) the event of
site of  63 (17%) of abnormal
recurrence patients had findings not
stage III clearly
To determine disease indicative of
survival after metastatic
recurrence disease
To determine
whether the

patient
developed
another
primary
melanoma
Rinne et To analyse the Case Series N=48 patients with high  Chest Index Test: PET 
al sensitivity, risk melanoma in whom Radiograph, Reference Test:
specificity and PET was performed for re- abdominal Histology/clinical
accuracy of staging as part of follow- sonography, detection of
PET as up high res recurrence
compared with ultrasound of
conventional regional Diagnostic
tumour staging lymph nodes, Accuracy of
methods. X-Ray CT of Imaging
thorax and
abdomen,
contrast MRI
of the brain
Romano Retrospective N=340 total  Physical exam  Time and site 
et al study every 3 of first
(2010) Stage IIIA=95 months for recurrence
Stage IIIB=155 the first 2  Method of
Stage IIIC=90 years and detection
every 6  Overall
months Survival
thereafter (no
end time
specified)
 Follow-up
included
medical

oncology
visits, surgical
and
dermatologic
visits
 CT scans,
CBCs,
comprehensiv
e panels and
lactate
dehydrogenas
e were
obtained
before the
follow-up
visits

3 MEDLINE, EMBASE, COCHRANE, NHS EED. Studies conducted in any OECD country were
4 considered (Guidelines Manual 2009).
5  303 possibly relevant papers were identified. Of these, eight full papers relating to this topic
6 were obtained for appraisal. A further four papers were excluded for not reporting an
7 incremental analysis and two further papers were excluded as not being relevant to the
8 PICO. Two papers (Mooney et al (1997) and Krug et al (2009)) were included in the current
9 review of published economic evidence for this topic.
10  Mooney et al was a cost-utility analysis comparing a strategy of adding annual CXR screening
11 for local, regional or metastatic recurrence to usual follow-up in patients diagnosed with
12 intermediate-thickness, local, cutaneous melanoma.
13  When both costs and health benefits were discounted at 5% the addition of annual CXR
14 screening to usual follow-up resulted in an ICER of $215,000 per QALY compared to usual
15 follow-up. During one-way sensitivity analysis the lowest ICER was $109,000 when the
16 increase in survival benefit from surgery for lung recurrences was increased from 8 months
17 to 15 months. Shortening the duration follow-up with CXRs reduced the ICER but still always
18 resulted in a cost per QALY in excess of $100,000, above common thresholds for cost-
19 effectiveness, when compared to usual follow-up.
20  Mooney et al. was deemed only partially applicable to the decision problem that we are
21 evaluating. This is primarily because the study did not consider a UK healthcare setting (USA
22 setting).
23  Very serious limitations were identified with Mooney et al. including not all relevant costs
24 being included in the analysis and lack of probabilistic sensitivity analysis.
25  Krug et al was a cost-effectiveness analysis comparing the use of FDG PET-CT versus whole
26 body CT during follow-up in patients with resected stage IIc and stage III melanoma where
27 there is suspicion of pulmonary metastasised melanoma. The study reported effectiveness
28 outcomes in terms of cost per life month gained. Typically papers which do not report
29 quality of life based outcomes are excluded but given the paucity of economic evidence on
30 this topic an exception was made.
31  The base-case concluded that the inclusion of PET-CT was both cost saving and health
32 improving with a reduction in costs of €1,048 and an increase in survival of 0.2 life months.
33 During probabilistic sensitivity analysis in 71.0% of iterations PET-CT was both cost saving
34 and health improving whilst it was cost increasing and health decreasing in 22.6% of trials.
35  Krug et al was deemed only partially applicable to the decision problem that we are
36 evaluating. This is primarily because the study did not consider a UK setting (Belgian
37 healthcare setting).

1  Potentially serious limitations were identified with Krug et al most notably the lack of
2 transparency around the clinical inputs used in the model.
3  Given the fundamental differences in the interventions considered the studies were not
4 compared.
7 were obtained for appraisal. A further 4 papers were excluded as they only reported costs
8 and 2 were excluded as they were not relevant to the PICO. Two papers (Mooney et al
9 (1997) and Krug et al (2010)) were included in the current review of published economic
10 evidence for this topic.
11  Mooney et al was a cost-utility analysis, conducted from a US healthcare payer perspective.

12 The study reported cost-effectiveness results in terms of cost per QALY over a 20 year time
13 horizon.
14  Krug et al was a cost-utility analysis, conducted from a Belgian healthcare payer perspective.
15 The study reported outcomes in terms of QALYs over a 10 year time horizon.
16  No cost-effectiveness evidence was identified comparing setting (primary/secondary care) of

17 follow-up or healthcare professional conducting follow-up.
18  No cost-effectiveness studies were identified which considered a UK healthcare setting.
 Studies that compare costs and health consequences of

303  295
interventions were included (i.e. true cost-effectiveness
analyses)
possibly relevant papers papers excluded based on title &
identified abstract  Studies conducted in OECD countries were included
 Studies that presented incremental results or presented

enough information for incremental results to be derived

 Studies that matched the population, interventions,
comparators and outcomes specified in PICO
8  6
full text paper obtained papers excluded based on full text
papers included in
evidence review

Applicability
Minor limitations
Potentially serious
Krug et al. 2010
limitations
Very serious Mooney et al. 1997

limitations
2  Mooney et al and Krug et al are deemed only partially applicable to the decision problem
3 that we are evaluating. This is primarily because the studies did not consider a UK healthcare
4 setting. Krug et al also did not express health effect values in terms of quality adjusted life
5 years (QALYs).
6  Very serious limitations were identified with Mooney et al. including not all relevant costs
7 being included in the analysis and lack of probabilistic sensitivity analysis.
8  Potentially serious limitations were identified with Krug et al most notably the lack of
9 transparency around the clinical inputs used in the model.
10 References
11 Mooney MM, Mettling C, Michalek AM et al ‘Life-long screening of patients with intermediate-

12 thickness cutaneous melanoma for asymptomatic pulmonary recurrences: a cost-effectiveness
13 analysis’ Cancer 80.6 (1997): p1052-1064.
14 Krug B, Crott R, Roch I et al ‘Cost-effectiveness analysis of FDG PET-CT in the management of

15 pulmonary metastases from malignant melanoma’ Acta Oncologica 49.2 (2010): p192-200.

Evidence Tables
Modified GRADE profiles for included economic studies
Study 1
Mooney et Hypothetical Usual follow-up. Not Not Reference One-way Sensitivity Analysis Partially Very Serious
al. cohort of reported reported One-way sensitivity analyses Applicable Limitations.
2000 patients were conducted with ICER
diagnosed with ranging from $109,000/QALY Not conducted
intermediate- to $765,000/QALY for the from a UK
thickness lifetime (20year) screening perspective.
[Clark’s level option. When altering the
III], local, frequency and total duration
cutaneous Usual follow-up plus life-long Not Not $7552 $215 000
melanoma 0.035 QALYs2 of the screening program the
annual CXR for local, regional reported Reported ICER ranged from $143,000 to
or metastatic recurrence. $240, 000. Screening was
always more costly and
effective.
Comments:
1
Calculated by NCC-C health economist from reported data

Study Population Comparators Costs Effects Incr costs Incr effects ICERError! Uncertainty Applicability Limitations
Bookmark
not defined.
Study 2
Krug et al Patients with Follow-up with suspected $4 384 90.41 Life Reference Probabilistic Sensitivity Partially Potentially serious
2010 resected stage IIc pulmonary metastases months Analysis: Applicable limitations
and stage III being examined with whole Not conducted
malignant body CT. PET-CT was dominant in from a UK health
melanoma. 71.0% of iterations and service
dominated in 22.6% of perspective.
iterations versus WB-CT.
Follow-up with suspected $3 438 90.61 Life -€946 0.20 PET-CT dominant
pulmonary metastases Months (Both cost saving
being examined with and health
fluorine-18 fluoro-2- improving).
deoxyglucose (FDG)
positron emission
tomography (PET) with X-
Ray computed
tomography(CT)
Comments:


Study 1
Author: Type of analysis: Base case (population): 1)Usual follow-up Incremental cost-effectiveness Ratio(Cost per Funding:
Mooney Cost-Utility Hypothetical cohort of QALY)3 National Institutes
Year: patients diagnosed with 2) Usual follow-up plus life- of Health
1997 Model structure: intermediate-thickness long annual CXR for local, Health benefits discounted 5% Comments
Country: Markov Model [Clark’s level III], local, regional or metastatic
US cutaneous melanoma recurrence Basecase $215,000
Cycle length: Benefit reduced 3 months survival $765,000
1 year Sample size: Hypothetical Benefit increased 15 months survival $109,000
Cohort Low recurrence probability $309,000
Time horizon: High recurrence probability $164,000
20 Years Age (Mean): CXR reduced $30 $180,000
52 years CXR increased $80 $306,000
Perspective: Specificity CXR reduced 90% $292,000
US Healthcare Payer Gender: Specificity CXR increased 98% $166,000
53% Male Reduce surgical candidates 40% $280,000
Source of base-line data: Increase surgical candidates 70% $177,000
% of detected cases amenable to %Asymptomatic lung recurrences reduce $277,000
surgery, annual probabilities of %Asymptomatic lung recurrences increase
recurrence and systemic recurrence and %systemic recurrences decrease $195,000
asymptomatic lung recurrences are %systemic recurrences increases $268,000
taken from Roswell Park Cancer Surgical morbidity decreased 0 months $180,000
Institute (RCPI) data. The RPCI data is Surgical morbidity increased 2 months $188,000
a retrospective cohort study consisting Discount rates cost 3% $251,000
of a cohort of 1004 patients who Discount rates cost 6% $244,000
presented between 1971 to 1995with Discount rate health 5% $203,000
local, cutaneous melanoma. Annual cost increase 5% $195,000
Annual cost increase 8% $198,000
$235,000
Source of effectiveness data: Program length
Retrospective US studies were used to
estimate difference in survival between 5 years
surgery and nonsurgical patients the 5 years4 $168,000
largest of which followed up 945 10 years $143,000
patients with pulmonary metastatic 10 years4 $174,000
melanoma. 20 years4 $156,000
20 years5 $198,000
Diagnostic accuracy of screening was $240,000
taken from one diagnostic accuracy
study and RCPI data. Health benefits not discounted
3
Changes in % lost to follow-up, growth rate for costs, discount rate for costs, mortality rate and cost of chest CT scans also considered with impact being reported as less than 10% change in
ICER. No figures were reported.
4
Chest X-Ray every 6 months in years 1-2.
5
Chest x-ray screening annually with a decrease of 50% in the sensitivity of the screening regimen in years 1-5

Source of utility data: Base case

Utility values were taken from two Benefit reduced 3 months survival $165,000
previous cost-effectiveness studies of Benefit increased 15 months survival $589,000
metastatic breast cancer and hepatitis B. Low recurrence probability $82,000
In these studies clinical opinion was High recurrence probability $242,000
used to estimate utility scores for CXR reduced $30 $124,000
complete remission and progressive CXR increased $80 $138,000
disease. Specificity CXR reduced 90% $235,000
Specificity CXR increased 98% $224,000
Source of cost data: Reduce surgical candidates 40% $128,000
Costs were taken from various sources Increase surgical candidates 70% $216,000
in the medical literature. %Asymptomatic lung recurrences reduce $137,000
%Asymptomatic lung recurrences increase $212,000
The cost of chest x-ray (CXR) was taken %systemic recurrences decrease
from medicare reimbursement costs. %systemic recurrences increases $151,000
Surgical morbidity decreased 0 months $205,000
Surgical morbidity increased 2 months $139,000
Currency unit: US$ Discount rates cost 3% $145,000
Cost year: 1996 Discount rates cost 6% $193,000
Discounting: Annual cost increase 8% $156,000
Costs: 5% per annum $152,000
Benefits: 0%, 5% Program length $181,000
5 years
5 years4
10 years $147,000
10 years4 $125,000
20 years4 $143,000
20 years5 $128,000
$152,000
$174,000
Incremental cost-effectiveness Ratio(Cost per
Life Year)
Health benefits discounted 5%
Base case
Benefit reduced 3 months survival
Benefit increased 15 months survival $199,000
Low recurrence probability $721,000
High recurrence probability $100,000
CXR reduced $30 $286,000
CXR increased $80 $151,000
Specificity CXR reduced 90% $166,000
Reduce surgical candidates 40% $269,000

Increase surgical candidates 70% $154,000

%Asymptomatic lung recurrences reduce $259,000
%systemic recurrences decrease $255,000
%systemic recurrences increases
Surgical morbidity decreased 0 months $180,000
Discount rates cost 3% $166,000
Discount rate health 5% $232,000
$179,000
Program length $183,000
$217,000
5 years
5 years4
10 years
10 years4 $155,000
20 years4 $132,000
20 years5 $161,000
$144,000
$183,000
Health benefits not discounted $220,000
Base case
Benefit reduced 3 months survival
Benefit increased 15 months survival
Low recurrence probability $150,000
High recurrence probability $540,000
CXR reduced $30 $74,000
CXR increased $80 $219,000
Specificity CXR reduced 90% $112,000
Reduce surgical candidates 40% $213,000
Increase surgical candidates 70% $203,000
%Asymptomatic lung recurrences reduce $116,000
%systemic recurrences decrease $124,000
%systemic recurrences increases $192,000
Surgical morbidity decreased 0 months
$169,000
Program length $141,000

$138,000
5 years $164,000
5 years4
10 years
10 years4
20 years4 $133,000
20 years5 $113,000
$130,000
$116,000
$138,000
$157,000
Changes in % lost to follow-up, growth rate for costs, discount rate for costs, mortality rate and cost of chest CT scans also considered with impact being reported as less than 10% change in ICER. No figures were
reported.
1
Chest X-Ray every 6 months in years 1-2.
1
Chest x-ray screening annually with a decrease of 50% in the sensitivity of the screening regimen in years 1-5

Study2
Author: Type of analysis: Base case (population): 1) Follow-up with suspected Effectiveness (Life Months): Funding:
Krug Cost-Effectiveness Patients with resected stage pulmonary metastases being Basecase:
Year: IIc and stage III malignant examined with whole body CT PET-CT 90.61 Comments
2010 Model structure: melanoma. (WB-CT). WB-CT 90.42 Derivation of
Country: Markov Model clinical inputs
Belgium Sample size: Hypothetical 2) Follow-up with suspected Undiscounted effects: unclear.
Cycle length: Cohort pulmonary metastases being PET-CT 97.15 Demographics of
Monthly examined with fluorine-18 WB-CT 96.93 group not
Age (Median): fluoro-2-deoxyglucose (FDG) reported.
Time horizon: Not Stated positron emission tomography Total costs:
10 Year (PET) with X-Ray computed Basecase:
Gender: tomography(CT) PET-CT $3 438
Perspective: Not stated WB-CT $4 384
Belgium healthcare system
ICER (cost per Life Month):
Source of base-line data: Basecase:
Not Stated PET-CT versus WB-CT Dominant
Source of effectiveness data: Undiscounted effects:

Base-line data has been taken from PET-CT versus WB-CT Dominant
published sources and confirmed by

expert opinion. Detailed explanation of

choosing and use of the clinical inputs Uncertainty:
has not been presented.
Probabilistic Sensitivity Analysis: PET-CT was
The probability of developing dominant in 71.0%
pulmonary metastasis was derived from of iterations and
data from the Duke Comprehensive dominated in 22.6%
Cancer Centre as large US database. of iterations versus
WB-CT
Source of utility data:

N/A
Source of cost data:

Unit costs were taken from the public
prices of RIZIV/INAMI as published by
the Health Insurance institute Belgium.
As video assisted thoracoscopy was not
priced the surgery cost was based on
stapled wedge resection, lobectomy,
segmentectomy or pneumectomy.
Resource use was taken from

standardised administrative databases of
19 hospitals between 2005 and 2006.
Currency unit:
Euro(€)
Cost year:
2009
Discounting:
Costs:3.5% per Annum
LMG:1.5% per Annum

1 7.2 Brain Imaging
2 Review question: In patients with melanoma who are undergoing body imaging as part of
3 follow-up and who have no neurological signs or symptoms, should brain imaging be
4 included?
5 Background
6 Patients with node positive or metastatic body disease are at risk of additional metastases within the
7 brain. The probability of a patient having brain metastases increases with increasing stage of
8 disease. A patient with large volume metastatic disease within the chest, abdomen and pelvis is at
9 greater risk of having occult brain metastatic disease compared to a patient who has one involved
10 node. Some centres will routinely image the brain when completing body CT whilst others do not.
11 Detecting asymptomatic metastatic brain disease may facilitate earlier treatment either with
12 radiotherapy or chemotherapy. Questions to consider include:
13 1. What is the probability of having brain metastases when imaging the body?
14 2. What threshold / probability do we choose when deciding to image the brain?
15 3. Is the threshold that triggers body imaging the same threshold we should us to trigger brain
16 imaging?
17 4. Is there an effective treatment for brain metastases that can delay the onset of symptoms and / or
18 improve survival in asymptomatic patients?

Asymptomatic Imaging for brain chest, abdo, pelvis Survival (Lead time bias may
Patients who have metastasis in addition and no imaging for be an issue here that is
undergone to chest, abdo, pelvis. brain metastasis difficult to quantify.)
treatment for Identification of malignant
melanoma with brain metastases
curative intent, HRQL
undergoing imaging
for follow up..
Searches:
Can we apply date limits to the search The GDG did not feel that it was appropriate to apply
date limits to the searches
Are there any study design filters to be used The GDG felt that randomised trials would be the
(RCT, systematic review, diagnostic test). most important study type to answer this question
however they were aware that it was unlikely that
such a trial existed and therefore considered it
inappropriate to apply and study design filters to the
searches.

excluded.



be produced.
List subgroups here and planned statistical Nothing to add

analyses.
2 Search Results
3 Two searches were performed for L2, one with follow up terms and one with imaging terms, to best
4 retrieve possible relevant references for the asymptomatic population.
5 The results of Topics L2 were combined into one Reference Manager database due to the high
6 duplication of results between the searches.
7 Follow-up

found
Medline 1946-2013 106 25 20/11/2013
Premedline 19 Nov 2013 4 0 20/11/2013
Embase 1947-2013 163 27 20/11/2013
November 2013
SSCI)

1 Imaging

found
Medline 1946-2013 115 27 26/11/2013
Premedline 25 Nov 2013 7 1 26/11/2013
Embase 1947-2013 200 33 26/11/2013
November 2013
SSCI)
2 Total References retrieved (after de-duplication): 53
3 Update Search
5 Topic L1 and L2 Follow up

retrieved search
Medline 4 1 08/10/2014
Embase 22 1 08/10/2014
6 Topic L1 and L2 Imaging

retrieved search
Medline 4 1 08/10/2014
Embase 32 0 08/10/2014
7 Medline search strategy (Follow-up)

8 1. exp Melanoma/
9 2. melanoma$.tw.

1 5. dubreuilh.tw.
2 6. LMM.tw.
3 7. or/1-6
7 11. or/8-10
8 12. 7 and 11
14 18. ((post-treatment or posttreatment) adj1 evaluation*).tw.
16 20. ((post-treatment or posttreatment) adj1 monitoring).tw.
17 21. ((post-treatment or posttreatment) adj1 surveillance).tw.
18 22. or/13-21
19 23. 12 and 22
20 Medline search strategy (Imaging)

21 1. exp Melanoma/
22 2. melanoma$.tw.
25 5. dubreuilh.tw.
26 6. LMM.tw.
27 7. or/1-6
31 11. or/8-10
32 12. 7 and 11
43 23. spect.tw.
47 27. or/13-26
48 28. 12 and 27

1 Screening Results

Did not include brain imaging
to PICO

study designs (n=0)
(n=0)
2
3
5 None of the studies indentified for this topic included brain imaging as part of the follow-up
6 protocols for asymptomatic patients.

1 References
2 Excluded Studies
3 Abbott, R. A., et al (2011) The role of positron emission tomography with computed tomography in
4 the follow-up of asymptomatic cutaneous malignant melanoma patients with a high risk of disease
5 recurrence. Melanoma Research 21;5:446-449.
6 Abbott, R. and Harries, M.(2009) Positron-emission tomography with computed tomography

7 (PET/CT) in melanoma follow-up. British Journal of Dermatology Conference[var.pagings].
9 Baker, J. J. M.(2011) Routine restaging PET/CT and detection of recurrence in sentinel lymph node
10 positive stage III melanoma. Annals of Surgical Oncology Conference[var.pagings]
12 Beasley, G. M., et al (2012). A multicenter prospective evaluation of the clinical utility of F-18 FDG-
13 PET/CT in patients with AJCC stage IIIB or IIIC extremity melanoma. Annals of Surgery 256;2:350-356.
14 Buzaid, A. C. T. (1995) Role of computed tomography in the staging of patients with local-regional
15 metastases of melanoma. Journal of Clinical Oncology 13:8;2104-2108.
17 Cromwell, K. D., et al (2012) Variability in melanoma post-treatment surveillance practices by

18 country and physician specialty: a systematic review. Melanoma Research 22;5:376-385
20 Danielsen, M., (2013) Positron emission tomography in the follow-up of cutaneous malignant
21 melanoma patients: a systematic review. [Review]. American Journal of Nuclear Medicine and
22 Molecular Imaging 4;1:17-28.
24 DeRose, E. R., et al (2011) Utility of 3-year torso computed tomography and head imaging in
25 asymptomatic patients with high-risk melanoma. Melanoma Research 21;4:364-369.
27 Francken, A. B., et al (2007) Detection of first relapse in cutaneous melanoma patients: Implications
28 for the formulation of evidence-based follow-up guidelines. Annals of Surgical Oncology 14;6:1924-
29 1933.
31 Garbe C. et al (2003) Prospective evaluation of a follow-up schedule in cutaneous melanoma

32 patients: recommendations for an effective follow-up strategy Journal of Clinical Oncology 21;3:520-
33 529
34 Hofmann, U., et al (2002) Primary staging and follow-up in melanoma patients--monocenter

35 evaluation of methods, costs and patient survival. British Journal of Cancer 87;2:151-157
36 Kuvshinoff, B. W., Kurtz, C., and Coit, D. G.(1997) Computed tomography in evaluation of patients
37 with stage III melanoma. Annals of Surgical Oncology 4:3;252-258.

1 Koskivuo, I. O., et al (2007) Whole body positron emission tomography in follow-up of high risk
2 melanoma. Acta Oncologica 46;5:685-690.
3 Kottschade, L. A. S.(2009) Positron emission tomography in early detection of relapse in high-risk

4 melanoma patients: A retrospective review. Community Oncology 6;8:344-347.
5 Leiter U. et al (2012) Hazard rates for recurrent and secondary cutaneous melanoma: an analysis of
6 33,384 patients in the German Central Malignant Melanoma Registry Journal of the American
7 Academy of Dermatology 66:37-45
8 Meyers, M. O., et al (2009) Method of detection of initial recurrence of stage II/III cutaneous
9 melanoma: analysis of the utility of follow-up staging. Annals of Surgical Oncology 16;4:941-
10 947.Murchie et al Miranda, E. P., et al (2004) Routine imaging of asymptomatics melanoma patients
11 with metastasis to sentinel lymph nodes rarely identifies systemic disease. Archives of Surgery
12 139;8:831-836.
13 Reason: Not a follow-up population
14 Mooney, M. M., et al (1997) Life-long screening of patients with intermediate-thickness cutaneous

15 melanoma for asymptomatic pulmonary recurrences: a cost-effectiveness analysis. Cancer
16 80:6;1052-1064.
18 Mooney, M. M., (1998) Impact on survival by method of recurrence detection in stage I and II
19 cutaneous melanoma. Annals of Surgical Oncology 5:1;54-63.
20 Morton, R. L., Craig, J. C., and Thompson, J. F. (2009) The role of surveillance chest X-rays in the
21 follow-up of high-risk melanoma patients. Annals of Surgical Oncology 16;3:571-577
22 Murchie et al (2010) Patient satisfaction with GP-led melanoma follow-up: a randomised controlled
23 trial British Journal of Cancer 102;1447-1455
24 Orfaniotis, G., et al (2012) Findings of computed tomography in stage IIB and IIC melanoma: a six-
25 year retrospective study in the South-East of Scotland. Journal of Plastic, Reconstructive and
26 Aesthetic Surgery 65;9:1216-1219.
28 Panagiotou, I. E. B. (2001) Evaluation of imaging studies at the initial staging and during follow-up of
29 patients with local-regional malignant melanoma. Journal of B U.ON 64:411-414.
31 Poo-Hwu, W. J., Ariyan, S., Lamb, L., Papac, R., Zelterman, D., Hu, G. L., Brown, J., Fischer, D.,
32 Bolognia, J., and Buzaid, A. C. Follow-up recommendations for patients with American Joint
33 Committee on Cancer Stages I-III malignant melanoma. Cancer 86[11], 2252-2258. 1-12-1999.
34 Rinne, D., Baum, R. P., Hor, G., and Kaufmann, R.(1998) Primary staging and follow-up of high risk
35 melanoma patients with whole-body 18F-fluorodeoxyglucose positron emission tomography: results
36 of a prospective study of 100 patients. Cancer 82:9;1664-1671
37 Romano E. Et al (2010) Site and timing of first relapse in stage III melanoma patients: implications for
38 follow-up guidelines Journal of Clinical Oncology 28:3042-3047

1 Rueth, N. M., et al (2013) Is Surveillance Imaging Effective for Detecting Surgically Treatable
2 Recurrences in Patients With Melanoma? A Comparative Analysis of Stage-Specific Surveillance
3 Strategies. Annals of Surgery [Oct 3], epub ahead of print.
4 Romano, E. and Scordo, M. (2009) Characteristics of first relapse in stage III melanoma patients with
5 no evidence of disease (NED): Guidelines for follow-up. Journal of Clinical Oncology
8 Tsao, H., et al (2004) Early detection of asymptomatic pulmonary melanoma metastases by routine
9 chest radiographs is not associated with improved survival. Archives of Dermatology 140;1:67-70.
10 Reason: No brain metastases dataWeiss, M., et al (1995) Utility of follow-up tests for detecting
11 recurrent disease in patients with malignant melanomas. JAMA 274:21;1703-1705.
13

1 Review question: Where imaging is indicated, is CT or MRI the most appropriate method
2 of imaging for brain metastasis as part of follow-up for asymptomatic patients?
3 Background
4 Both MRI and CT can be used to image the brain. Both techniques are readily available in most
5 hospitals. Body staging is routinely completed with CT and in selected patients PET-CT. Imaging the
6 brain using CT during the CT body examination is more convenient to the patient. In addition this
7 would be quicker and cheaper as compared to completing body imaging and a separate MRI brain
8 study. An additional brain MRI may result in two separate hospital visits for the patient. MRI is
9 however more accurate in detecting and characterizing brain pathology.

Asymptomatic CT for brain imaging MRI for brain Identification of brain
Patients who have imaging metastases
undergone HRQL
treatment for Survival
melanoma with Number of metastases
curative intent,
undergoing imaging
for follow up.
Searches:
Can we apply date limits to the search The GDG did not feel that it was appropriate to apply
date limits to the searches
Are there any study design filters to be used The GDG felt that randomised trials would be the
(RCT, systematic review, diagnostic test). most important study type to answer this question
however they were aware that it was unlikely that
such a trial existed and therefore considered it
inappropriate to apply and study design filters to the
searches.

excluded.



be produced.
List subgroups here and planned statistical Nothing to add

analyses.
2 Search Results

Medline 1946-2013 13 7 27/11/2013
Premedline 26 Nov 2013 1 0 27/11/2013
November 2013
Embase 1947-2013 33 11 27/11/2013
SSCI)
3
4


retrieved search
Medline 0 0 08/10/2014
Embase 7 0 08/10/2014
2 1. exp Melanoma/
3 2. melanoma$.tw.
6 5. dubreuilh.tw.
7 6. LMM.tw.
8 7. or/1-6
12 11. or/8-10
13 12. 7 and 11
14 13. exp Neoplasm Metastasis/
15 14. exp central nervous system neoplasms/
16 15. exp Brain/
17 16. 14 or 15
18 17. 13 and 16
19 18. ((brain or cereb* or intracranial or meninge* or central nervous system) adj3 (metastas* or
20 spread or involvement or carcinosis)).tw.
21 19. 17 or 18

1 30. spect.tw.
5 32. or/18-31
6 34. 12 and 19 and 32
7 Screening Results

No Comparators
to PICO

study designs (n=0)
(n=0)
8
10 No evidence was identified comparing CT scans to MRI scans for the identification of brain
11 metastases in asymptomatic patients treated for melanoma.

1 References
2 Excluded
3 Holtas, S., Cronqvist, S., Holtas, S., and Cronqvist, S. (1981) Cranial computed tomography of patients
4 with malignant melanoma. Neuroradiology 22:3;123-127.
6 Weisberg, L. A.(1985) Computerized tomographic findings in intracranial metastatic malignant

7 melanoma. Computerized Radiology 9:6;365-372.
9 Merimsky, O., et al (1992) Cerebral metastatic melanoma: correlation between clinical and CT
10 findings. Melanoma Research 2:5-6;385-391.
12 Reider-Groswasser, I., et al (1996). Computed tomography features of cerebral spread of malignant

13 melanoma. American Journal of Clinical Oncology 19:1;49-53.
15 Schlamann, M., et al (2008). [Cerebral MRI in neurological asymptomatic patients with malignant
16 melanoma]. [German]. Rofo: Fortschritte auf dem Gebiete der Rontgenstrahlen und der
17 Nuklearmedizin 180:2;143-147.
18 Reason: No comparator/Foreign Language
19 Zukauskaite, R., et al (2013) Asymptomatic brain metastases in patients with cutaneous metastatic
20 malignant melanoma. Melanoma Research 23;1:21-26.
22 Buzaid, A. C., et al (1995) Role of computed tomography in the staging of patients with local-regional
23 metastases of melanoma. Journal of Clinical Oncology 13;8:2104-2108.
25 Miranda, E. P., et al (2004) Routine imaging of asymptomatic melanoma patients with metastasis to
26 sentinel lymph nodes rarely identifies systemic disease. Archives of Surgery 139;8:831-836.
28 Fogarty, G. B., Tartaguia, C., Fogarty, G. B., and Tartaguia, C. (2006) The utility of magnetic resonance
29 imaging in the detection of brain metastases in the staging of cutaneous melanoma. Clinical
30 Oncology (Royal College of Radiologists) 18;4:360-362.
31 Reason: Not follow-up patients/No comparator
32 Noor, R. (2010). Frequency of radiologically confirmed brain metastasis from time of diagnosis of
33 stage IV disease in patients with melanoma. Journal of Clinical Oncology Conference[var.pagings].
35

1 8. Other management issues during follow-up
2 8.1 Managing suboptimal vitamin D levels
3 Review question: How should sub-optimal vitamin D levels be managed in people with
4 melanoma (including supplements and monitoring)?
5 Background
6 The relationship between Vitamin D, sun exposure, cancer and malignant melanoma is complicated
7 and not well understood. What we do know is that normal vitamin D levels are needed to ensure
8 good healthy bones and that Vitamin D can be made in the body in response to exposure to
9 sunshine. We also know that often, when patients are diagnosed with melanoma, they will be given
10 advice to avoid excess sunshine because people worry about a link between exposure to the sun and
11 the development of skin cancer. What is also confusing is that there seem to be some studies that
12 suggest that low levels of Vitamin D are associated with melanomas that don’t have such a good
13 outlook and are more likely to cause problems. So we need to find out whether we should be
14 measuring Vitamin D levels in patients with melanoma when they are first diagnosed and, if the
15 results are low, whether we should be offering patients vitamin D supplements or not. This whole
16 problem is made even more complicated by the fact that we are not really sure what the best levels
17 of Vitamin D are, the amount of sunshine that is needed to ensure the right amount of vitamin D is
18 made in the body and how best to give Vitamin D supplements to people who are short of this
19 vitamin.

Patients with melanoma &  Vitamin D supplements  No 1. Overall
deficient or insufficient levels  Vitamin D level supplements Survival
of vitamin D: supplements & monitoring  No 2. Evidence of
 Vitamin D level monitoring monitoring impaired
Vitamin 25-Hydroxy Vitamin  Dietary intervention  Sun avoidance bone health
D2 D3 levels  Lifestyle advice ((including advice 3. Cardiovascula
sun exposure advice at r disease?
specific times of the day e.g.
early morning / late
afternoon: see Genomel &
BAD websites)
Searches:
Can we apply date limits to the search (Please No date limits to be applied to the searches
appropriate)

Are there any study design filters to be used (RCT, Any study type but preferably
systematic review, diagnostic test).  Meta-analysis vitamin D supplementation
trials
 Systematic review vitamin D and bone
health
 Systematic review vitamin D and cancer
survival
Systematic reviews metabolic syndrome or

cardiovascular disease
List useful search terms. (This can include such Vitamin D

interventions etc) Definition of vitamin D insufficiency/deficiency
Vitamin D levels and skin type (levels reported to be

lower in white people with skin which burns rather
than white people who do not burn i.e. people at
risk of melanoma (with fair skin)
25 hydroxyvitamin D2/D3
3 Relevant studies will be identified through sifting the abstracts and excluding studies clearly not
4 relevant to the PICO. In the case of relevant or potentially relevant studies, the full paper will be
5 ordered and reviewed, whereupon studies considered to be not relevant to the topic will be
6 excluded.
7 Studies which are identified as relevant will be critically appraised and quality assessed using GRADE
8 methodology and NICE checklists. Data relating to the identified outcomes will be extracted from
9 relevant studies.
10 If possible a meta-analysis of available study data will be carried out to provide a more complete
11 picture of the evidence body as a whole.
12 An evidence summary outlining key issues such as volume, applicability and quality of evidence and
13 presenting the key findings from the evidence as it relates to the topic of interest will be produced.
14 Search Results

Medline 1946-2013 224 74 03/12/2013
Premedline 24 13 03/12/2013
Embase 1947-2013 518 184 04/12/2013
June 2013 (all

years)
SSCI)
1 Update Search
3 of December 2013 onwards.

Medline 26 10 15/10/2014
Embase 91 19 15/10/2014
1 reference found in Pubmed 15/10/2014

5 1. exp Melanoma/
6 2. melanoma*.tw.
7 3. (maligna* adj1 lentigo*).tw.
8 4. (Hutchinson* adj1 (freckle* or melano*)).tw.
9 5. dubreuilh.tw.
10 6. LMM.tw.
11 7. or/1-6
12 8. Vitamin D/
13 9. vitamin d.tw.
14 10. (Calciol or Cholecalciferol* or Hydroxycholecalciferol* or Hydroxyvitamins D or Hydroxyvitamin D
15 or Calcidiol or 25-Hydroxyvitamin D3 or 25 Hydroxyvitamin D3 or 25-Hydroxycholecalciferol or 25
16 Hydroxycholecalciferol or Hidroferol or Calcifediol or Calderol or Dedrogyl or Dihydroxyvitamin D or
17 Dihydroxycholecalciferol or Bocatriol or Calcitriol or Calcijex or Decostriol or MC1288 or MC-1288 or
18 MC 1288 or Osteotriol or Renatriol or Rocaltrol or Silkis or Sitriol or Soltriol or Tirocal or 25-
19 dihydroxy-20-epi-Vitamin D3 or Calciferol* or Ergocalciferol* or Hydroxyvitamin D2 or Ercalcidiol* or
20 Hydroxyergocalciferol or Dihydrotachysterin or Tachystin or Calcamine or Deparal or Ricketon or
21 Trivitan or Vigorsan or Diaverene or Hydroxycalcidiol or Secalciferol* or Dihydroxycholecalciferol or
22 Delakmin or Calcidiol*).tw.
23 11. or/8-10
24 12. 7 and 11
25

1 Screening Results

Expert Reviews
Abstract Only
No Comparators
to PICO

study designs (n=1)
(n=0)
4 The evidence relating to the management of vitamin D levels in melanoma patients consisted of one
5 systematic review (Gandini et al 2008) and a number of cohort studies and case-control studies
6 (Rosso et al, 2007; Nurnberg et al, 2009; Newton-Bishop et al, 2009; Gandini et al, 2013; Davies et al,
7 2011; Idorn et al, 2011). .


Rosso et al Cohort study Cases = 260 To investigate survival Interviews using a questionnaire which included Not clearly stated though
(2007) (Retrospectiv Controls = 416 in a cohort of socio-demographic variables including age at appears to be survival
e ananlysis melanoma patients diagnosis, sex, level of education and
of a Case- with detailed occupation, host factors including pigmentation
Control information on sun and skin reaction to sun exposure and sun
Study) exposure and other exposure history.
risk factors
Gandini et Systematic N=6 studies To investigate Vitamin D intake Dose-response effect of
al (2008) Review and (721cutaneous whether FokI and vitamin D intake on
Meta- melanom cases, Bsml, 25(OH)D serum Estimates using Vitamin D intake in food were melanoma risk
analysis 4084 non- levels and intake of chosen over intake from supplementation.
melanoma skin vitamin D impact skin
cancer) cancer risk. Estimates in the individual studies were
adjusted for afe, hair colour and family history
of cutaneous melanoma (Wienstock, 1992) and
for age, sex, dysplastic nevi, education and skin
type (Millen, 2004).
Nurnberg Case-Control Cases=205 To evaluate the Self-administered questionnaire Not clearly stated
et al Study patients with possible association of (association of vitamin D
(2009) histologically a direct measure of levels with a number of
proven cutaneous vitamin D status, factors as outlined in the aim
melanoma serum vitamin D levels of the study)
Controls=141 (71 and an indirect
volunteers measure of vitamin D
visiting the Dept status (UV-exposure)
of Dermatology; on the incidence and


70 patients of the clinical outcome of
Dept of melanoma patients.
Orthopaedic
Surgery)
Newton- Retrospectiv Retrospective To test the findings Patient reported questionnaire collecting data Risk of relapse
Bishop et e Pilot Study Pilot Study: from a retrospective on regular use of vitamins, minerals, fish oils,
al (2009) Prospective N=271 patients pilot study that fire or other food supplements 1 year prior to
Cohort Study with melanoma vitamin D may protect interview).
against melanoma
Relapsers=131 recurrence
Non-
relapsers=169
Prospective Relapse/Survival data colloected via annual
Cohort Study: patient questionnaire, cancer registry and
n=872 patients clinical notes.
with stage I-IIIA
melanoma Patient reporte height and weight used to
calculate BMI.
Serum 25(OH)D levels measured
Davies et Case-Control Cases=960 Not clearly stated but Questionnaire and telephone interview Predictors of blood vitamin D
al (2011) Study Controls=513 seems to be to collecting data on sun exposure including: concentrations
investigate the effect Weekday exposure and weekend exposure in
of a number of factors sunny and in colder weather
including Holiday sun exposure at low and higher
supplementation, sun latitudes


exposure and
sunscreen use on
blood vitamin D
concentrations.
Idorn et al Descriptive Cases=42 To assess changes in Interviews about sun exposure behaviour Changes in UV exposure in
(2011) Case-Control Controls=26 UVR exposure in patients with cutaneous
Study patients with melanoma according to time
cutaneous melanoma of diagnosis.
using objective
surrogate parameters
Gandini et Cohort Study N=742 To investigate if Self administered Self administered Melanoma Recurrence
al (2013) (2 groups, i different indicators of questionnaire at questionnaire during
retrospective UV exposure, initial diagnosis follow-up
,1 collected before and
prospectivee after diagnosis are Median time from
) associated with diagnosis to
Breslow Thickness and questionnaire: 2.6 years
recurrence (1-6 years interquartile
range)

1 Study Quality
2 All studies included in the review were cohort studies or case-control studies and one systematic
3 review and meta-analysis of case-control studies. There was a high degree of heterogeneity between
4 the studies in relation to the methodology, populations and outcomes and none of the studies could
5 be considered to directly report on the comparisons of interest in the PICO and the outcomes
6 reported were not those listed in the PICO
7 Inconsistency could not be assessed as the degree of heterogeneity across the individual studies
8 means that it would not be appropriate to make any direct comparisons between the results of
9 individual studies.
10 Many of the studies considered the potential effect of confounders when conducting the analysis
11 and adjusted for a range of potential confounders however the list of potential confounders was
12 varied across the individual studies. It is possible that a dose-response relationship might exist
13 between vitamin D levels and melanoma risk however the evidence is too poor and limited to
14 upgrade the quality of evidence on this basis.
15 Many of the studies relied on self-reporting of data through the use of questionnaires and therefore
16 there is a high risk of recall bias. Many of the studies also reported their outcomes based on the
17 whole population in the study rather than separately by cases and controls.
19 One very low quality case-control study reported that patients who had serum vitamin levels
20 <10ng/ml had earlier distant disease compared with patients serum levels >20ng/ml though the
21 difference was not statistically significant (24.37 months versus 29.47; p=0.641) (Nurnberg et al.
22 2009).
23 Moderate quality evidence from a prospective cohort study including 872 patients, reported that,
24 after adjusting for age, sex, Townsend score, tumour site, Breslow thickness and BMI on multivariate
25 analysis, higher serum vitamin D levels showed a protective effect for relapse free survival (HR=0.79,
26 95% CI 0.64-0.96) and overall survival (HR=0.83, 95% CI 0.68-1.02) per 20nmol/L increase in serum
27 vitamin D levels (Newton-Bishop et al, 2009).
28 Moderate quality evidence from one prospective cohort study indicates uncertainty over whether
29 Vitamin D supplementation affects relapse free survival (HR=0.81, 95% CI 0.56-1.17) or overall
30 survival (HR=0.71; 95% CI 0.47-1.09) (Newton-Bishop et al, 2009) .
31 Moderate quality evidence from one prospective cohort study reported no evidence of a harmful
32 effect of high serum levels of vitamin D with no adverse events observed at the highest levels of
33 vitamin D (Newton-Bishop et al, 2009).
34 Moderate quality evidence from one prospective cohort study reported that inheritance of the BsmI
35 A allele was associated with a poorer outcome from melanoma in patients with low vitamin D levels
36 but not in those with high vitamin D levels (p for interaction=0.02) (Newton-Bishop et al, 2009).
37 Moderate quality evidence from a systematic review and meta-analysis indicates a possible
38 protective effect for cutaneous melanoma when comparing the highest versus lowest intake of
39 vitamin D supplements (Summary relative risk 0.63; 95% CI 0.42-0.94) (Gandini et al, 2008).

GRADE Table 8.1 How should sub-optimal levels of vitamin D be managed in patients with melanoma

Distant Disease (Nurnberg et al. 2009).
1
1 observational studies serious No serious inconsistency no serious indirectness no serious imprecision none VERY LOW
Relapse Free Survival (Newton-Bishop et al, 2009)

1
1 observational studies serious No serious inconsistency no serious indirectness no serious imprecision none MODERATE
Adverse Events (Newton-Bishop et al (2009)

1
1 observational studies serious No serious inconsistency no serious indirectness no serious imprecision none MODERATE
1
All studies were retrospective reviews

1 Evidence Summary
2 Vitamin D and 25(OH)D serum levels in melanoma patients
3 In a hospital based case-control study evaluating the possible association of a direct measure of
4 vitamin D status, serum vitamin D levels and an indirect measure of vitamin D status (UV-exposure)
5 on the incidence and clinical outcome of melanoma patients., both groups showed a high level of
6 vitamin D deficiency (defined as serum 25(OH)D levels <20ng/ml) with 78.1% of melanoma patients
7 and 63.1% of controls deficient. Median 25(OH)d serum levels were not significantly different in
8 melanoma patients as compared with controls (14.3 ng/ml versus 15.6 ng/ml p=0.44 (Nurnberg et al,
9 2009).
10 In melanoma patients specifically, younger patients had a significantly higher median serum
11 25(OH)D level compared with the older population (p=0.053) (Nurnberg et al, 2009).
12 The study found no statistically significant associations when 25(OH)D levels were compared with
13 respect to age, gender or body mass index (Nurnberg et al, 2009).
14 In a prospective cohort study investigating whether vitamin D may protect against melanoma
15 recurrence (Newton-Bishop et al, 2009), serum vitamin D levels varied with season and, taking
16 60nmol/L as optimal, the majority of patients had suboptimal levels (64%). Serum vitamin D levels
17 were also found to be lower in younger patients (p<0.001; adjusted for sex, month of venipuncture
18 and BMI)
19 Reported vitamin D supplementation was associated with higher serum vitamin D levels while
20 increased Breslow thickness was associated with lower serum vitamin D levels (adjusted for age, sex,
21 body mass index and month sampled).
Mean serum 95% CI P value

vitamin D levels
BMI
<24.9 54 nmol/L 51-56 nmol/L <0.005
24.9-29.9 55 nmol/L 53-57 nmol/L
>29.9 48 nmol/L 24.9-29.9 nmol/L
Reported Vitamin D Supplementation
Supplementation 60 nmol/L 57-63 nmol/L 0.001
No Supplementation 50 nmol/L 48-52 nmol/L
Breslow Thickness (mm)
<0.75 55.8 nmol/L 52.5-59.0 nmol/L 0.002
0.75-1 54.9 nmol/L 52.0-57.8 nmol/L

1-2 53.7 nmol/L 51.3-56.2nmol/L
2-3 51.6 nmol/L 47.8-55.4nmol/L
>3 48.5 nmol/L 44.8-52. nmol/L
1 Table 8.2: Mean Serum Vitamin D levels in melanoma patients (data from Newton-Bishop et al,
2 2009)
3 5(OH)D serum levels and solar UV-exposure
4 25(OH)D serum levels were significantly associated with sun-exposure; patients with infrequent sun
5 exposure in the previous two years had lower levels compared with those who had more frequent
6 exposure (Nurnberg et al, 2009).
7 In a UK population based case control study investigating the effect of a number of factors including
8 supplementation, sun exposure and sunscreen use on blood vitamin D concentrations. (Davies et al,
9 2011), vitamin D level was found to vary by season with higher mean levels vitamin recorded during
10 the summer months.
11 For most comparisons under investigation, little difference was observed between cases and control
12 with the strongest association seen between vitamin D levels overall and holiday exposure at low
13 latitudes (adjusted mean levels increased by 9.1 units between the lowest and highest group of
14 exposure) (Davies et al, 2011).
15 A strong association was observed between vitamin D levels and average weekend exposure in
16 recent warmer months, with weaker correlations with daily exposure and average holiday exposure.
17 Individuals with greater sun sensitivity had lower overall vitamin D levels and increased freckling on
18 the shoulders (surrogate for greater habitual sun exposure in the fair skinned) was associated with
19 higher levels. There was a strong positive association between freckling and higher reported levels of
20 sun exposure (Davies et al, 2011).
21 Use of low protection sun screen compared with no sunscreen was associated with higher levels of
22 serum vitamin D in the total dataset (adjusted estimate 5.72, p=0.002) though no effect of high SPF
23 sunscreen use was observed.
24 In the total dataset (cases and controls) the LOESS curve increased to a plateau of just under
25 60nmol/L in individuals reporting an average of 5hours per day of weekend sun exposure for non-
26 sensitive phenotypes. A lower plateau was reached for individuals reporting an average of 6 hours
27 per day of weekend sun exposure. In melanoma cases not taking supplements the 60 nmol/L plateau
28 was reached after 6hour average exposure in those with non-sensitive phenotypes but was not
29 reached at all in sun-sensitive individuals.
30 The 60nmol/L plateau was reached in those taking vitamin D supplements irrespective of sun
31 exposure (Davies et al, 2011).
32 In participants reporting more than 5hours in the sun at weekends, there was a mean difference of
33 14.7nmol/L in levels for participants who were homozygous for the variant allele in the gene coding
34 for the vitamin D binding protein (rs2282679) (Davies et al, 2011).

1 In a case-control study assessing changes in UVR exposure in patients with cutaneous melanoma
2 using objective surrogate parameters (Idorn et al, 2011), recently diagnosed patients had
3 significantly higher winter serum vitamin D compared with controls (p=0.02, R2=0.60) and patients
4 diagnosed within the past year (p=0.01) indicating higher UVR exposure dose the summer before
5 melanoma diagnosis.
6 Serum vitamin D was significantly lower in recently diagnosed patients compared with controls
7 (p=0.005, R2=0.51) and patients diagnosed in the past (p=0.008) indicating a lower UVR exposure in
8 the first summer following diagnosis while no difference between the groups in summer serum
9 vitamin D levels (Idorn et al 2011).
10 Idorn et al (2011) reported that prior to diagnosis of cutaneous melanoma, recently diagnosed
11 patients used sunscreen more often than patients diagnosed in the past (p<0.04) and controls
12 (p=0.02, R2=0.81).
13 A significant group variance was observed in solarium use between the 3 groups (p=0.05) with a
14 higher percentage of recently diagnosed patients reporting the use of a solarium.
15 Gardening was reportedly more frequent in patients diagnosed in the past (p=0.008) and this group
16 also reported more days of gardening than the rest of the participants (p=0.002) (Idorn et al, 2011).
17 Idorn et al (2011) reported a significant group variance in the severity and frequency of sunburn
18 after diagnosis; patients diagnosed in the past reported only mild sunburn (p=0.04) and fewer
19 episodes of sunburn (p=0.03) than the rest of the participants.
20 Recently diagnosed patients used a significantly higher sun protection factor (p=0.002, R2=0.83) and
21 had significantly more days using sunscreen (p=0.02, R2=0.66) than did controls.
22 25(OH)D serum levels in stage I versus stage IV melanoma
23 Patients with stage I melanoma had significantly higher serum 25(OH)D levels when compared with
24 patients with stage IV melanoma (p=0.006) (Nurnberg et al, 2009).
25 Tumour thickness in primary cutaneous melanoma
26 Patients with serum 25(OH)D levels <10ng/ml) had thicker primary cutaneous melanomas compared
27 with patients with serum levels >20ng/ml (2.55mm versus 1.5mm; p=0.078 ) (Nurnberg et al, 2009).
28 In a cohort study investigating if different indicators of UV exposure, collected before and after
29 diagnosis are associated with Breslow Thickness and recurrence Gandini et al (2013) reported that
30 ulcerated cutaneous melanoma and cutaneous melanoma diagnosis during the summer were more
31 common in those without holidays. Breslow categories were associated with holidays, the
32 proportion of thick melanomas (>4mm) was significantly lower in patients having holidays compared
33 with no holidays (8% versus 20%, p for trend 0.002).
34 A significant negative association between very thick melanomas and number of weeks of holidays
35 (p for trend 0.001) was observed and after adjustment for confounding factors (age, gender,
36 education, grade of clinician at visit, history of NMSC and season at diagnosis) there was significant
37 association between holidays before diagnosis and lower Breslow thickness (p=0.003) (Gandini et al,
38 2011).

1 Sun exposure during peak hours, history of NMSC, sun bed use, cutaneous melanoma body site, skin
2 type, and season of diagnosis were not found to be significantly associated with Breslow thickness
3 while holidays were significantly associated with Breslow thickness in a dose-response manner
4 (p=0.007) (Gandini et al, 2013).
5 Gandini et al (2013) reported a significant interaction between the effect of holidays: women had a
6 significantly lower Breslow thickness if they had a history of holidays (p=0.004) whereas for men this
7 protective effect was not significant (p=0.88).
8 Melanoma Recurrence
9 In a cohort study investigating if different indicators of UV exposure, collected before and after
10 diagnosis are associated with Breslow Thickness and recurrence Gandini et al (2013) reported a
11 median follow-up of 44 months (range 1-72) for group 1 and 40 months (range 2-75) for group 2.
12 Overall, 6% of patients had a melanoma recurrence and 5% had a second primary cancer.
13 Holiday before diagnosis was not associated with risk of recurrence (HR=4.19, 95% CI 0.53-33.36,
14 p=0.18).
15 For holidays during follow-up the 5-year cumulative incidence of melanoma recurrences was 8% for
16 those having holidays after diagnosis compared to 17% for those without (HR=0.30, 95% CI 0.10-
17 0.87).
18 A dose response relationship was observed between the risk of melanoma recurrence and number
19 of weeks of holidays: the hazards ratio for up to 2 weeks of holidays compared with no holidays was
20 0.74 (95% CI 0.16-3.45) and for more than 2 weeks of holidays compared with no holidays was 0.28
21 (95% CI 0.08-0.98) (Gandini et al, 2013).
22 Distant metastatic disease
23 Patients who had serum levels <10ng/ml had earlier distant disease compared with patients serum
24 levels >20ng/ml (24.37 months versus 29.47; p=0.641) (Nurnberg et al, 2009).
25 Season of diagnosis and clinical outcome
26 In patients diagnosed in the summer the median time between primary excision and lympogenous
27 metastasis was 13.7 months compared to 1.2 months in patients diagnosed in autumn (p=0.486)
28 (Nurnberg et al, 2009).
29 For distant metastasis in patients diagnosed in autumn median time between primary excision and
30 distant metastasis was 14.2 months compared with 31.7 months for patients diagnosed in the
31 summer (p=0.057) (Nurnberg et al, 2009).
Median serum 25(OH)D level P value
Age
14-34 years 16.95ng/ml 0.053
>65 years 14.3 ng/ml

Median serum 25(OH)D level P value
Sun Exposure in previous 2 years
<50 days 8.16ng/ml 0.001
>150 25.90ng/ml
Disease Stage
Stage Ia/b 16.40ng/ml 0.006
Stage IV 13.10ng/ml
1 Table 8.3: Median Serum Vitamin D levels (reported in Nurnberg et al, 2009)
2 Vitamin D Intake from food and/or supplementation
3 From one systematic review and meta-analysis, summary relative risk indicates a possible protective
4 effect for cutaneous melanoma when comparing the highest versus lowest intake ( 0.92; 95% CI
5 0.25-3.44) however the I2 of 71 indicates high heterogeneity. Taking out the oldest study removed
6 the heterogeneity and the summary relative risk shows a significant positive effect (0.63; 95% CI
7 0.42-0.94). Dose response estimates suggested a protective effect of cutaneous melanoma when
8 excluding the oldest study and inclusion of non-melanoma skin cancer in the analysis did not show
9 any indication of an association with vitamin D intake (Gandini et al, 2008).
10 In a retrospective pilot study, median time from diagnosis to relapse was 6.6 years (range 3.1-28.1
11 years) and for non-relapsers was 7.4 years (range, 3.2-31.7 years) and 38% of relapsers and 47% of
12 non-relapsers reported using any supplements before relapse (OR=0.7; 95% CI 0.4-1.2) (Newton-
13 Bishop et al 2009).
14 31% of relapsers and 38% of non-relapsers reported regular use intake of vitamin D in the year prior
15 to interview (OR=0.6; 95% CI, 0.4-1.1; p=0.09). Serum vitamin D levels were significantly higher in
16 patients reporting the use of vitamin D supplements (mean 54 nmol/L; 95% CI, 51-58 nmol/L)
17 compared with those not taking supplements (mean, 43 nmol/L; 95% CI, 40-47 nmol/L) but no
18 significant difference was observed in serum vitamin D levels between relapsers and non-relapsers
19 (p=0.3) (Newton-Bishop et al 2009).
20 In a UK population based case control study investigating the effect of a number of factors including
21 supplementation, sun exposure and sunscreen use on blood vitamin D concentrations. (Davies et al,
22 2011), participants who were homozygous for the variant allele in the gene coding for the vitamin D
23 binding protein (rs2282679) had lower mean seasonally adjusted serum vitamin D levels when
24 compared with wild type (on average 11.8nmol/L lower). Stratification of the data by exposures,
25 genotype appeared to me most strongly associated with supplementation; wild type participants
26 who were supplementing had serum vitamin D levels 18.8nmol/L higher than homozygous
27 participants on average.
28 In a prospective cohort study investigating whether vitamin D may protect against melanoma
29 recurrence (Newton-Bishop et al, 2009), univariate analysis suggested that increases of 20nmol/L in

1 serum vitamin D levels were associated with a reduced risk of relapse (HR=0.75; 95% CI, 0.64-0.90)
2 and overall survival (HR=0.80; 95% CI 0.68-0.96) across all seasons. After adjusting for age, sex,
3 Townsend score, tumour site, Breslow thickness and BMI on multivariate analysis, higher serum
4 vitamin D levels showed a protective effect for relapse free survival (HR=0.79, 95% CI 0.64-0.96) and
5 overall survival (HR=0.83, 95% CI 0.68-1.02) per 2020nmol/L increase in serum vitamin D levels.
25 hydroxyvitamin D3 level (Per 20nmol/L increase)
Relapse from melanoma Overall Death
Hazard Ratio 95% CI Hazard Ratio 95% CI
January – March 0.72 0.56-0.96 0.72 0.54-0.96
April-June 0.85 0.67-1.08 0.80 0.62-1.06
July-September 0.77 0.63-0.96 0.85 0.70-1.04
October-December 0.77 0.60-0.98 0.82 0.64-1.04
6 On univariate analysis, Vitamin D supplementation showed no significant effect on relapse free

7 survival (HR=0.81, 95% CI 0.56-1.17) or on overall survival (HR=0.71; 95% CI 0.47-1.09) and there was
8 no evidence of an effect of VDR genotype on outcome (Newton-Bishop et al, 2009).
9 There was no evidence of a harmful effect of high serum levels of vitamin D and no adverse events
10 were observed at the highest levels of vitamin D.
11

1 References
2 Included
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7 Journal of Cancer 45;4:634-641.
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10 Nurnberg, B., et al (2009) Reduced serum 25-hydroxyvitamin D levels in stage IV melanoma patients.
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14 Idorn, L. W., Philipsen, P. A., and Wulf, H. C. (2011) Sun exposure before and after a diagnosis of
15 cutaneous malignant melanoma: estimated by developments in serum vitamin D, skin pigmentation
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17 Gandini, S., et al (2013) Sunny Holidays before and after Melanoma Diagnosis Are Respectively
18 Associated with Lower Breslow Thickness and Lower Relapse Rates in Italy. PLoS ONE [Electronic
19 Resource] 8;11:e78820.
20
21 Excluded
22 Afzal, S., Nordestgaard, B. G., and Bojesen, S. E. (2013) Plasma 25-hydroxyvitamin D and risk of non-
23 melanoma and melanoma skin cancer: a prospective cohort study. Journal of Investigative
24 Dermatology 133;3:629-636.
26 Bade, B., et al (2012). Low serum 25-hydroxyvitamin D concentrations are associated with increased
27 risk for melanoma and unfavourable prognosis. Experimental Dermatology 21;3:e15.
29 Boniol, M., Armstrong, B. K., and Dore, J. F. (2006) Variation in incidence and fatality of melanoma by
30 season of diagnosis in New South Wales, Australia. Cancer Epidemiology Biomarkers & Prevention
31 15;3:524-528.
33 Buttigliero, C., et al (2011) Prognostic role of vitamin d status and efficacy of vitamin D
34 supplementation in cancer patients: a systematic review. [Review]. The Oncologist 16;9:1215-1227
35 Reason: Only included in melanoma study which was picked up and reviewed independently
36 Caini, S., et al (2014). Vitamin D and melanoma and non-melanoma skin cancer risk and prognosis: A
37 comprehensive review and meta-analysis. European Journal of Cancer 50;15:2649-2658

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2 melanoma. Photodermatology, Photoimmunology & Photomedicine 9;3:109-112.
4 Delong, L., et al (2010). Vitamin D levels and oral supplementation update in patients with skin
5 cancer. Journal of Investigative Dermatology 130;S66.
7 Denzer, N., Vogt, T., and Reichrath, J. (2011) Vitamin D receptor (VDR) polymorphisms and skin
8 cancer: A systematic review. Dermato-endocrinology 3;3:205-210.
10 El, Hayderi L., et al (2011). Seasonal variations in vitamin D levels in melanoma patients: A single-
11 center prospective pilot comparative study. Melanoma Research 21;e14-e15.
13 Failla, V., et al (2012) Seasonal variations in vitamin D levels in melanoma patients: a single-centre
14 prospective pilot comparative study. Journal of the European Academy of Dermatology &
15 Venereology 26;5:651-653.
17 Field, S., et al (2013) Do vitamin A serum levels moderate outcome or the protective effect of
18 vitamin Don outcome from malignant melanoma? Clinical Nutrition 32;6:1012-1016.
20 Field, S., et al (2013). A clinical audit of the effect of targeted advice and vitamin D supplementation
21 on serum vitamin D levels in patients with melanoma. British Journal of Dermatology 169; 43.
23 Freedman, D. M., et al (2010) Serum 25-hydroxyvitamin D and cancer mortality in the NHANES III
24 study (1988-2006). Cancer Research 70;21:8587-8597.
26 Gambichler, T., et al (2013) Serum 25-hydroxyvitamin D serum levels in a large German cohort of
27 patients with melanoma. British Journal of Dermatology 168;3:625-628.
29 Gandini, S., et al (2013) Could sunny holidays improve melanoma prognosis? JDDG - Journal of the
30 German Society of Dermatology 11;1.
32 Gandini, S., et al (2009). Why vitamin D for cancer patients? Ecancermedicalscience 3;160.
34 Gupta, D., et al (2011). A. Prevalence of serum vitamin D deficiency and insufficiency in cancer:
35 Review of the epidemiological literature. Experimental and Therapeutic Medicine 2;2:181-193.
37 Hill, N., et al (2010) Vitamin D levels and oral supplementation in patients with skin cancer. Journal
38 of the American Academy of Dermatology 62;3 SUPPL. 1:AB66.

1 Hutchinson, P. E., et al (2010) Higher serum 25-hydroxy vitamin D3 levels at presentation are
2 associated with improved survival from melanoma, but there is no evidence that later prevailing
3 levels are protective. Journal of Clinical Oncology 28;27:e492-e493.
4 Reason: Letter
5 Kumar, R., et al (2012) The impact of sun protective behavior and vitamin D supplementation on
6 vitamin D level in melanoma patients. Journal of Clinical Oncology 30;15 SUPPL. 1
8 Lazzeroni, M., et al (2013). Vitamin D supplementation and cancer: Review of randomized controlled
9 trials. Anti-Cancer Agents in Medicinal Chemistry 13;1:118-125.
11 Mandelcorn-Monson, R et al (2011) Sun exposure, vitamin D receptor polymorphisms FokI and BsmI
12 and risk of multiple primary melanoma. Cancer Epidemiology 35;6: e105-e110.
14 Marks, R., et al (1995) The Effect of Regular Sunscreen Use on Vitamin-D Levels in An Australian
15 Population - Results of A Randomized Controlled Trial. Archives of Dermatology 131;4:415-421.
17 MacKie, R. M. (2010) Serum vitamin D levels in melanoma patients in Scotland. Pigment Cell and
18 Melanoma Research 23;6:894.
20 Major, J. M., et al (2012) Pre-diagnostic circulating vitamin D and risk of melanoma in men. PLoS ONE
21 [Electronic Resource] 7;4: e35112.
23 Millen, A. E., et al (2004) Diet and melanoma in a case-control study. Cancer Epidemiology,
24 Biomarkers & Prevention 13;6:1042-1051.
25 Reason: Included in Systematic Review
26 Miller, P. E., et al (2009) Dietary supplement use in adult cancer survivors. Oncology Nursing Forum
27 36;1:61-68.
29 Mocellin, S. and Nitti, D (2008). Vitamin D receptor polymorphisms and the risk of cutaneous
30 melanoma: a systematic review and meta-analysis. [Review] [49 refs]. Cancer 113;9:2398-2407.
31 Reason: Not relevant to PICO (Population comparisons/outcomes)
32 Meyskens, F. L., et al (1988) Randomized phase III trial of high dose vitamin A versus placebo for
33 stage I malignant melanoma [abstract]. Proceedings of the American Society of Clinical Oncology
34 7;247
36 Newton-Bishop, J. A., et al (2009) Serum 25-hydroxyvitamin D3 levels are associated with breslow
37 thickness at presentation and survival from melanoma. Journal of Clinical Oncology 27;32:5439-
38 5444.
40 Ogbah, Z., et al (2013). Serum 25-hydroxyvitamin D3 levels and vitamin D receptor variants in
41 melanoma patients from the Mediterranean area of Barcelona: 25-hydroxyvitamin D3 levels and

1 VDR variants in melanoma patients from Barcelona. BMC Medical Genetics 14;1:26.
3 Pandit, T., et al (2011) The effect of malignant melanoma on serum 25(OH)vitamin d levels in elderly
4 patients. Journal of the American Geriatrics Society 59;S55-S56.
6 Pilz, S., et al (2013) Vitamin D and cancer mortality: Systematic review of prospective
7 epidemiological studies. Anti-Cancer Agents in Medicinal Chemistry 13;1:107-117.
9 Pongprutthipan, M., Alam, M., and Kim, N. (2012) Comparison of 25-hydroxy vitamin D level in white
10 women receiving vitamin D supplementation and not receiving supplementation: A randomized
11 controlled trial. Journal of the American Academy of Dermatology 66;4 SUPPL. 1:AB174. 2012.
13 Reichrath, J., et al (2004) No evidence for reduced 25-hydroxyvitamin D serum level in melanoma
14 patients. Cancer Causes & Control 15;1:97-98.
15 Reason: Letter
16 Reichrath, J. (2011) Serum levels of 25(OH)D and VDR polymorphisms in malignant melanoma:
17 Results from pilot studies in Homburg. Anticancer Research 31;4:1498.
19 Reeder, A. I., Jopson, J. A., and Gray, A. R. (2012) "Prescribing sunshine": a national, cross-sectional
20 survey of 1,089 New Zealand general practitioners regarding their sun exposure and vitamin D
21 perceptions, and advice provided to patients. BMC Family Practice 13;85.
23 Rhodes, L. E., et al (2010) Recommended Summer Sunlight Exposure Levels Can Produce Sufficient
24 (>= 20 ng ml(-1)) but Not the Proposed Optimal (>= 32 ng ml(-1)) 25(OH)D Levels at UK Latitudes.
25 Journal of Investigative Dermatology 130;5:1411-1418.
27 Suppa, M., et al (2011) Determinants of melanoma risk in a large case-control study: The role of skin
28 aging and vitamin D. Melanoma Research 21;e6.
29 Reason: Abstract
30 Tang, J. Y., et al (2011) Calcium plus vitamin D supplementation and the risk of nonmelanoma and
31 melanoma skin cancer: post hoc analyses of the women's health initiative randomized controlled
32 trial. Journal of Clinical Oncology 29;22:3078-3084.
34 van der Pols, J. C., et al (2013) Vitamin D status and skin cancer risk independent of time outdoors:
35 11-year prospective study in an Australian community. Journal of Investigative Dermatology 133;3:
36 637-641.
37 Reason: Not enough melanoma data
38 Weinstock, M. A., et al (1992) Case-control study of melanoma and dietary vitamin D: implications
39 for advocacy of sun protection and sunscreen use. Journal of Investigative Dermatology 98;5:809-
40 811.

Evidence Tables
Study Quality (Systematic Reviews)
Clearly Includes studies Rigorous Study quality Adequate Quality

focused relevant to literature assessed? description of
Question? review question? search? methodology?
Gandini et al Yes Yes Yes Unclear Yes Moderate

(2008)
Appropriate Precise definition Valid method of Investigators blind Investigators blind to Quality
length of follow- of an outcome measuring to participants potential confounders and
intervention?
Gandini et al Unclear Unclear Yes Unclear Unclear Low

(2013)
Newton-Bishop et Yes Yes Yes Unclear Unclear Moderate

al (2009)
Rosso et al (2008) Yes No Unclear No No Very Low

Study Quality (case-control studies)
Clearly Comparable Same Participation Participants Cases clearly Clearly Measures Exposure Confounders Confidence Quality
focused populations Exclusion Rate for and non- defined and established to prevent measured identified Intervals
Question for cases Criteria cases and participants differentiated that cases influence in provided
and for cases controls compared? from controls are not of primary standard,
Controls? and controls knowledge valid
controls? method
Nurnberg Yes Unclear Unclear Unclear No Yes Yes Unclear Yes No No Very Low
et al
(2009)
Davies et Yes Unclear Unclear Unclear No Yes Yes Unclear Unclear Yes No Very Low
al (2011) (standard
error)
Idorn et Yes Unclear Yes Cases: 35% No Yes Yes Unclear Unclear No No Very Low
al (2011) (31/89) (qualitative
reporting)
Controls:
27% (15/56)


Type/Setting
Rosso et al Cohort study To investigate N= 260/305 patients Interviews using a questionnaire Not clearly stated though appears to be survival
(2007) (Retrospective survival in a cohort with a histological which included socio-
ananlysis of a of melanoma diagnosis of cutaneous demographic variables including
Case-Control patients with melanoma age at diagnosis, sex, level of 3.5% (9) of participants lost to follow-up.
Study) detailed (Participation Rate: education and occupation, host
information on sun 85%) factors including pigmentation No significant differences in baseline
Population exposure and other and skin reaction to sun exposure characteristics
based (Turin, risk factors N=186 female/74 male and sun exposure history.
Italy) (recruitment of females
extended to aloow for Univariate Analysis
investigation of the role
of oral contraceptives in No significant associations:
melanoma).
Sunscreen Use: HR=0.96 (95% CI, 0.41-1.4)
Mean Age: 56 years (12- Sunburn in childhood: HR 0.96 (95% CI 0.51-1.8)

92)
Lifelong exposure: HR 1.4 (95% CI, 0.79-2.5)
Follow Up: Median 17
Sports: HR 0.64 (95% CI, 0.32-1.3)
years (1 month – 21
years) Hobbies: HR: 0.60 (95% CI, 0.27-1.3)
Outdoor Work/chronic sun exposure: HR 1.3

(95% CI, 0.65-2.5)


Type/Setting
1-59 weeks spent at the beach (lifetime) versus
not visiting the beach: HR 0.41 (95% CI, 0.18-
0.90) (decreased risk of death from melanoma)
>60 weeks at the beach (lifetime) versus not

visiting the beach: HR 0.39 (95% CI, 0.19-0.79;
p=0..015) (decreased risk of death from
melanoma)
Effects of lesion thickness, number of weeks

spent lifetime on the beach, age, sex and
education.
Nurnberg Case-Control To evaluate the Cases=205 patients with Self-administered questionnaire Not clearly stated (association of vitamin D levels
et al Study possible histologically proven with a number of factors as outlined in the aim of
(2009) association of a cutaneous melanoma the study)
Hospital Based direct measure of


Type/Setting
(Germany) vitamin D status, Controls=141 (71
serum vitamin D volunteers visiting the
levels and an Dept of Dermatology; Vitamin D and 25(OH)D serum levels in
indirect measure of 70 patients of the Dept melanoma patients and controls
vitamin D status of Orthopaedic Surgery) Both groups showed a high level of vitamin D
(UV-exposure) on deficiency (defined as serum 25(OH)D levels
the incidence and <20ng/ml) with 78.1% of melanoma patients and
clinical outcome of 63.1% of controls deficient.
melanoma
patients.
Median 25(OH)d serum levels were not

significantly different in melanoma patients as
compared with controls (14.3 ng/ml versus 15.6
ng/ml p=0.44).
No statistically significant associations were

found when 25(OH)D levels were compared with
respect to age, gender or body mass index.
In melanoma patients younger patients had a

significantly higher median serum 25(OH)D level
compared with the older population (p=0.053)


Type/Setting
25(OH)D serum levels and solar UV-exposure
25(OH)D serum levels were significantly

associated with sun-exposure; patients with
infrequent sun exposure in the previous two
years had lower levels compared with those who
had more frequent exposure.
25(OH)D serum levels in stage I versus stage IV

melanoma
Patients with stage I melanoma had significantly

higher serum 25(OH)D levels when compared
with patients with stage IV melanoma (p=0.006)
Tumour thickness in primary cutaneous

melanoma
Patients with serum 25(OH)D levels <10ng/ml)

had thicker primary cutaneous melanomas
compared with patients with serum levels
>20ng/ml (2.55mm versus 1.5mm; p=0.078).


Type/Setting
Distant metastatic disease
Patients who had serum levels <10ng/ml had

earlier distant disease compared with patients
serum levels >20ng/ml (24.37 months versus
29.47; p=0.641)
Season of diagnosis and clinical outcome
In patients diagnosed in the summer the median

time between primary excision and lympogenous
metastasis was 13.7 months compared to 1.2
months in patients diagnosed in autumn
(p=0.486).
For distant metastasis in patients diagnosed in

autumn median time between primary excision
and distant metastasis was 14.2 months
compared with 31.7 months for patients
diagnosed in the summer (p=0.057)


Type/Setting
Newton- Retrospective To test the findings Retrospective Pilot Patient reported questionnaire Measured serum vitamin D use
Bishop et Pilot Study from a Study: N=271 patients collecting data on regular use of
al (2009) retrospective pilot with melanoma vitamins, minerals, fish oils, fire
Prospective study that vitamin or other food supplements 1 year Measured serum vitamin D use was higher in
Cohort Study D may protect Relapsers=131 prior to interview). patients reporting vitamin D supplementation
against melanoma Non-relapsers=169 compared with not taking vitamin D
Population recurrence supplements:
based
(Northern Mean: 54nmol/L (95% CI 51-58nmol/L) vs.
England) 43nmol/L (95% CI 40-47nmol/L); p=0.0001)
Non-relapsers had higher serum vitamin D levels

compared with non-relapsers:
Mean: 49nmol/L (95% CI 45-52nmol/L) vs.

46nmol/L (95% CI 41-50nmol/L); p=0.3
Prospective Cohort Relapse/Survival data colloected Risk of relapse

Study: n=872 patients via annual patient questionnaire,
with stage I-IIIA cancer registry and clinical notes.
melanoma Univariate Analysis
Patient reporte height and weight
used to calculate BMI. Increases of 20nmol/L in serum vitamin D levels
were associated with a reduced risk of relapse
Serum 25(OH)D levels measured and better overall survivalconsistently accross
seasons:


Type/Setting
Relapse Free Survival: HR=0.75 (95% CI, 0.64-

0.90)
Overall Survival: HR=0.80 (95% CI, 0.68-0.96)
Reported vitamin D supplementation showed no

statistically significant effect on outcome:
Relapse Free Survival: HR=0.81 (95% CI 0.56-1.17)
Overall Survival: HR=0.71 (95% CI 0.47-1.09)
Adjustment for age, sex, townsend score, tumour

site, breslow thickness, and BMI
Relapse free survival: HR=0.79 (95% CI, 0.64-0.96)
Overall Survival: HR=0.83 (95% CI, 0.68-1.02)


Type/Setting
Gandini et Cohort Study To investigate if N=742 patients with Self Self Melanoma Recurrence
al (2013) (2 groups, i different indicators cutaneous melanoma, administered administered
retrospective, of UV exposure, two cohorts of patients questionnaire at questionnaire
1 prospective) collected before with no overlap initial diagnosis during follow- Ulcerated melanoma and melanoma diagnosis
and after diagnosis up during summer months were more frequent in
Hospital based are associated with Group at diagnosis those without holidays
(Milan, Italy) Breslow Thickness N=289 Median time
and recurrence Group during follow-up from diagnosis
N=402 to
Breslow categories were associated with
questionnaire:
holidays:
Median age at 2.6 years (1-6
diagnosis: 47 years (IQR: years The proportion of thick melanomas was
37-60) interquartile significantly lower among patients having
Thick Melanoma range) holidays versus patients not having holidays
(Breslow >1mm): 55%
(n=378) 8% versus 2%; p for trend=0.002).
Very thick melanomas were negatively associated

with number of weeks of holiday in a dose-
response manner (no sunny holiday, 1-2 weeks
per year and >2 weeks per year) p for trend =
0.001)
Melanoma Recurrence


Type/Setting
Median follow-up was 44 months (range 1-72) for
group 1 and 40 months (range 2-75) for group 2.
Overall, 6% of patients had a melanoma
recurrence and 5% had a second primary cancer.
Holiday before diagnosis was not associated with

risk of recurrence (HR=4.19, 95% CI 0.53-33.36,
p=0.18)
For holidays during follow-up the 5-year

cumulative incidence of melanoma recurrences
was 8% for those having holidays after diagnosis
compared to 17% for those without (HR=0.30,
95% CI 0.10-0.87).
A dose response relationship was observed

between the risk of melanoma recurrence and
number of weeks of holidays: the hazards ratio
for up to 2 weeks of holidays compared with no
holidays was 0.74 (95% CI 0.16-3.45) and for
more than 2 weeks of holidays compared with no
holidays was 0.28 (95% CI 0.08-0.98).


Type/Setting
Gandini et Systematic To investigate N=721 (from 3 studies Vitamin D intake Dose-response effect of vitamin D intake on
al (2008) Review and whether FokI and including patients with melanoma risk
Meta-analysis Bsml, 25(OH)D cutaneous melanoma) Estimates using Vitamin D intake
serum levels and in food were chosen over intake Vitamin D intake highest versus lowest levels
intake of vitamin D Weinstock et al (1992): from supplementation.
impact skin cancer Hospital based case- Individual study estimates:
risk (only vitamin D control study – 165 Estimates in the individual studies Weinstock et al (1992) RR: 1.80 (0.90-3.50)
intake is relevant cases were adjusted for afe, hair colour Millen et al (2004) RR 0.61 (0.40-0.95)
to the current Millen et al (2004): and family history of cutaneous Vinceti et al (2005) RR 0.76 (0.23-2.50)
topic). hospital based case- melanoma (Wienstock, 1992) and
control study – 497 for age, sex, dysplastic nevi, Pooled Estimates
Data abstraction cases education and skin type (Millen, RR 0.92 (0.25-.044), p=0.03; I2=71
included: Vincenti et al(2005): 2004). RR 0.63 (0.42-0.94); p=0.73, I2=0 (Excluding
Study Population based case- Weinstock)
characteristics control study – 59 cases
(year of
publication, study
design, location,
exclusion of
subjects among
controls and
adjustmens for
confounders)
Exposure
evaluation
(laboratory
methods to detect


Type/Setting
VDR
polymorphisms,
dietry assessment
method used for
vitamin D intake,
time of evaluation
with respect to
diagnosis, values of
vitamin D intake,
supplementation
used).
Study Population
(number & sources
of cases and
controls, sub-type
of cases, history of
familial melanoma
or other cancers,
gender, race)
VDR estimates
(number of cases
and controls
genotypes for
specific
polyporphisms,
case and control
genotype


Type/Setting
frequency,
reported RR’s with
95% CI)
Vitamin D
intake(number of
cases and controls
for each category
of vitamin D intake
and reported RR’
with 95% CI)
Davies et Case-Control Not clearly stated Cases=960 patients Questionnaire and telephone Predictors of blood vitamin D concentrations
al (2011) Study but seems to be to diagnosed with interview collecting data on sun
investigate the melanoma exposure including:
Population effect of a number Controls=513 (same Weekday exposure and weekend Vitamin D levels and Sun Exposure
based (UK) of factors including sex, 5 year age group exposure in sunny and in colder
supplementation, weather The strongest association was seen between
recruited through the
Recruitment sun exposure and Holiday sun exposure at low and vitamin D levels overall and holiday exposure at
family doctor of the
was within 3-6 sunscreen use on higher latitudes low latitudes (adjusted mean levels increased by
cases and siblings of
months of blood vitamin D 9.1 units between the lowest and highest group
cases)
melanoma concentrations. of exposure).
diagnosis were
possible.
Strong association between vitamin D levels and
average weekend exposure in recent warmer
months, with weaker correlations with daily
exposure and average holiday exposure.


Type/Setting
Individuals with greater sun sensitivity had lower

overall vitamin D levels and increased freckling
on the shoulders (surrogate for greater habitual
sun exposure in the fair skinned) was associated
with higher levels. There was a strong positive
association between freckling and higher
reported levels of sun exposure.
Use of low protection sun screen compared with

no sunscreen was associated with higher levels of
serum vitamin D in the total dataset (adjusted
estimate 5.72, p=0.002) though no effect of high
SPF sunscreen use was observed.
In the total dataset (cases and controls) the

LOESS curve increased to a plateau of just under
60nmol/L in individuals reporting an average of
5hours per day of weekend sun exposure for non-
sensitive phenotypes. A lower plateau was
reached for individuals reporting an average of 6
hours per day of weekend sun exposure.
In melanoma cases not taking supplements the


Type/Setting
60 nmol/L plateau was reached after 6hour
average exposure in those with non-sensitive
phenotypes but was not reached at all in sun-
sensitive individuals.
The 60nmol/L plateau was reached in those

taking vitamin D supplements irrespective of sun
exposure.
Serum vitamin D levels were an estimated 5.79

units lower in participants (total dataset) carrying
1 copy of rs2282679 (p<0.0001) and 10.8 units
lower in participants carrying two copies of the
minor allele (p<0.0001) when compared with
homozygotes for the common allele.
Participants who were homozygous for the

variant allele in the gene coding for the vitamin D
binding protein (rs2282679) had lower mean
seasonally adjusted serum vitamin D levels when
compared with wild type (on average 11.8nmol/L
lower). Stratification of the data by exposures,
genotype appeared to me most strongly
associated with supplementation; wild type


Type/Setting
participants who were supplementing had serum
vitamin D levels 18.8nmol/L higher than
homozygous participants on average.
In participants reporting more than 5hours in the

sun at weekends, there was a mean difference of
14.7nmol/L in levels for homozygotes.
Idorn et al Descriptive To assess changes Cases=42 Interviews about sun exposure Changes in UV exposure in patients with
(2011) Case-Control in UVR exposure in behaviour cutaneous melanoma according to time of
Study patients with Controls=26 diagnosis.
cutaneous
melanoma using
objective surrogate Interview 1: Sun exposure before diagnosis
parameters
Prior to diagnosis of cutaneous melanoma,
recently diagnosed patients used sunscreen more
often than patients diagnosed in the past
(p<0.04) and controls (p=0.02, R2=0.81)
A significant group variance was observed in

solarium use between the 3 groups (p=0.05) with
a higher percentage of recently diagnosed
patients reporting the use of a solarium.
Interview 2: Sun exposure after diagnosis


Type/Setting
Gardening was more frequent in patients
diagnosed in the past (p=0.008) and this group
also reported more days of gardening than the
rest of the participants (p=0.002).
No significant group variance was observed when

comparing recently diagnosed patients with each
of the two other groups.
There was significant group variance in the

severity and frequency of sunburn after
diagnosis; patients diagnosed in the past
reported only mild sunburn (p=0.04) and fewer
episodes of sunburn (p=0.03) than the rest of the
participants.
No significant group variance was observed when

comparing recently diagnosed patients with each
of the two other groups.
Recently diagnosed patients used a significantly

higher sun protection factor (p=0.002, R2=0.83)
and had significantly more days using sunscreen
(p=0.02, R2=0.66) than did controls.


Type/Setting
Serum vitamin D concentrations
Recently diagnosed patients had significantly

higher winter serum vitamin D compared with
controls (p=0.02, R2=0.60) and patients diagnosed
within the past year (p=0.01) indicating higher
UVR exposure dose the summer before
melanoma diagnosis.
Serum vitamin D was significantly lower in

recently diagnosed patients compared with
controls (p=0.005, R2=0.51) and patients
diagnosed in the past (p=0.008) indicating a lower
UVR exposure in the first summer following
diagnosis.
No difference between the groups in summer

serum vitamin D levels.
Pigment Protection Factor
Recently diagnosed patients were matched to

controls according to constitutive skin
pigmentation and had almost identical C-PPF
whereas patients diagnosed in the past had


Type/Setting
significantly lower C-PPF compared with controls
(p=0.03).
Summer F-PPF and F-∆PPF were lower in recently

diagnosed patients compared with controls and
patients diagnosed in the past indicating a lower
UVR exposure dose the summer after diagnosis.
Correlations between vitamin D and pigment

protection factor
Summer serum vitamin D and summer F-PPF

were positively correlated (p=0.003, R2=0.19)
when considering all participants.
Serum vitamin D and F-∆PPF were positively

correlated (p=0.04, R2=0.09)
Winter serum vitamin D and winter F-PPF showed

no correlation.
Relation between questions from interview 2 and

vitamin D and pigment protection factor
Higher summer 25(OH)D, ∆25(OH)D, summer F-

PPF and F-∆PPF were related to higher sun


Type/Setting
exposure, less use of sunscreen and lower SPF.

1 8.2 Concurrent Drug Therapies
2 Review question: What is the most effective approach to the management of risks to
3 patients associated with concurrent drug therapies used to treat other conditions, which
4 may affect the prognosis from melanoma (for example, immunosuppressants, levadopa,
5 metformin, HRT, COCP)?
6 Background
7 Melanoma patients may receive a number of drugs as treatment for concurrent medical illnesses.
8 These drugs may have effects which could be harmful in terms of the melanoma or conversely
9 potentially helpful. The use of immune-suppressants for auto-immune disease is important but may
10 be deleterious in terms of survival if patients have also had a melanoma. Non-steroidal anti-
11 inflammatory drugs are associated with improved outcomes from cardiovascular disease and they
12 could also improve survival from cancer theoretically at least as a result of suppression of the
13 grumbling inflammation which is thought to accompany the obesity related chronic inflammation
14 syndrome. In this question we will review the evidence that concurrent exposures may affect
15 melanoma risk. It is likely that there will be more data on risk of new cancers in patients receiving a
16 given drug than data on the likelihood of relapse from melanoma in patients treated with the drug in
17 question. Others have extrapolated from one (risk of new cancers) to the other (risk of recurrence)
18 which is far from perfect but may be all that can be done currently.

Patients diagnosed with Choice of drug to treat Each other Overall Survival
melanoma and are at risk due concurrent medical problem. (stopping/reducin Progression free
to concurrent therapies at any g dose, changing) survival
time.  Duration of treatment QoL
(concurrent treatment) Melanoma
 Number of Agents specific survival
(Drug list for Concurrent
immunosuppressant, disease specific
Levadopa, Metformin, HRT, survival
COCP)
Searches:
Are there any study design filters to be used (RCT,

systematic review, diagnostic test).
List useful search terms. Immunosuppressive drugs and Cancer
… and specific drugs e.g. azathioprine or anti TNF

NSAIDs or aspririn and Cancer
Metformin and melanoma
Levodopa and melanoma risk
Melanoma and parkinsons
B blockers and melanoma
HRT and melanoma
Contraceptive pill and melanoma
Some reviews seem to be addressed to specific

concurrent diseases e.g. immunosuppression for
inflammatory bowel disease e.g. risk of cancer after
organ transplant
Notes Include studies with mixed skin cancer populations

(BCC/SCC/Melanoma) if available and either report
only melanoma patients if possible or downgrade
the quality of the evidence for indirectness
Duration of treatment (concurrent treatment)

Number of Agents
1 Search Results
2 Literature search details

found search
Medline 1946-2013 3580 24/04/2014
Premedline Apr 23 2014 93 24/04/2014
Embase 1947-2013 8811 28/04/2014

April 2014
Total References retrieved (after initial sift and de-duplication): 409

1 Update Search
3 of April 2014 onwards.

retrieved search
Medline 79 4 15/10/2014
Embase 148 4 15/10/2014
1 reference found in Pubmed 15/10/204
5 1. exp Melanoma/
6 2. melanoma$.tw.
9 5. dubreuilh.tw.
10 6. LMM.tw.
11 7. or/1-6
12 8. (acetylsalicylic acid or aspirin).tw.
13 9. Aspirin/
14 10. 8 or 9
15 11. exp Anti-inflammatory Agents, Non-Steroidal/
16 12. (((non?steroidal or non-steroidal) adj (anti?inflammatory or anti-inflammatory or
17 antinflammatory)) or NSAID*).tw.
18 13. (Aceclofenac or Acemetacin or Celecoxib or Dexibuprofen or Dexketoprofen or Diclofenac or
19 Etodolac or Etoricoxib or Fenbufen or Fenoprofen or Flurbiprofen or Ibuprofen or Indometacin or
20 Ketoprofen or Mefenamic acid or Meloxicam or Nabumetone or Naproxen or Piroxicam or Sulindac
21 or Tenoxicam or Tiaprofenic acid or tolfenamic acid or clotam rapid).tw.
22 14. or/11-13
23 15. exp Adrenergic beta-Antagonists/
24 16. (propranolol or angilol or inderal-la or half-inderal or inderal or bedranol or prograne or slo-pro
25 or acebutolol or sectral or atenolol or tenormin or bisoprolol or cardicor or emcor or carvedilol or
26 eucardic or celiprolol or celectol or co-tenidone or tenoret or tenoretic or esmolol or brevibloc or
27 labetalol or trandate or metoprolol or betaloc or lopresor or nadolol or corgard or nebivolol or
28 nebilet or hypoloc or oxprenolol or trasicor or slow-trasicor or pindolol or visken or sotalol or beta-
29 cardone or sotacor or timolol or betim).tw.
30 17. (beta adj3 block*).tw.
31 18. (b adj3 block*).tw.

1 19. (beta adj2 antagonist*).tw.

2 20. or/15-19
3 21. Contraceptive Agents/
4 22. Contraceptive Agents, Female/
5 23. exp Contraceptives, Oral/
6 24. exp Menstruation-Inducing Agents/
7 25. (Loestrin20 or Mercilon or Femodette or Brevinor or Cilest or Eugynon30 or Loestrin30 or
8 Microgynon30 or Norimin or Norinyl-1 or Ovranette or Ovysmen or Yasmin or Femodene or
9 Marvelon or Minulet or BiNovum or Logynon or Qlaira or Synphase or Triadene or Tri-Minulet or
10 Trinordial or TriNovum or Evra patch or Cerazette or Femulen or Micronor or Microval or Neogest or
11 Norgeston or Noriday or Medroxyprogesterone acetate or Depo-provera or Norethisterone enantate
12 or Noristerat or Etonogestrel-releasing implant or Implanon or Nexplanon or Mirena).tw.
13 26. ((progestogen* or progestin* or progestagen* or estrogen* or oestrogen* or combined) adj3
14 contracepti*).tw.
15 27. or/21-26
16 28. exp Hormone Replacement Therapy/
17 29. ((hormon* or oestrogen* or estrogen* or oestradiol or estradiol or progesteron* or progestin or
18 progestagen*) and replacement).tw.
19 30. hormone substitution.tw.
20 31. hrt.tw.
21 32. ((hormon* or oestrogen* or estrogen* or oestradiol or estradiol or progesteron* or progestin or
22 progestagen*) adj2 (therap* or treatment*)).tw.
23 33. or/28-32
24 34. exp Immunosuppressive Agents/
25 35. (immunosuppressant* or immunosuppressive agent* or immune-suppressant*).tw.
26 36. (6-Mercaptopurine or Antilymphocyte serum or Azaserine or Azathioprine or Busulfan or
27 Cladribine or Coformycin or Cyclophosphadamide or Cyclosporin* or Ciclosporin* or Cytarabine or
28 Ellipticine* or Fluorouracil or Gliotoxin or Methotrexate or Muromonab-CD3 or Sirolimus or
29 Tacrolimus or Thalidomide or Thioinosine or Triamcinolone Acetonide).tw.
30 37. or/34-36
31 38. Metformin/
32 39. (metformin or glucophage or dimethylbiguanidine or dimethylguanylguanidine).tw.
33 40. 38 or 39
34 41. Levodopa/
35 42. (l 34 dihydroxyphenylalanine or l-dopa or l-34-dihydroxyphenylalanine or arodopa or 3-hydroxy-
36 l-tyrosine or l dopa or 3 hydroxy l tyrosine or dopaflex or dopar or levodopa or levopa).tw.
37 43. 41 or 42
38 44. exp Parkinson Disease/
39 45. (parkinson* or parkinson's or hemiparkinson* or hemi-parkinson* or antiparkinson* or anti-
40 Parkinson*).tw.
41 46. exp Parkinsonian Disorders/
42 47. (parkinsonian disorders or parkinsonian syndrome).tw.
43 48. paralysis agitan*.tw.
44 49. hypokinetic rigid syndrome.tw.
45 50. or/44-49
46 51. 10 or 14 or 20 or 27 or 33 or 37 or 40 or 43 or 50
47 52. 7 and 51
48

1 Screening Results

searching other sources
431 0

431 349

82 66

15
4 Hormone replacement therapy (HRT)
5 Low quality evidence from an observational study of 206 patients with melanoma followed up for a
6 median of 10.6 years (MacKie and Bray, 2004) suggests a lower overall mortality rate in those
7 receiving HRT than in those not receiving HRT (mortality rate 1.2% versus 3.3%; HR=0.17, 95% CI
8 0.05 to 0.62).
9 No evidence was found about the effect of hormone replacement therapy on progression free
10 survival, quality of life, melanoma specific survival or concurrent disease specific survival in patients
11 with melanoma.
12 Indirect evidence comes from studies comparing the rates of melanoma in women receiving
13 hormone therapy to those not receiving such therapy:
14  Low quality evidence from 8 case control and 2 cohort studies including 110113 patients
15 (Gandini et al, 2011) suggests uncertainty over whether hormone replacement therapy is
16 associated with an increased risk of melanoma, OR 1.16 (95% CI 0.93 to 1.44).
17  Moderate quality evidence from a randomized trial of hormone replacement therapy (Tang
18 et al, 2011) suggests uncertainty about the relative rates of melanoma, HR = 0.92 (95% CI
19 0.61 to 1.37; HRT versus no HRT).
20  The evidence from these studies suggests that, even at the upper limit of the effect
21 confidence interval, the absolute increase in melanoma risk is likely to be small.

1 Oral contraceptives
2 No evidence was found about the effect of oral contraceptives on outcomes in patients with
3 melanoma.
4 Indirect evidence comes from studies comparing the rates of melanoma in women taking oral
5 contraceptives therapy to those not taking oral contraceptives. Low quality evidence from 4 cohort
6 and 16 case control studies including 301347 women (Gandini et al, 2011) suggests that oral
7 contraceptive use is not associated with an increased risk of melanoma, OR 1.04 (95% CI 0.92 to
8 1.18).
9 β-blockers
10 Low quality evidence comes from three cohort studies (De Giorgi et al, 2013; Livingston et al, 2013;
11 Lemeshow et al, 2011) including 4641 patients with melanoma, 557 of whom had received
12 treatment with β-blockers. Pooling the adjusted hazards ratios suggests better overall survival in
13 those treated with β-blockers (HR = 0.80, 95%CI 0.67 to 0.94). One study (De Giorgi et al, 2013) also
14 reported better disease free survival (defined as the time to melanoma recurrence or death from
15 any cause) in the group taking β-blockers (rate of recurrence or death was 2.5% versus 8%; HR =
16 0.03, 95% CI 0.01 to 0.17).
17 Immunosuppressive therapy
18 No evidence was found about the use of immunosuppressive therapy in transplant patients with
19 melanoma.
20 One systematic review of low quality, retrospective studies reported that transplant recipients had a
21 pooled estimate of 2.4 times (95% CI 2.0-2.9) the risk of melanoma when compared with the general
22 population (I2=46%, p=0.04). Adjusting for type of organ graft and most recent year of transplant in
23 the cohort reduced the I2 to 0%. (Dahlke et al (2014).
24 Low quality indirect evidence comes from the rates of melanoma in two observational studies
25 including 3686 kidney or heart transplant patients receiving immunosuppressive therapy (Jensen et
26 al, 1999; Bastiaannet et al, 2007). The standardized incidence ratio (SIR) ranged from 1.7 to 3.4
27 suggesting an increased risk of melanoma in this population. The evidence from these studies
28 suggests if 1000 patients were treated for a year with immunosuppressive therapy we would expect
29 one additional melanoma (assuming an incidence rate of 0.5 per 1000 in the untreated population).
30 Metformin for type 2 diabetes
31 No evidence was found about the use of metformin therapy in patients with melanoma and type 2
32 diabetes.
33 Low quality indirect evidence comes from a systematic review of 2 randomised trials of metformin
34 for type 2 diabetes (Franciosi et al 2013), including 6576 patients followed over 4 to 5 years of
35 treatment. There was uncertainty over whether metformin increased or decreased the rate of
36 melanoma compared to other treatments (0.08% versus 0.15%; OR = 0.87, 95%CI 0.36 to 2.66).

1 Levadopa
2 No evidence was found about the use of levadopa therapy in patients with melanoma and
3 Parkinson’s disease.
4 Very low quality indirect evidence comes from a screening study of 2106 patients with Parkinson’s
5 disease (Bertoni et al, 2010), 1786 of whom had previously been treated with levadopa. There was
6 uncertainty over whether levadopa treatment was associated with an increased or decreased
7 prevalence of melanoma compared to other treatments (4.3% versus 5%; OR = 0.84, 95%CI 0.48 to
8 1.47).
9 Methotrexate
10 No evidence was found about the use of treatments for rheumatoid arthritis in patients with
11 melanoma.
12 Very low quality indirect evidence comes from an observational study of 459 patients treated with
13 methotrexate (Buchbinder et al, 2008). The SIR for melanoma was 3.0 (95%CI 1.2 to 6.2) suggesting
14 an increased relative risk of melanoma in this group, although the absolute increased risk is likely to
15 be of the order of one additional melanoma per 1000 patient-years of treatment.
16 Non steroidal anti-inflammatory drugs (NSAIDs)
17 No evidence was found about the use of NSAIDs in patients with melanoma.
18 Low quality indirect evidence comes from a meta-analysis of 10 case-control and observational
19 studies, including 6999 patients with melanoma and 490332 controls (Hu et al, 2014). There was no
20 increased risk of melanoma in patients treated with aspirin (RR=0.96, 95%CI 0.89 to 1.03) or with
21 non-aspirin NSAIDs (RR=1.05, 95%CI 0.96 to 1.14).
22 Very low quality evidence from one case control study (Siiskonen, 2013) including 11318 patients
23 with melanoma and 6786 controls suggest that propionic acid derivative NSAIDs are associated with
24 an increased risk of melanoma (OR=1.33, 95%CI 1.14 to 1.54).
25 Quinolones
26 No evidence was found about the use of quinolones in patients with melanoma. Very low quality
27 indirect evidence comes from one case control study (Siiskonen, 2013) including 11318 patients with
28 melanoma and 6786 controls which observed an increased risk of melanoma in people treated with
29 quinolones(OR=1.33, 95%CI 1.01 to 1.76).

GRADE Table8.3 : hormone replacement therapy
No of Design Risk of Inconsistency Indirectness Imprecision Other Exogenous No exogenous Relative Absolute
studies bias considerations hormones hormones (95% CI)
Melanoma
20 observational no serious no serious serious no serious none 2548 cases 30922 controls and 7642 OR 1.16 1 more per 1000
studies1 risk of bias inconsistency indirectness imprecision patients from cohort studies (0.93 to (from 0 fewer to 2 VERY LOW
1.44) more)
0.51%2
Melanoma (in RCTs of HRT)
1 855randomized no serious no serious serious no serious none 46/13816 49/13531 HR 0.92 0 fewer per 1000
trials risk of bias inconsistency indirectness imprecision3 (0.33%) (0.36%) (0.61 to (from 1 fewer to 1 MODERATE
1.37) more)
Overall mortality (in melanoma patients) (follow-up median 10.6 years)
1 observational no serious no serious no serious no serious none 1/83 4/123 HR 0.173 27 fewer per 1000
studies risk of bias inconsistency indirectness imprecision (1.2%) (3.3%) (0.048 to (from 12 fewer to LOW
0.621) 31 fewer)
1
case-control
2
Control risk from large UK cohort study included in Gandini et al (2011) (Hannaford, 2007).
3
Although the confidence interval for the relative effect is large the difference in the absolute event rate is very small – so the study was not downgraded for imprecision.

GRADE Table 8.4: oral contraceptive use
No of Design Risk of bias Inconsistency Indirectness Imprecision Other Oral contraceptives Control Relative Absolute
Melanoma
20 observational no serious no serious serious2 no serious none 4171 cases 13644 controls and 283532 OR 1.04 0 more per 1000
studies1 risk of bias inconsistency imprecision women from cohort studies (0.92 to (from 0 fewer to 1 VERY
1.18) more) LOW
0.51%3
1
case-control and other study designs together
2
Most of the included women did not have melanoma.
3
Rate reported in Hannaford (2007) UK cohort study
GRADE Table 8.5: immunosuppressive therapy in kidney or heart transplant patients
No of Design Risk of bias Inconsistency Indirectness Imprecision Other Immunosuppression Control Relative Absolute
Melanoma (follow-up 7.3 years)
2 observational no serious risk no serious Serious3 no serious none 13/23288 0.0179%2 SIR ranged from -
studies of bias inconsistency imprecision (0.06%)1 1.7 to 3.4 LOW
1 Systematic No serious No serious No serious serious LOW

Review4 risk of bias inconsistency imprecision
1
Rate per person-years (the total number of patients was 3686).
2
Based on the reported expected rates of melanoma from the included studies (0.00007 to 0.00023 per person-year)
3
The included patients did not all have melanoma

4
This was a systematic review of a number of poor quality retrospective observational studies

GRADE Table 8.6: beta blockers for hypertension
No of Design Risk of bias Inconsistency Indirectness Imprecision Other Beta- No beta- Relative Absolute
studies considerations blockers blockers (95% CI)
Melanoma recurrence or mortality (follow-up median 4.2)
1 observational Serious1 no serious no serious serious none 2/79 53/662 HR 0.03 (0.01 78 fewer per 1000
studies inconsistency indirectness (2.5%) (8%) to 0.17) (from 66 fewer to 79 VERY
fewer) LOW
Overall mortality
3 observational no serious no serious no serious no serious none 194/557 1113/4084 HR 0.80 (0.67 48 fewer per 1000
studies risk of bias inconsistency indirectness imprecision (34.8%) (27.3%) to 0.94) (from 14 fewer to 81 LOW
fewer)
1
Significant difference in the baseline characteristics of the two groups
GRADE Table 8.7: metformin for type 2 diabetes
No of Design Risk of bias Inconsistency Indirectness Imprecision Other Metformin Control Relative Absolute
Melanoma (follow-up 4-6 years)
2 858randomized no serious risk no serious Serious2 serious1 none 2/2576 6/4000 OR 0.87 (0.36 to 0 fewer per 1000 (from 1
trials of bias inconsistency (0.78%) (0.15%) 2.66) fewer to 2 more) LOW
1
Low event rate

2
This study was not done in melanoma patients
GRADE Table 8.8: methotrexate for rheumatoid arthritis
No of Design Risk of bias Inconsistency Indirectness Imprecision Other Methotrexate Control Relative Absolute
Melanoma (follow-up median 9.3 years)
1 observational no serious no serious serious serious1 none 7/4145 (0.06%) SIR 3.0 (1.2 1 more per 1000 patient-
studies risk of bias inconsistency indirectness3 (0.17%)2 to 6.2) years (0 more to 3 more) VERY
LOW
1
2
There were 4145 person years of follow-up in 459 patients
3
GRADE Table 8.9: levadopa for Parkinson’s disease
No of Design Risk of bias Inconsistency Indirectness Imprecision Other Levadopa Control Relative Absolute
Melanoma
1 observational no serious no serious serious no serious none 76/1786 16/320 OR 0.84 (0.48 8 fewer per 1000 (from
studies risk of bias inconsistency indirectness1 imprecision (4.3%) (5%) to 1.47) 25 fewer to 22 more) VERY
LOW
1

GRADE Table 8.10: NSAIDs
Quality assessment No of patients Effect Quality Importance
No of Design Risk of bias Inconsistency Indirectness Imprecision Other NSAIDs Control Relative Absolute
Melanoma (in studies of aspirin)
8 observational no serious risk no serious serious2 no serious none -3 RR 0.96 (0.89 -

studies1 of bias inconsistency imprecision to 1.03) VERY LOW
Melanoma (in non-aspirin NSAIDs)
5 observational no serious risk no serious serious2 no serious none -3 RR 1.05 (0.96 -

studies1 of bias inconsistency imprecision to 1.14) VERY LOW
Melanoma (in propionic acid derivative (phototoxic) NSAIDs)
1 observational no serious risk no serious serious2 no serious none 1318 cases 6786 OR 1.33 (1.14 -
studies of bias inconsistency imprecision controls to 1.54) VERY LOW
1
case-control and other study designs together
2
Most participants in the included studies did not have melanoma.
3
Numbers of patients not reported for subgroup analyses

GRADE Table 8.11: quinolones
No of Design Risk of bias Inconsistency Indirectness Imprecision Other Quinolones Control Relative Absolute
Melanoma
1 observational no serious risk of no serious serious2 no serious none 1318 cases 6786 OR 1.33 (1.01 to -
studies1 bias inconsistency imprecision controls 1.76) VERY
LOW
-
1
case-control
2
Not all patients had melanoma in this study

1 References
2 Included Studies
3 Bastiaannet, E., Homan-van der Heide JJ, Ploeg, R. J., Hoekstra, H. J. No increase of melanoma after
4 kidney transplantation in the northern part of The Netherlands. Melanoma Research 17[6], 349-353.
5 2007.
6 Bertoni, John M., Arlette, John Philip, Fernandez, Hubert H., Fitzer-Attas, Cheryl, Frei, Karen, Hassan,
7 Mohamed N., Isaacson, Stuart H., Lew, Mark F., Molho, Eric, Ondo, William G., Phillips, Tania J.,
8 Singer, Carlos, Sutton, James P., Wolf, John E Jr, and North American Parkinson’s and Melanoma
9 Survey Investigators. Increased melanoma risk in Parkinson disease: a prospective clinicopathological
10 study. Archives of Neurology 67[3], 347-352. 2010.
11 Buchbinder, R., Barber, M., Heuzenroeder, L., Wluka, A. E., Giles, G., Hall, S., Harkness, A., Lewis, D.,
12 Littlejohn, G., Miller, M. H., Ryan, P. F., Jolley, D. Incidence of melanoma and other malignancies
13 among rheumatoid arthritis patients treated with methotrexate. Arthritis & Rheumatism 59[6], 794-
14 799. 15-6-2008.
15 Dahlke, E., Murray, C. A., Kitchen, J., and Chan, A. W. Systematic review of melanoma incidence and
16 prognosis in solid organ transplant recipients. Transplantation Research 3, 10. 2014.
17 De Giorgi, V., Gandini, S., Grazzini, M., Benemei, S., Marchionni, N., & Geppetti, P. (2013). Effect of
18 beta-Blockers and Other Antihypertensive Drugs On the Risk of Melanoma Recurrence and Death.
19 Mayo Clinic Proceedings, 88, 1196-1203.
20 Franciosi, M., Lucisano, G., Lapice, E., Strippoli, G. F., Pellegrini, F., Nicolucci, A. Metformin therapy
21 and risk of cancer in patients with type 2 diabetes: systematic review. PloS ONE [Electronic
22 Resource] 8[8], e71583. 2013.
23 Gandini, S., Iodice, S., Koomen, E., Di, Pietro A., Sera, F., Caini, S., Gandini, Sara, Iodice, Simona,
24 Koomen, Els, Di Pietro, Alessandra, Sera, Francesco, and Caini, Saverio. Hormonal and reproductive
25 factors in relation to melanoma in women: current review and meta-analysis. [Review]. European
26 Journal of Cancer 47[17], 2607-2617. 2011.
27 Hu, H., Xie, Y., Yang, G., Jian, C., and Deng, Y. Nonsteroidal anti-inflammatory drug use and the risk of
28 melanoma: a meta-analysis. European Journal of Cancer Prevention 23[1], 62-68. 2014.
29 Jensen, P., Hansen, S., Moller, B., Leivestad, T., Pfeffer, P., Geiran, O., Fauchald, P., and Simonsen, S.
30 Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive
31 therapy regimens. Journal of the American Academy of Dermatology 40[2 Pt 1], 177-186. 1999.
32 Lemeshow, S., Sorensen, H. T., Phillips, G., Yang, E. V., Antonsen, S., Riis, A. H., Lesinski, G. B.,
33 Jackson, R., Glaser, R.. beta-Blockers and survival among Danish patients with malignant melanoma:
34 a population-based cohort study. Cancer Epidemiology, Biomarkers & Prevention 20[10], 2273-2279.
35 2011.
36 Livingstone, E., Hollestein, L. M., van Herk-Sukel, M. P., Poll-Franse, L., Nijsten, T., Schadendorf, D.,
37 de, Vries E., Livingstone, E., Hollestein, L. M., van Herk-Sukel, M. P. P., Poll-Franse, L., Nijsten, T.,

1 Schadendorf, D., and de Vries, E. beta-Blocker use and all-cause mortality of melanoma patients:
2 results from a population-based Dutch cohort study. European Journal of Cancer 49[18], 3863-3871.
3 2013.
4 MacKie, R. M., Bray, C. A., MacKie, R. M., and Bray, C. A. Hormone replacement therapy after surgery
5 for stage 1 or 2 cutaneous melanoma. British Journal of Cancer 90[4], 770-772. 23-2-2004.
6 Tang, J. Y., Spaunhurst, K. M., Chlebowski, R. T., Wactawski, Wende J., Keiser, E., Thomas, F.,
7 Anderson, M. L., Zeitouni, N. C., Larson, J. C., and Stefanick, M. L. Menopausal hormone therapy and
8 risks of melanoma and nonmelanoma skin cancers: women’s health initiative randomized trials.
9 Journal of the National Cancer Institute 103[19], 1469-1475. 2011.
10 Olsen, J. H., Tangerud, K., Wermuth, L., Frederiksen, K., Friis, S., Olsen, Jorgen H., Tangerud, Karina,
11 Wermuth, Lene, Frederiksen, Kirsten, and Friis, Soren. Treatment with levodopa and risk for
12 malignant melanoma. Movement Disorders 22[9], 1252-1257. 15-7-2007
13 Siiskonen, S. J., Koomen, E. R., Visser, L. E., Herings, R. M., Guchelaar, H. J., Stricker, B. H., and
14 Nijsten, T. E. Exposure to phototoxic NSAIDs and quinolones is associated with an increased risk of
15 melanoma. European Journal of Clinical Pharmacology 69[7], 1437-1444. 2013.
16 Excluded Studies
17 Adam, S. A., Sheaves, J. K., Wright, N. H., Mosser, G., Harris, R. W., Vessey, M. P., Adam, S. A.,
18 Sheaves, J. K., Wright, N. H., Mosser, G., Harris, R. W., and Vessey, M. P. A case-control study of the
19 possible association between oral contraceptives and malignant melanoma. British Journal of Cancer
20 44[1], 45-50. 1981.
21 Reason: included in Gandini 2011 systematic review
22 Amato, M. P., Pracucci, G., Ponziani, G., Siracusa, G., Fratiglioni, L., Amaducci, L. Long-term safety of
23 azathioprine therapy in multiple sclerosis. Neurology 43[4], 831-833. 1993.
24 Reason: not relevant to PICO – looks at all cancer risk
25 Asgari, M. M., Maruti, S. S., White, E., Asgari, Maryam M., Maruti, Sonia S., and White, Emily. A large
26 cohort study of nonsteroidal anti-inflammatory drug use and melanoma incidence. Journal of the
27 National Cancer Institute 100[13], 967-971. 2-7-2008.
28 Reason: included in Hu 2014 systematic review)
29 Bain, C., Hennekens, C. H., Speizer, F. E., Rosner, B., Willett, W., Belanger, C., Bain, C., Hennekens, C.
30 H., Speizer, F. E., Rosner, B., Willett, W., and Belanger, C. Oral contraceptive use and malignant
31 melanoma. Journal of the National Cancer Institute 68[4], 537-539. 1982.
33 Bajaj, A., Driver, J. A., Schernhammer, E. S., Bajaj, A., Driver, J. A., & Schernhammer, E. S. (2010).
34 Parkinson’s disease and cancer risk: a systematic review and meta-analysis. Cancer Causes & Control,
35 21, 697-707.
36 Reason: Systematic review – primary outcome was cancer – excluding melanoma and other skin
37 cancers

1 Barrett, W. L., First, M. R., Aron, B. S., and Penn, I. Clinical course of malignancies in renal transplant
2 recipients. Cancer 72[7], 2186-2189. 1-10-1993.
3 Reason: Non comparative – describes clinical course only
4 Baurain, J.-F. Outcomes of ipilimumab treatment-related adverse events in patients with metastatic
5 melanoma (MM) who received systemic corticosteroids in a phase III trial. Journal of Clinical
6 Oncology Conference[var.pagings]. 2012.
7 Reason: abstract – not relevant to PICO
8 Beral, V., Evans, S., Shaw, H., Milton, G., Beral, V., Evans, S., Shaw, H., and Milton, G. Oral
9 contraceptive use and malignant melanoma in Australia. British Journal of Cancer 50[5], 681-685.
10 1984.
11 Reason: study included in Gandini systematic review
12 Biglia, N., Gadducci, A., Ponzone, R., Roagna, R., Sismondi, P., Biglia, Nicoletta, Gadducci, Angelo,
13 Ponzone, Riccardo, Roagna, Riccardo, and Sismondi, Piero. Hormone replacement therapy in cancer
14 survivors. [Review] [134 refs]. Maturitas 48[4], 333-346. 20-8-2004.
15 Reason: outdated review – see Gandini 201
16 Birch-Johansen, F., Jensen, A., Olesen, A. B., Christensen, J., Tjonneland, A., Kjaer, S. K., Birch-
17 Johansen, Fatima, Jensen, Allan, Olesen, Anne Braae, Christensen, Jane, Tjonneland, Anne, and
18 Kjaer, Susanne K. Does hormone replacement therapy and use of oral contraceptives increase the
19 risk of non-melanoma skin cancer? Cancer Causes & Control 23[2], 379-388. 2012.
20 Reason: non-melanoma skin cancer
21 Borne, E., Desmedt, E., Duhamel, A., Mirabel, X., Dziwniel, V., Maire, C., Florin, V., Martinot, V.,
22 Penel, N., Vercambre-Darras, S., Mortier, L.. Oral metronomic cyclophosphamide in elderly with
23 metastatic melanoma. Investigational New Drugs 28[5], 684-689. 2010.
24 Reason: not relevant to PICO
25 Caldarola, G., Battista, C., Pellicano, R., Caldarola, Giacomo, Battista, Claudia, and Pellicano,
26 Riccardo. Melanoma onset after estrogen, thyroid, and growth hormone replacement therapy.
27 Clinical Therapeutics 32[1], 57-59. 2010.
28 Reason: Case report
29 Chakravarty, E. F. and Farmer, E. R. Risk of skin cancer in the drug treatment of rheumatoid arthritis.
30 Expert Opinion on Drug Safety 7[5], 539-546. 2008.
32 Chakravarty, E. F., Michaud, K., Wolfe, F., Chakravarty, Eliza F., Michaud, Kaleb, and Wolfe, Frederick.
33 Skin cancer, rheumatoid arthritis, and tumor necrosis factor inhibitors. Journal of Rheumatology
34 32[11], 2130-2135. 2005.
35 Reason: Non melanoma skin cancer
36 Clark, D. A. Do anti-TNF-alpha drugs increase cancer risk in rheumatoid arthritis patients?

37 Inflammopharmacology 21[2], 125-127. 2013.
38 Reason: expert review – non melanoma skin cancer

1 Cuchural, G. J., Jr., Levey, A. S., Pauker, S. G., Cuchural, G. J. J., Levey, A. S., and Pauker, S. G. Kidney
2 failure or cancer. Should immunosuppression be continued in a transplant patient with malignant
3 melanoma? Medical Decision Making 4[1], 82-107. 1984.
4 Reason: Decision model – no primary data
5 Curiel-Lewandrowski, C., Nijsten, T., Gomez, M. L., Hollestein, L. M., Atkins, M. B., Stern, R. S., Curiel-
6 Lewandrowski, Clara, Nijsten, Tamar, Gomez, Maria L., Hollestein, Loes M., Atkins, Michael B., and
7 Stern, Robert S. Long-term use of nonsteroidal anti-inflammatory drugs decreases the risk of
8 cutaneous melanoma: results of a United States case-control study. Journal of Investigative
9 Dermatology 131[7], 1460-1468. 2011.
10 Reason: included in Hu 2014 systematic review
11 Curiel-Lewandrowski, C., Swetter, S. M., Einspahr, J. G., Hsu, C. H., Nagle, R., Sagerman, P., Tangrea,
12 J., Parnes, H., Alberts, D. S., Chow, H. H. Randomized, double-blind, placebo-controlled trial of
13 sulindac in individuals at risk for melanoma: evaluation of potential chemopreventive activity.
14 Cancer 118[23], 5848-5856. 1-12-2012.
15 Reason: chemoprevention
16 De Giorgi, V. The effect of beta-blocker treatment in patients with cutaneous melanoma. Journal of
17 Clinical Oncology Conference[var.pagings]. 2011.
18 Reason: abstract only – see De Giorgi 2013
19 De Giorgi, V., Grazzini, M., Gandini, S., Benemei, S., Lotti, T., Marchionni, N., and Geppetti, P.
20 Treatment With beta-Blockers and Reduced Disease Progression in Patients With Thick Melanoma.
21 Archives of Internal Medicine 171[8], 779-781. 2011.
22 Reason: Patients included in De Giorgi 2013
23 Dommasch, E. D. A. The safety of tumor necrosis factor antagonists in psoriasis: A systematic review
24 and meta-analysis of randomized controlled trials. Journal of Investigative Dermatology
25 Conference[var.pagings], April. 2010.
26 Reason: abstract only
27 Eigentler, T. K. C. Palliative therapy of disseminated malignant melanoma: A systematic review of 41

28 randomised clinical trials. Lancet Oncology 4[12], 748-759. 2003.
30 Ellerbroek, W. C. and Ellerbroek, W. C. Oral contraceptives and malignant melanoma. JAMA 206[3],
31 649-650. 14-10-1968.
32 Reason: letter – case report
33 Faraj, B. A., Camp, V. M., Murray, D. R., Kutner, M., Hearn, J., Nixon, D., Plasma L-dopa in the
34 diagnosis of malignant melanoma. Clinical Chemistry 32[1 Pt 1], 159-161. 1986.
35 Feskanich, D., Hunter, D. J., Willett, W. C., Spiegelman, D., Stampfer, M. J., Speizer, F. E., Colditz, G.
36 A., Feskanich, D., Hunter, D. J., Willett, W. C., Spiegelman, D., Stampfer, M. J., Speizer, F. E., and
37 Colditz, G. A. Oral contraceptive use and risk of melanoma in premenopausal women. British Journal
38 of Cancer 81[5], 918-923. 1999.

1 Fiala, K. H., Whetteckey, J., Manyam, B. V., Fiala, K. H., Whetteckey, J., & Manyam, B. V. (2003).
2 Malignant melanoma and levodopa in Parkinson’s disease: causality or coincidence?. [Review] [35
3 refs]. Parkinsonism & Related Disorders, 9, 321-327.
4 Reason: collection of case reports)
5 Field S. beta-blockers and survival from melanoma. Pigment Cell and Melanoma Research
6 Conference[var.pagings], 1070. 2011.
7 Reason:abstract only
8 Frankenthaler, A., Sullivan, R. J., Wang, W., Renzi, S., Seery, V., Lee, M. Y., and Atkins, M. B. Impact of
9 concomitant immunosuppression on the presentation and prognosis of patients with melanoma.
10 Melanoma Research 20[6], 496-500. 2010.
11
12 Gallagher, R. P., Elwood, J. M., Hill, G. B., Coldman, A. J., Threlfall, W. J., Spinelli, J. J., Gallagher, R. P.,
13 Elwood, J. M., Hill, G. B., Coldman, A. J., Threlfall, W. J., and Spinelli, J. J. Reproductive factors, oral
14 contraceptives and risk of malignant melanoma: Western Canada Melanoma Study. British Journal of
15 Cancer 52[6], 901-907. 1985.
17 Gurney, H., Coates, A., Kefford, R., Gurney, H., Coates, A., and Kefford, R. The use of L-dopa and
18 carbidopa in metastatic malignant melanoma. Journal of Investigative Dermatology 96[1], 85-87.
19 1991.
21 Hannaford, P. C., Villard-Mackintosh, L., Vessey, M. P., Kay, C. R., Hannaford, P. C., Villard-
22 Mackintosh, L., Vessey, M. P., and Kay, C. R. Oral contraceptives and malignant melanoma. British
23 Journal of Cancer 63[3], 430-433. 1991.
24 Reason: Vessey 2006 study included in Gandini systematic review
25 Hartmann, B. W., Huber, J. C., Hartmann, B. W., and Huber, J. C. The mythology of hormone
26 replacement therapy. [Review] [98 refs]. British Journal of Obstetrics & Gynaecology 104[2], 163-
27 168. 1997.
29 Hartmann, D. W. R. Unanticipated side effects from treatment with high-dose mechlorethamine in

30 patients with malignant melanoma. Cancer Treatment Reports 65[3-4], 327-328. 1981.
32 Helmrich, S. P., Rosenberg, L., Kaufman, D. W., Miller, D. R., Schottenfeld, D., Stolley, P. D., Shapiro,
33 S., Helmrich, S. P., Rosenberg, L., Kaufman, D. W., Miller, D. R., Schottenfeld, D., Stolley, P. D., and
34 Shapiro, S. Lack of an elevated risk of malignant melanoma in relation to oral contraceptive use.
35 Journal of the National Cancer Institute 72[3], 617-620. 1984.
37 Holly, E. A. and Holly, E. A. Cutaneous melanoma and oral contraceptives: a review of case-control
38 and cohort studies. Recent Results in Cancer Research 102, 108-117. 1986.
39 Reason: outdated review superceeded by Gandini systematic review

1 Holly, E. A., Cress, R. D., Ahn, D. K., Holly, E. A., Cress, R. D., and Ahn, D. K. Cutaneous melanoma in
2 women. Reproductive factors and oral contraceptive use. American Journal of Epidemiology 141[10],
3 943-950. 15-5-1995.
5 Holly, E. A., Weiss, N. S., Liff, J. M., Holly, E. A., Weiss, N. S., and Liff, J. M. Cutaneous melanoma in
6 relation to exogenous hormones and reproductive factors. Journal of the National Cancer Institute
7 70[5], 827-831. 1983.
9 Holman, C. D., Armstrong, B. K., Heenan, P. J., Holman, C. D., Armstrong, B. K., and Heenan, P. J.
10 Cutaneous malignant melanoma in women: exogenous sex hormones and reproductive factors.
11 British Journal of Cancer 50[5], 673-680. 1984.
12 Reason: study included in Gandini 2011 systematic review
13 Jeter, J. M., Bonner, J. D., Johnson, T. M., Gruber, S. B., Jeter, Joanne M., Bonner, Joseph D., Johnson,
14 Timothy M., and Gruber, Stephen B. Nonsteroidal anti-inflammatory drugs and risk of melanoma.
15 Journal of Skin Cancer 2011, 598571. 2011.
17 Jeter, J. M., Han, J., Martinez, M. E., Alberts, D. S., Qureshi, A. A., Feskanich, D., Jeter, J. M., Han, J.,
18 Martinez, M. E., Alberts, D. S., Qureshi, A. A., and Feskanich, D. Non-steroidal anti-inflammatory
19 drugs, acetaminophen, and risk of skin cancer in the Nurses’ Health Study. Cancer Causes & Control
20 23[9], 1451-1461. 2012.
22 Johannesdottir, S. A., Chang, E. T., Mehnert, F., Schmidt, M., Olesen, A. B., Sorensen, H. T.,
23 Johannesdottir, Sigrun Alba, Chang, Ellen T., Mehnert, Frank, Schmidt, Morten, Olesen, Anne Braae,
24 and Sorensen, Henrik Toft. Nonsteroidal anti-inflammatory drugs and the risk of skin cancer: a
25 population-based case-control study. Cancer 118[19], 4768-4776. 1-10-2012.
27 Johnson, D. M. H. Rheumatoid arthritis complicating adjuvant interferon-alpha therapy for malignant

28 melanoma [3]. Journal of Rheumatology 26[4], 1009-1010. 1999.
29 Reason: case report
30 Joosse, A., Koomen, E. R., Casparie, M. K., Herings, R. M., Guchelaar, H. J., Nijsten, T., Joosse, Arjen,
31 Koomen, Elsje R., Casparie, Mariel K., Herings, Ron M. C., Guchelaar, Henk Jan, and Nijsten, Tamar.
32 Non-steroidal anti-inflammatory drugs and melanoma risk: large Dutch population-based case-
33 control study. Journal of Investigative Dermatology 129[11], 2620-2627. 2009.
35 Karagas, M. R., Stukel, T. A., Dykes, J., Miglionico, J., Greene, M. A., Carey, M., Armstrong, B., Elwood,
36 J. M., Gallagher, R. P., Green, A., Holly, E. A., Kirkpatrick, C. S., Mack, T., Osterlind, A., Rosso, S., and
37 Swerdlow, A. J. A pooled analysis of 10 case-control studies of melanoma and oral contraceptive use.
38 British Journal of Cancer 86[7], 1085-1092. 8-4-2002.
39 Reason: outdated systematic review superceeded by Gandini systematic review

1 Koomen, E. R. J. Effect of statins on melanoma of the skin. Pharmaceutisch Weekblad 142[42], 133-
2 137. 2007.
4 Koomen, E. R., Joosse, A., Herings, R. M., Casparie, M. K., Bergman, W., Nijsten, T., Guchelaar, H. J.,
5 Koomen, E. R., Joosse, A., Herings, R. M. C., Casparie, M. K., Bergman, W., Nijsten, T., and Guchelaar,
6 H. J. Is statin use associated with a reduced incidence, a reduced Breslow thickness or delayed
7 metastasis of melanoma of the skin? European Journal of Cancer 43[17], 2580-2589. 2007.
8 Koomen, E. R., Joosse, A., Herings, R. M., Casparie, M. K., Guchelaar, H. J., Nijsten, T., Koomen, Elsje
9 R., Joosse, Arjen, Herings, Ron M. C., Casparie, Mariel K., Guchelaar, Henk Jan, and Nijsten, Tamar.
10 Does use of estrogens decrease the Breslow thickness of melanoma of the skin? Oral contraceptives
11 and hormonal replacement therapy. Melanoma Research 19[5], 327-332. 2009.
12 Reason: Study included in Gandini 2011 systematic review
13 Koomen, E. R., Joosse, A., Herings, R. M., Casparie, M. K., Guchelaar, H. J., Nijsten, T., Koomen, E. R.,
14 Joosse, A., Herings, R. M. C., Casparie, M. K., Guchelaar, H. J., and Nijsten, T. Estrogens, oral
15 contraceptives and hormonal replacement therapy increase the incidence of cutaneous melanoma:
16 a population-based case-control study. Annals of Oncology 20[2], 358-364. 2009.
18 Le, M. G., Cabanes, P. A., Desvignes, V., Chanteau, M. F., Mlika, N., Avril, M. F., Le, M. G., Cabanes, P.
19 A., Desvignes, V., Chanteau, M. F., Mlika, N., and Avril, M. F. Oral contraceptive use and risk of
20 cutaneous malignant melanoma in a case-control study of French women. [Review] [21 refs]. Cancer
21 Causes & Control 3[3], 199-205. 1992.
23 Lens, M. B., Reiman, T., and Husain, A. F. Use of tamoxifen in the treatment of malignant melanoma
24 – Systematic review and melaanalysis of randomized controlled trials. Cancer 98[7], 1355-1361.
25 2003.
27 Lens, M., Bataille, V., Lens, Marko, and Bataille, Veronique. Melanoma in relation to reproductive
28 and hormonal factors in women: current review on controversial issues. [Review] [38 refs]. Cancer
29 Causes & Control 19[5], 437-442. 2008.
31 Lerner, A. B., Nordlund, J. J., Kirkwood, J. M., Lerner, A. B., Nordlund, J. J., and Kirkwood, J. M. Effects
32 of oral contraceptives and pregnancy on melanomas. New England Journal of Medicine 301[1], 47. 5-
33 7-1979.
34 Reason: letter
35 Letellier, S., Garnier, J. P., Spy, J., Stoitchkov, K., Le, Bricon T., Baccard, M., Revol, M., Kerneis, Y.,
36 Bousquet, B., Letellier, S., Garnier, J. P., Spy, J., Stoitchkov, K., Le Bricon, T., Baccard, M., Revol, M.,
37 Kerneis, Y., and Bousquet, B. Development of metastases in malignant melanoma is associated with
38 an increase in the plasma L-dopa/L-tyrosine ratio. Melanoma Research 9[4], 389-394. 1999.

1 Li, S., Liu, Y., Zeng, Z., Peng, Q., Li, R., Xie, L., Qin, X., and Zhao, J. Association between non-steroidal
2 anti-inflammatory drug use and melanoma risk: a meta-analysis of 13 studies. Cancer Causes and
3 Control 24[8], 1505-1516. 2013.
4 Reason: chemoprevention
5 Liu, R., Gao, X., Lu, Y., Chen, H., Liu, Rui, Gao, Xiang, Lu, Yi, and Chen, Honglei. Meta-analysis of the
6 relationship between Parkinson disease and melanoma. [Review]. Neurology 76[23], 2002-2009. 7-6-
7 2011.
8 Reason: Study does not does not explicitly address the relationship between therapy and melanoma
9 Lukacs, L. Serum L-DOPA oxidase activity in patients with malignant cutaneous melanoma. Orvosi
10 Hetilap 125[41], 2483-2486. 1984.
12 McCourt, C., Coleman, H. G., Murray, L. J., Cantwell, M. M., Dolan, O., Powe, D. G., and Cardwell, C.
13 R. Beta-blocker usage after malignant melanoma diagnosis and survival: a population-based nested
14 case-control study. British Journal of Dermatology 170[4], 930-938. 2014.
15 Mackintosh, L. J., Geddes, C. C., Herd, R. M., Mackintosh, L. J., Geddes, C. C., and Herd, R. M. Skin
16 tumours in the West of Scotland renal transplant population. British Journal of Dermatology 168[5],
17 1047-1053. 2013.
18 Reason: does not analyze melanoma separately – mostly BCC and SCC
19 Nijsten, T., Koomen, E. R., Joosse, A., Herings, R., Casparie, M., and Guchelaar, H. Oestrogens, oral
20 contraceptives and hormonal replacement therapy increase the incidence of cutaneous melanoma:
21 a population based case control study. Journal of Investigative Dermatology 128, S82. 2008.
23 Osterlind, A., Tucker, M. A., Stone, B. J., Jensen, O. M., Osterlind, A., Tucker, M. A., Stone, B. J., and
24 Jensen, O. M. The Danish case-control study of cutaneous malignant melanoma. III. Hormonal and
25 reproductive factors in women. International Journal of Cancer 42[6], 821-824. 15-12-1988.
26 Palmer, J. R., Rosenberg, L., Strom, B. L., Harlap, S., Zauber, A. G., Warshauer, M. E., Shapiro, S., Oral
27 contraceptive use and risk of cutaneous malignant melanoma. Cancer Causes & Control 3[6], 547-
28 554. 1992.
29 Pfahlberg, A., Hassan, K., Wille, L., Lausen, B., and Gefeller, O. Systematic review of case-control
30 studies: oral contraceptives show no effect on melanoma risk (Structured abstract). Public Health
31 Reviews 25[3-4], 309-315. 1997.
32 Reason: outdated systematic review – see Gandini 2011
33 Sandyk, R. Accelerated growth of malignant melanoma by levodopa in Parkinson’s disease and role
34 of the pineal gland. International Journal of Neuroscience 63[1-2], 137-140. 1992.
36 Sober, A. J., Wick, M. M., Sober, A. J., and Wick, M. M. Levodopa therapy and malignant melanoma.
37 JAMA 240[6], 554-555. 11-8-1978.
38 Reason: case report

1 Ybot, I., V. Malignancy frequency analysis in a Parkinson’s disease patients sample. Movement
2 Disorders Conference[var.pagings], 2010. 2010.
4 Wilson, J. C., Murray, L. J., Hughes, C. M., and Anderson, L. A. Non-Steroidal Anti-Inflammatory Drug
5 and Aspirin Use and the Risk of Malignant Melanoma – A Systematic Review and Meta-Analysis.
6 Pharmacoepidemiology and Drug Safety 21, 419. 2012.
8 Zanetti, R., Franceschi, S., Rosso, S., Bidoli, E., Colonna, S., Zanetti, R., Franceschi, S., Rosso, S., Bidoli,
9 E., and Colonna, S. Cutaneous malignant melanoma in females: the role of hormonal and
10 reproductive factors. International Journal of Epidemiology 19[3], 522-526. 1990.
11 Reason: included in Gandini 2011 review

Evidence Tables
Study Design Population Intervention and Follow up Outcomes Comments

comparison
Bastiaannet Cohort study, 1125 kidney Triple drug Total 8165 patient years Standaradised incidence Not a study of intercurrent
(2007) Netherlands transplantation immunosupression in 1125 patients ratio for melanoma drug therapy in patients
patients therapy with melanoma.
(cyclosporin,
mycophenoltae Retrospective
mofetil and SIR calculated using
prednisolone). expected rates on the
basis of age and calendar
period using Netherlands
Cancer Registry data.
Bertoni Cohort study, 2106 patients Patients were N/A Incidence of melanoma Not a study of intercurrent
(2010) US with idiopathic screened for drug therapy in patients
Parkinson melanoma and with melanoma.
disease. asked about
history of Allocation to treatment
levadopa therapy groups likely to be biased.
(N=1786) versus Analysis not adjusted for
no levadopa melanoma risk factors.
theray (N=320)
Buchbinder Cohort study, 458 patients Methotrexate Average follow up 9.3 Standardised incidence Not a study of intercurrent
(2008) Australia with rheumoid years, total 4145 person- ratio for melanoma drug therapy in patients
arthritis years in 458 patients. with melanoma.


comparison
SIR calculated using
expected rates on the
basis of age, gender and
calendar period using
Victorian Cancer Registry
data.
Dahlke et al Systematic N=17 studies Incidence of post

(2014) Review which reported transplant melanoma
the incidence of
melanoma in a From 12 studies,
transplant recipients had a
Studies population
based cohort of pooled estimate of 2.4
published times (95% CI 2.0-2.9) the
post 1995 in solid organ
transplant risk of melanoma when
English or compared with the general
French. recipients (5
were excluded population (I2=46%,
to avoid double p=0.04).
counting) Adjusting for type of organ
graft and most recent year
of transplant in the cohort
N=1 population reduced the I2 to 0%.
based study
reporting
outcomes of Studies of renal or liver
pre-transplant transplant recipients had


comparison
melanoma an absolute increase in SIR
of 0.29 compared with
studies of heart or lung
0 studies of transplant recipients
post-transplant (p=0.01)
melanoma.
Studies that included

patients transplanted after
the year 2000 had an
increase in SIR of 0.41
compared with older
studies (p=0.03).
Prognosis of post-
transplant melanoma
No studies were identified

reporting on outcomes of
de novo melanoma arising
post-transplantation.
One retrospective study

(n=638 patients of post


comparison
transplant melanoma)
reported that overall
survival rates were worse
in the transplant
population compared with
the general population.
The study also reported

that patients with a
Breslow depth of 1.51-
3mm and Clark levels III/IV
had significantly worse
outcomes compared with
the expected survival rates
in the general population
(Brewer et al).
A second study reported

worse outcomes for late
stage (T3/T4) melanoma in
transplant recipients
compared with the general
population. (HR=11.49,
95% CI 3.6-36.8)


comparison
Post transplantation
prognosis of pre-transplant
melanoma
One study reported that

2/19 patients with a
history of pre-transplant
melanoma had a
recurrence after transplant
(Chapman et al).
Brewer et al reported no
recurrences and 2
melanoma metastases in
59 patients (mean follow-
up was 10.5 years)
A third study (Matin et al)

reported no post
transplant deaths after a
median of 14 years post-
melanoma follow-up and a
median of 5 years of post-


comparison
transplant follow-up.
De Giorgi Cohort study, 741 patients Beta-blocker use Median 4.2 years Overall survival, Disease Baseline differences in
(2013) Italy with melanoma of at least 1 year progression (analyses were patient characteristics
(N=79) versus no adjusted for age, tumour (older and more
such treatment thickness and ulceration) hypertension in the beta-
(N=662) blocker group).
Franciosi Systematic 259043 patients Metformin Median 4 and 5 years in Incidence of melanoma Not a study of intercurrent
(2013) review of Analysis therapy the 2 included RCTs that drug therapy in patients
randomised included 2 RCTs reported melanoma with melanoma.
and and one rates.
observational observational Search cut-off April 2012.
studies study. Metholodgy appropriate
Gandini Systematic Analysis Oral contraceptive Not reported Incidence of melanoma Not a study of intercurrent
(2011) review of included 5626 (OC) and or drug therapy in patients
case control patients with hormone with melanoma.
and cohort melanoma and replacement
studies from 344,342 therapy (HRT) Patient characteristics
US, Europe controls. (ever used) versus were poorly reported (e.g.
and Australia never used OC or mean age of cases only
19 case-control HRT reported in 4/25 studies).
studies: Patients 12/25 studies adjusted for
with melanoma


comparison
and controls pheno-photo types
selected from
population or 9/25 studies adjusted for
hospital. 6 sun exposure
cohort studies: Meta-analysis pools case-
control and cohort studies
(assumes OR=RR?) which
may be valid due to low
event rate.
Hu (2014) Systematic 10 case-control 6999 patients with Not reported Melanoma Not a study of intercurrent
review of or cohort melanoma and drug therapy in patients
case-control studies 490332 controls. with melanoma.
and cohort
studies Likely to be baseline
differences in these
studies - but meta-
analyses used adjusted
effect estimates wherever
possible.
Meta-analysis pools case-

control and cohort studies
(assumes OR=RR?) which
may be valid due to low
event rate.


comparison
Jensen Cohort study, 2561 heart or Triple drug Median 4.8 years (15123 Standardised incidence Not a study of intercurrent
(1999) Norway kidney immunosupression person years in total) ratio for melanoma drug therapy in patients
transplantation therapy with melanoma.
patients (cyclosporin,
azathioprine and Retrospective.
prednisolone) or SIR calculated using
dual therapy in expected rates on the
those treated pre basis of age, calendar
1983. period and gender using
Norway Cancer Registry
data.
Lemeshow Cohort study, 4179 melanoma Β-blocker use in Median follow-up 4.9 Overall survival (adjusted Patients treated with b-
(2011) Denmark patients the 90 day period years for age and comorbidity blockers tended to have
period prior to index score) poorer baseline prognosis
melanoma – authors attempted to
diagnosis (N=275) adjust for this.
versus no use
(N=2916)
Livingsone Cohort study, 709 melanoma Β-blocker use Median 3.7 years in Overall survival (adjusted Patients treated with b-
(2013) Netherlands patients (N=203) versus no beta-blocker group and for age and sex) blockers tended to have
use (N=506) 2.8 years in control poorer baseline prognosis
– authors attempted to
adjust for this.
MacKie Cohort study, 206 women Any HRT (N=83) Median 10.6 years Overall survival, melanoma Baseline differences
(2003) UK aged between versus no HRT between groups – analysis


comparison
40 and 60 (N=123) (minimum 5 years) specific survival adjusted for ulceration,
following tumour thickness and age.
surgery for
stage I or II
melanoma
Siikskonen Case-control Cases with Phototoxic drug 3 years. Exposure to Melanoma Not a study of intercurrent
(2013) study, melanoma use versus no such phototoxic drug was drug therapy in patients
Netherlands (N=1318) versus use. defined as within the 3 with melanoma.
controls years before diagnosis of
(N=6786) melanoma – but Retrospective.
excluding the year prior 15 drugs included in model
to diagnosis due to the
latent period. Risk factors for melanoma
(e.g. lifestyle and family
history) were not
incorporated into the
model
Tang (2011) RCT 27347 HRT versus Mean 5.6 years for Incidence of melanoma Not a study of intercurrent
postmenopausal plabeco (2 trials – combined HRT trial and drug therapy in patients
women combined HRT for 7.1 years for the with melanoma.
those with intact estrogen alone trial
uterus only). Appropriate randomisation
Combined method
estrogen plus Unclear allocation
progestion concealment
(N=8506) versus


comparison
placebo (N=8102). Groups comparable at
Estrogen only baseline
(N=5310) versus
placebo (N=5429). Double blind study
Attrition bias unclear
Low risk of detection bias

1 Appendix
2 Health Economic Search Strategies
3 For the purposes of the health economics search, a full search was undertaken with no date limit to
4 ensure full coverage of topics for the economic plan and for dealing with different health economic
5 analyses. For Medline, Embase and Web of Science, the last two year were searched.
Medline Embase
1. exp Melanoma/ 1. Melanoma/
2. melanoma$.tw. 2. melanoma$.tw.
3. (maligna$2 adj2 lentigo$1).tw. 3. Amelanotic Melanoma/
4. (hutchinson$ adj1 (freckle$ or 4. Malignant Lentigo/

melano$)).tw.tw.
5. (maligna$2 adj2 lentigo$1).tw.
5. dubreuilh.tw.
6. (hutchinson$ adj1 (freckle$ or
6. LMM.tw. melano$)).tw.tw.
7. or/1-6 7. dubreuilh.tw.
8. LMM.tw.
9. or/1-8
Database name No of references found Finish date of search
Medline 155 26/09/2012
Premedline 3 26/09/2012
Embase 165 09/10/2012
Cochrane: HTA 46 28/09/2012
Cochrane: NHSEED 23 28/09/2012
HEED 71 28/09/2012
8 Update Search:
Database name No of references found Finish date of search

Medline 144 15/10/2014
Premedline 14 15/10/2014
Embase 232 15/10/2014
Cochrane: HTA 0 15/10/2014
Cochrane: NHSEED 0 15/10/2014
HEED
2 Excluded Health Economic Studies

3 Agnese DM, Abdessalam SF, Burak WE Jr, Magro CM, Pozderac RV, Walker MJ “Cost effectiveness of
4 sentinel lymph node biopsy in thin melanomas.” Surgery 134:542-548. 2003.
5 Reason: Not a cost utility study
6 Bares, C. B., Trask,P.C. & Schwartz, S.M. “An exercise in cost effectiveness analysis: treating
7 emotional distress in melanoma patients.” Journal of Clinical Psychology in Medical Settings
8 9(3):193-200. 2002.
10 Basseres N, Grob JJ, Richard MA, Thirion X, Zarour H, Noe C, Collet-Vilette, AM, Lota I. & Bonerandi
11 J J “Cost effectiveness of surveillance of stage 1 melanoma: a retrospective appraisal based on a 10-
12 year experience in a dermatology department in France” Dermatology 191:199-203. 1995.
14 Bastiaannet E, Uyl-de Groot CA, Brouwers AH, van der Jagt EJ, Hoekstra OS, Oyen W, Verzijlbergen F,
15 van Ooijen B, Thompson JF, Hoekstra HJ."Cost effectiveness of adding FDG-PET or CT to the
16 diagnostic work-up of melanoma patients stage III." Pigment Cell and Melanoma Research
17 Conference.var.pagings (2010): 941.
18 Reason:Not a cost utility study
19 Bastiaannet E, Uyl-de Groot CA, Brouwers AH, van der Jagt EJ, Hoekstra OS, Oyen W, Verzijlbergen F,
20 van Ooijen B, Thompson JF, Hoekstra HJ “Cost effectiveness of adding FDG-PET or CT to the
21 diagnostic work-up of patients with stage III melanoma” Annals of Surgery 255[4], 771-76. 2012.
23 Bessen T ."Imaging follow-up in melanoma: The potential role of health economic modelling."
24 Pigment Cell and Melanoma Research Conference.var.pagings (2010): 880.
25 Reason:Conference abstract

1 Buck AK, Herrmann K, Stargardt T, Dechow T, Krause BJ, Schreyögg J. "Economic evaluation of PET
2 and PET/CT in oncology: evidence and methodologic approaches. ." Journal of Nuclear Medicine
3 Technology 38.1 (2010): 6-17.
4 Reason: Not relevant to population in PICO
5 Campbell TM. Y & Youker S "Practical application and decision-making in Mohs micrographic surgery
6 and cutaneous oncology." Operative Techniques in Otolaryngology - Head and Neck Surgery 22.1
7 (2011): 101-13.
8 Reason:Not a cost effectiveness study
9 Cashin RP, Lui P, Machado M, Hemels ME, Corey-Lisle PK, Einarson TR."Advanced cutaneous
10 malignant melanoma: a systematic review of economic and quality-of-life studies. " Value in Health
11 11.2 (2008): 259-71.
12 Reason:Review of economic papers-appraised independently.
13 Chuang T.-Y "Mohs Surgery -The myth and the truth." Dermatologica Sinica 26.1 (2008): 1-9.
14 Reason:Not a cost utility study.
15 Colombo GL, Matteo SD, Mir LM. "Cost effectiveness analysis of electrochemotherapy with the
16 Cliniporator vs other methods for the control and treatment of cutaneous and subcutaneous
17 tumors." Therapeutics and Clinical Risk Management 4.2 (2008): 541-48.
19 Covarelli P, Badolato M, Tomassini GM, Poponesi V, Listorti C, Castellani E, Boselli C, Noya G.

20 “Sentinel lymph node biopsy under local anaesthesia versus general anaesthesia: reliability and cost
21 effectiveness analysis in 153 patients with malignant melanoma”. In Vivo 26(2):315-318. 2012.
23 Davids V, Kidson SH, & Hanekom GS."Melanoma patient staging: histopathological versus molecular
24 evaluation of the sentinel node." Melanoma Research 13.3 (2003): 313-24.
26 DeRose ER, Pleet A, Wang W, Seery VJ, Lee MY, Renzi S, Sullivan RJ, Atkins MB. "Utility of 3-year
27 torso computed tomography and head imaging in asymptomatic patients with high-risk melanoma."
28 Melanoma Research 21.4 (2011): 364-69.
30 Hengge UR, Wallerand A, Stutzki A, Kockel N. "Cost effectiveness of reduced follow-up in malignant
31 melanoma." Journal der Deutschen Dermatologischen Gesellschaft 5.10 (2007): 898-907.

1 Hettiaratchy SP, Kang N, O'Toole G, Allan R, Cook MG, Powell BW."Sentinel lymph node biopsy in
2 malignant melanoma: a series of 100 consecutive patients." British Journal of Plastic Surgery 53.7
3 (2000): 559-62.
5 Hoekstra HJ. "Cost effectiveness of melanoma follow-up." Pigment Cell and Melanoma Research
6 Conference.var.pagings (2010): 880.
7 Reason: Conference abstract
8 Johnson TM, Bradford CR, Gruber SB, Sondak VK, Schwartz JL. "Staging Workup, Sentinel Node
9 Biopsy, and Follow-up Tests for Melanoma: Update of Current Concepts." Archives of Dermatology
10 140.1 (2004): 107-13.
12
13 Johnston K, Levy AR, Lorigan P, Maio M, Lebbe C, Middleton M, Testori A, Bédane C, Konto C,
14 Dueymes A, Sbarigia U, van Baardewijk M. "Economic impact of healthcare resource utilisation
15 patterns among patients diagnosed with advanced melanoma in the United Kingdom, Italy, and
16 France: Results from a retrospective, longitudinal survey (MELODY study)." European Journal of
17 Cancer 48.14 (2012): 2175-82.
18 Reason: Cost of illness study
19 Kansal AR, Shaul AJ, Stern S, Busam K, Doucet CA, Chalfin DB “Cost effectiveness of a FISH assay for
20 the diagnosis of melanoma in the USA.”Expert Rev Pharmacoecon Outcomes Res. (2013) 13(3):371-
21 80.
22 Reason:Patient group not relevant to PICO
23 Li LX, Scolyer RA, Ka VS, McKinnon JG, Shaw HM, McCarthy SW, Thompson JF. "Pathologic review of
24 negative sentinel lymph nodes in melanoma patients with regional recurrence: a clinicopathologic
25 study of 1152 patients undergoing sentinel lymph node biopsy." American Journal of Surgical
26 Pathology 27.9 (2003): 1197-202.
28 Losina E, Walensky RP, Geller A, Beddingfield FC 3rd, Wolf LL, Gilchrest BA, Freedberg KA. ‘Visual
29 screening for malignant melanoma: a cost effectiveness analysis’. Archives of Dermatology . 143.1
30 (2007) 21-8
31 Reason: Not relevant to scope of guideline
32 Morton R & Howard K "Economic considerations in melanoma care." Pigment Cell and Melanoma
33 Research Conference.var.pagings (2010): 879-80.

1 Reason:Conference Abstract
2 Munn, S. "Is teledermoscopy a safe and cost-effective model for triage of pigmented lesions and
3 suspected melanoma in the U.K.?" British Journal of Dermatology Conference.var.pagings (2011):
4 July.
5 Reason:Conference abstract
6 Picchio M, Mansueto M, Crivellaro C, Guerra L, Marcelli S, Arosio M, Sironi S, Gianolli L, Grimaldi A,

7 Messa C. “PET/CT and contrast enhanced CT in single vs. two separate sessions: A cost analysis
8 study." Quarterly Journal of Nuclear Medicine and Molecular Imaging 56.3 (2012): 309-16.
10 Stoffels I, Dissemond J, Körber A, Hillen U, Poeppel T, Schadendorf D, Klode J. “Reliability and cost
11 effectiveness of sentinel lymph node excision under local anaesthesia versus general anaesthesia for
12 malignant melanoma: A retrospective analysis in 300 patients with malignant melanoma AJCC Stages
13 I and II.” Journal of the European Academy of Dermatology and Venereology 25(3):306_Çô310. 2011.
15 Stoffels I, Dissemond J, Schulz A, Hillen U, Schadendorf D, Klode J"Reliability and cost effectiveness of
16 complete lymph node dissection under tumescent local anaesthesia vs. general anaesthesia: a
17 retrospective analysis in patients with malignant melanoma AJCC stage III." Journal of the European
18 Academy of Dermatology & Venereology 26.2 (2012): 200-06.
20 Thomas, J. M.” Prognostic false-positivity and cost effectiveness in sentinel node biopsy in
21 melanoma.” Annals of Surgical Oncology 16(10):2961. 2009.
22 Reason:Letter to the editor
23
24 Tiern Tierneyv EP & Hanke CW."Cost effectiveness of Mohs micrographic surgery: review of the
25 literature." Journal of Drugs in Dermatology: JDD 8.10 (2009): 914-22.
26 Reason:Review identified no relevant cost utility studies.
27 van Akkooi AC, Voit CA, Verhoef C, Eggermont AM."Potential cost effectiveness of US-guided FNAC
28 in melanoma patients as a primary procedure and in follow-up." Ann Surg.Oncol 17.2 (2010): 660-62.
29 Reason:Letter to the editor
30 van der Velde-Zimmermann D, Schipper ME, de Weger RA, Hennipman A, Borel Rinkes IH "Sentinel
31 node biopsies in melanoma patients: a protocol for accurate, efficient, and cost-effective analysis by
32 preselection for immunohistochemistry on the basis of Tyr-PCR." Annals of Surgical Oncology 7.1
33 (2000): 51-54.

1 von Schulthess GK, Steinert HC, Dummer R, Weder W. "Cost effectiveness of whole-body PET
2 imaging in non-small cell lung cancer and malignant melanoma." Academic Radiology 5 Suppl 2
3 (1998): S300-S302.
5 Wilson EC, Emery JD, Kinmonth AL, Prevost AT, Morris HC, Humphrys E, Hall PN, Burrows N,
6 Bradshaw L, Walls J, Norris P, Johnson M, Walter FM. ‘The cost effectiveness of a novel SIAscopic
7 diagnostic aid for the management of pigmented skin lesions in primary care: a decision-analytic
8 model’ Value in Health. 16.2 (2013) 356-66
9 Reason:Primary care setting outside the scope of the guideline
10

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DRAFT FOR CONSULTATION

15 Developed for NICE by the National Collaborating Centre for Cancer

18 ©2015 National Collaborating Centre for Cancer

Melanoma: DRAFT evidence review (January 2015) Page 1 of 886

Melanoma: DRAFT evidence review (January 2015) Page 2 of 886

1 4. Stage 0-II melanoma ......................................................................................................... 397

Melanoma: DRAFT evidence review (January 2015) Page 3 of 886

Melanoma: DRAFT evidence review (January 2015) Page 4 of 886

2 1. Communication and Support

25 Question in PICO Format

Population Intervention Outcomes

27 How will the information be searched?

Melanoma: DRAFT evidence review (January 2015) Page 5 of 886

2 The Review Strategy

Database name Dates Covered No of references Finish date of

15 Medline search strategy (This search strategy is adapted to each database)

Melanoma: DRAFT evidence review (January 2015) Page 6 of 886

1 3. (maligna$ adj1 lentigo$).tw.

Melanoma: DRAFT evidence review (January 2015) Page 7 of 886

Melanoma: DRAFT evidence review (January 2015) Page 8 of 886

15 Information needs at diagnosis

22 Information needs during treatment

26 Information needs during follow up

Melanoma: DRAFT evidence review (January 2015) Page 9 of 886

11 General support needs

27 Support needs at diagnosis

Melanoma: DRAFT evidence review (January 2015) Page 10 of 886

Melanoma: DRAFT evidence review (January 2015) Page 11 of 886

2 Patient thought they were seen as soon as necessary 84% 87% 2

6 Staff gave complete explanation of purpose of test(s) 84% N.S. N.S.

9 Given complete explanation of test results in understandable way 78% 85% 1

Finding out what was wrong

Deciding best treatment

Patient’s views definitely taken into account by doctors and nurses

17 Possible side effects explained in an understandable way 75% 74% 6

18 Patient given written information about side effects 82% 68% 13

Melanoma: DRAFT evidence review (January 2015) Page 12 of 886

Clinical nurse specialist

22 Patient finds it easy to contact their CNS 75% N.S. N.S.

Support for patients

25 Hospital staff gave information about support groups 82% 85% 2

Hospital staff gave information about impact cancer could have on

27 Hospital staff gave information on getting financial help 54% 52% 9

30 Taking part in cancer research discussed with patient 32% 18% 12

32 % ans. they've had an operation in last 12 months 56% N.R. N.R.

34 Patient given written information about the operation 74% 68% 7

40 Patient’s family definitely had opportunity to talk to doctor 66% 74% 1

Melanoma: DRAFT evidence review (January 2015) Page 13 of 886

44 Always / nearly always enough nurses on duty 61% 74% 1

Hospital care and treatment

Information before leaving and home support

Day / outpatient care

Staff definitely did everything to control side effects of radiotherapy (of

Staff definitely did everything to control side effects of chemotherapy (of

Melanoma: DRAFT evidence review (January 2015) Page 14 of 886

Care from general practices

Overall NHS care

68 Patient offered written assessment and care plan 22% 20% 10