Esmoo

REVIEW
Guidelines for the diagnosis and treatment of basal cell carcinoma: a GRADE
approach for evidence evaluation and recommendations by the Italian
Association of Medical Oncology
P. Queirolo1 , M. Cinquini2 , G. Argenziano3 , F. Bassetto4 , P. Bossi5 , A. Boutros6 , C. Clemente7 , V. de Giorgi8,9 ,
M. Del Vecchio10 , R. Patuzzo11 , K. Peris12,13 , P. Quaglino14 , A. Reali15 , I. Zalaudek16 & F. Spagnolo17,18
1
Division of Melanoma, Sarcomas and Rare Tumors, European Institute of Oncology, Milan; 2Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan;
3
Dermatology Unit, Department of Mental and Physical Health and Preventive Medicine, University of Campania Luigi Vanvitelli, Naples; 4Clinic of Plastic Surgery,
Department of Neuroscience, Padua University Hospital, Padua; 5Medical Oncology, Department of Medical and Surgical Specialties, Radiological Sciences and Public
Health University of Brescia, ASST-Spedali Civili, Brescia; 6Department of Internal Medicine and Medical Specialties, School of Medicine, University of Genoa, Genoa;
7
UO SMEL-2, Surgical Pathology, Department of Pathology and Laboratory Medicine, IRCCS-Policlinico San Donato, Milan; 8Dermatology Unit, Azienda USL Toscana
Centro, Florence; 9Section of Dermatology, Department of Health Sciences, University of Florence, Florence; 10Department of Medical Oncology, Fondazione IRCCS
Istituto Nazionale dei Tumori, Milan; 11Fondazione IRCCS Istituto Nazionale Dei Tumori, Melanoma and Sarcoma Unit, Milan; 12Dermatology, Department of
Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome; 13Dermatology, Department of Medical and Surgical Sciences, Fondazione Policlinico
Universitario A. Gemelli IRCCS, Rome; 14Department of Medical Sciences, Clinic of Dermatology, University of Turin, Turin; 15Radiation Oncology Department, Michele
e Pietro Ferrero Hospital, Verduno; 16Dermatology Clinic, Maggiore Hospital, University of Trieste, Trieste; 17Oncologia Medica 2, IRCCS Ospedale Policlinico San
Martino, Genoa; 18Department of Integrated Surgical and Diagnostic Sciences (DISC), University of Genoa, Genoa, Italy
Available online 23 October 2023
Basal cell carcinoma (BCC) is the most common form of cancer, with a high impact on the public health burden and
social costs. Despite the overall prognosis for patients with BCC being excellent, if lesions are allowed to progress,
or in a small subset of cases harboring an intrinsically aggressive biological behavior, it can result in local spread
and significant morbidity, and conventional treatments (surgery and radiotherapy) may be challenging. When a BCC
is not amenable to either surgery or radiotherapy with a reasonable curative intent, or when metastatic spread
occurs, systemic treatments with Hedgehog inhibitors are available. These guidelines were developed, applying the
GRADE approach, on behalf of the Italian Association of Medical Oncologists (AIOM) to assist clinicians in treating
patients with BCC. They contain recommendations with regard to the diagnosis, treatment and follow-up, from
primitive tumors to those locally advanced or metastatic, addressing the aspects of BCC management considered as
priorities by a panel of experts selected by AIOM and other national scientific societies. The use of these guidelines
in everyday clinical practice should improve patient care.
Key words: basal cell carcinoma, skin cancer, keratinocyte carcinoma, GRADE, guidelines
INTRODUCTION registries. Important consequences are that the public health

Keratinocyte carcinomas, characterized by the malignant burden and social costs associated with keratinocyte carci-
proliferation of epidermal keratinocytes, are the most com- nomas are probably underestimated. In the AIRTUM 2019
mon form of cancer.1 As in the USA and most European report, 64 000 new cases of basal cell carcinomas (BCCs) and
countries, data on the incidence of keratinocyte carcinomas 19 000 new cases of cutaneous squamous cell carcinoma
from a unified national registry are not available in Italy. High (CSCC) were estimated for year 2018.2 In a recent paper from
incidence of keratinocyte carcinomas, heterogeneity of the United States Global Burden of Disease, the incidence and
treatments and low mortality are a challenge in obtaining prevalence per 100 000 persons for BCC were 525 and 51.2,
accurate incidence data and consistent registration in cancer respectively, whilst disability adjusted life years (DALY) and
mortality rates were 0.2 and zero, respectively.3
Overall, the prognosis for patients with BCC is excellent;
*Correspondence to: Prof. Francesco Spagnolo, Oncologia Medica 2, IRCCS however, if BCC is allowed to progress, or in a small subset
Ospedale Policlinico San Martino, Largo R. Benzi 10, 16132, Genova, Italy. of cases harboring an intrinsically aggressive biological
Tel: þ390105558901
E-mail: francesco.spagnolo85@gmail.com (F. Spagnolo).
behavior, it can result in local spread and significant
morbidity, and treatment with surgery and radiotherapy
2059-7029/© 2023 The Author(s). Published by Elsevier Ltd on behalf of
European Society for Medical Oncology. This is an open access article under the
may be challenging. When a BCC is not amenable to either
CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). surgery or radiotherapy with a reasonable curative intent
Volume 8 - Issue 6 - 2023 https://doi.org/10.1016/j.esmoop.2023.102037 1

ESMO Open P. Queirolo et al.
[i.e. locally advanced BCC (laBCC)], systemic treatments - Question 6: Should electrochemotherapy be recommen-
with Hedgehog inhibitors are available. BCC may also ded in subjects with BCC and relative contraindications
spread to distant sites, although metastatic BCC (mBCC) to conventional treatments (surgery and radiotherapy)
with histologically confirmed metastases is extremely rare, compared with standard surgical excision or
with an estimated incidence of 0.0028%-0.55%.4-6 radiotherapy?
These guidelines were developed, applying the GRADE - Question 7: Should standard surgical excision be recom-
approach,7 on behalf of the Italian Association of Medical mended in subjects with non-recurrent, operable BCC
Oncologists (AIOM) to assist clinicians in treating patients compared with imiquimod?
with BCC. They contain recommendations with regard to - Question 8: Should standard surgical excision be recom-
the diagnosis, treatment and follow-up, from primitive tu- mended in subjects with non-recurrent, operable BCC
mors to those locally advanced or metastatic, addressing compared with topical 5-fluorouracil?
the aspects of BCC management considered as priorities by - Question 9: Should standard surgical excision be recom-
a panel of experts selected by AIOM and other national mended in subjects with non-recurrent, operable BCC
scientific societies. The use of these guidelines in everyday compared with photodynamic therapy?
clinical practice should improve patient care. - Question 10: Should standard surgical excision be recom-
mended in subjects with non-recurrent, operable BCC
METHODS compared with cryotherapy?
- Question 11: Should standard surgical excision be recom-
The panel of AIOM guidelines on BCC mended in subjects with non-recurrent, operable BCC
The AIOM guidelines on basal cell carcinoma are updated compared with laser treatments?
every year by a panel composed of academics and clinicians - Question 12: Should standard surgical excision be recom-
with expertise in medical oncology, surgery, dermatology, mended in subjects with non-recurrent, operable BCC
radiotherapy and pathology, and clinical research method- compared with cauterization?
ology. The draft of the updated guidelines is then sent to - Question 13: Should standard surgical excision be recom-
external reviewers before the final publication on the AIOM mended in subjects with non-recurrent, operable BCC
website (www.aiom.it). The external reviewers are nomi- compared with radiotherapy?
nated by AIOM and other relevant scientific societies (Ital- - Question 14: Should radiotherapy be recommended after
ian Melanoma Intergroup; Italian Society Of Medical, surgical excision of BCC with positive margins compared
Surgical And Aesthetic Dermatology and of Sexually Trans- with re-excision?
mitted Diseases; Italian Association of Radiotherapy and - Question 15: Should baseline radiological tumor assess-
Clinical Oncology; Italian Society of Pathology; Italian Soci- ment be recommended in subjects with laBCC and
ety of Oncologic Surgery; Italian Society of Medical and mBCC?
Interventional Radiology). - Question 16: Should radiological tumor assessment be
recommended in the follow-up of subjects with laBCC
and mBCC?
Development of clinical question - Question 17: Should treatment with Hedgehog pathway
The clinical question was developed according to the inhibitors be recommended in subjects with laBCC and
P.I.C.O. acronym requiring the definition of: population (P), mBCC compared with follow-up/best supportive care?
intervention (I), comparison (C) and outcomes (O).
Panel members decided to address the following clinical Panel members decided to define, as the population of
questions: interest, the Italian population at high risk of developing
- Question 1: Should sunscreen creams with solar protec- BCC, or who have received a diagnosis of BCC.
tion factor 30 be recommended in subjects who are
exposed to solar ultraviolet radiation (UVR) to reduce Identification of outcomes
the incidence of BCC?
Panel members identified, through a prioritization process,
- Question 2: Should dermoscopy be recommended in sub-
the outcomes of benefit and harm, judging them as ‘critical’
jects with suspicious skin lesions compared with visual in-
or ‘important’ for the decision-making.
spection only for the detection of BCC?
- Question 3: Should reflectance confocal microscopy be rec-
ommended in subjects with suspicious skin lesions Search strategy and selection of evidence
compared with dermoscopy only for the detection of BCC? For each question, a systematic literature search was car-
- Question 4: Should a surgical excision with 3 mm clin- ried out searching PubMed, Embase and Cochrane Library
ical margins be recommended in subjects with operable without language or date restriction up to December 2019.
BCC compared with surgical excision with <3 mm clinical The full search strategy is available as Supplementary
margins? material, available at https://doi.org/10.1016/j.esmoop.
- Question 5: Should Mohs surgery be recommended in 2023.102037. Main articles were cross-referenced to
subjects with recurrent or high-risk BCC compared with check that all the relevant literature was fully identified. The
standard surgical excision? PRISMA flow-chart for each question is reported as
2 https://doi.org/10.1016/j.esmoop.2023.102037 Volume 8 - Issue 6 - 2023

P. Queirolo et al. ESMO Open
Supplementary material, available at https://doi.org/10. farmers, road workers, lifeguards, .) are chronically
1016/j.esmoop.2023.102037. exposed to solar UVR due to occupational reasons, BCC may
To answer the proposed questions, systematic reviews or be considered as an occupational disease in this subset of
randomized controlled trials were searched. If not found, workers.11 In a recent review and meta-analysis, including
non-randomized studies were retrieved. Narrative reviews, one prospective cohort study and 18 case-control studies,
and case reports, were excluded. 95% of studies reported higher risks among outdoor
workers.12
Quality of evidence evaluation The association between nodular BCC and chronic UVR
According to the GRADE approach, an evaluation of the exposure is supported by the prevalent localization on the
certainty of evidence for each selected outcome was carried head and neck region, and the increased incidence with
out. The GRADE evaluation encompasses five main do- ageing. Superficial BCC is instead more associated with
mains: study limitations, imprecision, indirectness, incon- intermittent sun exposure and predominant location on the
sistency and publication bias. Based on the study design, trunk. In addition to chronic exposure, epidemiological data
the certainty level starts at a prespecified level (high cer- show that solar UVR exposure at a young age is an impor-
tainty for randomized controlled trials). The detection of tant predictive factor for the subsequent development of
limitations in one or more of the five domains can lead to BCCs.13 Frequent use of indoor tanning is also a relevant
downgrading the certainty of evidence. The final judgment risk factor, and the most important one in young
can be one of the following: high, moderate, low and very subjects.14,15 In addition to UVR, a subset of BCCs may be
low. A summary of the certainty of evidence and a quan- associated with other risk factors such as immunosuppres-
titative synthesis of the effects for each outcome are re- sion, ionizing radiation and arsenic exposure.
ported in a dedicated evidence profile table. The prevalent role of UVR in the risk of development of
BCC highlights the importance of primary prevention mea-
sures. Strategies of primary prevention should rely on both
Evidence to decision framework
proper photo-protection and sun exposure, and should
The evidence to decision (EtD) framework provides a trans- include different scopes such as increased awareness,
parent and structured approach to support the decision- avoiding excessive sun exposure and/or protection through
making process.8 It allows summarizing the evidence in clothing, and the correct use of sunscreen creams.
relation to the priority of the problem, the substantiality of Numerous case-control studies tried to analyze the impact
the desirable and undesirable effects, balance of the effects, of sunscreen creams on the development of skin cancer, but
certainty of evidence, patients values and preference, use of the results are discordant. In a review by Burnett and
resources, equity, acceptability and feasibility. Wang,16 the analysis of literature data highlighted that use
of sunscreen creams may reduce the incidence of CSCC,
Benefit/harm balance and clinical recommendation without compromising the blood levels of vitamin D. The
At this point of the decision-making process, the panel regular and proper use of sunscreen creams also reduced
voted one of the following options for the balance between the incidence of actinic keratoses, which are well known
benefits and harms of the intervention and the comparison: markers of damage from chronic UVR exposure.17 In the
favorable, uncertain/favorable, uncertain/unfavorable and study conducted by Olsen et al.,10 the fraction of skin
unfavorable. The panel also voted on the strength of the cancers that could be prevented by regular use of sunscreen
recommendation according to the following options: strong was estimated, and it was as high as 14% for melanoma and
in favor, conditional in favor, conditional against, strong 9.3% for CSCC, but no estimates were provided for BCC.
against the intervention. Eleven randomized studies investigating the effects of
The AGREE reporting checklist was followed to guide the behavioral counseling to prevent skin cancer were included
reporting of the present recommendation.9 in a meta-analysis conducted by Lin et al.,18 showing how
counseling could reduce solar and artificial UVR exposure,
GRADE QUESTIONS and increase the use of sunscreen creams. In the same
analysis, 35 observational studies focusing on the associa-
Primary prevention tion of solar UVR exposition and skin cancer were identified,
The main risk factor associated with the development of but only in one study did the regular use of sunscreen
BCC is exposure to UVR. The incidence of BCC is higher in creams show reduction in the incidence of CSCC, with no
subjects with fair skin, and with history of chronic solar UVR significant difference for BCC.
exposure. Numerous epidemiological studies highlighted
Question 1. Should sunscreen creams with solar protection
that the incidence of BCC is lower in subjects with dark skin
factor 30 be recommended in subjects who are exposed
and in those who are less exposed to solar UVR. In an
to solar UVR to reduce the incidence of BCC?
Australian study, the analysis of the incidence of keratino-
cyte carcinomas in Australia showed that the rate of solar Recommendation. In subjects who are exposed to solar
UVR-induced keratinocyte carcinomas was essentially 100%, UVR, sunscreen creams with solar protection factor 30
and that a fraction of these tumors could be prevented with may be considered as a first option measure to reduce the
regular sunscreen use.10 As some outside workers (e.g. incidence of BCC.

Strength of recommendation. Conditional in favor. exposition, and may be associated with some outside oc-
cupations or may be recreational. The fact that BCC de-
Overall quality of evidence. Moderate. velops earlier in life compared with CSCC, and that it often
Motivation/comments on the benefit/risk balance. In the arises in the trunk in addition to the chronically exposed
Cochrane systematic review by Sánchez et al.,19 only one anatomical areas, suggests that BCC requires an inferior
randomized study assessing the role of photo-protection for cumulative dosage of UVR than that necessary to induce a
the prevention of keratinocyte carcinomas was identified. In CSCC.
this randomized trial (named the Nambour trial from the
Australian region where it was conducted), 1621 partici- Secondary prevention
pants were randomized to four groups: BCC most commonly arises on chronically sun-exposed
daily applications of sunscreen creams with solar anatomical sites (such as head and neck, dorsum of the
protection factor 15 plus beta-carotene supplementation hands, forearms), but may also arise on the trunk and other
daily applications of sunscreen creams with solar less sun-exposed anatomical regions. BCC may have het-
protection factor 15 plus beta-carotene supplementa- erogeneous clinical presentations depending on location,
tion placebo skin type, ulceration and presence of pigmentation.
beta-carotene supplementation only Differential diagnosis between BCC and other skin lesions
beta-carotene supplementation placebo only is not always easy. Both neoplastic (such as melanoma,
B-cell cutaneous lymphoma, CSCC, actinic keratosis,
The following outcomes were defined by the panel of Bowen’s disease, keratoacanthoma and adnexal tumors),
experts as essential for the assessment of risks and benefits and non-neoplastic skin lesions (such as seborrheic
balance: incidence of BCC; incidence of solar or actinic keratosis, hemangioma, dermal nevus, dermatofibroma,
keratosis (as a marker of actinic damage). telangiectatic granuloma, fibrous papule, sebaceous hyper-
The results of the study did not demonstrate any plasia, molluscum contagiosum, psoriasis, eczema) must be
difference in the incidence nor in the number of BCCs be- included in the differential diagnosis of BCC.
tween the four groups (total diagnosed BCCs: 1621; risk Dermoscopy may be used to increase the diagnostic
ratio 1.03, 95% confidence interval [CI] 0.74-1.43). sensibility of skin lesions. In cases of BCC diagnosis, it may
Despite the randomized trial not demonstrating any sig- help in the differentiation of BCC from melanoma, invasive
nificant effects of the intervention for the prevention of and in situ CSCC, and benign tumors.22,23 Dermoscopic
BCC, the panel voted for a favorable damage/benefit ratio, criteria for BCC are the absence of brown reticular lines
supporting their use to prevent BCC in subjects who are (pigment network), branching and linear vessels (arborising
exposed to solar UVR (see Notes to recommendation 1). The and superficial telangiectasias), multiple erosions, ulcera-
panel did not identify any probable uncertainty or variability tion, bluish-gray clods of variable size (ovoid nests and
on how the population may evaluate the analyzed out- globules and focused dots), radial lines connected to a
comes. See Supplementary material (Question 1), available common base (leaf-like areas), radial lines converging to a
at https://doi.org/10.1016/j.esmoop.2023.102037, for evi- central dot or clod (spoke-wheel areas) and clods within a
dence to decision results, quality of evidence and implica- clod (concentric structure).24
tions for future results.
Question 2. Should dermoscopy be recommended in sub-
Notes to recommendation 1. Due to the challenges related jects with suspicious skin lesions compared with visual in-
to the evaluation of the efficacy of sunscreen creams for the spection only for the detection of BCC?
prevention of BCC in randomized trials, other types of
studies were taken into consideration to answer the ques- Recommendation. In subjects with suspicious skin lesions,
tion. Current literature data demonstrate an association the use of dermoscopy should be recommended as the first
between use of sunscreen creams and reduction of CSCC option compared with visual inspection only for the
and actinic keratosis incidence, but results on the preven- detection of BCC.
tion of BCC are discordant.10,16,17 The primary endpoint of
the Nambour trial was incidence of keratinocyte carcinomas Strength of recommendation. Strong in favor.
after a follow-up of 4.5 years,19,20 which was probably too Overall quality of evidence. High.
short to detect any impact of sunscreen creams on the
incidence of BCC. In an analysis with longer follow-up, in Motivation/comments on the benefit/risk balance. In the
fact, a trend towards an increased time between the multicenter, two-arm, randomized study conducted by
diagnosis of the first BCC and the subsequent has emerged Argenziano et al.25 and published in 2006, the diagnostic
in the group using sunscreen creams.21 accuracy for skin tumors of dermoscopy versus visual in-
In addition to clinical data, preclinical evidence demon- spection only was assessed in a cohort of general practi-
strates with a high level of certainty that solar UVR expo- tioners undergoing a 1-day dermoscopy training based on a
sition is the main risk factor for the development of BCC specific three-point checklist. This study has been con-
and CSCC. The exposition modality most frequently associ- ducted in one center in Italy and one in Spain. General
ated with keratinocyte carcinomas is chronic, cumulative practitioners who underwent dermoscopy training were

randomized into two groups: in the control group, the Similarly, Pellacani et al.27 reported a reduction of NNT from
doctors had only the possibility to conduct a visual in- 14.6 to 6.8 without and with reflectance confocal micro-
spection of their patients, whereas doctors in the experi- scopy, respectively. Among the 836 lesions included in both
mental group could make use of dermoscopy in addition to studies, however, only 31 (3.7%) were BCCs, limiting the
visual inspection. The study consisted of four steps: in step 1 assessment of reflectance confocal microscopy for the
(1-day training courses), 88 general practitioners were diagnostic accuracy of BCC specifically.
trained in two 2-h sessions on the clinical and dermoscopic In the multicenter study by Nelson et al.,28 published in
diagnosis, respectively, of keratinocyte carcinomas; in step 2 2016, 87 patients with 100 BCCs were assessed. Patients
(general practitioners randomization and patients who had a suspected BCC by visual inspection and der-
screening), doctors were randomized to either the control moscopy were included in the study; all lesions were
or experimental group; in step 3, (expert evaluation), all analyzed with dermoscopy and reflectance confocal micro-
patients were evaluated by two blinded dermatologists; in scopy evaluation. All collected images were evaluated by
step 4 (surgical excision and histologic exam), all lesions eight experts. An improvement of the diagnostic sensitivity
considered as malignant by the general practitioners were was shown with reflectance confocal microscopy compared
surgically removed and subjected to histologic analysis. with dermoscopy only (76.5% versus 67.6%, respectively);
Among 2522 patients, a statistically significant difference the positive predictive value was 98.6% for reflectance
was observed in terms of diagnostic sensitivity (79.2% confocal microscopy and 97.0% for dermoscopy. The dif-
versus 54.1%) and negative predictive value in favor of ference, however, was not statistically significant. The main
dermoscopy compared with visual inspection only. Speci- limitations of this study are the retrospective design and
ficity and positive predictive value were not different the assessment based on images of lesions already sus-
(71.8% versus 71.3%). The histologic exam of the excised pected for being BCCs.
lesions revealed that in the control group, 23 lesions were In the study conducted by Witkowski et al.29 and pub-
not properly diagnosed at visual inspection versus only 6 lished in 2016,the diagnostic accuracy of dermoscopy versus
lesions for the dermoscopy group. reflectance confocal microscopy was assessed for pink BCC.
The panel did not identify any probable uncertainty or Two hundred and sixty consecutively registered pink BCCs
variability on how the population may evaluate the (with <10% pigmentation), clinically equivocal, were
analyzed outcomes. The balance between outcomes of analyzed for a period of 2 years. Dermoscopic and reflec-
benefit and outcomes of damage favors the use of der- tance confocal microscopy images of each lesion were
moscopy in addition to visual inspection compared with assessed by two blinded experts who should define the
visual inspection only. Dermoscopy is easy to implement in diagnosis and clinical management. The sensitivity and
centers where it is not commonly used, without a relevant specificity of dermoscopic diagnosis were 85.1% and 92.4%,
impact on costs or logistic challenges. See Supplementary respectively, for a positive predictive value of 89.8%. The
material (Question 2), available at https://doi.org/10. sensitivity and specificity of reflectance confocal microscopy
1016/j.esmoop.2023.102037, for table of evidence, quality were 85.1% and 93.8%, respectively, for a positive predic-
of evidence and implications for future results. tive value of 91.5%. Combined dermoscopy plus reflectance
confocal microscopy positive predictive value was 94.6%.
Question 3. Should reflectance confocal microscopy be The panel did not identify any probable uncertainty or
recommended in subjects with suspicious skin lesions variability on how the population may evaluate the
compared with dermoscopy only for the detection of BCC? analyzed outcomes. The balance between outcomes of
Recommendation. In subjects with suspicious skin lesions, benefit and outcomes of damage favors the use of reflec-
the use of reflectance confocal microscopy for the detection tance confocal microscopy compared with only dermo-
of BCC may be considered as the first option compared with scopy. However, reflectance confocal microscopy is not
dermoscopy only. widely accessible across Italy. See Supplementary material
(Question 3), available at https://doi.org/10.1016/j.
Strength of recommendation. Conditional in favor. esmoop.2023.102037, for table of evidence, quality of evi-
dence and implications for future results.
Overall quality of evidence. Moderate.
Motivation/comments on the benefit/risk balance. The Treatment of primary BCC
studies by Alarcon et al.26 and Pellacani et al.,27 both Treatment of primary BCC mostly relies on surgical excision
published in 2014, showed that the use of reflectance with histologic examination.30 The excisional biopsy is
confocal microscopy may reduce the number needed to preferably carried out with a 3-4 mm margin of healthy
treat (NNT), measured as the rate of equivocal lesions which surrounding tissue and extended to the subcutaneous tis-
are excised for each melanoma. Specifically, Alarcon et al.26 sue; in cases of very large lesions or anatomic regions at
observed a reduction of non-necessary surgical procedures high reconstructive complexity (such as face, hands), inci-
following reflectance confocal microscopy with an NNT sional or punch biopsies are frequently used to confirm the
reduction from 3.73 with dermoscopy only to 2.87 with diagnosis of BCC with a histologic exam before radical
dermoscopy followed by reflectance confocal microscopy. excision.30

Surgical treatment of primary BCC achieves optimal results Photodynamic therapy is based on the application of a
in terms of rate of cure and rate of relapse.30 In selected photosensitizer to the tumor lesion followed by illumina-
cases, however, other treatment modalities may be used tion of the lesion with visible light, resulting in subse-
based on patient preferences and clinical conditions (which quent selective tumor cell death. The therapeutic
can be a contraindication to surgery) and/or on tumor char- protocol usually consists of two sessions 1 week apart,
acteristics, such as anatomical location, dimension, number of which may be repeated in cases of incomplete clinical
lesions. The most commonly used non-surgical treatments for response. Superficial lesions are the most responsive to
primary BCC include curettage and electrodessication, cryo- this treatment modality, which usually results in excel-
therapy, CO2 laser ablation, intralesional or topical agents, lent or good aesthetic results.36
photodynamic therapy. Punch or incisional biopsies allow the
histologic examination of the lesion before treatment to avoid The effectiveness of photodynamic therapy compared
using these non-surgical therapies improperly. with imiquimod or fluorouracil in patients with histologi-
A recent Cochrane meta-analysis confirmed that overall cally confirmed superficial BCC was assessed in a single-
non-surgical treatments are less effective than surgery in blind, non-inferiority, randomized multicenter trial. Pa-
low-risk BCC, however recurrence rates are acceptable and tients were randomly assigned to receive treatment with
cosmetic outcomes are probably superior. Even if the grade methyl aminolevulinate photodynamic therapy (two ses-
of evidence is low to moderate, imiquimod shows the best sions with an interval of 1 week), imiquimod cream (once
evidence to support its activity.31 daily, five times a week for 6 weeks), or fluorouracil cream
Curettage and electrodessication, despite the simple and (twice daily for 4 weeks). A total of 601 patients were
fast application, do not allow for a proper histologic eval- randomized to receive photodynamic therapy, imiquimod,
uation of the lesion, and no strong literature data support or fluorouracil. At 12 months after treatment, 52 of 196
the therapeutic success of this approach in terms of rate of patients treated with photodynamic therapy, 31 of 189
relapse.32 In particular, the main limitations of curettage treated with imiquimod, and 39 of 198 treated with fluo-
and electrodessication are: scalp lesions, due to the rouracil had tumor residue or recurrence. The proportion of
possible hair follicles involvement; lesions involving the tumor-free patients at both 3- and 12-month follow-up was
hypodermis; high-risk BCC.32 72.8%, 83.4% and 80.1%, respectively. In summary, topical
Cryotherapy uses the cytotoxicity of liquid nitrogen to fluorouracil was non-inferior and imiquimod was superior to
freeze and destroy cutaneous lesions, whereas CO2 laser photodynamic therapy.34 This finding was confirmed at a 3-
ablation destroys tumor cells through a rapid intracellular year follow-up analysis.37
temperature increase. Both techniques achieved similar In selected cases of BCC at high risk of relapse, and/or
results in terms of rate of relapse and aesthetic results, and arising in anatomical areas requiring a minimally invasive
have the same limitations as curettage and electro- approach, non-conventional surgical treatments such as
dessication.33 In a three-arm study, 240 patients with BCC Mohs micrographic surgery and complete circumferential
were randomized to receive either surgery or cryotherapy peripheral and deep margin assessment (CCPDMA) are
or pulse CO2 laser ablation. Cryotherapy and pulse CO2 laser available in specialized centers.38-40 In terms of cure and
ablation achieved similar results in terms of 3-month relapse rates, Mohs micrographic surgery achieves better
complete remissions and aesthetic outcomes, but were results than CCPDMA.38-40 In a prospective, multicenter
both inferior compared with surgery.33 case series which included all patients in Australia treated
The most commonly used topical treatments include 5- with Mohs micrographic surgery for BCC, who were moni-
fluorouracil cream, imiquimod and photodynamic tored by the Skin and Cancer Foundation between 1993 and
therapy34: 2002, cure rates at 5 years were 98%-99% for primary BCCs
Topical 5-fluorouracil is most frequently used as a 5% and 95% for recurrent lesions.41
cream for the treatment of low-risk superficial BCC Electrochemotherapy (ECT) is a local treatment modality
only, as it has shown low cure rates for nodular or for cutaneous and subcutaneous tumors, where electric
high-risk BCC. Despite patients having to avoid solar pulses are used to cause increased permeability of cell
UVR exposition during treatment (3-4 weeks), the main membranes in the tumor mass, enabling dramatically
advantage of this treatment modality is the good enhanced effectiveness of bleomycin and other hydrophilic
aesthetic results;34 chemotherapy drugs.42,43 In a European prospective study
Imiquimod is commonly used as a 5% formulation cream including patients with skin tumors arising in the head and
for the treatment of superficial and small nodular BCC in neck area, ECT was used for the treatment of 105 patients
low-risk anatomical areas, where a relapse would not be with recurrent or locally advanced tumors. Response rate
associated with a relevant local morbidity, in patients was higher for BCC (97%) compared with other tumor types
with contraindication to surgical excision or with low (74%).42 In a retrospective, single-center analysis, 84 pa-
life expectancy. This treatment modality may be associ- tients with BCC not amenable to conventional treatments
ated with erythema and with some very rare systemic received ECT, with a complete response rate of 50%.43 In a
adverse events such as fatigue, exfoliative dermatitis recent report from the INSPECT group on >2000 tumor
and flu-like symptoms. Imiquimod is generally applied lesions, the response rate in 282 cases of BCC was 96%, with
once daily, five to seven times a week for 6 weeks;35 85% complete response rate.44 In a randomized non-

inferiority study comparing ECT with the gold standard Strength of recommendation. Conditional in favor.
surgery, the two treatments showed statistical equivalence
in terms of recurrence (one in the surgery group and five in Overall quality of evidence. Very low.
the ECT group at 5-year follow-up).44 Motivation/comments on the benefit/risk balance. One
Question 4. Should a surgical excision with 3 mm clinical randomized trial comparing Mohs with standard surgery was
margins be recommended in subjects with operable BCC identified.46-48 The results of the study were reported for the
compared with surgical excision with <3 mm clinical first time in 2004 by Smeets et al.,48 then by Mosterd et al.47
margins? in 2008 with longer follow-up and, finally, by van Loo et al.46
in 2014 with a 10-year follow-up time. The study analyzed the
Recommendation. In subjects with operable BCC, a surgical outcomes of 408 primary BCCs (204 treated with conven-
excision with 3 mm clinical margins should be considered tional surgery and 204 with Mohs micrographic surgery;
as the first option compared with surgical excision with <3 among these, 68 patients with 78 primary BCCs were not
mm clinical margins. randomized) and 204 recurrent BCCs (102 treated with con-
ventional surgery and 102 with Mohs micrographic surgery;
Strength of recommendation. Strong in favor. among these, 42 patients with 42 primary BCCs were not
Overall quality of evidence. Moderate. randomized). Patients included in this study had at least one
treatment-naive 1 cm BCC located in the H area (i.e. peri-
Motivation/comments on the benefit/risk balance. In the orbital, eyelids, periauricular, temple, ears, central face, lips,
meta-analysis published in 2010 by Gulleth et al.,45 37 and nose), or a BCC with a high-risk histotype (morpheaform,
studies assessing the surgical margins of BCC were included, micronodular, trabecular, infiltrative or basosquamous); in the
for a total of 16 066 treatment-naive lesions in 10 261 recurrent BCC group, patients with at least one recurrent BCC
patients. The diameters of BCC included in the meta- of the face were included, both if it was a first or second
analysis were 11.7 mm 5.9 mm (from 3 to 30 mm) and recurrence.47 As for primary tumors, 5-year follow-up was
the excisional margins were on average 3.9 1.4 mm (from completed by 251 patients (129 BCCs treated with Mohs
1 to 10 mm). We focused on the comparison between a 3 micrographic surgery and 141 with conventional surgery),
mm clear margin or a narrower margin, and to respond to whereas in the recurrent BCC group, 137 patients (75 BCCs
this question we defined recurrence rate and functional- treated with MMS and 59 with conventional surgery)
aesthetic results as essential outcomes, and quality of the completed 5-year follow-up.47 In the report published in 2014
scars, pathological accuracy, pathological scarring and by van Loo et al.,46 10-year follow-up data were available for
wound breakdown as important outcomes. Gulleth’s meta- only 140 lesions (accounting for 35.3% of all primary tumors)
analysis showed a relative risk of 1.60 on comparison be- in 129 patients.
tween 3 mm excisional biopsy with 4 mm excisional biopsy The panel identified relapse rate and rate of complete
in BCC, namely 15 more recurrences every 1000 excisions excisions confirmed at pathologic examination as essential
(95% CI 1-37 more recurrences). The relative risk was 2.40 outcomes of benefit, and number of re-interventions as an
when 2 mm was compared with 4 mm, namely 55 more important outcome of benefit. The essential outcome of
recurrences every 1000 excisions (95% CI 27-97 more re- damage was duration of surgical procedures, whereas
currences). No data were available regarding the outcomes aesthetic and functional results were defined as important
of damage such as scarring and cosmetic results. outcomes of damage.
The panel did not identify any probable uncertainty or In the analysis reported by van Loo et al.,46 after a mean
variability on how the population may evaluate the follow-up of 10 years, a relative risk (RR) ¼ 0.27 (95% CI
analyzed outcomes. The balance between outcomes of 0.08-0.94) in favor of Mohs compared with conventional
benefit and outcomes of damage favors the surgical excision surgery was observed, namely eight fewer relapses every
of operable BCCs with 3 mm clinical margins compared 100 procedures (95% CI 10-1 fewer relapses). As for rate of
with <3 mm clinical margins. The intervention is equally complete excisions confirmed at pathologic examination,
accessible over all the country. See Supplementary material the analysis reported by Smeets et al.48 showed that RR ¼
(Question 4), available at https://doi.org/10.1016/j.esmoop. 1.12 was achieved with Mohs surgery (95% CI 0.95-1.32),
2023.102037, for evidence to decision results, quality of equivalent to eight more complete excisions with Mohs
evidence and implications for future results. compared with conventional surgery (95% CI from 3 fewer
to 22 more complete excisions). The surgical complications
Question 5. Should Mohs surgery be recommended in
were reported in the analysis published by Mosterd et al.47
subjects with recurrent or high-risk BCC compared with
in 2008 with a mean follow-up of 5 years. The RR was 0.43
standard surgical excision?
(95% CI 0.20-0.94), namely 11 fewer surgical complications
Recommendation. In subjects with recurrent or high-risk with Mohs surgery every 100 procedures (95% CI 15-1
BCC, Mohs surgery may be considered as the first option fewer procedures). The number of re-interventions and
compared with standard surgical excision. duration of procedures were not evaluated in any analysis.

Considering the lower risk of surgical complications with centers in which it is not available yet without great costs,
Mohs surgery, and the better results in terms of outcomes of and should be acceptable by all stakeholders;49 however, to
benefits, the balance between risks and benefits favors Mohs date, such a treatment modality is not equally distributed
compared with conventional surgery. The panel did not iden- across Italy. See Supplementary material (Question 6),
tify any probable uncertainty or variability on how the popu- available at https://doi.org/10.1016/j.esmoop.2023.102037,
lation may evaluate the analyzed outcomes. Mohs surgery for evidence to decision results, quality of evidence and
must be carried out by a highly specialized and trained implications for future results.
multidisciplinary team, however, and it is not easily imple-
mentable in many centers across the country. Thus, the Considerations on subgroups of patients. ECT may be
recommendation in favor of Mohs surgery may cause inequity considered as an option compared with conventional sur-
and low accessibility to such treatment. See Supplementary gery and radiotherapy in selected cases of BCC, especially
material (Question 5), available at https://doi.org/10.1016/j. those located around the eye and on the nose,50 and when
esmoop.2023.102037, for evidence to decision results, qual- multiple lesions must be treated.
ity of evidence and implications for future results.
Question 7. Should standard surgical excision be recom-
Question 6. Should ECT be recommended in subjects with mended in subjects with non-recurrent, operable BCC
BCC and relative contraindications to conventional treat- compared with imiquimod?
ments (surgery and radiotherapy) compared with standard
surgical excision or radiotherapy? Recommendation. In subjects with non-recurrent, operable
BCC, surgical excision should be recommended as the first
Recommendation. In subjects with BCC and relative con- option compared with imiquimod.
traindications to conventional treatments (surgery and
radiotherapy), ECT should not be considered as the first Strength of recommendation. Conditional in favor.
option compared with standard surgical excision or Overall quality of evidence. Very low.
radiotherapy.
Motivation/comments on the benefit/risk balance. The
Strength of recommendation. Conditional against. SINS (Surgery versus Imiquimod for Nodular and Superficial
Overall quality of evidence. Very low. basal cell carcinomas) study was a non-inferiority, ran-
domized trial with parallel groups the results of which were
Motivation/comments on the benefit/risk balance. The reported across three publications. In the first report,
outcomes of benefit defined as essential by the panel were published in 2010 by Ozolins et al.51 the study design and
rate of relapse, rate of complete responses, overall survival, methods were described; the second publication (Bath-
relapse-free survival and overall subjective satisfaction. Scar- Hextall et al.,52 2014) reported the results with a 3-year
ring, pain, rate of infection, rate of any-grade adverse events, follow-up; finally, in the third paper (Williams et al.,53
rate of grade 3-5 adverse events and duration of adverse 2017), the results with a 5-year follow-up were reported.
events were considered as essential outcomes of damage. A total of 501 patients were enrolled in the study, and
Only one randomized study, published by Clover et al.44 401 were included in the 3-year modified ‘intention-to-
in 2020, addressed this question. One hundred patients treat-group’. Patients were included if they had at least one
with primary BCCs were randomized to either ECT (52 pa- superficial or nodular BCC (morpheaform histotype was
tients) or surgery (48 patients). Some 45 and 42 patients, excluded), <2 cm wide, which had not received a previous
respectively, received the allocated treatment. Patients treatment and was not arising in a high-risk anatomical area
were followed up to 6 months for complete response (nose, ear, eye, eye lids, temple). Patients were randomized
evaluation, and up to 5 year for the duration of response. to receive either topical imiquimod 5% cream or surgery.
Less complete responses were achieved with ECT compared Imiquimod was applied for 6 weeks in cases of superficial
with surgery (RR: 0.93, 95% CI 0.82-1.06), and a higher BCC and 12 weeks for nodular BCC. Surgical excision was
relapse rate (14% versus 3%, for an RR: 4.86; 95% CI 0.60- carried out with a 4 mm clinical margin.
39.63). The risk of superficial ulceration, surgical infections The outcomes of benefit defined as essential by the panel
and post-operative pain were higher for ECT compared with were response rate, relapse rate, time to recurrence and
surgical excision. No results in terms of overall survival, aesthetic results; acute and chronic sequelae and overall
relapse-free survival and overall subjective satisfaction were toxicities were considered as essential outcomes of
reported. In addition to that, due to the small sample size damage.
and the low number of events, results were not statistically At a minimum follow-up of 5 years, response rate was
significant. Nevertheless, the panel judged the damage/risk 98% in patients receiving surgery and 83% in those treated
balance as probably in favor of the control treatment (i.e. with imiquimod (RR: 1.18, equal to 15 more responses
conventional surgery). every 100 patients, 95% CI 9-22 more responses). As for
The panel did not identify any probable uncertainty or relapse rate, an RR of 0.21 (95% CI 0.05-0.94) in favor of
variability on how the population may evaluate the analyzed surgery (4 fewer relapses every 100 patients, 95% CI 0-5
outcomes. The intervention should be easy to implement in fewer relapses). Non-optimal cosmetic results were

observed in 16.4% of patients in the surgery group Strength of recommendation. Strong in favor.
compared with 34.7% for imiquimod (RR: 0.47; 95% CI 0.31-
0.70), acute sequelae such as discomfort in, respectively, 7% Overall quality of evidence. Low.
and 9.6% (RR: 0.72; 95% CI 0.39-1.33) and bleeding in 3.5% Motivation/comments on the benefit/risk balance. To
and 8.4% (RR: 0.41; 95% CI 0.19-0.92). On the contrary, pain respond to this question, the panel identified through a
located at the lesion site was more frequent in patients systematic literature search two meta-analyses published by
treated with surgery than those receiving imiquimod (7.4% Wang et al.54 in 2015 including a total of 1583 patients and
versus 4.8%; RR: 1.54; 95% CI 0.75-3.15), as well as swelling by Zou et al.55 in 2016 including 596 patients. The different
(8.3% versus 4%; RR: 2.07; 95% CI 0.98-4.35). population size reflected the different inclusion criteria of
Overall, the balance between risks and benefits was in the two meta-analyses. Wang’s meta-analysis included
favor of surgery. The panel did not identify any probable randomized trials assessing photodynamic therapy
uncertainty or variability on how the population may eval- compared with other treatment modalities (mostly surgery,
uate the analyzed outcomes. The intervention is easily but also other therapies such as imiquimod);54 Zou’s anal-
accessible across the country and should be acceptable by all ysis included only randomized trials comparing photody-
stakeholders. See Supplementary material (Question 7), namic therapy with surgery in patients with histologically
available at https://doi.org/10.1016/j.esmoop.2023.102037, confirmed nodular BCC.55
for evidence to decision results, quality of evidence, and The outcomes of benefit defined as essential by the panel
implications for future results. were response rate, relapse rate, time to recurrence,
Considerations on subgroups of patients. The results of the aesthetic results; acute and chronic sequelae, and overall
SINS study showed the superiority of surgery compared toxicities were considered as essential outcomes of
with imiquimod, but highlighted that imiquimod may also damage.
obtain long-term responses in a high rate of patients. For In the analysis reported by Wang et al.,54 photodynamic
this reason, imiquimod could be considered as an option in therapy was associated with a lower rate of complete re-
selected patients with low-risk, superficial BCC when mul- sponses compared with surgery (RR: 0.93; 95% CI 0.89-
tiples lesions must be treated, and/or in presence of 0.98), with a higher 1-year relapse rate (RR: 12.42; 95% CI
comorbidities increasing the complexity and risks of surgical 2.34-66.02) and 5-year relapse rate (RR: 6.79; 95% CI 2.43-
intervention. 18.96).
The meta-analysis reported by Zou et al.55 focused on the
Question 8. Should standard surgical excision be recom- efficacy of photodynamic therapy versus surgery in patients
mended in subjects with non-recurrent, operable BCC with nodular BCC. Five randomized trials were included in
compared with topical 5-fluorouracil? this analysis for a total of 596 patients with histologically
confirmed nodular BCC. The results did not demonstrate a
Recommendation. In subjects with non-recurrent, operable significant difference between the two treatments, but
BCC, surgical excision should be recommended as the first photodynamic therapy showed an increased cumulative risk
option compared with topical 5-fluorouracil. of relapse. As for the overall rate of relapse, both meta-
Strength of recommendation. Conditional in favor. analyses reported results favoring surgery, with an RR:
0.16 (95% CI 0.06-0.45) in Wang’s report,54 and an RR: 0.12
Overall quality of evidence. Expert opinion. (95% CI 0.04-0.33) in Zou’s analysis.55
Overall, the balance between risks and benefits was in
Motivation/comments on the benefit/risk balance. No favor of surgery. The panel did not identify any probable
studies comparing surgery with topical 5-fluorouracil were uncertainty or variability on how the population may eval-
identified through our systematic literature search. In the uate the analyzed outcomes. The intervention is easily
absence of data documenting the activity of topical 5- accessible across the country, and should be acceptable by
fluorouracil for the treatment of BCC, such a treatment all stakeholders. See Supplementary material (Question 9),
modality is not recommended in subjects with non- available at https://doi.org/10.1016/j.esmoop.2023.
recurrent, operable BCC. See Supplementary material 102037, for evidence to decision results, quality of evi-
(Question 8), available at https://doi.org/10.1016/j. dence and implications for future results.
esmoop.2023.102037, for quality of evidence and implica-
tions for future results. Considerations on subgroups of patients. In Wang’s report,
the subgroup analysis showed that surgery benefit was not
Question 9. Should standard surgical excision be recom- confirmed considering nodular BCC only (RR: 0.93; 95% CI
mended in subjects with non-recurrent, operable BCC 0.85-1.01); in addition to that, no significant differences
compared with photodynamic therapy? were found when only BCCs arising in the face were
Recommendation. In subjects with non-recurrent, operable analyzed (RR: 0.99; 95% CI 0.89-1.10). Finally, the clinical
BCC, surgical excision should be recommended as the first activity of photodynamic therapy strictly depended on the
option compared with photodynamic therapy. type of photosensitizing agent.54 In the comparisons

between photodynamic therapy and imiquimod, the effi- Recommendation. In subjects with non-recurrent, operable
cacy of these two treatments was similar. The results of the BCC, surgical excision should be recommended as the first
meta-analyses showed the superiority of surgery compared option compared with laser treatments.
with photodynamic therapy, but highlighted that photody-
namic therapy may also obtain long-term responses in a Strength of recommendation. Conditional in favor.
subgroup of patients. For this reason, photodynamic ther- Overall quality of evidence. Expert opinion.
apy could be considered as an option in selected patients
with low-risk BCC, especially when multiples lesions of the Motivation/comments on the benefit/risk balance. No
face must be treated, and/or in presence of comorbidities studies comparing surgery with laser treatments were
increasing the complexity and risks of surgical intervention. identified through our systematic literature search. In the
absence of data documenting the activity of laser treat-
Question 10. Should standard surgical excision be recom- ments for BCC, such a treatment modality is not recom-
mended in subjects with non-recurrent, operable BCC mended in subjects with non-recurrent, operable BCC. See
compared with cryotherapy? Supplementary material (Question 11), available at
Recommendation. In subjects with non-recurrent, operable https://doi.org/10.1016/j.esmoop.2023.102037, for quality
BCC, surgical excision should be recommended as the first of evidence and implications for future results.
option compared with cryotherapy. Question 12. Should standard surgical excision be recom-
Strength of recommendation. Strong in favor. mended in subjects with non-recurrent, operable BCC
compared with cauterization?
Overall quality of evidence. Low.
Recommendation. In subjects with non-recurrent, operable
Motivation/comments on the benefit/risk balance. Only BCC, surgical excision should be recommended as the first
one randomized study answering this question was found option compared with cauterization.
through our systematic literature search. In this study,
published by Thissen et al.56 in 2000, 96 patients were Strength of recommendation. Conditional in favor.
enrolled if they had a <2 cm wide superficial or nodular Overall quality of evidence. Expert opinion.
BCC, located in the head and neck area. Patients were
randomized to receive either conventional surgical excision Motivation/comments on the benefit/risk balance. No
or cryotherapy. studies comparing surgery with cauterization were identi-
The outcomes of benefit defined as essential by the panel fied through our systematic literature search. In the absence
were response rate, relapse rate, time to recurrence and of data documenting the activity of cauterization for the
aesthetic results; acute and chronic sequelae, and overall treatment of BCC, such a treatment modality is not rec-
toxicities were considered as essential outcomes of ommended in subjects with non-recurrent, operable BCC.
damage. See Supplementary material (Question 12), available at
No outcomes of damage as defined by the panel were https://doi.org/10.1016/j.esmoop.2023.102037, for quality
reported in the paper. The authors reported aesthetic re- of evidence and implications for future results.
sults and 1-year relapse rate.
One-year relapse rate was in favor of surgery, with three
The role of radiotherapy
patients relapsing in the cryotherapy group versus no pa-
tients among those undergoing surgical excision (RR: 0.170; Exclusive radiotherapy is commonly used for the treatment
95% CI 0.009-3.230, 5 relapses every 100 treated patients; of inoperable BCC; in cases of lesions developing in
95% CI from 6 fewer relapses to 14 more). All patients anatomical locations where surgery could cause unaccept-
receiving surgery had histologic examination, whereas this able aesthetic results or negatively impact on patients’
information was lacking in those who received cryotherapy. quality of life;57 in cases of frail patients with limited life
Overall, the balance between risks and benefits was in expectancy, or patients with multiple comorbidities which
favor of surgery. The panel did not identify any probable limit the range of treatment modalities.58,59 Radiotherapy is
uncertainty or variability on how the population may eval- generally contraindicated in patients with genodermatosis
uate the analyzed outcomes. The intervention is easily such as xeroderma pigmentosum, and some soft tissues
accessible across the country, and should be acceptable by diseases such as scleroderma and lupus.60 Three large
all stakeholders. See Supplementary material (Question 10), retrospective studies assessed the efficacy of exclusive
available at https://doi.org/10.1016/j.esmoop.2023. radiotherapy as first-line treatment of BCC arising in the
102037, for evidence to decision results, quality of evi- head and neck area. Overall, 3609 patients received radio-
dence and implications for future results. therapy within these studies. Regardless of the radiotherapy
technique and fractionation schedules, the cure rates at 5
Question 11. Should standard surgical excision be recom- years were 96%,61 95.8%62 and 94.8%.63
mended in subjects with non-recurrent, operable BCC Adjuvant radiotherapy after surgical excision of primary
compared with laser treatments? BCC is not commonly used due to the very low overall risk

of relapse. The role of adjuvant radiotherapy has been radiotherapy treatment modalities used in the study are
investigated, however, in cases of BCC with large subcu- currently overcome. The panel did not identify any probable
taneous extension, bone involvement, postsurgical residues uncertainty or variability on how the population may eval-
after multiple treatments, lymph node involvement and uate the analyzed outcomes. The intervention is equally
perineural invasion.64 accessible across the country. See Supplementary material
BCCs may be irradiated through different modalities, (Question 13), available at https://doi.org/10.1016/j.
using low-energy photons, 4-12 MeV electrons, interstitial esmoop.2023.102037, for evidence to decision results,
brachytherapy65,66 or high conformation techniques (three- quality of evidence and implications for future results.
dimensional conformal radiotherapy [3D-CRT] or intensity-
modulated radiotherapy [IMRT]). The energy to be used is Question 14. Should radiotherapy be recommended after
defined based on the thickness of the lesion assessed surgical excision of BCC with positive margins compared
through ultrasound or CT scan, while volume may be eval- with re-excision?
uated clinically and should include a 1 cm margin for <2 cm Recommendation. After surgical excision of BCC with pos-
wide BCCs, and a 1.5 cm margin for wider lesions.59 Margins itive margins, radiotherapy should not be recommended as
are tailored when BCCs arise in specific anatomical regions the first option compared with re-excision.
such as nasolabial folds and preauricular area. Numerous
fractionation schedules are described in literature, with Strength of recommendation. Conditional against.
hypofractionated schedules with 35 Gy in 5-7 fractions
three times a week62 or 25-30 Gy in 5-6 weekly Overall quality of evidence. Very low.
fractions,58,59 moderate hypofractionation with 45 Gy in 9 Motivation/comments on the benefit/risk balance. The
fractions along 3 weeks63 or conventional fractionation.67 assessments were based on the following outcomes of
Question 13. Should standard surgical excision be recom- benefit and damage: rate of relapse, relapse-free survival,
mended in subjects with non-recurrent, operable BCC quality of life, rate of acute and chronic sequelae. Due to
compared with radiotherapy? the paucity of literature, two case series were analyzed to
answer this this question.
Recommendation. In subjects with non-recurrent, operable In the series published in 2004 by Wilson et al.,69 all
BCC, surgical excision should be recommended as the first consecutive patients with BCC treated between 1990 and
option compared with radiotherapy. 1999 at the Unit of Oral and Maxillofacial Surgery of St.
Richard’s and Worthing & Southlands Hospital and a mini-
Strength of recommendation. Strong in favor. mum follow-up of 1 year were included in the analysis.
Overall quality of evidence. Moderate. Among these patients, 235 BCCs were incompletely excised.
The authors compared the outcomes of radiotherapy, sur-
Motivation/comments on the benefit/risk balance. One gery or observation only for these lesions: 84 BCCs were
randomized study comparing surgery and radiotherapy for treated with radiotherapy, 11 were re-excised, and 140 were
the treatment of primary BCC was identified through our followed up based on age, comorbidities, patients’ prefer-
systematic literature search.68 In this one study, published ence, entity of margins involvement, anatomical area, his-
by Avril et al.68 in 1997, 347 patients with BCCs arising in tological subtype and surgeon’s preference. In both patients
the face and <4 cm wide were randomized to either sur- treated with surgery or radiotherapy, no relapses were
gery (174 patients) or radiotherapy (173 patients). After a observed, whereas among 140 BCCs in the observation only
mean follow-up of 41 months, the relapse rate was 0.7% group, 29 relapsed after 5-76 months (mean 25 months).69
(95% CI 0.1% to 3.9%) with surgery and 7.5% (95% CI 4.2% In the study published in 1991 by Liu et al.,70 the out-
to 13.1%) with radiotherapy. The hazard ratio was 0.18 (95% comes of radiotherapy and observation only were
CI 0.06-0.56) and the RR 0.12 (95% CI 0.02-0.98). In the compared in patients with incompletely excised BCCs
group of patients treated with radiotherapy, 55% received treated between 1970 and 1985 at Princess Margaret
brachytherapy, 33% contact therapy and 12% a conven- Hospital in Toronto. Patients with evidence of macroscopic
tional technique. Good cosmetic results were achieved in relapse were excluded from the analysis, as well as patients
87% of patients in the surgery group versus 69% with with no follow-up. Overall, 187 patients were included in
radiotherapy. Surgical complications such as scar retraction the study: among these patients, 119 with incompletely
were more frequent in the first year after treatment, and excised BCC were treated with radiotherapy, 1 with surgery
their frequency tended to be progressively lower after- and 67 were followed up without any further treatment. At
wards. Telangiectasias and dyschromias were the most 10 years, 9.2% of patients receiving treatment had a
frequently reported complications in the radiotherapy relapse, compared with 59.7% in the observation group (RR:
group; their frequency was stable on follow-up.68 0.15; 95% CI 0.08-0.28), equal to 51 fewer relapses every
The study demonstrated a significant advantage of sur- 100 incomplete excisions (95% CI from 55 to 43 fewer
gical excision over radiotherapy in terms of local disease relapses).70
control for <4 cm wide BCCs arising in the head and neck The panel did not identify any probable uncertainty or
area. It must be noted, however, that some of the variability on how the population may evaluate the

analyzed outcomes. The intervention is equally available only in case reports and small case series, with no proper
across the country, and should be acceptable by all stake- investigations in prospective clinical trials. Cisplatin was
holders. See Supplementary material (Question 14), avail- the most commonly used chemotherapy; combination
able at https://doi.org/10.1016/j.esmoop.2023.102037, for regimens included etoposide, 5-fluorouracil, bleomycin,
evidence to decision results, quality of evidence and im- cyclophosphamide and Adriamycin.75 A response rate as
plications for future results. high as 75% was reported in literature for both locally
advanced and metastatic cases; however, important limi-
tations are the high risk of selection bias and small sizes of
Management of locally advanced and mBCC the case series. Systemic retinoids have also been used for
The choice of a medical approach mainly relies on a shared the treatment of multiple BCCs76: in a study including 12
definition of laBCC. Essentially, the definition of laBCC patients with Gorlin syndrome, isotretinoin p.o. was
overlaps with the field of application of systemic treat- administrated with a response rate of 16%; however,
ments. As a matter of fact, this term was not used before treatment was not well tolerated, with 41% of patients
the introduction of effective targeted treatments for BCC. interrupting treatment due to drug toxicity. As for
Locally advanced BCC includes a heterogeneous range of epidermal growth factor receptor (EGFR) inhibitors, only
lesions not amenable for treatment with surgery and very limited data are available from case reports, insuffi-
radiotherapy with curative intents. Thus, the definition of cient to state any indications for the use of this class of
laBCC may include a range of subjectivities and in- drugs for advanced BCC.77 Finally, treatments targeting the
terpretations deriving from the experience, oncologic Hedgehog pathway achieved encouraging results in phase I
competence and personal approach of the specialists trials and received the approval by the regulatory agencies
treating such disease.71 This assessment is often based on for the treatment of advanced BCC.78-81 Specifically, vis-
the discussion within a multidisciplinary group, including modegib received approval from the Food and Drug
surgeons (dermatologist, plastic surgeon, head and neck Administration, European Medicines Agency (EMA) and
surgeon, .), radiotherapist and medical oncologist. Agenzia Italiana del Farmaco (AIFA) for the treatment of
Surgery may be contraindicated based on several factors: both laBCC and mBCC, after achieving a response rate of
low chances of achieving a curative resection due to the 67% and 38%, respectively, with a median time to best
extension and/or anatomical location of the tumor. The response of only 2.6-2.8 months. Most adverse events were
rate of BCCs >5 cm wide are rare,72 and are usually asso- low grade (grade 1-2 according to the Common Terminol-
ciated with psychiatric disorders, immunosuppression or ogy Criteria for Adverse Events grading system). The adverse
negligence events most frequently reported were muscle cramps, al-
complexity in terms of reconstructive phase. Despite be- opecia, dysgeusia, loss of weight, fatigue, loss of appetite,
ing in a very limited proportion of cases, thanks to the diarrhea and nausea. Time to occurrence of adverse events
advances of plastic and reconstructive surgery, the clin- was about to 2 months for the majority of adverse events,
ical conditions of patients and/or the local extension and longer for alopecia and gastrointestinal disorders (w4
and type of tissue invasion of the tumor may be contra- months), and loss of weight (w6 months). However, despite
indications to the reconstructive phase adverse events being mostly low grade, the long duration of
substantial deformity or morbidity caused by surgery. In toxicity is a challenge for an optimal compliance to treat-
cases of tumors arising in some anatomical areas, such ment, and a relevant proportion of patients interrupted
as eye, ear, nose and extremities, the radical surgical therapy due to adverse events in clinical trials. Mean
excision may be contraindicated due to anticipated unac- duration of treatment with vismodegib was 13 months.82
ceptable cosmetic and functional results More recently, sonidegib, another inhibitor of the
recurrent tumors after two or more surgical resections, Hedgehog pathway, was approved by the regulatory
where another surgical procedure may be associated agencies for the treatment of laBCC.83-85 The BOLT study
with a high risk of relapse enrolled 230 patients, 79 and 151 in the 200 mg and 800
any clinical condition or comorbidities which may be mg groups, respectively. The overall response rates by
contraindications to surgical options central review were 56% for laBCC and 8% for mBCC in the
200 mg group and 46% for laBCC and 17% for mBCC in the
Radiotherapy may also be contraindicated when it was 800 mg group. The 200 mg dosage is the currently approved
already used in the same anatomical area, when the one. The pattern of toxicities was similar to that observed
extension of the area to be treated is too wide and in with vismodegib, and no new safety concerns emerged at
presence of clinical contraindications such as risk of devel- the 42 month analysis.85
oping second tumors, DNA repair pathogenic conditions, The clinical differences between vismodegib and soni-
genodermatosis. degib in patients with laBCC are unclear, as no head-to-head
Systemic treatments are indicated in cases of laBCC and randomized trials were conducted. Moreover, there were
mBCC. Before the introduction of targeted therapies, important differences in the designs of their pivotal studies,
chemotherapy was the only treatment available in this BOLT for sonidegib and ERIVANCE for vismodegib, most
setting.73,74 Numerous drugs and combination regimens importantly related to the assessment of response. In the
have been used, despite their outcomes being published ERIVANCE study, the conventional Response Evaluation

Criteria in Solid Tumors (RECIST) was used, and in the BOLT baseline assessment is also necessary to properly evaluate
trial, the more stringent modified RECIST was used to assess the response to systemic treatments in cases of laBCC with
responses. In a recent consensus paper, clinical experts in deep tissue involvement and mBCC. Based on these con-
the management of laBCC concluded that both vismodegib siderations, and despite the lack of evidence in literature,
and sonidegib were associated with similar clinical activity the panel believes that the balance of risks and benefits of a
and patterns of toxicities, despite their pharmacokinetic baseline radiological tumor assessment in patients with
profiles showing important differences, such as volume of laBCC and mBCC is favorable. The panel did not identify any
distribution and half-life. Further studies are needed to probable uncertainty or variability on how the population
understand how these differences may impact clinical may evaluate the analyzed outcomes. The intervention is
practice.86 equally available across the country, and should be
Treatment breaks are commonly used to reduce the acceptable by all stakeholders. See Supplementary material
severity and duration of Hedgehog pathway inhibitor- (Question 15), available at https://doi.org/10.1016/j.
related adverse events. No specific recommendations on esmoop.2023.102037, for quality of evidence and implica-
the optimal application of treatment breaks exist, however, tions for future results.
and it mostly relies on the experience of clinicians. Ac-
cording to AIFA, treatment breaks for a maximum of 4 and 3 Question 16. Should radiological tumor assessment be
consecutive weeks for vismodegib and sonidegib, respec- recommended in the follow-up of subjects with laBCC and
tively, are allowed for the management of treatment- mBCC?
related toxicities. Studies investigating the effects of Recommendation. In the follow-up of subjects with laBCC
longer treatment breaks have been conducted, but to date and mBCC, radiological tumor assessment may be recom-
such schedules are not approved.87 mended as the first option compared with no radiological
Itraconazole, an antifungal drug, also inhibits the tumor assessment.
Hedgehog signaling pathway. In a study assessing the effect
of itraconazole on the Hedgehog pathway and on tumor Strength of recommendation. Conditional in favor.
size in human BCC tumors, a total of 29 patients were
enrolled, 19 of whom were treated with itraconazole. Four Overall quality of evidence. Expert opinion.
partial responses and four stable disease were achieved, Motivation/comments on the benefit/risk balance. No
showing that itraconazole has anti-BCC activity in humans. studies comparing radiological tumor assessment in the
To date, however, itraconazole is not approved for the follow-up of subjects with laBCC and mBCC with no radio-
treatment of advanced BCC due to the very limited data logical assessment were identified through our systematic
about its activity and safety.88 literature search. Since laBCC and mBCC are often the re-
Question 15. Should baseline radiological tumor assess- sults of previous treatment failures, however, and for
ment be recommended in subjects with laBCC and mBCC? laBCCs, their involvement of deep tissue is often clinically
meaningful, the panel, despite the lack of evidence in
Recommendation. In subjects with laBCC and mBCC, literature, believes that the balance of risks and benefits of
baseline radiological tumor assessment may be recom- a radiological tumor assessment in the follow-up of patients
mended as the first option compared with no baseline with laBCC and mBCC is favorable, and that the type and
radiological tumor assessment. frequency of assessments should be at clinicians’ judgment.
The panel did not identify any probable uncertainty or
Strength of recommendation. Conditional in favor.
variability on how the population may evaluate the
Overall quality of evidence. Expert opinion. analyzed outcomes. The intervention is equally available
across the country, and should be acceptable by all stake-
Motivation/comments on the benefit/risk balance. No holders. See Supplementary material (Question 16), avail-
studies comparing baseline radiological tumor assessment able at https://doi.org/10.1016/j.esmoop.2023.102037, for
with no assessment in subjects with laBCC and mBCC were quality of evidence and implications for future results.
identified through our systematic literature search. The lack
of evidence was expected due to the recent introduction of Question 17. Should treatment with Hedgehog pathway
the definition for laBCC and the extreme rarity of mBCC. inhibitors be recommended in subjects with laBCC and
Since patients with laBCC often harbor tumors with deep mBCC compared with follow-up/best supportive care?
tissue involvement, the panel determined that whether a
baseline radiological assessment is necessary in patients Recommendation. In subjects with laBCC and mBCC,
with advanced BCC was a question worth addressing. In treatment with Hedgehog pathway inhibitors should be
addition to that, since the identification of a locally recommended as the first option compared with follow-up/
advanced and/or metastatic disease may precede the best supportive care.
administration of a systemic treatment, the detection of an Of note, both vismodegib and sonidegib received the
additional neoplastic disease at baseline radiological approval by the regulatory agencies for the treatment of
assessment may help for the evaluation of risks and bene- laBCC, whereas only vismodegib received the indication for
fits in a population characterized by an old mean age. A mBCC.

Starting from April 2021, updates were made to the AIFA and treated with cemiplimab between November 2017 and
register of sonidegib to allow the switch to the molecule in January 2019. The primary endpoint was objective
patients pretreated with Hedgehog pathway inhibitors response. At a median follow-up of 15 months, an objective
should the prescriber deem it necessary to adopt the response by independent central review was observed in 26
schedule every other day for a better management of the (31%; 95% CI 21 to 42%) of 84 patients. The median time to
adverse reactions. response was 4.3 months (interquartile range: 4.3-7.2
months), with an 80% disease control rate (95% CI 70% to
Strength of recommendation. Strong in favor (the panel 88%) and a durable disease control rate of 60%. The median
decided to adopt a strong recommendation in favor of progression-free survival was 19 months (95% CI 9 months-
treatment with Hedgehog pathway inhibitors despite a very not evaluable). The safety profile was consistent with the
low quality of evidence for the following reasons: the known adverse events associated with anti-programmed
absence of a therapeutic standard for locally advanced BCC cell death protein 1 (PD-1) agents, even considering the
and mBCC has made it impossible to conduct randomized advanced age of the included patients (median age: 70
clinical trials; in daily clinical practice, to date there is no years). The observed immune-related toxicities were
therapeutic alternative to the use of Hedgehog pathway manageable, with a total of nine (11%) serious immune-
inhibitors for the treatment of locally advanced BCC and related adverse events, particularly colitis and adrenal
mBCC). insufficiency.90 The positive opinion by the EMA CHMP was
Overall quality of evidence. Very low. followed by the approval by the European Commission in
June 2021.
Motivation/comments on the benefit/risk balance. The
outcomes of benefit defined as essential to answer this
question were disease control rate, response rate, duration FUNDING
of response and progression-free survival. The rate of any- None declared.
grade and grade 3-5 adverse events, and their duration,
were considered as essential outcomes of damage, in
DISCLOSURE
addition to specific adverse events such as loss of weight
and muscle spasms. PQ reports consulting or Advisory role for Roche/Gen-
Three non-randomized trials were identified through our entech, Novartis, Merck Sharp & Dohme (MSD), Bristol
systematic literature search.83,84,89 Due to the lack of a Myers Squibb (BMS), Pierre Fabre, Sanofi, Sun Pharma
control arm, it was not possible to estimate the relative and Advanced Research Company, Merck Serono. Travel, ac-
absolute effects of treatment with regard to the predefined commodations, expenses from MSD Oncology, Sanofi/
outcomes. Considering the high response and disease Regeneron. FB reports advisory role for Sun Pharma.
control rate, and an impact of toxicities judged as moder- Speaker fee, travel/accommodations for presentations or
ate, however, the panel voted for a balance between risks lectures for Sanofi/Regeneron. Honoraria as consultant for
and benefits favoring the systemic treatment with Hedge- Roche, Novartis. PB reports consulting or advisory role for
hog inhibitors compared with follow-up/best supportive Merck, Sanofi, MSD, Sun Pharma, Angelini, Molteni, BMS,
care. GlaxoSmithKline (GSK); research funding by GSK, MSD,
The panel did not identify any probable uncertainty or Sanofi, BMS. MDV reports consulting or advisory role for
variability on how the population may evaluate the Novartis, MSD, BMS, Pierre Fabre, Immunocore. KP reports
analyzed outcomes. The intervention is equally available advisory board roles with AbbVie, LEO Pharma, Janssen,
across the country, and should be acceptable by all stake- Almirall, Eli Lilly, Galderma, Novartis, Pierre Fabre, Sun
holders. See Supplementary material (Question 17), avail- Pharma and Sanofi. PQ reports advisory board and speaker
able at https://doi.org/10.1016/j.esmoop.2023.102037, for fee from Sanofi, Sun Pharma, IGEA. IZ reports advisory
evidence to decision results, quality of evidence and im- board and speaker fee from Sanofi, Sun Pharma, Philogen,
plications for future results. Regeneron, Novartis, MSD, Cieffe Derma, La Roche Posay,
BMS, Almirall. FS reports honoraria for presentations or
lectures from Sanofi Genzyme, Roche, BMS, Novartis, Merk,
Final considerations Sun Pharma, MSD, Pierre Fabre; participation on advisory
On 20 May 2021, the EMA’s Committee for Medicinal board for Novartis, Philogen Sun Pharma and MSD. All other
Products for Human Use (CHMP) adopted a positive opinion authors have declared no conflicts of interest.
recommending a change to the terms of the marketing
authorization for cemiplimab. The CHMP adopted new in-
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Available online 23 October 2023

INTRODUCTION registries. Important consequences are that the public health

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