clinical practice guidelines Annals of Oncology 24 (Supplement 6): vi64–vi72, 2013

doi:10.1093/annonc/mdt354

Early colon cancer: ESMO Clinical Practice Guidelines

for diagnosis, treatment and follow-up†
R. Labianca1, B. Nordlinger2, G. D. Beretta3, S. Mosconi1, M. Mandalà1, A. Cervantes4 & D. Arnold5
on behalf of the ESMO Guidelines Working Group*

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1
Ospedale Papa Giovanni XXIII, Bergamo, Italy; 2Hospital Ambroise Parè, Paris, France; 3Humanitas Gavazzeni Clinic, Bergamo, Italy; 4Department of Hematology
and Medical Oncology, INCLIVA, University of Valencia, Valencia, Spain; 5Department of Medical Oncology, Tumor Biology Center, Freiburg, Germany

These Clinical Practice Guidelines are endorsed by the Japanese Society of Medical Oncology (JSMO)

general information declined by 6% per quinquennium in men and 8% per

quinquennium in women. The analysis updated to 2007
incidence and epidemiology showed a greater reduction of the mortality rate in the young
Colorectal cancer (CRC) is the third most common tumour in population (aged 30–49 years) with ∼10% per quinquennium
men and the second in women, accounting for 10% of all [4]. In Europe, the 5-year survival for colon cancer in different
tumour types worldwide. Incidence is higher in males (ratio: geographical settings ranged from 28.5% to 57% in men and
1.4) and for both genders there is a 10-fold difference in from 30.9% to 60% in women: the pooled estimation for 51
incidence between several regions. With 608 000 deaths registries of 23 countries is 46.8% in men and 48.4% in
clinical practice

estimated each year (∼8% of all cancer deaths), CRC is the women [5].
guidelines

fourth most common cancer-related cause of death in the The risk of developing colon cancer depends on factors
world [1]. which can be classified into lifestyle or behavioural factors
As a general observation, there has been an increasing (such as smoking, high red meat consumption, obesity,
incidence in countries where the overall risk of large bowel physical inactivity) and genetically determinant factors.
cancer was low, while in historically high-risk countries either a According to international guidelines [6, 7], screening tests
stabilisation (Western Europe and Australia) or a decrease are stratified according to the personal risk of disease. Age is
(USA, Canada and New Zealand) in incidence was reported [2]. considered the major unchangeable risk factor for sporadic
A gradient of incidence and mortality between North Western colon cancer: nearly 70% of patients with colon cancer are
and South Eastern Europe has been observed: new CRC cases over 65 years of age, and this disease is rare before 40 years
increased in historically low-risk areas such as Spain and even if data from SEER and Western registries show an
Eastern Europe [3]. This growing incidence reflects increased incidence in the 40–44 years group and a decrease
modifications in lifestyle behaviours and their consequences in the oldest groups [8].
related with ‘westernisation’ such as obesity, physical inactivity, Individuals with:
heavy alcohol consumption, high red meat consumption and
(i) a personal history of adenoma, colon cancer, inflammatory
smoking.
bowel disease (Crohn’s disease and ulcerative colitis),
Mortality has declined progressively in many Western
(ii) significant family history of CRC or polyps,
countries: this can be attributed to cancer screening
(iii) an inherited syndrome (5–10% of all colon cancers) such
programmes, removal of adenomas, early detection of
as familial adenomatous polyposis coli and its variants
cancerous lesions and availability of more effective therapies,
(1%), Lynch-associated syndromes [hereditary non-
chiefly for early stage disease. Mortality rates for CRC in the
polyposis colon cancer (3–5%)], Turcot-, Peutz-Jeghers-
European Union (EU) vary between 15 and 20 of 100 000
and MUTYH-associated polyposis syndromes,
males and between 9 and 14 of 100 000 females and have
decreased in both Western and Northern Countries, are considered at high risk of colon cancer and must be actively
particularly in females. In 10 years (1997–2007), EU mortality screened and, in cases of inherited syndromes, also referred for
genetic counselling [7, 9].
*Correspondence to: ESMO Guidelines Working Group, ESMO Head Office, Via, L. Taddei
4, CH-6962 Viganello-Lugano, Switzerland;
E-mail: clinicalguidelines@esmo.org screening principles
†
The aim of screening is to detect a pre-cancer condition in a
Approved by the ESMO Guidelines Working Group: April 2002, last update July 2013.
This publication supersedes the previously published version—Ann Oncol 2010; 21 healthy population, as well as very early-stage malignancies
(Suppl. 5): v70–v77. which can be treated with a clearly curative intention.

© The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: journals.permissions@oup.com.
Annals of Oncology clinical practice guidelines
For average-risk populations, the European Guidelines for survival [11]. A systematic review and meta-analysis of the
quality assurance in CRC screening and diagnosis [10] provide published literature were carried out to assess the diagnostic
‘guiding principles and evidence-based recommendations on accuracy (sensitivity, specificity, and positive and negative
quality assurance which should be followed when implementing ratios) of alarm features in predicting large bowel cancer,
CRC screening using the various modalities currently adopted in resulting in a pooled prevalence of CRC of 6% (95% CI: 5% to
publically mandated programmes in EU member States’. 8%) in >19 000 cases, and only dark red rectal bleeding and
The recommendations are: abdominal mass had a specificity of >95%, suggesting that the
presence of either characteristic strongly indicates a diagnosis of
Only the faecal occult blood test (FOBT) for men and CRC [12]. Colon cancer can occur as multiple or synchronous
women aged 50–74 (or 70) years has been recommended (2.5%) with identical or different histological patterns and stages
to date. In average-risk populations, the guaiac (g) FOBT of development.
reduced mortality from CRC by ∼15% [I] in different age Patients with synchronous primary tumours have the same

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groups [I, V]. The benefit from annual screening appears to prognosis as patients with single site colon cancers.
be greater than for biennial screening and the test interval Metachronous primary tumours arise in up to 3% during 5
should not exceed 2 years [II, B]. years after surgery, and the incidence increases up to 9% after
Faecal immunochemical testing appears to be superior to several decades in long-term survivors.
gFOBT with respect to the detection rate and positive
predictive value for adenomas and cancer [III]; the test
interval should not exceed 3 years [V]. diagnostic procedures
Flexible sigmoidoscopy (FS) reduces CRC incidence and
Endoscopy is the main procedure for diagnosis and can be
mortality when carried out in an organised screening
carried out by either sigmoidoscopy (as >35% of tumours are
programme [II]; the optimal interval should not be <10
located in the rectosigmoid) or ( preferably) a total colonoscopy.
years and may even be extended to 20 years [IV, C]. The
The advantages of endoscopy are many, e.g. determination of
preferred age range is likely to be between 55 and 64 years
the exact localisation and biopsy of the lesion, detection of
[III, C]. After age 74, average risk FS screening should be
(further) synchronous precancerous or cancerous lesions and
discontinued, given the increasing co-morbidity in this
removal of polyps. Before surgery, if a complete colonoscopy
population [V, D].
cannot be carried out for whatever reason, the rest of the colon
Colonoscopy: limited evidence exists on the efficacy in
should be visualised by combining limited left-sided
reducing CRC incidence and mortality [III]. A note of
colonoscopy with barium enema in order to study the proximal
caution is the observation that colonoscopy screening may
colon. Virtual colonoscopy or CT colonography are not yet
not be as effective in the right colon as in other segments of
standard investigations, but are valuable instruments to identify
the large bowel [IV]. The age range is 50–74 years [V, D]
with precision the location of the tumour or to detect
with the optimal age for a single colonoscopy being around
synchronous lesions or polyps, and they are potentially helpful
55 years [IV, C]. The optimal interval should not be <10
for patients eligible for laparoscopic resection. In any case, if not
years and may even be extended up to 20 years [III, C].
carried out before, a complete colonoscopy should be carried
Combination of FOBT and sigmoidoscopy: there is no
out within 3–6 months after surgery [V, B].
current evidence for extra benefit from adding a once-only
sigmoidoscopy to FOBT screening [II].
New screening technologies are still under evaluation:
pathology
computed tomography (CT) colonography, stool DNA
testing and capsule endoscopy should therefore not be used The standard assessment should include the morphological
for screening in the average-risk population [V, D]. description of the specimen, surgical procedure carried out,
definition of tumour site and size, presence or absence of
macroscopic tumour perforation, histological type and
diagnosis grade, extension of tumour into the bowel wall and
adjacent organs (T stage), distance of cancer from resected
symptoms margins ( proximal, distal and radial), presence or absence
Colon cancer arises from the mucosa of the bowel, generally of tumour deposits, lymphovascular and/or perineural
growing towards the lumen and/or spreading to adjacent invasion, presence of tumour budding, site and number of
organs. Symptoms are associated with relatively large tumours removed regional lymph nodes and their possible
and/or advanced disease stages, and are generally not specific infiltration by cancer cells (N stage), and finally the
for colon cancer. Change in bowel habits, general or localised possible involvement of other organs (e.g. liver) if
abdominal pain, weight loss without other specific causes, submitted for removal or biopsy (M stage) [13].
weakness, iron deficiency and anaemia are the most common The pathological stage must be reported according to the
symptoms, and depends on the location and stage of the American Joint Cancer Committee (AJCC)/ Union for
primary tumour; they are associated with worse prognosis and International Cancer Control (UICC) TNM classification, 7th
their number (but not their duration) is inversely related to edition (Table 1).

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clinical practice guidelines Annals of Oncology

staging and risk assessment Table 1. Continued

staging procedures Stage T N M Dukes MACe

Once a colon cancer is diagnosed, clinical examination, Anatomic stage/prognostic groups
laboratory tests and instrumental screening should be carried 0 Tis N0 M0 – –
out in order to detect or to exclude metastatic disease. Clinical I T1 N0 M0 A A
examination may show visceromegaly (hepatomegaly or T2 N0 M0 A B1
lymphadenopathy), ascites and/or synchronous tumours IIA T3 N0 M0 B B2
(chiefly in women: ovarian, endometrial and breast cancers). IIB T4a N0 M0 B B2
Liver enzymes are generally obtained preoperatively, even if they IIC T4b N0 M0 B B3
can be normal in the presence of metastases. Ultrasonography IIIA T1-T2 N1/N1c M0 C C1
of the liver and the whole abdomen may be useful, but a CT T1 N2a M0 C C1

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scan is usually more appropriate, in order to detect a metastatic IIIB T3-T4a N1/N1c M0 C C2
T2-T3 N2a M0 C C1/C2
spread to the liver or complications related to the tumour
T1-T2 N2b M0 C C1
( perforation, fistula, obstruction…) [V, B]. However, sensitivity
IIIC T4a N2a M0 C C2
of the CT scan in detecting peritoneal implants is relatively poor
T3-T4a N2b M0 C C2
(and influenced by lesion size). Magnetic resonance imaging
T4b N1-N2 M0 C C3
might be useful for locally advanced tumours and could also be IVA Any T Any N M1a – –
the preferred first-line investigation for evaluating liver IVB Any T Any N M1b – –
metastases in patients who have not previously undergone
a
therapy [14]. The clinical benefit of routine chest CT scan is This includes cancer cells confined within the glandular basement
controversial and its use is not generally recommended [III, D]. membrane (intraepithelial) or mucosal lamina propria (intramucosal) with
Similarly, the routine use of positron emission tomography no extension through the muscularis mucosae into the submucosa.
b
(PET) with the glucose analogue 18-fluoro-2-deoxy-D-glucose Direct invasion in T4 includes invasion of other organs or other segments
(FDG-PET) is not recommended at the time of initial diagnosis, of the colorectum as a result of direct extension through the serosa, as
as it does not modify the treatment approach in the vast confirmed on microscopic examination (for example, invasion of the
majority of patients [15]. sigmoid colon by a carcinoma of the caecum) or, for cancers in a
The preoperative evaluation of the serum marker retroperitoneal or subperitoneal location, direct invasion of other organs or
carcinoembryonic antigen (CEA) is useful for postoperative structures by virtue of extension beyond the muscularis propria (that is, a
tumour on the posterior wall of the descending colon invading the left
kidney or lateral abdominal wall; or a mid or distal rectal cancer with
Table 1. The TNM staging system, AJCC/UICC 7th edition
invasion of prostate, seminal vesicles, cervix or vagina).
c
Tumour that is adherent to other organs or structures, grossly, is classified
Primary tumour (T) cT4b. However, if no tumour is present in the adhesion, microscopically, the
TX Primary tumour cannot be assessed classification should be pT1-4a depending on the anatomical depth of wall
T0 No evidence of primary tumour invasion. The V and L classifications should be used to identify the presence
Tis Carcinoma in situ: intraepithelial or invasion of lamina propriaa or absence of vascular or lymphatic invasion, whereas the PN site-specific
T1 Tumour invades submucosa factor should be used for perineural invasion.
T2 Tumour invades muscularis propria d
A satellite peritumoural nodule in the pericolorectal adipose tissue of a
T3 Tumour invades through the muscularis propria into the primary carcinoma without histologic evidence of residual lymph node in
pericolorectal tissues the nodule may represent discontinuous spread, venous invasion with
T4a Tumour penetrates into the surface of the visceral peritoneumb extravascular spread (V1/2) or a totally replaced lymph node (N1/2).
T4b Tumour directly invades or is adherent to other organs or structuresb,c Replaced nodes should be counted separately as positive nodes in the N
Regional lymph nodes (N)d category, whereas discontinuous spread or venous invasion should be
NX Regional lymph nodes cannot be assessed classified and counted in the site-specific factor category Tumour Deposits.
N0 No regional lymph node metastasis e
MAC is the modified Astler–Coller classification.
N1 Metastasis in one to three regional lymph nodes Edge et al. [17]. Used with the permission of the American Joint Committee
N1a Metastasis in one regional lymph node on Cancer (AJCC), Chicago, IL. The original source for this material is the
N1b Metastasis in two to three regional lymph nodes AJCC Cancer Staging Handbook, 7th edition (2010) published by Springer
N1c Tumour satellite deposits in subsierose or in non peritonealised Science and Business Media LLC, www.springer.com.
tissues
N2 Metastases in ≥4 regional lymph nodes (a: 4–6, b: ≥7)
follow-up of CRC patients (or for use in the treatment of
Distant metastases (M)
metastatic disease), while it has a low predictive value for
M0 No distant metastases
diagnosis in asymptomatic patients due to its relatively low
M1 Distant metastases
sensitivity and specificity [16]. The CEA level may have a
M1a Metastases confined to one organ or site (for example liver, lung,
ovary, nonregional node)
prognostic value in the preoperative setting (>5 ng/dl suggests a
M1b Metastases in more than one organ/site or the peritoneum
worse prognosis). An increased preoperative value not
normalised after 1 month following surgical resection may
continued indicate persistent disease.

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Annals of Oncology clinical practice guidelines
Surgical staging includes an assessment of liver metastases, and therefore the use of any predictive marker information for
nodal spread of disease and extension of the tumour through decision making is not indicated [IV, C].
the bowel wall and onto adjacent structures. For adequate pN- Generally, adjuvant treatment is recommended for stage III
staging, at least 12 nodes have to be examined [17]. This is and ‘high-risk’ stage II patients [A]. The first issue is therefore
particularly important for determination of stage II status, as it how to define the risk. The 5-year survival after surgical
has been shown that patient prognosis is much better if at least resection alone is:
14 tumour-free nodes have been presented. It is not entirely
clear, however, if this is a surgical (resecting more nodes) or a (i) stage I: 85%–95%,
pathological (finding more nodes and preventing inaccurate (ii) stage II: 60%–80%,
classification of stage II) issue. Intra-operative ultrasound is a (iii) stage III: 30%–60%.
more accurate assessment for liver metastases: occult liver The wide ranges reflect major differences in prognosis
metastases can be found in 15% of patients; in 5% these are

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depending upon the stage subset, tumour grading and the other
solitary and could easily be resected. biological characteristics discussed below.
Several newer predictors have been recently examined,
including microsatellite instability (MSI)/mismatch repair
risk assessment (MMR), 18q deletion, k-ras mutations, TP53, TGFBR2, DCC
Although local failure rates are very low in colon cancer, and thymidilate synthase gene expression.
systemic recurrence of the disease following surgery is frequent The most promising risk factors at the present time are
and is very often the ultimate cause of death. The prognosis of represented by allelic loss of chromosome 18q (negative for
colon cancer is clearly related to the staging features of the TNM prognosis) and MSI/MMR ( positive for prognosis). In
classification, including the degree of penetration of the tumour particular, MSI/MMR may be useful to identify a small (10%–
through the bowel wall and the presence, or absence, of nodal 15%) subset of stage II patients who are at a very low risk of
involvement. However, many additional parameters such as recurrence and in whom the benefits of chemotherapy are very
grading, lymphatic or venous or perineural invasion, lymphoid unlikely. Beyond this prognostic information, the MSI/MMR
inflammatory response and involvement of resection margins, status is not useful for guidance on treatment decisions,
which are reflected by the Dukes’ and TNM classifications, have reflecting the heterogeneity of data for the potential predictive
been shown to have strong prognostic impact. Furthermore, value [19–22]. In stage III, the role of MSI/MMR status is not
factors such as p53, k-ras and bcl-2 expression, TGF-alpha, clear: conflicting data exist on the potential benefit of treatment
EGFR, proliferation index and aneuploidy are under evaluation with 5-FU alone in the older studies and in the more recent
for their single or combined value under high-risk conditions. analyses [23], whereas no conclusive data are available for
Bowel obstruction and perforation are clinical indicators of a oxaliplatin. Therefore, MSI/MMR does not need to be
poor prognosis. determined if an oxaliplatin combination is planned [IV, D].
Elevated pre-treatment serum levels of CEA and/or The general consensus suggests that patients with stage II are
carbohydrate antigen 19-9 (CA 19-9) have a negative prognostic considered at high risk if they present at least one of the
significance. An age of >70 years at presentation is not a following clinical characteristics: lymph nodes sampling <12;
contraindication to standard therapies; acceptable morbidity poorly differentiated tumour; vascular or lymphatic or
and mortality, as well as long-term survival, are achieved in this perineural invasion; tumour presentation with obstruction or
patient population. Some retrospective studies suggested that tumour perforation and pT4 stage [II].
perioperative blood transfusions could impair the prognosis, but During risk assessment, one must integrate all known
these findings were not confirmed by a large, multi-institutional, tumour-related prognostic factors starting from the stage and
prospective randomised trial which demonstrated no benefit for grade and deriving a rough estimate of the chances of relapse.
autologous blood transfusions when compared with allogeneic For example, a patient with a stage II G3 adenocarcinoma with
transfusions [18]. blood vessel invasion, presence of tumour budding and high
Risk assessment is particularly important in order to decide thymidine labelling index, is likely to have >70% chance of
when to propose an adjuvant treatment to an individual patient. relapse, much higher in comparison to another patient with a
As it is well known, adjuvant therapy is a systemic treatment stage IIIA G1 lesion but with opposite pathological and
administered after primary tumour resection with the aim of biological parameters.
reducing the risk of relapse and death. It is well established that Another important problem is tailoring the decision to each
in colon cancer, adjuvant therapy decreases the risk of death by individual patient’s clinical characteristics. In this context, the
absolute 3%–5% in stage II with single-agent 5-FU and by most debated issue is the impact of age on decision making.
10%–15% in stage III with fluoropyrimidines alone plus a The median age of patients presenting with CRC is 72 years,
further 4%–5% with oxaliplatin-containing combinations [I, A]. whereas the median age of patients in clinical trials is 63 years
Each treatment option, including observation alone, should be and <10% of patients >70 years are accrued in the studies.
thoroughly discussed with the patient, taking into consideration When facing an elderly patient (>age 70) with a resected high-
prognostic aspects of the tumour disease, non-disease-related risk CRC, one must keep in mind that:
characteristics (such as performance status, age, comorbidities, (i) the life expectancy of a 70-year old otherwise healthy
etc.) and the individual’s preferences. individual is ∼8 years for men and 14 years for women; (ii)
Notably, there is no evidence for a predictive marker toxicity of chemotherapy is similar below and above age 70 [II];
regarding the benefit of adjuvant chemotherapy for early CRC, (iii) the efficacy of adjuvant treatments is similar in elderly

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clinical practice guidelines Annals of Oncology

people compared with that in the general population [II]; (iv) supply and distribution of regional lymph nodes. The resection
data from pooled analyses indicate that patients >70 years may should include a segment of colon of at least 5 cm on either side
not benefit significantly from oxaliplation-based combinations of the tumour, although wider margins are often included
in the adjuvant setting. However, they may have a similar because of obligatory ligation of the arterial blood supply [IV, B].
benefit to younger patients from 5-FU-based chemotherapy To clearly define stage II versus III and to identify and
[24]. A subset analysis of the MOSAIC trial also confirms that eradicate potential lymph node metastases, at least 12 lymph
patients over 70 years may not further benefit from the addition nodes must be resected [IV, B].
of oxaliplatin [25]. Laparoscopic approach has now received wide acceptance for
Recently, nomograms have been developed and are also several types of surgical procedures of major abdominal surgery.
available for CRC. These statistics-based tools attempt to Laparoscopic colectomy can be safely carried out for colon
provide all proven prognostic factors and to quantify the risk of cancer, particularly for left-sided cancer [I]. For right-sided
5- and 10-year death as precisely as possible [26]. colonic cancers, the benefit is less obvious since anastomosis

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must be hand sewn, which requires a laparotomy [IV]. The
long-term oncological results of laparoscopic colectomy are
management of local/locoregional similar to those of the conventional approach [27] [I].
disease Advantages of laparoscopy over the conventional approach are
treatment of malignant polyps reduced pain, reduced length of hospital stay and reduced
duration of ileus [28] [II]. It is recognised that a laparoscopic
Complete endoscopic polypectomy should be carried out approach should only be carried out if the following criteria are
whenever the morphological structure of the polyp permits. The met:
presence of invasive carcinoma in a polyp requires a thorough
review with the pathologist for histological features that are (i) technically experienced surgeons,
associated with an adverse outcome. Making the decision to (ii) lack of serious abdominal adhesion due to prior major
undergo surgical resection for a neoplastic polyp that contains abdominal surgery,
invasive carcinoma involves the uncertainties of predicting and (iii) no locally advanced disease and/or acute bowel obstruction
balancing adverse disease outcome against operative risk. or perforation.
Unfavourable histological findings include lymphatic or venous
invasion, grade 3 differentiation, level 4 invasion (invades the Obstructive colorectal cancers can be treated in one or two
submucosa of the bowel wall below the polyp) or involved stages. Two-stage procedures can include colostomy followed by
margins of excision. Although level 4 invasion and involved colonic resection, or Hartmann’s procedure followed by
margins of excision are two of the most important prognostic colostomy closure and anastomosis. An alternative is a one-
factors, their absence does not necessarily preclude an adverse stage procedure with either subtotal colectomy and ileorectal
outcome. Several staging systems to stratify the aggressiveness of anastomosis or, in selected cases, segmental resection after
polyps have been proposed such as involvement of submucosae intraoperative colonic lavage [III]. Endoscopic stenting can be
(sm1, sm2, sm3: involves the superficial, middle and deep thirds used to relieve obstruction from rectosigmoid cancer and
of the submucosa, respectively), invasion into the stalk, absolute allow subsequent one-step resection. Obstructive right-sided
thickness of the invasive tumour beyond the muscolaris cancers can be treated by colonic resection and immediate
mucosae. When unfavourable histological features are present in anastomosis [IV].
a polyp from a patient with an average operative risk, resection
is recommended [IV, B]. The pedunculated polyp with invasive treatment by stage
carcinoma confined to the head, with no other unfavourable Stage 0 (Tis N0 M0)
factors, has a minimal risk for an adverse outcome. The Treatment options are:
consensus is that endoscopic polypectomy is adequate treatment
with proper follow-up examination [IV, B]. Invasion of the stalk (i) Local excision or simple polypectomy.
but with clear margins of excision and favourable histological (ii) Segmentary en-bloc resection for larger lesions not amenable
features may be treated with endoscopic polypectomy with a to local excision.
similar risk as level 2 invasion (invades the muscularis mucosa Stage I (T1-2 N0 M0)
but is limited to the head and neck of the stalk). Pedunculated
polypoid carcinomas can be treated using the same criteria as (old staging: Dukes’ A or modified Astler–Coller A and B1).
other pedunculated polyps with invasive carcinoma. Invasive Wide surgical resection and anastomosis. No adjuvant
carcinoma in a sessile polyp should usually be interpreted as chemotherapy.
having level 4 invasion. Consequently, standard surgical Stage II A, B, C (T3 N0 M0, T4 a-b N0 M0)
resection is recommended in patients with average operative Standard treatment options:
risk [IV, B]. (i) Wide surgical resection and anastomosis.
(ii) Following surgery, adjuvant therapy should not be routinely
localised disease recommended for unselected patients. In high-risk patients
The goal of surgery is a wide resection of the involved segment who present at least one of the previously mentioned
of bowel together with the removal of its lymphatic drainage. clinical high-risk features (see above), adjuvant therapy
The extent of the colonic resection is determined by the blood could be considered in clinical practice [II, B].

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Annals of Oncology clinical practice guidelines
Stage III (any T, N1-N2, M0) event-free survival for IFL, when compared with FL. The
PETACC-3 trial [35] compared LV5FU2 or AIO regimen plus
(i) Wide surgical resection and anastomosis. irinotecan with LV5FU2 or AIO regimen alone. Results did not
(ii) Following surgery, the standard treatment is a doublet show any significant advantage for the regimen with irinotecan
schedule with oxaliplatin and a fluoropyrimidine. Although in terms of DFS.
all three combination regimens are superior to 5-FU/FA There is currently no role for targeted agents associated with
alone [I, A], FOLFOX4 or XELOX should be preferred to chemotherapy in the adjuvant setting for colon cancer. All trials
FLOX. When oxaliplatin is contraindicated, monotherapy evaluating bevacizumab, NSABP C-08 [36], AVANT [37] or
with infusional or oral fluoropyrimidines should be cetuximab, NCCTG NO147 [38] and PETACC-8 [39] are
preferred to bolus 5-FU FU/LV. negative, probably due to different biological characteristics in
early when compared with advanced disease.
In the adjuvant setting many questions are still unanswered:

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treatment options
The benefit of combinations with oxaliplatin has been (i) The optimal duration of adjuvant treatment: 3 or 6
demonstrated in three landmark trials. In the MOSAIC study months? In Italy, the TOSCA trial investigates whether 3
[29], the addition of oxaliplatin to 5-FU/LV (FOLFOX schema), months of FOLFOX4 or XELOX treatment are not inferior
demonstrated a significantly increased disease-free survival to 6 months with the same schedule in terms of
(DFS) at 3 years, with a reduction in the risk of recurrence of recurrence-free survival (RFS) in stage II and III colon
23% compared with the control arm (LV5FU2).The update at cancer patients. Together with other studies (SCOT,
the 6-year follow-up confirmed the benefit in DFS of adjuvant France, US, Greece, Japan…), this trial forms the backbone
treatment with FOLFOX4, and an advantage was also observed of a large international collaboration (‘IDEA’) which will
in overall survival (OS), but for stage III patients only [30]. give a definitive answer regarding the duration of adjuvant
The NSABP C-07 trial compared the efficacy of bolus FU/ therapy in stage III patients.
LV + oxaliplatin (FLOX) versus FU/LV alone (Roswell Park (ii) The validation of prognostic/predictive factors: interesting
schedule); 3-year DFS was 76.5% versus 71.6% for FLOX and and potentially positive data are expected from large subset
FULV, respectively [31], and the magnitude of reduction in the analyses from large trials, such as PETACC-3, AVANT and
risk of recurrence was similar to that of the MOSAIC trial. The PETACC-8.
spectrum of toxicity between MOSAIC and NSABP-C07 was (iii) The possible role of aspirin in this setting: from a large
different: grade 3–4 diarrhoea occurred more often with FLOX study [40], it appears that the regular use of this drug after
than with FOLFOX, while grade 3 sensory neuropathy was diagnosis of CRC leads to an increase in cancer-specific
observed in 12% with FOLFOX and 8% with FLOX. FLOX survival and OS but only in patients with mutated PIK3CA
should probably not be used in clinical practice, due to its cancer. Further studies on this topic are needed to confirm
toxicity and also due to a lack of OS benefit. The XELOXA these exciting findings.
international phase III study [32] assessed the safety and efficacy
of adjuvant capecitabine plus oxaliplatin (XELOX) versus bolus personalised medicine
FU/LV (Mayo Clinic or Roswell Park regimen) in stage III In this disease setting, more research is needed to identify
patients: the arm including the oral compound was well molecular markers which could lead to advances in
tolerated and superior to the i.v fluoropyrimidine. As personalised medicine.
capecitabine does not require a central venous access, it may be
preferred in many patients [IV, B]. follow-up and long-term implications
In case a clinically relevant neurotoxicity occurs, oxaliplatin
should be stopped and fluoropyrimidine continued, as it follow-up
contributes to about two-third to the therapeutic effect of Despite optimal primary treatment, with adequate surgery with
adjuvant FOLFOX/XELOX. or without adjuvant chemotherapy, 30%–50% of patients with
As stated before, in special situations monotherapy with colon cancer will relapse, and most of those patients will die
capecitabine or 5-FU/LV in infusion can be an alternative from their disease.
approach. The X-ACT trial showed that capecitabine is an Detecting relapse in advance is the main goal of surveillance
active agent with a favourable toxicity profile and may reduce after primary treatment, but this is clinically meaningful only if
overall costs compared with i.v. treatments [I]: after 4.3 years it improves survival. Furthermore, follow-up can be expensive
of follow-up, the data still confirm the equivalence in terms of and resource-consuming in terms of both money and
DFS between capecitabine and 5-FU/LV [33] in stage procedures for a national health system, so intensive
III patients. surveillance needs to be justified with a good level of evidence.
Negative trials are related to irinotecan in combination with In the past, there was no strong evidence that regular follow-up
5-FU (bolus or infusional). The CALGB-89803 trial [34] could improve the outcome for patients radically resected for
compared 5-FU/LV + irinotecan (IFL) with the Roswell Park colon cancer. Several trials failed to demonstrate a benefit, and
scheme in more than 1200 patients. The trial was prematurely results of old meta-analyses were unfortunately based on
closed because of an elevated rate of mortality in the IFL group nonrandomised data or mix of randomised and cohort studies.
with respect to the FL regimen (2.2% versus 0.8%). Efficacy In the last 10 years, four further systematic reviews [41–44]
results indicated no improvement in terms of either OS or have been published. All of these studies demonstrated improved

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clinical practice guidelines Annals of Oncology

survival in patients undergoing more intensive surveillance when detection of intraluminal recurrent cancer, and therefore there
compared with those with minimal or no follow-up. The is no indication of intensive endoscopic follow-up. If a colon
estimated OS gain was between 7% and 13%. On the basis of without tumour or polyps is observed 1 year after resection,
these data, intensive follow-up should now be considered colonoscopy should be carried out after 3–5 years. In this field,
standard practice for colon cancer patients [I, A] [45]. specific recommendations are based mainly on level II and III
The improvement in OS has been attributed to earlier evidence, particularly concerning timing intervals and duration
detection of recurrent disease and in particular, to a higher rate of follow-up [48].
of detection of isolated locoregional relapses. The same rate of A recently reported analysis of individual patient data from
recurrence for intensive and minimal follow-up was reported large adjuvant colon cancer randomised trials including >20 000
[46], but with an anticipation of 8.5 months in the intensive patients indicated that 82% of stage III and 74% of stage II colon
group. Detection of isolated local recurrences was increased in cancer recurrences are diagnosed within the first 3 years after
the intensive group (15% compared with 9%, with RR 1.61 and primary cancer resection [49].

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P = 0.011), and also a small non-significant increase in the Suggested recommendations are as follows [50]:
detection of hepatic metastases was reported. Absolute
reduction in mortality was 9%–13%, comparable with the (i) Intensive follow-up must be carried out in colon cancer
benefit observed with adjuvant chemotherapy in stage III. In patients [I, A].
addition, trials included in this analysis were conducted before (ii) History and physical examination and CEA determination
the modern multidisciplinary approach to metastatic disease, are advised every 3–6 months for 3 years and every 6–12
and therefore, the real benefit in clinical practice at the present months at years 4 and 5 after surgery [II, B].
time could be even more evident. (iii) Colonoscopy must be carried out at year 1 and every 3–5
Despite these results, recent data still showed low adherence years thereafter, looking for metachronous adenomas and
to follow-up recommendations. This could be due to difficulties cancers [III, B].
in determining which is the best surveillance test. (iv) CT scan of chest and abdomen every 6–12 months for the
Indeed, although pooled data suggest a survival advantage first 3 years can be considered in patients who are at higher
related to intensive follow-up, the heterogeneity of the studies risk of recurrence [II, B].
included in these meta-analyses does not allow assessment of (v) CEUS could substitute for abdominal CT scan [III, C].
which kind of surveillance must be applied in clinical practice. It (vi) Other laboratory and radiological examinations are of
seems clear that more investigations are better than fewer, which unproven benefit and must be restricted to patients with
in turn are better than no follow-up at all, but it is nearly suspicious symptoms.
impossible to recommend an optimal strategy with an adequate
level of evidence. As a matter of fact, ‘intensive’ procedures in
one trial can be similar to ‘minimal’ procedures in another trial, long-term implications: survivorship care plans
and surveillance intervals and duration of follow-up cannot be Follow-up is therefore standard practice after completing
extrapolated by meta-analyses data. Only trials including CEA cancer treatment. It consists of periodic visits and investigations,
testing and/or liver imaging achieve significant improvements in which usually take place in a specialist cancer setting sometimes
survival, but all studies considering liver imaging also included for prolonged periods after the treatment ends. However, there
blood CEA monitoring; CEA testing alone does not show has been growing awareness in recent years that optimal
benefit in individual studies and has demonstrated a reduction cancer survivorship care involves more than surveillance tests.
in mortality only in meta-analyses [47]. Despite this, CEA rise is In this setting, the primary practitioner should have a significant
often the first signal of recurrence: a positive value could be role [51].
detected 1.5–6 months before clinical/instrumental detection Survivors of CRC now represent the third largest group of
with other test(s). There are false-positive rates of CEA long-term cancer survivors in Western countries, ∼11% of the
elevation of 7%–16% and false-negative rates of up to 40%. CEA population.
test monitoring is also effective in patients without elevation in Survivorship care plans are an increasing priority within the
the preoperative setting: in these patients, a subsequent cancer system, and supporting colon cancer patients and their
elevation was observed in 44% of recurrent patients. There is no providers in staying on track with recommended follow-up is
evidence that other laboratory tests can be useful. only part of helping patients to regain their health and stay well
As far as liver imaging is concerned, a CT scan has been after treatment.
shown to be more sensitive than ultrasonography (0.67 Data from the Tjandra surveillance meta-analysis [44]
compared with 0.43), but a modern contrast enhancement reported benefit in the intensive arm, but this benefit was less
ultrasound scan (CEUS) can substantially increase the significant. In fact, in this systematic revision it was observed
sensitivity of ultrasonography. Chest recurrence could be that, despite benefit in OS and in re-resection rate, the cancer-
detected by the CT scan: in colon cancer, lung is the first site of related mortality was not improved and the survival benefit was
relapse in 20% of patients and pulmonary resection could not due to early detection and treatment of recurrent disease.
determine a 30% 5-year survival. In contrast, there are no data Other factors contributing to a survival advantage of
in favour of regular use of chest X-rays. surveillance in these patients might include the management of
Metachronous primary cancer could be detected with an co-morbidities, promotion of beneficial dietary and lifestyle
incidence of 0.7% within the first 2 years after curative surgery, factors and increased psychosocial support.
but there is no evidence favouring a survival benefit through the Major elements in survivorship care are as follows [52]:

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Annals of Oncology clinical practice guidelines
(i) Prevention of recurrent and new cancer (classic end-point issues are equal in importance in the care of index cancer. This
of follow-up), simple consideration is often not applied in clinical practice. A
(ii) Intervention for cancer sequelae and their treatment recent analysis [54] showed that survivors were overall less likely
(rehabilitation), to receive recommended follow-up for chronic conditions, such
(iii) Assessment of medical and psychological late effects as angina, congestive heart failure and chronic lung disease, and
(modern end-point of follow-up), to receive less of some types of preventive care compared with
(iv) Health promotion (lifestyle promotion, co-morbidity matched controls. For example, diabetic cancer survivors were
prevention, etc.). less likely to have preventive eye examinations, and the data
showed a trend toward less intensive monitoring of HbA1c.
Most long-term survivors of CRC report very good quality of Even though at the present time, this issue can be considered
life following their treatment, but several problems are still still experimental, the development of Survivorship Care Plans
observed. Some patients can have bowel dysfunction: diarrhoea, will certainly be one of the major topics in the near future for

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constipation, bowel obstruction, pain. Hemicolectomy can lead gastro intestinal medical oncologists.
to loose stools but this usually improves over time and surgery
can also lead to adhesions. It is important to carry out dietary
counselling and suggest use of over-the-counter medications note
(e.g., fibre laxative, stool softeners, antidiarrhoeals). Survivors Levels of evidence and grades of recommendation have been
who received oxaliplatin can experience numbness or painful applied using the system shown in Table 2. Statements without
sensations [53]. grading were considered justified standard clinical practice by
More than 76% of colon cancer survivorships are >65 years of the experts and the ESMO faculty.
age, so long-term employment is not a problem for a majority,
but in young people employment and financial concerns should
be an important issue to consider. conflict of interest
Despite colon cancer survivors often staying well, higher rates Prof. Labianca has reported research grants from Roche and
of psychological depression have been reported. Assessment of Sanofi. Prof. Arnold has reported research grants from Roche
distress should be considered but evidence on the effectiveness and Sanofi. The other authors have reported no potential
of psychosocial interventions among survivors of CRC is conflicts of interest.
limited.
The majority of colon cancer survivors die of other causes.
Consequently, care for general medical and preventive health references
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