Early colon cancer: ESMO Clinical Practice Guidelines [631086]

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 *
1Ospedale 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
incidence and epidemiology
Colorectal cancer (CRC) is the third most common tumour in
m e na n dt h es e c o n di nw o m e n ,a c c o u n t i n gf o r1 0 %o fa l ltumour types worldwide. Incidence is higher in males (ratio:1.4) and for both genders there is a 10-fold difference inincidence between several regions. With 608 000 deathsestimated each year ( ∼8% of all cancer deaths), CRC is the
fourth most common cancer-related cause of death in the
world [ 1].
As a general observation, there has been an increasing
incidence in countries where the overall risk of large bowelcancer was low, while in historically high-risk countries either astabilisation (Western Europe and Australia) or a decrease(USA, Canada and New Zealand) in incidence was reported [ 2].
A gradient of incidence and mortality between North Western
and South Eastern Europe has been observed: new CRC casesincreased in historically low-risk areas such as Spain andEastern Europe [ 3]. This growing incidence re flects
modi fications in lifestyle behaviours and their consequences
related with ‘westernisation ’such as obesity, physical inactivity,
heavy alcohol consumption, high red meat consumption and
smoking.
Mortality has declined progressively in many Western
countries: this can be attributed to cancer screeningprogrammes, removal of adenomas, early detection ofcancerous lesions and availability of more effective therapies,chiefly for early stage disease. Mortality rates for CRC in the
European Union (EU) vary between 15 and 20 of 100 000
males and between 9 and 14 of 100 000 females and havedecreased in both Western and Northern Countries,particularly in females. In 10 years (1997 –2007), EU mortalitydeclined by 6% per quinquennium in men and 8% per
quinquennium in women. The analysis updated to 2007showed a greater reduction of the mortality rate in the youngpopulation (aged 30 –49 years) with ∼10% per quinquennium
[4]. In Europe, the 5-year survival for colon cancer in different
geographical settings ranged from 28.5% to 57% in men and
from 30.9% to 60% in women: the pooled estimation for 51registries of 23 countries is 46.8% in men and 48.4% inwomen [ 5].
The risk of developing colon cancer depends on factors
which can be classi fied into lifestyle or behavioural factors
(such as smoking, high red meat consumption, obesity,
physical inactivity) and genetically determinant factors.
According to international guidelines [ 6,7], screening tests
are strati fied according to the personal risk of disease. Age is
considered the major unchangeable risk factor for sporadiccolon cancer: nearly 70% of patients with colon cancer areover 65 years of age, and this disease is rare before 40 years
even if data from SEER and Western registries show an
increased incidence in the 40 –44 years group and a decrease
in the oldest groups [ 8].
Individuals with:
(i) a personal history of adenoma, colon cancer, in flammatory
bowel disease (Crohn ’s disease and ulcerative colitis),
(ii) signi ficant family history of CRC or polyps,
(iii) an inherited syndrome (5 –10% of all colon cancers) such
as familial adenomatous polyposis coli and its variants
(1%), Lynch-associated syndromes [hereditary non-
polyposis colon cancer (3 –5%)], Turcot-, Peutz-Jeghers-
and MUTYH-associated polyposis syndromes,
are considered at high risk of colon cancer and must be actively
screened and, in cases of inherited syndromes, also referred for
genetic counselling [ 7,9].
screening principles
The aim of screening is to detect a pre-cancer condition in a
healthy population, as well as very early-stage malignancieswhich can be treated with a clearly curative intention.†Approved by the ESMO Guidelines Working Group: April 2002, last update July 2013.
This publication supersedes the previously published version —Ann Oncol 2010; 21
(Suppl. 5): v70 –v77.*Correspondence to: ESMO Guidelines Working Group, ESMO Head Of fice, Via, L. Taddei
4, CH-6962 Viganello-Lugano, Switzerland;
E-mail: clinicalguidelines@esmo.orgclinical practice
guidelinesclinical practice guidelinesAnnals of Oncology 24 (Supplement 6): vi64 –vi72, 2013
doi:10.1093/annonc/mdt354
© The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
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For average-risk populations, the European Guidelines for
quality assurance in CRC screening and diagnosis [ 10] provide
‘guiding principles and evidence-based recommendations on
quality assurance which should be followed when implementing
CRC screening using the various modalities currently adopted in
publically mandated programmes in EU member States ’.
The recommendations are:
Only the faecal occult blood test (FOBT) for men and
women aged 50 –74 (or 70) years has been recommended
to date. In average-risk populations, the guaiac (g) FOBTreduced mortality from CRC by ∼15% [I] in different age
groups [I, V]. The bene fit from annual screening appears to
be greater than for biennial screening and the test intervalshould not exceed 2 years [II, B].
Faecal immunochemical testing appears to be superior to
gFOBT with respect to the detection rate and positivepredictive value for adenomas and cancer [III]; the testinterval should not exceed 3 years [V].Flexible sigmoidoscopy (FS) reduces CRC incidence andmortality when carried out in an organised screening
programme [II]; the optimal interval should not be <10
years and may even be extended to 20 years [IV, C]. Thepreferred age range is likely to be between 55 and 64 years[III, C]. After age 74, average risk FS screening should bediscontinued, given the increasing co-morbidity in thispopulation [V, D].Colonoscopy: limited evidence exists on the ef ficacy in
reducing CRC incidence and mortality [III]. A note of
caution is the observation that colonoscopy screening maynot be as effective in the right colon as in other segments ofthe large bowel [IV]. The age range is 50 –74 years [V, D]
with the optimal age for a single colonoscopy being around55 years [IV, C]. The optimal interval should not be <10
years and may even be extended up to 20 years [III, C].
Combination of FOBT and sigmoidoscopy: there is nocurrent evidence for extra bene fit from adding a once-only
sigmoidoscopy to FOBT screening [II].New screening technologies are still under evaluation:computed tomography (CT) colonography, stool DNAtesting and capsule endoscopy should therefore not be used
for screening in the average-risk population [V, D].
diagnosis
symptoms
Colon cancer arises from the mucosa of the bowel, generally
growing towards the lumen and/or spreading to adjacentorgans. Symptoms are associated with relatively large tumoursand/or advanced disease stages, and are generally not speci fic
for colon cancer. Change in bowel habits, general or localisedabdominal pain, weight loss without other speci fic causes,
weakness, iron de ficiency and anaemia are the most common
symptoms, and depends on the location and stage of theprimary tumour; they are associated with worse prognosis andtheir number (but not their duration) is inversely related tosurvival [ 11]. A systematic review and meta-analysis of the
published literature were carried out to assess the diagnosticaccuracy (sensitivity, speci ficity, and positive and negative
ratios) of alarm features in predicting large bowel cancer,
resulting in a pooled prevalence of CRC of 6% (95% CI: 5% to
8%) in >19 000 cases, and only dark red rectal bleeding andabdominal mass had a speci ficity of >95%, suggesting that the
presence of either characteristic strongly indicates a diagnosis ofCRC [ 12]. Colon cancer can occur as multiple or synchronous
(2.5%) with identical or different histological patterns and stagesof development.
Patients with synchronous primary tumours have the same
prognosis as patients with single site colon cancers.Metachronous primary tumours arise in up to 3% during 5years after surgery, and the incidence increases up to 9% afterseveral decades in long-term survivors.
diagnostic procedures
Endoscopy is the main procedure for diagnosis and can becarried out by either sigmoidoscopy (as >35% of tumours arelocated in the rectosigmoid) or (preferably) a total colonoscopy.
The advantages of endoscopy are many, e.g. determination of
the exact localisation and biopsy of the lesion, detection of(further) synchronous precancerous or cancerous lesions andremoval of polyps. Before surgery, if a complete colonoscopycannot be carried out for whatever reason, the rest of the colonshould be visualised by combining limited left-sided
colonoscopy with barium enema in order to study the proximal
colon. Virtual colonoscopy or CT colonography are not yetstandard investigations, but are valuable instruments to identifywith precision the location of the tumour or to detectsynchronous lesions or polyps, and they are potentially helpfulfor patients eligible for laparoscopic resection. In any case, if notcarried out before, a complete colonoscopy should be carried
out within 3 –6 months after surgery [V, B].
pathology
The standard assessment shoul d include the morphological
description of the specimen, s urgical procedure carried out,
definition of tumour site and size, presence or absence of
macroscopic tumour perforation, histological type andgrade, extension of tumour into the bowel wall andadjacent organs (T stage), distance of cancer from resectedmargins (proximal, distal and radial), presence or absence
of tumour deposits, lymphovascular and/or perineural
invasion, presence of tumour budding, site and number ofremoved regional lymph nodes and their possibleinfiltration by cancer cells (N stage), and finally the
possible involvement of other organs (e.g. liver) ifsubmitted for removal or biopsy (M stage) [ 13].
The pathological stage must be reported according to the
American Joint Cancer Committee (AJCC)/ Union forInternational Cancer Control (UICC) TNM classi fication, 7th
edition (Table 1).Annals of Oncology clinical practice guidelines
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staging and risk assessment
staging procedures
Once a colon cancer is diagnosed, clinical examination,
laboratory tests and instrumental screening should be carriedout in order to detect or to exclude metastatic disease. Clinicalexamination may show visceromegaly (hepatomegaly or
lymphadenopathy), ascites and/or synchronous tumours
(chiefly in women: ovarian, endometrial and breast cancers).
Liver enzymes are generally obtained preoperatively, even if theycan be normal in the presence of metastases. Ultrasonographyof the liver and the whole abdomen may be useful, but a CTscan is usually more appropriate, in order to detect a metastatic
spread to the liver or complications related to the tumour
(perforation, fistula, obstruction …) [V, B]. However, sensitivity
of the CT scan in detecting peritoneal implants is relatively poor(and in fluenced by lesion size). Magnetic resonance imaging
might be useful for locally advanced tumours and could also bethe preferred first-line investigation for evaluating liver
metastases in patients who have not previously undergone
therapy [ 14]. The clinical bene fit of routine chest CT scan is
controversial and its use is not generally recommended [III, D].Similarly, the routine use of positron emission tomography(PET) with the glucose analogue 18- fluoro-2-deoxy-
D-glucose
(FDG-PET) is not recommended at the time of initial diagnosis,as it does not modify the treatment approach in the vast
majority of patients [ 15].
The preoperative evaluation of the serum marker
carcinoembryonic antigen (CEA) is useful for postoperative
follow-up of CRC patients (or for use in the treatment of
metastatic disease), while it has a low predictive value fordiagnosis in asymptomatic patients due to its relatively lowsensitivity and speci ficity [ 16]. The CEA level may have a
prognostic value in the preoperative setting (>5 ng/dl suggests a
worse prognosis). An increased preoperative value not
normalised after 1 month following surgical resection mayindicate persistent disease.Table 1. Continued
Stage T N M Dukes MACe
Anatomic stage/prognostic groups
0 Tis N0 M0 ––
IT 1 N 0 M 0 AA
T2 N0 M0 A B1
IIA T3 N0 M0 B B2IIB T4a N0 M0 B B2IIC T4b N0 M0 B B3IIIA T1-T2 N1/N1c M0 C C1
T1 N2a M0 C C1
IIIB T3-T4a N1/N1c M0 C C2
T2-T3 N2a M0 C C1/C2T1-T2 N2b M0 C C1
IIIC T4a N2a M0 C C2
T3-T4a N2b M0 C C2T4b N1-N2 M0 C C3
IVA Any T Any N M1a ––
IVB Any T Any N M1b ––
aThis includes cancer cells con fined within the glandular basement
membrane (intraepithelial) or mucosal lamina propria (intramucosal) withno extension through the muscularis mucosae into the submucosa.
bDirect invasion in T4 includes invasion of other organs or other segments
of the colorectum as a result of direct extension through the serosa, asconfirmed on microscopic examination (for example, invasion of the
sigmoid colon by a carcinoma of the caecum) or, for cancers in aretroperitoneal or subperitoneal location, direct invasion of other organs orstructures 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 withinvasion of prostate, seminal vesicles, cervix or vagina).
cTumour that is adherent to other organs or structures, grossly, is classi fied
cT4b. However, if no tumour is present in the adhesion, microscopically, theclassi fication should be pT1-4a depending on the anatomical depth of wall
invasion. The V and L classi fications should be used to identify the presence
or absence of vascular or lymphatic invasion, whereas the PN site-speci fic
factor should be used for perineural invasion.
dA satellite peritumoural nodule in the pericolorectal adipose tissue of a
primary carcinoma without histologic evidence of residual lymph node inthe nodule may represent discontinuous spread, venous invasion withextravascular spread (V1/2) or a totally replaced lymph node (N1/2).Replaced nodes should be counted separately as positive nodes in the Ncategory, whereas discontinuous spread or venous invasion should beclassi fied and counted in the site-speci fic factor category Tumour Deposits.
eMAC is the modi fied Astler –Coller classi fication.
Edge et al. [ 17]. Used with the permission of the American Joint Committee
on Cancer (AJCC), Chicago, IL. The original source for this material is theAJCC Cancer Staging Handbook, 7th edition (2010) published by SpringerScience and Business Media LLC, www.springer.com .Table 1. The TNM staging system, AJCC/UICC 7th edition
Primary tumour (T)
TX Primary tumour cannot be assessedT0 No evidence of primary tumourTis Carcinoma in situ : intraepithelial or invasion of lamina propria
a
T1 Tumour invades submucosa
T2 Tumour invades muscularis propriaT3 Tumour invades through the muscularis propria into the
pericolorectal tissues
T4a Tumour penetrates into the surface of the visceral peritoneum
b
T4b Tumour directly invades or is adherent to other organs or structuresb,c
Regional lymph nodes (N)d
NX Regional lymph nodes cannot be assessedN0 No regional lymph node metastasisN1 Metastasis in one to three regional lymph nodesN1a Metastasis in one regional lymph nodeN1b Metastasis in two to three regional lymph nodesN1c Tumour satellite deposits in subsierose or in non peritonealised
tissues
N2 Metastases in ≥4 regional lymph nodes (a: 4 –6, b:≥7)
Distant metastases (M)M0 No distant metastasesM1 Distant metastasesM1a Metastases con fined to one organ or site (for example liver, lung,
ovary, nonregional node)
M1b Metastases in more than one organ/site or the peritoneum
continuedclinical practice guidelinesAnnals of Oncology
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Surgical staging includes an assessment of liver metastases,
nodal spread of disease and extension of the tumour throughthe bowel wall and onto adjacent structures. For adequate pN-staging, at least 12 nodes have to be examined [ 17]. This is
particularly important for determination of stage II status, as it
has been shown that patient prognosis is much better if at least14 tumour-free nodes have been presented. It is not entirelyclear, however, if this is a surgical (resecting more nodes) or apathological ( finding more nodes and preventing inaccurate
classi fication of stage II) issue. Intra-operative ultrasound is a
more accurate assessment for liver metastases: occult liver
metastases can be found in 15% of patients; in 5% these are
solitary and could easily be resected.
risk assessment
Although local failure rates are very low in colon cancer,
systemic recurrence of the disease following surgery is frequent
and is very often the ultimate cause of death. The prognosis ofcolon cancer is clearly related to the staging features of the TNMclassi fication, including the degree of penetration of the tumour
through the bowel wall and the presence, or absence, of nodalinvolvement. However, many additional parameters such as
grading, lymphatic or venous or perineural invasion, lymphoid
inflammatory response and involvement of resection margins,
which are re flected by the Dukes ’and TNM classi fications, have
been shown to have strong prognostic impact. Furthermore,factors such as p53, k-ras and bcl-2 expression, TGF-alpha,EGFR, proliferation index and aneuploidy are under evaluationfor their single or combined value under high-risk conditions.
Bowel obstruction and perforation are clinical indicators of a
poor prognosis.
Elevated pre-treatment serum levels of CEA and/or
carbohydrate antigen 19-9 (CA 19-9) have a negative prognosticsignificance. An age of >70 years at presentation is not a
contraindication to standard therapies; acceptable morbidity
and mortality, as well as long-term survival, are achieved in this
patient population. Some retrospective studies suggested thatperioperative blood transfusions could impair the prognosis, butthese findings were not con firmed by a large, multi-institutional,
prospective randomised trial which demonstrated no bene fit for
autologous blood transfusions when compared with allogeneictransfusions [ 18].
Risk assessment is particularly important in order to decide
when to propose an adjuvant treatment to an individual patient.As it is well known, adjuvant therapy is a systemic treatmentadministered after primary tumour resection with the aim ofreducing the risk of relapse and death. It is well established thatin colon cancer, adjuvant therapy decreases the risk of death by
absolute 3% –5% in stage II with single-agent 5-FU and by
10%–15% in stage III with fluoropyrimidines alone plus a
further 4% –5% with oxaliplatin-containing combinations [I, A].
Each treatment option, including observation alone, should bethoroughly discussed with the patient, taking into considerationprognostic aspects of the tumour disease, non-disease-related
characteristics (such as performance status, age, comorbidities,
etc.) and the individual ’s preferences.
Notably, there is no evidence for a predictive marker
regarding the bene fit of adjuvant chemotherapy for early CRC,and therefore the use of any predictive marker information for
decision making is not indicated [IV, C].
Generally, adjuvant treatment is recommended for stage III
and‘high-risk ’stage II patients [A]. The first issue is therefore
how to de fine the risk. The 5-year survival after surgical
resection alone is:
(i) stage I: 85% –95%,
(ii) stage II: 60% –80%,
(iii) stage III: 30% –60%.
The wide ranges re flect major differences in prognosis
depending upon the stage subset, tumour grading and the other
biological characteristics discussed below.
Several newer predictors have been recently examined,
including microsatellite instability (MSI)/mismatch repair(MMR), 18q deletion, k-ras mutations, TP53, TGFBR2, DCCand thymidilate synthase gene expression.
The most promising risk factors at the present time are
represented by allelic loss of chromosome 18q (negative for
prognosis) and MSI/MMR (positive for prognosis). Inparticular, MSI/MMR may be useful to identify a small (10% –
15%) subset of stage II patients who are at a very low risk ofrecurrence and in whom the bene fits of chemotherapy are very
unlikely. Beyond this prognostic information, the MSI/MMR
status is not useful for guidance on treatment decisions,
reflecting the heterogeneity of data for the potential predictive
value [ 19–22]. In stage III, the role of MSI/MMR status is not
clear: con flicting data exist on the potential bene fit of treatment
with 5-FU alone in the older studies and in the more recentanalyses [ 23], whereas no conclusive data are available for
oxaliplatin. Therefore, MSI/MMR does not need to be
determined if an oxaliplatin combination is planned [IV, D].
The general consensus suggests that patients with stage II are
considered at high risk if they present at least one of thefollowing clinical characteristics: lymph nodes sampling <12;poorly differentiated tumour; vascular or lymphatic orperineural invasion; tumour presentation with obstruction or
tumour perforation and pT4 stage [II].
During risk assessment, one must integrate all known
tumour-related prognostic factors starting from the stage andgrade and deriving a rough estimate of the chances of relapse.For example, a patient with a stage II G3 adenocarcinoma withblood vessel invasion, presence of tumour budding and highthymidine labelling index, is likely to have >70% chance of
relapse, much higher in comparison to another patient with a
stage IIIA G1 lesion but with opposite pathological andbiological parameters.
Another important problem is tailoring the decision to each
individual patient ’s clinical characteristics. In this context, the
most debated issue is the impact of age on decision making.
The median age of patients presenting with CRC is 72 years,
whereas the median age of patients in clinical trials is 63 yearsand <10% of patients >70 years are accrued in the studies.When facing an elderly patient (>age 70) with a resected high-risk CRC, one must keep in mind that:
(i) the life expectancy of a 70-year old otherwise healthy
individual is ∼8 years for men and 14 years for women; (ii)
toxicity of chemotherapy is similar below and above age 70 [II];(iii) the ef ficacy of adjuvant treatments is similar in elderlyAnnals of Oncology clinical practice guidelines
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people compared with that in the general population [II]; (iv)
data from pooled analyses indicate that patients >70 years maynot bene fit signi ficantly from oxaliplation-based combinations
in the adjuvant setting. However, they may have a similar
benefit to younger patients from 5-FU-based chemotherapy
[24]. A subset analysis of the MOSAIC trial also con firms that
patients over 70 years may not further bene fit from the addition
of oxaliplatin [ 25].
Recently, nomograms have been developed and are also
available for CRC. These statistics-based tools attempt toprovide all proven prognostic factors and to quantify the risk of
5- and 10-year death as precisely as possible [ 26].
management of local/locoregional
disease
treatment of malignant polyps
Complete endoscopic polypectomy should be carried out
whenever the morphological structure of the polyp permits. Thepresence of invasive carcinoma in a polyp requires a thoroughreview with the pathologist for histological features that areassociated with an adverse outcome. Making the decision toundergo surgical resection for a neoplastic polyp that containsinvasive carcinoma involves the uncertainties of predicting and
balancing adverse disease outcome against operative risk.
Unfavourable histological findings include lymphatic or venous
invasion, grade 3 differentiation, level 4 invasion (invades thesubmucosa of the bowel wall below the polyp) or involvedmargins of excision. Although level 4 invasion and involvedmargins of excision are two of the most important prognostic
factors, their absence does not necessarily preclude an adverse
outcome. Several staging systems to stratify the aggressiveness ofpolyps have been proposed such as involvement of submucosae(sm1, sm2, sm3: involves the super ficial, middle and deep thirds
of the submucosa, respectively), invasion into the stalk, absolutethickness of the invasive tumour beyond the muscolaris
mucosae. When unfavourable histological features are present in
a polyp from a patient with an average operative risk, resectionis recommended [IV, B]. The pedunculated polyp with invasivecarcinoma con fined to the head, with no other unfavourable
factors, has a minimal risk for an adverse outcome. Theconsensus is that endoscopic polypectomy is adequate treatmentwith proper follow-up examination [IV, B]. Invasion of the stalk
but with clear margins of excision and favourable histological
features may be treated with endoscopic polypectomy with asimilar risk as level 2 invasion (invades the muscularis mucosabut is limited to the head and neck of the stalk). Pedunculatedpolypoid carcinomas can be treated using the same criteria asother pedunculated polyps with invasive carcinoma. Invasive
carcinoma in a sessile polyp should usually be interpreted as
having level 4 invasion. Consequently, standard surgicalresection is recommended in patients with average operativerisk [IV, B].
localised disease
The goal of surgery is a wide resection of the involved segmentof bowel together with the removal of its lymphatic drainage.The extent of the colonic resection is determined by the bloodsupply and distribution of regional lymph nodes. The resection
should include a segment of colon of at least 5 cm on either sideof the tumour, although wider margins are often includedbecause of obligatory ligation of the arterial blood supply [IV, B].
To clearly de fine stage II versus III and to identify and
eradicate potential lymph node metastases, at least 12 lymphnodes must be resected [IV, B].
Laparoscopic approach has now received wide acceptance for
several types of surgical procedures of major abdominal surgery.Laparoscopic colectomy can be safely carried out for coloncancer, particularly for left-sided cancer [I]. For right-sided
colonic cancers, the bene fit is less obvious since anastomosis
must be hand sewn, which requires a laparotomy [IV]. Thelong-term oncological results of laparoscopic colectomy aresimilar to those of the conventional approach [ 27] [I].
Advantages of laparoscopy over the conventional approach arereduced pain, reduced length of hospital stay and reduced
duration of ileus [ 28] [II]. It is recognised that a laparoscopic
approach should only be carried out if the following criteria aremet:
(i) technically experienced surgeons,
(ii) lack of serious abdominal adhesion due to prior major
abdominal surgery,
(iii) no locally advanced disease and/or acute bowel obstruction
or perforation.
Obstructive colorectal cancers can be treated in one or two
stages. Two-stage procedures can include colostomy followed bycolonic resection, or Hartmann ’s procedure followed by
colostomy closure and anastomosis. An alternative is a one-stage procedure with either subtotal colectomy and ileorectal
anastomosis or, in selected cases, segmental resection after
intraoperative colonic lavage [III]. Endoscopic stenting can beused to relieve obstruction from rectosigmoid cancer andallow subsequent one-step resection. Obstructive right-sidedcancers can be treated by colonic resection and immediateanastomosis [IV].
treatment by stage
Stage 0 (Tis N0 M0)
Treatment options are:
(i) Local excision or simple polypectomy.
(ii) Segmentary en-bloc resection for larger lesions not amenable
to local excision.
Stage I (T1-2 N0 M0)
(old staging: Dukes ’A or modi fied Astler –Coller A and B1).
Wide surgical resection and anastomosis. No adjuvantchemotherapy.Stage II A, B, C (T3 N0 M0, T4 a-b N0 M0)Standard treatment options:
(i) Wide surgical resection and anastomosis.
(ii) Following surgery, adjuvant therapy should not be routinely
recommended for unselected patients. In high-risk patients
who present at least one of the previously mentioned
clinical high-risk features (see above), adjuvant therapycould be considered in clinical practice [II, B].clinical practice guidelinesAnnals of Oncology
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Stage III (any T, N1-N2, M0)
(i) Wide surgical resection and anastomosis.
(ii) Following surgery, the standard treatment is a doublet
schedule with oxaliplatin and a fluoropyrimidine. Although
all three combination regimens are superior to 5-FU/FAalone [I, A], FOLFOX4 or XELOX should be preferred to
FLOX. When oxaliplatin is contraindicated, monotherapy
with infusional or oral fluoropyrimidines should be
preferred to bolus 5-FU FU/LV.
treatment options
The bene fit of combinations with oxaliplatin has been
demonstrated in three landmark trials. In the MOSAIC study[29], the addition of oxaliplatin to 5-FU/LV (FOLFOX schema),
demonstrated a signi ficantly increased disease-free survival
(DFS) at 3 years, with a reduction in the risk of recurrence of
23% compared with the control arm (LV5FU2).The update atthe 6-year follow-up con firmed the bene fit in DFS of adjuvant
treatment with FOLFOX4, and an advantage was also observedin overall survival (OS), but for stage III patients only [ 30].
The NSABP C-07 trial compared the ef ficacy of bolus FU/
LV + oxaliplatin (FLOX) versus FU/LV alone (Roswell Park
schedule); 3-year DFS was 76.5% versus 71.6% for FLOX and
FULV, respectively [ 31], and the magnitude of reduction in the
risk of recurrence was similar to that of the MOSAIC trial. Thespectrum of toxicity between MOSAIC and NSABP-C07 wasdifferent: grade 3 –4 diarrhoea occurred more often with FLOX
than with FOLFOX, while grade 3 sensory neuropathy was
observed in 12% with FOLFOX and 8% with FLOX. FLOX
should probably not be used in clinical practice, due to itstoxicity and also due to a lack of OS bene fit. The XELOXA
international phase III study [ 32] assessed the safety and ef ficacy
of adjuvant capecitabine plus oxaliplatin (XELOX) versus bolusFU/LV (Mayo Clinic or Roswell Park regimen) in stage IIIpatients: the arm including the oral compound was well
tolerated and superior to the i.v fluoropyrimidine. As
capecitabine does not require a central venous access, it may bepreferred in many patients [IV, B].
In case a clinically relevant neurotoxicity occurs, oxaliplatin
should be stopped and fluoropyrimidine continued, as it
contributes to about two-third to the therapeutic effect of
adjuvant FOLFOX/XELOX.
As stated before, in special situations monotherapy with
capecitabine or 5-FU/LV in infusion can be an alternativeapproach. The X-ACT trial showed that capecitabine is anactive agent with a favourable toxicity pro file and may reduce
overall costs compared with i.v. treatments [I]: after 4.3 yearsof follow-up, the data still con firm the equivalence in terms of
DFS between capecitabine and 5-FU/LV [ 33] in stage
III patients.
Negative trials are related to irinotecan in combination with
5-FU (bolus or infusional). The CALGB-89803 trial [ 34]
compared 5-FU/LV + irinotecan (IFL) with the Roswell Parkscheme in more than 1200 patients. The trial was prematurely
closed because of an elevated rate of mortality in the IFL group
with respect to the FL regimen (2.2% versus 0.8%). Ef ficacy
results indicated no improvement in terms of either OS orevent-free survival for IFL, when compared with FL. The
PETACC-3 trial [ 35] compared LV5FU2 or AIO regimen plus
irinotecan with LV5FU2 or AIO regimen alone. Results did notshow any signi ficant advantage for the regimen with irinotecan
in terms of DFS.
There is currently no role for targeted agents associated with
chemotherapy in the adjuvant setting for colon cancer. All trialsevaluating bevacizumab, NSABP C-08 [ 36], AVANT [ 37]o r
cetuximab, NCCTG NO147 [ 38] and PETACC-8 [ 39]a r e
negative, probably due to different biological characteristics inearly when compared with advanced disease.
In the adjuvant setting many questions are still unanswered:
(i) The optimal duration of adjuvant treatment: 3 or 6
months? In Italy, the TOSCA trial investigates whether 3
months of FOLFOX4 or XELOX treatment are not inferior
to 6 months with the same schedule in terms ofrecurrence-free survival (RFS) in stage II and III coloncancer patients. Together with other studies (SCOT,France, US, Greece, Japan …), this trial forms the backbone
of a large international collaboration ( ‘IDEA
’) which will
give a de finitive answer regarding the duration of adjuvant
therapy in stage III patients.
(ii) The validation of prognostic/predictive factors: interesting
and potentially positive data are expected from large subsetanalyses from large trials, such as PETACC-3, AVANT andPETACC-8.
(iii) The possible role of aspirin in this setting: from a large
study [ 40], it appears that the regular use of this drug after
diagnosis of CRC leads to an increase in cancer-speci fic
survival and OS but only in patients with mutated PIK3CAcancer. Further studies on this topic are needed to con firm
these exciting findings.
personalised medicine
In this disease setting, more research is needed to identify
molecular markers which could lead to advances in
personalised medicine.
follow-up and long-term implications
follow-up
Despite optimal primary treatment, with adequate surgery with
or without adjuvant chemotherapy, 30% –50% of patients with
colon cancer will relapse, and most of those patients will diefrom their disease.
Detecting relapse in advance is the main goal of surveillance
after primary treatment, but this is clinically meaningful only ifit improves survival. Furthermore, follow-up can be expensive
and resource-consuming in terms of both money and
procedures for a national health system, so intensivesurveillance needs to be justi fied with a good level of evidence.
In the past, there was no strong evidence that regular follow-up
could improve the outcome for patients radically resected forcolon cancer. Several trials failed to demonstrate a bene fit, and
results of old meta-analyses were unfortunately based on
nonrandomised data or mix of randomised and cohort studies.
In the last 10 years, four further systematic reviews [ 41–44]
have been published. All of these studies demonstrated improvedAnnals of Oncology clinical practice guidelines
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survival in patients undergoing more intensive surveillance when
compared with those with minimal or no follow-up. Theestimated OS gain was between 7% and 13%. On the basis ofthese data, intensive follow-up should now be considered
standard practice for colon cancer patients [I, A] [ 45].
The improvement in OS has been attributed to earlier
detection of recurrent disease and in particular, to a higher rateof detection of isolated locoregional relapses. The same rate ofrecurrence for intensive and minimal follow-up was reported[46], but with an anticipation of 8.5 months in the intensive
group. Detection of isolated local recurrences was increased in
the intensive group (15% compared with 9%, with RR 1.61 and
P = 0.011), and also a small non-signi ficant increase in the
detection of hepatic metastases was reported. Absolutereduction in mortality was 9% –13%, comparable with the
benefit observed with adjuvant chemotherapy in stage III. In
addition, trials included in this analysis were conducted before
the modern multidisciplinary approach to metastatic disease,
and therefore, the real bene fit in clinical practice at the present
time could be even more evident.
Despite these results, recent data still showed low adherence
to follow-up recommendations. This could be due to dif ficulties
in determining which is the best surveillance test.
Indeed, although pooled data suggest a survival advantage
related to intensive follow-up, the heterogeneity of the studies
included in these meta-analyses does not allow assessment ofwhich kind of surveillance must be applied in clinical practice. Itseems clear that more investigations are better than fewer, whichin turn are better than no follow-up at all, but it is nearlyimpossible 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,
and surveillance intervals and duration of follow-up cannot beextrapolated by meta-analyses data. Only trials including CEAtesting and/or liver imaging achieve signi ficant improvements in
survival, but all studies considering liver imaging also includedblood CEA monitoring; CEA testing alone does not show
benefit in individual studies and has demonstrated a reduction
in mortality only in meta-analyses [ 47]. Despite this, CEA rise is
often the first signal of recurrence: a positive value could be
detected 1.5 –6 months before clinical/instrumental detection
with other test(s). There are false-positive rates of CEAelevation of 7% –16% and false-negative rates of up to 40%. CEA
test monitoring is also effective in patients without elevation in
the preoperative setting: in these patients, a subsequentelevation was observed in 44% of recurrent patients. There is noevidence that other laboratory tests can be useful.
As far as liver imaging is concerned, a CT scan has been
shown to be more sensitive than ultrasonography (0.67
compared with 0.43), but a modern contrast enhancement
ultrasound scan (CEUS) can substantially increase thesensitivity of ultrasonography. Chest recurrence could bedetected by the CT scan: in colon cancer, lung is the first site of
relapse in 20% of patients and pulmonary resection coulddetermine a 30% 5-year survival. In contrast, there are no datain favour of regular use of chest X-rays.
Metachronous primary cancer could be detected with an
incidence of 0.7% within the first 2 years after curative surgery,
but there is no evidence favouring a survival bene fit through thedetection of intraluminal recurrent cancer, and therefore there
is no indication of intensive endoscopic follow-up. If a colonwithout tumour or polyps is observed 1 year after resection,colonoscopy should be carried out after 3 –5 years. In this field,
specific recommendations are based mainly on level II and III
evidence, particularly concerning timing intervals and durationof follow-up [ 48].
A recently reported analysis of individual patient data from
large adjuvant colon cancer randomised trials including >20 000patients indicated that 82% of stage III and 74% of stage II coloncancer recurrences are diagnosed within the first 3 years after
primary cancer resection [ 49].
Suggested recommendations are as follows [ 50]:
(i) Intensive follow-up must be carried out in colon cancer
patients [I, A].
(ii) History and physical examination and CEA determination
are advised every 3 –6 months for 3 years and every 6 –12
months at years 4 and 5 after surgery [II, B].
(iii) Colonoscopy must be carried out at year 1 and every 3 –5
years thereafter, looking for metachronous adenomas and
cancers [III, B].
(iv) CT scan of chest and abdomen every 6 –12 months for the
first 3 years can be considered in patients who are at higher
risk of recurrence [II, B].
(v) CEUS could substitute for abdominal CT scan [III, C].
(vi) Other laboratory and radiological examinations are of
unproven bene fit and must be restricted to patients with
suspicious symptoms.
long-term implications: survivorship care plans
Follow-up is therefore standard practice after completing
cancer treatment. It consists of periodic visits and investigations,which usually take place in a specialist cancer setting sometimesfor prolonged periods after the treatment ends. However, therehas been growing awareness in recent years that optimal
cancer survivorship care involves more than surveillance tests.
In this setting, the primary practitioner should have a signi ficant
role [ 51].
Survivors of CRC now represent the third largest group of
long-term cancer survivors in Western countries, ∼11% of the
population.
Survivorship care plans are an increasing priority within the
cancer system, and supporting colon cancer patients and theirproviders in staying on track with recommended follow-up isonly part of helping patients to regain their health and stay wellafter treatment.
Data from the Tjandra surveillance meta-analysis [ 44]
reported bene fit in the intensive arm, but this bene fit was less
significant. In fact, in this systematic revision it was observed
that, despite bene fit in OS and in re-resection rate, the cancer-
related mortality was not improved and the survival bene fitw a s
not due to early detection and treatment of recurrent disease.Other factors contributing to a survival advantage ofsurveillance in these patients might include the management of
co-morbidities, promotion of bene ficial dietary and lifestyle
factors and increased psychosocial support.
Major elements in survivorship care are as follows [ 52]:clinical practice guidelinesAnnals of Oncology
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(i) Prevention of recurrent and new cancer (classic end-point
of follow-up),
(ii) Intervention for cancer sequelae and their treatment
(rehabilitation),
(iii) Assessment of medical and psychological late effects
(modern end-point of follow-up),
(iv) Health promotion (lifestyle promotion, co-morbidity
prevention, etc.).
Most long-term survivors of CRC report very good quality of
life following their treatment, but several problems are stillobserved. Some patients can have bowel dysfunction: diarrhoea,constipation, bowel obstruction, pain. Hemicolectomy can leadto loose stools but this usually improves over time and surgerycan also lead to adhesions. It is important to carry out dietary
counselling and suggest use of over-the-counter medications
(e.g., fibre laxative, stool softeners, antidiarrhoeals). Survivors
who received oxaliplatin can experience numbness or painfulsensations [ 53].
More than 76% of colon cancer survivorships are >65 years of
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.
Despite colon cancer survivors often staying well, higher rates
of psychological depression have been reported. Assessment ofdistress should be considered but evidence on the effectivenessof psychosocial interventions among survivors of CRC islimited.
The majority of colon cancer survivors die of other causes.
Consequently, care for general medical and preventive healthissues are equal in importance in the care of index cancer. This
simple consideration is often not applied in clinical practice. Arecent analysis [ 54] showed that survivors were overall less likely
to receive recommended follow-up for chronic conditions, such
as angina, congestive heart failure and chronic lung disease, and
to receive less of some types of preventive care compared withmatched controls. For example, diabetic cancer survivors wereless likely to have preventive eye examinations, and the datashowed a trend toward less intensive monitoring of HbA1c.
Even though at the present time, this issue can be considered
still experimental, the development of Survivorship Care Plans
will certainly be one of the major topics in the near future for
gastro intestinal medical oncologists.
note
Levels of evidence and grades of recommendation have beenapplied using the system shown in Table 2. Statements without
grading were considered justi fied standard clinical practice by
the experts and the ESMO faculty.
conflict of interest
Prof. Labianca has reported research grants from Roche and
Sanofi. Prof. Arnold has reported research grants from Roche
and Sano fi. The other authors have reported no potential
conflicts of interest.
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