Early colon cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Abstract

Colorectal cancer (CRC) is the third most common tumour in men and the second in women, accounting for 10% of all tumour types worldwide. Incidence is higher in males (ratio: 1.4) and for both genders there is a 10-fold difference in incidence between several regions. With 608 000 deaths estimated each year (∼8% of all cancer deaths), CRC is the fourth most common cancer-related cause of death in the world [1.GLOBOCAN 2008 website: globocan.iarc.fr. (12 July 2013, date last accessed).Google Scholar]. As a general observation, there has been an increasing incidence in countries where the overall risk of large bowel cancer was low, while in historically high-risk countries either a stabilisation (Western Europe and Australia) or a decrease (USA, Canada and New Zealand) in incidence was reported [2.Jemal A. Center M. deSantis C. Ward E.M. Global patterns of cancer incidence and mortality rates and trends.Cancer Epidemiol Biomarkers Prev. 2010; 19: 1893-1907doi:10.1158/1055-9965.EPI-10-0437Crossref PubMed Scopus (2114) Google Scholar]. A gradient of incidence and mortality between North Western and South Eastern Europe has been observed: new CRC cases increased in historically low-risk areas such as Spain and Eastern Europe [3.Center M.M. Jemal A. Ward E. International trends in colorectal cancer incidence rates.Cancer Epidemiol Biomarkers Prev. 2009; 18: 1688-1694doi:10.1158/1055-9965.EPI-09-0090Crossref PubMed Scopus (661) Google Scholar]. This growing incidence reflects modifications 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 screening programmes, removal of adenomas, early detection of cancerous 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 have decreased in both Western and Northern Countries, particularly in females. In 10 years (1997–2007), EU mortality declined by 6% per quinquennium in men and 8% per quinquennium in women. The analysis updated to 2007 showed a greater reduction of the mortality rate in the young population (aged 30–49 years) with ∼10% per quinquennium [4.Bossetti C. Levi F. Rosato V. et al.Recent trends in colorectal cancer mortality in Europe.Int J Cancer. 2011; 129: 180-191doi:10.1002/ijc.25653Crossref Scopus (133) Google Scholar]. 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 51 registries of 23 countries is 46.8% in men and 48.4% in women [5.Coleman M.P. Quaresma M. Berrino F. et al.Cancer survival in five continents: a worldwide population-based study (CONCORD).Lancet Oncol. 2008; 9: 730-756doi:10.1016/S1470-2045(08)70179-7Abstract Full Text Full Text PDF PubMed Scopus (964) Google Scholar]. The risk of developing colon cancer depends on factors which can be classified into lifestyle or behavioural factors (such as smoking, high red meat consumption, obesity, physical inactivity) and genetically determinant factors. According to international guidelines [6.American Cancer Society Guidelines. Colorectal cancer early detection. http://www.cancer.org.Google Scholar, 7.Schmoll H.J. Van Cutsem E. Stein A. et al.ESMO consensus guidelines for management of patients with colon and rectal cancer: a personalized approach to clinical decision making.Ann Oncol. 2012; 23: 2479-2516doi:10.1093/annonc/mds236Abstract Full Text Full Text PDF PubMed Scopus (1098) Google Scholar], screening tests are stratified according to the personal risk of disease. Age is considered the major unchangeable risk factor for sporadic colon cancer: nearly 70% of patients with colon cancer are over 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.Davis D.M. Marcet J.E. Frattini J.C. et al.Is it time to lower the recommended screening age for colorectal cancer?.J Am Coll Surg. 2011; 213: 352-361doi:10.1016/j.jamcollsurg.2011.04.033Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar]. Individuals with:(i)a personal history of adenoma, colon cancer, inflammatory bowel disease (Crohn's disease and ulcerative colitis),(ii)significant 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.Schmoll H.J. Van Cutsem E. Stein A. et al.ESMO consensus guidelines for management of patients with colon and rectal cancer: a personalized approach to clinical decision making.Ann Oncol. 2012; 23: 2479-2516doi:10.1093/annonc/mds236Abstract Full Text Full Text PDF PubMed Scopus (1098) Google Scholar, 9.Balmaña J. Balaguer F. Cervantes A. Arnold D. Familial risk-colorectal cancer: ESMO Clinical Practice Guidelines.Ann Oncol. 2013; 24: vi72-79Google Scholar]. The aim of screening is to detect a pre-cancer condition in a healthy population, as well as very early-stage malignancies which can be treated with a clearly curative intention. For average-risk populations, the European Guidelines for quality assurance in CRC screening and diagnosis [10.European guidelines for quality assurance in colorectal cancer screening and diagnosis.in: Segnan N. Patnick J. von Karsa L. 2010Google Scholar] 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) FOBT reduced mortality from CRC by ∼15% [I] in different age groups [I, V]. The benefit from annual screening appears to be greater than for biennial screening and the test interval should not exceed 2 years [II, B].Faecal immunochemical testing appears to be superior to 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].Flexible sigmoidoscopy (FS) reduces CRC incidence and mortality 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]. The preferred age range is likely to be between 55 and 64 years [III, C]. After age 74, average risk FS screening should be discontinued, given the increasing co-morbidity in this population [V, D].Colonoscopy: limited evidence exists on the efficacy in reducing CRC incidence and mortality [III]. A note of caution is the observation that colonoscopy screening may not be as effective in the right colon as in other segments of the large bowel [IV]. The age range is 50–74 years [V, D] with the optimal age for a single colonoscopy being around 55 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 no current evidence for extra benefit from adding a once-only sigmoidoscopy to FOBT screening [II].New screening technologies are still under evaluation: computed tomography (CT) colonography, stool DNA testing and capsule endoscopy should therefore not be used for screening in the average-risk population [V, D]. Colon cancer arises from the mucosa of the bowel, generally growing towards the lumen and/or spreading to adjacent organs. Symptoms are associated with relatively large tumours and/or advanced disease stages, and are generally not specific for colon cancer. Change in bowel habits, general or localised abdominal pain, weight loss without other specific causes, weakness, iron deficiency and anaemia are the most common symptoms, and depends on the location and stage of the primary tumour; they are associated with worse prognosis and their number (but not their duration) is inversely related to survival [11.McDermott F.T. Hughes E.S. Pihl E. et al.Prognosis in relation to symptom duration in colon cancer.Br J Surg. 1981; 68: 846-849doi:10.1002/bjs.1800681206Crossref PubMed Scopus (57) Google Scholar]. A systematic review and meta-analysis of the published literature were carried out to assess the diagnostic accuracy (sensitivity, specificity, 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 and abdominal mass had a specificity of >95%, suggesting that the presence of either characteristic strongly indicates a diagnosis of CRC [12.Ford A.C. Veldhuyzen van Zanten S.J.O. Rodgers C.C. et al.Diagnostic utility of alarm features for colorectal cancer: systematic review and meta-analysis.Gut. 2008; 57: 1545-1553doi:10.1136/gut.2008.159723Crossref PubMed Scopus (117) Google Scholar]. Colon cancer can occur as multiple or synchronous (2.5%) with identical or different histological patterns and stages of 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 5 years after surgery, and the incidence increases up to 9% after several decades in long-term survivors. Endoscopy is the main procedure for diagnosis and can be carried out by either sigmoidoscopy (as >35% of tumours are located 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 and removal of polyps. Before surgery, if a complete colonoscopy cannot be carried out for whatever reason, the rest of the colon should 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 yet standard investigations, but are valuable instruments to identify with precision the location of the tumour or to detect synchronous lesions or polyps, and they are potentially helpful for patients eligible for laparoscopic resection. In any case, if not carried out before, a complete colonoscopy should be carried out within 3–6 months after surgery [V, B]. The standard assessment should include the morphological description of the specimen, surgical procedure carried out, definition of tumour site and size, presence or absence of macroscopic tumour perforation, histological type and grade, extension of tumour into the bowel wall and adjacent organs (T stage), distance of cancer from resected margins (proximal, distal and radial), presence or absence of tumour deposits, lymphovascular and/or perineural invasion, presence of tumour budding, site and number of removed regional lymph nodes and their possible infiltration by cancer cells (N stage), and finally the possible involvement of other organs (e.g. liver) if submitted for removal or biopsy (M stage) [13.Washington M.K. Berlin J. Branton P. et al.Protocol for the examination of specimens from patients with primary carcinoma of the colon and rectum.Arch Pathol Lab Med. 2009; 133: 1539-1551Crossref PubMed Google Scholar]. The pathological stage must be reported according to the American Joint Cancer Committee (AJCC)/ Union for International Cancer Control (UICC) TNM classification, 7th edition (Table 1).Table 1The TNM staging system, AJCC/UICC 7th editionPrimary tumour (T)TXPrimary tumour cannot be assessedT0No evidence of primary tumourTisCarcinoma in situ: intraepithelial or invasion of lamina propriaaThis includes cancer cells confined within the glandular basement membrane (intraepithelial) or mucosal lamina propria (intramucosal) with no extension through the muscularis mucosae into the submucosa.T1Tumour invades submucosaT2Tumour invades muscularis propriaT3Tumour invades through the muscularis propria into the pericolorectal tissuesT4aTumour penetrates into the surface of the visceral peritoneumbDirect invasion in T4 includes invasion of other organs or other segments of the colorectum as a result of direct extension through the serosa, as confirmed on microscopic examination (for example, invasion of the sigmoid colon by a carcinoma of the caecum) or, for cancers in a retroperitoneal or subperitoneal location, direct invasion of other organs or 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 invasion of prostate, seminal vesicles, cervix or vagina).T4bTumour directly invades or is adherent to other organs or structuresbDirect invasion in T4 includes invasion of other organs or other segments of the colorectum as a result of direct extension through the serosa, as confirmed on microscopic examination (for example, invasion of the sigmoid colon by a carcinoma of the caecum) or, for cancers in a retroperitoneal or subperitoneal location, direct invasion of other organs or 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 invasion of prostate, seminal vesicles, cervix or vagina).,cTumour that is adherent to other organs or structures, grossly, is classified cT4b. However, if no tumour is present in the adhesion, microscopically, the classification should be pT1-4a depending on the anatomical depth of wall invasion. The V and L classifications should be used to identify the presence or absence of vascular or lymphatic invasion, whereas the PN site-specific factor should be used for perineural invasion.Regional lymph nodes (N)dA satellite peritumoural nodule in the pericolorectal adipose tissue of a primary carcinoma without histologic evidence of residual lymph node in the nodule may represent discontinuous spread, venous invasion with extravascular spread (V1/2) or a totally replaced lymph node (N1/2). Replaced nodes should be counted separately as positive nodes in the N category, whereas discontinuous spread or venous invasion should be classified and counted in the site-specific factor category Tumour Deposits.NXRegional lymph nodes cannot be assessedN0No regional lymph node metastasisN1Metastasis in one to three regional lymph nodesN1aMetastasis in one regional lymph nodeN1bMetastasis in two to three regional lymph nodesN1cTumour satellite deposits in subsierose or in non peritonealised tissuesN2Metastases in ≥4 regional lymph nodes (a: 4–6, b: ≥7)Distant metastases (M)M0No distant metastasesM1Distant metastasesM1aMetastases confined to one organ or site (for example liver, lung, ovary, nonregional node)M1bMetastases in more than one organ/site or the peritoneumStageTNMDukesMACeMAC is the modified Astler–Coller classification.Anatomic stage/prognostic groups0TisN0M0––IT1N0M0AAT2N0M0AB1IIAT3N0M0BB2IIBT4aN0M0BB2IICT4bN0M0BB3IIIAT1-T2N1/N1cM0CC1T1N2aM0CC1IIIBT3-T4aN1/N1cM0CC2T2-T3N2aM0CC1/C2T1-T2N2bM0CC1IIICT4aN2aM0CC2T3-T4aN2bM0CC2T4bN1-N2M0CC3IVAAny TAny NM1a––IVBAny TAny NM1b––Edge et al. [17.Edge S.B. Byrd D.R. Compton C.C. et al.AJCC Cancer Staging Manual.in: 7th edition. Springer, New York, NY2010: 143-164Crossref Google Scholar]. Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, IL. The original source for this material is the AJCC Cancer Staging Handbook, 7th edition (2010) published by Springer Science and Business Media LLC, www.springer.com.a This includes cancer cells confined within the glandular basement membrane (intraepithelial) or mucosal lamina propria (intramucosal) with no extension through the muscularis mucosae into the submucosa.b Direct invasion in T4 includes invasion of other organs or other segments of the colorectum as a result of direct extension through the serosa, as confirmed on microscopic examination (for example, invasion of the sigmoid colon by a carcinoma of the caecum) or, for cancers in a retroperitoneal or subperitoneal location, direct invasion of other organs or 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 invasion of prostate, seminal vesicles, cervix or vagina).c Tumour that is adherent to other organs or structures, grossly, is classified cT4b. However, if no tumour is present in the adhesion, microscopically, the classification should be pT1-4a depending on the anatomical depth of wall invasion. The V and L classifications should be used to identify the presence or absence of vascular or lymphatic invasion, whereas the PN site-specific factor should be used for perineural invasion.d A satellite peritumoural nodule in the pericolorectal adipose tissue of a primary carcinoma without histologic evidence of residual lymph node in the nodule may represent discontinuous spread, venous invasion with extravascular spread (V1/2) or a totally replaced lymph node (N1/2). Replaced nodes should be counted separately as positive nodes in the N category, whereas discontinuous spread or venous invasion should be classified and counted in the site-specific factor category Tumour Deposits.e MAC is the modified Astler–Coller classification. Open table in a new tab Edge et al. [17.Edge S.B. Byrd D.R. Compton C.C. et al.AJCC Cancer Staging Manual.in: 7th edition. Springer, New York, NY2010: 143-164Crossref Google Scholar]. Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, IL. The original source for this material is the AJCC Cancer Staging Handbook, 7th edition (2010) published by Springer Science and Business Media LLC, www.springer.com. Once a colon cancer is diagnosed, clinical examination, laboratory tests and instrumental screening should be carried out in order to detect or to exclude metastatic disease. Clinical examination 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 they can be normal in the presence of metastases. Ultrasonography of the liver and the whole abdomen may be useful, but a CT scan 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 influenced by lesion size). Magnetic resonance imaging might be useful for locally advanced tumours and could also be the preferred first-line investigation for evaluating liver metastases in patients who have not previously undergone therapy [14.Koh J.L. Yan T.D. Glenn D. Morris D.L. Evaluation of preoperative computed tomography in estimating peritoneal cancer index in colorectal peritoneal carcinomatosis.Ann Surg Oncol. 2009; 16: 327-333doi:10.1245/s10434-008-0234-2Crossref PubMed Scopus (255) Google Scholar]. The clinical benefit 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.Niekel M.C. Bipat S. Stoker J. Diagnostic imaging of colorectal liver metastases with CT, MR imaging, FDG PET, and/or FDG PET/CT: a meta-analysis of prospective studies including patients who have not previously undergone treatment.Radiology. 2010; 257: 674-684doi:10.1148/radiol.10100729Crossref PubMed Scopus (412) Google Scholar]. 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 for diagnosis in asymptomatic patients due to its relatively low sensitivity and specificity [16.Thirunavukarasu P. Sukumar S. Sathaiah M. et al.C-stage in colon cancer: implications of carcinoembryonic antigen biomarker in staging, prognosis, and management.J Natl Cancer Inst. 2011; 103: 689-697doi:10.1093/jnci/djr078Crossref PubMed Scopus (123) Google Scholar]. 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 may indicate persistent disease. Surgical staging includes an assessment of liver metastases, nodal spread of disease and extension of the tumour through the bowel wall and onto adjacent structures. For adequate pN-staging, at least 12 nodes have to be examined [17.Edge S.B. Byrd D.R. Compton C.C. et al.AJCC Cancer Staging Manual.in: 7th edition. Springer, New York, NY2010: 143-164Crossref Google Scholar]. This is particularly important for determination of stage II status, as it has been shown that patient prognosis is much better if at least 14 tumour-free nodes have been presented. It is not entirely clear, however, if this is a surgical (resecting more nodes) or a pathological (finding more nodes and preventing inaccurate classification 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. 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 of colon cancer is clearly related to the staging features of the TNM classification, including the degree of penetration of the tumour through the bowel wall and the presence, or absence, of nodal involvement. However, many additional parameters such as grading, lymphatic or venous or perineural invasion, lymphoid inflammatory response and involvement of resection margins, which are reflected by the Dukes' and TNM classifications, 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 evaluation for 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 prognostic significance. 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 that perioperative blood transfusions could impair the prognosis, but these findings were not confirmed by a large, multi-institutional, prospective randomised trial which demonstrated no benefit for autologous blood transfusions when compared with allogeneic transfusions [18.Busch O.R. Hop W.C. Hoynck van Pependrecht M.A. et al.Blood transfusions and prognosis in colorectal cancer.N Engl J Med. 1993; 328: 1372-1376doi:10.1056/NEJM199305133281902Crossref PubMed Scopus (509) Google Scholar]. 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 treatment administered after primary tumour resection with the aim of reducing the risk of relapse and death. It is well established that in 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 be thoroughly discussed with the patient, taking into consideration prognostic 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 benefit 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 define 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 reflect 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, DCC and 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). In particular, MSI/MMR may be useful to identify a small (10%–15%) subset of stage II patients who are at a very low risk of recurrence and in whom the benefits 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.Ribic C.M. Sargent D.J. Moore M.J. et al.Tumor microsatellite instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer.N Engl J Med. 2003; 349: 247-257doi:10.1056/NEJMoa022289Crossref PubMed Scopus (1811) Google Scholar, 20.Sargent D.J. Marsoni S. Monges G. et al.Defective mismatch repair as a predictive marker for the lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer.J Clin Oncol. 2010; 28: 3219-3226doi:10.1200/JCO.2009.27.1825Crossref PubMed Scopus (1165) Google Scholar, 21.Sinicrope F.A. Foster N.R. Thibodeau S.N. et al.DNA mismatch repair status and colon cancer recurrence and survival in clinical trials of 5-fluorouracil-based adjuvant therapy.J Natl Cancer Inst. 2011; 103: 863-875doi:10.1093/jnci/djr153Crossref PubMed Scopus (400) Google Scholar, 22.Tejpar S. Saridaki Z. Delorenzi M. et al.Microsatellite instability, prognosis and drug sensitivity of stage II and III colorectal cancer: more complexity to the puzzle.J Natl Cancer Inst. 2011; 103: 841-844doi:10.1093/jnci/djr170Crossref PubMed Scopus (52) Google Scholar]. In stage III, the role of MSI/MMR status is not clear: conflicting data exist on the potential benefit of treatment with 5-FU alone in the older studies and in the more recent analyses [23.Roth A.D. Delorenzi M. Tejpar S. et al.Integrated analysis of molecular and clinical prognostic factors in stage II/III colon cancer.J Natl Cancer Inst. 2012; 104: 1635-1646doi:10.1093/jnci/djs427Crossref PubMed Scopus (194) Google Scholar], 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 the following clinical characteristics: lymph nodes sampling <12; poorly differentiated tumour; vascular or lymphatic or perineural 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 and grade and deriving a rough estimate of the chances of relapse. For example, a patient with a stage II G3 adenocarcinoma with blood vessel invasion, presence of tumour budding and high thymidine 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 and biological 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 years and <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 efficacy of adjuvant treatments is similar in elderly people compared with that in the general population [II]; (iv) data from pooled analyses indicate that patients >70 years may not benefit significantly from oxaliplation-based combinations in the adjuvant setting. However, they may have a sim