Title: Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
Abstract: In 2012, there were 447 000 new cases of colorectal cancer (CRC) in Europe. CRC is the second most frequent cancer and represents 13.2% and 12.7% of all cancer cases in men and women, respectively. CRC was responsible for 215 000 deaths in Europe in 2012. This represents 11.6% and 13.0% of all cancer deaths in men and women, respectively [1.Ferlay J. Steliarova-Foucher E. Lortet-Tieulent J. et al.Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012.Eur J Cancer. 2013; 49: 1374-1403Abstract Full Text Full Text PDF PubMed Scopus (4002) Google Scholar]. Approximately 25% of patients present with metastases at initial diagnosis and almost 50% of patients with CRC will develop metastases, contributing to the high mortality rates reported for CRC. The CRC-related 5-year survival rate approaches 60%. Clinical or biochemical suspicion of metastatic disease should always be confirmed by adequate radiological imaging [usually a computed tomography (CT) scan or, alternatively, magnetic resonance imaging (MRI) or ultrasonography]. A fluorodeoxyglucose-positron emission tomography (FDG-PET) scan can be useful in determining the malignant characteristics of tumoural lesions, especially when combined with a CT scan or in the case of elevated tumour markers [carcinoembryonic antigen (CEA)] without indications of the location of relapse on CT scan in the surveillance of CRC. An FDG-PET scan is also especially useful to characterise the extent of metastatic disease and to look for extrahepatic metastases (or extrapulmonary metastases) when the metastases are potentially resectable. Histology of the primary tumour or metastases is always necessary before chemotherapy is started. For metachronous metastases, histopathological or cytological confirmation of metastases should be obtained, if the clinical or radiological presentation is atypical or very late (e.g. later than 3 years) after the initial diagnosis of the primary tumour. Resectable metastases do not need histological or cytological confirmation before resection. The optimal treatment strategy for patients with metastatic CRC (mCRC) should be discussed in a multidisciplinary expert team. In order to identify the optimal treatment strategy for patients with mCRC, the staging should include at least clinical examination, blood counts, liver and renal function tests, CEA and CT scan of the abdomen and chest (or alternatively MRI). The evaluation of the general condition, organ function and concomitant non-malignant diseases determines the therapeutic strategy for patients with mCRC. The general condition and performance status of the patient are strong prognostic and predictive factors. Known laboratory prognostic factors are white blood cell count, alkaline phosphatase level, lactate dehydrogenase, serum bilirubin and albumin. Additional examinations, as clinically needed, are recommended before major abdominal or thoracic surgery with potentially curative intent. An FDG-PET scan can give additional information on equivocal lesions before resection of metastatic disease, or can identify new lesions in the case of planned resection of metastatic disease. The majority of patients have metastatic disease that initially is not suitable for potentially curative resection. It is, however, important to select patients in whom the metastases are suitable for resection and those with initially unresectable disease in whom the metastases can become suitable for resection after a major response has been achieved with combination chemotherapy. The aim of the treatment in the last group of patients may therefore be to convert initially unresectable mCRC to resectable disease. The optimal treatment strategy for patients with clearly unresectable mCRC is rapidly evolving. The treatment of patients should be seen as a continuum of care in which the determination of the goals of the treatment is important: prolongation of survival, cure, improving tumour-related symptoms, stopping tumour progression and/or maintaining quality of life. However, there is increasing evidence that other ablative techniques may be helpful methods of control of oligometastatic disease, even after some weeks of initial systemic treatment and in case of non-curative intention [IV, B]. Therefore, re-evaluation of patients during treatment in a multidisciplinary team including interventional radiologists and radiation oncologists (for radiofrequency ablations, stereotactic body radiation therapy (SBRT) and infusional ablative methods) is recommended. The outcome of patients with mCRC has clearly improved during recent years with median survival now reaching (nearly) 30 months in clinical trials. The backbone of first-line palliative chemotherapy alone, as well in combination with targeted agents, consists of a fluoropyrimidine (FP) [intravenous (i.v.) 5-fluorouracil (5-FU) or the oral FP capecitabine] in various combinations and schedules [2.Douillard J.Y. Cunningham D. Roth A.D. et al.Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial.Lancet. 2000; 355: 1041-1047Abstract Full Text Full Text PDF PubMed Scopus (2988) Google Scholar, 3.de Gramont A. Figer A. Seymour M. et al.Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer.J Clin Oncol. 2000; 18: 2938-2947Crossref PubMed Scopus (3495) Google Scholar]. Infused regimens of 5-FU/leucovorin (LV) are less toxic than bolus regimens and should preferably be used. The oral FP capecitabine is an alternative to i.v. 5-FU/LV [4.Van Cutsem E. Hoff P.M. Harper P. et al.Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised phase III trials.Br J Cancer. 2004; 90: 1190-1197Crossref PubMed Scopus (363) Google Scholar, 5.Cassidy J. Clarke S. Dıaz-Rubio E. et al.Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer.J Clin Oncol. 2008; 26: 2006-2012Crossref PubMed Scopus (730) Google Scholar]. Combination chemotherapy with 5-FU/LV/oxaliplatin (FOLFOX) or 5-FU/LV/irinotecan (FOLFIRI) provides higher response rates (RRs), longer progression-free survival (PFS) and better survival than 5-FU/LV alone [I, B] [2.Douillard J.Y. Cunningham D. Roth A.D. et al.Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial.Lancet. 2000; 355: 1041-1047Abstract Full Text Full Text PDF PubMed Scopus (2988) Google Scholar, 3.de Gramont A. Figer A. Seymour M. et al.Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer.J Clin Oncol. 2000; 18: 2938-2947Crossref PubMed Scopus (3495) Google Scholar, 6.Tournigand C. André T. Achille E. et al.FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study.J Clin Oncol. 2004; 22: 229-237Crossref PubMed Scopus (2674) Google Scholar, 7.Grothey A. Sargent D. Goldberg R.M. Schmoll H.J. Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil leucovorin, irinotecan, and oxaliplatin in the course of treatment.J Clin Oncol. 2004; 22: 1209-1214Crossref PubMed Scopus (957) Google Scholar]. FOLFOX and FOLFIRI as chemotherapy alone have similar activity and are both partners for biologicals, but have a different toxicity profile: more alopecia and, in most trials, more severe diarrhoea for irinotecan and more polyneuropathy for oxaliplatin [I, B] [6.Tournigand C. André T. Achille E. et al.FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study.J Clin Oncol. 2004; 22: 229-237Crossref PubMed Scopus (2674) Google Scholar, 8.Rougier P. Van Cutsem E. Bajetta E. et al.Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer.Lancet. 1998; 352: 1407-1412Abstract Full Text Full Text PDF PubMed Scopus (988) Google Scholar]. They also have potentially different interactions with biologicals. Both regimens consist of a 46- to 48-h administration every 2 weeks (q 2 weeks) with a bolus of 5-FU administration (LV5FU2) regimens [6.Tournigand C. André T. Achille E. et al.FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study.J Clin Oncol. 2004; 22: 229-237Crossref PubMed Scopus (2674) Google Scholar, 7.Grothey A. Sargent D. Goldberg R.M. Schmoll H.J. Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil leucovorin, irinotecan, and oxaliplatin in the course of treatment.J Clin Oncol. 2004; 22: 1209-1214Crossref PubMed Scopus (957) Google Scholar]. The dose of oxaliplatin in combination regimens with 5-FU/LV is between 85 and 130 mg/m² q 2 weeks; there is, however, no evidence that the dose at the higher range is more active. Therefore, a dose of 85 mg/m² is usually proposed. Four randomised studies have shown that combination chemotherapy was not superior to sequential treatment in terms of overall survival (OS), and therefore sequential therapy starting with FP alone remains a valid option in selected and frail patients for treatment with chemotherapy alone [9.Seymour M.T. Maughan T.S. Ledermann J.A. et al.Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial.Lancet. 2007; 370: 143-152Abstract Full Text Full Text PDF PubMed Scopus (477) Google Scholar, 10.Koopman M. Antonini N.F. Douma J. et al.Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial.Lancet. 2007; 370: 135-142Abstract Full Text Full Text PDF PubMed Scopus (536) Google Scholar, 11.Tebbutt N.C. Wilson K. Gebski V.J. et al.Capecitabine, bevacizumab, and mitomycin in first-line treatment of metastatic colorectal cancer: results of the Australasian Gastrointestinal Trials Group Randomized Phase III MAX Study.J Clin Oncol. 2010; 28: 3191-3198Crossref PubMed Scopus (328) Google Scholar, 12.Ducreux M. Malka D. Mendiboure J. et al.Sequential versus combination chemotherapy for the treatment of advanced colorectal cancer (FFCD 2000-05). an open-label, randomised, phase 3 trial.Lancet Oncol. 2011; 12: 1032-1044Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar] [I, B]. Nevertheless, combination chemotherapy remains the preferred option as it allows better tumour growth control plus the option of de-escalation to FP alone. There are, however, no perfect selection criteria for determining which patients are still candidates for upfront FP therapy. It is estimated that today ∼15% of patients are treated initially with an FP alone. The exposure to all three cytotoxics (FP, oxaliplatin and irinotecan) in various sequences may result in the longest survival, as a retrospective analysis indicates [7.Grothey A. Sargent D. Goldberg R.M. Schmoll H.J. Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil leucovorin, irinotecan, and oxaliplatin in the course of treatment.J Clin Oncol. 2004; 22: 1209-1214Crossref PubMed Scopus (957) Google Scholar]. The combination of capecitabine plus oxaliplatin (CAPOX; capecitabine 2000 mg/m²/day; day 1–14 q 3 weeks and oxaliplatin 130 mg/m² day 1 q 3 weeks) is an alternative to the combination of infused 5-FU/LV and oxaliplatin [I, A] based on similar activity and safety profiles. The original 3-weekly regimen of capecitabine/irinotecan seems to be more toxic than 5-FU/LV/irinotecan. This regimen is therefore less well established and less frequently used. A dose-reduced regimen seems be less toxic, while maintaining the activity (capecitabine 1600 mg/m²/day for 2 weeks and irinotecan 200 mg/m² day 1 q 3 weeks). The data on triplet combination cytotoxic treatment with 5-FU, oxaliplatin and irinotecan are interesting, but remain controversial: an Italian randomised phase III study showed a better outcome for patients treated with FOLFOXIRI compared with FOLFIRI, while a Greek study did not show any difference [13.Falcone A. Ricci S. Brunetti I. et al.Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest.J Clin Oncol. 2007; 25: 1670-1676Crossref PubMed Scopus (951) Google Scholar, 14.Souglakos J. Androulakis N. Syrigos K. et al.FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG).Br J Cancer. 2006; 94: 798-805Crossref PubMed Scopus (325) Google Scholar]. Second-line chemotherapy should be offered to patients with good performance status and adequate organ function. In patients refractory to an irinotecan-based regimen, second-line treatment must consist of an oxaliplatin-containing combination (FOLFOX and CAPOX). In patients refractory to FOLFOX or CAPOX, an irinotecan-based regimen is proposed as second-line treatment: irinotecan monotherapy (350 mg/m² q 3 weeks) and FOLFIRI are options [8.Rougier P. Van Cutsem E. Bajetta E. et al.Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer.Lancet. 1998; 352: 1407-1412Abstract Full Text Full Text PDF PubMed Scopus (988) Google Scholar]. There is evidence that FOLFIRI has a better therapeutic index in second-line compared with irinotecan monotherapy, also because there are clear safety advantages of FOLFIRI compared with irinotecan q 3 weekly [9.Seymour M.T. Maughan T.S. Ledermann J.A. et al.Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial.Lancet. 2007; 370: 143-152Abstract Full Text Full Text PDF PubMed Scopus (477) Google Scholar] [I, B]. Monoclonal antibodies (bevacizumab) or proteins (aflibercept) against vascular endothelial growth factor (VEGF) and against the epidermal growth factor receptor (EGFR) in combination with chemotherapy should be considered in patients with mCRC, since they improve the outcome of mCRC. Only trials with a combination of cytotoxics and a biological targeted treatment consistently reported a median survival exceeding 24 months. Bevacizumab, an antibody that binds circulating VEGF-A, increases the activity of any active cytotoxic regimen. Bevacizumab has been shown to increase the survival, PFS and RR in first-line treatment in combination with 5-FU/LV/irinotecan and in combination with 5-FU/LV or capecitabine alone [I, B] [11.Tebbutt N.C. Wilson K. Gebski V.J. et al.Capecitabine, bevacizumab, and mitomycin in first-line treatment of metastatic colorectal cancer: results of the Australasian Gastrointestinal Trials Group Randomized Phase III MAX Study.J Clin Oncol. 2010; 28: 3191-3198Crossref PubMed Scopus (328) Google Scholar, 15.Hurwitz H. Fehrenbacher L. Novotny W. et al.Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer.N Engl J Med. 2004; 350: 2335-2342Crossref PubMed Scopus (9029) Google Scholar, 16.Kabbinavar F. Irl C. Zurlo A. Hurwitz H. Bevacizumab improves the overall and progression-free survival of patients with metastatic colorectal cancer treated with 5-fluorouracil-based regimens irrespective of baseline risk.Oncology. 2008; 75: 215-223Crossref PubMed Scopus (46) Google Scholar, 17.Cunningham D. Lang I. Marcuello E. et al.Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label, randomised phase 3 trial.Lancet Oncol. 2013; 14: 1077-1085Abstract Full Text Full Text PDF PubMed Scopus (446) Google Scholar]. Bevacizumab has also been shown to improve the PFS in combination with an FP plus oxaliplatin in the first-line treatment of mCRC [I, B] [18.Saltz L.B. Clarke S. Diaz-Rubio E. et al.Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study.J Clin Oncol. 2008; 26: 2013-2019Crossref PubMed Scopus (2487) Google Scholar]. The combination of FOLFOXIRI plus bevacizumab has shown better PFS and RR than FOLFIRI plus bevacizumab in a trial with also one of the longest survivals reported to date [19.Cremolini C. Loupakis F. Masi G. et al.FOLFOXIRI/bevacizumab versus FOLFIRI/bevacizumab as first-line treatment in unresectable metastatic colorectal cancer: results of phase III TRIBE trial by GONO Group.Ann Oncol. 2013; 24: iv21Abstract Full Text Full Text PDF Google Scholar]. Bevacizumab is usually continued in combination with a cytotoxic agent/combination until progression or toxicity. Bevacizumab also improves the survival and PFS in combination with FOLFOX in second-line treatment [I, B] [20.Giantonio B. Catalano P.J. Meropol N.J. et al.Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200.J Clin Oncol. 2007; 25: 1539-1544Crossref PubMed Scopus (1986) Google Scholar]. It has also been shown that continuing bevacizumab while changing the cytotoxic backbone, in second line after progression in first line, improves the outcome (survival and PFS) [21.Bennouna J. Sastre J. Arnold D. et al.Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial.Lancet Oncol. 2013; 14: 29-37Abstract Full Text Full Text PDF PubMed Scopus (863) Google Scholar] [I, B]. Bevacizumab has specific class-related side-effects: hypertension, proteinuria, arterial thrombosis, mucosal bleeding, gastrointestinal perforation and wound healing problems, but does not increase the chemotherapy-related side-effects. There are no validated predictive molecular markers available for bevacizumab. Aflibercept, a recombinant fusion protein, that blocks the activity of VEGF-A, VEGF-B and placenta growth factor, improves survival, PFS and RR when combined in second line with FOLFIRI in oxaliplatin pre-treated patients, whether or not the patients were pre-treated with bevacizumab in first line [22.Van Cutsem E. Tabernero J. Lakomy R. et al.Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen.J Clin Oncol. 2012; 30: 3499-3506Crossref PubMed Scopus (1000) Google Scholar]. Aflibercept has a similar VEGF-related toxicity pattern compared with bevacizumab, but it increases the chemotherapy-related adverse events: diarrhoea, neutropenia, asthenia and stomatitis. Regorafenib is an oral multitarget tyrosine kinase inhibitor that has shown significant improvement of survival and PFS in patients refractory to all available cytotoxics and to bevacizumab and to the anti-EGFR antibodies; it can be proposed as a standard treatment in last line in fit and motivated patients with mCRC [I, B] [23.Grothey A. Van Cutsem E. Sobrero A. et al.Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial.Lancet. 2013; 381: 303-312Abstract Full Text Full Text PDF PubMed Scopus (1835) Google Scholar]. The anti-EGFR antibodies cetuximab and panitumumab are active in different lines of treatment and in various combinations. It has been demonstrated that the (potential) benefit of anti-EGFR antibodies in all treatment lines and either as a single agent or in combination with any chemotherapy regimen is limited to patients in whom a RAS mutation is excluded. It was shown that the ‘expanded RAS’ analysis (also including the detection of mutations in exons 3 and 4 of the KRAS gene as well as mutations in the NRAS [exons 2–4] gene) is superior to the KRAS (exon 2) analysis in predicting both more efficacy in the expanded RAS wild-type (WT) patients and a potential detrimental effect in patients harbouring any RAS mutation in their tumour genome [II, A] [24.Douillard J.Y. Siena S. Cassidy J. et al.Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study.J Clin Oncol. 2010; 28: 4697-4705Crossref PubMed Scopus (1454) Google Scholar, 25.Douillard J.Y. Oliner K.S. Siena S. et al.Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer.N Engl J Med. 2013; 369: 1023-1034Crossref PubMed Scopus (1629) Google Scholar, 26.Ciardiello F. Lenz H.-J. Köhne C.-H. et al.Treatment outcome according to tumor RAS mutation status in CRYSTAL study patients with metastatic colorectal cancer (mCRC) randomized to FOLFIRI with/without cetuximab.J Clin Oncol. 2014; 32 (5s (suppl; abstr 3506))Crossref Google Scholar, 27.Bokemeyer C. Köhne C.-H. Ciardiello F. et al.Treatment outcome according to tumor RAS mutation status in OPUS study patients with metastatic colorectal cancer (mCRC) randomized to FOLFOX4 with/without cetuximab.J Clin Oncol. 2014; 32 (5s (suppl; abstr 3505))Crossref Google Scholar]. Therefore, the availability of an expanded RAS status is a prerequisite for any use of an anti-EGFR antibody. According to the European Medicines Agency (EMA), anti-EGFR antibodies must not be used otherwise [28.http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion/human/000558/WC500155463.pdf (10th July 2014, date last accessed)Google Scholar]. For further information, see the ‘personalised medicine’ section. Of note, even if trials in the following paragraph are reported with the previous KRAS WT status, the recommendation is to have expanded RAS analysis WT status as a mandatory precondition. The activity of the anti-EGFR antibodies is as relevant in later as in early lines of the treatment of mCRC. Cetuximab and panitumumab are active as single agents in chemorefractory mCRC. It has been shown that cetuximab improves the survival of chemorefractory patients compared with best supportive care (BSC) [I, B] [29.Jonker D.J. O'Callaghan C.J. Karapetis C.S. et al.Cetuximab for the treatment of colorectal cancer.N Engl J Med. 2007; 357: 2040-2048Crossref PubMed Scopus (1662) Google Scholar, 30.Karapetis C.S. Khambata-Ford S. Jonker D.J. et al.K-ras mutations and benefit from cetuximab in advanced colorectal cancer.N Engl J Med. 2008; 359: 1757-1765Crossref PubMed Scopus (3051) Google Scholar]. Panitumumab improves the PFS compared with BSC in chemorefractory metastatic (K)RAS WT CRC [I, B] [31.Van Cutsem E. Peeters M. Siena S. et al.Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer.J Clin Oncol. 2007; 25: 1658-1664Crossref PubMed Scopus (1693) Google Scholar, 32.Amado R.G. Wolf M. Peeters M. et al.Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer.J Clin Oncol. 2008; 26: 1626-1634Crossref PubMed Scopus (2733) Google Scholar]. The panitumumab trial did not show a survival difference due to the cross-over design of the trial [31.Van Cutsem E. Peeters M. Siena S. et al.Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer.J Clin Oncol. 2007; 25: 1658-1664Crossref PubMed Scopus (1693) Google Scholar, 32.Amado R.G. Wolf M. Peeters M. et al.Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer.J Clin Oncol. 2008; 26: 1626-1634Crossref PubMed Scopus (2733) Google Scholar]. Both anti-EGFR antibodies have a comparable clinical activity as single agents in chemorefractory patients, as shown in a phase III head-to-head comparison trial [I, B] [33.Price T.J. Peeters M. Kim T.W. et al.Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study.Lancet Oncol. 2014; 15: 569-579Abstract Full Text Full Text PDF PubMed Scopus (321) Google Scholar]. In chemorefractory patients, the combination of cetuximab with irinotecan is more active than cetuximab monotherapy [II, A] and has become the reference treatment in fit chemorefractory (K)RAS WT mCRC patients [29.Jonker D.J. O'Callaghan C.J. Karapetis C.S. et al.Cetuximab for the treatment of colorectal cancer.N Engl J Med. 2007; 357: 2040-2048Crossref PubMed Scopus (1662) Google Scholar, 31.Van Cutsem E. Peeters M. Siena S. et al.Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer.J Clin Oncol. 2007; 25: 1658-1664Crossref PubMed Scopus (1693) Google Scholar, 32.Amado R.G. Wolf M. Peeters M. et al.Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer.J Clin Oncol. 2008; 26: 1626-1634Crossref PubMed Scopus (2733) Google Scholar, 34.Cunningham D. Humblet Y. Siena S. et al.Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan refractory metastatic colorectal cancer.N Engl J Med. 2004; 351: 337-345Crossref PubMed Scopus (4521) Google Scholar]. 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Middleton G. et al.Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial.Lancet Oncol. 2013; 14: 749-759Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar]. Both cetuximab and panitumumab increase the activity of a cytotoxic doublet in the first-line treatment of (K)RAS WT patients. Survival, PFS and RR benefits have been demonstrated for the combination of FOLFIRI/cetuximab compared with FOLFIRI alone in the first-line treatment of (K)RAS WT patients [I, B] [38.Van Cutsem E. Köhne C.H. Hitre E. et al.Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer.N Engl J Med. 2009; 360: 1408-1417Crossref PubMed Scopus (3185) Google Scholar, 39.Van Cutsem E. Köhne C.H. 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Köhne C.-H. et al.Effect of KRAS and NRAS mutations on treatment outcomes in patients with metastatic colorectal cancer (mCRC) treated first-line with cetuximab plus FOLFOX4: new results from the OPUS study.J Clin Oncol. 2014; 32 (; abstr LBA444)Google Scholar]. Panitumumab also increases objective RR (ORR), PFS and OS when