ESMO Consensus Guidelines for management of patients with colon and rectal cancer. A personalized approach to clinical decision making

Ferlay, 2010, Estimates of cancer incidence and mortality in Europe in 2008, Eur J Cancer, 46, 765, 10.1016/j.ejca.2009.12.014 Jemal, 2011, Global cancer statistics, CA Cancer J Clin, 61: 69–90 Dykewicz, 2001, Summary of the Guidelines for Preventing Opportunistic Infections among Hematopoietic Stem Cell Transplant Recipients, Clin Infect Dis, 33, 139, 10.1086/321805 Ferlay, 2010, Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008, Int J Cancer, 127, 2893, 10.1002/ijc.25516 La Vecchia, 2010, Cancer mortality in Europe, 2000-2004, and an overview of trends since 1975, Ann Oncol, 21, 1323, 10.1093/annonc/mdp530 Malvezzi, 2011, European cancer mortality predictions for the year 2011, Ann Oncol, 22, 947, 10.1093/annonc/mdq774 Burn, 2011, Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial, Lancet, 378, 2081, 10.1016/S0140-6736(11)61049-0 Kohne, 2002, Clinical determinants of survival in patients with 5-fluorouracil-based treatment for metastatic colorectal cancer: results of a multivariate analysis of 3825 patients, Ann Oncol, 13, 308, 10.1093/annonc/mdf034 Graf, 1991, Determinants of prognosis in advanced colorectal cancer, Eur J Cancer, 27, 1119, 10.1016/0277-5379(91)90307-Y Graf, 1994, Appraisal of a model for prediction of prognosis in advanced colorectal cancer, Eur J Cancer, 30A, 453, 10.1016/0959-8049(94)90417-0 Kemeny, 1983, Prognostic factors in advanced colorectal carcinoma. Importance of lactic dehydrogenase level, performance status, and white blood cell count, Am J Med, 74, 786, 10.1016/0002-9343(83)91066-5 Steinberg, 1986, Prognostic indicators of colon tumors. The Gastrointestinal Tumor Study Group experience, Cancer, 57, 1866, 10.1002/1097-0142(19860501)57:9<1866::AID-CNCR2820570928>3.0.CO;2-T Seymour, 2011, Chemotherapy options in elderly and frail patients with metastatic colorectal cancer (MRC FOCUS2): an open-label, randomised factorial trial, Lancet, 377, 1749, 10.1016/S0140-6736(11)60399-1 Sorbye, 2007, Patient characteristics and stratification in medical treatment studies for metastatic colorectal cancer: a proposal for standardization of patient characteristic reporting and stratification, Ann Oncol, 18, 1666, 10.1093/annonc/mdm267 Roth, 2010, Molecular and clinical determinants of survival following relapse after curative treatment of stage II-III colon cancer (CC). Results of the translational study on the PETACC 3 - EORTC 40993 - SAKK 60-00 trial, J Clin Oncol, 28, 10.1200/JCO.2009.23.3452 Roth, 2009, Stage-specific prognostic value of molecular markers in colon cancer: Results of the translational study on the PETACC 3-EORTC 40993-SAKK 60-00 trial, J Clin Oncol, 27, 10.1200/jco.2009.27.15_suppl.4002 Sinicrope, 2011, DNA mismatch repair status and colon cancer recurrence and survival in clinical trials of 5-Fluorouracil-based adjuvant therapy, J Natl Cancer Inst, 103, 863, 10.1093/jnci/djr153 Hutchins, 2011, Value of Mismatch Repair, KRAS, and BRAF Mutations in Predicting Recurrence and Benefits From Chemotherapy in Colorectal Cancer, J Clin Oncol, 29, 1261, 10.1200/JCO.2010.30.1366 Roth, 2010, Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial, J Clin Oncol, 28, 466, 10.1200/JCO.2009.23.3452 Bertagnolli, 2011, Microsatellite instability and loss of heterozygosity at chromosomal location 18q: prospective evaluation of biomarkers for stages II and III colon cancer–a study of CALGB 9581 and 89803, J Clin Oncol, 29, 3153, 10.1200/JCO.2010.33.0092 Parsons, 2012, Correlation of tumour BRAF mutations and MLH1 methylation with germline mismatch repair (MMR) gene mutation status: a literature review assessing utility of tumour features for MMR variant classification, J Med Genet, 49, 151, 10.1136/jmedgenet-2011-100714 Ogino, 2012, Predictive and prognostic roles of BRAF mutation in stage III colon cancer: results from intergroup trial CALGB 89803, Clin Cancer Res, 18, 890, 10.1158/1078-0432.CCR-11-2246 O'Connell, 2010, Relationship between tumor gene expression and recurrence in four independent studies of patients with stage II/III colon cancer treated with surgery alone or surgery plus adjuvant fluorouracil plus leucovorin, J Clin Oncol, 28, 3937, 10.1200/JCO.2010.28.9538 Salazar, 2011, Gene expression signature to improve prognosis prediction of stage II and III colorectal cancer, J Clin Oncol, 29, 17, 10.1200/JCO.2010.30.1077 Gray, 2011, Validation study of a quantitative multigene reverse transcriptase-polymerase chain reaction assay for assessment of recurrence risk in patients with stage II colon cancer, J Clin Oncol, 29, 4611, 10.1200/JCO.2010.32.8732 Adams, 2011, Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial, Lancet Oncol, 12, 642, 10.1016/S1470-2045(11)70102-4 Russo, 2005, Prognostic and predictive factors in colorectal cancer: Kirsten Ras in CRC (RASCAL) and TP53CRC collaborative studies, Ann Oncol, 16, iv44, 10.1093/annonc/mdi907 De Roock, 2010, Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis, Lancet Oncol, 11, 753, 10.1016/S1470-2045(10)70130-3 Barault, 2008, Mutations in the RAS-MAPK, PI(3)K (phosphatidylinositol-3-OH kinase) signaling network correlate with poor survival in a population-based series of colon cancers, Int J Cancer, 122, 2255, 10.1002/ijc.23388 Tol, 2009, BRAF mutation in metastatic colorectal cancer, N Engl J Med, 361, 98, 10.1056/NEJMc0904160 Tejpar, 2009, Microsatellite instability (MSI) in stage II and III colon cancer treated with 5FU-LV or 5FU-LV and irinotecan (PETACC 3-EORTC 40993-SAKK 60/00 trial), J Clin Oncol, 27, 10.1200/jco.2009.27.15_suppl.4001 Sargent, 2010, Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer, J Clin Oncol, 28, 3219, 10.1200/JCO.2009.27.1825 Ribic, 2003, Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer, N Engl J Med, 349, 247, 10.1056/NEJMoa022289 Bertagnolli, 2009, Microsatellite instability predicts improved response to adjuvant therapy with irinotecan, fluorouracil, and leucovorin in stage III colon cancer: Cancer and Leukemia Group B Protocol 89803, J Clin Oncol, 27, 1814, 10.1200/JCO.2008.18.2071 Karapetis, 2008, K-ras mutations and benefit from cetuximab in advanced colorectal cancer, N Engl J Med, 359, 1757, 10.1056/NEJMoa0804385 Tejpar, 2012, Association of KRAS G13D Tumor Mutations With Outcome in Patients With Metastatic Colorectal Cancer Treated With First-Line Chemotherapy With or Without Cetuximab, J Clin Oncol, 10.1200/JCO.2012.42.2592 De Roock, 2010, Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab, Jama, 304, 1812, 10.1001/jama.2010.1535 Peeters, 2011, Evaluation of Individual Codon 12 and 13 Mutant (MT) KRAS Alleles as Prognostic and Predictive Biomarkers of Response to Panitumumab (pmab) in Patients with Metastatic Colorectal Cancer (mCRC), Eur J Cancer, 47, 16, 10.1016/S0959-8049(11)70132-0 Maughan, 2011, Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial, Lancet, 377, 2103, 10.1016/S0140-6736(11)60613-2 Seymour, 2011, Addition of panitumumab to irinotecan: Results of PICCOLO, a randomized controlled trial in advanced colorectal cancer (aCRC), J Clin Oncol, 29, 10.1200/jco.2011.29.15_suppl.3523 Di Nicolantonio, 2008, Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer, J Clin Oncol, 26, 5705, 10.1200/JCO.2008.18.0786 Bokemeyer, 2012, Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials, Eur J Cancer, 48, 1466, 10.1016/j.ejca.2012.02.057 Price, 2011, Impact of KRAS and BRAF Gene Mutation Status on Outcomes From the Phase III AGITG MAX Trial of Capecitabine Alone or in Combination With Bevacizumab and Mitomycin in Advanced Colorectal Cancer, J Clin Oncol, 29, 2675, 10.1200/JCO.2010.34.5520 Hurwitz, 2009, The clinical benefit of bevacizumab in metastatic colorectal cancer is independent of K-ras mutation status: analysis of a phase III study of bevacizumab with chemotherapy in previously untreated metastatic colorectal cancer, Oncologist, 14, 22, 10.1634/theoncologist.2008-0213 Weickhardt, 2011, Vascular endothelial growth factors (VEGF) and VEGF receptor expression as predictive biomarkers for benefit with bevacizumab in metastatic colorectal cancer (mCRC): Analysis of the phase III MAX study, J Clin Oncol, 29, 10.1200/jco.2011.29.15_suppl.3531 Kopetz, 2010, Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: efficacy and circulating angiogenic biomarkers associated with therapeutic resistance, J Clin Oncol, 28, 453, 10.1200/JCO.2009.24.8252 Loupakis, 2011, Pharmacodynamic and pharmacogenetic angiogenesis-related markers of first-line FOLFOXIRI plus bevacizumab schedule in metastatic colorectal cancer, Br J Cancer, 104, 1262, 10.1038/bjc.2011.85 Braun, 2008, Predictive biomarkers of chemotherapy efficacy in colorectal cancer: results from the UK MRC FOCUS trial, J Clin Oncol, 26, 2690, 10.1200/JCO.2007.15.5580 Koopman, 2009, 7, 321 Koopman, 2009, Predictive and prognostic markers for the outcome of chemotherapy in advanced colorectal cancer, a retrospective analysis of the phase III randomised CAIRO study, Eur J Cancer, 45, 1999, 10.1016/j.ejca.2009.04.017 Boige, 2010, Pharmacogenetic assessment of toxicity and outcome in patients with metastatic colorectal cancer treated with LV5FU2, FOLFOX, and FOLFIRI: FFCD 2000-05, J Clin Oncol, 28, 2556, 10.1200/JCO.2009.25.2106 Glimelius, 2011, Mesorectal fascia instead of circumferential resection margin in preoperative staging of rectal cancer, J Clin Oncol, 29, 2142, 10.1200/JCO.2010.34.4473 Bipat, 2004, Rectal cancer: local staging and assessment of lymph node involvement with endoluminal US, CT, and MR imaging–a meta-analysis, Radiology, 232, 773, 10.1148/radiol.2323031368 Kim, 2009, Locally advanced rectal cancer: added value of diffusion-weighted MR imaging in the evaluation of tumor response to neoadjuvant chemo- and radiation therapy, Radiology, 253, 116, 10.1148/radiol.2532090027 Lambregts, 2011, Diffusion-weighted MRI for selection of complete responders after chemoradiation for locally advanced rectal cancer: a multicenter study, Ann Surg Oncol, 18, 2224, 10.1245/s10434-011-1607-5 Curvo-Semedo, 2011, Rectal cancer: assessment of complete response to preoperative combined radiation therapy with chemotherapy–conventional MR volumetry versus diffusion-weighted MR imaging, Radiology, 260, 734, 10.1148/radiol.11102467 van Stiphout, 2011, Development and external validation of a predictive model for pathological complete response of rectal cancer patients including sequential PET-CT imaging, Radiother Oncol, 98, 126, 10.1016/j.radonc.2010.12.002 Nagtegaal, 2005, Low rectal cancer: a call for a change of approach in abdominoperineal resection, J Clin Oncol, 23, 9257, 10.1200/JCO.2005.02.9231 Nagtegaal, 2012, Has the new TNM classification for colorectal cancer improved care?, Nat Rev Clin Oncol, 9, 119, 10.1038/nrclinonc.2011.157 Hofheinz, 2012, Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial, Lancet Oncol, 13, 579, 10.1016/S1470-2045(12)70116-X Roh, 2011, The impact of capecitabine and oxaliplatin in the preoperative multimodality treatment in patients with carcinoma of the rectum: NSABP R-04, J Clin Oncol, 29, 10.1200/jco.2011.29.15_suppl.3503 Gerard, 2010, Comparison of two neoadjuvant chemoradiotherapy regimens for locally advanced rectal cancer: results of the phase III trial ACCORD 12/0405-Prodige 2, J Clin Oncol, 28, 1638, 10.1200/JCO.2009.25.8376 Aschele, 2011, Primary Tumor Response to Preoperative Chemoradiation With or Without Oxaliplatin in Locally Advanced Rectal Cancer: Pathologic Results of the STAR-01 Randomized Phase III Trial, J Clin Oncol, 29, 2773, 10.1200/JCO.2010.34.4911 Rodel, 2012, Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial, Lancet Oncol, 13, 679, 10.1016/S1470-2045(12)70187-0 Bonnetain, 2011, An analysis of preoperative chemoradiotherapy with 5FU/leucovorin for T3-4 rectal cancer on survival in a pooled analysis of EORTC 22921 and FFCD 9203 trials: Surrogacy in question?, J Clin Oncol, 29, 10.1200/jco.2011.29.15_suppl.3506 Ceelen, 2009, Preoperative chemoradiation versus radiation alone for stage II and III resectable rectal cancer: a systematic review and meta-analysis, Int J Cancer, 124, 2966, 10.1002/ijc.24247 Valentini, 2011, Nomograms for predicting local recurrence, distant metastases, and overall survival for patients with locally advanced rectal cancer on the basis of European randomized clinical trials, J Clin Oncol, 29, 3163, 10.1200/JCO.2010.33.1595 Sauer, 2004, Preoperative versus postoperative chemoradiotherapy for rectal cancer, N Engl J Med, 351, 1731, 10.1056/NEJMoa040694 Roh, 2009, Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03, J Clin Oncol, 27, 5124, 10.1200/JCO.2009.22.0467 Frykholm, 1993, Preoperative or postoperative irradiation in adenocarcinoma of the rectum: final treatment results of a randomized trial and an evaluation of late secondary effects, Dis Colon Rectum, 36, 564, 10.1007/BF02049863 Fernandez-Martos, 2010, J Clin Oncol, 28, 859, 10.1200/JCO.2009.25.8541 Chau, 2006, Neoadjuvant capecitabine and oxaliplatin followed by synchronous chemoradiation and total mesorectal excision in magnetic resonance imaging-defined poor-risk rectal cancer, J Clin Oncol, 24, 668, 10.1200/JCO.2005.04.4875 Maréchal, 2010, Chemotherapy induction followed by preoperative chemoradiation versus preoperative chemoradiation alone in locally advanced rectal cancer (LARC): A randomized controlled phase II study, J Clin Oncol, 28, 10.1200/jco.2010.28.15_suppl.3637 Dewdney, 2011, J Clin Oncol, 29 Schrag, 2010, Neoadjuvant FOLFOX-bev, without radiation, for locally advanced rectal cancer, J Clin Oncol, 28, 10.1200/jco.2010.28.15_suppl.3511 Maas, 2011, Wait-and-See Policy for Clinical Complete Responders After Chemoradiation for Rectal Cancer, J Clin Oncol, 29, 4633, 10.1200/JCO.2011.37.7176 Rouanet, 2006, Sphincter preserving surgery after preoperative treatment for ultra-low rectal carcinoma. A French multicenter prospective trial: GRECCAR 1, J Clin Oncol, 24, 10.1200/jco.2006.24.18_suppl.3527 Prolongation of the disease-free interval in surgically treated rectal carcinoma, 1985, Gastrointestinal Tumor Study Group, N Engl J Med, 312, 1465 O'Connell, 1994, Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery, N Engl J Med, 331, 502, 10.1056/NEJM199408253310803 Kim, 2011, Randomized trial of postoperative adjuvant therapy in Stage II and III rectal cancer to define the optimal sequence of chemotherapy and radiotherapy: 10-year follow-up, Int J Radiat Oncol Biol Phys, 81, 1025, 10.1016/j.ijrobp.2010.07.012 Tveit, 1997, Randomized controlled trial of postoperative radiotherapy and short-term time-scheduled 5-fluorouracil against surgery alone in the treatment of Dukes B and C rectal cancer. Norwegian Adjuvant Rectal Cancer Project Group, Br J Surg, 84, 1130 Krook, 1991, Effective surgical adjuvant therapy for high-risk rectal carcinoma, N Engl J Med, 324, 709, 10.1056/NEJM199103143241101 Li, 1992, [Combination of surgery, radiotherapy and chemotherapy for rectal cancer–a 423 cases report], Zhonghua Zhong Liu Za Zhi, 14, 213 Bosset, 2006, Chemotherapy with preoperative radiotherapy in rectal cancer, N Engl J Med, 355, 1114, 10.1056/NEJMoa060829 Gray, 2007, Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study, Lancet, 370, 2020, 10.1016/S0140-6736(07)61866-2 Cionini L, 2010, Final results of randomized trial on adjuvant chemotherapy after preoperative chemoradiation in rectal cancer, Radiother Oncol, 96, S113 Gray, 2008, Adjuvant chemotherapy for rectal cancer: authors' reply, Lancet, 371, 1503, 10.1016/S0140-6736(08)60651-0 Collette, 2007, J Clin Oncol, 25, 4379, 10.1200/JCO.2007.11.9685 Bujko, 2010, Does adjuvant fluoropyrimidine-based chemotherapy provide a benefit for patients with resected rectal cancer who have already received neoadjuvant radiochemotherapy? A systematic review of randomised trials, Ann Oncol, 21, 1743, 10.1093/annonc/mdq054 Glimelius, 2010, Adjuvant chemotherapy in rectal cancer–an issue or a nonissue?, Ann Oncol, 21, 1739, 10.1093/annonc/mdq263 Nordlinger, 2008, Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial, Lancet, 371, 1007, 10.1016/S0140-6736(08)60455-9 Morton, 2011, FOxTROT: Randomized phase II study of neoadjuvant chemotherapy (CT) with or without an anti-EGFR monoclonal antibody for locally advanced, operable colon cancer: Planned interim report, J Clin Oncol, 29, 10.1200/jco.2011.29.15_suppl.3568 Quah, 2008, Identification of patients with high-risk stage II colon cancer for adjuvant therapy, Dis Colon Rectum, 51, 503, 10.1007/s10350-008-9246-z Chang, 2007, Lymph node evaluation and survival after curative resection of colon cancer: systematic review, J Natl Cancer Inst, 99, 433, 10.1093/jnci/djk092 Teixeira, 2010, Efficacy of FOLFOX4 as adjuvant therapy in stage II colon cancer (CC): A new analysis of the MOSAIC trial according to risk factors, J Clin Oncol, 28, 10.1200/jco.2010.28.15_suppl.3524 Yothers, 2011, The efficacy of oxaliplatin (Ox) when added to 5-fluorouracil/leucovorin (FU/L) in stage II colon cancer, J Clin Oncol, 29, 10.1200/jco.2011.29.15_suppl.3507 Kuebler, 2007, Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07, J Clin Oncol, 25, 2198, 10.1200/JCO.2006.08.2974 Andre, 2004, Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer, N Engl J Med, 350, 2343, 10.1056/NEJMoa032709 Andre, 2009, Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial, J Clin Oncol, 27, 3109, 10.1200/JCO.2008.20.6771 Haller, 2011, Capecitabine Plus Oxaliplatin Compared With Fluorouracil and Folinic Acid As Adjuvant Therapy for Stage III Colon Cancer, J Clin Oncol, 29, 1465, 10.1200/JCO.2010.33.6297 Schmoll, 2007, Phase III trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: a planned safety analysis in 1,864 patients, J Clin Oncol, 25, 102, 10.1200/JCO.2006.08.1075 Lembersky, 2006, Oral uracil and tegafur plus leucovorin compared with intravenous fluorouracil and leucovorin in stage II and III carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project Protocol C-06, J Clin Oncol, 24, 2059, 10.1200/JCO.2005.04.7498 Twelves, 2005, Capecitabine as adjuvant treatment for stage III colon cancer, N Engl J Med, 352, 2696, 10.1056/NEJMoa043116 Jackson McCleary, 2009, Impact of older age on the efficacy of newer adjuvant therapies in >12,500 patients (pts) with stage II/III colon cancer: Findings from the ACCENT Database, J Clin Oncol, 27, 10.1200/jco.2009.27.15_suppl.4010 Haller, 2010, Efficacy findings from a randomized phase III trial of capecitabine plus oxaliplatin versus bolus 5-FU/LV for stage III colon cancer (NO16968): Impact of age on disease-free survival (DFS), J Clin Oncol, 28, 10.1200/jco.2010.28.15_suppl.3521 Sanoff, 2012, Comparative Effectiveness of Oxaliplatin vs Non-Oxaliplatin-containing Adjuvant Chemotherapy for Stage III Colon Cancer, J Natl Cancer Inst, 104, 211, 10.1093/jnci/djr524 O'Connor, 2011, Adjuvant Chemotherapy for Stage II Colon Cancer With Poor Prognostic Features, J Clin Oncol, 29, 3381, 10.1200/JCO.2010.34.3426 Chau, 2005, A randomised comparison between 6 months of bolus fluorouracil/leucovorin and 12 weeks of protracted venous infusion fluorouracil as adjuvant treatment in colorectal cancer, Ann Oncol, 16, 549, 10.1093/annonc/mdi116 Berglund, 2008, Is it deleterious to delay the start of adjuvant chemotherapy in colon cancer stage III?, Ann Oncol, 19, 400, 10.1093/annonc/mdm582 Hershman, 2006, Timing of adjuvant chemotherapy initiation after surgery for stage III colon cancer, Cancer, 107, 2581, 10.1002/cncr.22316 Biagi, 2011, Association between time to initiation of adjuvant chemotherapy and survival in colorectal cancer: a systematic review and meta-analysis, Jama, 305, 2335, 10.1001/jama.2011.749 Andre, 2003, Semimonthly versus monthly regimen of fluorouracil and leucovorin administered for 24 or 36 weeks as adjuvant therapy in stage II and III colon cancer: results of a randomized trial, J Clin Oncol, 21, 2896, 10.1200/JCO.2003.10.065 Poultsides, 2009, Outcome of primary tumor in patients with synchronous stage IV colorectal cancer receiving combination chemotherapy without surgery as initial treatment, J Clin Oncol, 27, 3379, 10.1200/JCO.2008.20.9817 McCahill, 2010, A phase II trial of 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) chemotherapy plus bevacizumab (bev) for patients (pts) with unresectable stage IV colon cancer and a synchronous asymptomatic primary tumor: Results of NSABP C-10, J Clin Oncol, 28, 10.1200/jco.2010.28.15_suppl.3527 Weber, 2000, Survival after resection of multiple hepatic colorectal metastases. Ann Surg Oncol, 7, 643 Choti, 2002, Trends in long-term survival following liver resection for hepatic colorectal metastases, Ann Surg, 235, 759, 10.1097/00000658-200206000-00002 Tomlinson, 2007, Actual 10-year survival after resection of colorectal liver metastases defines cure, J Clin Oncol, 25, 4575, 10.1200/JCO.2007.11.0833 Adam, 2011, Impact of the type and modalities of preoperative chemotherapy on the outcome of liver resection for colorectal metastases, J Clin Oncol, 29, 10.1200/jco.2011.29.15_suppl.3519 Mitry, 2008, Adjuvant chemotherapy after potentially curative resection of metastases from colorectal cancer: a pooled analysis of two randomized trials, J Clin Oncol, 26, 4906, 10.1200/JCO.2008.17.3781 Portier, 2006, Multicenter randomized trial of adjuvant fluorouracil and folinic acid compared with surgery alone after resection of colorectal liver metastases: FFCD ACHBTH AURC 9002 trial, J Clin Oncol, 24, 4976, 10.1200/JCO.2006.06.8353 Langer, 2002, Fluorouracil (FU) plus l-leucovorin (l-LV) versus observation after potentially curative resection of liver or lung metastases from colorectal cancer (CRC): results of the ENG (EORTC/NCIC CTG/GIVIO) randomized trial, Proc Am Soc Clin Oncol, 21 Ychou, 2009, A randomized phase III study comparing adjuvant 5-fluorouracil/folinic acid with FOLFIRI in patients following complete resection of liver metastases from colorectal cancer, Ann Oncol, 20, 1964, 10.1093/annonc/mdp236 Kemeny, 1999, Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer, N Engl J Med, 341, 2039, 10.1056/NEJM199912303412702 Kemeny, 2002, Combined-modality treatment for resectable metastatic colorectal carcinoma to the liver: surgical resection of hepatic metastases in combination with continuous infusion of chemotherapy–an intergroup study, J Clin Oncol, 20, 1499 Voest, 2011, A randomized two-arm phase III study to investigate bevacizumab in combination with capecitabine plus oxaliplatin (CAPOX) versus CAPOX alone in post radical resection of patients with liver metastases of colorectal cancer, J Clin Oncol, 29, 10.1200/jco.2011.29.15_suppl.3565 Gaujoux, 2011, Complete radiological response of colorectal liver metastases after chemotherapy: what can we expect?, Dig Surg, 28, 114, 10.1159/000323820 Benoist, 2006, Complete response of colorectal liver metastases after chemotherapy: does it mean cure?, J Clin Oncol, 24, 3939, 10.1200/JCO.2006.05.8727 Adam, 2004, Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival, Ann Surg, 240, 644, 10.1097/01.sla.0000141198.92114.f6 Neumann, 2009, Nonresponse to pre-operative chemotherapy does not preclude long-term survival after liver resection in patients with colorectal liver metastases, Surgery, 146, 52, 10.1016/j.surg.2009.02.004 de Haas, 2008, R1 resection by necessity for colorectal liver metastases: is it still a contraindication to surgery?, Ann Surg, 248, 626, 10.1097/SLA.0b013e31818a07f1 Khatri, 2005, Extending the frontiers of surgical therapy for hepatic colorectal metastases: is there a limit?, J Clin Oncol, 23, 8490, 10.1200/JCO.2004.00.6155 Engels, 2011, Phase II study of helical tomotherapy for oligometastatic colorectal cancer, Ann Oncol, 22, 362, 10.1093/annonc/mdq385 Wong, 2010, 2009 clinical evidence review on radiofrequency ablation of hepatic metastases from colorectal cancer, J Clin Oncol, 28, 493, 10.1200/JCO.2009.23.4450 Ruers, 2012, Radiofrequency ablation combined with systemic treatment versus systemic treatment alone in patients with non-resectable colorectal liver metastases: a randomized EORTC Intergroup phase II study (EORTC 40004), Ann Oncol, 10.1093/annonc/mds053 Inoue, 2004, Benefits of surgery for patients with pulmonary metastases from colorectal carcinoma, Ann Thorac Surg, 78, 238, 10.1016/j.athoracsur.2004.02.017 Kabbinavar, 2009, Addition of bevacizumab to fluorouracil-based first-line treatment of metastatic colorectal cancer: pooled analysis of cohorts of older patients from two randomized clinical trials, J Clin Oncol, 27, 199, 10.1200/JCO.2008.17.7931 Sargent, 2009, Pooled safety and efficacy analysis examining the effect of performance status on outcomes in nine first-line treatment trials using individual data from patients with metastatic colorectal cancer, J Clin Oncol, 27, 1948, 10.1200/JCO.2008.20.2879 Folprecht, 2008, Irinotecan/fluorouracil combination in first-line therapy of older and younger patients with metastatic colorectal cancer: combined analysis of 2,691 patients in randomized controlled trials, J Clin Oncol, 26, 1443, 10.1200/JCO.2007.14.0509 Goldberg, 2006, Pooled analysis of safety and efficacy of oxaliplatin plus fluorouracil/leucovorin administered bimonthly in elderly patients with colorectal cancer, J Clin Oncol, 24, 4085, 10.1200/JCO.2006.06.9039 Arkenau, 2008, Efficacy of oxaliplatin plus capecitabine or infusional fluorouracil/leucovorin in patients with metastatic colorectal cancer: a pooled analysis of randomized trials, J Clin Oncol, 26, 5910, 10.1200/JCO.2008.16.7759 Rothenberg, 2008, Capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/folinic acid plus oxaliplatin (FOLFOX-4) as second-line therapy in metastatic colorectal cancer: a randomized phase III noninferiority study, Ann Oncol, 19, 1720, 10.1093/annonc/mdn370 Porschen, 2007, Phase III study of capecitabine plus oxaliplatin compared with fluorouracil and leucovorin plus oxaliplatin in metastatic colorectal cancer: a final report of the AIO Colorectal Study Group, J Clin Oncol, 25, 4217, 10.1200/JCO.2006.09.2684 Diaz-Rubio, 2007, J Clin Oncol, 25, 4224, 10.1200/JCO.2006.09.8467 Cassidy, 2008, 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, 26, 2006, 10.1200/JCO.2007.14.9898 Kohne, 2008, Irinotecan combined with infusional 5-fluorouracil/folinic acid or capecitabine plus celecoxib or placebo in the first-line treatment of patients with metastatic colorectal cancer. EORTC study 40015, Ann Oncol, 19, 920, 10.1093/annonc/mdm544 Fuchs, 2007, Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study, J Clin Oncol, 25, 4779, 10.1200/JCO.2007.11.3357 Jordan, 2004, Phase II trial of capecitabine/irinotecan and capecitabine/oxaliplatin in advanced gastrointestinal cancers, Clin Colorectal Cancer, 4, 46, 10.3816/CCC.2004.n.009 Koopman, 2007, Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial, Lancet, 370, 135, 10.1016/S0140-6736(07)61086-1 Reinacher-Schick, 2008, Activity of the combination of bevacizumab (Bev) with capecitabine/irinotecan (CapIri/Bev) or capecitabine/oxaliplatin (CapOx/Bev) in advanced colorectal cancer (ACRC): A randomized phase II study of the AIO Colorectal Study Group (AIO trial 0604), J Clin Oncol, 26, 10.1200/jco.2008.26.15_suppl.4030 Ducreux, 2009, Efficacy and safety of bevacizumab (BEV)-based combination regimens in patients with metastatic colorectal cancer (mCRC): Randomized phase II study of BEV+FOLFIRI versus BEV+XELIRI (FNCLCC ACCORD 13/0503 study), J Clin Oncol, 27, 10.1200/jco.2009.27.15_suppl.4086 Muro, 2010, Irinotecan plus S-1 (IRIS) versus fluorouracil and folinic acid plus irinotecan (FOLFIRI) as second-line chemotherapy for metastatic colorectal cancer: a randomised phase 2/3 non-inferiority study (FIRIS study), Lancet Oncol, 11, 853, 10.1016/S1470-2045(10)70181-9 Morelli, 2010, Triplet schedule of weekly 5-fluorouracil and alternating irinotecan or oxaliplatin in advanced colorectal cancer: a dose-finding and phase II study, Oncol Rep, 23, 1635 Souglakos, 2006, Br J Cancer, 94, 798, 10.1038/sj.bjc.6603011 Falcone, 2007, J Clin Oncol, 25, 1670, 10.1200/JCO.2006.09.0928 Ychou, 2008, Tritherapy with fluorouracil/leucovorin, irinotecan and oxaliplatin (FOLFIRINOX): a phase II study in colorectal cancer patients with non-resectable liver metastases, Cancer Chemother Pharmacol, 62, 195, 10.1007/s00280-007-0588-3 Bajetta, 2007, Capecitabine plus oxaliplatin and irinotecan regimen every other week: a phase I/II study in first-line treatment of metastatic colorectal cancer, Ann Oncol, 18, 1810, 10.1093/annonc/mdm347 Vasile, 2009, A multicenter phase II study of the combination of oxaliplatin, irinotecan and capecitabine in the first-line treatment of metastatic colorectal cancer, Br J Cancer, 100, 1720, 10.1038/sj.bjc.6605075 Zarate, 2010, Oxaliplatin, irinotecan and capecitabine as first-line therapy in metastatic colorectal cancer (mCRC): a dose-finding study and pharmacogenomic analysis, Br J Cancer, 102, 987, 10.1038/sj.bjc.6605595 von Moos, 2010, Oxaliplatin, irinotecan and capecitabine (OCX) for first-line treatment of advanced/metastatic colorectal cancer: a phase I trial (SAKK 41/03), Onkologie, 33, 295, 10.1159/000313598 Tebbutt, 2010, 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, 28, 3191, 10.1200/JCO.2009.27.7723 Kabbinavar, 2005, Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial, J Clin Oncol, 23, 3697, 10.1200/JCO.2005.05.112 Hurwitz, 2004, Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer, N Engl J Med, 350, 2335, 10.1056/NEJMoa032691 Hochster, 2008, Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study, J Clin Oncol, 26, 3523, 10.1200/JCO.2007.15.4138 Saltz, 2008, Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study, J Clin Oncol, 26, 2013, 10.1200/JCO.2007.14.9930 Douillard, 2010, 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, 28, 4697, 10.1200/JCO.2009.27.4860 Van Cutsem, 2011, Cetuximab Plus Irinotecan, Fluorouracil, and Leucovorin As First-Line Treatment for Metastatic Colorectal Cancer: Updated Analysis of Overall Survival According to Tumor KRAS and BRAF Mutation Status, J Clin Oncol, 29, 2011, 10.1200/JCO.2010.33.5091 Douillard, 2011, Final results from PRIME: Randomized phase III study of panitumumab (pmab) with FOLFOX4 for first 2011 line metastatic colorectal cancer (mCRC), J Clin Oncol, 29, 10.1200/jco.2011.29.15_suppl.3510 Van Cutsem, 2009, Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer, N Engl J Med, 360, 1408, 10.1056/NEJMoa0805019 Bokemeyer, 2010, Cetuximab with chemotherapy (CT) as first-line treatment for metastatic colorectal cancer (mCRC): Analysis of the CRYSTAL and OPUS studies according to KRAS and BRAF mutation status, J Clin Oncol, 28, 10.1200/jco.2010.28.15_suppl.3506 Bokemeyer, 2011, Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study, Ann Oncol, 22, 1535, 10.1093/annonc/mdq632 Folprecht, 2010, Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase 2 trial, Lancet Oncol, 11, 38, 10.1016/S1470-2045(09)70330-4 Kohne, 2011, Efficacy of chemotherapy plus cetuximab according to metastatic site in KRAS wild-type metastatic colorectal cancer (mCRC): Analysis of CRYSTAL and OPUS studies, J Clin Oncol, 29, 10.1200/jco.2011.29.15_suppl.3576 Tveit, 2010, Randomized Phase III study of 5-Fluorouracil/folinate/oxaliplatin given continously or intermittently with or without cetuximab, as first-line treatment of metastatic colorectal cancer: The NORDIC VII study (NCT00145314), Ann Oncol, 21 Bokemeyer, 2009, Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer, J Clin Oncol, 27, 663, 10.1200/JCO.2008.20.8397 Tol, 2009, Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer, N Engl J Med, 360, 563, 10.1056/NEJMoa0808268 Hecht, 2009, A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer, J Clin Oncol, 27, 672, 10.1200/JCO.2008.19.8135 Nalluri, 2008, Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis, JAMA, 300, 2277, 10.1001/jama.2008.656 Ranpura, 2010, Risk of cardiac ischemia and arterial thromboembolic events with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis of randomized controlled trials, Acta Oncol, 49, 287, 10.3109/02841860903524396 Ranpura, 2010, Increased risk of high-grade hypertension with bevacizumab in cancer patients: a meta-analysis, Am J Hypertens, 23, 460, 10.1038/ajh.2010.25 Nie, 2009, Meta-analysis: the efficacy and safety of monoclonal antibody targeted to epidermal growth factor receptor in the treatment of patients with metastatic colorectal cancer, J Dig Dis, 10, 247, 10.1111/j.1751-2980.2009.00393.x Su, 2009, Risk of high-grade skin rash in cancer patients treated with cetuximab–an antibody against epidermal growth factor receptor: systemic review and meta-analysis, Oncology, 77, 124, 10.1159/000229752 Van Cutsem, 2012, 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, 10.1200/JCO.2012.42.8201 Pericay, 2012, Phase 2 randomized, noncomparative open-label study of aflibercept and modified FOLFOX6 in the first line treatment of metastatic colorectal cancer (AFFIRM), Ann Oncol, 23, O, 10.1016/S0923-7534(19)66488-4 Grothey, 2012, J Clin Oncol, 30, 10.1200/JCO.2011.40.4194 Van Cutsem, 2011, A Phase I/II, Open-label, Randomised Study of BIBF 1120 Plus mFOLFOX6 Compared to Bevacizumab Plus mFOLFOX6 in Patients with Metastatic Colorectal Cancer, Eur J Cancer, 47, 12, 10.1016/S0959-8049(11)70113-7 Schmoll, 2012, Cediranib With mFOLFOX6 Versus Bevacizumab With mFOLFOX6 As First-Line Treatment for Patients With Advanced Colorectal Cancer: A Double-Blind, Randomized Phase III Study (HORIZON III), J Clin Oncol, 10.1200/JCO.2012.42.5355 Alberts, 2005, Oxaliplatin, fluorouracil, and leucovorin for patients with unresectable liver-only metastases from colorectal cancer: a North Central Cancer Treatment Group phase II study, J Clin Oncol, 23, 9243, 10.1200/JCO.2005.07.740 Quenet F, 2004, Resection of previously unresectable liver metastases from colorectal cancer after chemotherapy with CPT-11/L-OHP/LV5FU (Folfirinox): A prospective phase II trial, Proc Am Soc Clin Oncol, 23 Giacchetti, 1999, Long-term survival of patients with unresectable colorectal cancer liver metastases following infusional chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin and surgery, Ann Oncol, 10, 663, 10.1023/A:1008347829017 Garufi, 2009, POCHER (preoperative chemotherapy for hepatic resection) with cetuximab (Cmab) plus CPT-11/5-fluorouracil (5-FU)/leucovorin(FA)/oxaliplatin (L-OHP) (CPT-11-FFL) in unresectable colorectal liver metastases (CLM), J Clin Oncol, 27, 10.1200/jco.2009.27.15_suppl.e15020 Masi, 2010, Bevacizumab with FOLFOXIRI (irinotecan, oxaliplatin, fluorouracil, and folinate) as first-line treatment for metastatic colorectal cancer: a phase 2 trial, Lancet Oncol, 11, 845, 10.1016/S1470-2045(10)70175-3 Bruera, 2010, "Poker" association of weekly alternating 5-fluorouracil, irinotecan, bevacizumab and oxaliplatin (FIr-B/FOx) in first line treatment of metastatic colorectal cancer: a phase II study, BMC Cancer, 10, 567, 10.1186/1471-2407-10-567 Wong, 2011, A multicentre study of capecitabine, oxaliplatin plus bevacizumab as perioperative treatment of patients with poor-risk colorectal liver-only metastases not selected for upfront resection, Ann Oncol, 22, 2042, 10.1093/annonc/mdq714 Cassidy, 2008, Surgery with curative intent in patients (pts) treated with first-line chemotherapy (CT)+bevacizumab (BEV) for metastatic colorectal cancer (mCRC): First BEAT and NO16966, J Clin Oncol, 26, 10.1200/jco.2008.26.15_suppl.4022 Grothey, 2005, Overall survival of patients with advanced colorectal cancer correlates with availability of fluorouracil, irinotecan, and oxaliplatin regardless of whether doublet or single-agent therapy is used first line, J Clin Oncol, 23, 9441, 10.1200/JCO.2005.04.4792 Seymour, 2007, Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial, Lancet, 370, 143, 10.1016/S0140-6736(07)61087-3 Cunningham, 2009, Two different first-line 5-fluorouracil regimens with or without oxaliplatin in patients with metastatic colorectal cancer, Ann Oncol, 20, 244, 10.1093/annonc/mdn638 Ackland, 2005, A meta-analysis of two randomised trials of early chemotherapy in asymptomatic metastatic colorectal cancer, Br J Cancer, 93, 1236, 10.1038/sj.bjc.6602841 Nordic Gastrointestinal Tumor Adjuvant Therapy Group, 1992, Expectancy or primary chemotherapy in patients with advanced asymptomatic colorectal cancer: a randomized trial, J Clin Oncol, 10, 904, 10.1200/JCO.1992.10.6.904 Vauthey, 2006, Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases, J Clin Oncol, 24, 2065, 10.1200/JCO.2005.05.3074 Nakano, 2008, Sinusoidal injury increases morbidity after major hepatectomy in patients with colorectal liver metastases receiving preoperative chemotherapy, Ann Surg, 247, 118, 10.1097/SLA.0b013e31815774de Benoist, 2009, The role of preoperative chemotherapy in patients with resectable colorectal liver metastases, Ann Surg Oncol, 16, 2385, 10.1245/s10434-009-0492-7 Folprecht, 2005, Neoadjuvant treatment of unresectable colorectal liver metastases: correlation between tumour response and resection rates, Ann Oncol, 16, 1311, 10.1093/annonc/mdi246 Tournigand, 2006, OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-Go fashion in advanced colorectal cancer–a GERCOR study, J Clin Oncol, 24, 394, 10.1200/JCO.2005.03.0106 Chibaudel, 2009, Can chemotherapy be discontinued in unresectable metastatic colorectal cancer? The GERCOR OPTIMOX2 Study, J Clin Oncol, 27, 5727, 10.1200/JCO.2009.23.4344 Labianca, 2011, Intermittent versus continuous chemotherapy in advanced colorectal cancer: a randomised 'GISCAD' trial, Ann Oncol, 22, 1236, 10.1093/annonc/mdq580 Maughan, 2003, Comparison of intermittent and continuous palliative chemotherapy for advanced colorectal cancer: a multicentre randomised trial, Lancet, 361, 457, 10.1016/S0140-6736(03)12461-0 Grothey, 2008, Intermittent oxaliplatin (oxali) administration and time-to-treatment-failure (TTF) in metastatic colorectal cancer (mCRC): Final results of the phase III CONcePT trial, J Clin Oncol, 26, 10.1200/jco.2008.26.15_suppl.4010 Diaz-Rubio, 2012, First-Line XELOX Plus Bevacizumab Followed by XELOX Plus Bevacizumab or Single-Agent Bevacizumab as Maintenance Therapy in Patients with Metastatic Colorectal Cancer: The Phase III MACRO TTD Study, Oncologist, 17, 15, 10.1634/theoncologist.2011-0249 Wasan, 2012, Intermittent chemotherapy (CT) plus continuous or intermittent cetuximab (C) in the first-line treatment of advanced colorectal cancer (aCRC): Results of the two-arm phase II randomized MRC COIN-b trial, J Clin Oncol, 30, 10.1200/jco.2012.30.4_suppl.536 Rothenberg, 2003, Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial, J Clin Oncol, 21, 2059, 10.1200/JCO.2003.11.126 Arnold, 2012, Bevacizumab (BEV) plus chemotherapy (CT) continued beyond first progression in patients with metastatic colorectal cancer (mCRC) previously treated with BEV plus CT: Results of a randomized phase III intergroup study (TML study), J Clin Oncol, 30, CRA3503, 10.1200/jco.2012.30.15_suppl.cra3503 Tournigand, 2004, FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study, J Clin Oncol, 22, 229, 10.1200/JCO.2004.05.113 Giantonio, 2007, 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, 25, 1539, 10.1200/JCO.2006.09.6305 Peeters, 2010, Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer, J Clin Oncol, 28, 4706, 10.1200/JCO.2009.27.6055 Van Cutsem, 2007, 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, 25, 1658, 10.1200/JCO.2006.08.1620 Cunningham, 2004, Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer, N Engl J Med, 351, 337, 10.1056/NEJMoa033025 Sobrero, 2008, EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer, J Clin Oncol, 26, 2311, 10.1200/JCO.2007.13.1193 Wilke, 2008, Cetuximab plus irinotecan in heavily pretreated metastatic colorectal cancer progressing on irinotecan: MABEL Study, J Clin Oncol, 26, 5335, 10.1200/JCO.2008.16.3758 Jonker, 2007, Cetuximab for the treatment of colorectal cancer, N Engl J Med, 357, 2040, 10.1056/NEJMoa071834 Roila, 2010, Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference, Ann Oncol, 21, v232, 10.1093/annonc/mdq194 Rapoport, 2010, Aprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with a broad range of moderately emetogenic chemotherapies and tumor types: a randomized, double-blind study, Support Care Cancer, 18, 423, 10.1007/s00520-009-0680-9 Wolf, 2010, Placebo-controlled trial to determine the effectiveness of a urea/lactic acid-based topical keratolytic agent for prevention of capecitabine-induced hand-foot syndrome: North Central Cancer Treatment Group Study N05C5, J Clin Oncol, 28, 5182, 10.1200/JCO.2010.31.1431 Kang, 2010, Pyridoxine is not effective to prevent hand-foot syndrome associated with capecitabine therapy: results of a randomized, double-blind, placebo-controlled study, J Clin Oncol, 28, 3824, 10.1200/JCO.2010.29.1807 Zhang, 2011, The effect of COX-2 inhibitor on capecitabine-induced hand-foot syndrome in patients with stage II/III colorectal cancer: a phase II randomized prospective study, J Cancer Res Clin Oncol, 137, 953, 10.1007/s00432-010-0958-9 Lacouture, 2010, Skin toxicity evaluation protocol with panitumumab (STEPP), a phase II, open-label, randomized trial evaluating the impact of a pre-Emptive Skin treatment regimen on skin toxicities and quality of life in patients with metastatic colorectal cancer, J Clin Oncol, 28, 1351, 10.1200/JCO.2008.21.7828 Potthoff, 2011, Interdisciplinary management of EGFR-inhibitor-induced skin reactions: a German expert opinion, Ann Oncol, 22, 524, 10.1093/annonc/mdq387 de Gramont, 2000, Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer, J Clin Oncol, 18, 2938, 10.1200/JCO.2000.18.16.2938 Albers, 2011, Interventions for preventing neuropathy caused by cisplatin and related compounds, Cochrane Database Syst Rev, 2, 10.1002/14651858.CD005228.pub3 Grothey, 2011, Intravenous calcium and magnesium for oxaliplatin-induced sensory neurotoxicity in adjuvant colon cancer: NCCTG N04C7, J Clin Oncol, 29, 421, 10.1200/JCO.2010.31.5911 Benson, 2004, Recommended Guidelines for the Treatment of Cancer Treatment-Induced Diarrhea, J Clin Oncol, 22, 2918, 10.1200/JCO.2004.04.132 Aapro, 2011, 2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours, Eur J Cancer, 47, 8, 10.1016/j.ejca.2010.10.013 Elias, 2010, Peritoneal colorectal carcinomatosis treated with surgery and perioperative intraperitoneal chemotherapy: retrospective analysis of 523 patients from a multicentric French study, J Clin Oncol, 28, 63, 10.1200/JCO.2009.23.9285 Labianca, 2010, Primary colon cancer: ESMO Clinical Practice Guidelines for diagnosis, adjuvant treatment and follow-up, Ann Oncol, 21, v70, 10.1093/annonc/mdq168 Schmiegel, 2009, Colorectal carcinoma: the management of polyps, (neo)adjuvant therapy, and the treatment of metastases, Dtsch Arztebl Int, 106, 843 Desch, 2005, Colorectal cancer surveillance: 2005 update of an American Society of Clinical Oncology practice guideline, J Clin Oncol, 23, 8512, 10.1200/JCO.2005.04.0063 Braendengen, 2008, Randomized phase III study comparing preoperative radiotherapy with chemoradiotherapy in nonresectable rectal cancer, J Clin Oncol, 26, 3687, 10.1200/JCO.2007.15.3858 Haller, 2012, Impact of age and medical comorbidity (MC) on adjuvant treatment outcomes for stage III colon cancer (CC): A pooled analysis of individual patient data from four randomized controlled trials, J Clin Oncol, 30, 10.1200/jco.2012.30.15_suppl.3522 Bystrom, 2004, Phase I study of UFT plus leucovorin with radiotherapy in patients with inextirpable non-rectal gastrointestinal cancer, Radiother Oncol, 70, 171, 10.1016/j.radonc.2004.01.004 Schiebe, 2002, Phase I study of oral uracil and Tegafur plus leucovorin and pelvic radiation in patients with recurrent rectal cancer, Anticancer Drugs, 13, 1005, 10.1097/00001813-200211000-00004 Jakobsen, 2011, The dose-effect relationship in preoperative chemoradiation of locally advanced rectal cancer: Preliminary results of a phase III trial, J Clin Oncol, 29, 10.1200/jco.2011.29.15_suppl.3512 Vestermark, 2008, Long-term results of a phase II trial of high-dose radiotherapy (60 Gy) and UFT/l-leucovorin in patients with non-resectable locally advanced rectal cancer (LARC), Acta Oncol, 47, 428, 10.1080/02841860701798866 Schmoll, 2011, Do we need oncology trials tailored for the elderly or frail?, Lancet, 377, 1725, 10.1016/S0140-6736(11)60654-5 Schmoll, 2007, Single agent fluorouracil for first-line treatment of advanced colorectal cancer as standard?, Lancet, 370, 105, 10.1016/S0140-6736(07)61062-9