Skip to main content

Advertisement

Log in

Current controversies in the management of metastatic colorectal cancer

  • Review Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

The factors affecting the decisions for the treatment for patients with metastatic colorectal cancer (mCRC) are related to the patient, the tumor, and the treatment itself. Both cetuximab and panitumumab are anti-EGFR monoclonal antibody options for patients with RAS wild-type tumors. Several trials comparing these agents with bevacizumab are analyzed in this paper. The liver is the most common site of metastases in patients with CRC, and perioperative chemotherapy has been shown to yield benefits in this setting. In the second-line treatment for mCRC, maintenance with bevacizumab after progression following first-line treatment is convenient in some groups of patients with mCRC. Also, aflibercept has demonstrated benefits in response rate, progression-free survival, and overall survival in second-line treatment, whereas regorafenib provides benefits to patients progressing on all standard therapies. Several novel therapeutic options for patients with mCRC are under development, and these are discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocakova I, Ruff P, Blasinska-Morawiec M, Smakal M, Canon JL, Rother M, Oliner KS, Wolf M, Gansert J (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(31):4697–4705. doi:10.1200/JCO.2009.27.4860

    Article  CAS  PubMed  Google Scholar 

  2. Kopetz S, Chang GJ, Overman MJ, Eng C, Sargent DJ, Larson DW, Grothey A, Vauthey JN, Nagorney DM, McWilliams RR (2009) Improved survival in metastatic colorectal cancer is associated with adoption of hepatic resection and improved chemotherapy. J Clin Oncol 27(22):3677–3683. doi:10.1200/JCO.2008.20.5278

    Article  PubMed Central  PubMed  Google Scholar 

  3. Stintzing S, Fischer von Weikersthal L, Decker T, Vehling-Kaiser U, Jager E, Heintges T, Stoll C, Giessen C, Modest DP, Neumann J, Jung A, Kirchner T, Scheithauer W, Heinemann V (2012) FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer-subgroup analysis of patients with KRAS: mutated tumours in the randomised German AIO study KRK-0306. Ann Oncol 23(7):1693–1699. doi:10.1093/annonc/mdr571

    Article  CAS  PubMed  Google Scholar 

  4. Van Cutsem E, Kohne CH, Lang I, Folprecht G, Nowacki MP, Cascinu S, Shchepotin I, Maurel J, Cunningham D, Tejpar S, Schlichting M, Zubel A, Celik I, Rougier P, Ciardiello F (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(15):2011–2019. doi:10.1200/JCO.2010.33.5091

    Article  PubMed  CAS  Google Scholar 

  5. Folprecht G, Gruenberger T, Bechstein WO, Raab HR, Lordick F, Hartmann JT, Lang H, Frilling A, Stoehlmacher J, Weitz J, Konopke R, Stroszczynski C, Liersch T, Ockert D, Herrmann T, Goekkurt E, Parisi F, Kohne CH (2010) Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase 2 trial. Lancet Oncol 11(1):38–47. doi:10.1016/S1470-2045(09)70330-4

    Article  CAS  PubMed  Google Scholar 

  6. Morris EJ, Forman D, Thomas JD, Quirke P, Taylor EF, Fairley L, Cottier B, Poston G (2010) Surgical management and outcomes of colorectal cancer liver metastases. Br J Surg 97(7):1110–1118. doi:10.1002/bjs.7032

    Article  CAS  PubMed  Google Scholar 

  7. Papamichael D (2014) Siog crc guidelines. J Geriatr Oncol 5(Suppl 1):S7. doi:10.1016/j.jgo.2014.06.047

    Article  Google Scholar 

  8. Naeim A, Ward PR, Wang HJ, Dichmann R, Liem AK, Chan D, Patel R, Hu EH, Tchekmedyian NS, Wainberg ZA, Hecht JR (2013) A phase II trial of frontline capecitabine and bevacizumab in poor performance status and/or elderly patients with metastatic colorectal cancer. J Geriatr Oncol 4(4):302–309. doi:10.1016/j.jgo.2013.05.001

    Article  PubMed  Google Scholar 

  9. Ward P, Hecht JR, Wang HJ, Dichmann R, Liem AK, Chan D, Patel R, Hu EH, Tchekmedyian NS, Wainberg ZA, Naeim A (2014) Physical function and quality of life in frail and/or elderly patients with metastatic colorectal cancer treated with capecitabine and bevacizumab: an exploratory analysis. J Geriatr Oncol 5(4):368–375. doi:10.1016/j.jgo.2014.05.002

    Article  PubMed  Google Scholar 

  10. Ghiringhelli F, Hennequin A, Drouillard A, Lepage C, Faivre J, Bouvier AM (2014) Epidemiology and prognosis of synchronous and metachronous colon cancer metastases: a French population-based study. Dig Liver Dis 46(9):854–858. doi:10.1016/j.dld.2014.05.011

    Article  PubMed  Google Scholar 

  11. van Gestel YR, Thomassen I, Lemmens VE, Pruijt JF, van Herk-Sukel MP, Rutten HJ, Creemers GJ, de Hingh IH (2014) Metachronous peritoneal carcinomatosis after curative treatment of colorectal cancer. Eur J Surg Oncol 40(8):963–969. doi:10.1016/j.ejso.2013.10.001

    Article  PubMed  Google Scholar 

  12. Poultsides GA, Servais EL, Saltz LB, Patil S, Kemeny NE, Guillem JG, Weiser M, Temple LK, Wong WD, Paty PB (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(20):3379–3384. doi:10.1200/JCO.2008.20.9817

    Article  PubMed Central  PubMed  Google Scholar 

  13. McCahill LE, Yothers G, Sharif S, Petrelli NJ, Lai LL, Bechar N, Giguere JK, Dakhil SR, Fehrenbacher L, Lopa SH, Wagman LD, O’Connell MJ, Wolmark N (2012) Primary mFOLFOX6 plus bevacizumab without resection of the primary tumor for patients presenting with surgically unresectable metastatic colon cancer and an intact asymptomatic colon cancer: definitive analysis of NSABP trial C-10. J Clin Oncol 30(26):3223–3228. doi:10.1200/JCO.2012.42.4044

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Ferrand F, Malka D, Bourredjem A, Allonier C, Bouche O, Louafi S, Boige V, Mousseau M, Raoul JL, Bedenne L, Leduc B, Deguiral P, Faron M, Pignon JP, Ducreux M (2013) Impact of primary tumour resection on survival of patients with colorectal cancer and synchronous metastases treated by chemotherapy: results from the multicenter, randomised trial Federation Francophone de Cancerologie Digestive 9601. Eur J Cancer 49(1):90–97. doi:10.1016/j.ejca.2012.07.006

    Article  CAS  PubMed  Google Scholar 

  15. Gresham G, Renouf DJ, Chan M, Kennecke HF, Lim HJ, Brown C, Cheung WY (2014) Association between palliative resection of the primary tumor and overall survival in a population-based cohort of metastatic colorectal cancer patients. Ann Surg Oncol 21(12):3917–3923. doi:10.1245/s10434-014-3797-0

    Article  PubMed  Google Scholar 

  16. Karoui M, Roudot-Thoraval F, Mesli F, Mitry E, Aparicio T, Des Guetz G, Louvet C, Landi B, Tiret E, Sobhani I (2011) Primary colectomy in patients with stage IV colon cancer and unresectable distant metastases improves overall survival: results of a multicentric study. Dis Colon Rectum 54(8):930–938. doi:10.1097/DCR.0b013e31821cced0

    Article  PubMed  Google Scholar 

  17. Temple LK, Hsieh L, Wong WD, Saltz L, Schrag D (2004) Use of surgery among elderly patients with stage IV colorectal cancer. J Clin Oncol 22(17):3475–3484. doi:10.1200/JCO.2004.10.218

    Article  PubMed  Google Scholar 

  18. Venderbosch S, de Wilt JH, Teerenstra S, Loosveld OJ, van Bochove A, Sinnige HA, Creemers GJ, Tesselaar ME, Mol L, Punt CJ, Koopman M (2011) Prognostic value of resection of primary tumor in patients with stage IV colorectal cancer: retrospective analysis of two randomized studies and a review of the literature. Ann Surg Oncol 18(12):3252–3260. doi:10.1245/s10434-011-1951-5

    Article  PubMed Central  PubMed  Google Scholar 

  19. Missiaglia E, Jacobs B, Di Narzo AF, Soneson C, Roth A, Bosman F, d’Ario G, Klingbiel D, Yan P, Delorenzi M, Tejpar S (2013) Proximal and distal colon tumors as distinct biologic entities with different prognoses. J Clin Oncol 31(15 Suppl):3526

    Google Scholar 

  20. Caiazza F, Ryan EJ, Doherty G, Winter DC, Sheahan K (2015) Estrogen receptors and their implications in colorectal carcinogenesis. Front Oncol 5:19. doi:10.3389/fonc.2015.00019

    Article  PubMed Central  PubMed  Google Scholar 

  21. Gervaz P, Bucher P, Neyroud-Caspar I, Soravia C, Morel P (2005) Proximal location of colon cancer is a risk factor for development of metachronous colorectal cancer: a population-based study. Dis Colon Rectum 48(2):227–232. doi:10.1007/s10350-004-0805-7

    Article  PubMed  Google Scholar 

  22. Raj KP, Taylor TH, Wray C, Stamos MJ, Zell JA (2011) Risk of second primary colorectal cancer among colorectal cancer cases: a population-based analysis. J Carcinog 10:6. doi:10.4103/1477-3163.78114

    Article  PubMed Central  PubMed  Google Scholar 

  23. Ringland CL, Arkenau HT, O’Connell DL, Ward RL (2010) Second primary colorectal cancers (SPCRCs): experiences from a large Australian Cancer Registry. Ann Oncol 21(1):92–97. doi:10.1093/annonc/mdp288

    Article  CAS  PubMed  Google Scholar 

  24. Phipps AI, Chan AT, Ogino S (2013) Anatomic subsite of primary colorectal cancer and subsequent risk and distribution of second cancers. Cancer 119(17):3140–3147. doi:10.1002/cncr.28076

    Article  PubMed Central  PubMed  Google Scholar 

  25. Benedix F, Kube R, Meyer F, Schmidt U, Gastinger I, Lippert H, Colon/Rectum Carcinomas Study G (2010) Comparison of 17,641 patients with right- and left-sided colon cancer: differences in epidemiology, perioperative course, histology, and survival. Dis Colon Rectum 53(1):57–64. doi:10.1007/DCR.0b013e3181c703a4

    Article  PubMed  Google Scholar 

  26. Maughan TS, Adams RA, Smith CG, Meade AM, Seymour MT, Wilson RH, Idziaszczyk S, Harris R, Fisher D, Kenny SL, Kay E, Mitchell JK, Madi A, Jasani B, James MD, Bridgewater J, Kennedy MJ, Claes B, Lambrechts D, Kaplan R, Cheadle JP, Investigators MCT (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(9783):2103–2114. doi:10.1016/S0140-6736(11)60613-2

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Smith CG, Fisher D, Claes B, Maughan TS, Idziaszczyk S, Peuteman G, Harris R, James MD, Meade A, Jasani B, Adams RA, Kenny S, Kaplan R, Lambrechts D, Cheadle JP (2013) Somatic profiling of the epidermal growth factor receptor pathway in tumors from patients with advanced colorectal cancer treated with chemotherapy ± cetuximab. Clin Cancer Res 19(15):4104–4113. doi:10.1158/1078-0432.CCR-12-2581

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Lievre A, Bachet JB, Le Corre D, Boige V, Landi B, Emile JF, Cote JF, Tomasic G, Penna C, Ducreux M, Rougier P, Penault-Llorca F, Laurent-Puig P (2006) KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 66(8):3992–3995. doi:10.1158/0008-5472.CAN-06-0191

    Article  CAS  PubMed  Google Scholar 

  29. Van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D’Haens G, Pinter T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P (2009) Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 360(14):1408–1417. doi:10.1056/NEJMoa0805019

    Article  PubMed  Google Scholar 

  30. Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocakova I, Ruff P, Blasinska-Morawiec M, Smakal M, Canon JL, Rother M, Williams R, Rong A, Wiezorek J, Sidhu R, Patterson SD (2013) Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 369(11):1023–1034. doi:10.1056/NEJMoa1305275

    Article  CAS  PubMed  Google Scholar 

  31. Schirripa M, Cremolini C, Loupakis F, Morvillo M, Bergamo F, Zoratto F, Salvatore L, Antoniotti C, Marmorino F, Sensi E, Lupi C, Fontanini G, De Gregorio V, Giannini R, Basolo F, Masi G, Falcone A (2015) Role of NRAS mutations as prognostic and predictive markers in metastatic colorectal cancer. Int J Cancer 136(1):83–90. doi:10.1002/ijc.28955

    Article  CAS  PubMed  Google Scholar 

  32. Loupakis F, Cremolini C, Salvatore L, Masi G, Sensi E, Schirripa M, Michelucci A, Pfanner E, Brunetti I, Lupi C, Antoniotti C, Bergamo F, Lonardi S, Zagonel V, Simi P, Fontanini G, Falcone A (2014) FOLFOXIRI plus bevacizumab as first-line treatment in BRAF mutant metastatic colorectal cancer. Eur J Cancer 50(1):57–63. doi:10.1016/j.ejca.2013.08.024

    Article  CAS  PubMed  Google Scholar 

  33. Prahallad A, Sun C, Huang S, Di Nicolantonio F, Salazar R, Zecchin D, Beijersbergen RL, Bardelli A, Bernards R (2012) Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 483(7387):100–103. doi:10.1038/nature10868

    Article  CAS  PubMed  Google Scholar 

  34. Yang H, Higgins B, Kolinsky K, Packman K, Bradley WD, Lee RJ, Schostack K, Simcox ME, Kopetz S, Heimbrook D, Lestini B, Bollag G, Su F (2012) Antitumor activity of BRAF inhibitor vemurafenib in preclinical models of BRAF-mutant colorectal cancer. Cancer Res 72(3):779–789. doi:10.1158/0008-5472.CAN-11-2941

    Article  CAS  PubMed  Google Scholar 

  35. Leggett B, Whitehall V (2010) Role of the serrated pathway in colorectal cancer pathogenesis. Gastroenterology 138(6):2088–2100. doi:10.1053/j.gastro.2009.12.066

    Article  CAS  PubMed  Google Scholar 

  36. Snover DC, Jass JR, Fenoglio-Preiser C, Batts KP (2005) Serrated polyps of the large intestine: a morphologic and molecular review of an evolving concept. Am J Clin Pathol 124(3):380–391. doi:10.1309/V2EP-TPLJ-RB3F-GHJL

    Article  PubMed  Google Scholar 

  37. Torlakovic E, Skovlund E, Snover DC, Torlakovic G, Nesland JM (2003) Morphologic reappraisal of serrated colorectal polyps. Am J Surg Pathol 27(1):65–81

    Article  PubMed  Google Scholar 

  38. Hawkins N, Norrie M, Cheong K, Mokany E, Ku SL, Meagher A, O’Connor T, Ward R (2002) CpG island methylation in sporadic colorectal cancers and its relationship to microsatellite instability. Gastroenterology 122(5):1376–1387

    Article  CAS  PubMed  Google Scholar 

  39. Samowitz WS, Albertsen H, Herrick J, Levin TR, Sweeney C, Murtaugh MA, Wolff RK, Slattery ML (2005) Evaluation of a large, population-based sample supports a CpG island methylator phenotype in colon cancer. Gastroenterology 129(3):837–845. doi:10.1053/j.gastro.2005.06.020

    Article  CAS  PubMed  Google Scholar 

  40. Weisenberger DJ, Siegmund KD, Campan M, Young J, Long TI, Faasse MA, Kang GH, Widschwendter M, Weener D, Buchanan D, Koh H, Simms L, Barker M, Leggett B, Levine J, Kim M, French AJ, Thibodeau SN, Jass J, Haile R, Laird PW (2006) CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet 38(7):787–793. doi:10.1038/ng1834

    Article  CAS  PubMed  Google Scholar 

  41. Jass JR (2000) WHO International Classification of Tumors: pathology and genetics of tumors of the digestive system, vol 135-136. Hyperplastic polyposis. Springer, Berlin

    Google Scholar 

  42. Kambara T, Simms LA, Whitehall VL, Spring KJ, Wynter CV, Walsh MD, Barker MA, Arnold S, McGivern A, Matsubara N, Tanaka N, Higuchi T, Young J, Jass JR, Leggett BA (2004) BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum. Gut 53(8):1137–1144. doi:10.1136/gut.2003.037671

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Yang S, Farraye FA, Mack C, Posnik O, O’Brien MJ (2004) BRAF and KRAS mutations in hyperplastic polyps and serrated adenomas of the colorectum: relationship to histology and CpG island methylation status. Am J Surg Pathol 28(11):1452–1459

    Article  PubMed  Google Scholar 

  44. Rosenberg DW, Yang S, Pleau DC, Greenspan EJ, Stevens RG, Rajan TV, Heinen CD, Levine J, Zhou Y, O’Brien MJ (2007) Mutations in BRAF and KRAS differentially distinguish serrated versus non-serrated hyperplastic aberrant crypt foci in humans. Cancer Res 67(8):3551–3554. doi:10.1158/0008-5472.CAN-07-0343

    Article  CAS  PubMed  Google Scholar 

  45. Wu JM, Montgomery EA, Iacobuzio-Donahue CA (2008) Frequent beta-catenin nuclear labeling in sessile serrated polyps of the colorectum with neoplastic potential. Am J Clin Pathol 129(3):416–423. doi:10.1309/603UQKM7C2KELGJU

    Article  CAS  PubMed  Google Scholar 

  46. Goldstein NS (2006) Small colonic microsatellite unstable adenocarcinomas and high-grade epithelial dysplasias in sessile serrated adenoma polypectomy specimens: a study of eight cases. Am J Clin Pathol 125(1):132–145

    Article  PubMed  Google Scholar 

  47. Sandmeier D, Benhattar J, Martin P, Bouzourene H (2009) Serrated polyps of the large intestine: a molecular study comparing sessile serrated adenomas and hyperplastic polyps. Histopathology 55(2):206–213. doi:10.1111/j.1365-2559.2009.03356.x

    Article  PubMed  Google Scholar 

  48. Rajagopalan H, Bardelli A, Lengauer C, Kinzler KW, Vogelstein B, Velculescu VE (2002) Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature 418(6901):934. doi:10.1038/418934a

    Article  CAS  PubMed  Google Scholar 

  49. Cancer Genome Atlas N (2012) Comprehensive molecular characterization of human colon and rectal cancer. Nature 487(7407):330–337. doi:10.1038/nature11252

    Article  CAS  Google Scholar 

  50. Dienstmann R, Salazar R, Tabernero J (2014) The evolution of our molecular understanding of colorectal cancer: what we are doing now, what the future holds, and how tumor profiling is just the beginning. American Society of Clinical Oncology Educational Book/ASCO American Society of Clinical Oncology Meeting:91–99. doi:10.14694/EdBook_AM.2014.34.91

  51. Budinska E, Popovici V, Tejpar S, D’Ario G, Lapique N, Sikora KO, Di Narzo AF, Yan P, Hodgson JG, Weinrich S, Bosman F, Roth A, Delorenzi M (2013) Gene expression patterns unveil a new level of molecular heterogeneity in colorectal cancer. J Pathol 231(1):63–76. doi:10.1002/path.4212

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Roepman P, Schlicker A, Tabernero J, Majewski I, Tian S, Moreno V, Snel MH, Chresta CM, Rosenberg R, Nitsche U, Macarulla T, Capella G, Salazar R, Orphanides G, Wessels LF, Bernards R, Simon IM (2014) Colorectal cancer intrinsic subtypes predict chemotherapy benefit, deficient mismatch repair and epithelial-to-mesenchymal transition. Int J Cancer 134(3):552–562. doi:10.1002/ijc.28387

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Schlicker A, Beran G, Chresta CM, McWalter G, Pritchard A, Weston S, Runswick S, Davenport S, Heathcote K, Castro DA, Orphanides G, French T, Wessels LF (2012) Subtypes of primary colorectal tumors correlate with response to targeted treatment in colorectal cell lines. BMC Med Genomics 5:66. doi:10.1186/1755-8794-5-66

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. De Sousa EMF, Wang X, Jansen M, Fessler E, Trinh A, de Rooij LP, de Jong JH, de Boer OJ, van Leersum R, Bijlsma MF, Rodermond H, van der Heijden M, van Noesel CJ, Tuynman JB, Dekker E, Markowetz F, Medema JP, Vermeulen L (2013) Poor-prognosis colon cancer is defined by a molecularly distinct subtype and develops from serrated precursor lesions. Nat Med 19(5):614–618. doi:10.1038/nm.3174

    Article  CAS  Google Scholar 

  55. Marisa L, de Reynies A, Duval A, Selves J, Gaub MP, Vescovo L, Etienne-Grimaldi MC, Schiappa R, Guenot D, Ayadi M, Kirzin S, Chazal M, Flejou JF, Benchimol D, Berger A, Lagarde A, Pencreach E, Piard F, Elias D, Parc Y, Olschwang S, Milano G, Laurent-Puig P, Boige V (2013) Gene expression classification of colon cancer into molecular subtypes: characterization, validation, and prognostic value. PLoS Med 10(5):e1001453. doi:10.1371/journal.pmed.1001453

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  56. Sadanandam A, Lyssiotis CA, Homicsko K, Collisson EA, Gibb WJ, Wullschleger S, Ostos LC, Lannon WA, Grotzinger C, Del Rio M, Lhermitte B, Olshen AB, Wiedenmann B, Cantley LC, Gray JW, Hanahan D (2013) A colorectal cancer classification system that associates cellular phenotype and responses to therapy. Nat Med 19(5):619–625. doi:10.1038/nm.3175

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  57. Perez-Villamil B, Romera-Lopez A, Hernandez-Prieto S, Lopez-Campos G, Calles A, Lopez-Asenjo JA, Sanz-Ortega J, Fernandez-Perez C, Sastre J, Alfonso R, Caldes T, Martin-Sanchez F, Diaz-Rubio E (2012) Colon cancer molecular subtypes identified by expression profiling and associated to stroma, mucinous type and different clinical behavior. BMC Cancer 12:260. doi:10.1186/1471-2407-12-260

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Calon A, Espinet E, Palomo-Ponce S, Tauriello DV, Iglesias M, Cespedes MV, Sevillano M, Nadal C, Jung P, Zhang XH, Byrom D, Riera A, Rossell D, Mangues R, Massague J, Sancho E, Batlle E (2012) Dependency of colorectal cancer on a TGF-beta-driven program in stromal cells for metastasis initiation. Cancer Cell 22(5):571–584. doi:10.1016/j.ccr.2012.08.013

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  59. Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, Juan T, Sikorski R, Suggs S, Radinsky R, Patterson SD, Chang DD (2008) Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26(10):1626–1634. doi:10.1200/JCO.2007.14.7116

    Article  CAS  PubMed  Google Scholar 

  60. Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Kohne CH (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(10):1466–1475. doi:10.1016/j.ejca.2012.02.057

    Article  CAS  PubMed  Google Scholar 

  61. Van Cutsem E, Lenz HJ, Kohne CH, Heinemann V, Tejpar S, Melezinek I, Beier F, Stroh C, Rougier P, van Krieken JH, Ciardiello F (2015) Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol. doi:10.1200/JCO.2014.59.4812

    Google Scholar 

  62. Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocakova I, Ruff P, Blasinska-Morawiec M, Smakal M, Canon JL, Rother M, Oliner KS, Tian Y, Xu F, Sidhu R (2014) Final results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann Oncol 25(7):1346–1355. doi:10.1093/annonc/mdu141

    Article  CAS  PubMed  Google Scholar 

  63. Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, Heintges T, Lerchenmuller C, Kahl C, Seipelt G, Kullmann F, Stauch M, Scheithauer W, Hielscher J, Scholz M, Muller S, Link H, Niederle N, Rost A, Hoffkes HG, Moehler M, Lindig RU, Modest DP, Rossius L, Kirchner T, Jung A, Stintzing S (2014) FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol 15(10):1065–1075. doi:10.1016/S1470-2045(14)70330-4

    Article  CAS  PubMed  Google Scholar 

  64. Schwartzberg LS, Rivera F, Karthaus M, Fasola G, Canon JL, Hecht JR, Yu H, Oliner KS, Go WY (2014) PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol 32(21):2240–2247. doi:10.1200/JCO.2013.53.2473

    Article  CAS  PubMed  Google Scholar 

  65. Lenz H, Niedzwiecki D, Innocenti F, Blanke C, Mahony MR, O’Neil BH, Shaw JE, Polite B, Hochster H, Atkins J, Goldberg R, Mayer R, Schilsky RL, Bertagnolli M, Venook A (2014) CALGB/SWOG 80405: phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (PTS) with expanded RAS analyses untreated metastatic adenocarcinoma of the colon or rectum (mCRC). Ann Oncol. doi:10.1093/annonc/mdu438.13

    PubMed  Google Scholar 

  66. Khattak MA, Martin H, Davidson A, Phillips M (2015) Role of first-line anti-epidermal growth factor receptor therapy compared with anti-vascular endothelial growth factor therapy in advanced colorectal cancer: a meta-analysis of randomized clinical trials. Clin Colorectal Cancer. doi:10.1016/j.clcc.2014.12.011

    PubMed  Google Scholar 

  67. Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, Bechstein WO, Primrose JN, Walpole ET, Finch-Jones M, Jaeck D, Mirza D, Parks RW, Collette L, Praet M, Bethe U, Van Cutsem E, Scheithauer W, Gruenberger T (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(9617):1007–1016. doi:10.1016/S0140-6736(08)60455-9

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  68. Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, Bechstein WO, Primrose JN, Walpole ET, Finch-Jones M, Jaeck D, Mirza D, Parks RW, Mauer M, Tanis E, Van Cutsem E, Scheithauer W, Gruenberger T (2013) Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial. Lancet Oncol 14(12):1208–1215. doi:10.1016/S1470-2045(13)70447-9

    Article  CAS  PubMed  Google Scholar 

  69. Primrose J, Falk S, Finch-Jones M, Valle J, O’Reilly D, Siriwardena A, Hornbuckle J, Peterson M, Rees M, Iveson T, Hickish T, Butler R, Stanton L, Dixon E, Little L, Bowers M, Pugh S, Garden OJ, Cunningham D, Maughan T, Bridgewater J (2014) Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis: the New EPOC randomised controlled trial. Lancet Oncol 15(6):601–611. doi:10.1016/S1470-2045(14)70105-6

    Article  CAS  PubMed  Google Scholar 

  70. Adam R, Wicherts DA, de Haas RJ, Ciacio O, Levi F, Paule B, Ducreux M, Azoulay D, Bismuth H, Castaing D (2009) Patients with initially unresectable colorectal liver metastases: is there a possibility of cure? J Clin Oncol 27(11):1829–1835. doi:10.1200/JCO.2008.19.9273

    Article  PubMed  Google Scholar 

  71. Folprecht G, Grothey A, Alberts S, Raab HR, Kohne CH (2005) Neoadjuvant treatment of unresectable colorectal liver metastases: correlation between tumour response and resection rates. Ann Oncol 16(8):1311–1319. doi:10.1093/annonc/mdi246

    Article  CAS  PubMed  Google Scholar 

  72. Petrelli F, Barni S (2012) Resectability and outcome with anti-EGFR agents in patients with KRAS wild-type colorectal liver-limited metastases: a meta-analysis. Int J Colorectal Dis 27(8):997–1004. doi:10.1007/s00384-012-1438-2

    Article  CAS  PubMed  Google Scholar 

  73. Okines A, Puerto OD, Cunningham D, Chau I, Van Cutsem E, Saltz L, Cassidy J (2009) Surgery with curative-intent in patients treated with first-line chemotherapy plus bevacizumab for metastatic colorectal cancer First BEAT and the randomised phase-III NO16966 trial. Br J Cancer 101(7):1033–1038. doi:10.1038/sj.bjc.6605259

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  74. Heinemann V, Modest DP, FvW L, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran S, Heintges T, Lerchenmüller C, Kahl C, Seipelt G, Kullmann F, Stauch M, Scheithauer W, Held S, Giessen C, Möhler M, Jagenburg A, Stintzing S (2014) Independent radiological evaluation of objective response, early tumor shrinkage, and depth of response in FIRE-3 (AIO KRK-0306). Ann Oncol 25(Suppl 2):ii117

    Article  Google Scholar 

  75. Falcone A, Ricci S, Brunetti I, Pfanner E, Allegrini G, Barbara C, Crino L, Benedetti G, Evangelista W, Fanchini L, Cortesi E, Picone V, Vitello S, Chiara S, Granetto C, Porcile G, Fioretto L, Orlandini C, Andreuccetti M, Masi G, Gruppo Oncologico Nord O (2007) 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 25(13):1670–1676. doi:10.1200/JCO.2006.09.0928

    Article  CAS  PubMed  Google Scholar 

  76. Van Cutsem E, Cervantes A, Nordlinger B, Arnold D (2014) Metastatic colorectal cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 25(Suppl 3):iii1–iii9. doi:10.1093/annonc/mdu260

    Article  PubMed  Google Scholar 

  77. Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Colon Cancer version 2.2015. http://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed November 2014

  78. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Rectal cancer. version 1.2015. http://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf. Accessed November 2014

  79. Giantonio BJ (2009) Targeted therapies: Goldie-Coldman and bevacizumab beyond disease progression. Nat Rev Clin Oncol 6(6):311–312. doi:10.1038/nrclinonc.2009.66

    Article  CAS  PubMed  Google Scholar 

  80. Bennouna J, Sastre J, Arnold D, Osterlund P, Greil R, Van Cutsem E, von Moos R, Vieitez JM, Bouche O, Borg C, Steffens CC, Alonso-Orduna V, Schlichting C, Reyes-Rivera I, Bendahmane B, Andre T, Kubicka S (2013) Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol 14(1):29–37. doi:10.1016/S1470-2045(12)70477-1

    Article  CAS  PubMed  Google Scholar 

  81. Kubicka S, Greil R, Andre T, Bennouna J, Sastre J, Van Cutsem E, von Moos R, Osterlund P, Reyes-Rivera I, Muller T, Makrutzki M, Arnold D (2013) Bevacizumab plus chemotherapy continued beyond first progression in patients with metastatic colorectal cancer previously treated with bevacizumab plus chemotherapy: ML18147 study KRAS subgroup findings. Ann Oncol 24(9):2342–2349. doi:10.1093/annonc/mdt231

    Article  CAS  PubMed  Google Scholar 

  82. Holash J, Davis S, Papadopoulos N, Croll SD, Ho L, Russell M, Boland P, Leidich R, Hylton D, Burova E, Ioffe E, Huang T, Radziejewski C, Bailey K, Fandl JP, Daly T, Wiegand SJ, Yancopoulos GD, Rudge JS (2002) VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci USA 99(17):11393–11398. doi:10.1073/pnas.172398299

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  83. Kim ES, Serur A, Huang J, Manley CA, McCrudden KW, Frischer JS, Soffer SZ, Ring L, New T, Zabski S, Rudge JS, Holash J, Yancopoulos GD, Kandel JJ, Yamashiro DJ (2002) Potent VEGF blockade causes regression of coopted vessels in a model of neuroblastoma. Proc Natl Acad Sci USA 99(17):11399–11404. doi:10.1073/pnas.172398399

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  84. Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausova J, Macarulla T, Ruff P, van Hazel GA, Moiseyenko V, Ferry D, McKendrick J, Polikoff J, Tellier A, Castan R, Allegra C (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 30(28):3499–3506. doi:10.1200/JCO.2012.42.8201

    Article  PubMed  CAS  Google Scholar 

  85. Tabernero J, Van Cutsem E, Lakomy R, Prausova J, Ruff P, van Hazel GA, Moiseyenko VM, Ferry DR, McKendrick JJ, Soussan-Lazard K, Chevalier S, Allegra CJ (2014) Aflibercept versus placebo in combination with fluorouracil, leucovorin and irinotecan in the treatment of previously treated metastatic colorectal cancer: prespecified subgroup analyses from the VELOUR trial. Eur J Cancer 50(2):320–331. doi:10.1016/j.ejca.2013.09.013

    Article  CAS  PubMed  Google Scholar 

  86. Joulain F, Proskorovsky I, Allegra C, Tabernero J, Hoyle M, Iqbal SU, Van Cutsem E (2013) Mean overall survival gain with aflibercept plus FOLFIRI vs placebo plus FOLFIRI in patients with previously treated metastatic colorectal cancer. Br J Cancer 109(7):1735–1743. doi:10.1038/bjc.2013.523

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  87. Sobrero AF, Maurel J, Fehrenbacher L, Scheithauer W, Abubakr YA, Lutz MP, Vega-Villegas ME, Eng C, Steinhauer EU, Prausova J, Lenz HJ, Borg C, Middleton G, Kroning H, Luppi G, Kisker O, Zubel A, Langer C, Kopit J, Burris HA 3rd (2008) EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol 26(14):2311–2319. doi:10.1200/JCO.2007.13.1193

    Article  CAS  PubMed  Google Scholar 

  88. Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, Andre T, Chan E, Lordick F, Punt CJ, Strickland AH, Wilson G, Ciuleanu TE, Roman L, Van Cutsem E, Tian Y, Sidhu R (2014) Final results from a randomized phase 3 study of FOLFIRI ± panitumumab for second-line treatment of metastatic colorectal cancer. Ann Oncol 25(1):107–116. doi:10.1093/annonc/mdt523

    Article  CAS  PubMed  Google Scholar 

  89. Wilhelm SM, Dumas J, Adnane L, Lynch M, Carter CA, Schutz G, Thierauch KH, Zopf D (2011) Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer 129(1):245–255. doi:10.1002/ijc.25864

    Article  CAS  PubMed  Google Scholar 

  90. Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, Humblet Y, Bouche O, Mineur L, Barone C, Adenis A, Tabernero J, Yoshino T, Lenz HJ, Goldberg RM, Sargent DJ, Cihon F, Cupit L, Wagner A, Laurent D (2013) Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381(9863):303–312. doi:10.1016/S0140-6736(12)61900-X

    Article  CAS  PubMed  Google Scholar 

  91. Tougeron D, Desseigne F, Etienne PL, Dourthe LM, Mineur L, Paule B, Hollebecque A, Tresch E, Spaeth D, Michel P, Dauba J, Laplaige P, Borg C, Bechade D, Clisant S, Phelip J, Fouchardiere CDL, André T, Adenis A (2014) REBECCA: a large cohort study of regorafenib (REG) in the real-life setting in patients (PTS) previously treated for metastatic colorectal cancer (mCRC). Ann Oncol 25(Suppl 4):205–206. doi:10.1093/annonc/mdu333.104

    Google Scholar 

  92. Napolitano S, Martini G, Rinaldi B, Martinelli E, Donniacuo M, Berrino L, Vitagliano D, Morgillo F, Barra G, De Palma R, Merolla F, Ciardiello F, Troiani T (2015) Primary and acquired resistance of colorectal cancer to anti-EGFR monoclonal antibody can be overcome by combined treatment of regorafenib with cetuximab. Clin Cancer Res. doi:10.1158/1078-0432.CCR-15-0020

    Google Scholar 

  93. Mathijssen RH, Loos WJ, Verweij J, Sparreboom A (2002) Pharmacology of topoisomerase I inhibitors irinotecan (CPT-11) and topotecan. Curr Cancer Drug Targets 2(2):103–123

    Article  CAS  PubMed  Google Scholar 

  94. Garrett CR, Bekaii-Saab TS, Ryan T, Fisher GA, Clive S, Kavan P, Shacham-Shmueli E, Buchbinder A, Goldberg RM (2013) Randomized phase 2 study of pegylated SN-38 (EZN-2208) or irinotecan plus cetuximab in patients with advanced colorectal cancer. Cancer 119(24):4223–4230. doi:10.1002/cncr.28358

    Article  CAS  PubMed  Google Scholar 

  95. Jameson GS, Hamm JT, Weiss GJ, Alemany C, Anthony S, Basche M, Ramanathan RK, Borad MJ, Tibes R, Cohn A, Hinshaw I, Jotte R, Rosen LS, Hoch U, Eldon MA, Medve R, Schroeder K, White E, Von Hoff DD (2013) A multicenter, phase I, dose-escalation study to assess the safety, tolerability, and pharmacokinetics of etirinotecan pegol in patients with refractory solid tumors. Clin Cancer Res 19(1):268–278. doi:10.1158/1078-0432.CCR-12-1201

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  96. Yoshino T, Mizunuma N, Yamazaki K, Nishina T, Komatsu Y, Baba H, Tsuji A, Yamaguchi K, Muro K, Sugimoto N, Tsuji Y, Moriwaki T, Esaki T, Hamada C, Tanase T, Ohtsu A (2012) TAS-102 monotherapy for pretreated metastatic colorectal cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol 13(10):993–1001. doi:10.1016/S1470-2045(12)70345-5

    Article  CAS  PubMed  Google Scholar 

  97. Dienstmann R, Patnaik A, Garcia-Carbonero R, Cervantes A, Benavent M, Rosello S, Tops BB, van der Post RS, Argiles G, Skartved NJ, Hansen UH, Hald R, Pedersen MW, Kragh M, Horak ID, Braun S, Van Cutsem E, Tolcher AW, Tabernero J (2015) Safety and activity of the first-in-class Sym004 Anti-EGFR antibody mixture in patients with refractory colorectal cancer. Cancer Discov 5(6):598–609. doi:10.1158/2159-8290.CD-14-1432

    Article  CAS  PubMed  Google Scholar 

  98. Oppenheim DE, Spreafico R, Etuk A, Malone D, Amofah E, Pena-Murillo C, Murray T, McLaughlin L, Choi BS, Allan S, Belousov A, Passioukov A, Gerdes C, Umana P, Farzaneh F, Ross P (2014) Glyco-engineered anti-EGFR mAb elicits ADCC by NK cells from colorectal cancer patients irrespective of chemotherapy. Br J Cancer 110(5):1221–1227. doi:10.1038/bjc.2014.35

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  99. Schaefer G, Haber L, Crocker LM, Shia S, Shao L, Dowbenko D, Totpal K, Wong A, Lee CV, Stawicki S, Clark R, Fields C, Lewis Phillips GD, Prell RA, Danilenko DM, Franke Y, Stephan JP, Hwang J, Wu Y, Bostrom J, Sliwkowski MX, Fuh G, Eigenbrot C (2011) A two-in-one antibody against HER3 and EGFR has superior inhibitory activity compared with monospecific antibodies. Cancer Cell 20(4):472–486. doi:10.1016/j.ccr.2011.09.003

    Article  CAS  PubMed  Google Scholar 

  100. Delord JP, Tabernero J, Garcia-Carbonero R, Cervantes A, Gomez-Roca C, Berge Y, Capdevila J, Paz-Ares L, Roda D, Delmar P, Oppenheim D, Brossard SS, Farzaneh F, Manenti L, Passioukov A, Ott MG, Soria JC (2014) Open-label, multicentre expansion cohort to evaluate imgatuzumab in pre-treated patients with KRAS-mutant advanced colorectal carcinoma. Eur J Cancer 50(3):496–505. doi:10.1016/j.ejca.2013.10.015

    Article  CAS  PubMed  Google Scholar 

  101. Giovannucci E, Pollak M, Platz EA, Willett WC, Stampfer MJ, Majeed N, Colditz GA, Speizer FE, Hankinson SE (2000) Insulin-like growth factor I (IGF-I), IGF-binding protein-3 and the risk of colorectal adenoma and cancer in the Nurses’ Health Study. Growth Horm IGF Res 10(Suppl A):S30–S31

    Article  PubMed  Google Scholar 

  102. Eder JP, Vande Woude GF, Boerner SA, LoRusso PM (2009) Novel therapeutic inhibitors of the c-Met signaling pathway in cancer. Clin Cancer Res 15(7):2207–2214. doi:10.1158/1078-0432.CCR-08-1306

    Article  CAS  PubMed  Google Scholar 

  103. Smyth EC, Sclafani F, Cunningham D (2014) Emerging molecular targets in oncology: clinical potential of MET/hepatocyte growth-factor inhibitors. OncoTargets Ther 7:1001–1014. doi:10.2147/OTT.S44941

    Article  CAS  Google Scholar 

  104. Trarbach T, Moehler M, Heinemann V, Kohne CH, Przyborek M, Schulz C, Sneller V, Gallant G, Kanzler S (2010) Phase II trial of mapatumumab, a fully human agonistic monoclonal antibody that targets and activates the tumour necrosis factor apoptosis-inducing ligand receptor-1 (TRAIL-R1), in patients with refractory colorectal cancer. Br J Cancer 102(3):506–512. doi:10.1038/sj.bjc.6605507

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  105. Balmanno K, Chell SD, Gillings AS, Hayat S, Cook SJ (2009) Intrinsic resistance to the MEK1/2 inhibitor AZD6244 (ARRY-142886) is associated with weak ERK1/2 signalling and/or strong PI3 K signalling in colorectal cancer cell lines. Int J Cancer 125(10):2332–2341. doi:10.1002/ijc.24604

    Article  CAS  PubMed  Google Scholar 

  106. De Smaele E, Ferretti E, Gulino A (2010) Vismodegib, a small-molecule inhibitor of the hedgehog pathway for the treatment of advanced cancers. Curr Opin Investig Drugs 11(6):707–718

    PubMed  Google Scholar 

  107. Aleshin A, Finn RS (2010) SRC: a century of science brought to the clinic. Neoplasia 12(8):599–607

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  108. Dienstmann R, Markman B, Tabernero J (2012) Application of monoclonal antibodies as cancer therapy in solid tumors. Curr Clin Pharmacol 7(2):137–145

    Article  CAS  PubMed  Google Scholar 

  109. Lipson EJ (2013) Re-orienting the immune system: durable tumor regression and successful re-induction therapy using anti-PD1 antibodies. Oncoimmunology 2(4):e23661. doi:10.4161/onci.23661

    Article  PubMed Central  PubMed  Google Scholar 

  110. Bokemeyer C, Bondarenko I, Hartmann JT, de Braud F, Schuch G, Zubel A, Celik I, Schlichting M, Koralewski P (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(7):1535–1546. doi:10.1093/annonc/mdq632

    Article  CAS  PubMed  Google Scholar 

  111. Maughan TS, Adams RA, Smith CG, Meade AM, Seymour MT, Wilson RH, Idziaszczyk S, Harris R, Fisher D, Kenny SL, Kay E, Mitchell JK, Madi A, Jasani B, James MD, Bridgewater J, Kennedy MJ, Claes B, Lambrechts D, Kaplan R, Cheadle JP (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(9783):2103–2114. doi:10.1016/S0140-6736(11)60613-2

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  112. Tveit KM, Guren T, Glimelius B, Pfeiffer P, Sorbye H, Pyrhonen S, Sigurdsson F, Kure E, Ikdahl T, Skovlund E, Fokstuen T, Hansen F, Hofsli E, Birkemeyer E, Johnsson A, Starkhammar H, Yilmaz MK, Keldsen N, Erdal AB, Dajani O, Dahl O, Christoffersen T (2012) Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study. J Clin Oncol 30(15):1755–1762. doi:10.1200/JCO.2011.38.0915

    Article  CAS  PubMed  Google Scholar 

  113. Garufi C, Torsello A, Tumolo S, Ettorre GM, Zeuli M, Campanella C, Vennarecci G, Mottolese M, Sperduti I, Cognetti F (2010) Cetuximab plus chronomodulated irinotecan, 5-fluorouracil, leucovorin and oxaliplatin as neoadjuvant chemotherapy in colorectal liver metastases: POCHER trial. Br J Cancer 103(10):1542–1547. doi:10.1038/sj.bjc.6605940

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  114. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350(23):2335–2342. doi:10.1056/NEJMoa032691

    Article  CAS  PubMed  Google Scholar 

  115. Saltz LB, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang T-S, Rivera F, Couture F, Sirzén F, Cassidy J (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(12):2013–2019. doi:10.1200/jco.2007.14.9930

    Article  CAS  PubMed  Google Scholar 

  116. Masi G, Loupakis F, Salvatore L, Fornaro L, Cremolini C, Cupini S, Ciarlo A, Del Monte F, Cortesi E, Amoroso D, Granetto C, Fontanini G, Sensi E, Lupi C, Andreuccetti M, Falcone A (2010) Bevacizumab with FOLFOXIRI (irinotecan, oxaliplatin, fluorouracil, and folinate) as first-line treatment for metastatic colorectal cancer: a phase 2 trial. Lancet Oncol 11(9):845–852. doi:10.1016/S1470-2045(10)70175-3

    Article  CAS  PubMed  Google Scholar 

  117. Cremolini C, Loupakis F, Antoniotti C, Lonardi S, Masi G, Salvatore L, Cortesi E, Tomasello G, Spadi R, Zaniboni A, Tonini G, Barone C, Vitello S, Longarini R, Bonetti A, D’Amico M, Di Donato S, Granetto C, Boni L, Falcone A (2015) Early tumor shrinkage and depth of response predict long-term outcome in metastatic colorectal cancer patients treated with first-line chemotherapy plus bevacizumab: results from phase III TRIBE trial by the Gruppo Oncologico del Nord Ovest. Ann Oncol. doi:10.1093/annonc/mdv112

    Google Scholar 

  118. Gruenberger B, Tamandl D, Schueller J, Scheithauer W, Zielinski C, Herbst F, Gruenberger T (2008) Bevacizumab, capecitabine, and oxaliplatin as neoadjuvant therapy for patients with potentially curable metastatic colorectal cancer. J Clin Oncol 26(11):1830–1835. doi:10.1200/jco.2007.13.7679

    Article  CAS  PubMed  Google Scholar 

  119. Wong R, Cunningham D, Barbachano Y, Saffery C, Valle J, Hickish T, Mudan S, Brown G, Khan A, Wotherspoon A, Strimpakos AS, Thomas J, Compton S, Chua YJ, Chau I (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(9):2042–2048. doi:10.1093/annonc/mdq714

    Article  CAS  PubMed  Google Scholar 

  120. Gruenberger T, Bridgewater JA, Chau I, Garcia Alfonso P, Rivoire M, Lasserre S, Waterkamp D, Adam R (2013) Randomized, phase II study of bevacizumab with mFOLFOX6 or FOLFOXIRI in patients with initially unresectable liver metastases from colorectal cancer: Resectability and safety in OLIVIA. ASCO Meeting Abstracts 31(15 Suppl):3619

  121. Giantonio BJ, Catalano PJ, Meropol NJ, O’Dwyer PJ, Mitchell EP, Alberts SR, Schwartz MA, Benson AB 3rd (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(12):1539–1544. doi:10.1200/JCO.2006.09.6305

    Article  CAS  PubMed  Google Scholar 

  122. Fuchs CS, Marshall J, Mitchell E, Wierzbicki R, Ganju V, Jeffery M, Schulz J, Richards D, Soufi-Mahjoubi R, Wang B, Barrueco J (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(30):4779–4786. doi:10.1200/JCO.2007.11.3357

    Article  CAS  PubMed  Google Scholar 

  123. Cunningham D, Lang I, Marcuello E, Lorusso V, Ocvirk J, Shin DB, Jonker D, Osborne S, Andre N, Waterkamp D, Saunders MP (2013) 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 14(11):1077–1085. doi:10.1016/S1470-2045(13)70154-2

    Article  CAS  PubMed  Google Scholar 

  124. Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, Andre T, Chan E, Lordick F, Punt CJ, Strickland AH, Wilson G, Ciuleanu TE, Roman L, Van Cutsem E, Tzekova V, Collins S, Oliner KS, Rong A, Gansert J (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(31):4706–4713. doi:10.1200/JCO.2009.27.6055

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors wish to thank Ana Martín from HealthCo S.L. (Madrid, Spain) for her help in preparing the first draft of this manuscript. The necessary scientific meetings along with medical writing services were supported financially by Sanofi Spain. Sanofi Spain was given the opportunity to comment on the first draft of the manuscript, but all the decisions about its content were taken by the authors. All authors have approved the final version of the submitted manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ruth Vera.

Ethics declarations

Conflict of interest

The authors declare that they do not have any conflict of interest that may inappropriately influence this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vera, R., Alonso, V., Gállego, J. et al. Current controversies in the management of metastatic colorectal cancer. Cancer Chemother Pharmacol 76, 659–677 (2015). https://doi.org/10.1007/s00280-015-2808-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-015-2808-6

Keywords

Navigation