Abstract
Colorectal cancer remains one of the most common causes of cancer death in the US, with approximately a quarter of patients presenting with metastatic disease at the time of diagnosis. Recent advances over the past 2 decades have increased the repertoire of chemotherapeutic agents for this disease and extended median overall survival to more than 20 months. An increasing body of evidence also supports the addition of targeted agents, those directed towards vascular endothelial growth factor and epidermal growth factor receptors, to expand treatment options for patients with metastatic disease. Ongoing trials are exploring the optimal combinations of these drugs as well as promising new investigational agents that take advantage of the genetic aberrations that drive tumour biology. This review aims to summarize the pertinent data on available cytotoxic and biological agents used to extend survival in metastatic colorectal cancer patients and provide a modern approach to treatment strategies while acknowledging the areas of controversy on which future clinical trials should be based.
Similar content being viewed by others
References
Jemal A, Siegel R, Xu J, et al. Cancer statistics. CA Cancer J Clin 2010 Sep-Oct; 60(5): 277–300
Ferlay J, Shin HR, Bray F, et al. GLOBOCAN 2008: cancer incidence and mortality worldwide. IARC CancerBase No. 10 [online]. Available from URL: http://globocan.iarc.fr/[Accessed 2011 May 4]
Van Cutsem E, Geboes K. The multidisciplinary management of gastrointestinal cancer: the integration of cytotoxics and biologicals in the treatment of metastatic colorectal cancer. Best Pract Res Clin Gastroenterol 2007; 21(6): 1089–108
Sun W, Haller DG. Adjuvant therapy for colon cancer. Curr Oncol Rep 2005 May; 7(3): 181–5
Longley DB, Harkin DP, Johnston PG. 5-Fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 2003 May; 3(5): 330–8
Project ACCM-a. Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: evidence in terms of response rate. Advanced Colorectal Cancer Meta-Analysis Project. J Clin Oncol 1992 Jun; 10(6): 896–903
Machover D, Goldschmidt E, Chollet P, et al. Treatment of advanced colorectal and gastric adenocarcinomas with 5-fluorouracil and high-dose folinic acid. J Clin Oncol 1986 May; 4(5): 685–96
Machover D, Schwarzenberg L, Goldschmidt E, et al. Treatment of advanced colorectal and gastric adenocarcinomas with 5-FU combined with high-dose folinic acid: a pilot study. Cancer Treat Rep 1982 Oct; 66(10): 1803–7
Madajewicz S, Petrelli N, Rustum YM, et al. Phase I-II trial of high-dose calcium leucovorin and 5-fluorouracil in advanced colorectal cancer. Cancer Res 1984 Oct; 44(10): 4667–9
de Gramont A, Bosset JF, Milan C, et al. Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French intergroup study. J Clin Oncol 1997 Feb; 15(2): 808–15
Meta-Analysis Group in Cancer. Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol 1998 Jan; 16(1): 301–8
Delaunoit T, Goldberg RM, Sargent DJ, et al. Mortality associated with daily bolus 5-fluorouracil/leucovorin administered in combination with either irinotecan or ox-aliplatin: results from Intergroup Trial N 9741. Cancer 2004 Nov 15; 101(10): 2170–6
Walko CM, Lindley C. Capecitabine: a review. Clin Ther 2005 Jan; 27(1): 23–44
Miwa M, Ura M, Nishida M, et al. Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer 1998 Jul; 34(8): 1274–81
de Gramont A, Louvet C, Andre T, et al. Modulation of 5-fluorouracil with folinic acid in advanced colorectal cancers. Groupe d'etude et de recherche sur les cancers de l'ovaire et digestifs (GERCOD). Rev Med Interne 1997; 18 Suppl. 4: 372s-8s
Hoff PM, Cassidy J, Schmoll HJ. The evolution of fluoropyrimidine therapy: from intravenous to oral. Oncologist 2001; 6 Suppl. 4: 3–11
Kohne CH, Wils J, Lorenz M, et al. Randomized phase III study of high-dose fluorouracil given as a weekly 24-hour infusion with or without leucovorin versus bolus fluorouracil plus leucovorin in advanced colorectal cancer: European organization of Research and Treatment of Cancer Gastrointestinal Group Study 40952. J Clin Oncol 2003 Oct 15; 21(20): 3721–8
Van Cutsem E, Twelves C, Cassidy J, et al. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol 2001 Nov 1; 19(21): 4097–106
Hoff PM, Ansari R, Batist G, et al. Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol 2001 Apr 15; 19(8): 2282–92
Cassidy J, Twelves C, Van Cutsem E, et al. First-line oral capecitabine therapy in metastatic colorectal cancer: a favorable safety profile compared with intravenous 5-fluor-ouracil/leucovorin. Ann Oncol 2002 Apr; 13(4): 566–75
Miura K, Kinouchi M, Ishida K. 5-FU metabolism in cancer and orally-administrable 5-FU drugs. Cancers 2010; 2: 1717–30
Raida M, Schwabe W, Hausler P, et al. Prevalence of a common point mutation in the dihydropyrimidine dehydrogenase (DPD) gene within the 5'-splice donor site of intron 14 in patients with severe 5-fluorouracil (5-FU)-related toxicity compared with controls. Clin Cancer Res 2001 Sep; 7(9): 2832–9
Mattison LK, Fourie J, Desmond RA, et al. Increased prevalence of dihydropyrimidine dehydrogenase deficiency in African-Americans compared with Caucasians. Clin Cancer Res 2006 Sep 15; 12(18): 5491–5
Ando Y, Saka H, Asai G, et al. UGT1A1 genotypes and glucuronidation of SN-38, the active metabolite of irinotecan. Ann Oncol 1998 Aug; 9(8): 845–7
Innocenti F, Undevia SD, Iyer L, et al. Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol 2004 Apr 15; 22(8): 1382–8
Iyer L, Das S, Janisch L, et al. UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity. Pharmacogenomics J 2002; 2(1): 43–7
Pitot HC, Wender DB, O'Connell MJ, et al. Phase II trial of irinotecan in patients with metastatic colorectal carcinoma. J Clin Oncol 1997 Aug; 15(8): 2910–9
Rothenberg ML, Eckardt JR, Kuhn JG, et al. Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer. J Clin Oncol 1996 Apr; 14(4): 1128–35
Rougier P, Bugat R, Douillard JY, et al. Phase II study of irinotecan in the treatment of advanced colorectal cancer in chemotherapy-naive patients and patients pretreated with fluorouracil-based chemotherapy. J Clin Oncol 1997 Jan; 15(1): 251–60
Cunningham D, Pyrhonen S, James RD, et al. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 1998 Oct 31; 352(9138): 1413–8
Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 2000 Mar 25; 355(9209): 1041–7
Saltz LB, Cox JV, Blanke C, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 2000 Sep 28; 343(13): 905–14
Fuchs CS, Marshall J, Mitchell E, et al. 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 2007 Oct 20; 25(30): 4779–86
Kohne CH, De Greve J, Hartmann JT, et al. 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 2008 May; 19(5): 920–6
Koopman M, Antonini NF, Douma J, et al. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet 2007 Jul 14; 370(9582): 135–42
de Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000 Aug; 18(16): 2938–47
Andre T, Boni C, Navarro M, et al. 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 2009 Jul 1; 27(19): 3109–16
Cassidy J, Clarke S, Diaz-Rubio E, et al. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol 2008 Apr 20; 26(12): 2006–12
Goldberg RM, Sargent DJ, Morton RF, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004 Jan 1; 22(1): 23–30
Tournigand C, Andre T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004 Jan 15; 22(2): 229–37
Colucci G, Gebbia V, Paoletti G, et al. Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell'Italia Meridionale. J Clin Oncol 2005 Aug 1; 23(22): 4866–75
Tournigand C, Cervantes A, Figer A, et al. 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 2006 Jan 20; 24(3): 394–400
Chibaudel B, Maindrault-Goebel F, Lledo G, et al. Can chemotherapy be discontinued in unresectable metastatic colorectal cancer? The GERCOR OPTIMOX2 Study. J Clin Oncol 2009 Dec 1; 27(34): 5727–33
Sanoff HK, Sargent DJ, Campbell ME, et al. Five-year data and prognostic factor analysis of oxaliplatin and irinotecan combinations for advanced colorectal cancer: N 9741. J Clin Oncol 2008 Dec 10; 26(35): 5721–7
Souglakos J, Androulakis N, Syrigos K, et al. FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG). Br J Cancer 2006 Mar 27; 94(6): 798–805
Falcone A, Ricci S, Brunetti I, et al. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol 2007 May 1; 25(13): 1670–6
Ychou M, Viret F, Kramar A, et al. Tritherapy with fluor-ouracil/leucovorin, irinotecan and oxaliplatin (FOLFIR-INOX): a phase II study in colorectal cancer patients with non-resectable liver metastases. Cancer Chemother Pharmacol 2008 Jul; 62(2): 195–201
Ellis LM, Hicklin DJ. VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev Cancer 2008 Aug; 8(8): 579–91
Takahashi Y, Kitadai Y, Bucana CD, et al. Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res 1995 Sep 15; 55(18): 3964–8
Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004 Jun 3; 350(23): 2335–42
Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E 3200. J Clin Oncol 2007 Apr 20; 25(12): 1539–44
Hochster HS, Hart LL, Ramanathan RK, et al. 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 2008 Jul 20; 26(21): 3523–9
Saltz LB, Clarke S, Diaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 2008 Apr 20; 26(12): 2013–9
Tabernero J, Aranda E, Gomez A, et al. Phase III study of first-line XELOX plus bevacizumab (BEV) for 6 cycles followed by XELOX plus BEV or single-agent (s/a) BEV as maintenance therapy in patients (pts) with metastatic colorectal cancer (mCRC): The MACRO Trial (Spanish Cooperative Group for the Treatment of Digestive Tumors [TTD]) [ASCO abstract 3501]. J Clin Oncol 2010; 28: 15s
Vaidyanathan G, Groman A, Wilding G, et al. Stop and go FOLFOX plus bevacizumab chemotherapy in the first-line treatment of metastatic colorectal cancer. Oncology 2010 Nov 12; 79(1-2): 67–71
Porebska I, Harlozinska A, Bojarowski T. Expression of the tyrosine kinase activity growth factor receptors (EGFR, ERB B2, ERB B3) in colorectal adenocarcinomas and adenomas. Tumour Biol 2000 Mar-Apr; 21(2): 105–15
Oda K, Matsuoka Y, Funahashi A, et al. A comprehensive pathway map of epidermal growth factor receptor signaling. Mol Syst Biol. Epub 2005 May 25
Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004 Jul 22; 351(4): 337–45
Arnold D, Hohler T, Dittrich C, et al. Cetuximab in combination with weekly 5-fluorouracil/folinic acid and oxaliplatin (FUFOX) in untreated patients with advanced colorectal cancer: a phase Ib/II study of the AIO GI Group. Ann Oncol 2008 Aug; 19(8): 1442–9
Tabernero J, Van Cutsem E, Diaz-Rubio E, et al. Phase II trial of cetuximab in combination with fluorouracil, leucovorin, and oxaliplatin in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 2007 Nov 20; 25(33): 5225–32
Sobrero AF, Maurel J, Fehrenbacher L, et al. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol 2008 May 10; 26(14): 2311–9
Van Cutsem E, Kohne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009 Apr 2; 360(14): 1408–17
Bokemeyer C, Bondarenko I, Makhson A, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 2009 Feb 10; 27(5): 663–71
Ocvirk J, Brodowicz T, Wrba F, et al. Cetuximab plus FOLFOX6 or FOLFIRI in metastatic colorectal cancer: CECOG trial. World J Gastroenterol 2010 Jul 7; 16(25): 3133–43
Lievre A, Bachet JB, Le Corre D, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 2006 Apr 15; 66(8): 3992–5
Maughan TS, Adams R, Smith CS, et al., COIN Trial Management Group and Trial Investigators. Oxaliplatin and fluoropyrimidine chemotherapy plus or minus cetuximab: the effect of infusional 5-FU or capecitabine on the outcomes of the MRC COIN trial in advanced colorectal cancer (ACRC) [abstract 402]. ASCO GI conference; 2010 Jan 22–24; Orlando (FL)
Tveit K, Guren T, Glimelius B, et al. Randomized phase III study of 5-fluorouracil/folinate/oxaliplatin given continuously or intermittently with or without cetuximab, as first-line treatment of metastatic colorectal cancer: The NORDIC VII study (NCT00145314), by the Nordic Colorectal Cancer Biomodulation Group [abstract 365]. J Clin Oncol 2011; 29: 365
Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 2007 May 1; 25(13): 1658–64
Douillard JY, Siena S, Cassidy J, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 2010 Nov 1; 28(31): 4697–705
Peeters M, Price TJ, Cervantes A, et al. 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 2010 Nov 1; 28(31): 4706–13
Saltz LB, Lenz HJ, Kindler HL, et al. Randomized phase II trial of cetuximab, bevacizumab, and irinotecan compared with cetuximab and bevacizumab alone in irinotecan-refractory colorectal cancer: the BOND-2 study. J Clin Oncol 2007 Oct 10; 25(29): 4557–61
Tol J, Koopman M, Cats A, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med 2009 Feb 5; 360(6): 563–72
Hecht JR, Mitchell E, Chidiac T, et al. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol 2009 Feb 10; 27(5): 672–80
Goldberg RM, Rothenberg ML, Van Cutsem E, et al. The continuum of care: a paradigm for the management of metastatic colorectal cancer. Oncologist 2007 Jan; 12(1): 38–50
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
McRee, A.J., Goldberg, R.M. Optimal Management of Metastatic Colorectal Cancer. Drugs 71, 869–884 (2011). https://doi.org/10.2165/11591770-000000000-00000
Published:
Issue Date:
DOI: https://doi.org/10.2165/11591770-000000000-00000