Opinion statement
For the past several decades, the therapy for metastatic colorectal cancer had modest benefits because of the limited therapeutic options. Bolus 5-fluorouracil (5FU) and leucovorin (LV) were the standard of care in the United States until 2002, with a response rate of 25% and a median survival of 10 to 12 months. However, with the advent of new agents, namely oxaliplatin and irinotecan, there has been a dramatic change in the way we treat metastatic colorectal cancer. Based on many well-conducted large randomized trials, we have evidence that combination chemotherapy incorporating oxaliplatin or irinotecan with infusional 5FU/LV is superior to 5FU/LV, with doubling of overall survival (OS) to approximately 20 months. There remains some uncertainty as to the best first-line regimen. This might be irrelevant because studies have shown that OS is dependent on exposure to all the active agents, regardless of the time period of exposure. Bevacizumab, which uses anti-angiogenic strategies, has improved diseasefree survival (DFS) and OS when combined with standard chemotherapy and is a vital component of metastatic colorectal cancer therapy. However, there are no data supporting its use past progression. Cetuximab, an epithelial growth factor receptor inhibitor, is mainly used in irinotecan-refractory patients. In spite of all these advances, 5-year OS rates continue to be limited. Patients with curative resection of metastatic disease seem to have longer DFS and better 5-year OS rates. This should be a potential goal for responding patients with upfront unresectable, organ-limited disease.
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References and Recommended Reading
World Health Organization: Global cancer rates could increase by 50% to 15 million by 2020. Available at: http://www.who.int/mediacentre/releases/2003/pr27/en/print.html. Accessed April 9, 2006.
Jemal A, Siegal R, Taylor M, et al.: Cancer statistics, 2006. CA Cancer J Clin 2006, 56:106–130.
Buroker TR, O'Connell MJ, Wieand HS, et al.: Randomized comparison of two schedules of fluorouracil and leucovorin in the treatment of advanced colorectal cancer. J Clin Oncol 1994, 12:14–20.
Dorr TR, Von Hoff DD: Drug monographs. In Cancer Chemotherapy Handbook, edn 2. Edited by Dorr TR, Von Hoff DD. East Norwalk, CT: Appleton and Lange; 1994:500–515.
Meta-analysis Group in Cancer. Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol 1998, 16:301–308.
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, 343:905–914. This is one of the first trials that showed that combination chemotherapy is better than bolus 5FU/LV alone.
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 randomized trial. Lancet 2000, 355:1041–1047.
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, 22:23–30. This pivotal trial established the superiority of infusional 5FU and oxaliplatin (FOLFOX4), making it the first choice in metastatic colorectal cancer.
Sargent DJ, Niedzwiecki D, O'Connell MJ, et al.: Recommendation for caution with irinotecan, fluorouracil, and leucovorin for colorectal cancer. N Engl J Med 2001, 345:144–145.
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, 24:394–400.
André T, Louvet C, Maindrault-Goebel F, et al.: CPT-11 (irinotecan) addition to bimonthly, high-dose leucovorin and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for pretreated metastatic colorectal cancer. GERCOR. Eur J Cancer 1999, 35:1343–1347.
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, 22:229–237. The results of this study seem to suggest that FOLFOX and FOLFIRI are equivalent.
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, 23:4866–4875.
Seymour MT, for the UK NCRI Colorectal Clinic Studies Group: Fluorouracil, Oxaliplatin, and CPT-11 (Irinotecan), Use and Sequencing (MRC FOCUS): a 2135-patient randomized trial in advanced colorectal cancer (ACRC). J Clin Oncol 2005, 23(Suppl):3518.
Grothey A, Sargent D: 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 2005, 23:9441–9442. This is a pooled analysis of all the important phase III trials in metastatic colorectal cancer, helping to establish the key concept that exposure to all the active drugs is crucial.
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, 19:4097–4106.
Cassidy J, Tabernero J, Twelves C, et al.: XELOX (capecitabine plus oxaliplatin): active first-line therapy for patients with metastatic colorectal cancer. J Clin Oncol 2004, 22:2084–2091.
Patt YZ, Liebmann J, Diamandidis S, et al.: Capecitabine (X) plus irinotecan (XELIRI) as first-line treatment for metastatic colorectal cancer (MCRC): final safety findings from a phase II trial [abstract 3602]. J Clin Oncol 2004, 22(Suppl 14):270s.
Grothey A, Jordan K, Kellner O, et al.: Capecitabine/irinotecan (CAPIRI) and capecitabine/oxaliplatin (CAPOX) are active second-line protocols in patients with advanced colorectal cancer (ACRC) after failure of first-line combination therapy: results of a randomized phase II study [abstract 3534]. J Clin Oncol 2004, 22(Suppl 14):253s.
Kohne C, de Greve J, Bokemeyer C, et al.: Capecitabine plus irinotecan versus 5-FU/FA/irinotecan +/- celecoxib in first line treatment of metastatic colorectal cancer. Safety results of the prospective multicenter EORTC phase III study 40015 [abstract 3525]. J Clin Oncol 2005, 23(Suppl 16):252s.
Hochster HS, Welles L, Hart L, et al.: Safety and efficacy of bevacizumab (Bev) when added to oxaliplatin/fluoropyrimidine (O/F) regimens as first-line treatment of metastatic colorectal cancer (mCRC): TREE 1 & 2 studies [abstract 3515]. J Clin Oncol 2005, 23(Suppl 16):249s.
Arkenau H, Schmoll H, Kubicka S, et al.: Infusional 5-fluorouracil/folinic acid plus oxaliplatin (FUFOX) versus capecitabine plus oxaliplatin (CAPOX) as first line treatment of metastatic colorectal cancer (MCRC): results of the safety and efficacy analysis [abstract 3507]. J Clin Oncol 2005, 23(Suppl 16):247s.
Falcone A, Masi G, Murr R, et al.: Biweekly irinotecan, oxaliplatin, and infusional 5FU/LV (FOLFOXIRI) versus FOLFIRI as first-line treatment of metastatic colorectal cancer (MCRC): results of a randomized, phase III trial by the Gruppo Oncologico Nord Ovest (GONO) [abstract 199]. Program and abstracts of the 2006 Gastrointestinal Cancers Symposium. San Francisco, CA, January 26–28, 2006. This is the first randomized study that has looked at combining all three active agents, with very promising results.
Hurwitz H, Fehrenbacher L, Novotny W, et al.: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004, 350:2335–2342. This pivotal trial proved that bevacizumab is an important addition to traditional chemotherapy.
Giantonio BJ, Catalano PJ, Meropol NJ, et al.: Highdose bevacizumab in combination with FOLFOX4 improves survival in patients with previously treated advanced colorectal cancer: results from the Eastern Cooperative Oncology Group (ECOG) study E3200 [abstract 169a]. Paper presented at the American Society of Clinical Oncology Gastrointestinal Symposium. Hollywood, FL, January 27–29, 2005.
Hochester HS, Welles L, Hart L, et al.: Bevacizumab with oxaliplatin-based chemotherapy in the first-line therapy of metastatic colorectal cancer: preliminary results of the randomized “Tree-2” trial [abstract 241]. Paper presented at the American Society of Clinical Oncology Gastrointestinal Symposium. Hollywood, FL, January 27–29, 2005.
Schrag D: The price tag on progress--chemotherapy for colorectal cancer. N Engl J Med 2004, 351:317–319.
Ellis LM, Curley SA, Grothey A: Surgical resection after downsizing of colorectal liver metastasis in the era of bevacizumab. J Clin Oncol 2005, 23:4853–4855.
Cunningham D, Humblet Y, Siena S, et al.: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004, 351:337–345.
Sobrero A, Scheithauer W, Maurel J, et al.: Cetuximab plus irinotecan for metastatic colorectal cancer (mCRC): safety analysis of the first 400 patients in a randomized phase III trial (EPIC) [abstract 3580]. J Clin Oncol 2004, 23(Suppl 16):266s.
Diaz Rubio ED, Tabernero J, van Cutsem E, et al.: Cetuximab in combination with oxaliplatin/5-fluorouracil (5-FU)/folinic acid (FA) (FOLFOX-4) in the first-line treatment of patients with epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer: an international phase II study [abstract 3535]. J Clin Oncol 2004, 23(Suppl_16):254s.
Chung KY, Shia J, Kemeny NE, et al.: Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J Clin Oncol 2005, 23:1803–1810.
Saltz L, Lenz H, Kindler H, et al.: Interim report of randomized phase II trial of cetuximab/bevacizumab/irinotecan (CBI) versus cetuximab/irinotecan (CB) in irinotecan-refractory colorectal cancer. Paper presented at the American Society of Clinical Oncology Gastrointestinal Symposium. Hollywood, FL, January 27–29, 2005.
Poston GJ, Adam R, Alberts S, et al.: OncoSurge: a strategy for improving resectability with curative intent in metastatic colorectal cancer. J Clin Oncol 2005, 23:7125–7134.
Adam R, Avisar E, Ariche A, et al.: Five-year survival following hepatic resection after neoadjuvant therapy for nonresectable colorectal metastases. Ann Surg Oncol 2001, 8:347–353.
Delaunoit T, Alberts SR, Sargent DJ, et al.: Chemotherapy permits resection of metastatic colorectal cancer: experience from Intergroup N9741. Ann Oncol 2005, 16:425–429.
Alberts SR, Horvath WL, Sternfeld WC, et al.: Oxaliplatin, 5-fluorouracil, and leucovorin (FOLFOX4) for patients with unresectable liver-only metastases from colorectal cancer: a North Central Cancer Treatment Group (NCCTG) phase II study. J Clin Oncol 2005, 23:9243–9249.
Ensminger WD: Intrahepatic arterial infusion of chemotherapy: pharmacologic principles. Semin Oncol 2002, 29:119–125.
Rougier P, Laplanche A, Huguier M, et al.: Hepatic arterial infusion of floxuridine in patients with liver metastases from colorectal carcinoma: long-term results of a prospective randomized trial. J Clin Oncol 1992, 10:1112–1118.
Martin JK, O'Connell MJ, Wieand HS, et al.: Intra-arterial floxuridine vs systemic fluorouracil for hepatic metastases from colorectal cancer. A randomized trial. Arch Surg 1990, 125:1022–1027.
Reappraisal of hepatic arterial infusion in the treatment of nonresectable liver metastases from colorectal cancer. Meta-Analysis Group in Cancer. J Natl Cancer Inst 1996, 88:252–258.
Ducreux M, Ychou M, Laplanche A, et al.: Hepatic arterial oxaliplatin infusion plus intravenous chemotherapy in colorectal cancer with inoperable hepatic metastases: a trial of the gastrointestinal group of the Federation Nationale des Centres de Lutte Contre le Cancer. J Clin Oncol 2005, 23:4881–4887.
Kemeny N, Huang Y, Cohen AM, et al.: Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med 1999, 341:2039–2048
Kemeny NE, Gonen M: Hepatic arterial infusion after liver resection. N Engl J Med 2005, 352:734–735.
Kemeny NE, Niedzwiecki D, Hollis DR, et al.: Hepatic arterial infusion versus systemic therapy for hepatic metastases from colorectal cancer: a randomized trial of efficacy, quality of life, and molecular markers (CALGB 9481). J Clin Oncol 2006, 24:1395–1403.
Kemeny NE, Fong Y, Jarnagin W, et al.: A phase I trial of systemic oxaliplatin combinations with hepatic arterial infusion in patients with unresectable liver metastases from colorectal cancer. J Clin Oncol 2005, 23:4888–4896.
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Patiyil, S., Alberts, S.R. Metastatic colorectal cancer: Therapeutic options. Curr. Treat. Options in Oncol. 7, 389–398 (2006). https://doi.org/10.1007/s11864-006-0007-8
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DOI: https://doi.org/10.1007/s11864-006-0007-8