“Overall, progress in metastatic colorectal cancer (CRC) has been real, but modest, while hype and cost increases have been substantial,” said Leonard Saltz, MD, Chief of the Gastrointestinal Oncology Service at Memorial Sloan-Kettering Cancer Center, New York.
The backbone of treatment is still 5-fluorouracil [5-FU], which was patented in 1957 and remains “arguably the single best drug we have in CRC,” he noted. “Virtually every drug since then has been a relative failure in terms of its intention to replace 5-FU.” Instead, new drugs have found a role in combination therapy, he added, as none have been effective enough as single agents.
In this regard, FOLFOX (leucovorin, fluorouracil, oxaliplatin) and FOLFIRI (leucovorin, fluorouracil, irinotecan) produce essentially the same outcomes in terms of response rates, time to progression, and overall survival (OS). Dr. Saltz further noted that due to its neurotoxic potential, FOLFOX’s place as the preferred initial regimen in the United States may be somewhat misguided. Instead, he suggested that clinicians consider and discuss with their patients the toxicity profiles of both regimens and together choose between FOLFOX and FOLFIRI according to the patient’s preferences and tolerance for the associated potential adverse events.
Updated results from the MOSAIC trial of FOLFOX confirmed that approximately one fourth of patients have some degree of peripheral neuropathy (primarily, but not limited to, grade 1) 1 year after treatment. At 4 years, residual symptoms of neuropathy (probably permanent) still exist for more than 10% of patients.1 “This is a reason we need to think about reducing the patient’s exposure to oxaliplatin,” he said.
The OPTIMOX1 study defined standard practice by showing that a “stop and go” approach to giving oxaliplatin could be as effective as continuous treatment, with less neurotoxicity.2 CapeOx (capecitabine, oxaliplatin) is also an option, he said, but he cautioned that oral agents are not the right choice for some patients. Continuing an oral regimen, especially one containing an emetogenic agent such as oxaliplatin, is a large responsibility to give to some patients. Appropriate patients for consideration of oral agents are those who are both highly motivated and capable of accurately adhering to a complicated oral schedule.
Dr. Saltz has disclosed that he receives research support from Amgen Inc.; Bayer HealthCare; Bristol-Myers Squibb Company; CureTech Ltd.; Eli Lilly and Company; Genentech, Inc.; ImClone Systems Incorporated; National Cancer Institute; OSI Pharmaceuticals, Inc.; Astellis; Biothera; Immunomedex; Pfizer Inc.; Roche Laboratories, Inc.; Synta Pharmaceuticals Corp.; and Taiho Parmaceuticals Co., Ltd and serves as a consultant for Bayer HealthCare; CureTech Ltd.; Genentech, Inc.; Genomic Health, Inc.; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Roche Laboratories, Inc.; and Taiho Parmaceuticals Co., Ltd.
Andre T, Boni C, Navarro M. 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;27:3109–3116.
Tournigand C, Cervantes A, Figer A. OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer—a CERCOR study. J CLin Oncol 2006;24:394–400.
Hurwitz H, Fehrenbacher L, Novotny W. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335–2342.
Saltz LB, Clark S, Diaz-Rubio E. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 2008;26:2013–2019.
Bennouna J, Sastre J, Arnold D. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomized phase 3 trial. Lancet Oncol 2013;14:29–37.
Cunningham D, Humblet Y, Siena S. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004;351:337–345.
Van Cutsem E, Kohne CH, Hitre E. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009;360:1408–1417.
Bokemeyer C, Bondarenko I, Makhson A. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 2009;27:663–671.
Douillard JY, Siena S, Cassidy J. Final results from PRIME: randomized phase 3 study of panitumumab with FOLFOX4 for 1st-line medical colorectal cancer [abstract]. J Clin Oncol 2011;29(Supp 15):Abstract 3510.
Van Cutsem E, Tabernero J, Lakomy R. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer. J Clin Oncol 2012;30:3499–3506.
Grothey A, Van Cutsem E, Sobrero A. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicenter, randomized, placebo-controlled, phase 3 trial. Lancet 2013;381(9863):303–312.
Vakiani E, Janakiraman M, Shen R. Comparative genomic analysis of primary versus metastatic colorectal carcinomas. J Clin Oncol 2012;30:2956–2962.
Kopetz, Desai J, Chan E. PLX4032 in metastatic colorectal cancer patient with mutant BRAF tumors [abstract]. J Clin Oncol 2010;28(Suppl 15): Abstract 3534.
Tejpar S, Bokemeyer C, Celik I. Influence of KRAS G13D mutations on outcome in patients with metastatic colorectal cancer treated with first-line chemotherapy with or without cetuximab [abstract]. J Clin Oncol 2011;29(Suppl 15): Abstract 3511.
Peeters M, Douillard JY, Van Cutsem E. Mutant KRAS codon 12 and 13 alleles in patients with metastatic colorectal cancer: assessment as prognostic and predictive biomarkers of response to panitumumab. J Clin Oncol 2013;31:759–765.
Tol J, Koopman M, Cats A. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med 2009;360:563–572.