New combinations in metastatic colorectal cancer: what are our expectations?

The Oncologist 2005;10:320–322 www.TheOncologist.com Correspondence: Herbert Hurwitz, M.D., Room 3802, Duke University Medical Center, Durham, North Carolina 27710, USA. Telephone: 919-681-5257; Fax: 919-684-9712; e-mail: [email protected] Received September 22, 2004; accepted for publication March 11, 2005. ©AlphaMed Press 1083-7159/2005/$12.00/0 Colorectal cancer is the fourth most commonly diagnosed cancer and the second leading cause of cancer-related deaths in the U.S. [1]. Almost a third of patients already have metastatic disease at diagnosis, and half the patients diagnosed and resected with early-stage disease subsequently develop metastases [2]. Nearly all patients with metastatic cancer die of their disease. For many decades, the only effective first-line treatment for metastatic colorectal cancer remained fluorouracil (FU). Subsequently, coadministration of FU with leucovorin (LV) increased response rates and time to progression, but only marginally improved overall survival [3, 4]. Various attempts were made to optimize this regimen using different doses and schedules, but although these modifications revealed interesting differences in their side-effect profiles, they failed to deliver noticeably improved clinical benefit. Similarly, capecitabine (Xeloda®; Hoffmann-La Roche Inc., Nutley, NJ, http://www.roche.us), an oral FU prodrug, while more convenient and with a more acceptable sideeffect profile, has not increased survival over that achieved with i.v. regimens [5, 6]. As oncology entered the 21st Century, however, the deadlock that had characterized metastatic colorectal cancer for so many years began to shift. Combinations of newer agents with FU in the first-line setting for this hitherto intractable disease have improved survival. The first of these recent arrivals was the topoisomerase-I inhibitor, irinotecan (Camptosar®; Pfizer Pharmaceuticals Inc., New York, NY, http://www.pfizer.com). When added to bolus or infusional FU, irinotecan results in a greater overall survival rate and a longer time to progression than FU/LV alone [7, 8]. However, this agent has significant toxicities, which can occasionally be severe, particularly when given with bolus FU. The second agent to show a survival benefit when added to FU in the first-line setting was oxaliplatin (Eloxatin®; Sanofi-Synthélabo Inc., New York, NY, http://www.sanofisynthelabo.us), a third-generation platinum compound. In the first such trial, results were encouraging, although the improvement in overall survival was not statistically higher than with FU/LV; however, it should be noted that crossover may have obscured a small impact on overall survival [9]. More recently, a bigger phase III study of oxaliplatin combined with a bolus/infusional FU regimen (FOLFOX4) produced a superior response rate, time to progression, and overall survival compared with the bolus irinotecan/FU/LV (IFL) regimen [10]. Based on these data, FOLFOX4 was approved in the U.S. for the first-line treatment of colorectal cancer. However, oxaliplatin also carries a significant toxicity profile—one of these toxicities (namely neuropathy) is cumulative and often necessitates treatment interruption after 6 months. The year 2004 also saw the approval of two new biologic agents for colorectal cancer—bevacizumab (Avastin®; The Oncologist Gastrointestinal Cancer Commentary