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Optimizing the Use of Irinotecan in Colorectal Cancer

^a Gastrointestinal and Lymphoma Units, The Royal Marsden Hospital, London and Surrey, UK; ^b Ottawa Regional Cancer Centre, Ottawa, Canada; ^c Department of Internal Medicine (Cancer Research), West German Cancer Center, University of Essen Medical School, Essen, Germany; ^d University Hospital Gasthuisberg, Leuven, Belgium

Correspondence: David Cunningham, M.D., Royal Marsden Hospital, 203 Fulham Road, London, SW3 6JJ, United Kingdom. Telephone: 44-208-661-3156; Fax: 44-208-643-9414; e-mail: d.cunningham{at}icr.ac.uk

The introduction of new agents with novel mechanisms of action has led to considerable changes in the management of colorectal cancer in recent years. One of these novel agents, irinotecan, has been shown to offer survival benefits in both the first- and second-line treatment of advanced/metastatic colorectal cancer. Irinotecan monotherapy improves survival compared with both best supportive care and infused 5-fluorouracil (5-FU) in patients with 5-FU-pretreated disease, without impacting negatively on patients' quality of life. As a result, irinotecan monotherapy is now considered to be the standard treatment in this setting. Irinotecan in combination with 5-FU/leucovorin (LV) was subsequently evaluated as first-line therapy for metastatic colorectal cancer in two randomized, phase III studies. Both trials confirmed that irinotecan plus infused or bolus 5-FU/leucovorin LV provide a modest survival benefit without compromising patients' quality of life. Combined irinotecan/5-FU/LV represents a new standard in the first-line treatment of metastatic colorectal cancer.

In an attempt to further improve efficacy and tolerability, recent studies have investigated irinotecan in combination with capecitabine as first-line treatment for colorectal cancer. The replacement of infused 5-FU with oral capecitabine provides a more convenient treatment option. A phase I study was conducted to establish the maximum tolerated dose, and demonstrated encouraging antitumor activity and a manageable safety profile with the combination. This article provides a brief overview of the pivotal clinical trial data for irinotecan and discusses how irinotecan-based therapy may be improved in the future. It also discusses potential optimization of irinotecan use through identification of patient subpopulations most likely to benefit from combination or sequential strategies, and the potential of new, oral agents such as capecitabine to replace i.v. 5-FU as a combination partner for irinotecan.

Key Words. Capecitabine • 5-FU • Irinotecan • Colorectal cancer • Fluoropyrimidines

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