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Combined Therapy with Weekly Irinotecan, Infusional 5-Fluorouracil and the Selective COX-2 Inhibitor Rofecoxib Is a Safe and Effective Second-Line Treatment in Metastatic Colorectal Cancer

^a Division of Medical Oncology, San Filippo Neri Hospital, Rome, Italy; ^b Division of Medical Oncology, Umberto I Hospital, Frosinone, Italy; ^c Medical Statistic and Biometry Unit, Istituto Nazionale per lo studio e la Cura dei Tumori, Milan, Italy

Key Words. COX-2 inhibitors • Irinotecan • 5-Fluorouracil • Metastatic colorectal cancer

Giampietro Gasparini, Division of Medical Oncology, Azienda Complesso Ospedaliero di Rilevanza Nazionale San Filippo Neri, Via C. Martinotti 20, 00135 Rome, Italy. Telephone: 39-06-33062237; Fax: 39-06-33062445; e-mail: gasparini.oncology{at}tiscalinet.it

The purpose of this study was to determine the tolerability and activity of rofecoxib (Vioxx^®; Merck & Co., Inc., Whitehouse Station, NJ, http://www.merck.com) combined with weekly irinotecan (Camptosar^®; Pfizer Pharmaceuticals, New York, http://www.pfizer.com) and infusional 5-fluorouracil (5-FU) as second-line therapy in metastatic colorectal cancer (MCRC). Enrolled patients had previously treated metastatic disease, were aged 18 to 75 years, and had adequate performance status. A cycle of treatment consisted of i.v. irinotecan on days 1, 8, 15, and 22, rofecoxib at an oral dose of 50 mg/day, and infusional 5-FU at a fixed dose of 200 mg/m² per day for 5 weeks followed by 3 weeks of therapy with rofecoxib alone. In the dose-finding study, the starting dose of irinotecan was 87.5 mg/m² and further dose escalations were planned by increments of 12.5 mg/m² up to 125 mg/m². Forty-eight consecutive patients were enrolled in the study. Among the 15 cases enrolled in the dose-finding study, one patient experienced grade 3 reversible diarrhea as the dose-limiting toxicity, at the fourth dose level tested. Therefore, the dose of irinotecan for the phase II study was 125 mg/m², and 33 patients were enrolled and received a total of 75 cycles. Hematological side effects were moderate, with grade 4 neutropenia recorded in only two patients. The most common nonhematological toxicity was diarrhea, occurring in 25 patients (75.8%) and considered to be of grade 3 in 12 patients (36.4%). Sixteen patients achieved partial responses (48.5%; 95% confidence interval [CI], 30.8%–66.5%), and another 10 patients (30.3%) had stable disease. The median time to progression was 7 months (95% CI, 5–12) and the median overall survival (OS) was 18 months; the 1-year estimated OS rate was 69.4%. The unique schedule tested in this study is feasible, is well-tolerated, and has promising activity in patients with MCRC after progression on oxaliplatin (Eloxatin^®; Sanofi-Synthelabo Inc., New York, http://www.sanofi-synthelabo.us)-based chemotherapy.