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

• Published in: The oncologist (Dayton, Ohio) Ohio), 2005-10, Vol.10 (9), p.710-717
• Main Authors: Gasparini, Giampietro, Gattuso, Domenico, Morabito, Alessandro, Longo, Raffaele, Torino, Francesco, Sarmiento, Roberta, Vitale, Stefano, Gamucci, Teresa, Mariani, Luigi
• Format: Article
• Language: English
• Subjects: 5‐Fluorouracil; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Camptothecin - administration & dosage; Camptothecin - adverse effects; Camptothecin - analogs & derivatives; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - mortality; COX‐2 inhibitors; Fluorouracil - administration & dosage; Fluorouracil - adverse effects; Humans; Irinotecan; Lactones - administration & dosage; Lactones - adverse effects; Metastatic colorectal cancer; Middle Aged; Neoplasm Metastasis; Sulfones - administration & dosage; Sulfones - adverse effects
• ISSN: 1083-7159; 1549-490X
• DOI: 10.1634/theoncologist.10-9-710

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.