Should Capecitabine Replace Infusional Fluorouracil and Leucovorin When Combined With Oxaliplatin in Metastatic Colorectal Cancer

For many decades, fluorouracil (FU) has been the cornerstone of therapy for metastatic colorectal cancer. It has been administered parenterally because of the erratic absorption of oral administration and is usually given with leucovorin, a reduced folate that stabilizes the binding of the drug to thymidylate synthase, thereby enhancing the inhibition of DNA synthesis. Various dose schedules of FU and leucovorin have been examined, having similar antitumor efficacy but different toxicity profiles, with a “loading” schedule of bolus treatments on 5 consecutive days every 4 to 5 weeks leading to significant neutropenia and stomatitis, a weekly bolus program resulting in frequent diarrhea, and a 48-hour biweekly infusion resulting in a slightly higher likelihood of a “handfoot” syndrome. Capecitabine (Xeloda; Roche, Basel, Switzerland), an orallyadministered prodrug, is extensively absorbed from the intestine and undergoes a three-step enzymatic conversion to FU. The “hand-foot” syndrome is its most distinguishing adverse effect, similar to that observed with infusional FU. Randomized trials have shown capecitabine and the loading schedule of bolus FU and leucovorin to be equally effective when given to treat metastatic colorectal cancer or as adjuvant therapy. As monotherapy, capecitabine has been reported to have a favorable safety, convenience, and cost-effectiveness profile. The introduction of newer cytotoxic drugs such as oxaliplatin and irinotecan as well as the development of targeted agents including inhibitors of the epidermal growth factor receptor (ie, cetuximab [Erbitux; ImClone Systems Inc, New York, NY; BristolMyers Squibb Company, Princeton, NJ] and panitumumab [Vectibix; Amgen, Thousand Oaks, CA]) and the vascular endothelial growth factor receptor (ie, bevacizumab [Avastin; Genentech, South San Francisco, CA]) have made monotherapy for colorectal cancer obsolete. Adding oxaliplatin or irinotecan to infusional FU and leucovorin (FOLFOX and FOLFIRI, respectively) has extended the median survival for patients with metastatic disease from about 12 months to more than 16 months; adding both oxaliplatin and irinotecan with or without bevacizumab has prolonged the median survival to greater than 20 months. Capecitabine has been examined as a substitute for infusional FU and leucovorin in combination with oxaliplatin (“Xelox” or “CapOx”) or irinotecan (“Xeliri” or “CapIri”) in phase II trials, with observed outcomes similar to those reported with FOLFOX and FOLFIRI. At least five randomized comparisons of Xelox with oxaliplatin combined with various infusional FU schedules have been undertaken in patients previously untreated for metastatic colorectal cancer. The results of two of these comparative studies— one conducted in Spain by Diaz-Rubio et al and the other in Germany by Porchen et al—appear in this issue of the Journal. Both of these trials were designed to show noninferiority for the capecitabine-containing combination using time to tumor progression (TTP) as the primary end point. The reported outcomes are remarkably similar. In the Spanish study, 342 eligible patients were randomly assigned to receive Xelox (oxaliplatin 130 mg/m day 1 and capecitabine 1,000 mg/m twice daily days 1 through 14) every 21 days or FUOX (oxaliplatin [85 mg/m day 1] and parenteral FU [1,125 mg/m/d of infusion on day 1 through 2 and 8 through 9]) every 14 days. The authors report a lack of a statistical difference in median TTP favoring the FUOX (9.5 v 8.9 months, P .153) with the same trend noted for median overall survival (20.8 v 18.1 months; P .145). In the German study, 476 patients were randomly assigned to receive either CapOx (oxaliplatin 70 mg/m days 1 and 8 and capecitabine 1,000 mg/m twice daily days 1 through 14) every 3 weeks, or FUFOX (oxaliplatin 50 mg/m, leucovorin 500 mg/m in a 2-hour infusion, and FU 2,000 mg/m in a 22-hour infusion) each week. A statistically indistinguishable difference again favored the infusional FU program (ie, FUFOX) in terms of median TTP (8.0 v 7.1 months; P .117) and median overall survival (18.8 v 17.3 months; P .26). The authors of both these studies are appropriately cautious in their interpretation of the data with neither investigative group suggesting that the capecitabinecontaining alternative should supplant infusional FU. If oxaliplatin/capecitabine and oxaliplatin/infusional FU regimens have equal efficacy in treating metastatic colorectal cancer (as has also been observed in the preliminary analyses of two additional phase III comparisons), what other criteria should be considered in distinguishing between these two alternatives? Three factors, all previously proposed in support of capecitabine as monotherapy, merit such consideration; these include: comparative tolerability, patient convenience, and cost. Any assessment of tolerance of capecitabine alone or capecitabine combined with drugs such as oxaliplatin or irinotecan is dependent on the parenteral FU treatment program, which serves JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 25 NUMBER 27 SEPTEMBER 2