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Originally published as JCO Early Release 10.1200/JCO.2007.11.6582 on August 20 2007 © 2007 American Society of Clinical Oncology.
Should Capecitabine Replace Infusional Fluorouracil and Leucovorin When Combined With Oxaliplatin in Metastatic Colorectal Cancer?
Dana-Farber Cancer Institute, Boston, MA For many decades, fluorouracil (FU) has been the cornerstone of therapy for metastatic colorectal cancer.1 It has been administered parenterally because of the erratic absorption of oral administration2 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.3 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 "hand-foot" syndrome.1 Capecitabine (Xeloda; Roche, Basel, Switzerland), an orally-administered 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 cancer4,5 or as adjuvant therapy.6 As monotherapy, capecitabine has been reported to have a favorable safety, convenience, and cost-effectiveness profile.7-9 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; Bristol-Myers 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 irinotecan10 with or without bevacizumab11 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")12,13 or irinotecan ("Xeliri" or "CapIri")13 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.14-18 The results of two of these comparative studies—one conducted in Spain by Díaz-Rubio et al14 and the other in Germany by Porchen et al15—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,14 342 eligible patients were randomly assigned to receive Xelox (oxaliplatin 130 mg/m2 day 1 and capecitabine 1,000 mg/m2 twice daily days 1 through 14) every 21 days or FUOX (oxaliplatin [85 mg/m2 day 1] and parenteral FU [1,125 mg/m2/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,15 476 patients were randomly assigned to receive either CapOx (oxaliplatin 70 mg/m2 days 1 and 8 and capecitabine 1,000 mg/m2 twice daily days 1 through 14) every 3 weeks, or FUFOX (oxaliplatin 50 mg/m2, leucovorin 500 mg/m2 in a 2-hour infusion, and FU 2,000 mg/m2 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 capecitabine-containing 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 comparisons16,17), 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 as the basis for comparison. The initial phase III assessments of single-agent capecitabine in treating metastatic colorectal cancer that claimed a superior safety profile, involved a comparison with the "loading schedule" of bolus FU and leucovorin, arguably the least tolerable manner in which to administer this combination.19 The Spanish14 and German15 investigators who compared oxaliplatin/capecitabine with oxaliplatin/infusional FU noted a similar toxicity profile between the two treatment options. Additional comparisons of CapOx versus FOLFOX18 (or CapIri versus FOLFIRI20) in North America, however, have shown poorer tolerance for the twice-daily 1,000 mg/m2 capecitabine dose commonly utilized in Europe, leading to a dose reduction to twice-daily 850 mg/m218; the explanation for this geographic variability in tolerance remains unclear.21 An advantage of capecitabine as monotherapy, which undoubtedly contributed to its greater preference with patients,9 was the convenience of the oral treatment, minimizing visits to clinic infusion rooms. The avoidance of clinic infusion fees diminished the impact of the higher cost of capecitabine, making the oral approach appear to be cost-effective.7 The addition of a parenterally administered compound—oxaliplatin—requires periodic infusion room visits, making a reassessment of the cost-efficacy issue timely. Tables 1 and 2 represent a comparison of the number of clinic visits and the estimated cost ($USD) for a 12-week course of therapy of: Xelox and FUOX, as administered in the Spanish study published in this issue of the Journal14; FOLFOX-4 as utilized in the MOSAIC trial which demonstrated the value of adding oxaliplatin to infusional FU/leucovorin as adjuvant therapy22; and a modified FOLFOX-6 (mFOLFOX-6; modified because of a reduction in the oxaliplatin dose from the original 100 mg/m2 to 85 mg/m2), which is now widely given in North America and is included in the ongoing Intergroup adjuvant study (NO147) for stage III colon cancer.23 Since most oncology nurses request central venous access for the administration of oxaliplatin out of concern for the ill effects that might ensue if the drug extravasates, it is assumed that all patients will have undergone portacath placement. The cost of chemotherapy is based on the average wholesale price (AWP)24 and was computed for a patient with a body surface area of 1.8 m2. Utilizing the present fee schedule at the Dana-Farber Cancer Institute, a charge of $275 was assessed for each visit to the clinic infusion room, and a similar charge of $275 was levied each time an infusion pump was newly attached.
Table 1 details the four treatment regimens, the duration of each treatment cycle, the required number of clinic visits per cycle, and the subsequent number of treatment visits for each 12 weeks of therapy. It is assumed that patients are able to have the infusion needle removed from their portacath at the conclusion of the FU treatment without having to return to the clinic. In terms of patient convenience, fewer clinic visits are associated with the Xelox regimens than with the three infusional FU alternatives, with the smallest difference being between Xelox and mFOLFOX-6 (4 v 6 visits during the 12-week period). The estimated comparative costs for the four chemotherapy regimens over a 12-week treatment interval are presented in Table 2. These costs range from $25,728 to $50,228. Despite the requirement for additional clinic visits, each of the three infusional FU alternatives appears to be appreciably less expensive than the Xelox, in large part because of the wide pricing difference between capecitabine and FU. Based on this estimate, 12 weeks of treatment with Xelox costs 95.2% (ie, $24,500) more than 12 weeks of treatment with mFOLFOX-6. The complexities in determining the cost of such treatment programs has been the focus of a recent commentary.25 The results of Díaz-Rubio et al14 and Porschen et al15 confirm that patients with metastatic colorectal cancer have a median survival approaching 20 months if treated with an oxaliplatin/fluoropyrimidine combination. Substituting capecitabine for infusional FU in such combinations could be justified if the outcome results, toxicity profile, and cost were (at least) indistinguishable. The available data for such comparisons show therapeutic "noninferiority," probable toxicity equivalence (with geographic variability), but a cost almost two-fold higher for the capecitabine. The case for such a substitution, therefore, is not convincing, and at present, when using an oxaliplatin plus fluoropyrimidine combination, FOLFOX would seem to remain the standard of care. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
NOTES published online ahead of print at www.jco.org on August 20, 2007 REFERENCES
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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