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Journal of Clinical Oncology, Vol 26, No 11 (April 10), 2008: pp. 1907-1908 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.9640
Capecitabine and Irinotecan As First-Line Treatment of Advanced Colorectal CancerDepartment of Medical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands To the Editor: Fuchs et al1 recently published their results of a randomized trial (BICC-C) of irinotecan in combination with either infusional fluorouracil (FU; FOLFIRI), bolus (mIFL), or oral capecitabine (CapeIRI) in patients with advanced colorectal cancer. The CapeIRI schedule consisted of once every 3 weeks cycles of capecitabine 1000 mg/m2 bid, day 1 through 14, plus irinotecan 250 mg/m2 on day 1. Of 141 patients treated with CapeIRI, grade 3 to 4 vomiting occurred in 15.6% of patients, diarrhea occurred in 47.5%, and dehydration occurred in 19.1%—significantly more frequently compared with FOLFIRI or mIFL schedules. The CapeIRI treatment arm was discontinued because of toxicity concerns. Although the results on objective response rates and overall survival were not statistically different among the three regimens, the progression-free survival (PFS) was significantly better for FOLFIRI when compared with CapeIRI (7.6 v 5.8 months, respectively; P = .015). Recently, the results of the European Organisation for Research and Treatment of Cancer study (EORTC 40015) with a comparable design were published.2 This study aimed to demonstrate the noninferiority of capecitabine to FU when added to irinotecan in the first-line treatment of metastatic colorectal cancer. CapeIRI was given at the same dose and schedule as in the BICC-C trial. After enrollment of only 85 patients, the EORTC trial was prematurely discontinued because of the occurrence of seven treatment-related deaths (8%). The most common grade 3 to 4 toxicity was diarrhea, which was reported more frequently in the CapeIRI versus the FOLFIRI treatment arm (35% v 10%, respectively). No significant differences were seen for grade 3 to 4 nausea and vomiting between the treatment arms. Small sample size and confounding safety issues did not allow valid conclusions to be drawn concerning the relative efficacy of CapeIRI versus FOLFIRI. The results of the BICC-C and EORTC studies on the toxicity of CapeIRI are in contrast to the results of our randomized phase III study (Capecitabine, Irinotecan, and Oxaliplatin in Advanced Colorectal Cancer [CAIRO] study of the Dutch Colorectal Cancer Group), which included the largest patient cohort to date that received the same CapeIRI regimen as first-line treatment (n = 402).3 In this study, grade 3 to 4 diarrhea was observed in 26% of patients, which is in line with the incidence of between 19% and 26% in four phase II studies involving a total of 210 patients.4-7 The median PFS for CapeIRI in the CAIRO study was 7.8 months. Several comments can be made regarding these conflicting data on toxicity and efficacy of CapeIRI. First, both the BICC-C and the EORTC studies involved an additional randomization to either celecoxib or placebo. The BICC-C study did not report the results with celecoxib. In the EORTC study, no apparent effect of celecoxib on the incidence of diarrhea was observed; however, the number of patients was too small for a meaningful conclusion. Although a possible effect of celecoxib on the incidence of diarrhea could not be excluded, preclinical results have shown a protective effect of celecoxib on irinotecan-induced mucosal injury,8 which makes a causative role of celecoxib unlikely. Second, the difference in the incidence of toxicity may be explained by regional differences that have been observed for the tolerability of capecitabine.9 This observation needs additional confirmation, but the high incidence of grade 3 to 4 diarrhea of 36% in the European EORTC study2 suggests that this phenomenon may be more complex than a difference between United States and non-European versus European patients. Third, although strict criteria for the grading of diarrhea are available, we should acknowledge that the scoring of this event is usually performed retrospectively and is therefore subjective to bias from both patients and physicians. Also, inadequate action from patients or physicians at the onset of diarrhea may result in artificially high incidence of grade 3 to 4 diarrhea. Physician and patient education should remain a high priority, and on-site reviews of patient files may reveal additional useful information in case of unusual or unsuspected toxic events.3 Fourth, in the BICC-C study, a lower median PFS was observed for CapeIRI compared with FOLFIRI (5.8 v 7.6 months, respectively). This is lower compared with the median PFS of 7.8 months for CapeIRI in the CAIRO study.3 Although cross-study comparisons may be erroneous, it should be noted that important prognostic variables, such as serum lactate dehydrogenase and the number of involved organs,10 were not provided in the BICC-C study. Therefore, imbalances in these characteristics may have influenced the outcome of this study. Also, the median number of cycles and/or dose-intensities are not provided as a possible explanation for the differences in PFS. Given the acceptable safety and efficacy profile in the largest patient cohort reported to date, we conclude that a once every 3 weeks CapeIRI regimen of capecitabine 1,000 mg/m2 twice daily on days 1 through 14, and irinotecan 250 mg/m2 on day 1, is a feasible and effective treatment option for patients with advanced colorectal cancer. In patients who are considered at risk for severe diarrhea, the dose of capecitabine and irinotecan may be reduced to 850 and 200 mg/m2, respectively.6 Schedules of FOLFIRI in general produce less diarrhea, but this must be balanced against the use of ambulatory infusion devices and more frequent patient visits. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Cornelis J.A. Punt, Roche (C), Pfizer Inc (C) Stock Ownership: None Honoraria: Cornelis J.A. Punt, Roche, Pfizer Inc Research Funding: None Expert Testimony: None Other Remuneration: None REFERENCES
1. Fuchs CS, Marshall J, Mitchell E, et al: Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: Results from the BICC-C Study. J Clin Oncol 25:4779-4786, 2007 2. Kohne CH, De Greve J, Hartmann JT, et al: Irinotecan combined with infusional 5-fluorouracil/folinic acid or capecitabine plus celecoxib or placebo in the first-line treatment of patients with metastatic colorectal cancer. EORTC study 40015. Ann Oncol doi:10.1093/annonc/mdm544 [epub ahead of print on December 6, 2007] 3. Koopman M, Antonini NF, Douma J, et al: Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet 370:135-142, 2007[CrossRef][Medline] 4. Bajetta E, Di BM, Mariani L, et al: Randomized multicenter Phase II trial of two different schedules of irinotecan combined with capecitabine as first-line treatment in metastatic colorectal carcinoma. Cancer 100:279-287, 2004[CrossRef][Medline] 5. Borner MM, Bernhard J, Dietrich D, et al: A randomized phase II trial of capecitabine and two different schedules of irinotecan in first-line treatment of metastatic colorectal cancer: Efficacy, quality-of-life and toxicity. Ann Oncol 16:282-288, 2005 6. Patt YZ, Lee FC, Liebmann JE, et al: Capecitabine plus 3-weekly irinotecan (XELIRI regimen) as first-line chemotherapy for metastatic colorectal cancer: Phase II trial results. J Clin Oncol 30:350-357, 2007[CrossRef] 7. Rea DW, Nortier JW, Ten Bokkel Huinink WW, et al: A phase I/II and pharmacokinetic study of irinotecan in combination with capecitabine as first-line therapy for advanced colorectal cancer. Ann Oncol 16:1123-1132, 2005 8. Javle MM, Cao S, Durrani FA, et al: Celecoxib and mucosal protection: Translation from an animal model to a phase I clinical trial of celecoxib, irinotecan, and 5-fluorouracil. Clin Cancer Res 13:965-971, 2007 9. Haller DG, Cassidy J, Clarke S, et al: Tolerability of fluoropyrimidines appears to differ by region. J Clin Oncol 24:18s, 2006 (abstr 3514)[CrossRef] 10. Sorbye H, Kohne CH, Sargent DJ, et al: Patient characteristics and stratification in medical treatment studies for metastatic colorectal cancer: A proposal for standardization of patient characteristic reporting and stratification. Ann Oncol 18:1666-1672, 2007
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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