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Relationship of Baseline Serum Bilirubin to Efficacy and Toxicity of Single-Agent Irinotecan in Patients With Metastatic Colorectal Cancer

From the Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Pfizer Oncology, New York, NY; and Committee on Clinical Pharmacology and Pharmacogenomics, Department of Medicine and Cancer Research Center, University of Chicago, Chicago, IL

Address reprint requests to Jeffrey A. Meyerhardt, MD, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115; e-mail: jmeyerhardt{at}partners.org

PURPOSE: To examine the predictive value of baseline serum bilirubin measurement for chemotherapy-related toxicity or efficacy among patients receiving irinotecan for metastatic colorectal cancer.

METHODS: We performed a secondary analysis of a cohort of 287 patients treated in a multicenter, phase III study with single-agent irinotecan administered either weekly or once every 3 weeks. Patients were grouped into three categories of baseline bilirubin measurements (0 to 0.4, 0.5 to 0.9, and 1.0 to 1.5 mg/dL). We performed analyses of overall survival, time to progression, and treatment-related toxicity based on bilirubin category, as well as using bilirubin as a continuous variable.

RESULTS: With a median follow-up of 15.8 months, baseline serum bilirubin was not predictive of 1-year survival (42.4%, bilirubin 0 to 0.4; 42.3%, bilirubin 0.5 to 0.9; 48.1%, bilirubin 1.0 to 1.5 mg/dL), median overall survival (10.1, 9.7, and 15.6 months, respectively; P = .5), or median time to progression (2.8, 3.0, and 4.1 months, respectively; P = .5). Patients with elevated bilirubin had a significantly greater risk grade 3 to 4 neutropenia; however, this was limited to patients treated on a weekly schedule (P trend = .03) and not once every 3 weeks (P trend = .8). Other toxicities were not significantly different by initial bilirubin measurement.

CONCLUSION: Although modest elevations of bilirubin (1.0 to 1.5 mg/dL) are associated with increased grade 3 to 4 neutropenia in patients treated with weekly irinotecan, baseline serum bilirubin does not reliably predict overall irinotecan-related toxicity or efficacy. Additional methods, including potential application of pharmacogenetic information, are needed to optimize irinotecan dosing and tailor therapy to individual patients.

Supported by Pfizer Oncology, New York, NY. Dr Meyerhardt is supported in part by a K07 award from the National Cancer Institute (1K07CA097992-01A1) and an American Society of Clinical Oncology career development award.

Authors’ disclosures of potential conflicts of interest are found at the end of this article.

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Related Correspondence

• Relationship of Serum Bilirubin to Toxicity in Patients With Metastatic Colorectal Cancer Treated With Single-Agent High-Dose Irinotecan
  Andrew Kramar, Sophie Gourgou-Bourgade, and Marc Ychou
  JCO 2005 23: 650 [Full Text]

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