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Thymidine Phosphorylase Expression Is Associated With Response to Capecitabine Plus Irinotecan in Patients With Metastatic Colorectal Cancer

Neal J. Meropol, Philip J. Gold, Robert B. Diasio, Michael Andria, Mandeep Dhami, Thomas Godfrey, Albert J. Kovatich, Kirk A. Lund, Edith Mitchell, Roland Schwarting

From the Fox Chase Cancer Center; Thomas Jefferson University, Philadelphia; MDR Global Systems, Windber, PA; Swedish Cancer Institute, Seattle; Rockwood Clinic-Oncology Department, Spokane, WA; University of Alabama, Birmingham, AL; Roche Laboratories Inc, Nutley, NJ; Eastern Connecticut Hematology & Oncology, Norwich, CT; and Loma Linda University Cancer Institute, Loma Linda, CA.

Address reprint requests to Neal J. Meropol, MD, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA 19111; e-mail: Neal.Meropol{at}fccc.edu

Purpose To evaluate the clinical activity and toxicity of capecitabine plus irinotecan as first-line therapy for patients with metastatic colorectal cancer (mCRC), and to describe the association of expression of thymidine phosphorylase (TP), thymidylate synthase (TS), and dihydropyrimidine dehydrogenase (DPD) with antitumor activity.

Patients and Methods Patients with previously untreated mCRC received irinotecan days 1 and 8 intravenously, and capecitabine days 2 to 15 orally in 21-day cycles. Doses were irinotecan 125 mg/m² and capecitabine 1,000 mg/m² bid (n = 15; cohort 1), or irinotecan 100 mg/m² and capecitabine 900 mg/m² bid (n = 52; cohort 2). Tissues from primary and metastatic sites were assessed for TP, TS, and DPD gene and protein expression.

Results An unacceptable level of GI toxicity in the first 15 patients led to a protocol modification in starting doses. The response rate was 45% (30 of 67 patients). Overall survival was associated with TP expression assessed by immunohistochemistry in both primary tumors (P = .045) and metastases (P = .001). Objective tumor response was associated with TP expression in primary tumors (odds ratio, 4.77; 95% CI, 1.25 to 18.18), with a similar trend in metastases (odds ratio, 8.67; 95% CI, 0.95 to 79.1). TP gene expression in primary tumors was also associated with response.

Conclusion These data indicate that capecitabine plus irinotecan is an active regimen against mCRC. The biomarker analysis (including metastatic tissue) was feasible in a multicenter setting, and provides preliminary evidence that TP expression may be a predictive marker for response.

Supported by Roche Laboratories Inc.

Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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