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Phase I Study of Capecitabine With Concomitant Radiotherapy for Patients With Locally Advanced Pancreatic Cancer: Expression Analysis of Genes Related to Outcome

From the Department of Medicine, Division of Hematology-Oncology, Division of Gastroenterology and Hepatology, Division of Radiation Oncology, Department of Pharmacology/Toxicology, and University of Alabama at Birmingham Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Department of Mathematics and Statistics, Auburn University, Auburn, AL

Address reprint requests to M. Wasif Saif, MD, MBBS, Yale University School of Medicine, Section of Medical Oncology, 333 Cedar St, New Haven, CT 06520; e-mail: wasif.saif{at}yale.edu

PURPOSE: To establish the feasibility of capecitabine with concurrent radiotherapy (XRT) in patients with locally advanced (LA) pancreatic cancer and evaluate the effect of XRT on thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD), and tumor necrosis factor-alpha (TNF-).

PATIENTS AND METHODS: Fifteen patients with LA pancreatic cancer received three-dimensional conformal XRT to a dose of 50.4 Gy with capecitabine at escalating doses from 600 to 1,250 mg/m² bid (Monday through Friday). Following chemo-XRT, stable and responding patients were treated with capecitabine 2,000 mg/m² orally bid for 14 days every 21 days. Tumor specimens were procured with endoscopic ultrasound–guided fine-needle aspiration 1 week before and 2 weeks after chemo-XRT to evaluate TP, DPD, and TNF- mRNA levels.

RESULTS: Dose-limiting grade 3 diarrhea was observed in two of six patients treated at a capecitabine dose of 1,000 mg/m² with XRT. Three patients (20%) achieved partial response. Mean percent difference in TP pre- and post-XRT was 119.2% (P = .1934). There was no significant differences in mean TNF-, or DPD levels pre- and post-XRT (P = .1934 and .4922, respectively). TP and TNF- levels were not significantly correlated both at pre- and post-XRT (P = .670 and P < .154, respectively). Median value of TP:DPD ratios at baseline was 2.65 (range, 0.36 to 11.08). No association between TP:DPD ratio and efficacy of capecitabine or severity of toxicities was identified.

CONCLUSION: The recommended dose for phase II evaluation is capecitabine 800 mg/m² bid (Monday through Friday) with concurrent XRT. This approach offers an easy alternative to intravenous fluorouracil as a radiosensitizer in these patients. Role of TP and TP:DPD ratio warrants further investigation in a larger clinical trial.

Supported by Grant No. 1 P20 CA101955-01 (Pancreatic SPORE) and a grant from Roche Laboratories.

Presented 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 are found at the end of this article.

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