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Phase II Study of Capecitabine With Concomitant Radiotherapy for Patients With Locally Advanced Pancreatic Cancer: Up-Regulation of Thymidine Phosphorylase

Purpose:The objectives of this phase II study were to evaluate the effect of radiation (XRT) on thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD), and tumor necrosis factor-&agr; (TNF-&agr;) and the efficacy of capecitabine-XRT in patients with locally advanced pancreatic cancer. Patients and Methods:Twenty patients received 50.4 Gy XRT with capecitabine 1,600 mg/m2 on Monday through Friday for 6 weeks determined from our phase I study (Saif MW, Eloubeidi MA, Russo S, et al. J Clin Oncol. 2005;23:8679–8687). After capecitabine-XRT, stable and responding patients received capecitabine 2,000 mg/m2 for 14 days every 3 weeks till progression. Restaging was performed every 9 weeks. Tumor specimens were procured with endoscopic ultrasound-fine needle aspiration before and at week 2 after capecitabine-XRT was started to evaluate the effect of XRT on TP, DPD, and TNF-&agr; mRNA levels, determined by reverse transcriptase-polymerase chain reaction. Results:Among 20 patients, 4 (20%) had a partial response and 13 (65%) had stable disease. Two patients underwent surgical resection (10%). The 6-month survival rate was 84%, and the 1-year survival was 58%. Grade ≥3 toxicities included nausea/vomiting (5%), thrombosis (5%), hyperbilirubinemia (5%), and grade 3 gastrointestinal bleeding (5%). TP was elevated during week 2 when compared with the pre-XRT TP (P = 0.01). However, no such effect of XRT was found either on DPD (P = 0.22) or on TNF-&agr; (P = 0.6). No correlation between TP and TNF-&agr; was noticed. Also, no association between TP/DPD ratio and efficacy of capecitabine was identified. Conclusions:This phase II study further confirms our phase I results and suggests that capecitabine-XRT is an effective, tolerable, and convenient alternative to an infusional 5-fluorouracil regimen for patients with pancreatic cancer. Although results support the use of capecitabine-XRT and TP was up-regulated, there appears to be additional genes associated with the response to capecitabine.