Phase II study of capecitabine with concomitant radiotherapy for patients with locally advanced pancreatic cancer: up-regulation of thymidine phosphorylase

Cancer J. Jul-Aug 2007;13(4):247-56. doi: 10.1097/PPO.0b013e31813c12b8.

Abstract

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-alpha (TNF-alpha) 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/m(2) 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/m(2) 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-alpha 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 > or =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-alpha (P = 0.6). No correlation between TP and TNF-alpha 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.

Publication types

  • Clinical Trial, Phase II
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antimetabolites, Antineoplastic / adverse effects
  • Antimetabolites, Antineoplastic / therapeutic use*
  • Capecitabine
  • Combined Modality Therapy
  • Deoxycytidine / adverse effects
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / therapeutic use
  • Dihydrouracil Dehydrogenase (NADP) / analysis
  • Dihydrouracil Dehydrogenase (NADP) / genetics
  • Dihydrouracil Dehydrogenase (NADP) / metabolism
  • Female
  • Fluorouracil / adverse effects
  • Fluorouracil / analogs & derivatives*
  • Fluorouracil / therapeutic use
  • Humans
  • Male
  • Middle Aged
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / mortality
  • Pancreatic Neoplasms / radiotherapy
  • Pancreatic Neoplasms / therapy*
  • RNA, Messenger / analysis
  • RNA, Messenger / metabolism
  • Survival Rate
  • Thrombocytopenia / chemically induced
  • Thymidine Phosphorylase / analysis
  • Thymidine Phosphorylase / genetics
  • Thymidine Phosphorylase / metabolism*
  • Treatment Outcome
  • Tumor Necrosis Factor-alpha / analysis
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism
  • Up-Regulation

Substances

  • Antimetabolites, Antineoplastic
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • Deoxycytidine
  • Capecitabine
  • Dihydrouracil Dehydrogenase (NADP)
  • Thymidine Phosphorylase
  • Fluorouracil