title: Phase II study of capecitabine with concomitant radiotherapy for patients with locally advanced pancreatic cancer: up-regulation of thymidine phosphorylase.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Departments of Medical Oncology, Yale University School of Medicine, New Haven, CT 06520, USA. wasif.saif@yale.edu
authors.forename: Muhammad Wasif
authors.initials: MW
authors.lastname: Saif
authors.forename: Glenda
authors.initials: G
authors.lastname: Black
authors.forename: Shalija
authors.initials: S
authors.lastname: Roy
authors.forename: Diana
authors.initials: D
authors.lastname: Bell
authors.forename: Suzanne
authors.initials: S
authors.lastname: Russo
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Eloubeidi
authors.forename: Adam
authors.initials: A
authors.lastname: Steg
authors.forename: Martin R
authors.initials: MR
authors.lastname: Johnson
authors.forename: Daniel
authors.initials: D
authors.lastname: Zelterman
authors.forename: Robert B
authors.initials: RB
authors.lastname: Diasio
mesh_terms: D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000627:therapeutic use*; D000069287:Capecitabine; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000532:radiotherapy / Q000628:therapy*; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D015996:Survival Rate; D013921:Thrombocytopenia / Q000139:chemically induced; D013939:Thymidine Phosphorylase / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000964:Antimetabolites, Antineoplastic; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D003841:Deoxycytidine; D000069287:Capecitabine; D042943:Dihydrouracil Dehydrogenase (NADP); D013939:Thymidine Phosphorylase; D005472:Fluorouracil