Phase II study of capecitabine with concomitant radiotherapy for patients with locally advanced pancreatic cancer: up-regulation of thymidine phosphorylase.
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.
Saif
Muhammad Wasif
MW
Departments of Medical Oncology, Yale University School of Medicine, New Haven, CT 06520, USA. wasif.saif@yale.edu
Black
Glenda
G
Roy
Shalija
S
Bell
Diana
D
Russo
Suzanne
S
Eloubeidi
Mohamed A
MA
Steg
Adam
A
Johnson
Martin R
MR
Zelterman
Daniel
D
Diasio
Robert B
RB
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
D000964:Antimetabolites, Antineoplastic; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D003841:Deoxycytidine; D000069287:Capecitabine; D042943:Dihydrouracil Dehydrogenase (NADP); D013939:Thymidine Phosphorylase; D005472:Fluorouracil