Phase I study of capecitabine with concomitant radiotherapy for patients with locally advanced pancreatic cancer: expression analysis of genes related to outcome.
OBJECTIVE
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-alpha).


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-alpha 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-alpha, or DPD levels pre- and post-XRT (P = .1934 and .4922, respectively). TP and TNF-alpha 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.


CONCLUSIONS
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.
Saif
M Wasif
MW
Department of Medicine, Division of Hematology-Oncology, University of Alabama at Birmingham, USA. wasif.saif@yale.edu
Eloubeidi
Mohammaed A
MA
Russo
Suzanne
S
Steg
Adam
A
Thornton
Jennifer
J
Fiveash
John
J
Carpenter
Mark
M
Blanquicett
Carmello
C
Diasio
Robert B
RB
Johnson
Martin R
MR
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; 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) / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D005260:Female; D005472:Fluorouracil / Q000031:analogs & derivatives; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D006402:Hematologic Diseases / Q000209:etiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D018714:Radiotherapy, Adjuvant / Q000009:adverse effects; D013223:Statistics as Topic; D016019:Survival Analysis; D013939:Thymidine Phosphorylase / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D014409:Tumor Necrosis Factor-alpha; D003841:Deoxycytidine; D000069287:Capecitabine; D042943:Dihydrouracil Dehydrogenase (NADP); D013939:Thymidine Phosphorylase; D005472:Fluorouracil