Prognostication of pancreatic adenocarcinoma by expression of thymidine phosphorylase/dihydropyrimidine dehydrogenase ratio and its correlation with survival.

Abstract

BACKGROUND:

Dihydropyrimidine dehydrogenase (DPD) is the first rate limiting enzyme that catabolizes 5-fluorouracil. Thymidine phosphorylase (TP) catalyzes the last step that converts capecitabine into 5-fluorouracil. The TP/DPD ratio has suggested a positive correlation with the efficacy of capecitabine in human xenograft models. This is the first human study that analyzes the association of TP/DPD ratio with overall survival and disease-free survival in cases of locally advanced pancreatic cancer (LAPC).

METHODS:

A total of 35 patients with newly diagnosed LAPC received 50.4 Gy radiotherapy with capecitabine 1,600 mg/m(2) followed by capecitabine 2,000 mg/m(2) x 14 days every 3 weeks till progression. Tumor specimens were procured with endoscopic ultrasound-guided fine-needle aspiration before and after week 2 of starting capecitabine radiotherapy to evaluate TP and DPD mRNA levels by reverse transcription polymerase chain reaction (RT-PCR).

RESULTS:

The paired t-tests showed no relationship between mRNA TP or DPD levels or TP/DPD ratio and disease-free survival. The log-rank test revealed that the lower TP/DPD ratio was statistically significantly associated with a higher overall survival with an average of 304 days in the lower TP/DPD ratio group and 172 days in the higher TP/DPD group (a difference of 132 days).

CONCLUSIONS:

We found a survival benefit of approximately 4 months in our study correlating with lower TP/DPD ratio and this is quite significant in a disease whose > 5-year survival is < 5%. The TP/DPD ratio may be used as an independent marker for prognostication for LAPC and it may help in determining the chemotherapy duration, choices and possibly toxicities as well. Larger studies are needed to study the relation ship between TP/DPD ratio with these efficacy parameters.

• Authors: Muhammad Wasif Saif, Sharukh Hashmi, Diana Bell, Robert B Diasio
• Journal: Expert opinion on drug safety (Expert Opin Drug Saf) Vol. 8 Issue 5 Pg. 507-14 (Sep 2009) ISSN: 1744-764X [Electronic] England
• PMID: 19663627 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites, Antineoplastic
• Biomarkers, Tumor
• Neoplasm Proteins
• Prodrugs
• Deoxycytidine
• Capecitabine
• Dihydrouracil Dehydrogenase (NADP)
• TYMP protein, human
• Thymidine Phosphorylase
• Fluorouracil

Topics

• Adenocarcinoma (drug therapy, enzymology, mortality, pathology, radiotherapy, surgery)
• Aged
• Antimetabolites, Antineoplastic (pharmacokinetics, therapeutic use)
• Biomarkers, Tumor
• Biopsy, Fine-Needle
• Capecitabine
• Combined Modality Therapy
• Deoxycytidine (analogs & derivatives, pharmacokinetics, therapeutic use)
• Dihydrouracil Dehydrogenase (NADP) (analysis)
• Disease-Free Survival
• Female
• Fluorouracil (analogs & derivatives, pharmacokinetics, therapeutic use)
• Humans
• Kaplan-Meier Estimate
• Male
• Middle Aged
• Neoplasm Proteins (analysis)
• Pancreatectomy
• Pancreatic Neoplasms (drug therapy, enzymology, mortality, pathology, radiotherapy, surgery)
• Prodrugs (pharmacokinetics, therapeutic use)
• Prognosis
• Survival Analysis
• Thymidine Phosphorylase (analysis)