A phase I study of eniluracil/5-FU in combination with radiation therapy for potentially resectable and/or unresectable cancer of the pancreas and distal biliary tract.

Abstract

PURPOSE:

Eniluracil is an effective inactivator of dihydropyrimidine dehydrogenase (DPD). It allows for oral dosing of 5-fluorouracil (5-FU), which may potentially improve the antitumor activity of 5-FU when delivered concurrently with radiotherapy while avoiding the inconvenience and morbidity of continuous infusion (CI) 5-FU. We addressed the safety of oral eniluracil/5-FU combined with radiation therapy and determined the profile of dose-limiting toxicities and recommended Phase II dose (RPTD) in patients with pancreatic and hepatobiliary cancers.

METHODS AND MATERIALS:

Patients with resectable or locally advanced pancreatic and biliary cancer received eniluracil (starting at 6.0 mg/m(2) q12h)/5-FU (starting at 0.6 mg/m(2) q12h). Eniluracil/5-FU were given concurrently with preoperative radiation to 4500 cGy followed by 540 cGy by reduced fields. Surgery was considered 4 weeks after completion of therapy.

RESULTS:

Thirteen patients were enrolled. Chemoradiotherapy was completed in all patients. The MTD was not reached and, thus, the RPTD of eniluracil/5-FU was determined to be 10 mg/m(2) q12h/1 mg/m(2) q12h. Two patients with locally advanced disease had a 30-45 percent cross-sectional tumor reduction, one of which underwent margin-negative resection. Two of 5 patients with pancreatic cancer, and 1 of 3 patients with cholangiocarcinoma, with underwent exploratory surgery had margin-negative resections. One patient had a pathologic complete response (pCR). Patient 5-FU plasma exposure increased slightly from Day 8 to Day 31.

CONCLUSION:

Preoperative chemoradiation with oral eniluracil/5-FU is feasible, well tolerated, and potentially effective in the neoadjuvant setting. Further investigation of oral fluoropyrimidines as radiosensitizers for pancreaticobiliary malignancies is warranted.

• Authors: Brian G Czito, Timothy J Hong, Darrel P Cohen, William P Petros, Douglas S Tyler, Theodore N Pappas, Daohai Yu, Catherine G Lee, Albert C Lockhart, Michael A Morse, Nishan Fernando, Herbert I Hurwitz
• Journal: Cancer investigation (Cancer Invest) Vol. 24 Issue 1 Pg. 9-17 (Feb 2006) ISSN: 0735-7907 [Print] England
• PMID: 16466986 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• eniluracil
• Uracil
• Fluorouracil

Topics

• Aged
• Antineoplastic Combined Chemotherapy Protocols
• Biliary Tract Neoplasms (therapy)
• Combined Modality Therapy
• Enzyme Inhibitors (administration & dosage, pharmacokinetics)
• Female
• Fluorouracil (administration & dosage, pharmacokinetics)
• Humans
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoadjuvant Therapy
• Pancreatic Neoplasms (therapy)
• Radiotherapy
• Treatment Outcome
• Uracil (administration & dosage, analogs & derivatives, pharmacokinetics)