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.
OBJECTIVE
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
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.


CONCLUSIONS
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.
Czito
Brian G
BG
Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA. czito001@mc.duke.edu
Hong
Timothy J
TJ
Cohen
Darrel P
DP
Petros
William P
WP
Tyler
Douglas S
DS
Pappas
Theodore N
TN
Yu
Daohai
D
Lee
Catherine G
CG
Lockhart
Albert C
AC
Morse
Michael A
MA
Fernando
Nishan
N
Hurwitz
Herbert I
HI
D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001661:Biliary Tract Neoplasms / Q000628:therapy*; D003131:Combined Modality Therapy; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D010190:Pancreatic Neoplasms / Q000628:therapy*; D011878:Radiotherapy; D016896:Treatment Outcome; D014498:Uracil / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics
D004791:Enzyme Inhibitors; C073482:eniluracil; D014498:Uracil; D005472:Fluorouracil