Phase I trial of low dose N‐phosphonacetyl‐L‐aspartic acid and high dose 5‐fluorouracil administered concomitantly with radiation therapy for unresectable localized adenocarcinoma of the pancreas

Bach Ardalan, Antonio Ucar, Rajender Reddy, Alan S. Livingstone, Arnold Markoe, James Schwade, Stephen P. Richman, Kim Donofrio

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Background. Preclinical and clinical data suggest that N-phosphonacetyl- L-aspartic acid (PALA) can augment the cytotoxic effects of 5-fluorouracil (5-FU). In addition, the combination of 5-FU and radiation therapy has been used with success in prolonging survival and providing palliation of symptoms in patients with advanced unresectable pancreatic carcinoma. This Phase I study was undertaken to determine the feasibility and evaluate the qualitative and quantitative toxicities of PALA and escalating doses of 5-FU administered concomitantly with radiation therapy in patients with locally advanced nonmetastatic pancreatic adenocarcinoma. Methods. Ten previously untreated patients with advanced nonmetastatic adenocarcinoma of the pancreas were treated with 250 mg/m2 of PALA given as an intravenous bolus followed 24 hours later by 5-FU, which was given by continuous 24-hour infusion every week. The 5-FU doses were assigned according to a Phase I drug escalation (1000 mg/m2, 1300 mg/m2, and 1700 mg/m2). Radiation therapy was delivered concurrently with chemotherapy at a dose of 180 cGy per fraction (900 cGy per week) over 6 1/2 weeks. PALA and 5-FU were continued weekly after the end of radiation therapy, with disease assessments made every 8 weeks. Chemotherapy was continued until the disease progressed. Results. All 10 patients were evaluable. The maximum tolerated dose (MTD) of 5-FU was 1300 mg/m2. Two of the four patients treated at the 1700 mg/m2 dose level experienced dose- limiting toxicities, nausea/vomiting and mucositis, respectively. Toxicities were mild to moderate at the 1000 mg/m2 and 1300 mg/m2 dose levels. Two patients treated with 5-FU at the 1300 mg/m2 dose level had complete responses, and one patient treated at the 1700 mg/m2 dose level had a partial response. The median survival was 12.5 months, and four patients survived more than 1 year. Conclusions. PALA and 5-FU administered concomitantly with radiation therapy is an active regimen in locally advanced, unresectable pancreatic cancer. Dose-limiting toxicities are nausea/vomiting and mucositis. The MTD of 5-FU is 1300 mg/m2. The regimen is well tolerated and administered in an outpatient setting.

Original languageEnglish (US)
Pages (from-to)1869-1873
Number of pages5
JournalCancer
Volume74
Issue number7
DOIs
StatePublished - Oct 1 1994

Keywords

  • 5- fluorouracil
  • N-phosphonacetyl-L-aspartic acid (PALA)
  • pancreatic carcinoma
  • Phase I trial
  • radiation therapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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