A phase I/II trial of continuous hepatic intra-arterial infusion of 5-fluorouracil, mitoxantrone, and cisplatin (FMP therapy) for advanced hepatocellular carcinoma.

Abstract

e14556 Background: The aim of this study was to investigate the maximum-tolerated dose and determine the recommended dose, based on the frequency of dose-limiting toxicities, of continuous hepatic intra-arterial infusion of 5-fluorouracil, mitoxantrone and cisplatin (FMP therapy) in a phase I study protocol, and to evaluate the efficacy and toxicity of FMP therapy at the recommended dose for advanced hepatocellular carcinoma (HCC) in a phase II study protocol. Methods: Forty-five patients with advanced HCC who were not candidates for surgical resection, local ablation or transcatheter arterial embolization, had no history of prior chemotherapy, were enrolled. The therapy consisted of intra-arterial administration of cisplatin (P) and mitoxantrone (M) on day 1, and continuous intra-arterial infusion of 5-fluorouracil (F) from day 1 through day 5 (F/M/P[mg/m2]: Level1; 400/4/60, Level 2; 400/6/60, Level 3; 500/6/60). The treatment was repeated every four weeks for a maximum of six courses, until the appearance of evidence of tumor progression or of unacceptable toxicity. Results: In the phase I part of the study, one of six patients at level 1 developed DLT, including grade 3 pulmonary embolism, while none of the patients at either level 2 or 3 exhibited any signs of dose-limiting toxicity. Therefore, the recommended dose of FMP therapy was determined to be the level 3 dose. In the phase II part, 36 patients were enrolled. Nine patients (25%) achieved a partial response, and the response rate was 25% (95% confidence interval: 12- 42%). The overall median survival time, 1-year survival rate and median progression-free survival were 11.3 months, 46.9% and 7.0 months, respectively. The main grade 3 and 4 hematological and non-hematological toxicities were leukopenia (36%), neutropenia (39%) and thrombocytopenia (19%), and elevation of the serum levels of aspartate aminotransferase (22%) and alanine aminotransferase (14%). These toxicities were generally transient and well tolerated. Conclusions: In patients with advanced HCC, hepatic arterial infusion of FMP was feasible, however, no favorable tumor response or survival benefit could be demonstrated. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Lilly, Taiho Pharmaceutical