Weekly paclitaxel followed by 24 hour infusion high-dose 5-fluorouracil and leucovorin (T-HDFL) chemotherapy for hormone-refractory prostate cancer (HRPC)

Abstract

4738 Background: Paclitaxel (T) & 5FU had been used to treat advanced prostate cancer with some success. In vitro data suggested T & 5FU had sequence-dependent synergistic cytotoxicity on many cancer cell lines. Weekly T & HDFL had been proven to be more tolerable & at least equally effective in many kinds of cancers. We generalized this observation to a phase II trial for patients with HRPC. Methods: (1) The cytotoxicity of T & 5FU alone or in combination with different schedules was studied in 2 androgen-independent CaP cell lines: DU145 & PC3, using MTT assay & median-effect analysis. (2) T-HDFL regimen: paclitaxel 90 mg/m2 IV 1hr on D 1, 8; 5FU 2,000 mg/m2 & leucovorin 300 mg/m2 IV 24 hr on D 2, 9; q 21 days. Premeds including dexamethasone 5 mg were given before T. Between Nov 1999 & Dec 2003, 18 patients (median age 71, range 50–75) with HRPC who had failed multiple lines of hormone manipulation (castration, use and withdrawal of anti-androgens) were enrolled. Two had measurable diseases, 16 had only bone metastasis, & 17 had elevated PSA levels (median 227 ng/ml, range 97 – 2,329). Results: (1) Combined cytotoxicity was more synergistic when T –> 5FU 24 hr later & was less synergistic when 5FU –> T. It was noted in both PC3 & DU145. (2) 52 courses had been given totally, with an average of 2.9 courses / pt (range: 1–8). All 18 pts were eligible for analysis of toxicity. NCI Gr 3/4 leukopenia & thrombocytopenia occurred in 3 pts each. There were neither febrile neutropenia nor treatment-related mortality. Gr 3/4 nausea, vomiting, mucositis, & diarrhea did not occur. One partial response & 1 stable disease were found among the 2 pts with measurable diseases. Sixteen pts were eligible for evaluation of PSA response (PSA reduction >50% for at least 6 weeks) with 7 responders & 2 pts with obvious PSA progression. The PSA response rate was 44% (95% CI 19 – 69%). The median overall & progression-free survival had not been reached. Analgesic amount decreased or PS enhanced in 78% of pts. Conclusions: T –> 5FU 24 hours later is the most synergistic sequence. T-HDFL with a much lower toxicity profile is worth further testing to define its role in HRPC. No significant financial relationships to disclose.