Paclitaxel and High-Dose Oral Estramustine in Patients with Hormone-Refractory Prostate Carcinoma

ABSTRACT & COMMENTARY

Synopsis: Weekly paclitaxel chemotherapy combined with 3 days of high-dose oral estramustine was evaluated in a Phase I trial for patients with hormone refractory prostate cancer. PSA declines of 50% occurred in 8 of 12 patients treated at the 2 highest dose levels. This regimen was generally well tolerated with less hematologic, neurologic and gastrointestinal toxicity than had been seen with other regimens combining these 2 agents. However, thromboembolic events were still problematic. The PSA response rate was similar for other paclitaxel/estramustine regimens and may prove more acceptable for this patient population.

Source: Ferrari AC, et al. Cancer. 2001;91:2039-2045.

Over the last decade, chemotherapy has been used with increasing frequency for patients with hormone refractory prostate cancer. Mitoxantrone combined with prednisone has been approved by the FDA for this indication but the need for more effective and well-tolerated regimens is clearly recognized. The combination of estramustine and paclitaxel, 2 agents with minimal single agent activity in prostate cancer, has been promising. PSA and measurable disease response rates of 53% and 44%, respectively, were observed when paclitaxel was given as a 96-hour infusion with daily estramustine.1 One-fifth of the patients developed grade 3 or 4 granulocytopenia and neuropathy and 10% had serious gastrointestinal toxicity and thrombotic complications.

In an attempt to decrease the toxicity and increase the acceptability of the regimen, Ferrari and associates conducted a Phase I trial of weekly intravenous paclitaxel over 1 hour combined with 3 days of estramustine starting 2 days before chemotherapy. The MTDs for paclitaxel and estramustine were 90 mg/m2 and 600 mg/m2, respectively. Eighteen patients were studied in cohorts of 3, 3, 6, and 6 patients. Three patients experienced grade 3 or 4 toxicity: one patient had grade 3 nausea and diarrhea (cohort 3), one patient grade 3 neutropenia (cohort 4), and one patient developed edema followed by a thromboembolic event (cohort 4). Grade 1 or 2 toxicities included neuropathy (3 patients) and gastrointestinal side effects (8 patients). Eight of the 12 patients entered into the 2 highest cohorts had reductions of their PSAs by at least 50% and 7 of these had reductions of at least 75%. Only 3 patients had measurable disease, one of whom had a 50% decrease in tumor size. The median duration of response was 16.7 weeks (range 3+ to 48.6 weeks).

COMMENT BY MICHAEL J. HAWKINS, MD

Low dose, well-tolerated regimens have had some limited activity in prostate cancer. Increased dose intensity has often been associated with an unacceptable toxicity profile. Paclitaxel and estramustine is a potentially attractive combination for the treatment of hormone refractory prostate cancer but had previously been associated with a high incidence of grade 3 and 4 toxicities. Neurotoxicity and gastrointestinal side effects appear to be substantially less using this regimen of low-dose weekly paclitaxel and intermittent high-dose estramustine. A high incidence of side effects and poor patient tolerance has limited greater use of chemotherapy in this disease. This regimen requires more extensive testing but appears to reduce to an acceptable level some of the side effects associated with these drugs when given on other regimens.

Reference

1. Hudes GR, et al. J Clin Oncol. 1997;15:3156-3163.