Paclitaxel-Estramustine Improves Survival

SAN FRANCISCO—Patients with hormone-refractory prostate cancer benefited from a regimen combining paclitaxel (Taxol) and estramustine (Emcyt, Estracyt) in two phase II trials discussed at the 37th Annual Meeting of the American Society of Clinical Oncology (ASCO).

William R. Berry, MD, of US Oncology, Cary, North Carolina, reported that combining the two drugs raised the response rate to 48% from 28% for a control group of patients who received paclitaxel alone.

The combination regimen also improved time to progression and survival rates, though the findings were not statistically significant, said Dr. Berry, who is also chairman of the genitourinary cancer research committee for Houston-based US Oncology.

"I think the combination of weekly Taxol and estramustine is a very tolerable regimen and more effective than weekly Taxol alone," he told ONI. "I personally don’t plan to use weekly Taxol without estramustine."

Palliative Effects a Surprise

Gary R. Hudes, MD, of Fox Chase Cancer Center, reported that the combination’s palliative effects surprised researchers who conducted a separate study that included quality of life evaluations. The regimen was well tolerated and reduced pain, he said. Opiate use went down for 65.7% of patients, with those reporting the highest pain at baseline also reporting the greatest decrease.

This Eastern Cooperative Oncology Group (ECOG) trial was conducted in the hope that it would show that the combination does not detract from quality of life, Dr. Hudes said. "That was our goal, but we found it improved quality of life. That was an important finding," he told ONI.

A randomized phase III trial of the combination appears likely. Dr. Hudes said that several oncology groups were negotiating protocols for a large study that may also include docetaxel (Taxotere) in a comparison arm. "The next randomized trial is probably going to be an Intergroup trial that will look at the best of these taxane-based chemotherapies," he said.

The drugs all act on the same target, microtubules, but seem to be more effective in combination than alone, Dr. Hudes noted. He suggested that while paclitaxel and estramustine both bind to tubulin, they may bind in different spots, creating an "additive effect" when used together.

"Each alone is not highly effective in treating prostate cancer, but when you put the two together you get a more significant result," he said.

US Oncology Trial

In the US Oncology study (abstract 696), 166 patients from 63 sites were randomized between December 1998 and December 1999, with follow-up through March 2001. All had metastatic disease, and the median age was 71.

One group received 28-day cycles of 100 mg/m² of paclitaxel on days 2, 9, and 16, and the other group received the same paclitaxel regimen plus 280 mg of twice-daily oral estramustine on days 1-3, 8-10, and 15-17. A PSA decrease of 50% or greater was used to define response.

Thromboembolic events were the one toxicity that caused concern, affecting six patients in the combination arm but only one in the control group. Dr. Berry’s group recommends prophylactic anticoagulant therapy when the combination regimen is used.

ECOG Study

The ECOG study (abstract 697) enrolled 63 eligible patients at 21 centers from January 1999 through October 1999. The patients’ median age was 70, all had metastatic disease, and 70% had pain.

Participants received a median of three 8-week chemotherapy cycles, during which 90 mg/m² of paclitaxel was administered by 1-hour infusion each week for 6 weeks. They were given 560 mg of estramustine divided into two doses, on the day before, of, and after each dose of paclitaxel.

One toxic death was reported. Grade 1-2 toxicities included fatigue (39% of patients), nausea (14%), and emesis (11%), but grade 3-4 toxicities occurred at less than half those rates.

Slightly more than half of the patients with elevated PSA concentrations (58.1%) had a decrease of 50% or better lasting 4 or more weeks, Dr. Berry reported. At a median follow-up of 15 months, 37 patients were alive, and 1-year survival was 70%. Ten patients (15.8%) were progression free