Emcyt/Taxol Studied in Refractory Prostate Ca

PHILADELPHIA--Ongoing trials of a protocol that provides prolongedexposure to estramustine phosphate (Emcyt) and paclitaxel (Taxol)have produced promising results in men with hormone-refractoryprostate cancer, Gary Hudes, MD, told Oncology News International.

"The number and quality of responses have impressed us. Thiscombination looks to be more active than Emcyt and vinblastine,although obviously it is going to take more experience to betterestimate the activity," said Dr. Hudes, associate member,Department of Medicine, Fox Chase Cancer Center.

Favorable results from a phase II study of estramustine/vinblastineat Fox Chase led Dr. Hudes' group "back to the laboratory"to look at estramustine and paclitaxel. "The rationale forthe two combinations was similar--combining drugs that have complementarytargets and different clinical toxicities," he said in hispresentation of the research at the Chemotherapy Foundation SymposiumXII, sponsored by Mount Sinai School of Medicine.

In these lab studies, prolonged exposure to estramustine/paclitaxelproduced synergistic cytotoxic effects against D-145 androgen-independentcell lines that were both estramustine sensitive and estramustineresistant. For the phase I study at Fox Chase Cancer Center, a96-hour infusion schedule of paclitaxel and continuous oral dailyadministration of estramustine were used to mimic the preclinicalmodel.

In the phase I trial, estramustine did not alter paclitaxel clearanceor distribution during the first cycle of treatment, and paclitaxelplasma levels were similar to those seen with single-agent use."This had been a concern because Taxol metabolism and clearancedepend on hepatic metabolism, and estramustine can affect hepaticenzymes," Dr. Hudes said.

The regimen for both the phase I and II studies is paclitaxel,120 mg/m² by 96-hour infusion every 3 weeks, and estramustinephosphate, 600 mg/m²/day orally in two or three divided dosesbetween meals, starting 1 day before the paclitaxel infusion andcontinuing throughout the protocol treatments. Patients receivea standard premedication regimen to prevent hypersensitivity reactions.

Dr. Hudes reported that of the 17 patients in the phase I study,four had hormone-refractory prostate cancer. Seven have receivedat least one cycle of treatment on the phase II study, and sixpatients who were not eligible for either study for a varietyof reasons have also been treated. The median age was 66, andmost patients were symptomatic.

The investigators have observed five partial responses, for a31.2% rate. "These responses look like they're going to bedurable. Several of them are ongoing. We have stable disease inseveral patients, some of them for more than 8 months, and progressionin two patients," he said.

Dr. Hudes described several measurable disease responses, includinga patient with liver metastases who had a partial response, "almosta complete response of 8 months," and two patients with lymphnode metastases, one whose partial response is ongoing for a monthand a second whose partial response lasted 7 months.

He also mentioned a patient with cancer-related coagulopathy whohad started with a platelet count of 26,000 and a fibrinogen levelof 60, with diffuse skin hemorrhage resistant to heparin. Afterfour cycles of estramustine/paclitaxel, his platelet count roseto 130,000 without transfusion, fibrinogen normalized, and PSAdecreased.

Most patients have tolerated estramustine with use of an antinauseamedication, but one patients had to be withdrawn from estramustineexcept during his paclitaxel infusion, when he could tolerateit, Dr. Hudes said.

Other observed toxicities have included transient increases inliver function studies, he said. Edema, probably due to estramustinefluid retention, has also been seen, along with mild to moderatediarrhea. There have been no problems with neurologic toxicity.

'Not the Easiest Schedule'

"This is obviously not the easiest schedule to use for palliativetherapy, and it would be nice to study estramustine and Taxolon some shorter infusions to see if the same activity can be achieved,"Dr. Hudes said.

It would also be useful for the manufacturer of estramustine todevelop an IV formulation, he said. "There is good reasonto believe that estramustine given in-travenously on a weeklyschedule will be less toxic than the daily oral schedule."