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Combination Chemotherapy Promising for Refractory Prostate Cancer

Combination Chemotherapy Promising for Refractory Prostate Cancer

LOS ANGELES--Early use of combination chemotherapy may have a role in the treatment of poor-prognosis, androgen-dependent prostate cancer, as well as androgen-independent patients, preliminary results from an ongoing study suggest. Evidence of anticancer activity has been seen in several patients treated with the combination of paclitaxel (Taxol), estramustine (Emcyt), and carboplatin (Paraplatin), William Kelly, DO, reported at the ASCO meeting.

"We have yet to find an effective chemotherapy regimen for refractory prostate cancer," said Dr. Kelly, a medical oncologist at Memorial Sloan-Kettering Cancer Center. "A major point of this study is that we’re changing the treatment paradigm. We’re moving chemotherapy up front, using it earlier in patients who have locally aggressive or metastatic disease."

Dr. Kelly said the study derived from clinical trial data, presented at ASCO in 1995, indicating that estramustine combined with a platinum-based compound has activity in patients with aggressive-phenotype prostate cancer.

Additionally, estramustine and pac-litaxel have been shown to have synergistic activity, and estramustine is known to increase drug retention. The combination has demonstrated efficacy in androgen-independent prostate cancer patients (J Clin Oncol 15:3156, 1997).

Attempt to Inhibit Drug Resistance

"We hypothesized that giving chemotherapy that includes estramustine might inhibit drug resistance prior to or during androgen deprivation and enhance tumor cell kill," Dr. Kelly said.

The investigators evaluated a three-drug combination in 21 patients with androgen-independent prostate cancer (who had progressed on primary hormonal therapy) and 19 with poor-prognosis androgen-dependent cancer, classified as poor risk on the basis of tumor stage, Gleason grade, PSA level, and metastatic pattern.

For both groups of patients, chemotherapy consisted of weekly doses of paclitaxel (60 to 100 mg/m²); estra-mustine at a dose of 10 mg/kg 5 days a week; and carboplatin every 4 weeks at a dosage resulting in an AUC of 6.

For most of the androgen-dependent group, follow-up is too short to draw conclusions about the effect of therapy, Dr. Kelly said. In the androgen-independent cohort, 13 of 17 patients evaluable for response had PSA declines of 50% or greater. Four of eight patients with soft tissue disease had partial responses lasting 4 to 7 months; three others had disease stabilization. The remaining patients have been followed for too brief a time to evaluate.

Notable toxicities in the androgen-dependent group were one case of cardiac ischemia and one deep-vein thrombosis. In the androgen-independent group, single episodes of grade 3 cardiac arrhyth-mia, deep-vein thrombosis, pulmonary embolism, and thrombophlebitis have been seen.

A majority of patients in both groups experienced anemia and thrombocyto-penia, but most cases were grade 1 or 2. Mild or moderate diarrhea, nausea, vomiting, and dyspnea occurred in about 20% to 45% of patients in each group.

"Our results show that this combination regimen can be administered safely and that it has activity in androgen-independent prostate cancer," Dr. Kelly said. "However, we need to strive to make this regimen more tolerable if it is going to be successful."

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