Estramustine and Docetaxel for Metastatic Hormone Refractory Prostate Cancer: A
May 1, 1999
Estramustine and Docetaxel for Metastatic Hormone Refractory Prostate Cancer: A Phase I Study
abstract & commentary
Source: Kreis W, et al. Ann Oncol 1999;10:33-38.
Hormone refractory metastatic prostate cancer is a common problem in our practices and little evidence for a benefit associated with the administration of chemotherapy in this setting has been accumulated. However, the introduction of the taxanes, which have antitumor effects in a broad spectrum of cancer types, has led to preclinical and clinical exploration of their effects in prostate cancer.
In vitro, it has been reported that docetaxel is more active than paclitaxel in prostate cancer cell lines and shows synergistic antitumor effects when used together with estramustine, the nitrogen mustard analogue linked to estradiol.1 Therefore, an effort to put estramustine and docetaxel together in a regimen for prostate cancer was undertaken at the Don Monti Division of Oncology at North Shore Hospital in Manhassat, NY.
Estramustine dose was kept constant at 14 mg/kg daily (given in 3 divided doses) with docetaxel administered every 21 days over one hour together with dexamethasone 8 mg po bid for five days beginning one day before docetaxel administration. Four groups of patients were entered at different docetaxel doses 40, 60, 70, and 80 mg/m2. Patients previously exposed to estramustine or a taxane were excluded, as were those who had been exposed to more than two prior chemotherapy regimens. Patients had normal renal, hematopoietic, and hepatic function. The mean age was 66 years.
Seventeen patients were entered. All experienced grade 1-2 nausea and vomiting, presumably from the estramustine. Grade 1-3 diarrhea was seen in 10 of 17 patients at all docetaxel levels. Alopecia was seen at all dose levels. Hematologic toxicity was dose-related; grade 4 leukopenia occurred at the 80 mg/m2 dose and prohibited administration of subsequent cycles on time. In contrast, all six patients entered on the 70 mg/m2 dose were able to receive multiple cycles of docetaxel and grade 4 neutropenia was observed in only two of the patients. Occasionally, patients had grade 3 elevations of liver enzymes.
Responses were not the primary end point of this phase I study. However, one of the six patients with measurable soft tissue disease experienced a partial response with the disappearance of lung metastases and a reduction in liver lesions. Eighty-two percent of the patients (14 of 17) had biochemical responses with at least a 50% reduction in prostate-specific antigen level for periods ranging from 1 to 11+ months. Antitumor activity was documented in four of five patients entered at the lowest docetaxel level. Patients tolerated an average of five cycles of therapy (range 2-12). Ten patients withdrew from the study based on progressive disease. Three had gastrointestinal toxicity that prompted termination of treatment. Two withdrew because of fatigue. Two patients developed thromboses; one venous, one arterial.
Commentary
Prostate cancer is a difficult tumor to treat and it poses substantial biologic and clinical barriers to new drug development. When the tumor becomes hormone refractory, it is notoriously drug resistant. In addition, it usually spreads to bones and causes lesions in which antitumor response is not evaluable. Efforts to use the levels of prostate-specific antigen to gauge response have not been thoroughly validated. Furthermore, patients with prostate cancer are usually older and have intercurrent illnesses that may complicate the course of treatment.
Estramustine was specifically designed to treat prostate cancer, but its single agent antitumor effects are exceedingly modest. Efforts to improve the response rate by adding other agents, including vinblastine,2 etoposide, and paclitaxel,3 have not been notably successful. Based on in vitro data suggesting that docetaxel might be more effective than paclitaxel in combination with estramustine,1 and evidence that dexamethasone could further enhance the synergy between estramustine and docetaxel, Kreis and collegues undertook the current phase I study. If biochemical changes in the serum prostate-specific antigen level can be taken as a surrogate marker for tumor response,4 the regimen is active. Indeed, 24% of the patients in this study had normal serum prostate-specific antigen levels for some period of time.
Kreis et al were concerned about the gastrointestinal toxicity from the estramustine and recommended that phase II studies consider studying a regimen of estramustine at 12 mg/kg/d plus docetaxel at 70 mg/m2 every three weeks and assess whether dexamethasone is contributing antitumor effects in addition to ameliorating docetaxel toxicity.
References
1. Kreis W, et al. Br J Urol 1997;79:196-202.
2. Hudes GR, et al. J Clin Oncol 1992;10:1754-1761.
3. Dreicer R. Semin Urol Oncol 1997;15:28-32.
4. Sridhara R, et al. J Clin Oncol 1995;13:2944-2953.
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