Strategies Incorporating Hormonal Therapy and Cytotoxic Chemotherapy

The benefit of cytotoxic chemotherapy for patients with hormone-refractory prostate cancer is now firmly established.171,172 Several attempts have been made to determine whether response to and duration of clinical remission from hormonal therapy can be improved by the early addition of cytotoxic chemotherapy. Generally, with the notable exception of a combination of estramustine with selected cy-totoxic drugs (see below, Estramustine in Combination with Cytotoxic Drugs), these attempts have met with limited success. The Southwest Oncology Group studied the combination of endocrine therapy (estrogens or or-chiectomy) with doxorubicin and cyclophos-phamide randomized against endocrine therapy alone with addition of the same chemotherapy regimen at progression.173 This trial accrued between September 1982 and October 1986. Patients on the combined chemo-endocrine therapy arm had a slightly higher response rate (63%) compared to those on endocrine therapy alone (48%), but this was not statistically significant (p = 0.059). The response rate for patients failing endocrine therapy and then receiving chemotherapy was low, with only 3/27 patients having a response. Despite differences in the initial response, time to disease progression and overall survival were the same in each group and randomization was not a factor predictive of outcome when recognized prognostic factors were placed in a multivariate model.

The combination of suramin, hydrocortisone, and androgen deprivation in patients with hormone-naive metastatic prostate cancer demonstrated high rates of major toxicity in a phase II Southwest Oncology Group study.174 An evaluation of suramin and aminoglutethimide in patients progressing despite castration suggested that the combination added little to responses seen with aminoglutethimide alone.175 A phase III trial comparing suramin and hydrocor-

tisone with hydrocortisone alone in symptomatic hormone-refractory prostate cancer reported high symptomatic response in the suramin arm with a median 8-month duration of response and tolerable side effects.176 The reasons for these differences in reported toxicity are unclear.

Attempts at combining mitomycin and aminoglutethimide in hormone-refractory prostate cancer resulted in high rates of toxicity and limited, short-lived responses in a small proportion of patients.177 The combination of mitox-antrone with LHRH antagonist and flutamide provided no benefit in patients with metastatic disease over CAB alone.178 However, this comparative study did suggest that there may be benefit of such a combination in patients with locally advanced prostate cancer. While this study suffered from methodological problems related to balance of known prognostic factors between the two groups compared, its results provide impetus for prospective randomized controlled studies to test the potential benefit of chemotherapy in combination with CAB in patients with locally advanced disease.

In the phase III Southwest Oncology Group study 9921, CAB with and without mitoxantrone as adjuvant therapy will be assessed in patients treated with radical prostatectomy who have poor prognostic features such as high Gleason score, extracapsular extension, seminal vesicle involvement, and/or lymph node involvement in the surgical specimen. A phase III study (RTOG 9902) will evaluate CAB with or without pacli-taxel, estramustine, and etoposide in patients with clinical extracapsular extension, high biopsy Gleason score, and/or serum PSA between 20 and 100 ng/ml, who are undergoing definitive radiation therapy. Randomized studies to prospectively evaluate castration with and without chemotherapy in locally advanced disease will be forthcoming soon.

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