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Michigan Oncology Journal Spring 98

New Therapy for Hormone Refractory Prostate Cancer

---David C. Smith, M.D.,
Assistant Professor of Internal Medicine

Kenneth J. Pienta, M.D.,
Associate Professor of Internal Medicine and Director of the Urologic Oncology Program

The vast majority of men with metastatic prostate cancer will respond to hormonal therapy with a reduction in disease activity and improvement in quality of life. Unfortunately, the median duration of response is 18 months. Metastatic prostate cancer remains an incurable disease with a significant impact in terms of morbidity and mortality. Previous attempts at therapy in patients with hormone-refractory disease had limited success and were associated with significant toxicity. This led to skepticism about the role of chemotherapy in the treatment of advanced prostate cancer (1). This skepticism has been challenged by new developments resulting from trials guided by a better understanding of the biology of prostate cancer and appropriate study endpoints.

Secondary Hormonal Therapy
Secondary hormonal therapy is of limited use in the treatment of metastatic prostate cancer. Responses to hormonal agents in this setting are limited in both number and duration (2). However, two aspects of hormonal therapy continue to play important roles in hormone-refractory disease. The first is maintenance of androgen suppression. The growth of metastatic prostate cancer can be acceler-ated by administration of exogenous androgens, and review of a large clinical trials database has shown a superior overall survival for patients in whom primary androgen deprivation is maintained. Maintenance of castration levels of testosterone makes sense from a biologic perspective, since there are likely cells present which can respond to androgens.

The second issue is antiandrogen withdrawal. Withdrawal responses have been described with estrogens, progestational agents and all of the antiandrogens. The response rate to this maneuver is low (15% to 25%), with a typical duration of a few months. Nonetheless, withdrawal is required prior to institution of any additional therapy, since it will complicate the assessment of response to subsequent therapy (3).

Estramustine-Based Chemotherapy
Estramustine (Emcyt) was initially designed as an alkylating agent. It has been shown, however, that it acts by binding to proteins of the nuclear matrix and microtubular assembly. This observation led to the development of several new combinations in which estramustine is used with agents that act at these sites (4). The combination of estramustine and vinblastine targets the microtubule assembly. Phase II trials of this combination showed that 30% of patients had sustained decreases in serum prostate specific antigen (PSA) and 31% of patients with measurable disease had partial responses. Therapy was generally well-tolerated, although higher doses of vinblastine in one trial resulted in greater myelosuppression and neurotoxicity.

Our initial investigations combined estramustine and etoposide, targeting the nuclear matrix. In sequential phase II trials, a total of 114 patients were registered. Approximately 50% of patients had a " 50% decrease in the PSA, and response was demonstrated in patients with both soft tissue disease (50%) and disease limited to bone (5,6). Similar studies of the combination of estramustine and paclitaxel showed that 53% of patients had a " 50% decline in the PSA, and four of nine patients with measurable disease had objective responses. This combination acts at the microtubular apparatus. We conducted a phase II trial using oral estramustine, oral etoposide and intravenous paclitaxel aimed at both sites of activity (7). Sixty-three percent of patients enrolled had a " 50% decrease in PSA, and eight of 15 patients with measurable disease had at least a partial response. These trials serve as the basis for an ongoing phase II trial, which adds carboplatin to the three-drug regimen, and phase III trials currently under development.

Other Chemotherapy
Mitoxantrone plus a glucocorticoid versus a glucocorticoid alone have now been compared in phase III trials (8). Mitoxantrone plus prednisone was superior to prednisone alone in terms of palliative response, although there was no difference in overall survival. Palliation was seen in 38% of patients randomized to the combination, compared to 21% of patients randomized to prednisone alone. Similar preliminary results have been reported for mitoxantrone plus hydrocortisone versus hydrocortisone alone.

Suramin has shown activity in the treatment of hormone-refractory prostate cancer with a promising response rate and significant toxicity (9). Objective responses have been seen and PSA levels were reduced > 50% in 60% of patients. Although the toxicities are reported to be manageable, fatigue, malaise, weakness, anorexia and wasting are common. A randomized phase III trial of suramin with palliative endpoints appears to be positive on initial reports.

Oral cyclophosphamide also has significant activity in prostate cancer (8). Sixty percent of patients had improvement in symptoms when treated with 100 mg/m2 per day for 14 days and 30% had a decrease in PSA levels of " 50%. We have recently used cyclophosphamide, either with prednisone alone, or with prednisone and diethylstilbestrol (10). By PSA criteria, the response rate was 40%. This regimen was extremely well tolerated.

Many new agents are being evaluated in hormone-refractory prostate cancer. We have recently com-pleted a study of an oral form of platinum and are in the process of opening a new trial using an oral 5-FU analog. Other ongoing studies include novel trials utilizing inhibitors of angiogenesis, metastasis and tissue invasion.

Conclusion
Until recently, chemotherapy was thought to play little or no role in the treatment of patients with advanced prostate cancer. Recent trials have shown that a significant proportion of patients can have benefit, both in terms of objective response and palliative effect, when treated with chemotherapy. Ongoing studies will determine their value and provide a basis for the development of more effective combinations, which hopefully will show a significant benefit in terms of survival.

 

References

  1. Tannock IF, Boyd NF, De Boer G, Erlichman C, Fine S, Larocque G, et al. Is there evidence that chemotherapy is of benefit to patients with carcinoma of the prostate? J Clin Oncol. 3:1013-1021, 1985.
  2. Smith DC. Secondary hormonal therapy. Sem Urol Oncol. 15:3-12, 1997.
  3. Scher HI, Kelly WK. Flutamide withdrawal syndrome: its impact on clinical trials in hormone-refractory prostate cancer. J Clin Oncol. 11:1566-1572,1993.
  4. Hudes G. Estramustine-based chemotherapy. Sem Urol Oncol. 15:13-19, 1997.
  5. Pienta KJ, Redman BG, Bandekar R, Strawderman M, Cease K, Esper PS, Naik H, Smith DC. A phase II trial of oral estramustine and oral etoposide in hormone refractory prostate cancer. Urology. 50:401-6, 1997.
  6. Pienta KJ, Redman BG, Hussain M, Cummings G, Esper PS, Appel C, Flaherty LE. A combination of oral estramustine and oral etoposide for the treatment of hormone refractory prostate cancer. J Clin Oncol. 12:2005-2011, 1994.
  7. Smith DC, Esper PS, Todd RF III, Pienta KJ. Paclitaxel, estramustine, and etoposide in patients with hormone-refractory prostate cancer (HRPC): A phase II trial. Proc Am Soc Clin Oncol. 16:310a, 1997.
  8. Siu LL, Moore MJ. Other chemotherapy regimens including mitoxantrone and suramin. Sem Urol Oncol. 15:20-27, 1997.
  9. Eisenberger MA, Sinibaldi VJ, Reyno LM, et al: Phase regimen of suramin in patients with hormone-refractory prostatecancer. J Clin Oncol. 13:2174-2186, 1995.
  10. Pienta KJ, Esper PS, Smith DC. The oral regimen of Cytoxan, prednisone and diethylstilbesterol (CPD) is an active, non-toxic treatment for patients with hormone refractory prostate cancer. Proc Amer Soc Clin Oncol. 16:310a, 1997.

 

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Please note: The articles listed in the Cancer Center's News Archive are here for historical purposes. The information and links may no longer be up-to-date.