Early Prostate Cancer Trials evaluating bicalutamide 150 milligrams

Prostate cancer research is about 10 to 15 years behind breast cancer research. For a long time, adjuvant tamoxifen in patients with breast cancer has been known to reduce mortality.

Prostate cancer is even more sensitive to hormonal manipulation. For example, many men with metastatic prostate cancer will have tumor regression with hormonal therapy, which I don’t believe is as striking in women with breast cancer.

The Early Prostate Cancer Trials evaluating bicalutamide 150 milligrams are certainly important in terms of size (1.1). These are important trials evaluating the reduction in mortality associated with adjuvant bicalutamide therapy. As the data mature over the next several years, the truth will be evident. I hope these trials will demonstrate that the introduction of a hormonal manipulation early in the course of the disease might have an impact on survival, as is the case with breast cancer.

Use of bicalutamide 150 milligrams in a nonprotocol setting

I present bicalutamide 150 milligrams as an option because the European studies found equivalent survival for patients with MO disease who were treated with either an LHRH agonist or bicalutamide 150 milligrams. If the patient’s disease fails on bicalutamide 150 milligrams, then an LHRH agonist can be used. If a man will be on hormonal therapy for a long time, the side effects of an LHRH agonist should be considered — the effect on sexuality, bone density, muscle strength and hot flashes. Studies have demonstrated that hormonal therapy affects quality of life.

Psychologists at our institution have conducted studies of sleep disorders and depression associated with hormonal manipulation. Since bicalutamide has fewer of these side effects than LHRH agonists, I offer it to patients.

Strategies to reduce bicalutamide-associated gynecomastia

Of the patients treated with bicalutamide 150 milligrams, 75 percent will have significant gynecomastia. I usually propose pretreatment radiation therapy to the breast, which has been shown to reduce breast enlargement by at least 50 percent. Because bicalutamide blocks the peripheral action of testosterone, the feedback mechanism is blocked and a slight increase in testosterone occurs. The excess testosterone is transformed into estrogen.

In men, estrogen is not counterbalanced at the breast by testosterone, which leads to gynecomastia. Hence, the mechanism for gynecomastia seems to be an excess estrogen effect with an absence of testosterone effect on the breast. The addition of tamoxifen, which blocks estrogen, might prevent bicalutamide-associated gynecomastia.

Two studies have shown that tamoxifen can reduce bicalutamide-associated gynecomastia by almost 85 percent. However, one study suggested tamoxifen might affect the efficacy of bicalutamide 150 milligrams. I’m the principal investigator of an international study that will determine whether tamoxifen reduces the incidence of gynecomastia in men with high-risk prostate cancer who are being treated with bicalutamide 150 milligrams.

We’re evaluating different doses of tamoxifen (10 or 20 milligrams) combined with bicalutamide 150 milligrams. After one year, tamoxifen is discontinued, bicalutamide is continued, and the PSA is monitored. One trial with an aromatase inhibitor has been conducted (1.2), but that strategy was not as effective and has been abandoned in favor of tamoxifen.

Role of prostatectomy in men with high-risk disease

In the United States, many men with high-risk prostate cancer are guided toward some therapy other than surgery. In my opinion, the opposite should occur. I believe that in patients with higher-grade and higher-risk cancer, surgery as a primary treatment adds to the chance of survival quite significantly. The surgical morbidity in a man with higher-risk cancer is not different from the surgical morbidity in a man with lower-risk cancer. I have a very different attitude than many American doctors.

Our results in these men with high-risk disease (Gleason ≥7, PSA ≥10 or 20 ng/ mL depending on the Gleason score, and a clinically palpable tumor) are quite spectacular. Patients we have treated with prostatectomy have a 90 percent 10- year survival rate, compared to patients treated with radiation therapy who typically have a 10-year survival rate of about 50 percent. A few studies, mostly from the Mayo Clinic, suggest that long-term survival may be better when using surgery as the primary treatment and adjuvant radiation therapy or hormonal therapy (or both) if the PSA fails — about 15 percent of those cases.

The only randomized trial comparing radiation therapy and surgery was a small series from Japan that was published in Urology in 1999. In that trial, patients with stage B2 and C cancers were treated with hormone therapy and then randomly assigned to surgery or radiation therapy. Although the radiation therapy doses administered were lower than those used today, patients treated with surgery showed a 10 percent difference in cancer mortality at five years. Hence, growing evidence suggests that even in high-risk cancer, treatment of the primary tumor makes a difference in survival.

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Dr Fradet is a Professor and Chairman of the Department of Surgery at the Université Laval and CHUQ, L’Hôtel-Dieu de Québec in Québec, Canada.