Treatment of Hormone-refractory Prostate Cancer
Treatment options for patients with metastatic HRPC include second-line hormonal manipulations, chemotherapy, bisphosphonates, and/or radiation/radioisotope therapy to reduce skeletal morbidity. Second-line hormonal manipulation may sometimes temporarily lower PSA levels, but these regimens have not been shown to improve survival. It is now the standard of care to stop antiandrogens when patients progress onto hormone therapy. Whether there is any clinical benefit to changing antiandrogens or increasing the dose of a given antiandrogen remains unknown.
In 1996, chemotherapy (mitoxantrone plus prednisone) demonstrated significant palliative benefits in HRPC, significantly reducing pain (p<0.0001) and improving QoL compared with prednisone alone.6 However, overall survival was not improved. This treatment regimen was subsequently approved for HRPC based on palliative benefit. Subsequently, in 2004, docetaxel plus estramustine was compared with mitoxantrone plus prednisone every three weeks, and this trial demonstrated the first survival benefit in this patient population.7 Median survival was increased by two months (p=0.01) in patients treated with docetaxel plus estramustine. A significant increase in PSA response (p<0.0001) was also observed in the docetaxel plus estramustine group. There was, however, significant added toxicity due to estramustine. A similar international trial comparing two different schedules of docetaxel (either every three weeks or weekly) plus prednisone versus mitoxantrone plus prednisone for 30 weeks demonstrated a significant 2.5-month survival advantage (p=0.009) in patients treated with docetaxel (every three weeks) compared with the mitoxantrone plus prednisone group.8 In contrast, docetaxel plus prednisone administered weekly did not demonstrate a significant improvement in survival. Docetaxel plus prednisone also significantly improved pain response and PSA response rates compared with mitoxantrone plus prednisone (p=0.01 and p=0.0005, respectively). In general, docetaxel was well tolerated. Grade 3/4 toxicities included neutropenia, with 3% of the patients in the docetaxel (every three weeks) group being hospitalized with febrile neutropenia compared with 2% of the patients in the mitoxantrone plus prednisone group. Common non-hematological adverse events included alopecia, fatigue, and nausea. By significantly improving survival and reducing both PSA and pain levels, docetaxel has now become the firstchoice chemotherapy in HRPC.