Stage IV Prostate Cancer
A large proportion of men experience hot flushes after bilateral orchiectomy or treatment with LHRH agonists. These hot flushes can persist for years. Varying levels of success in the management of these symptoms have been reported with DES, clonidine, cyproterone acetate, or medroxyprogesterone acetate.
In addition to hormonal therapy, adjuvant treatment has been tested using bisphosphonates. In MRC-PR05, 311 men with bone metastases who were starting or responding to standard hormonal therapy were randomly assigned to oral sodium clodronate (2,080 mg per day) or a matching placebo for up to 3 years. At a median follow-up of 11.5 years, OS was better in the clodronate arm: HR of death was 0.77 (95% CI, 0.60-0.98; P = 0.032). Five- and 10-year survival rates were 30% and 17% in the clodronate arm versus 21% and 9% in the placebo arm.[Level of evidence: 1iA] A parallel study (MRC-PR04) in men with locally advanced but nonmetastatic disease showed no benefit associated with clodronate. Confirmatory trials about the effect of bisphosphonates on OS, such as CALGB-90202 and CALGB-70604, are ongoing.
After tumor progression on one form of hormonal manipulation develops, an objective tumor response to any other form is uncommon. Some studies, however, suggest that withdrawal of flutamide (with or without aminoglutethimide administration) is associated with a decline in PSA values and that one may need to monitor for this response before initiating new therapy.[35,36,37] Low-dose prednisone may palliate symptoms in about 33% of cases. (Refer to the Recurrent Prostate Cancer section of this summary for more information.)
- Hormonal manipulations effectively used as initial therapy for prostate cancer: 
- Orchiectomy alone or with an androgen blocker as seen in the SWOG-8894 trial, for example.
- LHRH agonists such as leuprolide in daily or depot preparations. (These agents may be associated with tumor flare when used alone; therefore, the initial concomitant use of antiandrogens should be considered in the presence of liver pain, ureteral obstruction, or impending spinal cord compression.)[17,19,20,40][Level of evidence: 1iiA]
- Leuprolide plus flutamide; however, the addition of an antiandrogen to leuprolide has not been clearly shown in a meta-analysis to improve survival.
- Estrogens (DES, chlorotrianisene, ethinyl estradiol, conjugated estrogens USP, and DES-diphosphate). (DES is no longer commercially available in the United States.)
- External-beam radiation therapy (EBRT) for attempted cure (highly selected stage M0 patients).[42,43] Definitive radiation therapy should be delayed 4 to 6 weeks after TURP to reduce incidence of stricture.
Hormonal therapy should be considered in addition to EBRT.
- Palliative radiation therapy. A single fraction of 8 Gy has been shown to have similar benefits on bone pain relief and quality of life as multiple fractions (3 Gy � 10) as evidenced in the RTOG-9714 trial.[45,46][Level of evidence: 1iiC] (Refer to the PDQ summary on Pain for more information.)
- Palliative surgery (TURP).
- Careful observation without further immediate treatment (in selected patients).
- Radical prostatectomy with immediate orchiectomy is under clinical evaluation. An uncontrolled, retrospective review of a large series of patients with any T, N1-3, M0 disease treated at the Mayo Clinic by concurrent radical prostatectomy and orchiectomy showed prolongation of intervals to local and distant progression; however, a significant increase in survival has not been demonstrated.