Stage IV Prostate Cancer
When trials of androgen suppression versus androgen suppression plus either nilutamide or flutamide were examined in a subset analysis, the absolute survival rate at 5 years was better for the combined therapy group (2.9% better, 95% CI, 0.3-5.5); however, when trials of androgen suppression versus androgen suppression plus cyproterone acetate were examined, the absolute survival trend at 5 years was worse for the combined therapy group (2.8% worse, 95% CI, -7.6 to +2.0).
The AHCPR has performed a systematic review of the available randomized clinical trial evidence of single hormonal therapies and combined androgen blockade performed by its Technology Evaluation Center, an evidence-based Practice Center of the Blue Cross and Blue Shield Association. A meta-analysis of randomized trials comparing various hormonal monotherapies in men with stage III or stage IV prostate cancer (predominantly stage IV) came to the following conclusions:
- OS at 2 years using any of the LHRH agonists is similar to treatment with orchiectomy or 3 mg per day of DES (HR = 1.26; 95% CI, 0.92-1.39).
- Survival rates at 2 years are similar or worse with nonsteroidal antiandrogens compared with orchiectomy (HR = 1.22; 95% CI, 0.99-1.50).
- Treatment withdrawals, used as a surrogate for adverse effects, occurred less with LHRH agonists (0%-4%) than with nonsteroidal antiandrogens (4%-10%).[Level of evidence: 1iiA]
Combined androgen blockade was of no greater benefit than single hormonal therapy and with less patient tolerance. Also, the evidence was judged insufficient to determine whether men newly diagnosed with asymptomatic metastatic disease should have immediate androgen-suppression therapy or should have therapy deferred until they have clinical signs or symptoms of progression.
When used as the primary therapy for patients with stage III or stage IV prostate cancer, androgen suppression with hormonal therapy is usually given continuously until there is disease progression. Some investigators have proposed intermittent androgen suppression as a strategy to attain maximal tumor cytoreduction followed by a period without therapy to allow tumor repopulation by hormone-sensitive cells. Theoretically, the strategy might provide tumor hormone responsiveness for a longer period of time. An animal model suggested that intermittent androgen deprivation (IAD) could prolong the duration of androgen dependence of hormone-sensitive tumors. A systematic review of all five randomized trials addressing this issue found no reliable data on the relative effectiveness of intermittent versus continuous androgen suppression for OS, prostate cancer-specific survival, disease progression, or quality of life.[Level of evidence: 1iiA] All five trials were small and had short follow-up. Intermittent therapy therefore remains under evaluation. In a subsequent randomized trial, 626 men with clinically advanced prostate cancer (T3-T4, M0-M1, PSA ?4 ng/mL) who responded to an initial 3-month induction course of cyproterone acetate plus an LHRH analogue were randomly assigned to either continue the regimen or cease treatment until there was evidence of progression. After 100 months of follow-up (median 51 months), there was no difference in OS (HR = 0.99; 95% CI, 0.80-1.23; P = 0.84) for continuous androgen deprivation (CAD) versus IAD. Quality of life between the two treatment strategies was similar, but IAD was associated with lower rates of hot flushes and gynecomastia. Replication of these findings would be important, and there are ongoing trials such as SWOG-9346 to address this further.[Level of evidence: 1iiA]