Prostate Cancer Treatment (PDQ®): Treatment - Health Professional Information [NCI] - Stage IV Prostate Cancer Treatment
Continuous versus intermittent hormonal therapy
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, this 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.
Evidence (continuous vs. intermittent hormonal therapy):
- 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 on 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 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 LH-RH analog 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 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]
In addition to hormonal therapy, adjuvant treatment with bisphosphonates has been tested.
- 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.[Level of evidence: 1iA]
- At a median follow-up of 11.5 years, OS was better in the clodronate arm: HRdeath of 0.77 (95% CI, 0.60–0.98; P = .032).
- Five- and 10-year survival rates were 30% and 17% in the clodronate arm versus 21% and 9% in the placebo arm.
- 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.
Bisphosphonates and decreasing risk of bone metastases
Patients with locally advanced nonmetastatic disease (T2–T4, N0–N1, and M0) are at risk for developing bone metastases, and bisphosphonates are being studied as a strategy to decrease this risk. However, a placebo-controlled, randomized trial (MRC-PR04) of a 5-year regimen of the first-generation bisphosphonate clodronate in high oral doses (2,080 mg per day) had no favorable impact on either time to symptomatic bone metastasis or survival.[Level of evidence: 1iA]