Stage IV Prostate Cancer Treatment
In some series, pretreatment levels of PSA are inversely correlated with progression-free duration in patients with metastatic prostate cancer who receive hormonal therapy. After hormonal therapy is initiated, a PSA reduction to beneath a detectable level provides information regarding the duration of progression-free status; however, decreases in PSA of less than 80% may not be very predictive.
Orchiectomy and estrogens yield similar results, and selection of one or the other depends on patient preference and the morbidity of expected side effects. Estrogens are associated with the development or exacerbation of cardiovascular disease, especially in high doses. DES at a dose of 1 mg per day is not associated with cardiovascular complications as frequent as those found at higher doses; however, the use of DES has decreased because of cardiovascular toxic effects. DES is no longer commercially available in the United States.
The psychological implications of orchiectomy are objectionable to many patients, and many will choose an alternative therapy if effective. Combined orchiectomy and estrogens are not indicated to be superior to either treatment administered alone.
A large proportion of men experience hot flushes after bilateral orchiectomy or treatment with LH-RH 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.
After tumor progression on one form of hormonal manipulation, 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 and that one may need to monitor for this response before initiating new therapy.[15,16,17] Low-dose prednisone may palliate symptoms in about 33% of cases. (Refer to the Recurrent Prostate Cancer section of this summary for more information.)
Immediate versus deferred hormonal therapy
Some patients may be asymptomatic and careful observation without further immediate therapy may be appropriate.
Evidence (immediate vs. deferred hormonal therapy):
- A meta-analysis of seven randomized controlled trials comparing early (adjuvant or neoadjuvant) with deferred hormonal treatment (LH-RH agonists and/or antiandrogens) in patients with locally advanced prostate cancer, whether treated with prostatectomy, radiation therapy, or watchful waiting or active surveillance, showed improved overall mortality with early treatment (relative risk, 0.86; 95% CI, 0.82–0.91).[Level of evidence: 1iiA]
- In a small, randomized trial of 98 men who underwent radical prostatectomy plus pelvic lymphadenectomy and were found to have nodal metastases (stage T1–2, N1, M0), immediate continuous hormonal therapy with the LH-RH agonist goserelin or with orchiectomy was compared with deferred therapy until documentation of disease progression.[Level of evidence: 1iA]; 
- After a median follow-up of 11.9 years, both OS (P = .04) and prostate cancer–specific survival (P = .004) were superior in the immediate adjuvant therapy arm.
- At 10 years, the survival rate in the immediate therapy arm was about 80% versus about 60% in the deferred therapy arm.
- Another trial (RTOG-8531) with twice as many randomly assigned patients showed no difference in OS with early versus late hormonal manipulation.
- Immediate hormonal therapy with goserelin or orchiectomy has also been compared with deferred hormonal therapy for clinical disease progression in a randomized trial (EORTC-30846) of men with regional lymph node involvement but no clinical evidence of metastases (any T, N+, M0). None of the 234 men had a prostatectomy or prostatic radiation therapy.[Level of evidence; 1iiA]
- After a median follow-up of 8.7 years, the HR for OS in the deferred versus immediate hormonal therapy arms was 1.23 (95% CI, 0.88–1.71).
- No statistically significant difference in OS between deferred and immediate hormonal therapy was found, but the trial was underpowered to detect small or modest differences.
- Immediate hormonal treatment (e.g., orchiectomy or LH-RH analog) versus deferred treatment (e.g., watchful waiting with hormonal therapy at progression) was examined in a randomized study in men with locally advanced or asymptomatic metastatic prostate cancer.[Level of evidence: 1iiA]
- The initial results showed better OS and prostate cancer-specific survival with immediate treatment.
- The incidence of pathologic fractures, spinal cord compression, and ureteric obstruction were also lower in the immediate treatment arm.
- In another trial, 197 men with stage III or stage IV prostate cancer were randomly assigned to have a bilateral orchiectomy at diagnosis or at the time of symptomatic progression (or at the time of new metastases that were deemed likely to cause symptoms).[Level of evidence: 1iiA]
- Over a 12-year period of follow-up, no statistically significant difference was observed in OS.