Stage III Prostate Cancer
Since many stage III patients have urinary symptoms, control of symptoms is an important consideration in treatment. This may often be accomplished by radiation therapy, radical surgery, transurethral resection of the prostate, or hormonal manipulation.
- Radiation therapy.[3,4,25,26] EBRT designed to decrease exposure of normal tissues using methods such as CT-based 3-D conformal treatment planning is under clinical evaluation.
- Hormonal manipulations effectively used as initial therapy for prostate cancer:
- Leuprolide or other LHRH agonists (goserelin) in daily or depot preparations. (These agents may be associated with tumor flare.)
- Estrogen (diethylstilbestrol [DES] is no longer available in the United States).
- Nonsteroidal antiandrogen (e.g., flutamide, nilutamide, and bicalutamide) or steroidal antiandrogen (cyproterone acetate).
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:[Level of evidence: 1iiA]
- 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 to 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%).
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 remains under evaluation. In a subsequent randomized trial, 626 men with clinically advanced prostate cancer (T3-T4, M0-M1, PSA ?4) that 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 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]
- Palliative surgery (transurethral resection).
- Interstitial implantation combined with EBRT is being used in selected T3 patients, but little information is available.
- Clinical trials employing alternative forms of radiation therapy. A randomized trial from the RTOG reported improved local control and survival with mixed-beam (neutron/photon) radiation therapy compared with standard photon radiation therapy. A subsequent randomized study from the same group compared fast-neutron radiation therapy with standard photon radiation therapy. Local-regional control was improved with neutron treatment, but no difference in OS was seen, though follow-up was shorter in this trial. Fewer complications were seen with the use of a multileaf collimator. Proton-beam radiation therapy is also under investigation.
- Other clinical trials.
- Ultrasound-guided percutaneous cryosurgery is under clinical evaluation. Cryosurgery is a surgical technique under development that involves destruction of prostate cancer cells by intermittent freezing of the prostate tissue with cryoprobes, followed by thawing.[Level of evidence: 3iiiC];[52,53][Level of evidence: 3iiiDiv] Cryosurgery is less well established than standard prostatectomy, and long-term outcomes are not as well established as with prostatectomy or radiation therapy. Serious toxic effects include bladder outlet injury, urinary incontinence, sexual impotence, and rectal injury. The technique of cryosurgery is under development. Impotence is common. The frequency of other side effects and the probability of cancer control at 5 years' follow-up have varied among reporting centers, and series are small compared with surgery and radiation therapy.[52,53]