Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. Refer to the PDQ levels of evidence summary for more information.

Treatment selection depends on age, coexisting medical illnesses, symptoms, and whether distant metastases (most often bone) or only regional lymph node involvement is present. The most common symptoms originate from the urinary tract or from bone metastases. Palliation of the former with transurethral resection or radiation therapy and of the latter with radiation therapy or hormonal therapy is an important part of the management of these patients.

T4, N0, M0, or any T, N1-3, M0 patients:

The Agency for Health Care Policy and Research (AHCPR) has had a systematic review of the available randomized, clinical trial evidence comparing radiation therapy to radiation therapy with prolonged androgen suppression performed by its Technology Evaluation Center, and evidence-based Practice Center of the Blue Cross and Blue Shield Association. Some patients with bulky T2b tumors were included in the studied groups. The meta-analysis found a difference in 5-year overall survival in favor of radiation therapy plus continued androgen suppression compared to radiation therapy alone (hazard ratio=0.631, 95% confidence interval=0.479-0.831).[1][Level of evidence: 1iiA] This reduction in overall mortality indicates that adjuvant androgen suppression should be initiated at the time of radiation and continued for several years. The optimal duration of therapy remains to be determined. The issue of utility of neoadjuvant hormonal therapy remains to be determined.

Any T, any N, M1 patients:
Hormonal treatment is the mainstay of therapy for distant metastatic (stage D2) prostate cancer. Cure is rarely, if ever, possible, but striking subjective or objective responses to treatment occur in the majority of patients. Initial results from a randomized study of immediate hormonal treatment (orchiectomy or LHRH analogue) versus deferred treatment (watchful waiting with hormonal therapy at progression) in men with locally advanced or asymptomatic metastatic prostate cancer showed better overall survival and prostate cancer-specific survival with the immediate treatment. The incidence of pathologic fractures, spinal cord compression, and ureteric obstruction were also lower in the immediate treatment arm.[2][Level of evidence: 1iiA]

In some series, pre-treatment levels of prostate-specific antigen (PSA) are inversely correlated with progression-free duration in patients with metastatic prostate cancer who receive hormonal therapy. After hormonal therapy is instituted, reduction of PSA to undetectable levels provides information regarding the duration of progression-free status. However, decreases in PSA of less than 80% may not be very predictive.[3] Orchiectomy and estrogens yield similar results, and selection of 1 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. Diethylstilbestrol (DES) in a dose of 1 milligram per day is not associated with as frequent cardiovascular complications as are higher doses; however, the use of DES has decreased due to cardiovascular toxic effects. The psychologic implications of orchiectomy are objectionable to many patients and many will choose alternative therapy if effective.[4] There is no indication that combined orchiectomy and estrogens are superior to either treatment administered alone.[5]

Approaches using LHRH agonists and/or antiandrogens in patients with stage IV prostate cancer have produced response rates similar to standard hormonal treatments.[6,7] In a randomized trial, the LHRH analogue leuprolide (1 milligram subcutaneously every day) was found to be as effective as DES (3 milligrams orally every day) in any T, any N, M1 patients, but caused less gynecomastia, nausea/vomiting, and thromboembolisms.[8] In other randomized studies, the depot LHRH analogue goserelin (Zoladex) was found to be as effective as orchiectomy [9-11] or DES at a dose of 3 milligrams per day.[7] A depot preparation of leuprolide (Depo Lupron), which is therapeutically equivalent to leuprolide, is available as a monthly or 3-monthly depot. Castration has been shown to be superior to monotherapy with bicalutamide.[12] A small randomized study comparing 1 milligram of DES orally 3 times per day to 250 milligrams of flutamide 3 times per day in patients with metastatic prostate cancer showed similar response rates with both regimens, but superior survival with DES. There was more cardiovascular and/or thromboembolic toxic effects, of borderline statistical significance, associated with the DES treatment.[13][Level of evidence: 1iA] A variety of combinations of hormonal therapy have been tested.

Based on the fact that the adrenal glands continue to produce androgens after surgical or medical castration, case series studies were performed in which antiandrogen therapy was added to castration. Promising results from such case series led to widespread use of the strategy, known as "maximal androgen blockage" (MAB) or "complete androgen blockade." However, subsequent randomized controlled trials cast doubt on the efficacy of adding an antiandrogen to castration. In a large randomized controlled trial comparing treatment with bilateral orchiectomy plus either the antiandrogen flutamide or placebo, there was no difference in overall survival.[14][Level of evidence: 1iA] Although it has been suggested that MAB may improve the more subjective end point of response rate, prospectively assessed quality of life was worse in the flutamide arm than in the placebo arm, primarily due to more diarrhea and worse emotional function in the flutamide-treated group.[15][Level of evidence: 1iC] A meta-analysis of 22 randomized trials of 5,710 patients comparing conventional surgical or medical castration to MAB - castration plus prolonged use of an antiandrogen such as flutamide, cyproterone acetate, or nilutamide - showed no significant improvement in survival associated with MAB.[16][Levels of evidence: 1i,1iiA]

The AHCPR has had 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. Equivalence was shown between orchiectomy and the available LHRH agonists. Additionally, combined androgen blockade was of no greater benefit than single hormonal therapy 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.[1]

A large proportion of men experience hot flushes after bilateral orchiectomy or treatment with LHRH agonists. These hot flushes can persist for years.[17] Varying levels of success in the management of these symptoms have been reported with DES, clonidine, cyproterone acetate, or medroxyprogesterone acetate (Megace).

After tumor progression on 1 form of hormonal manipulation develops, an objective tumor response to any other form is uncommon.[18] However, some studies suggest that withdrawal of flutamide (with or without aminoglutethimide administration) may be associated with a decline in PSA values and that 1 may need to monitor for this response before initiating new therapy.[19-21] Chemotherapy may be appropriate in selected patients, but remains under evaluation. To date, no evidence exists that indicates chemotherapy prolongs survival.[22] Low-dose prednisone may palliate symptoms in about a third of the cases.[23] Refer to PDQ or to CancerNet (http://cancernet.nci.nih.gov) for information about clinical trials for patients with stage IV prostate cancer.

Treatment options:

1. Hormonal manipulations effectively used as initial therapy for prostate cancer: [24]

a) orchiectomy alone or with an androgen blocker.[25] Orchiectomy plus nilutamide produces superior objective response rates, bone pain relief, and freedom from progression rates compared to orchiectomy alone. However, the addition of an antiandrogen to surgical castration has not been shown to improve survival in a meta-analysis.[1,16][Level of evidence: 1iiA]

b) LHRH agonists such as leuprolide in daily or depot preparations.[6,8,9,26] (These agents may be associated with tumor flare when used alone and therefore, the initial concomitant use of antiandrogens should be considered in the presence of liver pain, ureteral obstruction, or impending spinal cord compression.)[Level of evidence: 1iiA]

c) leuprolide plus flutamide.[27] However, the addition of an antiandrogen to leuprolide has not been shown to improve survival in a meta-analysis.[16]

d) estrogens (DES, chlorotrianisene, ethinyl estradiol, conjugated estrogens U.S.P., DES-diphosphate).

2. External-beam irradiation for attempted cure (highly selected stage M0 patients).[28,29] Definitive radiation therapy should be delayed 4 to 6 weeks after transurethral resection to reduce incidence of stricture.[30]

Hormonal therapy should be considered in addition to external-beam irradiation.[1]

3. Palliative radiation therapy.

4. Palliative surgery (transurethral resection).

5. Careful observation without further immediate treatment (in selected patients).

6. Radical prostatectomy with immediate orchiectomy is under clinical evaluation.[31] 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.

7. Systemic chemotherapy for hormone-refractory disease is under clinical evaluation.[22,32,33]

1. Relative effectiveness and cost-effectiveness of methods of androgen suppression in the treatment of advanced prostatic cancer. Summary, Evidence Report/Technology Assessment: Number 4, January 1999. Agency for Health Care Policy and Research, Rockville, MD. Available at: http://www.ahcpr.gov/clinic/prossumm.htm. Accessed 6/14/99.
2. Medical Research Council Prostate Cancer Working Party Investigators Group: Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council Trial. British Journal of Urology 79(2): 235-246, 1997.
3. Matzkin H, Eber P, Todd B, et al.: Prognostic significance of changes in prostate-specific markers after endocrine treatment of stage D2 prostatic cancer. Cancer 70(9): 2302-2309, 1992.
4. Cassileth BR, Seidmon ED, Soloway MS, et al.: Patients' choice of treatment in stage D prostate cancer. Urology 33(5, Suppl): 57-62, 1989.
5. Byar DP: The Veterans Administration Cooperative Urological Research Group's studies of cancer of the prostate. Cancer 32(5): 1126-1130, 1973.
6. Parmar H, Edwards L, Phillips RH, et al.: Orchiectomy versus long-acting D-Trp-6-LHRH in advanced prostatic cancer. British Journal of Urology 59(3): 248-254, 1987.
7. Waymont B, Lynch TH, Dunn JA, et al.: Phase III randomised study of Zoladex versus stilboestrol in the treatment of advanced prostate cancer. British Journal of Urology 69(6): 614-620, 1992.
8. The Leuprolide Study Group: Leuprolide versus diethylstilbestrol for metastatic prostate cancer. New England Journal of Medicine 311(20): 1281-1286, 1984.
9. Peeling WB: Phase III studies to compare goserelin (Zoladex) with orchiectomy and with diethylstilbestrol in treatment of prostatic carcinoma. Urology 33(5, Suppl): 45-52, 1989.
10. Vogelzang NJ, Chodak GW, Soloway MS, et al.: Goserelin versus orchiectomy in the treatment of advanced prostate cancer: final results of a randomized trial. Urology 46(2): 220-226, 1995.
11. Kaisary AV, Tyrrell CJ, Peeling WB, et al.: Comparison of LHRH analogue (Zoladex) with orchiectomy in patients with metastatic prostatic carcinoma. British Journal of Urology 67(5): 502-508, 1991.
12. Bales GT, Chodak GW: A controlled trial of bicalutamide versus castration in patients with advanced prostate cancer. Urology 47(Suppl 1A): 38-43, 1996.
13. Chang A, Yeap B, Davis T, et al.: Double-blind, randomized study of primary hormonal treatment of stage D2 prostate carcinoma: flutamide versus diethylstilbestrol. Journal of Clinical Oncology 14(8): 2250-2257, 1996.
14. Eisenberger MA, Blumenstein BA, Crawford ED, et al.: Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. New England Journal of Medicine 339(15): 1036-1042, 1998.
15. Moinpour CM, Savage MJ, Troxel A, et al.: Quality of life in advanced prostate cancer: results of a randomized therapeutic trial. Journal of the National Cancer Institute 90(20): 1537-1544, 1998.
16. Prostate Cancer Trialists' Collaborative Group: Maximum androgen blockade in advanced prostate cancer: an overview of 22 randomised trials with 3283 deaths in 5710 patients. Lancet 346(8970): 265-269, 1995.
17. Karling P, Hammar M, Varenhorst E: Prevalence and duration of hot flushes after surgical or medical castration in men with prostatic carcinoma. Journal of Urology 152(4): 1170-1173, 1994.
18. Small EJ, Vogelzang NJ: Second-line hormonal therapy for advanced prostate cancer: a shifting paradigm. Journal of Clinical Oncology 15(1): 382-388, 1997.
19. Scher HI, Kelly WK: Flutamide withdrawal syndrome: its impact on clinical trials in hormone-refractory prostate cancer. Journal of Clinical Oncology 11(8): 1566-1572, 1993.
20. Sartor O, Cooper M, Weinberger M, et al.: Surprising activity of flutamide withdrawal, when combined with aminoglutethimide, in treatment of "hormone-refractory" prostate cancer. Journal of the National Cancer Institute 86(3): 222-227, 1994.
21. Small EJ, Srinivas S: The antiandrogen withdrawal syndrome: experience in a large cohort of unselected patients with advanced prostate cancer. Cancer 76(8): 1428-1434, 1995.
22. Eisenberger MA: Chemotherapy for prostate carcinoma. Journal of the National Cancer Institute Monographs 7: 151-163, 1988.
23. Tannock I, Gospodarowicz M, Meakin W, et al.: Treatment of metastatic prostatic cancer with low-dose prednisone: evaluation of pain and quality of life as pragmatic indices of response. Journal of Clinical Oncology 7(5): 590-597, 1989.
24. Scott WW, Menon M, Walsh PC: Hormonal therapy of prostatic cancer. Cancer 45(7): 1929-1936, 1980.
25. Eisenberger MA, Southwest Oncology Group: Phase III Comparison of Flutamide vs Placebo Following Bilateral Orchiectomy in Patients with Stage D2 Adenocarcinoma of the Prostate (Summary Last Modified 12/92), SWOG-8894, clinical trial, closed, 09/15/1994.
26. Sharifi R, Soloway M: Clinical study of leuprolide depot formulation in the treatment of advanced prostate cancer. Journal of Urology 143(1): 68-71, 1990.
27. Crawford ED, Eisenberger MA, McLeod DG, et al.: A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. New England Journal of Medicine 321(7): 419-424, 1989.
28. Bagshaw MA: External radiation therapy of carcinoma of prostate. Cancer 45(7): 1912-1921, 1980.
29. Ploysongsang S, Aron BS, Shehata WM, et al.: Comparison of whole pelvis versus small-field radiation therapy for carcinoma of prostate. Urology 27(1): 10-16, 1986.
30. Seymore CH, El-Mahdi AM, Schellhammer PF: The effect of prior transurethral resection of the prostate on post radiation urethral strictures and bladder neck contractures. International Journal of Radiation Oncology, Biology, Physics 12(9): 1597-1600, 1986.
31. Zincke H: Extended experience with surgical treatment of stage D1 adenocarcinoma of prostate: significant influences of immediate adjuvant hormonal treatment (orchiectomy) on outcome. Journal of Urology 33(5, Suppl): 27-36, 1989.
32. Hudes GR, Greenberg R, Krigel RL, et al.: Phase II study of estramustine and vinblastine, two microtubule inhibitors, in hormone-refractory prostate cancer. Journal of Clinical Oncology 10(11): 1754-1761, 1992.
33. Pienta KJ, Redman B, Hussain M, et al.: Phase II evaluation of oral estramustine and oral etoposide in hormone-refractory adenocarcinoma of the prostate. Journal of Clinical Oncology 12(10): 2005-2012, 1994.

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