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Prostate Cancer Treatment (Professional) (cont.)

Stage IV Prostate Cancer

Note: 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 summary on Levels of Evidence for more information.)

Stage IV prostate cancer is defined by the American Joint Committee on Cancer's TNM classification system:[1]

  • T4, N0, M0, any prostate-specific antigen (PSA), any Gleason.
  • Any T, N1, M0, any PSA, any Gleason.
  • Any T, any N, M1, any PSA, any Gleason.

Extraprostatic invasion with microscopic bladder neck invasion (T4) is included with T3a.

Treatment selection depends on age, coexisting medical illnesses, symptoms, and the presence of distant metastases (most often bone) or regional lymph node involvement only. The most common symptoms originate from the urinary tract or from bone metastases. Palliation of symptoms from the urinary tract with transurethral resection of the prostate (TURP) or radiation therapy and palliation of symptoms from bone metastases with radiation therapy or hormonal therapy are an important part of the management of these patients. Bisphosphonates are also under clinical evaluation for the management of bone metastases.[2]

The Agency for Health Care Policy and Research (AHCPR) (now the Agency for Healthcare Research and Quality) performed a systematic review of the available randomized clinical trial evidence comparing radiation therapy with radiation therapy and prolonged androgen suppression performed by its Technology Evaluation Center, an evidence-based Practice Center of the Blue Cross and Blue Shield Association.[3][Level of evidence: 1iiA] Some patients with bulky T2b tumors were included in the studied groups. The meta-analysis found a difference in 5-year overall survival (OS) in favor of radiation therapy plus continued androgen suppression using a luteinizing hormone-releasing hormone (LHRH) agonist or orchiectomy, compared with radiation therapy alone (hazard ratio [HR] = 0.631; 95% confidence interval [CI], 0.479–0.831). This reduction in overall mortality indicates that adjuvant androgen suppression should be initiated at the time of radiation therapy and continued for several years. The optimal duration of therapy and the issue of utility of neoadjuvant hormonal therapy have not been determined.

Likewise, a meta-analysis of seven randomized controlled trials comparing early (adjuvant or neoadjuvant) to deferred hormonal treatment (LHRH agonists and/or antiandrogens) in patients with locally advanced prostate cancer, whether treated by prostatectomy, radiation therapy, or watchful waiting, showed improved overall mortality (RR = 0.86; 95% CI, 0.82–0.91).[4][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 LHRH agonist goserelin or with orchiectomy was compared with deferred therapy until documentation of disease progression.[5][Level of evidence: 1iA];[6] After a median follow-up of 11.9 years, both OS and prostate cancer–specific survival were superior in the immediate adjuvant therapy arm (P = .04 and P = .004, respectively). At 10 years, the survival rate in the immediate therapy arm was about 80% versus about 60% for the deferred therapy arm.[7] Another trial (RTOG-8531), with twice as many patients in a randomization, showed no difference in OS with early versus late hormonal manipulation.[8]

Bicalutamide has not been shown to improve OS in patients with localized or locally advanced prostate cancer. The Early Prostate Cancer program is a large, randomized, placebo-controlled, international trial that compared bicalutamide (150 mg orally per day) plus standard care (radical prostatectomy, radiation therapy, or watchful waiting, depending on local custom) with standard care alone for men with nonmetastatic localized or locally advanced prostate cancer (T1–2, N0, NX; T3–4, any N; or any T, N+).[9] Less than 2% of the 8,113 men had known node disease. At a median follow-up of 7.4 years, there was no difference in OS between the bicalutamide and placebo groups (about 76% in both arms [HR = 0.99; 95% CI, 0.91–1.09; P = .89]).[9][Level of evidence: 1iA]

Immediate hormone therapy with goserelin or orchiectomy has also been compared with deferred hormone therapy for clinical disease progression in a randomized trial (EORTC-30846) of men with regional lymph node involvement but no clinical metastases (any T, N+, M0).[10] None of the 234 men received prostatectomy or prostatic radiation therapy. After a median follow-up of 8.7 years, the HR for OS in the deferred versus immediate hormone therapy arms was 1.23 (95% CI, 0.88–1.71). No statistically significant difference in OS between deferred and immediate hormone therapy was found, but the trial was underpowered to detect small or modest differences.[10][Level of evidence: 1iiA]

Patients with locally advanced nonmetastatic disease (T2–T4, N0–N1, 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.[11][Level of evidence: 1iA]

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 most patients. Initial results from a randomized study of immediate hormonal treatment (e.g., orchiectomy or LHRH analog) versus deferred treatment (e.g., watchful waiting with hormonal therapy at progression) in men with locally advanced or asymptomatic metastatic prostate cancer showed better OS 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.[12][Level of evidence: 1iiA] In another trial, 197 men with stage III or stage IV prostate cancer were randomly assigned to receive 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). Over a 12-year period of follow-up, no statistically significant difference was observed in OS.[13][Level of evidence: 1iiA]

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 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.[14] 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. Diethylstilbestrol (DES) in 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, and DES is no longer commercially available in the United States. The psychological implications of orchiectomy are objectionable to many patients, and many will choose alternative therapy if effective.[15] Combined orchiectomy and estrogens are not indicated to be superior to either treatment administered alone.[16]

Approaches using LHRH agonists and/or antiandrogens in patients with stage IV prostate cancer have produced response rates similar to standard hormonal treatments.[17,18] In a randomized trial, the LHRH analog leuprolide (1 mg subcutaneously every day) was found to be as effective as DES (3 mg orally every day) in any T, any N, M1 patients but caused less gynecomastia, nausea and vomiting, and thromboembolisms.[19] In other randomized studies, the depot LHRH analog goserelin was found to be as effective as orchiectomy [20,21,22] or DES at a dose of 3 mg per day.[18] A depot preparation of leuprolide, which is therapeutically equivalent to daily leuprolide, is available as a monthly or 3-monthly depot. Castration has been shown to be superior to monotherapy with bicalutamide.[23] A small randomized study comparing 1 mg of DES orally 3 times per day to 250 mg of flutamide 3 times per day in patients with metastatic prostate cancer showed similar response rates with both regimens but superior survival with DES. More cardiovascular and/or thromboembolic toxic effects of borderline statistical significance were associated with the DES treatment.[24][Level of evidence: 1iA] A variety of combinations of hormonal therapy have been tested.

On the basis 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. Subsequent randomized controlled trials, however, 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, no difference in OS was reported.[25][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 because of more diarrhea and worse emotional function in the flutamide-treated group.[26][Level of evidence: 1iC] A meta-analysis of 27 randomized trials of 8,275 patients comparing conventional surgical or medical castration to MAB—castration plus prolonged use of an antiandrogen such as flutamide, cyproterone acetate, or nilutamide—did not show a statistically significant improvement in survival associated with MAB.[27][Level of evidence: 1iA]

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).[27]

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:

  1. 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).
  2. Survival rates at 2 years are similar or worse with nonsteroidal antiandrogens compared with orchiectomy (HR = 1.22; 95% CI, 0.99–1.50).
  3. Treatment withdrawals, used as a surrogate for adverse effects, occurred less with LHRH agonists (0%–4%) than with nonsteroidal antiandrogens (4%–10%).[28][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.[3]

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.[29] 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.[30][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.[31] 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.[29][Level of evidence: 1iiA]

A large proportion of men experience hot flushes after bilateral orchiectomy or treatment with LHRH agonists. These hot flushes can persist for years.[32] Varying levels of success in the management of these symptoms have been reported with DES, clonidine, cyproterone acetate, or medroxyprogesterone acetate.

In addition to hormonal therapy, adjuvant treatment has been tested using bisphosphonates.[33] 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. At a median follow-up of 11.5 years, OS was better in the clodronate arm: HR of death was 0.77 (95% CI, 0.60–0.98; P = 0.032). Five- and 10-year survival rates were 30% and 17% in the clodronate arm versus 21% and 9% in the placebo arm.[33][Level of evidence: 1iA] 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.

After tumor progression on one form of hormonal manipulation develops, an objective tumor response to any other form is uncommon.[34] Some studies, however, suggest that withdrawal of flutamide (with or without aminoglutethimide administration) is associated with a decline in PSA values and that one may need to monitor for this response before initiating new therapy.[35,36,37] Low-dose prednisone may palliate symptoms in about 33% of cases.[38] (Refer to the Recurrent Prostate Cancer section of this summary for more information.)

Treatment options:

  1. Hormonal manipulations effectively used as initial therapy for prostate cancer: [39]
    1. Orchiectomy alone or with an androgen blocker as seen in the SWOG-8894 trial, for example.
    2. LHRH agonists such as leuprolide in daily or depot preparations. (These agents may be associated with tumor flare when used alone; therefore, the initial concomitant use of antiandrogens should be considered in the presence of liver pain, ureteral obstruction, or impending spinal cord compression.)[17,19,20,40][Level of evidence: 1iiA]
    3. Leuprolide plus flutamide;[41] however, the addition of an antiandrogen to leuprolide has not been clearly shown in a meta-analysis to improve survival.[27]
    4. Estrogens (DES, chlorotrianisene, ethinyl estradiol, conjugated estrogens USP, and DES-diphosphate). (DES is no longer commercially available in the United States.)
  2. External-beam radiation therapy (EBRT) for attempted cure (highly selected stage M0 patients).[42,43] Definitive radiation therapy should be delayed 4 to 6 weeks after TURP to reduce incidence of stricture.[44]

    Hormonal therapy should be considered in addition to EBRT.[3]

  3. Palliative radiation therapy. A single fraction of 8 Gy has been shown to have similar benefits on bone pain relief and quality of life as multiple fractions (3 Gy × 10) as evidenced in the RTOG-9714 trial.[45,46][Level of evidence: 1iiC] (Refer to the PDQ summary on Pain for more information.)
  4. Palliative surgery (TURP).
  5. Careful observation without further immediate treatment (in selected patients).[47]
  6. Radical prostatectomy with immediate orchiectomy is under clinical evaluation.[48] 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.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IV prostate cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

  1. Prostate. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 457-68.
  2. Dearnaley DP, Sydes MR, Mason MD, et al.: A double-blind, placebo-controlled, randomized trial of oral sodium clodronate for metastatic prostate cancer (MRC PR05 Trial). J Natl Cancer Inst 95 (17): 1300-11, 2003.
  3. Seidenfeld J, Samson DJ, Aronson N, et al.: Relative effectiveness and cost-effectiveness of methods of androgen suppression in the treatment of advanced prostate cancer. Evid Rep Technol Assess (Summ) (4): i-x, 1-246, I1-36, passim, 1999.
  4. Boustead G, Edwards SJ: Systematic review of early vs deferred hormonal treatment of locally advanced prostate cancer: a meta-analysis of randomized controlled trials. BJU Int 99 (6): 1383-9, 2007.
  5. Messing EM, Manola J, Sarosdy M, et al.: Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med 341 (24): 1781-8, 1999.
  6. Eisenberger MA, Walsh PC: Early androgen deprivation for prostate cancer? N Engl J Med 341 (24): 1837-8, 1999.
  7. Messing EM, Manola J, Yao J, et al.: Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. Lancet Oncol 7 (6): 472-9, 2006.
  8. Lawton CA, Winter K, Grignon D, et al.: Androgen suppression plus radiation versus radiation alone for patients with stage D1/pathologic node-positive adenocarcinoma of the prostate: updated results based on national prospective randomized trial Radiation Therapy Oncology Group 85-31. J Clin Oncol 23 (4): 800-7, 2005.
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  10. Schröder FH, Kurth KH, Fosså SD, et al.: Early versus delayed endocrine treatment of pN1-3 M0 prostate cancer without local treatment of the primary tumor: results of European Organisation for the Research and Treatment of Cancer 30846--a phase III study. J Urol 172 (3): 923-7, 2004.
  11. Mason MD, Sydes MR, Glaholm J, et al.: Oral sodium clodronate for nonmetastatic prostate cancer--results of a randomized double-blind placebo-controlled trial: Medical Research Council PR04 (ISRCTN61384873). J Natl Cancer Inst 99 (10): 765-76, 2007.
  12. Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council Trial. The Medical Research Council Prostate Cancer Working Party Investigators Group. Br J Urol 79 (2): 235-46, 1997.
  13. Studer UE, Hauri D, Hanselmann S, et al.: Immediate versus deferred hormonal treatment for patients with prostate cancer who are not suitable for curative local treatment: results of the randomized trial SAKK 08/88. J Clin Oncol 22 (20): 4109-18, 2004.
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  18. Waymont B, Lynch TH, Dunn JA, et al.: Phase III randomised study of zoladex versus stilboestrol in the treatment of advanced prostate cancer. Br J Urol 69 (6): 614-20, 1992.
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  20. 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.
  21. Vogelzang NJ, Chodak GW, Soloway MS, et al.: Goserelin versus orchiectomy in the treatment of advanced prostate cancer: final results of a randomized trial. Zoladex Prostate Study Group. Urology 46 (2): 220-6, 1995.
  22. Kaisary AV, Tyrrell CJ, Peeling WB, et al.: Comparison of LHRH analogue (Zoladex) with orchiectomy in patients with metastatic prostatic carcinoma. Br J Urol 67 (5): 502-8, 1991.
  23. Bales GT, Chodak GW: A controlled trial of bicalutamide versus castration in patients with advanced prostate cancer. Urology 47 (1A Suppl): 38-43; discussion 48-53, 1996.
  24. Chang A, Yeap B, Davis T, et al.: Double-blind, randomized study of primary hormonal treatment of stage D2 prostate carcinoma: flutamide versus diethylstilbestrol. J Clin Oncol 14 (8): 2250-7, 1996.
  25. Eisenberger MA, Blumenstein BA, Crawford ED, et al.: Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. N Engl J Med 339 (15): 1036-42, 1998.
  26. Moinpour CM, Savage MJ, Troxel A, et al.: Quality of life in advanced prostate cancer: results of a randomized therapeutic trial. J Natl Cancer Inst 90 (20): 1537-44, 1998.
  27. Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials. Prostate Cancer Trialists' Collaborative Group. Lancet 355 (9214): 1491-8, 2000.
  28. Seidenfeld J, Samson DJ, Hasselblad V, et al.: Single-therapy androgen suppression in men with advanced prostate cancer: a systematic review and meta-analysis. Ann Intern Med 132 (7): 566-77, 2000.
  29. Calais da Silva FE, Bono AV, Whelan P, et al.: Intermittent androgen deprivation for locally advanced and metastatic prostate cancer: results from a randomised phase 3 study of the South European Uroncological Group. Eur Urol 55 (6): 1269-77, 2009.
  30. Conti PD, Atallah AN, Arruda H, et al.: Intermittent versus continuous androgen suppression for prostatic cancer. Cochrane Database Syst Rev (4): CD005009, 2007.
  31. Tombal B: Intermittent androgen deprivation therapy: conventional wisdom versus evidence. Eur Urol 55 (6): 1278-80, 2009.
  32. Karling P, Hammar M, Varenhorst E: Prevalence and duration of hot flushes after surgical or medical castration in men with prostatic carcinoma. J Urol 152 (4): 1170-3, 1994.
  33. Dearnaley DP, Mason MD, Parmar MK, et al.: Adjuvant therapy with oral sodium clodronate in locally advanced and metastatic prostate cancer: long-term overall survival results from the MRC PR04 and PR05 randomised controlled trials. Lancet Oncol 10 (9): 872-6, 2009.
  34. Small EJ, Vogelzang NJ: Second-line hormonal therapy for advanced prostate cancer: a shifting paradigm. J Clin Oncol 15 (1): 382-8, 1997.
  35. Scher HI, Kelly WK: Flutamide withdrawal syndrome: its impact on clinical trials in hormone-refractory prostate cancer. J Clin Oncol 11 (8): 1566-72, 1993.
  36. Sartor O, Cooper M, Weinberger M, et al.: Surprising activity of flutamide withdrawal, when combined with aminoglutethimide, in treatment of "hormone-refractory" prostate cancer. J Natl Cancer Inst 86 (3): 222-7, 1994.
  37. Small EJ, Srinivas S: The antiandrogen withdrawal syndrome. Experience in a large cohort of unselected patients with advanced prostate cancer. Cancer 76 (8): 1428-34, 1995.
  38. 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. J Clin Oncol 7 (5): 590-7, 1989.
  39. Scott WW, Menon M, Walsh PC: Hormonal therapy of prostatic cancer. Cancer 45 (7 Suppl): 1929-36, 1980.
  40. Sharifi R, Soloway M: Clinical study of leuprolide depot formulation in the treatment of advanced prostate cancer.The Leuprolide Study Group. J Urol 143 (1): 68-71, 1990.
  41. Crawford ED, Eisenberger MA, McLeod DG, et al.: A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med 321 (7): 419-24, 1989.
  42. Bagshaw MA: External radiation therapy of carcinoma of the prostate. Cancer 45 (7 Suppl): 1912-21, 1980.
  43. Ploysongsang S, Aron BS, Shehata WM, et al.: Comparison of whole pelvis versus small-field radiation therapy for carcinoma of prostate. Urology 27 (1): 10-6, 1986.
  44. 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. Int J Radiat Oncol Biol Phys 12 (9): 1597-600, 1986.
  45. Kaasa S, Brenne E, Lund JA, et al.: Prospective randomised multicenter trial on single fraction radiotherapy (8 Gy x 1) versus multiple fractions (3 Gy x 10) in the treatment of painful bone metastases. Radiother Oncol 79 (3): 278-84, 2006.
  46. Chow E, Harris K, Fan G, et al.: Palliative radiotherapy trials for bone metastases: a systematic review. J Clin Oncol 25 (11): 1423-36, 2007.
  47. Stattin P, Holmberg E, Johansson JE, et al.: Outcomes in localized prostate cancer: National Prostate Cancer Register of Sweden follow-up study. J Natl Cancer Inst 102 (13): 950-8, 2010.
  48. Zincke H: Extended experience with surgical treatment of stage D1 adenocarcinoma of prostate. Significant influences of immediate adjuvant hormonal treatment (orchiectomy) on outcome. Urology 33 (5 Suppl): 27-36, 1989.
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