domingo, 2 de junio de 2019

Prostate Cancer Treatment (PDQ®) 7/7 —Health Professional Version - National Cancer Institute

Prostate Cancer Treatment (PDQ®)—Health Professional Version - National Cancer Institute

National Cancer Institute



Prostate Cancer Treatment (PDQ®)–Health Professional Version



Stage IV Prostate Cancer Treatment

Overview

Stage IV prostate cancer is defined by the American Joint Committee on Cancer TNM (tumor, node, metastasis) classification system:[1]
Stage IVA
  • Any T, N1, M0, any prostate-specific antigen (PSA), any Gleason.
Stage IVB
  • Any T, N0, M1, any PSA, any Gleason.
Extraprostatic extension with microscopic bladder neck invasion (T4) is included with T3a.
Treatment selection depends on the following factors:
  • Age.
  • Coexisting medical illnesses.
  • Symptoms.
  • 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 may also be used for the management of bone metastases.[2]

Standard Treatment Options for Stage IV Prostate Cancer

Standard treatment options for patients with stage IV prostate cancer include the following:
  1. Hormonal manipulations.
  2. Hormonal manipulations with chemotherapy.
  3. Bisphosphonates.
  4. External-beam radiation therapy (EBRT) with or without hormonal therapy.
  5. Palliative radiation therapy.
  6. Palliative surgery with TURP.
  7. Watchful waiting or active surveillance/active monitoring.

Hormonal manipulations

Hormonal treatment is the mainstay of therapy for metastatic (Jewett stage D2) prostate cancer. Cure is rarely, if ever, possible, but striking subjective or objective responses to treatment occur in most patients. The most effective hormonal approach employs a combination of androgen deprivation therapy (ADT) plus abiraterone acetate, an inhibitor of cytochrome P450c17, a critical enzyme in androgen biosynthesis.
  1. In the randomized, double-blind LATITUDE (NCT01715285) trial, 1,199 men with high-risk metastatic castration-sensitive prostate cancer were given ADT plus either abiraterone acetate (1,000 mg PO qd) and prednisone (5 mg PO qd) or ADT plus abiraterone-prednisone placebos.[3] High-risk disease was defined as having at least two of the following three factors: Gleason score of 8 or higher, three or more bone lesions, or measurable visceral metastases.
    • After a median follow-up of 30.4 months, the trial was stopped because of a clear overall survival (OS) benefit in the abiraterone study group: median survival not reached versus 34.7 months OS (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.51–0.76; P <.001).[3][Level of evidence: 1iA]
    • Abiraterone therapy was well tolerated, but there was an increase in the mineralocorticoid effects of grade 3 or 4 hypertension and hypokalemia compared with the placebo study group.
    • A collection of patient-reported outcomes and Health-Related Quality of Life (HRQOL) data showed clinical benefits in pain progression, prostate cancer–related symptoms, fatigue, functional decline, and overall HRQOL in the abiraterone-acetate study group compared with the placebo group.[4][Level of evidence: 1iC]
  2. In the randomized, open-label STAMPEDE trial, 1,917 men (about 95% newly diagnosed; about 50% had metastatic disease and about 50% had locally advanced or node-positive disease) were treated with ADT alone or ADT plus abiraterone acetate (1,000 mg PO qd) and prednisolone (5 mg PO qd).[5] Local radiation therapy was mandated after 6 to 9 months for men with node-negative nonmetastatic disease and optional for those with node-positive nonmetastatic disease. Hormone therapy was curtailed at 2 years or until progression. Radiation therapy was planned in about 40% of study participants.
    • With a median follow-up of 40 months, the 3-year OS was 83% in the abiraterone study group compared with 76% in the ADT-only study group (HRdeath, 0.63; 95% CI, 0.52–0.76; P< .001).[5][Level of evidence: 1iA] Although there was no clear evidence of heterogeneity in relative treatment differences in metastatic disease versus nonmetastatic disease, absolute differences were much smaller in men with nonmetastatic disease and not statistically significant, perhaps because of the short follow-up (HRdeath, 0.75; 95% CI, 0.49–1.18).
    • The main additional differences in toxicity associated with abiraterone compared with ADT alone were hypertension (5% vs. 1%), mild increase in blood aminotransferase levels (6% vs. < 1%), and respiratory disorders (5% vs. 2%).
Hormonal manipulations effectively used as initial therapy for prostate cancer include the following:[6]
  • Orchiectomy alone or with an androgen blocker as seen in the Southwest Oncology Group (SWOG-8894) trial.
  • Luteinizing hormone-releasing hormone (LH-RH) 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.[7-10][Level of evidence: 1iiA]
  • Leuprolide plus flutamide;[11] however, the addition of an antiandrogen to leuprolide has not been clearly shown in a meta-analysis to improve survival.[12]
  • Estrogens (diethylstilboestrol [DES], chlorotrianisene, ethinyl estradiol, conjugated estrogens-USP and DES-diphosphate). DES is no longer commercially available in the United States.
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.[13]
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 qd 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.[14] Combined orchiectomy and estrogens are not indicated to be superior to either treatment administered alone.[15]
A large proportion of men experience hot flushes after bilateral orchiectomy or treatment with LH-RH agonists. These hot flashes can persist for years.[16] 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.[17] 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.[18-20] Low-dose prednisone may palliate symptoms in about 33% of cases.[21] Newer hormonal approaches, such as inhibition of androgen receptors, have been shown to improve OS and quality of life (QOL) after tumor progression despite ADT. (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):
  1. 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/active monitoring, showed improved overall mortality with early treatment (relative risk, 0.86; 95% CI, 0.82–0.91).[22][Level of evidence: 1iiA]
  2. 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.[23][Level of evidence: 1iA]; [24]
    • After a median follow-up of 11.9 years, 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.[25]
  3. Another trial (RTOG-8531) with twice as many randomly assigned patients showed no difference in OS with early versus late hormonal manipulation.[26]
  4. 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.[27][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.
  5. Immediate hormonal treatment (e.g., orchiectomy or LH-RH agonist) 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.[28][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.
  6. 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).[29][Level of evidence: 1iiA]
    • Over a 12-year period of follow-up, no statistically significant difference was observed in OS.
Luteinizing hormone-releasing hormone (LH-RH) agonists or antiandrogens
Approaches using LH-RH agonists or antiandrogens in patients with stage IV prostate cancer have produced response rates similar to other hormonal treatments.[7,30]
Evidence (LH-RH agonists or antiandrogens):
  1. In a randomized trial, the LH-RH agonist leuprolide (1 mg subcutaneously [SQ] qd) was found to be as effective as DES (3 mg PO qd) in any T, any N, M1 patients, but caused less gynecomastia, nausea and vomiting, and thromboembolisms.[8]
  2. In other randomized studies, the depot LH-RH agonist goserelin was found to be as effective as orchiectomy [9,31,32] or DES at a dose of 3 mg qd.[30] A depot preparation of leuprolide, which is therapeutically equivalent to daily leuprolide, is available as a monthly or 3-monthly depot.
  3. A systematic evidence review compared nonsteroidal antiandrogen monotherapy with surgical or medical castration from 11 randomized trials in 3,060 men with locally advanced, metastatic, or recurrent disease after local therapy.[33] Use of nonsteroidal antiandrogens as monotherapy decreased OS and increased the rate of clinical progression and treatment failure.[33][Level of evidence: 1iiA]
  4. A small randomized study comparing 1 mg DES PO tid with 250 mg of flutamide tid 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 DES treatment.[34][Level of evidence: 1iA] A variety of combinations of hormonal therapy have been tested.
Maximal androgen blockade (MAB)
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 the case series led to widespread use of the strategy, known as MAB or total androgen blockade. Subsequent randomized controlled trials, however, cast doubt on the efficacy of adding an antiandrogen to castration.
Evidence (MAB):
  1. In a large, randomized, controlled trial comparing treatment with bilateral orchiectomy plus either the antiandrogen flutamide or placebo, no difference in OS was reported.[35][Level of evidence: 1iA]
    • Although it has been suggested that MAB may improve the more subjective endpoint of response rate, prospectively assessed QOL 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.[36][Level of evidence: 1iC]
  2. A meta-analysis of 27 randomized trials of 8,275 patients comparing conventional surgical or medical castration with 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.[12][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).[12]
  3. The Agency for Health Care Policy and Research (now the Agency for Healthcare Research and Quality) has performed a systematic review of the available randomized, clinical trial evidence of single hormonal therapies and total 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:[37][Level of evidence: 1iiA]
    • OS at 2 years using any of the LH-RH agonists is similar to treatment with orchiectomy or 3 mg every 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 with orchiectomy (HR, 1.22; 95% CI, 0.99–1.50).
    • Treatment withdrawals, used as a surrogate for adverse effects, occurred less with LH-RH agonists (0%–4%) than with nonsteroidal antiandrogens (4%–10%).
    Total 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.[38]
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 often given continuously until there is disease progression. Another option is intermittent androgen suppression as a strategy to attain maximal tumor cytoreduction followed by a period without therapy to allow treatment-free periods. Theoretically, this strategy might provide tumor hormone responsiveness for a longer period. An animal model suggested that intermittent androgen deprivation (IAD) could prolong the duration of androgen dependence of hormone-sensitive tumors.[39]
Evidence (continuous vs. intermittent hormonal therapy):
  1. A systematic review of 15 randomized trials that compared continuous versus intermittent ADT for patients with advanced or recurrent prostate cancer found no significant difference in OS, which was reported in eight of the trials (HR, 1.02; 95% CI, 0.93–1.11); prostate cancer-specific survival, reported in five of the trials (HR,1.02; 95% CI, 0.87–1.19); or progression-free survival (PFS), reported in four of the trials (HR, 0.94; 95% CI, 0.84–1.05). The meta-analysis fulfilled prespecified criteria for noninferiority of OS (upper bound of 1.15 for the HRdeath, 1.15).[40][Level of evidence: 1iiA] However, of the 15 trials, all but one had an unclear or high risk of bias according to prespecified criteria.
    • There was minimal difference in patient-reported QOL, but most trials found better physical and sexual functioning in patients in the IAD arms.

Hormonal manipulations with chemotherapy

The addition of chemotherapy has been shown in randomized trials to improve OS compared with ADT alone, with efficacy that appears to be comparable with hormonal therapy, which includes ADT plus abiraterone acetate. However, the two approaches have not been directly compared in a randomized study.
The addition of docetaxel has been tested in combination with long-term hormone therapy in the first-line management of metastatic prostate cancer and has been shown to improve results more than hormone therapy alone. A systematic evidence review and meta-analysis of randomized trials in hormone-sensitive metastatic prostate cancer summarizes these data.[41]
Evidence (hormonal manipulations with chemotherapy):
  1. In the analysis of three randomized trials (3,206 men), the HRdeath associated with the addition of docetaxel to standard of care was 0.77 (95% CI, 0.68–0.87; P < .0001), representing an absolute improvement of 9% in 4-year survival (95% CI, 5–14).[41][Level of evidence: 1iiA]
  2. In the CHAARTED trial (NCT00309985), 790 patients with metastatic, hormone-sensitive disease were randomly assigned to receive ADT with or without docetaxel (75 mg/m2 intravenously [IV] every 3 weeks for 6 cycles).[42,43] Previous adjuvant ADT was permissible if it lasted 12 months or less and progression had occurred within 12 months of completion. Patients were prospectively stratified as having a high- versus low-volume disease, with high volume defined as presence of visceral metastases or at least four bone lesions, with at least one lying outside the vertebral column or pelvis. About 65% of patients had high-volume disease by this definition.
    • With a median follow-up of 53.7 months, median OS in the ADT-plus-docetaxel arm was 57.6 months and in the ADT-alone arm, it was 47.2 months (HRdeath, 0.72; 95% CI, 0.59–0.89; P = .0018).[43][Level of evidence: 1iiA]
    • The survival advantage was observed only in patients with high-volume disease. In the group with high-volume disease, there was a clear improvement in median OS (61.2 months vs. 34.4 months) (HR, 0.63; 95% CI, 0.50–0.79; P < .001). However, there was no observed difference in survival in men with low-volume disease (median OS, 63.5 months vs. not reached) (HR, 1.04; 95% CI, 0.70–1.55; P = .86). The test for heterogeneity of efficacy was statistically significant (P = .033).
    • Comparison of QOL between the two study groups, as measured by the Functional Assessment of Cancer Therapy-Prostate (FACT-P) scale, was not found to exceed the prospectively defined minimally important difference at any time point over the 12 months of planned assessment.[44]

Bisphosphonates

In addition to hormonal therapy, adjuvant treatment with bisphosphonates has been tested.[45]
Evidence (bisphosphonates):
  1. 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 qd) or a matching placebo for up to 3 years.[45][Level of evidence: 1iA]
    • At a median follow-up of 11.5 years, OS was better in the clodronate arm: HRdeath, 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.
  2. A parallel study (MRC-PR04) in men with locally advanced but nonmetastatic disease showed no benefit associated with clodronate.
  3. CALGB-90202 [NCT00079001] was a randomized controlled trial that compared zoledronic acid (4 mg IV every 4 weeks) with placebo in 645 men with androgen deprivation-sensitive prostate cancer that was metastatic to bone. Patients who progressed on hormone-therapy resistance received open-label, zoledronic acid.[46][Level of evidence: 1iDiii]
    • There was no difference between the two study arms in risk of the primary endpoint of time to skeletal-related events (defined as the need for palliative bone radiation, clinical fracture, spinal cord compression, bone surgery, or death from prostate cancer) after up to 7 years of follow-up.
    • There were also no differences in PFS or OS.
  4. In another negative randomized trial, NCT00268476, 1,245 men with locally advanced (M0) or metastatic (M1) prostate cancer, who were initiating long-term hormonal therapy, were randomly assigned to one of three arms (ratio of 2:1:1): standard of care, celecoxib (400 mg bid for 1 year), and celecoxib plus zoledronic acid (4 mg IV for six 3-week cycles, then 4-week cycles for 2 years).[47]
    • After a median follow-up of 69 months, there was no detectable improvement in survival associated with either celecoxib or celecoxib plus zoledronic acid.
    • Although survival was better in patients with M disease who received celecoxib plus zoledronic acid than in patients with M1 disease who received the standard of care (HRdeath, 0.78; 95% CI, 0.62–0.98), a formal test for interaction with metastasis status was not statistically significant; therefore, the unexpected finding can only be considered hypothesis-generating.
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 qd) had no favorable impact on either time to symptomatic bone metastasis or survival.[48][Level of evidence: 1iA]

External-beam radiation therapy (EBRT) with or without hormonal therapy

EBRT may be used for attempted cure in highly selected stage M0 patients.[49,50] Definitive radiation therapy should be delayed 4 to 6 weeks after TURP to reduce incidence of stricture.[51]
Hormonal therapy should be considered in addition to EBRT.[38,52]
Evidence (radiation therapy with or without hormonal therapy):
  1. The Blue Cross and Blue Shield Association Technology Evaluation Center, an evidence-based practice center of the Agency for Healthcare Research and Quality (AHRQ), performed a systematic review of the available randomized clinical trial evidence comparing radiation therapy with radiation therapy and prolonged androgen suppression.[38][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 OS in favor of radiation therapy plus continued androgen suppression using an LH-RH agonist or orchiectomy compared with radiation therapy alone (HR, 0.63; 95% CI, 0.48–0.83).
    • 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.
  2. The duration of neoadjuvant hormonal therapy has been tested in a randomized trial (TROG 96.01 [ACTRN12607000237482]) of 818 men with locally advanced (T2b, T2c, T3, and T4), nonmetastatic cancer treated with radiation therapy (i.e., 66 Gy in 2 Gy daily fractions to the prostate and seminal vesicles but not including regional nodes). In an open-label design, patients were randomly assigned to radiation therapy alone, 3 months of neoadjuvant androgen deprivation therapy (NADT) (goserelin 3.6 mg SQ each month plus flutamide 250 mg PO tid) for 2 months before and during radiation, or 6 months of NADT for 5 months before and during radiation.[52][Level of evidence: 1iiA]
    • After a median follow-up of 10.6 years, there were no statistically significant differences between the radiation alone group and the radiation plus 3 months of NADT group.
    • However, the 6-month NADT arm showed better prostate cancer-specific mortality and overall mortality than radiation alone; 10-year all-cause mortality 29.2% versus 42.5% (HR, 0.63; 95% CI, 0.48–0.83, P = .0008).
  3. The duration of neoadjuvant hormonal therapy was tested in another trial (RTOG-9910 [NCT00005044]) of 1,489 eligible men with intermediate-risk prostate cancer (T1b–4, Gleason score 2–6, and PSA >10 but ≤100 ng/mL; T1b–4, Gleason score 7, and PSA <20; or T1b–1c, Gleason score 8–10, and PSA <20) and no evidence of metastases. The men were randomly assigned to receive short-course neoadjuvant–androgen suppression (an LHRH agonist plus bicalutamide or flutamide for 8 weeks before and 8 weeks during radiation therapy) or long-course neoadjuvant-androgen suppression (28 weeks before and 8 weeks during radiation therapy). Both groups received 70.2 Gy radiation in 39 daily fractions to the prostate and 46.8 Gy to the iliac lymph nodes.[53][Levels of evidence: 1iiA and 1iiB]
    • After a median of 9.4 years, 10-year prostate specific mortality, the primary endpoint, was low in both study arms: 5% versus 4% (HR, 0.81; 95% CI, 0.48–1.39).[53][Level of evidence: 1iiB]
    • No statistically significant differences in overall mortality or in locoregional disease progression were found.[53][Level of evidence: 1iiA]
    • There was also no apparent differential effect of androgen suppression duration among any of the risk-group subsets.

Palliative radiation therapy

A single fraction of 8 Gy has been shown to have similar benefits on bone pain relief and QOL as multiple fractions (3 Gy × 10) as was evidenced in the RTOG-9714 (NCT00003162) trial.[54]; [55][Level of evidence: 1iiC] (Refer to the PDQ summary on Cancer Pain for more information.)

Palliative surgery with transurethral resection of the prostate (TURP)

Transurethral resection of the prostate may be useful in relieving urinary obstruction as part of palliative care in advanced prostate cancer.

Watchful waiting or active surveillance/active monitoring

Careful observation without further immediate treatment (in selected asymptomatic patients).[56]

Treatment Options Under Clinical Evaluation for Stage IV Prostate Cancer

Treatment options under clinical evaluation for patients with stage IV prostate cancerinclude the following:
  1. Radical prostatectomy with immediate orchiectomy.
    • An uncontrolled, retrospective review of a large series of patients with any T, N1–3, M0 disease treated at the Mayo Clinic with concurrent radical prostatectomy and orchiectomy was associated with intervals to local and distant progression; however, increase in OS has not been demonstrated.[57] Patient selection factors make such study designs difficult to interpret.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
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  22. 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. [PUBMED Abstract]
  23. 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. [PUBMED Abstract]
  24. Eisenberger MA, Walsh PC: Early androgen deprivation for prostate cancer? N Engl J Med 341 (24): 1837-8, 1999. [PUBMED Abstract]
  25. 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. [PUBMED Abstract]
  26. 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. [PUBMED Abstract]
  27. 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. [PUBMED Abstract]
  28. 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. [PUBMED Abstract]
  29. 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. [PUBMED Abstract]
  30. 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. [PUBMED Abstract]
  31. 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. [PUBMED Abstract]
  32. 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. [PUBMED Abstract]
  33. Kunath F, Grobe HR, Rücker G, et al.: Non-steroidal antiandrogen monotherapy compared with luteinising hormone-releasing hormone agonists or surgical castration monotherapy for advanced prostate cancer. Cochrane Database Syst Rev (6): CD009266, 2014. [PUBMED Abstract]
  34. 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. [PUBMED Abstract]
  35. 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. [PUBMED Abstract]
  36. 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. [PUBMED Abstract]
  37. 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. [PUBMED Abstract]
  38. 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. [PUBMED Abstract]
  39. 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. [PUBMED Abstract]
  40. Magnan S, Zarychanski R, Pilote L, et al.: Intermittent vs Continuous Androgen Deprivation Therapy for Prostate Cancer: A Systematic Review and Meta-analysis. JAMA Oncol 1 (9): 1261-9, 2015. [PUBMED Abstract]
  41. Vale CL, Burdett S, Rydzewska LH, et al.: Addition of docetaxel or bisphosphonates to standard of care in men with localised or metastatic, hormone-sensitive prostate cancer: a systematic review and meta-analyses of aggregate data. Lancet Oncol 17 (2): 243-56, 2016. [PUBMED Abstract]
  42. Sweeney CJ, Chen YH, Carducci M, et al.: Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. N Engl J Med 373 (8): 737-46, 2015. [PUBMED Abstract]
  43. Kyriakopoulos CE, Chen YH, Carducci MA, et al.: Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer: Long-Term Survival Analysis of the Randomized Phase III E3805 CHAARTED Trial. J Clin Oncol 36 (11): 1080-1087, 2018. [PUBMED Abstract]
  44. Morgans AK, Chen YH, Sweeney CJ, et al.: Quality of Life During Treatment With Chemohormonal Therapy: Analysis of E3805 Chemohormonal Androgen Ablation Randomized Trial in Prostate Cancer. J Clin Oncol 36 (11): 1088-1095, 2018. [PUBMED Abstract]
  45. 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. [PUBMED Abstract]
  46. Smith MR, Halabi S, Ryan CJ, et al.: Randomized controlled trial of early zoledronic acid in men with castration-sensitive prostate cancer and bone metastases: results of CALGB 90202 (alliance). J Clin Oncol 32 (11): 1143-50, 2014. [PUBMED Abstract]
  47. Mason MD, Clarke NW, James ND, et al.: Adding Celecoxib With or Without Zoledronic Acid for Hormone-Naïve Prostate Cancer: Long-Term Survival Results From an Adaptive, Multiarm, Multistage, Platform, Randomized Controlled Trial. J Clin Oncol 35 (14): 1530-1541, 2017. [PUBMED Abstract]
  48. 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. [PUBMED Abstract]
  49. Bagshaw MA: External radiation therapy of carcinoma of the prostate. Cancer 45 (7 Suppl): 1912-21, 1980. [PUBMED Abstract]
  50. 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. [PUBMED Abstract]
  51. 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. [PUBMED Abstract]
  52. Denham JW, Steigler A, Lamb DS, et al.: Short-term neoadjuvant androgen deprivation and radiotherapy for locally advanced prostate cancer: 10-year data from the TROG 96.01 randomised trial. Lancet Oncol 12 (5): 451-9, 2011. [PUBMED Abstract]
  53. Pisansky TM, Hunt D, Gomella LG, et al.: Duration of androgen suppression before radiotherapy for localized prostate cancer: radiation therapy oncology group randomized clinical trial 9910. J Clin Oncol 33 (4): 332-9, 2015. [PUBMED Abstract]
  54. 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. [PUBMED Abstract]
  55. 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. [PUBMED Abstract]
  56. 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. [PUBMED Abstract]
  57. 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. [PUBMED Abstract]

Recurrent or Hormone-Resistant Prostate Cancer Treatment

Overview

In recurrent or hormone-resistant prostate cancer, the selection of further treatment depends on many factors, including:
  • Previous treatment.
  • Site of recurrence.
  • Coexistent illnesses.
  • Individual patient considerations.
Definitive radiation therapy can be given to patients with disease that fails only locally after prostatectomy.[1-4] A randomized trial (RTOG-9601 [NCT00002874]) has shown improved overall survival (OS) and prostate–cancer-specific survival with the addition of high-dose bicalutamide to radiation therapy compared with radiation therapy alone in men with locally recurrent prostate cancer after radical prostatectomy.[5]
  • In the trial, 760 men who were initially treated with radical prostatectomy for tumor stage T2 or T3, and who had a detectable prostate-specific antigen (PSA) level of 0.2 to 4.0 ng/mL, but no evidence of metastases, were randomly assigned to receive radiation (64.8 Gy over 36 fractions) and either bicalutamide (150 mg PO qd) or placebo for 24 months. The median interval from surgery to PSA detectability was 1.4 years and from surgery to randomization was 2.1 years. Median follow-up was 13 years.
  • Actuarial OS at 12 years was 76.3% in the bicalutamide group versus 71.3% in the placebo group (P = .04; hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.59–0.99).[5][Level of evidence: 1iA]
  • Prostate–cancer-specific mortality at 12 years was 5.8% (bicalutamide) versus 13.4% (placebo), (HR, 0.49; 95% CI, 0.32–0.74; P < .001).[5][Level of evidence: 1iB]
  • Most treatment-related toxicities were similar between the two groups, except for gynecomastia, which occurred in 69.7% of the men on bicalutamide versus 10.9% of those on placebo. This side effect may be mitigated by prophylactic breast irradiation, which was not used in this study because of the double-blinded design.
Some patients with a local recurrence after definitive radiation therapy can be salvaged with prostatectomy;[6] however, only about 10% of patients treated initially with radiation therapy will have local relapse only. In these patients, prolonged disease control is often possible with hormonal therapy, with median cancer-specific survival of 6 years after local failure.[7]
Cryosurgical ablation of recurrence after radiation therapy is associated frequently with a high complication rate. This technique is still undergoing clinical evaluation.[8]
Hormonal therapy is used to manage most relapsing patients with disseminated disease who initially received locoregional therapy with surgery or radiation therapy. (Refer to the Standard Treatment Options for Stage IV Prostate Cancer section of this summary for more information.)

Immediate Versus Deferred Hormonal Therapy

Refer to the Treatment Option Overview for Prostate Cancer section for information on the use of immediate hormonal therapy (bicalutamide or luteinizing hormone-releasing hormone [LH-RH] agonists) plus radiation in the setting of locally recurrent prostate cancer after radical prostatectomy.
PSA is often used to monitor patients after initial therapy with curative intent, and elevated or rising PSA is a common trigger for additional therapy even in asymptomatic men. Despite how common the situation is, it is not clear whether additional treatments given because of rising PSA in asymptomatic men with prostate cancer increase OS. The quality of evidence is limited.
  1. After radical prostatectomy, detectable PSA levels identify patients at elevated risk of local treatment failure or metastatic disease;[9] however, a substantial proportion of patients with elevated or rising PSA levels after initial therapy with curative intent may remain clinically free of symptoms for extended periods.[10] In a retrospective analysis of nearly 2,000 men who had undergone radical prostatectomy with curative intent and who were followed for a mean of 5.3 years, 315 men (15%) demonstrated an abnormal PSA of 0.2 ng/mL or higher, which is evidence of biochemical recurrence.[11]
    • Of these 315 men, 103 men (34%) developed clinical evidence of recurrence.
    • The median time to development of clinical metastasis after biochemical recurrence was 8 years.
    • After the men developed metastatic disease, the median time to death was an additional 5 years.
  2. After radiation therapy with curative intent, persistently elevated or rising PSA may be a prognostic factor for clinical disease recurrence. However, reported case series have used a variety of definitions of PSA failure. Criteria have been developed by the American Society for Therapeutic Radiology and Oncology Consensus Panel.[12,13] The implication of the various definitions of PSA failure for OS is not known, and as in the surgical series, many biochemical relapses (rising PSA alone) may not be clinically manifested in patients treated with radiation therapy.[14,15]
  3. A randomized trial (PMCC-VCOG-PR-0103 [NCT00110162]) of androgen deprivation therapy (ADT) in men who received curative therapy but have a rising PSA, provides some evidence of improved OS associated with immediate versus delayed therapy.[16] The study had important shortcomings.
    1. Two groups of men were randomly assigned to open-label, immediate-versus-delayed (at least 2-year delay) ADT:
      • Group 1 included men who had a PSA relapse after curative therapy (89% of the study population).
      • Group 2 included asymptomatic men who were considered unsuitable for curative treatment because of age, comorbidity, or locally advanced disease (11% of the study population).
      Planned accrual was 750 patients, but because of slow accrual, the trial closed at 293 patients.
    2. In groups 1 and 2 combined, with a median follow-up of 5 years, the 5-year OS rate was 86.4% in the delayed ADT study arm versus 91.2% in the immediate ADT study arm (log rank, P = .047).[16][Level of evidence: 1iiA] After full adjustment for baseline characteristics, the HR for OS was 0.54 (95% CI, 0.27–1.06; P = .074).
    3. For group 1 only (those with PSA relapse after curative therapy, N = 261), the estimated 5-year survival rate was 78.2% versus 84.3% with delayed-versus-immediate ADT (log rank, P = .10; fully adjusted HR, = 0.59; 95% CI, 0.26–1.30, P= .19).
    4. Toxicity was greater in the immediate ADT study arm compared with delayed therapy. Serious (grade 4) adverse events were reported in 42% of patients in the immediate ADT study arm versus 31% of patients in the delayed therapy arm. Quality of life (QOL) fell by 6.1% (considered a small but clinically importantdrop) with immediate ADT versus 3% with delayed ADT (considered a trivialdrop); but this was not a statistically significant difference (P = .14).[16] Sexual activity was lower and hormone-related symptoms (hot flashes and sore or enlarged nipples) were clinically and statistically significantly worse in the immediate ADT arm compared with the delayed therapy arm.[17]

Hormonal Therapy for Recurring Disease

Nonsteroidal antiandrogen monotherapy versus surgical or medical castration

A systematic evidence review compared nonsteroidal antiandrogen monotherapy with surgical or medical castration from 11 randomized trials in 3,060 men with locally advanced, metastatic, or recurrent disease after local therapy.[18] Use of nonsteroidal antiandrogens as monotherapy decreased OS and increased the rate of clinical progression and treatment failure.[18][Level of evidence: 1iiA]

Continuous versus intermittent hormonal therapy

Most men who are treated for recurrence after initial local therapy are asymptomatic, and the recurrence is detected by a rising PSA. It is possible that intermittent androgen deprivation (IAD) therapy can be used as an alternative to continuous androgen deprivation (CAD) therapy (ADT) to improve QOL and decrease the amount of time during which the patient experiences the side effects of hormonal therapy, without decreasing the survival rate.
  1. This important clinical question was addressed in a noninferiority-designed, randomized, controlled trial with 1,386 men who had rising PSA levels (>3 ng/mL, with serum testosterone >5 nmol/L) more than 1 year after primary or salvage radiation therapy for localized prostate cancer.[19][Levels of evidence: 1iiA, 1iiB, 1iiC]
    • The ADT arm consisted of 8-month treatment cycles with a LH-RH agonist (combined with a nonsteroidal antiandrogen for at least the first 4 weeks) that was reinstituted if the PSA level exceeded 10 ng/mL. The study was powered to detect (with 95% confidence) an 8% lower OS rate in the IAD group compared with the CAD group at 7 years.
    • After a median follow-up of 6.9 years (maximum follow-up 11.2 years), OS in the two groups was nearly identical, and the study was stopped (median survival, 8.8 vs. 9.1 years; HRdeath, 1.02; 95% CI, 0.86–1.21). This fulfilled the prospective criterion of noninferiority.
    • In a retrospective analysis, prostate–cancer-specific mortality was also similar in the two arms (HR, 1.18; 95% CI, 0.90–1.55; P = 0.24). In addition, IAD was statistically significantly better than CAD in several QOL domains, such as hot flashes, desire for sexual activity, and urinary symptoms. Patients on the IAD study arm received a median of 15.4 months of treatment versus 43.9 months on the CAD arm.
    • The study does not address the unanswered question about whether the initiation of any ADT for an elevated PSA after initial local therapy extends survival compared with delay until clinically symptomatic progression. Of note, 59% of all deaths were unrelated to prostate cancer, and only 14% of all patients died of prostate cancer.
  2. A systematic review of 15 randomized trials that compared continuous versus IAD therapy for patients with advanced or recurrent prostate cancer found no significant difference in OS, which was reported in eight of the trials (HR, 1.02; 95% CI, 0.93–1.11); prostate–cancer-specific survival, reported in five of the trials (HR, 1.02; 95% CI, 0.87–1.19); or progression-free survival (PFS), reported in four of the trials (HR, 0.94; 95% CI, 0.84–1.05). The meta-analysis fulfilled prespecified criteria for noninferiority of OS (upper bound of 1.15 for the HR of 1.15).[20][Level of evidence: 1iiA] However, of the 15 trials, all but one had an unclear or high risk of bias according to prespecified criteria.
    • There was minimal difference in patient-reported QOL, but most trials found better physical and sexual functioning in patients in the IAD arms.

Hormonal approaches

As noted above, studies have shown that chemotherapy with docetaxel or cabazitaxel and immunotherapy with sipuleucel-T can prolong OS in patients with hormone-resistant metastatic prostate cancer. Nevertheless, hormonal therapy has also been shown to improve survival even in men who have progressed after other forms of hormonal therapy as well as chemotherapy. Some forms of hormonal therapy are effective in the management of metastatic hormone–refractory prostate cancer.
Evidence (hormonal approaches):
  1. Abiraterone acetate is an inhibitor of androgen biosynthesis that works by blocking cytochrome P450c17 (CYP17). Abiraterone has mineralocorticoid effects, producing an increased incidence of fluid retention and edema, hypokalemia, hypertension, and cardiac dysfunction. In addition, abiraterone is associated with hepatotoxicity.[21] However, compared with other therapies, abiraterone toxicities are mild. In a double-blinded placebo-controlled trial, 1,088 men with progressing hormone refractory disease (serum testosterone <50 ng per deciliter on previous antiandrogen therapy), no previous chemotherapy, and Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 to 1 were given prednisone (5 mg PO bid) plus either abiraterone acetate (1,000 mg PO qd) or placebo.[22,23][Level of evidence: 1iA] The coprimary endpoints were radiologic PFS and OS. Four sequential analyses were planned.
    • At the second interim analysis, after a median follow-up of 22.2 months, the study was stopped and unblinded because of aggregate efficacy and safety as assessed by the data monitoring committee. At that point, the radiologic PFS had reached the prespecified stopping boundary in favor of abiraterone (median PFS, 16.5 months vs. 8.3 months [HR, 0.53; 95% CI, 0.45–0.62; P < .001]).
    • At the fourth (and final) analysis with a median follow-up of 49.2 months (maximum 60 months), 65% had died in the abiraterone-acetate study arm and 71% had died in the placebo study arm (HR, 0.81; 95% CI, 0.70–0.93: P = .033). Median OS was 34.7 versus 30.3 months.[23][Level of evidence: 1iA]
    • Median time to health-related QOL deterioration was long in the abiraterone study arm, as assessed by the Functional Assessment of Cancer Therapy-Prostate Version 4 (FACT-P) total score (12.7 months vs. 8.3 months; HR, 0.78; 95% CI, 0.66-0.92; P = .003) and by the prostate–cancer-specific subscale (11.1 months vs. 5.8 months; HR, 0.70; 95% CI, 0.60–0.83; P < .0001).[24][Level of evidence: 1iC]
    • In addition, patients in the abiraterone study group had statistically significant longer median times to opiate use for pain, initiation of cytotoxic chemotherapy, decline in PS, and PSA progression.[22,24][Levels of evidence: 1iC and 1iDiii]
  2. Men with metastatic prostate cancer who had biochemical or clinical progression after treatment with docetaxel (N = 1,195) were randomly assigned in a 2:1 ratio to receive either abiraterone acetate (1,000 mg) (n = 797) or placebo (n = 398) PO qd (COU-AA-301 [NCT00638690]). Both groups received prednisone (5 mg PO bid).[25][Level of evidence; 1iA]
    • After a median follow-up of 12.8 months, the trial was stopped when an interim analysis showed an OS advantage in the abiraterone group. The final report of the trial was published after a median follow-up of 20.2 months.
    • Median OS was 15.8 months in the abiraterone group versus 11.2 months in the placebo group (HRdeath, 0.74; 95% CI, 0.64–0.86; P < .0001).
    • Compared with placebo, abiraterone was also associated with delay in median time to deterioration in the FACT-P QOL score (59.9 weeks vs. 36.1 weeks, P < .0001) and clinically important improvement in QOL in men with functional status impairment at baseline (48% vs. 32%, P < .0001).[26][Level of evidence: 1iC]
  3. Enzalutamide, an androgen-receptor signaling inhibitor, has been shown to increase OS and QOL in men with metastatic prostate cancer that has progressed despite ADT. In the PREVAIL (NCT03260517) study, 1,717 asymptomatic or mildly symptomatic men with recurrent metastatic prostate cancer despite ADT were randomly assigned to receive enzalutamide (160 mg PO qd) versus placebo.[27,28][Levels of evidence: 1iA, 1iC]
    • After a median follow-up of 22 months, the study was stopped because of an OS benefit in the enzalutamide study arm (HR, 0.72; 95% CI, 0.6–0.84; P < .001). The proportion of men who had died was 28% versus 35%, and the median OS was 32.4 versus 30.2 months.
    • Median time until decline in global QOL, measured by the FACT-P score, was 11.3 months versus 5.6 months in the enzalutamide and placebo groups (P < .001), and delayed occurrence of first skeletal-related event requiring clinical intervention was also shown.[27,28][Levels of evidence: 1iC, 1iDi]
    • Grade 3 or worse adverse events were more common in the enzalutamide group (43% vs. 37%), primarily because of differences in hypertension, fatigue, and falls. Because patients receiving enzalutamide were on assigned therapy for an average of 1 year longer than those on placebo, the duration of response was longer in patients receiving enzalutamide, and this difference may have contributed to the increase in adverse events.
  4. Enzalutamide has also been shown to increase survival in patients with progressive prostate cancer who previously received ADT as well as docetaxel. In a double-blind, placebo-controlled trial, 1,129 men were randomly assigned in a 2:1 ratio to receive enzalutamide (160 mg PO qd) versus placebo.[29-32][Levels of evidence: 1iA, 1iC]
    • After a median follow-up of 14.4 months, the study was stopped at the single-planned interim analysis because improved OS, the primary endpoint, was found in the enzalutamide study group (median OS, 18.4 months; 95% CI, 17.3 to not-yet-reached vs. 13.6 months; 95% CI, 11.3–15.8; HRdeath, 0.63; 95% CI, 0.53–0.75; P < .001). In addition, QOL, measured by the FACT-P questionnaire, was superior in the enzalutamide arm, as was time to first skeletal-related event.[30,32]
    • A seizure was reported in five of the 800 men in the enzalutamide study group versus none in the placebo group; however, the relationship to enzalutamide is not clear. Of the reported seizures, two patients had brain metastases, one patient had just received intravenous (IV) lidocaine, and one seizure was not witnessed.
  5. Apalutamide, a competitive inhibitor of the androgen receptor, has been tested in the setting of clinically nonmetastatic, hormone-resistant prostate cancer (defined as PSA doubling time ≤10 months while undergoing hormonal therapy).[33]
    • In the trial, 1,207 men were randomly assigned in a 2:1 ratio to either daily apalutamide (240 mg PO) or a placebo. All continued their previous ADT. With a median follow-up of 20.3 months, metastasis-free survival was 40.5 months in the apalutamide group compared with 16.2 months on placebo (HR, 0.28; 95% CI, 0.23–0.35; P < .001).[33][Level of evidence: 1iDii]
    • There was a trend toward improved OS in the apalutamide group, but it did not reach statistical significance at the time of the report (HR, 0.70; 95% CI, 0.47–1.04; P = .07).
    • There were increases in a number of toxicities associated with apalutamide treatment, which included the following: bone fractures (11.7% vs. 6.5%), hypothyroidism (8.1% vs. 2.0%), fatigue (30.4% vs. 21.1%), hypertension (24.8% vs. 19.8%), rash (23.8% vs. 5.5%), diarrhea (20.3% vs. 15.1%), weight loss (16.1% vs. 6.3%), arthralgias (15.9% vs. 7.5%), and falls (15.6% vs. 9.0%).
Because there are no head-to-head comparisons, there are no trials to help decide which of these agents should be used first or in what sequence.
Even among patients with metastatic hormone-refractory prostate cancer, some heterogeneity is found in prognosis and in retained hormone sensitivity. In such patients who have symptomatic bone disease, several factors are associated with worsened prognosis: poor performance status, elevated alkaline phosphatase, abnormal serum creatinine, and short (<1 year) previous response to hormonal therapy.[34] The absolute level of PSA at the initiation of therapy in relapsed or hormone-refractory patients has not been shown to be of prognostic significance.[35]
Some patients whose disease has progressed on combined androgen blockade can respond to a variety of second-line hormonal therapies. Aminoglutethimide, hydrocortisone, flutamide withdrawal, progesterone, ketoconazole, and combinations of these therapies have produced PSA responses in 14% to 60% of patients treated and have also produced clinical responses of 0% to 25% when assessed. The duration of these PSA responses has been in the range of 2 to 4 months.[36] Survival rates are similar whether ketoconazole plus hydrocortisone is initiated at the same time as antiandrogen (e.g., flutamide, bicalutamide, or nilutamide) withdrawal or when PSA has risen after an initial trial of antiandrogen withdrawal as seen in the CLB-9583 (NCT00002760) trial, for example.[37][Level of evidence: 1iiA] Data on whether PSA changes while on chemotherapy are predictive of survival are conflicting.[35,38]
Patients treated with either luteinizing-hormone agonists or estrogens as primary therapy are generally maintained with castrate levels of testosterone. One study from ECOG showed that a superior survival resulted when patients were maintained on primary androgen deprivation;[9] however, another study from SWOG (formerly the Southwest Oncology Group) did not show an advantage to continued androgen blockade.[39]

Prevention of bone metastases

Painful bone metastases can be a major problem for patients with prostate cancer. Many strategies have been studied for palliation, including:[40-44]
  • External-beam radiation therapy (EBRT).
  • Bone-seeking radionuclides (strontium chloride Sr 89 [89Sr]).
  • Denosumab (a monoclonal antibody that inhibits osteoclast function).
  • Pain medication.
  • Corticosteroids.
  • Bisphosphonates.
(Refer to the PDQ summary on Cancer Pain for more information.)
Evidence (palliation for bone metastases using radiation therapy):
  1. EBRT for palliation of bone pain can be very useful. A single fraction of 8 Gy has been shown to have similar benefits on bone pain relief and QOL as multiple fractions (3 Gy × 10) was seen in the RTOG-9714 (NCT00003162) trial, for example.[45,46][Level of evidence: 1iiC]
Evidence (palliation for bone metastases using strontium chloride):
The use of radioisotopes such as 89Sr has been shown to be effective as palliative treatment of some patients with osteoblastic metastases. As a single agent, 89Sr has been reported to decrease bone pain in 80% of patients treated.[47]
  1. A multicenter randomized trial of a single IV dose of 89Sr (150 MBq: 4 mCi) versus palliative EBRT was done in men with painful bone metastases from prostate cancer despite hormone treatment.[48][Level of evidence: 1iiA]; [49]
    • Similar subjective pain response rates were shown in both groups: 34.7% for 89Sr versus 33.3% for EBRT alone.
    • OS was better in the EBRT group than in the 89Sr group (P = .046; median survival, 11.0 months vs. 7.2 months).
    • No statistically significant differences in time to subjective progression or in PFS were seen.
    • When used as an adjunct to EBRT, 89Sr was shown to slow disease progression and to reduce analgesic requirements, compared with EBRT alone.
Evidence (palliation or prevention of bone metastases using denosumab):
  1. A placebo-controlled randomized trial (NCT00321620) compared denosumab with zoledronic acid for the prevention of skeletal events (pathologic fractures, spinal cord compression, or the need for palliative bone radiation or surgery) in men with hormonal therapy-resistant prostate cancer with at least one bone metastasis.[40]
    • The trial reported that denosumab was more effective than zoledronic acid; median time to first on-study skeletal event was 20.7 versus 17.1 months (HR, 0.82; 95% CI, 0.71–0.95).
    • Serious adverse events were reported in 63% of denosumab patients versus 60% in patients on zoledronic acid. The cumulative incidence of osteonecrosis of the jaw was low in both study arms (2% in the denosumab arm vs. 1% in the zoledronic acid arm). There was grade 3 to 4 toxicity. There was no difference in survival. The incidence of hypocalcemia was higher in the denosumab arm (13% vs. 6%).[50]
  2. A randomized, placebo-controlled trial included 1,432 men with castration-resistant prostate cancer with no evidence of any metastases who were given denosumab (120 mg administered subcutaneously every 4 weeks) to prevent the first evidence of bone metastasis (whether symptomatic or not).[50][Level of Evidence: 1iDiii]
    • After a median follow-up of 20 months, median bone metastasis-free survival was 29.5 versus 25.2 months in the denosumab versus placebo arms (HR, 0.85; 95% CI, 0.73–0.98; P = .028).
    • Symptomatic bone metastases were reported in 69 (10%) denosumab patients versus 96 (13%) placebo patients (HR, 0.67; 95% CI, 0.49–0.92; P = .01).
    • There were no differences in OS between the two groups.
    • Osteonecrosis occurred in 33 (5%) of men on the denosumab arm versus none on the placebo arm. Hypocalcemia occurred in 12 (2%) versus 2 (<1%) men, and urinary retention in 54 (8%) of men on denosumab versus 31 (4%) of men on placebo.

Treatment Options for Recurrent Prostate Cancer

Treatment options for patients with recurrent prostate cancer include the following:

Chemotherapy for hormone-resistant prostate cancer

Evidence (chemotherapy for hormone-resistant prostate cancer):
  1. A randomized trial showed improved pain control in patients with hormone-resistant prostate cancer treated with mitoxantrone plus prednisone compared with those treated with prednisone alone.[51] Differences in OS or measured global QOL between the two treatments were not statistically significant.
  2. Docetaxel has been shown to improve OS compared with mitoxantrone. In a randomized trial involving patients with hormone-refractory prostate cancer, docetaxel (75 mg/m2 every 3 weeks) and docetaxel (30 mg/m2 weekly for 5 out of every 6 weeks) were compared with mitoxantrone (12 mg/m2 every 3 weeks). All patients received oral prednisone (5 mg bid). Patients in the docetaxel arms also received high-dose dexamethasone pretreatment for each docetaxel administration (8 mg given at 12 hours, 3 hours, and 1 hour before the 3-week regimen; 8 mg given at 1 hour before the 5 out-of-every-6 weeks' regimen).[52]
    • OS at 3 years was statistically significantly better in the 3-weekly docetaxel arm (18.6%) than in the mitoxantrone arm (13.5%, HRdeath, 0.79; 95% CI, 0.67–0.93).
    • However, the OS rate for the 5 out-of-every-6 weeks' docetaxel regimen was 16.8%, which was not statistically significantly better than mitoxantrone.
    • QOL was also superior in the docetaxel arms compared with mitoxantrone (P = .009).[53][Levels of evidence: 1iiA, 1iiC]
  3. In another randomized trial involving patients with hormone-refractory prostate cancer, a 3-week regimen of estramustine (280 mg PO tid for days 1 to 5, plus daily warfarin and 325 mg aspirin to prevent vascular thrombosis), and docetaxel (60 mg/m2 intravenously [IV] on day 2, preceded by dexamethasone [20 mg × 3 starting the night before]) was compared with mitoxantrone (12 mg/m2 IV every 3 weeks) plus prednisone (5 mg qd).[54][Level of evidence: 1iiA]
    • After a median follow-up of 32 months, median OS was 17.5 months in the estramustine/docetaxel arm versus 15.6 months in the mitoxantrone arm (HRdeath, 0.80; 95% CI, 0.67–0.97; P = .02).
    • Global QOL and pain palliation measures were similar in the two treatment arms.[55][Level of evidence: 1iiC]
  4. A 2-weekly regimen of docetaxel has been compared with a 3-weekly regimen. OS appeared to be better in the 2-week regimen, and hematologic toxicity was less.[56][Level of evidence: 1iiA]
    • In the trial, 361 men with metastatic hormone-resistant prostate cancer were randomly assigned to receive docetaxel either in a 2-weekly regimen (50 mg/m2 IV) or a 3-weekly regimen (75 mg/m2 IV) until progression. All patients were also to receive prednisolone (10 mg PO qd) and dexamethasone (7.5–8.0 mg qd), starting the day before and continuing for 1 to 2 days after each docetaxel dose. Fifteen randomly assigned patients (4.2%) were thought to be ineligible in retrospect or withdrew consent, and they were dropped from the analysis.
    • With a median follow-up of 18 months, there was a small difference in time to treatment failure, the primary endpoint of the study (5.6 months [95% CI, 5.0–6.2] vs. 4.9 months [95% CI, 4.5–5.4]; P = .014). However, there was a larger difference in median OS, a secondary endpoint, in favor of the 2-week regimen (19.5 months [95% CI, 15.9–23.1] vs. 17.0 months [95% CI, 15.0 –19.1]; P = .02).
    • There was a lower rate of grade 3 to 4 neutropenia with the 2-week regimen (36% vs. 53%; P < .0001) and a lower rate of febrile neutropenia (4% vs. 14%; P = .001).
  5. In patients with metastatic hormone/castrate-refractory prostate cancer (mCRPC) and no prior chemotherapy, cabazitaxel and docetaxel appeared to provide similar results with respect to OS.[57]
    • In the FIRSTANA trial (NCT01308567), 1,168 men with mCRPC were randomly assigned (1:1:1 ratio) to receive cabazitaxel 20 mg/m2, cabazitaxel 25 mg/m2, or docetaxel 75 mg/m2 IV every 3 weeks (plus prednisone 10 mg PO qd) until disease progression. Median OS was similar across all three study arms and not statistically significantly different (24.5 vs. 25.2 vs. 24.3 months, respectively), with virtually overlapping survival curves.[57][Level of evidence; 1iiA]
    • However, toxicities varied across the study arms, with adverse event rates of 41.2%, 60.1%, and 46.0%, respectively, which required urgent treatment.
  6. In patients with mCRPC whose disease progressed during or after treatment with docetaxel, cabazitaxel was shown to improve survival compared with mitoxantrone in a randomized trial (NCT00417079).[58] In this trial, 755 such men were treated with prednisone (10 mg PO qd) and randomly assigned to receive either cabazitaxel (25 mg/m2 IV) or mitoxantrone (12 mg/m2 IV) every 3 weeks.[58][Level of evidence; 1iiA]
    • Median OS was 15.1 months in the cabazitaxel arm and 12.7 months in the mitoxantrone study arm (HRdeath, 0.70; 95% CI, 0.59–0.83; P < .0001).
  7. In a noninferiority-design randomized trial comparing cabazitaxel (20 mg/m2 IV every 3 weeks) with cabazitaxel (25 mg/m2 IV every 3 weeks) in a similar population of 1,200 men with mCRPC who had received prior docetaxel, the lower dose of cabazitaxel fulfilled noninferiority criteria with respect to OS (HRdeath, 1.024; CI, upper bound at 1.184), but with less toxicity.[59][Level of evidence; 1iiA]
Other chemotherapy regimens reported to produce subjective improvement in symptoms and reduction in PSA level include the following:[60][Level of evidence: 3iiiDiii]; [61]
  • Paclitaxel.
  • Estramustine/etoposide.
  • Estramustine/vinblastine.
  • Estramustine/paclitaxel.
A study suggests that patients whose tumors exhibit neuroendocrine differentiation are more responsive to chemotherapy.[62]

Immunotherapy

Sipuleucel-T, an active cellular immunotherapy, has been shown to increase OS in patients with hormone-refractory metastatic prostate cancer. Sipuleucel-T consists of autologous peripheral blood mononuclear cells that have been exposed ex vivo to a recombinant fusion protein (PA2024) composed of prostatic acid phosphatase fused to granulocyte-macrophage colony-stimulating factor.
Side effects are generally consistent with cytokine release and include chills, fever, headache, myalgia, sweating, and influenza-like symptoms, usually within the first 24 hours of infusion. No increase in autoimmune disorders or secondary malignancies has been noted.[63]
Evidence (immunotherapy):
  1. In the largest trial (Immunotherapy for Prostate Adenocarcinoma Treatment: IMPACTtrial [NCT00065442]), 512 patients with hormone-refractory metastatic disease were randomly assigned in a 2:1 ratio to receive sipuleucel-T (n = 341) versus placebo (n = 171) by IV in a 60-minute infusion every 2 weeks for a total of 3 doses.[64] Patients with visceral metastases, pathologic bone fractures, or ECOG performance status worse than 0–1 were excluded from the study. At documented disease progression, patients in the placebo group could receive, at the physician’s discretion, infusions manufactured with the same specifications as sipuleucel-T but using cells that had been cryopreserved at the time that the placebo was prepared (63.7% of the placebo patients received these transfusions). Time to disease progression and time to development of disease-related pain were the initial primary endpoints, but the primary endpoint was changed before unblinding based upon survival differences in two previous trials of similar design (described below).[64][Level of evidence: 1iA]
    • After a median follow-up of 34.1 months, the overall mortality was 61.6% in the sipuleucel-T group versus 70.8% in the placebo group (HRdeath, 0.78; 95% CI, 0.61–0.98; P = .03). However, the improved survival was not accompanied by measurable antitumor effects.
    • There was no difference between the study groups in rate of disease progression. In 2011, the estimated price of sipuleucel-T was $93,000 for a 1-month course of therapy. This translates into an estimated cost of about $276,000 per year-of-life saved.[65]
  2. The same investigators previously performed two smaller trials (NCT00005947) of nearly identical design to the IMPACT trial.[66,67]
    • The combined results of the two smaller trials, involving a total of 225 patients randomly assigned in a 2:1 ratio of sipuleucel-T to placebo were like those in the IMPACT trial. The HRdeath was 0.67 (95% CI, 0.49–0.91), but the time-to-progression rates were not statistically significantly different.
Low-dose prednisone may palliate symptoms in some patients.[68]
Evidence (low-dose prednisone for palliation):
  1. A randomized comparison of prednisone (5 mg qid) with flutamide (250 mg tid) was conducted in patients with disease progression after androgen ablative therapy (castration or LH-RH agonist).[69]
    • Prednisone and flutamide produced similar OS, symptomatic response, PSA response, and time to progression; however, there were statistically significant differences in pain, nausea and vomiting, and diarrhea in patients who received prednisone. (Refer to the PDQ summaries on Cancer Pain and Treatment-Related Nausea and Vomiting; refer to the PDQ summary on Gastrointestinal Complications for information on diarrhea.)
Ongoing clinical trials continue to explore the value of chemotherapy for these patients.[10-13,51,60-62]

Radiopharmaceutical Therapy

Alpha emitter radiation

Radium Ra 223 (223Ra) emits alpha particles (i.e., two protons and two neutrons bound together, identical to a helium nucleus) with a half-life of 11.4 days. It is administered by IV and selectively taken up by newly formed bone stroma. The high-energy alpha particles have a short range of <100 mcM. 223Ra improved OS in patients with prostate cancer metastatic to the bone.
Evidence (alpha emitter radiation):
  1. In a placebo-controlled trial, 921 men with symptomatic castration-resistant prostate cancer, two or more bone metastases, and no known visceral metastases, were randomly assigned in a 2:1 ratio to receive 223Ra at a dose of 50kBq per kg body weight every 4 weeks for six injections versus placebo. All study participants had already received docetaxel, were not healthy enough to receive it, or declined it.[70,71]
    • Median OS was 14.9 months in the 223Ra study group versus 11.3 months in the placebo groups (HRmortality, 0.70; 95% CI, 0.58–0.83; P < .001).[70][Level of evidence: 1iA]
    • The rates of symptomatic skeletal events (33% vs. 38%) and spinal cord compression (4% vs. 7%) were also statistically significantly improved.
    • Prospectively measured, QOL was also better in the 223Ra study group (25% vs. 16% had a ≥10 point improvement on a scale of 0 to 156; P = .02).[70][Level of evidence: 1iC]
    • With administration of 223Ra at a dose of 50kBq per kg of body weight every 4 weeks for 6 injections, the side effects were like those of a placebo.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
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  68. 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. [PUBMED Abstract]
  69. Fosså SD, Slee PH, Brausi M, et al.: Flutamide versus prednisone in patients with prostate cancer symptomatically progressing after androgen-ablative therapy: a phase III study of the European organization for research and treatment of cancer genitourinary group. J Clin Oncol 19 (1): 62-71, 2001. [PUBMED Abstract]
  70. Parker C, Nilsson S, Heinrich D, et al.: Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 369 (3): 213-23, 2013. [PUBMED Abstract]
  71. Sartor O, Coleman R, Nilsson S, et al.: Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial. Lancet Oncol 15 (7): 738-46, 2014. [PUBMED Abstract]

Key References for Prostate Cancer

These references have been identified by members of the PDQ Adult Treatment Editorial Board as significant in the field of prostate cancer treatment. This list is provided to inform users of important studies that have helped shape the current understanding of and treatment options for prostate cancer. Listed after each reference are the sections within this summary where the reference is cited.

Changes to This Summary (02/05/2019)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
General Information About Prostate Cancer
Updated statistics with estimated new cases and deaths for 2019 (cited American Cancer Society as reference 15).
Stage Information for Prostate Cancer
Editorial changes were made to this section.
This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of prostate cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewer for Prostate Cancer Treatment is:
  • Timothy Gilligan, MD (Cleveland Clinic Taussig Cancer Institute)
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”
The preferred citation for this PDQ summary is:
PDQ® Adult Treatment Editorial Board. PDQ Prostate Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/prostate/hp/prostate-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389471]
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.
  • Updated: February 5, 2019
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