martes, 24 de septiembre de 2019

Prostate Cancer Treatment (PDQ®) 7/8 –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's 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 prostate cancer. Cure is rarely, if ever, possible, but striking subjective or objective responses to treatment occur in most patients. The cornerstone of hormonal therapy for prostate cancer is medical or surgical castration to stop the production of testosterone by the testes. This is commonly referred to as androgen deprivation therapy (ADT) and can be achieved with bilateral orchiectomy or with administration of gonadotropin-releasing hormone (GnRH) agonists or antagonists. The most effective purely hormonal approach employs a combination of ADT and one of the following agents:
  • Abiraterone acetate, an inhibitor of cytochrome P450c17, a critical enzyme in androgen biosynthesis.
  • Apalutamide, a competitive inhibitor of the androgen receptor.
  • Enzalutamide, an androgen-receptor signaling inhibitor.
Randomized controlled trials have reported that combination therapy with any one of these drugs plus ADT results in longer overall survival than does ADT alone.
  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 (NCT00268476), 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%).
  3. In the randomized, controlled, double-blind phase III TITAN trial (NCT02489318), 1,052 men with metastatic, castration-sensitive prostate cancer were randomly assigned to receive ADT alone or ADT plus either apalutamide (240 mg PO qd) or placebo.[6]
    • Two-year OS was 82.4% in the apalutamide group compared to 73.5% in the placebo group (HR, 0.67; 95% CI, 0.51−0.89).
    • Radiographic progression-free survival (PFS) was 68.2% in the apalutamide group compared to 47.5% in the placebo group (HR, 0.48; 95% CI, 0.39−0.60).
    • Grade 3 or 4 adverse events were reported in 42.2% of patients in the apalutamide group and 40.8% of patients in the placebo group.
    • Apalutamide has been associated with an increased risk of seizure, so men with a history of or predisposition to seizures were excluded from this trial.
  4. In the randomized, controlled, open-label phase III ENZAMET trial (NCT02446405), 1,125 men with castrate-sensitive prostate cancer were randomly assigned to receive ADT alone or ADT plus enzalutamide (160 mg PO qd).[7]
    1. Three-year OS was 80% in the combined-therapy arm compared to 72% in the ADT monotherapy arm (HR, 0.67; 95% CI, 0.52−0.86).
    2. PSA PFS (HR, 0.39, P < .001) and clinical PFS (HR = 0.40, P < .001) were also longer in the combined-therapy arm.
    3. Serious adverse events were reported in 42% of patients in the enzalutamide arm compared to 34% in the monotherapy arm.
      • Treatment was discontinued more frequently in the enzalutamide arm (33 vs. 14 events), and seizures and fatigue were more common in the enzalutamide arm: seven men had seizures in the enzalutamide arm (1%) versus none in the ADT-alone arm.
      • Six percent of men in the combined-therapy arm reported grade 3 to 4 fatigue compared to 1% in the ADT-alone arm.
Hormonal manipulations effectively used as initial therapy for prostate cancer include the following:[8]
  • 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.[9-12][Level of evidence: 1iiA]
  • Leuprolide plus flutamide;[13] however, the addition of an antiandrogen to leuprolide has not been clearly shown in a meta-analysis to improve survival.[14]
  • 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.[15]
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.
The psychological implications of orchiectomy are objectionable to many patients, and many will choose an alternative therapy if effective.[16] Combined orchiectomy and estrogens are not indicated to be superior to either treatment administered alone.[17]
A large proportion of men experience hot flushes after bilateral orchiectomy or treatment with LH-RH agonists. These hot flashes can persist for years.[18] 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.[19] 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.[20-22] Low-dose prednisone may palliate symptoms in about 33% of cases.[23] 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).[24][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.[25][Level of evidence: 1iA]; [26]
    • 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.[27]
  3. Another trial (RTOG-8531) with twice as many randomly assigned patients showed no difference in OS with early versus late hormonal manipulation.[28]
  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-30846Exit Disclaimer) 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.[29][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.[30][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).[31][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.[9,32]
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.[10]
  2. In other randomized studies, the depot LH-RH agonist goserelin was found to be as effective as orchiectomy [11,33,34] or DES at a dose of 3 mg qd.[32] 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.[35] Use of nonsteroidal antiandrogens as monotherapy decreased OS and increased the rate of clinical progression and treatment failure.[35][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.[36][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.[37][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.[38][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.[14][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).[14]
  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:[39][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.[40]
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. It was proposed that 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.[41] However, randomized controlled trials in humans have failed to support the hypothesis that IAD would delay the development of castration-resistant disease. If there are benefits from IAD, they appear to be in the realm of physical and sexual functioning.
Evidence (continuous vs. intermittent hormonal therapy):
  1. A systematic review of 15 randomized trials that compared continuous androgen deprivation therapy 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 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).[42][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.[43]
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).[43][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).[44,45] 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).[45][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.[46]

Bisphosphonates

In addition to hormonal therapy, adjuvant treatment with bisphosphonates has been tested.[47]
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.[47][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.[48][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 (STAMPEDE [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).[49]
    • 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.[50][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.[51,52] Definitive radiation therapy should be delayed 4 to 6 weeks after TURP to reduce incidence of stricture.[53]
Hormonal therapy should be considered in addition to EBRT.[40,54]
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.[40][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).
  2. In a randomized, prospective clinical trial, 18 months of androgen suppression with an LH-RH agonist appears to have provided results that were similar to 36 months with respect to OS and disease-specific survival.[55][Levels of evidence: 1iiA, 1iiB] In the trial, 630 men with stage II to stage IVA cancer (clinical stage T3–T4, or PSA >20 ng/ml, or Gleason score >7) received 70 Gy of radiation in 35 fractions alone plus a total of either 18 or 36 months of goserelin acetate.
    • With a median follow-up of 9.4 years, OS was nearly identical in each study arm (62% at 10 years; HRdeath = 1.02; 95% CI, 0.81–1.29, P = .8), as was prostate cancer–specific survival (HRprostate death = 0.95; 95% CI, 0.58–1.55, P = .8).
    • Global quality of life was nearly identical on both study arms, but sexual activity and interest in sex was moderately better in the 18-month arm.[55][Level of evidence: 1iiC]
  3. The optimal duration of neoadjuvant hormonal therapy has been studied. 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). 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.[54][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).
  4. 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 LH-RH 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.[56][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).[56][Level of evidence: 1iiB]
    • No statistically significant differences in overall mortality or in locoregional disease progression were found.[56][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.[57]; [58][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).[59]

Treatment Options Under Clinical Evaluation for Stage IV Prostate Cancer

Treatment options under clinical evaluation for patients with stage IV prostate cancer include 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.[60] 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.
References
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  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. [PUBMED Abstract]
  3. Fizazi K, Tran N, Fein L, et al.: Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med 377 (4): 352-360, 2017. [PUBMED Abstract]
  4. Chi KN, Protheroe A, Rodríguez-Antolín A, et al.: Patient-reported outcomes following abiraterone acetate plus prednisone added to androgen deprivation therapy in patients with newly diagnosed metastatic castration-naive prostate cancer (LATITUDE): an international, randomised phase 3 trial. Lancet Oncol 19 (2): 194-206, 2018. [PUBMED Abstract]
  5. James ND, de Bono JS, Spears MR, et al.: Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. N Engl J Med 377 (4): 338-351, 2017. [PUBMED Abstract]
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