Stage IV Prostate Cancer Treatment
Stage IV prostate cancer is defined by the American Joint Committee on Cancer's TNM classification system:
- T4, N0, M0, any prostate-specific antigen (PSA), any Gleason.
- Any T, N1, M0, any PSA, any Gleason.
- Any T, any N, M1, any PSA, any Gleason.
Extraprostatic extension with microscopic bladder neck invasion (T4) is included with T3a.
Treatment selection depends on the following factors:
- Coexisting medical illnesses.
- 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.
Standard Treatment Options for Stage IV Prostate Cancer
Standard treatment options for stage IV prostate cancer include the following:
Hormonal treatment is the mainstay of therapy for distant metastatic (Jewett stage D2) prostate cancer. Cure is rarely, if ever, possible, but striking subjective or objective responses to treatment occur in most patients.
Hormonal manipulations effectively used as initial therapy for prostate cancer include the following:
- Orchiectomy alone or with an androgen blocker as seen in the 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.[4-7][Level of evidence: 1iiA]
- Leuprolide plus flutamide; however, the addition of an antiandrogen to leuprolide has not been clearly shown in a meta-analysis to improve survival.
- 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.
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 per day is not associated with cardiovascular complications as frequent as those found at higher doses; however, the use of DES has decreased because of cardiovascular toxic effects. 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. Combined orchiectomy and estrogens are not indicated to be superior to either treatment administered alone.
A large proportion of men experience hot flushes after bilateral orchiectomy or treatment with LH-RH agonists. These hot flushes can persist for years. 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. 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.[15-17] Low-dose prednisone may palliate symptoms in about 33% of cases. Newer hormonal approaches, such as inhibition of androgen receptors, have been shown to improve overall survival (OS) and quality of life after tumor progression despite androgen deprivation therapy. (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):
- 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, showed improved overall mortality with early treatment (relative risk, 0.86; 95% confidence interval (CI), 0.82–0.91).[Level of evidence: 1iiA]
- In a small, randomized trial of 98 men who underwent radical prostatectomy plus pelvic lymphadenectomy and were found to have nodal metastases (stage T1–2, N1, M0), immediate continuous hormonal therapy with the LH-RH agonist goserelin or with orchiectomy was compared with deferred therapy until documentation of disease progression.[Level of evidence: 1iA]; 
- 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.
- Another trial (RTOG-8531) with twice as many randomly assigned patients showed no difference in OS with early versus late hormonal manipulation.
- 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.[Level of evidence; 1iiA]
- After a median follow-up of 8.7 years, the hazard ratio (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.
- 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.[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.
- 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).[Level of evidence: 1iiA]
- Over a 12-year period of follow-up, no statistically significant difference was observed in OS.
LH-RH agonists or antiandrogens
Evidence (LH-RH agonists or antiandrogens):
- In a randomized trial, the LH-RH agonist leuprolide (1 mg subcutaneously every day) was found to be as effective as DES (3 mg orally every day) in any T, any N, M1 patients, but caused less gynecomastia, nausea and vomiting, and thromboembolisms.
- In other randomized studies, the depot LH-RH agonist goserelin was found to be as effective as orchiectomy [6,28,29] or DES at a dose of 3 mg per day. A depot preparation of leuprolide, which is therapeutically equivalent to daily leuprolide, is available as a monthly or 3-monthly depot.
- Castration has been shown to be superior to monotherapy with bicalutamide.
- A small randomized study comparing 1 mg DES orally 3 times per day with 250 mg of flutamide 3 times per day in patients with metastatic prostate cancer showed similar response rates with both regimens but superior survival with DES. More cardiovascular and/or thromboembolic toxic effects of borderline statistical significance were associated with DES treatment.[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.
- In a large, randomized, controlled trial comparing treatment with bilateral orchiectomy plus either the antiandrogen flutamide or placebo, no difference in OS was reported.[Level of evidence: 1iA]
- Although it has been suggested that MAB may improve the more subjective endpoint of response rate, prospectively assessed quality of life was worse in the flutamide arm than in the placebo arm primarily because of more diarrhea and worse emotional function in the flutamide-treated group.[Level of evidence: 1iC]
- 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.[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).
- The Agency for Health Care Policy and Research (AHCPR) (now AHRQ) 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:[Level of evidence: 1iiA]
- OS at 2 years using any of the LH-RH agonists is similar to treatment with orchiectomy or 3 mg per day of DES (HR, 1.26; 95% CI, 0.92–1.39).
- Survival rates at 2 years are similar or worse with nonsteroidal antiandrogens compared 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.
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 of time. An animal model suggested that intermittent androgen deprivation (IAD) could prolong the duration of androgen dependence of hormone-sensitive tumors.
Evidence (continuous vs. intermittent hormonal therapy):
- A systematic review of all five randomized trials addressing this issue found no reliable data on the relative effectiveness of intermittent versus continuous androgen suppression on OS, prostate cancer-specific survival, disease progression, or quality of life.[Level of evidence: 1iiA] All five trials were small and had short follow-up.
- In a subsequent randomized trial, 626 men with clinically advanced prostate cancer (T3–T4, M0–M1, PSA ≥4 ng/ml) who responded to an initial 3-month induction course of cyproterone acetate plus an LH-RH agonist were randomly assigned to either continue the regimen or cease treatment until there was evidence of progression.
- After 100 months of follow-up (median 51 months), there was no difference in OS (HR, 0.99; 95% CI, 0.80–1.23; P = 0.84) for continuous androgen deprivation (CAD) therapy (ADT) versus IAD therapy.
- Quality of life between the two treatment strategies was similar, but IAD was associated with lower rates of hot flushes and gynecomastia.
- A larger, randomized trial designed to determine whether survival using IAD is noninferior to CAD could not rule out a 20% higher relative risk of death using intermittent therapy.[Level of evidence: 1iiA] The trial registered 3,040 men with newly diagnosed metastatic prostate cancer and a serum PSA of 5 or higher ng/ml who were treated initially with an LH-RH agonist plus an antiandrogen for 7 months. Then, 1,535 of the men in whom the PSA level fell to 4 or lower ng/ml were randomly assigned to continue their hormone therapy, or to stop until the PSA level rose to 20 ng/ml (or to their baseline PSA level at study entry). The trial was designed as a noninferiority study to rule out a survival rate that was 20% worse in the IAD therapy group compared with the CAD therapy group (i.e., an upper boundary of the HRdeath <1.20 in a one-tailed comparison).
- Median OS from the date of random assignment was 5.8 years compared with 5.1 years in the continuous therapy and intermittent therapy groups, respectively (HRdeath, 1.10; 90% CI, 0.99–1.23). Therefore, inferiority of the intermittent therapy group's treatment schedule could not be ruled out.
- In preplanned quality-of-life analyses, intermittent therapy was associated with better erectile function (P ≤ .001) and mental health (P = .003) at 3 months following random assignment, for an additional year of quality-of-life assessment.[Level of evidence: 1iiC] However, the fact that patients were not blinded to treatment assignment may have affected these self-reported endpoints.
- In another study, 852 men with locally advanced or metastatic prostate cancer were enrolled and received ADT (ADT included administration of the LH-RH-agonist–goserelin acetate 3.6 mg subcutaneously every 28 days) for 24 weeks (with cyproterone acetate 100 mg given orally twice daily for the initial 12.5 days). The 554 patients whose initial PSA decreased to less than 10 ng/ml or by more than 50%, if initial PSA was greater than 20 ng/ml, were randomly assigned to either an open-label strategy of intermittent ADT (IAD therapy included stopping ADT, with intermittent reinstitution whenever the PSA rose above 20 ng/ml or above the initial baseline value) or CAD therapy (CAD therapy included administration of a continuous LH-RH agonist or a bilateral orchiectomy).
- After a median follow-up of 65 months, outcomes in the IAD versus CAD study groups were:
- Median time to death: 45.2 versus 45.7 months.
- Median time to death due to prostate cancer: 45.2 versus 44.3 months.
- Median time to treatment failure: 29.9 versus 30.5 months.
- None of these differences were statistically significant.[Level of evidence: 1iiA]
- After a median follow-up of 65 months, outcomes in the IAD versus CAD study groups were:
In addition to hormonal therapy, adjuvant treatment with bisphosphonates has been tested.
- In MRC-PR05, 311 men with bone metastases who were starting or responding to standard hormonal therapy were randomly assigned to oral sodium clodronate (2,080 mg per day) or a matching placebo for up to 3 years.[Level of evidence: 1iA]
- At a median follow-up of 11.5 years, OS was better in the clodronate arm: HRdeath of 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.
- A parallel study (MRC-PR04) in men with locally advanced but nonmetastatic disease showed no benefit associated with clodronate.
- CALGB-90202 [NCT00079001] was a randomized controlled trial that compared zoledronic acid (4 mg intravenously 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.[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 progression-free survival or OS.
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 per day) had no favorable impact on either time to symptomatic bone metastasis or survival.[Level of evidence: 1iA]
External-beam radiation therapy (EBRT) with or without hormonal therapy
Evidence (radiation therapy with or without hormonal therapy):
- 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.[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.
- 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 subcutaneously each month plus flutamide 250 mg by mouth 3 times per day) for 2 months prior to and during radiation, or 6 months of NADT for 5 months prior to and during radiation.[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).
Palliative radiation therapy
A single fraction of 8 Gy has been shown to have similar benefits on bone pain relief and quality of life as multiple fractions (3 Gy × 10) as was evidenced in the RTOG-9714 (NCT00003162) trial.; [Level of evidence: 1iiC] (Refer to the PDQ summary on 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
Careful observation without further immediate treatment (in selected asymptomatic patients).
Treatment Options Under Clinical Evaluation for Stage IV Prostate Cancer
Treatment options under clinical evaluation include the following:
- 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. Patient selection factors make such study designs difficult to interpret.
- Continuous ADT plus chemotherapy for metastatic disease.
- The addition of chemotherapy to ADT at the first documentation of metastatic disease has not been shown to improve survival compared with the initiation of effective chemotherapy at the onset of ADT resistance. In a trial of 385 men with metastatic disease (71% of whom had metastatic disease at initial diagnosis), patients were randomly assigned to receive ADT with or without docetaxel (75 mg/m2 administered intravenously every 3 weeks, plus corticosteroid premedication, for up to nine cycles), with the option to add docetaxel in the ADT-alone study arm at progression.
- OS on both study arms was similar (HRsurvival, 1.01; 95% CI, 0.75–1.36). Hematologic toxicity and quality of life were worse in the ADT-plus-docetaxel study arm while patients were receiving docetaxel.[Level of evidence: 1iiA]
- Studies about the early addition of other active agents to ADT are warranted.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IV prostate cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
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