Current Clinical Trials

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

Stage IV prostate cancer is defined by the following staging systems:

• American Joint Committee on Cancer's (AJCC) TNM classification system:
  • T4, N0, M0, any G.
  • Any T, N1, M0, any G.
  • Any T, any N, M1, any G.
• Jewett staging system: stages D1 or D2.

Treatment selection depends on age, coexisting medical illnesses, symptoms, and the presence of distant metastases (most often bone) or regional lymph node involvement only. The most common symptoms originate from the urinary tract or from bone metastases. Palliation of symptoms from the urinary tract with transurethral resection of the prostate (TURP) or radiation therapy and palliation of symptoms from bone metastases with radiation therapy or hormonal therapy are an important part of the management of these patients. Bisphosphonates are also under clinical evaluation for the management of bone metastases.[1]

Treatment information for patients whose disease has the following classifications:

• AJCC's TNM classification system:
  • T4, N0, M0, any G.
  • Any T, N1, M0, any G.
• Jewett staging system: stage D1.

The Agency for Health Care Policy and Research (AHCPR) (now the Agency for Healthcare Research and Quality) performed a systematic review of the available randomized clinical trial evidence comparing radiation therapy with radiation therapy and prolonged androgen suppression performed by its Technology Evaluation Center, an evidence-based Practice Center of the Blue Cross and Blue Shield Association.[2][Level of evidence: 1iiA] Some patients with bulky T2b tumors were included in the studied groups. The meta-analysis found a difference in 5-year overall survival (OS) in favor of radiation therapy plus continued androgen suppression using a luteinizing hormone-releasing hormone (LHRH) agonist or orchiectomy, compared with radiation therapy alone (hazard ratio [HR] = 0.631; 95% confidence interval [CI], 0.479–0.831). This reduction in overall mortality indicates that adjuvant androgen suppression should be initiated at the time of radiation therapy and continued for several years. The optimal duration of therapy and the issue of utility of neoadjuvant hormonal therapy have not been determined.

Likewise, a meta-analysis of seven randomized controlled trials comparing early (adjuvant or neoadjuvant) to deferred hormonal treatment (LHRH agonists and/or antiandrogens) in patients with locally advanced prostate cancer, whether treated by prostatectomy, radiation therapy, or watchful waiting, showed improved overall mortality (RR=0.86; 95% CI, 0.82–0.91).[3][Level of evidence: 1iiA]

In a small randomized trial of 98 men who underwent radical prostatectomy plus pelvic lymphadenectomy and were found to have nodal metastases (stage T1–2 N1, M0), immediate continuous hormonal therapy with the LHRH agonist goserelin or with orchiectomy was compared with deferred therapy until documentation of disease progression.[4][Level of evidence: 1iA];[5] After a median follow-up of 11.9 years, both OS and prostate cancer-specific survival were superior in the immediate adjuvant therapy arm (P = .04 and P = .004, respectively). At 10 years, the survival rate in the immediate therapy arm was about 80% versus about 60% for the deferred therapy arm.[6] Another trial (RTOG-8531) with twice as many patients in a randomization showed no difference in OS with early versus late hormonal manipulation.[7]

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

Immediate hormone therapy with goserelin or orchiectomy has also been compared with deferred hormone therapy for clinical disease progression in a randomized trial (EORTC-30846) of men with regional lymph node involvement but no clinical metastases (any T, N+, M0).[9] None of the 234 men received prostatectomy or prostatic radiation therapy. After a median follow-up of 8.7 years, the HR for OS in the deferred versus immediate hormone therapy arms was 1.23 (95% CI, 0.88–1.71). No statistically significant difference in OS between deferred and immediate hormone therapy was found, but the trial was underpowered to detect small or modest differences.[9][Level of evidence: 1iiA]

Patients with locally advanced nonmetastatic disease (T2–T4, N0–N1, M0) are at risk for developing bone metastases, and bisphosphonates are being studied as a strategy to decrease this risk. However, a placebo-controlled randomized trial (MRC-PRO4) 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.[10][Level of evidence: 1iA]

Treatment information for patients whose disease has the following classifications:

• AJCC's TNM classification system: Any T, any N, M1, any G.
• Jewett staging system: stage D2.

Hormonal treatment is the mainstay of therapy for distant metastatic (stage D2) prostate cancer. Cure is rarely, if ever, possible, but striking subjective or objective responses to treatment occur in most patients. Initial results from a randomized study of immediate hormonal treatment (orchiectomy or LHRH analog) versus deferred treatment (watchful waiting with hormonal therapy at progression) in men with locally advanced or asymptomatic metastatic prostate cancer showed better OS and prostate cancer-specific survival with the immediate treatment. The incidence of pathologic fractures, spinal cord compression, and ureteric obstruction were also lower in the immediate treatment arm.[11][Level of evidence: 1iiA] In another trial, 197 men with stage III or stage IV prostate cancer were randomly assigned to receive bilateral orchiectomy at diagnosis or at the time of symptomatic progression (or at the time of new metastases that were deemed likely to cause symptoms). Over a 12-year period of follow-up, no statistically significant difference was observed in overall survival.[12][Level of evidence: 1iiA]

In some series, pretreatment levels of prostate-specific antigen (PSA) are inversely correlated with progression-free duration in patients with metastatic prostate cancer who receive hormonal therapy. After hormonal therapy is instituted, reduction of PSA to undetectable levels provides information regarding the duration of progression-free status; however, decreases in PSA of less than 80% may not be very predictive.[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. Diethylstilbestrol (DES) in a dose of 1 mg per day is not associated with cardiovascular complications as frequent as those found at higher doses; however, the use of DES has decreased because of cardiovascular toxic effects, and DES is no longer commercially available in the United States. The psychological implications of orchiectomy are objectionable to many patients, and many will choose alternative therapy if effective.[14] Combined orchiectomy and estrogens are not indicated to be superior to either treatment administered alone.[15]

Approaches using LHRH agonists and/or antiandrogens in patients with stage IV prostate cancer have produced response rates similar to standard hormonal treatments.[16,17] In a randomized trial, the LHRH analog leuprolide (1 mg subcutaneously every day) was found to be as effective as DES (3 mg orally every day) in any T, any N, M1 patients but caused less gynecomastia, nausea and vomiting, and thromboembolisms.[18] In other randomized studies, the depot LHRH analog goserelin was found to be as effective as orchiectomy [19-21] or DES at a dose of 3 mg per day.[17] 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.[22] A small randomized study comparing 1 mg of DES orally 3 times per day to 250 mg of flutamide 3 times per day in patients with metastatic prostate cancer showed similar response rates with both regimens but superior survival with DES. More cardiovascular and/or thromboembolic toxic effects of borderline statistical significance were associated with the DES treatment.[23][Level of evidence: 1iA] A variety of combinations of hormonal therapy have been tested.

On the basis that the adrenal glands continue to produce androgens after surgical or medical castration, case series studies were performed in which antiandrogen therapy was added to castration. Promising results from such case series led to widespread use of the strategy, known as maximal androgen blockage (MAB) or complete androgen blockade. Subsequent randomized controlled trials, however, cast doubt on the efficacy of adding an antiandrogen to castration. In a large randomized controlled trial comparing treatment with bilateral orchiectomy plus either the antiandrogen flutamide or placebo, no difference in OS was reported.[24][Level of evidence: 1iA] Although it has been suggested that MAB may improve the more subjective end point of response rate, prospectively assessed quality of life was worse in the flutamide arm than in the placebo arm, primarily because of more diarrhea and worse emotional function in the flutamide-treated group.[25][Level of evidence: 1iC] A meta-analysis of 27 randomized trials of 8,275 patients comparing conventional surgical or medical castration to MAB—castration plus prolonged use of an antiandrogen such as flutamide, cyproterone acetate, or nilutamide—did not show a statistically significant improvement in survival associated with MAB.[26][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).[26]

The AHCPR has performed a systematic review of the available randomized clinical trial evidence of single hormonal therapies and combined androgen blockade performed by its Technology Evaluation Center, an evidence-based Practice Center of the Blue Cross and Blue Shield Association. A meta-analysis of randomized trials comparing various hormonal monotherapies in men with stage III or stage IV prostate cancer (predominantly stage IV) came to the following conclusions:

1. OS at 2 years using any of the LHRH agonists is similar to treatment with orchiectomy or 3 mg per day of DES (HR = 1.26; 95% CI, 0.92–1.39).
2. Survival rates at 2 years are similar or worse with nonsteroidal antiandrogens compared with orchiectomy (HR = 1.22; 95% CI, 0.99–1.50).
3. Treatment withdrawals, used as a surrogate for adverse effects, occurred less with LHRH agonists (0%–4%) than with nonsteroidal antiandrogens (4%–10%).[27][Level of evidence: 1iiA]

Combined androgen blockade was of no greater benefit than single hormonal therapy and with less patient tolerance. Also, the evidence was judged insufficient to determine whether men newly diagnosed with asymptomatic metastatic disease should have immediate androgen suppression therapy or should have therapy deferred until they have clinical signs or symptoms of progression.[2]

When used as the primary therapy for patients with stage III or stage IV prostate cancer, androgen suppression with hormonal therapy is usually given continuously until there is disease progression. However, some investigators have proposed intermittent androgen suppression as a strategy to attain maximal tumor cytoreduction followed by a period without therapy to allow tumor repopulation by hormone-sensitive cells. Theoretically, tumor hormone responsiveness for a longer period of time. However, a systematic review of all five randomized trials addressing this issue found no reliable data on the relative effectiveness of intermittent versus continuous androgen suppression for OS, prostate cancer specific survival, disease progression, or quality of life.[28][Level of evidence: 1iiA] All five trials were small and had short follow-up. Intermittent therapy therefore remains under evaluation, pending further analysis of results from clinical trials, including the CAN NCIC PR7 trial and the SWOG 9346 trial.

A large proportion of men experience hot flushes after bilateral orchiectomy or treatment with LHRH agonists. These hot flushes can persist for years.[29] 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 develops, an objective tumor response to any other form is uncommon.[30] Some studies, however, suggest that withdrawal of flutamide (with or without aminoglutethimide administration) is associated with a decline in PSA values and that one may need to monitor for this response before initiating new therapy.[31-33] Low-dose prednisone may palliate symptoms in about 33% of cases.[34] (Refer to the Recurrent Prostate Cancer section of this summary for more information.)

Standard treatment options:

1. Hormonal manipulations effectively used as initial therapy for prostate cancer: [35]
   1. Orchiectomy alone or with an androgen blocker as seen in the SWOG-8894 trial, for example.
   2. LHRH agonists such as leuprolide in daily or depot preparations.[16,18,19,36] (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.)[Level of evidence: 1iiA]
   3. Leuprolide plus flutamide;[37] however, the addition of an antiandrogen to leuprolide has not been clearly shown in a meta-analysis to improve survival.[26]
   4. Estrogens (DES, chlorotrianisene, ethinyl estradiol, conjugated estrogens USP, and DES-diphosphate). (DES is no longer commercially available in the United States.)



2. External-beam radiation therapy (EBRT) for attempted cure (highly selected stage M0 patients).[38,39] Definitive radiation therapy should be delayed 4 to 6 weeks after TURP to reduce incidence of stricture.[40]

   Hormonal therapy should be considered in addition to EBRT.[2]




3. Palliative radiation therapy. A single fraction of 8 Gy has been shown to have similar benefits on bone pain relief and quality of life as multiple fractions (3 Gy × 10) as evidenced in the RTOG-9714 trial.[41,42][Level of evidence: 1iiC]



4. Palliative surgery (TURP).



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



6. Radical prostatectomy with immediate orchiectomy is under clinical evaluation.[43] An uncontrolled, retrospective review of a large series of patients with any T, N1–3, M0 disease treated at the Mayo Clinic by concurrent radical prostatectomy and orchiectomy showed prolongation of intervals to local and distant progression; however, a significant increase in survival has not been demonstrated.

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

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

References

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2. 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]
   
   
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23. 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]
    
    
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