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.)

In prostate cancer, the selection of further treatment depends on many factors, including previous treatment, site of recurrence, coexistent illnesses, and individual patient considerations. Definitive radiation therapy can be given to patients who fail only locally following prostatectomy.[1-4] An occasional patient can be salvaged with prostatectomy after a local recurrence following definitive radiation therapy;[5] 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.[6] Cryosurgical ablation of recurrence following radiation therapy is associated frequently with elevated prostate-specific antigen (PSA) and a high complication rate. This technique is still undergoing clinical evaluation.[7] Most relapsing patients who initially received locoregional therapy with surgery or radiation therapy will fail with disseminated disease and are managed with hormonal therapy. The management of these patients with stage IV disease is discussed in the preceding section. Palliative radiation therapy for bone pain can be very useful. Because of the poor prognosis in prostate cancer patients with relapsing or progressive disease after hormonal therapy, clinical trials are appropriate. These include phase I and phase II trials of new chemotherapeutic or biologic agents.

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 hormone therapy.[8] 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.[9] 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.[10] Survival rates are similar whether ketoconazole plus hydrocortisone is initiated at the same time as anti-androgen (e.g., flutamide, bicalutamide, or nilutamide) withdrawal or when PSA has risen after an initial trial of anti-androgen withdrawal as seen in the CALGB-9583 trial, for example.[11][Level of evidence: 1iiA] Data on whether PSA changes while on chemotherapy are predictive of survival are conflicting.[9,12]

Patients treated with either luteinizing hormone agonists or estrogens as primary therapy are generally maintained with castrate levels of testosterone. One study from the Eastern Cooperative Oncology Group showed that a superior survival resulted when patients were maintained on primary androgen deprivation;[13] however, another study from the Southwest Oncology Group did not show an advantage to continued androgen blockade.[14]

Painful bone metastases can be a major problem for patients with prostate cancer. Many strategies have been studied for palliation, including pain medication, radiation therapy, corticosteroids, bone-seeking radionuclides, gallium nitrate, and bisphosphonates.[15-18] External-beam radiation therapy (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 quality of life as multiple fractions (3 Gy × 10) as seen in the RTOG-9714 trial, for example.[19,20][Level of evidence: 1iiC] Also, the use of radioisotopes such as strontium chloride Sr 89 has been shown to be effective as palliative treatment of some patients with osteoblastic metastases. When this isotope is given alone, it decreased bone pain in 80% of patients treated [21] and is similar to responses with local or hemibody radiation therapy.[22] When used as an adjunct to EBRT, strontium chloride Sr 89 was shown to slow disease progression and to reduce analgesic requirements, compared with EBRT alone.[23]

A multicenter randomized trial of a single intravenous dose of strontium chloride Sr 89 (150 MBq: 4 mCi) versus palliative EBRT in men with painful bone metastases from prostate cancer despite hormone treatment showed similar subjective pain response rates: 34.7% versus 33.3%, respectively. Overall survival was better in the EBRT group than in the strontium chloride Sr 89 group (P = .046; median survival 11.0 vs. 7.2 months). No statistically significant differences in time-to-subjective progression or in progression-free survival were seen.[24][Level of evidence: 1iiA]

Low-dose prednisone may palliate symptoms in some patients.[25] In a randomized comparison of prednisone (5 mg 4 times per day) with flutamide (250 mg 3 times per day) in patients with disease progression after androgen ablative therapy (castration or luteinizing hormone-releasing hormone [LHRH] agonist), prednisone and flutamide produced similar survival, symptomatic response, PSA response, and time to progression;[26] however, there were statistically significant differences in pain, nausea and vomiting, and diarrhea in patients who received prednisone. Ongoing clinical trials continue to explore the value of chemotherapy for these patients.[27-34]

A randomized trial showed improved pain control in hormone-resistant patients treated with mitoxantrone plus prednisone compared with those treated with prednisone alone.[31] Differences in overall survival (OS) or measured global quality of life between the two treatments were not statistically significant.

In randomized trials of men with hormone-refractory prostate cancer, regimens of docetaxel given every 3 weeks have produced better OS (at 21–33 months) than mitoxantrone.[35,36][Level of evidence: 1iiA]

In a randomized trial of patients with hormone-refractory prostate cancer, docetaxel (75 mg/M² every 3 weeks) and docetaxel (30 mg weekly for 5 out of every 6 weeks) were compared with mitoxantrone (12 mg/M² every 3 weeks).[35] All patients received oral prednisone (5 mg twice per day). Patients in the docetaxel arms also received high-dose dexamethasone pretreatment for each docetaxel administration (8 mg were given at 12 hours, 3 hours, and 1 hour prior to the 3-week regimen; 8 mg were given at 1 hour prior to the 5 out-of-every-6 weeks' regimen). OS at 3 years was statistically significantly better in the 3-weekly docetaxel arm (18.6%) than in the mitoxantrone arm (13.5%, hazard ratio [HR] for death = 0.79; 95% confidence interval [CI], 0.67–0.93). The OS rate for the 5 out-of-every-6 weeks' docetaxel regimen was 16.8%, which was not statistically significantly better than mitoxantrone. Quality of life was also superior in the docetaxel arms compared with mitoxantrone (P = .009).[37][Levels of evidence: 1iiA; 1iiC]

In another randomized trial of patients with hormone-refractory prostate cancer, a 3-week regimen of estramustine (280 mg orally 3 times a day for days 1 to 5, plus daily warfarin and 325 mg of aspirin to prevent vascular thrombosis), and docetaxel (60 mg/M² intravenously on day 2, preceded by dexamethasone [20 mg times 3 starting the night before]) was compared with mitoxantrone (12 mg/M² intravenously every 3 weeks) plus prednisone (5 mg daily).[36] After a median follow-up of 32 months, median OS was 17.5 months in the estramustine arm versus 15.6 months in the mitoxantrone arm (P = .02; HR for death = 0.80; 95% CI, 0.67–0.97).[36][Level of evidence: 1iiA] Global quality of life and pain palliation measures were similar in the two treatment arms.[38][Level of evidence: 1iiC]

Other chemotherapy regimens reported to produce subjective improvement in symptoms and reduction in PSA level include the following:[32][Level of evidence: 3iiiDiii];[33]

• Paclitaxel.
• Estramustine/etoposide.
• Estramustine/vinblastine.
• Estramustine/paclitaxel.

One study suggests that patients whose tumors exhibit neuroendocrine differentiation are more responsive to chemotherapy.[34]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent 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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23. Porter AT, McEwan AJ, Powe JE, et al.: Results of a randomized phase-III trial to evaluate the efficacy of strontium-89 adjuvant to local field external beam irradiation in the management of endocrine resistant metastatic prostate cancer. Int J Radiat Oncol Biol Phys 25 (5): 805-13, 1993.  [PUBMED Abstract]
    
    
24. Oosterhof GO, Roberts JT, de Reijke TM, et al.: Strontium(89) chloride versus palliative local field radiotherapy in patients with hormonal escaped prostate cancer: a phase III study of the European Organisation for Research and Treatment of Cancer, Genitourinary Group. Eur Urol 44 (5): 519-26, 2003.  [PUBMED Abstract]
    
    
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26. 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]
    
    
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30. Hudes GR, Greenberg R, Krigel RL, et al.: Phase II study of estramustine and vinblastine, two microtubule inhibitors, in hormone-refractory prostate cancer. J Clin Oncol 10 (11): 1754-61, 1992.  [PUBMED Abstract]
    
    
31. Tannock IF, Osoba D, Stockler MR, et al.: Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol 14 (6): 1756-64, 1996.  [PUBMED Abstract]
    
    
32. Petrylak DP, Macarthur RB, O'Connor J, et al.: Phase I trial of docetaxel with estramustine in androgen-independent prostate cancer. J Clin Oncol 17 (3): 958-67, 1999.  [PUBMED Abstract]
    
    
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