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Prostate Cancer Treatment (Professional) (cont.)

Recurrent Prostate Cancer

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.)

Overview

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.[1,2,3,4] 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 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.

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.[8,9,10,11] (Refer to the PDQ summary on Pain for more information.) 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.[12,13][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. As a single agent, strontium chloride Sr 89 has been reported to decrease bone pain in 80% of patients treated [14] and is similar to responses with local or hemibody radiation therapy.[15]

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 (OS) 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.[16][Level of evidence: 1iiA] 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.[17]

Chemotherapy for Hormone-Refractory Prostate Cancer

A randomized trial showed improved pain control in hormone-resistant patients treated with mitoxantrone plus prednisone compared with those treated with prednisone alone.[18] Differences in 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.[19,20][Level of evidence: 1iiA]

  1. 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).[19] 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). 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. Quality of life was also superior in the docetaxel arms compared with mitoxantrone (P = .009).[21][Levels of evidence: 1iiA; 1iiC]
  2. 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).[20] 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 (P = .02; HRdeath = 0.80; 95% CI, 0.67–0.97).[20][Level of evidence: 1iiA] Global quality of life and pain palliation measures were similar in the two treatment arms.[22][Level of evidence: 1iiC]

In hormone-resistant patients whose disease progresses during or after treatment with docetaxel, cabazitaxel was shown to improve survival compared to mitoxantrone in a randomized trial (NCT00417079).[23] In the trial, 755 such men were treated with daily oral prednisone (10 mg) and randomly assigned to receive either cabazitaxel (25 mg/M2 I.V.) or mitoxantrone (12 mg/M2 I.V.) every 3 weeks. Median OS in the cabazitaxel and mitoxantrone study arms was 15.1 and 12.7 months, respectively (HR of death = 0.70; 95% CI, 0.59–0.83; P < .0001).[23][Level of evidence: 1iiA]

Other chemotherapy regimens reported to produce subjective improvement in symptoms and reduction in PSA level include the following:[24][Level of evidence: 3iiiDiii];[25]

One study suggests that patients whose tumors exhibit neuroendocrine differentiation are more responsive to chemotherapy.[26]

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 (gmCSF).

  1. In the largest trial (the Immunotherapy for Prostate Adenocarcinoma Treatment: IMPACT [NCT00065442] trial), 512 patients with hormone-refractory metastatic disease were randomly assigned in a 2:1 ratio to receive sipuleucel-T (341 patients) versus placebo (171 patients) intravenously by 60-minute infusion every 2 weeks for a total of 3 times.[27] Patients with visceral metastases, pathologic bone fractures, or Eastern Cooperative Oncology Group (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 prior to study unblinding based upon survival differences in two prior trials of similar design (described below).

    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).[27][Level of evidence: 1iA] 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 is $93,000 for a 1-month course of therapy. This translates into an estimated cost of about $276,000 per year of life saved.[28]

  2. The same investigators performed two prior smaller trials (NCT00005947 ) of nearly identical design to the IMPACT trial.[29,30] The combined results of the two smaller trials, conducted on a total of 225 patients randomized in a 2:1 ratio of sipuleucel-T to placebo were similar to 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.

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, a 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. Abiraterone inhibits androgen biosynthesis by blocking cytochrome P450 c17 (CYP17). Men with metastatic prostate cancer who had biochemical or clinical progression after treatment with docetaxel (n = 1195) were randomly assigned in a 2:1 ratio to receive either abiraterone acetate (1000 mg) (n = 797) or placebo (n = 398) orally once a day (COU-AA-301 [NCT00638690]).[31] Both groups received prednisone (5 mg) orally twice a day. 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. Median OS was 14.8 months in the abiraterone group versus 10.9 months in the placebo group (HRdeath = 0.65; 95% CI, 0.54–0.77; P < .001).[31][Level of evidence: 1iA] Abiraterone has mineralocorticoid effects, producing an increased incidence of fluid retention and edema, hypokalemia, and hypertension.

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.[32] 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.[33] 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.[34] 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 CLB-9583 trial, for example.[35][Level of evidence: 1iiA] Data on whether PSA changes while on chemotherapy are predictive of survival are conflicting.[33,36]

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;[37] however, another study from the Southwest Oncology Group did not show an advantage to continued androgen blockade.[38]

Low-dose prednisone may palliate symptoms in some patients.[39] 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;[40] however, there were statistically significant differences in pain, nausea and vomiting, and diarrhea in patients who received prednisone. (Refer to the Pain and the Nausea and Vomiting summaries; for information on diarrhea, refer to the Gastrointestinal Complications summary.) Ongoing clinical trials continue to explore the value of chemotherapy for these patients.[18,24,25,26,41,42,43,44]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials 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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  3. Carter GE, Lieskovsky G, Skinner DG, et al.: Results of local and/or systemic adjuvant therapy in the management of pathological stage C or D1 prostate cancer following radical prostatectomy. J Urol 142 (5): 1266-70; discussion 1270-1, 1989.
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  30. Small EJ, Schellhammer PF, Higano CS, et al.: Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol 24 (19): 3089-94, 2006.
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  38. Hussain M, Wolf M, Marshall E, et al.: Effects of continued androgen-deprivation therapy and other prognostic factors on response and survival in phase II chemotherapy trials for hormone-refractory prostate cancer: a Southwest Oncology Group report. J Clin Oncol 12 (9): 1868-75, 1994.
  39. 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.
  40. 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.
  41. Debruyne FJ, Murray R, Fradet Y, et al.: Liarozole--a novel treatment approach for advanced prostate cancer: results of a large randomized trial versus cyproterone acetate. Liarozole Study Group. Urology 52 (1): 72-81, 1998.
  42. Eisenberger MA: Chemotherapy for prostate carcinoma. NCI Monogr (7): 151-63, 1988.
  43. Pienta KJ, Redman B, Hussain M, et al.: Phase II evaluation of oral estramustine and oral etoposide in hormone-refractory adenocarcinoma of the prostate. J Clin Oncol 12 (10): 2005-12, 1994.
  44. 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.
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