Prostate Cancer Treatment (Professional) (cont.)
Recurrent Prostate Cancer Treatment
In recurrent prostate cancer, the selection of further treatment depends on many factors, including:
- Previous treatment.
- Site of recurrence.
- Coexistent illnesses.
- Individual patient considerations.
Definitive radiation therapy can be given to patients with disease that fails only locally following prostatectomy.[1,2,3,4] An occasional patient can be salvaged with prostatectomy after a local recurrence following definitive radiation therapy; 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.
Cryosurgical ablation of recurrence following radiation therapy is associated frequently with a high complication rate. This technique is still undergoing clinical evaluation.
Hormonal therapy is used to manage most relapsing patients with disseminated disease who initially received locoregional therapy with surgery or radiation therapy. (Refer to the Standard Treatment Options for Stage IV Prostate Cancer section of this summary for more information.)
It is not clear whether additional treatments given on the basis of rising PSA in asymptomatic men with prostate cancer increase OS. Biochemical evidence of failure on the basis of elevated or rising PSA alone, therefore, may not be sufficient to alter treatment, and using surrogate endpoints for clinical decision-making is, therefore, controversial.
PSA is often used to monitor patients after initial therapy with curative intent, and elevated or rising PSA is a common trigger for additional therapy even in asymptomatic men. After radical prostatectomy, detectable PSA levels identify patients at elevated risk of local treatment failure or metastatic disease; however, a substantial proportion of patients with elevated or rising PSA levels after initial therapy with curative intent may remain clinically free of symptoms for extended periods of time.
- For example, in a retrospective analysis of nearly 2,000 men who had undergone radical prostatectomy with curative intent and who were followed for a mean of 5.3 years. 315 men (15%) demonstrated an abnormal PSA of 0.2 ng/ml or higher, which is evidence of biochemical recurrence.
- Of these 315 men, 103 men (34%) developed clinical evidence of recurrence.
- The median time to development of clinical metastasis after biochemical recurrence was 8 years.
- After the men developed metastatic disease, the median time to death was an additional 5 years.
Likewise, after radiation therapy with curative intent, persistently elevated or rising PSA may be a prognostic factor for clinical disease recurrence. However, reported case series have used a variety of definitions of PSA failure. Criteria have been developed by the American Society for Therapeutic Radiology and Oncology Consensus Panel.[11,12] The implication of the various definitions of PSA failure for overall survival (OS) is not known, and as in the surgical series, many biochemical relapses (rising PSA alone) may not be clinically manifested in patients treated with radiation therapy.[13,14]
Hormonal Therapy for Recurring Disease
Intermittent versus continuous androgen suppression therapy
The majority of men who are treated for recurrence after initial local therapy are asymptomatic, and the recurrence is detected by a rising PSA. It is possible that intermittent androgen deprivation therapy (IAD) can be used as an alternative to continuous androgen deprivation (CAD) therapy (ADT) in an attempt to improve quality of life and decrease the amount of time during which the patient experiences the side effects of hormonal therapy, without decreasing the survival rate.
- This important clinical question was addressed in a "noninferiority" designed, randomized, controlled trial with 1,386 men who had rising PSA levels (>3 ng/ml, with serum testosterone >5 nmol/L) more than 1 year after primary or salvage radiation therapy for localized prostate cancer.[Levels of evidence: 1iiA, 1iiB, 1iiC]
- The ADT arm consisted of 8-month treatment cycles with an LH-RH agonist (combined with a nonsteroidal antiandrogen for at least the first 4 weeks) that was reinstituted if the PSA level exceeded 10 ng/ml. The study was powered to detect (with 95% confidence) an 8% lower OS rate in the IAD group compared with the CAD group at 7 years.
- After a median follow-up of 6.9 years (maximum follow-up 11.2 years), OS in the two groups was nearly identical, and the study was stopped (median survival 8.8 vs. 9.1 years; hazard ratio [HR]death of 1.02; 95% confidence interval [CI], 0.86–1.21). This fulfilled the prospective criterion of noninferiority.
- In a retrospective analysis, prostate cancer-specific mortality was also similar in the two arms (HR, 1.18; 95% CI, 0.90–1.55; P = 0.24). In addition, IAD was statistically significantly better than CAD in several quality-of-life domains, such as hot flashes, desire for sexual activity, and urinary symptoms. Patients on the IAD study arm received a median of 15.4 months of treatment versus 43.9 months on the CAD arm.
- The study does not address the unanswered question about whether the initiation of any ADT for an elevated PSA after initial local therapy extends survival compared with delay until clinically symptomatic progression. Of note, 59% of all deaths were unrelated to prostate cancer, and only 14% of all patients died of prostate cancer.
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, 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.
Evidence (hormonal approaches):
- 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 = 1,195) were randomly assigned in a 2:1 ratio to receive either abiraterone acetate (1,000 mg) (n = 797) or placebo (n = 398) orally once a day (COU-AA-301 [NCT00638690]). Both groups received prednisone (5 mg) orally twice a day.[Level of evidence; 1iA]
- 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. The final report of the trial was published after a median follow-up of 20.2 months.
- Median OS was 15.8 months in the abiraterone group versus 11.2 months in the placebo group (HRdeath of 0.74; 95% CI, 0.64–0.86; P < .0001).
- Abiraterone has mineralocorticoid effects, producing an increased incidence of fluid retention and edema, hypokalemia, and hypertension.
- Enzalutamide, an androgen-receptor signaling inhibitor, has been shown to increase survival in patients with progressive prostate cancer who received prior androgen deprivation therapy as well as docetaxel. In a double-blind, placebo-controlled trial, 1,129 men were randomly assigned in a 2:1 ratio to receive enzalutamide (160 mg orally per day) versus placebo.[Levels of evidence; 1iA, 1iC]
- After a median follow-up of 14.4 months, the study was stopped at the single-planned interim analysis because improved OS, the primary endpoint, was found in the enzalutamide study group (median OS, 18.4 months; 95% CI, 17.3 to not yet reached vs. 13.6 months; 95% CI, 11.3–15.8; HRdeath of 0.63; 95% CI, 0.53–0.75; P < .001). In addition, quality of life, measured by the FACT-P questionnaire, was superior in the enzalutamide arm.
A seizure was reported in five of the 800 men in the enzalutamide study group, versus none in the placebo group; however, the relationship to enzalutamide is not clear. Of the reported seizures, two patients had brain metastases, one patient had just received intravenous lidocaine, and one seizure was not witnessed.
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 hormonal therapy. 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.
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. Survival rates are similar whether ketoconazole plus hydrocortisone is initiated at the same time as antiandrogen (e.g., flutamide, bicalutamide, or nilutamide) withdrawal or when PSA has risen after an initial trial of antiandrogen withdrawal as seen in the CLB-9583 trial, for example.[Level of evidence: 1iiA] Data on whether PSA changes while on chemotherapy are predictive of survival are conflicting.[19,22]
Patients treated with either luteinizing-hormone agonists or estrogens as primary therapy are generally maintained with castrate levels of testosterone. One study from ECOG showed that a superior survival resulted when patients were maintained on primary androgen deprivation; however, another study from SWOG (formerly the Southwest Oncology Group) did not show an advantage to continued androgen blockade.
Palliation for bone metastases
Painful bone metastases can be a major problem for patients with prostate cancer. Many strategies have been studied for palliation, including:[24,25,26,27,28]
- External-beam radiation therapy (EBRT).
- Bone-seeking radionuclides (strontium chloride Sr 89).
- Denosumab (a monoclonal antibody that inhibits osteoclast function).
- Pain medication.
- Gallium nitrate.
(Refer to the PDQ summary on Pain for more information.)
Evidence (palliation for bone metastases using 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.[29,30][Level of evidence: 1iiC]
Evidence (palliation for bone metastases using strontium chloride):
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,
- A multicenter, randomized trial of a single intravenous dose of strontium chloride Sr 89 (150 MBq: 4 mCi) versus palliative EBRT was done in men with painful bone metastases from prostate cancer despite hormone treatment.[Level of evidence: 1iiA]; 
- Similar subjective pain response rates were shown in both groups: 34.7% for strontium chloride Sr 89 versus 33.3% for EBRT alone.
- OS was better in the EBRT group than in the strontium chloride Sr 89 group (P = .046; median survival 11.0 months vs. 7.2 months).
- No statistically significant differences in time-to-subjective progression or in progression-free survival were seen.
- 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.
Evidence (palliation for bone metastases using denosumab):
- A placebo-controlled, randomized trial (NCT00321620) compared denosumab with zoledronic acid for the prevention of skeletal events (pathologic fractures, spinal cord compression, or the need for palliative bone radiation or surgery) in men with hormonal therapy-resistant prostate cancer with at least one bone metastasis.
- The trial reported that denosumab was more effective than zoledronic acid; median time to first on-study skeletal event was 20.7 versus 17.1 months (HR, 0.82; 95% CI, 0.71–0.95).
- Serious adverse events were reported in 63% of denosumab patients versus 60% in patients on zoledronic acid. The cumulative incidence of osteonecrosis of the jaw was low in both study arms (2% in the denosumab arm vs. 1% in the zoledronic acid arm). There was grade 3 to 4 toxicity. There was no difference in survival. The incidence of hypocalcemia was higher in the denosumab arm (13% vs. 6%).
Treatment Options for Recurrent Prostate Cancer
Treatment options for recurrent prostate cancer include the following:
- Chemotherapy for hormonal management of prostate cancer.
Chemotherapy for hormonal management of prostate cancer
Evidence (chemotherapy for hormonal management of prostate cancer):
- A randomized trial showed improved pain control in patients with hormone-resistant prostate cancer treated with mitoxantrone plus prednisone compared with those treated with prednisone alone. Differences in OS or measured global quality of life between the two treatments were not statistically significant.
- In a randomized trial involving 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). 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 given at 12 hours, 3 hours, and 1 hour prior to the 3-week regimen; 8 mg 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%, HRdeath of 0.79; 95% 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).[Levels of evidence: 1iiA, 1iiC]
- In another randomized trial involving 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 aspirin to prevent vascular thrombosis), and docetaxel (60 mg/m2 intravenously [IV] on day 2, preceded by dexamethasone [20 mg times 3 starting the night before]) was compared with mitoxantrone (12 mg/m2 IV every 3 weeks) plus prednisone (5 mg daily).[Level of evidence: 1iiA]
- 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 of 0.80; 95% CI, 0.67–0.97).
- Global quality of life and pain palliation measures were similar in the two treatment arms.[Level of evidence: 1iiC]
In patients with hormone-resistant prostate cancer whose disease progressed during or after treatment with docetaxel, cabazitaxel was shown to improve survival compared with mitoxantrone in a randomized trial (NCT00417079). In this trial, 755 such men were treated with daily oral prednisone (10 mg) and randomly assigned to receive either cabazitaxel (25 mg/m2 IV) or mitoxantrone (12 mg/m2 IV) every 3 weeks.[Level of evidence; 1iiA]
- Median OS was 15.1 months in the cabazitaxel arm and 12.7 months in the mitoxantrone study arm (HRdeath of 0.70; 95% CI, 0.59–0.83; P < .0001).
Other chemotherapy regimens reported to produce subjective improvement in symptoms and reduction in prostate-specific antigen (PSA) level include the following:[Level of evidence: 3iiiDiii]; 
A study suggests that patients whose tumors exhibit neuroendocrine differentiation are more responsive to chemotherapy.
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.
- In the largest trial (Immunotherapy for Prostate Adenocarcinoma Treatment: IMPACT trial [NCT00065442]), 512 patients with hormone-refractory metastatic disease were randomly assigned in a 2:1 ratio to receive sipuleucel-T (n = 341) versus placebo (n =171) intravenously by 60-minute infusion every 2 weeks for a total of 3 doses. 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).[Level of evidence: 1iA]
- 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 of 0.78; 95% CI, 0.61–0.98; P = .03). 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 was $93,000 for a 1-month course of therapy. This translates into an estimated cost of about $276,000 per year of life saved.
- The same investigators performed two prior smaller trials (NCT00005947) of nearly identical design to the IMPACT trial.[45,46]
- The combined results of the two smaller trials, involving a total of 225 patients randomly assigned 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.
Low-dose prednisone may palliate symptoms in some patients.
Evidence (low-dose prednisone for palliation):
- A randomized comparison of prednisone (5 mg 4 times per day) with flutamide (250 mg 3 times per day) was conducted in patients with disease progression after androgen ablative therapy (castration or luteinizing hormone-releasing hormone agonist).
- Prednisone and flutamide produced similar overall survival, symptomatic response, PSA response, and time to progression; however, there were statistically significant differences in pain, nausea and vomiting, and diarrhea in patients who received prednisone. (Refer to the PDQ summaries on Pain and Nausea and Vomiting; refer to the PDQ summary on Gastrointestinal Complications for information on diarrhea.)
Ongoing clinical trials continue to explore the value of chemotherapy for these patients.[9,10,11,12,34,40,41,42]
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.
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