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Daily anti-androgen therapy improves survival for patients with recurrent prostate cancer
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The addition of 2 years of daily anti-androgen therapy with bicalutamide to salvage radiation therapy significantly prolonged long-term OS without increasing toxicity among men with prostate cancer whose diseased recurred after radical prostatectomy, according to results of a double blind phase 3 trial presented at the ASTRO annual meeting.
Most men who have a recurrence following the surgical removal of their prostate are treated with salvage radiation therapy to the surgical site. Because androgens stimulate prostate cancer cell growth, William U. Shipley, MD, FACR, FASTRO, the Andres Soriano distinguished professor of radiation oncology at Massachusetts General Hospital and Harvard Medical School, and colleagues predicted that long-term anti-androgen therapy, when combined with salvage radiation therapy, could improve OS and other cancer control outcomes for those patients whose disease recurred following prostatectomy.
“Over the last 25 years, many men with intermediate-risk prostate cancer have undergone radical prostatectomy, yet many will face recurrence in 1 to 4 years with a rising PSA,” Shipley said in a press release. “Our results show that salvage radiation therapy plus androgen blockage, when compared to radiation therapy with a placebo, improved long-term OS and reduced death from prostate cancer without adding significantly to radiation toxicity.”
The RTOG 9601 trial — conducted between 1998 and 2003 — included 761 men with prostate cancer who had undergone a radical prostatectomy and had or had developed PSA levels between 0.2 ng/mL to 4 ng/mL and with disease classified as T2pN0 (confined to prostate, no lymph nodes affected; 33%) or T3pN0 (grown outside the prostate, still no lymph nodes affected; 67%).
Patients received 64.8 Gy radiation in 36 fractions of 1.8 Gy with placebo (n = 377) or 150 mg bicalutamide (n = 384) for 24 months.
Median follow up was 12.6 years. The rate of 10-year OS was 82% for the bicalutamide arm and 78% in the placebo arm (HR = 0.75; 95% CI, 0.58-0.98).
PSA progression was defined as a PSA greater than 0.5 ng/mL in patients whose treatment had resulted in undetected PSA, or when the PSA rose 0.3 ng/mL above entry PSA. Ten-year freedom from PSA progression occurred in significantly more patients in the experimental arm (46% vs. 30%; P ˂ .001).
Anti-androgen therapy also reduced the 12-year incidence rates of prostate cancer-related death at 12 years (2.3% vs. 7.5%; P < .001) and cancer metastasis (14% vs. 23%; P < .001).
Grade 3 adverse events in the bowel or bladder appeared comparable in both groups; however, 70% of the men in the anti-androgen group experienced grade 1 or 2 gynecomastia compared with 11% of the placebo arm.
“Because prostate cancer progresses slowly, follow-up over 12 years was necessary to demonstrate a statistically better patient survival with combined anti-androgen therapy and radiation therapy,” Shipley said in the release. “Further statistical analyses, which are underway, may identify subgroups of prostate cancer patients who may not benefit from hormone therapy added to salvage radiation therapy, and others for whom it may be especially beneficial.” – by Anthony SanFilippo
For more information: Shipley WU, et al. LBA 5. Presented at: ASTRO Annual Meeting; Oct. 18-21, 2015; San Antonio, Texas.
Disclosure: The trial was supported by AstraZeneca and the NCI.
Perspective
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Michael Zelefsky, MD
Recently reported long-term follow-up results from the RTOG 9601 trial represent a landmark study highlighting the importance of long-term androgen deprivation therapy in conjunction with salvage radiotherapy after radical prostatectomy. This study is the first randomized prospective trial to demonstrate an OS benefit among patients treated with anti-androgen therapy after developing a biochemical relapse following surgery. The study reported a 4% survival benefit at 10 years for patients treated with anti-androgen therapy consisting of daily bicalutamide administered for a duration of 2 years before and during the course of salvage radiotherapy. This 4% survival benefit appeared to be related to a 5% reduction in prostate cancer-related deaths observed in the hormonal therapy arm. There were no significant toxicity differences reported between the treatment arms except for the anticipated gynecomastia, which would be expected among patients receiving high-dose bicalutamide.
Because this study was conducted almost 2 decades ago, its study design may not be completely applicable to current treatment practices employed in the urologic community. Specifically, the overwhelming majority of patients currently treated with salvage radiotherapy are referred with PSA levels less than 0.5 ng/ml, and in this current study significant percentages of the treatment cohorts presented with such low baseline pre-radiation PSA levels. It is therefore unclear if patients with very early PSA relapses — who often manifest nowadays with detectable PSAs at levels of 0.1 ng/ml to 0.3 ng/ml — would require prolonged anti-androgen therapy with their salvage radiotherapy for a duration of 2 years to produce a survival advantage. In addition, it may be difficult to extrapolate from the benefits of 24 months of bicalutamide at 150 mg daily to the need for 2 years of more commonly practiced ADT regimens, often in the form of luteinizing hormone-releasing hormone agonist treatment, especially in the setting of a very early biochemical relapse manifesting as a detectable PSA.
Notwithstanding these limitations, the RTOG 9601 results reported by Shipley and colleagues are extremely important, providing level 1 evidence that anti-androgen therapy is a critical adjunct to salvage radiotherapy for patients who present with biochemically relapsing disease following radical prostatectomy. The improved outcomes noted after 10 years provide evidence for the first time that a survival advantage can be achieved in the setting of salvage radiotherapy. Ongoing studies will further address these issues, but only after long-term follow-up of outcomes can be obtained to determine whether in the setting of very early PSA relapses prolonged ADT would result in survival benefits when combined with salvage radiotherapy.Click Here to Manage Email Alerts