A recent review of two phase III randomized controlled trials demonstrated that addition of androgen deprivation therapy (ADT) to salvage pelvic radiation therapy (RT) for prostate cancer recurrence after radical prostatectomy reduces the risk of metastases and improves overall survival.
However, according to a clinical decision-making framework developed by the review’s authors (Eur Urol [epub ahead of print], July 14, 2017), an individualized approach provides the most benefit in patients with more adverse features such as higher PSA level or adverse pathology.
Nearly one-third of men treated with radical prostatectomy will experience recurrent prostate cancer and are often treated with salvage radiation therapy. Addition of ADT to RT for the intact prostate has been shown to reduce the risk of recurrence or progression, but the use of ADT in the setting of salvage RT, while often used, has been poorly understood.
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The two trials have distinct features in terms of patient population, the type of ADT used, and outcomes. In the American study, RTOG 9601, bicalutamide (Casodex), 150 mg per day was used for 2 years along with salvage RT. The European study, GETUG-16, used hormone therapy with the LHRH analog goserelin (Zoladex) for 6 months. RTOG 9601 recruited patients with, on average, more adverse features such as higher PSA level, higher rate of positive surgical margins, persistently elevated PSA level, and higher Gleason score. Further, RTOG 9601 showed a lower risk of metastases and an overall survival advantage while GETUG-16 so far has only demonstrated a biochemical recurrence advantage from adding the hormone therapy to salvage RT.
The authors highlight the differences and present a framework to enable clinicians to select the most appropriate patients for the combination of ADT with salvage RT. Because the benefit from the ADT was not demonstrated until the second decade, men with less than 10 years of life expectancy may be treated with salvage RT alone. In both trials, the largest benefit from ADT was noted in men with pre-salvage RT PSA >0.5 ng/mL or >0.7 ng/mL, so men with a higher PSA level may be better candidates for this combined approach. Similarly, men with higher grade cancers and positive surgical margins demonstrated lower risk of metastases and improved overall survival with the addition of ADT.
Side effects differ between studies
Using this type of framework can allow us to individualize the therapy in order to reduce the risk of side effects to those individuals who are less likely to benefit from the addition of ADT. These side effects in both studies were different, as expected, due to the type of hormone suppression used. In RTOG 9601, gynecomastia was noted in up to 70% of men and a higher risk of liver toxicity was noted. In GETUG-16, the use of goserelin was associated with a significantly high rate (45%) of hot flashes and sweating when compared to the salvage RT-alone group. Other potential side effects from hormone therapy, such as worsening of cardiovascular morbidity, were not reported.
Still, some questions remained regarding the type and the duration of ADT. Is it better to use bicalutamide for 2 years compared to goserelin for 6 months, especially since the latter study has not shown a decrease in metastases or improved survival? Or could more potent antiandrogens such as enzalutamide (XTANDI) be used for a shorter duration and with improved benefit?
While we await the answers to some of these questions through ongoing clinical trials, patient factors and tumor factors such as life expectancy, pre-salvage RT PSA, and adverse pathologic features are the most important variables that can help the clinician select the patients who are most likely to benefit from the combination of ADT with salvage RT.
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