1. Samson, Kurt

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CHICAGO-Current long-term hormone replacement therapy for men with low postoperative prostate-specific antigen (PSA) levels may need to be reevaluated, according to new data presented at the 2019 ASTRO Annual Meeting.

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Secondary analysis of data from the NRG Oncology/RTOG 9601 study, a randomized, phase III trial initially reported in 2017, found that adding 2 years of anti-androgen therapy after surgery negatively reduced their survival.


Analysis of the trial's data resulted in a recommendation that such patients receive both post-surgical radiation and long-term hormone therapy. However, in this secondary data review, researchers found that for some patients this course of treatment may be harmful.


"What we showed for the first time is that a patient's PSA level is a predictive biomarker," said Daniel Spratt, MD, Laurie Snow Research Professor of Radiation Oncology and Chair of the Genitourinary Clinical Research Program at the University of Michigan Rogel Cancer Center.


"We discovered that we can use a patient's PSA to better select which men should receive hormone therapy, and predict who will benefit and who will not, but also which men may actually be harmed by it," he told a press conference. "We found that the lower the PSA, the more harm the patient experienced."


The findings were based on data for 760 prostate cancer patients, treated between 1998 and 2003 at more than 100 centers, whose cancer returned following prostate excision.


In the original study, patients were randomized to either post-surgical radiation therapy plus a nonsteroidal anti-androgen (bicalutamide 150 mg/day) or placebo for 2 years, after which overall survival rates were compared.



In this secondary analysis, the investigators first divided 118 patients into two groups based upon their pre-radiation PSA levels. They included patients with PSAs greater than 1.5 ng/mL (n=118) and those with PSAs lower than 1.5 ng/mL (n=642). There was no overall survival benefit for men with PSA levels lower than 1.5 ng/mL.


Spratt re-examined what happened to patients with lower PSA levels in light of changes over the past 2 decades in how recurrent prostate cancer is treated. When RTOG 9601 was enrolling patients, it was standard to allow PSA to rise to high levels following radical prostatectomies before initiating radiation therapy, but that's no longer the case.


The researchers further analyzed data for a subset of patients with PSA levels equal to or less than 0.6 ng/mL (n=389), closer to today's standard for post-surgical radiation treatment. In these patients, they found that they were twice as likely to die from causes other than cancer when hormone therapy was added, with a greatest risk of death (sHR 4.14 [1.57-10.89]) among men with the lowest PSA levels (0.2-0.3 ng/mL, n=148). These patients were also between three and four times more likely to suffer a combination of severe cardiac events and neurological problems (OR 3.57 [1.09-15.97], p=0.05).


Guideline Changes Needed

"We went into this study expecting that men with low PSAs probably would derive minimal benefit from hormone therapy, but we were surprised at the magnitude of harm that these patients experienced," said Spratt. "A lot of these side effects have been reported over the past few decades, but demonstrating this in a clinical trial to this extent has not been done before."


Because of this, Spratt said he believes clinical guidelines for such patients should be reconsidered.


"Patients with high PSAs, over 1.5 ng/mL, should continue to receive long-term hormone therapy in addition to radiation," he said. "It improves their survival substantially. But for patients with PSAs below 0.6 ng/mL who receive postoperative radiation therapy, there needs to be a real discussion about the fact that hormone therapy has not been shown to help these men live longer. Our study shows that long-term hormone therapy could actually hurt their survival and cause them other problems. A lot of shared decision-making is needed before recommending hormone therapy to all men with low PSAs."


The researchers are now enrolling postoperative patients with prostate cancer in another study (BALANCE trial/NRG GU-006) that will look more closely at which patients might benefit from hormone therapy and those who might be at risk, based on genetic testing of their tumors.



Colleen A. F. Lawton, MD, FASTRO, Professor and Vice Chair of Radiation Oncology at the Medical College of Wisconsin, was not convinced that the findings, on their own, are enough to change the current thinking on such patients.


"I don't feel that these findings warrant changes in treatment guidelines," she told Oncology Times. "The issue in this study is likely bicalutamide, used at the 150 mg level, for androgen deprivation therapy. It apparently caused some cardiac issues, but also caused gynecomastia (breast growth) in more than three-fourths of the patients."


Gynecomastia was reported as a significant toxicity when the first reports of this trial were released, she noted.


"Most oncologists use an LHRH agonist for androgen deprivation in these patients, as was done in the other salvage trial (GETUG-AFU 16). Patients who have higher postop PSA levels likely benefit more from the addition of ADT to radiation, but exactly where the benefit lies in terms of PSA levels is still not known," she told concluded.


Kurt Samson is a contributing writer.