ATLANTA—As time goes by, revisiting data from important clinical studies can reveal better ways to manage selected patients. Case in point: a secondary analysis of the historic RTOG 9202 prostate cancer trial, reported here at the ASTRO Annual Meeting, has concluded that long-term hormonal therapy after radiotherapy offered no additional benefit for men with intermediate-risk disease when compared with short-term hormonal therapy after radiotherapy (Abstract 61—accessible via online.myiwf.com/astro2013/Abstract.aspx).
The original RTOG 9202 study evaluated two years vs. four months of adjuvant androgen deprivation in men who at that time were considered to have high-risk disease due to high Gleason scores and stage T2c-4 tumors (Hanks et al: JCO 2003;21:3972-3978). When the trial was first published, the long-term androgen deprivation plus radiotherapy arm showed significant improvement over the short-term arm.
The secondary analysis, however, looked at men who by today's standards would fall into an intermediate-risk category. The results showed that patients who received short-term hormonal therapy plus radiotherapy did just as well as men who received long-term hormonal therapy in terms of PSA control, overall survival, and disease recurrence rate.
“Most clinicians have felt that ‘more is better’ when it came to blocking testosterone in prostate cancer patients, but for the specific endpoints we focused on, this was clearly not the case,” said lead author Amin Mirhadi, MD, a radiation oncologist at Cedars-Sinai Medical Center in Los Angeles.
Most of the 1,554 men in the original trial had high-risk disease, and most were slightly underdosed compared with what would be administered today. The secondary analysis was done for 133 patients who would today be classified as having intermediate-risk disease, either based on having stage T2 disease and a PSA level less than 10 ng/mL and a Gleason score of 7; having T2 disease and a PSA level in the range of 10-20 ng/mL and Gleason less than 7. This left 74 men in the short-term androgen-deprivation arm and 59 in the long-term arm.
With approximately 11 years of median follow up, the secondary analysis showed no statistically significant difference in overall survival: 10-year overall survival was 61 percent for short-term vs. 65 percent for long-term androgen deprivation.
Ten-year disease-specific survival was 96 percent for each study arm, and ten-year PSA failure rates were 53 percent and 55 percent, respectively.
“Given the small number of disease-specific deaths observed and the lack of a benefit with respect to any of our other endpoints, this secondary analysis does not suggest that exploration of longer duration hormonal therapy is worth testing in this intermediate-risk subset,” Mirhadi concluded.
Endorsing a Standard of Care
Asked to comment for this article, Jeff M. Michalski, MD, Professor and Vice Chairman of the Department of Radiation Oncology and Chief of the Genitourinary Service at Washington University School of Medicine, called RTOG 9202 and its secondary analysis “very affirmative in terms of endorsing radiation and temporary hormone therapy as a standard of care.”
He noted that when RTOG 9202 was designed in 1992, the risk classifications for prostate cancer hadn't yet been defined and the trial looked at a more heterogeneous patient population. Risk classifications incorporating the patient's presenting PSA, Gleason score, and clinical stage were developed later by Anthony D'Amico, MD.
“So while most patients in RTOG 9202 had high-risk prostate cancer by today's definition, some also had intermediate-risk,” Michalski said. “Now this secondary analysis appears to show that four months of hormone therapy is all that one would require.”
He said RTOG 9202 should be considered in tandem with outcomes in another study presented at this meeting, RTOG 9910 from Pisansky and colleagues (Abstract 1, OT 10/25/13 issue). That study looked at seven months of hormone therapy before radiotherapy plus two months during radiotherapy for a total of nine months, versus two months of hormone therapy before radiation plus two months during for a total of four months. The results also showed no difference between the long course and the short course of hormonal therapy.
“So this analysis of RTOG 9202 by Mirhadi and the 9910 study by Pisansky tell us, from two different directions, from two different eras, for two different patient populations, that four months of hormone therapy along with radiation therapy is going to cure most of these men, and the likelihood of them dying from prostate cancer is in the low single digits.”
Michalski pointed out that while the Pisansky study might be considered a negative study, it actually is not, “because that trial—remarkably—has a prostate cancer death rate of only around three percent. That means in 10 years, with the combination of hormone therapy and radiation therapy, that 97 percent of people are not dying from prostate cancer. That's good news.
“And the fact that you can do that with just four months of hormone therapy, tells a great story,” Michalski continued. “When a patient has decided that treatment is right for him, we can confidently say that radiation therapy with temporary hormone therapy has a high likelihood of curing the disease and presents an excellent alternative to other treatment options such as prostatectomy. Because if there's only going to be a three percent chance of dying from prostate cancer in a decade or longer, that's a pretty good outcome and should be considered a standard-of-care option relative to radical prostatectomy.”
The challenge for researchers in prostate cancer is that patient outcomes are getting so good that improving on them in the future will be increasingly difficult,” he said.
“This means we need to change our direction and emphasize improving the men's quality of life by reducing the side effects associated with both radiation therapy and hormone therapy. And I think we're coming to that point very soon.”
Importantly, Michalski said, as both studies show, one of the real problems with hormone therapy is duration. “The techniques of radiation have improved, management of side effects of radiation and of hormone therapy improved, and I think surgeons can no longer claim their treatment as the gold standard.”