ATLANTA—Randomized, controlled clinical trials, the gold standards of medical practice, aren't always helpful in choosing treatments. In men with locally advanced prostate cancer, for example, two seminal such trials (Widmark et al: Lancet 2009; 373:301-308 and Warde et al: Lancet 2011; 378: 2104-2111) showed that radiation therapy combined with androgen-deprivation therapy (ADT) decreased mortality compared with use of ADT alone in men with locally advanced disease.
“The problem is, these data don't apply to about one-third of men treated in the United States with prostate cancer,” said Justin E. Bekelman, MD, Assistant Professor of Radiation Oncology at the University of Pennsylvania, speaking during a presentation here at the American Society for Radiation Oncology Annual Meeting. “About one-third of men with high-risk prostate cancer in the ‘real world’ have screening-detected, T1 disease, and these trials allowed only patients with T2 to T4 disease. And one-third of patients with high-risk prostate cancer treated with either ADT or ADT-RT are over age 76—men who were also excluded from those trials.”
To determine whether the findings from the above two randomized controlled trials (RCTs) extend to real-world clinical practice, Bekelman and colleagues at the University of Philadelphia and Fox Chase Cancer Center conducted a retrospective, observational cohort study with SEER-Medicare data (Abstract 96—accessible via http://online.myiwf.com/astro2013/Abstract.aspx).
Using observational and statistical methods they duplicated the results of the two cited trials with patients who would not have been eligible for those trials.
“We found that in certain patient subgroups not eligible for those trials, radiotherapy still led to improvements in overall and in prostate cancer-specific survival,” he said. “This suggests that the treatment of men with prostate cancer above the age of 76 still requires radiotherapy, and that using radiotherapy in the elderly can still lead to survival improvements.”
The study included men age 65 or older with stage T1c Gleason 8-10 prostate cancer or stage T2/T3, moderately to poorly differentiated prostate cancer, classified into ADT or ADT-RT treatment groups.
The analytic cohorts included 31,451 patients: 4,642 ADT and 8,282 ADT-RT patients in an “RCT-like cohort” with inclusion/exclusion criteria similar to those in the two RCTs; 8,694 ADT and 5,646 ADT-RT patients in a cohort of age 76 to 85; and 2,017 ADT and 2,260 ADT-RT patients in a screen-detected cohort of T1c, Gleason 8-10 tumors.
In the RCT-like cohort, use of ADT-RT was associated with reduced overall mortality (hazard ratio 0.63) and disease-specific mortality (hazard ration of 0.63). These observational effect estimates were close to the meta-analytic estimates from the RCTs, Bekelman said.
In the “elderly” cohort of patients, use of ADT-RT was again associated with reduced overall mortality (hazard ratio 0.63) and disease-specific mortality (hazard ratio 0.51). And in the “screen-detected cohort,” ADT-RT was associated with reduced overall mortality (hazard ratio 0.50) and disease-specific mortality (hazard ratio 0.25).
Older Patients: To Treat or Not?
“Among patients who are older and patients who have screen-detected cancers, the question is should we treat or not—will the cancer actually impact the patient's survival?” Bekelman said. “But patients included in this study are men with the most aggressive types of prostate cancer. So then the question becomes, even when patients are older than 75 years, or even if we can't palpate a lesion but they still have pathologically aggressive disease, is very aggressive treatment with both ADT and RT appropriate?”
Bekelman said his study's findings challenge the thinking about the treatment of the elderly: “It isn't a question that could be addressed in a randomized, controlled trial because so few men over the age of 80 participate in trials,” he said, adding that the time may be ripe for an evidence-based guideline on the use of radiation and ADT in men with high-risk prostate cancer.
“The wrong message from this work is that we should start treating all patients with prostate cancer,” Bekelman said. “The right message is that there are patient subgroups that are not represented in the evidence for ADT plus RT—those with screen-detected high-risk cancers and the very elderly—where adding radiation to hormone therapy may still improves survival.”
Trials Had Strict Eligibility Criteria
Asked for his opinion for this article, Jeff Michael Michalski, MD, MBA, Professor and Vice Chairman of the Department of Radiation Oncology and Chief of the Genitourinary Service at Washington University School of Medicine, said that each of the randomized controlled clinical trials cited showed that hormones and radiation were better than hormones alone—“in fact almost a halving of the prostate cancer death rate, with a significant improvement in the overall survival.
“But these large, randomized trials had very strict eligibility criteria, so the question is, are these results generalizable? Can we say that a man walking into my office today who may not have been perfectly fit for one of those studies, should we treat him as if he were on one of those studies, with the better arm?”
The study showed, Michalski continued, that in every circumstance, whether the men would or would not have qualified for the study because they were too old, or because they may have had earlier disease than one would have anticipated, that those patients still benefited from the combination of radiation and the hormone therapy—“thus validating in a very large cohort of patients, the results of the randomized trials reported in The Lancet,” he said.
“When you have patients who have high-risk cancer or locally advanced cancer, you shouldn't sell them short,” he continued. “You shouldn't treat them with hormones only; you should give them radiation unless there is some reason not to give them radiation like prior pelvic radiation or pelvic surgery, or a serious health problem that doesn't predict for a good short-term survival.
“But if they're fit enough to tolerate the radiation therapy, there's a very good likelihood that they'll have better survival, and accompanying a better survival is also improved quality of life.”
And about changing practice? “I hope it does; it should,” he said. “I think we're going to see more patients referred for radiation therapy because it's clear that they benefit from it.”© 2013 by Lippincott Williams & Wilkins, Inc.
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