Multimodal Treatment in Patients With Gleason Score 9–10 Prostate Cancer
University of California, Los Angeles (UCLA) researchers have discovered that a combination of high doses of radiotherapy and hormonal therapy provides the best chance of decreasing the mortality rate in men with aggressive prostate cancer. The findings, published by Kishan et al in JAMA, also suggest that such a multimodal treatment approach has the best chance of preventing metastatic disease and improving overall long-term survival.
The study, led by UCLA researcher Amar Kishan, MD, in collaboration with researchers at 11 institutions across the United States, is the first of its kind to compare outcomes between extremely dose-escalated radiotherapy and traditional treatments, such as radiation and prostatectomy, in men with cancers classified as Gleason score 9 or 10.
"The type of aggressive form of prostate cancer that we focused on has sometimes been regarded as so high risk that some patients even forgo local treatments, like surgery or radiation, because they are worried that the cancer has already spread and is incurable," said Dr. Kishan, Assistant Professor in the Departments of Radiation Oncology and Urology and a member of the Institute of Urologic Oncology at UCLA. “Our findings in fact show just the opposite—in this study, the patients with the best outcomes were those who received an aggressive therapy that included so-called ‘extremely dose-escalated radiotherapy’ along with hormonal therapy.”
Study Background
The study builds upon previous research led by Dr. Kishan and colleagues, which provided the first convincing evidence that surgery and standard radiation-based treatments offer equivalent outcomes for men with prostate cancer, and suggested a potential benefit over both to extremely dose-escalated radiation. The ideal therapeutic approach for these patients has long been controversial, in part because technologies and radiation-based treatments strategies have evolved significantly over time. The effectiveness of these approaches is of even greater importance for the most aggressive forms of prostate cancer, which are more likely to lead to metastatic disease and eventually death.
Several studies have shown that increasing the dose of radiotherapy beyond standard doses (known as extreme dose-escalation) in combination with hormonal therapy has improved short-term outcomes, but no prior study has shown a difference in mortality rates or long-term survival in any group of patients with prostate cancer. Previous research comparing patients treated with radical prostatectomy to radiotherapy-based treatments have generally included patients treated over the span of multiple decades, many of whom were treated with lower doses of radiation and/or with insufficient hormonal therapy.
Dr. Kishan's team hypothesized that by using a large pool of patients with aggressive disease treated within a contemporary timeframe, they could better assess the effectiveness of modern treatments in these high-risk patients.
Method
In the 3-year study, the UCLA-led team analyzed 1,809 men who were treated for Gleason score 9–10 prostate cancer from 2000 to 2013 at UCLA and other sites in the United States and Europe. The findings specifically included advanced prostate cancer patients who were treated since 2000 because the standard of care for these patients has significantly improved over time. The scientists used institutional databases to identify patients and obtained clinical follow-up to assess long-term treatment outcomes.
Findings
Of 1,809 men, 639 underwent radical prostatectomy, 734 were treated with external-beam radiotherapy (EBRT), and 436 with EBRT plus brachytherapy boost. Median ages were 61, 67.7, and 67.5 years; median follow-up was 4.2, 5.1, and 6.3 years, respectively.
By 10 years, 91 patients undergoing radical prostatectomy, 186 receiving EBRT, and 90 treated with EBRT plus brachytherapy boost had died.
Adjusted 5-year prostate cancer–specific mortality rates were 12% for those treated with radical prostatectomy (95% confidence interval [CI] = 8%–17%); 13% for those treated with EBRT (95% CI = 8%–19%); and 3% for those treated with EBRT plus brachytherapy boost (95% CI = 1%–5%). EBRT plus brachytherapy boost was associated with significantly lower prostate cancer–specific mortality than either radical prostatectomy or EBRT (cause-specific hazard ratios [HRs] of 0.38 [95% CI = 0.21–0.68] and 0.41 [95% CI = 0.24–0.71]).
Adjusted 5-year incidence rates of distant metastasis were 24% for radical prostatectomy (95% CI = 19%–30%); 24% for EBRT (95% CI = 20%–28%); and 8% for EBRT plus brachytherapy boost (95% CI = 5%–11%). EBRT plus brachytherapy boost was associated with a lower rate of distant metastasis (propensity-score-adjusted cause-specific HRs of 0.27 [95% CI = 0.17–0.43] for radical prostatectomy and 0.30 [95% CI = 0.19–0.47] for EBRT).
Adjusted 7.5-year all-cause mortality rates were 17% for radical prostatectomy (95% CI = 11%–23%); 18% for EBRT (95% CI = 14%–24%); and 10% for EBRT plus brachytherapy boost (95% CI = 7%–3%). Within the first 7.5 years of follow-up, EBRT plus brachytherapy was associated with significantly lower all-cause mortality (cause-specific HRs of 0.66 [95% CI = 0.46–0.96] for radical prostatectomy and 0.61 [95% CI = 0.45–0.84] for EBRT).
Implications and Limitations
The findings have the potential to help physicians better identify men with prostate cancer who will benefit from a multimodal therapeutic approach and advise patients of the effectiveness of different treatment options.
“There are, of course, limitations to this study,” Dr. Kishan added. “Most notably, it was a retrospective study, meaning patients received a certain type of treatment largely based on patient and physician preferences, rather than in the context of a trial. It is possible that outcomes in the standard radiation group were worse because the patients themselves were sicker and not good candidates for the boost of radiation. From the surgery standpoint, nearly 40% of patients did get postoperative radiation—which is much higher than in other studies—but some might argue that if postoperative radiation was used even more frequently, surgical outcomes would have been better.”
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
