Men with localized prostate cancer lived longer when treated with external beam radiation therapy (EBRT) plus androgen deprivation therapy (ADT) but not EBRT with a brachytherapy boost (BT), a meta-analysis showed.
The addition of ADT led to a statistically significant 30% reduction in the hazard for overall survival (OS), whereas BT did not improve OS compared with EBRT alone. A network meta-analysis further supported the superiority of EBRT plus ADT versus EBRT plus BT.
“Our findings suggest that current practice patterns of omitting ADT with EBRT plus BT may result in inferior OS compared with EBRT plus ADT in men with intermediate- and high-risk prostate cancer,” William C. Jackson, MD, of the University of Michigan Medical Center in Ann Arbor, and co-authors concluded in an article published online in the Journal of Clinical Oncology. “ADT for these men should remain a critical component of treatment regardless of radiotherapy delivery method until randomized evidence demonstrates otherwise.”
Two Options, No Direct Comparisons
Multiple studies demonstrated inferior outcomes with EBRT alone versus combination therapy for men with localized unfavorable-risk prostate cancer. The addition of ADT to EBRT has been shown to reduce local treatment failure, improve biochemical control, reduce the risk of metastasis, and improve OS. The addition of BT, representing a type of local treatment intensification, reduces local recurrence and biochemical failure, the authors noted in their introduction.
Some researchers hypothesized that a higher dose of radiotherapy would reduce the benefits of ADT. However, a large European trial showed that ADT offered similar benefits across a range of radiation doses.
Whether ADT affords the same benefits in the setting of extreme radiotherapy dose-escalation with BT remains untested. Despite a lack of evidence to support omission of ADT from treatment for men with intermediate- and high-risk prostate cancer, analyses of clinical practice patterns have shown that use of brachytherapy is significantly associated with omission of ADT, involving 30-40% of cases, the authors continued.
To inform treatment decisions, investigators conducted a network meta-analysis, a statistical technique to collect and assimilate information from direct and indirect comparisons. They identified published randomized trials comparing EBRT with or without ADT and comparing EBRT with or without BT (irrespective of the addition of ADT).
Data analysis included six trials that compared EBRT alone or with ADT in a total of 4,663 men and three trials comparing EBRT with or without BT in 718 men. In two of the three BT trials, men also received ADT. The patients had intermediate- or high-risk prostate cancer in 84% of cases.
The results showed that adding ADT to EBRT significantly improved OS versus EBRT alone (hazard ratio [HR] 0.70, 95% CI 0.62-0.81). Separate analyses of trials that enrolled mostly men with high-risk disease versus those with intermediate-risk disease yielded similar results (HR 0.66, 95% CI 0.38-1.15 for high risk, HR 0.73, 95% CI 0.51-1.04 for intermediate risk).
In contrast, the addition of BT to EBRT (with or without ADT) did not improve OS (HR 0.94, 95% CI 0.70-1.27). The network meta-analysis showed that EBRT plus ADT significantly improved OS as compared with EBRT plus BT (HR 0.68, 95% CI 0.52-0.89). A cumulative incidence curve based on the network meta-analysis yielded an estimated 10-year overall mortality of 28% with EBRT plus ADT and 41% with EBRT plus BT.
The authors also compared EBRT plus ADT versus EBRT plus BT by means of Bayesian modeling. The analysis showed an 88% probability that EBRT plus ADT would lead to superior OS as compared with EBRT plus BT.
Finally, they ranked the probability that each treatment option (EBRT alone, EBRT plus ADT, EBRT plus BT) would produce superior OS, using a surface under the cumulative ranking curve (SUCRA). The SUCRA yielded probabilities of 27% for EBRT alone, 30% for EBRT plus BT, and 90% for EBRT plus ADT.
Concluding that the analyses demonstrated the superiority of EBRT plus ADT, the authors acknowledged that one of the trials of BT showed that the addition of BT to EBRT plus ADT further improved OS as compared with EBRT plus ADT.
“Thus, if a brachytherapy boost is to be used for intermediate- or high-risk disease, our data suggest that the addition of ADT is required to prevent inferior survival compared with EBRT with ADT alone,” they wrote.
The analysis added important information about optimal use of combination therapy to treat intermediate- and high-risk prostate cancer, said Mark A. Hallman, MD, PhD, of Fox Chase Cancer Center in Philadelphia.
“The use of ADT among high- and intermediate-risk cancers is further supported by this important meta-analysis,” said Hallman, who was not involved with the study. “However, this analysis importantly highlights the lack of data exploring the potential of brachytherapy as an effective and well-tolerated means to escalate therapy, and this analysis is not likely to silence existing controversies.”
“Significant limitations and deficits still exist even in this collection of high-quality prospective data. The available data do not inform the appropriate duration of ADT when brachytherapy is employed or adequately refine the population of patients most likely to benefit from brachytherapy. Trials dedicated to exploring the potential benefits specific to brachytherapy among high- and intermediate-risk patients are sorely needed.”
Jackson reported having no relevant relationships with industry. Multiple co-authors reported relationships with pharmaceutical companies, device manufacturers, and other commercial interests, as well as patent/royalty/intellectual property interests.