Biochemical recurrence (BCR) falls short as a reliable surrogate for overall survival in localized prostate cancer trials and may not be a suitable primary endpoint.
In trials of localized prostate cancer, BCR remains a controversial surrogate endpoint for overall survival.
The meta-analysis included 10,741 patients from 11 randomized clinical trials; the median follow-up was 9.2 years.
Interventions included radiotherapy dose escalation, in which high-dose radiotherapy was compared with conventional radiotherapy (n = 3639); short-term androgen deprivation therapy (ADT), in which radiotherapy plus short-term ADT was compared with radiotherapy alone (n = 3930); and ADT prolongation, in which radiotherapy plus long-term ADT was compared with radiotherapy plus short-term ADT (n = 3772).
Prentice criteria and the two-stage meta-analytic approach were used to assess BCR as a surrogate endpoint for overall survival.
The researchers assessed the treatment effect on BCR and on overall survival.
With regard to treatment effect on BCR, the three interventions significantly reduced BCR risk — dose escalation by 29%, short-term ADT by 47%, and ADT prolongation by 46%. With regard to survival, only short- and long-term ADT significantly improved overall survival, by 9% and 14%, respectively.
At 48 months, BCR was associated with significantly increased mortality risk: 2.46-fold increased risk for dose escalation, 1.51-fold greater risk for short-term ADT, and 2.31-fold higher risk for ADT prolongation.
However, after adjusting for BCR at 48 months, there was no significant treatment effect on overall survival (hazard ratio [HR], 1.10; [95% CI, 0.96 – 1.27]; HR, 0.96 [95% CI, 0.87 – 1.06]; HR, 1.00 [95% CI, 0.90 – 1.12], respectively).
Patient-level correlation between time to BCR and overall survival was low after censoring for noncancer-related deaths. The correlation between BCR-free survival and overall survival ranged from low to moderate.
Overall, “these results strongly suggest that BCR-based endpoints should not be the primary endpoint in randomized trials conducted for localized [prostate cancer],” the authors concluded. They added that metastasis-free survival represents a more appropriate measure.
The study was led by senior author Amar Kishan, MD, of the David Geffen School of Medicine, University of California, Los Angeles, and was published online on August 28 in the Journal of Clinical Oncology.
The trials used different definitions of BCR ― the older American Society of Therapeutic Radiation and Oncology definition, and the more current Phoenix criteria.
Some trials were conducted over 20 years ago, and a variety of factors, including patient selection, staging, diagnostic criteria, and therapeutic approaches, have evolved in that time.
Quality of life was not captured.
The study received support from Cancer Research UK, the UK National Health Service, the Prostate Cancer National Institutes of Health Specialized Programs of Research Excellence, the UK Department of Defense, the Prostate Cancer Foundation, and the American Society for Radiation Oncology. Authors’ relevant financial relationships are detailed in the published study.
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