In a retrospective cohort study reported in the Journal of Clinical Oncology, Derya Tilki, MD, of Martini-Klinik Prostate Cancer Center, University Hospital-Hamburg-Eppendorf, Hamburg, and colleagues found that adjuvant radiotherapy was associated with reduced risk for all-cause mortality vs early salvage radiotherapy among men at high risk for recurrence following radical prostatectomy for prostate cancer.1
As stated by the investigators: “Three randomized trials and an associated meta-analysis found no difference in progression-free survival when comparing adjuvant with early [salvage radiotherapy], which can cause many physicians to not offer adjuvant [radiotherapy], irrespective of the pathologic findings at [radical prostatectomy]. We provide evidence to support that adjuvant compared with early [salvage radiotherapy] may lower the risk of death in men with adverse pathology at [radical prostatectomy].”
Derya Tilki, MD
The study cohort consisted of 26,118 men with pT2–4N0 or N1M0 prostate cancer, consecutively treated between June 1989 and July 2016 with radical prostatectomy and pelvic lymph node assessment and then followed for potential treatment with adjuvant or early salvage radiotherapy at University Hospital Hamburg-Eppendorf, Charité University Hospital (Berlin) and University Hospital Ulm in Germany as well as the University of California, San Francisco, and Johns Hopkins Medical Institution in the United States. Follow-up started on the date of radical prostatectomy, and the database was last updated in October 2020.
The primary outcome measure was risk of all-cause mortality in men with adverse pathology, defined as positive pelvic lymph nodes (pN1) or a prostatectomy Gleason score of 8 to 10 and disease extending beyond the prostate (pT3/4). A treatment propensity score was used to minimize potential treatment selection bias in estimating the causal association of adjuvant vs early salvage radiotherapy on all-cause mortality risk. Analyses were performed to assess the effect of different definitions of adverse pathology on all-cause mortality risk—eg, exclusion of pN1 disease (based on exclusion of such patients in two of three randomized trials) and exclusion of salvage radiotherapy patients with persistent postsurgery prostate-specific antigen (PSA) level (also excluded in two trials). Multivariate analyses were adjusted for age at radical prostatectomy, prostate cancer prognostic factors, study site, and time-dependent use of postprostatectomy androgen-deprivation therapy.
Analyses of All-Cause Mortality
Median follow-up was 8.16 years (interquartile range = 6.0–12.1 years). Among the 26,118 patients, 2,104 (8.1%) died, including 539 from prostate cancer. Adverse pathology at radical prostatectomy was identified in 2,424 patients when those with pN1 disease were included; among these patients, 428 received adjuvant radiotherapy, 965 had no radiotherapy, and 1,031 received salvage radiotherapy. A total of 933 patients had adverse pathology when those with pN1 disease were excluded; among these patients, 109 received adjuvant radiotherapy, 379 had no radiotherapy, and 445 received salvage radiotherapy.
On multivariate analysis, compared with salvage radiotherapy, men receiving adjuvant radiotherapy had significantly lower risk of all-cause mortality when patients with pN1 disease were included (adjusted hazard ratio [HR] = 0.61, 95% confidence interval [CI] = 0.41–0.89, P =.01) and when those with pN1 disease were excluded (HR = 0.31, 95% CI = 0.12–0.78, P = .01). Compared with salvage radiotherapy, no significant differences in all-cause mortality risk were observed among patients receiving no radiotherapy when pN1 disease was included (HR = 1.09, 95% CI = 0.88–1.36, P = .42) or excluded (HR = 1.14, 95% CI = 0.83–1.57, P = .42).
In an analysis excluding patients in the salvage radiotherapy group with a persistent measurable postoperative PSA level, significantly reduced all-cause mortality risk with adjuvant radiotherapy was maintained when pN1 disease was included (total = 2,106; HR = 0.66, 95% CI = 0.44–0.99, P = .04) and excluded (total = 826; HR = 0.33, 95% CI = 0.13–0.85, P = .02).
Among 23,694 patients without adverse pathology at radical prostatectomy, 391 received adjuvant radiotherapy, 19,733 had no radiotherapy, and 3,570 received early salvage radiotherapy. Compared with salvage radiotherapy, no significant difference in risk for all-cause mortality was observed among men receiving adjuvant radiotherapy (HR = 0.78, 95% CI = 0.50–1.22, P = .28) or no radiotherapy (HR = 1.07, 95% CI = 0.93–1.23, P = .33).
10-Year All-Cause Mortality Rates
The 10-year adjusted point estimates of all-cause mortality when patients with pN1 disease were included were 13.8% (95% CI = 8.4%–22.1%) with adjuvant radiotherapy, 27.3% (95% CI = 22.5%–32.9%) with no radiotherapy, and 22.0% (95% CI = 18.3%–26.3%) for early salvage radiotherapy. When patients with pN1 disease were excluded, estimates were 5.1% (95% CI = 2.0%–12.8%) with adjuvant radiotherapy, 25.3% (95% CI = 19.0%–33.3%) with no radiotherapy, and 22.2% (95% CI = 17.6%–27.7%) with early salvage radiotherapy. Among patients without adverse pathology, estimates were 7.8% (95% CI = 4.6%–13.3%) for adjuvant radiotherapy, 8.8% (95% CI = 7.4%–10.5%) for no radiotherapy, and 8.0% (95% CI = 6.8%–9.2%) for early salvage radiotherapy.
The absolute differences in the 10-year adjusted point estimates of all-cause mortality for adjuvant radiotherapy vs early salvage radiotherapy were −8.2% (95% CI = −16.0 to −0.4) when pN1 disease was included and −17.0% (95% CI = −24.0 to −10.1) when pN1 disease was excluded. As noted by the investigators, the 95% confidence intervals for the differences exclude 0 and the size of the differences support the statistical significance of the differences and suggest they are clinically relevant differences.
The investigators concluded: “Adjuvant radiation therapy should be considered in men with pN1 or [prostatectomy] Gleason score 8 to 10 and pT3/4 [prostate cancer] given the possibility that a significant reduction in [all-cause mortality] risk exists.”
DISCLOSURE: Dr. Tilki has received honoraria from Exact Sciences, Ipsen, and Janssen; has served as a consultant or advisor to miR Scientific and Tolero Pharmaceuticals; has received research funding from Janssen; and has been reimbursed for travel, accommodations, or other expenses by Tolero Pharmaceuticals.
1. Tilki D, Chen MH, Wu J, et al: Adjuvant versus early salvage radiation therapy for men at high risk for recurrence following radical prostatectomy for prostate cancer and the risk of death. J Clin Oncol 39:2284-2293, 2021.
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