Quantifying the benefit of salvage radiation versus surveillance for biochemically recurrent prostate cancer after radical prostatectomy.
Authors: Basourakos Spyridon P , Boorjian Stephen A. , Schulte Phillip J. , Henning Grant , O'Byrne Jamie T , Tollefson Matthew K. , Frank Igor , Khanna Abhinav , Phillips Ryan , Stish Brad J. , Karnes R. Jeffrey , Sharma Vidit 
Published: February 2025

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Background:
The natural history of biochemical recurrence (BCR) after radical prostatectomy (RP) is heterogeneous, with most patients not progressing to metastasis. Determining the impact and optimal timing of salvage radiation therapy (SRT) remains challenging, particularly in the absence of prospective randomized trials with a surveillance control arm. Our objective isto quantify the oncologic benefit of SRT among men with BCR after RP.
Methods:
Patients who underwent RP at Mayo Clinic between 1990 and 2017 and developed BCR (PSA≥0.20ng/mL) were included. Patients treated with SRT were compared to those managed with surveillance using risk-set matching with time-dependent propensity scores, accounting for covariates at BCR and post-BCR. The primary outcome was metastases, analyzed via Kaplan-Meier and Cox proportional hazard models. The number needed to treat (NNT) with SRT to prevent progression was calculated using regression outputs at 5 and 15 years post-BCR. Interaction analyses identified factors modifying SRT’s effect on metastasis.
Results:
Of 6,881 patients with BCR, 2,109 received SRT. At a median follow-up of 10.2 years, 1,147 patients with BCR developed metastases. After 1:1 matching, SRT was associated with lower metastasis risk than surveillance at 5 years (12.7% vs 19.3%, p<0.0001) and 15 years (28.6% vs. 31.5%, p<0.001). SRT was independently associated with decreased metastasis risk (HR 0.75, 95%CI 0.63–0.90, p=0.002) on multivariable analysis, translating to NNT of 23 and 15 at 5 and 15 years, respectively (Table). Additionally, we noted a significant interaction between PSA at SRT and the association of SRT with metastasis (p-interaction=0.02), such that the reduction in metastatic progression with SRT vs. surveillance was restricted to the cohort of patients who received SRT for PSA>0.40ng/mL (HR 0.66, 95%CI 0.54–0.80, p<0.001).
Conclusions:
Most patients with BCR post-RP do not develop metastases. Indeed, the NNT with SRT to reduce metastasis versus surveillance indicates a generally indolent disease course. Further, the lack of a significant association of SRT with reduction of metastases in patients with a PSA≤0.40ng/mL underscores the importance of careful patient selection when considering early SRT. Our data establish the rationale for a randomized trial comparing early SRT versus surveillance for appropriately selected patients with BCR after RP.

Hazard ratios of SRT after matching by propensity scores, and number needed to treat for systemic progression, prostate cancer specific mortality and overall mortality.

DiseaseOutcome
Hazard Ratio(95% CI)
P value
Number Needed to Treat* (95% CI)

5 years

15 years

Systemic progression
0.75(0.63 – 0.90)

0.002

23(17 – 41)
15(11 – 27)

Prostate cancer mortality
0.81 (0.64 – 1.03)
0.086
103(62 – 494)
26(15 – 124)

Overall mortality
0.79 (0.70 – 0.89)

0.0001

38(29 – 62)
12(9 – 20)

*Number needed to treat (NNT) calculated using regression based absolute differences in event free survival between salvage radiation therapy (SRT) and observation.