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Background:  The NCCN Guidelines for Prostate Cancer currently recommend several definitive radiotherapy (RT) options for men with unfavorable intermediate-risk (UIR) prostate cancer: external-beam RT (EBRT) plus androgen deprivation therapy (ADT) or EBRT plus brachytherapy boost with or without ADT. However, brachytherapy alone with or without ADT is not well defined and is currently not recommended for UIR prostate cancer. We hypothesized that men treated with brachytherapy with or without ADT have comparable survival rates to men treated with EBRT with or without ADT.  Methods:  A total of 31,783 men diagnosed between 2004 and 2015 with UIR prostate cancer were retrospectively reviewed from the National Cancer Database. Men were stratified into 4 groups: EBRT (n=12,985), EBRT plus ADT (n=12,960), brachytherapy (n=4,535), or brachytherapy plus ADT (n=1,303). Inverse probability of treatment weighting (IPTW) was used to adjust for covariable imbalances, and weight-adjusted multivariable analysis (MVA) using Cox regression modeling was used to compare overall survival (OS) hazard ratios (HRs).  Results:  Relative to EBRT alone, the following treatments were associated with improved OS: EBRT plus ADT (HR, 0.92; 95% CI, 0.87–0.97;  P =.002), brachytherapy alone (HR, 0.90; 95% CI, 0.83–0.98;  P =.01), and brachytherapy plus ADT (HR, 0.78; 95% CI, 0.69–0.88;  P =.00006). Brachytherapy correlated with improved OS relative to EBRT in men who were not treated with ADT (HR, 0.92; 95% CI, 0.84–0.99;  P =.03) and in those receiving ADT (HR, 0.84; 95% CI, 0.75–0.95;  P =.004). At 10-year follow-up, 56% and 63% of men receiving EBRT and brachytherapy, respectively, were alive ( P &lt;.0001). IPTW was used to determine the average treatment effect of definitive brachytherapy. Relative to EBRT, definitive brachytherapy correlated with improved OS (HR, 0.90; 95% CI, 0.84–0.97;  P =.009) on weight-adjusted MVA.  Conclusions:  Definitive brachytherapy was associated with improved OS compared with EBRT. The addition of ADT to both EBRT and definitive brachytherapy was associated with improved OS. These results suggest that definitive brachytherapy should be considered as an option for men with UIR prostate cancer.

Outcomes of Patients With Unfavorable Intermediate-Risk Prostate Cancer Treated With External-Beam Radiotherapy Versus Brachytherapy Alone