Title: Combining Prostate-Specific Antigen Nadir and Time to Nadir Allows for Early Identification of Patients at Highest Risk for Development of Metastasis and Death Following Salvage Radiation Therapy
Abstract: Following definitive radiation therapy (RT) for prostate cancer, both PSA nadir (nPSA) and the time to nPSA (TnPSA) have been shown to be prognostic for clinically meaningful patient outcomes. Little is known regarding the prognostic capability of PSA nadir (nPSA) and time to nPSA (TnPSA) following salvage radiation therapy (SRT) for biochemical failure post-radical prostatectomy. We evaluated the impact of nPSA and TnPSA on biochemical failure (BF), distant metastasis (DM), prostate cancer-specific mortality (PCSM), and overall mortality (OM) following SRT. Four hundred sixty patients who received SRT without androgen deprivation therapy at our institution were included in this retrospective study. Univariate and multivariate analysis was performed using Kaplan-Meier methods and Cox proportional-hazards regression, respectively. A prognostic model using the identified prognostic variables was developed and validated in randomly allocated training and validation patient cohorts. Median follow-up post-SRT was 62 months. Median nPSA post-SRT was undetectable (interquartile range [IQR] <0.1-0.3 ng/mL) and median TnPSA was 6.7 months (IQR 4.4-11.1). On univariate analysis, a detectable nPSA (p < 0.01) and TnPSA <6 months (p6 months were assigned a score of 1. Those with a detectable nPSA and a TnPSA <6 months were assigned a score of 2. In the training cohort, the Nadir Score model strongly predicted BF (hazard ratio [HR]: 3.9, p < 0.0001) and DM (HR: 2.8, p < 0.0001), and was the only statistically significant predictor of PCSM (HR: 2.7, p = 0.0003) and OM (HR: 1.7, p = 0.002) on multivariate analysis. The model produced similar 5-year rates of BF (p < 0.0001), DM (p = 0.0001), PCSM (p = 0.02), and OM (p = 0.02) in the validation cohort. For patients with a Nadir Score of 2 in the validation cohort, 5-year rates of BF, DM, PCSM, and OM were 96%, 42%, 24%, and 30%, respectively. The combination of a detectable nPSA and a TnPSA <6 months after SRT strongly predicts patients at the highest risk for DM, PCSM, and OM. Patients with a detectable nPSA who reached nadir within 6 months following SRT are unlikely to have clinically localized disease and should be considered for prompt initiation of systemic therapies.