Working Towards a New Definition of Biochemical Failure in the Era of Stereotactic Body Radiation Therapy for Prostate Cancer

Abstract

Since the seminal Phoenix definition (nadir PSA+2) of biochemical failure (BCF) was published in 2006, increasingly more patients with low- and intermediate-risk prostate cancer (PCa) are being treated with stereotactic body radiation therapy (SBRT). Since SBRT leads to lower nadir PSA (nPSA) compared to conventionally fractionated RT, we investigated if an earlier nPSA+threshold can be used as an alternative definition of BCF.PSA kinetics from 9 institutions were retrospectively analyzed for patients with localized PCa treated definitively with SBRT alone from 2003 to 2018. Patients received 35 to 40 Gy in 5 fractions, 38 Gy in 4 fractions or 26 Gy in 2 fractions (EQD23 Gy = 70-95 Gy) per institutional standards. Cox multivariable regression model was used to determine the adjusted association of relative change in PSA kinetics with biochemical relapse-free survival (BRFS) and association of BCF with time to nadir+2.A total of 2061 patients were included. Median follow-up was 71.9 months (interquartile range [IQR], 41.2-96.0). BCF occurred in 140 (6.8%) of patients. Median nPSA was 0.16 ng/mL, median time to nPSA was 48 months. Sensitivity of Phoenix definition for BCF was 93%, compared to 96%, 100%, and 100% for nPSA+1.5, nPSA+1.0 and nPSA+0.5, respectively. False positive rate of Phoenix definition was 30%, compared to 41%, 58%, and 71% for nPSA+1.5, nPSA+1.0 and nPSA+0.5, respectively. In patients who developed BCF, lead time gained from an earlier nPSA+threshold definition compared to Phoenix definition was 6 (IQR 0-15.3), 0 (IQR 0-11.3), 0 (IQR 0-0) months for nPSA+0.5, nPSA+1.0 and nPSA+1.5, respectively. Relative change in PSA between 6 months and 18 months after treatment was significantly associated with BRFS (hazard ratio [HR] 1.73, 95% confidence interval [CI] 1.28-2.34, P < 0.0004). Among the 30% patients who had a false call of BCF due to PSA bounce, 48 (84.2%) reached nPSA+2 in ≤18 months, and 9 (15.8%) in > 18 months. In patients who had BCF, 27 (19.3%) reached nPSA+2 in ≤18 months, and 113 (80.7%) in > 18 months. Median time to nPSA+2 was significantly longer in patients with BCF (41 vs. 12 months, P < 0.002). BCF is associated with longer time to nPSA+2 (HR 0.13, 95% CI 0.09-0.20, P < 0.002).A lower nadir-based threshold provides minimal increase in sensitivity at the cost of a higher false positive rate and does not provide a clinically relevant lead time benefit for a pending BCF in patients with low- to intermediate-risk PCa undergoing SBRT. A rate-of-change based metric in the first 18 months post-SBRT is significantly associated with BRFS. Patients who have an early PSA bounce after SBRT rarely develop a true BCF and true BCF tends to happen later (> 18 months). Phoenix definition remains a valuable tool in the SBRT era. BCF should not be prematurely called which runs the risk of high rates of false positivity.