A Phase I Trial of Focal Salvage Stereotactic Body Radiation Therapy for Radiorecurrent Prostate Cancer.

Abstract

Locally recurrent prostate cancer after radiotherapy (RT) is an increasingly recognized entity with no standard management. NCT03253744 was a phase I trial with a primary objective of identifying the maximally tolerated dose (MTD) of a course of image-guided, focal, salvage stereotactic body radiotherapy (SBRT) for patients with local recurrence after prior definitive RT. Additional objectives included biochemical control and imaging response on mpMRI and 18F-DCFPyL (PSMA) PET/CT. SBRT was prescribed to three dose levels (DLs): 40Gy (DL1), 42.5Gy (DL2), and 45Gy (DL3) in 5 fractions. The prescription dose was delivered to a PTV defined by mpMRI and PSMA imaging and biopsy confirmed tumor volume. Dose escalation followed a 3+3 design with a 3-patient expansion at the MTD. Toxicities above baseline were scored using CTCAE v5.0 criteria for two years after completion of SBRT. Escalation was halted if 2 dose limiting toxicities (DLTs) were observed. DLTs were defined as any persistent (>4 days) grade 3 toxicity occurring within the first 3 weeks after SBRT, and any grade 3 GU or grade 4 GI toxicity thereafter. Imaging response was compared between baseline and 6-months by the Wilcoxon signed rank test. Between 08/2018 and 05/2022, 8 patients underwent salvage SBRT to 11 intraprostatic lesions with a median follow-up of 27 months. No DLTs were observed on DL1. Two patients were enrolled on DL2 and both experienced grade 3 GU toxicities, prompting de-escalation and expansion (n = 6) on DL1, the MTD. The most common toxicities were grade 2 GU toxicities: acute urinary urgency/frequency, acute weak urinary stream, and noninfective cystitis. One patient at DL1 had a self-limited episode of grade 2 GI toxicity (proctitis). No grade 3 GI toxicities were observed. All but two patients achieved an undetectable PSA nadir. Only one of these experienced biochemical failure (nadir + 2.0) at 33 months with suspicion of distant metastatic failure on restaging PET/CT. Imaging response was demonstrated by MRI in all lesions with heterogeneity in volumetric response (6% to 100%). A significant (p<0.01) response on PSMA PET/CT was observed for all measured parameters (SUVMax, SUVMean, GTVPSMA, Total Lesion PSMA [SUVMean × GTVPSMA]). Of the 11 lesions, 1 (9%) demonstrated a complete response (CR) by MRI and 9 (82%) by PSMA PET/CT. A single lesion increased in volume by 0.06 cc (16%) at 6-month PSMA PET/CT compared to baseline in the only patient who did not achieve an undetectable PSA nadir and did not have imaging suggestive of distant failure. On this phase I dose escalation study of salvage SBRT for isolated intraprostatic local failure after definitive RT, the MTD was 40Gy in 5 fractions. producing a 100% 24-month bPFS, with one late failure at 33 months occurring after the 24-month study period. The most frequent clinically significant toxicity was late grade 2 GU toxicity. Imaging response was demonstrated in all lesions on MRI and PSMA PET/CT with exception of a single lesion.