A Phase I Trial of Highly Conformal, Hypofractionated Post Prostatectomy Radiotherapy

Abstract

Increasingly hypofractionated dose schedules for post prostatectomy radiotherapy to the prostate bed were investigated on a phase I trial. The final toxicity results for patients treated on Arm 2 (no visible recurrence on pelvic MRI) are reported here. The primary objective of this trial was to determine the maximal tolerated hypofractionated dose (MTHD) regimen.Patients were treated on 1 of 3 dose levels (DL): 56.4 Gy in 20 fractions (DL1), 51.2 Gy in 15 fractions (DL2), and 44.2 Gy in 10 fractions (DL3). Patients underwent treatment to the prostate bed (RTOG Consensus); pelvic nodal irradiation was not allowed. Concurrent androgen deprivation therapy (ADT) was used at the discretion of the treating physician. Dose escalation followed a standard 3+3 design with an expansion for 6 additional patients at the maximal tolerated dose (MTHD). Dose limiting toxicity (DLT) was defined as grade 3 (G3) toxicity lasting > 4 days that occurred during or up to 21 days following RT. Toxicity was scored during RT and for 2 years following completion using the CTCAE v4.0. Toxicity was considered acute within 90 days of RT and late after 90 days.Between 01/2018 and 08/2019, 15 patients with a median age of 70 (47-76) underwent RT. Nine patients (60%) underwent concurrent ADT. Patients were classified as NCCN favorable-intermediate (n = 3), unfavorable-intermediate (n = 2), high-risk (n = 9), and very-high risk (n = 1). Three patients were treated at DL1, 3 at DL2, and 9 at DL3. Median follow up was 24 months (9.7-24.0). One patient was removed from study at 9.7 months for PSA progression. There were no DLTs, and no patients required a treatment break. Nine patients (60%) experienced a maximum acute G2 GI toxicity. Within these 9 patients there were 11 total acute G2 GI events consisting of diarrhea in 1 patient (duration: 37 days), proctitis in 5 patients (median duration: 25 days), and worsening hemorrhoids in 5 patients (median duration: 17 days, all occurred in patients with baseline G1 hemorrhoids). One patient developed acute G3 GI toxicity (proctitis) on DL3 which resolved to G2 with medical management in < 4 days. No acute G2 or G3 GU toxicities were observed, however acute G1 dysuria was common (n = 6). Late G2 GI and GU toxicity each occurred in 3 patients respectively. Late G3 GU toxicity occurred in 2 patients (self-limited hemorrhagic cystitis in a patient on DL2, worsening of baseline incontinence in a patient on DL3). There were no ≥ G4 acute or late toxicities.The MTHD for hypofractionated post-operative radiotherapy to the prostate bed was 44.2 Gy in 10 daily fractions. Consistent with recent reports on hypofractionation in the intact prostate setting, acute ≥G2 GI toxicity was observed frequently. Late toxicity rates were similar to rates reported in these prior studies.