Session Item

Current management for prostate cancer (PCa) relapse in irradiated prostate bed is based on palliative androgen deprivation therapy (ADT). Recently, stereotactic radiotherapy (SBRT) has been developed in this situation. Otherwise, data showed interaction between metformin and radiotherapy (9). We propose a phase I/II study of SBRT reirradiation for relapses in prostate bed, potentiated by metformin. We report phase 1 preliminary results.

We prospectively included patients with biochemical recurrence of PCa occurring at least 2 years after radiation therapy of prostate bed and ADT. Patient should have isolated local recurrence, visible on MRI and PET (Choline or PSMA), and PSA doubling time >6 months.Patient with grade ≥2 late post-radiotherapy gastro-urinary toxicity were excluded. Phase I will evaluate SBRT at 5x6Gy, every other day, then according to tolerance, 6x6Gy or5x5Gy. A dummy-run was performed and treatment plan of the first patient of each center was prospectively validated. Metformin is administered during 12 weeks. Patients were followed up weekly during SBRT and after every 4 weeks. Toxicities (SAEs) were graded according to the CTCAE 5.0. The phase I primary objective is the selection of the recommended dose for salvage-SBRT (5×6, 6×6 or 5×5Gy) based on dose-limiting toxicity (DLT), using a time-to-event continual reassessment method based on DLT. DLT is a grade ≥3 gastrointestinal or urinary toxicity or any other grade ≥4 adverse event that occurs during the 12 weeks following the start of SBRT.

From November 2020 to November 2021, 6 patients were treated by SBRT and metformin in 2 medical centers. According to the D’Amico classification, 2 patients were at intermediate risk  (33%), and 3 were at high risk (50%) (data missing for 1 patient). The median dose delivered to prostatic bed was of 66Gy  (range, 60-74) and pelvic node irradiation was delivered in 1 patient. ADT was associated with radiotherapy in 1 patient. Median time since first radiotherapy  was 8.3 years (range, 3.4-13.3). Median PSA at recurrence was 1.13 ng/mL (range, 0.18-2.62). Three patients were treated at 1st step 5x6 Gy, and due to the absence of DLT, the following 3 patients were treated at 2nd step 6x6 Gy. All patients received full dose of Metformin. In step 5x6Gy, there were 7 AEs. Toxicities due to SBRT were 2 diarrheas grade 1, 1 diarrhea grade 2, 1 fecal incontinence grade 1, 2 urinary incontinences grade 1, 1 hematuria grade 1, 1 pollakiuria grade 1. No Metformin-related AEs were observed. At step 6x6Gy, there were 5 AEs. Toxicities due to SBRT were 1 grade 1 diarrhea and 1 grade 1 urinary incontinence. Toxicities due to Metformin were 3 grade 1 diarrhea. No SAE, DLT or grade ≥3 toxicity were observed. At 6-month follow-up 5 patients (83%) had a biochemical response.

In this phase 1 no DLT were observed during the monitoring period of 12 weeks, allowing the opening of phase II at a dose of 6x6Gy.