Despite improvement in systemic therapy, patients with pancreatic ductal adenocarcinoma (PDAC) frequently experience local recurrence. We sought to determine the safety of hypofractionated proton beam radiotherapy (PBT) during adjuvant chemotherapy.
Nine patients were enrolled in a single-institution phase I trial (NCTXXXXXXXX) between 2019 and 2022. Patients had PDAC of the pancreatic head and underwent R0 or R1 resection and adjuvant modified FOLFIRINOX (mFFX) chemotherapy. The primary endpoint was to determine the dosing schedule of adjuvant PBT (5 Gy x 5 fractions) using limited treatment volumes given between cycles 6 and 7 of mFFX. Patients received PBT on days 15-19 in a 28-day cycle before starting cycle 7 (dose level 1, DL1) or on days 8-12 in a 21-day cycle before starting cycle 7 (DL2).
The median patient age was 66 (range 52-78), and the follow-up time from mFFX initiation was 12.5 months (range 6.2-37.4 months). No patients received preoperative therapy. Four had R1 resections and 5 had node-positive disease. Three patients were enrolled on DL1 and 6 patients on DL2. One dose-limiting toxicity (DLT) occurred at DL2 (prolonged grade 3 neutropenia resulting in discontinuation of mFFX after cycle 7). No other DLTs were observed. Four patients completed 12 cycles of mFFX (range 7-12, median 11). No patients have had local recurrence. Five of 9 patients had recurrence: 3 in the liver, 1 in the peritoneum, and 1 in the bone. Six patients are still alive, 4 of whom are recurrence-free. The median time to recurrence was 12 months (95% confidence interval [CI] 4-not reached [NR]), and median overall survival was NR (95% CI 6-NR, 2-year survival rate 57%).
PBT integrated within adjuvant mFFX was well tolerated, and no local recurrence was observed. These findings warrant in a phase II trial.

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