Phase I Dose Escalation Trial Using 3-Fraction SBRT for Locally Advanced Pancreatic Cancer

Abstract

This prospective multi-institutional study aimed to determine the safety and maximally tolerated dose of 3-fraction stereotactic body radiotherapy (SBRT) for locally advanced pancreatic cancer (LAPC).Patients with localized, histologically confirmed pancreatic adenocarcinoma deemed unresectable on radiographic multidisciplinary review without distant progression following induction chemotherapy for at least 2 months were eligible. Patients received 3-fraction LINAC-based SBRT at 3 dose levels, 27Gy, 30Gy and 33Gy following a modified 3+3 design, allowing for enrollment of additional patients at the last dose level during the 90-day observation period, provided no dose-limiting toxicities (DLTs) were observed. DLTs were defined as ≥ Grade 3 treatment-related GI toxicity within 90 days of RT as scored by CTCAE v.4. The secondary endpoints were overall survival (OS), local progression-free and distant metastasis-free survival (LPFS and DMFS, respectively), treatment-related toxicity and quality of life.Between 3/2016 and 4/2019, 23 consecutive evaluable LAPC patients were enrolled at two academic hospitals (14 and 9 patients, respectively), including 8 patients at 27Gy, 8 patients at 30Gy and 7 patients at 33Gy. The median age was 67 years (range 52 - 79 years), 9 patients (39%) were male, all were stage III, 12 (52%) had a head/uncinate tumor location, with a median tumor size of 3.5cm (range, 1.0 - 6.4cm) and a median CA19-9 of 60U/mL (range, < 1 - 4880U/mL). All received chemotherapy for a median of 4.0 months (range 2.5 -11.4 months). There was no grade ≥ 3 abdominal pain, dyspepsia, diarrhea, nausea, vomiting, or gastrointestinal hemorrhage. Four patients experienced grade ≥3 hematologic or metabolic adverse events not related to RT. Four patients underwent resections (pancreaticoduodenectomy = 3, Appleby = 1). Two-year rates of LPFS, DMFS and OS were 26.5%, 25.1% and 29.2%, respectively.For select LAPC patients, dose escalation to the target dose of 33Gy in 3 fractions resulted in no DLTs and disease outcomes comparable to conventional RT. These results warrant further exploration of hypofractionated SBRT schemes to maximize tumor control while enabling efficient integration of RT with systemic therapy for more expedient treatment options for these high-risk LAPC patients.