A safety study of intraoperative radiation therapy following stereotactic body radiation therapy and multi-agent chemotherapy in the treatment of localized pancreatic adenocarcinoma: study protocol of a phase I trial

Background: Localized pancreatic adenocarcinoma carries a poor prognosis even after aggressive therapy. Up to 40% of patients may develop locoregional disease as the first site of failure. As such, there may be a role for intensification of local therapy such as radiation therapy. Radiation dose escalation for pancreatic cancer is limited by proximity of the tumor to the duodenum. However, the duodenum is removed during Whipple procedure, allowing the opportunity to dose escalate with intraoperative radiation therapy (IORT). Although prior studies have shown potential benefit of IORT in pancreatic cancer, these studies did not utilize ablative doses (biologically effective dose [BED₁₀] > 100 Gy). Furthermore, the optimal radiation target volume in this setting is unclear. There has been increased interest in a “Triangle Volume” (TV), bordered by the celiac axis, superior mesenteric artery, common hepatic artery, portal vein, and superior mesenteric vein. Dissection of this area, has been advocated for by surgeons from Heidelberg as it contains extra-pancreatic perineural and lymphatic tracts, which may harbor microscopic disease at risk of mediating local failure. Interestingly, a recent analysis from our institution indicated that nearly all local failures occur in the TV. Therefore, the purpose of this protocol is to evaluate the safety of delivering an ablative radiation dose to the TV with IORT following neoadjuvant chemotherapy and stereotactic body radiation therapy (SBRT). Methods: Patients with non-metastatic pancreatic adenocarcinoma centered in the head or neck of the pancreas will be enrolled. Following treatment with multi-agent neoadjuvant chemotherapy, patients will undergo SBRT (40 Gy/5 fractions) followed by IORT (15 Gy/1 fraction) to the TV during the Whipple procedure. The primary objective is acute (< 90 days) toxicity after IORT measured by Clavien-Dindo classification. Secondary objectives include late (> 90 days) toxicity after IORT measured by Clavien-Dindo classification, overall survival, local progression-free survival, distant metastasis-free survival, and progression-free survival. Discussion: If the results show that delivering an ablative radiation dose to the TV with IORT after neoadjuvant chemotherapy and SBRT is safe and feasible, it warrants further investigation in a phase II trial to evaluate efficacy of this approach. Trial Registration This study was registered at ClinicalTrials.gov on 12/2/2021 (NCT05141513). https://clinicaltrials.gov/ct2/show/NCT05141513