Establishing the Gastroduodenal Maximum Tolerated Dose for Ablative 5-Fraction Stereotactic MR-guided Online Adaptive Radiation Therapy (SMART) in a Novel Swine Model

Abstract

Daily variations in abdominal anatomy introduce significant uncertainty in estimating the maximum tolerated dose (MTD). We investigated the gastroduodenal toxicity using stereotactic MR-guided online adaptive radiotherapy (SMART) to precisely control the dose to a novel swine model that closely matches human physiology and can be maintained at 80 kg. We hypothesized for a cumulative SMART course of 50 Gy in 5 fractions to the pancreas, the duodenum MTD is significantly > 37 Gy to 0.5 cc (D0.5cc).A total of 18 WMSTM were included at 3 duodenal dose levels: 37 Gy (n = 12), 43.5 Gy (n = 3), and 50 Gy (n = 3) in 5 fractions. We defined MTD as: > 10% (≥2 of 12) WMSTM present with dose limiting toxicity (DLT). A DLT was defined as ≥ Grade 3 non-hematologic toxicity due to RT per NCI CTCAE v4.0. All WMSTM underwent SMART on a clinical MR-guided radiotherapy (MRgRT) LINAC, under ventilation at breath hold (BH). Plans were IMRT and prescribed 50 Gy/5 fractions to pancreatic head, while maintaining uniform dose level (37, 43.5, 50 Gy) to duodenal circumference at 3 cm inferior to pylorus sphincter, typical uniform irradiated range 3-9 cc based on duodenal diameter. Circumference approach was used to eliminate underestimation of cumulative D0.5cc. Duodenal hotspot was 1.03% of the dose level (37, 43.5, 50 Gy) to 2 cc, 1.05% to 0.1 cc. Gated BH delivery was performed with sagittal plane tracking of the duodenum at 4 frames per second. Toxicity monitoring occurred for 30 days post-RT. Fecal occult blood test (FOBT) was done during RT and toxicity monitoring. Endoscopy occurred 14 days post-RT. Gross pathology was obtained at time of necropsy, 30 days post-RT.For the 37 Gy level, 1 of 12 WMSTM presented with DLT-pinpoint ulcer with surface damage on gross pathology (30 days post-RT). No DLT for 2 of 3 WMSTM at the 43.5 Gy level. One WMSTM at the 43.5 Gy level perforated on endoscopy, potentially due duodenal wall degradation and unknown RT-induced DLT on gross exam of emergency necropsy. Endoscopy was eliminated for the 50 Gy level. DLT was found for 2 of 3 WMSTM at the 50 Gy level upon gross pathology at necropsy, with each subject having 2-3 visible ulcerations at level of RT. One WMSTM at the 50 Gy level had duodenal pre-ulcer erosion at necropsy. All three WMSTM at 50 Gy level had visibly damaged papilla at necropsy. Another WMSTM at the 50 Gy level had common bile duct blockage, gall bladder obstruction, and jaundice at necropsy. FOBT were negative for all 18 WMSTM at 14 days post-RT.A duodenum D0.5cc of 37 Gy in 5 fractions was found to be safe in a swine model for a 50 Gy SMART course to the pancreas, showing the duodenal MTD is > 37 Gy - an increase from the RTOG 1112 limit (i.e., 30 Gy). Our results translate to a recommended MTD in human subjects and can potentially allow for greater tumor dose escalation and survival outcomes in future pancreatic patients. We are currently pursuing an expansion cohort to evaluate the MTD at 43.5 Gy.