title: Intraoperative radiotherapy with localized radioprotection: diminished duodenal toxicity with intraluminal WR2721.
abstract: The radiosensitive duodenum must be treated during IORT of human pancreatic head tumors, leading to an approximately 25% incidence of late bleeding. This study aimed to decrease the toxicity by administering WR2721 directly into the duodenal lumen. Duodenal toxicity in the canine was evaluated after intraoperative radiotherapy (IORT) with and without the intraluminal radioprotector WR2721. Eight adult dogs were divided into two groups. All underwent IORT using a 5.7 cm cone that covered the duodenum and pancreas. 30.0 Gy IORT was given with 6 MeV electrons. Cholecystojejunostomy and gastrojejunostomy were performed. Four dogs served as IORT only controls; one was unevaluable. Four dogs received WR2721, intraluminally at 720 mg/m2, in 16-18 ml Ringer's. Atraumatic clamps were placed on proximal and distal duodenum, without vascular compromise. WR2721 was injected into the duodenal lumen 30 minutes prior to IORT. Immediate postoperative recovery of the dogs receiving WR2721 was faster than controls. Necropsies were performed at 6 months. Grossly increased adhesions were noted in controls. Histopathologically, mucosal atrophy was greater in control dogs. Duodenal ulceration was noted in all controls, but in only one of four WR2721 dogs. Masson's trichrome and Verhoff Van Gieson stains demonstrated increased perivascular fibrosis, intimal proliferation, and fibrinoid medial necrosis of vessels in all controls, and one WR2721 dog. The other three WR2721 dogs had only mild perivascular fibrosis. Radioprotection, evaluated by the presence or absence of pancreatic atrophy, appeared to stop just beyond the bowel wall. In summary, WR2721 provided duodenal radioprotection in most dogs. The intraluminal administration of WR2721 allows decreased systemic side effects, and may eliminate tumor absorption. The study indicates that the intraluminal use of radioprotectors has broad potential application.
authors.affiliation: Department of Radiation Oncology, University of California, San Francisco 94143.
authors.forename: F E
authors.initials: FE
authors.lastname: Halberg
authors.forename: S M
authors.initials: SM
authors.lastname: LaRue
authors.forename: A A
authors.initials: AA
authors.lastname: Rayner
authors.forename: W M
authors.initials: WM
authors.lastname: Burnel
authors.forename: B E
authors.initials: BE
authors.lastname: Powers
authors.forename: A S
authors.initials: AS
authors.lastname: Chan
authors.forename: M C
authors.initials: MC
authors.lastname: Schell
authors.forename: E L
authors.initials: EL
authors.lastname: Gillette
authors.forename: T L
authors.initials: TL
authors.lastname: Phillips
mesh_terms: D004999:Amifostine / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D004285:Dogs; D004386:Duodenum / Q000473:pathology / Q000528:radiation effects*; D005260:Female; D008297:Male; D010190:Pancreatic Neoplasms / Q000532:radiotherapy* / Q000601:surgery
chemical_list: D004999:Amifostine