The Effect of Single-Dose Intraperitoneal Bevacizumab on Peritoneal Adhesion Formation

Abstract

Background: Intra-abdominal adhesions and their complications following abdominal surgery are serious problems, with an incidence of 67-93%. Prevention of peritoneal adhesion formation may eliminate the need for surgical intervention, decreasing complications, morbidity, and cost. Bevacizumab is a recombinant monoclonal antibody which specifically binds vascular endothelial growth factor, an important cytokine in adhesion formation, and neutralizes its biological activity. We developed an experimental model in rats to determine the effect of bevacizumab in preventing adhesion formation and analyzed its effect both micro-and macroscopically. Methods: We used 32 Wistar rats randomly divided into two groups: Group A (control) and Group B (bevacizumab), with 16 rats each. A modified cecum abrasion model was developed; 0.9% NaCl solution was administered intraperitoneally to Group A and bevacizumab to Group B. On day 15, adhesion formation was evaluated both macro-and microscopically. Results: Both micro-and macroscopic adhesion grades in Group B were significantly lower than those of control Group A; macroscopic grades were 2.69 ± 0.95 and 0.69 ± 0.8, and microscopic grades were 2.25 ± 1.06 and 0.5 ± 0.52 for Groups A and B, respectively. Conclusions: Bevacizumab was effective in preventing intraperitoneal adhesion formation in our study; however, its inhibitory effects on embryogenesis and the hematopoietic, endocrine, and immune systems may limit its clinical use.

The anti‐adhesive effect of anti‐VEGF agents in experimental models: A systematic review

“…Out of 15 studies, 11 studies investigated the role of bevacizumab, 3,19,35,42,44‐46,49‐52 two studies used an anti‐VEGF antibody other than bevacizumab, 53,54 one study used an anti‐VEGFR‐1 antibody, 55 and one study used a polyclonal rabbit anti‐VEGF antiserum 56 (Table 1). Bevacizumab was injected intracavitary at a dose of 5 mg/kg in three studies, 42,44,49 at 2.5 mg/kg in five studies, 3,19,35,49,50 while the intravenous route was used to administrate a dose of 5 mg/kg in two studies 45,46 or a dose of 1 mg/kg in one study 52 . Nine studies used a rat model, 3,19,35,42,44,49‐52 three studies used a rabbit model, 45,46,53 and three studies used a mouse model 54‐56 .…”

“…Bevacizumab was injected intracavitary at a dose of 5 mg/kg in three studies, 42,44,49 at 2.5 mg/kg in five studies, 3,19,35,49,50 while the intravenous route was used to administrate a dose of 5 mg/kg in two studies 45,46 or a dose of 1 mg/kg in one study 52 . Nine studies used a rat model, 3,19,35,42,44,49‐52 three studies used a rabbit model, 45,46,53 and three studies used a mouse model 54‐56 . Eleven studies used a model of peritoneal adhesions, 3,19,42,44,49‐52,54‐56 three studies used a pleural model, 45,46,53 while one study investigated the antiadhesive effect of bevacizumab in the pericardial cavity 35 .…”

“…Nine studies used a rat model, 3,19,35,42,44,49‐52 three studies used a rabbit model, 45,46,53 and three studies used a mouse model 54‐56 . Eleven studies used a model of peritoneal adhesions, 3,19,42,44,49‐52,54‐56 three studies used a pleural model, 45,46,53 while one study investigated the antiadhesive effect of bevacizumab in the pericardial cavity 35 . Tissue abrasion/denudation was the most common method of adhesion induction, used in eight studies, 3,19,35,44,50,52,54,56 pleurodesis with silver nitrate or Talc were used in three studies, 45,46,53 electrocautery in two studies, 51,55 and colonic anastomosis with polypropylene in two studies 42,49 .…”

“…Upon severe injury, VEGF‐A enhances the paracrine release of growth factors from endothelial cells and potentiates the regeneration of organs 16 . However, VEGF‐A has been implicated in the formation of adhesions after intra‐abdominal, pericardial or pleural interventions 3,9,17‐19 . Dysregulation of angiogenesis and overexpression of VEGF has been identified in the pathogenesis of overt fibrosis in several conditions, including the formation of keloid in wounds, tendon healing, and bleomycin‐induced pulmonary fibrosis 20‐26 .…”

“…In experimental models of rat colonic anastomoses, the intraperitoneal administration of bevacizumab does not seem to significantly affect the anastomosis integrity or wound healing 42,43 . Several preclinical studies have investigated the effect of VEGF blockade on the formation of adhesions, 3,19,44‐46 yet no systematic synthesis of the evidence has been performed to date. The aim of this study is to summarize current literature on the antiadhesive effects of VEGF blockade in experimental models of peritoneal, pleural, and pericardial surgery.…”