title: Bevacizumab enhances efficiency of radiotherapy in a lung adenocarcinoma rodent model: Role of αvβ3 imaging in determining optimal window.
abstract: BACKGROUND
  Earlier studies indicated that bevacizumab could favorably be combined with radiation. However excessive damage to tumor vasculature can result in radioresistance and clinical data suggest that treatment sequencing may be important when combining bevacizumab with radiation. The aim of this study was to evaluate whether αvβ3 scintigraphic imaging could provide information to determine the optimal combination schedule of bevacizumab and radiotherapy on a lung adenocarcinoma model in mice.
  
  
  METHODS
  The tumor volume and angiogenesis changes induced after bevacizumab and radiation treatment were evaluated using (99m)Tc-RGD on a microSPECT/CT. First, we determined the optimal dose regimen for bevacizumab and radiotherapy alone. Second, the combined effects of bevacizumab and radiation were evaluated according to the combination timing (radiation 2, 24, 48 hours after bevacizumab and 48 hours before bevacizumab).
  
  
  RESULTS
  The optimal dose regimen is 20mg/kg for bevacizumab and 12.5 Gy for radiotherapy with a significant decrease of tumoral uptake and volume at day 9 compared to the controls (+8.8%, +7.7%, and +44% volume, respectively, and +9.8%, +3.8%, and +207% uptake, respectively). Scintigraphic imaging showed a significant increased RGD tumor uptake two hours after bevacizumab treatment compared to 24 hours and controls (p=0.02). When bevacizumab treatment was combined with radiation, the best combination appears to be the administration of bevacizumab two hours prior to radiation with better results than single treatments (p < 0.05). On the contrary, bevacizumab given 24 hours prior to radiation led to less tumor growth delay compared to a single agent, without significant difference compared to the controls. Histological results confirmed these data with an increased percentage of necrosis (p=0.04) and a decrease of angiogenesis (p=0.04) in the optimal combination group.
  
  
  CONCLUSIONS
  The RGD tracer helps us identify the vascular normalization window and it shows a supra-additive effect of bevacizumab when administered two hours before radiotherapy.
authors.affiliation: Department of Nuclear Medicine, Henri Becquerel Cancer Center and Rouen University Hospital & QuantIF LITIS (Equipe d'Accueil (EA) 4108-Federation Recherche (FR) National Center for Scientific Research (CNRS) 3638), Faculty of Medicine, University of Rouen, Rouen, 76821, France. Electronic address: stephanie.becker@chb.unicancer.fr.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Becker
authors.affiliation: Department of Nuclear Medicine, Henri Becquerel Cancer Center and Rouen University Hospital & QuantIF LITIS (Equipe d'Accueil (EA) 4108-Federation Recherche (FR) National Center for Scientific Research (CNRS) 3638), Faculty of Medicine, University of Rouen, Rouen, 76821, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Bohn
authors.affiliation: Department of Nuclear Medicine, Henri Becquerel Cancer Center and Rouen University Hospital & QuantIF LITIS (Equipe d'Accueil (EA) 4108-Federation Recherche (FR) National Center for Scientific Research (CNRS) 3638), Faculty of Medicine, University of Rouen, Rouen, 76821, France.
authors.forename: Anne-Charlotte
authors.initials: AC
authors.lastname: Bouyeure-Petit
authors.affiliation: Department of Nuclear Medicine, Henri Becquerel Cancer Center and Rouen University Hospital & QuantIF LITIS (Equipe d'Accueil (EA) 4108-Federation Recherche (FR) National Center for Scientific Research (CNRS) 3638), Faculty of Medicine, University of Rouen, Rouen, 76821, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Modzelewski
authors.affiliation: Department of Radiation Oncology, Henri Becquerel Cancer Center, Rouen, 76821, France.
authors.forename: David
authors.initials: D
authors.lastname: Gensanne
authors.affiliation: Pathology Department, Henri Becquerel Cancer Center, Rouen, 76821, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Picquenot
authors.affiliation: Department of Radiation Oncology, Henri Becquerel Cancer Center, Rouen, 76821, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Dubray
authors.affiliation: Department of Nuclear Medicine, Henri Becquerel Cancer Center and Rouen University Hospital & QuantIF LITIS (Equipe d'Accueil (EA) 4108-Federation Recherche (FR) National Center for Scientific Research (CNRS) 3638), Faculty of Medicine, University of Rouen, Rouen, 76821, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Vera
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000068258:Bevacizumab / Q000494:pharmacology*; D059248:Chemoradiotherapy / Q000592:standards*; D005260:Female; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D051379:Mice; D057054:Molecular Imaging / Q000379:methods*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D015899:Tomography, Emission-Computed, Single-Photon; D014057:Tomography, X-Ray Computed; D047368:Tumor Burden; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D039302:Integrin alphaVbeta3; D011838:Radiation-Sensitizing Agents; D000068258:Bevacizumab
keywords: Bevacizumab; Carcinoma; Lung; Radiotherapy; Scintigraphic imaging; αvβ3