title: Mechanism-based modeling of the clinical effects of bevacizumab and everolimus on vestibular schwannomas of patients with neurofibromatosis type 2.
abstract: To describe the natural growth of vestibular schwannoma in patients with neurofibromatosis type 2 and to predict tumor volume evolution in patients treated with bevacizumab and everolimus.
  
  
  
  Clinical data, including longitudinal tumor volumes in patients treated by bevacizumab (n = 13), everolimus (n = 7) or both (n = 2), were analyzed by means of mathematical modeling techniques. Together with clinical data, data from the literature were also integrated to account for drugs mechanisms of action.
  
  
  
  We developed a model of vestibular schwannoma growth that takes into account the effect of vascular endothelial growth factors and mammalian target of rapamycin complex 1 on tumor growth. Behaviors, such as tumor growth rebound following everolimus treatment stops, was correctly described with the model. Preliminary results indicate that the model can be used to predict, based on early tumor volume dynamic, tumor response to variation in treatment dose and regimen.
  
  
  
  The developed model successfully describes tumor volume growth before and during bevacizumab and/or everolimus treatment. It might constitute a rational tool to predict patients' response to these drugs, thus potentially improving management of this disease.
authors.affiliation: Inria, Project Team NuMed, Ecole Normale Supérieure de Lyon, Lyon, France. aziz.ouerdani@inria.fr.
authors.forename: Aziz
authors.initials: A
authors.lastname: Ouerdani
authors.affiliation: Neurosurgery, Beaujon Hospital, Assistance Publique Hôpitaux de Paris, Clichy, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Goutagny
authors.affiliation: Neurosurgery, Pitié-Salpêtrière Hospital, Assistance Publique Hôpitaux de Paris, 75013, Paris, France.|Sorbonne Universités UPMC Univ, Paris 06, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Kalamarides
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Spain.
authors.forename: Iñaki F
authors.initials: IF
authors.lastname: Trocóniz
authors.affiliation: Inria, Project Team NuMed, Ecole Normale Supérieure de Lyon, Lyon, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Ribba
mesh_terms: D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D000068338:Everolimus / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008390:Markov Chains; D008875:Middle Aged; D008954:Models, Biological; D016518:Neurofibromatosis 2 / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D009464:Neuroma, Acoustic / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D055815:Young Adult
chemical_list: D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D000068338:Everolimus; D058570:TOR Serine-Threonine Kinases
keywords: Disease progression model; Mechanism-informed models; Mixed-effects models; NF2; Oncology; Population pharmacokinetics–pharmacodynamics; Vestibular schwannoma