title: In silico analysis suggests differential response to bevacizumab and radiation combination therapy in newly diagnosed glioblastoma.
abstract: Recently, two phase III studies of bevacizumab, an anti-angiogenic, for newly diagnosed glioblastoma (GBM) patients were released. While they were unable to statistically significantly demonstrate that bevacizumab in combination with other therapies increases the overall survival of GBM patients, there remains a question of potential benefits for subpopulations of patients. We use a mathematical model of GBM growth to investigate differential benefits of combining surgical resection, radiation and bevacizumab across observed tumour growth kinetics. The differential hypoxic burden after gross total resection (GTR) was assessed along with the change in radiation cell kill from bevacizumab-induced tissue re-normalization when starting therapy for tumours at different diagnostic sizes. Depending on the tumour size at the time of treatment, our model predicted that GTR would remove a variable portion of the hypoxic burden ranging from 11% to 99.99%. Further, our model predicted that the combination of bevacizumab with radiation resulted in an additional cell kill ranging from 2.6×10(7) to 1.1×10(10) cells. By considering the outcomes given individual tumour kinetics, our results indicate that the subpopulation of patients who would receive the greatest benefit from bevacizumab and radiation combination therapy are those with large, aggressive tumours and who are not eligible for GTR.
authors.affiliation: Department of Neurological Surgery, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Hawkins-Daarud
authors.affiliation: Department of Neurological Surgery, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Russell
authors.initials: R
authors.lastname: Rockne
authors.affiliation: Department of Neurological Surgery, Northwestern University, Chicago, IL 60611, USA.
authors.forename: David
authors.initials: D
authors.lastname: Corwin
authors.affiliation: Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA.
authors.forename: Alexander R A
authors.initials: AR
authors.lastname: Anderson
authors.affiliation: Department of Radiology, University of Washington, Seattle, WA 98195-7987, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Kinahan
authors.affiliation: Department of Neurological Surgery, Northwestern University, Chicago, IL 60611, USA kraeswanson@gmail.com.
authors.forename: Kristin R
authors.initials: KR
authors.lastname: Swanson
mesh_terms: D000068258:Bevacizumab / Q000627:therapeutic use*; D015687:Cell Hypoxia / Q000187:drug effects / Q000528:radiation effects; D059248:Chemoradiotherapy; D003198:Computer Simulation; D005909:Glioblastoma / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D006801:Humans; D008954:Models, Biological
chemical_list: D000068258:Bevacizumab
keywords: bevacizumab; glioblastoma; hypoxia; mathematical model; radiation; surgery