title: DW-MRI as a biomarker to compare therapeutic outcomes in radiotherapy regimens incorporating temozolomide or gemcitabine in glioblastoma.
abstract: The effectiveness of the radiosensitizer gemcitabine (GEM) was evaluated in a mouse glioma along with the imaging biomarker diffusion-weighted magnetic resonance imaging (DW-MRI) for early detection of treatment effects. A genetically engineered murine GBM model [Ink4a-Arf(-/-) Pten(loxP/loxP)/Ntv-a RCAS/PDGF(+)/Cre(+)] was treated with gemcitabine (GEM), temozolomide (TMZ) +/- ionizing radiation (IR). Therapeutic efficacy was quantified by contrast-enhanced MRI and DW-MRI for growth rate and tumor cellularity, respectively. Mice treated with GEM, TMZ and radiation showed a significant reduction in growth rates as early as three days post-treatment initiation. Both combination treatments (GEM/IR and TMZ/IR) resulted in improved survival over single therapies. Tumor diffusion values increased prior to detectable changes in tumor volume growth rates following administration of therapies. Concomitant GEM/IR and TMZ/IR was active and well tolerated in this GBM model and similarly prolonged median survival of tumor bearing mice. DW-MRI provided early changes to radiosensitization treatment warranting evaluation of this imaging biomarker in clinical trials.
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Galbán
authors.forename: Benjamin
authors.initials: B
authors.lastname: Lemasson
authors.forename: Terence M
authors.initials: TM
authors.lastname: Williams
authors.forename: Fei
authors.initials: F
authors.lastname: Li
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Heist
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Johnson
authors.forename: Judith S
authors.initials: JS
authors.lastname: Leopold
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Chenevert
authors.forename: Theodore S
authors.initials: TS
authors.lastname: Lawrence
authors.forename: Alnawaz
authors.initials: A
authors.lastname: Rehemtulla
authors.forename: Tom
authors.initials: T
authors.lastname: Mikkelsen
authors.forename: Eric C
authors.initials: EC
authors.lastname: Holland
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Galbán
authors.forename: Brian D
authors.initials: BD
authors.lastname: Ross
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D015415:Biomarkers; D001932:Brain Neoplasms / Q000473:pathology / Q000628:therapy*; D002460:Cell Line; D059248:Chemoradiotherapy; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D038524:Diffusion Magnetic Resonance Imaging; D004354:Drug Screening Assays, Antitumor; D005909:Glioblastoma / Q000473:pathology / Q000628:therapy*; D006801:Humans; D053208:Kaplan-Meier Estimate; D051379:Mice; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000473:pathology / Q000628:therapy; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D000077204:Temozolomide; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects / Q000528:radiation effects; D000093542:Gemcitabine
chemical_list: D018906:Antineoplastic Agents, Alkylating; D015415:Biomarkers; D011838:Radiation-Sensitizing Agents; D003841:Deoxycytidine; D003606:Dacarbazine; D000077204:Temozolomide; D000093542:Gemcitabine