title: Upfront boost Gamma Knife "leading-edge" radiosurgery to FLAIR MRI-defined tumor migration pathways in 174 patients with glioblastoma multiforme: a 15-year assessment of a novel therapy.
abstract: OBJECTIVE Glioblastoma multiforme (GBM) is composed of cells that migrate through the brain along predictable white matter pathways. Targeting white matter pathways adjacent to, and leading away from, the original contrast-enhancing tumor site (termed leading-edge radiosurgery [LERS]) with single-fraction stereotactic radiosurgery as a boost to standard therapy could limit the spread of glioma cells and improve clinical outcomes. METHODS Between December 2000 and May 2016, after an initial diagnosis of GBM and prior to or during standard radiation therapy and carmustine or temozolomide chemotherapy, 174 patients treated with radiosurgery to the leading edge (LE) of tumor cell migration were reviewed. The LE was defined as a region outside the contrast-enhancing tumor nidus, defined by FLAIR MRI. The median age of patients was 59 years (range 22-87 years). Patients underwent LERS a median of 18 days from original diagnosis. The median target volume of 48.5 cm3(range 2.5-220.0 cm3) of LE tissue was targeted using a median dose of 8 Gy (range 6-14 Gy) at the 50% isodose line. RESULTS The median overall survival was 23 months (mean 43 months) from diagnosis. The 2-, 3-, 5-, 7-, and 10-year actual overall survival rates after LERS were 39%, 26%, 16%, 10%, and 4%, respectively. Nine percent of patients developed treatment-related imaging-documented changes due to LERS. Nineteen percent of patients were hospitalized for management of edema, 22% for resection of a tumor cyst or new tumor bulk, and 2% for shunting to treat hydrocephalus throughout the course of their disease. Of the patients still alive, Karnofsky Performance Scale scores remained stable in 90% of patients and decreased by 1-3 grades in 10% due to symptomatic treatment-related imaging changes. CONCLUSIONS LERS is a safe and effective upfront adjunctive therapy for patients with newly diagnosed GBM. Limitations of this study include a single-center experience and single-institution determination of the LE tumor target. Use of a leading-edge calculation algorithm will be described to achieve a consistent approach to defining the LE target for general use. A multicenter trial will further elucidate its value in the treatment of GBM.
authors.affiliation: Neurosciences Institute.|Cancer Center, and.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Duma
authors.affiliation: Cancer Center, and.|Department of Radiation Oncology, Hoag Memorial Hospital Presbyterian, Newport Beach.
authors.forename: Brian S
authors.initials: BS
authors.lastname: Kim
authors.affiliation: Cancer Center, and.|Department of Radiation Oncology, Hoag Memorial Hospital Presbyterian, Newport Beach.
authors.forename: Peter V
authors.initials: PV
authors.lastname: Chen
authors.affiliation: Cancer Center, and.|Department of Radiation Oncology, Hoag Memorial Hospital Presbyterian, Newport Beach.
authors.forename: Marianne E
authors.initials: ME
authors.lastname: Plunkett
authors.affiliation: Cancer Center, and.|Department of Radiation Oncology, Hoag Memorial Hospital Presbyterian, Newport Beach.
authors.forename: Ralph
authors.initials: R
authors.lastname: Mackintosh
authors.affiliation: Department of Neurosurgery, University of California, Irvine, Orange; and.
authors.forename: Marlon S
authors.initials: MS
authors.lastname: Mathews
authors.affiliation: Neurosciences Institute.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Casserly
authors.affiliation: Neurosciences Institute.
authors.forename: Gustavo A
authors.initials: GA
authors.lastname: Mendez
authors.affiliation: Neurosciences Institute.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Furman
authors.affiliation: Neurosciences Institute.
authors.forename: Garrett
authors.initials: G
authors.lastname: Smith
authors.affiliation: Neurosciences Institute.|Department of Neurosurgery, Loma Linda University Health, Loma Linda, California.
authors.forename: Nathan
authors.initials: N
authors.lastname: Oh
authors.affiliation: Neurosciences Institute.
authors.forename: Chad A
authors.initials: CA
authors.lastname: Caraway
authors.affiliation: Neurosciences Institute.
authors.forename: Ami R
authors.initials: AR
authors.lastname: Sanathara
authors.affiliation: Cancer Center, and.
authors.forename: Robert O
authors.initials: RO
authors.lastname: Dillman
authors.affiliation: Neurosciences Institute.
authors.forename: Azzurra-Sky
authors.initials: AS
authors.lastname: Riley
authors.affiliation: Neurosciences Institute.
authors.forename: David
authors.initials: D
authors.lastname: Weiland
authors.affiliation: Neurosciences Institute.
authors.forename: Lian
authors.initials: L
authors.lastname: Stemler
authors.affiliation: Cancer Center, and.
authors.forename: Ruslana
authors.initials: R
authors.lastname: Cannell
authors.affiliation: Department of Neurosurgery, University of California, Irvine, Orange; and.
authors.forename: Daniela Alexandru
authors.initials: DA
authors.lastname: Abrams
authors.affiliation: Department of Neurosurgery, University of California, Irvine, Orange; and.
authors.forename: Alexa
authors.initials: A
authors.lastname: Smith
authors.affiliation: Department of Neurosurgery, University of California, Irvine, Orange; and.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Owen
authors.affiliation: Cancer Center, and.
authors.forename: Burton
authors.initials: B
authors.lastname: Eisenberg
authors.affiliation: Neurosciences Institute.|Cancer Center, and.
authors.forename: Michael
authors.initials: M
authors.lastname: Brant-Zawadzki
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001932:Brain Neoplasms / Q000000981:diagnostic imaging* / Q000473:pathology / Q000532:radiotherapy*; D002465:Cell Movement; D005500:Follow-Up Studies; D005909:Glioblastoma / Q000000981:diagnostic imaging* / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008875:Middle Aged; D016634:Radiosurgery / Q000379:methods; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
keywords: CTV = clinical tumor volume; FLAIR; GBM = glioblastoma multiforme; GTV = gross tumor volume; Gamma Knife; IFXRT = involved-field radiation therapy; KPS = Karnofsky Performance Scale; LE = leading edge; LERS = leading-edge radiosurgery; TRIC = treatment-related imaging change; astrocytoma; brain tumor; fluid-attenuated inversion recovery; glioblastoma multiforme; leading edge; migration; stereotactic radiosurgery