Baseline pretreatment contrast enhancing tumor volume including central necrosis is a prognostic factor in recurrent glioblastoma: evidence from single and multicenter trials

Benjamin M Ellingson; Robert J Harris; Davis C Woodworth; Kevin Leu; Okkar Zaw; Warren P Mason; Solmaz Sahebjam; Lauren E Abrey; Dana T Aftab; Gisela M Schwab; Colin Hessel; Albert Lai; Phioanh L Nghiemphu; Whitney B Pope; Patrick Y Wen; Timothy F Cloughesy

doi:10.1093/neuonc/now187

Baseline pretreatment contrast enhancing tumor volume including central necrosis is a prognostic factor in recurrent glioblastoma: evidence from single and multicenter trials

Neuro Oncol. 2017 Jan;19(1):89-98. doi: 10.1093/neuonc/now187. Epub 2016 Aug 31.

Authors

Benjamin M Ellingson¹, Robert J Harris², Davis C Woodworth², Kevin Leu², Okkar Zaw², Warren P Mason², Solmaz Sahebjam², Lauren E Abrey², Dana T Aftab², Gisela M Schwab², Colin Hessel², Albert Lai², Phioanh L Nghiemphu², Whitney B Pope², Patrick Y Wen², Timothy F Cloughesy²

Affiliations

¹ UCLA Brain Tumor Imaging Laboratory, Center for Computer Vision and Imaging Biomarkers, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California (B.M.E., R.J.H., D.C.W., K.L., O.Z.); Dept. of Radiological Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California (B.M.E., R.J.H., D.C.W., K.L., O.Z., W.B.P.); Dept. of Physics and Biology in Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California (B.M.E.); Dept. of Medicine, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada (W.P.M.);H. Lee Moffitt Cancer Center, Tampa, Florida (S.S.); F. Hoffman-La Roche, Ltd., Basel, Switzerland (L.E.A.); Exelixis, South San Francisco, California (D.T.A., G.M.S., C.H.); Dept. of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California (A.L., P.L.N., T.F.C.); Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, Massachusetts (P.Y.W.) bellingson@mednet.ucla.edu.
² UCLA Brain Tumor Imaging Laboratory, Center for Computer Vision and Imaging Biomarkers, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California (B.M.E., R.J.H., D.C.W., K.L., O.Z.); Dept. of Radiological Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California (B.M.E., R.J.H., D.C.W., K.L., O.Z., W.B.P.); Dept. of Physics and Biology in Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California (B.M.E.); Dept. of Medicine, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada (W.P.M.);H. Lee Moffitt Cancer Center, Tampa, Florida (S.S.); F. Hoffman-La Roche, Ltd., Basel, Switzerland (L.E.A.); Exelixis, South San Francisco, California (D.T.A., G.M.S., C.H.); Dept. of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California (A.L., P.L.N., T.F.C.); Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, Massachusetts (P.Y.W.).

Abstract

Background: The prognostic significance of baseline contrast enhancing tumor prior to second- or third-line therapy in recurrent glioblastoma (GBM) for overall survival (OS) remains controversial, particularly in the context of repeated surgical resection and/or use of anti-angiogenic therapy. In the current study, we examined recurrent GBM patients from both single and multicenter clinical trials to test whether baseline enhancing tumor volume, including central necrosis, is a significant prognostic factor for OS in recurrent GBM.

Methods: Included were 497 patients with recurrent GBM from 4 data sources: 2 single-center sites (University of Toronto, University of California Los Angeles) and 2 phase II multicenter trials (AVF3708G, Bevacizumab ± Irinotecan, NCT00345163; XL184-201, Cabozantinib, NCT00704288). T1 subtraction maps were used to define volume of contrast enhancing tumor, including central necrosis. Cox multivariable and univariate analyses were used to evaluate the relationship between tumor volume prior to second- or third-line therapy and OS.

Results: Both continuous measures of baseline tumor volume and tumors dichotomized into large (≥15cc) and small (<15cc) tumors were significant predictors of OS (P<.0001), independently of age and treatment. Univariate analysis demonstrated significant OS differences (P<.05) between large (≥15cc) and small (<15cc) tumors in patients under all therapeutic scenarios. Only patients treated with cabozantinib who previously failed anti-angiogenic therapy did not show an OS dependence on baseline tumor volume.

Conclusions: Baseline tumor volume is a significant prognostic factor in recurrent GBM. Clinical trial treatment arms must have a balanced distribution of tumor size, and tumor size should be considered when interpreting therapeutic efficacy.

Keywords: T1 subtraction; bevacizumab; cabozantinib; glioblastoma; recurrent; tumor volume.

Publication types

Clinical Trial, Phase II
Multicenter Study
Randomized Controlled Trial

MeSH terms

Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
Bevacizumab / administration & dosage
Biomarkers, Tumor / analysis
Brain Neoplasms / drug therapy
Brain Neoplasms / metabolism
Brain Neoplasms / pathology*
Camptothecin / administration & dosage
Camptothecin / analogs & derivatives
Contrast Media / metabolism*
Female
Follow-Up Studies
Glioblastoma / drug therapy
Glioblastoma / metabolism
Glioblastoma / pathology*
Humans
Irinotecan
Male
Middle Aged
Molecular Imaging / methods
Necrosis
Neoplasm Recurrence, Local / drug therapy
Neoplasm Recurrence, Local / metabolism
Neoplasm Recurrence, Local / pathology*
Neoplasm Staging
Prognosis
Retrospective Studies
Survival Rate
Tumor Burden

Substances

Biomarkers, Tumor
Contrast Media
Bevacizumab
Irinotecan
Camptothecin

Associated data

ClinicalTrials.gov/NCT00345163
ClinicalTrials.gov/NCT00704288