title: Baseline pretreatment contrast enhancing tumor volume including central necrosis is a prognostic factor in recurrent glioblastoma: evidence from single and multicenter trials.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors: 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.
authors: Benjamin M
authors: BM
authors: Ellingson
authors: 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.).
authors: Robert J
authors: RJ
authors: Harris
authors: 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.).
authors: Davis C
authors: DC
authors: Woodworth
authors: 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.).
authors: Kevin
authors: K
authors: Leu
authors: 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.).
authors: Okkar
authors: O
authors: Zaw
authors: 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.).
authors: Warren P
authors: WP
authors: Mason
authors: 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.).
authors: Solmaz
authors: S
authors: Sahebjam
authors: 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.).
authors: Lauren E
authors: LE
authors: Abrey
authors: 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.).
authors: Dana T
authors: DT
authors: Aftab
authors: 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.).
authors: Gisela M
authors: GM
authors: Schwab
authors: 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.).
authors: Colin
authors: C
authors: Hessel
authors: 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.).
authors: Albert
authors: A
authors: Lai
authors: 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.).
authors: Phioanh L
authors: PL
authors: Nghiemphu
authors: 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.).
authors: Whitney B
authors: WB
authors: Pope
authors: 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.).
authors: Patrick Y
authors: PY
authors: Wen
authors: 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.).
authors: Timothy F
authors: TF
authors: Cloughesy
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000008:administration & dosage; D014408:Biomarkers, Tumor / Q000032:analysis; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D003287:Contrast Media / Q000378:metabolism*; D005260:Female; D005500:Follow-Up Studies; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D057054:Molecular Imaging / Q000379:methods; D009336:Necrosis; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D009367:Neoplasm Staging; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate; D047368:Tumor Burden
chemical_list: D014408:Biomarkers, Tumor; D003287:Contrast Media; D000068258:Bevacizumab; D000077146:Irinotecan; D002166:Camptothecin
keywords: T1 subtraction; bevacizumab; cabozantinib; glioblastoma; recurrent; tumor volume