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

doi:10.1093/neuonc/now187

Clinical Trial

. 2017 Jan;19(1):89-98.

doi: 10.1093/neuonc/now187. Epub 2016 Aug 31.

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

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.).

PMID: 27580889
PMCID: PMC5193027
DOI: 10.1093/neuonc/now187

Clinical Trial

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 et al. Neuro Oncol. 2017 Jan.

. 2017 Jan;19(1):89-98.

doi: 10.1093/neuonc/now187. Epub 2016 Aug 31.

Authors

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.).

PMID: 27580889
PMCID: PMC5193027
DOI: 10.1093/neuonc/now187

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.

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Figures

**Fig. 1**
Patient flow diagram. Imaging and patient information were obtained from 4 different data sources: recurrent GBM patients treated at the University of Toronto treated with various chemotherapies (N = 50); recurrent GBM patients treated at UCLA with bevacizumab with and without concurrent chemotherapies (N = 63); recurrent GBM patients treated with bevacizumab with and without concurrent chemotherapies in the BRAIN trial (N = 162); and recurrent GBM patients treated with cabozantinib monotherapy in XL184-201 (N = 222). Patients from UCLA and the BRAIN trial were combined to create a larger cohort of bevacizumab treated patients (N = 225).

**Fig 2.**
Contrast-enhanced T1-weighted digital subtraction maps. In order to increase lesion conspicuity and increase automation in tumor segmentation, (A) pre- and (B) postcontrast T1-weighted images were intensity normalized, coregistered, and subtracted voxel-by-voxel, highlighting only areas of increased signal intensity following contrast administration. The resulting T1 subtraction maps (C) were used to quantify enhancing lesion volume, which also included areas of central necrosis.

**Fig. 3**
Influence of baseline contrast enhancing tumor volume on OS in a composite cohort of patients with recurrent GBM (N = 497). (A) Kaplan–Meier plots of OS in recurrent GBM grouped by baseline contrast enhancing tumor volume. Results demonstrate 3 distinct groupings of OS for tumors >15cc, between 5cc and 15cc, and less than 5cc. (B) In patients who expired at the time of evaluation (436 of 497 patients), results showed a significant log-linear trend indicating decreasing OS with increasing tumor volume. (C) Kaplan–Meier plots of OS in recurrent GBM patients stratified by large (≥15cc) and small (<15cc) tumor volume. (D) Kaplan–Meier plots of OS in recurrent GBM patients stratified by very small (<5cc) and larger (≥5cc) tumor volume.

**Fig 4.**
Influence of baseline contrast enhancing tumor volume on OS in recurrent GBM treated with bevacizumab. (A) Kaplan–Meier plots of OS in all recurrent GBM patients treated with bevacizumab (*N =* 225) stratified by large (≥15cc) and small (<15cc) tumor volume. (B) Kaplan–Meier plots of OS in recurrent GBM patients treated with bevacizumab monotherapy in the BRAIN trial (*N =* 82) stratified by large (≥15cc) and small (<15cc) tumor volume. (C) Kaplan–Meier plots of OS in recurrent GBM patients treated with concurrent bevacizumab and irinotecan in the BRAIN trial (*N =* 80) stratified by large (≥15cc) and small (<15cc) tumor volume. (D) Kaplan–Meier plots of OS in recurrent GBM patients treated with bevacizumab with or without chemotherapy at UCLA (*N =* 63) stratified by large (≥15cc) and small (<15cc) tumor volume.

**Fig 5.**
Influence of baseline contrast enhancing tumor volume on OS in recurrent GBM treated with chemotherapy (never receiving anti-angiogenic therapy) or cabozantinib (XL184). (A) Kaplan–Meier plots of OS in recurrent GBM patients treated with a variety of chemotherapies at the University of Toronto, but never treated with anti-angiogenic therapy, stratified by large (≥15cc) and small (<15cc) tumor volume. (B) Kaplan–Meier plots of OS in recurrent GBM patients treated with TMZ stratified by large (≥15cc) and small (<15cc) tumor volume. (C) Kaplan–Meier plots of OS in recurrent GBM patients treated with CCNU stratified by large (≥15cc) and small (<15cc) tumor volume. (D) Kaplan–Meier plots of OS in recurrent GBM patients treated with cabozantinib monotherapy stratified by large (≥15cc) and small (<15cc) tumor volume. (E) Kaplan–Meier plots of OS in a subset of recurrent GBM patients treated with cabozantinib monotherapy who never previously failed anti-VEGF therapy, stratified by large (≥15cc) and small (<15cc) tumor volume. (F) Kaplan–Meier plots of OS in a subset of recurrent GBM patients treated with cabozantinib who previously failed anti-VEGF therapies, stratified by large (≥15cc) and small (<15cc) tumor volume. Note similar, uniformly poor OS in patients with large and small tumors who previously failed these therapies.

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Comment in

Where size matters: imaging-based biomarkers for patient stratification.
Erickson BJ, Galanis E. Erickson BJ, et al. Neuro Oncol. 2017 Jan;19(1):7-8. doi: 10.1093/neuonc/now248. Neuro Oncol. 2017. PMID: 28031381 Free PMC article. No abstract available.

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References

1. Kelly PJ, Daumas-Duport C, Scheithauer BW, et al. Stereotactic histologic correlations of computed tomography- and magnetic resonance imaging-defined abnormalities in patients with glial neoplasms. Mayo Clin Proc. 1987;62(6):450–459. - PubMed
1. Kelly PJ, Daumas-Duport C, Kispert DB, et al. Imaging-based stereotaxic serial biopsies in untreated intracranial glial neoplasms. J Neurosurg. 1987;66(6):865–874. - PubMed
1. Barajas RF, Jr, Phillips JJ, Parvataneni R, et al. Regional variation in histopathologic features of tumor specimens from treatment-naive glioblastoma correlates with anatomic and physiologic MR imaging. Neuro Oncol. 2012;14(7):942–954. - PMC - PubMed
1. Earnest Ft, Kelly PJ, Scheithauer BW, et al. Cerebral astrocytomas: histopathologic correlation of MR and CT contrast enhancement with stereotactic biopsy. Radiology. 1988;166(3):823–827. - PubMed
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[1] Kelly PJ, Daumas-Duport C, Scheithauer BW, et al. Stereotactic histologic correlations of computed tomography- and magnetic resonance imaging-defined abnormalities in patients with glial neoplasms. Mayo Clin Proc. 1987;62(6):450–459. - PubMed

[2] Kelly PJ, Daumas-Duport C, Scheithauer BW, et al. Stereotactic histologic correlations of computed tomography- and magnetic resonance imaging-defined abnormalities in patients with glial neoplasms. Mayo Clin Proc. 1987;62(6):450–459. - PubMed

[3] Kelly PJ, Daumas-Duport C, Kispert DB, et al. Imaging-based stereotaxic serial biopsies in untreated intracranial glial neoplasms. J Neurosurg. 1987;66(6):865–874. - PubMed

[4] Kelly PJ, Daumas-Duport C, Kispert DB, et al. Imaging-based stereotaxic serial biopsies in untreated intracranial glial neoplasms. J Neurosurg. 1987;66(6):865–874. - PubMed

[5] Barajas RF, Jr, Phillips JJ, Parvataneni R, et al. Regional variation in histopathologic features of tumor specimens from treatment-naive glioblastoma correlates with anatomic and physiologic MR imaging. Neuro Oncol. 2012;14(7):942–954. - PMC - PubMed

[6] Barajas RF, Jr, Phillips JJ, Parvataneni R, et al. Regional variation in histopathologic features of tumor specimens from treatment-naive glioblastoma correlates with anatomic and physiologic MR imaging. Neuro Oncol. 2012;14(7):942–954. - PMC - PubMed

[7] Earnest Ft, Kelly PJ, Scheithauer BW, et al. Cerebral astrocytomas: histopathologic correlation of MR and CT contrast enhancement with stereotactic biopsy. Radiology. 1988;166(3):823–827. - PubMed

[8] Earnest Ft, Kelly PJ, Scheithauer BW, et al. Cerebral astrocytomas: histopathologic correlation of MR and CT contrast enhancement with stereotactic biopsy. Radiology. 1988;166(3):823–827. - PubMed

[9] Vogelbaum MA. Does extent of resection of a glioblastoma matter? Clin Neurosurg. 2012;59:79–81. - PubMed

[10] Vogelbaum MA. Does extent of resection of a glioblastoma matter? Clin Neurosurg. 2012;59:79–81. - PubMed

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

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

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