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

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.

© The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

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 (