Patterns of relapse and prognosis after bevacizumab failure in recurrent glioblastoma

Abstract

Background: Bevacizumab has recently been approved by the US Food and Drug Administration for recurrent glioblastoma (GBM). However, patterns of relapse, prognosis, and outcome of further therapy after bevacizumab failure have not been studied systematically.

Methods: We identified patients at Memorial Sloan-Kettering Cancer Center with recurrent GBM who discontinued bevacizumab because of progressive disease.

Results: There were 37 patients (26 men with a median age of 54 years). The most common therapies administered concurrently with bevacizumab were irinotecan (43%) and hypofractionated reirradiation (38%). The median overall survival (OS) after progressive disease on bevacizumab was 4.5 months; 34 patients died. At the time bevacizumab was discontinued for tumor progression, 17 patients (46%) had an increase in the size of enhancement at the initial site of disease (local recurrence), 6 (16%) had a new enhancing lesion outside of the initial site of disease (multifocal), and 13 (35%) had progression of predominantly nonenhancing tumor. Factors associated with shorter OS after discontinuing bevacizumab were lower performance status and nonenhancing pattern of recurrence. Additional salvage chemotherapy after bevacizumab failure was given to 19 patients. The median progression-free survival (PFS) among these 19 patients was 2 months, the median OS was 5.2 months, and the 6-month PFS rate was 0%.

Conclusions: Contrast enhanced MRI does not adequately assess disease status during bevacizumab therapy for recurrent glioblastoma (GBM). A nonenhancing tumor pattern of progression is common after treatment with bevacizumab for GBM and is correlated with worse survival. Treatments after bevacizumab failure provide only transient tumor control.

Figure 1 Neuroimaging before and after bevacizumab failure T1-weighted contrast (gadolinium)–enhanced (A and D), fluid-attenuation inversion recovery (FLAIR; B and E) magnetic resonance (MR) and [¹⁸F]fluorodeoxyglucose (FDG)-PET (C and F) before (A–C) and 3 weeks after (D–F) the last bevacizumab infusion, demonstrating increased FLAIR abnormality (E, arrow showing tumor crossing corpus callosum) without concurrent contrast enhancement of histologically proven recurrent disease (figure 2). Prebevacizumab FDG-PET demonstrated hypermetabolism (C, arrow) in the area of gadolinium enhancement that became substantially hypometabolic during bevacizumab therapy at the time of recurrence (F, arrow), which was a false negative. MR perfusion imaging (not shown) also demonstrated reduced blood flow at the type of recurrence, also a false negative. Resection demonstrated extremely high-grade tumor (figure 2, E–H).

Figure 2 Histopathology before and after bevacizumab failure Tumor tissue at recurrence before (A–D) and after (E–H) treatment with bevacizumab for patient shown in figure 1. (A) Persistent glioma with treatment effect (right) and necrosis (left) in a glioblastoma after radiation therapy and temozolomide but before bevacizumab (hematoxylin & eosin, ×25). (B) Persistent tumor is devoid of nuclear hypoxia-inducible factor 1α (HIF-1α) expression. (C) Vascular endothelial growth factor receptor 2 (VEGFR2) expression is confined to endothelial cells in tumor vasculature. (D) Carbonic anhydrase 9 (CA9) is not expressed in persistent tumor. (E) Recurrence resected 3 weeks after last bevacizumab demonstrating sarcomatous, spindle cell morphology with mitotic figures (arrows) and necrosis at right (hematoxylin & eosin, ×40). (F) Region of recurrent tumor demonstrating increased nuclear expression of HIF-1α. (G) VEGFR2 expression remains confined to endothelial cells in tumor vasculature. (H) Up-regulated CA9 expression in recurrent tumor is found neighboring regions of necrosis. (B–D and F–H: immunoperoxidase with hematoxylin counterstain, all ×40.)