Assessment of tumor oxygenation and its impact on treatment response in bevacizumab-treated recurrent glioblastoma

Abstract

Antiantiogenic therapy with bevacizumab in recurrent glioblastoma is currently understood to both reduce microvascular density and to prune abnormal tumor microvessels. Microvascular pruning and the resulting vascular normalization are hypothesized to reduce tumor hypoxia and increase supply of systemic therapy to the tumor; however, the underlying pathophysiological changes and their timing after treatment initiation remain controversial. Here, we use a novel dynamic susceptibility contrast MRI-based method, which allows simultaneous assessment of tumor net oxygenation changes reflected by the tumor metabolic rate of oxygen and vascular normalization represented by the capillary transit time heterogeneity. We find that capillary transit time heterogeneity, and hence the oxygen extraction fraction combine with the tumoral blood flow (cerebral blood flow) in such a way that the overall tumor oxygenation appears to be worsened despite vascular normalization. Accordingly, hazards for both progression and death are found elevated in patients with a greater reduction of tumor metabolic rate of oxygen in response to bevacizumab and patients with higher intratumoral tumor metabolic rate of oxygen at baseline. This implies that tumors with a higher degree of angiogenesis prior to bevacizumab-treatment retain a higher level of angiogenesis during therapy despite a greater antiangiogenic effect of bevacizumab, hinting at evasive mechanisms limiting bevacizumab efficacy in that a reversal of their biological behavior and relative prognosis does not occur.

Anti-Angiogenics: Their Role in the Treatment of Glioblastoma

“…In this context, it has been reported that early changes of magnetic resonance imaging (MRI) parameters can occur in glioblastoma patients who receive the anti-angiogenic multi-tyrosine kinase inhibitor cediranib, and those are in line with the normalization hypothesis (explained in the 'Introduction'), improving tumor perfusion, at least during a normalization time window, which might help radio-and chemotherapy [7,10,[34][35][36]. For bevacizumab, however, it has been suggested that tumor oxygenation might actually be worsened and not improved in patients during the phase where vascular normalization occurs, which would speak against the benefit from vascular normalization for additional cytotoxic therapy in this condition [11]. Of note, multimodal MRI patterns analyzed by novel machine learning algorithms, i.e.…”

Radiomic Profiling of Glioblastoma: Identifying an Imaging Predictor of Patient Survival with Improved Performance over Established Clinical and Radiologic Risk Models

“…ox.ac.uk/fsl/fslwiki/FSL) by P.K. and a neuroradiologist (D.B., with 15 years of experience in image processing) as described previously (14,16). First, brain voxels were isolated by generating a binary brain mask from the T1-weighted volume sequence by using the brain extraction tool (20) and were transferred to all other volume imaging sequences (postcontrast T1-weighted, FLAIR, diffusion-weighted imaging, ADC mapping, first temporal volume of dynamic susceptibility-weighted MR imaging raw data, relative CBV map) for each patient.…”

“…and D.B. on the T1 subtraction volume images to select the contrastenhancing portion of the whole tumor and the nonenhancing portion (defined as FLAIR hyperintense abnormality, excluding the contrast-enhancing and necrotic tumor portion) by using a region-growing segmentation algorithm implemented with software (ITK-SNAP; www.itksnap.org [23]), as described previously (Fig 1a) (14,16).…”

“…with customized in-house software implemented in Matlab (Mathworks, Natick, Mass) as described previously (14,16). The first volumes of the diffusion-weighted …”

“…The protocol included (a) unenhanced T1-weighted three-dimensional magnetization-prepared rapid acquisition gradient-echo imaging; (b) diffusion-weighted imaging with diffusion sensitizing gradients applied sequentially in the x, y, and z directions, with b values of 0 and 1200 sec/mm 2 and corresponding ADC maps generated with software (Syngo, Siemens); (c) dynamic susceptibility-weighted MR imaging with a T2*-weighted gradientecho echo-planar imaging sequence during the bolus injection of intravenous gadoterate meglumine (Dotarem; Guerbet, France) as described previously (13)(14)(15), followed by (d) postcontrast T1-weighted three-dimensional magnetization-prepared rapid acquisition gradient-echo and (e) FLAIR image acquisition. Details on MR imaging acquisition parameters are available in Appendix E1, section S2 (online).…”