Glioblastoma multiforme (GBM) is the most malignant subtype of glioma and is characterized by extreme heterogeneity, extensive neovasculature, and active angiogenesis. The current standard of care for patients with newly diagnosed GBM includes combined radio- and chemotherapy, which comprises a 6-week cycle of external beam radiation therapy and oral temozolomide followed by an additional 6 months of temozolomide.1,2
Antiangiogenic therapies have recently shown the potential for reducing tumor size and increasing 6-month progression-free survival (PFS).3,4
The recent phase II trial of the antiangiogenic agent bevacizumab, a monoclonal antibody directed against vascular endothelial growth factor (VEGF), used alone and in combination with irinotecan reported dramatic improvement in 6-month PFS and a high response rate in patients with recurrent GBM.5
It has been proposed that the use of adjuvant antiangiogenic therapy in combination with standard radio- and chemotherapy acts to normalize the tortuous tumor vasculature and improve delivery of chemotherapeutics and oxygen.6,7
Enzastaurin (LY317615) is one such antiangiogenic agent that is currently under investigation for its potential as an adjuvant therapy for patients with newly diagnosed GBM.8
Enzastaurin selectively inhibits protein kinase Cβ and has been reported to have both direct antitumor effects, through suppression of tumor cell proliferation and induced apoptosis, and indirect effects, through inhibition of tumor-induced angiogenesis.9
Unlike bevacizumab, enzastaurin is a non-VEGF antiangiogenic agent whose mechanism of action is not yet fully understood.10
Preclinical reports have shown that enzastaurin and radiation are synergistic in combination to induce apoptosis in glioma models.11
One of the first multicenter phase II clinical studies of enzastaurin was reported by Robertson et al.,12
who described a favorable toxicity profile and a single-agent activity in a population of 55 patients with refractory diffuse large B-cell lymphoma. The authors highlight the possibility of differential sensitivity to enzastaurin based on a small subset of the study population who showed a long-term response but showed steady-state drug levels similar to those of the rest of the population. In the recurrent GBM population, enzastaurin has not been shown to have superior efficacy compared with the cytotoxic chemotherapeutic agent lomustine,13
yet there are several ongoing phase I/II trials that involve the use of adjuvant enzastaurin for patients newly diagnosed with GBM.8,14
The exciting potential of adjuvant antiangiogenic therapy for improving disease management and increasing PFS has simultaneously highlighted unresolved questions in the field regarding the evaluation of response. As described in van den Bent et al.,15
there are numerous challenges in evaluating response to antiangiogenic therapies in neuro-oncology. Classic Macdonald criteria16
have used a reduction in contrast-enhancing volume as a surrogate marker for antitumor effects. For antiangiogenic therapies, the apparent reduction in enhancing volume could be due to the transient normalization of the blood–brain barrier rather than the antitumor activity.17,18
This complicates the definition of progression and the use of 6-month PFS as a surrogate endpoint of overall survival. As the paradigm for GBM therapy shifts from a purely cytotoxic approach to now incorporating targeted therapies with cytostatic effects, there is a need to explore the use of functional imaging techniques in order to better evaluate and define new criteria for evaluating response to therapy.
A number of noninvasive imaging techniques have been used to assess changes in microvasculature and response to therapy.19–21
Dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) has been shown to improve sensitivity compared with conventional MRI alone in determining the glioma grade.22
Within the context of antiangiogenic therapy, Batchelor et al.3
used both DSC and dynamic contrast-enhanced (DCE) MRI, with a variety of other advanced imaging techniques, to evaluate the normalization of vasculature in recurrent GBM patients receiving adjuvant AZD2171 during the first 112 days of therapy. The authors observed a rapid functional vascular normalization in terms of both a reduction in vessel size and overall permeability, which was found to be reversible upon drug “holiday.” The changes in DSC and DCE imaging–derived perfusion parameters combined with differences in circulating collagen IV levels between pretherapy and 1-day post-therapy were combined to create a “vascular normalization index” that was predictive of overall survival (OS) and PFS for patients with recurrent GBM who received this therapy.23
How these parameters evolve during the full course of therapy for patients with newly diagnosed GBM and how they relate to radiographic response and outcome remain unknown.
The previous work with DSC perfusion MRI has made it an alluring technique for evaluating response to antiangiogenic therapy. There is the potential for addressing challenges specific to assessing the efficacy of antiangiogenic agents in clinical trials, including (i) the identification of subpopulations that would benefit most from this therapy and (ii) the recognition of early markers of progressive disease in the case of tumor recurrence.17
The present study was designed to investigate the use of DSC perfusion MRI to identify early predictors of overall response to antiangiogenic therapy as well as to evaluate distinct changes in MR parameters during therapy that may be predictive of imminent progression.