Response assessment criteria for glioblastoma: practical adaptation and implementation in clinical trials of antiangiogenic therapy

Abstract

Since 1990, the primary criteria used for assessing response to therapy in high-grade gliomas were those developed by Macdonald and colleagues, which incorporated 2-dimensional area measurements of contrast-enhancing tumor regions, corticosteroid dosing, and clinical assessment to arrive at a designation of response, stable disease, or progression. Recent advances in imaging technology and targeted therapeutics, however, have exposed limitations of the Macdonald criteria and have highlighted the need for reevaluation of response assessment criteria. In 2010, the Response Assessment in Neuro-Oncology (RANO) Working Group published updated criteria to address this need and to standardize response assessment for high-grade gliomas. In 2009, prior to the publication of the RANO criteria, the randomized, placebo-controlled, multicenter, phase 3 AVAglio trial was designed and initiated to investigate the effectiveness of radiotherapy and temozolomide with or without bevacizumab in newly diagnosed glioblastoma. The AVAglio protocol enacted specific measures to adapt the Macdonald criteria to the frontline treatment setting and to antiangiogenic agent evaluation, including the incorporation of a T2/fluid-attenuated inversion recovery component, qualitative assessment of irregularly shaped contrast-enhancing lesions, and a decision tree for confirming or ruling out pseudoprogression. Moreover, the protocol outlines practical means by which these adapted response criteria can be implemented in the clinic. This article describes the evolution of radiographic response criteria for high-grade gliomas and highlights the similarities and differences between those implemented in the AVAglio study and those subsequently published by RANO.

Trial registration: ClinicalTrials.gov NCT00943826.

Fig. 1

Overview of treatment and radiologic assessment schedule in AVAglio. Disease assessment consists of radiologic assessment, neurologic examination, including the mini-mental state examination, and determination of corticosteroid use. Cy cycle, d days, HRQoL health-related quality of life, PD progressive disease; w weeks

Fig. 2

Illustration of a disease assessment of progressive disease based on non–contrast-enhancing lesions in a 35 year old male with left frontal glioblastoma. T1 contrast magnetic resonance imaging (MRI) obtained immediately after completion of chemoradiation and bevacizumab (a); 6 months later and continuing chemotherapy and bevacizumab (b); and 12 months after completion of chemoradiation and bevacizumab while continuing chemotherapy and bevacizumab (c); show no evidence of contrast-enhancing tumor progression. T2 MRI obtained immediately after completion of chemoradiation and bevacizumab (d); and 6 months later while continuing chemotherapy and bevacizumab (e); show no tumor progression, but MRI obtained 12 months after completion of chemoradiation and bevacizumab while continuing chemotherapy and bevacizumab (f); shows clear evidence of T2 non–contrast-enhancing tumor progression with architectural distortion of the left lateral ventricle (arrow)

Fig. 3

Decision-making flow chart in patients with signs of pseudoprogression in AVAglio. PD progressive disease

Fig. 4

Illustration of pseudoprogression in a 52-year-old patient with left parietal malignant glioma. T1 contrast-enhancing magnetic resonance imaging (MRI) shows a gross total resection (a). Four weeks after completion of chemoradiation, MRI showed a new area of contrast enhancement surrounding the collapsed surgical cavity (b). Two months after initiation of maintenance temozolomide, MRI showed diminution of the contrast enhancing area (c), which was further diminished after an additional months (d)