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.

Bevacizumab plus Radiotherapy–Temozolomide for Newly Diagnosed Glioblastoma

“…Specifically, assessment of nonenhancing tumor components was included, and a specific algorithm was used to assess pseudoprogression. 25 These adaptations are consistent with current international consensus guidelines. 26 Assessments were carried out at baseline; 28 days after completion of the concurrent-therapy phase; during cycles 2, 4, and 6 of the maintenance phase; every 9 weeks throughout the monotherapy phase; and at the time of disease progression.…”

“…33 The adapted Macdonald Response Criteria, which were used to assess progression, anticipated some of the key features of the Response Assessment in Neuro-Oncology (RANO) Working Group criteria, which were not available at the time of the initiation of our study. 25,26 The adapted Macdonald Response Criteria addressed the observed limitations of imaging assessment by including qualitative evaluation of both noncontrast-enhancing components (by means of T 2 -weighted imaging or fluid-attenuated inversion recovery [FLAIR]) and small contrastenhancing lesions (at least one diameter <10 mm). These criteria also addressed the transient increases in tumor enhancement (pseudoprogression) associated with front-line chemoradiotherapy by standardizing the assessment of pseudoprogression with the use of a strict algorithm, resulting in lower incidences of pseudoprogression than those in previous studies.…”

“…The determination of progression was based on imaging assessment (MRI), clinical assessment, and glucocorticoid use 25 (Table S1 in the Supplementary Appendix). Radiographic criteria were adapted to address specific concerns related to the effect of antiangiogenic therapy on imaging.…”

Re-defining response and treatment effects for neuro-oncology immunotherapy clinical trials

“…On the one hand, radiographic improvement is felt to provide a straightforward indication of anti-tumor effect because immunotherapies do not decrease tumor vessel permeability leading to pseudoresponse as been observed following anti-angiogenic agents [26]. On the other hand, worsened radiographic findings following administration of an immunotherapeutic may be more challenging to interpret.…”

Regulation of C6 glioma cell migration by thymol

“…Moreover, the diagnosis and treatment of glioma are difficult, its pathology and pattern of invasion and migration are poorly understood (6,7). Several studies have reported that the pathological response of glioma, which is the malignant process of infiltration into the extensive normal tissue, is due to the activation of mitogen-activated protein kinase (MAPK), protein kinase Cα (PKCα) and matrix metalloproteinases (MMPs) (8)(9)(10)(11).…”