Updated Response Assessment Criteria for High-Grade Gliomas: Response Assessment in Neuro-Oncology Working Group

Abstract

Currently, the most widely used criteria for assessing response to therapy in high-grade gliomas are based on two-dimensional tumor measurements on computed tomography (CT) or magnetic resonance imaging (MRI), in conjunction with clinical assessment and corticosteroid dose (the Macdonald Criteria). It is increasingly apparent that there are significant limitations to these criteria, which only address the contrast-enhancing component of the tumor. For example, chemoradiotherapy for newly diagnosed glioblastomas results in transient increase in tumor enhancement (pseudoprogression) in 20% to 30% of patients, which is difficult to differentiate from true tumor progression. Antiangiogenic agents produce high radiographic response rates, as defined by a rapid decrease in contrast enhancement on CT/MRI that occurs within days of initiation of treatment and that is partly a result of reduced vascular permeability to contrast agents rather than a true antitumor effect. In addition, a subset of patients treated with antiangiogenic agents develop tumor recurrence characterized by an increase in the nonenhancing component depicted on T2-weighted/fluid-attenuated inversion recovery sequences. The recognition that contrast enhancement is nonspecific and may not always be a true surrogate of tumor response and the need to account for the nonenhancing component of the tumor mandate that new criteria be developed and validated to permit accurate assessment of the efficacy of novel therapies. The Response Assessment in Neuro-Oncology Working Group is an international effort to develop new standardized response criteria for clinical trials in brain tumors. In this proposal, we present the recommendations for updated response criteria for high-grade gliomas.

Pseudoprogression, radionecrosis, inflammation or true tumor progression? challenges associated with glioblastoma response assessment in an evolving therapeutic landscape

“…Per 2010 RANO criteria, such histopathological analysis should be unequivocal, for instance showing solid tumor areas with >70% tumor cell nuclei, a high or progressive increase in MIB-1 proliferation index compared with prior biopsy, or evidence of histologic progression of the tumor compared with prior biopsy [8]. However, per RANO criteria, some imaging findings also allow the determination of true progression.…”

“…However, per RANO criteria, some imaging findings also allow the determination of true progression. First, at any time point following completion of chemoradiotherapy, new enhancement outside of the high-dose/80% isodose radiation volume, which is reasonably thought to cover all tumor (and not other infectious/inflammatory/ischemic disease, for instance) allows the determination of progressive disease [8].…”

“…Because of the high incidence of pseudoprogression particularly within the first 12 weeks after the completion of chemoradiotherapy, one must wait at least 12 weeks to categorize enhancing lesions that have increased in size by 25% or more in the sum of the products of their perpendicular diameters as progressive disease [8]. There can be continued uncertainty beyond 12 weeks as pseudoprogression can occur several months after the completion of chemoradiotherapy [64], although it is rarely seen after 6 months.…”

“…Additionally, clinical studies examining the efficacy of new anti-angiogenic agents have noticed a substantial decrease in contrast enhancement and edema [9,10] resulting in a "pseudoresponse." In 2010, the current Response Assessment in Neuro-Oncology (RANO) criteria were drafted [8]. Although the RANO criteria corrects for a number of deficiencies (Tables 1, 2), there remain significant limitations to the standard approach to response assessment, particularly in the current therapeutic environment consisting of immunotherapies, radiosensitizers, anti-angiogenic agents, and therapies with multiple targets or mechanisms of action (Table 3) .…”

Therapeutic options in recurrent glioblastoma—An update

“…Limitations included the observation of "pseudoprogression" as a transient increase of contrast-enhancing tumor especially within the first 3 months after completion of radiotherapy as well as "pseudoresponses" with divergent effects on contrast-enhanced T1-images versus T2/fluid-attenuated inversion recovery (FLAIR) sequences especially with use of antiangiogenic agents. Since 2010, the updated criteria for Response Assessment in Neuro-Oncology (RANO) add restricted parameters for diagnosis of progressive disease within 3 months after completion of radiochemotherapy and integrate the evaluation of T2/FLAIR sequences as well of corticosteroid use [10]. Recently, the same group has provided an international consensus protocol based on the development of the EORTC Brain Tumor Group for uniform evaluation in clinical trials and practice [11].…”