A Neuroradiologist's Guide to Operationalizing the Response Assessment in Neuro-Oncology (RANO) Criteria Version 2.0 for Gliomas in Adults

Abstract

Radiographic assessment plays a crucial role in the management of patients with central nervous system (CNS) tumors, aiding in treatment planning and evaluation of therapeutic efficacy by quantifying response. Recently, an updated version of the Response Assessment in Neuro-Oncology (RANO) criteria (RANO 2.0) was developed to improve upon prior criteria and provide an updated, standardized framework for assessing treatment response in clinical trials for gliomas in adults. This article provides an overview of significant updates to the criteria including (1) the use of a unified set of criteria for high and low grade gliomas in adults; (2) the use of the post-radiotherapy MRI scan as the baseline for evaluation in newly diagnosed high-grade gliomas; (3) the option for the trial to mandate a confirmation scan to more reliably distinguish pseudoprogression from tumor progression; (4) the option of using volumetric tumor measurements; and (5) the removal of subjective non-enhancing tumor evaluations in predominantly enhancing gliomas (except for specific therapeutic modalities). Step-by-step pragmatic guidance is hereby provided for the neuroradiologist and imaging core lab involved in operationalization and technical execution of RANO 2.0 in clinical trials, including the display of representative cases and in-depth discussion of challenging scenarios.

Graphical abstract

FIG 1.

Flow-chart to identify target lesions for CE (A), non-CE (B), and “mixed” (C) tumors. * the size condition for measurable disease is: ≥10 mm on 3 ⊥ planes for 3D images with thin slice (more often applied to CE disease), or ≥ 10 mm on in-plane ⊥ diameters and visible on ≥2 slices for 2D images with thicker slice (more often applied to non-CE disease). Of note, these conditions apply to trials employing bidimensional measurements for treatment response assessment, while for trials employing volumetric segmentations various strategies can be applied for the identification of target lesions (please refer to the dedicated paragraph in the main text). ° “mixed” tumors is short for “tumors with both CE and non-CE components”. ^† in mixed tumors, up to a total of 4 target lesions is allowed (i.e., x + y ≤ 4).

FIG 2.

Guidelines and tips for bidirectional “2D” measurements. The measurement protocol for target lesions with 3D images and 2D imaging (A) is used both to verify that the lesion meets the criteria for “measurable disease” and to obtain measurements to calculate the tumor burden. Measurements in CE tumors (B) should not include the surgical cavity or cystic areas, and should avoid areas where the lesion shows necrotic features or is not distinguishable from post-surgical meningeal thickening. In non-CE tumors (C), the presence of infiltrative disease with unclear boundaries can pose a serious challenge when performing measurements. If possible, slices where the tumor shows more defined margins should be preferred for target lesion measurements. In “mixed” tumors (D), the CE lesions lie within the boundaries of non-CE lesions. CE and non-CE target lesions should be measured separately and not necessarily on the same plane/slice. Then, longitudinal changes in CE- and non-CE tumor burden are tracked in parallel to define the response category.

FIG. 3

Schema for determining radiographic treatment response assessment as per RANO 2.0. To assess MR/PR, the change in tumor burden should be compared to the baseline MRI, while for PD it should be compared to the nadir. In clinical trials applying the “mixed” tumor criteria, the whole evaluation should be performed in parallel for both the CE and the non-CE tumor burden at each timepoint in order to assign the response category (e.g., PD, SD, PR, …), then the overall response category is assigned based on both CE and non-CE categories: PD+SD/MR/PR/CR=PD; MR/PR+SD=MR/PR; CR+SD/MR/PR=SD/MR/PR; SD+SD=SD (see text for details). ° the additional categories preliminary and durable “minor response” (MR: > –50% and < –25% 2D or > –65% and < –40% 3D) should be taken into consideration, only for non-CE disease. * confirmation scans obtained after ≥4 weeks to confirm PD can be waived in the following scenarios: in CE tumors ≥3 months after RT completion and if the treatment does not include agents highly associated with PsP; in the evaluation of non-CE progression in non-CE tumors or mixed tumors (as PsP is typically contrast-enhancing). Confirmation scans after ≥4 weeks to confirm durable MR/PR/CR are always required. If a patient is lost to follow-up (censored) before obtaining a confirmation scan (when required), the last timepoint showing preliminary CR/PR/MR/PD is classified as SD.

FIG 4.

RANO 2.0 evaluations in example cases of newly-diagnosed CE glioblastoma. In case A, radiographic findings are stable (stable disease, SD) for 13.1 months from baseline, in the absence of measurable disease around the resection cavity. The appearance of a new measurable CE nodule after ≥12 weeks after RT completion (at 16.8 months in this case) classifies PD generally without the need of a confirmatory scan (unless clearly required by the trial), and the study treatment is stopped. In case B, the first follow-up scan shows early progressive disease (PD) <12 weeks after RT completion, “preliminary PD” (prel. PD) is annotated, the patient is kept on treatment, and a confirmation scan is obtained after ≥4 weeks. After confirmation of PD, the treatment is stopped and the confirmed PD (conf. PD) event is backdated to the day of preliminary PD. The time interval between the post-RT baseline scan and the date of confirmed PD corresponds to the time of progression (TTP). In case C, the first follow-up scan shows early PD <12 weeks after RT completion, annotated as preliminary PD. The confirmation scan after >4 weeks shows substantially stable findings, with no further size increase of the target lesion, therefore the preliminary PD timepoint is reclassified as pseudoprogression (PsP), and the patient is kept on treatment.

FIG 5.

Proposed implementation of volumetric (3D) assessments. A preliminary evaluation should be performed to confirm the presence of measurable disease according to the classic bidimensional criteria. If 2D-defined measurable disease is present, the volumetric tumor burden may be computed by including the whole segmentation of the appropriate tissue (e.g., only CE tissue for CE tumors) which comprises both 2D-defined measurable components and 2D-defined non-measurable components (A). A quality check should always be performed by the reader to correct errors in the segmentation, for instance to exclude vascular structures or healthy meningeal tissue. If 2D-defined measurable disease is absent, the volumetric tumor burden should be set to “non-measurable”, regardless of the 3D segmentation (B). In the cases shown, T₁-subtraction maps were used to only include in the segmentation voxels that showed increased T₁-weighted signal when comparing post- to pre-contrast T₁-weighted normalized images.