Shankar, Lalitha

PURPOSE The Response Assessment in Neuro-Oncology (RANO) criteria for high-grade gliomas (RANO-HGG) and low-grade gliomas (RANO-LGG) were developed to improve reliability of response assessment in glioma trials. Over time, some limitations of these criteria were identified, and challenges emerged regarding integrating features of the modified RANO (mRANO) or the immunotherapy RANO (iRANO) criteria. METHODS Informed by data from studies evaluating the different criteria, updates to the RANO criteria are proposed (RANO 2.0). RESULTS We recommend a standard set of criteria for both high- and low-grade gliomas, to be used for all trials regardless of the treatment modalities being evaluated. In the newly diagnosed setting, the postradiotherapy magnetic resonance imaging (MRI), rather than the postsurgical MRI, will be used as the baseline for comparison with subsequent scans. Since the incidence of pseudoprogression is high in the 12 weeks after radiotherapy, continuation of treatment and confirmation of progression during this period with a repeat MRI, or histopathologic evidence of unequivocal recurrent tumor, are required to define tumor progression. However, confirmation scans are not mandatory after this period nor for the evaluation of treatment for recurrent tumors. For treatments with a high likelihood of pseudoprogression, mandatory confirmation of progression with a repeat MRI is highly recommended. The primary measurement remains the maximum cross-sectional area of tumor (two-dimensional) but volumetric measurements are an option. For IDH wild-type glioblastoma, the nonenhancing disease will no longer be evaluated except when assessing response to antiangiogenic agents. In IDH-mutated tumors with a significant nonenhancing component, clinical trials may require evaluating both the enhancing and nonenhancing tumor components for response assessment. CONCLUSION The revised RANO 2.0 criteria refine response assessment in gliomas.

Abstract BACKGROUND The Response Assessment in Neuro-Oncology (RANO) criteria for high-grade gliomas (RANO-HGG) and low-grade gliomas (RANO-LGG) were developed to improve reliability of response assessment in glioma trials. Over time some limitations of these criteria were identified, and uncertainty emerged regarding integrating features of the modified RANO (mRANO) or the immunotherapy RANO (iRANO) criteria. MATERIAL AND METHODS Informed by data from a cohort of glioblastoma patients and other evaluations of RANO criteria that allowed evaluation of features of the different criteria, the RANO working group developed updates to the RANO criteria (RANO 2.0). RESULTS Based on the 2021 WHO classification of gliomas, we recommend a standard set of criteria for both high and low-grade gliomas, to be used for all trials regardless of the treatment modalities being evaluated. In the newly diagnosed setting, the post-radiotherapy MRI, rather than the post-surgical MRI, will be used as the baseline for future comparison. Since the incidence of pseudoprogression is high in the 12 weeks following radiotherapy, continuation of treatment and confirmation of progression during this period with a repeat MRI, or histopathologic evidence of unequivocal recurrent tumor, is required to define tumor progression. However, confirmation scans are not mandatory after this period nor for recurrent tumors. For treatments with a high likelihood of pseudoprogression, mandatory confirmation of progression with a repeat MRI is highly recommended. The primary measurement remains the maximum cross-sectional area of tumor (2-dimensional) but volumetric measurements are an option. For IDH-wildtype glioblastoma, the non-enhancing disease will no longer be evaluated. In IDH-mutated tumors with a significant non-enhancing component, clinical trials may require evaluating both the enhancing and non-enhancing tumor components for response assessment. CONCLUSION These criteria represent a work in progress that will hopefully improve the assessment of response in glioma trials. Future updates will incorporate novel developments, advanced imaging techniques, and endpoints as they become validated.

Abstract The Response Assessment in Neuro-Oncology (RANO) criteria for high-grade gliomas (RANO-HGG) and low-grade gliomas (RANO-LGG) were developed to improve the reliability of response assessment in glioma trials. Over time some limitations of these criteria were identified, and uncertainty emerged regarding integrating features of the modified RANO (mRANO) or the immunotherapy RANO (iRANO) criteria. Informed by data from a cohort of glioblastoma patients and other evaluations of RANO criteria that allowed evaluation of features of the different criteria, we propose updates to the RANO criteria (RANO 2.0). Based on the 2021 WHO classification of gliomas, we recommend a standard set of criteria for both high and low-grade gliomas, to be used for all trials regardless of the treatment modalities being evaluated. In the newly diagnosed setting, the post-radiotherapy MRI, rather than the post-surgical MRI, will be used as the baseline for future comparison. Since the incidence of pseudoprogression is high in the 12 weeks following radiotherapy, continuation of treatment and confirmation of progression during this period with a repeat MRI, or histopathologic evidence of unequivocal recurrent tumor, is required to define tumor progression. However, confirmation scans are not mandatory after this period nor for recurrent tumors. For treatments with a high likelihood of pseudoprogression, mandatory confirmation of progression with a repeat MRI is an option. The primary measurement remains the maximum cross-sectional area of tumor (2-dimensional) but volumetric measurements are an option. For IDH-wildtype glioblastoma, the non-enhancing disease will no longer be evaluated. In IDH-mutated tumors with a significant non-enhancing component, clinical trials may require evaluating both the enhancing and non-enhancing tumor components for response assessment.

2017 Background: Response Assessment in Neuro-Oncology (RANO) criteria for high-grade and low-grade glioma (HGG and LGG) were developed to improve reliability of response assessment in glioma trials. Several limitations of the original RANO criteria have been reported. Methods: To address limitations of the original RANO criteria, a large cohort of patients with newly diagnosed and recurrent glioblastoma were evaluated comparing RANO-HGG with modified RANO (mRANO) and immunotherapy RANO (iRANO) criteria to inform the following proposed updates (RANO 2.0). Results: Based on the 2021 WHO classification of glioma, we recommend a single common set of criteria for all gliomas regardless of WHO grade and IDH mutational status. These criteria will be used for all trials regardless of the treatment modalities being evaluated. In newly diagnosed glioblastoma, the post-radiotherapy MRI, usually obtained approximately 4 weeks after completion of radiotherapy, rather than the post-surgical MRI as proposed in original RANO criteria, will be used as the baseline for comparison of subsequent scans. Since the incidence of pseudoprogression is high in the first 3 months following radiotherapy, confirmation of progression during this period with a repeat MRI (in 4-8 weeks) will be required for determining radiographic progression of disease (PD) if the patient is clinically stable. However, confirmation scans are not mandatory after this period nor for recurrent tumors since these scans do not appear to improve reliability in determining progression. For agents with a high likelihood of producing pseudoprogression such as viral therapies and some other immunotherapies, mandatory confirmation of progression with a repeat MRI is an option. The primary measurement will remain the 2-dimensional maximum cross-sectional area of tumor as the simplest method, but where resources are available, volumetric measurements are an option. For IDH wild-type tumors with contrast enhancement, non-enhancing tumor will no longer be evaluated with the possible exception of patients receiving antiangiogenic therapies. However, in tumors with a significant non-enhancing component, both the contrast enhancing and non-enhancing components will be evaluated as target lesions. Conclusions: We hope that these and other proposed changes by the RANO working group will improve response assessment in glioma clinical trials and help the development of more effective therapy for patients.

Abstract Despite the widespread clinical use of dynamic susceptibility contrast (DSC) MRI, DSC-MRI methodology has not been standardized, hindering its utilization for response assessment in multicenter trials. Recently, the DSC-MRI Standardization Subcommittee of the Jumpstarting Brain Tumor Drug Development Coalition issued an updated consensus DSC-MRI protocol compatible with the standardized brain tumor imaging protocol (BTIP) for high-grade gliomas that is increasingly used in the clinical setting and is the default MRI protocol for the National Clinical Trials Network. After reviewing the basis for controversy over DSC-MRI protocols, this paper provides evidence-based best practices for clinical DSC-MRI as determined by the Committee, including pulse sequence (gradient echo vs spin echo), BTIP-compliant contrast agent dosing (preload and bolus), flip angle (FA), echo time (TE), and post-processing leakage correction. In summary, full-dose preload, full-dose bolus dosing using intermediate (60°) FA and field strength-dependent TE (40–50 ms at 1.5 T, 20–35 ms at 3 T) provides overall best accuracy and precision for cerebral blood volume estimates. When single-dose contrast agent usage is desired, no-preload, full-dose bolus dosing using low FA (30°) and field strength-dependent TE provides excellent performance, with reduced contrast agent usage and elimination of potential systematic errors introduced by variations in preload dose and incubation time.

10602 Background: Progressive disease (PD) according to RECIST 1.1 (Eisenhauer et al, 2009) is defined as one or more of (1) PD of measurable target lesions, (2) the presence of a new lesion (NL) or (3) the unequivocal PD of non-target disease (NT-PD). We explored the impact of these components, varying over time, on predicting overall survival (OS) in the RECIST database residing at EORTC (Bogaerts et al, 2009). Methods: Data was selected from 12 randomized clinical trials (3530 patients with breast, lung or colorectal cancer). A maximum of 5 target lesions was used to determine the sum of diameters. The following were calculated or assigned at each measurement time t: best response (BR) was best % improvement from baseline up to t (0% if no improvement - 100% if complete response (CR)); tumor growth (TG) was the weekly rate of increase from nadir to t (0 if no increase; irrespective of prior shrinkage), presence of NL (yes/no), and occurrence of NT-PD (yes/no); categories were not mutually exclusive. OS was analyzed by tumor type using a Cox regression model, adjusting for baseline sum, and including BR, TG, presence of NL and NT-PD as time dependent covariates. Results: Thirty-six percent of patients had NL, 26% had NT-PD, 11% achieved CR and 14% did not have shrinkage of target lesions, while 46% experienced TG (median strongest growth per patient of 0.5 mm/week). Regardless of tumor type, the presence of NL (Hazard Ratio (HR) ranging 1.4-2.5), NT-PD (HR 1.2-2.5) and TG (per 1mm/week increase; HR 1.1-1.4) were associated with worse OS, while achieving CR was associated with a longer OS (HR 0.2-0.8). Further analyses exploring the functional shape of the association between BR and TG, and OS are ongoing. This includes putting TG in contrast with the more usual % cutoff defining target PD. Conclusions: All three components of PD according to RECIST are independently strongly associated with OS. Quantification such as this will enable a better understanding of the role of each component (e.g. clinical aspect of NT-PD assessment) in PD evaluation. Work is ongoing to incorporate this information into an updated RECIST with enhanced prediction of subsequent survival.

AbstractA recent meeting was held on March 22, 2019, among the FDA, clinical scientists, pharmaceutical and biotech companies, clinical trials cooperative groups, and patient advocacy groups to discuss challenges and potential solutions for increasing development of therapeutics for central nervous system metastases. A key issue identified at this meeting was the need for consistent tumor measurement for reliable tumor response assessment, including the first step of standardized image acquisition with an MRI protocol that could be implemented in multicenter studies aimed at testing new therapeutics. This document builds upon previous consensus recommendations for a standardized brain tumor imaging protocol (BTIP) in high-grade gliomas and defines a protocol for brain metastases (BTIP-BM) that addresses unique challenges associated with assessment of CNS metastases. The “minimum standard” recommended pulse sequences include: (i) parameter matched pre- and post-contrast inversion recovery (IR)–prepared, isotropic 3D T1-weighted gradient echo (IR-GRE); (ii) axial 2D T2-weighted turbo spin echo acquired after injection of gadolinium-based contrast agent and before post-contrast 3D T1-weighted images; (iii) axial 2D or 3D T2-weighted fluid attenuated inversion recovery; (iv) axial 2D, 3-directional diffusion-weighted images; and (v) post-contrast 2D T1-weighted spin echo images for increased lesion conspicuity. Recommended sequence parameters are provided for both 1.5T and 3T MR systems. An “ideal” protocol is also provided, which replaces IR-GRE with 3D TSE T1-weighted imaging pre- and post-gadolinium, and is best performed at 3T, for which dynamic susceptibility contrast perfusion is included. Recommended perfusion parameters are given.

PURPOSE The mode of action of targeted cancer agents (TCAs) differs from classic chemotherapy, which leads to concerns about the role of RECIST in evaluating tumor response in trials with TCAs. We investigated the performance of RECIST using a pooled database from 50 clinical trials with at least one TCA. METHODS We examined the impact of the number of target lesions (TLs) on within-patient variability of tumor response. The prognostic effect of TL response (at 12 weeks or on study on the basis of a maximum five TLs) on survival was studied through landmark and time-dependent Cox models adjusted for baseline tumor load, occurrence of new lesions, or unequivocal progression of nontarget disease. RESULTS Data were obtained from 23,259 patients with cancer (36% lung, 28% colorectal, 11% breast, and 25% other); 15,620 received TCAs, predominantly transduction or angiogenesis inhibitors, as a single agent (37%), combined with other TCAs (7%), or as chemotherapy (56%); 28% received chemotherapy only; and 5% received best supportive care or placebo. A total of 17,222 patients contributed to the analyses. Within-patient variability decreased with increasing number of TLs, similarly for TCAs (with/without chemotherapy) and chemotherapy only. Mixed responses occurred proportionally in all treatment classes. Landmark analyses showed an ordinal relationship between percentage change from baseline to 12 weeks and overall survival, and demonstrated a clear distinction between tumor shrinkage and progressive disease according to RECIST. Time-dependent analysis showed no marked improvement in the ability to predict survival on the basis of TL tumor growth compared with nontarget progression or new lesion occurrence, regardless of treatment. Similar results were seen for major tumor types and different classes of TCAs. CONCLUSION This work reinforces that RECIST version 1.1 perform well for response assessment of TCAs.

2534 Background: The Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 were derived from an international collaborative effort supported by data from clinical trials (16 studies, 9147 patients) on cytotoxic chemotherapy (CT), providing a standard tool for response assessment. RECIST’s role has been questioned for TCA. Using a pooled individual patient database (IPD) from clinical trials performed by industry and cooperative groups, we assessed whether modifications to RECIST are required to evaluate antitumor activity of TCA. Methods: Data were collected from phase 2 and 3 clinical trials testing TCA in solid tumors. To study the occurrence of mixed responses, the variability of response of lesions within patients was studied. Furthermore, response was correlated with survival through landmark analyses and time dependent Cox models. Results: Clinical data were obtained from 23,259 patients, mainly with lung (36%), colorectal (28%) or breast cancer (11%). 15,620 patients (67%) received a TCA, mainly transduction or angiogenesis inhibitors, either as single agent (37%) or combined with other TCAs (7%) or CT (56%); 28% received CT only and 5% best supportive care or placebo. Within-patient variability reduced as the number of lesions used for response assessment increased, and did so similarly for TCAs (+/- CT) and CT. Mixed responses seemed to occur similarly across these treatment categories as well. Landmark analyses showed improving overall survival by % tumor shrinkage and a clear distinction between the effect of tumor shrinkage and progressive disease (PD) according to RECIST 1.1. This was confirmed by time dependent analysis. In addition target lesion growth showed no marked improvement in overall survival prediction over and above the other components of RECIST 1.1 PD (new lesions, non-target PD), regardless of treatment (TCA, CT or both) received. Similar results were seen focusing on major tumor types and classes of TCA. Conclusions: Using a large IPD dataset we demonstrated that RECIST 1.1 performs equally well for response assessment of TCA as for CT. No modifications are required.