This review describes the definition, incidence, clinical implications, and magnetic resonance imaging (MRI) findings of pseudoprogression of brain tumors, in particular, but not limited to, high‐grade glioma. Pseudoprogression is an important clinical problem after brain tumor treatment, interfering not only with day‐to‐day patient care but also the execution and interpretation of clinical trials. Radiologically, pseudoprogression is defined as a new or enlarging area(s) of contrast agent enhancement, in the absence of true tumor growth, which subsides or stabilizes without a change in therapy. The clinical definitions of pseudoprogression have been quite variable, which may explain some of the differences in reported incidences, which range from 9–30%. Conventional structural MRI is insufficient for distinguishing pseudoprogression from true progressive disease, and advanced imaging is needed to obtain higher levels of diagnostic certainty. Perfusion MRI is the most widely used imaging technique to diagnose pseudoprogression and has high reported diagnostic accuracy. Diagnostic performance of MR spectroscopy (MRS) appears to be somewhat higher, but MRS is less suitable for the routine and universal application in brain tumor follow‐up. The combination of MRS and diffusion‐weighted imaging and/or perfusion MRI seems to be particularly powerful, with diagnostic accuracy reaching up to or even greater than 90%. While diagnostic performance can be high with appropriate implementation and interpretation, even a combination of techniques, however, does not provide 100% accuracy. It should also be noted that most studies to date are small, heterogeneous, and retrospective in nature. Future improvements in diagnostic accuracy can be expected with harmonization of acquisition and postprocessing, quantitative MRI and computer‐aided diagnostic technology, and meticulous evaluation with clinical and pathological data.

Level of Evidence: 3

Technical Efficacy: Stage 2

J. Magn. Reson. Imaging 2018;48:571–589.

/pdf/pseudoprogression-of-brain-tumors-2cl4gg3hf2.pdf

Pseudoprogression of brain tumors

BACKGROUND Distinction between tumor and treatment related changes is crucial for clinical management of patients with high-grade gliomas. Our purpose was to evaluate whether dynamic susceptibility contrast-enhanced (DSC) and dynamic contrast enhanced (DCE) perfusion-weighted imaging (PWI) metrics can effectively differentiate between recurrent tumor and posttreatment changes within the enhancing signal abnormality on conventional MRI. METHODS A comprehensive literature search was performed for studies evaluating PWI-based differentiation of recurrent tumor and posttreatment changes in patients with high-grade gliomas (World Health Organization grades III and IV). Only studies published in the "temozolomide era" beginning in 2005 were included. Summary estimates of diagnostic accuracy were obtained by using a random-effects model. RESULTS Of 1581 abstracts screened, 28 articles were included. The pooled sensitivities and specificities of each study's best performing parameter were 90% and 88% (95% CI: 0.85-0.94; 0.83-0.92) and 89% and 85% (95% CI: 0.78-0.96; 0.77-0.91) for DSC and DCE, respectively. The pooled sensitivities and specificities for detecting tumor recurrence using the 2 most commonly evaluated parameters, mean relative cerebral blood volume (rCBV) (threshold range, 0.9-2.15) and maximum rCBV (threshold range, 1.49-3.1), were 88% and 88% (95% CI: 0.81-0.94; 0.78-0.95) and 93% and 76% (95% CI: 0.86-0.98; 0.66-0.85), respectively. CONCLUSIONS PWI-derived thresholds separating viable tumor from treatment changes demonstrate relatively good accuracy in individual studies. However, because of significant variability in optimal reported thresholds and other limitations in the existing body of literature, further investigation and standardization is needed before implementing any particular quantitative PWI strategy across institutions.

/pdf/mr-perfusion-weighted-imaging-in-the-evaluation-of-high-2zbadkj0wu.pdf

MR perfusion-weighted imaging in the evaluation of high-grade gliomas after treatment: a systematic review and meta-analysis.

The wide variety of treatment options that exist for glioblastoma, including surgery, ionizing radiation, anti-neoplastic chemotherapies, anti-angiogenic therapies, and active or passive immunotherapies, all may alter aspects of vascular permeability within the tumor and/or normal parenchyma. These alterations manifest as changes in the degree of contrast enhancement or T2-weighted signal hyperintensity on standard anatomic MRI scans, posing a potential challenge for accurate radiographic response assessment for identifying anti-tumor effects. The current review highlights the challenges that remain in differentiating true disease progression from changes due to radiation therapy, including pseudoprogression and radionecrosis, as well as immune or inflammatory changes that may occur as either an undesired result of cytotoxic therapy or as a desired consequence of immunotherapies.

/pdf/pseudoprogression-radionecrosis-inflammation-or-true-tumor-999gqecknw.pdf

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

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.

/pdf/consensus-recommendations-for-a-dynamic-susceptibility-24fhqfsr8p.pdf

Consensus recommendations for a dynamic susceptibility contrast MRI protocol for use in high-grade gliomas.

Purpose
This meta-analysis examined roles of several metabolites in differentiating recurrent tumor from necrosis in patients with brain tumors using MR perfusion and spectroscopy.

/pdf/differentiating-radiation-induced-necrosis-from-recurrent-5dgtx6ljzq.pdf

Differentiating Radiation-Induced Necrosis from Recurrent Brain Tumor Using MR Perfusion and Spectroscopy: A Meta-Analysis

BACKGROUND AND PURPOSE: Treatment-related changes and recurrent tumors often have overlapping features on conventional MR imaging. The purpose of this study was to assess the utility of DWI and DSC perfusion imaging alone and in combination to differentiate treatment-related effects and recurrent high-grade gliomas. MATERIALS AND METHODS: We retrospectively identified 68 consecutive patients with high-grade gliomas treated by surgical resection followed by radiation therapy and temozolomide, who then developed increasing enhancing mass lesions indeterminate for treatment-related changes versus recurrent tumor. All lesions were diagnosed by histopathology at repeat surgical resection. ROI analysis was performed of the enhancing lesion on the ADC and DSC maps. Measurements made by a 2D ROI of the enhancing lesion on a single slice were recorded as ADC Lesion and rCBV Lesion , and measurements made by the most abnormal small fixed diameter ROI as ADC ROI and rCBV ROI . Statistical analysis was performed with Wilcoxon rank sum tests with P = .05. RESULTS: Ten of the 68 patients (14.7%) had treatment-related changes, while 58 patients (85.3%) had recurrent tumor only ( n = 19) or recurrent tumor mixed with treatment effect ( n = 39). DWI analysis showed higher ADC Lesion in treatment-related changes than in recurrent tumor ( P = .003). DSC analysis revealed lower relative cerebral blood volume (rCBV) Lesion and rCBV ROI in treatment-related changes ( P = .003 and P = .011, respectively). Subanalysis of patients with suspected pseudoprogression also revealed higher ADC Lesion ( P = .001) and lower rCBV Lesion ( P = .028) and rCBV ROI ( P = .032) in treatment-related changes. Applying a combined ADC Lesion and rCBV Lesion model did not outperform either the ADC or rCBV metric alone. CONCLUSIONS: Treatment-related changes showed higher diffusion and lower perfusion than recurrent tumor. Similar correlations were found for patients with suspected pseudoprogression.

http://www.ajnr.org/content/ajnr/early/2015/01/15/ajnr.A4218.full.pdf

Diffusion and Perfusion MRI to Differentiate Treatment-Related Changes Including Pseudoprogression from Recurrent Tumors in High-Grade Gliomas with Histopathologic Evidence

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Diffusion and Perfusion MRI to Differentiate Treatment-Related Changes Including Pseudoprogression from Recurrent Tumors in High-Grade Gliomas with Histopathologic Evidence