Treatment-associated imaging changes in newly diagnosed MGMT promoter-methylated glioblastoma undergoing chemoradiation with or without cilengitide.

BACKGROUND: Radiological progression may originate from progressive disease (PD) or pseudoprogression/treatment-associated changes. We assessed radiological progression in O6-methylguanine-DNA methyltransferase (MGMT) promoter-methylated glioblastoma treated with standard-of-care chemoradiotherapy with or without the integrin inhibitor cilengitide according to the modified response assessment in neuro-oncology (RANO) criteria of 2017. METHODS: Patients with ≥ 3 follow-up MRIs were included. Preliminary PD was defined as a ≥ 25% increase of the sum of products of perpendicular diameters (SPD) of a new or increasing lesion compared to baseline. PD required a second ≥25% increase of the SPD. Treatment-associated changes require stable or regressing disease after preliminary PD. RESULTS: Of the 424 evaluable patients, 221 patients (52%) were randomized into the cilengitide and 203 patients (48%) into the control arm. After chemoradiation with or without cilengitide, preliminary PD occurred in 274 patients (65%) during available follow-up, and 88 of these patients (32%) had treatment-associated changes, whereas 67 patients (25%) had PD. The remaining 119 patients (43%) had no further follow-up after preliminary PD. Treatment-associated changes were more common in the cilengitide arm than in the standard-of-care arm (24% vs. 17%; relative risk, 1.3; 95% CI, 1.004-1.795; P = .047). Treatment-associated changes occurred mainly during the first 6 months after RT (54% after 3 months vs. 13% after 6 months). CONCLUSIONS: With the modified RANO criteria, the rate of treatment-associated changes was low compared to previous studies in MGMT promoter-methylated glioblastoma. This rate was higher after cilengitide compared to standard-of-care treatment. Confirmatory scans, as recommended in the modified RANO criteria, were not always available reflecting current clinical practice.

Standardized brain tumor imaging protocols for clinical trials: current recommendations and tips for integration.

Standardized MRI acquisition protocols are crucial for reducing the measurement and interpretation variability associated with response assessment in brain tumor clinical trials. The main challenge is that standardized protocols should ensure high image quality while maximizing the number of institutions meeting the acquisition requirements. In recent years, extensive effort has been made by consensus groups to propose different "ideal" and "minimum requirements" brain tumor imaging protocols (BTIPs) for gliomas, brain metastases (BM), and primary central nervous system lymphomas (PCSNL). In clinical practice, BTIPs for clinical trials can be easily integrated with additional MRI sequences that may be desired for clinical patient management at individual sites. In this review, we summarize the general concepts behind the choice and timing of sequences included in the current recommended BTIPs, we provide a comparative overview, and discuss tips and caveats to integrate additional clinical or research sequences while preserving the recommended BTIPs. Finally, we also reflect on potential future directions for brain tumor imaging in clinical trials.

Evaluation of RANO Criteria for the Assessment of Tumor Progression for Lower-Grade Gliomas.

PURPOSE: The Response Assessment in Neuro-Oncology (RANO) criteria for lower-grade gliomas (LGGs) define tumor progression as ≥25% change in the T2/FLAIR signal area based on an operator's discretion of the perpendicular diameter of the largest tumor cross-section. Potential sources of error include acquisition inconsistency of 2D slices, operator selection variabilities in both representative tumor cross-section and measurement line locations, and the inability to quantify infiltrative tumor margins and satellite lesions. Our goal was to assess the accuracy and reproducibility of RANO in LG. MATERIALS AND METHODS: A total of 651 FLAIR MRIs from 63 participants with LGGs were retrospectively analyzed by three blinded attending physicians and three blinded resident trainees using RANO criteria, 2D visual assessment, and computer-assisted 3D volumetric assessment. RESULTS: RANO product measurements had poor-to-moderate inter-operator reproducibility (r2 = 0.28-0.82; coefficient of variance (CV) = 44-110%; mean percent difference (diff) = 0.4-46.8%) and moderate-to-excellent intra-operator reproducibility (r2 = 0.71-0.88; CV = 31-58%; diff = 0.3-23.9%). When compared to 2D visual ground truth, the accuracy of RANO compared to previous and baseline scans was 66.7% and 65.1%, with an area under the ROC curve (AUC) of 0.67 and 0.66, respectively. When comparing to volumetric ground truth, the accuracy of RANO compared to previous and baseline scans was 21.0% and 56.5%, with an AUC of 0.39 and 0.55, respectively. The median time delay at diagnosis was greater for false negative cases than for false positive cases for the RANO assessment compared to previous (2.05 > 0.50 years, p = 0.003) and baseline scans (1.08 > 0.50 years, p = 0.02). CONCLUSION: RANO-based assessment of LGGs has moderate reproducibility and poor accuracy when compared to either visual or volumetric ground truths.

Pseudoprogression of Vestibular Schwannoma after Stereotactic Radiosurgery with Cyberknife®: Proposal for New Response Criteria.

(1) Background: Transient increase in volume of vestibular schwannomas (VS) after stereotactic radiosurgery (SRS) is common and complicates differentiation between treatment-related changes (pseudoprogression, PP) and tumor recurrence (progressive disease, PD). (2) Methods: Patients with unilateral VS (n = 63) underwent single fraction robotic-guided SRS. Volume changes were classified according to existing RANO criteria. A new response type, PP, with a >20% transient increase in volume was defined and divided into early (within the first 12 months) and late (>12 months) occurrence. (3) Results: The median age was 56 (range: 20-82) years, the median initial tumor volume was 1.5 (range: 0.1-8.6) cm3. The median radiological and clinical follow-up time was 66 (range: 24-103) months. Partial response was observed in 36% (n = 23), stable disease in 35% (n = 22) and PP in 29% (n = 18) of patients. The latter occurred early (16%, n = 10) or late (13%, n = 8). Using these criteria, no case of PD was observed. (4) Conclusion: Any volume increase after SRS for vs. assumed to be PD turned out to be early or late PP. Therefore, we propose modifying RANO criteria for SRS of VS, which may affect the management of vs. during follow-up in favor of further observation.

Distinct MRI pattern of "pseudoresponse" in recurrent glioblastoma multiforme treated with regorafenib: Case report and literature review.

Antiangiogenic agents can induce a distinct MRI pattern in glioblastoma, characterized by a decrease in the contrast enhancement on T1-weighted images and a simultaneous hyperintensity on T2-weighted or fluid-attenuated inversion recovery images.

Volumetric study reveals the relationship between outcome and early radiographic response during bevacizumab-containing chemoradiotherapy for unresectable glioblastoma.

PURPOSE: Although we have shown the clinical benefit of bevacizumab (BEV) in the treatment of unresectable newly diagnosed glioblastomas (nd-GBM), the relationship between early radiographic response and survival outcome remains unclear. We performed a volumetric study of early radiographic responses in nd-GBM treated with BEV. METHODS: Twenty-two patients with unresectable nd-GBM treated with BEV during concurrent temozolomide radiotherapy were analyzed. An experienced neuroradiologist interpreted early responses on fluid-attenuated inversion recovery (FLAIR) and gadolinium-enhanced T1-weighted images (GdT1WI). Volumetric changes were evaluated using diffusion-weighted imaging (DWI) and GdT1WI according to the Response Assessment in Neuro-Oncology (RANO) criteria. The results were categorized into improved (complete response [CR] or partial response [PR]) or non-improved (stable disease [SD] or progressive disease [PD]) groups; outcomes were compared using Kaplan-Meier analysis. RESULTS: The volumetric GdT1WI improvement was a significant predictive factor for overall survival (OS) prolongation (p = 0.0093, median OS: 24.7 vs. 13.6 months); however, FLAIR and DWI images were not predictive. The threshold for the neuroradiologist's interpretation of improvement in GdT1WI was nearly 20% of volume reduction, which was lesser than 50%, the definition of PR applied in the RANO criteria. However, even less stringent neuroradiologist interpretation could successfully predict OS prolongation (improved vs. non-improved: p = 0.0067, median OS: 17.6 vs. 8.3 months). Significant impact of OS on the early response in volumetric GdT1WI was observed within the cut-off range of 20-50% (20%, p = 0.0315; 30%, p = 0.087; 40%, p = 0.0456). CONCLUSIONS: Early response during BEV-containing chemoradiation can be a predictive indicator of patient outcome in unresectable nd-GBM.

Sodium fluorescein shows high surgeon-reported usability in glioblastoma surgery.

INTRODUCTION: Glioblastoma has a high mortality rate. Current treatment includes largest possible surgical resection of the tumour using neuronavigation and fluorescence to better identify tumour tissue. In recent years, sodium fluorescein has been reintroduced in neurosurgery as a fluorescence to increase the resection rate. In this study we aimed to measure the surgeons experience of using sodium fluorescein to locate and remove tumour tissue. Furthermore we describe a case of sodium fluorescein tissue distribution. MATERIAL AND METHODS: 13 patients with glioblastoma and seven patients with cerebral metastases undergoing surgical resection were included. Surgery was performed using microscope alternating between white light and the YELLOW 560 filter, which visualized sodium fluorescein. Surgeons graded its usability in terms of location and removal on a scale from one to four. The resection rate was determined by neuroradiologists. Tissue samples obtained during surgery were analysed in relation to fluorescence and dysmorphic cells. RESULTS: Surgeons reported high usability in terms of location and removal of tumours using sodium fluorescein with medians of four in all groups, except for sub-total resections which had a median of three. Surgical complications were minimal and both resection rate and survival rate was within international standards. Histological analysis showed a visual correlation between tumorous tissue and intensity of fluorescence. CONCLUSION: Sodium fluorescence is an effective and useful tool for surgeons during fluorescence-guided surgery for the resection of glioblastoma and cerebral metastases.

Treatment-related changes in glioblastoma: a review on the controversies in response assessment criteria and the concepts of true progression, pseudoprogression, pseudoresponse and radionecrosis.

The assessment of response to therapy in glioblastoma remains a challenge, because the surrogate measures of survival are subject to radiographic misinterpretation. A solid and reliable definition of progression is needed for both clinical decision-making and for evaluating response within the clinical trials. Historically, assessment criteria have used radiologic and clinical features aimed to correctly classify patients into progressive or non-progressive disease. The widely used RANO criteria are a valuable tool in disease evaluation, both in the clinical setting and in the clinical trials. However, assessment criteria have certain limitations that emerging image techniques have tried to overcome. Differentiating true progression from treatment-related changes (like pseudoprogression or pseudoresponse) is crucial in order not to prematurely discontinue adjuvant chemotherapy or redirect the patient to second-line options. This fact underscores the need for advanced radiologic techniques, like specific diffusion and perfusion MRI sequences, MR spectroscopy and PET, which seem to play a role in distinguishing these phenomena.

Assessment of Brain Tumor Response: RANO and Its Offspring.

OPINION STATEMENT: Treatment options for most nervous system tumors remain limited and patients are often confronted with significant morbidity and reduced life expectancy. However, significant efforts are underway to find more effective therapies for patients with primary and secondary brain tumors. As more and more clinical trials for nervous system tumors are being conducted, it is increasingly important to optimize the conduct of clinical trials in neuro-oncology. One of the key aspects in this regard is the development of objective and standardized criteria that allow for accurate response assessment in clinical trials and prevent the misclassification of responders and non-responders. Such misclassification may lead to premature discontinuation of an actually effective agent, thereby withholding a potentially active treatment from the patient. Conversely, patients may be inappropriately continued on an inactive treatment. Moreover, such misclassification may confound the data obtained in such studies and may lead to false conclusions with regards to the efficacy of the investigated drug. Therefore, reliable response assessment criteria are necessary that not only accurately capture radiographic changes but also account for treatment-related changes and incorporate the assessment of clinical status and quality of life (QoL). The Response Assessment in Neuro-Oncology (RANO) working group is an international collaboration of neuro-oncologists, medical oncologists, radiation oncologists, neurosurgeons, neuroradiologists, and regulatory groups (among others) commissioned to develop objective and tumor-specific response criteria for various tumor subtypes. This article reviews the currently available response criteria for high-grade glioma, low-grade glioma, and brain metastases and discusses some of the barriers to accurate assessment of treatment response in neuro-oncology.

Standardized MRI assessment of high-grade glioma response: a review of the essential elements and pitfalls of the RANO criteria.

Accurately evaluating response in the treatment of high-grade gliomas presents considerable challenges. This review looks at the advancements made in response criteria while critically outlining remaining weaknesses, and directs our vision toward promising endpoints to come. The 2010 guidelines from the Response Assessment in Neuro-Oncology (RANO) working group have enhanced interpretation of clinical trials involving novel treatments for high-grade glioma. Yet, while the criteria are considered clinically applicable to high-grade glioma trials, as well as reasonably accurate and reproducible, RANO lacks sufficient detail for consistent implementation in certain aspects and leaves some issues from the original Macdonald guidelines unresolved. To provide the most accurate assessment of response to therapeutic intervention currently possible, it is essential that trial oncologists and radiologists not only have a solid understanding of RANO guidelines, but also proper insight into the inherent limitations of the criteria. With the expectation of improved data collection as a standard, the author anticipates that the next high-grade glioma response criteria updates will incorporate advanced MRI methods and quantitative tumor volume measurements, availing a more accurate interpretation of response in the future.

Advanced MR Imaging in Neuro-oncology.

The value of magnetic resonance (MR) imaging for the clinical management of brain tumour patients has greatly increased in recent years through the introduction of functional MR sequences. Previously, MR imaging for brain tumours relied for the most part on contrast-enhanced T1-weighted MR sequences but today with the help of advanced functional MR sequences, the pathophysiological aspects of tumour growth can be directly visualised and investigated. This article will present the pathophysiological background of the MR sequences relevant to neuro-oncological imaging as well as potential clinical applications. Ultimately, we take a look at possible future developments for ultra-high-field MR imaging.

Response Assessment in Neuro-Oncology (RANO): more than imaging criteria for malignant glioma.

The introduction of antiangiogenic therapies for the treatment of malignant glioma and the effect of these agents on standard imaging studies were the stimuli for forming a small group of investigators to critically evaluate the limitations of the Macdonald criteria in assessing response to treatment. The initial goal of this group was to highlight the challenges in accurately determining the efficacy of therapeutic interventions for malignant glioma and to develop new criteria that could be implemented in clinical care as well as in the design and conduct of clinical trials. This initial Response Assessment in Neuro-Oncology (RANO) effort started in 2008 and over the last 7 years, it has expanded to include a critical review of response assessment across several tumor types as well as endpoint selection and trial design to improve outcome criteria for neuro-oncological trials. In this paper, we review the overarching principles of the RANO initiative and the efforts to date. We also highlight the diverse and expanding efforts of the multidisciplinary groups of investigators who have volunteered their time as part of this endeavor.

Differentiation between vasogenic-edema versus tumor-infiltrative area in patients with glioblastoma during bevacizumab therapy: a longitudinal MRI study.

BACKGROUND: Treatment with bevacizumab is associated with substantial radiologic response in patients with glioblastoma (GB). However, following this initial response, changes in T2-weighted MRI signal may develop, suggesting an infiltrative pattern of tumor progression. The aim of this study was to differentiate between vasogenic-edema versus tumor-infiltrative area in GB patients. METHODS AND MATERIALS: Fourteen patients with GB were longitudinally scanned, before and during intravenous bevacizumab therapy (5/10mg/kg every 2-weeks). A total of 40 MR scans including conventional, diffusion, dynamic susceptibility contrast, dynamic contrast enhancement imaging, and MR-spectroscopy (MRS) were analyzed. Classification of non-enhancing fluid-attenuation-inversion-recovery (FLAIR) area was performed based on mean diffusivity, cerebral blood volume and flow maps, and further characterized using multiple MRI parameters. RESULTS: The non-enhancing FLAIR lesion area was classified into: vasogenic-edema, characterized by reduced perfusion and increased FLAIR values; or tumor-infiltrative area, characterized by increased perfusion. Tumor-infiltrative area demonstrated a higher malignant pattern on MRS compared to areas of vasogenic-edema. Substantial reductions of the enhanced T1-weighted (58 ± 10%) and hyperintense FLAIR (53 ± 9%) lesion volumes were detected mainly during the first weeks of therapy, with a shift to an infiltrative pattern of tumor progression thereafter, as detected by an increase in tumor-infiltrative area in the majority of patients, which correlated with progression-free survival (week 8: r=-0.86, p=0.003, week 16: r=-0.99, p=0.001). CONCLUSION: Characterization of non-enhancing hyperintense FLAIR lesion area in GB patients can provide an MR-based biomarker, indicating a shift to an infiltrative progression pattern, and may improve therapy response assessment in patients following bevacizumab therapy.

Evaluation of pseudoprogression in patients with glioblastoma multiforme using dynamic magnetic resonance imaging with ferumoxytol calls RANO criteria into question.

BACKGROUND: Diagnosis of pseudoprogression in patients with glioblastoma multiforme (GBM) is limited by Response Assessment in Neuro-Oncology (RANO) criteria to 3 months after chemoradiotherapy (CRT). Frequency of pseudoprogression occurring beyond this time limit was determined. Survival comparison was made between pseudoprogression and true progression patients as determined by using perfusion magnetic resonance imaging with ferumoxytol (p-MRI-Fe). METHODS: Fifty-six patients with GBM who demonstrated conventional findings concerning for progression of disease post CRT were enrolled in institutional review board-approved MRI protocols. Dynamic susceptibility-weighted contrast-enhanced p-MRI-Fe was used to distinguish true progression from pseudoprogression using relative cerebral blood volume (rCBV) values. rCBV of 1.75 was assigned as the cutoff value. Participants were followed up using RANO criteria, and survival data were analyzed. RESULTS: Twenty-seven participants (48.2%) experienced pseudoprogression. Pseudoprogression occurred later than 3 months post CRT in 8 (29.6%) of these 27 participants (ie, 8 [14.3%] of the 56 patients meeting the inclusion criteria). Overall survival was significantly longer in participants with pseudoprogression (35.2 months) compared with those who never experienced pseudoprogression (14.3 months; P < .001). CONCLUSIONS: Pseudoprogression presented after 3 months post CRT in a considerable portion of patients with GBM, which raises doubts about the value of the 3-month time limit of the RANO criteria. Accurate rCBV measurement (eg, p-MRI-Fe) is suggested when there are radiographical concerns about progression of disease in GBM patients, regardless of any time limit. Pseudoprogression correlates with significantly better survival outcomes.

Infiltrative patterns of glioblastoma: Identification of tumor progress using apparent diffusion coefficient histograms.

PURPOSE: To investigate whether apparent diffusion coefficient (ADC) histogram analysis can differentiate between patients presenting T2-progress and patients presenting stable T2-signal in glioblastoma. MATERIALS AND METHODS: Fourteen patients presenting an isolated T2-progress and a matched control group exhibiting stable disease were included. Relative ADC value distribution within tumoral and peritumoral FLAIR hyperintensities were evaluated using ADC-histogram analysis. Severity and frequency of ADC shift between baseline, T2-progress, and subsequent T1-progress were analyzed using the Wilcoxon test. RESULTS: The shift of ADC histograms either to higher or to lower values in case of T2-progress was significantly more severe than in the control group (P value 0.05). Furthermore, a significant shift toward lower ADC values (P value 0.02) was detected when comparing ADC histograms of patients with T2-progress and subsequent T1-progress. CONCLUSION: The basis for the observed ADC shift in isolated T2-progress may be time dependent: Initially, formation of peritumoral edema may cause an increase of ADC values that is followed by tumor cells infiltrating the surrounding tissue, causing a subsequent decrease of ADC values. The shift toward lower ADC values in case of subsequent T1-progress confirms this hypothesis and provides further evidence for T2-progress being an intermediate step between stable disease (SD) and T1-progress.

Discrepant MR and [(18)F]Fluoroethyl-L-Tyrosine PET Imaging Findings in a Patient with Bevacizumab Failure.

Antiangiogenic treatment using bevacizumab may cause difficulties in distinguishing between antivascular and true antitumor effects when using MRI response criteria based on changes of contrast enhancement (i.e., Macdonald criteria). Furthermore, more precise tumor response assessment criteria (i.e., RANO criteria), which incorporate nonenhancing T2/FLAIR sequences into Macdonald criteria, may be influenced by other causes of T2/FLAIR hyperintensity (e.g., radiation-induced gliosis). The authors present discrepant MR and [(18)F]fluoroethyl-L-tyrosine PET imaging findings in a patient with bevacizumab treatment failure.