Response Assessment In Neuro-Oncology Criteria Research Articles

Contrast enhancing spots as a new pattern of late onset pseudoprogression in glioma patients.

Magnet resonance imaging (MRI) of gliomas is assessed by Response Assessment in Neuro-Oncology Criteria (RANO), which define new contrast-enhancing lesions as a sign for tumor recurrence. Pseudoprogression after radiotherapy may mimic tumor progression in MRI but is usually limited to the first months after irradiation. We noted a late onset pattern of new contrast-enhancing spots (NCES) appearing years after radiotherapy. We prospectively collected 23 glioma patients with 26 NCES (three patients had two separate NCES events) between 2014 and 2016 in our weekly tumor board without further selection by diagnosis, molecular markers or pretreatment. Retrospective analysis revealed a homogeneous collective of young patients (median age of 49years at NCES) with mainly IDH-mutated glioma (61%). Initial histology showed 26% glioblastoma, 52% grade III and 22% grade II glioma. NCES occurred at late follow-up with a median of 52months after tumor diagnosis and 30months after the last radiotherapy. The majority of NCES regressed spontaneously within a median of 10months (n = 11) or remained stable without further therapy with a median follow-up of 26months (n = 7). Only 4 NCES developed MRI morphologically into tumor recurrence. Two NCES were resected without any histopathological proof of tumor recurrence, and in 2 other cases NCES were defined as ischemic stroke or radionecrosis. We hypothesize that the late onset phenomenon of NCES predominantly represents a form of radiation-induced vasculopathy that is different from early pseudoprogression and should be considered especially in younger patients with IDH-mutated glioma before initiation of new therapy.

Cancer genetic markers according to radiotherapeutic response in patients with primary glioblastoma – Radiogenomic approach for precision medicine

Background and purposeTo find genetic markers associated with response to radiotherapy (RT) in glioblastoma (GB) patients. Materials and methodsFrom Jan 2009 to Dec 2016, 161 patients with newly diagnosed IDH-wild type GB were treated with surgery and adjuvant concurrent chemoradiotherapy with the Stupp’s regimen, and then genomic research proceeded with their surgical specimens. Among the 161 patients, 49 with clinically measurable disease on postoperative MRI were analyzed. The response evaluation to RT was based on Response Assessment in Neuro-Oncology (RANO) criteria. For genomic analyses to compare between patients with progression and non-progression, Fisher test for DNA mutations and copy number alterations and the Gene Set Enrichment Analysis (GSEA) were performed. ResultsRT responses were non-progressive and progressive disease (PD) in 22 (44.9%) and 27 patients (55.1%), respectively. After three months, seven of PD exhibited pseudoprogression. For true response adjusting pseudoprogression from PD, 1-year progression-free survival for true Non-Responders (tNR-group) and true Responders (tR-group) were 0% and 45.4% (p < 0.001), and overall survival were 52.5% and 81.1% (p = 0.046), respectively. In genomic analyses, the tNR-group had more CDKN2A deletions (94.4% vs. 55.6%, p = 0.013), EGFR mutations (33.3% vs. 3.7%, p = 0.012) and less TP53 mutations (22.2% vs. 40.7%, p = 0.333) than the tR-group. In GSEA, immune-related gene sets were enriched in the tNR-group, and in contrast, some gene sets related with cell cycle were enriched in tR-groups. ConclusionThe RANO criteria were feasible for the short-term response evaluation from RT despite of pseudoprogression. Genomic differences such as CDKN2A deletion, EGFR mutation, and immune- or inflammation-related related gene sets enrichment were found to be potentially predictive markers of RT.

Shape Features of the Lesion Habitat to Differentiate Brain Tumor Progression from Pseudoprogression on Routine Multiparametric MRI: A Multisite Study.

Differentiating pseudoprogression, a radiation-induced treatment effect, from tumor progression on imaging is a substantial challenge in glioblastoma management. Unfortunately, guidelines set by the Response Assessment in Neuro-Oncology criteria are based solely on bidirectional diametric measurements of enhancement observed on T1WI and T2WI/FLAIR scans. We hypothesized that quantitative 3D shape features of the enhancing lesion on T1WI, and T2WI/FLAIR hyperintensities (together called the lesion habitat) can more comprehensively capture pathophysiologic differences across pseudoprogression and tumor recurrence, not appreciable on diametric measurements alone. A total of 105 glioblastoma studies from 2 institutions were analyzed, consisting of a training (n = 59) and an independent test (n = 46) cohort. For every study, expert delineation of the lesion habitat (T1WI enhancing lesion and T2WI/FLAIR hyperintense perilesional region) was obtained, followed by extraction of 30 shape features capturing 14 "global" contour characteristics and 16 "local" curvature measures for every habitat region. Feature selection was used to identify most discriminative features on the training cohort, which were evaluated on the test cohort using a support vector machine classifier. The top 2 most discriminative features were identified as local features capturing total curvature of the enhancing lesion and curvedness of the T2WI/FLAIR hyperintense perilesional region. Using top features from the training cohort (training accuracy = 91.5%), we obtained an accuracy of 90.2% on the test set in distinguishing pseudoprogression from tumor progression. Our preliminary results suggest that 3D shape attributes from the lesion habitat can differentially express across pseudoprogression and tumor progression and could be used to distinguish these radiographically similar pathologies.

Cancer Genetic Markers According to Radiotherapeutic Response in Patients with Glioblastoma - Radiogenomic Approach for Precision Medicine

To find genetic markers associated with response to radiotherapy (RT) in glioblastoma (GM) patients. From Jan 2009 to Dec 2016, 161 patients with newly diagnosed IDH-wild type GM were treated with surgery and adjuvant concurrent chemoradiotherapy (CCRT) with the Stupp’s regimen at one institution, and proceeded genomic analyses with surgical specimens. Of the patients, 49 patients with clinically measurable disease on postoperative MRI were analyzed. Response evaluation to RT was based on Response Assessment in Neuro-Oncology (RANO) criteria and MRI at the time of 3 or 4 months after the end of CCRT was compared with baseline MRI. To identify pseudo-progression, we checked further follow-up MRI and clinical events including re-operation, additional RT or gamma knife surgery, and change of treatment for the next 3 months, which was regarded as true progression. To compare the genomic characteristics between patients with progression or non-responder group (NR-group) and non-progression or responder group (R-group) after RT, we performed genomic analyses with whole-exome sequencing, RNA sequencing and targeted-exome panel. The Fisher test to compare mutations and copy number alterations and the single-sample Gene Set Enrichment Analysis (GSEA) score to interpret gene expression were used. The median age was 57 years (range 22-82) and surgical extension was subtotal resection for all 49 patients. RT responses were complete response (CR) or partial response (PR), stable disease (SD), and progressive disease (PD) in 7 (14.3%), 15 (30.6%), and 27 patients (55.1%), respectively. After further evaluation for 3 months, 7 of 27 patients (25.9%) with PD were pseudoprogression. Median follow-up period was 15 months (range 2-46) and 90% of patients experienced intracranial PD, eventually. One-year progression-free survival (PFS) and overall survival (OS) rate were 25.8% and 69.6%, respectively. With RANO response, 1-year PFS for patients with CR / PR / SD or R-group and PD or NR-group were 43.2% and 12.5% (p = 0.013), and OS were 74.2% and 65.5% (p = 0.349), respectively. After adjusting pseudoprogression from NR-group, 1-year PFS for R- and NR-group were 45.4% and 0 (p < 0.001), and OS were 81.1% and 52.5% (p = 0.046), respectively. With genomic analyses, NR-group had more CDKN2A and EGFR mutations with statistical significance and TP53 mutations seemed more frequent in R-group without statistical significance. In GSEA, immune-related gene sets were enriched in NR-group, and in contrast, some gene sets related with cell cycle were enriched in R-group. RT response evaluation with RANO criteria was related with disease progression despite of pseudo-progression, and this study showed the possibility of difference in genetic signatures according to RT response. To suggest molecular based strategies including RT and provide successful precision medicine for GM patients, therefore, further studies with larger patient number should be followed.

Oligometastatic Disease State Is Associated with Improved Local Control in Patients Undergoing Three or Five Fraction Spine Stereotactic Body Radiotherapy

The objective of our study was to describe the local control (LC) outcomes with 3- or 5-fraction stereotactic body radiotherapy (SBRT) to the spine in patients with oligometastatic (≤5 systemic metastases) versus polymetastatic disease (>5 metastases). We retrospectively reviewed the outcomes of patients who had undergone SBRT for spinal metastases. No patients had undergone previous surgical intervention or had spinal cord compression. All patients were treated with 3-fraction (median dose, 27 Gy; range, 24-30 Gy) or 5-fraction (median dose, 35 Gy; range, 25-40 Gy) SBRT. The Kaplan-Meier method and Spine Response Assessment in Neuro-Oncology criteria were used to determine LC. We included 61 patients with a total of 72 distinct SBRT targets who had been treated from August 2007 to June 2017. The median follow-up period was 13.58 months. We treated 20 targets and 52 targets with 3 and 5 fractions, respectively. Thirteen patients (18.1%) had undergone previous RT to the SBRT area. Twenty patients (35% of the distinct SBRT targets) had an oligometastatic disease state. The 1-year LC rate was 83% for the entire cohort. On univariable analysis, polymetastases (1-year LC, 73.8% vs. 100%; P= 0.07) showed a trend toward worse LC. On multivariable analysis, patients with an oligometastatic state (hazard ratio, 0.21; P= 0.04) had improved LC. Our study was hypothesis-generating in that patients with an oligometastatic disease state appear to have improved LC after SBRT, suggesting a biological advantage exists with local therapy for this group of patients not seen for patients with polymetastatic disease.

Utility of Magnetic Resonance Perfusion Imaging in Quantifying Active Tumor Fraction and Radiation Necrosis in Recurrent Intracranial Tumors

Ancillary criteria to identify tumor recurrence such as the McDonald criteria or Response Assessment in Neuro-Oncology criteria can provide false diagnoses. Magnetic resonance perfusion (MRP) imaging has been proposed to differentiate post-treatment changes from recurrence. We investigated the utility of MRP to quantify the histological fraction of active tumor (AT), treatment-related changes, and radiation necrosis in recurrent post-treatment intracranial tumors. We conducted an exploratory single-blind study of patients with intracranial glioblastoma or metastases with previous radiation therapy and MRP before surgery. Biopsy specimens (n= 19) were analyzed for the percentage of AT, radiation necrosis, and treatment effect. Nonparametric Spearman's rho analysis and multivariable analysis of covariance were performed to assess the correlation between quantitative MRP and AT histological fraction. The mean patient age was 58 ± 11.5 years. The mean relative cerebral blood volume (rCBV) and relative cerebral blood flow (rCBF) were 1.33 ± 0.71 and 1.34 ± 0.73, respectively. On analysis of covariance, significant associations were identified between increased rCBF (P=0.0004) and increased rCBV (P= 0.007) and percentage of AT. A significant interaction was identified between rCBF and rCBV and tumor histological features (glioblastoma vs. metastases; P= 0.003 and P= 0.03, respectively). An rCBF >1 predicted a mean AT fraction of ≥53% for all intracranial tumors and 74% for glioblastoma. MRP can help quantitatively predict tumor recurrence and/or progression for glioblastomas. The AT histological fraction correlated with quantitative radiologic measurements, including rCBV and rCBF. For metastases, MRP might not be as useful in predicting the AT fraction. Clinicians must be judicious with their use of MRP in predicting tumor recurrence and radiation necrosis.

NEUROIMAGING CLASSIFICATION OF PROGRESSION PATTERNS IN GLIOBLASTOMA: A SYSTEMATIC REVIEW

Our primary objective was to report the current neuroimaging classification systems of spatial patterns of progression in glioblastoma. In addition, we aimed to report the terminology used to describe ‘progression’ and to assess the compliance with the Response Assessment in Neuro-Oncology (RANO) Criteria. We conducted a systematic review to identify all neuroimaging studies of glioblastoma that have employed a categorical classification system of spatial progression patterns. Our review was registered with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) registry. From the included 157 results, we identified 129 studies that used labels of spatial progression patterns that were not based on radiation volumes (Group 1) and 50 studies that used labels that were based on radiation volumes (Group 2). In Group 1, we found 113 individual labels and the most frequent were: local/localised (58%), distant/distal (51%), diffuse (20%), multifocal (15%) and subependymal/subventricular zone (15%). We identified 13 different labels used to refer to ‘progression’, of which the most frequent were ‘recurrence’ (99%) and ‘progression’ (92%). We identified that 37% (n = 33/90) of the studies published following the release of the RANO classification were adherent compliant with the RANO criteria. Our review reports significant heterogeneity in the published systems used to classify glioblastoma spatial progression patterns. Standardization of terminology and classification systems used in studying progression would increase the efficiency of our research in our attempts to more successfully treat glioblastoma.

Combined iron oxide nanoparticle ferumoxytol and gadolinium contrast enhanced MRI define glioblastoma pseudoprogression.

Noninvasively differentiating therapy-induced pseudoprogression from recurrent disease in patients with glioblastoma is prospectively difficult due to the current lack of a biologically specific imaging metric. Ferumoxytol iron oxide nanoparticle MRI contrast characterizes innate immunity mediated neuroinflammation; therefore, we hypothesized that combined ferumoxytol and gadolinium enhanced MRI could serve as a biomarker of glioblastoma pseudoprogression. In this institutional review board-approved, retrospective study, we analyzed ferumoxytol and gadolinium contrast enhanced T1-weighted 3T MRI in 45 patients with glioblastoma over multiple clinical timepoints. Isocitrate dehydrogenase 1 (IDH-1) mutational status was characterized by exome sequencing. Sum of products diameter measurements were calculated according to Response Assessment in Neuro-Oncology criteria from both gadolinium and ferumoxytol enhanced sequences. Enhancement mismatch was calculated as the natural log of the ferumoxytol to gadolinium sum of products diameter ratio. Analysis of variance and Student's t-test assessed differences in mismatch ratios. P-value <0.05 indicated statistical significance. With the development of pseudoprogression we observed a significantly elevated mismatch ratio compared with disease recurrence (P < 0.01) within IDH-1 wild type patients. Patients with IDH-1 mutation demonstrated significantly reduced mismatch ratio with the development of pseudoprogression compared with disease recurrence (P < 0.01). Receiver operator curve analysis demonstrated 100% sensitivity and specificity for the use of mismatch ratios as a diagnostic biomarker of pseudoprogression. Our study suggests that ferumoxytol to gadolinium contrast mismatch ratios are an MRI biomarker for the diagnosis of pseudoprogression in patients with glioblastoma. This may be due to the unique characterization of therapy-induced neuroinflammation.

Nonmeasurable Speckled Contrast-Enhancing Lesions Appearing During Course of Disease Are Associated With IDH Mutation in High-Grade Astrocytoma Patients

Because treatment options at progression are limited for patients with glioma, accuracy in definition of progression is pivotal. Clinically asymptomatic, newly detected, nonmeasurable, speckled contrast-enhancing lesions (SCEs) without immediate relation to prior immune therapy or radiation therapy appear relatively frequently during the course of disease in patients with glioma and challenge the definition of progression based on Response Assessment in Neuro-oncology criteria. Therefore, data characterizing these SCEs are needed for recommendations of subsequent clinical management. Magnetic resonance imaging of 746 patients with glioma included in this study were retrospectively revised for appearance of newly detected SCEs during the course of disease. Associations with molecular and clinical baseline parameters and their prognostic impact were statistically analyzed, and frequency, natural course, and location of SCEs were described. SCEs occurred more frequently in World Health Organization grade 2 and 3 astrocytoma and oligodendroglial tumors and were significantly associated with isocitrate dehydrogenase mutation in World Health Organization grade 3 astrocytoma and glioblastoma. SCEs mostly remained stable or dissolved in follow-up magnetic resonance imaging, even if no new treatment was initiated. SCEs were frequently located within the tumor or tumor-associated fluid-attenuated inversion recovery abnormalities, but distant appearance also occurred. In patients with glioblastoma, SCEs were associated with a favorable prognosis, which was also observed in the subgroup of patients with glioblastoma with isocitrate dehydrogenase wildtype status. The data demonstrate a predominantly benign course of SCEs after their appearance and emphasize cautious definitions of progression and regular clinical and radiographic follow-up rather than premature initiation of new antitumor therapies until progression is confirmed.

Sequential Apparent Diffusion Coefficient for Assessment of Tumor Progression in Patients with Low-Grade Glioma.

Early and accurate identification of tumor progression in patients with low-grade gliomas is challenging. We aimed to assess the role of quantitative ADC analysis in the sequential follow-up of patients with low-grade gliomas as a potential imaging marker of tumor stability or progression. In this retrospective study, patients with a diagnosis of low-grade glioma with at least 12 months of imaging follow-up were retrospectively reviewed. Two neuroradiologists independently reviewed sequential MR imaging in each patient to determine tumor progression using the Response Assessment in Neuro-Oncology criteria. Normalized mean ADC (ADCmean) and 10th percentile ADC (ADC10) values from FLAIR hyperintense tumor volume were calculated for each MR image and compared between patients with stable disease versus tumor progression using univariate analysis. The interval change of ADC values between sequential scans was used to differentiate stable disease from progression using the Fisher exact test. Twenty-eight of 69 patients who were evaluated met our inclusion criteria. Fifteen patients were classified as stable versus 13 patients as having progression based on consensus reads of MRIs and the Response Assessment in Neuro-Oncology criteria. The interval change of ADC values showed greater concordance with ultimate lesion disposition than quantitative ADC values at a single time point. The interval change in ADC10 matched the expected pattern in 12/13 patients with tumor progression (overall diagnostic accuracy of 86%, P <.001). On average, the ADC10 interval change predicted progression 8 months before conventional MR imaging. The interval change of ADC10 values can be used to identify progression versus stability of low-grade gliomas with a diagnostic accuracy of 86% and before apparent radiologic progression on conventional MR imaging.

Durable response to bevacizumab in adults with recurrent pilocytic astrocytoma

Background:Adult pilocytic astrocytomas are rare and highly vascular tumors.Aim:We hypothesized that they may be uniquely responsive to bevacizumab (BEV).Patients:We present four adult patients with pathologically diagnosed WHO grade I pilocytic astrocytoma who had robust and durable responses to BEV at time of recurrence. Three patients developed radiographic changes on MRI, consistent with progressive disease based on response assessment in neuro-oncology criteria. Median time to recurrence was 8.5 months.Methods:All patients were treated with six cycles of BEV for recurrence.Results:At the end of treatment, all patients had achieved a clinical and radiographic response. Median follow-up time after BEV is 20.5 months.Conclusion:This suggests that BEV may have true antitumor activity in adult pilocytic astrocytomas and may be important for achieving durable disease control.

Neuroimaging classification of progression patterns in glioblastoma: a systematic review.

Our primaryobjective was to report thecurrent neuroimaging classification systems of spatial patterns of progression in glioblastoma.In addition, we aimed to report the terminology used to describe 'progression' and to assess the compliance with the Response Assessment in Neuro-Oncology (RANO) Criteria. We conducted a systematic review to identify all neuroimaging studies of glioblastoma that have employed a categorical classification system of spatial progression patterns. Our review was registered with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) registry. From the included 157 results, we identified 129 studies that used labels of spatial progression patterns that were notbased on radiation volumes (Group 1) and 50 studies that used labels that were based on radiation volumes(Group 2). In Group 1, we found 113 individual labels and the most frequent were: local/localised (58%), distant/distal (51%), diffuse (20%), multifocal (15%) and subependymal/subventricular zone (15%). We identified 13 different labels used to refer to 'progression', of which the most frequent were 'recurrence' (99%) and 'progression' (92%). We identified that37% (n = 33/90) of thestudies published following the release of the RANO classification were adherent compliant with the RANO criteria. Our review reports significant heterogeneity in the published systems used to classify glioblastoma spatial progression patterns. Standardization of terminology and classification systems used in studying progression would increase the efficiency of our research in our attempts to more successfully treat glioblastoma.

Imaging Criteria in Neuro-oncology.

The identification of more effective therapies for brain tumors has been limited in part by the lack of reliable criteria for determining response and progression. Since its introduction in 1990, the MacDonald criteria have been used in neuro-oncology clinical trials to determine response, but they fail to address issues such as pseudoprogression, pseudoresponse, and nonenhancing tumor progression that have arisen with more recent therapies. The Response Assessment in Neuro-Oncology (RANO) working group, a multidisciplinary international group consisting of neuro-oncologists, medical oncologists, neuroradiologists, neurosurgeons, radiation oncologists, and neuropsychologists, was formed to improve response assessment and clinical trial endpoints in neuro-oncology. Although it was initially focused on response assessment for gliomas, the scope of the RANO group has been broadened to include brain metastases, leptomeningeal metastases, spine tumors, pediatric brain tumors, and meningiomas. In addition, subgroups have focused on response assessment during immunotherapy and use of positron emission tomography, as well as determination of neurologic function, clinical outcomes assessment, and seizures. The RANO criteria are currently a collective work in progress, and refinements will be needed in the future based on data from clinical trials and improved imaging techniques.

Bevacizumab in Recurrent High-Grade Gliomas: A Canadian Retrospective Study.

Bevacizumab has been used in recurrent glioblastoma (rGBM) since 2010 in Canada. Given its cost, potential toxicities, and unclear efficacy, further studies are required to better define suitable candidates for therapy. A single-center retrospective review of patients started on bevacizumab for rGBM from 2012 to 2015 was performed. Patient demographics, tumor characteristics, treatment regimen, and dates of clinical progression and death were collected. Overall survival (OS) and progression-free survival (PFS) were used as clinical outcomes and estimates. Radiological response was assessed using modified Response Assessment in Neuro-Oncology criteria. A total of 80 patients were included. There were 67 reported deaths, and the median OS was 9.2 months (95% confidence interval [CI 95%]=7.0-10.1 months), with a 12-month OS of 31% (CI 95%=21.9-43.5%). Some 79 patients were included for analysis of clinical progression, among whom 61 had documented clinical progression. The median clinical PFS was 4.6 months (CI 95%=3.8-6.4 months), and the 6-month clinical PFS was 39% (CI 95%=29.0-52.9%). Addition of chemotherapy did not improve clinical outcomes. A total of 68 patients were included for radiological progression analysis, with 58 radiological progressions. The median radiological PFS was 5.8 months (CI 95%=4.2-6.7 months), and the 6-month radiological PFS was 46% (CI 95%=35.6-60.0%). This is the first reported Canadian experience with bevacizumab for rGBM. Our clinical outcomes are consistent with published data from multicenter phase II and III trials on bevacizumab in rGBM. More research is required to determine which subtype(s) of patients with rGBM could benefit from bevacizumab upon recurrence.

Imaging and clinical end points in brain metastases trials.

Imaging and clinical end points in brain metastases trials.

Response Assessment in Neuro-Oncology criteria, contrast enhancement and perfusion MRI for assessing progression in glioblastoma.

The purpose of the study was to evaluate Response Assessment in Neuro-Oncology (RANO) criteria in glioblastoma multiforme (GBM), with respect to the Macdonald criteria and changes in contrast-enhancement (CE) volume. Related variations in relative cerebral blood volume (rCBV) were investigated. Forty-three patients diagnosed between 2006 and 2010 were included. All underwent surgical resection, followed by temozolomide-based chemoradiation. MR images were retrospectively reviewed. Times to progression (TTPs) according to RANO criteria, Macdonald criteria and increased CE volume (CE-3D) were compared, and the percentage change in the 75th percentile of rCBV (rCBV75) was evaluated. After a median follow-up of 22.7months, a total of 39 patients had progressed according to RANO criteria, 32 according to CE-3D, and 42 according to Macdonald. Median TTPs were 6.4, 9.3, and 6.6months, respectively. Overall agreement was 79.07% between RANO and CE-3D and 93.02% between RANO and Macdonald. The mean percentage change in rCBV75 at RANO progression onset was over 73% in 87.5% of patients. In conclusion, our findings suggest that CE-3D criterion is not yet suitable to assess progression in routine clinical practice. Indeed, the accurate threshold is still not well defined. To date, in our opinion, early detection of disease progression by RANO combined with advanced MRI imaging techniques like MRI perfusion and diffusion remains the best way to assess disease progression. Further investigations that would examine the impact of treatment modifications after progression determined by different criteria on overall survival would be of great value.

Disease progression patterns of bevacizumab responders with recurrent malignant gliomas.

Tumor progression in patients with recurrent malignant glioma who respond to bevacizumab (BEV) is difficult to assess. The current study reviewed the clinical and radiological results of patients following a BEV-based chemotherapy regimen, and evaluated disease progression patterns in patients who responded to BEV therapy. From August 2011 to November 2015, 24 patients (18 glioblastoma cases and 6 anaplastic astrocytoma cases) were treated with BEV-based chemotherapy. In total, 6 patients were treated with BEV alone and 18 patients were treated with BEV combined with irinotecan. The male-female ratio was 10:14, and the median age was 47.5 years (range, 29–69). Patient performance status (PS) was classified using the Eastern Cooperative Oncology Group PS scores as follows: PS 1 (n=3), PS 2 (n=9), PS 3 (n=9) and PS 4 (n=3). Treatment-associated complications were also analyzed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Treatment responses were estimated using the Response Assessment in Neuro-Oncology Criteria. Progression-free survival (PFS) following treatment, patterns of disease progression and overall survival following treatment failure were also analyzed. The median PFS was 2.8 months (range, 0.6–10.1). In total, 2 patients did not continue treatment due to rectal bleeding and severe hematologic toxicity. Amongst the BEV responders (n=16, 72.7%), there was clinical deterioration without significant radiological progression in 2 patients (n=2, 12.5%). Radiological progression of non-enhancing lesions without enhancement flare-ups was observed in 6 patients (42.9%). A total of 3 of those lesions were diffuse and 3 were focal. Increased lesion enhancement was observed in 8 patients (57.1%). Of the non-responders (n=6, 27.3%), diffuse enlargement of non-enhancing lesions was detected in 2 patients and an increase in lesion enhancement occurred in 4 patients. BEV complete responders (n=3) radiologically progressed with enlarged T2/fluid attenuation inversion recovery lesions without enhancement, followed by enhancement flare-ups. Following BEV treatment failure, 8 patients received a number of adjuvant treatments and the overall survival was 4.5 months (range, 0.4–34.0). Clinical symptoms and radiological alterations of non-enhancing lesions must be evaluated in order to assess tumor progression in the BEV responders, particularly in patients who have achieved complete remission.

Outcome evaluation of patients with newly diagnosed anaplastic gliomas treated in a single institution.

To evaluate the outcome of newly diagnosed anaplastic glioma patients treated in our institution in relation to the 2016 WHO classification suggestions. This retrospective study included patients who underwent surgery plus adjuvant chemotherapy alone or concomitant and adjuvant chemoradiotherapy. Response was recorded using the Response Assessment in Neuro-Oncology criteria. 123 patients were analyzed. The median progression-free survival time and the 2, 3 and 5 years progression-free survival rate were 27 months, 65.5, 21.2 and 21.2%; the 2, 3 and 5 years overall survival rate were 89.7, 83.0 and 58.4%. From the univariate/multivariate analysis, the factors conditioning survival were Karnofsky performance scale, extent of resection, IDH1 mutation status and presence of 1p/19q codeletion. The choice of adjuvant treatment have to consider molecular assessment and, in our experience, the extent of surgical resection.

Abstract CT060: STARTRK-2: A global phase 2, open-label, basket study of entrectinib in patients with locally advanced or metastatic solid tumors harboring TRK, ROS1, or ALK gene fusions

Abstract Background: Entrectinib is a potent, CNS-penetrant, oral inhibitor of the tyrosine kinases TRKA/B/C (encoded by the genes NTRK1/2/3, respectively), ROS1, and ALK with IC50s &amp;lt; 2 nM (biochemical kinase assay). Two Phase 1 studies ALKA-372-001 and STARTRK-1 have enrolled more than 130 patients with advanced or metastatic solid tumors harboring TRKA/B/C, ROS1, or ALK molecular alterations, with or without CNS disease. Previously, we reported an objective response rate of 79% in 24 tyrosine kinase inhibitor-naïve patients with TRK, ROS1, or ALK gene fusions who were treated at doses that achieved therapeutic exposures consistent with the Recommended Phase 2 Dose (RP2D) (Drilon et al, AACR 2016). Entrectinib was well tolerated, with predominantly Grades 1 or 2 adverse events that were reversible with dose modification. Responses were observed in NSCLC, colorectal cancer, mammary analog secretory carcinoma, melanoma, and renal cell carcinoma, as early as 4 weeks after starting treatment and lasting as long as &amp;gt; 2 years. Notably, a complete CNS response was achieved in a patient with SQSTM1-NTRK1-rearranged lung cancer. Methods: STARTRK (Studies of Tumor Alterations Responsive to Targeting Receptor Kinases)-2 is a potentially registration-enabling Phase 2 basket study of entrectinib for the treatment of patients with advanced solid tumors that harbor a TRK, ROS1, or ALK gene fusion. In order to determine enrollment eligibility and assignment to a specific tumor type basket, patients are screened for gene fusions either locally, including by ctDNA, or centrally at Ignyta’s CLIA/CAP diagnostic laboratory using next generation sequencing. The study’s eligibility criteria were designed to maximize enrollment of these rare patients by allowing CNS disease, Eastern Cooperative Oncology Group (ECOG) performance status 2, and any prior line of therapy, with the exception of TRK, ROS1, or ALK inhibitors. Patients with ALK- or ROS1-rearranged NSCLC who had previously been treated with crizotinib and experienced CNS-only progression are also eligible. In addition, a “non-evaluable” basket allows enrollment of patients confirmed to have gene fusions who do not meet all the inclusion or exclusion criteria. Entrectinib is administered orally on a continuous daily dosing regimen, at a dose of 600 mg once-daily in repeated 4-week cycles. Safety is assessed by monitoring of adverse events, laboratory tests, and clinic visits. Tumor assessments (computed tomography (CT) or magnetic resonance imaging (MRI)) of the chest, abdomen, pelvis (depending on tumor type), plus bone and/or brain as applicable, are performed at the end of Cycle 1 and every 8 weeks thereafter. All CT and MRI scans are read by a central independent imaging laboratory using the Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 and the Response Assessment in Neuro-Oncology Criteria (RANO) or RANO - Brain Metastases (RANO-BM), as applicable, for patients with primary or secondary CNS disease, respectively. Blood and tissue are collected at the time of progression for biomarker analyses for potential mechanisms of resistance to entrectinib. Patients remain on study treatment until documented radiographic progression as assessed by blinded independent central review (BICR), development of unacceptable toxicity, or withdrawal of consent. Citation Format: Alexander Drilon, Kamalesh Kumar Sankhala, Stephen V. Liu, Byoung Chul Cho, Collin Blakely, Cheng E. Chee, Marwan Fakih, Jonathan Polikoff, Zachary Hornby, Lisa Schechet, David Luo, Edna Chow Maneval, Pratik S. Multani, Robert C. Doebele. STARTRK-2: A global phase 2, open-label, basket study of entrectinib in patients with locally advanced or metastatic solid tumors harboring TRK, ROS1, or ALK gene fusions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT060. doi:10.1158/1538-7445.AM2017-CT060

Bevacizumab as a last-line treatment for glioblastoma following failure of radiotherapy, temozolomide and lomustine.

In previous trials, bevacizumab failed to prolong the overall survival time in newly diagnosed glioblastoma and at the first recurrence. Randomized clinical trials at the second or further recurrence following the failure of radiotherapy, temozolomide and lomustine, and retrospective analyses focusing on this specific cohort, are not yet available. A total of 62 patients with glioblastoma who received bevacizumab after the failure of standard care, including radiotherapy, temozolomide and lomustine, were retrospectively identified. Patient characteristics, previous treatment details, concomitant therapy, response based on the Response Assessment in Neuro-Oncology criteria, and progression-free survival (PFS) and overall survival (OS) times and rates were evaluated. Furthermore, the PFS and OS times and rates were analyzed for responders and non-responders. Of the patients, 54.8% (n=34) responded to treatment [complete response (CR) 3.2%, n=2; partial response (PR) 51.6%, n=32]. The median PFS time was 3.5 months and the median OS time was 7.5 months. The PFS rate at 6 months was 21.5% and the OS rate at 12 months was 11.5%. Responders (CR or PR) experienced a superior median PFS time compared with non-responders (i.e. stable or progressive disease; 5.4 vs. 1.9 months; P<0.0001) and a superior PFS rate at 6 months (34.9 vs. 7.1%; P<0.0001). The median OS time (8.6 vs. 6.4 months; P<0.0001) and OS rate at 12 months (21.3 vs. 0%; P<0.0001) were also superior in patients who exhibited a response to bevacizumab treatment. In conclusion, the objective response rate and the PFS and OS times and rates indicate that bevacizumab has activity in patients with glioblastoma following the failure of radiotherapy, temozolomide, and lomustine. A randomized trial comparing bevacizumab with best supportive care in these patients is advised.