Marizomib for patients with newly diagnosed glioblastoma: a randomized phase 3 trial.

BACKGROUND: Standard treatment for patients with newly diagnosed glioblastoma includes surgery, radiotherapy (RT) and temozolomide (TMZ) chemotherapy (TMZ/RT→TMZ). The proteasome has long been considered a promising therapeutic target because of its role as a central biological hub in tumor cells. Marizomib is a novel pan-proteasome inhibitor that crosses the blood brain barrier. METHODS: EORTC 1709/CCTG CE.8 was a multicenter, randomized, controlled, open label phase 3 superiority trial. Key eligibility criteria included newly diagnosed glioblastoma, age > 18 years and Karnofsky performance status > 70. Patients were randomized in a 1:1 ratio. The primary objective was to compare overall survival (OS) in patients receiving marizomib in addition to TMZ/RT→TMZ with patients receiving only standard treatment in the whole population, and in the subgroup of patients with MGMT promoter-unmethylated tumors. RESULTS: The trial was opened at 82 institutions in Europe, Canada and the US. A total of 749 patients (99.9% of planned 750) were randomized. OS was not different between the standard and the marizomib arm (median 17 vs 16.5 months; HR=1.04; p=0.64). PFS was not statistically different either (median 6.0 vs. 6.3 months; HR=0.97; p=0.67). In patients with MGMT promoter-unmethylated tumors, OS was also not different between standard therapy and marizomib (median 14.5 vs 15.1 months, HR=1.13; p=0.27). More CTCAE grade 3/4 treatment-emergent adverse events were observed in the marizomib arm than in the standard arm. CONCLUSIONS: Adding marizomib to standard temozolomide-based radiochemotherapy resulted in more toxicity, but did not improve OS or PFS in patients with newly diagnosed glioblastoma.

Combination of radiosurgery and immunotherapy in brain metastases: balance between efficacy and toxicities.

PURPOSE OF REVIEW: The incidence of brain metastasis is high and still increasing. Among local therapies, stereotactic radiosurgery (SRS) is an effective treatment option, optimally sparing normal brain, even for multiple brain metastases. Immune checkpoint inhibitors (ICIs) become the new standard of care in an increasing number of cancers, and the combination SRS and ICI is often proposed to patients, but few data have been published on the efficacy and the toxicity of this association. RECENT FINDINGS: Explaining this lack of consensus: retrospective studies with different primary cancers, various treatment lines and unknown levels of steroid exposure. Concerning the toxicity, the independent association of radionecrosis with brain-PTV volume was confirmed, and a decreased dose of SRS is now tested in a randomized study. Finally, a 'concurrent' delivery of SRS and ICI (within a 4 weeks' interval) seems the optimal schedule; fractionated radiosurgery for large brain metastasis should be favored. Radio-sensitizing nanoparticles and devices aiming to increase the permeability of the blood brain barrier should be considered in future combinations. SUMMARY: The efficacy/toxicity balance of SRS-ICI combination should be regularly re-evaluated, anticipating continued progress in ICI and SRS delivery, with more long-survivors potentially exposed to long-term toxicities. Patients should be included in clinical trials and clearly informed to participate more closely in the final choice.

Anticancer drug delivery by focused ultrasound-mediated blood-brain/tumor barrier disruption for glioma therapy: From benchside to bedside.

The therapeutic management of gliomas remains particularly challenging. Brain tumors present multiple obstacles that make therapeutic innovation complex, mainly due to the presence of blood-tumor and blood-brain barriers (BTB and BBB, respectively) which prevent penetration of anticancer agents into the brain parenchyma. Focused ultrasound-mediated BBB disruption (FUS-BBBD) provides a physical method for non-invasive, local, and reversible BBB disruption. The safety of this technique has been demonstrated in small and large animal models. This approach promises to enhance drug delivery into the brain tumor and therefore to improve survival outcomes by repurposing existing drugs. Several clinical trials continue to be initiated in the last decade. In this review, we provide an overview of the rationale behind the use of FUS-BBBD in gliomas and summarize the preclinical studies investigating different approaches (free drugs, drug-loaded microbubbles and drug-loaded nanocarriers) in combination with this technology in in vivo glioma models. Furthermore, we discuss the current state of clinical trials and devices developed and review the challenges to overcome for clinical use of FUS-BBBD in glioma therapy.

European Cancer Organisation Essential Requirements for Quality Cancer Care: Adult glioma.

European Cancer Organisation Essential Requirements for Quality Cancer Care (ERQCCs) are explanations of the organisation and actions necessary to provide high-quality care to patients with a specific cancer type. They are compiled by a working group of European experts representing disciplines involved in cancer care, and provide oncology teams, patients, policymakers and managers with an overview of the essential requirements in any healthcare system. The focus here is on adult glioma. Gliomas make up approximately 80% of all primary malignant brain tumours. They are highly diverse and patients can face a unique cognitive, physical and psychosocial burden, so personalised treatments and support are essential. However, management of gliomas is currently very heterogeneous across Europe and there are only few formally-designated comprehensive cancer centres with brain tumour programmes. To address this, the ERQCC glioma expert group proposes frameworks and recommendations for high quality care, from diagnosis to treatment and survivorship. Wherever possible, glioma patients should be treated from diagnosis onwards in high volume neurosurgical or neuro-oncology centres. Multidisciplinary team working and collaboration is essential if patients' length and quality of life are to be optimised.

Target volume delineation for radiotherapy of meningiomas: an ANOCEF consensus guideline.

PURPOSE: Radiotherapy is, with surgery, one of the main therapeutic treatment strategies for meningiomas. No prospective study has defined a consensus for the delineation of target volumes for meningioma radiotherapy. Therefore, target volume definition is mainly based on information from retrospective studies that include heterogeneous patient populations. The aim is to describe delineation guidelines for meningioma radiotherapy as an adjuvant or definitive treatment with intensity-modulated radiation therapy and stereotactic radiation therapy techniques. This guideline is based on a consensus endorsed by a multidisciplinary group of brain tumor experts, members of the Association of French-speaking Neuro-oncologists (ANOCEF). MATERIALS AND METHODS: A 3-step procedure was used. First, the steering group carried out a comprehensive review to identify divergent issues on meningiomas target volume delineation. Second, an 84-item web-questionnaire has been developed to precisely define meningioma target volume delineation in the most common clinical situations. Third, experts members of the ANOCEF were requested to answer. The first two rounds were completed online. A third round was carried out by videoconference to allow experts to debate and discuss the remaining uncertain questions. All questions remained in a consensus. RESULTS: Limits of the target volume were defined using visible landmarks on computed tomography and magnetic resonance imaging, considering the pathways of tumor extension. The purpose was to develop clear and precise recommendations on meningiomas target volumes. CONCLUSION: New recommendations for meningiomas delineation based on simple anatomic boundaries are proposed by the ANOCEF. Improvement in uniformity in target volume definition is expected.

Bevacizumab in real-life patients with recurrent glioblastoma: benefit or futility?

PURPOSE: Angiogenesis plays a key role in glioblastoma, but most anti-angiogenic therapy trials have failed to change the poor outcome of this disease. Despite this, and because bevacizumab is known to alleviate symptoms, it is used in daily practice. We aimed to assess the real-life benefit in terms of overall survival, time to treatment failure, objective response, and clinical benefit in patients with recurrent glioblastoma treated with bevacizumab. METHODS: This was a monocentric, retrospective study including patients treated between 2006 and 2016 in our institution. RESULTS: 202 patients were included. The median duration of bevacizumab treatment was 6 months. Median time to treatment failure was 6.8 months (95%CI 5.3-8.2) and median overall survival was 23.7 months (95%CI 20.6-26.8). Fifty percent of patients had a radiological response at first MRI evaluation, and 56% experienced symptom amelioration. Grade 1/2 hypertension (n = 34, 17%) and grade one proteinuria (n = 20, 10%) were the most common side effects. CONCLUSIONS: This study reports a clinical benefit and an acceptable toxicity profile in patients with recurrent glioblastoma treated with bevacizumab. As the panel of therapies is still very limited for these tumors, this work supports the use of bevacizumab as a therapeutic option.

Clinico-Radio-Histo-Molecular and Neurocognitive Characteristics of Diffuse Gliomas in Adolescent and Young Adults: A Comprehensive Review.

BACKGROUND: Diffuse gliomas are the most frequent neoplasms in adolescent and young adults (AYAs), especially high-grade gliomas, which have the highest mortality rate. Recent histo-molecular advances are in favour of specialized therapeutic management of AYA patients, which we have analysed in this comprehensive review of the literature. SUMMARY: A literature search was conducted to identify all studies concerning diffuse gliomas and AYAs (15-39 years). We assessed epidemiology, clinical and imaging findings, histo-molecular characteristics, neurosurgical and neuro-oncological management, prognosis, and health-related quality of life. KEY MESSAGES: Diffuse gliomas remain the most frequent brain tumours in the AYA population. Symptoms mainly depend on the tumour location, which varies due to histo-molecular profiles. Specific imaging patterns of histo-molecular subtypes of diffuse gliomas are identified; however, no specific pattern related to the age group has been identified. The literature review favours optimizing the extent of surgical resection for diffuse gliomas, whichever the grade, and suggests a dedicated management for these patients. It seems more relevant to consider the treatment according to the histo-molecular profile of the diffuse glioma rather than the age group. Clinical trials will allow AYA patients to benefit from innovative therapies that could improve their outcome. This literature review suggests the need for a close and long-term psychological follow-up for AYA patients with brain tumour during the transitional care, during adulthood, as well as for their family members. Collaborative efforts are needed between paediatric and adult neurosurgical and neuro-oncological teams, to move forward in the therapeutic management of AYA patients harbouring diffuse gliomas.

In Vivo 2-Hydroxyglutarate Monitoring With Edited MR Spectroscopy for the Follow-up of IDH-Mutant Diffuse Gliomas: The IDASPE Prospective Study.

BACKGROUND AND OBJECTIVES: D-2-hydroxyglutarate (2HG) characterizes IDH-mutant gliomas and can be detected and quantified with edited MRS (MEGA-PRESS). In this study, we investigated the clinical, radiologic, and molecular parameters affecting 2HG levels. METHODS: MEGA-PRESS data were acquired in 71 patients with glioma (24 untreated, 47 treated) on a 3 T system. Eighteen patients were followed during cytotoxic (n = 12) or targeted (n = 6) therapy. 2HG was measured in tumor samples using gas chromatography coupled to mass spectrometry (GCMS). RESULTS: MEGA-PRESS detected 2HG with a sensitivity of 95% in untreated patients and 62% in treated patients. Sensitivity depended on tumor volume (>27 cm3; p = 0.02), voxel coverage (>75%; p = 0.002), and expansive presentation (defined by equal size of T1 and FLAIR abnormalities, p = 0.04). 2HG levels were positively correlated with IDH-mutant allelic fraction (p = 0.03) and total choline levels (p < 0.001) and were higher in IDH2-mutant compared with IDH1 R132H-mutant and non-R132H IDH1-mutant patients (p = 0.002). In patients receiving IDH inhibitors, 2HG levels decreased within a few days, demonstrating the on-target effect of the drug, but 2HG level decrease did not predict tumor response. Patients receiving cytotoxic treatments showed a slower decrease in 2HG levels, consistent with tumor response and occurring before any tumor volume change on conventional MRI. At progression, 1p/19q codeleted gliomas, but not the non-codeleted, showed detectable in vivo 2HG levels, pointing out to different modes of progression characterizing these 2 entities. DISCUSSION: MEGA-PRESS edited MRS allows in vivo monitoring of 2-hydroxyglutarate, confirming efficacy of IDH inhibition and suggests different patterns of tumor progression in astrocytomas compared with oligodendrogliomas.

Radiomics in neuro-oncological clinical trials.

The development of clinical trials has led to substantial improvements in the prevention and treatment of many diseases, including brain cancer. Advances in medicine, such as improved surgical techniques, the development of new drugs and devices, the use of statistical methods in research, and the development of codes of ethics, have considerably influenced the way clinical trials are conducted today. In addition, methods from the broad field of artificial intelligence, such as radiomics, have the potential to considerably affect clinical trials and clinical practice in the future. Radiomics is a method to extract undiscovered features from routinely acquired imaging data that can neither be captured by means of human perception nor conventional image analysis. In patients with brain cancer, radiomics has shown its potential for the non-invasive identification of prognostic biomarkers, automated response assessment, and differentiation between treatment-related changes from tumour progression. Despite promising results, radiomics is not yet established in routine clinical practice nor in clinical trials. In this Viewpoint, the European Organization for Research and Treatment of Cancer Brain Tumour Group summarises the current status of radiomics, discusses its potential and limitations, envisions its future role in clinical trials in neuro-oncology, and provides guidance on how to address the challenges in radiomics.

Characteristics of Anaplastic Oligodendrogliomas Short-Term Survivors: A POLA Network Study.

BACKGROUND: Anaplastic oligodendrogliomas IDH-mutant and 1p/19q codeleted (AO) occasionally have a poor outcome. Herein we aimed at analyzing their characteristics. METHODS: We retrospectively analyzed the characteristics of 44 AO patients with a cancer-specific survival <5 years (short-term survivors, STS) and compared them with those of 146 AO patients with a survival ≥5 years (classical survivors, CS) included in the POLA network. RESULTS: Compared to CS, STS were older (P = .0001), less frequently presented with isolated seizures (P < .0001), more frequently presented with cognitive dysfunction (P < .0001), had larger tumors (P = .= .003), a higher proliferative index (P = .= .0003), and a higher number of chromosomal arm abnormalities (P = .= .02). Regarding treatment, STS less frequently underwent a surgical resection than CS (P = .= .0001) and were more frequently treated with chemotherapy alone (P = .= .009) or with radiotherapy plus temozolomide (P = .= .05). Characteristics independently associated with STS in multivariate analysis were cognitive dysfunction, a number of mitosis > 8, and the absence of tumor resection. Based on cognitive dysfunction, type of surgery, and number of mitosis, patients could be classified into groups of standard (18%) and high (62%) risk of <5 year survival. CONCLUSION: The present study suggests that although STS poor outcome appears to largely result from a more advanced disease at diagnosis, surgical resection may be particularly important in this population.

Prospective validation of a new imaging scorecard to assess leptomeningeal metastasis: A joint EORTC BTG and RANO effort.

BACKGROUND: Validation of the 2016 RANO MRI scorecard for leptomeningeal metastasis failed for multiple reasons. Accordingly, this joint EORTC Brain Tumor Group and RANO effort sought to prospectively validate a revised MRI scorecard for response assessment in leptomeningeal metastasis. METHODS: Coded paired cerebrospinal MRI of 20 patients with leptomeningeal metastases from solid cancers at baseline and follow-up after treatment and instructions for assessment were provided via the EORTC imaging platform. The Kappa coefficient was used to evaluate the interobserver pairwise agreement. RESULTS: Thirty-five raters participated, including 9 neuroradiologists, 17 neurologists, 4 radiation oncologists, 3 neurosurgeons, and 2 medical oncologists. Among single leptomeningeal metastases-related imaging findings at baseline, the best median concordance was noted for hydrocephalus (Kappa = 0.63), and the worst median concordance for spinal linear enhancing disease (Kappa = 0.46). The median concordance of raters for the overall response assessment was moderate (Kappa = 0.44). Notably, the interobserver agreement for the presence of parenchymal brain metastases at baseline was fair (Kappa = 0.29) and virtually absent for their response to treatment. 394 of 700 ratings (20 patients x 35 raters, 56%) were fully completed. In 308 of 394 fully completed ratings (78%), the overall response assessment perfectly matched the summary interpretation of the single ratings as proposed in the scorecard instructions. CONCLUSION: This study confirms the principle utility of the new scorecard, but also indicates the need for training of MRI assessment with a dedicated reviewer panel in clinical trials. Electronic case report forms with "blocking options" may be required to enforce completeness and quality of scoring.

Genome-driven medicine for patients with recurrent glioma enrolled in early phase trials.

BACKGROUND: Recent studies showed that patients with glioma can safely participate in early phase clinical trials; however, clinical benefits in this population were limited. We aimed to evaluate the benefit of molecular profiling to guide enrolment in early phase trials for patients with recurrent glioma. METHODS: Records of patients enrolled in early phase trials of cytotoxic therapies, small molecule inhibitors or monoclonal antibodies from 2008 to 2018 were reviewed for clinico-pathological characteristics, toxicity, response, progression-free survival and overall survival (OS). The primary objective was to evaluate response rates in molecularly-oriented versus non-molecularly-oriented patients. RESULTS: Eighty-eight patients were enrolled, of whom 45 (51.1%) patients were molecularly-oriented. Targets included IDH1/2 (n = 15), BRAF (n = 11), and FGFR1 (n = 3) mutations, FGFR2-3 fusions (n = 9), and mismatch repair deficiency (n = 7). Among patients with high-grade glioma (n = 74), the rate of stable disease ≥6 months and partial or complete response was 25.7% in molecularly-oriented versus 5.1% in non-molecularly-oriented patients (p = 0.02). Upon multivariable adjustment, baseline steroid use ≥20 mg prednisone equivalent per day was associated with shorter OS (OR 3.15 [95% CI 1.62-6.13], p = 0.0008), while molecular enrichment strategy was associated with longer OS (OR 0.40 [95% CI 0.22-0.73], p = 0.003). Nine (10.2%) patients experienced grade 3-4 toxicity and no dose limiting toxicity (DLT) occurred in both cohorts. CONCLUSION: The use of molecular profiling to guide enrolment in early phase trials is feasible and might provide benefits to selected patients with glioma. Further studies are warranted to confirm these results in larger randomised settings and identify the patients most likely to benefit from this approach.

Effect of Levetiracetam Use Duration on Overall Survival of Isocitrate Dehydrogenase Wild-Type Glioblastoma in Adults: An Observational Study.

BACKGROUND AND OBJECTIVES: The association between levetiracetam and survival with isocitrate dehydrogenase (IDH) wild-type glioblastomas is controversial. We investigated whether the duration of levetiracetam use during the standard chemoradiation protocol affects overall survival (OS) of patients with IDH wild-type glioblastoma. METHODS: In this observational single-institution cohort study (2010-2018), inclusion criteria were (1) age ≥18 years; (2) newly diagnosed supratentorial tumor; (3) histomolecular diagnosis of IDH wild-type glioblastoma; and (4) standard chemoradiation protocol. To assess the survival benefit of levetiracetam use during the standard chemoradiation protocol (whole duration, part time, and never subgroups), a Cox proportional hazard model was constructed. We performed a case-matched analysis (1:1) between patients with levetiracetam use during the whole duration of the standard chemoradiation protocol and patients with levetiracetam use part time or never according to the following criteria: sex, age, epileptic seizures at diagnosis, Radiation Therapy Oncology Group recursive partitioning analysis (RTOG-RPA) class, tumor location, preoperative volume, extent of resection, and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. Patients with unavailable O6-methylguanine-DNA methyltransferase promoter methylation status (48.5%) were excluded. RESULTS: A total of 460 patients were included. The median OS was longer in the 116 patients with levetiracetam use during the whole duration of the standard chemoradiation protocol (21.0 months; 95% confidence interval [CI] 17.2-24.0) than in the 126 patients with part-time levetiracetam use (16.8 months; 95% CI 12.4-19.0) and in the 218 patients who never received levetiracetam (16.0 months; 95% CI 15.5-19.4; p = 0.027). Levetiracetam use during the whole duration of the standard chemoradiation protocol (adjusted hazard ratio [aHR] 0.69; 95% CI 0.52-0.93; p = 0.014), MGMT promoter methylation (aHR 0.53; 95% CI 0.39-0.71; p < 0.001), and gross total tumor resection (aHR 0.57; 95% CI 0.44-0.74; p < 0.001) were independent predictors of longer OS. After case matching (n = 54 per group), a longer OS was found for levetiracetam use during the whole duration of the standard chemoradiation protocol (hazard ratio 0.63; 95% CI 0.42-0.94; p = 0.023). DISCUSSION: Levetiracetam use during the whole standard chemoradiation protocol possibly improves OS of patients with IDH wild-type glioblastoma. It should be considered in the antitumor strategy of future multicentric trials. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that in individuals with IDH wild-type glioblastoma, levetiracetam use throughout the duration of standard chemotherapy is associated with longer median OS.

Discriminating surgical bed cysts from bacterial brain abscesses after Carmustine wafer implantation in newly diagnosed IDH-wildtype glioblastomas.

Carmustine wafers can be implanted in the surgical bed of high-grade gliomas, which can induce surgical bed cyst formation, leading to clinically relevant mass effect. An observational retrospective monocentric study was conducted including 122 consecutive adult patients with a newly diagnosed supratentorial glioblastoma who underwent a surgical resection with Carmustine wafer implantation as first line treatment (2005-2018). Twenty-two patients (18.0%) developed a postoperative contrast-enhancing cyst within the surgical bed: 16 surgical bed cysts and six bacterial abscesses. All patients with a surgical bed cyst were managed conservatively, all resolved on imaging follow-up, and no patient stopped the radiochemotherapy. Independent risk factors of formation of a postoperative surgical bed cyst were age ≥ 60 years (p = 0.019), number of Carmustine wafers implanted ≥ 8 (p = 0.040), and partial resection (p = 0.025). Compared to surgical bed cysts, the occurrence of a postoperative bacterial abscess requiring surgical management was associated more frequently with a shorter time to diagnosis from surgery (p = 0.009), new neurological deficit (p < 0.001), fever (p < 0.001), residual air in the cyst (p = 0.018), a cyst diameter greater than that of the initial tumor (p = 0.027), and increased mass effect and brain edema compared to early postoperative MRI (p = 0.024). Contrast enhancement (p = 0.473) and diffusion signal abnormalities (p = 0.471) did not differ between postoperative bacterial abscesses and surgical bed cysts. Clinical and imaging findings help discriminate between surgical bed cysts and bacterial abscesses following Carmustine wafer implantation. Surgical bed cysts can be managed conservatively. Individual risk factors will help tailor their steroid therapy and imaging follow-up.

Surgery of Insular Diffuse Gliomas-Part 2: Probabilistic Cortico-Subcortical Atlas of Critical Eloquent Brain Structures and Probabilistic Resection Map During Transcortical Awake Resection.

BACKGROUND: Insular diffuse glioma surgery is challenging, and tools to help surgical planning could improve the benefit-to-risk ratio. OBJECTIVE: To provide a probabilistic resection map and frequency atlases of critical eloquent regions of insular diffuse gliomas based on our surgical experience. METHODS: We computed cortico-subcortical "eloquent" anatomic sites identified intraoperatively by direct electrical stimulations during transcortical awake resection of insular diffuse gliomas in adults. RESULTS: From 61 insular diffuse gliomas (39 left, 22 right; all left hemispheric dominance for language), we provided a frequency atlas of eloquence of the opercula (left/right; pars orbitalis: 0%/5.0%; pars triangularis: l5.6%/4.5%; pars opercularis: 37.8%/27.3%; precentral gyrus: 97.3%/95.4%; postcentral and supramarginal gyri: 75.0%/57.1%; temporal pole and superior temporal gyrus: 13.3%/0%), which tailored the transcortical approach (frontal operculum to reach the antero-superior insula, temporal operculum to reach the inferior insula, parietal operculum to reach the posterior insula). We provided a frequency atlas of eloquence identifying the subcortical functional boundaries (36.1% pyramidal pathways, 50.8% inferior fronto-occipital fasciculus, 13.1% arcuate and superior longitudinal fasciculi complex, 3.3% somatosensory pathways, 8.2% caudate and lentiform nuclei). Vascular boundaries and increasing errors during testing limited the resection in 8.2% and 11.5% of cases, respectively. We provided a probabilistic 3-dimensional atlas of resectability. CONCLUSION: Functional mapping under awake conditions has to be performed intraoperatively in each patient to guide surgical approach and resection of insular diffuse gliomas in right and left hemispheres. Frequency atlases of opercula eloquence and of subcortical eloquent anatomic boundaries, and probabilistic 3-dimensional atlas of resectability could guide neurosurgeons.

Surgery of Insular Diffuse Gliomas-Part 1: Transcortical Awake Resection Is Safe and Independently Improves Overall Survival.

BACKGROUND: Insular diffuse glioma resection is at risk of vascular injury and of postoperative new neurocognitive deficits. OBJECTIVE: To assess safety and efficacy of surgical management of insular diffuse gliomas. METHODS: Observational, retrospective, single-institution cohort analysis (2005-2019) of 149 adult patients surgically treated for an insular diffuse glioma: transcortical awake resection with intraoperative functional mapping (awake resection subgroup, n = 61), transcortical asleep resection without functional mapping (asleep resection subgroup, n = 50), and stereotactic biopsy (biopsy subgroup, n = 38). All cases were histopathologically assessed according to the 2016 World Health Organization classification and cIMPACT-NOW update 3. RESULTS: Following awake resection, 3/61 patients had permanent motor deficit, seizure control rates improved (89% vs 69% preoperatively, P = .034), and neurocognitive performance improved from 5% to 24% in tested domains, despite adjuvant oncological treatments. Resection rates were higher in the awake resection subgroup (median 94%) than in the asleep resection subgroup (median 46%; P < .001). There was more gross total resection (25% vs 12%) and less partial resection (34% vs 80%) in the awake resection subgroup than in the asleep resection subgroup (P < .001). Karnofsky Performance Status score <70 (adjusted hazard ratio [aHR] 2.74, P = .031), awake resection (aHR 0.21, P = .031), isocitrate dehydrogenase (IDH)-mutant grade 2 astrocytoma (aHR 5.17, P = .003), IDH-mutant grade 3 astrocytoma (aHR 6.11, P < .001), IDH-mutant grade 4 astrocytoma (aHR 13.36, P = .008), and IDH-wild-type glioblastoma (aHR 21.84, P < .001) were independent predictors of overall survival. CONCLUSION: Awake surgery preserving the brain connectivity is safe, allows larger resections for insular diffuse gliomas than asleep resection, and positively impacts overall survival.

Development of a Machine Learning Classifier Based on Radiomic Features Extracted From Post-Contrast 3D T1-Weighted MR Images to Distinguish Glioblastoma From Solitary Brain Metastasis.

OBJECTIVES: To differentiate Glioblastomas (GBM) and Brain Metastases (BM) using a radiomic features-based Machine Learning (ML) classifier trained from post-contrast three-dimensional T1-weighted (post-contrast 3DT1) MR imaging, and compare its performance in medical diagnosis versus human experts, on a testing cohort. METHODS: We enrolled 143 patients (71 GBM and 72 BM) in a retrospective bicentric study from January 2010 to May 2019 to train the classifier. Post-contrast 3DT1 MR images were performed on a 3-Tesla MR unit and 100 radiomic features were extracted. Selection and optimization of the Machine Learning (ML) classifier was performed using a nested cross-validation. Sensitivity, specificity, balanced accuracy, and area under the receiver operating characteristic curve (AUC) were calculated as performance metrics. The model final performance was cross-validated, then evaluated on a test set of 37 patients, and compared to human blind reading using a McNemar's test. RESULTS: The ML classifier had a mean [95% confidence interval] sensitivity of 85% [77; 94], a specificity of 87% [78; 97], a balanced accuracy of 86% [80; 92], and an AUC of 92% [87; 97] with cross-validation. Sensitivity, specificity, balanced accuracy and AUC were equal to 75, 86, 80 and 85% on the test set. Sphericity 3D radiomic index highlighted the highest coefficient in the logistic regression model. There were no statistical significant differences observed between the performance of the classifier and the experts' blinded examination. CONCLUSIONS: The proposed diagnostic support system based on radiomic features extracted from post-contrast 3DT1 MR images helps in differentiating solitary BM from GBM with high diagnosis performance and generalizability.

Adjuvant and concurrent temozolomide for 1p/19q non-co-deleted anaplastic glioma (CATNON; EORTC study 26053-22054): second interim analysis of a randomised, open-label, phase 3 study.

BACKGROUND: The CATNON trial investigated the addition of concurrent, adjuvant, and both current and adjuvant temozolomide to radiotherapy in adults with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas. The benefit of concurrent temozolomide chemotherapy and relevance of mutations in the IDH1 and IDH2 genes remain unclear. METHODS: This randomised, open-label, phase 3 study done in 137 institutions across Australia, Europe, and North America included patients aged 18 years or older with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas and a WHO performance status of 0-2. Patients were randomly assigned (1:1:1:1) centrally using a minimisation technique to radiotherapy alone (59·4 Gy in 33 fractions; three-dimensional conformal radiotherapy or intensity-modulated radiotherapy), radiotherapy with concurrent oral temozolomide (75 mg/m2 per day), radiotherapy with adjuvant oral temozolomide (12 4-week cycles of 150-200 mg/m2 temozolomide given on days 1-5), or radiotherapy with both concurrent and adjuvant temozolomide. Patients were stratified by institution, WHO performance status score, age, 1p loss of heterozygosity, the presence of oligodendroglial elements on microscopy, and MGMT promoter methylation status. The primary endpoint was overall survival adjusted by stratification factors at randomisation in the intention-to-treat population. A second interim analysis requested by the independent data monitoring committee was planned when two-thirds of total required events were observed to test superiority or futility of concurrent temozolomide. This study is registered with ClinicalTrials.gov, NCT00626990. FINDINGS: Between Dec 4, 2007, and Sept 11, 2015, 751 patients were randomly assigned (189 to radiotherapy alone, 188 to radiotherapy with concurrent temozolomide, 186 to radiotherapy and adjuvant temozolomide, and 188 to radiotherapy with concurrent and adjuvant temozolomide). Median follow-up was 55·7 months (IQR 41·0-77·3). The second interim analysis declared futility of concurrent temozolomide (median overall survival was 66·9 months [95% CI 45·7-82·3] with concurrent temozolomide vs 60·4 months [45·7-71·5] without concurrent temozolomide; hazard ratio [HR] 0·97 [99·1% CI 0·73-1·28], p=0·76). By contrast, adjuvant temozolomide improved overall survival compared with no adjuvant temozolomide (median overall survival 82·3 months [95% CI 67·2-116·6] vs 46·9 months [37·9-56·9]; HR 0·64 [95% CI 0·52-0·79], p<0·0001). The most frequent grade 3 and 4 toxicities were haematological, occurring in no patients in the radiotherapy only group, 16 (9%) of 185 patients in the concurrent temozolomide group, and 55 (15%) of 368 patients in both groups with adjuvant temozolomide. No treatment-related deaths were reported. INTERPRETATION: Adjuvant temozolomide chemotherapy, but not concurrent temozolomide chemotherapy, was associated with a survival benefit in patients with 1p/19q non-co-deleted anaplastic glioma. Clinical benefit was dependent on IDH1 and IDH2 mutational status. FUNDING: Merck Sharpe & Dohme.