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Intraoperative MRI is increasingly used in neurosurgery, although there is little evidence for its use. We aimed to assess efficacy of intraoperative MRI guidance on extent of resection in patients with glioma. In our prospective, randomised, parallel-group trial, we enrolled adults (≥18 years) with contrast enhancing gliomas amenable to radiologically complete resection who presented to Goethe University (Frankfurt, Germany). We randomly assigned patients (1:1) with computer-generated blocks of four and a sealed-envelope design to undergo intraoperative MRI-guided surgery or conventional microsurgery (control group). Surgeons and patients were unmasked to treatment group allocation, but an independent neuroradiologist was masked during analysis of all preoperative and postoperative imaging data. The primary endpoint was rate of complete resections as established by early postoperative high-field MRI (1·5 T or 3·0 T). Analysis was done per protocol. This study is registered with ClinicalTrials.gov, number NCT01394692. We enrolled 58 patients between Oct 1, 2007, and July 1, 2010. 24 (83%) of 29 patients randomly allocated to the intraoperative MRI group and 25 (86%) of 29 controls were eligible for analysis (four patients in each group had metastasis and one patient in the intraoperative MRI group withdrew consent after randomisation). More patients in the intraoperative MRI group had complete tumour resection (23 [96%] of 24 patients) than did in the control group (17 [68%] of 25, p=0·023). Postoperative rates of new neurological deficits did not differ between patients in the intraoperative MRI group (three [13%] of 24) and controls (two [8%] of 25, p=1·0). No patient for whom use of intraoperative MRI led to continued resection of residual tumour had neurological deterioration. One patient in the control group died before 6 months. Our study provides evidence for the use of intraoperative MRI guidance in glioma surgery: such imaging helps surgeons provide the optimum extent of resection. None.

Besides the use of temozolomide and radiotherapy for patients with favourable methylation status, little progress has been made in the treatment of adult glioblastoma. Local control of the disease by complete removal increases time to progression and survival. We assessed the efficacy and safety of a locally applied adenovirus-mediated gene therapy with a prodrug converting enzyme (herpes-simplex-virus thymidine kinase; sitimagene ceradenovec) followed by intravenous ganciclovir in patients with newly diagnosed resectable glioblastoma. For this international, open-label, randomised, parallel group multicentre phase 3 clinical trial, we recruited patients from 38 sites in Europe. Patients were eligible if they were aged 18–70 years, had newly diagnosed supratentorial glioblastoma multiforme amenable to complete resection, and had a Karnofsky score of 70 or more at screening. We used a computer-generated randomisation sequence to allocate patients in a one-to-one ratio (with block sizes of four) to receive either surgical resection of the tumour and intraoperative perilesional injection of sitimagene ceradenovec (1 × 1012 viral particles) followed by ganciclovir (postoperatively, 5 mg/kg intravenously twice a day) in addition to standard care or resection and standard care alone. Temozolomide, not being standard in all participating countries at the time of the study, was allowed at the discretion of the treating physician. The primary endpoint was a composite of time to death or re-intervention, adjusted for temozolamide use, assessed by intention-to-treat (ITT) analysis. This trial is registered with EudraCT, number 2004-000464-28. Between Nov 3, 2005, and April 16, 2007, 250 patients were recruited and randomly allocated: 124 to the experimental group and 126 to the standard care group, of whom 119 and 117 patients, respectively, were included in the ITT analyses. Median time to death or re-intervention was longer in the experimental group (308 days, 95% CI 283–373) than in the control group (268 days, 210–313; hazard ratio [HR] 1·53, 95% CI 1·13–2·07; p=0·006). In a subgroup of patients with non-methylated MGMT, the HR was 1·72 (95% CI 1·15–2·56; p=0·008). However, there was no difference between groups in terms of overall survival (median 497 days, 95% CI 369–574 for the experimental group vs 452 days, 95% CI 437–558 for the control group; HR 1·18, 95% CI 0·86–1·61, p=0·31). More patients in the experimental group had one or more treatment-related adverse events those in the control group (88 [71%] vs 51 [43%]). The most common grade 3–4 adverse events were hemiparesis (eight in the experimental group vs three in the control group) and aphasia (six vs two). Our findings suggest that use of sitimagene ceradenovec and ganciclovir after resection can increase time to death or re-intervention in patients with newly diagnosed supratentorial glioblastoma multiforme, although the intervention did not improve overall survival. Locally delivered gene therapy for glioblastoma should be further developed, especially for patients who are unlikely to respond to standard chemotherapy. Ark Therapeutics Ltd.

Outcome of low-grade glioma (WHO grade II) is highly variable, reflecting molecular heterogeneity of the disease. We compared two different, single-modality treatment strategies of standard radiotherapy versus primary temozolomide chemotherapy in patients with low-grade glioma, and assessed progression-free survival outcomes and identified predictive molecular factors. For this randomised, open-label, phase 3 intergroup study (EORTC 22033-26033), undertaken in 78 clinical centres in 19 countries, we included patients aged 18 years or older who had a low-grade (WHO grade II) glioma (astrocytoma, oligoastrocytoma, or oligodendroglioma) with at least one high-risk feature (aged >40 years, progressive disease, tumour size >5 cm, tumour crossing the midline, or neurological symptoms), and without known HIV infection, chronic hepatitis B or C virus infection, or any condition that could interfere with oral drug administration. Eligible patients were randomly assigned (1:1) to receive either conformal radiotherapy (up to 50·4 Gy; 28 doses of 1·8 Gy once daily, 5 days per week for up to 6·5 weeks) or dose-dense oral temozolomide (75 mg/m2 once daily for 21 days, repeated every 28 days [one cycle], for a maximum of 12 cycles). Random treatment allocation was done online by a minimisation technique with prospective stratification by institution, 1p deletion (absent vs present vs undetermined), contrast enhancement (yes vs no), age (<40 vs ≥40 years), and WHO performance status (0 vs ≥1). Patients, treating physicians, and researchers were aware of the assigned intervention. A planned analysis was done after 216 progression events occurred. Our primary clinical endpoint was progression-free survival, analysed by intention-to-treat; secondary outcomes were overall survival, adverse events, neurocognitive function (will be reported separately), health-related quality of life and neurological function (reported separately), and correlative analyses of progression-free survival by molecular markers (1p/19q co-deletion, MGMT promoter methylation status, and IDH1/IDH2 mutations). This trial is closed to accrual but continuing for follow-up, and is registered at the European Trials Registry, EudraCT 2004-002714-11, and at ClinicalTrials.gov, NCT00182819. Between Sept 23, 2005, and March 26, 2010, 707 patients were registered for the study. Between Dec 6, 2005, and Dec 21, 2012, we randomly assigned 477 patients to receive either radiotherapy (n=240) or temozolomide chemotherapy (n=237). At a median follow-up of 48 months (IQR 31–56), median progression-free survival was 39 months (95% CI 35–44) in the temozolomide group and 46 months (40–56) in the radiotherapy group (unadjusted hazard ratio [HR] 1·16, 95% CI 0·9–1·5, p=0·22). Median overall survival has not been reached. Exploratory analyses in 318 molecularly-defined patients confirmed the significantly different prognosis for progression-free survival in the three recently defined molecular low-grade glioma subgroups (IDHmt, with or without 1p/19q co-deletion [IDHmt/codel], or IDH wild type [IDHwt]; p=0·013). Patients with IDHmt/non-codel tumours treated with radiotherapy had a longer progression-free survival than those treated with temozolomide (HR 1·86 [95% CI 1·21–2·87], log-rank p=0·0043), whereas there were no significant treatment-dependent differences in progression-free survival for patients with IDHmt/codel and IDHwt tumours. Grade 3–4 haematological adverse events occurred in 32 (14%) of 236 patients treated with temozolomide and in one (<1%) of 228 patients treated with radiotherapy, and grade 3–4 infections occurred in eight (3%) of 236 patients treated with temozolomide and in two (1%) of 228 patients treated with radiotherapy. Moderate to severe fatigue was recorded in eight (3%) patients in the radiotherapy group (grade 2) and 16 (7%) in the temozolomide group. 119 (25%) of all 477 patients had died at database lock. Four patients died due to treatment-related causes: two in the temozolomide group and two in the radiotherapy group. Overall, there was no significant difference in progression-free survival in patients with low-grade glioma when treated with either radiotherapy alone or temozolomide chemotherapy alone. Further data maturation is needed for overall survival analyses and evaluation of the full predictive effects of different molecular subtypes for future individualised treatment choices. Merck Sharpe & Dohme-Merck & Co, Canadian Cancer Society, Swiss Cancer League, UK National Institutes of Health, Australian National Health and Medical Research Council, US National Cancer Institute, European Organisation for Research and Treatment of Cancer Cancer Research Fund.

Bevacizumab is frequently used in the treatment of recurrent WHO grade II and III glioma, but without supporting evidence from randomised trials. Therefore, we assessed the use of bevacizumab in patients with first recurrence of grade II or III glioma who did not have 1p/19q co-deletion. The TAVAREC trial was a randomised, open-label phase 2 trial done at 32 centres across Europe in patients with locally diagnosed grade II or III glioma without 1p/19q co-deletion, with a first and contrast-enhancing recurrence after initial radiotherapy or chemotherapy, or both. Previous chemotherapy must have been stopped at least 6 months before enrolment and radiotherapy must have been stopped at least 3 months before enrolment. Random group assignment was done electronically through the European Organisation for Research and Treatment of Cancer web-based system, stratified by a minimisation procedure using institution, initial histology (WHO grade II vs III), WHO performance status (0 or 1 vs 2), and previous treatment (radiotherapy, chemotherapy, or both). Patients were assigned to receive either temozolomide (150–200 mg/m2, orally) monotherapy on days 1–5 every 4 weeks for a maximum of 12 cycles, or the same temozolomide regimen in combination with bevacizumab (10 mg/kg, intravenously) every 2 weeks until progression. The primary endpoint was overall survival at 12 months in the per-protocol population. Safety analyses were done in all patients who started their allocated treatment. The study is registered at EudraCT (2009–017422–39) and ClinicalTrials.gov (NCT01164189), and is complete. Between Feb 8, 2011, and July 31, 2015, 155 patients were enrolled and randomly assigned to receive either monotherapy (n=77) or combination therapy (n=78). Overall survival in the per-protocol population at 12 months was achieved by 44 (61% [80% CI 53–69]) of 72 patients in the temozolomide group and 38 (55% [47–69]) of 69 in the combination group. The most frequent toxicity was haematological: 17 (23%) of 75 patients in the monotherapy group and 25 (33%) of 76 in the combination group developed grade 3 or 4 haematological toxicity. Other than haematological toxicities, the most common adverse events were nervous system disorders (59 [79%] of 75 patients in the monotherapy group vs 65 [86%] of 76 in the combination group), fatigue (53 [70%] vs 61 [80%]), and nausea (39 [52%] vs 43 [56%]). Infections were more frequently reported in the combination group (29 [38%] of 76 patients) than in the monotherapy group (17 [23%] of 75). One treatment-related death was reported in the combination group (infection after intratumoral haemorrhage during a treatment-related grade 4 thrombocytopenia). We found no evidence of improved overall survival with bevacizumab and temozolomide combination treatment versus temozolomide monotherapy. The findings from this study provide no support for further phase 3 studies on the role of bevacizumab in this disease. Roche Pharmaceuticals.

Temozolomide chemotherapy versus radiotherapy in patients with a high-risk low-grade glioma has been shown to have no significant effect on progression-free survival. If these treatments have a different effect on health-related quality of life (HRQOL), it might affect the choice of therapy. We postulated that temozolomide compromises HRQOL and global cognitive functioning to a lesser extent than does radiotherapy. We did a prospective, phase 3, randomised controlled trial at 78 medical centres and large hospitals in 19 countries. We enrolled adult patients (aged ≥18 years) with histologically confirmed diffuse (WHO grade II) astrocytoma, oligodendroglioma, or mixed oligoastrocytoma, with a WHO performance status of 2 or lower, without previous chemotherapy or radiotherapy, who needed active treatment other than surgery. We randomly assigned eligible patients (1:1) using a minimisation technique, stratified by WHO performance status (0–1 vs 2), age (<40 years vs ≥40 years), presence of contrast enhancement on MRI, chromosome 1p status (deleted vs non-deleted vs indeterminate), and the treating medical centre, to receive either radiotherapy (50·4 Gy in 28 fractions of 1·8 Gy for 5 days per week up to 6·5 weeks) or temozolomide chemotherapy (75 mg/m2 daily, for 21 of 28 days [one cycle] for 12 cycles). The primary endpoint was progression-free survival (results published separately); here, we report the results for two key secondary endpoints: HRQOL (assessed using the European Organisation for Research and Treatment of Cancer’s [EORTC] QLQ-C30 [version 3] and the EORTC Brain Cancer Module [QLQ-BN20]) and global cognitive functioning (assessed using the Mini-Mental State Examination [MMSE]). We did analyses on the intention-to-treat population. This study is closed and is registered at EudraCT, number 2004-002714-11, and at ClinicalTrials.gov, number NCT00182819. Between Dec 6, 2005, and Dec 21, 2012, we randomly assigned 477 eligible patients to either radiotherapy (n=240) or temozolomide chemotherapy (n=237). The difference in HRQOL between the two treatment groups was not significant during the 36 months’ follow-up (mean between group difference [averaged over all timepoints] 0·06, 95% CI −4·64 to 4·75, p=0·98). At baseline, 32 (13%) of 239 patients who received radiotherapy and 32 (14%) of 236 patients who received temozolomide chemotherapy had impaired cognitive function, according to the MMSE scores. After randomisation, five (8%) of 63 patients who received radiotherapy and three (6%) of 54 patients who received temozolomide chemotherapy and who could be followed up for 36 months had impaired cognitive function, according to the MMSE scores. No significant difference was recorded between the groups for the change in MMSE scores during the 36 months of follow-up. The effect of temozolomide chemotherapy or radiotherapy on HRQOL or global cognitive functioning did not differ in patients with low-grade glioma. These results do not support the choice of temozolomide alone over radiotherapy alone in patients with high-risk low-grade glioma. Merck Sharp & Dohme-Merck & Co, National Cancer Institute, Swiss Cancer League, National Institute for Health Research, Cancer Research UK, Canadian Cancer Society Research Institute, National Health and Medical Research Council, European Organisation for Research and Treatment of Cancer Cancer Research Fund.

The CATNON trial investigated the benefit of the addition of concurrent or adjuvant temozolomide to radiotherapy in individuals with anaplastic astrocytoma. We report the long-term follow-up of the study focusing on the individuals with isocitrate dehydrogenase (IDH) mutated (IDHmt) tumours. This randomised, open-label, phase 3 study in 137 institutions across Australia, Europe, and North America included participants aged 18 years or older with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas and a WHO performance status of 0–2. Participants were randomly assigned (1:1:1:1) centrally using a minimisation technique to radiotherapy alone (59·4 Gy in 33 fractions), 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. Participants 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. The eighth amendment of the study protocol (June 27, 2011) incorporated analysis of IDH mutational status into the study. We report the intention-to-treat analysis and the exploratory analysis within the population of participants with astrocytoma with an IDH mutation. As the safety data have been published previously, no safety data are reported. This trial is registered with ClinicalTrials.gov, NCT00626990, and is completed. Between Dec 4, 2007, and Sept 11, 2015, 1407 participants were registered and 751 participants were randomly allocated, 444 of whom were diagnosed with an IDHmt tumour. After a median follow-up for overall survival of 10·9 years (IQR 9·5–12·7), in the intention-to-treat population, adjuvant temozolomide improved overall survival compared with no adjuvant temozolomide (hazard ratio [HR] 0·65 [95% CI 0·54–0·77]), but concurrent did not compared with no concurrent temozolomide (HR 0·91 [0·76–1·08]). In univariable analysis of the participants with an IDHmt tumour, concurrent temozolomide had no statistically significant effect on overall survival (median 9·7 years [8·2–12·5] vs 7·2 years [6·2–9·4]; HR 0·81 [0·63–1·04]), but median overall survival was 12·5 years (95% CI 9·4–15·0) with adjuvant temozolomide compared with 6·0 years (5·1–7·2) with no adjuvant temozolomide (HR 0·54 [0·42–0·69]). No benefit of temozolomide, neither concurrent nor adjuvant, was observed in participants with IDH wild-type tumours. Methylation-based subtyping and several DNA alterations (eg, amplification of PDGFRA and CDK4, homozygous deletion of CDKN2A, and total copy number variation) were associated with worse outcome, none of which was predictive for benefit to temozolomide. Long-term follow-up confirms that radiotherapy followed by 12 cycles of adjuvant temozolomide without concurrent temozolomide during radiotherapy improves survival for individuals with aggressive IDHmt astrocytoma. MSD.

Background Multifocal manifestation of high-grade glioma is a rare disease with very unfavourable prognosis. The pathogenesis of multifocal glioma and pathophysiological differences to unifocal glioma are not fully understood. The optimal treatment of patients suffering from multifocal high-grade glioma is not defined in the current guidelines, therefore individual case series may be helpful as guidance for clinical decision-making. Methods Patients with multifocal high-grade glioma treated with conventionally fractionated radiation therapy (RT) in our institution with or without concomitant chemotherapy between April 2011 and April 2019 were retrospectively analysed. Multifocality was neuroradiologically assessed and defined as at least two independent contrast-enhancing foci in the MRI T1 contrast-enhanced sequence. IDH mutational status and MGMT methylation status were assessed from histopathology records. GTV, PTV as well as the V30Gy, V45Gy and D2% volumes of the brain were analysed. Overall and progression-free survival were calculated from the diagnosis until death and from start of radiation therapy until diagnosis of progression of disease in MRI for all patients. Results 20 multifocal glioma cases (18 IDH wild-type glioblastoma cases, one diffuse astrocytic glioma, IDH wild-type case with molecular features of glioblastoma and one anaplastic astrocytoma, IDH wild-type case) were included into the analysis. Resection was performed in two cases and stereotactic biopsy only in 18 cases before the start of radiation therapy. At the start of radiation therapy patients were 61 years old in median (range 42–84 years). Histopathological examination showed IDH wild-type in all cases and MGMT promotor methylation in 11 cases (55%). Prescription schedules were 60 Gy (2 Gy × 30), 59.4 Gy (1.8 Gy × 33), 55 Gy (2.2 Gy × 25) and 50 Gy (2.5 Gy × 20) in 15, three, one and one cases, respectively. Concomitant temozolomide chemotherapy was applied in 16 cases, combined temozolomide/lomustine chemotherapy was applied in one case and concomitant bevacizumab therapy in one case. Median number of GTVs was three. Median volume of the sum of the GTVs was 26 cm 3 . Median volume of the PTV was 425.7 cm 3 and median PTV to brain ratio 32.8 percent. Median D2% of the brain was 61.5 Gy (range 51.2–62.7) and median V30Gy and V45 of the brain were 59.9 percent (range 33–79.7) and 40.7 percent (range 14.9–64.1), respectively. Median survival was eight months (95% KI 3.6–12.4 months) and median progression free survival after initiation of RT five months (95% CI 2.8–7.2 months). Grade 2 toxicities were detected in eight cases and grade 3 toxicities in four cases consisting of increasing edema in three cases and one new-onset seizure. One grade 4 toxicity was detected, which was febrile neutropenia related to concomitant chemotherapy. Conclusion Conventionally fractionated RT with concomitant chemotherapy could safely be applied in multifocal high-grade glioma in this case series despite large irradiation treatment fields.

To evaluate diffusion tensor imaging (DTI)-based functional neuronavigation in surgery of cerebral gliomas with pyramidal tract (PT) involvement with respect to both perioperative assessment and follow-up outcome. A prospective, randomized controlled study was conducted between 2001 and 2005. A consecutive series of 238 eligible patients with initial imaging diagnosis of cerebral gliomas involving PTs were randomized into study (n = 118) and control (n = 120) groups. The study cases underwent DTI and three-dimensional magnetic resonance imaging scans. The maps of fractional anisotropy were calculated for PT mapping. Both three-dimensional magnetic resonance imaging data sets and fractional anisotropy maps were integrated by rigid registration, after which the tumor and adjacent PT were segmented and reconstructed for presurgical planning and intraoperative guidance. The control cases were operated on using routine neuronavigation. There was a trend for high-grade gliomas (HGGs) in the study group to be more likely to achieve gross total resection (74.4 versus 33.3%, P < 0.001). There was no significant difference of low-grade gliomas resection between the two groups. Postoperative motor deterioration occurred in 32.8% of control cases, whereas it occurred in only 15.3% of the study cases (P < 0.001). The 6-month Karnofsky Performance Scale score of study cases was significantly higher than that of control cases (86 +/- 20 versus 74 +/- 28 overall, P < 0.001; 93 +/- 10 versus 86 +/- 17 for low-grade gliomas, P = 0.013; and 77 +/- 27 versus 53 +/- 32 for HGGs, P = 0.001). For 81 HGGs, the median survival of study cases was 21.2 months (95% confidence interval, 14.1-28.3 mo) compared with 14.0 months (95% confidence interval, 10.2-17.8 mo) of control cases (P = 0.048). The estimated hazard ratio for the effect of DTI-based functional neuronavigation was 0.570, representing a 43.0% reduction in the risk of death. DTI-based functional neuronavigation contributes to maximal safe resection of cerebral gliomas with PT involvement, thereby decreasing postoperative motor deficits for both HGGs and low-grade gliomas while increasing high-quality survival for HGGs.

Single-agent sunitinib, an oral small molecule inhibitor of multiple tyrosine kinase receptors, was evaluated for treatment of patients with recurrent glioblastoma (GB) and anaplastic astrocytoma (AA). Fourteen AA and 16 GB patients, all previously treated with surgery, radiotherapy, and temozolomide, were enrolled in a prospective phase II study at either first or second relapse. Patients were treated with daily sunitinib for 4 consecutive weeks, followed by a 2-week break. For AA patients, the most common side effects were fatigue (86 %), diarrhea (43 %), hand-foot syndrome (36 %), neutropenia (36 %), thrombocytopenia (36 %), and nausea (29 %). In the GB cohort, the most common side effects were fatigue (56 %), diarrhea (44 %), neutropenia (31 %), and thrombocytopenia (25 %). Six of 14 (43 %) AA and 5 of 16 (31 %) GB patients experienced grade 3 or greater toxicities. Five patients discontinued study due to drug toxicities. There were no partial or complete responses in either cohort; 8/14 (57 %) AA and 5/16 (31 %) GB patients had stable disease at the first planned assessment. Progression-free survival at 6 months was 21.5 % (AA) and 16.7 % (GB). Median overall survival was 12.1 months (AA) and 12.6 months (GB). These results are comparable to those reported in the literature in patients treated with standard cytotoxic therapies. This is the largest reported trial of sunitinib in recurrent malignant astrocytic gliomas to date, as well as contains the largest AA cohort. Nonetheless, sunitinib did not demonstrate significant anti-glioma activity in patients with recurrent malignant astrocytic gliomas.