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Funder: Boehringer Ingelheim; doi: http://dx.doi.org/10.13039/100001003, BACKGROUND: Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults. Amplification or overexpression of the epidermal growth factor receptor gene, part of the ErbB family, occur in approximately 40% and 60% of patients with GBM, respectively. We present data from a dose-finding study of the ErbB inhibitor afatinib in combination with radiotherapy (RT), with or without temozolomide (TMZ), in patients with GBM. METHODS: This was a phase I, open-label, 3 + 3 dose-escalation trial in patients with newly-diagnosed, histologically-confirmed grade 4 malignant glioma and proven O6-methylguanine-DNA methyltransferase gene promoter methylation status. The primary endpoint was the maximum tolerated dose (MTD) of continuous daily afatinib when given in combination with RT, with (regimen M) or without (regimen U) concomitant TMZ treatment. RESULTS: Fifty-five patients were enrolled; 36 received ≥ 1 dose of trial medication (regimen M, n = 20, regimen U, n = 16). Afatinib was discontinued by all patients during the study. Reasons for afatinib discontinuation (regimen M/U) included disease progression (45%/50%), dose-limiting toxicity (10%/0%), and other adverse events (AEs; 35%/38%). The most frequently reported AEs with either regimen were diarrhea and rash, with no new safety signals identified. The MTD was determined as afatinib 30 mg in combination with daily TMZ and RT, and afatinib 40 mg in combination with RT alone. CONCLUSIONS: This study identified the MTD for afatinib in combination with RT, with and without TMZ, in patients with GBM. Further studies of afatinib in patients with GBM are warranted and should be based on appropriate biomarker-based preselection. TRIAL REGISTRATION: NCT00977431 (first posted September 15, 2009).

Cancer remains a leading cause of death in children and adolescents in the developed world. Despite advances in oncological management, rates of primary treatment failure remain significant. Radiation of recurrent or metastatic disease improves survival in adults but there is little data to support clinical decision making in the paediatric/teenage and young adult population.We present a retrospective case series of 14 patients treated with stereotactic ablative body radiotherapy or stereotactic radiosurgery at The Royal Marsden Hospital from September 2011 to December 2015. Eligible patients were aged25 years, with Lansky/Karnofsky performance status ≥60 with confirmed relapsed or metastatic tumour in fewer than three sites. Follow-up was in accordance with standard clinical care and included regular outpatient review and radiological surveillance. Local control, progression-free survival and overall survival are presented.Data for 14 patients with 18 treated lesions were included. The median patient age was 15 years (range 5-20 years). Nine patients were treated for local recurrence and five for metastatic lesions. All patients had already undergone multiple previous treatments. Eleven patients had undergone previous radiotherapy. The median interval between the completion of initial radiotherapy and reirradiation was 29.0 months (range 0.2-49.5 months). The median follow-up was 3.4 years (range 0.28-6.4 years). The 1-year local control rate was 78.6% and the 2-year local control rate was 57.1%. Overall median survival was 58.4 months (95% confidence interval 33.8-82.9 months). Cumulative biologically effective doses (BED) over 200 Gy were associated with late toxicity (P = 0.04).Radical doses of short-course hypofractionated radiotherapy can achieve excellent local control and may contribute to the prolongation of overall survival. There is a need for prospective trials exploring the use of ablative radiotherapy in metastatic disease in paediatric/teenage and young adult patients in order to establish safe and effective treatment schedules.

Geometric uncertainties in radiotherapy are conventionally addressed by defining a safety margin around the radiotherapy target. Misappropriation of such margins could result in disease recurrence from geometric miss or unnecessary irradiation of normal tissue. Numerous quantitative organ motion studies in adults have been published, but the first paediatric-specific studies were only published in recent years. In the very near future, intensity-modulated proton beam therapy and magnetic resonance-guided radiotherapy will be clinically implemented in the UK. Such techniques offer the ability to deliver radiotherapy to the pinnacle of precision and accuracy, if geometric uncertainty relating to internal organ motion and deformation can be optimally managed. The optimal margin to account for internal organ motion in children remains largely undefined. Continuing efforts to characterise motion in children and young people is necessary to optimally define safety margins and to realise the full potential of intensity-modulated radiotherapy, magnetic resonance-guided radiotherapy and intensity-modulated proton beam therapy. This overview offers a timely review of published reports on paediatric organ motion, in anticipation of the increasing application of advanced radiotherapy techniques in paediatric radiotherapy.

Background Glioblastoma (GBM) is the most common and most lethal primary brain tumor in adults. Clinical trials in older patients with GBM have explored the use of single and multimodality treatment regimens with modest survival benefits; however, trial criteria are commonly based on chronological age and do not reflect the heterogeneity of this cohort. Geriatric assessment (GA) techniques predict survival and treatment tolerance in other tumor sites and thus may objectively guide the decision-making process, but data are lacking in the neuro-oncology cohort. Methods We performed a prospective, multicenter feasibility study involving patients age 65 years or older with newly diagnosed GBM. A modified GA was undertaken in the outpatient setting prior to starting treatment. Feasibility was determined primarily by recruitment rate, alongside data completeness, impact on clinic time, and acceptability to patients and staff. Factors associated with survival were explored using Cox regression models. Results Fifty patients were recruited within a prespecified time period with a recruitment rate of 82% (target 80%). Data completeness was greater than 80% in all except one assessment. Median overall survival was 9.5 months (95% confidence interval [CI] 5.0-14.0 months). Among the GA screening factors analyzed, a baseline impaired Montreal Cognitive Assessment (hazard ratio [HR] = 2.7, 95% CI 1.128-6.530) and impairment in instrumental activities of daily living (HR = 2.9 95% CI 0.983-8.541) were associated with poorer survival. Conclusion In the first study of this kind among elderly GBM patients, we have shown that undertaking a neurologically focused GA screen is feasible and may provide useful prognostic information.

Purpose: The HERBY trial evaluated the benefit of the addition of the antiangiogenic agent Bevacizumab (BEV) to radiotherapy/temozolomide (RT/TMZ) in pediatric patients with newly diagnosed non-brainstem high-grade glioma (HGG). The work presented here aims to correlate imaging characteristics and outcome measures with pathologic and molecular data. Experimental Design: Radiological, pathologic, and molecular data were correlated with trial clinical information to retrospectively re-evaluate event-free survival (EFS) and overall survival (OS). Results: One-hundred thirteen patients were randomized to the RT/TMZ arm (n = 54) or the RT/TMZ+BEV (BEV arm; n = 59). The tumor arose in the cerebral hemispheres in 68 patients (Cerebral group) and a midline location in 45 cases (Midline group). Pathologic diagnosis was available in all cases and molecular data in 86 of 113. H3 K27M histone mutations were present in 23 of 32 Midline cases and H3 G34R/V mutations in 7 of 54 Cerebral cases. Total/near-total resection occurred in 44 of 68 (65%) Cerebral cases but in only 5 of 45 (11%) Midline cases (P < 0.05). Leptomeningeal metastases (27 cases, 13 with subependymal spread) at relapse were more frequent in Midline (17/45) than in Cerebral tumors (10/68, P < 0.05). Mean OS (14.1 months) and EFS (9.0 months) in Midline tumors were significantly lower than mean OS (20.7 months) and EFS (14.9 months) in Cerebral tumors (P < 0.05). Pseudoprogression occurred in 8 of 111 (6.2%) cases. Conclusions: This study has shown that the poor outcome of midline tumors (compared with cerebral) may be related to (1) lesser surgical resection, (2) H3 K27M histone mutations, and (3) higher leptomeningeal dissemination.

Purpose Bevacizumab (BEV) is approved in more than 60 countries for use in adults with recurrent glioblastoma. We evaluated the addition of BEV to radiotherapy plus temozolomide (RT+TMZ) in pediatric patients with newly diagnosed high-grade glioma (HGG). Methods The randomized, parallel group, multicenter, open-label HERBY trial ( ClinicalTrials.gov identifier: NCT01390948) enrolled patients age ≥ 3 years to ≤ 18 years with localized, centrally neuropathology-confirmed, nonbrainstem HGG. Eligible patients were randomly assigned to receive RT + TMZ (RT: 1.8 Gy, 5 days per week, and TMZ: 75 mg/m2 per day for 6 weeks; 4-week treatment break; then up to 12 × 28-day cycles of TMZ [cycle 1: 150 mg/m2 per day, days 1 to 5; cycles 2 to 12: 200 mg/m2 per day, days 1 to 5]) with or without BEV (10 mg/kg every 2 weeks). The primary end point was event-free survival (EFS) as assessed by a central radiology review committee that was blinded to treatment. We report findings of EFS at 12 months after the enrollment of the last patient. Results One hundred twenty-one patients were enrolled (RT+TMZ [n = 59]; BEV plus RT+TMZ [n = 62]). Central radiology review committee–assessed median EFS did not differ significantly between treatment groups (RT+TMZ, 11.8 months; 95% CI, 7.9 to 16.4 months; BEV plus RT+TMZ, 8.2 months; 95% CI, 7.8 to 12.7 months; hazard ratio, 1.44; P = .13 [stratified log-rank test]). In the overall survival analysis, the addition of BEV did not reduce the risk of death (hazard ratio, 1.23; 95% CI, 0.72 to 2.09). More patients in the BEV plus RT+TMZ group versus the RT+TMZ group experienced one or more serious adverse events (n = 35 [58%] v n = 27 [48%]), and more patients who received BEV discontinued study treatment as a result of adverse events (n = 13 [22%] v n = 3 [5%]). Conclusion Adding BEV to RT+TMZ did not improve EFS in pediatric patients with newly diagnosed HGG. Our findings were not comparable to those of previous adult trials, which highlights the importance of performing pediatric-specific studies.

Immunotherapeutics have revolutionized the management of solid malignancies over the last few years. Nevertheless, despite relative successes of checkpoint inhibitors in numerous solid tumour types, success in tumours of the central nervous system (CNS) has been lacking. There are several possible reasons for the relative lack of success of immunotherapeutics in this setting, including the immune microenvironment of glioblastoma, lymphocyte tracking through the blood-brain barrier (BBB) into the central nervous system and impairment of drug delivery into the CNS through the BBB. This review utilizes the cancer-immunity cycle as a conceptual framework through which the specific challenges associated with the development of immunotherapeutics for CNS malignancies can be viewed.

INTRODUCTION The prognostic impact of tumour marker (TM) decline rate has been demonstrated for extracranial poor prognostic non-seminomatous/germinomatous germ cell tumours (NGGCT). The current series aimed to assess if this finding can be applied to intracranial primaries. METHODS Patients were retrieved from the SIOP-CNS-GCT-96 database. They were selected if they had i/assessable values of serum alpha-fetoprotein (AFP) and/or human chorionic gonadotropin (HCG) before and 18 to 28 days after the first course of chemotherapy and ii/ available data for outcome. Decline rate was calculated using a logarithmic transformation and expressed as time to normalization (TTN) as published by Fizazi (JCO 2004). TTN≤ 9 weeks for AFP and ≤ 6 weeks for HCG were considered as favourable decline rate. Prognostic impact of TTN on outcomes was assessed using the log-rank test. RESULTS Out of 149 patients with NGGCT, 59 were evaluable for both HCG and AFP TTN of whom 44 (74%) had a favourable decline rate. After a median follow-up of 88 months (2–251), 20 relapses and 15 deaths occurred. The 5-year PFS rates were 72% and 60% in patients who had a favourable and an unfavourable TTN, respectively (p=0.15). The 5-year OS rates were 77 % and 69%, respectively (p=0.66). Separate analysis of TTN based only on AFP or only on HCG gave similar results. CONCLUSION Despite the use of a methodology similar to that used in extracranial NGGCT, no significant impact of serum TM decline on prognosis was observed, but insufficient statistical power cannot be ruled out.

Background Following promising results to increase survival and reduce treatment burden in intracranial non-germinomatous germ cell tumors (NGGCTs), we conducted a European study using dose-intense chemotherapy followed by risk-adapted radiotherapy. Methods All patients received 4 courses of cisplatin/etoposide/ifosfamide. Non-metastatic patients then received focal radiotherapy only (54 Gy); metastatic patients received 30 Gy craniospinal radiotherapy with 24 Gy boost to primary tumor and macroscopic metastatic sites. Results Patients with localized malignant NGGCT (n = 116) demonstrated 5-year progression-free survival (PFS) and overall survival (OS) of 0.72 ± 0.04 and 0.82 ± 0.04, respectively. Primary tumor sites were: 67 pineal, 35 suprasellar, 5 bifocal, 9 others. One patient died postsurgery in clinical remission; 3 patients progressed during treatment and 27 (23%) relapsed afterward. Fourteen were local, 6 combined, and 7 distant relapses (outside radiation field). Seventeen of the 27 relapsed patients died of disease. Patients with metastatic disease (n = 33) demonstrated 5-year PFS and OS of 0.68 ± 0.09 and 0.75 ± 0.08, respectively; 1 patient died following progression on treatment and 9 (27%) relapsed afterward (5 local, 1 combined, 3 distant). Only one metastatic patient with recurrence was salvaged. Multivariate analysis identified diagnostic alpha-fetoprotein level (serum and/or cerebrospinal fluid level >1000 ng/mL, 19/149 patients, of whom 11 relapsed; P < 0.0003) and residual disease following treatment, including after second-look surgery (n = 52/145 evaluable patients, 26 relapsed; P = 0.0002) as significant prognostic indicators in this cohort. Conclusion In localized malignant NGGCT, craniospinal radiotherapy could be avoided without increased relapses outside the radiotherapy field. Chemotherapy and craniospinal radiotherapy remain the gold standard for metastatic disease.

We aimed to retrospectively assess treatments/outcomes, including the value of high-dose-chemotherapy and autologous-stem-cell-rescue (HDC+AuSCR) and re-irradiation, in a large, European patient-cohort with relapsed intracranial germ-cell-tumors (GCTs) receiving uniform first-line therapy, including radiotherapy as standard-of-care. Fifty-eight UK/German patients (48 male/10 female) with relapsed intracranial-GCTs [13 germinoma/45 non-germinomatous GCT(NGGCT)] treated 1996-2010 as per the SIOP-CNS-GCT-96 protocol were evaluated. For germinoma, six patients relapsed with germinoma and five with NGGCT (one palliative, one teratoma patient excluded). Five-year overall-survival (OS) for the whole-group (n=11) was 55%. Four of six germinoma relapses and two of five relapsing with NGGCT were salvaged; patients were salvaged with either standard-dose-chemotherapy (SDC) and re-irradiation or HDC+AuSCR with/without re-irradiation. Of 45 relapsed NGGCT patients, 13 were excluded (3 non-protocol adherence, 5 teratoma, 5 palliation). Five-year OS for the remaining 32 relapsed malignant NGGCT patients treated with curative intent was 9%(95%CI: 2-26%). By treatment received, 5-year OS for the 10 patients receiving SDC and 22 patients treated with intention for HDC+AuSCR was 0%(0-0%) and 14%(3-36%), respectively. The three relapsed NGGCT survivors had raised HCG markers alone; two received additional irradiation. Patients with relapsed germinoma had better 5-year OS than those with relapsed NGGCT (55%vs.9%; p=0.007). Patients with relapsed germinoma were salvaged both with SDC and re-irradiation or HDC+AuSCR with/without re-irradiation; which both represent valid treatment options. Outcomes for malignant relapse following initial diagnosis of NGGCT were exceptionally poor; the few survivors received thiotepa-based HDC+AuSCR, which is a treatment option at first malignant relapse for such patients, with further surgery/irradiation where feasible. This article is protected by copyright. All rights reserved.

Pediatric high-grade gliomas (pHGG) constitute 8% to 12% of primary brain tumors in childhood. The most widely utilized treatment encompasses surgical resection followed by focal radiotherapy and temozolomide. However, experiences over past decades have not demonstrated improved outcomes. pHGG have been classified into different molecular subgroups defined by mutations in histone 3, IDH gene, MAPK pathway, and others, thereby providing a rationale for various targeted therapies. Additionally, immunotherapy and drug repurposing have also become attractive adjunctive treatments. This review focuses on past, present, and emerging treatments for pHGG integrating molecular research with the mainstream pediatric drug development in Europe and the United States to sketch a way forward in the development of novel therapeutic approaches. The implementation of randomized clinical trials with adaptive designs, underpinned by a robust biological rationale, and harnessing collaboration between the pharmaceutical industry, academia, regulators and patients/parents organizations will be essential to improve the outcomes for these children.

Background In the current study we used contrast-enhanced T1 subtraction maps to test whether early changes in enhancing tumor volume are prognostic for overall survival (OS) in newly diagnosed glioblastoma (GBM) patients treated with chemoradiation with or without bevacizumab (BV). Methods Seven hundred ninety-eight patients (404 BV and 394 placebo) with newly diagnosed GBM in the AVAglio trial (NCT00943826) had baseline MRI scans available, while 337 BV-treated and 269 placebo-treated patients had >4 MRI scans for response evaluation. The volume of contrast-enhancing tumor was quantified and used for subsequent analyses. Results A decrease in tumor volume during chemoradiation was associated with a longer OS in the placebo group (hazard ratio [HR] = 1.578, P < 0.0001) but not BV-treated group (HR = 1.135, P = 0.4889). Results showed a higher OS in patients on the placebo arm with a sustained decrease in tumor volume using a post-chemoradiation baseline (HR = 1.692, P = 0.0005), and a trend toward longer OS was seen in BV-treated patients (HR = 1.264, P = 0.0724). Multivariable Cox regression confirmed that sustained response or stable disease was prognostic for OS (HR = 0.7509, P = 0.0127) when accounting for age (P = 0.0002), KPS (P = 0.1516), postsurgical tumor volume (P < 0.0001), O6-methylguanine-DNA methyltransferase status (P < 0.0001), and treatment type (P = 0.7637) using the post-chemoradiation baseline. Conclusions The post-chemoradiation timepoint is a better baseline for evaluating efficacy in newly diagnosed GBM. Early progression during the maintenance phase is consequential in predicting OS, supporting the use of progression-free survival rates as a meaningful surrogate for GBM.

Background and purpose: To evaluate non-coplanar volumetric modulated arc radiotherapy (VMAT) trajectories for organ at risk (OAR) sparing in primary brain tumour radiotherapy. Materials and methods: Fifteen patients were planned using coplanar VMAT and compared against non-coplanar VMAT plans for three trajectory optimization techniques. A geometric heuristic technique (GH) combined beam scoring and Dijkstra's algorithm to minimize the importance-weighted sum of OAR volumes irradiated. Fluence optimization was used to perform a local search around coplanar and GH trajectories, producing fluence-based local search (FBLS) and FBLS+GH trajectories respectively. Results: GH, FBLS, and FBLS+GH trajectories reduced doses to the contralateral globe, optic nerve, hippocampus, temporal lobe, and cochlea. However, FBLS increased dose to the ipsilateral lens, optic nerve and globe. Compared to GH, FBLS+GH increased dose to the ipsilateral temporal lobe and hippocampus, contralateral optics, and the brainstem and body. GH and FBLS+GH trajectories reduced bilateral hippocampi normal tissue complication probability (p = 0.028 and p = 0.043, respectively). All techniques reduced PTV conformity; GH and FBLS+GH trajectories reduced homogeneity but less so for FBLS+GH. Conclusions: The geometric heuristic technique best spared OARs and reduced normal tissue complication probability, however incorporating fluence information into non-coplanar trajectory optimization maintained PTV homogeneity.

Evaluation of glioblastoma disease status may be complicated by treatment-induced changes and discordance between enhancing and nonenhancing MRI. Exploratory analyses are presented (prospectively assessed pseudoprogression and therapy-related tumor pattern changes) from the AVAglio trial (bevacizumab or placebo plus radiotherapy/temozolomide for newly diagnosed glioblastoma).MRI was done every 8 weeks (beginning 4 wk after chemoradiotherapy) using prespecified and standardized T1 and T2 protocols. Progressive disease (PD) at 10 weeks was reconfirmed at 18 weeks to distinguish pseudoprogression. Progression-free survival (PFS), excluding cases of confirmed pseudoprogression, was assessed (post-hoc/exploratory). Tumor progression patterns were determined at each disease assessment/PD (prespecified/exploratory).Of patients with PD in the bevacizumab and placebo arms, 143/354 (40.4%) and 155/387 (40.1%), respectively, had PD due to contrast-enhancing lesions, and 51/354 (14.4%) and 53/387 (13.7%) had PD due to nonenhancing lesions. Of all patients in the bevacizumab arm (n = 458), 2.2% had confirmed pseudoprogression versus 9.3% in the placebo arm (n = 463). Baseline characteristics did not differ between patients with/without pseudoprogression (including for MGMT status). Excluding confirmed pseudoprogression, PFS (hazard ratio: 0.65, 95% CI: 0.56-0.75; P.0001, bevacizumab vs placebo) was comparable to the intent-to-treat population. At PD, most patients had the same tumor focus (local/multifocal,84%) and infiltrative profile (88%) as at baseline; no shift to a diffuse or multifocal phenotype was observed.Pseudoprogression complicated progression assessment in a small but relevant number of patients but had negligible impact on PFS. Bevacizumab did not appear to adversely impact tumor progression patterns.

Background and purpose Magnetic resonance (MR) and computed tomography (CT) images are degraded in the presence of metallic implants. We investigate whether SEMAC (Slice Encoding for Metal Artifact Correction) MR is advantageous for radiotherapy (RT) planning. Methods Conventional and SEMAC MR protocols were compared (1.5 T). A spine fixation device suspended in gelatine, two patients with spine fixation devices and six patients with bilateral hip replacements were scanned with both conventional and SEMAC protocols. In spine patients the visibility of the spinal canal and spinal cord was assessed; in prostate patients, the visibility of the prostate, pelvic structures and the pelvic girdle. Results The signal loss volume surrounding the spine fixation device was reduced by approximately 20% when the SEMAC protocol was employed, and registration errors were reduced. For spine patients, the spinal canal was completely visible only using the SEMAC protocol. In hip replacement patients, metal artifacts were local; the signal loss extended to the internal surface of the acetabulum in eight implants with conventional protocols, but only in four using SEMAC. Conclusions SEMAC MR contributes towards correct co-registration of MR and CT images for RT planning, and is particularly relevant when the TV or OARs are close to implants.

Background We assessed the efficacy and safety of bevacizumab (BEV) through multiple lines in patients with recurrent glioblastoma who had progressed after first-line treatment with radiotherapy, temozolomide, and BEV. Patients and Methods TAMIGA (NCT01860638) was a phase II, randomized, double-blind, placebo-controlled, multicenter trial in adult patients with glioblastoma. Following surgery, patients with newly diagnosed glioblastoma received first-line treatment consisting of radiotherapy plus temozolomide and BEV, followed by six cycles of temozolomide and BEV, then BEV monotherapy until disease progression (PD1). Randomization occurred at PD1 (second line), and patients received lomustine (CCNU) plus BEV (CCNU + BEV) or CCNU plus placebo (CCNU + placebo) until further disease progression (PD2). At PD2 (third line), patients continued BEV or placebo with chemotherapy (investigator's choice). The primary endpoint was survival from randomization. Secondary endpoints were progression-free survival in the second and third lines (PFS2 and PFS3) and safety. Results Of the 296 patients enrolled, 123 were randomized at PD1 (CCNU + BEV, n = 61; CCNU + placebo, n = 62). The study was terminated prematurely because of the high drop-out rate during first-line treatment, implying underpowered inferential testing. The proportion of patients receiving corticosteroids at randomization was similar (BEV 33%, placebo 31%). For the CCNU + BEV and CCNU + placebo groups, respectively, median survival from randomization was 6.4 versus 5.5 months (stratified hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.69–1.59), median PFS2 was 2.3 versus 1.8 months (stratified HR, 0.70; 95% CI, 0.48–1.00), median PFS3 was 2.0 versus 2.2 months (stratified HR, 0.70; 95% CI, 0.37–1.33), and median time from randomization to a deterioration in health-related quality of life was 1.4 versus 1.3 months (stratified HR, 0.76; 95% CI, 0.52–1.12). The incidence of treatment-related grade 3 to 4 adverse events was 19% (CCNU + BEV) versus 15% (CCNU + placebo). Conclusion There was no survival benefit and no detriment observed with continuing BEV through multiple lines in patients with recurrent glioblastoma. Implications for Practice Previous research suggested that there may be value in continuing bevacizumab (BEV) beyond progression through multiple lines of therapy. No survival benefit was observed with the use of BEV through multiple lines in patients with glioblastoma who had progressed after first-line treatment (radiotherapy + temozolomide + BEV). No new safety concerns arose from the use of BEV through multiple lines of therapy.

BACKGROUND. Molecular alterations: point mutations, amplifications and deletions give cells the ability to bypass therapeutic approaches. Molecular profiling facilitates access to personalised strategies to treat patients harbouring such alterations. METHODS. A Next Generation Sequencing (NGS) panel comprising 78 genes (version1) or 92 genes (version2) has been piloted in the UK since March 2016, using formalin-fixed paraffin embedded tissue of children and young adults with solid tumours, including central nervous system (CNS) tumours. RESULTS. Of 156 cases profiled, patients with primary CNS tumours constituted the largest subset (59 patients; 38%). Main diagnoses included high grade astrocytoma (22 patients; 37%), ependymoma (8 patients; 14%) and medulloblastoma (8 patients 14%). In 66% of sequenced samples the panel detected at least one genetic alteration and a total of 54 distinct genetic alterations were uncovered; most frequently in TP53 (16; 14%), H3F3A (8; 7%) and ATRX (7; 6%). In 2 cases (3%), identification of therapeutic targets (BRAF mutations) led to treatment with a combination of BRAF and MEK inhibitors via compassionate access programmes in young adults who had exhausted standard treatment options and were beyond the age eligibility cut-off for enrolment in the ongoing paediatric BRAF/MEK inhibitor studies. CONCLUSIONS. Molecular profiling is increasingly being integrated into standard of care for patients with CNS tumours. However, the finding of truly actionable mutations with available targeted therapies remains limited in clinical practice. More efficient approaches to implement personalised medicine strategies for CNS tumour patients are still needed as is currently illustrated by initiatives such as ESMART (NCT02813135).

INTRODUCTION: The purpose of this study was to evaluate the implementation of the radiological aspects of HERBY trial, and the practicality and feasibility of including multimodal imaging (MMI) to the response assessment in neuro-oncology (RANO) criteria in a pediatric high grade glioma cohort. METHODS: We analyzed MMI compliance rates and scan quality for participating sites, adjudication rates and reading times for the central review process, the influence of the different RANO criteria in the final response, and the benefit of incorporating MMI to the decision process. RESULTS: MMI compliance rates were: diffusion 82%, perfusion 60% and spectroscopy 48%. Of the received data 2% of the structural scans and 23% of the MMI scans were not of sufficient quality. Adjudication rates due to differing neuroradiologist responses were 50%, which resulted in a total average reading time per patient of ~3 hours. Increase in diameters of the target enhancing lesion was a reason for progression in 8/86 cases (9.3%) but never the only radiological or clinical reason. EFS was predicted earlier in 5/86 (5.8%) patients by MMI (diffusion, n=4; perfusion, n=1). CONCLUSION: The addition of MMI to the response criteria was difficult to assess due to low return rates and data quality, but MMI helped to determine progression prediction than structural imaging alone. Increase of target lesion diameter measurement, which accounts for a large proportion of reading time, was never the only reason to stablish disease progression.

BACKGROUND: Bithalamic gliomas (BG) are rare brain tumours typically with a dismal prognosis, irrespective of histological grading. Limited information is available on survival outcomes for children and adolescents with BG. METHODS: Review of patients aged ≤18 years with clinico-radiological diagnosis of BG between 1995-2017 at our institution. Clinical, radiological, histological and outcome data were collected. Log-rank test was used for survival analyses. RESULTS: Sixteen eligible patients were identified (male-female ratio 1:1). Median age was 9.1 years (range, 0.9-17.9). Twelve (75%) patients had hydrocephalus at initial presentation. Fourteen (88%) underwent surgery (debulking: 1; biopsy: 13). Histology was consistent with low grade glioma (LGG; n=6), high grade glioma (HGG; n=6) or inconclusive (n=2). Methylation profiling was available in 5 cases: K27M-mutant (n=2) and histone 3 wild-type (n=3). One patient died prior to initiation of treatment from intratumoural haemorrhage. Thirteen (81%) patients received radiotherapy: alone (n=2), combined with temozolomide (n=8) or followed by other chemotherapy regimens (n=3). Two patients who were not irradiated received vincristine/carboplatin. Median progression-free (PFS) and overall survival (OS) for the whole cohort were 8.3 months (95%CI, 2.3-14.3) and 13.8 months (95%CI, 10.5-17.1), respectively. There was no difference in median PFS or OS between patients diagnosed as LGG or HGG (p=0.769 and p=0.512, respectively). CONCLUSIONS: Our data is consistent with prior reports showing poor survival of patients with BG, regardless of histological grade. Novel approaches based on the underlying biology of these tumours are desperately needed for this subset of patients.

CONTEXT: CNS Germinoma occur predominently in suprasellar and/or pineal sites. Combination chemo-radiotherapy is highly effective, but pituitary failures (PF) are recognised complications. We examined the presence of PF in survivors of SIOP CNSGCT96. PATIENTS AND METHODS: We evaluated 235 patients treated between 01/10/1996 and 31/12/2005. 180/235 were treated according to protocol and were alive with no recurrence at follow up in November 2009 (137 male, 43 female: mean age 13 years, observation time median 6.5 years). RESULTS: Of 180 patients examined, 69 had PF in follow-up, 5 showed diabetes insipidus only, 37 had anterior PF and 27 had both. PF at follow-up was distributed according to RT dose to the pituitary area (PA) as follows: 2 cases in the 26/180 with no prescribed RT dose to the PA; 9 of 65 receiving 24Gy to the PA; 58 of 89 receiving 40Gy to PA. 36 of the 69 patients with PF at follow-up, had no anterior PF at diagnosis; two of these 36 patients had no prescribed RT to PA, 4/36 had 24Gy to PA (11%) and 30/36 received 40Gy to PA (83%). CONCLUSION: Pituitary failures are a major long-term risk of CNS germinoma. 83% of patients who developed PF following treatment were treated with 40Gy prescribed RT dose to PA. Our results support the need to develop treatment strategies with a lower total RT dose to the PA, particularly with respect to the size of the tumor boost. (supported in part by German Cancer Aid)

BackgroundIn the current study, we pooled imaging data in newly diagnosed glioblastoma (GBM) patients from international multicenter clinical trials, single institution databases, and multicenter clinical trial consortiums to identify the relationship between postoperative residual enhancing tumor volume and overall survival (OS).MethodsData from 1511 newly diagnosed GBM patients from 5 data sources were included in the current study: (i) a single institution database from UCLA (N = 398; Discovery); (ii) patients from the Ben and Cathy Ivy Foundation for Early Phase Clinical Trials Network Radiogenomics Database (N = 262 from 8 centers; Confirmation); (iii) the chemoradiation placebo arm from an international phase III trial (AVAglio; N = 394 from 120 locations in 23 countries; Validation); (iv) the experimental arm from AVAglio examining chemoradiation plus bevacizumab (N = 404 from 120 locations in 23 countries; Exploratory Set 1); and (v) an Alliance (N0874) phase I/II trial of vorinostat plus chemoradiation (N = 53; Exploratory Set 2). Postsurgical, residual enhancing disease was quantified using T1 subtraction maps. Multivariate Cox regression models were used to determine influence of clinical variables, O6-methylguanine-DNA methyltransferase (MGMT) status, and residual tumor volume on OS.ResultsA log-linear relationship was observed between postoperative, residual enhancing tumor volume and OS in newly diagnosed GBM treated with standard chemoradiation. Postoperative tumor volume is a prognostic factor for OS (P < 0.01), regardless of therapy, age, and MGMT promoter methylation status.ConclusionPostsurgical, residual contrast-enhancing disease significantly negatively influences survival in patients with newly diagnosed GBM treated with chemoradiation with or without concomitant experimental therapy.

Purpose: Conventional techniques (3D-CRT) for craniospinal irradiation (CSI) are still widely used. Modern techniques (IMRT, VMAT, TomoTherapy®, proton pencil beam scanning [PBS]) are applied in a limited number of centers. For a 14-year-old patient, we aimed to compare dose distributions of five CSI techniques applied across Europe and generated according to the participating institute protocols, therefore representing daily practice. Material and methods: A multicenter (n = 15) dosimetric analysis of five different techniques for CSI (3D-CRT, IMRT, VMAT, TomoTherapy®, PBS; 3 centers per technique) was performed using the same patient data, set of delineations and dose prescription (36.0/1.8 Gy). Different treatment plans were optimized based on the same planning target volume margin. All participating institutes returned their best treatment plan applicable in clinic. Results: The modern radiotherapy techniques investigated resulted in superior conformity/homogeneity-indices (CI/HI), particularly in the spinal part of the target (CI: 3D-CRT:0.3 vs. modern:0.6; HI: 3D-CRT:0.2 vs. modern:0.1), and demonstrated a decreased dose to the thyroid, heart, esophagus and pancreas. Dose reductions of >10.0 Gy were observed with PBS compared to modern photon techniques for parotid glands, thyroid and pancreas. Following this technique, a wide range in dosimetry among centers using the same technique was observed (e.g., thyroid mean dose: VMAT: 5.6–24.6 Gy; PBS: 0.3–10.1 Gy). Conclusions: The investigated modern radiotherapy techniques demonstrate superior dosimetric results compared to 3D-CRT. The lowest mean dose for organs at risk is obtained with proton therapy. However, for a large number of organs ranges in mean doses were wide and overlapping between techniques making it difficult to recommend one radiotherapy technique over another.

Malignant germ cell tumors represent approximately 3% of childhood according to cancer registries in North America and Europe (Kaatsch and Grabow 2012). In contrast, these tumors account for approximately 11% of childhood tumors in some Asian countries (Echevarria et al. 2008). The World Health Organization divides intracranial germ cell tumors into pure germinoma and nongerminomatous germ cell tumors (NGGCT). These classifications are prognostic and determine therapeutic interventions, with pure germinomas having a more favorable prognosis and requiring less therapy. Up to 65% of germ cell tumors are classified as pure germinoma and the remaining one-third included NGGCTs (Jennings et al. 1985). NGGCTs include embryonal carcinoma, endodermal sinus tumor (also known as yolk sac tumor), choriocarcinoma, teratoma (immature and mature), and mixed tumors with more than one element. Approximately 25% of NGGCTs are mixed.

Bevacizumab (anti-vascular endothelial growth factor) prolongs progression-free survival (PFS) in newly diagnosed and recurrent glioblastoma. We hypothesized overall-survival (OS) benefit from continuing bevacizumab (BEV) through multiple lines of treatment (TML). Patients with newly diagnosed glioblastoma were enrolled in a multicenter, double-blind, placebo-controlled, randomized study (TAMIGA/NCT01860638). First-line (1L) treatment was radiotherapy plus temozolomide and BEV with maintenance treatment consisting of temozolomide plus BEV (six cycles) and BEV monotherapy until first disease progression (PD1). After PD1, patients were randomized to receive lomustine (CCNU) plus BEV or CCNU + placebo (P) until PD2. After PD2, patients received BEV plus chemotherapy (investigator choice; CIC) or P+CIC. Primary endpoint: OS. Secondary endpoints: PFS, OS rates, and safety. Overall, 296 patients were enrolled and 123 patients (due to withdrawal) were randomized at PD1 (BEV+CCNU, n=61; P+CCNU, n=62). After PD2, 25 patients in each arm received third-line treatment. Baseline characteristics were generally balanced. At randomization, 32.8% and 30.6% of the patients were receiving corticosteroids for BEV and placebo, respectively. The study terminated prematurely, due to the high withdrawal rate, implying underpowered (i.e. power=60%) inferential testing. For BEV versus placebo, respectively: median OS from randomization was 6.4 vs 5.5 months (HR=1.04, 95% CI 0.69–1.59); 6-month OS rate was 49.2% vs 38.7%; median time to corticosteroid initiation during second-line treatment was 5.8 vs 5.4 months; 86% and 83% had an adverse event (AE); 19% and 15% had ≥1 treatment-related grade ≥3 AEs; 21% and 15% had AEs leading to discontinuation. The study was underpowered for analysis of the primary endpoint. Descriptive analyses suggest neither an improvement nor detriment with the addition of BEV TML, in recurrent glioblastoma. No new safety signals were observed.

SUMMARY Tumors of the CNS are among the commonest malignancies occurring in teenage/young adult patients (i.e., those aged between 15 and 24 years). The treatment of this patient population is challenging. Adolescence and young adulthood are a turbulent period of life, with physical, emotional, social and cognitive changes. Best practice advocates their treatment in dedicated teenage/young adult units, with multidisciplinary team input and access to clinical trials. Treatment of CNS malignancies is dependent upon histological subtype and staging, with varying combinations of surgery, radiotherapy and chemotherapy used. Clinical trials directly targeted at this patient population are rare; treatments are based on pediatric protocols as studies have demonstrated improved outcomes in patients (with other malignancies) treated as such. Scope for improvement lies in minimizing patient risk of recurrence and long-term sequelae of treatment. Molecular characterization of tumors may provide further information.

Intracranial germinomas are rare primary central nervous system tumours that are highly sensitive to radiotherapy and chemotherapy. Recurrences are infrequent, with the majority occurring within 5 years. Although multidisciplinary treatments have resulted in good event-free survival, long-term outcomes, over decades, are relatively poorly reported. We present a rare case of a recurrence in the conus medullaris 12 years after complete remission of the primary pituitary germinoma. To the best of our knowledge, this represents the first case of a significantly delayed spinal recurrence, occurring at a very distant and uncommon site, from the primary tumour. This case highlights the importance of long-term follow-up, even after complete remission, in order to identify and limit disability from late spinal recurrences in a relatively young patient population. We consider the literature regarding identifying high risk patients, and the role of craniospinal irradiation in limiting late spinal recurrences.

High-grade gliomas are defined as tumors of glial origin with a very low incidence rate in infants and young children. They form part of the spectrum of primary intrinsic CNS and spinal cord tumors of children although their proportionate frequency of all primary CNS and spinal cord tumors is significantly lower compared to the adult population. The overwhelming number of newly diagnosed cases are sporadic primary tumors presenting with either signs of raised intracranial pressure, seizures, or other more nonspecific neurological symptoms. The initial management is aimed at restoring CSF flow, alleviation of existing mass effect, and establishing a pathological diagnosis. Ideally, the primary surgical approach is aimed at achieving a macroscopic complete excision without postoperative severe and permanent neurologic deficits. While primary chemotherapy is the preferred mode of adjuvant treatment in infants under the age of 3 years, the standard of care in all other patients is the use of combined focal radiotherapy and chemotherapy. Long-term outcome remains poor albeit appears generally slightly better than their adult counterparts.

Primary malignant brain tumours (PMBT) constitute less than 2% of all malignancies and carry a dismal prognosis. Treatment options at relapse are limited. First-in-human solid tumour studies have historically excluded patients with PMBT due to the poor prognosis, concomitant drug interactions and concerns regarding toxicities. Retrospective data were collected on clinical and tumour characteristics of patients referred for consideration of Ph1 trials in the Royal Marsden Hospital between June 2004 and August 2016. Survival analyses were performed using the Kaplan–Meier method, Cox proportional hazards model. Chi squared test was used to measure bivariate associations between categorical variables. 100pts with advanced PMBT were referred. At initial consultation, patients had a median ECOG PS 1, median age 48 years (range 18–70); 69% were men, 76% had glioblastoma; 68% were on AEDs, 63% required steroid therapy; median number of prior treatments was two. Median OS for patients treated on a Ph1 trials was 9.3 months (95% CI 5.9–12.9) versus 5.3 months (95% CI 4.1–6.1) for patients that did not proceed with a Ph1 trial, p = 0.0094. Steroid use, poor PS, neutrophil-to-lymphocyte ratio and treatment on a Ph1 trial were shown to independently influence OS. We report a survival benefit for patients with PMBT treated on Ph1 trials. Toxicity and efficacy outcomes were comparable to the general Ph1 population. In the absence of an internationally recognized standard second line treatment for patients with recurrent PMBT, more Ph1 trials should allow enrolment of patients with refractory PMBT and Ph1 trial participation should be considered at an earlier stage.

Six UK studies investigating stereotactic ablative radiotherapy (SABR) are currently open. Many of these involve the treatment of oligometastatic disease at different locations in the body. Members of all the trial management groups collaborated to generate a consensus document on appropriate organ at risk dose constraints. Values from existing but older reviews were updated using data from current studies. It is hoped that this unified approach will facilitate standardised implementation of SABR across the UK and will allow meaningful toxicity comparisons between SABR studies and internationally.

Summary Background Rindopepimut (also known as CDX-110), a vaccine targeting the EGFR deletion mutation EGFRvIII, consists of an EGFRvIII-specific peptide conjugated to keyhole limpet haemocyanin. In the ACT IV study, we aimed to assess whether or not the addition of rindopepimut to standard chemotherapy is able to improve survival in patients with EGFRvIII-positive glioblastoma. Methods In this randomised, double-blind, phase 3 trial, we recruited patients aged 18 years and older with glioblastoma from 165 hospitals in 22 countries. Eligible patients had newly diagnosed glioblastoma confirmed to express EGFRvIII by central analysis, and had undergone maximal surgical resection and completion of standard chemoradiation without progression. Patients were stratified by European Organisation for Research and Treatment of Cancer recursive partitioning analysis class, MGMT promoter methylation, and geographical region, and randomly assigned (1:1) with a prespecified randomisation sequence (block size of four) to receive rindopepimut (500 μg admixed with 150 μg GM-CSF) or control (100 μg keyhole limpet haemocyanin) via monthly intradermal injection until progression or intolerance, concurrent with standard oral temozolomide (150–200 mg/m 2 for 5 of 28 days) for 6–12 cycles or longer. Patients, investigators, and the trial funder were masked to treatment allocation. The primary endpoint was overall survival in patients with minimal residual disease (MRD; enhancing tumour 2 post-chemoradiation by central review), analysed by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01480479. Findings Between April 12, 2012, and Dec 15, 2014, 745 patients were enrolled (405 with MRD, 338 with significant residual disease [SRD], and two unevaluable) and randomly assigned to rindopepimut and temozolomide (n=371) or control and temozolomide (n=374). The study was terminated for futility after a preplanned interim analysis. At final analysis, there was no significant difference in overall survival for patients with MRD: median overall survival was 20·1 months (95% CI 18·5–22·1) in the rindopepimut group versus 20·0 months (18·1–21·9) in the control group (HR 1·01, 95% CI 0·79–1·30; p=0·93). The most common grade 3–4 adverse events for all 369 treated patients in the rindopepimut group versus 372 treated patients in the control group were: thrombocytopenia (32 [9%] vs 23 [6%]), fatigue (six [2%] vs 19 [5%]), brain oedema (eight [2%] vs 11 [3%]), seizure (nine [2%] vs eight [2%]), and headache (six [2%] vs ten [3%]). Serious adverse events included seizure (18 [5%] vs 22 [6%]) and brain oedema (seven [2%] vs 12 [3%]). 16 deaths in the study were caused by adverse events (nine [4%] in the rindopepimut group and seven [3%] in the control group), of which one—a pulmonary embolism in a 64-year-old male patient after 11 months of treatment—was assessed as potentially related to rindopepimut. Interpretation Rindopepimut did not increase survival in patients with newly diagnosed glioblastoma. Combination approaches potentially including rindopepimut might be required to show efficacy of immunotherapy in glioblastoma. Funding Celldex Therapeutics, Inc.

Aims There is now evidence to support giving single-agent chemotherapy, radiotherapy or hypofractionated concurrent chemoradiotherapy to older patients with glioblastoma (GBM). However, the clinical basis on which treatment decisions are made is under-researched and not standardised. This retrospective, multicentre study assessed whether pre-morbid characteristics or tumour imaging features could predict for overall survival in a cohort of older patients with GBM. Materials and methods Patients aged > 70 years, diagnosed with GBM at three neuro-oncology centres from 2010 to 2015 were retrospectively analysed. Demographic, clinical, radiological and treatment details were included in a multivariate model to examine for predictors of overall survival. Results In total, 339 patients were included with a median overall survival of 3.8 months. One and 2 year overall survival rates were 13% and 4%, respectively. The median age at diagnosis was 75 years. Pre-treatment characteristics predicting for overall survival included Eastern Cooperative Oncology Group performance status over 0 (performance status 1, hazard ratio 1.66, P = 0.042; performance status 2, hazard ratio 1.78, P = 0.031; performance status 3, hazard ratio 2.20, P = 0.008; performance status 4, hazard ratio 2.40, P = 0.021), radiological evidence of mass effect (hazard ratio 1.31, P = 0.049), multifocal tumours (hazard ratio 3.419, P = 0.013), presenting with seizures (hazard ratio 0.63, P = 0.008) and tumours confined to the cerebral hemisphere (hazard ratio 0.59, P = 0.048). Subtotal resection decreased risk of death by 37% ( P = 0.019) and total tumour resection by 44% ( P = 0.019). Palliative radiotherapy decreased risk of death by 41% ( P = 0.005), temozolomide alone by 60% ( P = 0.004) and radical chemoradiotherapy by 81% ( P Conclusion Clinical presentation, performance status and imaging characteristics are independent prognostic indicators of overall survival in older GBM patients, irrespective of age or treatment received.

ABSTRACT: Glioblastoma has a poor prognosis accompanied by debilitating neurological symptoms and impaired quality of life. Effective treatment strategies are needed, beyond the current standard of care (SOC), to improve outcomes. Glioblastomas are highly vascularized with elevated levels of VEGF, representing an appropriate target for selective therapies. The role of the anti-VEGF agent bevacizumab in newly diagnosed and recurrent glioblastoma is not fully clear at this time. Although bevacizumab has demonstrated improvements in progression-free survival in newly diagnosed and recurrent glioblastoma, there remain challenges in assessing disease progression after antiangiogenic treatment. The bevacizumab mechanism of action suggests a rationale for continuing bevacizumab treatment through multiple lines of therapy, strengthened by longer progression-free and overall survival observed with bevacizumab continuation beyond progression in a Phase III study in metastatic colorectal cancer and in pooled analyses of Phase II trials in glioblastoma. A novel study (randomized, double-blind, Phase IIIb; TAMIGA [MO28347]) aims to evaluate whether continuing bevacizumab plus lomustine (as second-line therapy) and SOC (third line and beyond) improves survival compared with placebo plus lomustine and then placebo plus SOC in patients with glioblastoma who progressed after first-line bevacizumab plus SOC.

Background Standard therapy for newly diagnosed glioblastoma is radiotherapy plus temozolomide. In this phase 3 study, we evaluated the effect of the addition of bevacizumab to radiotherapy–temozolomide for the treatment of newly diagnosed glioblastoma. Methods We randomly assigned patients with supratentorial glioblastoma to receive intravenous bevacizumab (10 mg per kilogram of body weight every 2 weeks) or placebo, plus radiotherapy (2 Gy 5 days a week; maximum, 60 Gy) and oral temozolomide (75 mg per square meter of body-surface area per day) for 6 weeks. After a 28-day treatment break, maintenance bevacizumab (10 mg per kilogram intravenously every 2 weeks) or placebo, plus temozolomide (150 to 200 mg per square meter per day for 5 days), was continued for six 4-week cycles, followed by bevacizumab monotherapy (15 mg per kilogram intravenously every 3 weeks) or placebo until the disease progressed or unacceptable toxic effects developed. The coprimary end points were investigator-assessed progression-free survival and overall survival. Results A total of 458 patients were assigned to the bevacizumab group, and 463 patients to the placebo group. The median progression-free survival was longer in the bevacizumab group than in the placebo group (10.6 months vs. 6.2 months; stratified hazard ratio for progression or death, 0.64; 95% confidence interval [CI], 0.55 to 0.74; P

BACKGROUND: An ageing population brings new challenges for oncologists in the management of older cancer patients. There is increasing use of a geriatric assessment (GA) to evaluate fitness for treatment and identify geriatric syndromes. GAs can predict for chemotherapy toxicity and overall survival however there is a paucity of data within the neuro oncology cohort. A criticism of GAs is that they are time and resource consuming. We conducted a feasibility study to assess whether a GA could be performed by members of the usual clinical staff in a UK NHS neuro oncology outpatient setting. MATERIAL AND METHODS: Patients aged ≥ 65 with a new diagnosis of GBM were prospectively recruited from neuro-oncology outpatient clinics across 3 UK centres. A modified GA was performed by the clinical nurse specialists and demographic, imaging and toxicity data collected. Feasibility was assessed primarily by recruitment rate. Secondary outcomes of completion rate, acceptability to staff and patients and overall survival were measured. After completion of the study, face to face semi-structured interviews with the nurses were performed; these were interpreted qualitatively using thematic analysis. RESULTS: Recruitment to the study completed within the 1 year study time. 22 women and 28 men were enrolled with a mean age of 71 (65–86). Median overall survival was 8.2 months. 41 patients received active treatment (17 palliative radiotherapy, 19 chemo radiation and 5 temozolomide alone). Of the 35 patients who were tested, 31% showed MGMT promoter methylation; no IDH mutations were detected. All centres achieved recruitment rates above the target of 80% (mean 92%, 95% CI 86%-96%). Mean assessment completion rate was 94% (95% CI 92–95%). The nurses reported that completing the assessment was manageable and that, in some cases, underlying patient factors were identified that led to changes in treatment plans. Univariable regression analysis showed the MoCA (HR 2.78, p=0.02), IADLs (HR 2.88, p=0.03), baseline mobility (HR 12.1 p=0.002), ECOG PS (HR 29.2 p=0.003) and level of anxiety (HR 3.5 p=0.001) were related to overall survival, alongside treatment received. Multivariate Cox regression modelling confirmed the MoCA score to be a significant independent predictive factor for overall survival. CONCLUSION: ASCO and SIOG promote the use of a GA in the management of older cancer patients and it is becoming widely used within other tumour groups. However, to the authors’ knowledge, this is the first study of a GA within the neuro oncology patient cohort, a group with its own particular symptom burden. We have shown that performing a GA is feasible within the confines of a busy UK outpatient clinic and that, within the accepted limits of the study size, the results can help predict overall survival irrespective of treatment received. Wider use of a neurologically focussed GA should now be explored with greater patient numbers.

To evaluate volumetric-modulated arc therapy (VMAT) for treatment of Hodgkin lymphoma (HL) in patients where conventional radiotherapy was not deliverable. A planning computed tomography (CT) scan was acquired for a twelve-year-old boy with Stage IIIB nodular sclerosing HL postchemotherapy with positive positron emission tomography scan. VMAT was used for Phase 1 (19.8 Gy in 11 fractions) and Phase 2 (10.8 Gy in 6 fractions) treatment plans. Single anticlockwise arc plans were constructed using SmartArc (Philips Radiation Oncology Systems, Fitchburg, WI) with control points spaced at 4°. The inverse-planning objectives were to uniformly irradiate the planning target volume (PTV) with the prescription dose while keeping the volume of lung receiving greater than 20 Gy (V20 Gy) to less than 30% and minimize the dose to the other adjacent organs at risk (OAR). Pretreatment verification was conducted and the treatment delivery was on an MLCi Synergy linear accelerator (Elekta Ltd, Crawley, UK). The planning results were retrospectively confirmed in a further 4 patients using a single PTV with a prescribed dose of 19.8 Gy in 11 fractions. Acceptable dose coverage and homogeneity were achieved for both Phase 1 and 2 plans while keeping the lung V20 Gy at 22.5% for the composite plan. The beam-on times for Phase 1 and Phase 2 plans were 109 and 200 seconds, respectively, and the total monitor units were 337.2 MU and 292.5 MU, respectively. The percentage of measured dose points within 3% and 3 mm for Phase 1 and Phase 2 were 92% and 98%, respectively. Both plans were delivered successfully. The retrospective planning study showed that VMAT improved PTV dose uniformity and reduced the irradiated volume of heart and lung, although the volume of lung irradiated to low doses increased. Two-phased VMAT offers an attractive option for large volume sites, such as HL, giving a high level of target coverage and significant OAR sparing together with efficient delivery.

GBM is the most frequent primary CNS tumor. RT + TMZ represents first-line therapy. ErbB pathway dysregulation contributes to GBM pathogenesis; EGFR activation is associated with RT resistance. This 3 + 3 dose-escalation study assessed afatinib, an irreversible ErbB family blocker, with RT ± TMZ in newly diagnosed GBM. Patients with MGMT promoter methylation received afatinib (20, 30, 40 mg/day) + RT + TMZ for 6 weeks (RT period), then afatinib 40 mg/day + TMZ for 6 months, then afatinib 40 mg/day until progression/undue adverse events (AEs; Regimen M). Those with unmethylated MGMT promoter received RT + afatinib then afatinib (Regimen U). Primary endpoint was maximum tolerated dose (MTD) of afatinib + RT ± TMZ; secondary endpoints were safety, pharmacokinetics and antitumor activity. Thirty-six patients were enrolled (M, 20; U, 16). In regimen M, 1/6 (20 mg), 0/6 (30 mg) and 2/5 (40 mg) evaluable patients had dose-limiting toxicities (DLTs) in the RT period (two Grade 4 thrombocytopenia, one Grade 3 vomiting); MTD of afatinib + RT + TMZ was 30 mg/day. In regimen U, 0/3 (20 mg) and 1/6 (40 mg) evaluable patients had DLTs (Grade 3 diarrhea); MTD of afatinib + RT was 40 mg/day. Common treatment-related AEs were diarrhea, rash, fatigue, nausea and thrombocytopenia; 80% and 75% had Grade 3 AEs in M and U. Pharmacokinetic evaluation suggested that afatinib with RT ± TMZ had no influence on afatinib exposure. Five patients in M and one in U had an objective response. Five patients (M, 4; U, 1) were long-term responders to afatinib (>12 months treatment); two had available tumor samples. Both had MGMT promoter methylation; one had a PTPN11 mutation, the other focal EGFR amplification with concomitant EGFRvIII allele amplification. Afatinib + RT ± TMZ appears tolerable; preliminary biomarker analysis may indicate patients likely to have long-term responses.

(32)P-chromic phosphate colloid treatments of astrocytoma and craniopharyngioma cystic brain tumours in paediatric patients are conventionally based on a sphere model under the assumption of uniform uptake. The aims of this study were to determine the distribution of the absorbed dose delivered by (32)P on a patient-specific basis and to evaluate the accuracy with which this can be predicted from a pretherapy administration of (99m)Tc-Sn colloid.Three patients were treated with (32)P-chromic phosphate colloid following (99m)Tc-Sn colloid administrations. Convolution dosimetry was performed using pretherapy and posttherapy sequential SPECT imaging, and verified with EGSnrc Monte Carlo radiation transport simulations. Mean absorbed doses to the cyst wall and dose-volume histograms were also calculated and compared with those obtained by the sphere model approach.Highly nonuniform uptake distributions of both the (99m)Tc and (32)P colloids were observed and characterized by dose-volume histograms to the cyst wall. Mean absorbed doses delivered to the cyst wall, obtained with the convolution method, were on average 21 % (SD 18 %) and 50 % (SD 30 %) lower than those predicted by the (99m)Tc distribution and the uniform assumption of the sphere model, respectively.Absorbed doses delivered to the cyst wall by (32)P are more accurately predicted from image-based patient-specific convolution dosimetry than from simple sphere models. These results indicate the necessity to perform personalized treatment planning and verification for intracavitary irradiation of cystic brain tumours treated with radiocolloids. Patient-specific dosimetry can be used to guide the frequency and levels of repeated administrations and would facilitate data collection and comparison to support the multicentre trials necessary to progress this therapy.

BACKGROUND: Cediranib, an oral pan-vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, failed to show benefit over lomustine in relapsed glioblastoma. One resistance mechanism for cediranib is up-regulation of epidermal growth factor receptor (EGFR). This study aimed to determine if dual therapy with cediranib and the oral EGFR inhibitor gefitinib improved outcome in recurrent glioblastoma. METHODS AND FINDINGS: This was a multi-center randomized, two-armed, double-blinded phase II study comparing cediranib plus gefitinib versus cediranib plus placebo in subjects with first relapse/first progression of glioblastoma following surgery and chemoradiotherapy. The primary outcome measure was progression free survival (PFS). Secondary outcome measures included overall survival (OS) and radiologic response rate. Recruitment was terminated early following suspension of the cediranib program. 38 subjects (112 planned) were enrolled with 19 subjects in each treatment arm. Median PFS with cediranib plus gefitinib was 3.6 months compared to 2.8 months for cediranib plus placebo (HR; 0.72, 90% CI; 0.41 to 1.26). Median OS was 7.2 months with cediranib plus gefitinib and 5.5 months with cediranib plus placebo (HR; 0.68, 90% CI; 0.39 to 1.19). Eight subjects (42%) had a partial response in the cediranib plus gefitinib arm versus five patients (26%) in the cediranib plus placebo arm. CONCLUSIONS: Cediranib and gefitinib in combination is tolerated in patients with glioblastoma. Incomplete recruitment led to the study being underpowered. However, a trend towards improved survival and response rates with the addition of gefitinib to cediranib was observed. Further studies of the combination incorporating EGFR and VEGF inhibition are warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT01310855.

Objective: \ud \ud Glioblastoma (GBM) is the commonest primary malignant brain tumour amongst the adult population. Incidence peaks in the 7th and 8th decades of life and as our global population ages, rates are increasing. GBM is an almost universally fatal disease with life expectancy in the range of 3–5 months amongst the elderly.\ud \ud Materials and Methods: \ud \ud The assessment of elderly GBM patients prior to treatment decisions is poorly researched and unstandardised. In order to begin tackling this issue we performed a cross-sectional survey across all UK based consultant neuro-oncologists to review their current practice in assessing elderly GBM patients.\ud \ud Results: \ud \ud There were 56 respondents from a total of 93 recipients (60% response rate). All respondents confirmed that at least some patients aged 70 or over were referred to their clinics from the local multidisciplinary team meeting (MDT). Only 18% of consultants routinely performed a cognitive or frailty screening test at initial consultation. Of those who performed a screening test, the majority reported that the results of the test changed their treatment decision in approximately 50% of cases. Participants ranked performance status as the most important factor in determining treatment decisions.\ud \ud Conclusions: \ud \ud Considering the heterogeneity of this patient population, we argue that performance status is a crude measure of vulnerability within this cohort. Elderly GBM patients represent a unique clinical scenario because of the complexity of distinguishing neuro-oncology related symptoms from general frailty. There is a need for specific geriatric assessment models tailored to the elderly neuro-oncology population in order to facilitate treatment decisions.

Identification of Patients Who Benefit From Bevacizumab in High-Grade Glioma-An Easy Question Turned Difficult : Treat the Scan or the Patient? Reply

ObjectiveIodine-131-labelled meta-iodobenzylguanidine (I-131-mIBG) therapy is an established treatment modality for relapsed/refractory neuroblastoma, most frequently administered according to fixed or weight-based criteria. We evaluate response and toxicity following a dosimetry-based, individualized approach.Materials and methodsA review of 44 treatments in 25 patients treated with I-131-mIBG therapy was performed. Patients received I-131-mIBG therapy following relapse (n=9), in refractory disease (n=12), or with surgically unresectable disease despite conventional treatment (n=4). Treatment schedule (including mIBG dose and number of administrations) was individualized according to the clinical status of the patient and dosimetry data from either a tracer study or previous administrations. Three-dimensional tumour dosimetry was also performed for eight patients.ResultsThe mean administered activity was 110897222MBq and the mean whole-body dose for a single administration was 1.79 +/- 0.57Gy. Tumour-absorbed doses varied considerably (3.70 +/- 3.37mGy/MBq). CTCAE grade 3/4 neutropenia was documented following 82% treatments and grade 3/4 thrombocytopenia following 71% treatments. Further acute toxicity was found in 49% of patients. All acute toxicities resolved with appropriate therapy. The overall response rate was 58% (complete or partial response), with a further 29% of patients having stable disease.ConclusionA highly personalized approach combining patient-specific dosimetry and clinical judgement enables delivery of high activities that can be tolerated by patients, particularly with stem cell support. We report excellent response rates and acceptable toxicity following individualized I-131-mIBG therapy. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

The processes involved in the treatment of paraspinal tumours by volumetric modulated arc therapy (VMAT) are described here by means of an illustrative case.Az single anticlockwise arc from gantry angle 179° to 181° was constructed using SmartArc (Philips Radiation Oncology Systems, Fitchburg, WI) with control points spaced at 2°. The dose prescription was 60 Gy in 30 fractions to cover the planning target volume (PTV) as uniformly as possible while sparing the 0.3-cm planning risk volume (PRV) around the spinal cord. The plan was verified before treatment using a diode array phantom and radiochromic film. Treatment delivery was on a Synergy linear accelerator with a beam modulator head (Elekta Ltd, Crawley, UK).Homogeneous dose coverage of the PTV was achieved with a D(2%) of 62.0 Gy and D(98%) of 55.6 Gy. Maximum spinal cord dose was 49.9 Gy to 0.1 cm(3) and maximum dose to the spinal cord PRV was 55.4 Gy to 0.1 cm(3). At pre-treatment verification, the percentage of the high-dose region receiving a dose within 3% and 3 mm of the planned dose was 98.8% with the diode array and 93.4% with film. Delivery time was 2 min 15 s and the course of treatment was successfully completed.VMAT was successfully planned, verified and delivered for this challenging tumour site. VMAT provides a very suitable method of treating complex paraspinal tumours, offering a high-quality conformal dose distribution with a short delivery time.

In this post-hoc, exploratory analysis, we examined outcomes for patients enrolled in the AVAglio trial of front-line bevacizumab or placebo plus radiotherapy/temozolomide who received only a single line of therapy.Patients with newly diagnosed glioblastoma received protocol-defined treatment until progressive disease (PD). Co-primary endpoints were investigator-assessed progression-free survival (PFS) and overall survival (OS). After confirmed PD, patients were treated at the investigators' discretion. PFS/OS were assessed in patients with a PFS event who did not receive post-PD therapy (Group 1) and patients with a PFS event who received post-PD therapy plus patients who did not have a PFS event at the final data cutoff (Group 2). Kaplan-Meier methodology was used. A multivariate Cox proportional hazards model for known prognostic variables was generated.Baseline characteristics were balanced. In patients with a PFS event who did not receive post-PD therapy (Group 1; n = 225 [24.4% of the intent-to-treat population]), the addition of bevacizumab to radiotherapy/temozolomide resulted in a 3.6-month extension in both median PFS (hazard ratio [HR]: 0.62, P = .0016) and median OS (HR: 0.67, P = .0102). Multivariate analyses supported this OS benefit (HR: 0.66). In the remaining patients (Group 2; n = 696), a 5.2-month PFS extension was observed in bevacizumab-treated patients (HR: 0.61, P.0001); OS was comparable between the treatment arms (HR: 0.88, P = .1502). No significant differences in safety were observed between the 2 groups.This exploratory analysis suggests that the addition of bevacizumab to standard glioblastoma treatment prolongs PFS and OS for patients with PD who receive only one line of therapy.

Pseudoprogression (PsP) is a treatment-related phenomenon which hinders response interpretation. Its prevalence and clinical impact have not been evaluated in children/adolescents. We assessed the characteristics, risk factors and prognosis of PsP in children/adolescents and young-adults diagnosed with non-brainstem high grade gliomas (HGG) and diffuse intrinsic pontine gliomas (DIPG). Patients aged 1-21 years diagnosed with HGG or DIPG between 1995 and 2012 who had completed radiotherapy were eligible. PsP was assessed according to study-specific criteria and correlated with first-line treatment, molecular biomarkers and survival. Ninety-one patients (47 HGG, 44 DIPG) were evaluable. Median age: 10 years (range, 2-20). Eleven episodes of PsP were observed in 10 patients (4 HGG, 6 DIPG). Rates of PsP: 8.5 % (HGG); 13.6 % (DIPG). Two episodes of PsP were based on clinical findings alone; nine episodes had concurrent radiological changes: increased size of lesions (n = 5), new focal enhancement (n = 4). Temozolomide, MGMT methylation or H3F3A mutations were not found to be associated with increased occurrence of PsP. For HGG, 1-year progression-free survival (PFS) was 41.9 % no-PsP versus 100 % PsP (p = 0.041); differences in 1-year overall survival (OS) were not significant. For DIPG, differences in 1-year PFS and OS were not statistically significant. Hazard ratio (95 %CI) of PsP for OS was 0.551 (0.168-1.803; p = 0.325) in HGG; and 0.308 (0.107-0.882; p = 0.028) in DIPG. PsP occurred in both pediatric HGG and DIPG patients at a comparable rate to adult HGG. PsP was associated with improved 1-yr PFS in HGG patients. PsP had a protective effect upon OS in DIPG patients.