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Metastatic spinal cord compression (MSCC) carries a poor prognosis and management is based on the likelihood of maintaining mobility and predicted survival.SCORAD is a randomised trial of 686 patients comparing a single dose of 8 Gy radiotherapy with 20 Gy in 5 fractions. Data was split into a training set (412, 60%) and a validation set (274, 40%). A multivariable Cox regression for overall survival (OS) and a logistic regression for ambulatory status at 8 weeks were performed in the training set using baseline factors and a backward selection regression to identify a parsimonious model with p ≤ 0.10. Receiver Operating Characteristic (ROC) analysis evaluated model prognostic performance in the validation set. Validation of the final survival model was performed in a separate registry dataset (n = 348).The survival Cox model identified male gender, lung, gastrointestinal, and other types of cancer, compression at C1-T12, presence of non-skeletal metastases and poor ambulatory status all significantly associated with worse OS (all p 0.05). The ROC AUC for the selected model was 75% (95%CI: 69-81) in the SCORAD validation set and 68% (95%CI: 62-74) in the external validation registry data. The logistic model for ambulatory outcome identified primary tumour breast or prostate, ambulatory status grade 1 or 2, bladder function normal and prior chemotherapy all significantly associated with increased odds of ambulation at 8 weeks (all p 0.05). The ROC AUC for the selected model was 72.3% (95% CI 62.6-82.0) in the validation set.Primary breast or prostate cancer, and good ambulatory status at presentation, are favourable prognostic factors for both survival and ambulation after treatment.

Suppl. Materials and Methods; 5 Suppl. Figures; 2 Suppl Tables and List of Participating Investigators Supplementary Figure S1. Definition of MGMT cut-off with a safety margin. Supplementary Figure S2. Comparison of Overall Survival in patients with vs without markers assessments. Supplementary Figure S3. Visualization of markers analyzed in the mTOR signaling pathway from KEGG. Supplementary Figure S4. Forest plot molecular markers Supplementary Figure S5. Complete Graphical summary of consensus cluster analysis based on the matrix obtained by the reconstitution of the data in using Non-linear Iterative Partial Least Squares (NIPALS) algorithm.

Purpose: EORTC 26082 assessed the activity of temsirolimus in patients with newly diagnosed glioblastoma harboring an unmethylated O6 methylguanine-DNA-methyltransferase (MGMT) promoter.Experimental Design: Patients (n = 257) fulfilling eligibility criteria underwent central MGMT testing. Patients with MGMT unmethylated glioblastoma (n = 111) were randomized 1:1 between standard chemo-radiotherapy with temozolomide or radiotherapy plus weekly temsirolimus (25 mg). Primary endpoint was overall survival at 12 months (OS12). A positive signal was considered >38 patients alive at 12 months in the per protocol population. A noncomparative reference arm of 54 patients evaluated the assumptions on OS12 in a standard-treated cohort of patients. Prespecified post hoc analyses of markers reflecting target activation were performed.Results: Both therapies were administered per protocol with a median of 13 cycles of maintenance temsirolimus. Median age was 55 and 58 years in the temsirolimus and standard arms, the WHO performance status 0 or 1 for most patients (95.5%). In the per protocol population, 38 of 54 patients treated with temsirolimus reached OS12. The actuarial 1-year survival was 72.2% [95% confidence interval (CI), 58.2–82.2] in the temozolomide arm and 69.6% (95% CI, 55.8–79.9) in the temsirolimus arm [hazard ratio (HR) 1.16; 95% CI, 0.77–1.76; P = 0.47]. In multivariable prognostic analyses of clinical and molecular factors, phosphorylation of mTORSer2448 in tumor tissue (HR 0.13; 95% CI, 0.04–0.47; P = 0.002), detected in 37.6%, was associated with benefit from temsirolimus.Conclusions: Temsirolimus was not superior to temozolomide in patients with an unmethylated MGMT promoter. Phosphorylation of mTORSer2448 in the pretreatment tumor tissue may define a subgroup benefitting from mTOR inhibition. Clin Cancer Res; 22(19); 4797–806. ©2016 AACR.

Rapid and relentless technological advances in an ever-more globalized world have shaped the field of radiation oncology in which we practise today. These developments have drastically modified the habitus 1 of health professionals and researchers at an individual and organisational level. In this article we present an analysis of trends in radiation oncology research over the last half a century. To do so, the data from >350,000 scientific publications pertaining to a yearly search of the PubMed database with the keywords cancer radiotherapy was analysed. This analysis revealed that, over the years, radiotherapy research output has declined relative to alternative cancer therapies, representing 64% in 1970 it decreased to 31% in 2019. Also, the pace of research has significantly accelerated with, in the last 15 years, a doubling in the number of articles published by the 10% most productive researchers. Researchers are also facing stronger competition today with a proportion of first authors that will never get to publish as a last author increasing steadily from 58% in 1970 to 84% in 2000. Additionally, radiotherapy research output is extremely unequally distributed in the world, with Africa and South America contributing to ∼3% of radiotherapy articles in 2019 while representing 23% of the world’s population. This disparity, reflecting economic situations and radiotherapy capabilities, has a knock-on effect for the provision of routine clinical treatment. Since research activity is inherent to delivery of high quality clinical care, this contributes to the global inequity of radiotherapy services. Learning from these trends is crucial for the future not only of radiation oncology research but also for effective and equitable cancer care.

Summary The number of patients with cancer in Africa has been predicted to increase from 844 279 in 2012 to more than 1·5 million in 2030. However, many countries in Africa still lack access to radiotherapy as a part of comprehensive cancer care. The objective of this analysis is to present an updated overview of radiotherapy resources in Africa and to analyse the gaps and needs of the continent for 2030 in the context of the UN Sustainable Development Goals. Data from 54 African countries on teletherapy megavoltage units and brachytherapy afterloaders were extracted from the Directory for Radiotherapy Centres, an electronic, centralised, and continuously updated database of radiotherapy centres. Cancer incidence and future predictions were taken from the GLOBOCAN 2018 database of the International Agency for Research on Cancer. Radiotherapy need was estimated using a 64% radiotherapy utilisation rate, while assuming a machine throughput of 500 patients per year. As of March, 2020, 28 (52%) of 54 countries had access to external beam radiotherapy, 21 (39%) had brachytherapy capacity, and no country had a capacity that matched the estimated treatment need. Median income was an important predictor of the availability of megavoltage machines: US$1883 (IQR 914–3269) in countries without any machines versus $4485 (3079–12480) in countries with at least one megavoltage machine (p=0·0003). If radiotherapy expansion continues at the rate observed over the past 7 years, it is unlikely that the continent will meet its radiotherapy needs. This access gap might impact the ability to achieve the Sustainable Development Goals, particularly the target to reduce preventable, premature mortality by a third, and meet the target of the cervical cancer elimination strategy of 90% with access to treatment. Urgent, novel initiatives in financing and human capacity building are needed to change the trajectory and provide comprehensive cancer care to patients in Africa in the next decade.

Aims: Childhood cancer survival is suboptimal inmost low- and middle-income countries (LMICs). Radiotherapy plays a significant role in the standard care of many patients. To assess the current status of paediatric radiotherapy, the International Atomic Energy Agency (IAEA) undertook a global survey and a review of practice in eight leading treatment centres in middle-income countries (MICs) under Coordinated Research Project E3.30.31; 'Paediatric radiation oncology practice in low and middle income countries: a patterns-of-care study by the International Atomic Energy Agency.' Materials and methods: A survey of paediatric radiotherapy practices was distributed to 189 centres worldwide. Eight leading radiotherapy centres in MICs treating a significant number of children were selected and developed a database of individual patients treated in their centres comprising 46 variables related to radiotherapy technique. Results: Data were received from 134 radiotherapy centres in 42 countries. The percentage of children treated with curative intent fell sequentially from high-income countries (HICs; 82%) to low-income countries (53%). Increasing deficiencies were identified in diagnostic imaging, radiation staff numbers, radiotherapy technology and supportive care. More than 92.3% of centres in HICs practice multidisciplinary tumour board decision making, whereas only 65.5% of centres in LMICs use this process. Clinical guidelines were used in most centres. Practice in the eight specialist centres in MICs approximated more closely to that in HICs, but only 52% of patients were treated according to national/international protocols whereas institution-based protocols were used in 41%. Conclusions: Quality levels in paediatric radiotherapy differ among countries but also between centres within countries. in many LMICs, resources are scarce, coordination with paediatric oncology is poor or non-existent and access to supportive care is limited. Multidisciplinary treatment planning enhances care and development may represent an area where external partners can help. Commitment to the use of protocols is evident, but current international guidelines may lack relevance; the development of resources that reflect the capacity and needs of LMICs is required. in some LMICs, there are already leading centres experienced in paediatric radiotherapy where patient care approximates to that in HICs. These centres have the potential to drive improvements in service, training, mentorship and research in their regions and ultimately to improve the care and outcomes for paediatric cancer patients. (C) 2020 The Royal College of Radiologists. Published by Elsevier Ltd.Y, IAEAInternational Atomic Energy Agency [E3.30.31], This study was funded through the IAEA Coordinated Research Project E3.30.31: Paediatric radiation oncology practice in low and middle income countries: a pattern of care study by the International Atomic Energy Agency.

Purpose Most new nasopharyngeal cancer cases occur in low-income and middle-income countries, and these patients experience poorer overall survival than that of new nasopharyngeal cancer cases in high-income countries. The goal of this research project is to determine whether the introduction of a radiation therapy quality assurance program can ultimately improve outcomes for nasopharyngeal cancer patients in lower-income and middle-income countries. This study reports the results of the first phase of the International Atomic Energy Agency Coordinated Research Project (325-E3-TM-47712). Methods and Materials This prospective study has 2 phases. Phase 1 is a survey of radiation therapy resources, patient characteristics and treatment, and results of radiation therapy quality assurance performed by the expert panel. An educational workshop reviewing phase 1 results for each center was completed before accrual of patients for phase 2. The ultimate aim of the study is to compare the first and second cohort of patients to see if quality assurance can result in fewer major protocol deviations and a 15% improvement in patients’ 3-year progression-free survival. Results Of 14 participating centers, 13 (93%) had computed tomography simulators and linear accelerators (LINAC) with intensity modulated radiation therapy (IMRT) capacity, median 3 LINAC (range, 1-13), and median 10 radiation oncologists (range, 5-51). The annual number of nasopharyngeal cancer cases irradiated was median 54 (range, 10-627). Five of 14 centers (36%) had no local radiation therapy quality assurance. For the current phase 1 study, 134 patients were evaluated, 82.1% had MRI staging, 99.3% had metastatic workup, 65.6% undifferentiated histology, 51% stage 3 and 49% stage 4. Radiation therapy quality assurance revealed 81 (60.4%) of 134 patients had major protocol violations in gross tumor volume and high dose planning target volume contours and/or dosimetry, 28.4% patients had borderline plans, 15 (11.2%) acceptable, and only 6 (4.2%) had inevitable compromise due to tumor extent. Conclusions This is the first International Atomic Energy Agency study to address the fundamental issue of treatment quality rather than altered treatment regimens. The high rate of unacceptable radiation therapy plans is a major concern, and we hope phase 2 will show a significant reduction and improved patient outcomes.

Aims We describe the absolute and per capita numbers of megavoltage radiotherapy machines (MVMs) in Western Africa from 1969 to 2019. Materials and methods Western Africa was defined in accordance with the United Nations' delineation and inclusive of 16 countries. A literature search for publications detailing the number of cobalt-60 machines (COs) and linear accelerators (LINACs) in radiotherapy centres was carried out. Population data from the World Bank Group and crude cancer rates from the International Agency for Research on Cancer were used to calculate ratios of million persons per MVM and MVMs per 1000 cancer cases. Results The numbers of MVMs in Western Africa in 1969, 1979, 1989, 1999 and 2009 were zero, two, three, six and nine, respectively. In 2019 there were 22 MVMs distributed across Ghana (five), Cote d’Ivoire (two), Mali (one), Mauritania (two), Nigeria (nine) and Senegal (three). Nine countries (56.3%) had no history of external beam radiotherapy (EBRT). The largest increase in absolute EBRT capacity occurred from 2017 to 2019, during which 13 MVMs were commissioned. The largest decrease in EBRT capacity occurred from 2015 to 2017, during which four LINACs and three COs were rendered non-operational. The ratio of million persons per MVM improved from 67.0 in 1979 to 17.8 in 2019. As of 2019, there was 0.09 MVM per 1000 cancer cases. Conclusions Western African nations have experienced an increase in the absolute number of MVMs and per capita radiotherapy capacity during the last 50 years, especially in the last decade. As non-functional LINACs contributed to a temporary decline in the EBRT infrastructure, dual use of CO/LINAC technologies may act to promote the availability of EBRT treatment in centres with capacity for multiple MVMs.

Background We previously reported the unexpected finding of significantly improved survival for newly diagnosed glioblastoma in patients when radiation therapy (RT) was initiated later (>4 wk post-op) compared with earlier (≤2 wk post-op). In that analysis, data were analyzed from 2855 patients from 16 NRG Oncology/Radiotherapy Oncology Group (RTOG) trials conducted prior to the era of concurrent temozolomide (TMZ) with RT. We now report on 1395 newly diagnosed glioblastomas from 2 studies, treated with RT and concurrent TMZ followed by adjuvant TMZ. Our hypothesis was that concurrent TMZ has a synergistic/radiosensitizing mechanism, making RT timing less significant. Methods Data from patients treated with TMZ-based chemoradiation from NRG Oncology/RTOG 0525 and 0825 were analyzed. An analysis comparable to our prior study was performed to determine whether there was still an impact on survival by delaying RT. Overall survival (OS) was investigated using the Kaplan-Meier method and Cox proportional hazards model. Early progression (during time of diagnosis to 30 days after RT completion) was analyzed using the chi-square test. Results Given the small number of patients who started RT early following surgery, comparisons were made between >4 and ≤4 weeks delay of radiation from time of operation. There was no statistically significant difference in OS (hazard ratio = 0.93; P = 0.29; 95% CI: 0.80-1.07) after adjusting for known prognostic factors (recursive partitioning analysis and O6-methylguanine-DNA methyltransferase methylation status). Similarly, the rate of early progression did not differ significantly (P = 0.63). Conclusions We did not observe a significant prognostic influence of delaying radiation when given concurrently with TMZ for newly diagnosed glioblastoma. The effects of early (1-3 wk post-op) or late (>5 wk) initiation of radiation tested in our prior study could not be replicated.

Purpose To determine the impact on overall survival with different salvage therapies, including no treatment, reirradiation, systemic therapy, or radiation and systemic therapy, in participants of a phase 3 clinical trial evaluating dose-dense versus standard-dose temozolomide for patients with newly diagnosed glioblastoma. Methods and Materials This analysis of patients from Trial RTOG 0525 investigated the effect of reirradiation or systemic treatment after tumor progression. Survival from first progression was compared between patients receiving no therapy, systemic therapy alone, radiation alone, and both modalities. The Cox proportional hazards model was used to compare the mortality hazard, controlling for potential confounders. Results The analysis included 637 patients who progressed and had information on their management, excluding those who died less than half a month after progression. A total of 267 patients (42%) received neither reirradiation nor systemic treatment at progression, 24 (4%) received radiation alone, 282 (44%) received systemic treatment only, and 64 (10%) received both radiation and systemic therapy. Patients who received no treatment had a median survival of 4.8 months, lower than with radiation treatment alone (8.2 months), systemic therapy alone (10.6 months), and both radiation and systemic therapy (12.2 months). In survival models controlling for potential confounders, those who received radiation alone had modestly better survival (hazard ratio HR 0.74, 95% confidence interval [CI] 0.43-1.28), whereas those who underwent systemic therapy either without (HR 0.42, 95% CI 0.34-0.53) or with radiation therapy (HR 0.44, 95% CI 0.30-0.63) had better survival. There was no significant survival difference between patients who received radiation only and those who received systemic therapy (either with radiation or alone). Conclusions Patients who received no salvage treatment had poorer survival than those who received radiation, chemotherapy, or the combination. However, patient selection for no treatment likely reflects poorer expected prognosis. There was no significant survival difference among those receiving radiation therapy, systemic therapy, or both. Ongoing clinical trials will help define the role of reirradiation after glioblastoma progression.

Importance: Malignant spinal canal compression, a major complication of metastatic cancer, is managed with radiotherapy to maintain mobility and relieve pain, although there is no standard radiotherapy regimen.Objective: To evaluate whether single-fraction radiotherapy is noninferior to 5 fractions of radiotherapy.Design, Setting, and Participants: Multicenter noninferiority randomized clinical trial conducted in 42 UK and 5 Australian radiotherapy centers. Eligible patients (n = 686) had metastatic cancer with spinal cord or cauda equina compression, life expectancy greater than 8 weeks, and no previous radiotherapy to the same area. Patients were recruited between February 2008 and April 2016, with final follow-up in September 2017.Interventions: Patients were randomized to receive external beam single-fraction 8-Gy radiotherapy (n = 345) or 20 Gy of radiotherapy in 5 fractions over 5 consecutive days (n = 341).Main Outcomes and Measures: The primary end point was ambulatory status at week 8, based on a 4-point scale and classified as grade 1 (ambulatory without the use of aids and grade 5 of 5 muscle power) or grade 2 (ambulatory using aids or grade 4 of 5 muscle power). The noninferiority margin for the difference in ambulatory status was -11%. Secondary end points included ambulatory status at weeks 1, 4, and 12 and overall survival.Results: Among 686 randomized patients (median [interquartile range] age, 70 [64-77] years; 503 (73%) men; 44% had prostate cancer, 19% had lung cancer, and 12% had breast cancer), 342 (49.8%) were analyzed for the primary end point (255 patients died before the 8-week assessment). Ambulatory status grade 1 or 2 at week 8 was achieved by 115 of 166 (69.3%) patients in the single-fraction group vs 128 of 176 (72.7%) in the multifraction group (difference, -3.5% [1-sided 95% CI, -11.5% to ∞]; P value for noninferiority = .06). The difference in ambulatory status grade 1 or 2 in the single-fraction vs multifraction group was -0.4% (63.9% vs 64.3%; [1-sided 95% CI, -6.9 to ∞]; P value for noninferiority = .004) at week 1, -0.7% (66.8% vs 67.6%; [1-sided 95% CI, -8.1 to ∞]; P value for noninferiority = .01) at week 4, and 4.1% (71.8% vs 67.7%; [1-sided 95% CI, -4.6 to ∞]; P value for noninferiority = .002) at week 12. Overall survival rates at 12 weeks were 50% in the single-fraction group vs 55% in the multifraction group (stratified hazard ratio, 1.02 [95% CI, 0.74-1.41]). Of the 11 other secondary end points that were analyzed, the between-group differences were not statistically significant or did not meet noninferiority criterion.Conclusions and Relevance: Among patients with malignant metastatic solid tumors and spinal canal compression, a single radiotherapy dose, compared with a multifraction dose delivered over 5 days, did not meet the criterion for noninferiority for the primary outcome (ambulatory at 8 weeks). However, the extent to which the lower bound of the CI overlapped with the noninferiority margin should be considered when interpreting the clinical importance of this finding.Trial Registration: ISRCTN Identifiers: ISRCTN97555949 and ISRCTN97108008.

Purpose Bevacizumab regimens are approved for the treatment of recurrent glioblastoma in many countries. Aberrant mesenchymal-epithelial transition factor (MET) expression has been reported in glioblastoma and may contribute to bevacizumab resistance. The phase II study GO27819 investigated the monovalent MET inhibitor onartuzumab plus bevacizumab (Ona + Bev) versus placebo plus bevacizumab (Pla + Bev) in recurrent glioblastoma. Methods At first recurrence after chemoradiation, bevacizumab-naïve patients with glioblastoma were randomly assigned 1:1 to receive Ona (15 mg/kg, once every 3 weeks) + Bev (15 mg/kg, once every 3 weeks) or Pla + Bev until disease progression. The primary end point was progression-free survival by response assessment in neuro-oncology criteria. Secondary end points were overall survival, objective response rate, duration of response, and safety. Exploratory biomarker analyses correlated efficacy with expression levels of MET ligand hepatocyte growth factor, O6-methylguanine–DNA methyltransferase promoter methylation, and glioblastoma subtype. Results Among 129 patients enrolled (Ona + Bev, n = 64; Pla + Bev, n = 65), baseline characteristics were balanced. The median progression-free survival was 3.9 months for Ona + Bev versus 2.9 months for Pla + Bev (hazard ratio, 1.06; 95% CI, 0.72 to 1.56; P = .7444). The median overall survival was 8.8 months for Ona + Bev and 12.6 months for Pla + Bev (hazard ratio, 1.45; 95% CI, 0.88 to 2.37; P = .1389). Grade ≥ 3 adverse events were reported in 38.5% of patients who received Ona + Bev and 35.9% of patients who received Pla + Bev. Exploratory biomarker analyses suggested that patients with high expression of hepatocyte growth factor or unmethylated O6-methylguanine–DNA methyltransferase may benefit from Ona + Bev. Conclusion There was no evidence of further clinical benefit with the addition of onartuzumab to bevacizumab compared with bevacizumab plus placebo in unselected patients with recurrent glioblastoma in this phase II study; however, further investigation into biomarker subgroups is warranted.

Congress of the Pediatric-Radiation-Oncology-Society (PROS) -- JUN 19-22, 2019 -- Bangkok, THAILAND, WOS: 000491350500054, [No abstract available], Pediat Radiat Oncol Soc

Purpose: EORTC 26082 assessed the activity of temsirolimus in patients with newly diagnosed glioblastoma harboring an unmethylated O6 methylguanine-DNA-methyltransferase (MGMT) promoter. Experimental Design: Patients (n = 257) fulfilling eligibility criteria underwent central MGMT testing. Patients with MGMT unmethylated glioblastoma (n = 111) were randomized 1:1 between standard chemo-radiotherapy with temozolomide or radiotherapy plus weekly temsirolimus (25 mg). Primary endpoint was overall survival at 12 months (OS12). A positive signal was considered >38 patients alive at 12 months in the per protocol population. A noncomparative reference arm of 54 patients evaluated the assumptions on OS12 in a standard-treated cohort of patients. Prespecified post hoc analyses of markers reflecting target activation were performed. Results: Both therapies were administered per protocol with a median of 13 cycles of maintenance temsirolimus. Median age was 55 and 58 years in the temsirolimus and standard arms, the WHO performance status 0 or 1 for most patients (95.5%). In the per protocol population, 38 of 54 patients treated with temsirolimus reached OS12. The actuarial 1-year survival was 72.2% [95% confidence interval (CI), 58.2–82.2] in the temozolomide arm and 69.6% (95% CI, 55.8–79.9) in the temsirolimus arm [hazard ratio (HR) 1.16; 95% CI, 0.77–1.76; P = 0.47]. In multivariable prognostic analyses of clinical and molecular factors, phosphorylation of mTORSer2448 in tumor tissue (HR 0.13; 95% CI, 0.04–0.47; P = 0.002), detected in 37.6%, was associated with benefit from temsirolimus. Conclusions: Temsirolimus was not superior to temozolomide in patients with an unmethylated MGMT promoter. Phosphorylation of mTORSer2448 in the pretreatment tumor tissue may define a subgroup benefitting from mTOR inhibition. Clin Cancer Res; 22(19); 4797–806. ©2016 AACR.

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.

This guideline provides recommendations for diagnostic and therapeutic procedures for patients with malignant gliomas. We differentiate evidence-based standards from reasonable options or non-evidence-based measures that should no longer be considered. The recommendations herein should provide a framework and assurance for the choice of diagnostic procedures and therapeutic measures and aim to reduce complications from unnecessary treatment and cost. The guideline contributes to a critical appreciation of concurrent drugs with a focus on the controlled use of anticonvulsants and steroids. It should serve as a guideline for all professionals involved in the diagnostics and care of glioma patients and also as a source of knowledge for insurance companies and other institutions involved in the cost regulation of cancer care in Europe. Implementation of the recommendations summarised here will need interdisciplinary structures of care for patients with brain tumours and structured processes of diagnostic and therapeutic procedures.

Inadequate penetration of the blood-brain barrier (BBB) by systemically administered chemotherapies including carboplatin is implicated in their failure to improve prognosis for patients with glioblastoma. Convection-enhanced delivery (CED) of carboplatin has the potential to improve outcomes by facilitating bypass of the BBB.We report the first use of an implantable CED system incorporating a novel transcutaneous bone-anchored port (TBAP) for intermittent CED of carboplatin in a patient with recurrent glioblastoma.The CED catheter system was implanted using a robot-assisted surgical method. Catheter targeting accuracy was verified by performing intra-operative O-arm imaging. The TBAP was implanted using a skin-flap dermatome technique modeled on bone-anchored hearing aid surgery. Repeated infusions were performed by attaching a needle administration set to the TBAP. Drug distribution was monitored with serial real-time T2-weighted magnetic resonance imaging (MRI).All catheters were implanted to within 1.5 mm of their planned target. Intermittent infusions of carboplatin were performed on three consecutive days and repeated after one month without the need for further surgical intervention. Infused volumes of 27.9 ml per day were well tolerated, with the exception of a single seizure episode. Follow-up MRI at eight weeks demonstrated a significant reduction in the volume of tumor enhancement from 42.6 ml to 24.6 ml, and was associated with stability of the patient's clinical condition.Reduction in the volume of tumor enhancement indicates that intermittent CED of carboplatin has the potential to improve outcomes in glioblastoma. The novel technology described in this report make intermittent CED infusion regimes an achievable treatment strategy.

Purpose Bevacizumab regimens are approved for the treatment of recurrent glioblastoma in many countries. Aberrant mesenchymal-epithelial transition factor (MET) expression has been reported in glioblastoma and may contribute to bevacizumab resistance. The phase II study GO27819 investigated the monovalent MET inhibitor onartuzumab plus bevacizumab (Ona + Bev) versus placebo plus bevacizumab (Pla + Bev) in recurrent glioblastoma. Methods At first recurrence after chemoradiation, bevacizumab-naïve patients with glioblastoma were randomly assigned 1:1 to receive Ona (15 mg/kg, once every 3 weeks) + Bev (15 mg/kg, once every 3 weeks) or Pla + Bev until disease progression. The primary end point was progression-free survival by response assessment in neuro-oncology criteria. Secondary end points were overall survival, objective response rate, duration of response, and safety. Exploratory biomarker analyses correlated efficacy with expression levels of MET ligand hepatocyte growth factor, O

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.

Glioblastoma multiforme (GBM) is the commonest primary malignant brain tumour in adults. Standard treatment comprises surgery, radiotherapy and chemotherapy; however this condition remains incurable as these tumours are highly invasive and involve critical areas of the brain making it impossible to remove them surgically or cure them with radiotherapy. In the majority of cases the tumour recurs within 2 to 3 cm of the original site of tumour resection. Furthermore, the blood-brain barrier profoundly limits the access of many systemically administered chemotherapeutics to the tumour. Convection-enhanced delivery (CED) is a promising technique of direct intracranial drug delivery involving the implantation of microcatheters into the brain. Carboplatin represents an ideal chemotherapy to administer using this technique as glioblastoma cells are highly sensitive to carboplatin in vitro at concentrations that are not toxic to normal brain in vivo. This protocol describes a single-centre phase I dose-escalation study of carboplatin administered by CED to patients with recurrent or progressive GBM despite full standard treatment. This trial will incorporate 6 cohorts of 3 patients each. Cohorts will be treated in a sequential manner with increasing doses of carboplatin, subject to dose-limiting toxicity not being observed. This protocol should facilitate the identification of the maximum-tolerated infused concentration of carboplatin by CED into the supratentorial brain. This should facilitate the safe application of this technique in a phase II trial, treating patients with GBM, as well as for the treatment of other forms of malignant brain tumours, including metastases.

Purpose Temozolomide (TMZ) is an alkylating agent licensed for treatment of high-grade glioma (HGG). No prospective comparison with nitrosourea-based chemotherapy exists. We report, to our knowledge, the first randomized trial of procarbazine, lomustine, and vincristine (PCV) versus TMZ in chemotherapy-naive patients with recurrent HGG. Patients and Methods Four hundred forty-seven patients were randomly assigned to PCV (224 patients) or TMZ (sub–random assignment: TMZ-5 [200 mg/m2 for 5 days, 112 patients] or TMZ-21 [100 mg/m2 for 21 days, 111 patients]) for up to 9 months or until progression. The primary outcomes were survival (PCV v TMZ) and 12-week progression-free survival (PFS; TMZ-5 v TMZ-21). This study is registered as ISRCTN83176944. Results Percentages of patients completing 9 months of treatment in the PCV, TMZ-5, and TMZ-21 arms were 17%, 26%, and 13%, respectively. Major toxicity was similar across all three groups. With a median follow-up time of 12 months and 382 deaths, there was no clear survival benefit when comparing PCV with TMZ (hazard ratio [HR], 0.91; 95% CI, 0.74 to 1.11; P = .350). For TMZ-5 versus TMZ-21, 12-week PFS rates were similar (63.6% and 65.7%, respectively; P = .745), but TMZ-5 improved overall PFS (HR, 1.38; 95% CI, 1.05 to 1.82; P = .023), survival (HR, 1.32; 95% CI, 0.99 to 1.75; P = .056), and global quality of life (49% v 19% improved > 10 points at 6 months, respectively; P = .005). Conclusion Although TMZ (both arms combined) did not show a clear benefit compared with PCV, comparison of the TMZ schedules demonstrated that the 21-day schedule was inferior to the 5-day schedule in this setting. This challenges the current understanding of increasing TMZ dose-intensity by prolonged scheduling.

Brain metastases (BM) are a significant complication of metastatic breast cancer (MBC). The high incidence of BM in HER2 overexpressing MBC is now well recognized, however, the optimal management of such patients is not yet clearly defined. We aimed to analyze factors affecting survival after diagnosis of BM in patients treated in our center.Retrospective analysis of survival in all patients treated with antineoplastic therapy for BM from MBC in our institution between May 1st 2002 and April 30th 2005, according to HER2 expression and use of trastuzumab after diagnosis of BM.The median survival of the 26 patients with HER2 overexpressing disease after diagnosis of BM was significantly longer than that of the 60 patients with HER2 nonoverexpressing disease (6.2 vs. 3.8 months, P = 0.027). Further analysis revealed that this seems to be due to the favorable outcome of the 70% (n = 18) of HER2 overexpressing patients who received trastuzumab after BM were diagnosed. Median survival of this group was 11.9 months, compared with 3.8 months (HER2 nonoverexpressing disease, P = 0.002) and 3.0 months (HER2 overexpressing disease not treated with trastuzumab after development of BM, P = 0.05).Patients with HER2 overexpressing MBC who received trastuzumab after diagnosis of BM survived longer than expected. This finding justifies an active therapeutic approach: disease progression within central nervous system does not preclude benefit from trastuzumab treatment.

Purpose This study aimed to estimate the treatment outcome of nasopharyngeal cancer (NPC) across the world and its correlation with access to radiation therapy (RT). Methods and Materials The age-standardized mortality (ASM) and age-standardized incidence (ASI) rates of NPC from GLOBOCAN (2012) were summarized, and [1−(ASM/ASI)] was computed to give the proxy relative survival (RS). Data from the International Atomic Energy Agency (IAEA) and the World Bank were used to assess the availability of RT in surrogate terms: the number of RT equipment units and radiation oncologists per million population. Results A total of 112 countries with complete valid data were analyzed, and the proxy RS varied widely from 0% to 83% (median, 50%). Countries were categorized into Good, Median, and Poor outcome groups on the basis of their proxy RS ( 55%). Eighty percent of new cases occurred in the Poor outcome group. Univariable linear regression showed a significant correlation between outcome and the availability of RT: proxy RS increased at 3.4% ( P P =.001) per unit increase in RT equipment and oncologist per million population, respectively. The median number of RT equipment units per million population increased significantly from 0.5 in the Poor, to 1.5 in the Median, to 4.6 in the Good outcome groups, and the corresponding number of oncologists increased from 1.1 to 3.3 to 7.1 ( P Conclusions Nasopharyngeal cancer is a highly treatable disease, but the outcome varies widely across the world. The current study shows a significant correlation between survival and access to RT based on available surrogate indicators. However, the possible reasons for poor outcome are likely to be multifactorial and complex. Concerted international efforts are needed not only to address the fundamental requirement for adequate RT access but also to obtain more comprehensive and accurate data for research to improve cancer outcome.

LBA10004 Background: SCC is a common complication of metastatic cancer. Most pts receive RT to improve neurological function and mobility and to relieve pain. There is no standard schedule (RT ranges from single dose 8Gy to 40Gy in 20 fractions). SCORAD III was conducted to show whether a single fraction is as effective as multifraction RT without compromising patient outcomes. Methods: Pts from 43 UK and 4 Australian sites were randomized (1:1) to receive external beam spinal canal RT as a single dose of 8Gy or 20Gy in 5 fractions; stratified by RT center, ambulatory status (AS), site of primary, and presence or absence of nonskeletal metastases. Eligible pts had spinal cord or cauda equina (C1-S2) compression confirmed by MRI/CT scan, treatable within a single radiation field, life expectancy >8 weeks (wks), no previous RT to the same area. Primary endpoint was AS at wk 8: graded 1 (full function) to 4 (no/flicker motor power). The noninferiority margin was 11% for comparing the proportion of patients with AS 1 or 2 at wk 8 (whether maintained from baseline or improved from AS 3-4). Results: 688 pts were randomized Feb 2008 to Apr 2016 (n=345 single dose, n=343 multifraction). 73% were male; median age 70 years; ambulatory with/without walking aids 66%; 44% prostate, 18% lung, 11% breast, 11% gastrointestinal. Baseline characteristics were balanced. 69.5% (114/164 pts evaluable at wk 8) single dose vs. 73.3% (129/176) multifraction had AS 1-2 at wk 8 (risk difference: -3.78%, 90%CI -11.85 to 4.28). Importantly, overall survival (OS) was very similar: median OS 12.4 wks single dose vs. 13.7 multifraction, (hazard ratio 1.02 [95%CI 0.86-1.21], p=0.81). Proportion of pts with adverse events was similar for grade 3-4 (20.6% single dose vs. 20.4% multifraction), but grade 1-2 events were lower with single dose (51.0% vs. 56.9%). Conclusions: Using a single dose of 8Gy in pts with metastatic SCC was as effective as multiple fractions for AS at 8 wks and OS. We now recommend using single dose RT in this setting, with the major benefit of requiring only a single instead of multiple hospital visits, important when considering the short survival in these pts. Clinical trial information: 97108008.

BACKGROUND: Glioblastomas are highly vascularized with elevated VEGF expression and have been shown to respond to the anti-VEGF antibody bevacizumab. High MET expression has been associated with shorter progression-free survival (PFS) in glioblastomas (Pierscianek, et al. Brain Pathol 2013). This phase II study investigated the monovalent MET inhibitor, onartuzumab, plus bevacizumab (Ona + Bev) versus placebo plus bevacizumab (Pl + Bev) in recurrent glioblastoma. METHODS: Bevacizumab-naive patients with glioblastoma at first recurrence following chemoradiation were randomized 1:1 to receive Ona (15mg/kg, q3w) + Bev (15mg/kg, q3w) or Pl + Bev until disease progression. Enrollment onto a third arm, Ona + Pl, was put on hold during assessment of safety data and was subsequently closed due to study conduct concerns (data not presented). Primary endpoint: PFS by RANO criteria (ITT and MET biomarker-positive subpopulations). Secondary endpoints: overall survival, objective response rate, duration of response, and safety. RESULTS: In the 129 patients enrolled (Ona + Bev n = 64, Pl + Bev n = 65) baseline characteristics were balanced; median age was 57 years; 43.4% had Karnofsky performance status 90-100%; 87.6% had measurable disease at baseline. Median number of bevacizumab cycles: 5 for Ona + Bev, 6 for Pl + Bev; median onartuzumab cycles, 4; median placebo cycles, 6. Grade ≥3 adverse events (AEs) were reported in 38.5% of Ona + Bev and 35.9% of Pl + Bev patients; serious AEs were reported in 30.8% and 29.7%, respectively. Grade 5 AEs: Ona + Bev n = 2 intestinal perforation; Pl + Bev n = 1 intracranial hemorrhage. AEs leading to study drug withdrawal were seen in 10.8% of Ona + Bev and 6.3% of Pl + Bev patients. AEs (all grades) with a difference in incidence of ≥10% between arms included peripheral edema (44.6% Ona + Bev, 14.1% Pl + Bev), hypertension (12.3% Ona + Bev, 32.8% Pl + Bev) and hypoalbuminemia (12.3% Ona + Bev, 1.6% Pl + Bev). Efficacy data are pending. CONCLUSION: The AEs observed were consistent with previous safety profiles for onartuzumab and bevacizumab with no new safety signals. Efficacy data will be presented.

BACKGROUND: The vascular endothelial growth factor receptor (VEGFR) 2 tyrosine kinase inhibitor cediranib failed to improve outcome in recurrent glioblastoma in a randomized phase III trial (Batchelor et al.). One resistance mechanism for cediranib is through up-regulation of epidermal growth factor receptor (EGFR). This study was designed to test if the efficacy of cediranib is improved with the addition of gefitinib (an EGFR inhibitor). METHODS: We planned to 1:1 randomize 112 subjects with recurrent/progressive glioblastoma to cediranib + gefitinib (C + G) or cediranib + placebo (C + P) (NCT01310855), with PFS as the primary endpoint. Secondary end-points: OS, radiographic response rate, PFS rate at 6 months, 12 months survival rate, steroid use, time to deterioration of neurological status, safety and tolerability. Recruitment was discontinued early following AstraZeneca's suspension of the cediranib programme. RESULTS: 38 subjects were randomized, the interim results on 34 subjects (17 in each arm) are currently available. 24 male and 10 female. Mean age 54 (range 30-71). KPS ≤80 (35%), >80 (65%). The base-line characteristics for subjects in the 2 arms of the study were well balanced. Median PFS (95% CI) C + G 4.0 mo (2.7, *n/c), C + P 4.1 mo (2.0, 7.3); 6 month PFS C + G 40%, C + P 26%; 12 month PFS n/c; C + G vs C + P HR = 0.49, 95% CI (0.22, 1.11, p = 0.15). OS (mo): Median C + G 7.7 (95% CI 3.8, n/c), C + P 5.5 (95% CI 2.5, 7.3); 12 month n/c; C + G vs C + P HR = 0.359, 95% CI (0.12, 1.1; p = 0.076). No safety concerns. CONCLUSIONS: These interim results demonstrate no difference in PFS, however there was a trend (p = 0.08) for improved OS with the combination. The final results of the study for all 38 subjects will be available. *n/c not calculable due to limited data at time of analysis

EGFR and EGFRvIII analysis is of current interest because of new EGFRvIII vaccine trials opened in the UK. EGFR activation promotes cellular proliferation via activation of MAPK and PI3K-Akt pathways. EGFRvIII is the most common variant resulting from an in-frame deletion of 801bp, leading to constitutively active EGFR.51 glioblastoma samples from a cohort of 50 patients were tested for EGFR amplification by FISH and immunohistochemistry and EGFRvIII expression by reverse-transcriptase PCR (RT-PCR), and immunohistochemistry. EGFR and EGFRvIII expression was compared with Overall Survival in the cohort.Overall 22/51 samples (43%) were positive for EGFR, 16/51 (31%) were positive for EGFRvIII and 13/51 (25%) were positive for both. 9/51 cases (18%) were positive for EGFR alone, and 3/51 (6%) were positive for EGFRvIII alone. Of the EGFR positive cases, 22/51 (43%) were positive by FISH, 24/51 (47%) were positive by IHC and 2/51 (4%) were discrepant between methods (positive by IHC but non-amplified by FISH). Of the EGFRvIII positive cases, 16/51 (31%) were positive by RT-PCR, 17/51 (33%) were positive by IHC and 1/51 (2%) sample was discrepant (positive by IHC but not by RT-PCR). Neither EGFRvIII or EGFR are predictive of overall survival in this cohort.In our cohort, 25/51 (49%) of GBM showed EGFR alterations, including 16/51 (31%) with EGFRvIII. There was high concordance between IHC and FISH (96%) and IHC and RT-PCR (98%) as diagnostic methods. Neither EGFR or EGFRvIII is predictive of overall survival in this cohort. These results are key for selecting patients for novel individualised anti-EGFR therapies.

Since its establishment in 1957, the International Atomic Energy Agency (IAEA) has striven to promote global access to reliable and affordable radiotherapy, with much of its latest focus being in developing countries. While nasopharyngeal cancer (NPC) is highly curable by radiotherapy with excellent outcomes in developed countries, the outcomes in low- and middle-income countries (LMICs) are disappointing. Although the reasons for this are complex and multifactorial, improving the accessibility and quality of radiotherapy in these countries is fundamental. With concerted effort from experts and advocates around the world, ongoing initiatives are supported by the IAEA to combat the challenges in LMICs.

INTRODUCTION: We previously reported the unexpected finding that survival was significantly improved in patients with newly-diagnosed GBM when radiation was initiated later (>4 weeks post-op) compared to earlier (≤2 weeks post-op). That analysis included 2855 patients from 16 RTOG trials conducted prior to the era of concurrent temozolomide (TMZ) with RT. We now report on 1127 patients from two studies involving newly-diagnosed GBM, treated with RT + TMZ followed by adjuvant TMZ. Our hypothesis was that concurrent TMZ has a synergistic/radiosensitizing mechanism, making RT timing less significant. METHODS: Data from patients on both arms of RTOG 0525 and the placebo arm of RTOG 0825 were investigated. An analysis comparable to our prior study was performed to determine whether there was still an impact on survival by delaying RT in the RT + TMZ era. Overall survival was investigated using Cox proportional hazard model. Progression from diagnosis to 30 days after RT completion was analyzed using Chi-square test. RESULTS: 94.9% of the patients started RT 2-5 weeks post-op. Given the small number of patients who started RT early, comparisons were made between >4 and ≤4 weeks delay of radiation. There was no statistically significant difference for overall survival (p-value = 0.29; HR = 0.93; 95% CI: 0.80-1.07) after adjusting for RPA and MGMT methylation status. Similarly, the rate of early progression did not differ significantly (p-value = 0.59). CONCLUSIONS: We did not see a significant prognostic influence of delaying radiation within the range of 2-5 weeks post-op when given concurrently with TMZ for newly-diagnosed GBM. TMZ may "level the playing field" for patients treated with chemoradiation and offset the effect of RT delay that was seen when RT was given alone; however, the effects of early initiation of radiation tested previously could not be replicated. Supported by National Cancer Institute grants U10CA21661, U10CA180868, U10CA180822 and U10CA37422, Merck & Co. and Genentech.

BACKGROUND: There is limited evidence regarding which salvage treatment approach may be of most benefit for glioblastoma patients who progress following standard chemo-radiation treatment. METHODS: This secondary analysis of RTOG 0525 investigated the effect of reirradiation or systemic treatment in patients with tumor progression. Survival time was calculated from date of progression. Survival from first progression was estimated and compared between patients receiving neither radiation or systemic therapy, systemic therapy alone, or any radiation treatment. Patient characteristics were compared between groups and the Cox proportional hazards model was used to compare hazard of death controlling for potential confounders. RESULTS: A total of 637 patients who progressed with recorded information on their non-protocol therapy, excluding those who died less than half a month after progression, were analyzed. 267 patients (42%) received neither radiation or systemic treatment at progression. 88 patients (14%) received some form of radiation treatment. 282 patients (44%) received systemic treatment only. Patients who received no treatment had a median survival (MS) of 4.8 months, lower than radiation treatment (11.3 months), or systemic therapy (10.6 months). However, there was no survival difference between patients who received systemic therapy and those who received radiotherapy (p = 0.3808). Cox models, controlling for potential confounders, demonstrate no difference in hazard of death (1.13, 95% CI 0.8-1.5) between treatment arms. Patients receiving neither therapy had a statistically significant increased hazard of death (2.45, 95% CI: 1.9-3.1). CONCLUSIONS: Salvage treatments after GBM tumor progression were highly variable. Patients who received radiation with or without systemic therapy had a similar MS as those receiving systemic therapy only. Either treatment was statistically significantly better than no treatment. However, this may be the result of poorer functional status of untreated patients. SUPPORT: This project was supported by grants U10CA21661, U10CA180868, U10CA180822 and U10CA37422 from the NCI and Merck.

2015 Background: The phase II GO27819 study assessed the monovalent MET inhibitor, onartuzumab, plus the anti-VEGF antibody, bevacizumab (O+B) versus placebo plus bevacizumab (P+B) in recurrent GBM. Exploratory univariate biomarker analyses correlated efficacy with levels of the MET ligand HGF and MGMT methylation. Methods: GBM patients (pts) at first recurrence after chemoradiation were randomized 1:1 to receive O (15 mg/kg, q3w) + B (15 mg/kg, q3w) or P+B until progression. Primary endpoint: progression-free survival (PFS); secondary endpoints: overall survival (OS), objective response rate (ORR), safety; exploratory endpoint: biomarker analysis. Baseline tumor HGF levels were quantitatively assessed by cobas PCR; MGMT methylation was assessed by Quantitative Methylation Specific PCR. Results: In the ITT group (64 O+B, 65 P+B) no difference in PFS, OS or ORR was seen between the arms. A total of 119 pts (58 O+B, 61 P+B) had HGF-PCR results and 110 (56 O+B, 54 P+B) had MGMT data. Assessing the P+B arm on...

Background There is a high rate of isocitrate dehydrogenase (IDH) 1 and 2 mutations in low grade gliomas and in high grade gliomas derived from them. IDH analysis of gliomas is a novel adjunct to traditional classification and an independent prognostic marker. We compared antibody and sequencing methods for the detection of IDH mutations. Methods 88 samples from 74 patients were identified: 16 patients had WHO grade II gliomas, 30 had WHO grade III gliomas, and 28 had WHO grade IV glioblastoma multiforme (GBM). 31 samples had insufficient material available for DNA extraction. For immunohistochemistry, sections were stained with anti-IDH1R132H antibody. For sequencing, DNA was extracted from fresh, frozen tissue. Findings 20 (28%) of 72 patients were positive for the R132H IDH1 mutation by antibody. An IDH1 mutation was detected by molecular genetics in 21 (37%) of 57 patients, and no IDH2 mutations were detected (6% expected from previous studies). 5 (24%) of 21 patients had rare IDH1 mutations not detected by immunohistochemistry (7% expected). Three of these patients displayed the p.Arg132Cys mutation (two anaplastic astrocytomas, one fibrillary astrocytoma) and two displayed p.Arg132Gly (one anaplastic astrocytoma, one anaplastic oligoastrocytoma). Where sufficient tissue was available, immunohistochemistry and DNA analysis were fully concordant for the p.Arg132His mutation. We found a high rate of IDH1 mutations in lower grade lesions (WHO grade II and III) (54% [25/46]) and a low rate in GBMs (7% [2/28]). Both grade II gliomas and anaplastic astrocytomas showed a statistically different distribution of IDH1 mutation load compared with GBMs (p Interpretation A rationalised combined approach involving R132H antibody testing and sequencing of negative cases would be ideal for the detection of IDH1 mutations. Antibody testing is cheaper than sequencing but sequencing demonstrates rare IDH1 mutations not detected by immunohistochemistry. Funding Brain Tumour Bank Frenchay, British Neuropathological Society, and Brain Tumour Action.