Extent of MGMT promoter methylation modifies the effect of temozolomide on overall survival in patients with glioblastoma: a regional cohort study

BACKGROUND: MGMT methylation in glioblastoma predicts response to temozolomide but dichotomizing methylation status may mask the true prognostic value of quantitative MGMT methylation. This study evaluated whether extent of MGMT methylation interacts with the effect of temozolomide on overall survival. METHODS: We included consecutive glioblastoma patients aged ≥16 years diagnosed (April 2012–May 2020) at a neuro-oncology center. All patients had quantitative MGMT methylation measured using pyrosequencing. Those with MGMT methylated tumors were stratified into high and low methylation groups based on a cut-off using Youden index on 2-year survival. Our accelerated failure time survival models included extent of MGMT methylation, age, postoperative Karnofsky performance score, extent of resection, temozolomide regimen, and radiotherapy. RESULTS: There were 414 patients. Optimal cut-off point using Youden index was 25.9% MGMT methylation. The number of patients in the unmethylated, low and high methylation groups was 223 (53.9%), 81 (19.6%), and 110 (26.6%), respectively. In the adjusted model, high (hazard ratio [HR] 0.60, 95% confidence intervals [CI] 0.46–0.79, P = 0.005) and low (HR 0.67, 95% CI 0.50–0.89, P < 0.001) methylation groups had better survival compared to unmethylated group. There was no evidence for interaction between MGMT methylation and completed temozolomide regimen (interaction term for low methylation P = 0.097; high methylation P = 0.071). This suggests no strong effect of MGMT status on survival in patients completing temozolomide regimen. In patients not completing the temozolomide regimen, higher MGMT methylation predicted better survival (interaction terms P < 0.001). CONCLUSIONS: Quantitative MGMT methylation may provide additional prognostic value. This is important when assessing clinical and research therapies

Glioblastoma and the search for non-hypothesis driven combination therapeutics in academia

Glioblastoma (GBM) remains a cancer of high unmet clinical need. Current standard of care for GBM, consisting of maximal surgical resection, followed by ionisation radiation (IR) plus concomitant and adjuvant temozolomide (TMZ), provides less than 15-month survival benefit. Efforts by conventional drug discovery to improve overall survival have failed to overcome challenges presented by inherent tumor heterogeneity, therapeutic resistance attributed to GBM stem cells, and tumor niches supporting self-renewal. In this review we describe the steps academic researchers are taking to address these limitations in high throughput screening programs to identify novel GBM combinatorial targets. We detail how they are implementing more physiologically relevant phenotypic assays which better recapitulate key areas of disease biology coupled with more focussed libraries of small compounds, such as drug repurposing, target discovery, pharmacologically active and novel, more comprehensive anti-cancer target-annotated compound libraries. Herein, we discuss the rationale for current GBM combination trials and the need for more systematic and transparent strategies for identification, validation and prioritisation of combinations that lead to clinical trials. Finally, we make specific recommendations to the preclinical, small compound screening paradigm that could increase the likelihood of identifying tractable, combinatorial, small molecule inhibitors and better drug targets specific to GBM.Peer reviewe

Long‐term neurocognitive and other side effects of radiotherapy, with or without chemotherapy, for glioma

Background: Gliomas are brain tumours arising from glial cells with an annual incidence of 4 to 11 people per 100,000. In this review we focus on gliomas with low aggressive potential in the short term, i.e. low‐grade gliomas. Most people with low‐grade gliomas are treated with surgery and may receive radiotherapy thereafter. However, there is concern about the possible long‐term effects of radiotherapy, especially on neurocognitive functioning. Objectives: To evaluate the long‐term neurocognitive and other side effects of radiotherapy (with or without chemotherapy) compared with no radiotherapy, or different types of radiotherapy, among people with glioma (where 'long‐term' is defined as at least two years after diagnosis); and to write a brief economic commentary. Search methods: We searched the following databases on 16 February 2018 and updated the search on 14 November 2018: Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 11) in the Cochrane Library; MEDLINE via Ovid; and Embase via Ovid. We also searched clinical trial registries and relevant conference proceedings from 2014 to 2018 to identify ongoing and unpublished studies. Selection criteria: Randomised and non‐randomised trials, and controlled before‐and‐after studies (CBAS). Participants were aged 16 years and older with cerebral glioma other than glioblastoma. We included studies where patients in at least one treatment arm received radiotherapy, with or without chemotherapy, and where neurocognitive outcomes were assessed two or more years after treatment. Data collection and analysis: Two review authors independently extracted data and assessed risk of bias. We assessed the certainty of findings using the GRADE approach. Main results: The review includes nine studies: seven studies were of low‐grade glioma and two were of grade 3 glioma. Altogether 2406 participants were involved but there was high sample attrition and outcome data were available for a minority of people at final study assessments. In seven of the nine studies, participants were recruited to randomised controlled trials (RCTs) in which longer‐term follow‐up was undertaken in a subset of people that had survived without disease progression. There was moderate to high risk of bias in studies due to lack of blinding and high attrition, and in two observational studies there was high risk of selection bias. Paucity of data and risk of bias meant that evidence was of low to very low certainty. We were unable to combine results in meta‐analysis due to diversity in interventions and outcomes. The studies examined the following five comparisons. Radiotherapy versus no adjuvant treatment Two observational studies contributed data. At the 12‐year follow‐up in one study, the risk of cognitive impairment (defined as cognitive disability deficits in at least five of 18 neuropsychological tests) was greater in the radiotherapy group (risk ratio (RR) 1.95, 95% confidence interval (CI) 1.02 to 3.71; n = 65); at five to six years the difference between groups did not reach statistical significance (RR 1.38, 95% CI 0.92 to 2.06; n = 195). In the other study, one subject in the radiotherapy group had cognitive impairment (defined as significant deterioration in eight of 12 neuropsychological tests) at two years compared with none in the control group (very low certainty evidence). With regard to neurocognitive scores, in one study the radiotherapy group was reported to have had significantly worse mean scores on some tests compared with no radiotherapy; however, the raw data were only given for significant findings. In the second study, there were no clear differences in any of the various cognitive outcomes at two years (n = 31) and four years (n = 15) (very low certainty evidence). Radiotherapy versus chemotherapy One RCT contributed data on cognitive impairment at up to three years with no clear difference between arms (RR 1.43, 95% CI 0.36 to 5.70, n = 117) (low‐certainty evidence). High‐dose radiotherapy versus low‐dose radiotherapy Only one of two studies reporting this comparison contributed data, and at two and five years there were no clear differences between high‐ and low‐dose radiotherapy arms (very low certainty evidence). Conventional radiotherapy versus stereotactic conformal radiotherapy One study involving younger people contributed limited data from the subgroup aged 16 to 25 years. The numbers of participants with neurocognitive impairment at five years after treatment were two out of 12 in the conventional arm versus none out of 11 in the stereotactic conformal radiotherapy arm (RR 4.62, 95% CI 0.25 to 86.72; n = 23; low‐certainty evidence). Chemoradiotherapy versus radiotherapy Two RCTs tested for cognitive impairment. One defined cognitive impairment as a decline of more than 3 points in MMSE score compared with baseline and reported data from 2‐year (110 participants), 3‐year (91 participants), and 5‐year (57 participants) follow‐up with no clear difference between the two arms at any time point. A second study did not report raw data but measured MMSE scores over five years in 126 participants at two years, 110 at three years, 69 at four years and 53 at five years. Authors concluded that there was no difference in MMSE scores between the two study arms (P = 0.4752) (low‐certainty evidence). Two RCTs reported quality of life (QoL) outcomes for this comparison. One reported no differences in Brain‐QoL scores between study arms over a 5‐year follow‐up period (P = 0.2767; no raw data were given and denominators were not stated). The other trial reported that the long‐term results of health‐related QoL showed no difference between the arms but did not give the raw data for overall HRQoL scores (low‐certainty evidence). We found no comparative data on endocrine dysfunction; we planned to develop a brief economic commentary but found no relevant economic studies for inclusion. Authors' conclusions: Radiotherapy for gliomas with a good prognosis may increase the risk of neurocognitive side effects in the long term; however the magnitude of the risk is uncertain. Evidence on long‐term neurocognitive side effects associated with chemoradiotherapy is also uncertain. Neurocognitive assessment should be an integral part of long‐term follow‐up in trials involving radiotherapy for lower‐grade gliomas to improve the certainty of evidence regarding long‐term neurocognitive effects. Such trials should also assess other potential long‐term effects, including endocrine dysfunction, and evaluate costs and cost effectiveness

ESTRO-EANO guideline on target delineation and radiotherapy details for glioblastoma

BACKGROUND AND PURPOSE Target delineation in glioblastoma is still a matter of extensive research and debate. This guideline aims to update the existing joint European consensus on delineation of the clinical target volume (CTV) in adult glioblastoma patients. MATERIAL AND METHODS The ESTRO Guidelines Committee identified 14 European experts in close interaction with the ESTRO clinical committee and EANO who discussed and analysed the body of evidence concerning contemporary glioblastoma target delineation, then took part in a two-step modified Delphi process to address open questions. RESULTS Several key issues were identified and are discussed including i) pre-treatment steps and immobilisation, ii) target delineation and the use of standard and novel imaging techniques, and iii) technical aspects of treatment including planning techniques and fractionation. Based on the EORTC recommendation focusing on the resection cavity and residual enhancing regions on T1-sequences with the addition of a reduced 15 mm margin, special situations are presented with corresponding potential adaptations depending on the specific clinical situation. CONCLUSIONS The EORTC consensus recommends a single clinical target volume definition based on postoperative contrast-enhanced T1 abnormalities, using isotropic margins without the need to cone down. A PTV margin based on the individual mask system and IGRT procedures available is advised; this should usually be no greater than 3 mm when using IGRT

Pharmacokinetics, safety and tolerability of olaparib and temozolomide for recurrent glioblastoma: results of the phase I OPARATIC trial

Background: The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib potentiated radiation and temozolomide chemotherapy in pre-clinical glioblastoma models but brain penetration was poor. Clinically, PARP inhibitors exacerbate the hematological side-effects of temozolomide. The OPARATIC trial was conducted to measure penetration of recurrent glioblastoma by olaparib, and assess the safety and tolerability of its combination with temozolomide. Methods: Pre-clinical pharmacokinetic studies evaluated olaparib tissue distribution in rats and tumor-bearing mice. Adult patients with recurrent glioblastoma received various doses and schedules of olaparib and low-dose temozolomide in a 3+3 design. Suitable patients received olaparib prior to neurosurgical resection; olaparib concentrations in plasma, tumour core and tumour margin specimens were measured by mass spectrometry. A dose expansion cohort tested tolerability and efficacy of the recommended phase II dose (RP2D). Radiosensitizing effects of olaparib were measured by clonogenic survival in glioblastoma cell lines. Results: Olaparib was a substrate for multi-drug resistance protein-1 and showed no brain penetration in rats but was detected in orthotopic glioblastoma xenografts. Clinically, olaparib was detected in 71/71 tumor core specimens (27 patients, median 496nM) and 21/21 tumor margin specimens (9 patients, median 512.3nM). Olaparib exacerbated TMZ-related hematological toxicity, necessitating intermittent dosing. RP2D was olaparib 150mg (3 days/week) with TMZ 75mg/m2 daily for 42 days. Fourteen (36%) of 39 evaluable patients were progression-free at 6 months. Olaparib radiosensitized six glioblastoma cell lines at clinically relevant concentrations of 100 and 500 nM. Conclusions: Olaparib reliably penetrates recurrent glioblastoma at radiosensitizing concentrations, supporting further clinical development and highlighting the need for better pre-clinical models

Glioblastoma and the search for non-hypothesis driven combination therapeutics in academia

Glioblastoma (GBM) remains a cancer of high unmet clinical need. Current standard of care for GBM, consisting of maximal surgical resection, followed by ionisation radiation (IR) plus concomitant and adjuvant temozolomide (TMZ), provides less than 15-month survival benefit. Efforts by conventional drug discovery to improve overall survival have failed to overcome challenges presented by inherent tumor heterogeneity, therapeutic resistance attributed to GBM stem cells, and tumor niches supporting self-renewal. In this review we describe the steps academic researchers are taking to address these limitations in high throughput screening programs to identify novel GBM combinatorial targets. We detail how they are implementing more physiologically relevant phenotypic assays which better recapitulate key areas of disease biology coupled with more focussed libraries of small compounds, such as drug repurposing, target discovery, pharmacologically active and novel, more comprehensive anti-cancer target-annotated compound libraries. Herein, we discuss the rationale for current GBM combination trials and the need for more systematic and transparent strategies for identification, validation and prioritisation of combinations that lead to clinical trials. Finally, we make specific recommendations to the preclinical, small compound screening paradigm that could increase the likelihood of identifying tractable, combinatorial, small molecule inhibitors and better drug targets specific to GBM

A collaborative approach to exploring the future of Cancer treatment and care in relation to Precision Medicine: A design perspective.

The Precision Medicine and the Future of Cancer project was jointly conceived by the Innovation School at Glasgow School of Art and the Institute of Cancer Sciences at the University of Glasgow. Graduating year Product Design students from the Innovation School were presented with a challenge-based project to produce a vision of the future based on current trends that relate to Precision Medicine(PM) and Cancer treatment. This project involved working closely with scientists, clinicians, patients, industry and academic professionals from Glasgow University, staff at Queen Elizabeth University Hospital and Clinical Innovation Zone, staff at Beatson West of Scotland Cancer Centre, Patient Representatives and external design experts from Studio AndThen and GOODD design consultancy. The objective of this project was to investigate, in both analytical and speculative ways, future forms and functions of cancer treatment and care in relation to Precision Medicine, to develop future scenarios and design artefacts, services, and the experiences associated with them. One of the most significant societal shifts currently taking place within the field of PM is the transformation around what it means to be a patient and a professional working within this context. The public’s role is developing beyond once-passive patients into stakeholders valued within the medical industry and healthcare sector for their participation in clinical trials, and contribution towards policy-making and decision-making committees. This new dynamic is changing the traditional patient-doctor relationship and challenging the hegemony of medical practice at an institutional level. The impetus for this shift is relentless technological acceleration and increased scientific research, in particular driven by advances in PM. This project asked students to consider what will happen in a cancer landscape ten years from now, where PM has evolved to the extent that new forms of medical practice, cancer treatment and care transform how we interact with each other, with professionals and the world around us. The brief gave students the opportunity to reflect on the underlying complexities regarding the future of health, technological acceleration, post-capitalism and human agency, to envision a future world context, develop it as an experiential exhibit, and produce the designed products, services and experiences for the people who might live and work within it. The project was divided into two sections: The first was a collaborative stage where groups of students were assigned a specific area of focus from Social, Technological, Economic, Ethical, Educational, Political, Legal, Ecological [STEEEPLE]. These groups focused on researching and exploring their specific lenses and gathering as much information and understanding while working with external experts to further their knowledge. This group stage culminated in an exhibition of the collaborative understanding of what the future could look like in 10 years from now, after exploring the possible consequences of current actions. The second stage saw students explore their individual response to the world that had been defined in the first stage. Each student had their own response to the research by iteratively creating a design outcome that was appropriate to the subject matter. This culminated in each student having created a design product/service/experience relating to the future scenario. A full report (Project Process Journal [PPJ]) is included within the repository of each student which breaks down their process of designing and the outcome they have designed. The project aims to tackle the emerging possibilities where medical professionals and design can collaborate, to create a future where forms of medical practice are more preventative and are more appropriate for an aging population now and into the future. The deposited materials are arranged as follows: Readme files - two readme files relate to stage one and stage two of the project as outlined above. Overview poster - gives a visual overview of the structure and timeline of the project. Data folders - the data folders for stage one of the project are named for the lens through which each group viewed possible futures. The data folders for stage two of the project are named for the individual students who conducted the work