Variation in colorectal cancer treatment and outcomes in Scotland: real world evidence from national linked administrative health data.

Background: Colorectal cancer (CRC) is the fourth most common type of cancer in the United Kingdom and the second leading cause of cancer death. Despite improvements in CRC survival over time, Scotland lags behind its UK and European counterparts. In this study, we carry out an exploratory analysis which aims to provide contemporary, population level evidence on CRC treatment and survival in Scotland. Methods: We conducted a retrospective population-based analysis of adults with incident CRC registered on the Scottish Cancer Registry (Scottish Morbidity Record 06 (SMR06)) between January 2006 and December 2018. The CRC cohort was linked to hospital inpatient (SMR01) and National Records of Scotland (NRS) deaths records allowing a description of their demographic, diagnostic and treatment characteristics. Cox proportional hazards regression models were used to explore the demographic and clinical factors associated with all-cause mortality and CRC specific mortality after adjusting for patient and tumour characteristics among people identified as early-stage and treated with surgery. Results: Overall, 32,691 (73%) and 12,184 (27%) patients had a diagnosis of colon and rectal cancer respectively, of whom 55% and 53% were early-stage and treated with surgery. Five year overall survival (CRC specific survival) within this cohort was 72% (82%) and 76% (84%) for patients with colon and rectal cancer respectively. Cox proportional hazards models revealed significant variation in mortality by sex, area-based deprivation and geographic location. Conclusions: In a Scottish population of patients with early-stage CRC treated with surgery, there was significant variation in risk of death, even after accounting for clinical factors and patient characteristics.

Evidencing the impacts of health research: Insights from trials reported in the 2018 Australian Engagement and Impact Assessment.

ISSUE ADDRESSED: While definitions of impact may vary, they often refer to the wider benefits of research evidenced beyond academia. We evaluated case studies featuring randomised trials from the 2018 Engagement and Impact Assessment to better understand how the impacts of health research are evidenced and assessed within Australia. METHODS: We collated and evaluated 'high' scoring case studies submitted by higher education institutions with a focus on randomised trials across all areas of health research. A qualitative coding system was used for manual content analysis to assess the key characteristics of trials reported, subsequent impacts and the methods used to evidence impacts. RESULTS: A total of 14 case studies were identified citing 35 clinical trials. The majority of interventions were behavioural with a focus on mental, behavioural or neurodevelopmental disorders. Most trials were phase III, focused on the treatment of the indication and were funded by industry. Contribution to clinical guidelines was the highest cited research impact. While there was evidence of researchers seeking to maximise trial impact, case studies lacked details on the role of trial participants and other beneficiaries in generating impact. CONCLUSIONS: The impacts of health research can be improved through a better understanding of the priorities and agendas of funders, providing evidence of tangible impact rather than information that is contextual or predictive, and through the early development of impact strategies involving both researchers and beneficiaries. SO WHAT?: Large-scale impact exercises intended for a broad range of disciplines may not be reflective of the depth and scope of health sciences research including trials.

A Retrospective Analysis of Vitamin D Levels in Hospitalized COVID-19 Patients With Suspected Pulmonary Embolism.

Introduction Despite using anti-coagulation therapy in hospitalized coronavirus disease 2019 (COVID-19) patients, they have high rates of pulmonary embolism (PE) and deep vein thrombosis (DVT). The main objective of this study was to evaluate the association between vitamin D deficiency and thrombotic events (defined as the occurrence of a new PE or DVT) in hospitalized COVID-19 patients. Materials and Methods This was a retrospective, cross-sectional study of 208 hospitalized COVID-19 patients who received a computed tomographic pulmonary angiography (CTPA) based on clinical suspicion of PE between January 1, 2020, and February 5, 2021. A <20 ng/mL serum vitamin D level was used to categorize vitamin D deficiency. Nonparametric tests and multivariate binary logistic regression were used to evaluate the association between serum vitamin D levels and clinical outcomes. Results The mean vitamin D level was 26.7±13.0 ng/mL (n=208), and approximately one-third of patients were vitamin D deficient (n=68, 32.7%). No association was found between vitamin D deficiency and the occurrence of thrombotic events. The incidence of PE was 19.1% in vitamin D deficient patients compared to 11.4% in vitamin D sufficient patients (p=0.13). Vitamin D deficiency was positively associated with ICU admission (OR 3.047, 95%CI 1.57-5.91, p=0.001) and mortality (OR 3.76, 95%CI 1.29-11.01, p=0.016). Conclusions This study found no association between vitamin D deficiency and the occurrence of a new PE or DVT in hospitalized COVID-19 patients. Patients with vitamin D deficiency were more likely to be admitted to the ICU and had increased overall mortality.

Prevalence and Characteristics of Pictures in Cancer Screening Information: Content Analysis of UK Print Decision Support Materials.

This paper answers calls for further theoretical work into types of pictures used in health information. Pictures influence message reception, interpretation, and retention, making this an important area for research in health communication. A content analysis was used to produce a systematic and theory-orientated assessment of the use of pictures in cancer screening information materials (N = 44) produced for invitees to either cervical, breast or bowel screening in the United Kingdom. The main categories investigated in this study were function, content and style of the pictures. Pictures used in cancer screening information materials were twice as likely to be used to demonstrate what something looked like or depict a situation (display pictures) than to convey a specific cancer screening message (message pictures). The messages being conveyed were predominantly related to screening procedures (51%) or outcomes (38%) rather than screening experiences (6%) or decisions (9%). Pictures were rarely used to portray a narrative in the materials (n = 12). The paper brings conceptual clarity to the ways pictures can be, and have so far been used, to communicate cancer screening information. This study identifies that pictures conveying a cancer-related message, and pictures in the format of a narrative, should be used more often in print cancer screening communications.

Do clinical trials change practice? A longitudinal, international assessment of colorectal cancer prescribing practices.

INTRODUCTION: Over half of the 1.5 million individuals globally who are diagnosed with colorectal cancer (CRC) present with stage II-III disease. Understanding clinician attitudes towards treatment for this group is paramount to contextualise real-world outcomes and plan future trials. The aim of this study was to assess clinician awareness of trials assessing the optimal duration of CRC adjuvant therapy, their attitudes towards shorter treatment and their self-reported practice. METHODS: A survey was developed using OnlineSurveys® and distributed to clinicians in April 2019, with a follow-up survey disseminated to a subset of respondents in August 2020. Microsoft Excel® and Stata® were used for analysis. RESULTS: 265 clinicians replied to the first survey, with the majority aware of findings from the International Duration Evaluation of Adjuvant Therapy collaboration and contributory trials. Practice change was greatest for patients under 70 with low-risk stage III CRC, with most uncertainty around using 3-months of doublet chemotherapy for high-risk stage II disease. In August 2020, clinicians (n = 106) were more likely to use 3-months of FOLFOX for low-risk stage III disease and 3-months of CAPOX for stage II disease compared to April 2019. There was no indication that the COVID-19 pandemic had enduring changes on treatment decisions beyond those made in response to trial evidence. DISCUSSION: Clinicians use a risk-stratified approach to treat CRC the adjuvant setting. Lower utilisation of doublet chemotherapy for older and stage II patients has affected the extent of trial implementation. Active dialogue regarding how trial results apply to these groups may improve consensus.

Durvalumab (MEDI 4736) in combination with extended neoadjuvant regimens in rectal cancer: a study protocol of a randomised phase II trial (PRIME-RT).

BACKGROUND: Advances in multi-modality treatment of locally advanced rectal cancer (LARC) have resulted in low local recurrence rates, but around 30% of patients will still die from distant metastatic disease. In parallel, there is increasing recognition that with radiotherapy and systemic treatment, some patients achieve a complete response and may avoid surgical resection, including in many cases, the need for a permanent stoma. Extended neoadjuvant regimes have emerged to address these concerns. The inclusion of immunotherapy in the neoadjuvant setting has the potential to further enhance this strategy by priming the local immune microenvironment and engaging the systemic immune response. METHODS: PRIME-RT is a multi-centre, open label, phase II, randomised trial for patients with newly diagnosed LARC. Eligible patients will be randomised to receive either: short course radiotherapy (25 Gray in 5 fractions over one week) with concomitant durvalumab (1500 mg administered intravenously every 4 weeks), followed by FOLFOX (85 mg/m2 oxaliplatin, 350 mg folinic acid and 400 mg/m2 bolus 5-fluorouracil (5-FU) given on day 1 followed by 2400 mg/m2 5-FU infusion over 46-48 h, all administered intravenously every 2 weeks), and durvalumab, or long course chemoradiotherapy (50 Gray to primary tumour in 25 fractions over 5 weeks with concomitant oral capecitabine 825 mg/m2 twice per day on days of radiotherapy) with durvalumab followed by FOLFOX and durvalumab. The primary endpoint is complete response rate in each arm. Secondary endpoints include treatment compliance, toxicity, safety, overall recurrence, proportion of patients with a permanent stoma, and survival. The study is translationally rich with collection of bio-specimens prior to, during, and following treatment in order to understand the molecular and immunological factors underpinning treatment response. The trial opened and the first patient was recruited in January 2021. The main trial will recruit up to 42 patients with LARC and commence after completion of a safety run-in that will recruit at least six patients with LARC or metastatic disease. DISCUSSION: PRIME-RT will explore if adding immunotherapy to neoadjuvant radiotherapy and chemotherapy for patients with LARC can prime the tumour microenvironment to improve complete response rates and stoma free survival. Sequential biopsies are a key component within the trial design that will provide new knowledge on how the tumour microenvironment changes at different time-points in response to multi-modality treatment. This expectation is that the trial will provide information to test this treatment within a large phase clinical trial. Trial registration Clinicaltrials.gov NCT04621370 (Registered 9th Nov 2020) EudraCT number 2019-001471-36 (Registered 6th Nov 2020).

The Early Impact of the IDEA Collaboration Results: How the Results Changed Prescribing Practice.

Background: Traditionally, adjuvant treatment for colon cancer has been 6 months of combination chemotherapy. Six phase III trials tested the hypothesis that 3 months is noninferior in efficacy to 6 months and reduces long-term side effects for patients. The results were pooled in the International Duration Evaluation of Adjuvant therapy (IDEA) collaboration. Although this did not meet the noninferiority endpoint, a preplanned subgroup analysis by chemotherapy regimen did demonstrate noninferiority for capecitabine and oxaliplatin. Additionally, risk stratification by T and N stage was defined. Methods: In an effort to understand the real-life impact of these results, 4 months after the IDEA results, an online survey was distributed to clinicians to ask their approach to the adjuvant treatment of patients with stage III colon cancer. Results: The survey was completed by 458 clinicians from 12 countries. Assuming that 6 months of treatment was the pretrial standard of care, 89.5% of clinicians reported they had changed practice to prescribe 3 months of treatment for some patients. For patients with low-risk stage III disease, there was a preference for 3 months, and for patients with high-risk stage III disease, most clinicians still prescribed 6 months at that time. Overall, capecitabine and oxaliplatin regimen was the most popular. There were important differences in responses depending on the location of respondent and T and N stage of disease. Conclusion: This survey shows that the IDEA collaboration has been practice changing but reveals important differences in the way results are interpreted by individual clinicians.

Health economic studies of colorectal cancer and the contribution of administrative data: A systematic review.

INTRODUCTION: Several forces are contributing to an increase in the number of people living with and surviving colorectal cancer (CRC). However, due to the lack of available data, little is known about the implications of these forces. In recent years, the use of administrative records to inform research has been increasing. The aim of this paper is to investigate the potential contribution that administrative data could have on the health economic research of CRC. METHODS: To achieve this aim, we conducted a systematic review of the health economic CRC literature published in the United Kingdom and Europe within the last decade (2009-2019). RESULTS: Thirty-seven relevant studies were identified and divided into economic evaluations, cost of illness studies and cost consequence analyses. CONCLUSIONS: The use of administrative data, including cancer registry, screening and hospital records, within the health economic research of CRC is commonplace. However, we found that this data often come from regional databases, which reduces the generalisability of results. Further, administrative data appear less able to contribute towards understanding the wider and indirect costs associated with the disease. We explore several ways in which various sources of administrative data could enhance future research in this area.

Adverse events of radioimmunotherapy for non-Hodgkin lymphoma: A systematic review and meta-analysis.

Non-Hodgkin's lymphoma continues to be a highly prevalent entity in the general population. Currently, there are multiple treatment schemes based on chemotherapeutic agents with a great success rate. However, there is a non-negligible percentage of patients who may relapse or be refractory. In this sense, new therapeutic options have emerged in the search for adequate responses, such as monoclonal antibodies that target the CD20 molecule. Another valid option is radioimmunotherapy (RIT), which combines using monoclonal antibodies for the specific targeting of malignant cells and radiation to destroy these cells. Despite the promising results that favor RIT in several clinical studies in different target populations and types of NHL, one situation to consider is the association of this therapy and second neoplasms (acute myeloid leukemia (AML) or myelodysplastic syndrome (MSD)). In this sense, we have proposed this meta-analysis to analyze the published information and determine the incidence of this association and determine this therapy's safety.

Creation of the first national linked colorectal cancer dataset in Scotland: prospects for future research and a reflection on lessons learned.

INTRODUCTION: Current understanding of cancer patients, their treatment pathways and outcomes relies mainly on information from clinical trials and prospective research studies representing a selected sub-set of the patient population. Whole-population analysis is necessary if we are to assess the true impact of new interventions or policy in a real-world setting. Accurate measurement of geographic variation in healthcare use and outcomes also relies on population-level data. Routine access to such data offers efficiency in research resource allocation and a basis for policy that addresses inequalities in care provision. OBJECTIVE: Acknowledging these benefits, the objective of this project was to create a population level dataset in Scotland of patients with a diagnosis of colorectal cancer (CRC). METHODS: This paper describes the process of creating a novel, national dataset in Scotland. RESULTS: In total, thirty two separate healthcare administrative datasets have been linked to provide a comprehensive resource to investigate the management pathways and outcomes for patients with CRC in Scotland, as well as the costs of providing CRC treatment. This is the first time that chemotherapy prescribing and national audit datasets have been linked with the Scottish Cancer Registry on a national scale. CONCLUSIONS: We describe how the acquired dataset can be used as a research resource and reflect on the data access challenges relating to its creation. Lessons learned from this process and the policy implications for future studies using administrative cancer data are highlighted.

Three Versus Six Months of Adjuvant Doublet Chemotherapy for Patients With Colorectal Cancer: A Multi-Country Cost-Effectiveness and Budget Impact Analysis.

BACKGROUND: The Short Course Oncology Treatment (SCOT) trial demonstrated non-inferiority, less toxicity, and cost-effectiveness from a UK perspective of 3 versus 6 months of oxaliplatin-based chemotherapy for patients with colorectal cancer. This study assessed the cost-effectiveness of shorter treatment and the budget impact of implementing trial findings from the perspectives of all countries recruited to SCOT: Australia, Denmark, New Zealand, Spain, Sweden, and the United Kingdom. PATIENTS AND METHODS: Individual cost-utility analyses were performed from the perspective of each country. Resource, quality of life, and survival estimates from the SCOT trial (N = 6065) were used. Probabilistic sensitivity analysis and subgroup analyses were undertaken. Using undiscounted costs from these cost-utility analyses, the impact on country-specific healthcare budgets of implementing the SCOT trial findings was calculated over a 5-year period. The currency used was US dollars (US$), and 2019 was the base year. One-way and scenario sensitivity analysis addressed uncertainty within the budget impact analysis. RESULTS: Three months of treatment were cost saving and cost-effective compared to 6 months from the perspective of all countries. The incremental net monetary benefit per patient ranged from US$8972 (Spain) to US$13,884 (Denmark). The healthcare budget impact over 5 years for the base-case scenario ranged from US$3.6 million (New Zealand) to US$61.4 million (UK) and totaled over US$150 million across all countries. CONCLUSION: This study has widened the transferability of results from the SCOT trial, showing that shorter treatment is cost-effective from a multi-country perspective. The vast savings from implementation could fully justify the investment in conducting the SCOT trial.

Evaluating cancer research impact: lessons and examples from existing reviews on approaches to research impact assessment.

BACKGROUND: Performing cancer research relies on substantial financial investment, and contributions in time and effort from patients. It is therefore important that this research has real life impacts which are properly evaluated. The optimal approach to cancer research impact evaluation is not clear. The aim of this study was to undertake a systematic review of review articles that describe approaches to impact assessment, and to identify examples of cancer research impact evaluation within these reviews. METHODS: In total, 11 publication databases and the grey literature were searched to identify review articles addressing the topic of approaches to research impact assessment. Information was extracted on methods for data collection and analysis, impact categories and frameworks used for the purposes of evaluation. Empirical examples of impact assessments of cancer research were identified from these literature reviews. Approaches used in these examples were appraised, with a reflection on which methods would be suited to cancer research  impact evaluation going forward. RESULTS: In total, 40 literature reviews were identified. Important methods to collect and analyse data for impact assessments were surveys, interviews and documentary analysis. Key categories of impact spanning the reviews were summarised, and a list of frameworks commonly used for impact assessment was generated. The Payback Framework was most often described. Fourteen examples of impact evaluation for cancer research were identified. They ranged from those assessing the impact of a national, charity-funded portfolio of cancer research to the clinical practice impact of a single trial. A set of recommendations for approaching cancer research impact assessment was generated. CONCLUSIONS: Impact evaluation can demonstrate if and why conducting cancer research  is worthwhile. Using a mixed methods, multi-category assessment organised within a framework, will provide a robust evaluation, but the ability to perform this type of assessment may be constrained by time and resources. Whichever approach is used, easily measured, but inappropriate metrics should be avoided. Going forward, dissemination of the results of cancer research impact assessments will allow the cancer research community to learn how to conduct these evaluations.

Immune Checkpoint Inhibition as a Strategy in the Neoadjuvant Treatment of Locally Advanced Rectal Cancer.

The treatment of locally advanced rectal cancer (LARC) has seen major advances over the past 3 decades, with multimodality treatment now standard of care. Combining surgical resection with radiotherapy and/or chemotherapy can reduce local recurrence from around 20% to approximately 5%. Despite improvements in local control, distant recurrence and subsequent survival rates have not changed. Immune checkpoint inhibitors have improved patient outcomes in several solid tumor types in the neoadjuvant, adjuvant, and advanced disease setting; however, in colorectal cancer, most clinical trials have been performed in the metastatic setting and the benefits confined to microsatellite instability-high tumors. In this article, we review the current preclinical and clinical evidence for using immune checkpoint inhibition in the treatment of LARC and discuss the rationale for specifically exploring the use of this therapy in the neoadjuvant setting. We summarize and discuss relevant clinical trials that are currently in setup and recruiting to test this treatment strategy and reflect on unanswered questions that still need to be addressed within future research efforts.

Clinician Attitudes to Using Low-Dose Radiation Therapy to Treat COVID-19 Lung Disease.

PURPOSE: Current treatments for coronavirus disease 2019 (COVID-19) lung disease have limited efficacy. Low-dose radiation therapy (LDRT) has received both interest and criticism as a potential treatment for this condition. In this qualitative study we explored clinicians' perspectives to identify barriers to testing LDRT in clinical trials and implementing it in clinical practice. METHODS AND MATERIALS: Semistructured interviews were undertaken with 6 clinicians from 3 medical disciplines. Interviews were recorded, transcribed verbatim, and analyzed thematically, using a framework approach. Common themes regarding barriers to using LDRT for COVID-19 lung disease were identified from the data. RESULTS: Three categories of barriers emerged: (1) the potential to do harm to the patient, including difficulty in predicting harm and lack of existing data to inform quantification of risks; (2) the feasibility of trialing this novel treatment strategy in the clinical setting, in particular trial design and recruitment, patient selection and buy-in from relevant clinician groups; and (3) the logistics of delivering the treatment, in particular risks of transmission to other patients and resources required for patient transfer. CONCLUSIONS: This study identified several barriers that may impede the evaluation and subsequent implementation of LDRT as a treatment for COVID-19 lung disease, from the perspectives of clinicians in 3 relevant specialties. By documenting and articulating these concerns, we hope to enhance discussion of why these barriers exist, and enable them to be addressed in a proactive manner to facilitate research into the potential benefits of radiation treatment for patients with COVID-19 lung disease going forward.

Glasgow Early Treatment Arm Favirpiravir (GETAFIX) for adults with early stage COVID-19: A structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: The GETAFIX trial will test the hypothesis that favipiravir is a more effective treatment for COVID-19 infection in patients who have early stage disease, compared to current standard of care. This study will also provide an important opportunity to investigate the safety and tolerability of favipiravir, the pharmacokinetic and pharmacodynamic profile of this drug and mechanisms of resistance in the context of COVID-19 infection, as well as the effect of favipiravir on hospitalisation duration and the post COVID-19 health and psycho-social wellbeing of patients recruited to the study. TRIAL DESIGN: GETAFIX is an open label, parallel group, two arm phase II/III randomised trial with 1:1 treatment allocation ratio. Patients will be randomised to one of two arms and the primary endpoint will assess the superiority of favipiravir plus standard treatment compared to standard treatment alone. PARTICIPANTS: This trial will recruit adult patients with confirmed positive valid COVID-19 test, who are not pregnant or breastfeeding and have no prior major co-morbidities. This is a multi-centre trial, patients will be recruited from in-patients and outpatients from three Glasgow hospitals: Royal Alexandra Hospital; Queen Elizabeth University Hospital; and the Glasgow Royal Infirmary. Patients must meet all of the following criteria: 1. Age 16 or over at time of consent 2. Exhibiting symptoms associated with COVID-19 3. Positive for SARS-CoV-2 on valid COVID-19 test 4. Point 1, 2, 3, or 4 on the WHO COVID-19 ordinal severity scale at time of randomisation. (Asymptomatic with positive valid COVID-19 test, Symptomatic Independent, Symptomatic assistance needed, Hospitalized, with no oxygen therapy) 5. Have >=10% risk of death should they be admitted to hospital as defined by the ISARIC4C risk index: https://isaric4c.net/risk 6. Able to provide written informed consent 7. Negative pregnancy test (women of childbearing potential*) 8. Able to swallow oral medication Patients will be excluded from the trial if they meet any of the following criteria: 1. Renal impairment requiring, or likely to require, dialysis or haemofiltration 2. Pregnant or breastfeeding 3. Of child bearing potential (women), or with female partners of child bearing potential (men) who do not agree to use adequate contraceptive measures for the duration of the study and for 3 months after the completion of study treatment 4. History of hereditary xanthinuria 5. Other patients judged unsuitable by the Principal Investigator or sub-Investigator 6. Known hypersensitivity to favipiravir, its metabolites or any excipients 7. Severe co-morbidities including: patients with severe hepatic impairment, defined as: • greater than Child-Pugh grade A • AST or ALT > 5 x ULN • AST or ALT >3 x ULN and Total Bilirubin > 2xULN 8. More than 96 hours since first positive COVID-19 test sample was taken 9. Unable to discontinue contra-indicated concomitant medications This is a multi-centre trial, patients will be recruited from in-patients and outpatients from three Glasgow hospitals: Royal Alexandra Hospital; Queen Elizabeth University Hospital; and the Glasgow Royal Infirmary. INTERVENTION AND COMPARATOR: Patients randomised to the experimental arm of GETAFIX will receive standard treatment for COVID-19 at the discretion of the treating clinician plus favipiravir. These patients will receive a loading dose of favipiravir on day 1 of 3600mg (1800mg 12 hours apart). On days 2-10, patients in the experimental arm will receive a maintenance dose of favipiravir of 800mg 12 hours apart (total of 18 doses). Patients randomised to the control arm of the GETAFIX trial will receive standard treatment for COVID-19 at the discretion of the treating clinician. MAIN OUTCOMES: The primary outcome being assessed in the GETAFIX trial is the efficacy of favipiravir in addition to standard treatment in patients with COVID-19 in reducing the severity of disease compared to standard treatment alone. Disease severity will be assessed using WHO COVID 10 point ordinal severity scale at day 15 +/- 48 hours. All randomised participants will be followed up until death or 60 days post-randomisation (whichever is sooner). RANDOMISATION: Patients will be randomised 1:1 to the experimental versus control arm using computer generated random sequence allocation. A minimisation algorithm incorporating a random component will be used to allocate patients. The factors used in the minimisation will be: site, age (16-50/51-70/71+), history of hypertension or currently obsess (BMI>30 or obesity clinically evident; yes/no), 7 days duration of symptoms (yes/no/unknown), sex (male/female), WHO COVID-19 ordinal severity score at baseline (1/2or 3/4). BLINDING (MASKING): No blinding will be used in the GETAFIX trial. Both participants and those assessing outcomes will be aware of treatment allocation. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): In total, 302 patients will be randomised to the GETAFIX trial: 151 to the control arm and 151 to the experimental arm. There will be an optional consent form for patients who may want to contribute to more frequent PK and PD sampling. The maximum number of patients who will undergo this testing will be sixteen, eight males and eight females. This option will be offered to all patients who are being treated in hospital at the time of taking informed consent, however only patients in the experimental arm of the trial will be able to undergo this testing. TRIAL STATUS: The current GETAFIX protocol is version 4.0 12th September 2020. GETAFIX opened to recruitment on 26th October 2020 and will recruit patients over a period of approximately six months. TRIAL REGISTRATION: GETAFIX was registered on the European Union Drug Regulating Authorities Clinical Trials (EudraCT) Database on 15th April 2020; Reference number 2020-001904-41 ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001904-41/GB ). GETAFIX was registered on ISRCTN on 7th September 2020; Reference number ISRCTN31062548 ( https://www.isrctn.com/ISRCTN31062548 ). FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (see Additional file 2).

Evidencing the impact of cancer trials: insights from the 2014 UK Research Excellence Framework.

INTRODUCTION: An impactful clinical trial will have real-life benefits for patients and society beyond the academic environment. This study analyses case studies of cancer trials to understand how impact is evidenced for cancer trials and how impact evaluation can be more routinely adopted and improved. METHODS: The United Kingdom (UK) Government allocates research funding to higher-education institutions based on an assessment of the institutions' previous research efforts, in an exercise known as the Research Excellence Framework (REF). In addition to each institution's journal publications and research environment, for the first time in 2014, allocation of funding was also dependent on an evaluation of the wider, societal impact of research conducted. In the REF2014, impact assessment was performed by evaluation of impact case studies. In this study, case studies (n = 6637) submitted by institutions for the REF2014 were accessed and those focussing on cancer trials were identified. Manual content analysis was then used to assess the characteristics of the cancer trials discussed in the case studies, the impact described and the methods used by institutions to demonstrate impact. RESULTS: Forty-six case studies describing 106 individual cancer trials were identified. The majority were phase III randomised controlled trials and those recruiting patients with breast cancer. A list of indicators of cancer trial impact was generated using the previous literature and developed inductively using these case studies. The most common impact from a cancer trial identified in the case studies was on policy, in particular citation of trial findings in clinical guidelines. Impact on health outcomes and the economy were less frequent and health outcomes were often predicted rather than evidenced. There were few descriptions identified of trialists making efforts to maximise trial impact. DISCUSSION: Cancer trial impact narratives for the next REF assessment exercise in 2021 can be improved by evidencing actual rather than predicted Impact, with a clearer identification of the beneficiaries of cancer trials and the processes through which trial results are used. Clarification of the individuals responsible for performing impact evaluations of cancer trials and the provision of resources to do so needs to be addressed if impact evaluation is to be sustainable.

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 (TMZ) chemotherapy in preclinical glioblastoma models but brain penetration was poor. Clinically, PARP inhibitors exacerbate the hematological side effects of TMZ. The OPARATIC trial was conducted to measure penetration of recurrent glioblastoma by olaparib and assess the safety and tolerability of its combination with TMZ. METHODS: Preclinical 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 TMZ in a 3 + 3 design. Suitable patients received olaparib prior to neurosurgical resection; olaparib concentrations in plasma, tumor core and tumor 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 multidrug 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, 496 nM) and 21/21 tumor margin specimens (9 patients; median, 512.3 nM). Olaparib exacerbated TMZ-related hematological toxicity, necessitating intermittent dosing. RP2D was olaparib 150 mg (3 days/week) with TMZ 75 mg/m2 daily for 42 days. Fourteen (36%) of 39 evaluable patients were progression free at 6 months. Olaparib radiosensitized 6 glioblastoma cell lines at clinically relevant concentrations of 100 and 500 nM. CONCLUSION: Olaparib reliably penetrates recurrent glioblastoma at radiosensitizing concentrations, supporting further clinical development and highlighting the need for better preclinical models.

Treatment of newly diagnosed glioblastoma in the elderly: a network meta-analysis.

BACKGROUND: A glioblastoma is a fatal type of brain tumour for which the standard of care is maximum surgical resection followed by chemoradiotherapy, when possible. Age is an important consideration in this disease, as older age is associated with shorter survival and a higher risk of treatment-related toxicity. OBJECTIVES: To determine the most effective and best-tolerated approaches for the treatment of elderly people with newly diagnosed glioblastoma. To summarise current evidence for the incremental resource use, utilities, costs and cost-effectiveness associated with these approaches. SEARCH METHODS: We searched electronic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase to 3 April 2019, and the NHS Economic Evaluation Database (EED) up to database closure. We handsearched clinical trial registries and selected neuro-oncology society conference proceedings from the past five years. SELECTION CRITERIA: Randomised trials (RCTs) of treatments for glioblastoma in elderly people. We defined 'elderly' as 70+ years but included studies defining 'elderly' as over 65+ years if so reported. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods for study selection and data extraction. Where sufficient data were available, treatment options were compared in a network meta-analysis (NMA) using Stata software (version 15.1). For outcomes with insufficient data for NMA, pairwise meta-analysis were conducted in RevMan. The GRADE approach was used to grade the evidence. MAIN RESULTS: We included 12 RCTs involving approximately 1818 participants. Six were conducted exclusively among elderly people (either defined as 65 years or older or 70 years or older) with newly diagnosed glioblastoma, the other six reported data for an elderly subgroup among a broader age range of participants. Most participants were capable of self-care. Study quality was commonly undermined by lack of outcome assessor blinding and attrition. NMA was only possible for overall survival; other analyses were pair-wise meta-analyses or narrative syntheses. Seven trials contributed to the NMA for overall survival, with interventions including supportive care only (one trial arm); hypofractionated radiotherapy (RT40; four trial arms); standard radiotherapy (RT60; five trial arms); temozolomide (TMZ; three trial arms); chemoradiotherapy (CRT; three trial arms); bevacizumab with chemoradiotherapy (BEV_CRT; one trial arm); and bevacizumab with radiotherapy (BEV_RT). Compared with supportive care only, NMA evidence suggested that all treatments apart from BEV_RT prolonged survival to some extent. Overall survival High-certainty evidence shows that CRT prolongs overall survival (OS) compared with RT40 (hazard ratio (HR) 0.67, 95% confidence interval (CI) 0.56 to 0.80) and low-certainty evidence suggests that CRT may prolong overall survival compared with TMZ (TMZ versus CRT: HR 1.42, 95% CI 1.01 to 1.98). Low-certainty evidence also suggests that adding BEV to CRT may make little or no difference (BEV_CRT versus CRT: HR 0.83, 95% CrI 0.48 to 1.44). We could not compare the survival effects of CRT with different radiotherapy fractionation schedules (60 Gy/30 fractions and 40 Gy/15 fractions) due to a lack of data. When treatments were ranked according to their effects on OS, CRT ranked higher than TMZ, RT and supportive care only, with the latter ranked last. BEV plus RT was the only treatment for which there was no clear benefit in OS over supportive care only.   One trial comparing tumour treating fields (TTF) plus adjuvant chemotherapy (TTF_AC) with adjuvant chemotherapy alone could not be included in the NMA as participants were randomised after receiving concomitant chemoradiotherapy, not before. Findings from the trial suggest that the intervention probably improves overall survival in this selected patient population. We were unable to perform NMA for other outcomes due to insufficient data. Pairwise analyses were conducted for the following. Quality of life Moderate-certainty narrative evidence suggests that overall, there may be little difference in QoL between TMZ and RT, except for discomfort from communication deficits, which are probably more common with RT (1 study, 306 participants, P = 0.002). Data on QoL for other comparisons were sparse, partly due to high dropout rates, and the certainty of the evidence tended to be low or very low. Progression-free survival High-certainty evidence shows that CRT increases time to disease progression compared with RT40 (HR 0.50, 95% CI 0.41 to 0.61); moderate-certainty evidence suggests that RT60 probably increases time to disease progression compared with supportive care only (HR 0.28, 95% CI 0.17 to 0.46), and that BEV_RT probably increases time to disease progression compared with RT40 alone (HR 0.46, 95% CI 0.27 to 0.78). Evidence for other treatment comparisons was of low- or very low-certainty. Severe adverse events Moderate-certainty evidence suggests that TMZ probably increases the risk of grade 3+ thromboembolic events compared with RT60 (risk ratio (RR) 2.74, 95% CI 1.26 to 5.94; participants = 373; studies = 1) and also the risk of grade 3+ neutropenia, lymphopenia, and thrombocytopenia. Moderate-certainty evidence also suggests that CRT probably increases the risk of grade 3+ neutropenia, leucopenia and thrombocytopenia compared with hypofractionated RT alone. Adding BEV to CRT probably increases the risk of thromboembolism (RR 16.63, 95% CI 1.00 to 275.42; moderate-certainty evidence). Economic evidence There is a paucity of economic evidence regarding the management of newly diagnosed glioblastoma in the elderly. Only one economic evaluation on two short course radiotherapy regimen (25 Gy versus 40 Gy) was identified and its findings were considered unreliable. AUTHORS' CONCLUSIONS: For elderly people with glioblastoma who are self-caring, evidence suggests that CRT prolongs survival compared with RT and may prolong overall survival compared with TMZ alone. For those undergoing RT or TMZ therapy, there is probably little difference in QoL overall. Systemic anti-cancer treatments TMZ and BEV carry a higher risk of severe haematological and thromboembolic events and CRT is probably associated with a higher risk of these events. Current evidence provides little justification for using BEV in elderly patients outside a clinical trial setting. Whilst the novel TTF device appears promising, evidence on QoL and tolerability is needed in an elderly population. QoL and economic assessments of CRT versus TMZ and RT are needed. More high-quality economic evaluations are needed, in which a broader scope of costs (both direct and indirect) and outcomes should be included.