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Background For patients with oesophagogastric adenocarcinoma, surgery is the only curative option and despite the use of multimodality therapy, which combines it with chemotherapy and/or radiotherapy, more than 50% of patients will relapse and die. Many UK patients present with advanced disease which is already inoperable or metastatic at diagnosis. For these patients, standard care chemotherapy only offers them survival of less than a year. Nivolumab, a checkpoint blockade inhibitor, has been found to work in some advanced cancers. It is proposed, for those where immunotherapy hasn’t worked, that these immunologically evasive tumours need to be sensitized to immunotherapy drugs to allow them to act. Methods ELEVATE is a single arm phase II trial testing the overall response to nivolumab following temozolomide treatment in patients with advanced unresectable previously treated adenocarcinoma which is O 6 -methylguanine-DNA-methyltransferase (MGMT) methylated. 18 patients are being recruited from UK secondary care sites. To be eligible, participants must have been treated with at least 3 months of platinum and fluoropyrimidine chemotherapy. Participants will receive 50 mg/m 2 temozolomide continuously for 3 months. If their disease progresses during the 3 months, they will stop temozolomide and start nivolumab at a dose of 240mg every 2 weeks. If there is no progression after 3 months the participant will continue taking temozolomide in combination with nivolumab. All treatment will stop once the participant progresses on nivolumab. The primary endpoint is the best overall response to nivolumab, using both Response Evaluation Criteria in Solid Tumours version 1.1 and immunotherapy modified Response Evaluation Criteria in Solid Tumours. Secondary endpoints include progression-free survival, overall survival, and quality of life. Discussion ELEVATE will provide evidence for whether giving nivolumab after temozolomide in patients with previously treated advanced oesophagogastric adenocarcinoma is safe and biologically effective prior to future randomised trials. Trial registrations EudraCT Number: 2020-004771-41 (issued 01 October 2020); ISCRTN11398887 (registered 14 July 2021).

Background Mesothelioma is an incurable, apoptosis-resistant cancer caused in most cases by previous exposure to asbestos and is increasing in incidence. It represents a growing health burden but remains under-researched, with limited treatment options. Early promising signals of activity relating to both PD-L1- and PD-1-targeted treatment in mesothelioma implicate a dependency of mesothelioma on this immune checkpoint. There is a need to evaluate checkpoint inhibitors in patients with relapsed mesothelioma where treatment options are limited. Methods The addition of 12 months of nivolumab (anti-PD1 antibody) to standard practice will be conducted in the UK using a randomised, placebo-controlled phase III trial (the Cancer Research UK CONFIRM trial). A total of 336 patients with pleural or peritoneal mesothelioma who have received at least two prior lines of therapy will be recruited from UK secondary care sites. Patients will be randomised 2:1 (nivolumab:placebo), stratified according to epithelioid/non-epithelioid, to receive either 240 mg nivolumab monotherapy or saline placebo as a 30-min intravenous infusion. Treatment will be for up to 12 months. We will determine whether the use of nivolumab increases overall survival (the primary efficacy endpoint). Secondary endpoints will include progression-free survival, objective response rate, toxicity, quality of life and cost-effectiveness. Analysis will be performed according to the intention-to-treat principle using a Cox regression analysis for the primary endpoint (and for other time-to-event endpoints). Discussion The outcome of this trial will provide evidence of the potential benefit of the use of nivolumab in the treatment of relapsed mesothelioma. If found to be clinically effective, safe and cost-effective it is likely to become the new standard of care in the UK. Trial registration EudraCT Number: 2016–003111-35 (entered on 21 July 2016); ClinicalTrials.gov, ID: NCT03063450 . Registered on 24 February 2017.

219 HIV-negative adults ≤70 years with primary CNS lymphoma (PCNSL) were enrolled in the randomized IELSG32 trial. Enrolled patients were randomly assigned to receive methotrexate-cytarabine (arm A), or methotrexate-cytarabine-rituximab (B), or methotrexate-cytarabine-thiotepa-rituximab (MATRix; arm C). A second randomization allocated patients with responsive/stable disease to whole-brain irradiation (WBRT) or carmustine-thiotepa-conditioned autologous transplantation (ASCT). First results, after a median follow-up of 30 months, showed that MATRix significantly improves outcome, with both WBRT and ASCT being similarly effective. However, sound assessment of overall survival (OS), efficacy of salvage therapy, late complications, secondary tumors, and cognitive impairment requires longer follow-up. Herein, we report the results of this trial at a median follow-up of 88 months. As main findings, MATRix was associated with excellent long-lasting outcome, with a 7-year OS of 21%, 37%, and 56% respectively for arms A, B, and C. Notably, patients treated with MATRix and consolidation had a 7-year OS of 70%. The superiority of arm B on arm A suggests a benefit from the addition of rituximab. Comparable efficacy of WBRT and ASCT was confirmed. Salvage therapy was ineffective; benefit was recorded only in patients with late relapse re-treated with methotrexate. Eight (4%) patients developed a second cancer. Importantly, MATRix and ASCT did not result in higher non-relapse mortality or second tumors incidence. Patients who received WBRT experienced impairment in attentiveness and executive functions, whereas patients undergoing ASCT experienced improvement in these functions as well as in memory and quality of life.

IntroductionDynamic contrast-enhanced CT (DCE-CT) and positron emission tomography/CT (PET/CT) have a high reported accuracy for the diagnosis of malignancy in solitary pulmonary nodules (SPNs). The aim of this study was to compare the accuracy and cost-effectiveness of these.MethodsIn this prospective multicentre trial, 380 participants with an SPN (8–30 mm) and no recent history of malignancy underwent DCE-CT and PET/CT. All patients underwent either biopsy with histological diagnosis or completed CT follow-up. Primary outcome measures were sensitivity, specificity and overall diagnostic accuracy for PET/CT and DCE-CT. Costs and cost-effectiveness were estimated from a healthcare provider perspective using a decision-model.Results312 participants (47% female, 68.1±9.0 years) completed the study, with 61% rate of malignancy at 2 years. The sensitivity, specificity, positive predictive value and negative predictive values for DCE-CT were 95.3% (95% CI 91.3 to 97.5), 29.8% (95% CI 22.3 to 38.4), 68.2% (95% CI 62.4% to 73.5%) and 80.0% (95% CI 66.2 to 89.1), respectively, and for PET/CT were 79.1% (95% CI 72.7 to 84.2), 81.8% (95% CI 74.0 to 87.7), 87.3% (95% CI 81.5 to 91.5) and 71.2% (95% CI 63.2 to 78.1). The area under the receiver operator characteristic curve (AUROC) for DCE-CT and PET/CT was 0.62 (95% CI 0.58 to 0.67) and 0.80 (95% CI 0.76 to 0.85), respectively (p<0.001). Combined results significantly increased diagnostic accuracy over PET/CT alone (AUROC=0.90 (95% CI 0.86 to 0.93), p<0.001). DCE-CT was preferred when the willingness to pay per incremental cost per correctly treated malignancy was below £9000. Above £15 500 a combined approach was preferred.ConclusionsPET/CT has a superior diagnostic accuracy to DCE-CT for the diagnosis of SPNs. Combining both techniques improves the diagnostic accuracy over either test alone and could be cost-effective.Trial registration number NCT02013063

Background: Achieving evidence-based practice change in surgery has always been challenging, with many aspects of common clinical practice evolving through lower-level studies that are susceptible to bias and confounding rather than high-quality evidence. This challenge is even more pronounced in the setting of low-volume, high-complexity surgical oncology. Additionally, when the costs of interventions or technologies are high, designing and developing such studies within financially constrained national healthcare systems becomes even more complicated, potentially widening perceived healthcare inequalities between private and publicly funded systems. However, this is precisely the area where a lack of evidence can either hinder the development of significant new clinical advances or lead to the adoption of expensive and ineffective treatments. Here, we describe the novel approaches adopted in the design, development, and implementation of the ELECTRA trial, a randomised, controlled, double-blinded feasibility study with a planned extension to a late-phase trial. Methods: The Cancer Research UK ELECTRA (NCT05877352) trial is a three-armed randomised, controlled clinical trial designed to evaluate the incremental benefit of adding intraoperative electron beam radiotherapy (IOERT) to pelvic exenteration surgery for locally advanced and locally recurrent rectal cancer. ELECTRA is double-blinded, with patients, surgeons, and oncologists unaware of whether IOERT is administered or not. The primary feasibility outcome focuses on the ability to successfully recruit and randomise participants, while the subsequent primary outcome assesses IOERT field local control. Results: We describe the collaborative process involved in developing the trial, including national and international consultations to determine the best study design and the most optimal outcome measures to evaluate. We outline the extensive patient participation and input into the study design. Given the complexity and evolving nature of the field, with no clear international standardisations, we outline the processes used to address internationally agreed definitions, radiological standardisation, surgical learning curves, quality assurance, and pathological standardisation, as well as the broader impact and benefits of these activities. Finally, we describe the novel design utilised to facilitate the involvement of national and international units with varying levels of equipoise regarding IOERT. Conclusions: Historically, randomised clinical trials have not been the standard approach for evaluating surgical interventions due to their practical and methodological challenges, particularly in high-complexity, low-volume settings. Despite these difficulties, they remain the gold standard for evidence-based practice. The ELECTRA trial exemplifies a complex, innovative trial design that addresses an unmet need in a specialised area of high-complexity surgery. Using ELECTRA as an example, we highlight the genuine challenges in designing such complex trials and provide recommendations to facilitate the conduct of future well-designed surgical studies.

PurposeTo compare qualitative and semi-quantitative PET/CT criteria, and the impact of nodule size on the diagnosis of solitary pulmonary nodules in a prospective multicentre trial.MethodsPatients with an SPN on CT ≥ 8 and ≤ 30 mm were recruited to the SPUTNIK trial at 16 sites accredited by the UK PET Core Lab. Qualitative assessment used a five-point ordinal PET-grade compared to the mediastinal blood pool, and a combined PET/CT grade using the CT features. Semi-quantitative measures included SUVmax of the nodule, and as an uptake ratio to the mediastinal blood pool (SURBLOOD) or liver (SURLIVER). The endpoints were diagnosis of lung cancer via biopsy/histology or completion of 2-year follow-up. Impact of nodule size was analysed by comparison between nodule size tertiles.ResultsThree hundred fifty-five participants completed PET/CT and 2-year follow-up, with 59% (209/355) malignant nodules. The AUCs of the three techniques were SUVmax 0.87 (95% CI 0.83;0.91); SURBLOOD 0.87 (95% CI 0.83; 0.91, p = 0.30 versus SUVmax); and SURLIVER 0.87 (95% CI 0.83; 0.91, p = 0.09 vs. SUVmax). The AUCs for all techniques remained stable across size tertiles (p > 0.1 for difference), although the optimal diagnostic threshold varied by size. For nodules < 12 mm, an SUVmax of 1.75 or visual uptake equal to the mediastinum yielded the highest accuracy. For nodules > 16 mm, an SUVmax ≥ 3.6 or visual PET uptake greater than the mediastinum was the most accurate.ConclusionIn this multicentre trial, SUVmax was the most accurate technique for the diagnosis of solitary pulmonary nodules. Diagnostic thresholds should be altered according to nodule size.Trial registrationISRCTN - ISRCTN30784948. ClinicalTrials.gov - NCT02013063