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. 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). 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. EudraCT Number: 2016–003111-35 (entered on 21 July 2016); ClinicalTrials.gov, ID: NCT03063450 . Registered on 24 February 2017.
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.
4560 Background: Cure is possible for patients with relapsed germ cell tumours using further intensive cisplatin based combination chemotherapy. The Medical Research Council TIP trial reported a complete response (CR) rate of 19%, 1 year progression free survival (PFS) of 38% and overall survival (OS) 65% (Br J Cancer 2005;93:178). The previously reported phase I Gem-TIP trial demonstrated the feasibility of delivering full dose gemcitabine (Gem) in combination with TIP (J Clin Oncol 27, 2009 [suppl; abstr e16031]). We now report efficacy and safety data on an expanded cohort of patients treated within a phase II trial. Methods: Patients with germ cell cancers at first relapse following cisplatin based chemotherapy received a maximum of 4 cycles of Gem-TIP (Gem 1200mg/m2 d1, paclitaxel 175mg/m2 d1, ifosfamide 1g/m2 d2-6, cisplatin 20mg/m2d2-6) with pegfilgrastim 6mg d7 of a planned 21 day cycle. Subsequent cycles were started on adequate haematological recovery with no planned dose reductions. Results: 20 patients were treated, 19 male, 1 female, median age 32 years (range 20-61). Histology 6 seminoma, 14 non-seminoma. 6 patients had poor prognostic features using the Memorial criteria. The mean relative dose intensity (RDI) for TIP for patients treated with Gem-TIP was paclitaxel 95%, ifosfamide 91% and cisplatin 94% compared with 92%, 92% and 94% respectively in the MRC TIP trial. Response was CR 9 patients (45%), CR surgery 1 (5%), PR marker negative 6 (30%), incomplete response 3 (15%), 1 unevaluable. 1 year PFS was 57.9% (95% CI 33.2-76.3%), 1 year overall survival 84.2% (95% CI 58.7%-94.6%). Of the 16 patients with a favourable response this was sustained for 11 (69%) with a median overall follow up of 29 months. Toxicity was manageable and predominantly haematological. Grade 3/4 neutropaenia 60%, thrombocytopaenia 75% febrile neutropaenia 15%. There were no toxic deaths. Conclusions: The addition of gemcitabine to TIP chemotherapy is a feasible chemotherapy combination with no detrimental impact on RDI of TIP drugs and acceptable toxicity. Response rate and duration are improved on those reported in the MRC TIP trial and warrant further evaluation in a larger study. Clinical trial information: 37453564.
Background Current pathways recommend positron emission tomography–computerised tomography for the characterisation of solitary pulmonary nodules. Dynamic contrast-enhanced computerised tomography may be a more cost-effective approach. Objectives To determine the diagnostic performances of dynamic contrast-enhanced computerised tomography and positron emission tomography–computerised tomography in the NHS for solitary pulmonary nodules. Systematic reviews and a health economic evaluation contributed to the decision-analytic modelling to assess the likely costs and health outcomes resulting from incorporation of dynamic contrast-enhanced computerised tomography into management strategies. Design Multicentre comparative accuracy trial. Setting Secondary or tertiary outpatient settings at 16 hospitals in the UK. Participants Participants with solitary pulmonary nodules of ≥ 8 mm and of ≤ 30 mm in size with no malignancy in the previous 2 years were included. Interventions Baseline positron emission tomography–computerised tomography and dynamic contrast-enhanced computer tomography with 2 years’ follow-up. Main outcome measures Primary outcome measures were sensitivity, specificity and diagnostic accuracy for positron emission tomography–computerised tomography and dynamic contrast-enhanced computerised tomography. Incremental cost-effectiveness ratios compared management strategies that used dynamic contrast-enhanced computerised tomography with management strategies that did not use dynamic contrast-enhanced computerised tomography. Results A total of 380 patients were recruited (median age 69 years). Of 312 patients with matched dynamic contrast-enhanced computer tomography and positron emission tomography–computerised tomography examinations, 191 (61%) were cancer patients. The sensitivity, specificity and diagnostic accuracy for positron emission tomography–computerised tomography and dynamic contrast-enhanced computer tomography were 72.8% (95% confidence interval 66.1% to 78.6%), 81.8% (95% confidence interval 74.0% to 87.7%), 76.3% (95% confidence interval 71.3% to 80.7%) and 95.3% (95% confidence interval 91.3% to 97.5%), 29.8% (95% confidence interval 22.3% to 38.4%) and 69.9% (95% confidence interval 64.6% to 74.7%), respectively. Exploratory modelling showed that maximum standardised uptake values had the best diagnostic accuracy, with an area under the curve of 0.87, which increased to 0.90 if combined with dynamic contrast-enhanced computerised tomography peak enhancement. The economic analysis showed that, over 24 months, dynamic contrast-enhanced computerised tomography was less costly (£3305, 95% confidence interval £2952 to £3746) than positron emission tomography–computerised tomography (£4013, 95% confidence interval £3673 to £4498) or a strategy combining the two tests (£4058, 95% confidence interval £3702 to £4547). Positron emission tomography–computerised tomography led to more patients with malignant nodules being correctly managed, 0.44 on average (95% confidence interval 0.39 to 0.49), compared with 0.40 (95% confidence interval 0.35 to 0.45); using both tests further increased this (0.47, 95% confidence interval 0.42 to 0.51). Limitations The high prevalence of malignancy in nodules observed in this trial, compared with that observed in nodules identified within screening programmes, limits the generalisation of the current results to nodules identified by screening. Conclusions Findings from this research indicate that positron emission tomography–computerised tomography is more accurate than dynamic contrast-enhanced computerised tomography for the characterisation of solitary pulmonary nodules. A combination of maximum standardised uptake value and peak enhancement had the highest accuracy with a small increase in costs. Findings from this research also indicate that a combined positron emission tomography–dynamic contrast-enhanced computerised tomography approach with a slightly higher willingness to pay to avoid missing small cancers or to avoid a ‘watch and wait’ policy may be an approach to consider. Future work Integration of the dynamic contrast-enhanced component into the positron emission tomography–computerised tomography examination and the feasibility of dynamic contrast-enhanced computerised tomography at lung screening for the characterisation of solitary pulmonary nodules should be explored, together with a lower radiation dose protocol. Study registration This study is registered as PROSPERO CRD42018112215 and CRD42019124299, and the trial is registered as ISRCTN30784948 and ClinicalTrials.gov NCT02013063. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 26, No. 17. See the NIHR Journals Library website for further project information.
TPS8586 Background: Mesothelioma, an incurable, apoptosis-resistant cancer, represents a growing health burden but remains under-researched, with limited treatment options. Despite a significant number of clinical studies in the second line setting, no randomized study has been positive. Early promising signals of activity relating to both PD-L1 and PD-1 targeted treatment in mesothelioma warrant a randomized phase III trial to evaluate the efficacy of nivolumab. Methods: CONFIRM is the first ever placebo controlled, randomized phase III trial of a PD-1/PD-L1 immune checkpoint inhibitor in mesothelioma. The primary objective is to determine if nivolumab increases overall survival (OS). Secondary endpoints include progression-free survival; response rate; safety/tolerability; quality of life and cost per QALY. A translational study will determine if sensitivity to nivolumab differs according to PD-L1 expression (subgroups < 1%, 1-49%, ≥50%); and the correlation between OS and mutational burden, estimated by genome-wide analysis of CNAs, and immunotranscriptomic profile. The trial is coordinated by the CRUK Southampton Clinical Trials Unit, within the Centre for Cancer Immunotherapy, UK. The trial aims to recruit 336 patients with pleural or peritoneal mesothelioma who have received at least two prior lines of therapy, from UK sites between March 2017-2021. Current enrolment at 01 Feb 2018 was 63. Patients will be randomized 2:1 (treatment: control), stratified according to epithelioid vs. non-epithelioid, to receive 240mg nivolumab (anti PD-1 antibody) monotherapy or saline placebo as a 30 minute intravenous infusion. Allocation will be double blind. Treatment will be every 14 days until disease progression for max. 12 months. Trial follow up will continue for 6 months after the last participant has progressed, or completed or discontinued treatment. The trial is powered (80% with 2-sided 4% significance level) to detect a hazard ratio of 0.7 using an adjusted Cox regression model (time to event) and will be analyzed using intention-to-treat. This trial is funded by Cancer Research UK (C16728/A21400) and Bristol Myers Squibb (CA 209-841). Trial registrations: NCT03063450, ISRCTN79814141. Clinical trial information: NCT03063450.
Secondary CNS lymphoma is a rare but potentially lethal event in patients with diffuse large B-cell lymphoma. We aimed to assess the activity and safety of an intensive, CNS-directed chemoimmunotherapy consolidated by autologous haematopoietic stem-cell transplantation (HSCT) in patients with secondary CNS lymphoma.
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