Title: Mesothelioma and Radical Surgery 2: a multicentre randomised trial comparing (extended) pleurectomy decortication versus no (extended) pleurectomy decortication for patients with malignant pleural mesothelioma (MARS 2)
Funder: Department of Health and Social Care

Abstract: Design: MARS 2 is an active UK multicentre, parallel arm, open label, RCT comparing (extended) pleurectomy decortication versus no (extended) pleurectomy decortication with respect to overall survival in patients with malignant pleural mesothelioma. The pilot trial is recruiting to target of 50 randomisations before Apr 2017 and this application is to fund the full trial. Setting: MARS 2 is actively recruiting in 16 hospitals across the UK with expertise in clinical care for patients with mesothelioma. Literature review: 2 systematic reviews (Cao 2013 and Teh 2010) examined the published evidence consisting only of case series, confirming the absence of RCTs and control arms and were unable to comment on any survival differences or symptomatic benefits attributable to pleurectomy decortication. Target population: patients with tissue confirmed malignant pleural mesothelioma confined to one hemi-thorax. Inclusion criteria: histological confirmation of malignant pleural mesothelioma (all sub-types) and disease confined to one hemi-thorax. Exclusion criteria: Unable to give informed consent, unwilling to be randomised, disease not surgically resectable, ECOG status 2 or more, pre-operative FEV1 or TLco less than 20%, end organ failure. Health technologies being assessed: surgery for mesothelioma consisting of pleurectomy decortication which involves removal of the lining of the chest wall, lining of the lung, with additionally the sac of the heart and / or diaphragm (extended pleurectomy decortication) as required to achieve complete tumour removal but leaving the lung in-situ. Costs and outcomes: The primary outcome is overall survival. Secondary outcomes include health related quality of life, measures of safety, disease progression and cost effectiveness. Sample size: Clinicians and patients defined 30% relative difference in survival as important. We expect median survival (of a medically treated comparable cohort) of 16.8 months [14], with anticipated HR of 0.70 in favour of surgery, alpha 0.05, power of 0.80, 10% cross over to derive 327 participants. We expect 65 randomisations by Apr 2017, so the additional number for recruitment is 327-65=262. Care pathways: The current standard patient care is 6 cycles of chemotherapy (eg platinum and pemetrexed), the pathway of the intervention arm differs with 2 cycles of chemotherapy followed by surgery and then 4 cycles of chemotherapy. Project timetables: Apr 15 (n=0), Apr 16 (14 centres randomise total n=25), by Apr 17 (16 centres randomise total n=65). Apr 17 onwards randomise 22 participants per quarter for 3 years (22 x 4 x 3 = 264). Expertise in team: EL experienced surgical trialist leading as CI of MARS 2 and CI of VIOLET both currently recruiting ahead of target, DE for Qualitative Recruitment Intervention, JFR expertise in economics alongside clinical trials and led cost-effectiveness analysis of MesoVATS, SP experienced mesothelioma oncology trialist and CI for NEMO, DW expertise in mesothelioma surgery, RR expertise in respiratory medicine and mesothelioma trial conduct as CI of MesoVATS , MesoTRAP and advisor for tissue collection for Mesobank , DF expertise in mesothelioma oncology trials and translational research, LD well recognised patient advocate from Mesothelioma UK.

Lay abstract: Aims(s) of the research MARS 2 is an active pilot study that is demonstrating feasibility of recruitment into a trial comparing surgery versus no surgery for the treatment of patients with pleural mesothelioma. The full trial is designed to test the hypothesis that surgery is superior with respect to overall survival. Additional aims include the comparison of quality of life, cost effectiveness, improve recruitment into trials (by supporting and training the mesothelioma trials community) and provide tissue samples for research into early diagnosis, prediction of response to treatment and prognosis. Background to the research In the UK, over 2,000 patients are diagnosed yearly with pleural mesothelioma, a cancer of the lining of the chest wall and lung mainly due to previous (40 to 60 years ago) exposure to asbestos. Mesothelioma does not respond well to chemotherapy and is an extremely lethal form of cancer (half of patients in the UK die within 8.5 months of diagnosis), therefore surgery to remove as much of the disease as possible, is often considered as one of the most important treatment option. The only two surgical trials performed (both conducted in the UK) to date show neither extensive surgery (removing all disease in chest and entire lung - extra-pleural pneumonectomy) or limited surgery (removing some disease in the chest - partial pleurectomy) led to any improvement in survival, although there was some evidence of improved quality of life. Pleurectomy decortication is an intermediate form of surgery which removes disease in the chest but not the lung, but we do not know if this will prolong length of life and it will continue to be offered in an ad hoc and patchy manner in the UK (and worldwide) due to absence of high quality evidence of clinical efficacy. Design and methods The MARS 2 full trial will compare surgery (extended pleurectomy decortication) versus no surgery with respect to overall survival in patients with pleural mesothelioma. Patients deemed suitable for surgery will be approached and participants will receive 2 cycles of chemotherapy and a CT scan. If there is no significant worsening of cancer, participants will be randomised to either surgery and 4 further cycles of chemotherapy or no-surgery and 4 further cycles of chemotherapy. The trial is designed to detect a 30% relative difference in survival. An economic evaluation will be undertaken and experts in trial recruitment will be working closely with the trial team to optimise patient communication for recruitment. Our pilot trial is expected to recruit 65 patients by Apr 17 (exceeding our initial target of 50) and we aim to recruit a further 88 patients per year thereafter to complete total recruitment of 327 participants within the next 3 years. Patient and public involvement Patients and patient advocates were involved in the design of the trial, which sets out to address one of the top 10 most important questions prioritised by 103 patients and 242 carers as reported by the NIHR commissioned James Lind Alliance in 2013 for priority setting in mesothelioma research. Dissemination A full report will be written for HTA, we will write up findings for conference presentations and publication in peer-reviewed journals. We currently use social media to disseminate and publicise the trial via a website, Facebook and Twitter streams. Study findings are expected to change policy and practice in the UK and worldwide.

Research activity codes: 6.4 SURGERY
Health categories: CANCER AND NEOPLASMS