Extended pleurectomy decortication and chemotherapy versus chemotherapy alone for pleural mesothelioma (MARS 2): a phase 3 randomised controlled trial.

BACKGROUND: Extended pleurectomy decortication for complete macroscopic resection for pleural mesothelioma has never been evaluated in a randomised trial. The aim of this study was to compare outcomes after extended pleurectomy decortication plus chemotherapy versus chemotherapy alone. METHODS: MARS 2 was a phase 3, national, multicentre, open-label, parallel two-group, pragmatic, superiority randomised controlled trial conducted in the UK. The trial took place across 26 hospitals (21 recruiting only, one surgical only, and four recruiting and surgical). Following two cycles of chemotherapy, eligible participants with pleural mesothelioma were randomly assigned (1:1) to surgery and chemotherapy or chemotherapy alone using a secure web-based system. Individuals aged 16 years or older with resectable pleural mesothelioma and adequate organ and lung function were eligible for inclusion. Participants in the chemotherapy only group received two to four further cycles of chemotherapy, and participants in the surgery and chemotherapy group received pleurectomy decortication or extended pleurectomy decortication, followed by two to four further cycles of chemotherapy. It was not possible to mask allocation because the intervention was a major surgical procedure. The primary outcome was overall survival, defined as time from randomisation to death from any cause. Analyses were done on the intention-to-treat population for all outcomes, unless specified. This study is registered with ClinicalTrials.gov, NCT02040272, and is closed to new participants. FINDINGS: Between June 19, 2015, and Jan 21, 2021, of 1030 assessed for eligibility, 335 participants were randomly assigned (169 to surgery and chemotherapy, and 166 to chemotherapy alone). 291 (87%) participants were men and 44 (13%) women, and 288 (86%) were diagnosed with epithelioid mesothelioma. At a median follow-up of 22·4 months (IQR 11·3-30·8), median survival was shorter in the surgery and chemotherapy group (19·3 months [IQR 10·0-33·7]) than in the chemotherapy alone group (24·8 months [IQR 12·6-37·4]), and the difference in restricted mean survival time at 2 years was -1·9 months (95% CI -3·4 to -0·3, p=0·019). There were 318 serious adverse events (grade ≥3) in the surgery group and 169 in the chemotherapy group (incidence rate ratio 3·6 [95% CI 2·3 to 5·5], p<0·0001), with increased incidence of cardiac (30 vs 12; 3·01 [1·13 to 8·02]) and respiratory (84 vs 34; 2·62 [1·58 to 4·33]) disorders, infection (124 vs 53; 2·13 [1·36 to 3·33]), and additional surgical or medical procedures (15 vs eight; 2·41 [1·04 to 5·57]) in the surgery group. INTERPRETATION: Extended pleurectomy decortication was associated with worse survival to 2 years, and more serious adverse events for individuals with resectable pleural mesothelioma, compared with chemotherapy alone. FUNDING: National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (15/188/31), Cancer Research UK Feasibility Studies Project Grant (A15895).

Treatment Allocation and Survival in Patients Diagnosed with Nonmetastatic Muscle-invasive Bladder Cancer: An Analysis of a National Patient Cohort in England.

BACKGROUND: UK Bladder cancer survival remains low. Nonmetastatic muscle-invasive bladder cancer (MIBC) is potentially curable. It is unclear how many patients receive nonradical treatment owing to advanced age, comorbidities, or alternative factors. OBJECTIVE: To describe treatments and assess survival by disease stage and sex for all newly diagnosed nonmetastatic MIBC in England in 2016, and to observe associations between comorbidities and treatments. DESIGN, SETTING, AND PARTICIPANTS: All new nonmetastatic MIBC diagnoses in England in 2016 were identified retrospectively using National Cancer Registration and Analysis Service, Radiotherapy Datasets, Systemic Anti-Cancer Therapy, and Hospital Episode Statistics databases. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Age, Charlson Comorbidity Index (CCI), and treatments were ascertained, and 1-yr survival was estimated using Pohar-Perme and Kaplan-Meier methods. RESULTS AND LIMITATIONS: Nonmetastatic MIBC diagnoses were registered for 2519 patients (median age 76 yr). Radical cystectomy was performed in 24%, 37% of whom received neoadjuvant chemotherapy (NAC). Radical radiotherapy was performed in 29%, 48% of whom received NAC. NAC alongside radical treatment was associated with higher 1-yr overall survival (OS)-91% (88-93%) with NAC and 83% (80-85%) without (p = 0.05). Nonradical treatments occurred for 47%, with corresponding lower OS. Females with stage II and III disease had significantly lower net survival (NS). Radically treated patients had lower CCIs. CONCLUSIONS: This analysis provides an overview of all nonmetastatic MIBC diagnosed in England in 2016. Just over half of the patients received curative-intent treatment. Of them, only 43% received NAC. One-year OS was disparate, correlating with treatment intensity. Those receiving NAC and radical therapy demonstrated highest OS. Female patients had significantly inferior NS. The data highlight a prescient unmet research need to understand the patient demographic and reasons behind treatment allocation, to address the poor survival observed in those treated nonradically, and the low NAC utilisation. The significantly aged population requires specific future focus. PATIENT SUMMARY: We looked at all patients in England in 2016 who were diagnosed with bladder cancer invading the bladder muscle. Many patients were elderly, and the most intensive treatments aiming for cure were frequently not used. Survival in women was found to be considerably worse, as was survival for less intensively treated patients.

Mesothelioma and Radical Surgery 2 (MARS 2): protocol for a multicentre randomised trial comparing (extended) pleurectomy decortication versus no (extended) pleurectomy decortication for patients with malignant pleural mesothelioma.

INTRODUCTION: Mesothelioma remains a lethal cancer. To date, systemic therapy with pemetrexed and a platinum drug remains the only licensed standard of care. As the median survival for patients with mesothelioma is 12.1 months, surgery is an important consideration to improve survival and/or quality of life. Currently, only two surgical trials have been performed which found that neither extensive (extra-pleural pneumonectomy) or limited (partial pleurectomy) surgery improved survival (although there was some evidence of improved quality of life). Therefore, clinicians are now looking to evaluate pleurectomy decortication, the only radical treatment option left. METHODS AND ANALYSIS: The MARS 2 study is a UK multicentre open parallel group randomised controlled trial comparing the effectiveness and cost-effectiveness of surgery-(extended) pleurectomy decortication-versus no surgery for the treatment of pleural mesothelioma. The study will test the hypothesis that surgery and chemotherapy is superior to chemotherapy alone with respect to overall survival. Secondary outcomes include health-related quality of life, progression-free survival, measures of safety (adverse events) and resource use to 2 years. The QuinteT Recruitment Intervention is integrated into the trial to optimise recruitment. ETHICS AND DISSEMINATION: Research ethics approval was granted by London - Camberwell St. Giles Research Ethics Committee (reference 13/LO/1481) on 7 November 2013. We will submit the results for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBERS: ISRCTN-ISRCTN44351742 and ClinicalTrials.gov-NCT02040272.