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).

Inflammatory appearance of the parietal pleura at thoracoscopy - What does it hide?

BACKGROUND: Medical thoracoscopy (MT) is a well-established diagnostic procedure in cases of unexplained exudative pleural effusions. Despite the advantages of MT, challenges remain since occasionally malignancies mimic pleural inflammation. OBJECTIVES: To assess the relationship between the macroscopic appearance of the pleura at MT, the histology of the pleural biopsy and the final diagnosis after follow up. METHODS: Data was prospectively collected on patients undergoing MT over 8 years, using a standardised electronic thoracoscopy report. We report the sensitivity, specificity, positive and negative predictive values (PPV, NPV) of the macroscopic changes, the sensitivity of computer tomographic (CT) appearances and final outcome. RESULTS: A total of 228 thoracoscopies and biopsy were performed, 70 reports described benign macroscopic changes; of these 15.7% had malignant histology. When the final outcome was taken into account, the sensitivity of macroscopic appearance at MT was 91.5%, specificity 76.0%, PPV 88.6% and the NPV 81.4%. Nodular changes were more likely to be associated with malignancy (Chi2 75.5, p < 0.05). The CT scans performed prior to thoracoscopy had a poor sensitivity for the diagnosis of malignant pleural effusion (50%) and a good specificity in the diagnosis of benign disease (90.5%). CONCLUSION: A standardised structured report allows reliable evaluation of the macroscopic findings at MT. The PPV of the macroscopic findings for malignancy is relatively high; however, in a significant minority of cases despite benign-looking macroscopic changes the final diagnosis was malignancy. Careful consideration must be given in cases with benign histology to either monitoring or further diagnostic tests based on clinical suspicion.