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

The Lancet Respiratory Medicine 2024 May 10 [Link]

Eric Lim, David Waller, Kelvin Lau, Jeremy Steele, Anthony Pope, Clinton Ali, Rocco Bilancia, Manjusha Keni, Sanjay Popat, Mary O’Brien, Nadza Tokaca, Nick Maskell, Louise Stadon, Dean Fennell, Louise Nelson, John Edwards, Sara Tenconi, Laura Socci, Robert C Rintoul, Kelly Wood, Amanda Stone, Dakshinamoorthy Muthukumar, Charlotte Ingle, Paul Taylor, Laura Cove-Smith, Raffaele Califano, Yvonne Summers, Zacharias Tasigiannopoulos, Andrea Bille, Riyaz Shah, Elizabeth Fuller, Andrew Macnair, Jonathan Shamash, Talal Mansy, Richard Milton, Pek Koh, Andreea Alina Ionescu, Sarah Treece, Amy Roy, Gary Middleton, Alan Kirk, Rosie A Harris, Kate Ashton, Barbara Warnes, Emma Bridgeman, Katherine Joyce, Nicola Mills, Daisy Elliott, Nicola Farrar, Elizabeth Stokes, Vikki Hughes, Andrew G Nicholson, Chris A Rogers


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.