Extended pleurectomy decortication and chemotherapy versus chemotherapy alone for pleural mesothelioma (MARS 2): a phase 3 randomised controlled trial.
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Lim Eric, Waller David, Lau Kelvin, Steele Jeremy, Pope Anthony, Ali Clinton, Bilancia Rocco, Keni Manjusha, Popat Sanjay, O'Brien Mary, Tokaca Nadza, Maskell Nick, Stadon Louise, Fennell Dean, Nelson Louise, Edwards John, Tenconi Sara, Socci Laura, Rintoul Robert C, Wood Kelly, Stone Amanda, Muthukumar Dakshinamoorthy, Ingle Charlotte, Taylor Paul, Cove-Smith Laura, Califano Raffaele, Summers Yvonne, Tasigiannopoulos Zacharias, Bille Andrea, Shah Riyaz, Fuller Elizabeth, Macnair Andrew, Shamash Jonathan, Mansy Talal, Milton Richard, Koh Pek, Ionescu Andreea Alina, Treece Sarah, Roy Amy, Middleton Gary, Kirk Alan, Harris Rosie A, Ashton Kate, Warnes Barbara, Bridgeman Emma, Joyce Katherine, Mills Nicola, Elliott Daisy, Farrar Nicola, Stokes Elizabeth, Hughes Vikki, Nicholson Andrew G, Rogers Chris A, MARS 2 Investigators
Аннотация
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).