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

Abstract

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).

Figure 1

Trial profile Reasons why participants did not complete the initial two cycles of chemotherapy or have a repeat CT are provided in the appendix (p 24). Of the 392 participants who underwent a repeat CT scan after the initial two courses of chemotherapy, 35 had disease progression beyond surgically resectable limits and were excluded due to ineligibility. A further 33 participants had evidence of disease progression but were still deemed to be surgically resectable; 28 of these 33 participants were randomly assigned. *One participant assigned to the surgery group withdrew and received surgery privately, so no surgical data were available for this participant. One participant in the surgery group and two participants in the no-surgery group withdrew from completing quality-of-life questionnaires but continued with clinical follow-up and so are not included as withdrawals, as they were assessed for outcomes following the withdrawal.

Figure 2

(A) Overall survival and (B) progression-free survival (A) Median survival: surgery 19·3 months (IQR 10·0–33·7), no surgery 24·8 months (12·6–37·4). Survival probabilities at 24 months: surgery 0·41 (95% CI 0·34–0·49), no surgery 0·52 (0·44–0·59). (B) Median progression-free survival: surgery 10·6 months (IQR 6·3–21·6), no surgery 11·0 months (5·9–19·6). Survival probabilities at 24 months: surgery 0·22 (95% CI 0·16–0·29), no surgery 0·17 (0·12–0·24). HR=hazard ratio. RMST=restricted mean survival time.

Figure 3

(A) GHS–QoL scores and (B) EQ-5D utility scores over time in survivors QLQ-C30 GHS–QoL scores range from 0 to 100; higher scores indicate better health. For EQ-5D, scores range from –0·594 to 1; higher scores indicate better quality of life, and death has a score of zero. GHS–QoL=global health status–quality of life. MD=mean difference. Prerand=prerandomisation. QLQ-C30=European Organisation for Research and Treatment of Cancer core health-related quality of life questionnaire.

Figure 4

(A) Survival by histological subtype and (B) primary outcome sensitivity and exploratory analyses Estimates are provided for the period 0–42 months. Instrumental variable analysis accounts for crossovers. HR=hazard ratio. RMST=restricted mean survival time, months (95% CI). *Analysis using 4 × average half-life of chemotherapy drugs received to determine when time-varying covariate is switched off (=0). †Analysis turning time-varying covariate off (=0) 21 days after the end of chemotherapy (appendix pp 11–12).