Why the MARS2 Trial Does Not Mean the End of All Mesothelioma Surgery

Our plain-English summary of Why the MARS2 Trial Does Not Mean the End of All Mesothelioma Surgery, by D. Waller, R. Bilancia, L. Ventura, et al (Cancers, 2025).

The study

• Authors: D. Waller, R. Bilancia, L. Ventura, S. Tenconi, L. Socci, A. Bille
• Journal: Cancers
• Published: 2025;17(5)
• Cited by: 4 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background/objectives: The published report of the MARS2 trial suggested that the addition of extended pleurectomy/decortication to chemotherapy for pleural mesothelioma was harmful. Thus, the report goes on, all disease should be considered as unresectable and no further mesothelioma surgery for survival benefit should be considered. This statement has changed clinical practice in the UK; however, the design of the MARS2 trial has several limitations which should prevent its conclusions being over interpreted. These limitations include the following: the inclusion of too many patients who would fall outside contemporary selection criteria including age, co-morbidity and histology; the unnecessary resection of too much tissue, particularly the diaphragm, and operating on patients too late in the disease process due to less than rigorous staging.

Methods: We retrospectively analysed the selection and outcome of data of 79 of the 158 (50%) patients who underwent surgery in the surgical arm of the MARS2 study who were operated by the authors in four of the five trial surgical centres. We revised the clinical staging of these patients by applying the criteria in the forthcoming 9th TNM edition including the measurement of pleural thickness.

Results: Based on reported guidelines, the selection for surgery was reset as stage I or II epithelioid PM. We found that 52 (66%) of these patients (group A) would not have been considered for surgery using contemporary selection criteria for the following reasons: non-epithelioid PM in 5; cT/4 in 35; cT2N1 in 10 and 2 cT2N0 (pN1), which would have been detected on preoperative mediastinal biopsy. Of the 27 (34%) trial patients fulfilling current criteria (group B), 12 were cT1N0, 1 was cT1N1, 6 were cT1N0pN1 and 8 were cT2N0, all with epithelioid PM. The median survival of group B was 32 (1-72) months, which was significantly higher than in group A: 8.5 (1-55) months, p < 0.0005 (Mann-Whitney).

Conclusions: As contemporary selection criteria were not applied in MARS2, its conclusions cannot be universally applied to all those with PM. Together with the favourable postoperative survival in this selected group, we suggest that there is still scope for a further trial of surgery in early-stage epithelioid mesothelioma.

In plain English

This short communication was a post hoc, retrospective re-analysis of patients from the surgical arm of MARS2. MARS2 was a UK trial that compared extended pleurectomy/decortication plus chemotherapy with chemotherapy alone for pleural mesothelioma. The authors had operated on these patients, and the lead author described being the trial's lead recruiter. They examined 79 of the 158 patients who had surgery in MARS2, from four of the five trial surgical centres. They re-staged each patient from pre-treatment CT scans using the 9th TNM edition, including pleural thickness measurements. They assumed that current practice would operate only on epithelioid stage I or II disease. By these criteria, 52 patients (group A) would have been excluded and 27 (34%, group B) would have qualified. Median survival was 32 months (range 1 to 72) in group B versus 8.5 months (range 1 to 55) in group A, reported as a statistically significant difference. The authors concluded that MARS2's conclusions cannot be applied to all patients with pleural mesothelioma and that a further trial of surgery in early-stage epithelioid mesothelioma remains possible. The article did not study asbestos exposure.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Communication reporting a post hoc retrospective re-analysis of part of the surgical arm of the MARS2 randomised trial
• Who was studied: 79 of the 158 patients who had surgery in the MARS2 trial, operated on by the authors at four of the five UK trial surgical centres: St Bartholomew's 59, Glasgow 10, Sheffield 6, Guy's 4
• Exposure: No asbestos exposure was studied. The treatment examined was extended pleurectomy/decortication (surgery) in the MARS2 trial, with patients re-staged under the 9th TNM edition
• Main results:
  • Of the 79 patients, 52 (group A) had clinical stage T2N1 or above or non-epithelioid mesothelioma; only 27 (34%, group B) remained in epithelioid stage I or II
  • Reasons for exclusion in group A: 5 non-epithelioid on pre-treatment biopsy (4 biphasic, 1 pure sarcomatoid), 32 cT3/4, 3 with Psum over 30 mm, 10 cT2N1 and 2 cT2 pN1 (Table 2)
  • Group B consisted of 12 cT1N0, 8 cT2N0, 1 cT1N1 and 6 cT1 pN1 patients, all epithelioid
  • On postoperative pathology, epithelioid mesothelioma was reported in only 22 of the 79 (28%) patients, and only 12 of 79 (15%) remained in epithelioid stage I or II
  • Median survival was 32 (1 to 72) months in group B and 8.5 (1 to 55) months in group A, reported as significantly higher in group B (Mann–Whitney test)
• The authors' conclusion: The authors concluded that because contemporary selection criteria were not applied in MARS2, its conclusions cannot be universally applied to all patients with pleural mesothelioma, and that there is still scope for a further trial of surgery in early-stage epithelioid mesothelioma
• Limitations the authors state:
  • Data were available only from four of the five trial surgical centres; data from the Leicester centre and from one Sheffield surgeon were not available
  • The re-classification rested on the authors' assumption that modern specialist centres would operate only on epithelioid stage I or II disease

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Pleurectomy/Decortication (P/D), Chemotherapy, Pleural Mesothelioma, Unresectable, Histology, Diaphragm, Staging.

Related studies

• 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 — E. Lim, L. Darlison, et al. (2020)
• Patient experiences of participation in a radical thoracic surgical trial: findings from the Mesothelioma and Radical Surgery Trial 2 (MARS 2) — C. Warnock, K. Lord, et al. (2019)
• Strategies to address recruitment to a randomised trial of surgical and non-surgical treatment for cancer: results from a complex recruitment intervention within the Mesothelioma and Radical Surgery 2 (MARS 2) study — N. Mills, N. Farrar, et al. (2024)
• Extra-pleural pneumonectomy versus no extra-pleural pneumonectomy for patients with malignant pleural mesothelioma: clinical outcomes of the Mesothelioma and Radical Surgery (MARS) randomised feasibility study — T. Treasure, L. Lang-Lazdunski, et al. (2011)
• The MARS feasibility trial: conclusions not supported by data — W. Weder, R.A. Stahel, et al. (2011)
• How does the timing of chemotherapy affect outcome following radical surgery for malignant pleural mesothelioma? — A.J. Sharkey, K.J. O'Byrne, et al. (2016)

Browse more research in Cancers, or return to medical research.