Neoadjuvant systemic therapy for pleural mesothelioma patients: a systematic review

Our plain-English summary of Neoadjuvant systemic therapy for pleural mesothelioma patients: a systematic review, by I. Smesseim, J. Raskin, J.A. Burgers (Translational Lung Cancer Research, 2025).

The study

• Authors: I. Smesseim, J. Raskin, J.A. Burgers
• Journal: Translational Lung Cancer Research
• Published: 2025;14(10):4618-4627
• Type of article: Review
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Pleural mesothelioma is an aggressive malignancy with a poor prognosis. The role of surgery in its management remains controversial, with ongoing debate regarding the definition of resectable disease. Neoadjuvant therapy aims to reduce tumor burden. This systematic review evaluates prospective neoadjuvant trials in pleural mesothelioma to identify subgroups that may benefit from this approach.

Methods: A systematic search was conducted from inception to July 01, 2024, for phase II/III prospective trials evaluating neoadjuvant systemic therapy followed by surgery in adult patients with histologically confirmed pleural mesothelioma. Data were extracted on patient characteristics, treatment regimens, surgical outcomes, survival, and adverse events.

Results: Sixteen trials were found: 861/1,184 patients (72.7%) were male, median age ranged between 57-69 years. Neoadjuvant chemotherapy was used in 15 trials and immunotherapy in one trial. Surgery was performed in 61.8% of patients, with extrapleural pneumonectomy (EPP) being the predominant approach. Median overall survival in single-arm trials was 17.4 months [95% confidence interval (CI): 15.8-19.0], n=523 for the intention-to-treat population and 21.4 months (95% CI: 19.2-23.7), n=345 for the surgery population. The phase III trial (MARS-2) comparing neoadjuvant chemotherapy plus extended pleurectomy decortication versus chemotherapy alone found a shorter median survival in the surgery and chemotherapy group {19.3 months [interquartile range (IQR), 10.0-33.7 months] vs. 24.8 months (IQR, 12.6-37.4 months), P=0.01}.

Conclusions: This review shows that the predominant neoadjuvant approach consists of platinum doublet chemotherapy, but the role of immunotherapy is being explored. Additional randomized trials are needed to determine the optimal neoadjuvant strategy and patient subgroups most likely to benefit.

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In plain English

This systematic review gathered prospective phase II and III trials in which adults with pleural mesothelioma received systemic therapy before surgery (called neoadjuvant therapy). The authors searched MEDLINE and Embase up to July 1, 2024, and found 16 trials with 1,184 patients, of whom 861 (72.7%) were male. The article does not discuss asbestos exposure. Fifteen trials used chemotherapy, mostly platinum-based combinations. One trial used the immunotherapy drug durvalumab, alone or with tremelimumab. Surgery was performed in 61.8% of patients, most often extrapleural pneumonectomy. Across single-arm trials, the pooled median overall survival was 17.4 months (95% CI 15.8 to 19.0; n=523) for all enrolled patients and 21.4 months (95% CI 19.2 to 23.7; n=345) for those who had surgery. In the phase III MARS-2 trial, patients given chemotherapy plus extended pleurectomy decortication had shorter median survival than those given chemotherapy alone (19.3 vs 24.8 months, P=0.01). The authors concluded that evidence supporting surgery in these strategies is limited and that more randomized trials are needed. They noted that differences between the trials made direct comparisons difficult.

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: Systematic review of prospective trials (12 non-randomized phase II, 2 randomized phase II, 2 randomized phase III), with pooled estimates of median survival from the single-arm trials
• Who was studied: 16 trials of adults (aged 18 or over) with histology-proven pleural mesothelioma, 1,184 patients in total, of whom 861 (72.7%) were male; median ages ranged from 57 to 69 years; trials were conducted in Switzerland, the USA, Italy, Belgium, the Netherlands, Egypt, the UK, Germany and Japan; databases were searched from inception to July 01, 2024
• Exposure: No asbestos exposure was studied. The review examined systemic treatment given before surgery: chemotherapy in 15 trials (platinum plus gemcitabine, platinum plus pemetrexed, cisplatin-mitomycin-vinblastine, cisplatin-vinorelbine) and immunotherapy (durvalumab alone or with tremelimumab) in one trial
• Main results:
  • Across all included patients, surgery was performed in 61.8%, and extrapleural pneumonectomy (EPP) was the most common operation
  • In the single-arm trials, the pooled median overall survival for the intention-to-treat population (all enrolled patients) was 17.4 months (95% CI 15.8 to 19.0), n=523
  • In the single-arm trials, the pooled median overall survival for patients who underwent surgery was 21.4 months (95% CI 19.2 to 23.7), n=345
  • In the phase III MARS-2 trial (Lim 2024), median survival was 19.3 months (IQR 10.0 to 33.7) in the extended pleurectomy decortication plus chemotherapy group versus 24.8 months (IQR 12.6 to 37.4) in the chemotherapy-alone group, P=0.01
  • MARS-2 also reported more serious adverse events in the surgery group than in the chemotherapy group (incidence rate ratio 3.6, 95% CI 2.3 to 5.5, P less than 0.0001)
  • Across the trials, 90-day postoperative mortality ranged from 0 to 13.3%, and the share of each trial's intention-to-treat population ultimately deemed resectable ranged from 42% to 93%
  • In the single-arm studies, the most common grade 3 or higher events after neoadjuvant systemic therapy were neutropenia (9.5%), leukopenia (3.8%) and anemia (3.5%). After surgery, the most common were arrhythmias (11.1%), pulmonary hemorrhage (4.7%) and pulmonary infection (4.5%)
  • In the single immunotherapy trial (Lee 2023), three patients (27.3%) in the combination immunotherapy group developed grade 3 toxicities
• The authors' conclusion: The authors concluded that there is limited evidence supporting the role of surgery in neoadjuvant strategies for pleural mesothelioma, because MARS-2, the only study comparing neoadjuvant treatment with surgical treatment, showed significantly worse survival in the surgical group. They called for more randomized controlled trials and for standardized definitions and methods.
• Limitations the authors state:
  • Combining single-arm and randomized trials introduced variability in treatment protocols and outcome measures, making direct comparisons challenging
  • Most included trials were single-arm phase II studies, which limits how far the findings can be generalized
  • Patient selection criteria differed between trials, especially the definition of resectability, as did adjuvant treatment, so definitive conclusions are hard to draw
  • The surgical procedure changed over time, from EPP in earlier trials to extended P/D
  • Not all trials reported adverse events in the same way, and complete response was defined differently across studies

Topics

Medical terms in this study, explained in our Lexicon: Systemic Therapy, Pleural Mesothelioma, Systematic Review, Prognosis, Neoadjuvant Therapy, Tumor Burden, Immunotherapy, Extrapleural Pneumonectomy (EPP).

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