REPORT: Reaffirming the Role of Surgery in Pleural Mesothelioma Treatment

3. Analysis and Critique of MARS 2

The authors identify several critical flaws in MARS 2, undermining its conclusions:

Trial Design and Selection Bias

• Patients were randomized only after two cycles of chemotherapy, excluding those who progressed early or became unfit—leading to selection of chemotherapy responders.
• No intent-to-treat analysis was conducted, eliminating meaningful survival comparisons from diagnosis.

Inadequate Staging and Candidate Selection

• PET-CT and mediastinal staging were inconsistently used, violating standard protocols.
• Some patients had metastatic (M1) disease, which should exclude them from surgical candidacy.
• Inclusion of patients with biphasic and sarcomatoid histologies, which respond poorly to surgery, skewed results.

Surgical Quality and Volume Concerns

• Nearly half the surgeries were done at low-volume centers (≤3 ePDs/year).
• Significant variation in surgical techniques and lack of standardization.
• High R2 resection rate (22%), indicating incomplete tumor removal in many cases.
• 30-day and 90-day mortality rates (4% and 9%) were higher than contemporary benchmarks.

Chemotherapy Disparities

• Many surgical patients did not complete adjuvant chemotherapy (only 39% did), weakening the multimodal approach.
• Control arm patients had greater access to subsequent therapies, including immunotherapy, which improved their outcomes.

Taken together, these design and execution flaws—including biased patient selection, inadequate staging, suboptimal surgical quality, and unequal systemic therapy access—severely undermine the reliability of the MARS 2 findings. As the authors conclude, the trial's results should not be generalized to broader clinical practice or used to justify the elimination of surgery for appropriately selected mesothelioma patients.

4. Evidence Supporting Surgery in Multimodal Treatment

The authors also emphasized that, despite MARS 2’s findings, modern studies consistently show that ePD performed at experienced centers, as part of a multimodal regimen, can result in markedly superior survival outcomes compared to chemotherapy alone: 

In contrast, modern trials involving systemic therapy only report lower survival:

• CheckMate 743 (2021): OS of 18.1 months with nivolumab + ipilimumab
• MAPS Trial (2016): OS of 18.8 months with chemo + bevacizumab

5. Conclusion and Recommendations

While the MARS 2 trial adds to the conversation about mesothelioma treatment, it suffers from serious design flaws, bias in patient selection, inadequate staging, and surgical quality concerns that render its conclusions unreliable for broad clinical application. In contrast, high-quality, real-world data consistently supports the role of surgery in selected patients with epithelioid mesothelioma and favorable performance status.

Recommendations:

• Surgery remains essential for selected patients and should not be eliminated from the therapeutic armamentarium for pleural mesothelioma.
• Treatment decisions must be individualized, and surgery should be considered at high-volume, experienced centers as part of a comprehensive multimodal plan.
• Clinical interpretation of MARS 2 should be tempered with expert judgment and awareness of its limitations.