Cytoreductive Surgery for Pleural Mesothelioma: For Whom Is It Still an Option?

A Critical Appraisal of Patient Selection, Treatment Sequencing, and Current Evidence

Clarifying the terminology is essential to clarify the debate. “Surgery” in mesothelioma is not a single intervention; it includes procedures of different extent and purpose. In the current WHO classification, the disease is increasingly referred to as “pleural mesothelioma” or “diffuse pleural mesothelioma (DPM)” rather than “malignant pleural mesothelioma,” although the abbreviation MPM remains common in the literature.

Published in Lancet Respiratory Medicine in 2024, MARS2 (Mesothelioma and Radical Surgery 2) is the most important and most controversial study in this field. It was the first phase 3 trial to test eP/D in a randomized, controlled manner; until then, the entire evidence base for surgery rested on case series.

At first glance, this result was read as the end of surgery. However, as soon as MARS2 was published, the mesothelioma surgical community raised strong, methodologically serious criticisms. These criticisms matter because a “negative” study does not prove that an intervention is ineffective — this depends on whether the study tested that intervention correctly in the right patient group.

Alongside the gloomy picture from MARS2, studies reporting much more favorable results must be considered. Foremost among these is EORTC 1205 , a randomized phase 2 study evaluating a standardized P/D protocol with neoadjuvant and adjuvant cisplatin/pemetrexed.

An important contribution from Turkey also enters the picture here. The work in thoracic surgery of Hasan Fevzi Batırel, who has published extensively on mesothelioma surgery, showed in a 2018 series of 154 patients that macroscopic complete resection (MCR) was not associated with a survival advantage: 21,4 months with MCR versus 16,3 months without, not statistically significant. This was an important early signal questioning “complete resection at any cost” and anticipating MARS2’s results: aggressive surgery alone did not determine survival. Batırel’s studies contributed to shaping the current view that patient selection and surgical intensity must be balanced.

This is the point on which the whole debate turns. Read together, MARS2 and its criticisms suggest that surgery may harm an unselected population but may remain valuable in a carefully selected subgroup. Current expert opinion, including the updated ASCO 2026 guidelines, frames selection criteria as follows.

To keep the surgical debate in context, an essential fact must be emphasized: surgery’s “competitor” is no longer the old, weak chemotherapy. Systemic therapy has strengthened substantially in recent years, making the “no-surgery” arm far more competitive.

Even when surgery is planned, the increasingly strong trend is toward giving systemic therapy first as neoadjuvant/induction treatment. There are several logical reasons for this, and recent systematic reviews document the trend.

The shift in systemic treatment toward immunotherapy is also changing the neoadjuvant field. Case reports and early-phase studies describe surgery after neoadjuvant chemo-immunotherapy and even complete pathological response in selected cases; the feasibility of salvage P/D after immunotherapy has also been demonstrated. However, these approaches remain investigational, not routine standards.

Another modality added to surgery is hyperthermic intrathoracic chemotherapy (HITHOC/HITOC) : rinsing the chest cavity after cytoreduction with a heated chemotherapy solution, usually cisplatin. The rationale is to target residual microscopic disease with a high local dose plus the effect of heat.

When all the evidence is considered together, there is no single answer to “Should surgery be performed?” The answer depends on the patient, histology, stage, center, and overall treatment approach. The framework below summarizes the common conclusions of current literature.

The role of cytoreductive surgery in diffuse pleural mesothelioma has been fundamentally redefined over the past few years. MARS2 demonstrated at a randomized level that aggressive surgery does not improve survival in an unselected population and may even cause harm. However, its methodological criticisms and alternative evidence such as EORTC 1205 showed that surgery may still be valuable in well-selected patients at experienced centers. At the same time, strengthening systemic treatment through immunotherapy raised the benchmark for nonsurgical care and sharpened the decision by histology. Systemic treatment takes priority in non-epithelioid patients, while a multimodal approach in selected patients with early-stage epithelioid disease — preferably after neoadjuvant systemic therapy and with lung-sparing surgery — remains under discussion. The shared message of all the evidence is clear, including Hasan Fevzi Batırel’s early findings that macroscopic complete resection alone does not determine survival: the right question in mesothelioma is not “surgery or no surgery?” but “which patient, in what sequence, at which center, and within which overall treatment approach?” This decision can only be made through individual assessment of each patient by an experienced multidisciplinary team.

This article is a medical review intended for information; it does not provide individual treatment guidance or replace clinical guidelines. Decisions on surgery in diffuse pleural mesothelioma must be made by an experienced multidisciplinary oncology team based on each patient’s histology, stage, performance status, and individual characteristics. The studies discussed do not provide equal levels of evidence: MARS2 is randomized phase 3, EORTC 1205 is phase 2, and many other findings come from retrospective series or systematic reviews. Favorable survival outcomes in well-selected series may involve selection bias. MARS2’s results and the methodological criticisms directed at it should be considered together. Systemic therapy, including immunotherapy, is evolving rapidly; the information presented reflects the date the article was prepared. Randomized validation is limited for many approaches such as HITHOC and neoadjuvant immunotherapy. All data have been verified from Lancet Respiratory Medicine, Lancet, Annals of Thoracic Surgery, Journal of Clinical Oncology, Translational Lung Cancer Research, Annals of Oncology, and relevant current literature.