Everything You Need to Know about the MARS2 Trial for Mesothelioma Surgery

A diagnosis of pleural mesothelioma brings with it a number of difficult decisions. One of the biggest questions many patients face is whether surgery should be part of their treatment. For years, surgery was considered an important option for carefully selected patients, especially when the cancer appeared to be confined to one side of the chest. However, new research has challenged that belief and sparked an important debate among mesothelioma specialists worldwide.

Two recently published papers help explain why. The first is the MARS2 clinical trial, the largest randomized (the gold standard of science) study ever conducted to compare surgery plus chemotherapy with chemotherapy alone for pleural mesothelioma. The second is a follow-up perspective article written by international experts, with one group supporting the trial’s conclusions and another arguing that the study has important limitations.

For patients and families, the message is more nuanced than headlines suggesting that “surgery doesn’t work.” Instead, these papers suggest that the decision about surgery should be individualized and made by an experienced multidisciplinary mesothelioma team.

What did the MARS2 trial find?

The MARS2 trial enrolled 335 patients with resectable (operable) pleural mesothelioma after they had completed two cycles of chemotherapy. Participants were randomly assigned to either continue chemotherapy alone or undergo extended pleurectomy decortication (EPD), a lung-sparing operation that removes the lining of the lung and any visible tumor and is then followed by additional chemotherapy.

The results surprised many specialists. Patients assigned to surgery had a median survival of 19.3 months compared with 24.8 months for patients treated with chemotherapy alone. Surgery was also associated with substantially more serious complications, including respiratory problems, infections, and cardiac complications. Patients who underwent surgery also experienced worse quality of life during recovery and higher overall treatment costs.

Because this was a randomized clinical trial, many researchers consider it the strongest evidence available on the role of surgery in mesothelioma. The authors concluded that extended pleurectomy decortication should not be routinely offered as part of standard treatment because it was associated with worse outcomes than chemotherapy alone.

Why is there still disagreement among experts?

Although the MARS2 trial is an important milestone, it did not end the discussion. If anything, it intensified it. Soon after publication, leading thoracic surgeons and mesothelioma experts published a detailed perspective article that presented two opposing interpretations of the study.

Argument against Surgery

One group argued that MARS2 confirms what previous randomized studies have suggested: major surgery has never been proven to improve survival in mesothelioma. They note that many earlier reports supporting surgery came from highly selected patients treated at expert centers without comparison groups. Those patients often had better outcomes because they were healthier and had less aggressive disease, not necessarily because surgery itself prolonged survival.

This group believes that patients should receive treatments that have proven benefits and that future advances are more likely to come from improving systemic therapies such as immunotherapy, targeted therapies, and other novel treatments rather than relying on extensive surgery. They also point out that patients recovering from major surgery often cannot complete the full course of chemotherapy or receive additional treatments that may improve survival.

Argument for Surgery

The second group of experts agrees that MARS2 raises important questions but argues that the study should not be interpreted as evidence that surgery has no role.

Their main concern is patient selection.

They note that patients were randomized after only two cycles of chemotherapy rather than after the standard four to six cycles often recommended in treatment guidelines. They also point out that modern staging tools, including PET-CT scans and invasive mediastinal lymph node evaluation, were not consistently used throughout the study. Without these tests, some patients may have had more advanced disease than initially recognized.

The authors also argue that many patients included in MARS2 would not meet today’s surgical selection criteria. They believe surgery should be reserved for patients with early-stage disease, favorable tumor biology, good physical fitness, and treatment at highly specialized mesothelioma centers with experienced multidisciplinary teams.

Perhaps their greatest concern was the surgical mortality reported in the trial. Approximately 9% of patients died within 90 days of surgery, which they argue is substantially higher than rates reported by several experienced international centers. They believe this early mortality could have obscured any potential long-term benefit in carefully selected patients.

In other words, these experts do not believe MARS2 proves that surgery is ineffective. Instead, they believe it highlights how important careful patient selection and expert surgical care are.

What does this mean for patients today?

For most patients, these papers suggest that surgery should no longer be viewed as an automatic recommendation simply because the cancer appears resectable. Instead, it should be considered one possible option among several treatments.

Patients should understand that surgery for mesothelioma is a major operation with significant risks. Recovery can take months, and complications may delay or prevent additional treatments such as chemotherapy or immunotherapy.

At the same time, the perspective article makes it clear that many international experts still believe carefully selected patients may benefit from surgery, particularly when treated at experienced centers with specialized mesothelioma teams.

This means the question is no longer simply, “Can the tumor be removed?” Instead, the more important questions include:

• Is yours the right type of mesothelioma for surgery?
• Is the disease truly limited enough for surgery?
• Is the patient healthy enough to tolerate a major operation?
• Will surgery improve the overall treatment plan?
• Is the procedure being performed at a center with extensive mesothelioma experience?

These questions require input from thoracic surgeons, medical oncologists, radiation oncologists, radiologists, and pathologists who specialize in mesothelioma.

Should you get a surgical consultation?

Even though MARS2 has changed the conversation, it has not eliminated the role of surgical consultation.

Meeting with an experienced mesothelioma surgeon does not mean you must have surgery. Instead, it allows you to understand whether you might be a reasonable candidate, what the expected benefits and risks are in your specific situation, and whether non-surgical treatments may be among your options. It is simply another option in your treatment arsenal.

For some patients, the consultation may confirm that surgery is unlikely to help. For others, particularly those with favorable disease characteristics and excellent overall health, surgery may still be considered as part of a personalized multimodality treatment plan.

Seeking a second opinion at a high-volume mesothelioma center can also be valuable, especially if recommendations differ between physicians.

The bottom line

The MARS2 trial represents the strongest randomized evidence available and suggests that routine surgery for pleural mesothelioma does not improve survival and may increase complications and reduce quality of life. These findings have appropriately prompted many physicians to reconsider the traditional role of surgery.

However, the subsequent perspective article demonstrates that respected international experts remain divided about how broadly these findings should be applied. Critics argue that limitations in patient selection, staging, surgical expertise, and trial design may have prevented surgery from demonstrating its potential benefit in carefully selected patients.

For patients and families, the most important takeaway is that treatment decisions should be individualized rather than based on a single headline or study. Surgery is no longer considered an automatic recommendation for resectable mesothelioma, but neither has it been completely abandoned by the expert community.

If you have been diagnosed with pleural mesothelioma, it is reasonable to discuss surgery with a multidisciplinary team at an experienced mesothelioma center. Understanding both the potential risks and the ongoing scientific debate can help you make an informed decision that reflects your personal goals, overall health, and the characteristics of your disease.

Sources

Lim E, Opitz I, Woodard G, Bueno R, de Perrot M, Flores R, Gill R, Jablons D, Pass H. A Perspective on the MARS2 Trial. J Thorac Oncol. 2025 Mar;20(3):262-272. doi: 10.1016/j.jtho.2024.12.014. Epub 2025 Jan 8. PMID: 39772349.

Lim E, Waller D, Lau K, Steele J, Pope A, Ali C, Bilancia R, Keni M, Popat S, O’Brien M, Tokaca N, Maskell N, Stadon L, Fennell D, Nelson L, Edwards J, Tenconi S, Socci L, Rintoul RC, Wood K, Stone A, Muthukumar D, Ingle C, Taylor P, Cove-Smith L, Califano R, Summers Y, Tasigiannopoulos Z, Bille A, Shah R, Fuller E, Macnair A, Shamash J, Mansy T, Milton R, Koh P, Ionescu AA, Treece S, Roy A, Middleton G, Kirk A, Harris RA, Ashton K, Warnes B, Bridgeman E, Joyce K, Mills N, Elliott D, Farrar N, Stokes E, Hughes V, Nicholson AG, Rogers CA; MARS 2 Investigators. Extended pleurectomy decortication and chemotherapy versus chemotherapy alone for pleural mesothelioma (MARS 2): a phase 3 randomised controlled trial. Lancet Respir Med. 2024 Jun;12(6):457-466. doi: 10.1016/S2213-2600(24)00119-X. Epub 2024 May 10. PMID: 38740044; PMCID: PMC11136673.