Beyond MARS 2: Perspectives on Surgery in Pleural Mesothelioma With Jeffrey Velotta, MD

What MARS 2 Asked and Concluded

MARS 2 sought to determine whether adding surgery to chemotherapy improved outcomes compared with chemotherapy alone in pleural mesothelioma. As Dr. Velotta summarizes, “their conclusion was that surgery was not beneficial and that patients with just chemotherapy alone had improved survival versus the chemotherapy plus surgery group. Their recommendation was that surgery does not essentially have a benefit in the treatment of mesothelioma.” He emphasizes that the interpretation must be framed in the context of the specific patients, conduct, and design choices in the study.

Why the Results Are Problematic in Practice

Dr. Velotta reports a troubling downstream effect: “People that don’t know the data are not even giving surgery as an option,” which is leading to fewer referrals to surgeons and fewer cases being presented in tumor boards. He notes that mesothelioma was already prone to under-referral and therapeutic nihilism; post–MARS 2, he is seeing an accelerated drop in multidisciplinary evaluation, with many patients defaulting to systemic therapy or palliative care without comprehensive staging or surgical consultation.

He argues this shift is not supported by current evidence-based guidelines. Both the NCCN and the recently updated ASCO guidelines “recommend a multidisciplinary session and do not say no surgery at all.” Rather, they specify that surgery “could be considered” for carefully selected patients—typically earlier-stage, epithelioid histology—following full multidisciplinary review. “Even in those guidelines, despite MARS 2, they recommend that surgery is still in that armamentarium,” he says.

Key Limitations Cited in MARS 2

Dr. Velotta details several limitations that he believes bias the trial against surgery:

• Inadequate and inconsistent staging, with some patients effectively stage III–IV at operation.
• A neoadjuvant-first design, despite limited responsiveness of mesothelioma to chemotherapy, potentially deconditioning patients prior to major surgery.
• Extensive resections in sicker patients and inclusion of non-epithelioid histologies, increasing morbidity and diluting any surgery-related benefit.
• Postoperative systemic therapy imbalances, with “the majority in the surgery arm” not receiving additional chemotherapy that the chemo-alone arm did receive.

Taken together, he contends these factors do not reflect contemporary, optimized surgical selection, staging, and perioperative pathways.

Call for Multidisciplinary Standards and Better Trials

Dr. Velotta advocates maintaining rigorous multidisciplinary evaluation for all stage I–III patients: thoracic surgery, medical and radiation oncology, radiology, and pathology, with comprehensive staging (PET, EBUS/mediastinoscopy; laparoscopy in select cases). He stresses that surgeons’ early involvement mirrors lung cancer standards and should continue “MARS 2 or not.”

He also supports a new trial—a “MARS 3”—with design elements that address MARS 2’s shortcomings:

• Early-stage, appropriately staged candidates.
• Upfront surgery followed by chemotherapy versus chemotherapy alone.
• Conducted at high-volume centers with standardized surgical techniques and team-based perioperative care.
• Balanced, protocolized systemic therapy post-surgery.

“If that truly did show that surgery wasn’t beneficial, then yes, I would stop doing surgery,” he says. “But the likelihood of that happening is so rare based on all the issues that this trial had.”

Real-World Data and Practice Evolution

While awaiting better prospective data, Dr. Velotta points to their retrospective, real-world analysis from Kaiser Permanente Northern California, presented at the American Association of Thoracic Surgery, International Thoracic Surgical Oncology Summit (AATS, ITSOS) and submitted to the Journal of Thoracic and Cardiovascular Surgery, showing “significant improvement in survival in the surgery plus chemotherapy group versus the group that did not get surgery” (among patients otherwise eligible for surgery). He acknowledges retrospective limitations but views these data as an important counterweight to MARS 2.

MARS 2 has nonetheless influenced his practice—toward more stringent selection. He now prioritizes:

• Stage I–II (and select stage III) disease
• Epithelioid histology
• Robust physiologic fitness and thorough staging
• A realistic, team-based plan for multimodality therapy

Countering Misinformation and Rebuilding Pathways

To correct misinterpretations, Dr. Velotta cites several initiatives:

• ASCO’s post–MARS 2 guidance affirming a role for surgery in early-stage epithelioid disease
• An upcoming Society of Thoracic Surgeons expert consensus statement (multidisciplinary authorship) clarifying surgical indications
• Direct outreach to providers, patients, and advocacy groups to re-establish referral pathways and multidisciplinary reviews

He also warns of an unintended consequence: a drop in new diagnoses and biopsies. “You still have to biopsy,” he urges, emphasizing that earlier identification can enable “improved survival” with curative-intent multimodality treatment in appropriate patients.

His bottom line: “Let us as the surgeons evaluate, see that patient, and then they can say, no surgery, but let us evaluate that patient. Right now, I don’t think that’s happening enough.”

Key Takeaways for Oncology Teams

• Do not generalize MARS 2 to “no surgery for mesothelioma.” Current NCCN and ASCO guidelines still support surgery for carefully selected, typically early-stage epithelioid patients after multidisciplinary review.
• Maintain multidisciplinary workflows and comprehensive staging (PET, EBUS/mediastinoscopy; select laparoscopy), with early surgical input for stage I–III disease.
• Recognize MARS 2 limitations: staging heterogeneity, neoadjuvant-first design, inclusion of sicker/non-epithelioid patients, extensive resections, and postoperative therapy imbalances.
• Patient selection matters: prioritize early stage, epithelioid histology, and good performance status in high-volume centers with standardized techniques and coordinated perioperative care.
• Avoid nihilism: pursue timely biopsy and diagnosis; early identification can enable curative-intent multimodality strategies in appropriate candidates.
• Real-world retrospective data continue to suggest survival benefit with surgery plus chemotherapy versus chemotherapy alone among eligible patients; prospective, optimized trials are needed.
• Communicate clearly with patients and advocacy groups to ensure access to expert evaluation and prevent premature exclusion of surgical options.

About Dr. Velotta

Jeffrey Velotta, MD, FACS is a Thoracic Surgeon and the Surgical Director of the Mesothelioma Program at Kaiser Permanente Northern California and an Expert Contributor for The Mesothelioma Center at Asbestos.com. He specializes in the multidisciplinary management of pleural mesothelioma, with active clinical and research leadership focused on optimizing surgical selection, staging, and multimodality care. Dr. Velotta is a frequent contributor to professional forums on mesothelioma and an advocate for evidence-based, team-driven treatment pathways.