Stage 2 Pleural Mesothelioma: Borderline-Operable Disease and the Induction-Therapy Decision

A Stage 2 pleural mesothelioma diagnosis sits in the most uncomfortable place on the staging map. The disease is no longer confined the way Stage 1 disease is, but it has not progressed to the clearly inoperable territory of Stage 3. Some thoracic surgeons will offer an aggressive multimodal plan. Others will not. The decision turns on a small number of variables, and the goal of this guide is to make those variables visible.

This is written for someone who has just been told their stage and wants to understand what comes next. It draws on the AJCC and IASLC primary publications, the trial literature on induction therapy, and the recent MARS 2 results that have reshaped the surgery question. It does not tell anyone what to choose. The decision is patient-specific and belongs in a multidisciplinary clinic that sees mesothelioma every week.

What Stage 2 Means

The current staging system for pleural mesothelioma is the AJCC TNM classification, developed and revised by the IASLC Mesothelioma Staging Project. Two versions are in active use during this transition period: the 8th edition (Rusch and colleagues, Journal of Thoracic Oncology 2016) and the 9th edition (Nowak and colleagues, Journal of Thoracic Oncology 2024), with the 9th edition being adopted across cancer centers through 2025 and 2026.

The relevant T and N categories are:

In the 8th edition, Stage II is T2 N0 M0: the tumor has spread across all of the ipsilateral pleural surfaces but the regional nodes are still uninvolved and there is no distant spread. In the 9th edition, Stage II is T1-2 N1 M0: the boundary moves slightly to recognize that limited ipsilateral nodal involvement is biologically closer to early-stage than to advanced disease. The 9th edition also reclassifies T2 N0 disease into Stage IB, on the data showing it has prognosis closer to T1 disease than to nodal-positive disease.

For someone receiving a stage 2 diagnosis right now, it is reasonable to ask the oncology team which edition they are using. The answer affects what cohort the patient most resembles in the published literature. The full TNM definitions are detailed in our TNM staging system overview, and it is worth bringing the imaging and the pathology report to a multidisciplinary review at a high-volume mesothelioma center before the treatment plan is set.

The Borderline-Operable Decision

Stage 2 is where the operability question becomes a genuine clinical judgment rather than a default. At Stage 1, a fit patient with epithelioid disease and clear nodes is typically a surgical candidate. At Stage 3, the disease is usually inoperable. Stage 2 sits between these defaults, and the surgical literature uses the term borderline resectable to describe the cases where high-volume centers will operate but lower-volume centers may not.

The criteria used to define borderline resectable disease at major programs are remarkably consistent:

• Epithelioid or biphasic histology, with sarcomatoid disease typically excluded from surgery.
• ECOG performance status 0 or 1.
• Adequate pulmonary function, with FEV1 typically above 40% predicted and DLCO above 40%.
• No clinical evidence of T4 disease (no transdiaphragmatic, contralateral, or extensive mediastinal extension).
• No N2 nodal disease, where defined.
• No distant metastases.
• A realistic expectation that the operation can achieve a macroscopic complete resection.

Bueno and colleagues at the Brigham and Women’s International Mesothelioma Program have published extensively on selection for pleurectomy-decortication, and the BWH series shows that careful selection into a P/D operation can produce median overall survivals well above 20 months in patients whose disease would have been called borderline at a less specialized center. The same selection discipline applied poorly produces high perioperative morbidity without survival gain.

The single most important variable inside the borderline category is histology. Pure sarcomatoid disease is generally not offered surgery at any U.S. high-volume center. Biphasic disease is offered surgery selectively. Epithelioid disease is the histology in which the multimodal literature is strongest.

Induction Therapy: What It Is and What the Trials Show

Induction therapy means systemic treatment given before surgery. It serves three purposes: shrinking the tumor to improve the chance of a complete resection, identifying the patients whose disease is biologically aggressive enough to progress through chemotherapy and would not benefit from surgery, and starting systemic control of the disease early.

The classical induction regimen is pemetrexed plus a platinum agent (cisplatin or carboplatin) for three or four cycles, followed by restaging imaging, followed by surgery if the disease has not progressed. This regimen was studied formally by Krug, Pass, Rusch, and colleagues in a phase II multicenter trial published in the Journal of Clinical Oncology in 2009.

The Krug trial enrolled 83 patients with resectable pleural mesothelioma. Of those, 48% (40 patients) completed the full trimodality plan: induction chemotherapy, then extrapleural pneumonectomy, then hemithoracic radiation. In the intent-to-treat population, median overall survival was 29.1 months. In the surgical cohort, it was longer. Macroscopic complete resection was achieved in all 40 surgical patients (R0 in 27, R1 in 13). Postoperative 90-day mortality was 7% (3 of 40), with deaths from pneumonia, ARDS, and myocardial infarction. Treatment-related mortality across the full enrolled population was 4%.

The Krug data is a primary reference for what trimodality therapy actually delivers in selected patients, and it shows both the upside and the cost: a substantial subset of patients live well beyond historical mesothelioma survival numbers, but a meaningful fraction do not complete the plan, and surgical mortality is non-trivial even in expert hands.

Memorial Sloan Kettering, under Dr. Valerie Rusch, has been a primary developer of trimodality therapy for pleural mesothelioma over more than two decades, with the EORTC-LSSR phase II trial (Rusch et al., Journal of Thoracic Oncology 2009) and subsequent institutional series setting the operational template that other programs adapted. Mt. Sinai, under Dr. Raja Flores, refined the lung-sparing alternative, performing induction chemotherapy followed by pleurectomy-decortication in selected patients, with outcomes comparable to or better than the EPP literature at substantially lower perioperative risk.

Induction Immunotherapy: What Is Changing

The induction-therapy conversation is changing because of immunotherapy. The DREAM trial (Nowak et al., Lancet Oncology 2020) was a single-arm phase II study of durvalumab combined with cisplatin and pemetrexed as first-line therapy for unresectable pleural mesothelioma. Objective response rate was 48% (95% CI 36-60), median progression-free survival 6.2 months, and median overall survival 18.4 months. PrE0505, a U.S. cooperative-group phase II study, evaluated the same durvalumab-plus-chemotherapy combination and showed promising efficacy.

Those trials were in unresectable disease. The same regimens are now being tested as induction therapy in resectable disease, on the rationale that pre-operative checkpoint inhibition may produce major pathologic responses and prime an anti-tumor immune response that surgery preserves. The NEMO trial (NCT05932199) at Memorial Sloan Kettering is an ongoing phase II study of neoadjuvant nivolumab plus ipilimumab followed by surgery and adjuvant nivolumab. Investigators in Europe and North America are running parallel trials of atezolizumab and nivolumab in the neoadjuvant setting. Major pathologic response rates in early reports range from roughly 10% to 40% depending on the regimen, and the data is not yet mature enough to support induction immunotherapy as a standard of care outside a clinical trial.

For someone with Stage 2 disease in 2026, this means three induction strategies are actively in play:

1. Induction chemotherapy alone (pemetrexed plus platinum), the most established option with the largest body of published outcomes data.
2. Induction chemotherapy plus immunotherapy (chemo-immunotherapy combinations), where strong unresectable-disease data exists and resectable-disease trials are enrolling.
3. Induction immunotherapy alone (dual checkpoint blockade), where the most active investigation is concentrated, and which is generally available only on a clinical trial.

A patient at a high-volume center may be offered the standard induction-chemotherapy plan, may be offered enrollment in an active trial, or both as parallel options.

Sequencing Decisions: Induction, Surgery, Adjuvant

The trimodality sequence assumes induction first, then surgery, then adjuvant therapy (typically hemithoracic radiation in the EPP era, less consistently in the P/D era). Recent practice has put pressure on each part of that sequence.

The MARS 2 trial (Lim and colleagues, Lancet Respir Med 2024) randomized patients with resectable pleural mesothelioma to extended pleurectomy-decortication plus chemotherapy versus chemotherapy alone. The primary endpoint was overall survival, and the trial did not show that adding surgery improved survival. The result has been interpreted carefully across the surgical community. It does not show that surgery has no role; subgroup data and selection effects continue to be debated, and a 2025 review in Cancers summarized the consensus view as “MARS 2 does not mean the end of all mesothelioma surgery.” It does mean that the bar for offering surgery to a Stage 2 patient is higher in 2026 than it was in 2020.

Practical implications for the borderline-operable patient:

• The induction phase functions partly as a selection filter. Patients whose disease progresses through chemotherapy generally do not proceed to surgery.
• The surgical decision after induction is reassessed on restaging imaging, not committed at the front end.
• Pleurectomy-decortication has displaced extrapleural pneumonectomy as the default operation at most U.S. high-volume centers, on the basis of comparable survival with substantially lower perioperative risk.
• Adjuvant therapy after surgery varies by institution and by operation. EPP was traditionally followed by hemithoracic radiation. P/D is followed by adjuvant systemic therapy in some protocols, observation in others, and selectively by radiation to involved fields.

NEMO and the Modern Induction-Immunotherapy Approach

The NEMO trial (NCT05932199) is one of the most active induction-immunotherapy studies for pleural mesothelioma in the United States. It is a phase II study of neoadjuvant nivolumab plus ipilimumab followed by surgery and adjuvant nivolumab in patients with resectable disease, sponsored by Memorial Sloan Kettering Cancer Center, with first posting in July 2023 and estimated completion in 2027. The primary endpoints include pathologic complete response and major pathologic response rates, with safety and survival as secondary endpoints.

The NEMO design matters because it tests an immunotherapy-only induction strategy, mirroring the CheckMate-743 unresectable-disease regimen that produced 14% 5-year overall survival in advanced disease. If induction nivolumab plus ipilimumab can produce major pathologic responses at meaningful rates and preserve the surgical option, the operational sequence for Stage 2 disease would shift, with chemotherapy potentially moved into the adjuvant setting or held in reserve.

Other induction-immunotherapy trials are running in parallel, with different combinations (atezolizumab, nivolumab plus ipilimumab, durvalumab plus chemotherapy) and different surgical operations. Trial enrollment is concentrated at the high-volume mesothelioma centers. A patient asking about induction immunotherapy should ask which trials are open at the center they are seen at, and which are open at referring centers.

For broader context on the systemic therapy landscape, see our first-line treatment decision guide and the mesothelioma treatment hub.

Practical Questions for the Multidisciplinary Team

The borderline-operable decision is genuinely a decision, and it benefits from explicit conversation rather than implicit defaults. The following questions surface the variables that drive the recommendation.

The Stage 2 decision is one of the few places in mesothelioma care where the patient is genuinely choosing between fundamentally different treatment paths. A high-volume center will frame those paths clearly, attach trial data to each, and make the reasoning behind a specific recommendation visible. If the conversation is not happening that way, that itself is a signal worth acting on.

For the related Stage 1 decision, see our guide on operable disease and the multimodal treatment window. For a deeper look at the surgical operation itself, see our pleurectomy-decortication versus EPP comparison.

Frequently Asked Questions