Stage 1 Pleural Mesothelioma: Operable Disease and the Multimodal Treatment Window

If the diagnostic workup ends with a thoracic team using the words “stage 1” and “operable” in the same sentence, the conversation that follows is unusual in the broader pleural mesothelioma experience. Most people are diagnosed at stage III or IV. Stage I implies the disease is still confined to the parietal pleura on one side of the chest, with no lymph node involvement and no distant spread, and a curative-intent surgical pathway is on the table.

This guide is for the person newly told their disease is stage 1. It walks through what the staging system actually says, what the surgical options are, how multimodal therapy is sequenced around surgery, what the major randomized trials of the surgical question have shown, and the questions worth bringing to the next thoracic surgery and oncology appointments. It draws on the AJCC 8th edition criteria, the IASLC Mesothelioma Staging Project, and the primary publications of the modern surgical and trial literature.

What “Stage 1” Means in Pleural Mesothelioma

The current staging framework used at U.S. centers for pleural mesothelioma is the AJCC 8th edition, which has been in clinical use since 2017. It assembles three pieces of information: T (the local extent of the tumor), N (regional lymph node involvement), and M (distant metastasis). Stage I requires N0 and M0, meaning no nodes and no distant spread.

Within Stage I, the 8th edition splits Stage IA from Stage IB by the T descriptor:

• Stage IA: T1 N0 M0, tumor limited to the ipsilateral parietal pleura, possibly with focal involvement of the visceral pleura.
• Stage IB: T2 N0 M0, tumor that has progressed to involve the ipsilateral lung surface or diaphragmatic muscle, but with nodes and distant sites still clear.

The T descriptors used in the 8th edition were proposed by the IASLC Mesothelioma Staging Project (Nowak AK and colleagues, Journal of Thoracic Oncology, 2016) and based on multinational data from thousands of people with pleural mesothelioma. The 8th edition consolidated the older T1a and T1b subdivisions into a single T1 category. The forthcoming AJCC 9th edition will refine the framework further, but most U.S. mesothelioma programs are currently staging with the 8th edition criteria.

What this means in plain English: if a clinician is calling the disease stage 1, the tumor is anatomically still limited to one hemithorax with the surrounding pleura involved, no detectable lymph node disease, and no spread elsewhere. Among newly diagnosed cases, this is a minority. The NCI Mesothelioma Treatment PDQ summarizes that most patients present with locally advanced or metastatic disease.

Surgical Options at Stage 1: P/D vs EPP

Two cytoreductive operations have been used for pleural mesothelioma. The dominant question in the field over the past decade has been which of them, if either, belongs in the modern multimodal pathway for early-stage disease.

Pleurectomy/decortication (P/D) removes the pleura and visible tumor while preserving the underlying lung. The “extended” version (extended P/D) also resects the diaphragm and pericardium when those are involved. The lung remains in place and continues to function.

Extrapleural pneumonectomy (EPP) removes the entire ipsilateral lung along with the pleura, diaphragm, and pericardium. It is a more radical operation with a higher perioperative morbidity profile.

The Flores RM et al. multi-institutional analysis of 663 patients (Journal of Thoracic and Cardiovascular Surgery, 2008) is one of the largest comparative datasets and reported longer median survival overall with P/D than with EPP, with center-specific and stage-specific differences. The MARS feasibility trial in 2011 (Treasure T et al., Lancet Oncology) randomized 50 people with resectable disease to EPP plus radiotherapy versus no EPP after induction chemotherapy. The surgical arm did not improve overall survival, and the trial signaled possible harm from EPP.

The MARS 2 trial led by Eric Lim and colleagues, published in Lancet Respiratory Medicine in 2024, compared extended pleurectomy decortication plus chemotherapy with chemotherapy alone in resectable pleural mesothelioma. The primary endpoint of overall survival was not improved by adding extended P/D to chemotherapy. This is the strongest evidence to date on the surgical question for the disease as a whole, and it has reframed the early-stage decision rather than abolishing it.

The current consensus at most U.S. mesothelioma centers and reflected in the NCCN Clinical Practice Guidelines is that EPP is reserved for highly selected cases at experienced centers, and that P/D, when surgery is offered, is the preferred operation. For the deeper comparison and how the MARS 2 result is being interpreted, see our companion guide on pleurectomy/decortication versus EPP.

How Multimodal Therapy Is Sequenced

When surgery is on the table at stage 1, it is rarely a stand-alone decision. The cytoreductive operation is one component in a multimodal plan that combines systemic therapy and, in some protocols, radiation.

The CALGB 99304 phase 2 trial led by Lee Krug (J Clin Oncol 2009; PMID 19470929) studied a sequence that became the template for induction-then-surgery: three cycles of pemetrexed plus cisplatin, followed by EPP, followed by adjuvant hemithoracic radiation. Eligibility was clinical stage I to III disease, ECOG performance status 0 or 1, and non-sarcomatoid histology. The trial established the operational feasibility of the sequence and a reference benchmark, although the role of EPP itself has since been substantially narrowed by MARS and MARS 2.

Two contemporary sequencing approaches are commonly discussed:

Induction chemotherapy, then surgery, then adjuvant therapy

In this pathway, two or three cycles of pemetrexed plus a platinum agent are given before surgery to shrink tumor burden and identify patients whose disease is biologically responsive. Surgery (P/D in most current protocols) follows in responders. Adjuvant therapy can include additional chemotherapy or radiation depending on margins and the institutional protocol. The chemotherapy backbone of pemetrexed plus a platinum agent traces to the Vogelzang et al. trial (J Clin Oncol 2003).

Surgery first, then adjuvant systemic therapy

A second pathway proceeds directly to P/D in carefully selected patients with limited tumor burden, with adjuvant chemotherapy delivered postoperatively. The advantage is avoiding induction-related morbidity in someone who is unlikely to benefit; the trade-off is losing the in-vivo chemo-sensitivity test that induction provides.

The two FDA-approved first-line immunotherapy regimens, nivolumab plus ipilimumab and pembrolizumab plus pemetrexed and platinum, were tested and approved in unresectable disease (CheckMate-743 and IND.227 / KEYNOTE-483, respectively). Their pivotal-trial survival data does not directly apply to the stage 1 operable population. Whether those regimens are used in operable disease, in the postoperative adjuvant setting, or at recurrence, is a current research question and varies by center protocol.

What Major Institutional Series Show, and What They Don’t

Two pieces of context matter when reading the surgical literature on early-stage mesothelioma:

Selection bias is large. Programs that publish stage I, node-negative, epithelioid surgical outcomes are reporting on patients who already passed multiple selection filters: imaging-confined disease, biopsy-confirmed favorable histology, fitness for major thoracic surgery, and willingness to undergo a multi-month treatment course. The patients who reach those reports are not representative of newly diagnosed mesothelioma generally.

Long-tail outcomes exist but are uncommon. Single-institution series from high-volume programs have described long-term survivors after multimodal therapy in selected stage I, node-negative, epithelioid disease. The David Sugarbaker series at Brigham and Women’s Hospital and the work of Raja Flores at Mount Sinai are commonly cited. The reported medians vary across series and decades, and individual patient outcomes remain heterogeneous.

The honest framing for someone newly told they have stage 1 disease is that long-term survival is possible after multimodal therapy at an experienced center, that the literature describes a real subgroup of long survivors, and that the published medians do not predict any single person’s outcome.

Why Center Volume Matters at Stage 1

Pleural mesothelioma surgery is technically demanding and uncommon at most general thoracic centers. The procedure requires intraoperative judgment about resectability, frequent diaphragm and pericardial reconstruction, and postoperative management of pleural-space and pulmonary complications.

Both the NCCN guidelines and standard practice at U.S. mesothelioma programs recommend that surgery be performed at high-volume mesothelioma centers with multidisciplinary teams. The reasoning is simple: the operation, the perioperative management, and the multimodal sequencing are all dependent on accumulated institutional experience that low-volume centers have not had the opportunity to build.

For stage 1 disease specifically, the surgical decision is the most consequential decision in the treatment course. Getting a second opinion at a high-volume mesothelioma program, even when surgery has already been offered locally, is a reasonable step and one that experienced thoracic surgeons routinely encourage.

The reviewer for this guide, Dr. Raphael Bueno, directs the International Mesothelioma Program at Brigham and Women’s Hospital, one of the largest dedicated mesothelioma surgical and translational research programs in the United States. Other established U.S. programs include Memorial Sloan Kettering, Mount Sinai, MD Anderson, the University of Chicago, and Penn.

Practical Questions for the Surgical and Oncology Team

The stage 1 decision is built on specific patient-level data. The most useful conversation walks through each piece in turn.

• What is the histology on biopsy: epithelioid, biphasic, or sarcomatoid? If biphasic, what was the reported epithelioid-to-sarcomatoid ratio?
• What does the staging workup actually show on imaging, and are there any nodes that look suspicious on PET or EBUS?
• Is the recommendation P/D or extended P/D, and what is the institutional approach to EPP given MARS and MARS 2?
• What is the proposed sequencing: induction chemotherapy first, surgery first, or surgery only, and what is the reasoning?
• What is the center’s annual mesothelioma surgical volume and the perioperative mortality and major-complication rate for the proposed operation?
• What does the postoperative adjuvant plan look like, and what triggers a switch to systemic therapy at recurrence?
• Is there a clinical trial open at this center, including for postoperative immunotherapy or novel induction sequencing, that this case is eligible for?

How This Guide Fits the Rest of the Cluster

This is the stage 1 article in the MesoWatch stage cluster, which covers operable-disease decisions. For the population this guide does not describe, the first-line treatment decision for unresectable disease covers the options that most newly diagnosed people face. The companion piece on survival rates by stage and histology puts the stage 1 numbers into context. People who arrived at this stage through workup of a slow-developing symptom may also find the early warning signs and latency guide useful, and the broader treatment landscape hub indexes the rest of the cluster.

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