Extrapleural Pneumonectomy (EPP)

Extrapleural pneumonectomy (EPP) is the most aggressive surgical procedure used in the treatment of malignant pleural mesothelioma. The operation involves en bloc removal of the entire affected lung, the visceral and parietal pleura, the ipsilateral pericardium (the sac surrounding the heart), and the ipsilateral hemidiaphragm. The pericardium and diaphragm are then reconstructed using synthetic patches (typically Gore-Tex or other prosthetic materials). The goal of EPP is to achieve macroscopic complete resection (MCR) — removing all visible tumor — as part of a multimodal treatment approach that typically includes chemotherapy and radiation therapy.¹

EPP was pioneered in the 1970s and refined significantly by Dr. David Sugarbaker at Brigham and Women's Hospital in Boston, whose landmark studies demonstrated that EPP combined with heated intraoperative chemotherapy and adjuvant radiation could produce median survival times of 17 to 19 months in carefully selected patients with epithelioid histology, negative surgical margins, and no extrapleural lymph node involvement. The Butchart staging system, developed by Dr. Eric Butchart in 1976, was the first mesothelioma staging classification and was designed specifically around EPP surgical findings.²

The role of EPP has become increasingly controversial since the publication of the Mesothelioma and Radical Surgery (MARS) feasibility trial in 2011, which randomized patients to EPP versus no EPP after induction chemotherapy. The MARS trial reported higher mortality and no survival benefit in the EPP arm, though the study was criticized for small sample size (n=50 randomized), inclusion of centers with limited EPP experience, and methodological limitations. Despite these criticisms, the MARS findings accelerated a trend away from EPP and toward the lung-sparing alternative, pleurectomy/decortication (P/D).³

Today, EPP remains available at specialized mesothelioma centers but is performed less frequently than P/D. It is generally reserved for patients with early-stage (I–II) epithelioid mesothelioma who are young, physically fit, and able to tolerate single-lung physiology after the procedure. The decision between EPP and P/D remains one of the most debated questions in mesothelioma surgery, and treatment decisions should be made by a multidisciplinary team at a center with high-volume mesothelioma surgical experience.⁴

EPP is a treatment procedure, not a disease, so it does not cause symptoms. However, the indications for considering EPP include symptoms of advanced pleural mesothelioma:¹

• Progressive dyspnea from tumor encasement of the lung or large pleural effusions
• Chest wall pain from direct tumor invasion into intercostal muscles and ribs
• Persistent cough unresponsive to medical management
• Weight loss and fatigue from tumor metabolic burden
• Recurrent pleural effusions requiring repeated drainage

After EPP, patients experience significant postoperative symptoms including reduced exercise tolerance (from having only one lung), surgical wound pain, and a recovery period of 6 to 8 weeks or longer. Long-term adaptation to single-lung physiology is achievable in most patients but imposes permanent limitations on aerobic capacity.⁴

EPP is not a diagnostic procedure but a therapeutic one. The preoperative evaluation to determine EPP candidacy is extensive and includes:⁴

• Histological confirmation — Biopsy-proven mesothelioma is required before EPP. Thoracoscopy (VATS) is the preferred method for obtaining adequate tissue and assessing tumor extent on the pleural surfaces.¹
• CT and PET-CT staging — Cross-sectional imaging assesses tumor extent, lymph node involvement, and distant metastases. PET-CT provides metabolic information that helps identify occult metastatic disease that would contraindicate EPP.⁴
• Mediastinoscopy — Sampling of mediastinal lymph nodes to assess nodal involvement. Positive contralateral (N3) nodes generally exclude patients from EPP candidacy.²
• Pulmonary function testing — Quantitative ventilation-perfusion lung scanning determines predicted postoperative lung function. Patients must have sufficient reserve to tolerate pneumonectomy; typically a predicted postoperative FEV1 >0.8 liters is required.⁴
• Cardiac evaluation — Echocardiography and stress testing assess cardiac function, as EPP involves pericardial resection and shifts cardiac position. Patients with significant cardiac disease are poor EPP candidates.⁴
• Performance status — Only patients with good functional status (ECOG 0–1) are typically considered for EPP due to the procedure's physiological demands.⁴

EPP candidacy is heavily influenced by mesothelioma stage:²

• Stage I–II — Best EPP candidates. Tumor confined to the pleura (stage I) or extending into the lung, diaphragm, or pericardium (stage II). Macroscopic complete resection is most achievable.²
• Stage III — Locally advanced disease with chest wall invasion or nodal involvement. EPP is controversial and completeness of resection less certain.²
• Stage IV — Distant metastases or contralateral disease. EPP is generally not indicated.²

The Sugarbaker prognostic criteria identified three predictors of improved survival after EPP: epithelioid histology, negative resection margins, and negative extrapleural lymph nodes.²

EPP is itself a treatment — the most extensive surgical option for pleural mesothelioma. Through a posterolateral thoracotomy, the surgeon removes the lung, pleura, pericardium, and diaphragm en bloc, performs mediastinal lymph node dissection, and reconstructs the pericardium and diaphragm with prosthetic mesh. Operative time is 4 to 6 hours with a hospital stay of 7 to 14 days.²

Multimodal protocols:

• Sugarbaker protocol — EPP followed by adjuvant hemithoracic radiation (54 Gy) with or without chemotherapy. Reported median survival of 17 months in selected patients.²
• Neoadjuvant chemotherapy + EPP — 3–4 cycles of pemetrexed/cisplatin before surgery, followed by adjuvant radiation. Response to chemotherapy helps select patients likely to benefit from EPP.⁴
• SMART protocol — Surgery for Mesothelioma After Radiation Therapy. Accelerated hemithoracic radiation (5 fractions over 1 week) followed immediately by EPP. Developed at Princess Margaret Cancer Centre in Toronto.⁴

Complications:

• Operative mortality: 3–7% at experienced centers (higher at low-volume institutions)
• Major morbidity rate: 25–50%, including atrial fibrillation, pneumonia, empyema, bronchopleural fistula, and patch failure
• Cardiac herniation through pericardial defect (rare but potentially fatal if patch fails)
• Permanent reduction in exercise capacity from single-lung physiology

Prognosis after EPP depends heavily on patient selection. In the most favorable subset — patients with epithelioid histology, stage I–II disease, negative margins, and negative extrapleural nodes — median survival ranges from 17 to 24 months, with 5-year survival rates of 12–15%. In unselected patients or those with non-epithelioid histology, survival is significantly shorter.²

The MARS feasibility trial (2011) reported a median survival of 14.4 months in the EPP arm versus 19.5 months in the non-EPP arm, raising concerns about the net benefit of the procedure. However, critics noted the trial's small size, imbalances in prognostic factors, and inclusion of surgical centers with limited EPP experience. The subsequent MARS-2 trial evaluated P/D rather than EPP and may further inform the debate about the role of cytoreductive surgery in mesothelioma.³

Current consensus is that EPP may benefit a carefully selected minority of mesothelioma patients when performed by experienced surgeons at high-volume centers as part of a multimodal treatment plan. The trend in the field, however, has shifted toward pleurectomy/decortication, which preserves the lung and has lower perioperative morbidity and mortality while achieving comparable or superior survival in many studies.⁴

Life after EPP requires significant adaptation. Patients must adjust to functioning with a single lung, which permanently limits exercise capacity and aerobic fitness. Key aspects of post-EPP living include:⁴

• Pulmonary rehabilitation — Structured exercise programs help patients maximize the function of their remaining lung and rebuild strength after surgery
• Activity modification — Most patients can perform daily activities independently but may experience breathlessness with strenuous exertion, climbing stairs, or exercising at altitude
• Follow-up surveillance — Regular CT imaging (every 3–6 months) to monitor for local recurrence, which occurs in the majority of EPP patients
• Psychological support — The combination of a serious cancer diagnosis and major surgery creates significant emotional burden. Support groups, counseling, and family support services are important components of post-EPP care