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Surgery in Malignant Pleural Mesothelioma

Open ArchivePublished:August 16, 2018DOI:https://doi.org/10.1016/j.jtho.2018.08.001

      Abstract

      Surgical intervention plays an important role in the diagnosis, staging, and treatment of malignant pleural mesothelioma (MPM) and can be applied with curative or palliative intent. The overall aim of surgery should be, as in any oncologic surgery, the macroscopic complete resection (MCR) of the tumor. Most importantly, the majority of patients with the diagnosis of MPM should be appropriately staged and initially evaluated in a multidisciplinary setting, including medical oncology, radiation oncology, and surgery after histologic diagnosis. Surgical staging, including determination of the histologic subtype and lymph node status, as well as clinical staging with positron-emission tomography–computer tomography scan and determination of cardiopulmonary reserve are crucial. Herein, we summarize the role of surgical resection, specifically macroscopic complete resection, performed as extrapleural pneumonectomy or extended pleurectomy/decortication in multimodality treatment settings and advocate for optimal patient selection for one or the other procedure. In addition, the roles of surgery in diagnosis of MPM and in palliative care are discussed.

      Introduction

      Surgical intervention plays an important role in the diagnosis, staging, and treatment of malignant pleural mesothelioma (MPM) and can applied with curative or palliative intent. Most published guidelines include surgery as a major component of therapy for mesothelioma (e.g., the European Society for Medical Oncology and the National Comprehensive Cancer Network), as depicted in the European Society for Medical Oncology clinical practice guidelines for the following indications
      • Baas P.
      • Fennell D.
      • Kerr K.M.
      • et al.
      Malignant pleural mesothelioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      • Ettinger D.S.
      • Wood D.E.
      • Akerley W.
      • et al.
      NCCN Guidelines Insights: Malignant Pleural Mesothelioma, Version 3.2016.
      : (1) to obtain sufficient diagnostic samples of tumor tissue and to stage the patient; (2) for palliative management of pleural effusions when chest tube drainage is not sufficient; (3) as a part of a multimodality treatment, preferable as part of a study; and (4) for definitive resection to perform macroscopic complete resection (MCR) by means of (extended) pleurectomy/decortication ([e]P/D) or extrapleural pneumonectomy (EPP).
      The American Society of Clinical Oncology is recommending the use of curative-intent surgery with maximal cytoreduction in its 2018 guideline on the management of patients with MPM.
      • Kindler H.L.
      • Ismaila N.
      • Armato 3rd, S.G.
      • et al.
      Treatment of malignant pleural mesothelioma: American Society of Clinical Oncology Clinical Practice Guideline.
      In fact, it has been shown in an analysis of the present Surveillance, Epidemiology, and End Results database that surgery alone is a superior form of therapy in terms of overall survival when compared to no surgery or radiotherapy alone (Fig. 1).
      • Taioli E.
      • Wolf A.S.
      • Camacho-Rivera M.
      • et al.
      Determinants of survival in malignant pleural mesothelioma: a Surveillance, Epidemiology, and End Results (SEER) study of 14,228 patients.
      Figure thumbnail gr1
      Figure 1Survival according to type of treatment (Surveillance, Epidemiology and End Results database).
      Reprinted with permission.
      • Taioli E.
      • Wolf A.S.
      • Camacho-Rivera M.
      • et al.
      Determinants of survival in malignant pleural mesothelioma: a Surveillance, Epidemiology, and End Results (SEER) study of 14,228 patients.
      Indeed, most physicians in the majority of experienced mesothelioma treatment centers would agree that patients benefit from combinations of surgery with either neoadjuvant and/or adjuvant treatment that includes chemotherapy. The overall aim of surgery should be, as in any oncologic surgery, the MCR of the tumor. Maximal cytoreduction has been successfully used in other cancers that expand into a cavity such as ovarian cancer or pseudomyxoma peritonei.
      • Rice D.
      Standardizing surgical treatment in malignant pleural mesothelioma.
      MCR has been defined in a consensus report in 2011 as removal of all grossly visible and palpable tumor.
      • Rice D.
      • Rusch V.
      • Pass H.
      • et al.
      Recommendations for uniform definitions of surgical techniques for malignant pleural mesothelioma: a consensus report of the international association for the study of lung cancer international staging committee and the international mesothelioma interest group.
      However, some groups define MCR as resection with as complete as less than 1 cm of tumor left behind.
      • Sugarbaker D.J.
      • Wolf A.S.
      Surgery for malignant pleural mesothelioma.
      Using a completeness of cytoreduction score as used for the resection of peritoneal tumors could be useful for addressing this problem in the future.
      • Rice D.
      Standardizing surgical treatment in malignant pleural mesothelioma.
      MCR can be achieved by either EPP or (e)P/D. Rice et al.
      • Rice D.
      • Rusch V.
      • Pass H.
      • et al.
      Recommendations for uniform definitions of surgical techniques for malignant pleural mesothelioma: a consensus report of the international association for the study of lung cancer international staging committee and the international mesothelioma interest group.
      have recommended the following terminology to define surgical therapy for MPM: (1) EPP: en bloc resection of the parietal and visceral pleura with the ipsilateral lung, pericardium, and diaphragm. In cases where the pericardium and/or diaphragm are not involved by tumor, these structures may be left intact; (2) (e) P/D: parietal and visceral pleurectomy performed to remove all gross tumor with resection of the diaphragm and/or pericardium. The International Association for the Study of Lung Cancer (IASLC) Mesothelioma Domain suggests use of the term “extended” rather than “radical” in this instance as the latter implies a completeness of resection with added therapeutic benefit. There is currently insufficient evidence that resection of the pericardium and diaphragm provides either, except when it is required to accomplish MCR; (3) P/D: parietal and visceral pleurectomy performed to remove all gross tumor without diaphragm or pericardial resection, which is possible in a subset of cases; and (4) Partial pleurectomy: partial removal of parietal and/or visceral pleura for diagnostic or palliative purposes but leaving gross tumor behind (Fig. 2).
      Figure thumbnail gr2
      Figure 2Overview of surgical procedures performed in the curative and palliative treatment of malignant pleural mesothelioma. *Includes 30-day and in-hospital mortalities. Reprinted with permission.
      • Cao C.
      • Akhunji Z.
      • Fu B.
      • et al.
      Surgical management of malignant pleural mesothelioma: an update of clinical evidence.
      Most importantly, the majority of patients with the diagnosis of MPM should be initially evaluated in a multidisciplinary setting, including medical oncology, radiation oncology, and surgery after histologic diagnosis including determination of the histologic subtype and clinical staging with positron-emission tomography/computerized tomography scan and mediastinal staging. Patients should be carefully vetted before surgery from both functional and tumor-related perspectives. Tumor factors associated with improved survival include epithelioid histology, absence of lymph node involvements, limitation to the ipsilateral chest, and low tumor burden. Patients with evidence of any extrathoracic spread should be evaluated to confirm distant disease, for example, by laparoscopy for transdiaphragmatic involvement, before surgery. Patients with confirmed preoperative sarcomatoid histology are best candidates for clinical trials giving the usual poor outcome. Frail or elderly patients, those with ongoing weight loss and/or pain should be carefully assessed because of higher risk for extrathoracic involvement and perioperative morbidity. Likewise, patients with biopsy-confirmed positive lymph nodes should be considered for clinical trial before surgery. Patients presenting with pain are more likely to be unresectable and a careful search for evidence of extrathoracic invasion by magnetic resonance imaging should be made before consideration of surgery. Patients with poor performance scores should not be encouraged to undergo surgery.
      The present review aims to summarize the role of surgical MCR performed as EPP or (e)P/D in multimodality treatment settings and advocate the optimal patients’ selection for one or the other procedure. In addition, the role of surgery in diagnosis of MPM and in palliative settings will be discussed.

      Surgical Biopsies

      Histopathologic analysis of pleural tissue is mandatory for final MPM diagnosis but can be difficult because mesothelioma is a heterogeneous cancer and the pleura is also a common site for metastatic disease, including lung cancer which occurs nearly 100 times more commonly. Three principal histologic subtypes can be differentiated according to the WHO 2004 classification

      Travis W, Brambilla E, Muller-Hermelink H, et al. Pathology and genetics of tumours of the lung, pleura, thymus, and heart. In World Health Organization Classification of Tumours. Lyon, France: IARC Press; 2004.

      : the epithelioid, the sarcomatoid, and a mixture of both including at least 10% of each growth pattern — the biphasic subtype, and the desmoplastic subtype. The recommendation of the Guidelines of the European Respiratory Society and the European Society of Thoracic Surgeons strongly support a thoracoscopic tissue biopsy to obtain multiple and deep tissue biopsy specimens.
      • Van Schil P.E.
      • Opitz I.
      • Weder W.
      • et al.
      Multimodal management of malignant pleural mesothelioma: where are we today?.
      This may be even more important in the age of genomic medicine when multiple analyses are required. It has been shown that cytological assessment of pleural effusion may not be sensitive and specific enough when compared to a biopsy.
      • Scherpereel A.
      • Astoul P.
      • Baas P.
      • et al.
      Guidelines of the European Respiratory Society and the European Society of Thoracic Surgeons for the management of malignant pleural mesothelioma.
      Also, fine needle biopsies are not primarily recommended because they are associated with low sensitivity (∼30%).
      • Scherpereel A.
      • Astoul P.
      • Baas P.
      • et al.
      Guidelines of the European Respiratory Society and the European Society of Thoracic Surgeons for the management of malignant pleural mesothelioma.
      A conclusive diagnosis can only be made if the material is representative in terms of biopsy location (normal and abnormal pleura and deep enough to assess fat and/or muscle tumor invasion) and sufficient quantity provides enough material to allow immunohistochemical characterization.
      • Opitz I.
      Management of malignant pleural mesothelioma—The European experience.
      Usually a uniportal thoracoscopic approach is used in the sixth intercostal space at the site of a future incision for the larger resection so that port-site can be easily excised avoiding future local recurrences. In selected cases of MPM suspicion without additional pleural effusion, a mini-thoracotomy with direct open biopsy can be diagnostic.

      Extrapleural Pneumonectomy

      EPP was first attempted for curative resection of MPM by Butchart in 1976. In his published series of 29 surgical patients, EPP was performed through a posterolateral thoracotomy and entailed extrapleural dissection to include in the final specimen the pleura, lung, ipsilateral diaphragm, and pericardium. The resection is performed through intrapericardial control and division of the hilar structures including as well an extensive lymphadenectomy. The results were compared with 17 patients who received nonsurgical treatments. In this series, prolonged survival was achieved in 3 patients; however, the perioperative mortality rate was 31%.
      • Butchart E.G.
      • Ashcroft T.
      • Barnsley W.C.
      • et al.
      Pleuropneumonectomy in the management of diffuse malignant mesothelioma of the pleura. Experience with 29 patients.
      During the past 30 years, surgeons at the Brigham and Women’s Hospital, Memorial Sloan Kettering Cancer Center, New York University, Toronto General Hospital, University Hospitals of Vienna and Zurich, and others worked to standardize and modernize this operation and the perioperative care to significantly decrease the morbidity and mortality of EPP while extending overall survival in the setting of multimodality therapy.
      • Sugarbaker D.J.
      • Richards W.G.
      • Bueno R.
      Extrapleural pneumonectomy in the treatment of epithelioid malignant pleural mesothelioma: novel prognostic implications of combined N1 and N2 nodal involvement based on experience in 529 patients.
      • Flores R.M.
      • Krug L.M.
      • Rosenzweig K.E.
      • et al.
      Induction chemotherapy, extrapleural pneumonectomy, and postoperative high-dose radiotherapy for locally advanced malignant pleural mesothelioma: a phase II trial.
      • Lauk O.
      • Hoda M.A.
      • de Perrot M.
      • et al.
      Extrapleural pneumonectomy after induction chemotherapy: perioperative outcome in 251 mesothelioma patients from three high-volume institutions.
      Patient selection criteria and techniques for intraoperative and postoperative management have been refined over this time. Currently, EPP is defined as the en bloc resection of the pleura, lung, diaphragm, and pericardium, excision of previous biopsy and chest tube sites, and radical mediastinal lymphadenectomy and other lymph nodes such as found in the mammary chain, along the intercostal structure and in the costodiaphragmatic region, as well as reconstruction of the diaphragm and pericardium with prosthetic patches to prevent herniation.
      It was shown that EPP could be performed with acceptable morbidity and mortality (19% and 6%, respectively), while achieving MCR in the majority of patients.
      • Sugarbaker D.J.
      • Heher E.C.
      • Lee T.H.
      • et al.
      Extrapleural pneumonectomy, chemotherapy, and radiotherapy in the treatment of diffuse malignant pleural mesothelioma.
      As the number of patients in the series increased over time, the observation of extended survival in patients with epithelial histology and extrapleural node negative disease helped identify a subset of patients who would benefit from aggressive multimodality treatment.
      • Sugarbaker D.J.
      • Strauss G.M.
      • Lynch T.J.
      • et al.
      Node status has prognostic significance in the multimodality therapy of diffuse, malignant mesothelioma.
      In the early series, positive surgical margins did not appear to affect survival. However, subsequent analysis of 183 patients revealed that 20% of patients with negative resection margins, negative extrapleural lymph nodes, and epithelial histology experienced long-term median survival of 5 years.
      • Sugarbaker D.J.
      • Flores R.M.
      • Jaklitsch M.T.
      • et al.
      Resection margins, extrapleural nodal status, and cell type determine postoperative long-term survival in trimodality therapy of malignant pleural mesothelioma: results in 183 patients.
      These series established the groundwork for current practice of preoperative staging with mediastinoscopy and advanced imaging modalities, including magnetic resonance imaging and positron-emission tomography/computed tomography, to identify those patients who would benefit maximally from surgery and adjuvant therapy.
      Moreover, in an analysis of 117 patients surviving at least 3 years after EPP, clinicopathologic features including age, female gender, epithelial tumor histology, and normal white blood cell, hemoglobin, or platelet count were considered favorable prognostic factors.
      • Sugarbaker D.J.
      • Wolf A.S.
      • Chirieac L.R.
      • et al.
      Clinical and pathological features of three-year survivors of malignant pleural mesothelioma following extrapleural pneumonectomy.
      This study identified that even patients with advanced stage disease could experience prolonged survival, while acknowledging the heterogeneity of adjuvant therapy as well as the retrospective nature of the analysis. The study also showed comparable perioperative morbidity compared to other series suggesting that EPP-associated complications, when successfully managed, do not limit long-term survival.
      • Sugarbaker D.J.
      • Wolf A.S.
      • Chirieac L.R.
      • et al.
      Clinical and pathological features of three-year survivors of malignant pleural mesothelioma following extrapleural pneumonectomy.
      One of the most difficult decisions is whether to proceed to surgery or not. Laparoscopy or contralateral pleuroscopy should be performed in case of suspicion of intra-abdominal or contralateral disease in staging imaging. Mediastinal staging is performed via endobronchial ultrasound or mediastinoscopy to exclude N3 disease.
      • Scherpereel A.
      • Astoul P.
      • Baas P.
      • et al.
      Guidelines of the European Respiratory Society and the European Society of Thoracic Surgeons for the management of malignant pleural mesothelioma.
      For further decision-making, prognostic markers have been summarized to scores for an algorithm to follow by several groups.
      The analysis of prognostic factors to identify patient groups benefitting from multimodality therapy led to the development of different prognostic scores, such as the Multimodality Prognostic Score developed in a patient cohort receiving induction chemotherapy followed by EPP. This and other scores were developed to facilitate the decision for surgery after induction chemotherapy or in general.
      • Sandri A.
      • Guerrera F.
      • Roffinella M.
      • et al.
      Validation of EORTC and CALGB prognostic models in surgical patients submitted to diagnostic, palliative or curative surgery for malignant pleural mesothelioma.
      The Multimodality Prognostic Score score includes four variables: pre-chemotherapy tumor volume (>500 mL) measured by dedicated software, progressive disease after induction chemotherapy (according to modified Response Evaluation Criteria in Solid Tumor [RECIST] criteria), pre-chemotherapy CRP (>30 mg/mL), and nonepithelioid histologic subtype. It has been assessed in one cohort and validated in a second with significant prognostic impact on MPM patients’ survival treated in this protocol (Fig. 3).
      • Opitz I.
      • Friess M.
      • Kestenholz P.
      • et al.
      A new prognostic score supporting treatment allocation for multimodality therapy for malignant pleural mesothelioma: a review of 12 years' experience.
      Figure thumbnail gr3
      Figure 3Kaplan–Meier curve of overall survival (OS) in months of the multimodality prognostic score (including four variables: tumor volume pre-CTX > 500 mL, C-reactive protein level (CRP) pre-chemotherapy (CTX) > 30 mg/L, nonepithelioid histology in pre-CTX biopsy, and progressive disease according to modified Response Evaluation Criteria in Solid Tumors criteria). (A) Patients treated with induction chemotherapy followed by extrapleural pneumonectomy (EPP) (Zurich). (B) Patients treated with induction chemotherapy followed by EPP (Vienna).
      Adapted with permission.
      • Opitz I.
      • Friess M.
      • Kestenholz P.
      • et al.
      A new prognostic score supporting treatment allocation for multimodality therapy for malignant pleural mesothelioma: a review of 12 years' experience.
      Similarly, the Brigham and other groups developed molecular prognostic tests, which, coupled with tumor volume, lymph node status, and histology, also stratify patients in terms of risk of recurrence and death.
      • Gordon G.J.
      • Dong L.
      • Yeap B.Y.
      • et al.
      Four-gene expression ratio test for survival in patients undergoing surgery for mesothelioma.
      • Bueno R.
      Making the case for molecular staging of malignant pleural mesothelioma.
      Pass et al.
      • Pass H.I.
      • Goparaju C.
      • Espin-Garcia O.
      • et al.
      Plasma biomarker enrichment of clinical prognostic indices in malignant pleural mesothelioma.
      combined the European Organization for Research and Treatment of Cancer (EORTC) prognostic index and the Cancer and Leukemia Group B index with the plasma biomarkers osteopontin and mesothelin.
      • Curran D.
      • Sahmoud T.
      • Therasse P.
      • et al.
      Prognostic factors in patients with pleural mesothelioma: the European Organization for Research and Treatment of Cancer experience.
      • Herndon J.E.
      • Green M.R.
      • Chahinian A.P.
      • et al.
      Factors predictive of survival among 337 patients with mesothelioma treated between 1984 and 1994 by the Cancer and Leukemia Group B.
      The reduction in perioperative mortality rates to 3% to 7% in most recent series can be attributed to improved patient selection, technical experience, as well as improved postoperative care. Technical experience has led to decreased operative times and surgical adaptations that include the reconstruction of the diaphragm and pericardium with Gore-Tex (Newark, Delaware) mesh in all patients regardless of side, buttressing of the bronchial stump with well vascularized tissue, and advanced methods of hemostasis including argon beam coagulation and topical hemostatic agents for chest wall bleeding. Along with experience that has led to advances in operative technique, perioperative care has evolved significantly.
      The approach to postoperative management begins with a comprehensive intensive care unit team with experience in caring for post-pneumonectomy patients. In a series of 328 consecutive patients undergoing EPP, the most common complication after EPP was reversible atrial fibrillation (44%).
      • Sugarbaker D.J.
      • Jaklitsch M.T.
      • Bueno R.
      • et al.
      Prevention, early detection, and management of complications after 328 consecutive extrapleural pneumonectomies.
      Of the complications reported in this series, acute respiratory distress syndrome (ARDS) and pulmonary embolism were most frequently associated with death. To help prevent pulmonary complications, including ARDS, invasive hemodynamic monitoring is used to guide fluid management along with liberal use of bronchoscopy to help clear secretions. For those centers offering induction chemotherapy to their patients, the perioperative anesthesiological protocol is critical as it has been well documented that high intraoperative fraction of inspired oxygen and/or barotrauma can trigger postoperative ARDS.
      • Muraoka M.
      • Oka T.
      • Akamine S.
      • et al.
      Postoperative complications of pulmonary resection after platinum-based induction chemotherapy for primary lung cancer.
      The management can be very challenging in patients following pneumonectomy and — as depicted in Table 1 — it has been shown that the centers’ experience plays a crucial role here. Centers with less than five EPPs per year have a significantly higher incidence of postoperative ARDS.
      • Burt B.M.
      • Cameron R.B.
      • Mollberg N.M.
      • et al.
      Malignant pleural mesothelioma and the Society of Thoracic Surgeons Database: an analysis of surgical morbidity and mortality.
      Eventually, centers offering extracorporeal life support programs provide to date more experience in handling these patients.
      Table 1Morbidity and Mortality After EPP – STS-GTD (n = 225)
      Adapted with permission.
      • Burt B.M.
      • Cameron R.B.
      • Mollberg N.M.
      • et al.
      Malignant pleural mesothelioma and the Society of Thoracic Surgeons Database: an analysis of surgical morbidity and mortality.
      EPP
      ≥5/y<5/yp Value
      Cases31 (32.6)64 (67.4)< .001
      ARDS0 (0.0)8 (12.5).050
      Values presented as n (%) unless noted otherwise.
      ARDS, acute respiratory distress syndrome; EPP, extrapleural pneumonectomy; STS-GTD, STS General Thoracic Surgery Database.
      In general, it has been reported from the same STS database, that the center volume influences significantly morbidity and mortality after MPM surgery in univariate analysis (Table 2).
      Table 2Morbidity and Mortality After EPP – STS-GTD (n = 225)
      Adapted with permission.
      • Burt B.M.
      • Cameron R.B.
      • Mollberg N.M.
      • et al.
      Malignant pleural mesothelioma and the Society of Thoracic Surgeons Database: an analysis of surgical morbidity and mortality.
      UnivariateMultivariate
      OR (95% CI)p ValueOR (95% CI)p Value
      Procedure (EPP)6.99 (2.73-17.90)<.0016.51 (2.07-20.47).001
      Center volume <5 procedures/y3.42 (1.52-7.70).0021.38 (0.49-3.93).54
      CI, confidence interval; EPP, extrapleural pneumonectomy; OR, odds ratio.
      For monitoring the intrathoracic pressure and to avoid mediastinal shift, a 9-French red rubber catheter can be left in the pneumonectomy space postoperatively. As described by Wolf et al.,
      • Wolf A.S.
      • Jacobson F.L.
      • Tilleman T.R.
      • et al.
      Managing the pneumonectomy space after extrapleural pneumonectomy: postoperative intrathoracic pressure monitoring.
      the catheter can be used to evacuate fluid at increments of 150 mL to stabilize the mediastinum and avoid contralateral lung hyperexpansion and pulmonary edema.
      • Wolf A.S.
      • Jacobson F.L.
      • Tilleman T.R.
      • et al.
      Managing the pneumonectomy space after extrapleural pneumonectomy: postoperative intrathoracic pressure monitoring.
      Additionally, vocal cord weakness or paralysis may be encountered postoperatively as a result of recurrent laryngeal nerve injury or sacrifice due to involvement with tumor and must be diagnosed and treated promptly to prevent aspiration to the remaining lung.
      To identify those at risk for thrombotic events, including pulmonary embolism, all patients at Brigham and Women’s institution undergo noninvasive vascular studies to screen for deep vein thrombosis (DVT) preoperatively and on postoperative day 7. Other institutions recommend postoperative therapeutic anticoagulation for several weeks after surgery, but evidence is still lacking.
      • Lauk O.
      • Hoda M.A.
      • de Perrot M.
      • et al.
      Extrapleural pneumonectomy after induction chemotherapy: perioperative outcome in 251 mesothelioma patients from three high-volume institutions.
      In addition to these complications, bronchopleural fistula (BPF) and empyema can be catastrophic after EPP and pose a unique challenge for the thoracic surgeon. The regular use of perioperative intravenous antibiotics, intraoperative antibiotic lavage of the pneumonectomy space, and buttressing of the bronchial stump with well-vascularized tissues have helped to keep the incidence of BPF and empyema acceptable.
      • Wolf A.S.
      • Daniel J.
      • Sugarbaker D.J.
      Surgical techniques for multimodality treatment of malignant pleural mesothelioma: extrapleural pneumonectomy and pleurectomy/decortication.
      For a detailed discussion, Zellos et al.
      • Zellos L.
      • Jaklitsch M.T.
      • Al-Mourgi M.A.
      • et al.
      Complications of extrapleural pneumonectomy.
      offer a thorough review on the management of these complications. Overall, the frequency of empyema varies considerably in the literature between 3% and 30%. This might be related to the fact that some series do not report late empyema, which is in our experience the most frequent form of empyema, occurring several weeks after discharge. Over the past decades, the accelerated empyema treatment after pneumonectomy with repetitive debridement and subsequent vacuum-assisted closure (VAC, KCI Medical GmbH, Ruemlang, Zuerich, Switzerland) (device for negative pressure wound therapy) treatment, where chest was definitively closed within 8 days in 95% (71 of 75) of the patients, has been used.
      • Schneiter D.
      • Grodzki T.
      • Lardinois D.
      • et al.
      Accelerated treatment of postpneumonectomy empyema: a binational long-term study.

      Pleurectomy/Decortication

      The role of P/D in the management of MPM began as an attempt to palliate symptoms caused by the tumor, including dyspnea, cough, and chest pain.
      • Martini N.
      • Bains M.S.
      • Beattie Jr., E.J.
      Indications for pleurectomy in malignant effusion.
      • Soysal O.
      • Karaoglanoglu N.
      • Demiracan S.
      • et al.
      Pleurectomy/decortication for palliation in malignant pleural mesothelioma: results of surgery.
      This procedure has been performed for a long time in America and in Europe.
      • Wanebo H.J.
      • Martini N.
      • Melamed M.R.
      • et al.
      Pleural mesothelioma.
      In comparison to the early experience with EPP, the operative mortality for P/D / (e)P/D has been historically low (<10%), and reduced further in modern series to 0% to 2% as a result of the operation being performed for MCR in patients with early-stage disease.
      • Flores R.M.
      • Pass H.I.
      • Seshan V.E.
      • et al.
      Extrapleural pneumonectomy versus pleurectomy/decortication in the surgical management of malignant pleural mesothelioma: results in 663 patients.
      • Friedberg J.S.
      • Mick R.
      • Culligan M.
      • et al.
      Photodynamic therapy and the evolution of a lung-sparing surgical treatment for mesothelioma.
      • Kostron A.
      • Friess M.
      • Inci I.
      • et al.
      Propensity matched comparison of extrapleural pneumonectomy and pleurectomy/decortication for mesothelioma patients.
      More recently, P/D has become the most common surgical approach because of its perceived lower mortality, improved late pulmonary function, and ability to offer surgery in patients who are older or have limited cardiorespiratory reserve.
      The initial portion of the operation is essentially identical to EPP, including extended posterolateral thoracotomy, resection to remove the ipsilateral sixth rib, and extrapleural dissection to remove the tumor and parietal pleura from the chest wall, followed usually by resection of the diaphragm and portion of the pericardium. Alternatively, a broad lateral thoracotomy below the sixth rib can be applied and additional resection of the costal arch can provide a maximal exposure, so that resection of the rib can be avoided (Fig. 4). Once the entire specimen is only connected by the hilar structures, the parietal pleura is detached (sometimes en bloc), a careful dissection of the entire visceral pleura commences where all visible and palpable tumor down to the fissure is completely removed, and the lymph nodes are dissected. Besides the extension of P/D by performing diaphragmatic or pericardial resection, wedge resection, or even lobectomy, as well as chest wall resection or superior vena cava resection may be performed to achieve complete macroscopic resection.
      Figure thumbnail gr4
      Figure 4Lateral thoracotomy under sixth rib with additional resection of the costal arch for maximum exposure avoids second thoracotomy or excision of a rib (Archives of University Hospital Zurich, Opitz et al. 2018, unpublished results).
      The cavity is irrigated, bleeding is controlled and, on occasion, wedge resections are performed to remove particularly difficult tumors. The lung is then carefully repaired with a stapling device and/or sutures and sealant is applied to minimize air leak post operatively. P/D differs from EPP in that the underlying lung is spared, while complete decortication, or removal of visceral pleura, is performed. The evolution of P/D in the treatment of MPM has come to also include an operation known as (e)P/D which involves P/D as well as the removal of the diaphragm and/or pericardium. This is the operation usually used for curative intent complete macroscopic resection at our institutions, which necessitates diaphragmatic and pericardial reconstruction (Figure 4, Figure 5, Figure 6).
      Figure thumbnail gr5
      Figure 5The tumor is incised and the underlying lung is dissected free during pleurectomy/decortication.
      Reprinted with permission.
      • Wolf A.S.
      • Daniel J.
      • Sugarbaker D.J.
      Surgical techniques for multimodality treatment of malignant pleural mesothelioma: extrapleural pneumonectomy and pleurectomy/decortication.
      Figure thumbnail gr6
      Figure 6Two intraoperative photographs showing on the left side little tumor burden with a thin layer of visceral pleura to be peeled off, and on the right side more tumor burden. (Archives of University Hospital Zurich, Opitz et al. 2018, unpublished results).
      Despite origins in palliation, P/D / (e)P/D has become the most commonly accepted surgical procedure to achieve MCR and prolong survival, particularly in patients with limited, early-stage disease.
      • Flores R.M.
      • Pass H.I.
      • Seshan V.E.
      • et al.
      Extrapleural pneumonectomy versus pleurectomy/decortication in the surgical management of malignant pleural mesothelioma: results in 663 patients.
      The operation is no longer recommended for palliation alone and can be used successfully for the large majority of cases. The MARS 2 trial is currently assessing the role of P/D in a prospective randomized controlled trial and has recruited already 50 patients (status 31.12.2016). As tumor stage advances, the underlying lung parenchyma, fissures, and hilar structures become infiltrated by tumor making MCR by this approach exceedingly difficult, requiring significant dissection and operative time. During the course of P/D / (e)P/D, if MCR is not feasible, some centers consider to achieve MCR by performing EPP as an alternative if the patient is physiologically fit (assessed preoperatively by ventilation-perfusion [V/Q] scan, pulmonary function tests, and transthoracic echocardiography).
      • Rusch V.W.
      • Giroux D.
      • Kennedy C.
      • et al.
      Initial analysis of the international association for the study of lung cancer mesothelioma database.
      This is the case when tumor infiltrates lung parenchyma as shown in Figure 7. Peeling off the visceral pleura from the lung tissue would result in remaining lung tissue being unable to extend and leading to subsequent space problems as shown in Figure 8.
      Figure thumbnail gr7
      Figure 7Infiltration of the lung (photography courtesy of Alex Soltermann, Institute of Pathology, University Hospital Zurich).
      Figure thumbnail gr8
      Figure 8Status post-pleurectomy/decortication with unexpanded lungs in chest x ray and computed tomographic scan (Archives of University Hospital Zurich).
      Mirroring results from EPP series, epithelioid histology and early-stage disease remain significant predictors of survival in patients undergoing P/D / (e)P/D.
      • Flores R.M.
      • Pass H.I.
      • Seshan V.E.
      • et al.
      Extrapleural pneumonectomy versus pleurectomy/decortication in the surgical management of malignant pleural mesothelioma: results in 663 patients.
      • Neragi-Miandoab S.
      • Richards W.G.
      • Sugarbaker D.J.
      Morbidity, mortality, mean survival, and the impact of histology on survival after pleurectomy in 64 patients with malignant pleural mesothelioma.
      In mixed cohorts of patients undergoing EPP or P/D / (e)P/D, epithelial histology, early-stage disease, as well as nodal status continue to predict survival in the setting of multimodality treatment reiterating the importance of preoperative mediastinoscopy and radiographic staging regardless of surgical procedure performed.
      • Flores R.M.
      • Pass H.I.
      • Seshan V.E.
      • et al.
      Extrapleural pneumonectomy versus pleurectomy/decortication in the surgical management of malignant pleural mesothelioma: results in 663 patients.
      • Nakas A.
      • Waller D.
      • Lau K.
      • et al.
      The new case for cervical mediastinoscopy in selection for radical surgery for malignant pleural mesothelioma.
      In a systematic review of P/D / (e)P/D, Cao et al.
      • Cao C.
      • Tian D.H.
      • Pataky K.A.
      • et al.
      Systematic review of pleurectomy in the treatment of malignant pleural mesothelioma.
      report overall perioperative morbidity of 13% to 48%.
      • Cao C.
      • Tian D.H.
      • Pataky K.A.
      • et al.
      Systematic review of pleurectomy in the treatment of malignant pleural mesothelioma.
      Visceral pleurectomy often involves injury to the underlying lung parenchyma resulting in bleeding and air leak. In some centers, to help prevent these complications, the patient is maintained on mechanical ventilation with positive end expiratory pressure for the first 24 to 48 hours to keep the lung maximally inflated and help tamponade oozing from the lung. Other centers prefer to minimize positive pressure ventilation to reduce the air leak by extubating the patient immediately in the operating room at the end of the procedure. The most common surgical morbidity associated with P/D / (e)P/D is prolonged air leak and sequelae from prolonged chest tube drainage (3.5% to 57%).
      • Martini N.
      • Bains M.S.
      • Beattie Jr., E.J.
      Indications for pleurectomy in malignant effusion.
      • Soysal O.
      • Karaoglanoglu N.
      • Demiracan S.
      • et al.
      Pleurectomy/decortication for palliation in malignant pleural mesothelioma: results of surgery.
      • Flores R.M.
      • Pass H.I.
      • Seshan V.E.
      • et al.
      Extrapleural pneumonectomy versus pleurectomy/decortication in the surgical management of malignant pleural mesothelioma: results in 663 patients.
      • Friedberg J.S.
      • Mick R.
      • Culligan M.
      • et al.
      Photodynamic therapy and the evolution of a lung-sparing surgical treatment for mesothelioma.
      • Kostron A.
      • Friess M.
      • Inci I.
      • et al.
      Propensity matched comparison of extrapleural pneumonectomy and pleurectomy/decortication for mesothelioma patients.
      • Neragi-Miandoab S.
      • Richards W.G.
      • Sugarbaker D.J.
      Morbidity, mortality, mean survival, and the impact of histology on survival after pleurectomy in 64 patients with malignant pleural mesothelioma.
      • McCormack P.M.
      • Nagasaki F.
      • Hilaris B.S.
      • et al.
      Surgical treatment of pleural mesothelioma.
      Air leak is managed conservatively with maintenance of tube thoracostomy until resolution of the air leak or full expansion of the lung occurs and which may take 2 to 3 weeks.
      • Wolf A.S.
      • Daniel J.
      • Sugarbaker D.J.
      Surgical techniques for multimodality treatment of malignant pleural mesothelioma: extrapleural pneumonectomy and pleurectomy/decortication.
      P/D / (e)P/D may also involve significant blood loss (2 to 3 L) despite the advanced hemostatic techniques and should be anticipated by the surgical and anesthesia team and aminocaproic acid is frequently administered prophylactically.
      • Rusch V.W.
      Pleurectomy/decortication in the setting of multimodality treatment for diffuse malignant pleural mesothelioma.
      Coagulopathy is not uncommon after P/D / (e)P/D or EPP and should be treated aggressively with blood products, recombinant coagulation factors, and occasionally systemic antifibrinolytics in the setting of refractory bleeding.
      • Wolf A.S.
      • Daniel J.
      • Sugarbaker D.J.
      Surgical techniques for multimodality treatment of malignant pleural mesothelioma: extrapleural pneumonectomy and pleurectomy/decortication.
      In addition to these complications, P/D / (e)P/D shows a similar morbidity profile to that of EPP, including atrial fibrillation, DVT, myocardial infarction, and empyema.

      EPP and P/D — Comparison

      The role of surgery itself as part of the multimodality concept has been debated heavily after the release of the Mesothelioma and Radical Surgery (MARS I) trial.
      • Treasure T.
      • Lang-Lazdunski L.
      • Waller D.
      • et al.
      Extra-pleural pneumonectomy versus no extra-pleural pneumonectomy for patients with malignant pleural mesothelioma: clinical outcomes of the Mesothelioma and Radical Surgery (MARS) randomised feasibility study.
      The MARS I trial concluded that “EPP within trimodality therapy offers no benefit and possibly harms patients” although only 16 patients of 24 patients assigned to the EPP arm received radical surgery. The study was not designed nor powered to answer the question of benefit or not of EPP, but rather of the feasibility of such a trial. A definitive answer to this question would require an accrual of 670 patients to identify a survival benefit.
      • Weder W.
      • Stahel R.A.
      • Baas P.
      • et al.
      The MARS feasibility trial: conclusions not supported by data.
      Also, the criticism of an excessive morbidity and mortality rate is not supported by recently reported trials for trimodality therapy, including EPP, showing that morbidity remains high (22% to 82%) but seems to be manageable in terms of mortality in a range of 2% to 5% in experienced centers. Considering all studies published between 1985 and 2010, a wide range of mortality, from 0% to a maximum of 11.8%, is reported.
      • Cao C.Q.
      • Yan T.D.
      • Bannon P.G.
      • et al.
      A systematic review of extrapleural pneumonectomy for malignant pleural mesothelioma.
      In contrast, morbidity and mortality rates after (e)P/D are much lower as described in the previous paragraph.
      • Cao C.
      • Tian D.
      • Park J.
      • et al.
      A systematic review and meta-analysis of surgical treatments for malignant pleural mesothelioma.
      • Taioli E.
      • Wolf A.S.
      • Flores R.M.
      Meta-analysis of survival after pleurectomy decortication versus extrapleural pneumonectomy in mesothelioma.
      Nonetheless, the data on mortality and morbidity remains extremely heterogeneous because of differences in the patient cohorts and different definitions of morbidity. According to the results from a recently published propensity score matched analysis, both procedures appear to have similar rates of major morbidity and with 48% and 58% for EPP and P/D, respectively, in experienced centers, are comparable to published data ranging 10% to 82.6% and 5.9% to 55%, respectively.
      • Kostron A.
      • Friess M.
      • Inci I.
      • et al.
      Propensity matched comparison of extrapleural pneumonectomy and pleurectomy/decortication for mesothelioma patients.
      • Papaspyros S.
      • Papaspyros S.
      Surgical management of malignant pleural mesothelioma: impact of surgery on survival and quality of life-relation to chemotherapy, radiotherapy, and alternative therapies.
      Each operation bears its specific set of possible and frequent complications that derive from the very characteristics of each operation and both procedures are not directly comparable. After EPP, complications can become life threatening very quickly, such as BPF with subsequent empyema. Empyema can also occur without BPF, which happens usually at later times, weeks after the operation. In contrast, prolonged air leak can occur only after P/D. But this can in return also result in empyema due to ascending infection via the longtime remaining chest drains. Table 3 summarizes the most frequent complications after both procedures.
      Table 3Complications After P/D and EPP
      Adapted with permission.
      • Taioli E.
      • Wolf A.S.
      • Flores R.M.
      Meta-analysis of survival after pleurectomy decortication versus extrapleural pneumonectomy in mesothelioma.
      Author, YearNo. of Cases P/D; EPPComplications P/D

      Total (%); Specific (n)
      Complications EPP

      Total (%); Specific (n)
      Allen, 1994
      • Allen K.B.
      • Faber L.P.
      • Warren W.H.
      Malignant pleural mesothelioma. Extrapleural pneumonectomy and pleurectomy.
      56; 4026.8%; AR (5), PAL (6)30%; AR (3), BPF (2), CHT (1)
      Pass, Kranda, 1997
      • Pass H.I.
      • Kranda K.
      • Temeck B.K.
      • et al.
      Surgically debulked malignant pleural mesothelioma: results and prognostic factors.
      ; Pass, Temeck, 1997
      • Pass H.I.
      • Temeck B.K.
      • Kranda K.
      • et al.
      Phase III randomized trial of surgery with or without intraoperative photodynamic therapy and postoperative immunochemotherapy for malignant pleural mesothelioma.
      39; 39AR (2), PF (1)AR (14), BPF (7)
      Aziz, 2002
      • Aziz T.
      • Jilaihawi A.
      • Prakash D.
      The management of malignant pleural mesothelioma; single centre experience in 10 years.
      47; 6421%; ARDS (6)
      de Vries, 2003
      • de Vries W.J.
      • Long M.A.
      Treatment of mesothelioma in Bloemfontein, South Africa.
      29; 17PAL (3)
      Okada, 2008
      • Okada M.
      • Mimura T.
      • Ohbayashi C.
      • et al.
      Radical surgery for malignant pleural mesothelioma: results and prognosis.
      34; 3115%; AR (3)48%; AR (8), BPF (2), CHT (2), PF (2)
      Schipper, 2008
      • Schipper P.H.
      • Nichols F.C.
      • Thomse K.M.
      • et al.
      Malignant pleural mesothelioma: surgical management in 285 patients.
      44; 739%50.7%; ARDS (4), BPF (5), PE (3), PF (6)
      Borasio, 2008
      • Borasio P.
      • Berruti A.
      • Bille A.
      • et al.
      Malignant pleural mesothelioma: clinicopathologic and survival characteristics in a consecutive series of 394 patients.
      12; 1533%; AR (1)60%; AR (4)
      Mineo, 2010
      • Mineo T.
      • Ambrogi V.
      • Cufari M.
      • Pompeo E.
      May cyclooxygenase-2 (COX_2), p21 and p27 expression affect prognosis and therapeutic strategy of patients with malignant pleural mesothelioma?.
      44; 2713.6%; DVT (2)33%; AR (4), BPF (2), DVT (2)
      Luckraz, 2010
      • Luckraz H.
      • Rahman M.
      • Patel N.
      • et al.
      Three decades of experience in the surgical multi-modality management of pleural mesothelioma.
      90; 49AR (8)AR (2), BPF (7)
      Friedberg, 2011
      • Friedberg J.S.
      • Mick R.
      • Culligan M.
      • et al.
      Photodynamic therapy and the evolution of a lung-sparing surgical treatment for mesothelioma.
      14;14AR (3), CHT (2), DVT (4), PAL (1)AR (3), CHT (1), DVT (6) PE (1)
      Rena, 2012
      • Rena O.
      • Casadio C.
      Extrapleural pneumonectomy for early stage malignant pleural mesothelioma: a harmful procedure.
      37; 4024%; AR (2)62%; AR (17), ARDS (1), BPF (1), PE (1), PF (1)
      Nakas, 2012a
      • Nakas A.
      • Waller D.
      • Lau K.
      • et al.
      The new case for cervical mediastinoscopy in selection for radical surgery for malignant pleural mesothelioma.
      ; Nakas, 2012b
      • Nakas A.
      • von Meyenfeldt E.
      • Lau K.
      • et al.
      Long-term survival after lung-sparing total pleurectomy for locally advanced (International Mesothelioma Interest Group Stage T3-T4) non-sarcomatoid malignant pleural mesothelioma.
      85; 127PAL (20)
      Lang-Lazdunski, 2012
      • Lang-Lazdunski L.
      • Bille A.
      • Lal R.
      • et al.
      Pleurectomy/decortication is superior to extrapleural pneumonectomy in the multimodality management of patients with malignant pleural mesothelioma.
      61; 2527.7%; AR (2), ARDS (1), CHT (4), PAL (10)68%; AR (7), ARDS (1), BPF (2), PE (1)
      Bovolato, 2014
      • Bovolato P.
      • Casadio C.
      • Bille A.
      • et al.
      Does surgery improve survival of patients with malignant pleural mesothelioma?: a multicenter retrospective analysis of 1365 consecutive patients.
      202; 30110.4%; AR (9), PAL (5)21.6%; AR (32), ARDS (1), BPF (3), DVT (2), PE (3), PF (3)
      Kostron 2017
      • Kostron A.
      • Friess M.
      • Inci I.
      • et al.
      Propensity matched comparison of extrapleural pneumonectomy and pleurectomy/decortication for mesothelioma patients.
      26; 14158%; AR (4), ARDS (1), CHT (2), DVT (1), PAL (15)38%; AR (50), ARDS (2), BPF (17), CHT (10), DVT (1), PE (4), PF (7)
      AR, arrhythmia; ARDS, Adult respiratory distress syndrome; BPF, bronchopleural fistula; CHT, Chylothorax; DVT, deep vein thrombosis; PAL, prolonged air leak; PE, pulmonary embolism; PF, Patch failure; P/D, pleurectomy/decortication; EPP, extrapleural pneumonectomy.
      However, 90-day mortality data have been shown to be a better estimate for the risk of a thoracic operation
      • McMillan R.R.
      • Berger A.
      • Sima C.S.
      • et al.
      Thirty-day mortality underestimates the risk of early death after major resections for thoracic malignancies.
      ; recent data from the United Kingdom show a 13.5% 90-day mortality for EPP and 9.2% for P/D, whereas other centers report 8.0% and 0.0% 90-day mortality for EPP and P/D, respectively.
      • Sharkey A.J.
      • Tenconi S.
      • Nakas A.
      • Waller D.A.
      The effects of an intentional transition from extrapleural pneumonectomy to extended pleurectomy/decortication.
      In general, the comparison of EPP, (e)P/D, and P/D is difficult because the available large institutional reports use different inclusion and exclusion criteria as well as different treatment protocols with induction/adjuvant chemotherapy and/or induction/adjuvant chemotherapy as well as different intraoperative treatment. Another problem is the heterogeneous definition of morbidity and major morbidity and the different calculation of overall survival (OS) (from time of diagnosis, chemotherapy start, and surgery). These differences make it difficult to determine which surgical technique is more appropriate to achieve long survival with low morbidity and mortality.
      The Systematic Review Unit of the University in Sydney analyzed the surgical treatment of MPM including all relevant data on comparative outcomes of extended P/D and EPP in multimodality settings. In most studies, P/D was usually chosen for earlier stages and EPP for more advanced stages, a decision which is often taken only in the operating theater and not before, due to a lack of reliable clinical staging.
      Another important aspect to be considered is the quality of life (QoL) during and after treatment; however, unfortunately, there are not many data available. Rena et al.
      • Rena O.
      • Casadio C.
      Extrapleural pneumonectomy for early stage malignant pleural mesothelioma: a harmful procedure.
      have included QoL data in their 11 years institutional report comparing EPP and P/D and found a superiority of P/D of EPP in QoL after 6 and 12 months.
      • Rena O.
      • Casadio C.
      Extrapleural pneumonectomy for early stage malignant pleural mesothelioma: a harmful procedure.
      However, it has been reported for patients undergoing EPP that an improvement in QoL occurred for all parameters at 3 months postoperatively, and another study showing sustained improvement in quality of life after EPP.
      • Cao C.
      • Krog Andvik S.K.
      • Yan T.D.
      • et al.
      Staging of patients after extrapleural pneumonectomy for malignant pleural mesothelioma--institutional review and current update.
      • Ambrogi V.
      • Mineo D.
      • Gatti A.
      • et al.
      Symptomatic and quality of life changes after extrapleural pneumonectomy for malignant pleural mesothelioma.
      This holds particularly true for patients with shortness of breath because of entrapped lungs or due to an important V/Q mismatch. Table 4 summarizes the reporting of QoL after EPP.
      Table 4Quality of Life Reported in Studies Analyzing the Difference in Patients Undergoing (e)P/D or EPP
      Study DesignNo. of Patients in StudyModalitiesNo. of Surgeries CompletedMortalityOverall MorbidityQuality of Life
      P/D
      2012

      Rena et al.
      • Rena O.
      • Casadio C.
      Extrapleural pneumonectomy for early stage malignant pleural mesothelioma: a harmful procedure.
      Retrospective77ind. CTX (n = 64)

      adj. CTX (n = 13)
      37 P/DNone24%Below baseline after 6 and 12 months (except for cough and dyspnea)
      2012

      Mollberg et al.
      • Mollberg N.M.
      • Vigneswaran Y.
      • Kindler H.L.
      • et al.
      Quality of life after radical pleurectomy decortication for malignant pleural mesothelioma.
      Prospective28ind. CTX (n = 4)

      adj. CTX (n = 20
      28 (e)P/DNoneNRPS0: above baseline after 8-9 months (except for physical functioning and dyspnea)

      PS1: above baseline after 8-9 months (except for cognitive functioning, diarrhea, nausea/vomiting)
      2015

      Burkholder et al.
      • Burkholder D.
      • Hadi D.
      • Kunnavakkam R.
      • et al.
      Effects of extended pleurectomy and decortication on quality of life and pulmonary function in patients with malignant pleural mesothelioma.
      Retrospective36ind. CTX (n = 3)

      adj. CTX (n = 30)
      36 (e)P/DNoneNRPS0: mixed results after 7-8 months

      PS1/2: above baseline after 7-8 months
      EPP
      2007

      Weder et al.
      • Weder W.
      • Stahel R.A.
      • Bernhard J.
      • et al.
      Multicenter trial of neo-adjuvant chemotherapy followed by extrapleural pneumonectomy in malignant pleural mesothelioma.
      Prospective61ind. CTX

      ±adj. RT
      45 EPP30 d: 2.2%Major: 35%Overall less impaired after surgery, although it did not reach the baseline level 6 months thereafter
      2011

      Treasure et al.
      • Treasure T.
      • Lang-Lazdunski L.
      • Waller D.
      • et al.
      Extra-pleural pneumonectomy versus no extra-pleural pneumonectomy for patients with malignant pleural mesothelioma: clinical outcomes of the Mesothelioma and Radical Surgery (MARS) randomised feasibility study.
      Prospective50ind. CTX

      ± adj. therapy
      19 EPP30 d:10.5% in-hospital: 15.8%69%Below baseline after 6 weeks, 3, 6, 9, 12, 18, and 19 months
      2012

      Rena et al.
      • Rena O.
      • Casadio C.
      Extrapleural pneumonectomy for early stage malignant pleural mesothelioma: a harmful procedure.
      Retrospective77ind. CTX (n = 64)

      adj. CTX (n = 13)
      40 EPP30 d: 5%62%Below baseline after 6 and 12 months (except for cough and dyspnea)
      2012

      Ambrogi et al.
      • Ambrogi V.
      • Baldi A.
      • Schillaci O.
      • et al.
      Clinical impact of extrapleural pneumonectomy for malignant pleural mesothelioma.
      Prospective29adj. CTX29 EPP30 d: 1%Major: 41%Above baseline after 3 months
      adj. CTX, adjuvant chemotherapy; ind. CTX, induction chemotherapy; (e)P/D, (extended) pleurectomy/decortication; EPP, extrapleural pneumonectomy; NR, not reported; PS, performance score.
      All studies report QoL below baseline after EPP, some until after 12 months after the operation, or even 19 months, whereas other report return to baseline after 6 months.
      • Treasure T.
      • Lang-Lazdunski L.
      • Waller D.
      • et al.
      Extra-pleural pneumonectomy versus no extra-pleural pneumonectomy for patients with malignant pleural mesothelioma: clinical outcomes of the Mesothelioma and Radical Surgery (MARS) randomised feasibility study.
      • Rena O.
      • Casadio C.
      Extrapleural pneumonectomy for early stage malignant pleural mesothelioma: a harmful procedure.
      • Weder W.
      • Stahel R.A.
      • Bernhard J.
      • et al.
      Multicenter trial of neo-adjuvant chemotherapy followed by extrapleural pneumonectomy in malignant pleural mesothelioma.
      In a recent analysis of our own cohort of patients undergoing induction chemotherapy in a 2-year period, patients filled out the EORTC QLC-C30 and –C15 and SF-36 self-rating questionnaires preoperatively, 6 weeks, and 4 months after the operation. Some symptoms such as general health score, vitality, social functioning, and mental health were even better 4 months after the operation compared to preoperatively after both procedures (unpublished data).
      Regarding long-term oncological outcome, the analysis of the IASLC reported a survival advantage in patients undergoing EPP for early-stage disease with higher survival rates in comparison to patients undergoing P/D.
      • Rusch V.W.
      • Giroux D.
      • Kennedy C.
      • et al.
      Initial analysis of the international association for the study of lung cancer mesothelioma database.
      Cao et al.
      • Cao C.
      • Tian D.
      • Park J.
      • et al.
      A systematic review and meta-analysis of surgical treatments for malignant pleural mesothelioma.
      reported that there was insufficient data to perform a meta-analysis in their systematic review comparing EPP with P/D with respect to OS between both procedures. Median OS ranged between 13 and 29 months for extended P/D and 12 to 22 months for EPP. In general, the big ranges of reported survival data are also related to the fact that there are no clear recommendations for follow-up; clearly, for patients included in a more frequent follow-up program, recurrences are documented earlier. There are no validated recommendations regarding the follow-up of patients after surgery, or any other treatment. We recommend follow-up by the surgeon first at 2 and 6 weeks after surgery, then every 4 months for the first 2 years, 6 months until 5 years, then once a year. The British Thoracic Society guidelines recommend patients should be offered 3 to 4 monthly follow-up appointments with an oncologist, respiratory physician, or specialist nurse according to their current treatment plan.
      • Woolhouse I.
      • Bishop L.
      • Darlison L.
      • et al.
      BTS guideline for the investigation and management of malignant pleural mesothelioma.
      Progression-free survival, if reported, is usually longer after EPP in comparison to P/D, and especially the local recurrence rates are higher in P/D groups.
      • Flores R.M.
      • Pass H.I.
      • Seshan V.E.
      • et al.
      Extrapleural pneumonectomy versus pleurectomy/decortication in the surgical management of malignant pleural mesothelioma: results in 663 patients.
      The most recent comprehensive meta-analysis was conducted to compare if P/D or EPP is more beneficial to MPM patients.
      • Taioli E.
      • Wolf A.S.
      • Flores R.M.
      Meta-analysis of survival after pleurectomy decortication versus extrapleural pneumonectomy in mesothelioma.
      Twenty-four distinct data sets that evaluated long-term outcome of P/D versus EPP were analyzed. One thousand five hundred twelve patients received P/D and 1,391 EPP. The proportion of short-term mortality (perioperative and 30 days after surgery) was significantly higher in the EPP group (4.5%) versus the P/D group (1.7%). There was no significant difference in 2-year mortality between both groups (23.8% versus 25%) but the included studies showed statistically significant heterogeneity. Among the 17 studies reporting median survival, 53% reported higher median survival with EPP and 47% with P/D. Of the seven studies reporting at least a 2-year survival rate, survival was similar for the two cohorts. The analysis suggests that EPP is associated with a 2.5-fold higher short-term mortality than P/D; therefore, P/D should be preferred if MCR could be achieved (Fig. 9 and Table 5).
      Figure thumbnail gr9
      Figure 9Difference in median survival between pleurectomy decortications (P/D) and extrapleural pneumonectomy (EPP) (n = 17).
      Reprinted with permission.
      • Taioli E.
      • Wolf A.S.
      • Flores R.M.
      Meta-analysis of survival after pleurectomy decortication versus extrapleural pneumonectomy in mesothelioma.
      Table 5Overview of Reported Mortality and Morbidity and Overall Survival in Studies Reporting the Outcome of Patients Undergoing Extrapleural Pneumonectomy Versus Pleurectomy/Decortication or Pleurectomy in Multimodality Treatment Protocols
      Study DesignPatients in Study, nModalitiesEPP

      EPPs Completed, n
      MortalityOverall MorbidityMedian OS (mo)P/D and P

      P/D or P Completed, n
      MortalityOverall MorbidityMedian OS (mo)
      1991

      Branscheid et al
      • Branscheid D.
      • Krysa S.
      • Bauer E.
      • et al.
      Diagnostic and therapeutic strategy in malignant pleural mesothelioma.
      Retro301± Adj. CTX7630 d: 11.8%NR9.382 (palliative)30 d: 2.4%NR10.4
      1999

      Rusch et al
      • Rusch V.W.
      • Venkatraman E.S.
      Important prognostic factors in patients with malignant pleural mesothelioma, managed surgically.
      Retro231± Adj. therapy11530 d: 5.2%NRNR5930 d: 3.3%NRNR
      2002

      Aziz et al
      • Aziz T.
      • Jilaihawi A.
      • Prakash D.
      The management of malignant pleural mesothelioma; single centre experience in 10 years.
      Retro302± Intra-pleural CTX and adj. CTX6430 d: 9.1%Major: 21%No CTX: 13 adj. CTX:354730 d: 0%NR14
      2007

      Flores et al
      • Flores R.M.
      • Zakowski M.
      • Venkatraman E.
      • et al.
      Prognostic factors in the treatment of malignant pleural mesothelioma at a large tertiary referral center.
      Retro945Mixed

      ± ind. CTX

      ± adj. RT

      ± other
      20830 d: 5%NR14.317630 d: 3%NR15.8
      2008

      Schipper
      • Schipper P.H.
      • Nichols F.C.
      • Thomse K.M.
      • et al.
      Malignant pleural mesothelioma: surgical management in 285 patients.
      Retro285Mixed738.2%Major: 50.7%

      Minor: 34.2%
      16Subtotal P: 34

      Total P: 10
      SP: 2.9%

      TP: 0%b
      Major:

      SP: 5.9%

      TP: 20%

      Minor:

      SP: 11.8%

      TP: 10%
      SP: 8.1

      TP: 17.2
      2008

      Flores et al
      • Flores R.M.
      • Pass H.I.
      • Seshan V.E.
      • et al.
      Extrapleural pneumonectomy versus pleurectomy/decortication in the surgical management of malignant pleural mesothelioma: results in 663 patients.
      Retro663Mixed3857%NR122784%NR16
      2009

      Yan et al
      • Yan T.D.
      • Boyer M.
      • Tin M.M.
      • et al.
      Extrapleural pneumonectomy for malignant pleural mesothelioma: outcomes of treatment and prognostic factors.
      Retro424Mixed705.7%37%20177NRNRNR
      2010

      Luckraz et al
      • Luckraz H.
      • Rahman M.
      • Patel N.
      • et al.
      Three decades of experience in the surgical multi-modality management of pleural mesothelioma.
      Retro217± Adj. CTX

      ± adj. RT
      4930 d: 8.2% in-hospital: 10.2%41%NR9030 d: 1.1% in-hospital: 2.2%16%NR
      2012

      Nakas et al
      • Nakas A.
      • Waller D.
      • Lau K.
      • et al.
      The new case for cervical mediastinoscopy in selection for radical surgery for malignant pleural mesothelioma.
      Retro212NR127NRNR15.685NRNR13.4
      2012

      Nakas et al
      • Nakas A.
      • von Meyenfeldt E.
      • Lau K.
      • et al.
      Long-term survival after lung-sparing total pleurectomy for locally advanced (International Mesothelioma Interest Group Stage T3-T4) non-sarcomatoid malignant pleural mesothelioma.
      Retro165Mixed9830 d: 7%

      90 d: 17%
      68%14.7Total P: 6730 d: 3%

      90 d: 12%
      43%13.4
      2014

      Nakas et al
      • Nakas A.
      • Waller D.
      Predictors of long-term survival following radical surgery for malignant pleural mesothelioma.
      Retro252±CTX112NRNR19.2140NRNR16.2
      2014

      Burt et al
      • Burt B.M.
      • Cameron R.B.
      • Mollberg N.M.
      • et al.
      Malignant pleural mesothelioma and the Society of Thoracic Surgeons Database: an analysis of surgical morbidity and mortality.
      Retro225NR9530 d: 10.5%major: 24.2%NR13030 d: 3.1%Major: 3.8%NR
      2014

      Bovolato et al
      • Bovolato P.
      • Casadio C.
      • Bille A.
      • et al.
      Does surgery improve survival of patients with malignant pleural mesothelioma?: a multicenter retrospective analysis of 1365 consecutive patients.
      Retro1365+/- CTX30130 d: 4.1%

      90 d: 6.9%
      21.6%18.820230 d: 2.6%

      90 d: 6%
      10.4%20.5
      2016

      Sharkey et al
      • Sharkey A.J.
      • Tenconi S.
      • Nakas A.
      • et al.
      The effects of an intentional transition from extrapleural pneumonectomy to extended pleurectomy/decortication.
      Retro362mixed133In-hospital: 5.3%

      30 d: 6%

      90 d: 13.5%
      NR12.9229In-hospital: 6.6%

      30 d: 3.5%

      90 d: 9.2%
      NR12.3
      2016

      Infante et al
      • Infante M.
      • Morenghi E.
      • Bottoni E.
      • et al.
      Comorbidity, postoperative morbidity and survival in patients undergoing radical surgery for malignant pleural mesothelioma.
      Retro582+/- CTX

      +/- adj. RT
      9130 d: 3.3%

      90 d: 5.5%
      27%194730 d: 2.1%

      90 d: 6.4%
      26%30
      2016

      Batirel et al
      • Batirel H.F.
      • Metintas M.
      • Caglar H.B.
      • et al.
      Adoption of pleurectomy and decortication for malignant mesothelioma leads to similar survival as extrapleural pneumonectomy.
      Retro130mixed42NRNR18.366NRNR14.6
      2017 Kostron et al
      • Kostron A.
      • Friess M.
      • Inci I.
      • et al.
      Propensity matched comparison of extrapleural pneumonectomy and pleurectomy/decortication for mesothelioma patients.
      Retro167Ind CTX

      +/- adj. RT
      14130 d: 5%

      90 d: 10%
      Major: 38%23260%Major: 58%32
      Studies with more than 100 EPPs plus P/Ds completed were included.
      adj. CTX, adjuvant chemotherapy; ind. CTX, induction chemotherapy; (e)P/D, (extended) pleurectomy/decortication; EPP, extrapleural pneumonectomy; NR, not reported; OS, overall survival; PS0/1/2, performance score; SP, subtotal pleurectomy; TP, total pleurectomy; retro, retrospective.
      Currently a new feasibility study — MARS 2 — is recruiting in the United Kingdom (MARS 2: A Feasibility Study Comparing [Extended] Pleurectomy Decortication Versus no Pleurectomy Decortication in Patients with Malignant Pleural Mesothelioma; ClinicalTrials.gov Identifier: NCT02040272). After 2 cycles of induction chemotherapy with cisplatin/pemetrexed, patients will be randomized to receive chemotherapy only (4 cycles of cisplatin/pemetrexed) or lung-sparing surgery plus chemotherapy (4 cycles of cisplatin/pemetrexed). The primary endpoint of the study is the ability to randomize 50 patients within the first 24 months or the ability to recruit 25 patients within any 6-month period.

      Palliative Surgery

      Parenchyma-sparing debulking P/D or partial pleurectomy should be considered in symptomatic patients who decline or are not eligible for MCR due to stage or status, and have not responded to thoracentesis or catheter drainage, as freeing an entrapped lung may improve respiratory function.
      • Flores R.M.
      Surgical options in malignant pleural mesothelioma: extrapleural pneumonectomy or pleurectomy/decortication.
      This palliative surgical approach can also be performed by video-assisted thoracic surgery (VATS) with the intention to improve the QoL of these patients.
      • Waller D.A.
      • Morritt G.N.
      • Forty J.
      Video-assisted thoracoscopic pleurectomy in the management of malignant pleural effusion.
      • Halstead J.C.
      • Lim E.
      • Venkateswaran R.M.
      • et al.
      Improved survival with VATS pleurectomy-decortication in advanced malignant mesothelioma.
      • Martin-Ucar A.E.
      • Edwards J.G.
      • Rengajaran A.
      • et al.
      Palliative surgical debulking in malignant mesothelioma. Predictors of survival and symptom control.
      • Nakas A.
      • Trousse D.S.
      • Martin-Ucar A.E.
      • et al.
      Open lung-sparing surgery for malignant pleural mesothelioma: the benefits of a radical approach within multimodality therapy.
      Alternatively, indwelling pleural catheters, which can be placed in an outpatient setting and are easy to handle, are a very good alternative for a rapid palliation of recurring pleural effusions.
      • Freeman R.K.
      • Ascioti A.J.
      • Mahidhara R.S.
      A propensity-matched comparison of pleurodesis or tunneled pleural catheter in patients undergoing diagnostic thoracoscopy for malignancy.
      • Hunt B.M.
      • Farivar A.S.
      • Vallieres E.
      • et al.
      Thoracoscopic talc versus tunneled pleural catheters for palliation of malignant pleural effusions.
      Talc pleurodesis is efficient in prevention of pleural effusion recurrence but requires a full expansion of the lung.
      Recently the MesoVATS trial has randomized MPM patients to undergo VATS pleurectomy versus talc pleurodesis via an indwelling intercostal chest drain or via thoracoscopy. Survival rates were about the same but VATS pleurectomy significantly improved control of recurrent build-up of fluid in the lungs in the first 6 months after the procedure and improved quality of life for 12 months (Fig. 10).
      • Rintoul R.
      • Ritchie A.
      • Edwards J.
      • et al.
      MesoVATS Collaborators. Efficacy and cost of video-assisted thoracoscopic partial pleurectomy versus talc pleurodesis in patients with malignant pleural mesothelioma (MesoVATS): an open-label, randomised, controlled trial.
      Figure thumbnail gr10
      Figure 10Kaplan-Meier curves of overall survival, in all patients and by risk group overall survival in all randomly assigned patients with mesothelioma, per treatment group (A) and in high-risk and low-risk patients, per treatment group (B). The vertical line crosses the x axis at 1 year (primary endpoint). VAT-PP, video-assisted thoracoscopic partial pleurectomy.
      Reprinted with permission.
      • Rintoul R.
      • Ritchie A.
      • Edwards J.
      • et al.
      MesoVATS Collaborators. Efficacy and cost of video-assisted thoracoscopic partial pleurectomy versus talc pleurodesis in patients with malignant pleural mesothelioma (MesoVATS): an open-label, randomised, controlled trial.

      Surgery for Recurrence — Chest Wall Resection

      Locally recurrent disease is a common problem in patients who undergo surgery for MPM. It usually occurs in the ipsilateral thoracic cavity or chest wall and can occasionally spread to the retroperitoneum and abdominal cavity. In most cases, this type of recurrence is handled by localized radiation therapy and chemotherapy. However, there are special circumstances where the recurrence is limited and potentially resectable.
      The literature reporting the outcome of surgical second line treatments of MPM recurrence is scarce. The only available paper reporting specifically about the outcome of patients after chest wall resection (CWR) is Burt et al.
      • Burt B.M.
      • Ali S.O.
      • DaSilva M.C.
      • et al.
      Clinical indications and results after chest wall resection for recurrent mesothelioma.
      In this paper, 47 patients initially treated with EPP (n 3 2) or P/D (n = 15) were analyzed. Median time to relapse after radical surgery was 16.1 months. After CWR, 63% of the patients had direct closure of the defect, 28% required mesh construction, and 9% underwent a muscle flap closure. No morbidity or 30-day mortality occurred and the median hospital stay was 3 days (range, 0 to 12 days). The median survival after CWR was 20.4 months in patients with epithelioid histologic subtype (n = 32) and 7.4 months in patients with biphasic histologic subtype (n = 15) at initial EPP or P/D.
      Other papers report surgical treatment of relapse in general and include not only CWR, but also contralateral pleurectomy, resection of a mediastinal tumor, radical retroperitoneal resection, pectoral muscle resection, and upper lobe segmentectomy.
      • Kostron A.
      • Friess M.
      • Crameri O.
      • et al.
      Relapse pattern and second-line treatment following multimodality treatment for malignant pleural mesothelioma.
      • Okamoto T.
      • Yano T.
      • Haro A.
      • et al.
      Treatment for recurrence after extrapleural pneumonectomy for malignant pleural mesothelioma: a single institution experience.
      • Politi L.
      • Borzellino G.
      Second surgery for recurrence of malignant pleural mesothelioma after extrapleural pneumonectomy.
      In addition, the number of patients receiving second-line surgery was low and ranged from 2 to 16.
      • Kostron A.
      • Friess M.
      • Crameri O.
      • et al.
      Relapse pattern and second-line treatment following multimodality treatment for malignant pleural mesothelioma.
      • Okamoto T.
      • Yano T.
      • Haro A.
      • et al.
      Treatment for recurrence after extrapleural pneumonectomy for malignant pleural mesothelioma: a single institution experience.
      • Politi L.
      • Borzellino G.
      Second surgery for recurrence of malignant pleural mesothelioma after extrapleural pneumonectomy.
      For selected patients, curative CWR is an effective strategy with minimal morbidity and promising survival rates. Patients with prolonged time to relapse seem to benefit most. CWR can be applied in conjunction with other adjuvant modalities for the treatment of localized ipsilateral relapse. In particular, upcoming radiological strategies, such as stereotactic body radiation therapy for localized chest wall recurrences might be a good noninvasive alternative for this patient group (Fig. 11 and Table 6).
      Figure thumbnail gr11
      Figure 11Location of isolated ipsilateral chest wall recurrence of malignant pleural mesothelioma after cytoreductive surgery.
      Reprinted with permission.
      • Burt B.M.
      • Ali S.O.
      • DaSilva M.C.
      • et al.
      Clinical indications and results after chest wall resection for recurrent mesothelioma.
      Table 6Overview of Series Reporting About the Outcome After Chest Wall Resection as Second-Line Treatment of Localized MPM Recurrence
      Author, YearCases, nFirst Surgical TreatmentMedian Time to First RecurrenceChest Wall ResectionMedian OS After Surgery
      30-day mortality
      Okamoto et al., 2013
      • Okamoto T.
      • Yano T.
      • Haro A.
      • et al.
      Treatment for recurrence after extrapleural pneumonectomy for malignant pleural mesothelioma: a single institution experience.
      2EPPNRNRNR
      Burt et al., 2013
      • Burt B.M.
      • Ali S.O.
      • DaSilva M.C.
      • et al.
      Clinical indications and results after chest wall resection for recurrent mesothelioma.
      47EPP (32) or P/D (15)16.1 moNoneEpithelioid: 20.4 mo

      Biphasic: 7 mo
      Kostron et al., 2015
      • Kostron A.
      • Friess M.
      • Crameri O.
      • et al.
      Relapse pattern and second-line treatment following multimodality treatment for malignant pleural mesothelioma.
      16EPPNRNR16 mo
      Bertoglio et al., 2016
      • Bertoglio P.
      • Waller D.A.
      The role of thoracic surgery in the management of mesothelioma: an expert opinion on the limited evidence.
      1 (Case report)P/D withNRNRNR
      P/D, pleurectomy/decortication; EPP, extrapleural pneumonectomy; NR, not reported; OS, overall survival; MPM, malignant pleural mesothelioma.

      Conclusion

      Surgery has an important role in the interdisciplinary management of MPM at all stages; therefore, surgeons should be involved in the multimodality care of these patients. The surgical treatment continues to evolve in parallel with the medical treatment of this malignancy. In the past decade, there has been a movement to focus on P/D as the definitive treatment for this disease.

      Acknowledgments

      The authors thank Drs. Martina Friess and Chloé Spichiger for support in the reviewing of the article.

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