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Journal of Thoracic Oncology:
doi: 10.1097/JTO.0000000000000122

The Challenge of Malignant Pleural Mesothelioma: New Directions

Rusch, Valerie W. MD*; Rimner, Andreas MD; Krug, Lee M. MD

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*Thoracic Service, Department of Surgery, Department of Radiation Oncology, and Thoracic Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.

Disclosure: The authors declare no conflict of interest.

Address for correspondence: Valerie W. Rusch, MD, Thoracic Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065. E-mail:

Two articles in this issue of the Journal provide fresh insights into the management of malignant pleural mesothelioma (MPM), a very challenging disease. The article by Bovolato et al.1 retrospectively analyzes outcomes in 1365 MPM patients treated at six Italian institutions over a 30-year period, identifies significant prognostic factors, and attempts to define the contribution of surgical resection to overall survival. The article by Cho et al.2 at the University of Toronto reports the results of a novel phase II trial of immediate preoperative hemithoracic intensity-modulated radiation therapy (IMRT) followed by extrapleural pneumonectomy (EPP). In highly selected patients, this approach was associated with the best 3-year overall survival (84%) reported to date in MPM.

The Italian study corroborates data recently published by the International Association for the Study of Lung Cancer (IASLC) International Staging and Prognostic Factors Committee,3 including the substantial gap between clinical and pathological staging, the significance of prognostic factors such as tumor histology and patient age, and the apparently better outcomes associated with combined modality therapy. Important aspects of this analysis are the large number of patients analyzed, the long follow-up, and the apparently uniform approaches to surgical resection. Significant limitations include the variability in adjuvant therapy and the long duration of the study. Both radiation and chemotherapy for MPM have evolved considerably during the past 30 years, but little information about the criteria for adjuvant therapy or the treatment details is provided.

As in the analysis of the IASLC MPM database, it is difficult to identify differences in outcome based on surgical approach, that is, EPP versus pleurectomy/decortication. Stage-specific analyses are based on numbers of patients too small to be meaningful, and there are likely inherent differences between these two groups because surgeons apparently chose to perform an EPP predominantly in patients with more locally advanced disease. Even the analysis of outcome for multi- versus single-modality therapy may be strongly influenced by biases in patient selection. Perhaps the most convincing aspect of these results is that they are completely congruent with those of other large series, including the IASLC MPM database.

The prospective trial from the Toronto group proposes a completely new treatment algorithm. Immediate preoperative hypofractionated radiation has been used in other malignancies such as rectal cancer. Using it before EPP required close interaction with an experienced surgeon who can reliably select patients for this operation because not proceeding to pneumonectomy would expose the patient to severe radiation pneumonitis. This new treatment strategy does not seem to yield better local control than the more conventional approach of postoperative hemithoracic radiation after EPP4 but is associated with remarkably good survival in highly selected patients. Careful patient selection based on tumor stage, known prognostic factors, and cardiopulmonary reserve is clearly pivotal in this approach. The authors propose the intriguing hypothesis that preoperative IMRT may activate the immune system against tumor. Correlative studies to support or refute this idea are needed. As the authors point out, preoperative IMRT and EPP are applicable to a minority of patients (18% in their experience), but their results are sufficiently promising to warrant larger, preferably multicenter trials to test this treatment strategy. Such trials will also need to formalize the guidelines for adjuvant chemotherapy that, in the Toronto study, was administered in a very liberal time frame (<26 weeks postoperatively).

What both of these studies emphasize is the need to optimize patient selection in future trials. Historically, MPM studies have lumped together very heterogeneous patient populations, an approach that would not be acceptable in other malignancies. Clearly, conventional surgery, chemotherapy, and radiation have all had a modest effect on MPM, and novel treatment strategies are needed. With multiple reports now confirming the importance of both specific prognostic factors and tumor stage, future trials of either conventional or novel treatment modalities must have more stringent inclusion criteria. Outcomes in MPM patients are much more variable than originally thought. To make progress in this difficult cancer, strictly defined treatment5 needs to be studied prospectively in strictly defined MPM patient cohorts.

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1. Bovolato P, Casadio C, Billé A, et al. Does surgery improve survival of patients with malignant pleural mesothelioma A muticenter retrospective analysis of 1365 consecutive patients. J Thorac Oncol. 2014;9:383–389

2. Cho BCJ, Feld R, Leighl N, et al. A feasibility study evaluating surgery for mesothelioma after radiation therapy: the “SMART” approach for resectable malignant pleural mesothelioma. J Thorac Oncol. 2014;9:390–395

3. Rusch VW, Giroux D, Kennedy C, et al.IASLC Staging Committee. Initial analysis of the international association for the study of lung cancer mesothelioma database. J Thorac Oncol. 2012;7:1631–1639

4. Rusch VW, Rosenzweig K, Venkatraman E, et al. A phase II trial of surgical resection and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma. J Thorac Cardiovasc Surg. 2001;122:788–795

5. Rice D, Rusch V, Pass H, et al.International Association for the Study of Lung Cancer International Staging Committee and the International Mesothelioma Interest Group. 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. J Thorac Oncol. 2011;6:1304–1312

Copyright © 2014 by the European Lung Cancer Conference and the International Association for the Study of Lung Cancer.


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