Extrapleural Pneumonectomy Is Not Shown to Be Clinically Effective in the Treatment of Malignant Pleural Mesothelioma

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To the Editor:
We lead a working group of the European Association for Cardio-Thoracic Surgery tasked to consider guidance to members on malignant pleural mesothelioma. We are mindful of the need to reflect all the evidence and therefore we appreciate publication of the series of 527 extrapleural pneumonectomy (EPP) operations.1 We also appreciate the recognition of the Mesothelioma and Radical Surgery (MARS) trial in providing background to the report.2
The scene is set in the introduction by quoting a median survival of 7 to 12 months, but this may be misleading. The unwary reader3 might hold these survival figures in mind as a comparator for the overall survival after EPP. The majority would never have been surgical candidates; patients who might have been candidates for surgery were specifically excluded by protocol from the cited trial of pemetrexed.
On the contrary, among patients in a large published data set of 945 patients under consideration for possible surgery, there was no survival difference between those not operated on (N = 387; 41%) and those who had an exploratory thoracotomy without resection (N = 174; 18%) and was similar to those who had resection without other modalities of treatment (N = 177; 19%).4 All 3 groups survived an average of 17 to 18 months. Longer survival was recorded for the 22% who had adjuvant treatments, the effect of which will have played a part in survival. The sequential selection for second and subsequent treatments confounds analysis and introduces immortal time bias. There was no signal that surgical resection itself makes a difference.
In another study of EPP, when patients from the same institutional database who were not surgical candidates (on the basis of sarcomatoid histology, impaired functional performance, and age >76 years) were excluded stepwise from comparison, the difference in survival attributed to surgery dwindled.5 When outcomes for EPP were compared with lung-sparing pleurectomy decortication (P/D), survival was poorer after EPP despite P/D being used in worse patients.6
With respect to the authors’ conclusions, clinical effectiveness of EPP cannot be derived from the data in this article. Resection is probably always incomplete when the margins are checked with a microscope.7 The extent of lymph node involvement is a general prognostic feature for cancer, and the distinction between prognostic and predictive factors should be made.8
MARS was a difficult trial, and a defense of its conclusions is provided elsewhere.9 What merits attention is that unique feature of a randomized controlled trial, the control group: patients evaluated as eligible for EPP but who were randomly assigned to not have it had a median survival of 19.5 months.2 The accumulated evidence points away from EPP as clinically effective, and if taken in its totality, the published evidence now allows those advising patients to give informed counsel.10 The detrimental effects of EPP are well documented. Knowing there is no survival benefit should allow a discussion with patients about what they would value most in what is likely to be that last couple of years of life, whatever course of action is taken.
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