Cancer-Directed Surgery for Mesothelioma: A Team Sport

FOR RELATED ARTICLE, SEE PAGE 1292Malignant pleural mesothelioma (MPM) represents a rare and aggressive malignancy with a spectrum of histologic subtypes: epithelioid, biphasic, and sarcomatoid. Even in the earliest stage of the disease, survival is abysmal, with a median of 24 months and a rapid decline with advancing stage.1Rusch V.W. Chansky K. Kindler H.L. et al.The IASLC Mesothelioma Staging Project: proposals for the M descriptors and for revision of the TNM stage groupings in the forthcoming (eighth) edition of the TNM classification for mesothelioma.J Thorac Oncol. 2016; 11: 2112-2119Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar MPM is a disease thought to be secondary to chronic asbestos exposure; data from the United States show stable incidence in male patients since 1994, and unchanged incidence in female patients for decades, which suggests alternative drivers to this malignancy.2Carbone M. Adusumilli P.S. Alexander H.R. et al.Mesothelioma: scientific clues for prevention, diagnosis, and therapy.CA Cancer J Clin. 2019; 69: 402-429Crossref PubMed Scopus (235) Google Scholar FOR RELATED ARTICLE, SEE PAGE 1292 The rarity of this disease presents challenges the define of the optimal treatment approach; current National Comprehensive Cancer Network guidelines recommend multidisciplinary management, with some form of chemotherapy and potential surgical resection when feasible. However, it is unclear what type of surgery, chemotherapy, radiation, sequence, and/or combination of modalities is ideal. A particular question has been if there is a role for surgery in all three subtypes of MPM. In this issue of CHEST, Mansur et al3Mansur A. Potter A.L. Zurovec A.J. et al.An investigation of cancer-directed surgery for different histologic subtypes of malignant pleural mesothelioma.Chest. 2023; 163: 1292-1303Abstract Full Text Full Text PDF Scopus (1) Google Scholar sought to resolve the controversy regarding the role of surgery by analyzing the National Cancer Database from 2004 to 2017, stages I-IIIA. They specifically queried the role of surgery for histologic subtypes of MPM, with the controversial question of whether surgical resection benefits biphasic or sarcomatoid histologic conditions, as demonstrated by the changing guideline recommendations for and against in recent years. The group focused on patients who were receiving cancer-directed surgery, which included both curative intent surgery and diagnostic, exploratory, and palliative procedures. Surgery included surgery alone or in combination with chemotherapy or radiation. These conditions of these patients were compared with those patients who were receiving chemotherapy with or without radiation. Ultimately, only 7% of patients with MPM whose cases were in the National Cancer Database were suitable for analysis; most cases were excluded for incomplete data on histologic subtype and stage or were stage IIIB-IV. The analysis was extensive: separate multivariable analyses in each histologic subtype assessed whether surgery had prognostic significance after adjustment for 12 additional factors. This was repeated counting only curative-intent surgery and for any surgery in a 90-day landmark cohort (ie, excluding deaths with 90 days). Propensity scoring was performed for the probability of receiving surgery or chemotherapy in matched cohorts within each histologic subtype; this was repeated by involving only patients without co-morbidities. Kaplan-Meier graphs of the matched cohorts consistently demonstrated a benefit for surgery vs chemotherapy alone in epithelioid MPM with no difference identified in biphasic or sarcomatoid MPM, both in the larger matched cohorts and in the subsets without comorbidities. The multivariable analysis in epithelioid MPM also demonstrated a significant benefit for any surgery in the entire cohort, the landmark subset, and the entire cohort counting only curative-intent surgery. In contrast, no benefit was noted in sarcomatoid or biphasic MPM in the entire cohort or landmark subset, though there was a trend towards benefit in the curative-intent group (sarcomatoid hazard ratio, 0.64; P = .07; biphasic hazard ratio, 0.76; P = .09). There are limitations of this study and perhaps all studies that query the National Cancer Database, namely the challenge of teasing out a clear signal from confounders inherent to retrospectively collected databases. The real question is whether curative-intent surgery is beneficial for biphasic or sarcomatoid MPM. The fact that most of the analyses address any surgery (curative intent or not) potentially muddies the water. The cleanest analysis would be in cases with clear curative intent, without comorbidities, in which the patient survived a landmark interval, with a method of adjustment for confounders (eg, multivariable analysis or propensity matching). Mansur et al3Mansur A. Potter A.L. Zurovec A.J. et al.An investigation of cancer-directed surgery for different histologic subtypes of malignant pleural mesothelioma.Chest. 2023; 163: 1292-1303Abstract Full Text Full Text PDF Scopus (1) Google Scholar have performed these analyses, although not together in the same analysis. Multivariable analysis is most useful in showing a positive result; a negative result may reflect limited sample size. Although it the sample size appears to be reasonable in the entire cohort of biphasic and sarcomatoid histologic cases, it is unclear in the curative-intent and landmark subgroups. Thus, it is unclear whether the hint of a benefit for curative-intent surgery for sarcomatoid and biphasic MPM should be interpreted as a simple negative because the P > .05 or a potential signal that is limited by sample size. A prerequisite for propensity matching is that all potential prognostic factors are matched.4McMurry T.L. Hu Y. Blackstone E.H. Kozower B.D. Propensity scores: methods, considerations, and applications in the Journal of Thoracic and Cardiovascular Surgery.J Thorac Cardiovasc Surg. 2015; 150: 14-19Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar The reliability of propensity matching does not come from how well-matched the included factors are, but rather the assessment of missing factors and being able to argue that those missing factors are inconsequential. Performance status, achieving a macroscopic complete resection (the sine qua non of MPM),5Sugarbaker D.J. Macroscopic Complete resection: the goal of primary surgery in multimodality therapy for pleural mesothelioma.J Thorac Oncol. 2006; 1: 175-176Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar socioeconomic factors, and severity of comorbidities are all missing and further are not discussed in this analysis. Finally, the study period covers the preimmunotherapy era. The recent CheckMate 743 trial has demonstrated significant benefits of immunotherapy in unresectable MPM, specifically biphasic and sarcomatoid histologic conditions.6Baas P. Scherpereel A. Nowak A.K. et al.First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial.Lancet. 2021; 397: 375-386Abstract Full Text Full Text PDF PubMed Scopus (433) Google Scholar With the benefits seen in that trial, immunotherapy is being studied in resectable MPM and, much like non-small cell lung cancer, has the potential to be practice disrupting in the near future. Additional therapies are also showing potential in MPM. Mesothelin-targeted chimeric antigen receptor T-cell therapies have been created that show great promise in preclinical models,7Chintala N.K. Restle D. Quach H. et al.CAR T-cell therapy for pleural mesothelioma: rationale, preclinical development, and clinical trials.Lung Cancer. 2021; 157: 48-59Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar so much so that clinical trials are ongoing8Adusumilli P.S. Zauderer M.G. Rivière I. et al.A phase I trial of regional mesothelin-targeted CAR T-cell therapy in patients with malignant pleural disease, in combination with the anti–PD-1 agent pembrolizumab.Cancer Discov. 2021; 11: 2748-2763Crossref PubMed Scopus (127) Google Scholar and are just beginning to provide a glimmer of hope to patients with this devastating disease. Ultimately, this study clearly strengthens the argument for surgery in epithelioid MPM. It provides some data that this argument may not extend to biphasic or sarcomatoid subtypes, but aspects of the analysis hamper the ability to draw this conclusion . More importantly, the emerging role of immunotherapy and other personalized therapies are changing the context in which the role of curative-intent surgery for MPM is being viewed. Ultimately, these data highlight the recommendation that MPM is best managed as a team sport, one where the expertise and input of all treating providers are required to provide patients with the optimal, individualized therapy. B. C. G. has support from the NIH Paul Calabresi Clinical Oncology Career Development Program (K12CA157688)