Treatment of malignant pleural mesothelioma: lessons learned and quo vadis?

Macroscopic complete resection (MCR) is the goal of surgery and seems to have the most significant effect on survival in patients undergoing surgery-directed multimodality treatment (MMT) for malignant pleural mesothelioma (MPM) (1). For the authors, it is not questionable that Dr. David J. Sugarbaker and his team had, have and will have a significant impact on the term MCR and the surgery-directed MMT, respectively. Therefore, the authors read with great interest the recently published article on the new concepts in the treatment of MPM by Dr. David J. Sugarbaker et al. (2). Most respectfully, we take the opportunity to add some thoughts and comments on that topic.

Paradigm shift

Extrapleural pneumonectomy (EPP) has historically been considered as the standard surgical approach for MPM (3). The rationale of EPP was based on the philosophy of achieving “wider negative” margins in the pre-era of MMT options. In a survey of opinions and beliefs among 802 thoracic surgeons, EPP was believed to be more effective than pleurectomy/decortication (PD) (4). However, conceptually both EPP and RP share a similar risk of “oncological failure”: doubtful negative resection margins. Lung tissue, mediastinal organs and vessels, parietal and visceral pleura, as well as chest wall line up next to each other within few millimeters. It is doubtful whether a pneumonectomy leads to wider negative margins in most of the cases. Recurrence of disease occurs locally and distantly irrespective of the aggressiveness of surgery. Nonetheless, various international guidelines had advocated EPP for many decades (5,6).

But introducing more effective chemotherapy (7) resulted in survival that was more favorable after P/D compared to EPP at the beginning of the 90ies (8). More and more studies showed promising results whenever PD was the surgical treatment of choice (9-11). Surgical techniques and intraoperative additive treatments were developed resulting in improved overall survival and patients-reported outcomes like preserved pulmonary function and quality of life (11-16). A meta-analysis proved at least non-inferiority for PD compared to EPP with regard to various outcome measures (17). More and more centers previously advocating EPP have implemented PD as surgical treatment of choice in the interim (18-20).

In the recent guideline from North America, the NCCN panel declared both EPP and PD as reasonable surgical options to achieve MCR (21). On the other side, EPP has been abandoned in most European countries after publication of the very conflictive results of the MARS feasibility trial (22). Furthermore, extension of the surgical procedure from P/D to EPP in stages III and IV patients have not shown to lead to superior survival (9). The surgical landscape seems to evolve and a European guideline suggested that EPP should be performed only within clinical trials (23). A paradigm shift from aggressive EPP towards PD has occurred.

Patient selection

The precise role of each component in the MMT of MPM is unanswered. Nonetheless, long-term survival might be achieved only in patients undergoing surgery-based MMT protocols. A few years ago, the “SMART approach” (Induction radiotherapy followed by EPP) showed very promising long-term survival in the feasibility study (24). The cumulative 3-year survival was 84% in the first 25 patients after a follow-up of 23 months. Median survival was not reached. In the follow-up analysis, median survival was 28.3 months in a cohort of 90 patients (25). One interpretation of these developments might be the fact that very highly selected patients might profit most from different MMT approaches. However, the outcomes might be less enthusiastic whenever patients are included less selectively in MMT protocols. Thus, patient selection for the right treatment of MPM is the key component for success.

Future perspectives

There is a latency between asbestos exposure and the diagnosis of MPM up to 40 years (26). Nonetheless, screening using low-dose computed tomography on asbestos exposed workers has not been proven to be efficient (27). Similarly, patients with mesothelioma might have higher amount of serum biomarkers like mesothelin, osteopontin and fibulin-3, but no blood test has yet been accepted as standard of care (28-30). Since germline BAP1 mutations may also play a role in the development of MPM (31), “prophylactic treatment” might have a role in high-risk patients to avoid this dismal disease. Thus, prevention and early detection of the disease should be the focus of future research projects.

Acknowledgements

None.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

References

1. Sugarbaker DJ. Macroscopic complete resection: the goal of primary surgery in multimodality therapy for pleural mesothelioma. J Thorac Oncol 2006;1:175-6. [Crossref] [PubMed]
2. Wald O, Sugarbaker DJ. New Concepts in the Treatment of Malignant Pleural Mesothelioma. Annu Rev Med 2018;69:365-77. [Crossref] [PubMed]
3. Butchart EG, Ashcroft T, Barnsley WC, et al. Pleuropneumonectomy in the management of diffuse malignant mesothelioma of the pleura: experience with 29 patients. Thorax 1976;31:15-24. [Crossref] [PubMed]
4. Treasure T, Internullo E, Fiorentino F, et al. A survey of opinions and beliefs concerning surgery for malignant pleural mesothelioma amongst 802 members of the European Association for Cardio-Thoracic Surgery (EACTS), the European Society of Thoracic Surgeons (ESTS) and the Society of Thoracic Surgeons (STS). Interactive CardioVascular and Thoracic Surgery 2011;12:341-6. [Crossref] [PubMed]
5. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Malignant Pleural Mesothelioma. Available online: http://www.nccn.org/professionals/physician_gls/pdf/mpm.pdf, assessed on March 28, 2011.
6. ESMO Guidelines Working Group. Manegold C. Malignant pleural mesothelioma: ESMO Clinical Recommendations for diagnosis, treatment and follow-up. Ann Oncol 2007;18 Suppl 2:ii34-5. [PubMed]
7. Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 2003;21:2636-44. [Crossref] [PubMed]
8. Branscheid D, Krysa S, Bauer E, et al. Diagnostic and therapeutic strategy in malignant pleural mesothelioma. Eur J Cardiothorac Surg 1991;5:466-72. [Crossref] [PubMed]
9. Flores RM, Pass HI, Seshan VE, et al. Extrapleural pneumonectomy versus pleurectomy in the surgical management of malignant pleural mesothelioma: Results in 663 patients. J Thorac Cardiovasc Surg 2008;135:620-6. [Crossref] [PubMed]
10. Bölükbas S, Manegold C, Eberlein M, et al. Survival after trimodality therapy for malignant pleural mesothelioma: Radical Pleurectomy, chemotherapy with Cisplatin/Pemetrexed and radiotherapy. Lung Cancer 2011;71:75-81. [Crossref] [PubMed]
11. Friedberg JS, Culligan MJ, Mick R, et al. Radical Pleurectomy and Intraoperative Photodynamic Therapy for Malignant Pleural Mesothelioma. Ann Thorac Surg 2012;93:1658-65; discussion 1665-7.
12. Bölükbas S, Eberlein M, Schirren J. Thoracic shaping technique to avoid residual space after extended pleurectomy/decortication. Eur J Cardiothorac Surg 2013;44:563-4. [Crossref] [PubMed]
13. Lang-Lazdunski L, Bille A, Papa S, et al. Pleurectomy/decortication, hyperthermic pleural lavage with povidone-iodine, prophylactic radiotherapy, and systemic chemotherapy in patients with malignant pleural mesothelioma: A 10-year experience. J Thorac Cardiovasc Surg 2015;149:558-65; discussion 565-6. [Crossref] [PubMed]
14. Bölükbas S, Eberlein M, Schirren J. Prospective study on functional results after lung-sparing radical pleurectomy in the management of malignant pleural mesothelioma. J Thorac Oncol 2012;7:900-5. [Crossref] [PubMed]
15. Mollberg NM, Vigneswaran Y, Kindler HL, et al. Quality of Life After Radical Pleurectomy Decortication for Malignant Pleural Mesothelioma. Ann Thorac Surg 2012;94:1086-92. [Crossref] [PubMed]
16. Ploenes T, Osei-Agyemang T, Krohn A, et al. Changes in lung function after surgery for mesothelioma. Asian Cardiovasc Thorac Ann 2013;21:48-55. [Crossref] [PubMed]
17. Cao C, Tian D, Park J, et al. A systematic review and meta-analysis of surgical treatments for malignant pleural mesothelioma. Lung Cancer 2014;83:240-5. [Crossref] [PubMed]
18. Sharkey AJ, Tenconi S, Nakas A, et al. The effects of an intentional transition from extrapleural pneumonectomy to extended pleurectomy/decortication. Eur J Cardiothorac Surg 2016;49:1632-41. [Crossref] [PubMed]
19. Batirel HF, Metintas M, Caglar HB, et al. Adoption of pleurectomy and decortication for malignant mesothelioma leads to similar survival as extrapleural pneumonectomy. J Thorac Cardiovasc Surg 2016;151:478-84. [Crossref] [PubMed]
20. Kostron A, Friess M, Inci I, et al. Propensity matched comparison of extrapleural pneumonectomy and pleurectomy/decortication for mesothelioma patients. Interact Cardiovasc Thorac Surg 2017;24:740-6. [Crossref] [PubMed]
21. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Malignant Pleural Mesothelioma, Version 2.2017. Available online: http://www.nccn.org/professionals/physician_gls/pdf/mpm.pdf, assessed on December 17, 2017.
22. 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. Lancet Oncol 2011;12:763-72. [Crossref] [PubMed]
23. 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. Eur Respir J 2010;35:479-95. [Crossref] [PubMed]
24. Cho BC, 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;9:397-402. [Crossref] [PubMed]
25. de Perrot M, Dong Z, Bradbury P, et al. Impact of tumour thickness on survival after radical radiation and surgery in malignant pleural mesothelioma. Eur Respir J 2017.49. [PubMed]
26. Lanphear BP, Buncher CR. Latent period for malignant mesothelioma of occupational origin. J Occup Med 1992;34:718-21. [PubMed]
27. Fasola G, Belvedere O, Aita M, et al. Low-dose computed tomography screening for lung cancer and pleural mesothelioma in an asbestos-exposed population: baseline results of a prospective, nonrandomized feasibility trial – an Alpe-adria Thoracic Oncology Multidisciplinary Group Study (ATOM 002). Oncologist 2007;12:1215-24. [Crossref] [PubMed]
28. Hollevoet K, Reitsma JB, Creaney J, et al. Serum mesothelin for diagnosing malignant pleural mesothelioma: an individual patient data meta-analysis. J Clin Oncol 2012;30:1541-9. [Crossref] [PubMed]
29. Pass HI, Lott D, Lonardo F, et al. Asbestos exposure, pleural mesothelioma, and serum osteopontin levels. N Engl J Med 2005;353:1564-73. [Crossref] [PubMed]
30. Pass HI, Levin SM, Harbut MR, et al. Fibulin-3 as a blood and effusion biomarker for pleural mesothelioma. N Engl J Med 2012;367:1417-27. [Crossref] [PubMed]
31. Testa JR, Cheung M, Pei J, et al. Germline BAP1 mutations predispose to malignant mesothelioma. Nat Genet 2011;43:1022-5. [Crossref] [PubMed]