Surgical controversies in mesothelioma: MesoVATS addresses the role of surgical debulking

Malignant pleural mesothelioma (MPM) is a fatal malignancy with a diverse clinical spectrum inadequately captured by our current staging system(s) (1) and that remains poorly understood at the molecular level (2). Current treatment for this disease is comprised of multi-modality interventions, including surgical resection. Over the past 12 years or so, no significant reduction of mortality has been newly discovered other than therapy with anti-folate drugs improving survival in randomized control trials by a median of 12 weeks (3,4). The role and extent of curative intent surgery remains controversial since well-conducted, definitive trials have been difficult to execute and complete.

Recently, Rintoul and colleagues conducted only the second randomized surgical trial in mesothelioma, the MesoVATS study (5) appearing in the Lancet. The rationale for this trial was based largely on single institution, non-randomized studies that indicated video-assisted thoracoscopic partial pleurectomy (VAT-PP) seemed to improve symptom control compared against extra-pleural pneumonectomy (EPP) (6), and possibly increased survival compared with biopsy alone (7). The extent of tumor extirpation achieved with VAT-PP is a debulking only, to remove tumor from the parietal pleural and visceral pleura to re-expand the lung as much as practical. They compared VAT-PP to talc pleurodesis palliation in 196 patients with suspected MPM randomly assigned, of whom 175 had a confirmed diagnosis of MPM were analyzed (87 VAT-PP vs. 88 talc). Their power analysis indicated they would need 90 patients per group. Patients were enrolled between 2003 and 2012.

Intention-to-treat results showed that VAT-PP conferred no survival benefit over talc pleurodesis at 12 months, the primary endpoint. Overall survival at 1 year was 52% (95% CI, 41-62%) in the VAT-PP cohort and 57% (95% CI, 46–66%) in the talc cohort [hazard ratio 1.04 (95% CI, 0.76–1.42); P=0.81]. Secondary outcomes were also assessed including resolution of pleural effusion, quality of life, lung function, exercise tolerance, surgical complications, and economic costs.

There are some significant caveats to this multi-institutional study, however, which required nearly 10 years to accrue enough patients. During this period, clinical practices worldwide evolved from those used in this study. For example, positron-emission tomography (PET) and/or magnetic resonance imaging (MRI) became commonly used in clinical staging, and VATS talc poudrage was preferred over talc slurry via chest tube. These various changes in combination with some patients withdrawing from the study affected the final numbers of patients available for data reporting. In the comparator cohort receiving only talc as palliation, 35 of 72 (48%) patients were pleurodesed via chest tube and 34 of 73 (47%) patients were pleurodesed via a VATS approach. At 12 months, complete secondary outcome data were available for only 34 of 87 (39%) patients in the VAT-PP cohort compared to 37 of 88 (42%) patients in the talc cohort. The cost analysis was based on 98 patients who entered the study since 2009. Thus, the interpretations of this study are derived from subsets of enrolled patients, so some caution is needed when applying this data.

The most interesting finding(s), perhaps, from this study reveal the natural course of MPM in a modern patient cohort. The median overall survival in the palliative talc pleurodesis cohort was 13.5 months. This survival result was in the context of a typical, unselected MPM population recruited into this study. In total, 78% of patients who got randomized with a confirmed diagnosis of MPM were found to harbor an IMIG stage of III or IV and most had an ECOG performance status of 1. This result corroborates our commonly held notion of MPM patients usually presenting with advanced disease.

Not surprisingly, the median overall survival of 13.1 months for the VAT-PP cohort of MesoVATS is similar to the overall survival range of 7 to 14 months in the meta-analysis by Cao and colleagues (8) who reviewed 14 observational studies and case series of partial pleurectomy in MPM. VAT-PP is not a useful procedure to improve overall survival in the treatment of MPM as demonstrated by this study. The confounders in this study limit any further, wider extrapolations of the results. In MesoVATS, after their surgical procedure, visible tumor was often remaining on the pericardium and central diaphragm while no routine nodal sampling was performed.

In North America and other regions, partial pleurectomy, described in this study as VAT-PP, is not offered to MPM patients as a curative intent surgical procedure in the context of contemporary multi-modality treatment (www.nccn.org). It is unknown about the popularity of VAT-PP as a surgical technique in MPM. For lung sparing resections of MPM, surgeons adhere to the principal of removing all gross, macroscopic disease in the pleural space and of consistent, systematic mediastinal nodal sampling. Usually a thoracotomy is required for this more challenging type of dissection. If needed, the diaphragm and pericardium can be resected/reconstructed simultaneously (i.e., extended pleurectomy/decortication or e-P/D). A recent meta-analysis (9) of radical resections for MPM in selected patients who underwent e-P/D had lower perioperative morbidity and mortality with similar, or even superior, long-term survival compared to EPP, in the context of multi-modality therapy.

In summary, MesoVATS has demonstrated that thoracoscopic debulking (VAT-PP) does not improve survival for MPM. What still remains unanswered is whether more aggressive local intervention may improve outcome. The precise role of EPP remains unsettled, even with the completion of a feasibility study of radical surgery in MPM (10). Results of the MARS-2 trial are awaited, wherein they will investigate the role of e-P/D added to standard induction chemotherapy and randomly compared with chemotherapy only (www.clinicaltrials.gov). Also, the Lung Cancer Group of the European Organization for Research and Treatment of Cancer will conduct a randomized phase II trial in patients with early-stage MPM randomizing between four cycles of neoadjuvant chemotherapy followed by P/D or P/D followed by four cycles of the same chemotherapy given in adjuvant setting (10).

Acknowledgements

None.

Footnote

Provenance: This is a Guest Editorial commissioned by the Editorial Board Member Ying Liang (Department of Medical Oncology, Sun Yat-sen University Cancer Center (SYSUCC), Guangzhou, China).

Conflicts of Interest: The author has no conflicts of interest to declare.

Comment on: Rintoul RC, Ritchie AJ, Edwards JG, et al. 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. Lancet 2014;384:1118-27.

References

1. Rusch VW, Giroux D, Kennedy C, et al. Initial analysis of the international association for the study of lung cancer mesothelioma database. J Thorac Oncol 2012;7:1631-9. [PubMed]
2. Xu Y, Zheng M, Merritt RE, et al. miR-1 induces growth arrest and apoptosis in malignant mesothelioma. Chest 2013;144:1632-43. [PubMed]
3. van Meerbeeck JP, Gaafar R, Manegold C, et al. Randomized phase III study of cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma: an intergroup study of the European Organisation for Research and Treatment of Cancer Lung Cancer Group and the National Cancer Institute of Canada. J Clin Oncol 2005;23:6881-9. [PubMed]
4. 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. [PubMed]
5. Rintoul RC, Ritchie AJ, Edwards JG, et al. 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. Lancet 2014;384:1118-27. [PubMed]
6. Nakas A, Martin Ucar AE, Edwards JG, et al. The role of video assisted thoracoscopic pleurectomy/decortication in the therapeutic management of malignant pleural mesothelioma. Eur J Cardiothorac Surg 2008;33:83-8. [PubMed]
7. Halstead JC, Lim E, Venkateswaran RM, et al. Improved survival with VATS pleurectomy-decortication in advanced malignant mesothelioma. Eur J Surg Oncol 2005;31:314-20. [PubMed]
8. Cao C, Tian DH, Pataky KA, et al. Systematic review of pleurectomy in the treatment of malignant pleural mesothelioma. Lung Cancer 2013;81:319-27. [PubMed]
9. 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. [PubMed]
10. Hiddinga BI, van Meerbeeck JP. Surgery in mesothelioma--where do we go after MARS? J Thorac Oncol 2013;8:525-9. [PubMed]