Time to relinquish the concept of “resectability” in mesothelioma?

Up till now, surgery was an important consideration to improve the survival of patients with mesothelioma. However, results of the MARS 2 trial recently demonstrated that extended pleurectomy decortication combined with chemotherapy is associated with worse survival outcomes, a higher incidence of serious adverse events, and a diminished quality of life compared to platinum and pemetrexed chemotherapy alone. One could therefore wonder whether it is time to relinquish the concept of “resectability” in mesothelioma.

To date, systemic therapy with platinum and pemetrexed remains the standard of care for patients with mesothelioma. As the median survival for these patients is only 9-12 months, surgery is an important consideration to improve survival. Currently, (extended) pleurectomy decortication is the most common surgical procedure for mesothelioma worldwide. Numerous surgical cohorts report improved length of life, but despite its common use, its efficacy has never been evaluated in a randomised controlled trial. The MARS2 trial therefore investigated the impact of extended pleurectomy decortication combined with chemotherapy compared to chemotherapy alone in patients with mesothelioma.

Study design

MARS 2 is a UK multi-centre, open parallel group randomised controlled trial of chemotherapy (4 to 6 cycles) alone or chemotherapy and surgery (pleurectomy decortication or extended pleurectomy decortication) for patients with early-stage malignant pleural mesothelioma. The primary outcome is overall survival, and a minimally important difference defined as an overall 30% reduction in the risk of death (HR 0.70) with surgery. The total required sample size was estimated at 328 participants allowing for two-tailed statistical significance at 5% level with 80% power.

Results

In total, 335 patients were randomised to extended pleurectomy decortication and chemotherapy (N= 169) or chemotherapy with platinum and pemetrexed alone (N= 166). Median follow-up was 22.4 months. Patients randomised to surgery and chemotherapy exhibited a median survival of 19.3 months, while those randomised to chemotherapy alone demonstrated a median survival of 24.8 months. Further analysis indicated a 28% increase in the risk of death in the surgery group within the first 42 months (HR 1.28, p= 0.03), while no significant difference in survival emerged after 42 months (HR 0.48, p= 0.15). In addition, the research unveiled significant disparities in progression-free survival and adverse events between the two groups. Patients who underwent surgery experienced a 3.6-fold higher incidence of serious adverse events (CTCAE grade ≥3, p< 0.001), including cardiac disorders, respiratory, thoracic or mediastinal disorders, infections and infestations, surgical and medical procedures. Patients with non-epithelial histology had worse overall survival as compared to those with epithelioid histology (p= 0.05). Finally, those who had extended pleurectomy decortication reported poorer quality of life and well-being on various EORTC health-related quality of life scales, particularly in global health, physical functioning, social functioning, and role functioning. The surgery group also exhibited worse positive symptom scores, including pain, dyspnoea, insomnia, loss of appetite, and financial difficulties.

Conclusion

Extended pleurectomy decortication should not be offered to patients with pleural mesothelioma. In addition, classifying the disease as “unresectable” would increase survival by reducing the risk of death associated with surgery and could increase the open access to more effective systemic treatment regimens that are currently licensed for “unresectable” disease.

Reference

Lim E, et al. MARS 2: A Multicentre Randomised Trial Comparing (Extended) Pleurectomy Decortication versus No Radical Surgery for Mesothelioma. Presented at WCLC 2023: Abstract 1253.