Pleural mesothelioma is a cancer of the pleura, generally occurring several decades after exposure to asbestos fibres. There is no known cure for this tumour. Chemotherapy, radiotherapy and more recently systemic immunotherapy have been used successfully to treat pleural mesothelioma, with median survival times of around 12 to 18 months.
More than half of the patients cannot receive active treatment due to a low performance status or significant comorbidities. A quarter of the patients must stop immunotherapy treatment due to major, sometimes fatal side effects. For almost a century, excisional surgery has been an integral part of the treatment of this tumour, but for the past twenty years or so, the role of surgery has been controversial.
The randomised phase III study called MARS2 enrolled 335 patients and was published last year in Lancet Respiratory Medicine. MARS2 compared chemotherapy alone with preoperative chemotherapy (2 cycles) followed by pleurectomy/enlarged decortication and possibly 4 cycles of adjuvant chemotherapy. This study caused a great stir because once again, the surgery not only failed to increase median survival (19.3 versus 24.8 months), but considerably increased the risk of early death and reduced quality of life. It must be said that surgical mortality at 90 days was 8.9%, a very high figure and one never reported by specialised centres for this surgical procedure in the last twenty years.
The investigators indicated that they had suffered from a lack of patient selection, with tumour staging being incomplete in many patients and operability very questionable for such a major procedure. Only 39% of patients received the planned adjuvant chemotherapy after surgery. Nearly 40% of patients treated with chemotherapy alone received immunotherapy or second-line chemotherapy later to control their progressing cancer, but only 20% in the surgical group. In addition, several other important statistical methodology issues plagued the study. Nevertheless, the study's principal investigator, Prof. Eric Lim, stated that cytoreductive surgery offered no benefit in the treatment of pleural mesothelioma.
A few months later, the thoracic group of the EORTC published the randomised phase II study EORTC-L1205 in the European Respiratory Journal, in which 69 patients were randomised for pleurectomy/decortication with preoperative or adjuvant systemic chemotherapy (3 cycles). The patients were well selected and, for the same treatment and population, the surgical mortality rate was 1.7% at 90 days. The majority of patients (81%) had received the planned chemotherapy on time. Median survival was better: 27 months and 33.8 months depending on whether the surgery was performed before or close to chemotherapy. In both studies, the rates of postoperative complications were high and the median length of hospitalisation was 14 days.
In view of all these studies, we believe that patient selection, in particular by routinely using molecular and genomic biomarkers, advanced imaging by PET and CT or thoracic MRI, is fundamental to avoid heavy and futile surgeries. Surgical procedures should only be performed by experienced thoracic surgeons in expert centres with a significant volume and high-performance intensive care units, as surgical complications are frequent and sometimes serious. Systemic immunotherapy treatments achieve survival rates equivalent to multimodal treatment in patients with non-epithelial mesothelioma, and it therefore seems logical not to recommend cytoreductive surgery in these patients. Patients with epithelioid mesothelioma whose tumour appears to be completely removable should be referred to an expert centre for tumour board discussion and evaluation.
It is likely that a MARS3 study (selecting only epithelioid mesotheliomas for pleurectomy/decortication with preservation of the diaphragm) will emerge in the coming years and that it will provide a definitive answer to the question of the role of cytoreductive surgery in pleural mesothelioma.