Professor Loic Lang-Lazdunski MD PhD FRCS(Eng), Consultant Thoracic surgeon
Swiss Mesothelioma Clinic, Geneva, Switzerland
The recent publications of the randomized phase III MARS2 trial in the Lancet Respiratory Medicine and of the phase II randomized EORTC-L1205 trial in the European Respiratory Journal have reactivated the debate around the role of extirpative surgery in pleural mesothelioma. Extirpative surgery has been an important component of mesothelioma treatment for more than 50 years, but in the past two decades its role has been debated.
MARS2 recruited exclusively in the United Kingdom (UK) between 2015 and 2021 and all patients received treatment in the UK national health service (NHS). More than 1000 patients were screened and 335 finally randomized to receive chemotherapy only or chemotherapy followed by extended pleurectomy / decortication. 157 patients had surgery following 2 cycles of chemotherapy and 166 were allocated to chemotherapy only. Surgery was performed in dedicated NHS thoracic surgery units. The mortality was 4% at 30 days and 9% at 90 days in the surgical group, one of the highest mortality rates ever reported for that type of surgery. Only 60% of patients in the surgical group were able to receive one cycle of additional chemotherapy after surgery and 39% were able to receive the planned 6 cycles. Of note 86% of operated patients had epithelioid mesothelioma, the most favourable type of mesothelioma associated with longer survival. In MARS2, 83% of patients undergoing surgery had their hemi-diaphragm removed in order to clear the tumour completely. The observed median survival were 19.3 months in the surgery and chemotherapy group and 24.8 months in the chemotherapy only group, respectively. Of note, the most favourable group of patients with epithelioid mesothelioma had a median survival of less than 2 years following randomization for chemotherapy and surgery and those with non-epithelioid mesothelioma had a median survival of less than 12 months. The MARS2 investigators reported that cytoreductive surgery did not improve survival, but was associated with an increased risk of early mortality, was not cost-effective and was associated with poorer quality of life in patients suffering pleural mesothelioma.
EORTC-L1205 recruited patients in Belgium, The Netherlands and Egypt between 2016 and 2021. 64 patients were randomized to receive 3 cycles of chemotherapy before or after cytoreductive surgery. Interestingly, the same percentage of 86% of patients had the more favourable epithelioid mesothelioma type in that trial . 80% of patients were able to receive the planned chemotherapy protocol. The surgical procedure used in EORTC-L1205 was the same as in MARS2: extended pleurectomy / decortication and 81% of patients had their hemi-diaphragm removed to clear the tumour. The investigators reported that 84.5% of patients suffered a postoperative complication, but the mortality was 1.7% at 30 days and at 90 days. Median overall survival was much better than in MARS2 with numbers of 27.1 months and 33.8 months in the group having surgery followed by chemotherapy and the group having chemotherapy followed by surgery, respectively.
Those trials are important and send different messages: patient selection was poor in the MARS2 trial-this was confirmed by the lead thoracic surgeon Mr David Waller in the European Association for Cardiothoracic Surgery meeting 2023 following the presentation of MARS2-. Many patients in MARS2 were probably not fit for that kind of extensive surgery or had advanced-stage disease. Many suffered postoperative complications and complications resulted in death in almost 1 in 10 patients, unfortunately. Very few patients were able to receive additional chemotherapy following surgery and that probably influenced survival negatively. Twice as many patients in the chemotherapy-only group were able to receive further therapies aiming at prolonging life compared to the surgical group. MARS2 reported one of the highest mortality rates after pleurectomy / decortication in the past two decades and the survival of surgical patients in MARS2 is also one of the poorest reported in the past two decades. Interestingly, patients receiving chemotherapy only had a median survival of 2 years, highlighting the fact that patients who are relatively fit and do not have advanced-stage disease could survive longer than previously thought. Based on those findings, one can only agree that cytoreductive surgery is not a good option for patients treated in the UK NHS, increasing cost by approximately 20,000 $, reducing all quality of life indicators and increasing the risk of death in the first 42 months by 28%.
The EORTC-L1205 trial highlighted the fact that well-selected patients operated on by specialized mesothelioma surgeons could enjoy a longer median survival (19.3 months in MARS2 versus 33.8 months in EORTC-L1205). Surgery performed in specialized thoracic units in Belgium, Egypt and the Netherlands resulted in an acceptable 90-day mortality rate of 1.7%. It is important to note that a similar percentage of patients had their hemidiaphragm removed in MARS2 and EORTC-L1205 (83% and 81%, respectively) and the proportion of patients with epithelioid mesothelioma was similar in the two trials: 86%. A total of 80% of patients received the planned 3 cycles of chemotherapy in EORTC-L1205 versus 60% in MARS2. The hospital length of stay was similar in the two trials: 13 to 14 days.
As a thoracic surgeon and a mesothelioma specialist the take home message for me is simple: extended pleurectomy / decortication is associated with a high rate of postoperative complications, but those can be treated successfully in specialized units by senior thoracic surgeons and intensivists, resulting in an acceptable mortality rate of less than 2%. Selection of patients is key if one wishes to keep the postoperative mortality low and all patients should be cared initially in intensive care units, then in specialized thoracic units.
In my personal experience, I operated on 152 well-selected patients in London between 2004 and 2019. I was able to spare the hemidiaphragm in 87.5% of patients resulting in no 90-day mortality. Postoperative complications were common, but they were dealt with efficiently and successfully. More than 95% of patients received the planned chemotherapy either before or after surgery and approximately half of them received further therapies later including radiotherapy, immunotherapy, targeted therapy or more chemotherapy. Median survival in my experience was better than in MARS2 and comparable with EORTC-L1205: 31.7 months overall, but 35 months for those with epithelioid mesothelioma who represented 70% of the cohort (compared to 86% in the MARS2 cohort). It is interesting to note that I operated on a similar population of patients than the one selected in MARS2. Thus, patients I operated on at Guy’s hospital in London were referred from all the United Kingdom. However, I believe that my patients were better selected, received better care in a dedicated surgical intensive care unit , then in a dedicated thoracic ward and had closer and better follow-up, being more liberally referred for second-line and third-line therapies. Thus, cytoreductive surgery is never curative even when complete macroscopic resection has been achieved. In our experience, most patients suffered mesothelioma relapse locally within 30 months after extended pleurectomy / decortication, but they were able to receive further treatment and kept going for months or years. Another important technical point is to always try to preserve the diaphragm and pericardium to minimise the risk of respiratory failure, pneumonia, empyema, postoperatively. This helps reduce the risk of mortality, as highlighted in our experience. In addition, diaphragm-sparing surgery results in better pulmonary function, better quality of life and more patients being able to receive further therapy on relapse.
Being in a highly specialized network of mesothelioma specialists definitely helps as treatment decisions are made by experts in multimodality therapies who participate in clinical trials and are at the forefront of research and therapies in the field. Many specialized thoracic groups in Europe and North-America have reported better outcomes than MARS2 in the past decade and therefore MARS2 due to its many limitations should be considered an outlier. Several important clinical trials are currently evaluating the role of immunotherapy agents with cytoreductive surgery and preliminary results are very promising. Therefore, we believe that doctors treating mesothelioma patients should not give up on surgery and still refer their patients for expert surgical opinions. Decisions on multimodality therapies should be made collegially by pulmonologists, radiologists, medical and radiation oncologists, thoracic surgeons, anesthesiologists and histopathologists. Doctors should use state-of-the art imaging technology, established biological and clinical criteria, advanced biomarkers and genomics to select patients who might benefit from surgical options.
In our specialized Swiss Mesothelioma Clinic based in Geneva, Switzerland we do offer on-site or remote first or second opinions and international patients are welcome. Our physicians and surgeons have expertise in pleural mesothelioma. We offer a wide range of options including minimally invasive surgery and interventional radiology, cutting edge radiation therapy, chemotherapy and immunotherapy, targeted therapies and referral to selected clinical trials. We also perform advanced genomics allowing us to select the best individualized therapy for our patients. We routinely offer radical cytoreductive surgery (pleurectomy / decortication and hyperthermic intrapleural povidone-iodine), an operation we have been performing successfully for 20 years with no mortality.
We can be contacted by Email: llang-lazdunski@genolier.net or by phone +41 76 2289126
(Office hours 9:00 to 18:00 Monday to Friday, Central European Time).
We offer services at :
Clinique Générale Beaulieu, Chemin de Beau-Soleil 20, Geneva 1206, Switzerland
Clinique de Genolier, Route du Muids 3, Genolier 1272, Switzerland
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