The results of a recent study from the United Kingdom could spell the end of a long-standing treatment strategy for mesothelioma, according to data presented during the International Association for the Study of Lung Cancer (IASLC) 2023 World Conference on Lung Cancer.¹ When combined with chemotherapy, extended pleurectomy decortication was associated with a 28% increase in the risk of early death compared with chemotherapy alone (P = .03 ) and a 3.6-fold increase in the number of serious adverse events. Authors of the study emphasized that the surprising nature of these results may likely challenge this widely accepted surgical approach to treating mesothelioma.

“As a surgeon, you have no idea how much it pains me to conclude extended pleurectomy decortication, an operation that we have been offering for more than 70 years for mesothelioma, has been associated with a higher risk of death, more serious complications, poorer quality of life, and a higher cost compared with chemotherapy alone,” said lead study author Eric Lim, MD, a Consultant Thoracic Surgeon at the Royal Brompton Hospital and Professor of Thoracic Surgery at the National Heart and Lung Institute of Imperial College London.

Eric Lim, MD

Approximately 30,000 new cases of mesothelioma, a rare and aggressive cancer linked to asbestos exposure, are diagnosed each year around the world. Unfortunately, limited advancements have been made in systemic treatment in the early-stage resectable setting.

“Clinicians have relied on platinum and pemetrexed as the mainstay of treatment despite only a modest impact on overall survival,” said Dr. Lim. “As a result, surgery in the form of maximum cytoreduction to reduce or remove all visible disease is uniformly recommended in American guidelines, European guidelines, and even the IASLC international consensus statement.”

As Dr. Lim explained, there are two main types of maximum cytoreduction. Extrapleural pneumonectomy has been shown by the UK mesothelioma investigators to be associated with a 90% increase in the risk of death. As a result, much of the world is now turning to pleurectomy decortication as the principal type of cytoreduction offered worldwide. Pleurectomy decortication involves removing all visible disease in the visceral and parietal pleura and, if required, its ipsilateral hemidiaphragm and pericardium while sparing the lung. However, the principal operation offered worldwide has never been evaluated in a randomized controlled trial until now.

MARS-2 Trial Design

For this study, Dr. Lim and colleagues compared the clinical benefit and cost-effectiveness of (extended) pleurectomy decortication and chemotherapy vs chemotherapy alone for patients with pleural mesothelioma. Patients with tissue-confirmed mesothelioma confined to one hemithorax deemed resectable consented to receive two cycles of platinum-pemetrexed chemotherapy. After confirmation via CT scan that disease continued to be resectable, patients were randomly assigned to undergo extended pleurectomy decortication and up to four further cycles of platinum-pemetrexed chemotherapy or up to four further cycles of platinum-pemetrexed chemotherapy alone.

The study’s primary aim was to test the hypothesis that pleurectomy decortication and chemotherapy is superior (30% relative improvement) to chemotherapy alone. Secondary outcomes included progression-free survival, safety, health-related quality of life (EORTC QLQ-C30, EQ5D), and cost-effectiveness.

Wake-Up Call for Mesothelioma Treatment

Of the more than 1,000 patients screened, 169 participants were randomly assigned to surgery, and 166 were randomly assigned to chemotherapy alone. The baseline demographics and clinical stages were well balanced between the two groups, said Dr. Lim. In the overall population, 86% had epithelioid mesothelioma, 8.7% had biphasic mesothelioma, and 3.3% had sarcomatoid mesothelioma. The clinical stage was also well balanced between the two groups, with the majority in T1 to T2, N0 to N1 stages.

For those patients who underwent surgery, 97% had extended pleurectomy decortication or pleurectomy decortication alone. Macroscopic complete resection was achieved in 84% of participants, said Dr. Lim, who noted the 30-day mortality and 90-day mortality rates were 3.8% and 8.9%, respectively. The study’s primary outcome showed that extended pleurectomy decortication for mesothelioma was associated with a 28% increase in the risk of death in the first 42 months (P = .03).

“For the first time ever, we can show you the excellent survival of the patients who are otherwise fit enough to have surgery with an early-enough stage,” said Dr. Lim. “This excellent survival actually beats the vast majority of all contemporary surgical series to date.”

Dr. Lim continued: “In fact, the survival was so good in this early-stage cohort that we had to extend the trial by 6 months to get the prerequisite number of deaths, underscoring the phenomenal importance of having a randomized comparative cohort for all future studies on surgery for mesothelioma.”

Although no differences were observed in progression-free survival between the study arms, patients randomly assigned to surgery were 3.6-fold more likely to experience serious adverse events, which included cardiac disorders, thoracic disorders, infections, and repeat interventions.

“For the first time ever, investigators were also able to demonstrate in a randomized setting that patients with nonepithelioid histology had worse survival with a statistically significant interaction effect,” stated Dr. Lim. “Even if surgery was confined to the epithelioid subgroup alone, the risk of death was 12% higher.”

Findings also showed global quality of life was reduced with surgery, especially in the 6-week period. Every single statistically significant outcome was worse with surgery in all measures of the EORTC QLQ-C30 scale, said Dr. Lim, who noted surgery also added $20,102 to the cost of treatment on average.

“Utility is markedly reduced in the surgery arm,” said Dr. Lim. “To improve survival in early-stage mesothelioma, stopping surgery would increase survival by 28%. If we were to take things one step farther and relinquish the entire concept of resectability in mesothelioma, we would be able to open access to effective systemic treatments currently licensed for unresectable disease,” he concluded. 

DISCLOSURE: Dr. Lim has received funding from AstraZeneca, Bayer, Boehringer Ingelheim, Covidien/Medtronic, Guardant Health, Johnson and Johnson/Ethicon, Lilly Oncology, Medela, and Takeda; served as a consultant for Beigene, BMS, and Roche; has received honoraria from Medela; has patents issued or pending for Imperial Innovations (P52435GB and P57988GB); served as Chief Investigator for MARS 2 NIHR HTA (15/188/31) and RAMON NIHR HTA (131306); and is the Founder of My Cancer Companion, Healthcare Companion Ltd.

REFERENCE

1. Lim E, Waller D, Lau K, et al: MARS-2: A multicentre randomised trial comparing (extended) pleurectomy decortication versus no radical surgery for mesothelioma. 2023 World Conference on Lung Cancer. Abstract PL03.10. Presented September 11, 2023.