The moment Eric Lim, MB ChB, MD, Professor of Thoracic Surgery, Imperial College London, finished presenting data from the MARS2 trial at the 2023 World Conference on Lung Cancer, questions about the role of surgery in the treatment of malignant mesothelioma began circulating. And after a debate at the 2024 Targeted Therapies of Lung Cancer meeting, which took place February 21-24 in Santa Monica, California, it appears the controversy will continue.
Surgeon Erin Gillaspie, MD, of Creighton University, faced medical oncologist Hedy Kindler, MD, of the University of Chicago, to debate the role of surgery, if any, in the treatment of malignant mesothelioma.
Arguing in favor of surgery, Dr. Gillaspie discounted the power and relevance of the data from MARS2, which showed surgery increased the risk of death in the first 42 months by 28% (p=0.03). The data also showed that adding surgery to chemotherapy increased serious adverse events and both median survival and quality of life.
However, Dr. Gillaspie was quick to highlight several potential problems with the study. Her first criticism focused on patient selection.
“When we look at our guidelines, they recommend that we operate on patients with epithelioid histology,” she said. “But when we look at the MARS2 trial, 3.3% of patients had sarcomatoid histology and 8.7% had biphasic histology. When you look at the breakdown between the different arms, the majority of sarcomatoid patients ended up in the surgery arm. So we potentially have up to 12% of patients who never should have been included in a surgical trial.”
Dr. Gillaspie also questioned the MARS2 investigators’ staging methods.
“Staging is very complex,” she said. “We need to figure out if the patient is operable, so we need to look at their comorbid conditions, their pulmonary function tests. We need to get a CT scan and sometimes an MRI to help us distinguish the T stage. Sometimes we need to look in other places, so we need mediastinal pathologic staging, sometimes laparoscopy, sometimes contralateral VATS (video-assisted thoracoscopic surgery).”
However, as she pointed out, patients in the MARS2 trial only underwent CT scans.
“They claim they randomized patients equally between the two arms, but you cannot make that assertion if you haven’t done standard staging of your patients,” Dr. Gillaspie said. “When we started to break down the patient subgroups, one of the things we noticed is that patients who were relegated to surgery had much higher (incidence of) parenchymal lung involvement. So really these two groups were not created equally.”
Dr. Gillaspie also criticized the procedures done in the trial and how they were reported.
“Macroscopic reduction is what we are endeavoring to do for all of our surgical patients,” she said. “One of the things that I think is a little bit confusing about this trial is they use the word extended pleurectomy and decortication (EPD) to describe every single surgery that they do despite the fact that not all of them are extended pleurectomy and decortications… That’s a big problem. When we start to break it down, we see only 84% of patients had a macroscopic complete resection…
“When you do the wrong surgery on the wrong patient, when you don’t stage them appropriately, and you don’t give them that highest quality of surgery, of course you’re not going to see a benefit from surgery.”
Dr. Gillaspie argued that if you remove patients who shouldn’t have been included in the first place, the hazard ratio looks better. For example, she said not factoring in data from patients with sarcomatoid histology would take the hazard ratio from 1.28 to 1.12, which may no longer be statistically significant.
Dr. Gillaspie concluded that for the right patient, surgery still has a role in the treatment of malignant mesothelioma.
“When we look at our long-term survivors, one of the common underscoring features is major cytoreductive surgery,” she said.
Dr. Kindler, however, said the data no longer supports the use of surgery in malignant mesothelioma—if it ever did.
“The role of surgery for pleural mesothelioma has been controversial for many years because it never really worked very well,” she said. “Surgery is rarely performed in some countries. In most of the US, it had been more widely accepted until recently. The goal of surgery for pleural mesothelioma is maximal cytoreduction to remove all visible tumor, but an R0 resection is not possible. Surgery alone is not curative; another treatment modality is always required. As systemic therapies have improved, why not jettison the surgical component?”
Dr. Kindler said patients can now achieve deep and durable responses and significantly prolonged survival with doublet immunotherapy and chemo-immunotherapy.
Thanks to the publishing of CheckMate 743 in 2021 and the subsequent approval of nivolumab plus ipilimumab for malignant mesothelioma, we no longer need surgery to achieve long-term survival, she said.
“This was our first new drug in 16 years,” Dr. Kindler said. “As a front-line treatment, it yields durable survival, and we can see about a quarter of our patients are still alive and doing well at 3 years.”
Not only can systemic therapy rival surgery in terms of survival, Dr. Kindler argued that the data from MARS and MARS2 support the discontinuation of surgery for the treatment of malignant mesothelioma.
“The first hint that surgery might be harmful was the MARS trial, which suggested that surgery offered no benefit and possibly harmed patients,” she said. “Yes, it’s a problematic trial, but then the MARS2 trial put the final nail in the coffin for surgery… You could have heard a pin drop when Eric Lim presented the data that showed that overall survival was better without surgery. … We saw that decreased survival occurred with surgery regardless of histologic subtype, though some subtypes, such as the non-epithelial, did worse than others.
“There was no difference in progression free survival but there was increased morbidity with surgery. Quality of life was worse with surgery, and it persisted. Compared to those who were randomized to chemotherapy alone, an EPD for meso yielded a higher risk of death, more serious complications, poorer quality of life, and—need I mention it?—a higher cost. Thus, we need to relinquish the concept of resectability.”
Following the debate, a poll revealed the audience remained split on the benefit of surgery for the treatment of malignant mesothelioma. And so the debate and the controversy continue.
