Study Questions Use of Aggressive Surgery in Early Mesothelioma

SINGAPORE — Extended pleurectomy/decortication combined with platinum and pemetrexed chemotherapy was associated with worse outcomes in patients with resectable mesothelioma compared with chemotherapy alone, according to a randomized trial.

“As a surgeon, you have no idea how much it pains me to conclude that extended pleurectomy/decortication — an operation that we have been offering for over 70 years — has been associated with a higher risk of death, more serious complications, poorer quality of life, and higher costs, compared with mesothelioma patients who were randomized to chemotherapy alone,” said Eric Lim, MD, a thoracic surgeon at the Royal Brompton Hospital in London, during the World Conference on Lung Cancer Presidential Symposium on Monday.

The MARS2 trial included more than 300 patients and found that at a median follow-up of 22.4 months, those randomized to receive surgery and chemotherapy had an overall survival (OS) of 19.3 months, while those randomized to chemotherapy alone had a median OS of 24.8 months.

Lim presented hazard ratios for OS in two phases because the curves for the two groups overlapped, with surgery increasing the risk of death in the first 42 months after randomization by 28% (HR 1.28, 95% CI 1.02-1.60, P=0.03). The HR for the second part of the curve (42-plus months after randomization) showed no significant difference in OS between the two groups (HR 0.48, 95% CI 0.18-1.29, P=0.15).

“I would emphasize that we wouldn’t pay too much attention to the second part of the curve — where the curves overlap — because there were 15 participants in each arm at this stage,” Lim said.

“In order to improve survival in early-stage mesothelioma, stopping surgery would increase survival by 28%,” he said. “If we were to take things one step further 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.”

Did Surgery Affect OS?

However, in commenting on the study, discussant Paula A. Ugalde, MD, a thoracic surgeon at Brigham and Women’s Hospital, Dana-Farber Cancer Institute, and Harvard Medical School, in Boston, focused on that long-term survival data.

“The primary outcome of this trial was overall survival, and to simplify, [the curves] clearly show that there is no difference in overall survival between the two arms,” she said. “The P was not significant.”

Ugalde also questioned whether the outcome of the trial would have been different if conducted exclusively at high-volume centers.

She noted that patients were deemed eligible for surgery by the surgeons at each center. “As a surgeon myself, this is clearly related to the surgeon’s experience,” she remarked.

“Extended pleurectomy/decortication was defined in the trial as a surgery that requires diaphragmatic resection and/or pericardium resection,” she added. “This is clearly a very aggressive procedure.”

She pointed out that the procedure is not standardized throughout surgical centers. Furthermore, she suggested that the surgeons’ experience and center volume in this study is “unclear” and calculated that about half of the patients in this trial came from low-volume rather than high-volume centers.

“Should we assume that the surgical outcomes are similar between those centers?” she asked, with a slight shake of her head.

In responding to Ugalde’s comments, Lim said he “was expecting strong surgical opposition” and pointed to the first part of the OS curve, with its P-value of 0.03, as being statistically significant.

He also observed that, with the exception of one center, most of the operations in this trial were performed at national centers of expertise in the U.K.

Regarding the trial’s secondary outcomes, Lim reported:

• There was no difference in progression-free survival between the two groups (HR 0.90, 95% 0.72-1.11, P=0.33)
• Surgery led to a significantly increased risk of serious adverse events (incidence rate ratio 3.6, 95% CI 2.3-5.5, P
• Surgery also led to reduced quality-of-life scores in global health, physical functioning, social functioning, and role functioning
• Surgery resulted in higher costs of more than $20,000 per patient

In explaining the rationale behind the study, Lim noted that while extended pleurectomy/decortication is a commonly performed procedure to improve survival in patients with resectable mesothelioma,”it has never been evaluated in a randomized control trial — until now.”

The multicenter phase III trial was conducted over 6 years at several centers in the U.K. and was designed to test the hypothesis that extended pleurectomy/decortication and chemotherapy was superior (a 30% relative improvement) to chemotherapy alone.

A total of 335 participants were randomized, 169 to surgery and chemotherapy and 166 to chemotherapy alone. Baseline demographics were well-matched between the two groups. The median age was 69 years in both groups and 87% of the patients were men. The vast majority (86%) had epithelioid mesothelioma, 8.7% had biphasic mesothelioma, and 3.3% had sarcomatoid sarcoma.

Of those patients who underwent surgery, 88.5% underwent extended pleurectomy/decortication, and 8.3% pleurectomy/decortication alone. Lim reported that microscopic complete resection was achieved in 84% of patients.

In-hospital mortality was 3.8%, 30-day mortality was 3.8%, and 90-day mortality reached 8.9%.

Among those randomized to receive chemotherapy alone, 56% were able to complete six cycles of chemotherapy compared with 39.1% of those randomized to surgery.

“I realize I am not here to defend my specialty,” Lim concluded. “I am here for the patients who have literally given up their lives for this study, for which we owe an enormous debt of gratitude.”