Surgery After Radiotherapy May Improve Outcomes in Patients with Malignant Pleural Mesothelioma

A particular surgery performed following the completion of radiotherapy treatment among a group of patients with malignant pleural mesothelioma was associated with improved outcomes including overall survival, according to study results recently published in Lancet Oncology.

“Different treatment strategies have been tried (for malignant pleural mesothelioma) … however, these tumors continue to pose a therapeutic challenge,” the study authors wrote. “The overall survival rates remain poor — most patients with malignant pleural mesothelioma die within the first year of diagnosis and only 10.7% are alive after five years.”

Since there is no curative treatment option for the disease, the authors noted, and a lack of general treatment consensus from experts, they sought to analyze the feasibility of performing surgery for malignant mesothelioma after radiotherapy (SMART).

“We hypothesized that SMART could reduce distant relapses and possibly improve survival,” they wrote. “(Our results) show the best outcomes so far for patients with malignant pleural mesothelioma treated with surgery in a large prospective trial.”

SMART, which is a new approach for managing the disease, consists of a short, accelerated course of high-dose intensity-modulated radiotherapy (IMRT) on one side of the chest, followed by extrapleural pneumonectomy, a surgery where the diseased part of the lung is taken out, the study noted.

The trial, which took place between Nov. 2, 2008 and Oct. 31, 2019 at the Princess Margaret Cancer Centre in Toronto, Ontario, Canada, involved 96 patients. Each patient was 18 years or older, was previously treated for malignant pleural mesothelioma and had good respiratory function.

During the trial, the patients received 25 Gy of radiation in five days over one week to the entire side of the chest with the disease, along with a five Gy boost to other high-risk areas. It was then followed by the extrapleural pneumoectomy within one week. Study authors noted that chemotherapy was also offered to patients with cancer on the lymph nodes too.

The feasibility of SMART was defined by the number of patients with treatment-related death or side effects around 30-days after surgery. Study authors also examined treatment morbidity, overall survival, disease-free survival, local recurrence and other factors associated with greater treatment morbidity.

“When the protocol was written, the main concern was treatment toxicity, so the morbidity of extrapleural pneumonectomy was used as the comparator for what is clinically feasible,” the study authors wrote. “With growing experience, we became more comfortable managing these patients as seen by the relatively low rates of 30-day grade 4 (15%) and grade 5 (1%) complications and our definition of what is clinically feasible has expanded to accommodate these patients.”

The authors noted that these results emphasized the importance of the evaluation and selection of patients for SMART, as 30-day grade 4 complications – which are considered severe – can affect long-term survival after treatment.

After completing SMART, enrolled patients were followed up with for five years.

Through follow-up, authors found that 49% of patients had a 30-day perioperative morbidity event (side effects that occurred 30 days after surgery), during which one patient died due to pneumonia. After an average follow-up of 46.8 months, the five-year cumulative incidence of distant recurrence was 63.3%. The most common first sites of recurrence were the opposite side of the chest from the original disease (46%) and the peritoneal cavity (44%).

Authors noted that IMRT was well tolerated and had no acute, severe side effects. During surgery, swelling of the esophagus from radiotherapy was detected in 21% of patients. Fifty-one percent of patients had grade 0 to 2 events, while 49% had grade 3 and grade 4 complications within the 30 days of extrapleural pneumonectomy.

“The rate of grade 4 complications was relatively low compared with previous series, but still led to worse overall survival,” authors wrote. No toxicities from the adjuvant chemotherapy were reported.

Median overall survival was 24.4 months with an 18-month disease-free survival.

“Results suggest that extrapleural pneumonectomy after radiotherapy can be done with good early and long-term results. Minimizing grade 4 events on the protocol is technically demanding and might affect survival beyond the post-operative period,” study authors wrote.

In a post-trial analysis, the median overall survival was 42.8 months in patients (disease-free survival was 31.4 months) with epithelial malignant pleural mesotheliomas versus the 18 months in patients with biphasic malignant pleural mesothelioma (disease free was 10.7 months).

“Factors such as epithelial histology, ypN0 (negative) nodal status and absence of grade 4 complications correlated with significantly better overall survival in an exploratory analysis,” the authors wrote. “Although nodal status affected disease-free survival in biphasic mesothelioma, overall survival was worse for this group of patients compared with patients with epithelial histology regardless of nodal status; this suggests that biphasic histology had a bigger effect on survival than did nodal involvement.”

The authors noted that the study had several limitations, including no collection of data on quality of life and the fact that the treatment and protocol are technically demanding and challenging to learn and do successfully.

“Despite these results, extrapleural pneumonectomy has not been widely adopted. SMART remains an outlier; other studies have not consistently shown a similar survival advantage with extrapleural pneumonectomy,” study authors concluded.

Of note, the researchers are currently enrolling patients on the next phase of the study, the SMARTER trial.

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