In a Canadian single-center phase II feasibility study reported in The Lancet Oncology, Cho et al found that a treatment protocol (surgery for mesothelioma after radiotherapy, also known as SMART) consisting of hemithoracic intensity-modulated radiotherapy (IMRT) followed by extrapleural pneumonectomy produced good short- and long-term treatment outcomes but was associated with high rates of perioperative morbidity.

Study Details

In the trial, 96 patients with previously untreated resectable cT1–3N0M0 disease enrolled at Princess Margaret Cancer Centre between November 2008 and October 2019 received the SMART protocol, consisting of a short, accelerated course of high-dose hemithoracic IMRT followed by extrapleural pneumonectomy. Patients received 25 Gy in five daily fractions over 1 week to the entire ipsilateral hemithorax with a concomitant 5-Gy boost to high-risk areas followed by surgery within 1 week. Patients with ypN+ disease on final pathology could receive three cycles of adjuvant chemotherapy (usually cisplatin and raltitrexed or pemetrexed) at the discretion of the medical oncologist within 24 weeks of surgery.  

The primary endpoint was feasibility, which was defined as the number of patients with 30-day perioperative treatment-related death or morbidity (grade 3 or 4 events). It was hypothesized that the number of 30-day perioperative treatment-related deaths would not significantly exceed the prespecified base event rate of 8%, and that 30-day perioperative grade 3 or 4 events would not significantly exceed the prespecified base event rate of 35%. Analyses were performed in the intention-to-treat population.

Adverse Events

Surgery was performed at a median of 5 days (range = 2–12 days) after completion of IMRT. No grade ≥ 3 acute toxicities were associated with IMRT; radiotherapy-induced esophageal swelling was observed intraoperatively in 21% of patients.

Overall, 47 patients (49%) had 30-day perioperative grade 3 (n = 33, 34%) or 4 (n = 14, 15%) events, exceeding the prespecified 35% threshold (P = .0018). The most common was atrial fibrillation (25%, all grade 3). The most common grade 4 events were pneumonia (4%) and hemothorax (3%). One patient (1%) died from pneumonia within 30 days of surgery, a rate that did not exceed the prespecified 8% threshold (P = .997).

Overall, 13 patients started—and 7 completed—three cycles of adjuvant chemotherapy. Since it was given more than 30 days after surgery, no perioperative chemotherapy toxicity was reported.

Recurrence Rates

Disease recurrence was observed in 72 patients (75%), with the most common first sites being contralateral chest (46%) and peritoneal cavity (44%); 24 (25%) patients had no disease recurrence. After a median follow-up of 46.8 months (interquartile range = 13.4–61.2 months), the 5-year cumulative rates were 20.1% (95% confidence interval [CI] = 11.4%–28.8%) for local recurrence and 63.3% (95% CI = 52.3%–74.4%) for distant recurrence.

Median overall survival was 24.4 months (95% CI = 18.5–31.1 months). Median disease-free survival was 18.0 months (95% CI = 12.6–21.7 months).

The investigators concluded, “Results from this study suggest that extrapleural pneumonectomy after radiotherapy can be done with good early and long-term results. However, minimizing grade 4 events on the protocol is technically demanding and might affect survival beyond the postoperative period.”

John Cho, MD, of the Department of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by the Princess Margaret Hospital Foundation Mesothelioma Research Fund. For full disclosures of the study authors, visit thelancet.com.