The Lung ART trial was designed to demonstrate whether there is any benefit to the routine use of modern mediastinal postoperative radiotherapy in patients with non–small cell lung cancer (NSCLC) stage IIIA N2 (ie, patients with mediastinal nodal involvement) following complete resection and neo adjuvant or adjuvant chemotherapy. No difference in disease-free survival was observed between patients who received postoperative radiotherapy and those who did not in this large randomized phase III trial. These results were reported at a Presidential Symposium during the European Society for Medical Oncology (ESMO) Virtual Congress 2020.1
Cécile Le Pechoux, MD
“This study provides a long-awaited answer for the oncology community,” said lead study author Cécile Le Pechoux, MD, a radiation oncologist at Gustave Roussy, Villejuif, France. “Our study shows that postoperative radiotherapy cannot be recommended for all patients with stage III NSCLC with mediastinal nodal involvement. Possibly, however, for some patients, it might be useful because it does decrease the rate of mediastinal relapse by 50%. This must be put in balance with the risk of overadded cardiopulmonary toxicity. We need to do further analysis to determine if certain patients, in particular, could benefit from postoperative radiotherapy,” she noted.
“Adjuvant chemotherapy following complete resection has been the standard of care for this group of patients with stage IIIA N2. The addition of postoperative radiotherapy has been debated for many years. The risk of locoregional recurrence [for these patients] after complete resection and (neo)adjuvant therapy is between 30% and 60%,” she said.
Commenting on this study, ESMO President Solange Peters, MD, said: “This is a strongly awaited abstract on the use of postoperative radiotherapy in lung cancer. Until now, there has been a lack of evidence, and every center has adapted local guidelines [on the use of postoperative radiotherapy]. This is a deeply practice-changing study and will probably change guidelines.” Dr. Peters is Head of the Medical Oncology Service and Chair of Thoracic Oncology at the Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Solange Peters, MD
Study Details
Lung ART was designed as a phase III randomized trial in patients with NSCLC and mediastinal nodal involvement treated with surgery and (neo)adjuvant chemotherapy. Patients (n = 501) were randomly assigned 1:1 to receive conformal postoperative radiotherapy 54 Gy for 5.5 weeks vs no treatment after complete surgery with nodal exploration and (neo)adjuvant chemotherapy in 95% of patients (control group). The primary endpoint was disease-free survival. Secondary endpoints were overall survival, patterns of relapse, local failure, and treatment-related toxicity. The investigators prespecified that a 12% improvement in 3-year disease-free survival was needed to show significance.
Baseline factors were well balanced between the two treatment arms. About two-thirds of patients were male, the median age was 61, about 90% were current smokers, almost three-quarters had adenocarcinoma histology, about 96% received adjuvant chemotherapy, about 12% received neoadjuvant chemotherapy, and about 90% received pretreatment positron-emission tomography (PET) scans for staging.
Survival Outcomes
At a median follow-up of 4.8 years, the difference in disease-free survival was not statistically significant. Median disease-free survival was 30.5 months for the postoperative radiotherapy arm and 22.8 months for the control arm. The 3-year disease-free survival was 47.1% in the postoperative radiotherapy arm vs 43.8% in the control arm. Slightly more first disease-free survival events were reported in controls. Mediastinal relapse was significantly reduced with postoperative radiotherapy: 25% vs 46.1% for controls. The rate of 3-year overall survival was 66.5% for the postoperative radiotherapy arm vs 68.5% in the control arm.
“The rate of brain metastases as well as the rate of other metastatic sites is similar in both arms. We need to do further analysis of the data,” she said.
There was no difference in overall survival between the two arms. Death as the first disease-free survival event was reported in 21 patients in the postoperative radiotherapy arm (14.6%) and 8 in the control arm (5.3%).
Causes of death differed in the two arms. In the postoperative radiotherapy arm, 69.4% of deaths were due to disease progression or recurrence compared with 86.1% in controls. Death due to cardiopulmonary causes was reported in 16.2% of the postoperative radiotherapy arm compared with 2% of controls. Death due to radiotherapy or chemotherapy was reported in 3% and 0%, respectively.
“These are good results in terms of outcome since these patients are high-risk. More than two-thirds are [still] living at 3 years,” she continued.
Safety was assessed in 422 patients. Almost one-quarter (23.7%) of patients in the postoperative radiotherapy arm experienced at least one grade 3 or 4 toxicity vs 15% of the control arm. The rate of at least one early toxicity was higher in the postoperative radiotherapy arm: 11.6% vs 7.7% for controls. The rate of at least one late toxicity was also higher among patients in the postoperative radiotherapy arm: 14.6% vs 8.9% for controls.
“At the moment, conformal postoperative radiotherapy cannot be recommended as standard of care for all patients with completely resected stage III mediastinal node-positive NSCLC.”— Cécile Le Pechoux, MD
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Further Analysis Needed on Patterns of Failure, Toxicity
“Lung ART is the first European randomized study evaluating modern postoperative radiotherapy after complete resection in patients selected [for] having received (neo)adjuvant chemotherapy. The 3-year disease-free survival and overall survival were higher than expected in both arms. Mediastinal relapse was reduced by half in the postoperative radiotherapy arm. There was more toxicity in the postoperative radiotherapy arm, especially cardiopulmonary toxicity. This needs to be further explored,” Dr. Le Pechoux stated.
“At the moment, conformal postoperative radiotherapy cannot be recommended as standard of care for all patients with completely resected stage III mediastinal node-positive NSCLC. Further analyses are planned to determine the patterns of failure and predictive factors of efficacy and toxicity,” she said.
“We don’t know yet which patients would benefit from postoperative radiotherapy. This is the reason why we do further studies. We collected a lot of data, and it may be that postoperative radiotherapy would be more toxic to patients with tumors located closer to the heart or inferior nodal stations. For the moment, based on stratification factors, we don’t have anything that will give us a clue. We will do more digging. There is a lot to investigate,” she said.
DISCLOSURE: Dr. Le Pechoux has received honoraria from Prime Oncology; has received institutional honoraria from Lilly and Medscape; and has served in an institutional consulting or advisory role for Amgen, AstraZeneca, Nanobiotix, and Roche. Dr. Peters has received educational grants, provided consultation, attended advisory boards, and/or provided lectures for AbbVie, Amgen, AstraZeneca, Bayer, Biocartis, Bioinvent, Blueprint Medicines, Boehringer-Ingelheim, Bristol Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F. Hoffmann–La Roche, Foundation Medicine, Illumina, Janssen, Merck Sharp and Dohme, Merck Serono, Merrimack, Novartis, Pharma Mar, Pfizer, Regeneron, Sanofi, Seattle Genetics, Takeda, and Vaccibody (from whom she has received honoraria [all fees to institution]).
REFERENCE
1. Le Pechoux C, Pourel N, Barlesi F, et al: An international randomized trial, comparing post-operative conformal radiotherapy (PORT) to no PORT, in patients with completely resected non-small cell lung cancer (NSCLC) and mediastinal N2 involvement: Primary end-point analysis of Lung ART. ESMO Virtual Congress 2020. Abstract LBA3_PR. Presented September 20, 2020.
