Post-operative conformal radiotherapy not recommended for all patients with completely resected non-small cell lung cancer and mediastinal N2 involvement

After decades of controversy around the role of post-operative radiotherapy (PORT) in completely resected non-small cell lung cancer (NSCLC) patients, LungART is the first European randomised study evaluating modern PORT in patients with completely resected NSCLC and mediastinal N2 involvement. As presented by Dr. Le Pechoux, PORT was found to be associated with a non-statistically significant 15% increase in disease-free survival among stage IIIAN2 patients and was associated with more toxicities, especially cardio-pulmonary events. As a result, PORT cannot be recommended as the standard of care for these patients.

Introduction

For stage II and III non-small cell lung cancer (NSCLC) patients, adjuvant chemotherapy has been the standard of care for more than 15 years while post-operative radiotherapy (PORT) in completely resected NSCLC patients has been controversial since the publication of a meta-analysis in 1998.¹ This analysis indicated that PORT could be deleterious, especially in pN0-pN1 patients. However, since this publication in 1998, many changes have taken place in the management of stage III resected NSCLC patients, including better selection, use of (neo)adjuvant chemotherapy, better surgery, and radiotherapy. Recent retrospective studies or large database studies now seem to favour PORT, but no rust data are available. Therefore, the role of modern mediastinal PORT warranted further investigation in high-risk patients.

The LungART study is a multi-institutional, randomised, phase III trial comparing mediastinal PORT (54 Gy/ 27-30 fractions) to no PORT.² Patients were eligible if they had a performance status of 0-2, had a complete resection with nodal exploration and proven N2 disease. Prior (neo)adjuvant chemotherapy was allowed. The main endpoint of the trial was disease-free survival (DFS). In total, 500 patients and 292 events were required to show a 12% difference in 3-year DFS (bilateral test, power=80%). Baseline characteristics were well balanced between both study arms. Of note, around 40% of patients in the intention-to-treat population had unforeseen N2 disease and were therefore good candidates for the study. The vast majority of patients (81% in the control arm and 78% in the PORT arm) had lobectomy as type of surgery.

Results

At the data cut-off (May 31^st, 2019), 501 patients were included (249 control and 252 PORT) and 296 events had occurred. The median follow-up of study participants was 4.8 years. The median DFS improved from 22.8 months in the control arm to 30.5 months upon PORT treatment, however this difference was non-significant (HR [95%CI]: 0.85 [0.67-1.07], p=0.16). The 3-year DFS rates were 43.8% and 47.1%, respectively, which were both higher than expected. When specifically addressing DFS components in the first event, 46.1% of patients in the control arm had a mediastinal relapse vs. 25.0% in the PORT arm, while more patients in the PORT arm died (14.6% vs. 5.3%). Overall survival rates at three years were good, although not different between both study arms (68.5% for the control arm vs. 66.5% in the PORT arm). Overall, there were more deaths related to progression or recurrence in the control arm (86.1% vs. 69.4%), whereas there were more deaths related to cardio-pulmonary (16.2% vs. 2.0%) and radiotherapy or chemotherapy related toxicity (3.0% vs. 0%) in the PORT arm. As expected, more early toxicity (in the first three months after randomisation) of grade 3-4 was reported in the PORT arm (11.6%) as compared to the control arm (7.7%). Also late toxicity of grade 3-4 was more common in this population (14.6% vs. 8.9%). Especially late cardiac or pulmonary toxicity of grade 3-4 was more frequently reported in the PORT arm (10.8% vs. 4.9%). Finally, the prevalence of second cancers seems to be higher for patients in the PORT arm as compared to patients in the control arm (11.1% vs. 7.2%), especially second lung cancers (39.3% vs. 22.2%). However, these issues clearly need further analysis.

Conclusion

LungART is the first European randomised study evaluating modern PORT after complete resection in NSCLC patients selected predominantly with PET scan and having received (neo)adjuvant chemotherapy. The 3-year DFS was higher than expected in both arms and PORT was found to be associated with a non-statistically significant 15% increase in DFS among stage IIIAN2 patients. In addition, more toxicities (especially cardio-pulmonary events) were observed in the PORT arm and need to be further explored. In conclusion, conformal PORT cannot be recommended as standard of care in all completely resected stage IIIAN2 NSCLC patients.

References

1. PORT Meta-analysis Trialists Group. Postoperative radiotherapy in non-small-cell lung cancer: systematic review and meta-analysis of individual patient data from nine randomised controlled trials. Lancet;352(9124):2572-63.
2. 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 LungART (IFCT-0503, UK NCRI, SAKK) NCT00410683. Presented at ESMO 2020; Abstract LBA3.