The merits of post-operative radiotherapy (PORT) in completely resected non-small cell lung cancer (NSCLC) patients have been under debate for many years. The prospective phase 3 LungART trial now demonstrates that PORT cannot be recommended as a standard of care in all completely resected stage IIIA N2 NSCLC patients.
In 1998, a Lancet meta-analysis concluded PORT has no benefit for patients with N0 or N1 NSCLC . Since then, multiple changes have taken place in the management of N2 NSCLC patients, including use of adjuvant chemotherapy, patients’ workup, quality of surgery, and radiotherapy. Therefore, the role of PORT warranted further investigations in high risk patients (stage IIIA).
To evaluate the value of PORT in completely resected stage IIIA N2 NSCLC patients, the LungART trial was developed. LungART is a multi-institutional randomized phase 3 trial comparing mediastinal PORT (54 Gy/27-30 fractions) to no PORT. Patients were eligible if they were performance status 0-2, had a complete resection with nodal exploration, and proven N2 disease; prior (neo)-adjuvant chemotherapy was allowed. The main endpoint was disease-free survival (DFS). Between 2007 and 2018, 501 patients were included in the trial: 252 patients were randomized to PORT, and 249 to the control-arm. In the PORT arm, the compliance to radiotherapy was good: 96% of the patients received the dose of 54 Gy). Dr Cecile le Pechoux (Institute Gustave Roussy, France) presented the results of the trial.
The primary endpoint of the study was not met. The median DFS in the PORT arm was 30.5 months versus 22.8 months in controls (HR 0.85; P=0.16). DFS at 3 years follow-up was 47.1% and 43.8% in the PORT and control arm, respectively. However, the nature of the first events were different between the two arms. In the PORT arm, 25% of the first events were mediastinal relapses and 14.6% were deaths; whereas in the control arm, 46.1% of the first events were mediastinal relapses and 5.3% were deaths. Overall survival at 3 years was comparable in the two arms: 66.5% for PORT and 68.5 for controls.
In the control arm, 86.1% of deaths was due to recurrence versus 69.4% in the PORT arm. However, in the PORT arm, 16.2% of deaths were due to cardio-pulmonary causes versus 2% in the control arm and 5.1% of deaths were due to second primary tumours versus 1.0% in the control arm. In other words, giving PORT to 250 patients will avoid 19 patients dying from recurrence and/or progression of disease. However, 14 patients will die because of cardiopulmonary toxicity, 4 patients from second primary cancers, and 3 patients from radiotherapy/chemotherapy-related toxicity. In line with this, late cardiac/pulmonary toxicity was doubled in the PORT arm compared with the control arm: 10.8% versus 4.9%, respectively. Also, more secondary cancers were observed in the PORT arm compared with the control arm: 11.1% versus 7.2%, respectively.
In conclusion, LungART is the first European randomized study evaluating modern PORT after complete resection in patients selected predominantly with PET scan and having received (neo)adjuvant chemotherapy. PORT was associated with a non-statistically significant 15% increase in DFS among stage IIIA N2 patients. Therefore, PORT cannot be recommended as a standard of care in all completely resected stage IIIA N2 NSCLC patients.
- 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 1998;35:257-263.
- Le Pechoux C, 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. ESMO 202 Virtual, abstract LBA3.