Lancet Oncol 2021 Dec 15
Postoperative radiotherapy versus no postoperative radiotherapy in patients with completely resected non-small-cell lung cancer and proven mediastinal N2 involvement (Lung ART): an open-label, randomised, phase 3 trial.
Abstract
Background
In patients with non-small-cell lung cancer (NSCLC), the use of postoperative radiotherapy (PORT) has been controversial since 1998, because of one meta-analysis showing a deleterious effect on survival in patients with pN0 and pN1, but with an unclear effect in patients with pN2 NSCLC. Because many changes have occurred in the management of patients with NSCLC, the role of three-dimensional (3D) conformal PORT warrants further investigation in patients with stage IIIAN2 NSCLC. The aim of this study was to establish whether PORT should be part of their standard treatment.
Methods
Lung ART is an open-label, randomised, phase 3, superiority trial comparing mediastinal PORT to no PORT in patients with NSCLC with complete resection, nodal exploration, and cytologically or histologically proven N2 involvement. Previous neoadjuvant or adjuvant chemotherapy was allowed. Patients aged 18 years or older, with an WHO performance status of 0-2, were recruited from 64 hospitals and cancer centres in five countries (France, UK, Germany, Switzerland, and Belgium). Patients were randomly assigned (1:1) to either the PORT or no PORT (control) groups via a web randomisation system, and minimisation factors were the institution, administration of chemotherapy, number of mediastinal lymph node stations involved, histology, and use of pre-treatment PET scan. Patients received PORT at a dose of 54 Gy in 27 or 30 daily fractions, on five consecutive days a week. Three dimensional conformal radiotherapy was mandatory, and intensity-modulated radiotherapy was permitted in centres with expertise. The primary endpoint was disease-free survival, analysed by intention to treat at 3 years; patients from the PORT group who did not receive radiotherapy and patients from the control group with no follow-up were excluded from the safety analyses. This trial is now closed. This trial is registered with ClinicalTrials.gov number, NCT00410683.
Findings
Between Aug 7, 2007, and July 17, 2018, 501 patients, predominantly staged with 18F-fluorodeoxyglucose (18F-FDG) PET (456 [91%]; 232 (92%) in the PORT group and 224 (90%) in the control group), were enrolled and randomly assigned to receive PORT (252 patients) or no PORT (249 patients). At the cutoff date of May 31, 2019, median follow-up was 4·8 years (IQR 2·9-7·0). 3-year disease-free survival was 47% (95% CI 40-54) with PORT versus 44% (37-51) without PORT, and the median disease-free survival was 30·5 months (95% CI 24-49) in the PORT group and 22·8 months (17-37) in the control group (hazard ratio 0·86; 95% CI 0·68-1·08; p=0·18). The most common grade 3-4 adverse events were pneumonitis (13 [5%] of 241 patients in the PORT group vs one [<1%] of 246 in the control group), lymphopenia (nine [4%] vs 0), and fatigue (six [3%] vs one [<1%]). Late-grade 3-4 cardiopulmonary toxicity was reported in 26 patients (11%) in the PORT group versus 12 (5%) in the control group. Two patients died from pneumonitis, partly related to radiotherapy and infection, and one patient died due to chemotherapy toxicity (sepsis) that was deemed to be treatment-related, all of whom were in the PORT group.
Interpretation
Lung ART evaluated 3D conformal PORT after complete resection in patients who predominantly had been staged using (18F-FDG PET-CT and received neoadjuvant or adjuvant chemotherapy. 3-year disease-free survival was higher than expected in both groups, but PORT was not associated with an increased disease-free survival compared with no PORT. Conformal PORT cannot be recommended as the standard of care in patients with stage IIIAN2 NSCLC.
Funding
French National Cancer Institute, Programme Hospitalier de Recherche Clinique from the French Health Ministry, Gustave Roussy, Cancer Research UK, Swiss State Secretary for Education, Research, and Innovation, Swiss Cancer Research Foundation, Swiss Cancer League.
Related Questions
In resected N2 NSCLC, what nodal pathologic characteristics prompt you to recommend PORT?
Increasingly difficult question to answer with the evolution of neoadjuvant and adjuvant treatment paradigms. We know from both Lung ART and PORT-C that the addition of PORT in completely resected patients with N2 disease improves locoregional control across the cohort as a whole; however, this did ...
For NSCLC patients treated with neoadjuvant chemoimmunotherapy and surgery with ypN2 disease, what factors would cause you to recommend PORT?
This question is a tough one, and the multidisciplinary teams I work with are still trying to figure it out. This is mostly because only 13% (67/501) of randomized participants in the Lung ART study received neoadjuvant chemotherapy, and 0% received neoadjuvant chemoimmunotherapy; all had pN2 or ypN...
Would you offer postoperative radiation for a patient who initially had biopsy-proven multistation N2 NSCLC but had a nodal pCR upon surgical resection+ LND after neoadjuvant chemo-immunotherapy?
I would not routinely offer PORT for completely resected N2 disease based on lack of survival benefit from LungART (have my qualms about ~90% 3DCRT and the probable impact on cardiothoracic toxicity), particularly in a patient who appears to have had a fantastic response to neoadjuvant therapy. I th...
Are there any situations where you would consider neoadjuvant chemoradiation as opposed to chemoimmunotherapy for patients with resectable NSCLC prior to surgical resection?
For most of the last 2 decades, there has been a raging debate about the best perioperative approach for the management of patients with high-risk resectable NSCLC, such as patients for example, with preop documented nodal disease. Clinical studies have not been able to settle the key questions whet...
How do you approach adjuvant therapy for resected lung adenocarcinoma that was found unexpectedly postop to be N2?
Preliminary results of the phase 3 randomized LungART trial (NCT00410683) were recently presented at a virtual ESMO conference. 501 patients with pathologically confirmed N2 NSCLC s/p complete resection were randomized to postoperative RT (54 Gy) or observation. Almost all patients received chemothe...
How do you approach PORT for T3N0 NSCLC, which had chest wall invasion, now status post lobectomy with a microscopically positive margin?
PORT should still be offered/considered for R1 resection such as this T3N0 patient. It sounds as if this person, or someone in a similar scenario, would have been served well to have undergone NACT to help achieve R0 prior to surgery. But nonetheless, I would take the following approach (assuming ap...