Cecile Le Pechoux1, Nicolas Pourel2, Fabrice Barlesi3, Delphine Lerouge4, Delphine Antoni5, Bruno Lamezec6, Ursula Nestle7, Pierre Boisselier8, Eric Dansin9, Amaury Paumier10, Karine Peignaux11, François Thillays12, Gerard Zalcman13, Jeannick Madelaine14, Eric Pichon15, Anne Larrouy16, Armelle Lavole17, Delphine Argo-Leignel18, Marc Derollez19, Corinne Faivre-Finn20, Matthew Q Hatton21, Oliver Riesterer22, Emilie Bouvier-Morel23, Ariane Dunant23, John G Edwards24, Pascal Alexandre Thomas25, Olaf Mercier26, Aurelie Bardet27. 1. Department of Radiation Oncology, Gustave Roussy, Villejuif, France. Electronic address: cecile.lepechoux@gustaveroussy.fr. 2. Radiation Oncology, Institut Sainte Catherine, Avignon, France. 3. Department of Medical Oncology, Gustave Roussy, Villejuif, France; Aix-Marseille University, Centre National de la Recherche Scientifique, Institut National des Sciences et de la Recherche Médicale, Centre de Recherche en Cancérologie de Marseille, Assistance Publique - Hôpitaux de Marseille, Marseille, France. 4. Department of Radiation Oncology, Centre Baclesse, Caen, France. 5. Department of Radiation Oncology, Centre Paul Strauss, Strasbourg, France. 6. Radiation Oncology, Centre Armoricain de Radiothérapie, d'Imagerie médicale et d'Oncologie, St Brieuc, France. 7. Department of Radiation Oncology, University Hospital Freiburg, Freiburg, Germany; Department of Radiation Oncology, Kliniken Maria Hilf, Moenchengladbach, Germany. 8. Department of Radiation Oncology, Centre Val d'Aurelle, Montpellier, France. 9. Department of Medical Oncology, Centre Oscar Lambret, Lille, France. 10. Department of Radiation Oncology, Institut de cancérologie de l'Ouest Centre Paul Papin, Angers, France. 11. Department of Radiation Oncology, Centre Georges-Francois Leclerc, Dijon, France. 12. Department of Radiation Oncology, Institut de Cancérologie de l'Ouest Centre René Gauducheau, Nantes, France. 13. Department of Pneumology, Centre Hospitalier Universitaire de Caen, Caen, France; Department of Thoracic Oncology, Université de Paris, Centre d'Investigation Clinique-1425-Bichat-Claude Bernard Hospital, Assistance Publique-Hopitaux de Paris, Paris, France. 14. Department of Pneumology, Centre Hospitalier Universitaire de Caen, Caen, France. 15. Department of Pneumology, Centre Hospitalier Universitaire de Tours, Tours, France. 16. Radiation Oncology, Centre Specialisé Cancerologie Paris Nord, Sarcelles, France. 17. Department of Thoracic Oncology, Tenon University Hospital, Assistance Publique-Hopitaux de Paris, Paris, France. 18. Radiation Oncology, Centre Hospitalier de Bretagne Sud, Lorient, France. 19. Pneumology, Polyclinique du Val de Sambre, Maubeuge, France. 20. University of Manchester and The Christie NHS Foundation Trust, Manchester, UK. 21. Department of Clinical Oncology, Weston Park Hospital, Sheffield, UK. 22. Department of Radiation Oncology, University Hospital Zurich, University of Zurich, Zurich and Centre for Radiation Oncology, Cantonal Hospitals Aarau and Baden, Aarau, Switzerland. 23. International Center for Thoracic Cancers, and Department of Biostatistics and Epidemiology, Gustave Roussy, Villejuif, France. 24. Department of Cardiothoracic Surgery, Northern General Hospital, Sheffield, UK. 25. Department of Thoracic Surgery, Hôpital Nord, Assistance Publique-Hopitaux de Marseille, Aix-Marseille University, Marseille, France. 26. Department of Thoracic and Vascular Surgery and Heart-Lung Transplantation, Institut d'Oncologie Thoracique, Marie-Lannelongue Hospital, Paris-Saclay University, Le Plessis Robinson, France. 27. International Center for Thoracic Cancers, and Department of Biostatistics and Epidemiology, Gustave Roussy, Villejuif, France; Oncostat Unité Mixte de Recherche 1018, Inserm, University Paris-Saclay, labeled Ligue Contre le Cancer, Villejuif, France.
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.
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.
Authors: Filippo de Marinis; Ilaria Attili; Cesare Gridelli; Fabiana Cecere; Carlo Curcio; Francesco Facciolo; Lorenzo Spaggiari Journal: Front Oncol Date: 2022-07-22 Impact factor: 5.738