Lugano, Switzerland, 20 September 2020 - Post-operative radiotherapy (PORT) used in patients with non-small-cell lung cancer (NSCLC) following complete resection and after (neo) adjuvant chemotherapy shows no statistically significant difference in 3-year disease-free survival (DFS), according to data presented at ESMO 2020. These results give the oncology community a long-awaited answer. (1)
PORT in completely resected NSCLC patients has been a subject of debate for many years in patients with mediastinal nodal involvement (pN2), since a meta-analysis in 1998 threw doubt on the benefits associated with it. (2)
However, more recent times have seen better selection, (neo)-adjuvant chemotherapy in stage III resected patients, as well as improved radiotherapy and more recent non prospective studies suggested modern PORT could improve outcome. (3,4,5,6,7)
As such, there was a clear need for a large, randomised trial to assess the role of modern mediastinal PORT in adequately staged and surgically treated patients. This study provides more robust data to help clinicians to decide the best course of action for these patients.
The large randomised controlled trial presented at ESMO 2020, explored the role of modern mediastinal PORT in patients with completely resected NSCLC with histo/cytologically proven nodal involvement.
A total of 501 patients were entered into the intention-to-treat analysis, of which 252 received PORT over five weeks, and 249 entered the control arm (no PORT). Safety analysis was carried out in 487 patients.
Disease-free survival was of 47.1% in the PORT arm and 43.8% in the control arm, thus not statistically significant, with a hazard ratio of = 0.85 (95% CI = [0.67;1.07]; p value = 0.16) for patient receiving PORT compared to control.
Overall survival at three years was 66.5% (95% CI = [59;73]) of patients in the PORT arm compared to 68.5% (95% CI = [61;75]) in the control arm.
Study author Dr Cecile Le Pechoux, radiation oncologist from Institut Gustave Roussy, Paris, France, said: "PORT cannot be recommended for all patients with stage II and 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 into balance with the risk of over-added cardio-pulmonary toxicity. We need to do further analysis to determine if certain patients, in particular, could benefit from it" she added.
Prof Rafal Dziadziuszko, radiation oncologist from the Medical University of Gdansk, Poland, commented on the findings. "Radiotherapy to the mediastinum after surgery, after adjuvant chemotherapy shouldn't be recommended as standard of care. This will change the practice of many institutions that adopted standard use of radiotherapy in these patients. We can safely say there is no net benefit from such treatment but there is also potential harm, which we see from this study, so any potential benefits in some patients are offset by the predominantly higher risk of cardiopulmonary toxicities."
Notes to Editors
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(1) Abstract LBA3_PR '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 (IFCT-0503, UK NCRI, SAKK) NCT00410683.' will be presented by Cecile Le Pechoux during the Presidential Symposium II, on Sunday, 20 September 2020, 18:30 - 20:25 CEST. Annals of Oncology, Volume 31 Supplement 4, September 2020
(2) 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;352: 257-263
(3) Douillard JY, Rosell R, De Lena M, et al: Impact of postoperative radiation therapy on survival in patients with complete resection and stage I, II, or IIIA non-small-cell lung cancer treated with adjuvant chemotherapy: The adjuvant Navelbine International Trialist Association (ANITA) randomized trial. Int J Radiat Oncol Biol Phys 72:695-701, 2008
(4) Lally BE, Zelterman D, Colasanto JM, et al: Postoperative radiotherapy for stage II or III non-small-cell lung cancer using the Surveillance, Epidemiology, and End Results database. J Clin Oncol 2006; 24:2998-3006.
(5) John L Mikell, Theresa W Gillespie, William A Hall, et al. Postoperative radiotherapy is associated with better survival in non-small cell lung cancer with involved N2 lymph nodes: results of an analysis of the National Cancer Data Base. J Thorac Oncol. 2015;10(3):462-71. doi: 10.1097/JTO.0000000000000411.
(6) Robinson CG, Patel AP, Bradley JD, et al: Postoperative radiotherapy for pathologic N2 non-small-cell lung cancer treated with adjuvant chemotherapy: A review of the National Cancer Data Base. J Clin Oncol 2015; 33:870-876.
(7) Corso CD, Rutter CE, Wilson LD, Kim AW, Decker RH, Husain ZA. Re-evaluation of the role of postoperative radiotherapy and the impact of radiation dose for non-small-cell lung cancer using the National Cancer Database. J Thorac Oncol. 2015; 10(1):148-55. doi: 10.1097/JTO.0000000000000406.
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LBA3_PR - 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 (IFCT-0503, UK NCRI, SAKK) NCT00410683.
C. Le Pechoux1, N. Pourel2, F. Barlesi3, C. Faivre-Finn4, D. Lerouge5, G. Zalcman6, D. Antoni7, B. Lamezec8, U. Nestle9, P. Boisselier10, F. Thillays11, A. Paumier12, E. Dansin13, K. Peignaux14, J. Madelaine15, E. Pichon16, A. Larrouy17, O. Riesterer18, A. Lavole19, A. Bardet20
1Radiation Oncology, Gustave Roussy, Villejuif, France, 2Radiation Oncology, Institut Sainte Catherine, Avignon, France, 3France and Institut Gustave Roussy, Aix Marseille Universite, Aix-Marseille University, CRCM, APHM, Marseille, Villejuif, CEDEX 20, France, 4Clinical Oncology, The University of Manchester and The Christie NHS Foundation Trust, Manchester, UK, 5Radiation Oncology, Centre Baclesse, Caen, France, 6Department of Thoracic Oncology and CIC1425, Hopital Bichat-Claude Bernard, Assistance Publique Hopitaux de Paris, Universite; Paris-Diderot, Paris, France, 7Radiation Oncology, Institut de Cancerologie Strasbourg Europe, Strasbourg, France, 8Radiation Oncology, Clinique Armoricaine de Radiologie, St. Brieuc, France, 9Radiation Oncology, Universitatsklinikum Freiburg Klinik fur Innere Medizin Hamatologie, Onkologie und Stammzelltransplantation, Freiburg Im Breisgau, Germany, 10Radiation Oncology, ICM Regional Cancer Institute of Montpellier, Montpellier, CEDEX 5, France, 11Radiation Oncology, Institut de Cancerologie de l'ouest, Saint Herblain, France, 12Radiation Oncology, ICO Site Paul Papin, Angers, France, 13Medical Oncology, Centre Oscar Lambret, Lille, CEDEX, France, 14Radiation Oncology, Centre Georges Francois Leclerc, Dijon, France, 15Medical Oncology, Centre Hospitalier Caen, Caen, France, 16Pneumology, CHRU Bretonneau, Tours, CEDEX 9, France, 17Radiation Oncology, Centre de Cancerologie Paris Nord, Sarcelles, France, 18Radiation Oncology, University Hospital Zurich and Center for Radiation Oncology KSA-KSB, Cantonal Hospital Aurau, Zurich, Switzerland, 19Pneumology, Hopital Tenon, Paris, France, 20Biostatistics, Institut Gustave Roussy, Villejuif, France
Background: Adjuvant PORT has been controversial since publication of a meta-analysis showing PORT could be deleterious especially in pN0 pN1 pts. However, changes have taken place in the management of stage IIIAN2 NSCLC pts including use of adjuvant chemotherapy (CT), patients' workup, quality of surgery and radiotherapy. Therefore the role of PORT warranted further investigations in high risk pts.
Methods: LungART is a multi-institutional randomized phase III trial comparing mediastinal PORT (54 Gy/27-30 fractions) to no PORT. Pts were eligible if they were PS 0-2, had a complete resection with nodal exploration, proven N2 disease; prior (neo)-adjuvant CT was allowed. The main end-point was disease-free survival (DFS). 500 pts and 292 events were required to show an improvement in DFS from 30% to 42% with PORT (bilateral test). Secondary endpoints included toxicity, local control, patterns of recurrence, overall survival (OS), second cancers, prognostic and predictive factors of treatment effect.
Results: Between August 2007 and July 2018, 501 patients were randomized after surgery or after CT: 252 pts allocated to PORT, and 249 to CA. Median age was 61 (range=36-85), 66% male, histology: mostly adenocarcinoma (73%) and work-up included PET scan in 91% pts. Most patients received CT (post op 77%, pre-op 18%). Analysis for DFS was performed with a median FU of 4.8 yrs; toxicity evaluated on 487 pts (246 in CA). Early and late Gr 3-5 cardio-pulmonary toxicity was respectively 7 and 20% in PORT vs 3,2 and 7,7 % in CA. DFS hazard ratio was 0.85 (95% CI 0.67; 1.07); p=0.16; median DFS was 30.5 months in PORT arm [24;48] and 22.8 in CA [17;37]; 3-year DFS was 47.1% with PORT vs 43.8% with no PORT. 3-year OS was 66.5% with PORT vs 68.5% with no PORT.
Conclusions: LungART is the first European randomized study evaluating modern PORT after complete resection, in pts selected predominantly with PET scan and having received (neo)adjuvant CT. 3-year DFS was higher than expected in both arms and PORT was associated with a non-statistically significant 15% increase in DFS among stage IIIAN2 pts.
Clinical trial identification: NCT00410683
Legal entity responsible for the study: Gustave Roussy
Funding: French National Cancer Institute (INCa), French Health Ministry (PHRC), Gustave Roussy and CRUK grant (A13969).
Disclosure: C. Le Pechoux: Honoraria (institution): Amgen; Honoraria (institution), Advisory/Consultancy: Astra Zeneca; Honoraria (institution): Lilly; Honoraria (self): PrimeOncology; Honoraria (institution): Medscape; Honoraria (institution), Advisory/Consultancy: Roche; Honoraria (institution), Advisory/Consultancy: Nanobiotix. F. Barlesi: Honoraria (self), Personal Fees: Astra Zeneca; Honoraria (self): Bayer; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Boehringer-Ingelheim; Honoraria (self): Eli Lilly Oncology; Honoraria (self): F. Hoffmann-La Roche Ltd; Honoraria (self): Novartis; Honoraria (self): Merck; Honoraria (self): MSD; Honoraria (self): Pierre Fabre; Honoraria (self): Pfizer ; Honoraria (self): Takeda. C. Faivre-Finn: Advisory/Consultancy, Research grant/Funding (institution): Astra Zeneca; Research grant/Funding (institution): Elekta. G. Zalcman: Research grant/Funding (institution): Fondation Roche; Honoraria (self), Travel/Accommodation/Expenses: Astra Zeneca; Honoraria (self), Travel/Accommodation/Expenses: BMS; Honoraria (self): MSD; Honoraria (self), Advisory/Consultancy: Inventiva; Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: Abbvie; Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy: Da Volterra. J. Madelaine: Honoraria (self), Dr JM received support: Astra Zeneca; Honoraria (self): Chugai Pharma; Honoraria (self): Pfizer; Honoraria (self): Boehringer Ingelheim; Honoraria (self): MSD France; Honoraria (self): Roche SAS; Honoraria (self): Actelion; Honoraria (self): GSK; Honoraria (self): Bristol-Myers Squibb. A. Bardet: Advisory/Consultancy: Roche. All other authors have declared no conflicts of interest.
Annals of Oncology