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Journal of Clinical Oncology, Vol 25, No 7 (March 1), 2007: pp. 10e-11 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.6263
Need for a New Trial to Evaluate Adjuvant Postoperative Radiotherapy in Non–Small-Cell Lung Cancer Patients With N2 Mediastinal InvolvementDepartments of Radiotherapy and Biostatistics, Institut Gustave Roussy, Villejuif, France
Academic Hospital Maastricht/GROW/MAASTRO Clinic, Maastricht, the Netherlands
Department of Radiotherapy-Oncology, Centre Hospitalier Lyon Sud, Lyon, France
Department of Radiation Oncology, Vrije Universiteit University Medical Center, Amsterdam, the Netherlands
Department of Radiation Oncology, Institut Clinic de Malalties Oncohematologiques, Hospital Clinic i Universitari, Barcelona, Spain
Department of Oncology, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom
Pneumology Unit, Tenon University Hospital, Paris, France To the Editor: Lally et al are to be congratulated for their interesting study on postoperative radiotherapy in non–small-cell lung cancer, based on a population-based cohort of 7,465 patients with stage II and III disease.1 As even patients with a complete resection are at high risk of both local and distant recurrence, adjuvant treatments have been evaluated. The benefit of postoperative chemotherapy has been confirmed recently in several large trials of patients with stage II and III disease.2-4 However, even after combined adjuvant (or neoadjuvant) chemotherapy, 20% to 40% of the patients still have a local tumor failure. In consideration of this high proportion of local recurrence, a new interest in postoperative radiotherapy (PORT) has arisen, as underlined in recent studies. In the Adjuvant Navelbine International Trialist Association (ANITA) randomized trial evaluating adjuvant chemotherapy in stage IB to IIIA patients, PORT was an optional choice left up to the individual institutions before entering any patient in the trial; the descriptive analysis showed that radiotherapy could benefit patients with N2 disease. In a phase II study by Betticher et al5 reporting on the long-term results in patients with proven N2 nodal involvement, 60% of patients who were deemed suitable for resection after induction chemotherapy had a local recurrence. However, PORT remains a very controversial issue as results of the PORT meta-analysis indicated that it had a significant detrimental effect on survival, predominantly among patients who had no mediastinal involvement (either pN0 or pN1), presumably by increasing the rate of intercurrent deaths.6 Lally and colleagues selected patients treated between 1988 and 2002 from the Surveillance, Epidemiology, and End Results (SEER) database, of which 47% received PORT; they emphasize that the frequency of PORT use decreased significantly after publication of the meta-analysis. This meta-analysis has been criticized because the radiotherapy techniques used were considered suboptimal, resulting in higher morbidity and mortality rates in the PORT arm than in other more recent studies.7,8 Patients who were administered PORT in the Lally et al study were presumably treated with more modern radiotherapy techniques, though no details were provided. In resected pN2 disease, the authors of the meta-analysis concluded that the question of PORT remained valid and would merit further research. In the SEER analysis, survival improved significantly in N2 patients. However, one should be cautious about interpreting the results of such a retrospective study using a large database. As the study was not randomized, the patients who received PORT could have a different prognosis than those patients who did not receive PORT. The 3.5-year median follow-up of the study is too short to study late effect of radiotherapy. Although the results for two end points are unexpectedly similar, a subsequent increase in intercurrent death with PORT could result in a lower overall survival. We agree with the views expressed in the article and in the accompanying editorial that further rigorous evaluation of modern radiotherapy in the context of extensive use is warranted.1,9 A randomized trial is the best way to do it, and it is important to recall that postmastectomy radiotherapy in breast cancer was long considered deleterious until the publication of two large randomized studies10,11 using more modern radiotherapy techniques, which showed a clear improvement in both disease-free and overall survival. At present, based on level 1 evidence, patients who underwent a complete resection of the primary tumor with mediastinal lymph node dissection showing no mediastinal involvement (pN0 and pN1) should not have PORT. The data reported by Lally et al should encourage oncologists involved in lung cancer to address the question of PORT prospectively in patients with mediastinal involvement, as the number of potential long-term survivors is increasing with adjuvant chemotherapy. In order to avoid the errors of previous studies, it is very important to specify the surgery procedure (most particularly the lymph node exploration) as well as the radiotherapy technique. The question of PORT also remains among patients who have histologically proven N2 disease before preoperative chemotherapy, whatever their response is, whether persistent mediastinal involvement or mediastinal down-staging (from N2 histologically proven to pN0 or pN1). A new large, multi-institutional European phase III trial, Lung Adjuvant Radiotherapy Trial (Lung ART), will shortly commence and will compare 3D conformal PORT to no PORT, and will include patients who have proven N2 disease and a complete resection irrespective of whether adjuvant or neoadjuvant chemotherapy was used. Seven hundred patients will have to be included in order to show a 10% difference in terms of 3-year disease-free survival (bilateral test, power = 80%, alpha = 5%, from 30% to 40% at 3 years), which is the primary end point. The secondary end points would be overall survival, patterns of relapse, local failure, secondary cancers, and treatment-related toxicity. Because of toxicity reported in the old trials, quality assurance for conformal RT as well as translational research programs (predictive factors of efficacy and toxicity) are planned. This project, sponsored by the Fédération Nationale des Centres de Lutte contre le Cancer (FNCLCC), will soon start as a study associating the Intergroupe Francophone de Cancérologie Thoracique (IFCT), The European Organisation for Research and Treatment of Cancer (EORTC Radiation Oncology Group and Lung Group), and the Lung Adjuvant Radiotherapy Spanish Group. With a longer follow-up period (median of 5 years), this sample size could also show a difference in survival rate of 9% at 5 years. An exciting perspective would be if several international parallel trials with a similar design could start throughout the world, so as to be able to come up to a more powerful conclusion as to the role of PORT. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The authors indicated no potential conflicts of interest. REFERENCES
1. 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 24:2998-3006, 2006 2. International Adjuvant Lung cancer Trial Collaborative Group: Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 350:351-360, 2004 3. Winton TL, Livingston R, Johnson D, et al: Vinorelbine plus cisplatin vs observation in resected non-small cell lung cancer Intergroup. N Engl J Med 352:2589-2597, 2005 4. Douillard JY, Rosell R, De Lena M, et al: Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): A randomised trial. Lancet Oncol 7:719-727, 2006[CrossRef][Medline] 5. Betticher DC, Schmitz SFH, Totsch M, et al: Prognostic factors affecting long-term outcomes in patients with resected stage IIIA pN2 non-small-cell lung cancer: The 5-year follow-up of a phase II study. Br J Cancer 94:1099-1106, 2006[CrossRef][Medline] 6. PORT Meta-analysis Trialists Group: Post-operative radiotherapy in non-small cell lung cancer: Systematic review and meta-analysis of individual patient data from nine randomised controlled trials. Lancet 352:257-263, 1998[CrossRef][Medline] 7. Machtay M, Lee JH, Shrager JB, et al: Risk of death from intercurrent disease is not excessively increased by modern postoperative radiotherapy for high-risk resected non-small-cell lung carcinoma. J Clin Oncol 19:3912-3917, 2001 8. Wakelee HA, Stephenson P, Keller SM, et al: Post-operative radiotherapy (PORT) or chemoradiotherapy (CPORT) following resection of stages II and IIIA non-small cell lung cancer (NSCLC) does not increase the expected risk of death from intercurrent disease (DID) in Eastern Cooperative Oncology Group (ECOG) trial E3590. Lung Cancer 48:389-397, 2005[CrossRef][Medline] 9. Bonner JA, Spencer SA: Postoperative radiotherapy in non-small-cell lung cancer warrants further exploration in the era of adjuvant chemotherapy and conformal radiotherapy. J Clin Oncol 24:2978-2980, 2006 10. Overgaard M, Hansen PS, Overgaard J, et al: Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med 337:949-955, 1997 11. Ragaz J, Stewart MJ, Le N, et al: Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med 337:956-962, 1997 Related Article
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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