CLINICAL INVESTIGATION Lung PREOPERATIVE CHEMOTHERAPY VERSUS PREOPERATIVE CHEMORADIOTHERAPY FOR STAGE III (N2) NON–SMALL-CELL LUNG CANCER KRISTIN HIGGINS, M.D.,* JUNZO P. CHINO, M.D.,* LAWRENCE B. MARKS, M.D., y NEAL READY, M.D., z THOMAS A. D’AMICO, M.D., x ROBERT W. CLOUGH, B.A.,* AND CHRIS R. KELSEY, M.D.* Departments of *Radiation Oncology, z Medicine, Division of Medical Oncology, and x Surgery, Division of Cardiovascular and Thoracic Surgery, Duke University of Medical Center, Durham, NC; and y Department of Radiation Oncology, University of North Carolina, Chapel Hill, NC Purpose: To compare preoperative chemotherapy (ChT) and preoperative chemoradiotherapy (ChT-RT) in oper- able Stage III non–small-cell lung cancer. Methods and Materials: This retrospective study analyzed all patients with pathologically confirmed Stage III (N2) non–small-cell lung cancer who initiated preoperative ChT or ChT-RTat Duke University between 1995 and 2006. Mediastinal pathologic complete response (pCR) rates were compared using a chi-square test. The actuarial over- all survival, disease-free survival, and local control were estimated using the Kaplan-Meier method and compared using the log–rank test. Multivariate Cox regression analysis was also performed. Results: A total of 101 patients who initiated preoperative therapy with planned resection were identified. The me- dian follow-up was 20 months for all patients and 38 months for survivors. The mediastinal lymph nodes were re- assessed after preoperative therapy in 88 patients (87%). Within this group, a mediastinal pCR was achieved in 35% after preoperative ChT vs. 65% after preoperative ChT-RT (p = 0.01). Resection was performed in 69% after ChT and 84% after ChT-RT (p = 0.1). For all patients, the overall survival, disease-free survival, and local control rate at 3 years was 40%, 27%, and 66%, respectively. No statistically significant differences were found in the clin- ical endpoints between the ChT and ChT-RT subgroups. On multivariate analysis, a mediastinal pCR was associ- ated with improved disease-free survival (p = 0.03) and local control (p = 0.03), but not overall survival (p = 0.86). Conclusion: Preoperative ChT-RT was associated with higher mediastinal pCR rates but not improved survival. Ó 2009 Elsevier Inc. Lung cancer, induction therapy, preoperative therapy, chemotherapy, radiotherapy, surgery. INTRODUCTION Stage III (N2) non–small-cell lung cancer (NSCLC) encom- passes a wide range of presentations. Some patients present with a clinically negative mediastinum but are found to have microscopic N2 disease on staging mediastinoscopy, while others present with multistation, macroscopic disease detected on initial staging studies. The optimal treatment ap- proach for operable Stage III NSCLC has yet to be estab- lished. Upfront surgery for patients with clinically apparent N2 disease is unsatisfactory, with long-term survival rates of <10% (1). Multiple Phase II and III studies have been per- formed evaluating preoperative chemotherapy (ChT) or che- moradiotherapy (ChT-RT) (2–12), demonstrating relatively favorable outcomes. However, the optimal preoperative regimen has not been established (ChT vs. ChT-RT). Only limited data are avail- able from randomized trials comparing these approaches, making it difficult to draw firm conclusions. Furthermore, ad- vantages and disadvantages exist for both approaches, and the patient subgroups that will benefit from a more intensive, combined modality regimen have not been defined. At Duke University Medical Center, patients with operable Stage III (N2) NSCLC are often treated with preoperative therapy before planned resection. The present study com- pared the outcomes between ChT alone and ChT-RT at a sin- gle institution during a 12-year period. METHODS AND MATERIALS The institutional review board of the Duke University Medical Center approved this retrospective analysis. All patients with N2 NSCLC who were treated with preoperative therapy before planned surgical resection were identified from the Duke Comprehensive Reprint requests to: Kristin Higgins, M.D., Department of Radi- ation Oncology, Duke University Medical Center, DUMC Box 3085, Durham, NC 27710. Tel: (919) 668-1479; Fax: (919) 668- 7345; E-mail: kristin.higgins@duke.edu Presented at the 50th Annual Meeting of the American Society for Therapeutic Radiology and Oncology, September 21–25, 2008, Boston, MA as an oral presentation. Conflict of interest: none. Received Nov 6, 2008, and in revised form Jan 3, 2009. Accepted for publication Jan 8, 2009. 1462 Int. J. Radiation Oncology Biol. Phys., Vol. 75, No. 5, pp. 1462–1467, 2009 Copyright Ó 2009 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/09/$–see front matter doi:10.1016/j.ijrobp.2009.01.069