doi:10.1016/j.ijrobp.2007.03.011 CLINICAL INVESTIGATION Lung DOSE-DEPENDENT PULMONARY TOXICITY AFTER POSTOPERATIVE INTENSITY-MODULATED RADIOTHERAPY FOR MALIGNANT PLEURAL MESOTHELIOMA DAVID C. RICE, M.B., B.CH.,* W. ROY SMYTHE, M.D., † ZHONGXING LIAO, M.D., ‡ THOMAS GUERRERO, M.D., PH.D., ‡ JOE Y. CHANG, M.D., PH.D., ‡ MARY F. MCALEER, M.D., PH.D., ‡ MELENDA D. JETER, M.D., PH.D., ‡ ARLENE CORREA,PH.D.,* ARA A. VAPORCIYAN, M.D.,* H. HELEN LIU,PH.D, § RITSUKO KOMAKI, M.D., ‡ KENNETH M. FORSTER,PH.D., ¶ AND CRAIG W. STEVENS, M.D., PH.D. ¶ Departments of *Thoracic and Cardiovascular Surgery, ‡ Radiation Oncology, and § Radiation Physics, The University of Texas M. D. Anderson Cancer Center, Houston, TX; † Department of Surgery, Texas A&M University Medical School, College Station, TX; ¶ Division of Radiation Oncology, H. Lee Moffitt Cancer Center, Tampa, FL Purpose: To determine the incidence of fatal pulmonary events after extrapleural pneumonectomy and hemitho- racic intensity-modulated radiotherapy (IMRT) for malignant pleural mesothelioma. Methods and Materials: We retrospectively reviewed the records of 63 consecutive patients with malignant pleural mesothelioma who underwent extrapleural pneumonectomy and IMRT at the University of Texas M. D. Anderson Cancer Center. The endpoints studied were pulmonary-related death (PRD) and non– cancer-related death within 6 months of IMRT. Results: Of the 63 patients, 23 (37%) had died within 6 months of IMRT (10 of recurrent cancer, 6 of pulmonary causes [pneumonia in 4 and pneumonitis in 2], and 7 of other noncancer causes [pulmonary embolus in 2, sepsis after bronchopleural fistula in 1, and cause unknown but without pulmonary symptoms or recurrent disease in 4]). On univariate analysis, the factors that predicted for PRD were a lower preoperative ejection fraction (p  0.021), absolute volume of lung spared at 10 Gy (p  0.025), percentage of lung volume receiving >20 Gy (V 20 ; p  0.002), and mean lung dose (p  0.013). On multivariate analysis, only V 20 was predictive of PRD (p  0.017; odds ratio, 1.50; 95% confidence interval, 1.08 –2.08) or non– cancer-related death (p  0.033; odds ratio, 1.21; 95% confidence interval, 1.02–1.45). Conclusion: The results of our study have shown that fatal pulmonary toxicities were associated with radiation to the contralateral lung. V 20 was the only independent determinant for risk of PRD or non– cancer-related death. The mean V 20 of the non-PRD patients was considerably lower than that accepted during standard thoracic radiotherapy, implying that the V 20 should be kept as low as possible after extrapleural pneumonectomy. © 2007 Elsevier Inc. Mesothelioma, Radiation, Pneumonectomy, Toxicity, Pneumonitis. INTRODUCTION Malignant pleural mesothelioma (MPM) is a rare, but ag- gressive, cancer that is usually fatal. Newer chemotherapeu- tic regimens have resulted in an improved tumor response, but the median survival duration is only 12 months from the date of diagnosis (1). Radiotherapy (RT) as a primary treat- ment modality is of limited utility because the extensiveness of the tumor requires large fields and it is impossible to administer tumoricidal doses without injuring the adjacent lung and mediastinal organs. Extrapleural pneumonectomy (EPP), which includes en bloc resection of the lung, pleura, and ipsilateral diaphragm and pericardium, has shown modest efficacy, mainly in patients with early stage tumors of a favorable histologic type (2, 3). However, the diffuse nature of the tumor and the inability to resect it with margins of normal, uninvolved tissue place the entire ipsilateral chest wall, diaphragm insertion, pericardium, mediastinum, and bronchial stump at very high risk of local recurrence (30–60%) (4, 5). The addition of hemithoracic RT after EPP has been shown to Reprint requests to: David C. Rice, M.B., B.Ch., Department of Thoracic and Cardiovascular Surgery, Box 445, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. Tel: (713) 794-1477; Fax: (713) 794-4901; E-mail: drice@mdanderson.org Presented at the 48th Annual Meeting of the American Society for Therapeutic and Radiation Oncology (ASTRO), Philadelphia, PA, November 5–9, 2006. Conflict of interest: none. Received Jan 12, 2007, and in revised form Feb 27, 2007. Accepted for publication March 2, 2007. Int. J. Radiation Oncology Biol. Phys., Vol. 69, No. 2, pp. 350 –357, 2007 Copyright © 2007 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/07/$–see front matter 350