Predictors of severe long-term toxicity after re-irradiation for head and neck cancer Jae Y. Lee a,1 , Krithika Suresh a,d,1 , Rebecca Nguyen a , Eli Sapir a , Janell S. Dow a , George S. Arnould a , Francis P. Worden b , Matthew E. Spector c , Mark E. Prince c , Scott A. McLean c , Andrew G. Shuman c , Kelly M. Malloy c , Keith Casper c , Carol R. Bradford c , Matthew J. Schipper a,d , Avraham Eisbruch a,⇑ a Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, United States b Department of Internal Medicine, Hematology/Oncology, University of Michigan, Ann Arbor, MI, United States c Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, MI, United States d Department of Biostatistics, University of Michigan, Ann Arbor, MI, United States article info Article history: Received 19 May 2016 Received in revised form 23 June 2016 Accepted 24 June 2016 Keywords: Head and neck re-irradiation Interval to re-irradiation Re-irradiated volume Re-irradiation toxicity Dysphagia abstract Objective: To identify predictive factors of severe long-term toxicity after re-irradiation of recurrent/per- sistent or second-primary head and neck cancer. Methods: Outcomes and treatment plans of patients who underwent modern IMRT based re-irradiation to the head and neck from 2008–2015 were reviewed. Co-variables including demographic, clinical and oncologic factors, as well as interval to re-irradiation and re-irradiated planning tumor volume (PTV) were analyzed as predictors of developing severe (CTCAE grade P 3) long-term toxicity with death as a competing risk. Results: A total of 66 patients who met inclusion criteria were eligible for analysis. A median re- irradiation dose of 70 Gy was delivered at a median of 37.5 months after initial radiotherapy. Re- irradiation followed surgical resection in 25 (38%) patients, and concurrent chemotherapy was delivered to 41 (62%) patients. Median follow-up after re-irradiation was 23 months and median overall survival was 22 months (predicted 2 year overall survival 49%). Of the 60 patients who survived longer than 3 months after re-irradiation, 16 (25%) patients experienced severe long-term toxicity, with the majority (12 of 16) being feeding tube -dependent dysphagia. In multivariable analysis, shorter intervals to re- irradiation (<20 months) and larger re-irradiated PTVs (>100 cm 3 ) were independent predictors of devel- oping severe long-term toxicity. Patients with longer disease-free intervals and smaller PTVs had a 94% probability of being free of severe toxicity at two years. Conclusion: Selection of patients with longer re-irradiation intervals and requiring smaller re-irradiated PTVs can independently predict avoidance of severe long-term toxicity. Ó 2016 Elsevier Ltd. All rights reserved. Introduction Despite aggressive multimodality treatments involving a com- bination of surgery, radiation, and chemotherapy, a large subset of patients with head and neck squamous cell carcinoma (HNSCC) face the challenge of recurrent or second primary tumors that arise in tissues that have been previously irradiated. Locoregional recur- rences account for approximately half of failures in patients treated with definitive chemoradiation, though control rates are much higher in human papillomavirus (HPV)-positive oropharyngeal cancers [1,2]. However, given the traditional non-viral risk factors associated with HNSCC, patients without recurrent cancers still have an 18% risk of developing a second primary tumor [3]. Ulti- mately, locoregional tumor progression is a major source of severe morbidity and is the predominant cause of death in patients with head and neck cancer [4–6]. The preferred management of recurrent or second primary can- cers in previously irradiated tissue is surgical resection; however, a significant proportion of patients are not eligible for surgical resec- tion due to myriad patient and oncological variables [7]. Even in the subset of operable patients, outcomes with salvage surgery alone remain poor and disease-free survival is improved with adju- vant re-irradiation with or without concurrent chemotherapy in http://dx.doi.org/10.1016/j.oraloncology.2016.06.017 1368-8375/Ó 2016 Elsevier Ltd. All rights reserved. ⇑ Corresponding author at: 1500 East Medical Center Dr., Ann Arbor, MI 48109, United States. E-mail address: eisbruch@med.umich.edu (A. Eisbruch). 1 These authors contributed equally to this manuscript. Oral Oncology 60 (2016) 32–40 Contents lists available at ScienceDirect Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology