CASE REPORT Peter Andersen, MD, Section Editor Inflammatory vocal fold lesions associated with angiogenesis inhibition Dana M. Hartl, MD, PhD, 1* Erika Saavedra, MD, 2 Antoine Hollebecque, MD, 2 Rastilav Bahleda, MD, 2 Jacques Bosq, MD, 3 Christophe Massard, MD, 2 Jean–Charles Soria, MD, PhD, 2 1 Department of Head and Neck Oncology, Institut de Canc erologie Gustave Roussy, Villejuif, France, 2 D epartement des Innovations Th erapeutiques Pr  ecoces (DITEP), Institut de Canc erologie Gustave Roussy, Villejuif, France, 3 Department of Pathology, Institut de Canc erologie Gustave Roussy, Villejuif, France. Accepted 31 October 2013 Published online 10 March 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/hed.23550 ABSTRACT: Background. The vascular side effects of angiogenesis inhibitors are well known, but laryngeal effects are not widely reported. We report the first 5 cases, to our knowledge, of objective vocal fold lesions attributable to these therapies. Methods. Four patients treated with bevacizumab-paclitaxel or bevacizumab for metastatic breast or lung cancer and 1 patient treated with a pan-fibroblast growth factor receptor (FGFR) inhibi- tor presented with spontaneous dysphonia without other etiologic factors. Results. In all cases, we observed a well-limited mucosal lesion on the superior surface of the anterior portion both vocal folds, symmetrical, sparing the anterior commissure and the vocal process. Histopathology showed necrosis and inflammation. After discontinuation of treatment in 3 patients, their voices improved, but with persistent inflammation in 2 patients and vocal fold scarring in 1 patient. Conclusion. Clinicians should systematically perform laryngoscopy in case of dysphonia in patients treated with angiogenesis inhibitors in order to diagnose laryngeal lesions and rule out differential diagnoses. V C 2014 Wiley Periodicals, Inc. Head Neck 36: E81–E85, 2014 KEY WORDS: angiogenesis inhibitors, bevacizumab, dysphonia, vocal folds INTRODUCTION Blocking the tumor blood supply is a main goal in many modern cancer therapies. Inhibition of angiogenesis can be obtained by blocking the vascular endothelial growth factor (VEGF) pathway using monoclonal antibodies or small molecule tyrosine kinase inhibitors. One of the most well-known drugs, first approved by the American Food and Drug Administration in 2004, is bevacizumab, a humanized monoclonal antibody binding to VEGF-A, and shown to be effective to inhibit growth of many solid tumors, alone or in combination with conventional chemotherapy. Approved tyrosine kinase inhibitors tar- geting the VEGF receptors (VEGFR) include sunitinib, sorfenib, pazopanib, and vandetanib. Inhibition of the fibroblast growth factor, platelet-derived growth factor, and mammalian target of rapamycin pathways also inhibits angiogenesis. 1 Many of these new drugs alone or in combination are under investigation in clinical trials. Vascular-related side effects of these treatments — hypertension, thromboembolism, and bleeding — are often reported, and, if severe, may require withholding treatment or reducing doses. 2 For many of these drugs, dysphonia is also often reported, and, although not life- threatening, may contribute to a decrease in quality of life in these patients. However, the clinical aspects, natu- ral history, and pathophysiology of dysphonia because of angiogenesis inhibition are currently unknown. We previously reported the clinical appearance, voice handicap index, and acoustic measurements in 5 patients with dysphonia associated with VEGF inhibition 3 and, more recently, the first case of spontaneous vocal fold necrosis in a patient treated with bevacizumab and pacli- taxel. 4 This study is a report of the first 5 cases, to the best of our knowledge, of spontaneous vocal fold lesions observed in patients treated with bevacizumab. We herein describe the clinical aspects and natural history, with hypotheses as to the mechanism of this toxicity. CASE REPORTS Patients with advanced metastatic cancer treated with angiogenesis inhibitors and presenting with recent-onset dysphonia were referred for laryngoscopy. Patients with dysphonia because of recurrent nerve paralysis caused by a tumor in the neck or mediastinum were excluded from our study. Patients with similar, unexplained, clinically visible lesions of the vocal folds were retained for this study. Five patients were included in the present report because of the similarity of aspects of the vocal folds and are presented in chronological order (Table 1). Institu- tional approval was obtained and informed consent was provided by all patients. *Corresponding author: D. M. Hartl, Department of Head and Neck Oncology, Otolaryngology, Head and Neck Surgery, Institut Gustave Roussy, 114 rue Edouard Vaillant, 94805 Villejuif, France. E-mail: dana.hartl@gustaveroussy.fr This work was presented at the American Laryngological Association meeting, April 10–11, 2013, Orlando, Florida. HEAD & NECK—DOI 10.1002/HED SEPTEMBER 2014 E81