Tracheoesophageal Fistula Formation in Patients With Lung Cancer Treated With Chemoradiation and Bevacizumab

Abstract

PURPOSE Tracheoesophageal fistulae are rare complications of thoracic cancers and their treatments. Novel antiangiogenic agents in cancer treatment such as bevacizumab potentially impact wound healing and may contribute to tracheoesophageal fistula development. PATIENTS AND METHODS We conducted two independent phase II clinical trials in small-cell lung cancer and non-small-cell lung cancer using bevacizumab in combination with chemotherapy and radiation. Both trials were intended to assess preliminary efficacy and safety outcomes. Results For the limited-stage small-cell lung cancer trial, 29 patients were enrolled beginning April 2006, and closed early due to toxicity in March 2007 (14-month median follow-up). The locally advanced, non-small-cell lung cancer trial opened with enrollment limited to five patients in February 2007, and closed early due to safety in December 2007. In each trial, we observed tracheoesophageal fistulae development and related morbidity and mortality, prompting early trial closures, US Food and Drug Administration warnings, and a change in bevacizumab labeling. CONCLUSION The current data from the final reports from these two trials suggest bevacizumab and chemoradiotherapy are associated with a relatively high incidence of tracheoesophageal fistulae formation in both small-cell lung cancer and non-small-cell lung cancer settings. Strategies to safely incorporate novel antiangiogenic agents into combined-modality therapy in lung cancer are needed.

Novel Approaches of Chemoradiotherapy in Unresectable Stage IIIA and Stage IIIB Non-Small Cell Lung Cancer

“…However, the development of tracheoesophageal fistulae (Fig. 1) in two phase II trials led to early closure of the trials, U.S. Food and Drug Administration warnings, and a change in the bevacizumab package labeling [53]. Of the 25 patients enrolled in the two trials, suspected or confirmed tracheoesophageal fistulae were observed in five patients.…”

Limited-Stage Small Cell Lung Cancer: Current Chemoradiotherapy Treatment Paradigms

“…The progression-free and overall survival times were not longer in the overall study population, but in a subgroup analysis, patients with LS-SCLC who received vandetanib (n ϭ 23), versus placebo (n ϭ 23), experienced a longer overall survival time (hazard ratio, 0.45; p ϭ .07). A phase II trial investigated the combination of carboplatin, irinotecan, and bevacizumab in combination with TRT, and that trial was stopped early after two patients developed tracheoesophageal (TE) fistula and a third patient died from an aerodigestive hemorrhage [71]. Of note, the two patients developed TE fistula 2 and 5 months after completion of TRT.…”

Bronchial Necrosis Following Bevacizumab and Stereotactic Body Radiotherapy for Treatment of Metastatic Breast Cancer

“…Intrathoracic cavitation (not necessarily airway necrosis) after bevacizumab has been reported with a median time of 1.8 months (range 0.7-6.2 months) [3]. However case reports identifying airway necrosis and fistula formation, while sparse, appear to be reported in the range of 3 weeks to 10 months after bevacizumab therapy [4,[7][8][9]. The exact mechanism for this spontaneous hemorrhage/perforation remains unclear, but some propose impaired neovascularization and resultant dysfunctional wound healing.…”

“…Currently at least four reports have identified seven patients developing airway necrosis and intrathoracic fistula (esophageal, mediastinum, pleura) in the setting of bevacizumab and raditotherapy [4,[7][8][9]. Interesting all these reports involve patients with lung cancer.…”

“…Necrosis is described in association with radiotherapy [1,2] but has also recently been described in relation to chemotherapeutic agents utilized for lung cancer [3,4]. Bevacizumab is a recombinant humanized monoclonal antibody that inhibits vascular endothelial growth factor, thereby preventing angiogenesis and tumor growth.…”