Tracheoesophageal Fistula Development and Concurrent Chemoradiation and Bevacizumab in Non—Small-Cell Lung Cancer

Abstract

BackgroundWe previously reported the development of tracheoesophageal (TE) fistulae in patients with small-cell lung cancer (SCLC) treated with chemoradiation and concurrent and sequential bevacizumab (J Clin Oncol 2008; 26(15 suppl):410s [Abstract 7554]). In this phase II trial, we evaluated concurrent chemoradiation and bevacizumab in patients with unresectable stage III non—small-cell lung cancer (NSCLC) and observed similar fistula development. Patients and MethodsThis was a phase II trial designed to enroll 50 patients, with a primary aim of achieving a 40% improvement in historical 10-month median time to progression (α, .05; β, .20). Patients with newly diagnosed unresectable nonsquamous stage III NSCLC, measurable disease, Eastern Cooperative Oncology Group performance status 0/1, signed informed consent, and no pleural or pericardial effusions were eligible. Hemoptysis or need for anticoagulation were exclusion factors. Treatment was composed of induction, consolidation, and maintenance phases. Induction treatment included carboplatin area under the curve (AUC) = 5 intravenous (I.V.), pemetrexed 500 mg/m2 I.V., and bevacizumab 15 mg/kg I.V. weeks 1 and 4. Radiation was administered concurrently 1.8 Gy per day to 61.2 Gy. After a break in therapy from weeks 8 to 16, consolidative therapy commenced and included carboplatin AUC = 6 I.V., pemetrexed 500 mg/m2 I.V., and bevacizumab 15 mg/kg I.V. weeks 16, 19, and 22. Maintenance therapy was composed of bevacizumab 15 mg/kg every 3 weeks for 9 cycles. Patients were restaged after induction and consolidation phases (per Response Evaluation Criteria in Solid Tumors). ResultsEnrollment was staggered in groups of 5 for safety monitoring beginning in February 2007. Among the first 5 patients, 2 patients developed TE fistulae. Patient 1 developed a TE fistula 34 weeks into therapy (during the fourth maintenance bevacizumab and 26 weeks after chemoradiation). Patient 2 developed a TE fistula 40 weeks into therapy (during the sixth maintenance bevacizumab and 32 weeks after chemoradiation). Both patients experienced antecedent severe esophagitis. Both patients were managed with stents and are alive. The other 3 patients have not developed TE fistulae to date and are alive. The trial was subsequently closed for safety in December 2007. ConclusionTE fistula development has occurred in both SCLC and NSCLC trials where chemotherapy, bevacizumab, and radiation were administered. Strategies to safely incorporate novel therapies into standard chemoradiation lung cancer regimens are needed.