Phase I evaluation of TNFerade biologic plus chemoradiotherapy before esophagectomy for locally advanced resectable esophageal cancer.

Background: Neoadjuvant chemoradiotherapy followed by surgery is the primary treatment option for patients with locally advanced esophageal cancer. This multicenter phase I trial examined intratumoral injection of TNFerade biologic, an adenoviral vector that expresses the human tumor necrosis factor-α gene, with chemoradiotherapy in locally advanced esophageal cancer. Objectives: To assess pathologic complete response (pCR), time to disease progression, progression-free survival, survival, and safety and tolerance in patients treated with preoperative chemoradiation combined with endoscopy or EUS-guided intratumoral injection of TNFerade biologic. Design/Intervention: Five weekly injections of TNFerade biologic, dose-escalated logarithmically from 4 × 10⁸ to 4 × 10¹¹ particle units (PU), were given in combination with cisplatin 75 mg/m² and intravenous 5-fluorouracil 1000 mg/m²/d for 96 hours on days 1 and 29, and concurrent radiation therapy to 45 Gy. Surgery was performed 9 to 15 weeks after treatment. Setting: U.S. multicenter study. Patients: Patients with stage II and III esophageal cancer were enrolled. Main Outcome Measurements: Primary outcome measures were safety, feasibility, tolerability, and rate of pCR. Secondary outcome measures were overall survival (OS) and disease-free survival. Results: Twenty-four patients with a median age of 61 years were enrolled; 88% of the patients were men, 21% were stage II, and 79% were stage III. Six (29%) had a pCR, observed among 21 patients (20 who underwent esophagectomy and 1 at autopsy). Dose-limiting toxicities were not observed. The most frequent potentially related adverse events were fatigue (54%), fever (38%), nausea (29%), vomiting (21%), esophagitis (21%), and chills (21%). At the top dose of 4 × 10¹¹ PU, thromboembolic events developed in 5 of 8 patients. The median OS was 47.8 months. The 3- and 5-year OS rates and disease-free survival rates were 54% and 41% and 38% and 38%, respectively. Limitations: We included primarily adenocarcinoma. Conclusions: Preoperative TNFerade, in combination with chemoradiotherapy, is active and safe at doses up to 4 × 10¹⁰ PU and is associated with long survival. This regimen warrants additional studies. (Clinical trial registration number: NCT00051480.) [Copyright &y& Elsevier]