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 × 10(8) to 4 × 10(11) particle units (PU), were given in combination with cisplatin 75 mg/m(2) and intravenous 5-fluorouracil 1000 mg/m(2)/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 × 10(11) 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 × 10(10) PU and is associated with long survival. This regimen warrants additional studies.