BACKGROUND: Recombinant human lymphotoxin-a derivative (rhLT alpha-Da) is a lymphotoxin-a derivative that is missing 27 N-terminal amino acid residues. Previous studies indicated a benefit from the addition of rhLTa-Da to cisplatin-based treatment in patients with metastatic esophageal squamous cell carcinoma. The current study was conducted to evaluate the efficacy and safety of rhLTa-Da plus cisplatin and fluorouracil (PF) in patients with mESCC. METHODS: Patients from 15 centers in China were randomly assigned (1: 1: 1) to 3 arms (arm A, PF plus 10 mu g/m(2) daily rhLT alpha-Da; arm B, PF plus 20 mu g/m(2) daily rhLT alpha-Da; arm C, PF alone). The primary endpoints included progression-free survival (PFS) and the confirmed overall response rate (ORR). An exploratory analysis was performed to evaluate the role of serum tumor necrosis factor receptor II (TNFR II) in predicting the efficacy of rhLTa-Da. RESULTS: Between September 2010 and May 2013, 150 patients were enrolled. No significant differences in either PFS or ORR were observed between the 3 arms. However, in a small subset of patients who had low serum TNFR II levels, the median PFS was significantly longer for those in arm B than for these in other 2 arms (7.2 months [95% confidence interval, 5.1-8.6 months] for arm B vs 3.5 months [95% confidence interval, 1.7-5.5 months] for arm A [P = 5.022] and 4.0 months [95% confidence interval, 3.2-6.3 months] for arm C [P 5.027]). The addition of rhLTa-Da significantly increased the incidence of chills (P <.001). CONCLUSIONS: rhLT alpha-Da combined with the PF regimen failed to improve PFS and ORR in patients with mESCC, except in a small subset that had low serum TNFR II concentrations. (C) 2017 American Cancer Society.