Concurrent Chemoradiotherapy with Extended Nodal Irradiation and/or Erlotinib in Locally Advanced Esophageal Squamous Cell Cancer: Long-Term Follow-Up of a Randomized Phase 3 Trial

Background: The outcome of patients with locally advanced esophageal squamous cell cancer (ESCC) remain poor. The aim of this study was to report the long-term outcomes in a randomized controlled multicentre phase III study evaluating extended nodal irradiation (ENI) and erlotinib in locally advanced ESCC. Methods: A 2x2 factorial design was used to test two hypotheses: (1) that ENI was superior to conventional field irradiation (CFI); (2) that chemoradiotherapy plus erlotinib was superior to chemoradiotherapy in patients with locally advanced ESCC. Patients with histologically confirmed locally advanced ESCC or medically inoperable disease were randomly assigned (ratio 1:1:1:1) to receive concurrent chemotherapy with ENI or CFI with or without erlotinib (150 mg per day during chemoradiotherapy). The primary end point was overall survival (OS). We have explored the impact of epidermal growth factor receptor (EGFR) expression on efficacy of erlotinib plus chemradiotherapy. Findings: A total of 352 patients (88 assigned to each treatment group) were enrolled. After a minimum follow-up of 5 years for surviving patients, the 5-year survival rate was 44·92%, 34·82%, 33·81% and 19·62% in group A, B, C and D (P = 0·013). The median OS was 49·97 months, 26·50 months, 23·83 months, and 20·87 months in group A, B, C and D. The radiation field-by-erlotinib interaction test was not significant for OS (HR, 0·96; P = 0·871) and progression-free-survival (PFS) (HR, 0·97; P = 0·908). The ENI significantly improved OS compared with the standard CFI (median, 38·53 v 22·60 months; HR, 0·74; P = 0·018). The addition of erlotinib significantly improved OS (median, 39·38 v 27·42 months; HR, 0·75; P = 0·025). The patients with ESCC over expressing EGFR treated by erlotinib had a better OS and PFS than patients without EGFR expression. Interpretation: Concurrent chemoradiotherapy with ENI and/or erlotinib still improved survival outcomes with long-term follow-up in locally advanced ESCC. ENI should be adopted in concurrent chemoradiotherapy for ESCC patients. The patients with ESCC over expressing EGFR could significantly benefit from the erlotinib plus chemoradiotherapy. Funding Statement: The authors state: No commercial support was provided for this study. Declaration of Interests: All authors declare no competing interests. Ethics Approval Statement: All patients provided written informed consent, and the study was approved by the institutional review board or independent ethics committee of each participating center.