Chemoradiotherapy with extended nodal irradiation and/or erlotinib in locally advanced oesophageal squamous cell cancer: long-term update of a randomised phase 3 trial

Abstract

Background To report the long-term outcomes of a phase III trial designed to test two hypotheses: (1) elective nodal irradiation (ENI) is superior to conventional field irradiation (CFI), and (2) chemoradiotherapy plus erlotinib is superior to chemoradiotherapy in locally advanced oesophageal squamous cell cancer (ESCC). Methods Patients with locally advanced ESCC were randomly assigned (1:1:1:1 ratio) to one of the four groups: A: radiotherapy adoption of ENI with two cycles of concurrent TP chemotherapy (paclitaxel and cisplatin) plus erlotinib; B: radiotherapy adoption of ENI with two cycles of concurrent TP; C: radiotherapy adoption of CFI with two cycles of concurrent TP plus erlotinib and D: radiotherapy adoption of CFI with two cycles of concurrent TP. A total of 60 Gy of radiation doses was delivered over 30 fractions. We explored the impact of epidermal growth factor receptor (EGFR) expression on the efficacy of erlotinib plus chemoradiotherapy. Results A total of 352 patients (88 assigned to each treatment group) were enrolled. The 5-year survival rates were 44.9%, 34.8%, 33.8% and 19.6% in groups A, B, C and D, respectively (P = 0.013). ENI significantly improved OS compared with standard CFI (median, 38.5 vs 22.6 months; HR, 0.74; P = 0.018). The addition of erlotinib significantly improved OS (median, 39.4 vs 27.4 months; HR, 0.75; P = 0.025). Patients with overexpressing EGFR treated with erlotinib had a better OS and PFS than those without erlotinib. Conclusions Concurrent chemoradiotherapy with ENI and/or erlotinib improved long-term survival in locally advanced ESCC. Clinical trial registration Trial registration: NCT00686114.

Combining precision medicine and prophylaxis in oesophageal squamous cell carcinoma

“…7,8 These studies demonstrate the predictive impact of EGFR gene copy number gain (CNG), or high EGFR protein expression. 7,8 The new findings presented by Xie et al 5 extend this important observation, demonstrating that only patients with high EGFR expression (immunohistochemical [IHC] score +2, +3) appear to benefit from the addition of erlotinib to dCRT (median OS in erlotinib treated for EGFR IHC +2/3 vs. 0/+1, is 46.5 vs. 9.5 months; P = 0.007). The magnitude of benefit is striking.…”

“…In this issue of the British Journal of Cancer, Xie et al 5 report a Phase 3 randomised controlled trial (RCT) with a 2 × 2 factorial design investigating whether prophylactic elective nodal irradiation (ENI) dCRT is superior to conventional field irradiation (CFI) and whether dCRT plus the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib, is superior to dCRT alone. ENI includes the uninvolved lymph nodes in the treatment field, which are at risk for micrometastatic disease, while CFI includes only the metastatic nodes.…”

“…EGFR has an established role in ESCC pathogenesis and EGFR inhibitors can reverse the radioresistance of oesophageal cancer cells. In this article, 5 the authors provide a follow-up report on long-term outcomes, and importantly the results of a predictive biomarker analysis. They show that the early outcome benefits for ENI and erlotinib have been sustained.…”

“…The reported 5-year survival of 19.6% for CFI dCRT without erlotinib is entirely consistent with expectations, while 5-year OS of 44.9% for prophylactic ENI dCRT plus erlotinib represents an impressive incremental gain. Importantly, Xie et al 5 also provide reassurance regarding the late toxicity of ENI (plus erlotinib).…”

“…Taken together, these trials suggest therapeutic value for anti-EGFR treatments in ESCC that are EGFR IHC and/or EGFR CNG positive. However, even with appropriate biomarker selection, clinical resistance to anti-EGFR monotherapy in advanced stage ESCC (and OAC) often emerges rapidly, 7,8 which suggests that combination treatments with EGFR inhibitors are likely to be important for meaningful clinical benefit -in this context, the positive findings by Xie et al 5 with erlotinib added to dCRT take on greater significance.…”