A clinical report published in 1999, the RTOG (Radiation Therapy Oncology Group) 85-01 trial involving 134 patients with T1-3, N0-1 and M0 esophageal cancer, is of great interest in terms of clinical outcome because it demonstrated a 5-year survival rate of 26% [
1]. This treatment consists of infusions of 5-fluorouracil (5-FU) and cisplatin (CDDP), and concurrent radiation, without pre- or post-surgical resection. Simultaneously in Japan, a modified version was proposed by Ohtsu and his co-workers for advanced metastatic esophageal cancer [
2,
3]. Two independent clinical investigations have shown curative potential using this regimen for unresectable esophageal squamous cell carcinoma (ESCC) of T4 or M1a [
2,
3]. A long-term evaluation of efficacy and toxicity with 139 patients revealed a complete response (CR) rate of 56%, along with a 5-year survival rate of 29% [
4,
5]. Currently, definitive 5-FU/CDDP-based chemoradiotherapy is recognized as one of the most promising treatments for esophageal cancer [
6]. A series of studies performed to find a marker predictive of clinical outcome after treatment with a definitive 5-FU/CDDP-based chemoradiotherapy found a genetic polymorphism, G-1154A, of vascular endothelial growth factor to be a predictor of severe acute leukopenia and cheilitis, and the plasma concentration of 5-FU to be predictive of clinical response [
7‐
9].
Tumor necrosis factor (TNF)-α, a proinflammatory cytokine, plays a key role in the pathogenesis of inflammatory diseases. Its biological effects are elicited by binding to its two cognate cell surface receptors, TNFRSF1A/TNFR1 (p55/60) and TNFRSF1B/TNFR2 (p75/80), both of which are involved in increasing expression of other cytokines and immuno-regulatory molecules through the activation of nuclear factor κB. Through extensive examinations of expression and function, some genetic variations have been shown to explain inter-individual variation. Single nucleotide polymorphisms (SNPs) in the
TNF-α,
TNFRSF1A and
TNFRSF1B genes have been identified, however functional data pertaining to these polymorphisms in scarce. Nonetheless, the putative role of these polymorphisms in disease susceptibility has been examined in genetic association studies of various inflammatory disorders, including Crohn's disease [
10‐
13], ulcerative colitis [
10,
11,
14], systemic lupus erythematosus [
15‐
17] and rheumatoid arthritis [
18,
19]. More recently, given that cancer progression is preceded by a long period of subclinical inflammation [
20‐
22], the genetic polymorphisms of
TNF-α,
TNFRSF1A and
TNFRSF1B have been examined in terms of susceptibility to various cancers [
23‐
28]. In this study, genetic polymorphisms of the
TNFRSF1B gene, M196R/T587G, A1466G and C1493T, were evaluated in Japanese ESCC patients treated with a definitive 5-FU/CDDP-based chemoradiotherapy, and their predictive values of prognosis or severe acute toxicities were assessed. To our knowledge, this is the first paper to report that the
TNFRSF1B genotype is predictive of the clinical efficacy of cancer chemoradiotherapy.