Gastrointestinal (GI) toxicity is a common and costly side effect of chemoradiation and is frequently dose-limiting for treatment of oesophageal cancer. Interpatient variability in severity of toxicity indicates that risk markers exist and could be utilised to personalise treatment. Given that inflammation is an underlying tissue pathology in GI toxicity, immune activation may determine severity. As such, this study aimed to identify immune response genes as markers predictive of severe chemoradiation-induced GI toxicity in patients with oesophageal adenocarcinoma.
This was a multi-site, prospective study which recruited newly diagnosed patients with cancer of the oesophagus. RNA was extracted from whole blood collected prior to therapy, with 84 innate and adaptive immune response genes profiled using PCR array. GI toxicity was documented during the first cycle of chemoradiation and graded according to the NCI CTCAE v 4.0. Logistic regression was used to identify the greatest predictors of toxicity risk with regards to genes and other covariates.
Males diagnosed with oesophageal adenocarcinoma (N=19) and gastroesophageal junctional adenocarcinoma (N=10) were recruited between November 2009 and November 2014. All participants were treated with neoadjuvant or definitive chemoradiation consisting of cisplatin and 5-FU, and 2.5 Gy fractionated radiotherapy. Severe (grade 3) GI toxicity was experienced by 6/29 participants. Before correcting for false discovery rates, with univariate analysis there was significant up-regulation of 7 transcripts in this group compared to participants with no/mild toxicity, TLR6, IL1B, CD55, TLR8, TLR1, NLRC4 and TRAF6. Other covariates, including age, diagnosis, TNM stage, radiation dose, haemoglobin, and white cell counts were not significantly associated with toxicity.
These results indicate that pre-therapy expression of key mediators of inflammatory tissue damage may be up-regulated in peripheral blood of patients with an elevated risk of developing severe chemoradiation-induced GI toxicity.