Effect of Perioperative Interleukin-6 and Tumor Necrosis Factor-α on Long-Term Outcomes in Locally Advanced Gastric Cancer: Results from the CLASS-01 Trial

Abstract

Background. Little is known about the relation between perioperative inflammatory changes and long-term survival in cancer patients. The aim of the study was to assess the association of perioperative serum interleukin-6 (IL6) and tumor necrosis factor-α (TNFα) levels with the 5-year overall survival in locally advanced gastric cancer. Methods. The 135 eligible patients in one center of Nanfang Hospital were retrieved from CLASS-01 trial (NCT01609309), an open-label, multicenter, randomized clinical noninferiority trial conducted at 14 centers in China. Serum IL6 and TNFα levels were tested before surgery, and on postoperative day (POD) 1, POD3, and POD5, respectively, referring to IL6_0, IL6_1, IL6_3, and IL6_5 and TNFα_0, TNFα_1, TNFα_3, and TNFα_5. Kaplan-Meier methods and COX models were used for survival analysis. Results. High levels of IL6_0 (≥3.67 pg/mL) and TNFα_0 (≥14.8 pg/mL) presented worse disease-free survival (DFS) ( $P=0.0057$ for IL6_0 and $P=0.0014$ for TNFα_0) and overall survival (OS) ( $P=0.0021$ for IL6_0 and $P=0.0019$ for TNFα_0). Both high IL6_0 and high IL6_5 levels indicated worse prognosis than other combinations ( $P=0.0045$ for DFS and $P=0.0022$ for OS). In multivariate analysis, both high IL6_0 and high IL6_5 levels were significantly associated with poor DFS ( $\text{HR}=4.29$ , 95% CI: 1.42-12.95, $P=0.01$ ) and OS ( $\text{HR}=4.11$ , 95% CI: 1.35-12.49, $P=0.013$ ) after adjustment of tumor stage and TNFα_0. Also, high IL6_5 level was identified as the independent-related factor for postoperative infectious complications ( $\text{OR}=2.69$ , 95% CI: 1.03-7.01, $P=0.043$ ). Conclusions. Perioperative high serum IL6 and TNFα levels are negatively associated with 5-year survival outcomes in patients with locally advanced gastric cancer, indicating the potential survival benefits from perioperative anti-inflammatory treatment.