Beyond BCLC and AFP : A Circulating IL ‐6/ IL ‐8 Inflammatory Signature Refines Survival Prediction in Hepatocellular Carcinoma

Prognostic assessment in hepatocellular carcinoma (HCC) primarily relies on clinical staging integrating tumour burden, liver function, and performance status; circulating cytokines may capture complementary tumour‐host biology. To assess whether cytokines measured at diagnosis were associated with overall survival (OS) and improved prognostic stratification beyond AFP and BCLC, we retrospectively analysed 656 consecutive adults with HCC (median age 67 [IQR 59–75] years; 516 men, 78.7%). Viral liver disease predominated ( n = 432, 65.9%). BCLC stage was 0/A/B/C in 101 (15.4%)/301 (45.9%)/151 (23.0%)/103 (15.7%); BCLC D was excluded. Serum GM‐CSF, IFN‐γ, IL‐2, IL‐4, IL‐6, IL‐8, IL‐10, and TNF‐α were measured at diagnosis using Bio‐Plex 200 bead‐based multiplex immunoassay (Luminex xMAP technology). The primary endpoint was OS. Overall, IL‐6 and IL‐8 levels increased across BCLC stages and were the only cytokines significantly associated with OS (IL‐6: HR = 1.12, p < 0.001; IL‐8: HR = 1.14, p < 0.001). Using previously published cut‐offs, IL‐6 > 4.28 pg/mL (aHR = 2.01, p < 0.001) and IL‐8 > 17.60 pg/mL (aHR = 1.35, p = 0.033) were significantly associated with OS independently from age, sex, AFP > 400 ng/mL, BCLC stage, and HCC treatment. The combination of IL‐6/IL‐8 was able to stratify patients into low‐risk (neither cytokine elevated; n = 358), intermediate‐risk (one elevated; n = 155), and high‐risk (both elevated; n = 143) groups, with median OS of 53.0, 28.7, and 20.5 months, respectively (log‐rank p < 0.001). The C‐index was 0.619 for IL‐6/IL‐8, 0.588 for AFP, 0.674 for BCLC, and 0.717 for the combined BCLC + AFP + IL‐6/IL‐8 model, which significantly improved model fit over BCLC + AFP alone ( p < 0.001). Time‐dependent AUCs for the combined model were 0.787, 0.755, 0.763, and 0.768 at 12, 24, 36, and 60 months, respectively. In conclusion, circulating IL‐6 and IL‐8 measured at HCC diagnosis define a simple inflammatory prognostic model independently associated with OS. When combined with BCLC and AFP, the IL‐6/IL‐8 score improves baseline prognostic discrimination and shows acceptable internal calibration.