Abstract
Hepatocellular carcinoma (HCC) treatments, including transarterial chemoembolization (TACE) and systemic therapies (tyrosine kinase inhibitors [TKIs]/immune checkpoint inhibitors [ICIs]) are linked to hypothyroidism. This study aims to elucidate the clinical significance of treatment-induced hypothyroidism within a real-world cohort. We enrolled 130 HCC patients with baseline thyroid function measurements, and stratified into two cohorts: TACE monotherapy (n = 50) or TACE combined with TKIs/ICIs (n = 80). Primary subclinical or obvious hypothyroidism patients have a serum thyroid-stimulating hormone (TSH) value exceeding the upper limit of the normal range (> 4.94 uIU/L) while thyroid free tetraiodothyronine levels are normal or low. Overall survival (OS) was evaluated via Kaplan-Meier and Cox proportional models. Mortality rate in the whole study population was 25% (13/52) in patients with hypothyroidism vs. 48.7% (38/78) in patients without hypothyroidism (P = 0.007). When using TACE combining TKIs and ICIs, the mortality rate of patients with hypothyroidism were less than that of patients without hypothyroidism (16% [4/25] vs. 50% [8/16], respectively; P = 0.02). For entire cohort, the median OS cutoff in patients with hypothyroidism reached 37.5 months, and median OS was 23.33 months in patients without hypothyroidism (P = 0.015). For patients treated with TACE combined with TKIs + ICIs, the median OS cutoff in patients with hypothyroidism was not reached. But it was longer than those without hypothyroidism where median OS was 22.54 months (P = 0.005). In univariate and multivariate analysis, cancer-specific mortality correlated with some factors including sex, drinking, and hypothyroidism in the whole population as well as subgroups received TACE only or combination. In all patients, after adjustment for confounding factors, drinking showed an increased risk of HCC mortality (HR: 1.94, 95% CI: 1.04-3.61, P = 0.038) versus nondrinkers. Additionally, smoking and higher Child-Pugh score marginally associated with HCC mortality at significance levels of P = 0.042 and P = 0.041, respectively. TACE combination therapy exhibited lower risk on HCC specific mortality than those treated by TACE monotherapy group (HR: 0.45, 95% CI: 0.26-0.82, P = 0.009) among all patients receiving these therapies. Hypothyroidism was inversely related to HCC mortality among the TACE combination patients' group (HR: 0.30, 95% CI: 0.13-0.68, P = 0.04). The result becomes more pronounced in HCCs also administered by TKIs and ICIs (HR: 0.14, 95% CI: 0.03-0.60, P = 0.009). Treatment-induced hypothyroidism is prevalent among HCC patients receiving TACE combined with TKIs/ICIs and is associated with improved survival, potentially reflecting immune activation. Further multinational studies are warranted to validate these observations across diverse ethnic populations and treatment protocols.