Correlation between chemotherapy in hepatocellular carcinoma and the risk of second primary malignancies

• HCC chemotherapy lowers the risk of solid second primary malignancies. • Risks for subsequent HCC, lung, and colorectal cancers are reduced. • Advanced stage, higher grade, and older age elevate the risk of SPMs Treatments for hepatocellular carcinoma (HCC) currently include surgery, chemotherapy, interventional therapy, and immunotherapy. Recent investigations suggest that chemotherapy for certain malignancies may be linked to a higher risk of second primary malignancies (SPMs). However, the correlation between HCC chemotherapy and the risk of SPMs remains unclarified. This retrospective cohort study enrolled first-primary HCC cases utilizing data from the Surveillance, Epidemiology, and End Results (SEER) database. Multivariate logistic regression and Fine-Gray’s competing risk regression analyses were performed to calculate the cumulative incidence and relative risk (RR) of developing SPMs. We evaluated 9,983 two-year HCC survivors and 4,506 five-year HCC survivors. During follow-up, 69 patients developed second primary hematological malignancies (SPHMs) and 289 developed second primary solid malignancies (SPSMs). Patients receiving chemotherapy showed a significantly lower cumulative incidence of all SPSMs (HR = 0.70; p = 0.004) compared to those who did not receive chemotherapy. Specifically, chemotherapy was associated with a decreased risk of second primary HCC (RR = 0.47), lung cancer (RR = 0.36), and colorectal cancer (RR = 0.65). Stratified sensitivity analyses confirmed this inverse association remained robust across all evaluated demographic and clinical subgroups. Subgroup analyses indicated that patients over 60, unmarried individuals, and those with higher tumor grades, advanced stages, or prior radiotherapy had an elevated risk of developing SPSMs. Chemotherapy in HCC patients is correlated with a decreased incidence of SPSMs, specifically subsequent HCC, lung cancer, and colorectal cancer. Further translational studies are required to explore the underlying biological mechanisms.