Radiation-induced lymphopenia is associated with survival in patients with hepatocellular carcinoma treated with stereotactic body radiotherapy.

[BACKGROUND & AIMS] Stereotactic body radiotherapy (SBRT) is increasingly used in the treatment of hepatocellular carcinoma (HCC). Severe radiation-induced lymphopenia (RIL) occurs in 30% to 40% of patients undergoing conventional fractionated radiotherapy and is associated with worse survival. However, the incidence of RIL and its effect on survival in patients with HCC treated with SBRT remain unclear.

[METHODS] This is a retrospective study of patients with HCC treated with SBRT in a tertiary cancer center in Hong Kong between January 2013 to December 2023. Patient and tumor characteristics were reviewed. Pre- and post-SBRT lymphocyte counts were collected. Severe RIL is defined as an absolute lymphocyte count <0.5x10/L. Survival analysis was conducted to assess the impact of severe RIL. Logistic regression was performed to identify factors associated with occurrence of severe RIL.

[RESULTS] A total of 147 patients were included. Most patients had BCLC stage 0/A disease (64.5%), and the median tumor size was 2.6 cm (range, 0.5-11.4 cm). Severe RIL was observed in 17 (13.5%) patients following SBRT. Severe RIL was associated with shorter median progression-free survival (8.0 vs. 9.9 months; p = 0.029) and overall survival (18.5 vs. 33.0 months; p <0.001). Larger low-dose irradiated liver volumes were associated with severe RIL (per 10-cc increase in V5: odds ratio [OR], 1.02; p = 0.04; per 10-cc increase in V10: OR, 1.03; p = 0.03), as was the presence of portal hypertension (OR, 3.68; p = 0.03).

[CONCLUSIONS] Development of severe RIL in patients with HCC after SBRT is associated with poor survival. Minimizing low-dose radiation exposure to the liver is essential to reduce the risk of severe RIL.

[IMPACT AND IMPLICATIONS] Radiotherapy is an effective treatment for hepatocellular carcinoma (HCC) and is increasingly utilized across all disease stages. Radiation-induced lymphopenia (RIL) is associated with poor survival in many cancers but remains underexplored in HCC. The advent of stereotactic body radiotherapy enables highly precise radiation delivery, reducing toxicity, including RIL. In this study, we demonstrated that the incidence of severe RIL occurred significantly less frequently with stereotactic body radiotherapy than conventional fractionated radiotherapy in patients with HCC. We confirmed RIL as an independent predictor of inferior survival. We identified patients with portal hypertension, and those receiving larger low-dose liver irradiation volumes were at significantly higher risk of developing RIL. These results may guide clinicians in optimizing patient selection for radiotherapy and support the preferential use of advanced planning techniques in high-risk individuals to minimize RIL, potentially improving clinical outcomes.