Therapeutic outcome and related predictors of stereotactic body radiotherapy for small liver-confined HCC: a systematic review and meta-analysis of observational studies
Authors: Long Yanyan , Liang Yan , Li Shujie , Guo Jing , Wang Ying , Luo Yan , Wu Yongzhong 
Published: April 2021

Abstract
Background and purpose
Stereotactic body radiotherapy (SBRT) is a promising ablative modality for hepatocellular carcinoma (HCC) especially for those with small-sized or early-stage tumors. This study aimed to synthesize available data to evaluate efficacy and explore related predictors of SBRT for small liver-confined HCC (≤ 3 lesions with longest diameter ≤ 6 cm).

Materials and methods
A systematic search were performed of the PubMed and Cochrane Library databases. Primary endpoints were overall survival (OS) and local control (LC) of small HCC treated with SBRT, meanwhile, to evaluate clinical parameters associated with treatment outcome by two methods including subgroup comparisons and pooled HR meta-analysis. The secondary endpoint was treatment toxicity.

Results
After a comprehensive database review, 14 observational studies with 1238 HCC patients received SBRT were included. Pooled 1-year and 3-year OS rates were 93.0% (95% confidence interval [CI] 88.0–96.0%) and 72.0% (95% CI 62.0–79.0%), respectively. Pooled 1-year and 3-year LC rates were 96.0% (95% CI 91.0–98.0%) and 91.0% (95% CI 85.0–95.0%), respectively. Subgroup comparisons regarding Child–Pugh class (stratified by CP-A percentage 100%, 75–100%, 50–75%) showed there were statistically significant differences for both 1-year and 3-year OS rate (p < 0.01), while that regarding number of lesions, pretreatment situation, age (median/mean age of 65), macrovascular invasion, tumor size, and radiation dose (median BED10 of 100 Gy), there were no differences. In subgroup comparisons for LC rate, it showed number of lesions (1 lesion vs. 2–3 lesions) was significantly associated with 1-year LC rate (p = 0.04), though not associated with 3-year LC rate (p = 0.72). In subgroup comparisons categorized by other factors including pretreatment situation, age, CP-A percentage, macrovascular invasion, tumor size, and radiation dose, there were no significant differences for 1- or 3-year LC rate. To further explore the association between CP class and OS, the second method was applied by combining HR and 95% CIs. Results indicated CP-A was predictive of better OS (p = 0.001) with pooled HR 0.31 (95% CIs 0.11–0.88), which was consistent with subgroup comparison results. Concerning adverse effect of SBRT, pooled rates of grade ≥ 3 hepatic complications and RILD were 4.0% (95% CI 2.0–8.0%) and 14.7% (95% CI 7.4–24.7%), respectively.

Conclusion
The study showed that SBRT was a potent local treatment for small liver-confined HCC conferring excellent OS and LC persisting up to 3 years, even though parts of included patients were pretreated or with macrovascular invasion. CP-A class was a significant predictor of optimal OS, while number of lesions might affect short term tumor control (1-year LC). Tumor size and radiation dose were not vital factors impacting treatment outcome for such small-sized HCC patients. Because of the low quality of observational studies and heterogeneous groups of patients treated with SBRT, further clinical trials should be prospectively investigated in large sample sizes.