Adjuvant Stereotactic Body Radiotherapy After Marginal Resection for Hepatocellular Carcinoma With Micro-Vascular Invasion: A Randomized Controlled Trial

Background: Marginal resection frequently occurred in hepatectomy for hepatocellular carcinoma (HCC), which led to increased local recurrence, especially among patients with microvascular invasion (MVI). Stereotactic body radiotherapy (SBRT) shows effective in tumor controlling, while limited research reported the efficacy of SBRT as adjuvant setting for HCC after surgery. We hypothesized existence of residual tumor cells or foci in unsafe margin parenchyma caused local recurrence in HCC patients with MVI, and SBRT might be a solution to resolve the problem. This study aimed to investigate the efficacy of SBRT targeting on the susceptible area with residue MVI as adjuvant setting for HCC patients. Methods: This was a single center, randomized controlled trial conducted in Eastern Hepatobiliary Surgery Hospital, Shanghai, China. Participants with HCC and MVI receiving marginal resection were randomly assigned to postoperative adjuvant SBRT group or surgery alone (SA) group. SBRT was delivered by the CyberKnife® system (Accuracy Inc., Sunnyvale) with marker tracking devices. Patients in SBRT group received SBRT targeting on the resection marginal parenchyma where MVI most likely occurred one month after surgery. The disease-free survival (DFS) and overall survival (OS) were compared between the groups and the adverse events (AE) in the SBRT group were monitored. This trial was registered with ClinicalTrials.gov, NCT04891874. Findings: A total of 76 participants were enrolled from August 1, 2015 to December 31, 2016, with 38 in each group. The 1-, 3-, and 5-year DFS rates were 92.1%, 65.8%, and 56.1% in the SBRT group, versus 76.3%, 36.8%, and 26.3% in the SA group, respectively (p=0.005). The 1-, 3-, and 5-year OS rates were 100%, 89.5%, and 75.0% in the SBRT group, versus 100.0%, 68.4%, and 53.7% in the SA group, respectively (p=0.053). The total dose of SBRT for each participant was 35Gy and the biological effective dose (BED) is 59.5 Gy. The overall incidence of radiotherapy related AE was 31.6% (12/38), and no grade 3 or higher grade AE developed. Fatigue was the most frequent AE. Interpretation: SBRT on resection marginal parenchyma provides a safe therapeutic modality of adjuvant setting in MVI-positive HCC participants without satisfying resection margin. It prevents local recurrence and improves disease-free survival. Further evidence is necessary to evaluate its long-term survival outcome. Clinical Trial Registration Details: This trial was registered with ClinicalTrials.gov, NCT04891874. Funding Information: This research has received funding from the ‘Clinical science and technology innovation project of Shenkang Hospital Development Center’ (SHDC12020104). Declaration of Interests: The authors disclose no conflicts. Ethics Approval Statement: Detailed information of the clinical protocol was explained to every participants and written informed consent were collected before randomization. This trial was approved by the Institutional Ethics Committee of Shanghai Eastern Hepatobiliary Surgery Hospital. The study protocol conformed to the principles of Declaration of Helsinki (1983).