Zi-Liang Yang,1,* Yi-Xiang Gan,1,* Jing-Xuan Xu,2,* Yu-Hao Tang,1 Li-Ying Ouyang,3 Lu-Nan Qi,2,* Li Xu1,* 

1Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, People’s Republic of China; 2Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, People’s Republic of China; 3Intensive Care Unit, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Li Xu, Department of Liver Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, 651 E. Dongfeng Road, Guangzhou, 510060, People’s Republic of China, Tel +86 20-87343115, Fax +86 20-87343585, Email xuli@sysucc.org.cn

Background: While hepatectomy is the major curative treatment of hepatocellular carcinoma (HCC), high relapsing rates were observed. Of note, quite a few cases of tumor relapses were characterized by very quick appearance and disseminated lesions. This study aims to identify a special pattern of tumor relapse and to evaluate the prognostic significance of it for HCC patients after curative hepatectomy.
Methods: Medical records of HCC patients who underwent curative hepatectomy from January 1st 2018 to December 31st 2019 at Sun Yat-sen University Cancer Center (SYSUCC) were reviewed. Patients (n = 217) identified with tumor relapse during follow-up were included for analyses. Hyper-relapse disease (HRD) is defined as tumor relapse within 6 months from surgery, multiple intrahepatic lesions, as well as macrovascular invasion and/or extrahepatic metastasis. Kaplan–Meier method and Cox regression model were used to analyze overall survival (OS). Risk factors for HRD were explored using logistic regression analysis. External validation was performed using data from another center (n = 270).
Results: In SYSUCC cohort, 66 (30%) encountered HRD, 118 (54%) had non-HRD early recurrence (ER), and 33 (16%) had late recurrence (LR). The HRD group had shorter OS than the non-HRD ER and the LR groups (P < 0.001). COX analysis identified HRD and PIVKA-II > 1000 mAU/mL as risk factors of poorer OS. Intriguingly, local therapy (HR [95% CI]: 0.528 [0.290– 0.961]) was associated with better OS in contrast to systemic therapies (HR [95% CI]: 1.120 [0.596– 2.107]) after tumor relapse (p = 0.001). Logistic regression analysis identified microvascular invasion and HBV infection as independent factors associated with HRD. The worse outcome of the HRD group was validated in the external cohort, compared with the non-HRD ER group (P < 0.001).
Conclusion: HRD is a special pattern of HCC relapse with poor prognosis after curative hepatectomy. Appropriate local therapy might improve patient survival after tumor relapse.

Keywords: hyper-relapse disease, HRD, hepatocellular carcinoma, HCC, curative hepatectomy, prognosis