Xiufeng Liu,1,* Lijun Zhuang,1,* Fan Yang,2,* Ping Liu,1,* Zhaojun Xia,1 Ying Guo,1 Pingping Dong,3 Chao Chen,1 Zixiong Li1 

1Department of Oncology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, People’s Republic of China; 2Department of Nephrology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, People’s Republic of China; 3Department of Ethics Committee, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Chao Chen, Email njjloncologycc@163.com Zixiong Li, Email lzx1989@126.com

Introduction: AFP positivity (≥ 20 ng/mL) is often used as one of the diagnostic criteria for HCC. The aim of this study is to analyze the prognosis of advanced HCC with negative (< 20 ng/mL) AFP at baseline following systemic drug treatment.
Methods: In this study, 91 patients with AFP-negative advanced HCC who received systemic drug treatment in Nanjing Jinling Hospital from February 2011 to September 2023 were collected, and 213 patients with AFP-positive advanced HCC were collected as the control group. A propensity score model was used to adjust for potential confounding variables. Cox regression analysis was used to clarify the differences of prognosis in subgroups for HCC patients.
Results: Following propensity score matching with 1:2 ratio, 90 HCC patients from Group A (AFP-negative) and 180 from Group B (AFP-positive) were chosen to participate in the final analysis set. The OS of AFP-negative HCC patients was extended by 13.5 months compared to AFP-positive HCC patients. Within the AFP-negative HCC group, the top-ranked first-line treatment options were TKIs combo ICIs (mPFS = 9.5m, mOS = 37.1m), chemotherapy combo ICIs (mPFS = 8.1m, mOS = 15.5m), and TKIs (mPFS = 5.6m, mOS = 28.2m). Subgroup analysis indicated that among AFP-negative HCC patients, those without PVTT or with HBV DNA < 50lU/mL had longer survival time. For HCC patients who opted for TKIs combo ICIs as their first-line treatment and then switched to TKIs alone for second-line treatment, the mOS and 95% CI were 30.7 (24.8-NA) months.
Conclusion: The survival time of AFP-negative HCC patients was significantly longer than that of AFP positive HCC patients. Patients with no PVTT or HBV DNA < 50lU/mL have relatively better efficacy of systemic drug therapy. With the AFP-negative HCC patients, TKIs combo ICIs are preferentially recommended for the first-line therapy, and TKIs are used for the second-line therapy after progression.

Keywords: hepatocellular carcinoma, alpha-fetoprotein, systemic anti-tumor therapy, immune checkpoint inhibitors, multi-line therapy