This study included 207 advanced HCC patients receiving oral treatment with apatinib from December 2015 to September 2020 at Tianjin Medical University Cancer Institute and Hospital.
The inclusion criteria were as follows: ≥ 18 years old, ECOG PS score 0–2; clinically proven advanced HCC, ≥ 1 measurable lesions as defined by RECIST 1.1; BCLC stage B or C, Child–Pugh class A or B; previous HCC systemic therapy ≤ 1, life expectancy ≥ 12 weeks, bilirubin ≤ 3 mg/dl, AST and ALT ≤ 5 times the upper limit of normal value, serum creatinine ≤ 3.0 mg/dl or creatinine clearance ≥ 40 mL/min, urine protein ≤ 1 + , urine protein analysis ≥ 2 + , urine protein < 1000 mg/24 h, absolute neutrophil count ≥ 1.0*10^9/L, hemoglobin ≥ 10 g/dL, platelet ≥ 50*10^9/L; international normalization ratio ≤ 1.5, partial thromboplastin time ≤ 5 s above ULN.
The exclusion criteria were as follows: systemic anticancer therapy, local therapy or surgery within 28 days prior to entry into the study; ascites that were difficult to control; brain metastases with clinical signs or meningeal carcinogenesis; bleeding of esophageal or gastric varices within 3 months prior to the study; acute hepatitis; presence of progressive central nervous system disease; clinically significant bleeding or thrombotic events within 4 weeks prior to study registration; Child–Pugh class C.
This study was approved by the Medical Ethics Committee of the Tianjin Medical University Cancer Institute and Hospital (reference number bc2019090). The ethical review board considered that it was not necessary to obtain informed consent from the participants because this retrospective study anonymously processed all data.
The initial dose of oral apatinib was 500 mg/day or 250 mg/day. The three regimens of apatinib dose adjustment included 500 mg/day, 250 mg/day, and 250 mg/2 days. The dose of apatinib was reduced when grade 3/4 drug-related AEs occurred, and for patients who tolerated apatinib well, it was recommended to increase the dose. Treatment was discontinued when patients experienced unacceptable AEs, radiological progression defined by RECIST 1.1, or death.
Baseline assessment and tumor screening were performed within 21 days prior to apatinib treatment. Baseline and assessments were performed every 8–12 weeks, including physical examination, vital signs, ECOG PS assessment, electrocardiogram, and clinical and laboratory tests (AFP, liver function, and renal function). AEs were classified and ranked according to the National Cancer Institute General Terminology Standard (NCI-CTCAE v 4.0). A computed tomography or magnetic resonance imaging scan was performed every 8 weeks, and the tumor response was assessed according to RECIST 1.1.
We performed propensity score matching (PSM) to reduce the impact of potential confounding factors and biases. A multivariate logistic regression model including sex, age, performance status, Child–Pugh class (A or B), AFP level (AFP > 400 μg/L or AFP ≤ 400 μg/L), BCLC stage (B or C), initial apatinib dose (250 mg/day or 500 mg/day), previous history of hepatitis (no hepatitis, hepatitis B, hepatitis C), prior treatment-TACE (yes or no), vascular invasion (yes or no), and extrahepatic metastasis (yes or no) was used to calculate the propensity scores. Following the calculation result of propensity scores, the patients were matched using 1:1 nearest neighbor matching with a caliper distance set at 0.03. Before and after matching, the log-rank test was performed to compare the PFS and OS of groups with or without corresponding AEs. Univariate and multivariate analyses were performed using the Cox proportional hazard model to evaluate independent factors affecting OS and PFS. Kaplan–Meier survival analysis was performed to generate survival curves, progression-free survival curves and summary statistics. A Cox proportional hazards model was used to estimate the HR and 95% CI. A value of p < 0.05 was considered to be statistically significant. All statistical analyses in this study were performed with SPSS version 25.0 (IBM Corporation, Armonk, NY, USA).