As one of the most common malignancies with a poor prognosis, the incidence of liver cancer continues to increase (Siegel et al., 2021). Hepatocellular carcinoma (HCC) is a major type of primary liver cancer. HCC has become an important problem affecting human health and quality of life worldwide. In China, the hepatitis B virus (HBV) is a major risk factor for primary HCC; more than 80% of primary HCC patients are HBV hepatitis B surface antigen (HBsAg)‐positive (Kim et al., 2020). Besides HBV, high alpha fetoprotein (AFP), portal vein tumor thrombus (PVTT), and hepatitis C virus (HCV) also affect the prognosis of patients (Bruix et al., 2017a; Bruix et al., 20172018; Zheng et al., 2020a; Fu et al., 2020). Surgery is the preferred treatment for early primary liver cancer. Image-guided ablation, radiofrequency ablation, and microwave ablation are also applicated in the treatment of early HCC and the alternative treatment of surgery (Llovet et al., 2021). However, despite the best efforts to remove the tumor surgically, tumor recurrence still occurs in more than 50% of patients within 5 years of surgery (Heimbach et al., 2018). Outcomes of liver transplantation were considered superior than resection. However, organ shortage with prolonged waiting times plagued HCC patients, leading to tumour progression (Franssen et al., 2014). Radiotherapy can be used for HCC patients with different sizes and stages, particularly with small tumours not amenable to resection or transplantation. But radiotherapy only applied to selected patients (Wahl et al., 2016; Yang et al., 2019a). More research was needed to determine the best radiation modality and combination treatment options. Additionally, due to the insidious onset and insignificant early symptoms of HCC, most patients are diagnosed with advanced HCC. Transcatheter arterial chemoembolization (TACE) is mainly used in patients with unresectable HCC, and could effectively inhibit tumor progression (Burrel et al., 2012; Lencioni et al., 2016). However, TACE induces hypoxia in HCC tissues and increases the level of the pro-angiogenic factor, vascular endothelial growth factor (VEGF), in the remaining HCC tissues, leading to a significant neovascularization response and recurrence after treatment (Bergers et al., 2000). High VEGF receptor (VEGFR) expression promotes tumor nutrient supply, growth, metastasis, and recurrence, suggesting a poor prognosis. The previous monotherapy for first-line standard of care for patients with advanced and recurrent HCC are sorafenib and lenvatinib (Kudo et al., 2018; Benson et al., 2021). VEGF plays an important role in the occurrence and development of HCC; furthermore, drugs targeting VEGF and VEGF receptors have been used in patients with advanced HCC (Du et al., 2017). Attilizumab and antiangiogenic drugs bevacizumab have been recommended as first-line treatments for advanced HCC due to better efficacy ((Pawlik et al., 2004; Li et al., 2013; Nishikawa et al., 2013), (Pawlik et al., 2004; Li et al., 2013; Nishikawa et al., 2013). Sorafenib, a multitargeted tyrosine kinase inhibitor (TKI) and, previously, the only Food and Drug Administration (FDA)-approved, first-line-targeted drug for patients with advanced HCC (Llovet et al., 2008), extended overall survival (OS) by less than 3 months in some clinical trials (19). In the phase III randomized REFLECT trial, lenvatinib, s howed a median OS (mOS) of 13.6 months, compared with 12.3 months in the sorafenib group (Kudo et al., 2018). Based on the results, the FDA approved lenvatinib in 2018 as the first-line treatment of patients with unresectable HCC. Regorafenib, cabozantinib, and ramucirumab are recommended as second-line systemic therapies for HCC patients who have received sorafenib treatment according to the 2021 National Comprehensive Cancer Network® (NCCN) guidelines on hepatobiliary cancers (Benson et al., 2021). In addition, based on the phase Ib/II studies, three additional treatments, namely nivolumab, pembrolizumab and ipilimumab, have been approved by the FDA after first-line treatment with sorafenib (El-Khoueiry et al., 2017; Zhu et al., 2018; Yau et al., 2020). The latest CheckMate 459 study showed that first-line nivolumab treatment (16.4 months) did not significantly improve OS compared with sorafenib (14.7 months) (Yau et al., 2022). Nivolumab might be considered as an alternative therapeutic option for patients in whom TKIs and antiangiogenic drugs are contraindicated or have risks. However, many clinical studies have shown that a considerable number of patients with HCC are not sensitive to sorafenib, and the overall efficacy is far from satisfactory (Zhu et al., 2017; Xu et al., 2020). And current therapies would cause a variety of potential adverse reactions. Therefore, we still need to discover new effective and safe drugs for HCC treatment.

Apatinib, a novel TKI, inhibits the activity of VEGFR-2 tyrosine kinase in a highly selective manner, thereby inhibiting tumor growth by inhibiting tumor angiogenesis. Apatinib can inhibit tumor cell apoptosis and cell proliferation in vitro by blocking the VEGFR pathway and by inhibiting the growth of metastatic tumors in vivo (Li et al., 2018). Several clinical trials have shown that apatinib is effective in a variety of solid tumors. In China, apatinib is approved as a follow-up treatment for patients with advanced gastric adenocarcinoma or gastroesophageal junction adenocarcinoma that has progressed or relapsed after at least one round of seed system chemotherapy. In stage Ⅱ and Ⅲ studies, apatinib has been shown to be effective and safe in patients with gastric cancer (Zhang et al., 2017; Zheng et al., 2020b). A real world retrospective study by Zhang et al. (Zhang et al., 2017) showed that the efficacy and safety of apatinib were similar to the results of previous clinical trials. Apatinib therapy is beneficial and tolerable in patients with advanced gastric cancer who don’t respond to systemic therapy. In recent years, several studies have demonstrated its efficacy and safety in HCC, especially in patients insensitive to sorafenib (Liao et al., 2019). Apatinib increases radiosensitivity of HCC and decreases tumor growth via the suppression of the radiation-induced PI3K/AKT pathway. Additionally, combination immunization or TACE with apatinib also show good efficacy (Xu et al., 2021). TACE therapy creates an anoxic environment for the tumor, inducing high VEGFR expression and angiogenesis; this was the target attacked by apatinib. Therefore, in clinical treatment, physicians can develop an appropriate treatment combination and treatment dose based on the patient’s condition. Apatinib has been used in the treatment of advanced HCC, but its efficacy and combination therapy have not been systematically evaluated. To evaluate the efficacy and safety of apatinib in the real world, we retrospectively analyzed 178 patients with advanced HCC who had received apatinib from 2017 to 2020, and determined the influencing factors for progression-free survival (PFS) and OS. The results of this study provided a theoretical basis for the application of apatinib in patients with advanced HCC.

HCC is the third leading cause of cancer death worldwide (1). Most patients with HCC are diagnosed with advanced cancer with intrahepatic or distant metastases. Multiple clinical trials have demonstrated the potential survival benefit of apatinib as first- or second-line treatment for patients with advanced HCC (Qin, 2014; Qin et al., 2021). Combinations of other antitumor therapies, including radiotherapy, immunotherapy, and TACE, can increase this survival benefit (28, 29). In this retrospective study, we investigated the safety and efficacy of apatinib in patients with advanced HCC in the real world. The mPFS and mOS of the 178 patients were 7.0 and 16.0 months, respectively. The mOS in this study was significantly higher than that of sorafenib in patients with refractory advanced HCC, as reported in previous studies (Llovet et al., 2008; Cheng et al., 2009; Bruix et al., 2012). The IMbrave150 trial showed that the mPFS in the atezolizumab plus bevacizumab group was 6.8 months, and in the sorafenib group, it was 4.3 months (Finn et al., 2020). In our study, the mPFS of apatinib monotherapy was 4.4 months, close to that of sorafenib. In the case of combined immunotherapy, mPFS reached 8.0 months, even more than atezolizumab plus bevacizumab. The mPFS was 5.7 and 5.5 months for first- and second-line treatment of unresectable HCC with apatinib in combination with camrelizumab in the RESCUE trial (29). In our study, the immune checkpoint inhibitors in immunotherapy combinated apatinib included not only camrelizumab but also other drugs such as durvalumab, which may be responsible for the longer mPFS. In the RESORCE trial, regorafenib provided an OS of 10.6 months for patients with sorafenib progression, compared with a mOS of 8.7 months for apatinib monotherapy in our study, which was close to the efficacy of regorafenib monotherapy (Bruix et al., 2017b). The overall mPFS and mOS were significantly longer than those found in other retrospective studies involving apatinib (mPFS: 7.0 vs. 5.0 months; mOS: 16.0 vs. 13.0 months), especially as a second-line treatment; this may be due to the combination with immunotherapy (mOS: 14.0 months; mPFS: 8.0 months) or TACE (mOS: 20.0 months; mPFS: 11.0 months) in some patients in this study (Zhen et al., 2018; Qin et al., 2021). In a recent single-center retrospective study about unresectable HCC, apatinib plus camrelizumab demonstrated the mOS of 13.1 months, which was similar to our results (14.0 months) (Ju et al., 2021). Similar to other studies, apatinib combined with TACE significantly improved mPFS and mOS. In a study of combination of TACE and apatinib for the treatment of HCC,the mOS and mPFS in the combination group were only 10.0 and 5.5 months, lower than the 20.0 and 11.0 months in our study (Liu et al., 2021). In their study, most HCC was accompanied by vascular invasion or distant metastasis, which were the important factors impairing the prognosis of patients (Yang et al., 2019b). The promising efficacy of apatinib may be due to its ability to selectively target VEGFR-2 and a higher binding affinity than sorafenib. TACE induces hypoxia in HCC tissues and increases the level of VEGF in the remaining HCC tissues, leading to a significant neovascularization response (Tian et al., 2011). Therefore, the combination of apatinib and TACE can improve the efficacy.

In univariate analysis, there were no significant differences in mPFS and mOS between patients with different ages, sex, drug dose, Child–Pugh class, smoking or drinking history, and HBV/HCV status. Patients with ECOG score 0–1 had a longer mPFS than those with ECOG score 2, but the results were not statistically significant; meanwhile, different ECOG scores had a significant impact on mOS. HBV/HCV infection and drinking showed no influence on patients’ survival, which may be because viral infection and alcohol consumption are the pathogenic factors of HCC, and antiviral therapy and alcohol abstention are carried out after the diagnosis of HCC (Chong et al., 2015). The effect of HBV/HCV on the prognosis of HCC patients may be related to the treatment mode, and the current research is controversial (Papatheodoridi et al., 2021).It has been reported that in a population of HCC patients undergoing surgical resection, the presence or absence of HBV/HCV infection has no effect on patient prognosis (Pawlik et al., 2004; Li et al., 2013; Nishikawa et al., 2013). This result was interpreted as tumors in patients with HBV/HCV infection were more likely to form an envelope, limiting tumor growth (Pawlik et al., 2004; Li et al., 2013; Nishikawa et al., 2013). Previous studies have also shown that the presence of HBV/HCV in patients with advanced HCC does not adversely affect the efficacy of apatinib or sorafenib, but may even be beneficial to it (3). 60–90% of HCCs develop in persons with basic liver disease, which may lead persons to stop consuming alcohol and smoking, and may bias the true association (Turati et al., 2014; Petrick et al., 2018). Since only 4 patients received the 500 mg dose, with no significant survival difference, they were excluded from the multivariate analysis to avoid bias. In this retrospective study, AFP, PVTT, and combination therapy were identified as independent prognostic factors for OS, while line of apatinib, PVTT, and combination therapy were independent prognostic factors for PFS.

Among all patients, mPFS was significantly longer in first-line and second-line treatment patients than in third-line treatment patients, suggesting that earlier application of apatinib for HCC may lead to better survival (Qin, 2014). In the 28 patients with PR, 27 had 250 mg of apatinib as their first/second-line treatment. Early application of apatinib had better antitumor effect. However, there was no difference in survival between first-line and second-line treatment groups; this may be related to the choice of combination therapy. Unfortunately, although univariate analysis showed that different line of apatinib had an effect on the OS of patients with advanced HCC, Cox regression analysis did not show the same results. Extrahepatic metastasis is a known risk factor for patients with HCC, and this was supported by the results of the univariate analysis. AFP level and PVTT were considered important factors affecting the survival and prognosis of patients with HCC (Tandon and Garcia-Tsao, 2009). In our study, patients with AFP ≥400 ng/ml had 1.61-fold the risk of death compared with patients with AFP <400 ng/ml, while patients with PVTT had a 1.75-fold and 1.70-fold risk of progression and death, respectively, compared with patients without PVTT. In contrast, survival and prognosis were significantly worse in patients with venous PVTT, which is consistent with previous studies (3, 49).

Our study confirmed that apatinib combined with immunotherapy or TACE can significantly improve efficacy. In the 28 patients with PR, 21 patients were treated with apatinib combined with immunotherapy or TACE. Especially for patients with PVTT, apatinib combined with TACE has a longer survival than TACE alone (Fan et al., 2019). Numerous clinical studies have corroborated the benefits of TACE plus apatinib for advanced HCC. TACE therapy can create an anoxic environment for the tumor, which induces high VEGFR expression and angiogenesis; this is why the combination with apatinib is so effective (Pinato et al., 2018). Recently, the RESCUE trial showed that apatinib therapy combined with camrelizumab was controllable, safe, and showed a good curative effect in advanced HCC (Xu et al., 2021). The ORR was 34.3% in the first-line and 22.5% in the second-line cohort. mPFS in the cohorts were 5.7 and 5.5 months, respectively. Meanwhile, the mPFS of patients with HCC treated with combination immunotherapy was 8.0 months, which may be due to the use of multiple immunotherapy drugs, including carrelizumab and attilizumab, in our enrolled patients.

Apatinib, similar to other molecularly targeted drugs, can cause adverse reactions; this was a focus of the current study as well. Detailed information regarding this is shown in Table 5 The most common adverse reactions were secondary hypertension (29.21%), symptoms of fatigue (16.85%), hand and foot syndrome (16.29%), vomiting (14.04%), liver dysfunction (6.18%), and proteinuria (6.74%). These adverse reactions could be tolerated or were alleviated with symptomatic treatment. Of the 178 patients, 2 patients were admitted for severe diarrhea, dehydration, proteinuria, or bradycardia, and 1 patient was admitted for severe bone marrow suppression, which led to treatment discontinuation. The other patients experienced grade 1 or 2 adverse events. Hypertension, proteinuria, and reduced liver function were more common in the apatinib treatment group, while sorafenib was more likely to cause hand-foot syndrome (Zhao et al., 2016). The adverse effects of apatinib are relatively mild compared to other cytotoxic chemotherapies and targeted therapies. No deaths associated with apatinib treatment or irreversible organ or tissue damage were observed in our study. However, possible adverse reactions associated with apatinib still require further study.

This study had some limitations. First, this was a retrospective pilot study with patients from Jilin, Liaoning, Heilongjiang, and Inner Mongolia provinces. Second, the doses of apatinib taken by patients were mostly 250 mg, which was determined by the physician based on weight, general condition, and tolerability; it was significantly lower than the doses used in previous studies on gastric and breast cancer. Only 4 patients in this study received the 500 mg dose, therefore, it was difficult to elucidate the differences between the effects at various doses. Third, both HBV and HCV are important pathogenic factors of HCC, however, we did not analyze the two factors separately. Fourth, this is a single-arm study with a small sample size, and large randomized controlled trials are still needed to explore the efficacy and safety of apatinib for advanced HCC.

The result of our study suggested that apatinib is effective in treating advanced HCC. Apatinib combined with TACE or immunotherapy increased the survival benefit for patients with advanced HCC. The most common adverse reactions occurred in patients were secondary hypertension, gastrointestinal resistance, symptoms of fatigue, and hand and foot syndrome, which were tolerable and manageable.