INTRODUCTION
As the sixth most common neoplasm and third leading cause of cancer-related death, hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer worldwide.[ 1 ] China accounts for about a half of all new HCC cases and HCC-related deaths globally.[ 2 ] Most patients are not suitable for surgery at the time of diagnosis and many suffer disease progression or recurrence after first-line treatment. Therefore, it is important to explore effective second-line treatments for advanced HCC patients.
Currently, several kinds of multikinase inhibitors, such as sorafenib and lenvatinib, are available as first-line therapy for HCC. According to a multicenter, randomized, open-label, noninferiority phase 3 study, the median survival time of 954 eligible patients with untreated advanced HCC under lenvatinib and sorafenib were 13.6 (95% CI: 12.1–14.9) and 12.3 months (95% CI: 10.4–13.9).[ 3 ] A recent prospective study on lenvatinib showed a median overall survival (mOS) and median progression-free survival (mPFS) periods of 17.0 and 10.4 months, respectively.[ 4 ] Donafenib, another novel multikinase inhibitor considered as first-line therapy for Chinese patients with advanced HCC, demonstrated better mOS outcomes than sorafenib (12.1 vs. 10.3 months) according to an open-label, randomized, parallel-controlled, multicenter phase 2–3 trial on 668 patients with unresectable or metastatic HCC.[ 5 ]
Immune checkpoint inhibitors combined with tyrosine kinase inhibitors (TKIs) have been approved as first-line therapy for HCC. For instance, the combination of atezolizumab plus bevacizumab was more effective than sorafenib in a phase 3 trial.[ 6 ] A recent randomized, open-label, phase 2–3 study also reported favorable OS (mOS not reached vs. 10.4 months) and PFS (mPFS 4.6 months vs. 2.8 months) sintilimab plus bevacizumab compared with sorafenib.[ 7 ] Moreover, apatinib (a selective vascular endothelial cell growth factor 2 (VEGFR-2) inhibitor) combined with camrelizumab (an anti-PD-1 antibody) achieved an encouraging objective response rate (ORR) and 12 month OS (74.7%) as first-line treatment.[ 8 ] However, several systemic treatments have been approved as second-line therapy for HCC patients who suffered disease progression after first-line treatment. For example, the oral multikinase inhibitor regorafenib, broadly similar to sorafenib but with potentially more potent pharmacological activity, is already approved as second-line therapy for HCC patients.[ 9 ] According to the RESORCE study, regorafenib improved the OS of HCC patients who experienced progression during sorafenib treatment compared with placebo (mOS, 10.6 vs. 7.8 months).[ 10 ] Another TKI cabozantinib also demonstrated longer OS (mOS, 11.3 vs. 7.2 months) as second-line therapy of HCC previously treated with sorafenib.[ 11 ] In China, apatinib could significantly improve OS compared with placebo (median 8.7 vs. 6.8 months) as second-line treatment of advanced HCC, according to a randomized, double blind, placebo controlled, multicenter phase 3 study.[ 12 ] Accordingly, in December 2020, apatinib was approved for the treatment of patients with advanced HCC after first-line systemic therapy in China.[ 13 ]
Transarterial chemoembolization (TACE) is recommended to treat inoperable patients with advanced HCC. Several studies confirmed the better efficacy of sorafenib combined with TACE than that of either TACE or antiangiogenic treatments alone in advanced HCC therapy.[ 14–16 ] According to a recent study, regorafenib plus TACE demonstrated a good ORR and disease control rate (DCR) among patients with advanced HCC in a second-line setting.[ 17 ] Although diverse second-line treatments for advanced HCC have been approved, little real-world research has investigated the use of apatinib in combination with TACE. Therefore, we conducted this retrospective study to analyze the clinical efficacy and safety of apatinib combined with TACE as second-line therapy for advanced HCC patients.
MATERIALS AND METHODS
Patient eligibility
The present research is a retrospective real-world study, approved by the ethics committee of Shandong Provincial Hospital Affiliated to Shandong First Medical University in accordance with the ethical principles of the Declaration of Helsinki (revised in 2013). The need for informed consent was waived by the ethics committee due to the retrospective nature of the study.
Advanced HCC patients who failed in first-line therapy or could not tolerate it were enrolled in this study. First-line therapy included sorafenib or lenvatinib with or without TACE. Other inclusion criteria were the following: (I) ≥18 years; (II) stage B or C according to the BCLC staging system, not eligible for surgical therapy; (III) Child-Pugh (CP) Class A or B liver function; (IV) an Eastern Cooperative Oncology Group performance status score ≤1; and (V) ≥1 untreated target lesions that could be measured in one dimension according to modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.15.
The main exclusion criteria were (I) heart, lung, or kidney dysfunction; (II) current or previous pulmonary fibrosis or interstitial pneumonia; (III) active or prior autoimmune disease; (IV) previous or current gastrointestinal bleeding; and (V) current or previous central nervous system metastasis. All patients were informed about the use of apatinib plus TACE and decided based on the complete information.
Treatment
TACE was performed by two experienced radiologists (Jinhua Hu and Tao Li) with >7 years of experience in interventional therapy. A mixture of lipiodol and epirubicin was injected into the arterial branches followed by gelatin sponge in some patients during TACE, which was administered 1–4 times depending on tumor response and the patient’s liver function according to previous research.[ 18 ] Patients received 250 mg apatinib (Jiangsu Hengrui Medicine Co., Ltd) orally once daily after TACE treatment.
Efficacy and safety assessments
The primary endpoint was progression-free survival (PFS) and the secondary endpoint was DCR and ORR. PFS was identified as the time from the start of second-line therapy administration to radiological disease progression or death. OS was defined as the time from the start of second-line therapy until the date of death for all causes. Tumor response was evaluated during each follow-up according to the modified RECIST (mRECIST).
Adverse events were collected from the time of first apatinib administration until 30 days after the last administration and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.[ 19 ]
Statistical analysis
The present research was a retrospective real-world cohort study. Patients were followed until disease progression or death for any cause. Baseline demographics characteristics, radiological tumor response, and adverse events were analyzed with descriptive statistics. The Kaplan–Meier method was used to analyze survival curves and 95% CI for ORR and DCR were calculated by the Clopper–Pearson method. Univariate Cox regression models and Kaplan–Meier analysis were conducted to explore the relationship between clinical factors and prognosis in HCC. Statistical analyses were carried out with IBM SPSS Statistics version 21.0 (SPSS Inc., Chicago, IL).
RESULTS
Demographic and baseline characteristics
From May 9, 2019 to January 2, 2022, 72 advanced HCC patients with disease progression or intolerant to first-line therapy such as sorafenib or lenvatinib were treated by apatinib plus TACE [Figure 1 ]. The data cutoff was on March 12, 2022. The demographic and HCC baseline characteristics of patients are shown in Table 1 . The median follow-up duration was 14.7 months (4.5–26.0). Among 72 patients, 68.1% also suffered from liver cirrhosis while in 84.7% HCC was HBV related and in 30.6% it was accompanied by PVTT.
Figure 1: Recruitment flowchart of advanced HCC patients. TACE = transcatheter arterial chemoembolization ; TKIs = tyrosine kinase inhibitors
Table 1: Baseline characteristics observation index of patients
Efficacy and outcomes
The median time of primary therapy including sorafenib, lenvatinib, or TACE was 6.8 (3.6–13.6) months. The mPFS from the start of apatinib plus TACE was 7.1 (1.0–15.2) months and its 95% CI was 5.9–8.1 according to Kaplan–Meier analysis. The PFS and OS rate and curves of all patients are shown in Figure 2 . Univariate Cox regression analysis demonstrated that PVTT, ascites, and CP grade were associated with worse OS, whereas no association with sex, age, and AFP was observed [Table 2 ]. Moreover, no significant association was found between sex, age, PVTT, AFP, and PFS, despite the significant difference of PFS between HCC patients with PVTT and those without PVTT.
Figure 2: Kaplan–Meier estimate of total progression-free survival and overall survival (a) progression-free survival of all patients (b) overall survival in all patients
Table 2: Univariate analysis of clinical-pathological factors associated with PFS and OS
Subgroup analyses revealed a significant difference in the mPFS of advanced HCC patients with PVTT [6.6 (2.0–10.5) vs. 7.9 (1.0–10.2) months, P = 0.03] compared to those without PVTT [Figure 3 ]. No difference in PFS was found between HCC patients with AFP ≥400 ng/mL and those with AFP <400 ng/mL [Figure 3 ]. At the time of data cutoff, April 23, 2022, no patient achieved CR, 25 patients (34.7%) achieved PR, 10 patients (13.9%) had stable disease, and 23 patients (31.9%) had progressive disease, while 14 patients (19.4%) had died. The ORR and DCR were 34.7% (95% CI: 23.9%–46.9%) and 48.6% (95% CI: 36.7%–60.7%), respectively.
Figure 3: Kaplan–Meier curves showing the PFS of subgroup analyses (a) progression-free survival of HCC patients with or without PVTT and (b) progression-free survival of HCC patients with AFP ≥400 ng/mL or AFP < 400 ng/mL
By the cutoff date, 33 patients had died and 39 were undergoing survival follow-up and reached mO. The estimated mOS was 22.3 months (95% CI: 20.6–24.0) by Kaplan–Meier analysis [Figure 2 ]. Of 22 patients with PVTT, 12 died due to HCC development, and their mOS was significantly different from that of patients without PTT [14.7 months (95% CI: 12.8–16.6) vs. 23.0 months (95% CI: 18.2–27.8); P = 0.002]. No significant difference was found between HCC patients with AFP ≥400 ng/mL and those with AFP <400 ng/mL [Figure 4 ].
Figure 4: Kaplan–Meier curves showing the OS of subgroup analyses (a) OS of HCC patients with or without PVTT (P = 0.002) and (b) OS of HCC patients with AFP ≥400 ng/mL or AFP < 400 ng/mL (P > 0.05)
Adverse events
At least one adverse event due to apatinib was reported by 53 patients (73.6%) and various adverse events of grade ≥3 including hypertension, hand–foot syndrome, and proteinuria were detected in nine patients (12.5%; Table 3 ). The most common treatment-related adverse events of any grade due to apatinib were hypertension 35 (48.6%), appetite loss 30 (41.6%), and hand–foot syndrome 21 (29.2%). The profile of TACE-related adverse events in the present study was similar to that of previous studies, including elevated serum amylase, abdominal pain, and fever.[ 15 ]
Table 3: Apatinib-related adverse events
DISCUSSION
In the current study, we demonstrated that apatinib combined with TACE as second-line therapy could achieve an mPFS of 7.1 months among a cohort of advanced HCC patients. As a novel antiangiogenic agent that can target VEGFR-2, the efficacy of apatinib in advanced HCC and other cancers has been confirmed by recent clinical studies.[ 20 , 21 ] For instance, a mPFS of 7.0 months and a DCR of 73.6% were achieved by apatinib in a multicenter real-world retrospective study in the treatment of advanced HCC.[ 22 ] The study also demonstrated longer mOS of apatinib combined with TACE (20.0 months) than of apatinib alone (8.7 months).[ 22 ] In a second-line therapy setting, the RESCUE study found an mPFS of 5.5 months with apatinib combined with camrelizumab.[ 8 ] The efficacy of apatinib for advanced HCC therapy may be due to its selectively targeting of VEGFR-2, with a binding affinity 10-fold that of vatalanib or sorafenib. Therefore, it can efficiently block the migration and proliferation of vascular endothelial cells and decrease tumor microvessel density, which contribute to the inhibition of tumor growth.[ 23 , 24 ]
Use of TACE combined with other TKIs is also reported as second-line therapy. For instance, Wang et al . demonstrated that TACE plus regorafenib achieved a good ORR of 42.3% and an mPFS of 8 months after first-line targeted therapy[ 17 ] ; in our study, the ORR was 34.7% and the mPFS was 7.1 months. We speculated that the low apatinib dose (250 mg qd) used in the current study may explain the difference from the previous study where they used a dose of 80–160 mg once a day for the first three weeks of each four-week cycle. Accordingly, we speculate that the combination of TKIs and TACE may improve the outcome of advanced HCC as second-line therapy.
Several studies demonstrated that TKI plus TACE was superior to TKI alone in the treatment of advanced HCC. For example, Peng et al . found that lenvatinib plus TACE achieved an mPFS of 10.6 months compared with 6.4 months of lenvatinib alone (hazard ratio, 0.43; P < 0.01) in primary treatment of advanced HCC.[ 25 ] The synergistic effect of combining TACE with molecular targeted drugs is due to TACE’s induction of VEGFR expression and angiogenesis. Nowadays, TACE is not only considered the first-line treatment for patients with intermediate stage HCC but also used as second-line therapy. For instance, Han et al . investigated the combination of regorafenib and TACE as second-line therapy in a real-world study, showing an mPFS and mOS of 9.1 and 14.3 months, respectively.[ 26 ] Based on the above findings and our results, TACE may be important in the second-line therapy of advanced HCC. Therefore, HCC patients with refractory disease after first-line treatment could undergo TACE; however, further research is required to validate our findings.
Untreated HCC patients with PVTT (10%–60% HCC patients) usually have a dismal prognosis and short median survival time (2–4 months).[ 27–29 ] The present subgroup analyses revealed shorter mPFS of advanced HCC patients with PVTT than in advanced HCC patients without PVTT. The mPFS of advanced HCC patients with PVTT was 6.6 months with apatinib plus TACE. Similarly, Fan et al . demonstrated Median TTP time to tumor progression (mTTP) values of 6.1 months with TACE plus apatinib as primary therapy for advanced HCC patients with PVTT.[ 24 ] Another recent study found an mPFS of advanced HCC patients with PVTT of 7 months with TACE plus apatinib treatment, which was similar to our results.[ 30 ] Moreover, in that study, the mOS was 12.0 months (95% CI: 10.3–13.7) while it was 14.7 months (95% CI: 12.8–16.6) in our study. This difference may be due to the smaller number of HCC patients with PVTT in our study (22 vs. 85) and different ratio of PVTT types.
According to our results, apatinib in combination with TACE had a good safety profile; no death was induced by treatment-related adverse events in the current cohort. Most adverse events in the current study were grade 1 or 2. The most frequent adverse event related to apatinib was hypertension (48.6%), consistent with other studies. For instance, Yang et al . found hypertension in 40.9% of HCC patients treated with apatinib.[ 31 ] However, hypertension is usually not life threatening and can be controlled by antihypertensive drugs.
There are certain limitations to the present study. First, this study was retrospective and selection bias was inevitable. Second, the relatively small study sample might decrease the power of the statistical analysis. Third, this is a single-center study without control group. Therefore, further studies on larger populations or prospective research are needed to confirm our results.
In conclusion, apatinib plus TACE demonstrated promising clinical efficacy and acceptable safety as second-line therapy in a real-world cohort of advanced HCC patients who already received primary therapy.
Financial support and sponsorship
This work was supported by funds from Shandong Provincial Natural Science Foundation project in China (No.ZR2020MH053) and Medical and health Science and Technology Development Project of Shandong Province in China (No. 2019WS463 and No. 2019WS494).
Conflicts of interest
There are no conflicts of interest.
Acknowledgments
This work was supported by funds from Shandong Provincial Natural Science Foundation project in China (No.ZR2020MH053) and Medical and health Science and Technology Development Project of Shandong Province in China (No. 2019WS463 and No. 2019WS494).
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