Abstract
Background
Survival after resection of hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) still remains poor. Apatinib, a vascular endothelial cell growth factor receptor 2 inhibitor, has been shown to be safe and effective in patients with advanced HCC, so in the present study its efficacy and safety in the adjuvant setting was explored.
Methods
In this single-center, open-label phase II trial, the patients received apatinib (500 mg/day) until they experienced disease recurrence or intolerable toxicity. The primary endpoint was recurrence-free survival (RFS); the secondary endpoints included overall survival (OS) and safety.
Results
From a total of 49 patients who were screened between August 2017 and December 2018, 30 study participants received apatinib. According to the Liver Cancer Study Group of Japan classification of PVTT, there were 7, 11, and 12 participants with Vp1, Vp2, and Vp3, respectively. The median duration of treatment was 4.8 months [interquartile range (IQR): 2.0–8.8], and the median dose of apatinib was 339.7 mg/day (IQR: 267.7–500 mg/day). The median follow-up was 14.3 months (IQR: 12.3–19.3). The median RFS was 7.6 months [95% confidence interval (CI): 5.7–9.5 months]. The 1-year RFS rate and the 1-year OS rate were 36.1% and 93.3%, respectively. A total of 29 (96.7%) patients experienced adverse events, and 14 (46.7%) had grade 3 or 4 adverse events. No treatment-related deaths occurred.
Conclusions
Apatinib was well tolerated in patients after resection of HCC with PVTT. The median RFS in this group was improved compared with that previously reported.
Trial registration
No.: NCT03261791 (ClinicalTrials.gov).
Keywords: Apatinib, hepatocellular carcinoma (HCC), portal vein
Introduction
Liver cancer is the sixth most common cancer and the fourth leading cause of cancer-related death worldwide (1). Hepatocellular carcinoma (HCC) is the most common type of liver cancer (75–85%) (2), and the main treatment includes liver transplantation, liver resection, loco-regional therapy, and systemic therapy (2).
In China, 23% of patients with diagnosed HCC also have portal vein tumor thrombosis (PVTT) (3), which is an indicator of an advanced stage and a poor prognosis (4-6). Untreated patients with HCC and PVTT have a median survival of about 2.7–4.0 months. Chinese Liver Cancer Treatment Guidelines recommend surgical resection, systemic treatment, transarterial chemoembolization, and radiation therapy for the treatment of HCC with PVTT (7). On the other hand, the American Association for the Study of Liver Diseases only recommends systemic treatment for HCC patients with PVTT (8).
Surgical resection can improve the survival of selected patients with HCC and PVTT, but has been associated with a high incidence of tumor recurrence (5,6). Total resection of liver cancer tissue and tumor thrombus is very challenging, especially for small tumor thrombus and micro-metastasis. Wei et al. suggested a 1-year recurrence-free survival (RFS) rate of 14.9% and 1-year overall survival (OS) rate of 43.1% in patients who underwent hepatectomy (9). Other studies have reported a 1-year RFS rate of 31.7% and a median RFS of 4.1 months in patients with PVTT who underwent hepatectomy (6,10). Postoperative adjuvant therapy might also improve patients’ survival after hepatectomy.
Angiogenesis is involved in tumor growth and metastasis, and is an important factor in the control of HCC progression. Apatinib is a vascular endothelial growth factor receptor-2 inhibitor that has shown potent antitumor activity and good safety in a variety of solid tumors (11-13), including advanced HCC (14-16). Therefore, it might be a therapeutic option for controlling recurrence after resection of HCC with PVTT. Previous study evaluated an anti-angiogenic therapy, i.e., sorafenib, for patients with relatively low risk of recurrence with a negative result (STORM study). In the present study, we evaluated the efficacy and safety of adjuvant apatinib treatment in patients with HCC and PVTT, an indicator of a high risk of recurrence, after R0 resection, as a novel option for the management of such patients, who otherwise might face a poor prognosis. We present the following article in accordance with the STROBE reporting checklist (available at http://dx.doi.org/10.21037/atm-20-6181).
Methods
Study design and ethical statement
This single-center, open-label phase II trial was carried out at Zhongshan Hospital, Fudan University, China. The study was supported by Hengrui Co. Ltd., and registered at ClinicalTrials.gov (#NCT03261791). The sponsor collaborated with authors on the study design, but the authors collected and analyzed the data, and are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The trial was conducted in accordance with the Declaration of Helsinki (as revised in 2013), and approved by the Ethics Committee of Zhongshan Hospital (No. B2017-065R). Informed consent was given by all individual participants.
Participants
The eligibility criteria were: (I) 18–70 years of age; (II) pathologically proven HCC based on the surgically resected specimen; (III) liver resection with curative intention; (IV) PVTT assessed by preoperative imaging or intraoperative findings within 4 weeks of surgery; (V) no preoperative antitumor treatment; (VI) Eastern Cooperative Oncology Group performance status score of 0 or 1; (VII) Child-Pugh score of A or B7; (VIII) adequate organ function, defined as hemoglobin ≥90 g/L, platelets ≥80×109/L, total bilirubin ≤1.5 × the institutional upper limit of normal (ULN), alanine transaminase (ALT) and aspartate aminotransferase (AST) ≤3 × ULN, and serum creatinine ≤1.5 × ULN; and (IX) expected survival ≥6 months.
The key exclusion criteria were: (I) tumor invasion into intrahepatic or extrahepatic bile ducts, combined hepatocellular cholangiocarcinoma, or fibrolamellar HCC; (II) uncontrolled hypertension; and (III) medical history of myocardial ischemia, myocardial infarction, or arrhythmia.
Treatment
The patients received apatinib monotherapy until they experienced disease recurrence or intolerable toxicity occurred. Apatinib was given orally (500 mg/day) each day, during a cycle of 4 weeks. Dose adjustments, including interruptions and reductions, were allowed for the management of treatment-related adverse events (AEs). Follow-up imaging examinations (abdominal contrast-enhanced magnetic resonance imaging or computed tomography (CT) and chest CT were performed every 2 months or when tumor recurrence was suspected based on elevated serum levels of tumor biomarkers. Complete blood count, liver and renal function tests, serum tumor marker levels, and urine dry chemical analysis were also performed every 2 months during treatment and 1 month after discontinuation of treatment.
Assessment
The primary endpoint was RFS; tumor recurrence was determined by the investigators. RFS was defined as the time interval from liver resection to the diagnosis of intrahepatic relapse or distant metastasis, or death from any cause. The secondary endpoints included OS and safety. OS was defined as the time from HCC surgery to death from any cause. AEs were recorded and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. The investigators assessed the relationship between treatment and AEs. All the AEs reported in this study were treatment-related AEs per investigator assessment.
Statistical analysis
This was an exploratory study to preliminarily evaluate the efficacy and safety of apatinib as adjuvant treatment in patients who underwent R0 resection for HCC and PVTT; therefore, a small sample size of 30 was planned. The efficacy analyses were conducted on the intent-to-treat (ITT) population, which was defined as patients who received at least 1 dose of the study drug. The Kaplan-Meier product-limit method was used to estimate the median times of RFS and OS in the ITT population. AEs and serious AEs were analyzed in patients who received at least 1 dose of the study drug. Only descriptive statistics were used. Quantitative variables were shown as mean ± standard deviation or median [interquartile range (IQR)].
Results
Participant enrollment and baseline characteristics
Among a total of 49 patients who were screened between August 2017 and December 2018, 30 participants received apatinib (Figure 1). On February 27, 2020, 3 patients were still receiving apatinib treatment at a dosage of 250 mg/d. The baseline characteristics of the 30 participants (ITT population) are presented in Table 1. The median age was 55 years (IQR: 49–62 years), and 25 (83.3%) patients were male. According to the Liver Cancer Study Group of Japan (LCSGJ) classification of PVTT (17), there were 7 (23.3%), 11 (36.7%), and 12 (40.0%) participants with Vp1, Vp2, and Vp3, respectively.
Figure 1.
Patient flowchart. AFP, alpha-fetoprotein; HBV, hepatitis B virus; TACE, transarterial chemoembolization.
Table 1. Characteristics of the participants.
| Characteristics | Values (n=30) |
|---|---|
| Age, median [range], years | 55 [49–62] |
| Sex (male/female) | 25/5 |
| HBsAg (positive/negative) | 26/4 |
| Tumor size, mean ± SD, cm | 7.2±2.6 |
| No. of lesions (1/≥2/≥3) | 24/6 |
| Type of portal vein thrombosis (Vp1/Vp2/Vp3)† | 7/11/12 |
| α-fetoprotein, median (IQR), ng/mL | 179.5 (15.9–3,460.5) |
| Protein induced by vitamin K absence, median (IQR), mAU/mL | 978.5 (212.0–8,113.0) |
| Total bilirubin, mean ± SD, μmol/L | 13.9±6.0 |
| Alanine transaminase, mean ± SD, U/L | 41.0±24.7 |
| Albumin, mean ± SD, g/L | 43.8±3.8 |
| γ-glutamyl transferase, mean ± SD, U/L | 96.2±63.1 |
| International normalized ratio, mean ± SD | 1.0±0.1 |
| Hemoglobin, mean ± SD, g/L | 145.4±16.3 |
| Platelets, mean ± SD, ×109/L | 154.0±66.1 |
| Leukocytes, mean ± SD, ×109/L | 4.9±1.9 |
†, based on the Liver Cancer Study Group of Japan (LCSGJ) classification. IQR, interquartile range; SD, standard deviation.
Apatinib treatment
The median follow-up was 14.3 months (IQR: 12.3–19.3), and the median duration of treatment was 4.8 months (IQR: 2.0–8.8) (Table 2). The median dose of apatinib was 339.7 mg/d (IQR: 267.7–500 mg/d), and the median total drug exposure was 57.2 g (IQR: 25.8–78.8 g).
Table 2. Efficacy evaluation.
| Variables | Values |
|---|---|
| Median follow-up (months), median (IQR) | 14.3 (12.3–19.3) |
| Median duration of treatment (months), median (IQR) | 4.8 (2.0–8.8) |
| Median RFS (months) (95% CI) | 7.6 (5.7–9.5) |
| 1-year RFS rate (%) | 36.1 |
| 1-year OS rate (%) | 93.3 |
IQR, interquartile range; LCSGJ, Liver Cancer Study Group of Japan; OS, overall survival PVTT, portal vein tumor thrombosis; RFS, recurrence-free survival.
Efficacy
For patients with HCC and PVTT, the median RFS was 7.6 months [95% confidence interval (CI): 5.7–9.5 months]. The 1-year RFS rate was 36.1%, and the 1-year OS was 93.3% (Table 2, Figure 2).
Figure 2.
Recurrence-free survival after surgery.
Safety
During the treatment period, 29 (96.7%) patients experienced AEs of any grade, and 14 (46.7%) experienced grade 3 or 4 AEs. The treatment-related AEs are listed in Table 3. No treatment-related deaths occurred. The most common treatment-related AEs were thrombocytopenia (n=16, 53.3%), hand-foot syndrome (n=14, 46.7%), neutropenia (n=13, 43.3%), hypertension (n=9, 30.0%), increased ALT (n=7, 23.3%), and hoarseness (n=7, 23.3%).
Table 3. Treatment-related adverse events.
| Treatment-related adverse events | All grades, n (%) | Grade 3 or 4, n (%) |
|---|---|---|
| Any adverse event | 29 (96.7) | 14 (46.7) |
| Thrombocytopenia | 16 (53.3) | 5 (16.7) |
| Neutropenia | 13 (43.3) | 4 (13.3) |
| Proteinuria | 4 (13.3) | 3 (10.0) |
| Hypertension | 9 (30.0) | 3 (10.0) |
| ALT increased | 7 (23.3) | 1 (3.3) |
| AST increased | 3 (10.0) | 1 (3.3) |
| Diarrhea | 3 (10.0) | 1 (3.3) |
| Upper gastrointestinal hemorrhage | 1 (3.3) | 1 (3.3) |
| Hoarseness | 7 (23.3) | 1 (3.3) |
| Palmar-plantar erythrodysesthesia syndrome | 14 (46.7) | 1 (3.3) |
| Anorexia | 4 (13.3) | 0 |
| Headache | 3 (10.0) | 0 |
| Dizziness | 2 (6.7) | 0 |
| Fatigue | 2 (6.7) | 0 |
| Periodontal disease | 1 (3.3) | 0 |
ALT, alanine transaminase; AST, aspartate aminotransferase.
Treatment-related grade 3 or 4 AEs included thrombocytopenia (n=5, 16.7%), neutropenia (n=4, 13.3%), proteinuria (n=3, 10.0%), hypertension (n=3, 10.0%), increased ALT (n=1, 3.3%), increased AST (n=1, 3.3%), diarrhea (n=1, 3.3%), upper gastrointestinal hemorrhage (n=1, 3.3%), hoarseness (n=1, 3.3%), and hand–foot syndrome (n=1, 3.3%) (Table 3). The patient with gastrointestinal bleeding and hepatic encephalopathy was relieved of symptoms after drug withdrawal and hospitalization.
Discussion
Patients with HCC and PVTT have a poor prognosis. Because apatinib has been shown to be safe and effective in several solid tumors, including HCC, we conducted the first trial, to the best of our knowledge, evaluating the efficacy and safety of an anti-angiogenesis agent in patients with HCC and PVTT after R0 resection. The results showed that adjuvant apatinib had good treatment efficacy with a tolerable safety profile in these patients.
Previous studies have verified the efficacy of a dose of 500–850 mg/day of apatinib in patients with various solid tumors (11-13,18-26). Moreover, meta-analyses showed that the objective response rate and disease control rate were higher with the 850 and 750 mg/day dosages than with a lower dose (18-26). Most recently, apatinib 750 mg/day showed improved OS in comparison with placebo in a phase III clinical trial when used as second-line therapy in patients with a progressed tumor or those intolerant to previous systemic chemotherapy and/or sorafenib (27). Considering that previous studies have reported 77.4% treatment-related AEs of grade 3 or 4 (28), we chose a lower dosage for apatinib in the adjuvant setting. In this study, apatinib 500 mg/day was well tolerated, and there was 46.7% treatment-related AEs of grade 3 or 4.
Recent studies that included Eastern Asian patients suggested that surgical resection could be a treatment option for patients with Barcelona Clinic Liver Cancer (BCLC) C stage HCC, especially those with type I or II PVTT. Peng et al. (29) found a 1-year RFS and OS of 63.0% and 81.5%, respectively, in HCC patients with type I PVTT, and 20.9% and 46.3%, respectively, for type II PVTT among those who underwent hepatic resection for HCC. Kokudo et al. (30) examined patients with R1 or R2 resection, reporting a favorable long-term survival after resection with median RFS and OS for Vp1, Vp2, and Vp3 of 1.23 and 4.13 years, 0.82 and 2.49 years, and 0.56 and 1.58 years, respectively. Moreover, Zhang et al. (31) showed that for patients with type I or II PVTT and R0 resection (type I PVTT represented 34–48.7% of the patients), the median RFS was 4.9–8.1 months, and median OS was 9.3–10.4 months. In a group of patients with predominantly type I PVTT (>90%), the median RFS and OS were 11.0 and 12.4 months, respectively. Therefore, the extent of PVTT is associated with survival in patients with HCC. Patients with more extensive PVTT possibly have a larger residual lesion after surgery, and in those cases, adjuvant apatinib might be an option.
In the present study, the 1-year (36.1%) and median RFS (7.6 months), and 1-year OS (93.3%) were higher than in a previous study that recruited similar participants randomized to surgery (1-year OS, 43.1%) versus surgery plus radiation therapy (1-year OS, 75.2%) (9). These differing results could be partly explained by that the patients recruited in the present study had a better performance status than previous study, but also by the use of apatinib, which needs to be examined in a controlled trial. Nevertheless, the OS was substantially longer than the 8.9 months and 5.6 months (HCC with macrovascular invasion and/or extrahepatic spread) reported by the SHARP (32) and Asia-Pacific (33) trials, respectively, for sorafenib monotherapy. In addition, a small-series study reported that adjuvant sorafenib after HCC resection improved the time to progression and OS compared with surgery alone in patients with HCC and PVTT (34). Patients with adjuvant sorafenib therapy had an improved time to progression (29 vs. 22 months, P=0.041) and an improved OS (37 vs. 30 months, P=0.01).
Anti-angiogenesis targeted therapy has been shown to delay wound healing (35), so in the present trial, apatinib was started 4–6 weeks after surgery to ensure safety. The occurrence of grade 3 or 4 AE was, in general, comparable to that in the STORM trial conducted with patients who received sorafenib after HCC resection (i.e., 50% for grade 3 AEs and 2% for grade 4) (36). The most common apatinib-related AEs were hypertension and proteinuria, consistent with the known toxicity profile (11,14,15,18-20,22-24,26). No new toxicity signals were identified.
There are some limitations to the present study that need to be pointed out. This was a single-arm exploratory trial without a control group or randomization and the sample size is small. Thus, the results are not conclusive. In future study, we should introduce a control group with standard treatment in clinical practice (e.g., TACE). Nevertheless, our results revealed a high RFS and 1-year OS, suggesting that further studies on apatinib for HCC and PVTT might be warranted.
Conclusions
Apatinib was well tolerated after R0 resection for HCC with PVTT. The median RFS in this group was improved compared with previous reports. However, further, larger sample size trials, which will include a control group, should be performed to confirm these findings. Based on this study and another study carried out in our hospital (adjuvant therapy with apatinib plus SHR1210, clinicaltrial.gov identifier NCT03722875), a phase III randomized placebo-controlled clinical trial evaluating apatinib plus SHR1210 as adjuvant therapy is in plan.
Supplementary
The article’s supplementary files as
Acknowledgments
The authors thank the patients and their families, and thank Mei-Ling Li and Jin-Jin Zhu for assisting with the data collection.
Funding: This work was supported by Jiangsu Hengrui Medicine Co., Ltd.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The trial was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the ethics committee of Zhongshan Hospital (No. B2017-065R) and informed consent was given by all individual participants.
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at http://dx.doi.org/10.21037/atm-20-6181
Data Sharing Statement: Available at http://dx.doi.org/10.21037/atm-20-6181
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-6181). HCS reports personal fees from Bayer, personal fees from Eisai, personal fees from MSD, personal fees from Hengrui Co., Ltd., personal fees from Innovent Biologics, outside the submitted work; XDZ reports personal fees from Eisai, personal fees from MSD, personal fees from Hengrui Co. Ltd., outside the submitted work. The other authors have no conflicts of interest to declare.
(English Language Editor: K. Brown)
References
- 1.Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424. 10.3322/caac.21492 [DOI] [PubMed] [Google Scholar]
- 2.Cheung TT. Management of hepatocellular carcinoma: from bench to bedside and beyond. Transl Gastroenterol Hepatol 2019;4:54. 10.21037/tgh.2019.07.01 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Park JW, Chen M, Colombo M, et al. Global patterns of hepatocellular carcinoma management from diagnosis to death: the BRIDGE Study. Liver Int 2015;35:2155-66. 10.1111/liv.12818 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.A new prognostic system for hepatocellular carcinoma: a retrospective study of 435 patients: the Cancer of the Liver Italian Program (CLIP) investigators. Hepatology 1998;28:751-5. 10.1002/hep.510280322 [DOI] [PubMed] [Google Scholar]
- 5.Holzwanger DJ, Madoff DC. Role of interventional radiology in the management of hepatocellular carcinoma: current status. Chin Clin Oncol 2018;7:49. 10.21037/cco.2018.07.04 [DOI] [PubMed] [Google Scholar]
- 6.Sun JX, Shi J, Li N, et al. Portal vein tumor thrombus is a bottleneck in the treatment of hepatocellular carcinoma. Cancer Biol Med 2016;13:452-8. 10.20892/j.issn.2095-3941.2016.0059 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Zhou J, Sun HC, Wang Z, et al. Guidelines for Diagnosis and Treatment of Primary Liver Cancer in China (2017 Edition). Liver Cancer 2018;7:235-60. 10.1159/000488035 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Marrero JA, Kulik LM, Sirlin CB, et al. Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology 2018;68:723-50. 10.1002/hep.29913 [DOI] [PubMed] [Google Scholar]
- 9.Wei X, Jiang Y, Zhang X, et al. Neoadjuvant Three-Dimensional Conformal Radiotherapy for Resectable Hepatocellular Carcinoma With Portal Vein Tumor Thrombus: A Randomized, Open-Label, Multicenter Controlled Study. J Clin Oncol 2019;37:2141-51. 10.1200/JCO.18.02184 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Sun J, Zhang T, Wang J, et al. Biologically effective dose (BED) of stereotactic body radiation therapy (SBRT) was an important factor of therapeutic efficacy in patients with hepatocellular carcinoma (</=5 cm). BMC Cancer 2019;19:846. 10.1186/s12885-019-6063-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Scott LJ. Apatinib: A Review in Advanced Gastric Cancer and Other Advanced Cancers. Drugs 2018;78:747-58. 10.1007/s40265-018-0903-9 [DOI] [PubMed] [Google Scholar]
- 12.Liu G, Wang C, He Y, et al. Application effect of apatinib in patients with failure of standard treatment for advanced malignant tumours. BMC Pharmacol Toxicol 2019;20:61. 10.1186/s40360-019-0362-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Yang D, Dai R, Zhang Q, et al. Apatinib for heavily treated patients with non-small cell lung cancer: Report of a case series and literature review. Saudi J Biol Sci 2018;25:888-94. 10.1016/j.sjbs.2017.12.011 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Zhang Y, Fan W, Wang Y, et al. Apatinib for Patients With Sorafenib-Refractory Advanced Hepatitis B Virus Related Hepatocellular Carcinoma: Results of a Pilot Study. Cancer Control 2019;26:1073274819872216. 10.1177/1073274819872216 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Kong Y, Sun L, Hou Z, et al. Apatinib is effective for treatment of advanced hepatocellular carcinoma. Oncotarget 2017;8:105596-605. 10.18632/oncotarget.22337 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Qin S. Apatinib in Chinese patients with advanced hepatocellular carcinoma: A phase II randomized, open-label trial. J Clin Oncol 2014;32:abstr 4019.
- 17.Kudo M, Izumi N, Kokudo N, et al. Management of hepatocellular carcinoma in Japan: Consensus-Based Clinical Practice Guidelines proposed by the Japan Society of Hepatology (JSH) 2010 updated version. Dig Dis 2011;29:339-64. 10.1159/000327577 [DOI] [PubMed] [Google Scholar]
- 18.Chen J, Wang J. Efficacy and safety assessment of apatinib in patients with advanced gastric cancer: a meta-analysis. Onco Targets Ther 2018;11:4149-58. 10.2147/OTT.S157466 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Cheng H, Sun A, Guo Q, et al. Efficacy and safety of apatinib combined with chemotherapy for the treatment of advanced gastric cancer in the Chinese population: a systematic review and meta-analysis. Drug Des Devel Ther 2018;12:2173-83. 10.2147/DDDT.S170678 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Liu Y, Zhou C, Zhang K, et al. The combination of apatinib and S-1 for the treatment of advanced gastric cancer in China: A meta-analysis of randomized controlled trials. Medicine (Baltimore) 2018;97:e13259. 10.1097/MD.0000000000013259 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Peng L, Ye X, Hong Y, et al. Treatment-related toxicities of apatinib in solid tumors: a meta-analysis. Oncotarget 2018;9:32262-70. 10.18632/oncotarget.24215 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Sun D, Hou H, Zhang C, et al. The efficacy and safety of apatinib for refractory malignancies: a review and meta-analysis. Onco Targets Ther 2018;11:6539-54. 10.2147/OTT.S176429 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Wei Y, Liu J, Yan M, et al. Effectiveness and Safety of Combination Therapy of Transarterial Chemoembolization and Apatinib for Unresectable Hepatocellular Carcinoma in the Chinese Population: A Meta-Analysis. Chemotherapy 2019;64:94-104. 10.1159/000502510 [DOI] [PubMed] [Google Scholar]
- 24.Xue JM, Astere M, Zhong MX, et al. Efficacy and safety of apatinib treatment for gastric cancer, hepatocellular carcinoma and non-small cell lung cancer: a meta-analysis. Onco Targets Ther 2018;11:6119-28. 10.2147/OTT.S172717 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Yu GC, Yang J, Ye B, et al. Apatinib in the treatment of advanced non-small-cell lung cancer: A meta-analysis. Math Biosci Eng 2019;16:7659-70. 10.3934/mbe.2019383 [DOI] [PubMed] [Google Scholar]
- 26.Zhao S, Zhang T, Dou W, et al. A comparison of transcatheter arterial chemoembolization used with and without apatinib for intermediate- to advanced-stage hepatocellular carcinoma: a systematic review and meta-analysis. Ann Transl Med 2020;8:542. 10.21037/atm.2020.02.125 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Li Q, Qin S, Gu S, et al. Apatinib as second-line therapy in Chinese patients with advanced hepatocellular carcinoma: A randomized, placebo-controlled, double-blind, phase III study. J Clin Oncol 2020;38:abstr 4507.
- 28.Zhu XD, Li KS, Sun HC. Adjuvant therapies after curative treatments for hepatocellular carcinoma: Current status and prospects. Genes Dis 2020;7:359-69. 10.1016/j.gendis.2020.02.002 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Peng ZW, Guo RP, Zhang YJ, et al. Hepatic resection versus transcatheter arterial chemoembolization for the treatment of hepatocellular carcinoma with portal vein tumor thrombus. Cancer 2012;118:4725-36. 10.1002/cncr.26561 [DOI] [PubMed] [Google Scholar]
- 30.Kokudo T, Hasegawa K, Matsuyama Y, et al. Survival benefit of liver resection for hepatocellular carcinoma associated with portal vein invasion. J Hepatol 2016;65:938-43. 10.1016/j.jhep.2016.05.044 [DOI] [PubMed] [Google Scholar]
- 31.Zhang YF, Shang H, Zeng XL, et al. Postoperative adjuvant chemo (embolization) therapy for hepatocellular carcinoma with portal vein tumor thrombosis. Onco Targets Ther 2018;11:5407-17. 10.2147/OTT.S171612 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Sherman M, Mazzaferro V, Amadori D, et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma and vascular invasion or extrahepatic spread: A subanalysis from the SHARP trial. J Clin Oncol 2008;26:abstr 4584.
- 33.Cheng AL, Guan Z, Chen Z, et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma according to baseline status: subset analyses of the phase III Sorafenib Asia-Pacific trial. Eur J Cancer 2012;48:1452-65. 10.1016/j.ejca.2011.12.006 [DOI] [PubMed] [Google Scholar]
- 34.Li J, Hou Y, Cai XB, et al. Sorafenib after resection improves the outcome of BCLC stage C hepatocellular carcinoma. World J Gastroenterol 2016;22:4034-40. 10.3748/wjg.v22.i15.4034 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Bodnar RJ. Anti-Angiogenic Drugs: Involvement in Cutaneous Side Effects and Wound-Healing Complication. Adv Wound Care (New Rochelle) 2014;3:635-46. 10.1089/wound.2013.0496 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Bruix J, Takayama T, Mazzaferro V, et al. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol 2015;16:1344-54. 10.1016/S1470-2045(15)00198-9 [DOI] [PubMed] [Google Scholar]
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