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ORIGINAL ARTICLE
Year : 2020  |  Volume : 16  |  Issue : 5  |  Page : 1165-1170

Transcatheter arterial chemoembolization combined with low-dose apatinib in the treatment of unresectable hepatocellular carcinoma in elderly patients: Efficacy and safety


1 Department of Interventional Therapy, Linyi Cancer Hospital, Linyi; Affiliated provincial hospital, Shandong University School of Clinical Medicine, Jinan, Shandong Province, China
2 Hepatobiliary and Pancreatic Center, Beijing Tsinghua Changgeng Hospital, Changping District, Beijing; Department of Oncology, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning Province, China
3 Department of Interventional Therapy, Linyi Cancer Hospital, Linyi, Shandong Province, China
4 Department of Oncology, Binzhou People's Hospital, Binzhou, Shandong Province, China
5 Hepatobiliary and Pancreatic Center, Beijing Tsinghua Changgeng Hospital, Changping District, Beijing, China
6 Department of Oncology, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning Province, China

Date of Submission25-Nov-2019
Date of Decision01-Jul-2020
Date of Acceptance05-Aug-2020
Date of Web Publication29-Sep-2020

Correspondence Address:
Qiang Li
Department of Interventional Therapy, Linyi Cancer Hospital, No. 6 East Lingyuan Street, Linyi 276001, Shandong Province
China
Zhe Wang
Department of Oncology, Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Street, Dalian 116001, Liaoning Province
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_1030_19

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 > Abstract 


Context: Owing to the increasing age of the population, the incidence of hepatocellular carcinoma (HCC) in the elderly is increasing annually.
Aims: This study aims to investigate the clinical efficacy and safety of transcatheter arterial chemoembolization (TACE) combined with low-dose apatinib for unresectable HCC treatment in elderly patients (≥65 years).
Settings and Design: The clinical data from 61 elderly patients with unresectable HCC who were retrospectively analyzed.
Subjects and Methods: Of these 61 patients, 27 received TACE combined with low-dose (250 mg/qd) apatinib (experimental group), and 34 patients received the standard TACE treatment (control group). The short-term efficacy was evaluated according to the mRECIST1.1 standards, and the mid- and long-term efficacy and safety in the two groups of patients were evaluated.
Statistical Analysis Used: Statistical analyses were performed using the Statistical Package for the Social Sciences software (version 20.0; SPSS).
Results: Both the objective response rate and disease control rate of the experimental group were significantly higher than those of control group (P < 0.05). The 6-month and 12-month survival rates of the experimental group were significantly higher than those of control group too (P < 0.05). The median survival in the experimental group was longer than in the control group (26.0 months vs. 20.0 months). The adverse reactions related to the intake of apatinib were higher in the experimental than the control group, but were generally alleviated after symptomatic treatment.
Conclusions: TACE combined with low-dose apatinib provides an alternative treatment option for elderly patients with unresectable HCC. Our clinical study has proven its safety and efficacy.

Keywords: Apatinib, elderly persons, hepatocellular carcinoma, transcatheter arterial chemoembolization


How to cite this article:
Liu S, Zhao G, Yu G, Guo N, Zhang Y, Li Q, Wang Z. Transcatheter arterial chemoembolization combined with low-dose apatinib in the treatment of unresectable hepatocellular carcinoma in elderly patients: Efficacy and safety. J Can Res Ther 2020;16:1165-70

How to cite this URL:
Liu S, Zhao G, Yu G, Guo N, Zhang Y, Li Q, Wang Z. Transcatheter arterial chemoembolization combined with low-dose apatinib in the treatment of unresectable hepatocellular carcinoma in elderly patients: Efficacy and safety. J Can Res Ther [serial online] 2020 [cited 2020 Oct 26];16:1165-70. Available from: https://www.cancerjournal.net/text.asp?2020/16/5/1165/296421

Liu Song and Zhao Guangsheng are co-first authors





 > Introduction Top


Transcatheter arterial chemoembolization (TACE) is a standard nonsurgical treatment for liver cancer, and clinical studies have confirmed its feasibility and efficacy in elderly patients.[1],[2],[3] TACE combined with molecular-targeted therapy can further improve the survival time of patients with liver cancer.[4] Given the poor basal state of elderly patients with liver cancer, TACE combined with a standard dose of targeted therapy is poorly tolerated in these patients; they often cannot complete the treatment, which greatly impacts efficacy. In this study, we retrospective analyzed the safety and efficacy of TACE combined with low-dose apatinib for the treatment of unresectable hepatocellular carcinoma (HCC) in elderly patients.


 > Subjects and Methods Top


General information

Data from 61 elderly patients with unresectable HCC admitted to Linyi Cancer Hospital from January 2015 to September 2018 were collected. The inclusion criteria were: (1) males or females of ≥65 years of age; (2) patients that met the clinical diagnostic criteria for liver cancer or pathologically confirmed to have primary liver cancer; (3) liver function with a Child–Pugh score of Class A or B; (4) an Eastern Cooperative Oncology Group performance status score of 0–2; (5) normal cardiopulmonary and renal functions, with no treatment contraindications; (6) expected survival of longer than 3 months; (7) patients or family members understood the relevant treatment and signed the informed consent form. The exclusion criteria were: (1) chemotherapy contraindications; (2) dysfunction of the heart, lung, kidney, and other important organs; and (3) severe coagulopathy. The patients were divided into the experimental group (27 patients, treated with TACE combined with low-dose apatinib) and the control group (34 patients, treated with TACE alone) based on the intake of low-dose apatinib.

Treatments

TACE treatment technique: The Seldinger method was used to puncture the right femoral artery and the RH tube was inserted for routine celiac artery and common hepatic artery angiography. According to the location and the size of the tumor and whether the whole tumor was stained, additional angiographies of the phrenic arteries, superior mesenteric artery, left gastric artery, right renal artery, and other ectopic blood-supplying arteries were performed to identify the complete arterial blood supply of the tumor. Selective or superselective catheterization of the tumor feeding artery with a microcatheter was performed, the chemotherapy drugs (oxaliplatin 85 mg/m 2, fluorouracil 800 mg/m 2) were injected, and the epirubicin-iodized oil suspension was then injected slowly. The amount of chemotherapy drugs and iodized oil was determined by the size of the lesion and the abundance of blood supply (generally, 40–60 mg of epirubicin and 5–20 mL of iodized oil were used); if necessary, embolization using gelatin sponge particles was performed. A second angiography was performed after the embolization of target blood vessels, and the embolization effect was evaluated. Patients administered given routine antiemetic drugs before surgery, and routine symptomatic therapy, including hepatoprotective and analgesic treatments after surgery.

Mode of administration

Drug

Apatinib mesylate (brand name: Aitan, Jiangsu Hengrui Medicine Co., Ltd.). Experimental group: 7 days after the TACE treatment, patients started to receive oral apatinib, 250 mg, once daily, until the disease progressed or events that required termination of the treatment happened. Apatinib treatment was to be terminated if the following conditions occurred: (1) severe cardiac adverse events, such as myocardial infarction, persistent tachycardia, and significantly decreased ejection fraction; (2) severe bleeding; (3) severe arterial and venous thromboembolism; (4) gastrointestinal perforation; (5) hypertensive crisis; and (6) the patient became unable to tolerate the treatment.

The evaluation of efficacy and observation of adverse reactions

Outcome measures

Overall survival was the time from the first TACE treatment to the death of the patient or the last follow-up. Objective response rate (ORR) was the proportion of patients showing a complete response (CR) or a partial response (PR) in a treatment group. The disease control rate (DCR) was the proportion of patients with CR, PR, and stable disease (SD) in a treatment group.

Tumor response evaluation

The tumor response was evaluated according to the mRECIST 1.1 criteria. All patients were evaluated comprehensively once every 6–8 weeks after surgery. The re-examination included routine blood tests, liver and kidney function evaluation, AFP, plain chest computed tomography (CT) scan, and upper abdominal enhanced CT/magnetic resonance imaging. The treatment efficacy was evaluated on the basis of the imaging results, and tumor progression was observed to determine whether a second interventional treatment was necessary.

Observation of adverse reactions

Adverse reactions were evaluated according to the National Cancer Institute (NCI) common terminology criteria for adverse events (CTCAE) v3.0, and the safety was also assessed.

Statistical analysis

Statistical data analysis was computed using the SPSS 20.0 software package SPSS 20.0 software package (IBM, New York, US). Percentages (baseline data, ORR, DCR) were subjected to the c2 test; the median overall survival (mOS) and the corresponding curves were analyzed using the Kaplan–Meier method; and the log-rank test was used to compare the survival rate between the groups. A P < 0.05 was considered statistically significant.


 > Results Top


From January 2015 to September 2018, 61 elderly patients with unresectable HCC who were admitted to our hospital, comprising 43 men and 18 women, 65–83 years of age (average = 70.67 ± 7.56 years of age. There was no significant difference in the general characteristics of the two groups [P > 0.05, [Table 1].
Table 1: Comparison of clinical data between the two groups

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Short-term efficacy evaluation

The imaging re-examination results obtained in the first 1–2 months were used as indicators of the short-term efficacy. According to the mRECIST evaluation criteria, there were no cases of complete remission in either group. The experimental group had 18 cases of partial remission, 8 cases of SD, and 1 case of disease progression; the ORR was 66.66%, and the DCR was 96.29%. The control group had 15 cases of partial remission, 14 cases of SD, and 5 cases of disease progression; the ORR was 44.12%, and the DCR was 85.29%. The differences in both ORR and DCR between the two groups were statistically significant (c2 = 3.92, P = 0.03; c2 = 6.50, P = 0.01). The treatment process and imaging follow-up of typical cases are shown in [Figure 1] and [Table 2]
Figure 1: (a) Computed tomography showed multiple lesions in the liver. (b) Digital subtraction angiography showed hepatic artery thickening, disorder. (c) After two transcatheter arterial chemoembolization procedures and apatinib treatment, computed tomography showed tumor shrinkage, with almost no enhancement. (d) Digital subtraction angiography revealed tumor blood vessel normalization

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Table 2: Comparison of objective response rate and disease control rate between the two groups

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Mid- and long-term efficacy evaluation

Follow-ups were conducted until October 2019; the follow-up period was 13–43 months, with an average of 31.75 months. All patients completed their follow-ups. The experimental group had a 6-month survival rate of 100% and a 12-month survival rate of 92.59%. The control group had a 6-month survival rate of 91.17% and a 12-month survival rate of 82.35%. The 6-month and 12-month survival rates of the two groups were significantly different (c2 = 4.33, P = 0.03; c2 = 4.61, P = 0.03, respectively). The mOS of the experimental group was 26.0 months, and that of the control group was 20.0 months; this difference was statistically significant (c2 = 4.82, P = 0.02). The number of TACE procedures performed in the groups was (2.82 ± 0.91) and (4.54 ± 1.40), respectively; the difference was statistically significant (c2 = 5.47, P = 0.02), suggesting that TACE combined with apatinib can reduce the requirement for TACE [Table 3] and [Figure 2].
Table 3: Comparison of survival between the two groups

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Figure 2: Comparison of median survival curves between the two groups

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Adverse reactions

Patients in the experimental group had specific adverse reactions due to the intake of apatinib, which mainly involved fatigue (74.07%), hand-foot skin reaction (51.85%), hypertension (37.04%), myelosuppression (22.22%), proteinuria (18.52%), and diarrhea (18.52%). Two patients had severe blood pressure elevation after drug intake that required temporary discontinuation of medication; they were administered treatment to reduce blood pressure, after which the experimental treatment was gradually restored. The other patients experienced mild adverse reactions that were alleviated after symptomatic treatment and did not require medication to be discontinued. Patients who received TACE mainly had post-embolization syndrome, characterized by fever, nausea, vomiting, and abdominal pain, and did not have serious complications, such as severe liver failure [Table 4].
Table 4: Comparison of adverse reactions during the treatment in the two groups

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 > Discussion Top


The incidence of liver cancer in China is high, with elderly patients comprising approximately 47.5% of the total number of patients with liver cancer.[5] As elderly patients with liver cancer often have complications, such as cardiovascular and cerebrovascular diseases or diabetes, the treatment is more difficult.[6] Therefore, how to comprehensively improve the quality of life of elderly patients with liver cancer and prolong their survival are social healthcare problems that require urgent solutions. TACE is recognized as the first choice for the nonsurgical treatment of patients with liver cancer, and it is the standard treatment for intermediate or advanced stage liver cancer.[7] However, there are still some limitations of TACE: In particular, in patients with poor liver function and high tumor burden, the incidence of side effects and related complications after TACE is high, and ill-considered repetition of TACE treatments may increase the risk of death in patients.[8],[9] Sorafenib is a multi-kinase inhibitor that targets RAF kinase, vascular endothelial growth factor receptor (VEGFR)-1,-2,-3, platelet-derived growth factor receptor-p, c-kit, and RET.[10] The data from the Chinese subgroup of the START study showed that TACE combined with sorafenib for the treatment of liver cancer had a median time to progression (mTTP) of 415 days. For patients with high tumor burden and poor liver function, combination therapy can help control residual lesions, prolong the interval between TACE treatments, and indirectly protect liver function.[11] In recent years, it has also been reported that TACE combined with sorafenib for the treatment of liver cancer did not achieve the desired effect.[12] In addition, despite its relatively high cost, the side effects of sorafenib in the treatment of liver cancer are notable, and may even involve serious adverse events, such as irreversible liver and kidney failures, which greatly limit its clinical application.

Apatinib is a targeted tumor drug developed independently in China in recent years. As a small molecule VEGFR tyrosine kinase inhibitor, it inhibits the growth of endothelial cells of the tumor blood vessels, mainly by inhibiting VEGF-mediated VEGFR-2 phosphorylation and downstream molecular activation, to achieve anti-tumor effects.[13] A study of the treatment of patients with advanced HCC using apatinib showed a DCR of 81% and an mTTP of 10.4 months, suggesting that apatinib can benefit patients with advanced liver cancer.[14] Lu et al.[15] used TACE combined with apatinib in the treatment of intermediate and advanced stage liver cancer, and they reported a higher ORR and prolonged PFS for 6.5 months compared with TACE alone. As a multi-target drug, there are notable side effects associated with apatinib, and most patients have adverse reactions such as fatigue and loss of appetite. At present, for patients with liver cancer treated with TACE, the recommended oral dose of apatinib is 500 mg. However, most elderly patients cannot tolerate this dose, some patients cannot take the medication continuously, and some even have to terminate the treatment early. Studies have confirmed that low doses of apatinib can effectively inhibit VEGFR-2[16] and have a strong antitumor effect. Therefore, it is feasible for the elderly patients with liver cancer to receive a low oral dose of apatinib after TACE treatment.

The results of this study showed that the ORR and DCR of the combined treatment group were significantly better than those of the TACE group. The mOS of the experimental group was 26.0 months, 6.0 months longer than the control group. In addition, combination therapy significantly reduced the number of TACE procedures performed, which indirectly protected the liver function of elderly patients with liver cancer. Peripheral blood VEGF was elevated after TACE, a change considered to be the microenvironmental basis for the recurrence of liver tumor after TACE. Previous studies have shown that apatinib is a highly selective inhibitor of VEGFR-2, affecting the proliferation, migration, and adhesion of vascular endothelial cells, inhibiting the angiogenesis of HCC, and reducing the level of vascular endothelial growth factor, thereby inhibiting tumor growth.[17] In the combination therapy group, digital subtraction angiography (DSA) revealed reduced tumor vascularity, thinner vessels, and even the disappearance of tumor angiography, indirectly confirming the ability of apatinib to inhibit VEGF receptor expression. The normalization of blood vessels can reshape the tumor microenvironment, which is considered as the microenvironmental basis for the treatment of malignant tumors. This process is not solely contingent upon a sufficient amount of targeted drugs that inhibit angiogenesis, as small doses of targeted drugs or a combination of immunosuppressive agents can also achieve this goal.[18],[19]

The results of this study showed that the main adverse reactions after oral intake of apatinib were hypertension, followed by hand-foot syndrome, myelosuppression, proteinuria, and diarrhea; this was consistent with relevant reports.[20],[21] Hypertension often occurred 10–14 days after drug administration. The attributable mechanism was that apatinib also inhibits its own vasodilating effect while inhibiting VEGFR, and the vascular degeneration increases peripheral vascular resistance, which eventually leads to an increase rise in blood pressure. In general, routine internal medicine antihypertensive treatment was sufficient, and preventive antihypertensive treatment was ineffective. Apart from the two cases of third-degree blood pressure elevation in this study, no additional III-degree or higher adverse drug-related reactions occurred in other patients. Moreover, these two patients gradually restarted the medication after a short-term discontinuation of the drug, during which they received the antihypertensive treatment. These results indicated that TACE combined with low-dose apatinib was safe for the treatment of liver cancer in elderly patients.


 > Conclusions Top


The combination of low-dose apatinib treatment after TACE was able to suppress and kill the tumor cells remaining after TACE and avoid the “escape” of tumor cells by inhibiting the formation of new blood vessels, making it possible for the body to completely eliminate the liver tumor cells. The results of this study showed that TACE combined with low-dose apatinib was a safe and feasible treatment for elderly patients with liver cancer, prolonging their survival, and was an ideal option for the treatment liver cancer in elderly patients. The limitation of this study was that this was a single-center study, with selection bias; therefore, and randomized controlled trials with large sample sizes, as well as further basic research, are necessary to validate the efficacy and the relevant mechanisms of the combination therapy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  [Table 1], [Table 2], [Table 3], [Table 4]



 

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