Curative effect of transcatheter arterial chemoembolization combined with radiofrequency ablation in treating hepatic cell carcinoma and its effect on serum markers

Abstract

BACKGROUND:

Hepatic cell carcinoma (HCC) is more common in clinical practice, and has high malignant degree.

OBJECTIVE:

This study aims to analyze the curative effect of transcatheter arterial chemoembolization (TACE) combined with radiofrequency ablation (RFA) in treating hepatic cell carcinoma (HCC) and its effect on serum markers.

METHODS:

A total of 106 cases of patients with hepatic cell carcinoma treated in our hospital were randomly divided into two groups: observation group and control group. Patients in the observation group (53 cases) received transcatheter arterial chemoembolization combined with radiofrequency ablation therapy, while subjects in the control group (53 cases) received transcatheter arterial chemoembolization therapy. Differences in the overall effect, indicators of inflammation and oxidative stress, tumor activity-related indicators and tumor recurrence-related indicators between these two groups were compared.

RESULTS:

At one and two weeks after treatment, the number of cases of CR and PR in the observation group was higher than that in the control group, the number of cases of SD was not different from that in the control group, and the number of cases of PD was lower than that in the control group. At two weeks after treatment, differences in serum MDA, SOD, GSH, CRP, TNF- $\alpha$ and ESR between the two groups were significant. However, serum EC, VEGF, MMP, AFP, CA199 and GGT content was significantly lower in the observation group than that in the control group.

CONCLUTIONS:

Transcatheter arterial chemoembolization combined with radiofrequency ablation therapy can effectively control the growth of liver cancer lesions, reduce the levels of tumor-related serum markers, and inhibit the activity of tumor cells.

Keywords

Hepatic cell carcinoma transcatheter arterial chemoembolization radiofrequency ablation tumor markers

1. Introduction

Hepatic cell carcinoma (HCC) is a common clinical malignant tumor, and has high malignant degree. At present, liver tumor resection, liver transplantation and other therapies have a significant curative effect. However, only 20% of patients can be operated; furthermore, there is generally no clinical symptom in its early stage, and it is also very difficult to detect. Most patients have developed to the middle-late stage when they are clinically diagnosed, and they cannot receive surgical resection due to multiple lesions in the liver or with cirrhosis and other factors [1].

Most HCCs have a restored arterial blood supply suitable for transcatheter arterial chemoembolization (TACE). This procedure can effectively block the supply artery of a tumor, and induce the ischemic necrosis of tumor cells, reduce tumor volume and decrease the activity of tumor cells. However, due to the incomplete embolism agent filling in tumors, incomplete tumor cell necrosis, easy relapse after treatment and other problems, patients have to receive embolization many times; and its curative effect is not ideal.

Radiofrequency ablation (RFA) is a new minimally invasive therapy that locally destroys tumors. It is performed under CT or ultrasound guidance. An ablation needle is inserted into the tumor, and a high-frequency current generates heat around the electrode, which causes protein denaturation, membrane disintegration, coagulation and necrosis in local tumor cells. It is expected to fill the defects of TACE therapy, and its combination with TACE becomes a therapy that can effectively control the illness of patients with HCC [2]. In this study, the curative effect of transcatheter arterial chemoembolization combined with radiofrequency ablation in treating hepatic cell carcinoma and its effect on serum markers were mainly analyzed. The report is as follows.

2. Patients and methods

2.1 Patients

A total of 106 patients with hepatic cell carcinoma treated in Interventional Medicine Department of Navy General Hospital from June 2012 to June 2014 were enrolled into this study. All patients were diagnosed through cell biopsy pathology, and randomly divided into two groups: observation group and control group ( $n=$ 53, each group). Patients in the observation group received transcatheter arterial chemoembolization combined with radiofrequency ablation therapy. Among these patients, 30 patients were male and 23 patients were female; and their age ranged within 53–76 years old, with an average age of 63 $\pm$ 7 years. Subjects in the control group received transcatheter arterial chemoembolization therapy. Among these subjects, 31 subjects were male and 22 subjects were female; and the age of these subjects ranged within 55–74 years old, with an average age was of 63 $\pm$ 6 years old. The general information is shown in Table 1. All patients were confirmed with hepatic cell carcinoma through biopsy pathology, except for patients who could not receive surgical resection of liver cancer. The remaining patients flatly refused surgical treatment. All participants signed an informed consent. Differences in general information between the two groups were not statistically significant.

Table 1
The general information of patients

General information the TACE $+$ RFA group the TACE group

Case number

Man 30 31

Woman 23 22

Average age 63 $\pm$ 7 63 $\pm$ 6

Child-Pugh Classification

A 29 28

B 21 20

C 3 5

HBsAg positive 46 43

Tumor staging (UICC/AJCC 2010)

II 34 36

III (A.B) 19 17

General information the TACE $+$ RFA group the TACE group
Case number
Man	30	31
Woman	23	22
Average age	63 $\pm$ 7	63 $\pm$ 6
Child-Pugh Classification
A	29	28
B	21	20
C	3	5
HBsAg positive	46	43
Tumor staging (UICC/AJCC 2010)
II	34	36
III (A.B)	19	17

Figure 1.

Clinical efficacy of patients 1 week and 2 weeks after treatment. Left figure was the overall efficacy 1 week after treatment and right figure was the overall efficacy 2 weeks after treatment.

2.2 Treatment methods

Subjects in the control group received transcatheter arterial chemoembolization, and the detailed method was as follows: Routine disinfection and draping was performed. Then, femoral artery catheterization was conducted. Next, the artery catheter was inserted to develop a superior mesenteric artery, celiac trunk and proper hepatic artery; making the supply artery of the tumor clear and selectively inserting the artery catheter. After ensuring that the catheter was in position, 40–80 mg of cisplatin and 30–50 mg of epirubicin was injected. Then, the emulsion of 20 mg of pirarubicin $+$ 5–20 ml of iodized oil mixture was injected. Finally, gelatin foam was used for proximal artery embolism. Patients in the observation group received transcatheter arterial chemoembolization $+$ radiofrequency ablation, and the detailed method is as follows: The same TACE method was performed as that in control group. After completion, radiofrequency ablation was conducted, the patient’s posture was set according to the puncture path under CT guidance, CT scan locating was performed, and a 15 G RFA needle and RITA 1500 RF emitting device was used to treat the liver cancer lesions of patients. Lesion ablation temperature was set to 105 ${}^{\circ}$ C, the diameter of the ablation range might reach 5 cm, and single point puncture and ablation range superposition in different directions were adopted. After the ablation was completed, the needle was withdrawn; and the puncture channel was ablated to prevent the bleeding and implantation of metastatic tumor.

2.3 Observation indicators

2.3.1 Clinical efficacy assessment

At one and two weeks after treatment, the following criteria were referred to assess overall efficacy: complete remission (CR), refers to the disappearance of all lesions; partial remission (PR), refers to the reduction of the total major diameters of lesions by more than 30%; stable disease (SD), refers to the reduction in the total major diameters of lesions but less than PR or increase but less than PD; progressive disease (PD), refers to the increase in the total major diameters of lesions by more than 20% or the emergence of a new lesion.

2.3.2 Serum indicators

Before treatment and at two weeks after treatment, serum was collected and enzyme-linked immunosorbent assay was used to detect EC, VEGF, MMP, AFP, CA199, GGT, CRP and TNF- $\alpha$ content. Radioimmunoprecipitation was used to detect MDA, SOD and GSH content.

2.4 Statistical methods

SPSS 13.0 software was used to input and statistically analyze data, measurement data analyzed by t-test, and count data was analyzed by chi-square test. $P<$ 0.05 was considered statistically significant.

3. Results

3.1 Clinical efficacy assessment results

At one and two weeks after treatment, the overall efficacy assessment results of the two groups are shown in Fig. 1. The detailed analysis is as follows: at one and two weeks after treatment, the number of CR and PR cases was higher in the observation group than in the control group, the number of SD cases was not different from that of the control group, and the number of PD cases was lower than that in the control group.

3.2 Tumor activity-related indicators

Before and after treatment comparisons revealed that serum EC, VEGF and MMP content in the two groups were significantly lower at two weeks after treatment than before treatment. Comparison between the two groups revealed that before treatment, serum tumor activity-related indicators in the observation group were not different from that in the control group. At two weeks after treatment, serum EC, VEGF and MMP content were significantly lower in the observation group than in the control group. The specific numerical and statistical analysis is shown in Table 2.

Table 2
Comparison of serum EC, VEGF and MMP contents between two groups

Groups EC (ng/ml) VEGF (pg/ml) MMP (ng/L)

Before treatment After treatment Before treatment After treatment Before treatment After treatment

Observation group 2632.37 $\pm$ 178.76 1767.27 $\pm$ 115.66 407.09 $\pm$ 72.95 209.61 $\pm$ 37.62 127.76 $\pm$ 11.32 32.51 $\pm$ 4.37

Control group 2616.55 $\pm$ 209.25 2353.14 $\pm$ 158.52 410.27 $\pm$ 70.62 356.36 $\pm$ 59.46 128.21 $\pm$ 12.57 71.24 $\pm$ 7.33

t 0.218 7.594 0.321 6.894 0.183 7.039

P $>$ 0.05 $<$ 0.05 $>$ 0.05 $<$ 0.05 $>$ 0.05 $<$ 0.05

Groups	EC (ng/ml)	VEGF (pg/ml)	MMP (ng/L)
Observation group	2632.37 $\pm$ 178.76	1767.27 $\pm$ 115.66	407.09 $\pm$ 72.95	209.61 $\pm$ 37.62	127.76 $\pm$ 11.32	32.51 $\pm$ 4.37
Control group	2616.55 $\pm$ 209.25	2353.14 $\pm$ 158.52	410.27 $\pm$ 70.62	356.36 $\pm$ 59.46	128.21 $\pm$ 12.57	71.24 $\pm$ 7.33
t	0.218	7.594	0.321	6.894	0.183	7.039
P	$>$ 0.05	$<$ 0.05	$>$ 0.05	$<$ 0.05	$>$ 0.05	$<$ 0.05

3.3 Tumor recurrence-related indicators

Comparison between before and after treatment revealed that serum AFP, CA199 and GGT content in the two groups were significantly lower at two weeks after treatment than at before treatment. Furthermore, comparison between the two groups revealed that before treatment, serum tumor recurrence-related indicators in the observation group were not different from that in the control group. At two weeks after treatment, serum AFP, CA199 and GGT content were significantly lower in the observation group than in the control group. The specific numerical and statistical analysis is shown in Table 3.

Table 3
Comparison of tumor recurrence-related indicators before and after two groups received different treatment

Groups AFP (ng/ml) CA199 (U/L) GGT (U/L)

Before treatment After treatment Before treatment After treatment Before treatment After treatment

Observation group 183.29 $\pm$ 37.24 73.15 $\pm$ 9.42 80.17 $\pm$ 9.24 34.28 $\pm$ 5.02 150.26 $\pm$ 15.39 89.77 $\pm$ 9.32

Control group 182.16 $\pm$ 34.09 134.81 $\pm$ 21.24 79.44 $\pm$ 10.03 65.24 $\pm$ 8.21 149.21 $\pm$ 16.28 123.83 $\pm$ 11.73

t 0.184 7.284 0.218 6.824 0.183 7.892

P $>$ 0.05 $<$ 0.05 $>$ 0.05 $<$ 0.05 $>$ 0.05 $<$ 0.05

Groups	AFP (ng/ml)	CA199 (U/L)	GGT (U/L)
Observation group	183.29 $\pm$ 37.24	73.15 $\pm$ 9.42	80.17 $\pm$ 9.24	34.28 $\pm$ 5.02	150.26 $\pm$ 15.39	89.77 $\pm$ 9.32
Control group	182.16 $\pm$ 34.09	134.81 $\pm$ 21.24	79.44 $\pm$ 10.03	65.24 $\pm$ 8.21	149.21 $\pm$ 16.28	123.83 $\pm$ 11.73
t	0.184	7.284	0.218	6.824	0.183	7.892
P	$>$ 0.05	$<$ 0.05	$>$ 0.05	$<$ 0.05	$>$ 0.05	$<$ 0.05

3.4 The serum indicators for inflammation and oxidative stress

The analysis of serum indicators for inflammation and oxidative stress in the two groups at two weeks after treatment is shown in Table 4. There were no differences in serum MDA, SOD, GSH, CRP, TNF- $\alpha$ and ESR levels in the two groups.

Table 4
Comparison of serum indicators of inflammation and oxidative stress between two groups

SOD (U/ml) GSH (U/L) MDA ( $\mu$ g/L) CRP (mg/L) TNF- $\alpha$ ( $\mu$ g/L) ESR (mm/h)

Observation group 41.29 $\pm$ 5.52 61.48 $\pm$ 7.24 17.69 $\pm$ 2.15 14.28 $\pm$ 1.74 64.71 $\pm$ 7.24 17.52 $\pm$ 1.88

Control group 43.74 $\pm$ 4.92 62.16 $\pm$ 6.92 17.14 $\pm$ 1.92 13.89 $\pm$ 1.59 65.11 $\pm$ 6.75 17.79 $\pm$ 1.91

t 0.482 0.220 0.175 0.129 0.159 0.220

P $>$ 0.05 $>$ 0.05 $>$ 0.05 $>$ 0.05 $>$ 0.05 $>$ 0.05

	SOD (U/ml)	GSH (U/L)	MDA ( $\mu$ g/L)	CRP (mg/L)	TNF- $\alpha$ ( $\mu$ g/L)	ESR (mm/h)
Observation group	41.29 $\pm$ 5.52	61.48 $\pm$ 7.24	17.69 $\pm$ 2.15	14.28 $\pm$ 1.74	64.71 $\pm$ 7.24	17.52 $\pm$ 1.88
Control group	43.74 $\pm$ 4.92	62.16 $\pm$ 6.92	17.14 $\pm$ 1.92	13.89 $\pm$ 1.59	65.11 $\pm$ 6.75	17.79 $\pm$ 1.91
t	0.482	0.220	0.175	0.129	0.159	0.220
P	$>$ 0.05	$>$ 0.05	$>$ 0.05	$>$ 0.05	$>$ 0.05	$>$ 0.05

4. Discussion

Hepatic cell carcinoma (HCC) is more common in clinical practice, most patients are unable to receive surgical treatment due to multiple lesions, intrahepatic metastasis, or complications with liver cirrhosis [3]. Transcatheter arterial chemoembolization (TACE) is the main palliative therapy for HCC. However, TACE alone can only become a mild palliative therapy due to collateral circulation, multiple vascular blood supply, incomplete embolism of the treatment itself, and other factors in liver cancer. Furthermore, this procedure is only valid for approximately 50% of patients, and lesion necrosis rate is low [4, 5].

As a a new minimally invasive therapy, RFA can locally and completely destroy tumor cells and induce them to detach. This would eventually trigger tumor tissue loss and play a therapeutic role in destroying tumor cells [6, 7]. Studies have shown that the application of RFA treatment to patients with HCC has similar overall survival rates to that of surgery, demonstrating the effectiveness of RFA treatment. At the same time, RFA treatment has the advantages of small trauma, quick recovery, and so on. This has been a promising clinical method for the treatment of HCC at present, and it can be combined with TACE to change the current treatment status of HCC [8].

In the present study, subjects in the control group received conventional TACE therapy, while patients in the observation group received radiofrequency ablation based on TACE therapy. The assessment of overall efficacy revealed that the number of CR and PR cases was higher in the observation group than in the control group, the number of SD cases was not different from that in the control group, and the number of PD cases was lower than that in the control group. TACE treatment has the advantage of having 100–400 times of the drug concentration in the local tumor area. Hence, it can destroy tumor cells and cause fibrous septum disintegration within the tumor. However, in TACE, the inactivation of tumor cells is incomplete; and the rapidly established collateral circulation can cause tumor tissue proliferation again and expand the tumor volume. Hence, the curative effect of TACE alone on HCC is poor and macroscopically manifested as an unsatisfactory effect on the shrinking tumor area. However, after RFA was added, the killing effect on tumor cells was more complete, tumor tissues were inactivated and lost, and the mass rapidly shrank [9, 10]. In the present study, serum indicators of oxidative stress and inflammation in the two groups were analyzed to reflect the degree of trauma caused by the different treatment methods. Results revealed that differences in serum MDA, SOD, GSH, CRP, TNF- $\alpha$ and ESR levels in the two groups were not significant. This indicates that TACE combined with RFA does not increase trauma to the body.

Alpha-fetoprotein (AFP) is an important tumor marker, and its concentration in blood is closely correlated with changes in HCC. CA199 significantly increases in serum of patients with digestive system neoplasms. The study conducted by Tsuchiya et al. [11] revealed that CA199 level is elevated in most patients with primary liver carcinoma. Hence, CA199 can become one of the markers for judging the therapeutic effect and prognosis of primary liver cancer together with other indicators. In cases of liver cancer, due to the pressed bile duct and blocked bile discharge, glutamyl transpeptidase (GGT) content in liver cells increases [12]. Hence, serum GGT level dramatically increases. The combined application of the above AFP, CA199 and GGT can be used as indicators to judge the recurrence of primary liver cancer treatment. Furthermore, the above research results revealed that serum AFP, CA199 and GGT content after treatment were significantly lower in the observation group than in the control group. Moreover, this indicate that TACE combined with RFA treatment for patients with hepatic cell carcinoma has the thoroughness and integrity in killing tumor cells. This would make the body’s serum indicators become normal and reduce the likelihood of recurrence after treatment.

E-cadherin (EC) is a kind of Ca-dependent cell adhesion glycoprotein. It can maintain epithelial cell polarity and intercellular junctions, and plays an important role in cell migration and tissue differentiation. The development and metastasis of cancer involve EC function or expression deletion, and the downregulation of EC can reduce the intensity of cell adhesion within tissues. This would lead to increased cell activity, and allow cancer cells to cross through the basement membrane and invade surrounding tissues; which is the key to causing cancer cell invasion and metastasis. Vascular endothelial growth factor (VEGF) has been believed to be the cytokine with the strongest pro-angiogenesis effect in existing studies. It can directly regulate the function of vascular endothelial cells, promote their proliferation, and increase vascular permeability [13, 14]. In HCC cells, VEGF can be combined with receptors in blood vessels and lymphatic vessels, and promote tumor growth and metastasis. The matrix metalloproteinase (MMP) family is a family of zinc ion-dependent proteases that can degrade a variety of components in the extracellular matrix and promote tumor metastasis [15]. EC, VEGF and MMP all play important roles in the cancer cell invasion and metastasis process, and are also serum markers of the activity or malignant capacity of cancer cells. Furthermore, the above research results revealed that EC, VEGF and MMP levels after treatment were lower in the observation group than in the control group. This indicates that TACE combined with RFA treatment could effectively inhibit the activity of cancer cells and inhibit their capacity of invasion and metastasis.

Past studies suggest that oxidative stress and blood inflammatory factors are associated with the degree of organism injury after treatment. This result indicates that TACE combined RFA will not increase the trauma of the body.

In summary, it can be concluded that transcatheter arterial chemoembolization combined with radiofrequency ablation therapy can effectively reduce lesion volume in patients with hepatic cell carcinoma, inhibit tumor cell activity, and reduce long-term relapse. Hence, it is worth further popularization in clinical practice.

Fundings

National Natural Science Foundation of China (No.30670612); China International Medical Foundation (No.Z-2014-06-15322); Navy Logistics Department (No.HJHQ-20130987).

Footnotes

Conflict of interest

We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted.

References

Choi

Koom

W.S.

Kim

T.H.

et al., A Prospective Phase 2 Multicenter Study for the Efficacy of Radiation Therapy Following Incomplete Transarterial Chemoembolization in Unresectable Hepatocellular Carcinoma [J], Int J Radiat Oncol Biol Phys 90 (2014), 1051–1060.

J.K.

Yin

et al., Therapeutic effect of transcatheter arterial chemoembolization combined with radiofrequency ablation or 1251 interstitial brachytherapy on primary hepatocellular carcinoma: a comparative study [J], Journal of Interventional Radiology 18 (2009), 328–330.

Cruz

J.E.

Saksena

Jabbour

S.K.

et al., The power of genes: a case of unusually severe systemic toxicity after localized hepatic chemoembolization with irinotecan-eluted microspheres for metastatic colon cancer [J], Ann Pharmacother 48 (2014), 1646–1650.

Zhao

Zhang

Wei

et al., Transcatheter arterial chemoembolization combined with radiofrequency ablation for the treatment of hepatocellular carcinoma: a meta-analysis of long-term efficacy [J], Journal of Interventional Radiology 22 (2013), 387–389.

Tang

Y.L.

X.S.

and Guo

X.Z.

, Hepatic Resection after Initial Transarterial Chemoembolization Versus Transarterial Chemoembolization Alone for the Treatment of Hepatocellular Carcinoma: A Meta-analysis of Observational Studies [J], Asian Pac J Cancer Prev 16 (2015), 7871–7874.

Hammond

J.S.

Franko

Holloway

S.E.

et al., Gemcitabine transcatheter arterial chemoembolization for unresectable hepatocellular carcinoma [J], Hepatogastroenterology 61 (2014), 1339–1343.

Butros

S.R.

Shenoy

B.A.

Mueller

P.R.

et al., Radiofrequency ablation of intrahepatic cholangiocarcinoma: feasability, local tumor control, and long-term outcome [J], Clin Imaging 38 (2014), 490–494.

Casaccia

Santor

Bottino

et al., The procedure outcome of laparoscopic resection for ’small’ hepatocellular carcinoma is comparable to vlaparoscopic radiofrequency ablation [J], J Minim Access Surg 11 (2015), 231–235.

and Yu

, Gemcitabine combined with oxaliplatin into hepatic artery embolism chemotherapy clinical observation of treatment of advanced hepatocellular carcinoma [J], Strait Pharmaceutical Journal 27 (2014), 198–199.

10.

Camilo

C.G.

Yuman

Mithat

et al., A retrospective comparison of microwave ablation radiofrequency ablation for colorectal cancerhepatic metastases [J], Ann Surg Oncol 21 (2014), 4278–4283.

11.

Tsuchiya

Asahina

Tamaki

et al., Risk factors for exceeding the Milan criteria after successful radiofrequency ablation in patients with early-stage hepatocellular carcinoma [J], Liver Transpl 20 (2014), 291–297.

12.

Honda

Kimura

Aikata

et al., Pilot study of stereotactic body radiation therapy combined with transcatheter arterial chemoembolization for small hepatocellular carcinoma [J], Hepatogastroenterology 61 (2014), 31–36.

13.

Cao

Qin

et al., Prognostic Value of VEGF in Hepatocellular Carcinoma Patients Treated with Sorafenib: A Meta-Analysis [J], Med Sci Monit 18 (2015), 3144–3151.

14.

Chinh

C.D.

Thanh

L.L.

Nghia

S.H.

et al., Downregulation of Vascular Endothelial Growth Factor Enhances Chemosensitivity by Induction of Apoptosis in Hepatocellular Carcinoma Cells [J], Cell J 17 (2015), 273–287.

15.