High‐intensity focused ultrasound ablation combined with transcatheter arterial chemoembolization improves long‐term efficacy and prognosis of primary liver cancer

Abstract Background To investigate the clinical efficacy of high‐intensity focused ultrasound (HIFU) combined with transcatheter arterial chemoembolization (TACE) in the treatment of primary liver cancer (PLC) and its effect on the prognosis of patients. Methods A total of 132 patients with PLC admitted to our hospital were selected for the study, among whom 68 patients received TACE combined with HIUF and were assigned to the observation group (OG), whereas the remaining 54 patients were treated with TACE alone and were assigned to the control group (CG). The factors influencing the patients’ prognosis were also evaluated by multivariate analysis. Results The total effective rate of the OG was 83.82%, which was significantly higher than that of 55.56% of the CG (P < .05). No significant difference was found in incidence of adverse reactions between the two groups (P > .05). After treatment, the increases of CD3+, CD4+, CD4+/CD8+, and NK cells in the OG were more significant than those in the CG (P < .05). However, the decrease of CD8+ cells was more significant in the OG than that in the CG (P < .05). The 3‐year survival rate of patients in the OG was 61.76%, which was significantly higher than that of 40.74% in the CG (P < .05). Conclusion The application of TACE combined with HIFU is effective in treating PLC, which can prolong the life expectancy and improve the prognosis of patients with PLC without increasing the incidence of adverse reactions.

before the manifestation of symptoms. This generally leads to a loss of the optimal timing for surgical intervention. 2,3 Transcatheter arterial chemoembolization (TACE) is the mainstream clinical treatment for advanced PLC and the most recognized non-surgical treatment currently. [4][5][6] Although its antitumor effect has been acknowledged, TACE cannot kill tumor cells completely. This is complicated by the fact that repeated treatment can induce local ischemia and hypoxia at the embolized site, leading to an increased synthesis of vascular endothelial growth factor and hypoxia-inducing factor, thus aggravating liver damage. 7,8 The further complication is that several adverse reactions occur during treatment, resulting in unsatisfactory clinical effects. 9,10 In recent years, radiofrequency ablation has been widely applied in the clinical treatment of liver cancer due to its small damage, exact curative effect, and high safety. 11 As a new interventional therapy, high-intensity focused ultrasound (HIFU) ablation has attracted much attention in terms of its therapeutic value in malignant tumors. 12,13 For example, Vidal-Jove 14 considered HIFU to be a potentially effective and safe method for the treatment of malignant tumors, with a survival advantage in the treatment of unresectable pancreatic cancer. Zhang 15 reported that HIFU could achieve complete tumor necrosis even if the lesion was located near the major liver vessels and could be safely used to ablate tumors adjacent to the major blood vessels. Although HIFU has been proven to be more valuable in the treatment of pancreatic and liver cancers, few studies have been conducted on HIFU ablation combined with TACE in the treatment of PLC.
Therefore, in this study, we analyzed the clinical efficacy of TACE combined with HIFU in monitoring the liver function of patients with PLC, and examined the long-term survival rate of patients treated with this regimen and the main factors that affect prognosis, so as to provide a reference for the development of individualized treatment plan and prognosis for patients with PLC.

| General information
A total of 132 patients with PLC admitted to our hospital between June 2014 and August 2016 were selected as the study subjects.
Patients who were treated with TACE combined with HIUF were assigned in the observation group (OG) (n = 68) and those who were treated with TACE alone were assigned to the control group (CG) (n = 54). There were 44 males and 24 females in the OG, aged 37-63 years (average age 51.71 ± 11.26 years). In the CG, there were 38 males and 16 females, aged 41-65 years (average age 50.29 ± 10.27 years).

| Inclusion and exclusion criteria
Inclusion criteria: All the patients met the diagnostic criteria of PLC through puncture biopsy or according to the criteria of European Association for the Study of the Liver. 16 They neither received any prior treatment before admission nor surgical indication or antisurgical treatment. In addition, the patients and their family members were fully informed, and informed consent form was signed and provided by them. This study has been approved by the Ethics

| Treatment
After admission, patients in the CG received TACE alone. The specific methods were as follows: The Seldinger technique was used to percutaneously puncture the femoral artery into the hepatic artery, and the donor artery of the tumor was determined by DSA perfusion angiography, followed by the conduction of TACE. The number of times TACE was needed was determined every 3-4 weeks depending on the blood supply artery, with 1-3 times per person. Patients in the OG underwent ultrasound ablation on the 7th day after TACE treatment as those in the CG. JC200HIFU treatment system was adopted, with the parameters set as follows: frequency: 0.96 MHz, focal length: 134 mm, focus: (length × width) 6 × 2 mm 2 , and the focal field sound intensity range: 4000-12 000 W/cm 2 . Under general anesthesia, the treatment area was cleaned, prepared for skin treatment, and the location and size of the tumor were determined according to the imaging examination results. Next, the treatment position was adjusted and artificial pleural effusion was performed according to the patient's condition. After establishing the safety sound channel, the patient was subjected to HIFU ablation treatment. Intraoperatively, the gray scale changes in the target tissues, skin, and adjacent organs were closely monitored. The treatment was conducted from point to line, line to surface, and deep to shallow, with the coverage exceeding 1 cm of the tumor boundary.

| Efficacy evaluation
The study subjects were examined by abdominal CT or MRI before and 1 month after treatment. According to the volume change of tumor focus, the tumor volume reduction rate was measured and calculated as follows: volume reduction rate = (pretreatment volume-post-treatment volume)/pretreatment volume × 100%.

| Patient follow-up
All the 132 patients were followed up by telephone or interview every 3 months for 3 years until August 2019. Three months after treatment is the exact testing time of the immune function after treatment. The total survival period was considered from the first day after surgery to the last follow-up or death.

| Statistical analysis
The data were statistically analyzed by Statistic Package for Social Science (SPSS) 23.0 (IBM Corp, Armonk, New York, USA). The measurement data were expressed as mean ± standard deviation (mean ± SD), and the counting data were represented by [n (%)]. A t test of independent samples was employed for intergroup comparison of measurement data, and a paired t test was applied for intragroup comparison. The counting data within the group were expressed as the number of cases (%), and the chi-square test was used for comparison. P < .05 indicated a statistically significant difference.

| General information
There was no statistically significant difference in the general information between the two groups, including gender, age, smoking history,

Categories
The OG (n = 68) The CG (n = 54) t/χ 2 P  the total effective rate was 55.56%. Therefore, the total effective rate of the OG was significantly higher than that of the CG (P < .05) ( Table 2).

| Adverse reactions in the two groups
In the OG, there were 3 cases (4.41%) of skin burns, 2 (2.94%) of liver function injury, and 6 (8.82%) of nausea and loss of appetite, and the incidence of total adverse reactions was 16.18%. In the CG, there was 1 case (1.85%) of skin burns, 3 (5.56%) of liver function injury, and 5 (9.26%) of nausea and loss of appetite, and the total incidence of adverse reactions was 16.67%. The above data indicated that there was no significant difference in the incidence of skin burns, liver function injury, nausea, and loss of appetite between the OG and CG (P > .05) ( Table 3).

| Three-year survival of patients in the OG and CG after surgery
We found that the 3-year survival rate of the OG was higher than that of the CG, with a statistically significant difference (P < .05) ( Figure 2).

| Univariate analysis on the prognosis of patients with PLC
The clinical data of patients in the survival and death groups were collected for univariate analysis. It was observed that there was no difference in terms of gender, smoking history, tumor location, WBC, PLT, or tumor location between the two groups (P > .05). However, a significant difference was observed in the lesion size, bilirubin level, treatment methods, combined with collateral portal vein circulation, and AFP (P < .05) ( Table 5).

| Multivariate analysis of prognosis and survival of patients with PLC
Indicators with differences in univariate analysis were included in the assignment (the assignment tables are shown in Table 6), followed by multivariate Cox regression analysis. The results indicated that lesion size, bilirubin level, treatment methods, combined with portal vein collateral circulation, and AFP were independent risk factors affecting the prognosis of HCC (P < .05) ( Table 7).

| D ISCUSS I ON
PLC is one of the most common malignant tumors. According to clinical studies, people aged 40-50 years are the most susceptible to the occurrence of PLC, and its incidence in males is significantly higher than that in females. 18,19  interventional therapy, HIFU ablation has been recognized for its efficacy and safety in the treatment of liver cancers. [27][28][29] The results of this study showed that the clinical efficacy of the OG was significantly higher than that of the CG, and there was no significant difference in the incidence of skin burns, impairment of liver function, and abdominal discomfort between the two groups (P < .05).
Siyu 30 observed that the effective and total effective rates of TACE combined with HIFU were 61.1% and 94.4%, respectively, which were significantly higher than those in the CG. According to Luo,31 TACE combined with HIFU for PLC had a higher overall response rate and a lower incidence of damage to normal liver tissues, which could completely kill tumor cells and reduce postoperative local recurrence and metastasis rate with fewer adverse reactions. This was consistent with the results of our study that TACE combined with HIFU ablation was a feasible option with considerable efficacy.
The occurrence, progression, and metastasis of PLC are closely related to the immune function of the body. 32   depth. This should be explored in subsequent trials.
In conclusion, TACE combined with HIFU regimen has a better efficacy in treatment of PLC. It can also prolong the survival of patients without increasing the incidence of adverse reactions, which is clinically useful.

CO N FLI C T O F I NTE R E S T S
None.