Hepatectomy versus TILA-TACE in the treatment of Resectable Hepatocellular Carcinoma: study protocol for a randomized controlled trial

Abstract Background: Hepatectomy and transcatheter arterial chemoembolization (TACE) are common treatments for hepatocellular carcinoma (HCC). Targeting intratumoral lactic acidosis TACE (TILA-TACE) is a new therapeutic approach developed by our team that has superior response rate and effective rate than conventional TACE (cTACE). In this randomized-controlled trial, we will compare the efficacy of hepatectomy and TILA-TACE in patients clinically diagnosed with HCC to provide reliable clinical data for the subsequent effective treatment of HCC patients. Methods: A total of 230 resectable HCC patients will be given hepatectomy or TILA-TACE using a parallel-controlled approach, and the efficacy of the treatments Page 4 of 24 will be compared. The primary endpoint is the post-treatment progression-free survival (PFS) of the patients, and the secondary endpoints are the post-treatment overall survival (OS), 1-year, 3-year and 5-year survival, and the quality of life of the patients at each corresponding stage. Discussion: The aim of this study is to compare the efficacy of hepatectomy and TILA-TACE in the treatment of resectable HCC. Trial registration: ClinicalTrials.gov,NCT03314532.Registered 2017.


Background
Hepatocellular carcinoma (HCC) is one of the most common cancers in the world with major occurrences in eastern Asian countries such as China [1][2][3][4][5][6] .And its morbidity is still rising [7,8] ,more than 740,000 new cases are reported worldwide each year [9] . HCC is the third leading cause of cancer-related deaths in the world [10,11] . There are multiple treatment options for liver cancer including surgery, transcatheter arterial chemoembolization (TACE), liver transplantation, absolute ethanol injection, radiation therapy, and biological therapy [12] . Surgery is the primary radical treatment measure for HCC [13,14] , but its indication is narrow and is only suitable for certain group of patients.
Another common treatment for liver cancer, TACE, can not only block tumor blood supply, control tumor growth, or even cause necrosis and result in tumor shrinkage, it can also deliver target chemotherapy drugs to the tumor tissue.
The Barcelona Clinic Liver Cancer staging system (BCLC) is one of the more recognized staging criteria and has been recommended by the European Association for the Study of Liver and the American Association for the Study of Liver Diseases [15] . BCLC staging is based on patients' general condition, tumor condition, and liver function to identify the best treatment option and predict prognosis using evidence-based medicine. Surgical excision is recommended for BCLC stage 0, liver transplantation or radiofrequency ablation is recommended for BCLC stage A, and TACE treatment is recommended for BCLC stage B [12] . However, there are still some controversies on the efficacy of TACE treatment.
In recent years, development of technologies has led to improved methods including targeting-intratumoral-lactic-acidosis TACE (TILA-TACE). Early clinical practice has confirmed that compared with TACE, TILA-TACE has a relatively high response rate and efficiency [16] . In clinical practice, the current standard treatments for patients with surgically resectable HCC are controversial and there is no recommendation in the guidelines. Therefore in this study, we will conduct a randomized comparison study of the efficacy of surgical resection and TILA-TACE treatment.

Experimental design
A randomized controlled experimental design method will be adopted.

Grouping and sample size calculation
A parallel comparison design will be used. According to preliminary data, the disease progression-free periods were 67 weeks and 98 weeks after surgical resection and TILA-TACE treatment, respectively. An α value of 0.05 will be used to correspond to the statistical significance level. According to the 1:1 design, the degree of assurance will be set at 80%, the experimental inclusion time will be two years, and the follow-up missing rate will be controlled at 10%. Each group will require 115 cases for a total of 230 cases.
Cases will be randomized by computer into the following groups: (1) Surgery group: HCC resection.

Randomization
A total of 230 HCC patients who qualify the inclusion criteria will be randomized 1:1 into the hepatectomy group and TILA-TACE group (Fig. 1). Treatment will be assigned by the research coordinator based on the randomization table. Aside from the research coordinator, all other research personnel will be concealed from the treatments that the patients are receiving.

Case selection
Diagnostic criteria [17] 1. Evidence of cirrhosis and HBV/HCV infection b. If the diameter of the HSOL is <2cm, at least two of the imaging tests must show the above classical features.
3. Serum AFP≥400ug/L for 1 month or ≥200ug/L for 2 months and other causes of AFP elevation including pregnancy, germline/embryonal cancer, active liver disease and secondary liver cancer are excluded.
Lesion can be completely resected with no residual tumor at the margin of resection.

2.
Residual liver volume is sufficient to compensate for postoperative liver functions.

3.
If HCC is complicated by portal vein tumor thrombus, the tumor thrombus should be grade I or grade II based on the Liver Cancer Study Group of Japan criteria [18] .

Inclusion criteria
Ages 18-75 with no gender, ethnicity, religion, or geographical restrictions.
The following criteria will be used for the evaluation of tumor resectability and adequate remaining liver volume: ≥ 30% remaining liver volume/total liver volume for non-hepatitis patients; ≥ 40% remaining liver volume/total liver volume for hepatitis patients.
Imaging examination with no cancer embolus above the secondary branch of the portal vein.
New lesions found five years after liver cancer treatment.

Child-Pugh A or B grade liver function.
No concurrent malignancies in other systems.
Informed subjects who fully understand and willingly cooperate with the test program with signed relevant documents.

Exclusion criteria
Patients with one or more of the following conditions will be excluded from the study: Suffer from other malignancies.
Have received any other liver cancer treatments.
Pathological diagnosis as non-HCC.
Experience large blood vessel invasion, distant metastases, or unresectable liver cancer.
One or more organ failures.
Child-Pugh C grade liver function.

Case elimination criteria
Other drugs, surgery, or other treatment programs have been used without permission after inclusion in this study.
Accidental death other than death caused by HCC, such as car crash, earthquake, or other unforeseeable disasters.
The data of the eliminated cases will be archived, labeled, and used for statistical analysis of relapse and survival rates in other studies.

Control: HCC resection
Patients who are randomized to this group will receive hepatectomy. Principles of surgery: 1. Complete tumor resection by eye; 2. Absence of residual tumor at the margin of resection; 3. Regular/irregular hepatic segmentectomy, partial hepatectomy or extensive hepatectomy of liver tissues that are burdened by the tumor. After hepatectomy, >30% of residual liver volume should be spared in normal patients, and >40% of residual liver volume should be spared in cirrhosis patients [19] .

Intervention:TILA-TACE treatment
After successful femoral artery catheterization, 5-Fr angiography catheters will be used for complete radiography of the celiac artery, the hepatic artery proper, left and right hepatic arteries and their branches, and 2.8-Fr micro-catheters will be used for complete radiography of the tumor's nutrient arteries and the extrahepatic blood supply such as the inferior phrenic arteries. After micro-catheter superselective catheterization, lipiodolepirubicin emulsions and 5% sodium bicarbonate injection solutions will be used for perfusion of chemotherapy drugs. Different sizes of embolic microspheres will be used alternatively for chemoembolization. For nutrient arteries of relatively large tumors, different sizes of spring coils will be used to block the blood flow to eventually achieve total occlusion of the tumor's nutrient artery.

Clinical experimental procedures
For included cases, patient's disease history, symptoms, signs, and other situations will be examined and patients will sign the informed consent. The patient's age, height, weight, medical history, symptoms, signs, pathological test results, and TNM stages will be recorded. Patients will be grouped randomly using the digital method. According to test requirements, the study intends to be limited to five years. Day 0 will be set as the day when liver resection or the first TILA-TACE treatment is performed. Re-examinations will be conducted one-month post-treatment and every three months thereafter. The content of the re-examination will include symptoms and signs and adverse events. Routine blood tests, liver and renal functions, hepatobiliary-pancreatic-splenic B-ultrasonography, chest low dose high resolution CT, and liver MRI will be performed and the results will be recorded. Bone ECT will be checked every six months.
Disease-progression-free time will be used as the primary endpoint. The disease progression standards for surgical patients will be new intrahepatic or extrahepatic lesion images found during the re-examination. The progress of TILA-TACE patients will be evaluated using EASL criteria on the treated lesions. CR: no imageological residual tumor tissue; PR: residual tumor tissue < 50%; SD: residual tumor tissue > 50% but < 100%; PD: residual tumor tissue > 100%.
For subsequent records until the secondary endpoint, all results will be recorded in the Case Report Form (CFR) for assessing the clinical efficacy and safety with any adverse events observed and recorded. If the patient is unable to come to the hospital for reexamination, the re-examination would be conducted by follow-up methods such as telephone or mail.

Efficacy and safety evaluation
Observation index

Index for diagnosis:
The diagnostic indexes included cancer index, hepatobiliary-pancreatic-splenic B-ultrasonography, liver enhanced MRI, chest low dose high resolution CT, and bone ECT.

Index for therapeutic efficacy:
Index for primary efficacy: The primary efficacy index will be the disease-progression-free survival time of patients in the two groups post-treatment.
Index for secondary efficacy: The secondary efficacy index will be the overall survival period posttreatment, the 1-year, 3-year, and 5-year survival rates, and the assessment of quality-of-life of patients in the two groups at each stage.
be compared between the two groups. Additionally, the rates of the adverse events and adverse reactions occurring during the study will be compared between the two groups.
Statistical analysis will be carried out after all data are collected and p < 0.05 will be considered statistically significant.

Adverse events recording and reporting
Information of non-serious and serious adverse events occurring during treatment will be recorded on the CRF and Adverse event registration form (Appendix file 2.4). In this study, adverse reactions and complications including severe hepatic renal failure, possible chemotherapy drug allergy reaction, or embolization syndrome may occur in a very small portion of patients after TILA-TACE treatment. In light of this, we will fully evaluate liver and kidney functions before operation. Intensive management with care and caution will be used during the perioperative period. Scientific and rational operation procedures will be adopted to reduce complications. Close connections will be strengthened with relevant departments so that adverse events can be reported to the head of the department and the hospital supervisor at once and to the hospital adverse event ethics committee within the time limit.

Data management and statistical analysis
Data recording and auditing: Observation data will be recorded in the CRF by the attending doctor in black or blueblack pen to ensure the data will be recorded completely, accurately and truthfully in a timely manner. Any modifications made by relevant personnel will be signed and dated and amendments will not cover the originals. If possible, relevant laboratory testing sheets will be copied and pasted on the attached page at the end of the CRF.

Data entry:
A data entry program and database have been established for statistical analysis.

Statistical analysis:
Primary and secondary endpoint data in the database will be collected and processed using the SPSS 17.0 statistical software. Patient survival (1-year, 3-year, 5-year OS and PFS) in the two groups will be calculated using the Kaplan-Meier method. A linear mixed model will be constructed to compare the quality of life between the two patient groups at each corresponding stage. P<0.05 is considered statistically significant.

Informed consent
Specific content related to the study should be known by the subject and written informed consent must be obtained from the subject before implementing the study procedures.
The details are described in the consent form (Appendix file 5). The specific process to obtain informed consent is as follows: the doctor will inform the patient about his/her disease characteristics, treatment options, and related risks in detail and then the informed consent form is signed by the patient him/herself or by a legal guardian with capacity for civil conduct.

Discussion
This is a single-center randomized-controlled study aimed to compare the clinical efficacy of hepatectomy versus TILA-TACE in resectable HCC patients. Although both hepatectomy and TACE can be used as the clinical treatment for resectable HCC, the efficacy of these approaches is still debated. A randomized-controlled study by Lei Yin [20] found that patients who received hepatectomy and cTACE had a 3-year survival of 51.5% and 18.1% and a median survival time of 41 months and 18 months, respectively. Therefore, the authors concluded that the efficacy of hepatectomy is superior than cTACE. This finding was also supported by a retrospective non-randomized-controlled trial by Biao Yang et al [21][22][23][24] . who showed that hepatectomy provides significantly higher survival benefits to resectable HCC patients than TACE. In contrast, Lei Jianyong believe that hepatectomy should be used for patients with 1-3 intrahepatic nodules, whereas TACE is recommended for patients with >3 intrahepatic nodules [25] .
In our previous study, we found that the geometric mean of residual live tumor was 6.4 times lower after TILA-TACE than after cTACE. Complete or partial response rate were significantly higher in the TILA-TACE group than in the cTACE group, and the objective response rate of the two groups were 100% and 44.4%, respectively. This indicates that TILA-TACE has superior treatment response rate and effective rate than cTACE. In TILA-TACE provides superior post-treatment survival than cTACE [16] .
There is currently a lack of solid evidence on the efficacy of TILA-TACE versus hepatectomy in the treatment of resectable HCC, and we did not find any literature that compares the efficacy of the two treatment approaches. Further clinical studies, especially randomized-controlled studies, will be needed to provide insights to treatments that are more suitable for HCC patients.
In summary, we will conduct a prospective randomized-controlled study to compare the efficacy of hepatectomy and TILA-TACE in the treatment of resectable HCC in the hopes of providing reliable evidence for the clinical treatment of resectable HCC.  Schedule of enrolment, interventions, and assessments according to standard protocol items: recommendations for interventional trials (SPIRIT).

Supplementary Files
This is a list of supplementary files associated with the primary manuscript. Click to download.
Appendix file 5 Informed consent.pdf