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.
(2) TILA-TACE group: TILA-TACE treatment.
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.
1. Evidence of cirrhosis and HBV/HCV infection
2. Classical imaging features of HCC: MRI/CT/CEUS/EOB-MRI shows arterial hypervascularity and venous or delayed phase washout of the hepatic space-occupying lesion (HSOL).
a. If the diameter of the HSOL is ≥2cm, one of the imaging tests must show the above classical features.
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.
4. Liver biopsy indicates HCC.
Patients are clinically diagnosed with HCC if (1) + (2)a or (1) + (2)b + (3) are met, or pathologically diagnosed with HCC if (4) is met.
Definition of resectable HCC:
- Lesion can be completely resected with no residual tumor at the margin of resection.
- Residual liver volume is sufficient to compensate for postoperative liver functions.
- 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.
- Ages 18–75 with no gender, ethnicity, religion, or geographical restrictions.
- Diagnosed HCC patient.
- 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.
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.
- Incomplete surgical resection or TILA-TACE.
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.
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, lipiodol-epirubicin 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 re-examination, the re-examination would be conducted by follow-up methods such as telephone or mail.
Efficacy and safety evaluation
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 post-treatment, 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.
- Adverse events occurring during study period, such as anaphylaxis, embolization syndrome, or other related adverse reactions after TILA-TACE treatment or surgery-related complications will be closely monitored.
- General physical examinations will include (temperature, resting heart rate, respiration, blood pressure), routine blood tests, liver functions (TBill, AST, ALT, Alb), cancer markers, chest high resolution CT plain scan, liver enhanced MRI, hepatobiliary-pancreatic-splenic B-ultrasonography, and bone ECT.
- The adverse event rate will be the main index for safety evaluation.
Effectiveness evaluation standard
The disease-progression-free period of patients after treatment. This will be the time period from the beginning of treatment to the time that disease progression has been observed.
The overall survival period recorded from the beginning of the treatment, the follow-up, until the death of the patient or the end of the study period, as well as the 1-year, 3-year, and 5-year survival rates. In the meantime, the patient's quality-of-life will be recorded.
Changes in the physical examination and laboratory tests before and after treatments will 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 blue-black 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.
A data entry program and database have been established for 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.
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.