RCT of TAE Simultaneously Combined Thermal Ablation for Large Hepatocellular Carcinoma

Study Overview
=================
Brief Summary
-----------------
This study intends to evaluate the efficacy and safety of Transarterial embolization (TAE) simultaneously combined with thermal ablation for large hepatocellular carcinoma (HCC). Half participants will receive TAE simultaneously combined with thermal ablation and the other half receive TACE sequentially combined with thermal ablation, which is a conventional treatment for HCC patients.

Detailed Description
-----------------
The treatment method Transarterial chemoembolization (TACE) sequentially combined with thermal ablation is recommend for large HCC patients from NCCN Guideline and Chinese guideline Diagnosis and Treatment of Primary Liver Cancer. The details of this sequential method consist one or more times of TACE followed by thermal ablation at least one month later to make the tumor completely inactivate. The thermal ablations include multiple applicators radiofrequency or microwave ablations. However, this method includes such disadvantages. 1) The limitation of lipiodol dosage in one TACE session is 30ml so that many patients needs more sessions of TACE; (2) Lipiodol and chemical drugs is easy to leak when patients have hepatic arteriovenous fistula. (3) Repeated TACE could cause more serious side effects. (4) Tumors of many patients are still not controlled or grow too large to ablate after TACEs which increases the metastasis risk and affects the efficacy and survival time. However, TAE simultaneously combined with thermal ablation is another combination type which reduce the interval time between two procedures from one month to 1-3 days. TAE removes the chemical drugs and uses embolic agents such as Embosphere to obstruct vessels to enhance the effect of followed ablations. The main aim of reducing interval and remove chemical drugs is to make the tumor completely inactivate in one hospitalization like surgical operation, hoping bringing less side effects, better efficacy and longer survival time. Thus the investigators will launch a prospective, multicenter randomized controlled clinical trial to compare the 3-years overall survival, safety, social and economic benefit of TAE simultaneously combined with ablation and TACE sequentially combined with ablation. The investigators expect to acquire Ia-level evidence-based medical evidence which can be accepted by the clinical guideline, popularizing, demonstrating our therapy.

Official Title
-----------------
Randomized Controlled Trial of Transarterial Embolization Simultaneously Combined Thermal Ablation for Large Hepatocellular Carcinoma

Conditions
-----------------
Hepatocellular Carcinoma, Adult

Intervention / Treatment
-----------------
* Drug: Chemotherapy drug
* Drug: Embolic agents
* Procedure: Simultaneously
* Procedure: Sequentially
* Device: Ablation


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age between 18 to 70 years with estimated survival over 3 months Number of tumors < 3 Diameter of tumor between 5cm to 15cm No portal vein trunk tumoral thrombus or inferior vena cava tumoral thrombus With arteriovenous fistula or arterioportal shunt fistula that can be completely embolized Child-Pugh class A or B/Child score > 7;ECOG score < 2 Tolerable coagulation function or reversible coagulation disorders Laboratory examination test: WBC≥3.0×10E9/L; Hb≥3.0×10E9/L; PLT ≥50×10E9/L; INR < 2.3 or PT< 16.5s; Cr ≤ 145.5 umul/L Signed informed consent before recruiting Exclusion Criteria: Diffused HCC With portal vein trunk tumoral thrombus With inferior vena cava tumoral thrombus or hepatic vein tumor thrombus With lymphatic metastasis or extra hepatic metastasis Child-Pugh class C and can't be improved by expectant treatment Untreatable coagulation disorders, severe hemogram abnormal and bleeding tendency Massive intractable ascites ECOG score > 2

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TAE combined ablation simultaneously<br>TAE simultaneously combined with ablation.The treatment interval is 1-3 days between two procedures. TAE using embolic agents(Lipiodol/Gelatin sponge/PVA particles(300～500μm)/Blank microspheres). | Drug: Embolic agents<br>* Lipiodol/Gelatin sponge/PVA/Blank microspheres<br>* Other names: Embolization;Procedure: Simultaneously<br>* 1-3 days<br>* Other names: Treatment interval;Device: Ablation<br>* Radiofrequency ablation/Microwave ablation<br>* Other names: RFA/MWA;|
| Other: TACE combined ablation sequentially<br>TACE sequentially combined thermal ablation.The treatment interval is 1 month between two procedures. TACE using chemotherapy drug(Doxorubicin/platinum agents) and embolic agents(Lipiodol/Gelatin sponge/PVA particles(300～500μm)/Blank microspheres). | Drug: Chemotherapy drug<br>* Doxorubicin/Platinum agents<br>* Other names: Chemotherapy;Drug: Embolic agents<br>* Lipiodol/Gelatin sponge/PVA/Blank microspheres<br>* Other names: Embolization;Procedure: Sequentially<br>* 1 month<br>* Other names: Treatment interval;Device: Ablation<br>* Radiofrequency ablation/Microwave ablation<br>* Other names: RFA/MWA;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | From complete remission of the index large tumor to patient death or the completion of this trial | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence free survival | From complete remission of the index large tumor to tumor recurrence either in- or extra- hepatic or the completion of this trial | 3 years | 
| liver and renal function | Alanine aminotransferase,Ast,total bilirubin,albumin,creatinine,Urea nitrogen | 3 years | 
| Complications | number of participants with Complications | 3 years | 
| Times of interventional procedures | The number of procedures for each patient, either TACE/TAE or ablation | 3 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
HCC; Embolization; Ablation; simultaneously; sequentially