HAIC Versus TACE for Large Hepatocellular Carcinoma Staged BCLC A/B.

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) compared with transarterial chemoembolization (TACE) in patients with large hepatocellular carcinoma staged BCLC A/B.

Detailed Description
-----------------
Transarterial chemoembolization (TACE) is the most widely used palliative treatment for hepatocellular carcinoma (HCC) patients. While a number of studies demonstrate poor effect of TACE for patients with large hepatocellular carcinoma staged BCLC A/B especially for those with tumor larger than 10 cm. Our previous prospective study also revealed similar results of large HCC patients treated with TACE. Recently, the results of our preliminary pilot study suggested that, compared with TACE, hepatic arterial infusion chemotherapy (HAIC) may improve the survivals for HCC with large HCC. Thus, the investigators carried out this prospective randomized control to demonstrate the superiority of HAIC over TACE.

Official Title
-----------------
The Efficacy and Safety of Hepatic Arterial Infusion Chemotherapy Compared With Transarterial Chemoembolization as Initial Treatment in Patients With Large Hepatocellular Carcinoma Staged BCLC A/B.

Conditions
-----------------
HepatoCellular Carcinoma

Intervention / Treatment
-----------------
* Procedure: Hepatic arterial infusion chemotherapy
* Procedure: Transarterial chemoembolization
* Drug: Folfox Protocol
* Drug: TACE Drug Protocol


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age range from 18-75 years; KPS≥70; The diagnosis of HCC was based on the diagnostic criteria for HCC used by the European Association for the Study of the Liver (EASL), simultaneously staged as BCLC A or BCLC B based on Barcelona Clinic Liver Cancer staging system. Patients must have at least one tumor lesion that can be accurately measured; The sum of diameters of all lesions longer than 10 cm with the maximum lesion longer than 7 cm. Diagnosed as unresectable with consensus by the panel of liver surgery experts; Re commanded treated by TAI or TACE with consensus by the panel of liver MDT; No past history of TACE, TAI, chemotherapy or molecule-targeted treatment; No Cirrhosis or cirrhotic status of Child-Pugh class A only Meet the following laboratory parameters:(a) Platelet count ≥ 75,000/μL;(b)Hemoglobin ≥ 8.5 g/dL;(c) Total bilirubin ≤ 30mmol/L;(d) Serum albumin ≥ 32 g/L;(e) ASL and AST ≤ 6 x upper limit of normal;(f) Serum creatinine ≤ 1.5 x upper limit of normal;(g) INR > 2.3 or PT/APTT within normal limits;(h) Absolute neutrophil count (ANC) >1,500/mm3; Ability to understand the protocol and to agree to and sign a written informed consent document. Exclusion Criteria: Patients with clinically significant gastrointestinal bleeding within 30 days prior to study entry. Known of serious heart disease which can nor endure the treatment such as cardiac ventricular arrhythmias requiring anti-arrhythmic therapy Evidence of hepatic decompensation including ascites, gastrointestinal bleeding or hepatic encephalopathy Known history of HIV History of organ allograft Known or suspected allergy to the investigational agents or any agent given in association with this trial. Evidence of bleeding diathesis. Any other hemorrhage/bleeding event > CTCAE Grade 3 within 4 weeks of first dose of study drug Serious non-healing wound, ulcer, or bone fracture Known central nervous system tumors including metastatic brain disease Poor compliance that can not comply with the course of treatment and follow up.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 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: Hepatic arterial infusion chemotherapy<br>Procedure/Surgery: Hepatic arterial infusion chemotherapy Drug: Folfox Protocol. Hepatic intra-arterial infusion via the tumor feeding arteries of Oxaliplatin , fluorouracil, and leucovorin | Procedure: Hepatic arterial infusion chemotherapy<br>* A standard hepatic artery catheter was introduced via the femoral artery percutaneously. Selective catheterization of the proper hepatic artery was performed using standard diagnostic catheters and fluoroscopic guidance. In the event of multiple arterial supply(including superior-mesenteric artery), the proportion of the liver supplied by each artery was estimated by the arteriogram. After optimal positioning of the catheter in dominant supplying artery to ensure minimal reflux, the catheter was fixed and connected with infusion tube. In the condition of multiple tumors on both left and right lobe, the gastroduodenal artery was embolized and the catheter was positioned in the hepatic proper artery for infusion. Folfox Protocol were infused through the fixed catheter sequentially.<br>Drug: Folfox Protocol<br>* oxaliplatin,leucovorin and 5-FU<br>* Other names: Folfox for TAI;|
| Active Comparator: Transarterial chemoembolization<br>Procedure/Surgery: Transarterial chemoembolization Drug: TACE Drug Protocol. Hepatic intra-arterial infusion with lipiodol mixed with chemotherapy drugs (EADM, lobaplatin, with or without MMC), and embolization with polyvinyl alcohol particles (PVA). | Procedure: Transarterial chemoembolization<br>* Previous procedure was same with hepatic arterial infusion chemotherapy. After optimal positioning of the catheter, TACE Drug Protocol were injected.<br>Drug: TACE Drug Protocol<br>* lipiodol mixed with chemotherapy drugs(EADM , lobaplatin, with or without MMC) followed by polyvinyl alcohol particles (PVA)<br>* Other names: Drugs for transarterial chemotherapy and embolization;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival |  | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to progression |  | 24 months | 
| Adverse Events | Postoperative adverse events were graded based on CTCAE v4.03 | 30 Days after HAIC | 
| Number of of Patients developed Adverse Events | Number of of patients who developed adverse event. Postoperative adverse events were graded based on CTCAE v3.0 | 30 Days after HAIC | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Hepatic arterial infusion chemotherapy, Transarterial Chemoembolization, BCLC A/B