Efficacy and Safety of TACE on Downstaging Hepatocellular Carcinoma Beyond UCSF Criteria;

Study Overview
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Brief Summary
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This is a multicenter, randomized, parallel controlled study to determine the efficacy and safety of transcatheter arterial chemoembolization (TACE) on downstaging hepatocellular carcinoma beyond University of California, San Francisco (UCSF) criteria.

Official Title
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Efficacy and Safety of TACE on Downstaging Hepatocellular Carcinoma Beyond UCSF Criteria: a Multi-center, Randomized, Parallel-controlled Study

Conditions
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Hepatocellular Carcinoma

Intervention / Treatment
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* Procedure: DEB-TACE
* Procedure: cTACE
* Device: Drug-eluting Beads
* Drug: Epirubicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 to 70 years of age, of any sex; Patients who have histopathological or cytological proof of hepatocellular carcinoma (HCC) or meet the diagnostic criteria of Diagnosis, management, and treatment of hepatocellular carcinoma(V2017); Beyond UCSF criteria: Diameter of single HCC lesion is between 6.5 cm and 10 cm; The number of tumors ≤3 with the maximum diameter of 4.5-5cm and the total diameter ≤10cm; Multiple HCC lesions ≤5 nodules, each lesion diameter≤4 cm with a total diameter ≤10 cm. Patients cannot be treated with resection or liver transplantation; Patients with stage Ib，IIa，IIb in China liver cancer staging (CNLC) ; Child-Pugh's grade A or B (no more than 7 score); Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0-1; Patients with hepatitis B virus (HBV) infection should receive routine antiviral therapy; The function of main organs is normal and meet the following criteria: 1) Outcome of blood routine must meet the following criteria (No blood transfusion or blood products were performed within 4 days, and no g-CSF or other hematopoietic stimulants were used for correction): i. Hemoglobin(HB)≥90 g/L; ii. Absolute neutrophil count (ANC)≥1.5×109/L； iii. Platelet (PLT)≥80×109/L; 2) Outcome of hemal biochemistry examination meet the following criteria: i. Albumin (ALB) ≥29 g/L; ii. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)<2.5 × upper limit of normal (ULN); iii. Total bilirubin (TBIL) ≤2 × ULN; iv. Serum creatinine (SCr) ≤1.25 × ULN, or endogenous creatinine clearance > 45 ml/min (Cockcroft-Gault formula); 3) Patients who have normal livers with an Remnant Liver Volume (RLV)/Standard Liver Volume(SLV) >20% ; Patients who have cirrhosis with an RLV/SLV>40%; 9. Life expectancy of > 3 months; 10. Patients volunteered to participate in this study and signed informed consent, with good compliance.Exclusion Criteria. Exclusion Criteria: Patients with extrahepatic metastasis or main portal vein /main hepatic vein invasion; Patients with diffuse liver cancer; Patients with myocardial ischemia, myocardial infarction or poor controlled arrhythmia (including QTc≥470 ms) beyond stage Ⅱ; according to New York Heart Association (NYHA) standard, patients with heart failure in stage Ⅲ～Ⅳ; patients with an left ventricular ejection fraction(LVEF) <50%; Abnormal coagulation （International Normalized Ratio(INR)>1.5, Prothrombin Time(PT)>ULN+4s or Activated Partial Thromboplastin Time (APTT) >1.5 ×ULN）,or patients with bleeding tendency or undergoing thrombolytic or anticoagulant therapy; Patients unsuitable for the study in the opinion of the Investigator; Pregnant or breastfeeding women; women of childbearing ages unless using effective contraception; Patients with mental disorders or history of abuse of psychotropic substances; Infection with human immunodeficiency virus (HIV); A history of liver resection, liver transplantation, interventional therapy, or combined with other malignant tumors; Patients with active infection; Patients with contraindications to TACE or epirubicin; Floating population or with poor compliance; Patients in other clinical trials conducting with experimental-related drugs or devices within 4 weeks.

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Drug-eluting bead transarterial chemoembolization(DEB-TACE)<br> | Procedure: DEB-TACE<br>* Drug-eluting beads transcatheter arterial chemoembolization<br>Device: Drug-eluting Beads<br>* Drug-eluting beads<br>Drug: Epirubicin<br>* Chemotherapy drug for intra-arterial infusion<br>|
| Active Comparator: conventional transarterial chemoembolization(cTACE)<br> | Procedure: cTACE<br>* Transcatheter arterial chemoembolization<br>Drug: Epirubicin<br>* Chemotherapy drug for intra-arterial infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Downstaging success rate | Criteria for success rate in downstaging meet UCSF criteria or the standard for liver resection. | Within 6 months after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete response (CR) | Disappearance of any intratumoral arterial enhancement in all target lesions | 1, 3, 6 months after surgery | 
| Partial response (PR) | At least a 30% decrease in the sum of diameters of viable (enhancement in the arterial phase) target lesions, taking as reference the baseline sum of the diameters of target lesions | 1, 3, 6 months after surgery | 
| Stable disease (SD) | Number of the subjects that do not qualify for partial response or progressive disease measured by modified Response Evaluation Criteria in Solid Tumors( mRECIST) criteria | up to 6months after TACE procedure | 
| Progressive disease (PD) | An increase of at least 20% in the sum of the diameters of viable (enhancing) target lesions, taking as reference the smallest sum of the diameters of viable (enhancing) target lesions recorded since treatment started | 1, 3, 6 months after surgery | 
| Objective response (OR) | CR+PR | 1, 3, 6 months after surgery | 
| Duration of downstaging | Interval between initial TACE treatment and the success or failure of downstaging according to the UCSF criteria assessed by the dynamic enhanced CT ; | within 36 months | 
| Times of TACE treatments | Times of TACE surgery | within 36 months | 
| Changes of tumor biomarkers (AFP, PIVKA-Ⅱ) | AFP and PIVKA-II must be measured at 1week before, 1 week,1month after TACE or curative treatment; AFP ,PIVKA-II could be measured every 3-6 months during follow up according to the availability of equipment at the site | From 7 days before TACE or curative treatments to the endpoints of the trial.(Up to 36 months) | 
| Changes in liver function | Changes of the Child-pugh Score that used to assess the prognosis of chronic liver disease,consisting of 5 items(ascites,total bilirubin，albumin,prothrombin time and degree of encephalopathy),of which is scored 1-3 points,with 3 indicating greatest severity) | from the date of the first TACE to the end of the clinical trial or the death of the patient，Up to 36months | 
| Tumor-free survival (TFS) | as the time from surgery initiation to tumor recurrence or death from any cause | Within 36 months | 
| Progression-free survival (PFS) | as the time from surgery initiation to disease progression or death from any cause | Within 36 months | 
| Overall survival (OS) | as the time from surgery initiation to death from any cause | Within 36 months | 
| Recurrence rate of Hepatocellular carcinoma | Recurrence rate of hepatocellular carcinoma | Within 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatocellular Carcinoma