Chemoembolization With or Without Antiviral Therapy for Unresectable HBV-related HCC With Low HBV DNA Replication

Study Overview
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Brief Summary
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Although it is commonly accepted that antiviral therapy should be commenced before or during hepatocellular carcinoma (HCC) treatment if the patients have high viral loads and elevated ALT or total bilirubin values with signs of cirrhosis, the dilemma exists when HBV DNA and liver function (such as ALT, AST, TBIL) remains low level. Whether antiviral therapy make sense or not in these patients with no signs of hepatitis or high viral replication remains unclear, especially for the relatively advanced stage HCC patients receiving TACE. Thus, the investigators carried out this prospective control study to compare the survivals for patients after TACE between with or without antiviral therapy.

Detailed Description
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In highly endemic areas, hepatitis B virus (HBV) infection plays a primary role in the etiology of HCC and is frequently observed in HCC patients. Patients with HBV-related HCC usually have a history of chronic HBV infection. Chemotherapy for other malignancies has been associated with HBV reactivation. Furthermore, in end stage liver disease due to HBV, levels of HBV replication have been correlated with liver function. For TACE, reports on HBV reactivation have been inconsistent. Some studies have demonstrated HBV reactivation, some have not , and others have shown decreased HBV DNA levels . The exact mechanism by which this occurs is still unknown. Although anti-HBV therapy has been reported to suppress HBV reactivation in various clinical settings with immunosuppressive conditions, few reports were concerned with the TACE treatment of HBV-related HCC. Also, the long-term effects of antiviral therapy in relatively advanced HCC patients after HCC remains unclear. Although it is commonly accepted that antiviral therapy should be commenced before or during HCC treatment if the patients have high viral loads and elevated ALT or total bilirubin values with signs of cirrhosis, the dilemma exists when HBV DNA and liver function (such as ALT, AST, TBIL) remains low level. Therefore, we would call for the establishment of clinical practice guidelines on the antiviral therapy in HBV-related HCC patients, especially a consensus on the indications to administer nucleosides analogs (NAs). Thus , the purpose of the investigators' study is to prospectively study the efficacy of nucleosides analogs (NAs) in transcatheter arterial chemoembolization for nonresectable hepatocellular carcinoma with relatively low HBV DNA replication and Child-Pugh grade A based on multivariate analysis of prognostic factors. The HBV DNA and liver function parameters will be monitored closely. Once the reactivation occurs in the control group, antiviral therapy would be administered immediately. The study had a interim analysis to allow the trial to be stopped if significant differences were detected. The accumulated data were examined when half patient was enrolled in the clinical trial.

Official Title
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Chemoembolization With or Without Antiviral Therapy for Unresectable HBV-related Hepatocellular Carcinoma With Low HBV DNA Replication: Effectiveness and Safety. A Prospective and Randomized Clinical Trial

Conditions
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Hepatocellular Carcinoma

Intervention / Treatment
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* Drug: Lamivudine 100mg once daily; or Entecavir 0.5mg once daily.


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients from 18 to 75 years of age with a diagnosis of HCC. A diagnosis of HCC based on the diagnostic criteria for HCC used by the European Association for the Study of the Liver (EASL). The patient has not been previously treated with surgery, radiation therapy, radiofrequency ablation, percutaneous ethanol or acetic acid injection, or cryoablation, or any other treatment with chemotherapeutic agents or sorafenib. The patient has not been previously treated with any anti-viral agents, including interferon or nucleosides analogs (NAs). Adults patients with a diagnosis of HCC which is not amenable to surgical resection ,local ablative therapy or any other radically cured treatment. The MDT group of HCC agree to administer TACE in this patient. Patients must have at least one tumor lesion that can be accurately measured according to EASL criteria. No serious concurrent medical illness. Unresectable TNM stage Ⅲ or Ⅳ disease. Zubrod-ECOG-WHO performance status: 0 or 1. and the estimated survival more than 4 months. Not pregnant or breast-feeding patients No significant renal impairment (creatinine clearance < 30 mL/minute) or patients on dialysis No current infections requiring antibiotic therapy Not on anticoagulation or suffering from a known bleeding disorder No unstable coronary artery disease or recent MI Ability to understand the protocol and to agree to and sign a written informed consent document The following laboratory parameters at baseline: Platelet count ≥ 70,000/µL Hemoglobin ≥ 8.5 g/dL Absolute neutrophil count (ANC) >1,500/mm3 Total bilirubin ≤ 1.5 mg/dL Serum albumin ≥ 35 g/L Serum creatinine ≤ 1.5 x upper limit of normal PT prolong time less than 3 seconds Cirrhotic status of Child-Pugh class A only ALT<2×upper limit of normal Hepatitis B surface antigen positive If hepatitis B e antigen positive, HBV DNA level <2000IU/mL; If hepatitis B e antigen negative, HBV-DNA<200IU/mL. Exclusion Criteria: - History of HIV or HCV infection. 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. Patients with clinically significant gastrointestinal bleeding within 30 days prior to study entry. Any other hemorrhage/bleeding event > CTCAE Grade 3 within 4 weeks of study entry. Serious non-healing wound, ulcer, or bone fracture Known central nervous system tumors including metastatic brain disease Any event > grade 2 National Cancer Institute [NCI]-Common Terminology Criteria for Adverse Events [CTCAE] version 3.0 Severe complication after TACE. History of hepatotoxic medication within 8 wk prior to the current treatment. History of corticosteroid administration.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Anti-viral treatment<br>Oral antiviral drugs will be commenced after TACE. That is: Lamivudine 100mg once daily; or Entecavir 0.5mg once daily. | Drug: Lamivudine 100mg once daily; or Entecavir 0.5mg once daily.<br>* In experimental group, Lamivudine 100mg once daily; or Entecavir 0.5mg once daily will be commenced after TACE.<br>* Other names: Entecavir 0.5mg tablets (Bristol-Myers Squibb);|
| No Intervention: Control<br>No anti-viral therapy after TACE. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| overall survival |  | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HBV reactivation |  | 1 year |