RFA Combined With Oxaliplatin + 5-FluoroUracil/LeucoVorin (5-FU/LV) (FOLFOX4) for Recurrent HCC

Study Overview
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Brief Summary
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Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world. Partial hepatectomy and liver transplantation are considered to be standard curative therapies for HCC. When surgery is not possible, percutaneous ablation is usually considered to be alternative treatments for HCC. Recurrence is the most frequent serious adverse event observed during the follow-up of HCC patients treated for cure. Repeat hepatectomy is an effective treatment for HCC recurrence, with a 5-year survival rate of 19.4 to 56%. Unfortunately, repeat hepatectomy can be performed only in a small proportion of patients with HCC recurrence (10.4 to 31%), either because of the poor functional liver reserve or because of widespread recurrence. Radiofrequency ablation has been considered to be one of the most effective percutaneous ablations for early-stage HCC in patients with or without surgical prospects. Studies using RFA to treat HCC recurrence after hepatectomy have reported a 3-year survival rate of 62% to 68%, which is comparable to those achieved by surgery. RFA is particularly suitable to treat HCC recurrence after hepatectomy because these tumors are usually detected when they are small, and because RFA causes the least deterioration of liver function in the patients. However, according to our previous study, investigators found the recurrent rate after RFA was higher than 60%. Systemic chemotherapy is considered to be one of the main treatments for malignant tumors. HCC is known to be highly refractory to conventional systemic chemotherapy because of its heterogeneity and multiple etiologies. Before the advent of the molecular-targeted agent sorafenib, which has subsequently become the standard of care, no standard systemic drug or treatment regimen had shown an obvious survival benefit in HCC. Nowadays, there is no systemic chemotherapy regimen had been definitively recommended as the standard for treating HCC. Clinical activity of several regimens containing oxaliplatin (OXA) in advanced HCC had been demonstrated in phase II studies. In a phase II study of the FOLFOX4 (infusional fluorouracil [FU], leucovorin[LV], and OXA) regimen in Chinese patients with HCC, median overall survival (OS) was 12.4 months, mean time to progression was 2.0 months, and the response rate (RR) was 18.2%. The safety profile was acceptable. Recently, the results of a phase Ⅲ randomize study showed that FOLFOX4 served as palliative chemotherapy can induce higher overall survival, progression-free survival and response rate comparing to doxorubicin in patients with advanced hepatocellular carcinoma from Asia. The safety data was also acceptable. Therefore, investigators considered RFA to be an effective treatment for HCC recurrence after curative treatment. So our hypothesis is that RFA combined with FOLFOX4 can reduce high recurrence rate after RFA for recurrent HCC after hepatectomy. The aim of this open-lable, single prospective study is to evaluate the efficacy and safety of RFA combined with FOLFOX4 systemic chemotherapy for recurrent HCC after partial hepatectomy.

Official Title
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RFA Combined With Oxaliplatin + 5-FluoroUracil/LeucoVorin (5-FU/LV) (FOLFOX4) for Recurrent HCC:an Open Lable, Single-arm, Prospective Study

Conditions
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Hepatocellular Carcinoma

Intervention / Treatment
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* Procedure: RFA
* Drug: Oxaliplatin
* Drug: 5-Fluorouracil/Leucovorin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age 18 - 75 years; recurrence of HCC 12 months after initial hepatectomy; no other treatment received except for the initial hepatectomy; Single tumor≤5cm in diameter; or 2-3 lesions each ≤ 3.0 cm lesions visible on ultrasound and with an acceptable and safe path between the lesion and the skin as shown on ultrasound; no severe coagulation disorders (prothrombin activity < 40% or a platelet count of < 40,000 / mm3; Eastern Co-operative Oncology Group performance(ECOG) status 0 -1 Exclusion Criteria: severe coagulation disorders (prothrombin activity <40% or a platelet count of <40,000 / mm3); Child-Pugh class C liver cirrhosis or evidence of hepatic decompensation including ascites, esophageal or gastric variceal bleeding, or hepatic encephalopathy; Documented allergy to platinum compound or to other study drugs; Any previous oxaliplatin or doxorubicin treatment, except adjuvant treatment more than 12 months before the randomization. Previous or concurrent cancer that is distinct in primary site or histology from HCC History of cardiac disease congestive heart failure > New York Heart Association (NYHA) class 2; active coronary artery disease (myocardial infarction more than 6 months prior to study entry is permitted); cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers, calcium channel blocker or digoxin; uncontrolled hypertension (failure of diastolic blood pressure to fall below 90 mmHg, despite the use of 3 antihypertensive drugs). Active clinically serious infections (> grade 2 National Cancer Institute [NCI]- Common Terminology Criteria for Adverse Events [CTCAE] version 3.0) contraindications to carboplatin, epirubicin, mitomycin, lipiodol; Pregnant or breast-feeding patients; contraindications to RFA； Any condition that is unstable or which could jeopardize the safety of the patient and his/her compliance in the study; Known history of human immunodeficiency virus (HIV) infection Patients concomitantly receiving any other anti-cancer therapy, including interferon-α and herbal medicine which was approved by local authority to be used as anti-cancer medicine, except radiotherapy to non-target lesion (bone metastasis, etc) Do not give written informed consent

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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RFA+FOLFOX4<br>RFA: RFA was performed by using a commercially available system (RF 2000; Radio-Therapeutics Mountain View, CA), and a needle electrode with a 15 Ga insulated cannula with 10 hook-shaped expandable electrode tines with a diameter of 3.5 cm at expansion (LeVeen; RadioTherapeutics). Oxaliplatin + 5-Fluorouracil/Leucovorin: 4 weeks after RFA; Drug: Oxaliplatin + 5-Fluorouracil/Leucovorin Day 1: Oxaliplatin 85mg/m² 2h IV infusion, leucovorin 200mg/m² 2h IV infusion, 5-fluorouracil 400mg/m² IV bolus, 5-fluorouracil 600mg/m2 22h IV infusion. Day 2: Leucovorin 200mg/m² 2h IV infusion, 5-fluorouracil 400mg/m² IV bolus, 5-fluorouracil 600mg/m² 22h IV infusion. Repeated every 2 weeks | Procedure: RFA<br>* RFA: RFA was performed by using a commercially available system (RF 2000; Radio-Therapeutics Mountain View, CA), and a needle electrode with a 15 Ga insulated cannula with 10 hook-shaped expandable electrode tines with a diameter of 3.5 cm at expansion (LeVeen; RadioTherapeutics).<br>Drug: Oxaliplatin<br>* 4 weeks after RFA; Drug: Oxaliplatin Day 1: Oxaliplatin 85mg/m² 2h IV infusion. Repeated every 2 weeks<br>Drug: 5-Fluorouracil/Leucovorin<br>* 4 weeks after RFA; Drug: 5-Fluorouracil/Leucovorin Day 1, after Oxaliplatin 85mg/m² 2h IV infusion: Leucovorin 200mg/m² 2h IV infusion, 5-fluorouracil 400mg/m² IV bolus, 5-fluorouracil 600mg/m2 22h IV infusion. Day 2: Leucovorin 200mg/m² 2h IV infusion, 5-fluorouracil 400mg/m² IV bolus, 5-fluorouracil 600mg/m² 22h IV infusion. Repeated every 2 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence rate |  | 2 years | 
| Safety and Tolerability | Number of Participants with Adverse Events as a Measure of Safety and Tolerability | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence-free survival |  | 2 years | 
| Overall survival |  | 2 years |