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

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

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.

Study Overview

• Status: Unknown
• Conditions: Hepatocellular Carcinoma
• Intervention / Treatment: Procedure: RFA; Drug: Oxaliplatin; Drug: 5-Fluorouracil/Leucovorin

• Study Type: Interventional
• Enrollment (Anticipated): 28
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510080
      • Zhen-Wei Peng

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. age 18 - 75 years;
2. recurrence of HCC 12 months after initial hepatectomy;
3. no other treatment received except for the initial hepatectomy;
4. Single tumor≤5cm in diameter; or 2-3 lesions each ≤ 3.0 cm
5. lesions visible on ultrasound and with an acceptable and safe path between the lesion and the skin as shown on ultrasound;
6. no severe coagulation disorders (prothrombin activity < 40% or a platelet count of < 40,000 / mm3;
7. Eastern Co-operative Oncology Group performance(ECOG) status 0 -1

Exclusion Criteria:

1. severe coagulation disorders (prothrombin activity <40% or a platelet count of <40,000 / mm3);
2. Child-Pugh class C liver cirrhosis or evidence of hepatic decompensation including ascites, esophageal or gastric variceal bleeding, or hepatic encephalopathy;
3. 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.
4. Previous or concurrent cancer that is distinct in primary site or histology from HCC
5. 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).
6. 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;
7. Pregnant or breast-feeding patients;
8. contraindications to RFA；
9. Any condition that is unstable or which could jeopardize the safety of the patient and his/her compliance in the study;
10. Known history of human immunodeficiency virus (HIV) infection
11. 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)
12. Do not give written informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: RFA+FOLFOX4; 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; 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).; Drug: Oxaliplatin; 4 weeks after RFA; Drug: Oxaliplatin Day 1: Oxaliplatin 85mg/m² 2h IV infusion. Repeated every 2 weeks; Drug: 5-Fluorouracil/Leucovorin; 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

What is the study measuring?

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	Time Frame
Overall survival	2 years
Recurrence-free survival	2 years

Collaborators and Investigators

• Sponsor: Sun Yat-sen University

Publications and helpful links

General Publications

• Qin S, Bai Y, Lim HY, Thongprasert S, Chao Y, Fan J, Yang TS, Bhudhisawasdi V, Kang WK, Zhou Y, Lee JH, Sun Y. Randomized, multicenter, open-label study of oxaliplatin plus fluorouracil/leucovorin versus doxorubicin as palliative chemotherapy in patients with advanced hepatocellular carcinoma from Asia. J Clin Oncol. 2013 Oct 1;31(28):3501-8. doi: 10.1200/JCO.2012.44.5643. Epub 2013 Aug 26.
• Peng ZW, Zhang YJ, Liang HH, Lin XJ, Guo RP, Chen MS. Recurrent hepatocellular carcinoma treated with sequential transcatheter arterial chemoembolization and RF ablation versus RF ablation alone: a prospective randomized trial. Radiology. 2012 Feb;262(2):689-700. doi: 10.1148/radiol.11110637. Epub 2011 Dec 12.
• Peng ZW, Zhang YJ, Chen MS, Xu L, Liang HH, Lin XJ, Guo RP, Zhang YQ, Lau WY. Radiofrequency ablation with or without transcatheter arterial chemoembolization in the treatment of hepatocellular carcinoma: a prospective randomized trial. J Clin Oncol. 2013 Feb 1;31(4):426-32. doi: 10.1200/JCO.2012.42.9936. Epub 2012 Dec 26.

Study record dates

Study Major Dates

• Study Start: April 1, 2015
• Primary Completion (Anticipated): October 1, 2015
• Study Completion (Anticipated): April 1, 2017

Study Registration Dates

• First Submitted: April 16, 2015
• First Submitted That Met QC Criteria: April 21, 2015
• First Posted (Estimate): April 27, 2015

Study Record Updates

• Last Update Posted (Estimate): April 27, 2015
• Last Update Submitted That Met QC Criteria: April 21, 2015
• Last Verified: April 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Carcinoma, Hepatocellular; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Micronutrients; Vitamins; Antidotes; Vitamin B Complex; Fluorouracil; Oxaliplatin; Leucovorin
• Other Study ID Numbers: HCC001