Transarterial Chemotherapy Compared With Oral Chemotherapy in the Treatment of Advanced Hepatocellular Carcinoma

Randomized Control Trial of Transarterial Chemotherapy (TAC) Versus Oral Thalidomide and Capecitabine in the Treatment of Unresectable Hepatocellular Carcinoma

In India, majority of our patients have advanced hepatocellular carcinoma (HCC) at presentation and hence are unsuitable for the available curative treatment options. In such patients the treatment options are mainly palliative. Transarterial chemoembolization (TACE), transarterial chemotherapy (TAC) and various forms of oral chemotherapy are the only available options currently. Many patients have more advanced disease with the involvement of branches of portal vein. This further limits the therapeutic options. According to Barcelona Clinic Liver Cancer (BCLC) staging, involvement of portal vein precludes any standard form of therapy. TAC and oral chemotherapy has been tried in this group of patients by few researchers. Which treatment (TAC or oral chemotherapy) would be better suitable for advanced stage (BCLC C) needs to be explored. However, there are no randomized controlled trials (RCT's) available.

TAC is the procedure for treating patients of HCC with portal vein invasion where only the chemotherapeutic drugs are injected into the feeding vessels of the tumor with no subsequent embolization of the feeding vessels.

In order to select a modality which would produce better outcomes in advanced HCC patients (BCLC C), this study was planned.

Study Overview

• Status: Unknown
• Conditions: Hepatocellular Carcinoma
• Intervention / Treatment: Procedure: Transarterial chemotherapy; Drug: Oral chemotherapy

Detailed Description

1. Aim of the study: To see the efficacy of transarterial chemotherapy in prolonging the survival of patients with unresectable HCC when compared to oral chemotherapy 2. Diagnostic criteria

o Cirrhosis of liver- Diagnosis will be founded on the basis of clinical, biochemical, imaging and endoscopy findings.

o Hepatocellular carcinoma- when any one of the following is present

1. Two imaging modalities (dual phase CT (DPCT)/ contrast enhanced MRI) showing arterialization of the hepatic mass
2. Alpha feto protein (AFP) more than 400ng/ml along with arterialization on one imaging modality (DPCT/ contrast enhanced MRI)
3. Fine-needle aspiration cytology (FNAC)

3. Definitions

3.1. Unresectable HCC- • Liver mass larger than 5cm in diameter (single/ multiple) , involving main portal vein with underlying cirrhotic liver

3.2. Tumor response This will be based on Dual phase CT findings

• Complete response (CR)- Tumor fully covered with lipiodol showing no viable tissue
• Partial response (PR)- Tumor partially covered (>75%) by lipiodol
• Mild response (MR)- About 50 to 75% coverage of the tumor by lipiodol
• No response (NR) - About 25 to 50% coverage of the tumor by lipiodol
• Fresh lesions (FL)- Appearance of new mass lesions in the liver with or without recurrence at the site of previous mass

3.3 Patient tolerance Grade 1: no side effects Grade 2: moderate side effects Grade 3: severe side effects Grade 4: life threatening side effects

3.4 Performance status (PST score) PST score of 0-5 would be assessed on the following basis 0- No cancer related symptoms. Normal life style

1. Minor symptoms related to cancer. Capable of non-strenuous activity. Fully ambulatory
2. Ambulatory and capable of all self-care but unable to carry out any work activities. Confined to bed less than 50% of waking hours
3. Capable of only limited self-care. Confined to bed more than 50% of waking hours.
4. Completely disabled. Cannot carry on any self-care. Totally confined to bed.
5. Death

4. Sample Size Systematic review of RCT's for TAC show a 2-year survival of 40 %. Expecting that oral chemotherapy has a 2-year survival of 40% with 5% non-inferiority margin with 80% power and 5% error, a sample size of 124 patients in each arm would be required.(Total 248 patients)

5. Randomization

• Patients will be randomized after the confirmation of diagnosis and obtaining written consent

• Sequences will be generated by the Statistician
• Stratified randomization will be done. Two strata of child's A and B will be made

• Randomization will be done by drawing consecutively numbered opaque sealed envelopes Randomization into A (TAC) and B (oral chemotherapy) will be done

  6. Follow up post TAC

6.1 Clinical follow up

• All patients would be followed up in the Liver clinic monthly unless their clinical condition warrants earlier follow up
• Liver function tests/ complete blood count would also be done at each visit and AFP (if elevated earlier) every six months
• Patient tolerance, child's status would be estimated.

6.2 Imaging follow up

• At one month, a dual phase CT would be done to ascertain the response to therapy and the need to repeat the procedure. Subsequently, the DPCT would be done at 3 and 6 monthly intervals.

  7. Repeat TAC on follow up This would be done if any of the following is noted

• DPCT shows viable tumor
• Fresh lesions appear
• Elevated serum AFP occurs with or without appearance of viable mass on DPCT

• Study Type: Interventional
• Enrollment (Anticipated): 124
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• India
  • Delhi
    • New Delhi, Delhi, India, 110029
      • Recruiting
      • AII India Institute of Medical Sciences
      • Contact: Subrat K Acharya, DM; Phone Number: +91-11-26594934; Email: subratacharya2004@yahoo.com
      • Contact: Shalimar . ., DM; Phone Number: +91-9968405815; Email: drshalimar@yahoo.com
      • Principal Investigator: Subrat K Acharya, DM
      • Sub-Investigator: Shashi B. Paul, Ph.D
      • Sub-Investigator: Shivanand R Gamanagatti, M.D
      • Sub-Investigator: Sreenivas Vishnubhatla, Ph.D

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 80 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients above 12 years of age with performance status (PST) score of 0-2
• Unresectable HCC with underlying Child's A/B cirrhosis
• Blocked Main portal vein
• No history of drug allergy
• Informed written consent of patient.

Exclusion Criteria:

• Child's C cirrhosis
• Performance status 3-5
• Extra hepatic disease
• Co-morbid illness like coronary artery disease, congestive heart failure, chronic renal failure etc
• Previous history of encephalopathy/ upper gastrointestinal bleed in the last six months
• Pregnancy

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Transarterial chemotherapy; Doxorubicin 50mg, Cisplatin 100mg	Procedure: Transarterial chemotherapy; Femoral artery would be punctured at the upper thigh using 18 gauge needle under local anesthesia. Catheterization of the hepatic artery feeding the tumor would be done and placing the catheter tip beyond the gastroduodenal artery, the chemotherapeutic drugs would be administered. Mixture would be prepared by using Doxorubicin 50mg and Cisplatin 100mg. Hydrocortisone 100mg and augmenting dose of analgesic and sedative would be injected prior to the administration of the drug. The drug mixture would then be injected through the indwelling arterial catheter by continuously flushing alternately, repeatedly and rapidly between two-leur lock syringes.; Other Names: TAC
Placebo Comparator: Oral chemotherapy; Thalidomide---50-300mg once a day Capecitabine---- 500-1500mg once a day	Drug: Oral chemotherapy; Drugs used would be Thalidomide and Capecitabine in the following dosage schedule- Thalidomide---50mg once a day (OD) for 7 days, increased to 100mg OD for 7 days, 200mgOD for 7 days further increased to 300 mg OD. Capecitabine---- 500mg OD for 7 days, then 1000mg OD for next 7 days, increased to a maximum dose of 1500mg OD Maintenance dose - Capecitabine 1500 mg - every alternate week Thalidomide - 300 mg OD. Total leucocyte count & Platelet count would be monitored every 15 days; Other Names: OC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival rate-	Survival rate to be calculated from the start of Transarterial chemotherapy	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tumor response	Tumor response on dual phase contrast-enhanced computed tomography (CECT)	1 year

Collaborators and Investigators

• Sponsor: All India Institute of Medical Sciences, New Delhi
• Collaborators: Indian Council of Medical Research
• Investigators: Principal Investigator: Subrat K Acharya, D.M, All India Institute of Medical Sciences, New Delhi, India

Study record dates

Study Major Dates

• Study Start: January 1, 2006
• Primary Completion (Anticipated): December 1, 2014
• Study Completion (Anticipated): March 1, 2015

Study Registration Dates

• First Submitted: August 31, 2014
• First Submitted That Met QC Criteria: September 12, 2014
• First Posted (Estimate): September 16, 2014

Study Record Updates

• Last Update Posted (Estimate): September 16, 2014
• Last Update Submitted That Met QC Criteria: September 12, 2014
• Last Verified: September 1, 2014

More Information

Terms related to this study

• Keywords: Thalidomide; Transarterial chemotherapy; Capecitabine
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular
• Other Study ID Numbers: TAC-HCC

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No