1. Subjects Consecutive patients of unresectable HCC diagnosed from January 2006 at the
liver clinic, AIIMS will be included in the study if they fulfill the following
Inclusion criteria · Patients above 12 years of age with performance status (PST)score
· Unresectable HCC with underlying Child's A/B cirrhosis
· Normal Main portal vein and its branches
- Normal Inferior vena cava
- No history of drug allergy
- Informed written consent of patient.
- Less than 50% involvement of liver by HCC
· Unresectable HCC with underlying Child's C cirrhosis
· Performance status 3-5
· Extrahepatic disease
· Vascular involvement
- 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
- HCC in a female of child bearing age
2. Diagnostic criteria
- Cirrhosis of liver- Diagnosis will be founded on the basis of clinical,
biochemical and endoscopy findings.
- Hepatocellular carcinoma- when any one of the following is present
1. Any two imaging modalities(Ultrasound (US), dual phase CT (DPCT)/ contrast
enhanced MRI) showing arterialization of the hepatic mass
2. AFP more than 400ng/ml along with arterialisation on one imaging modality (DPCT/
contrast enhanced MRI)
· Patients will be randomized after the confirmation of diagnosis and obtaining written
· 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 (TACE) and B (TACE +oral chemotherapy) will be done.
1. Unresectable HCC-
· Liver mass larger than 5cm in diameter (single/ multiple), involving less than 50% of
· Multiple masses more than three in number and more than 3cm in diameter.
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. Patient tolerance- Grade 1: no side effects Grade 2: moderate side effects Grade 3:
severe side effects Grade 4: life threatening side effects
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-
5. Sample Size Systematic review of RCTs for TACE show a 2 year survival of 37%.
Expecting that addition of oral drugs would increase survival to 37 to 60%, for a power
of 80% and error of 5%, a sample size of 73 patients in each arm would be required
(Total 146 patients).
6. Procedure of TACE
· Patient would be admitted a day prior to the procedure
· Patient would be made to fast overnight with intravenous fluid infusion started for
· Pre-procedure analgesic (3rd generation antibiotic) would be started at a dose of 2gm
intravenously, 12 hourly, at least 12 hour before the procedure and continued 5 days
· Under local anesthesia, the Femoral artery would be punctured at the upper thigh with
a Medicut 18 gauge
· A catheter would be introduced through this route with the help of a guide wire and a
flush aortogram, superior mesenteric arterioportography and the celiac artery run would
be undertaken to define the size and location of the tumors, feeding vessels and to
assess the portal vein patency
· Superselective catheterization of the hepatic artery feeding the tumor would be done
· By placing the catheter tip beyond the gastroduodenal artery, the chemotherapeutic
drugs would be administered.
· Stable drug mixture would be prepared by using Doxorubicin 50mg, Cisplatin 100mg in
combination with 10-15ml of ionic contrast media and 10-20ml of lipiodol by
continuously agitating the mixture.
· 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 lever lock
syringes connected across a three way.
· Gelfoam particles would be injected following this for embolization
· Post procedure, devascularization would be confirmed by additional angiography of the
· Procedure would last approx 45mts-1 hour.
· Tight compression would be given at the punctured site and patient would be shifted
to the ward once complete hemostasis is achieved.
7. Follow up post TACE 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. 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.
- Once the tumor shows complete coverage, randomization into the two treatment
groups would be done
9. Repeat TACE 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
10. Oral chemotherapy Drugs used would be Thalidomide and Capecitabine in the
following dosage schedule-
Thalidomide---100mg once a day (OD) for 7 days, Increased to 200mg OD for 7 days,
further increased to 300mgOD for 7 days till a maximum of 600mg once a day is reached
Capecitabine---- 500mg OD for 7 days, then 1000mg OD for next 7 days, increased to a
maximum dose of 1500mg OD.
Total leucocyte count & Platelet count would be monitored every 15 days
11. Duration of follow up- Two years after achieving total coverage of the mass lesion
12. Outcome measures Following parameters will be used to ascertain the outcome of
1. Primary Outcome
1. Survival rate- calculated from the start of TACE
2. End point Group 1 - Progression of disease and repeat TACE is not possible
Group 2 - Death
2. Secondary Outcome
1. Tumor response on dual phase CECT
2. Patient tolerance
3. Childs' status of cirrhosis- will be ascertained at one and two years of
follow up depending upon the Childs' scoreScore <6- Childs'A, 7-9
Childs'B and >10 Childs'C
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Survival rate- calculated from the start of TACE
Subrat K Acharya, DM
All India Institute of Medical Sciences, New Delhi, India
India: All India Institute of Medical Sciences, New Delhi