Ethiodized Oil-based Transarterial Chemoembolization for Patients With Hepatocellular Carcinoma: A Randomized Controlled Trial of Aqueous Cisplatin Emulsion Versus Anhydrous Cisplatin Suspension
Phase: NA
Conditions: Hepatocellular Carcinoma
Sponsor: Chinese University of Hong Kong

 
 
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Study Protocol 
 
Ethiodized oil-based chemoembolization for hepatocellular carcinoma: 
Randomized controlled trial of aqueous cisplatin emulsion versus anhydrous 
cisplatin suspension 
 
 
 
 
 
 
 
 
 
 
 
Date: 16 July 2016 
 
This protocol was designed and developed by the Department of Imaging and 
Interventional Radiology, Department of Clinical Oncology, and Department of 
Surgery of the Chinese University of Hong Kong. It is intended to be used for this 
research within this own Institute and collaborating centers after obtaining individual 
patient’s informed consent. No other use or reproduction is authorized nor does the 
Institute assume any responsibility for any unauthorized use of this protocol. 
 

 
 
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Introduction 
 
Transcatheter arterial chemoembolization (TACE) has been playing an important role 
in the treatment algorithm for patients with multifocal or large intrahepatic lesions not 
eligible for surgical resection, transplantation, or local ablative therapy (1). In Hong 
Kong, the TACE regimen currently being utilized in the great majority of hospitals is 
based on an aqueous form of cisplatin (Platinol, Bristol-Myers Squibb Company, 
Princeton, New Jersey, 1mg per mL) mixed in a one-to-one ratio by volume with 
ethiodized oil (Lipiodol Ultra Fluid, Guerbet, France) to form a relatively large 
volume of 40mL emulsion at 20mg cisplatin as the maximum dose (2). Although 
TACE with this regimen has been shown to be effective in prolonging overall 
survival, there is probably room for further improvement because the objective tumor 
response rate is limited to 39% (3).   One of the approaches to improve the treatment 
effectiveness of TACE could be to increase the dose of chemotherapeutic agent. In 
the United States, the most common formulation of chemotherapeutic agent in TACE 
is the mixture of cisplatin 100mg, doxorubicin 50mg, and mitomycin C 10mg, 
dissolved in 10mL of water-soluble contrast medium, then emulsified in an equivalent 
volume of ethiodized oil to form a 20mL emulsion (4). We introduce a modified 
formulation in which a relatively high dose of cisplatin up to 100mg in anhydrous 
particle form (Chemoparticle cisplatin powder, Four Seasons International 
Limited, Hong Kong) is given as a suspension in 20mL of Ethiodized oil, this 
regimen has been used and found to achieve an improved objective tumor response 
rate of 51% (5). Pure cisplatin powder has been used in the formulation of cisplatin-
Lipiodol suspension for TACE in several phase I and phase II studies (6-9). 
Pharmacokinetics study showed the formulation of cisplatin-Lipiodol suspension can 

 
 
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effectively retain cisplatin within HCC with a delayed release of the drug to systemic 
circulation (7). It is hypothesized that treatment of HCC with ethiodized oil-based 
TACE using a formulation of anhydrous cisplatin suspension can lead to 
significant improvement in treatment outcome and comparable safety as 
compared to that using a formulation of aqueous cisplatin emulsion with. This 
study is aimed to compare the efficacy and safety of using the novel formulation 
versus the conventional formulation in TACE for treating patients with HCC. 
 
Materials and methods 
 
Study design 
This is a prospective, multi-center, parallel-group, open-label, phase III randomized 
control trial that is conducted in accordance to the Declaration of Helsinki and 
international standards of Good Clinical Practice, approved by the institution’s Ethics 
Committee, and registered in Clinicaltrial.gov. (NCT03268499). This is an 
investigator-initiated study without direct industry sponsorship. Eligible patients are 
randomized into either a treatment arm in the Suspension Group or a control arm in 
the Emulsion Group with a 1:1 ratio. Eligibility to the study is assessed according to 
newly acquired clinical and imaging data within 30 days. 
 
Eligibility criteria  
Assessment of eligibility is based on clinical, laboratory, and imaging data that are 
obtained within 30 days prior to randomization: 
 
Inclusion criteria 

 
 
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1. Written informed consent 
2. Age above 18 years 
3. Hepatocellular carcinoma (HCC) unsuitable for resection or ablation 
4. Child-Pugh A cirrhosis 
5. Eastern Cooperative Oncology Group performance score 0 or 1 
6. Barcelona Clinic Liver Cancer staging system below or equal to stage B 
7. No previous treatment for HCC except for liver resection 
8. HCC diagnosed by typical enhancement patterns on cross sectional imaging or 
histology.  
9. No extra-hepatic involvement on non-enhanced CT thorax and triphasic contrast 
enhanced CT abdomen. 
10. No invasion of portal vein or hepatic vein 
11. Massive expansive tumor morphology with measurable lesion on CT 
(characterized by well-defined spherical or globular configuration, with or without 
tumor capsule or satellite lesions)  
12. Total tumor mass < 50% liver volume 
13. Size of any individual tumor  10cm in largest dimension 
14. Serum creatinine < 130 umol/L or Creatinine clearance > 55 ml/min. 
 
Exclusion criteria 
1. Known active malignancy within the last 3 years  
2. History of acute tumor rupture presenting with hemo-peritoneum 
3. Biliary obstruction not amenable to percutaneous or endoscopic drainage 
4. History of hepatic encephalopathy 
5. Intractable ascites not controllable by medical therapy 

 
 
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6. History of variceal bleeding within last 3 months 
7. Infiltrative tumor morphology (characterized by ill- defined tumor margin and 
amorphous configuration) or diffuse tumor morphology (characterized by large 
number of small nodules) 
8. Un-correctable Arterio-portal venous shunt affecting >1 hepatic segment on CT 
9. Arterial-hepatic venous shunt with hepatic vein opacified in arterial phase on CT 
 
Randomization 
Stratified randomization with permuted block method and 1:1 ratio is performed 
centrally by an independent statistician. Stratification factors include the diameter of 
largest tumor (5cm or > 5cm) and total number of tumors (3 or > 3). Random 
permuted block method with block size of 4 to 6 is used according to a computer-
generated allocation sequence. The patients, doctors and other caretakers are 
unblinded to group allocation while data collectors and analysts who assess the study 
outcome and radiologists who assessed tumor response are blinded to group 
allocation.  
 
Sample size 
Based on the results of a preliminary study involving 13 subjects (Suspension Group) 
and 14 subjects (Emulsion Group), complete tumor response rates on 6-months CT 
scan were 84.6% (11/13) and 28.5% (4/14) respectively. Assuming the anticipated 
incidences to be 70% and 35% respectively, two-sided alpha level 0.05 and power 
85%, it is estimated that 70 subjects (35 subjects in each group) are required for the 
study. Assuming a 10% drop out rate from final analysis, the final sample size is set at 
80. 

 
 
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Study endpoints  
The primary endpoints:  
The primary efficacy endpoint is complete tumor response rate after the first 3 
treatments as evaluated by triphasic contrast enhanced CT at 6 months according to 
the Modified Response Evaluation Criteria in Solid Tumors (mRECIST)(10) criteria 
as well as DSA findings during the second and third treatment. Complete tumor 
response is defined as the absence of enhancing tumor on CT and/ or absence of 
residual tumor on selective DSA of the feeding arteries to the tumors and absence of 
enhancing tumor on the subsequent CT. The primary safety endpoint is severe adverse 
events occurring within 30 days of all treatment procedure, measured by the number 
of subjects involved, defined as any undesirable symptom, sign or medical condition 
which was fatal or life-threatening, required or prolonged hospitalization, resulted in 
persistent or significant disability/incapacity, or was medically significant, might 
jeopardize the patient and might require medical or surgical intervention. 
Secondary endpoints: 
1. Complete tumor response after the first treatment;  
2. Objective tumor response, defined as complete response or partial response at 6 
months, according to mRECIST criteria;  
3. Intralesional tumor progression, defined as tumor recurrence at the site of treated 
tumor after initial complete tumor response, or any degree of enlargement of treated 
tumor after initial partial response;  

 
 
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4. Extralesional tumor progression, defined as occurrence of new tumor at a new site 
of the liver;  
5. Extrahepatic tumor progression, defined as occurrence of venous invasion by tumor 
or extrahepatic tumor metastasis;  
6. Time to progression (TTP), defined as the interval between the randomization date 
and the date of specific type of tumor progression;  
7. Progression free survival, defined as the interval between the randomization date 
and the date of any kind of tumor progression or death from any cause;  
8. Overall survival (OS), defined as the interval between the randomization date and 
the date of death from any cause. In the absence of confirmation of death, survival 
time was censored at the last date the patient was known to be alive;  
9. Adverse events occurring within 30 days after the first treatment, measured by 
number of subjects involved. 
 
Treatment schedule  
 
Treatment is given within 4 weeks after randomization. Up to three treatments at 2 
months apart (baseline, 2 months, 4 months) are given. After 2 treatments have been 
given, the decision whether to give a third treatment or not is based on CT assessment 
at 3 months. The third treatment is omitted when there is no evidence of any residual 
tumor on the 3-months CT. A third treatment is given when there is residual tumor 
but without evidence of continuous tumor growth unresponsive to treatment, vascular 

 
 
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invasion or extrahepatic metastasis.  For patients with large tumors or bi-lobar tumors 
in which the tumor vasculature could not be completely filled with ethiodized oil 
emulsion or suspension in one treatment session, an additional treatment is performed 
within 4 weeks, provided the patients’ condition does not fall outside the eligibility 
criteria, the two sessions are considered as part of one treatment.   
Beyond 6 months, when there is CT evidence of residual tumors or occurrence of new 
intrahepatic tumors, TACE of the same formulation is given, otherwise no other 
treatment is given. Further treatment is withheld when there is CT evidence of 
continuous tumor growth unresponsive to treatment, extrahepatic tumor progression, 
or patients’ condition falling outside the eligibility criteria. Under such circumstances, 
systemic therapy is considered. 
Treatment procedure 
 
Prophylactic antibiotics is not mandatory but could be given according to the standard 
practice of individual centers. Patients are fasted for 4 hours before TACE. 
Intravenous hydration is started at the onset of fasting. The maximum drug dose to be 
delivered in one treatment session is 40mL of emulsion (20mg cisplatin) or 20mL of 
suspension (100mg cisplatin) for the Emulsion Group or Suspension Group 
respectively.  
 
Guidelines on preparation of cisplatin formulations 
1.Ethiodized oil-aqueous cisplatin emulsion:  
The formulation consists of 10mg aqueous cisplatin (10mL) mixed with 10mL 
ethiodized oil to form an emulsion (0.5mg cisplatin/mL emulsion)(Platinol, Bristol-

 
 
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Myers Squibb Company, Princeton, New Jersey)(Reference 11). The formulation is 
prepared with aseptic technique within a negative pressure isolator by a pharmacist or 
a radiology nurse in the pharmacy or the radiology department. Cisplatin for injection 
(Platinol, Bristol-Myers Squibb Company, Princeton, New Jersey) 10mg in 10mL is 
used to mix with 10mL of ethiodized oil (Lipiodol Ultra Fluid, Guerbet, France) using 
the pumping method through a two-way connector between two 20mL syringes, with 
aqueous cisplatin pumped into the ethiodized oil first, using 40 times forward and 
backward pumping, to create aqueous droplets encapsulation by ethiodized oil in the 
emulsion.  
2. Ethiodized oil-anhydrous cisplatin suspension:  
The formulation being introduced consists of a suspension of 100mg pure anhydrous 
cisplatin in 20mL ethiodized oil (5mg cisplatin /mL suspension)(Chemoparticle 
cisplatin powder, Four Seasons International Limited, Hong Kong). The formulation 
is prepared with aseptic technique by a pharmacist in the pharmacy or a radiology 
nurse in the radiology department. The use of negative pressure isolator is not 
mandatory because the cisplatin is in solid form and drug evaporation is not a 
concern. Anhydrous cisplatin powder is supplied in 20mg bottles (Chemoparticle 
cisplatin powder, Four Seasons International Limited, Hong Kong). Four mL of 
ethiodized oil is introduced slowly into the cisplatin containing bottle to capture the 
20mg cisplatin powder. Cisplatin powder is washed from the bottle wall into the 
suspension with gentle shaking of ethiodized oil against the bottle wall in all 
directions. The suspension is homogenized with the use of an ultrasonic vibrator for 1 
minute, or by shaking the bottle in a circular motion of about 5cm in diameter on a 
horizontal plane, with the bottle bottom down, for about 100 times. When the 

 
 
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suspension is homogenized, it is aspirated into a syringe. If the suspension is not 
prepared immediately before delivery into the patient, sedimentation of cisplatin 
powder would invariably occur, the suspension is then homogenized again with a 
pumping method through a two-way connector between two syringes.  
 
Patient preparation and TACE procedure specific to Suspension Group 
Within 60 minutes before TACE, antiemetic regimen is started as per standard clinical 
practice for highly emetogenic systemic chemotherapy, choices include 5-HT3 
antagonist (Zofran or Kytril), dexamethasone, NK1 receptor antagonist (SFI), or 
metoclopramide (Maxolon). After TACE, intravenous mannitol 40gm is given over 
30 minutes, and intravenous normal saline 1000mL (with addition of 20 mmol KCL, 
0.5gm Magnesium Sulfate, and 2.5ml 10% Ca Gluconate) is given over 12 hours. 
During transarterial delivery of the formulation, attention is paid to hold the syringe in 
a tip-down and vertical position to facilitate complete emptying of cisplatin powder 
together with ethiodized oil as the powder invariably falls gradually towards the tip of 
the syringe with time due to gravity.  
 
TACE procedure and procedure endpoint applicable to both groups 
 
Arterial catheterization to segmental, subsegmental, or sub-subsegmental level is 
achieved depending on the tumor size, to gain arterial access as close to the tumors as 
possible. The formulation is delivered under fluoroscopic control until the vasculature 
of all tumors is entirely filled, or until the maximum dose is reached. Inadvertent drug 
delivery to non-hepatic organs through non-hepatic arteries originating from hepatic 
arteries is avoided by controlling the rate of delivery or selective coil embolization. 

 
 
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The completeness of filling of tumor vasculature is assessed with flat panel CT or 
multi-planar CT. Attention is paid to identify non-hepatic arterial supply to tumors to 
ensure complete treatment of all tumor components. Embolization is performed using 
1mm-sized gelatin-sponge pellets following the delivery of cisplatin, with an aim to 
achieve flow reduction but not complete stasis.  
 
Patient assessment 
Pre-treatment evaluation 
1. Complete history and physical examination 
2. Non-enhanced CT thorax and triphasic abdominal CT scan  
3. Complete blood picture (CBP) and differential counts 
4. Liver and renal function tests (L/RFT) 
5. Serum AFP 
6. Clotting profile PT, APTT, INR 
7. HBsAg status  
8. Anti-HCV 
 
Peri-procedure evaluation 
1. Clinical observation during hospitalization 
2.  Blood test for CBP, L/RFT, INR at day 1 and day 2 of treatment procedure 
 
Radiological assessment 
Non-enhanced CT thorax and triphasic contrast enhanced CT of abdomen are 
performed at 3 months intervals from date of first treatment until untreatable 
progression, symptomatic progression, or death. 

 
 
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Clinical visits 
Patients are followed up at day 14, 30 days after each treatment. After the first 30 days, 
follow up are subsequently scheduled at 1 to 3 months intervals. 
Clinical observation and physical examination are carried out in each visit (including 
ECOG performance status) 
Blood tests on day 7 and in each visit include CBP, L/RFT, INR. Serum AFP is also 
checked after day 30. 
 (+/- 3 days applies to clinical visit and blood taking on day 7 and beyond) 
 
Laboratory findings were graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events Version 4.0.  
 
Outcome assessment 
 
Tumor response 
Triphasic contrast enhanced CT of abdomen is performed at 3 months intervals after 
the first treatment until untreatable progression, symptomatic progression, or death. 
Tumor response at 3 month and 6 month is classified into complete response (CR), 
partial response (PR), or stable disease (SD), according to Modified Response 
Evaluation Criteria in Solid Tumors (mRECIST)(10). Progresive disease is 
subdivided into intralesional progression, extralesional progression, and extrahepatic 
progression. Intralesional tumor progression is defined as tumor recurrence at the site 
of treated tumor after initial complete tumor response, or any degree of enlargement 
of treated tumor after initial partial response. Extralesional tumor progression is 

 
 
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defined as occurrence of new tumor at a new site of the liver. Extrahepatic tumor 
progression is defined as occurrence of venous invasion by tumor or extrahepatic 
tumor metastasis.  
Disease progression is adjudicated in retrospect at the time it is first detected. CT 
images are reviewed centrally for response classification by a team of independent 
radiologists. Discrepancy in classification among radiologists is resolved by 
consensus. 
 
Clinical outcome 
Patients are observed as in-patient for 3 to 5 days after TACE and followed clinically 
at day 14, 30 days after each treatment. After the first 30 days, clinics are scheduled at 
1 to 3-months intervals. Adverse events are graded according to the National Cancer 
Institute Common Terminology Criteria for Adverse Events Version 4.0. Serious 
adverse events are reported to the institution’s Clinical Research Ethics Committee 
within 24 hours of learning of its occurrence. 
 
Adverse events 
Information about all adverse events, whether volunteered by the patient, discovered 
by the investigators, or detected through physical examination, laboratory tests or by 
other means, will be collected and recorded on the Adverse Event Case Report Form 
(CRF) in every visit and followed as appropriate. An adverse event is defined as any 
undesirable symptom, sign or medical condition occurring after starting the trial even 
if the event is not considered to be related to the study medication or placebo. 
 
Serious adverse events 

 
 
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To ensure patient safety, every serious adverse event will be reported to the CREC 
within 24 hours of learning of its occurrence. A serious adverse event is an 
undesirable symptom, sign or medical condition which: 
1. is fatal or life-threatening, 
2. requires or prolongs hospitalization, 
3. results in persistent or significant disability/incapacity, or 
4. is medically significant, may jeopardize the patient and may require medical or 
surgical intervention to prevent one of the outcomes listed above. 
5.  
Statistical analysis 
Efficacy analyses are performed on the per-protocol population according to the 
treatment finally received with adherence to the protocol. Post-randomization exclusion 
is limited only to those who withdrew themselves from the study or who have not 
completed the required treatments. For continuous variables, median with inter-quarter 
range (IQR) are provided and compared using U test between the groups. For 
dichotomic variables, comparison between groups is performed using Chi-square test 
or Fisher’s exact test. The time-to-event data in months are estimated with the method 
of Kaplan-Meier analysis for TTP, PFS and OS, and presented with median and 95% 
confidence interval (CI). If the median is not reached, 3-year and 5-year rate are given. 
Survival outcomes between the groups are compared using log-rank test, hazard ratio 
(HR) and corresponding 95% confidence interval (CI) are computed using cox 
regression model. SPSS software is used for analysis. Statistical significance is p< 0.05. 
 
 

 
 
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