Emulsion Versus Suspension in Chemoembolization for Hepatocellular Carcinoma

Randomization with 1:1 ratio is centralized and performed by an independent statistician, it is stratified by the diameter of largest tumor less than or equal to 5cm or > 5cm, and total number of tumors less than or equal to 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 not blinded to group allocation. Data collectors and analysts who assess the study outcome and radiologists who assess tumor response are blinded to group allocation.

Assuming the complete response rates in the Suspension Group and Emulsion Group are 70% and 35% respectively, 85% power and 5% level of confidence, the sample size is estimated to be 70 (35 for each arm). Assuming 10 subjects to be withdrawn from the study or lost to follow-up, the final sample size is estimated to be 80.

• Lipiodol-based transarterial chemoembolization (Procedure), also known as Conventional chemoembolization, cTACE: Arterial catheterization to segmental, subsegmental, or sub-subsegmental level was achieved depending on the tumor size, to gain arterial access as close to the tumors as possible. The formulation was delivered under fluoroscopic control until the vasculature of all tumors was entirely filled, or until the maximum dose was reached.

Primary outcomes

• Number of Paticipants With Complete Tumor Response After the First 3 Treatments [Within 6 months after randomization]: Complete tumor response is defined according to the Modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria as well as DSA findings during the second and third treatment, it 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.
• Number of Participants With Severe Adverse Events of All Treatment Procedures Occurring Within 30 Days of the Treatment [within 30 days of the treatment]: Severe adverse events is 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 outcomes

• Number of Paticipants With Complete Tumour Response After the First Treatment [At 3 months after the first treatment]: Complete tumor response is defined according to the Modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria as well as DSA findings during the second and third treatment, it 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.
• Number of Participants With Complete or Partial Tumour Response at 6 Months [At 6 months after the first treatment]: Objective tumor response was defined as complete response or partial response. Partial response was defined by the modified RECIST criteria as at least a 30% decrease in the sum of diameters of viable (enhancement in the arterial phase) target lesions, taking as reference the baseline sum of the diameters of target lesions
• Number of Participants With Intralesional Tumour Progression From Randomization Date up to 78 Months [throughout follow-up period, up to 78 months]: 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;
• Number of Participants With Extralesional Tumour Progression From Randomization Date up to 78 Months [throughout follow-up period, up to 78 months]: Extralesional tumor progression is defined as occurrence of new tumor at a new site of the liver;
• Number of Participants With Extrahepatic Tumour Progression up to 78 Months [throughout follow-up period, up to 78 months]: Extrahepatic tumor progression is defined as occurrence of venous invasion by tumor or extrahepatic tumor metastasis;
• Time Interval in Months From Randomization Date to Occurrence of Any Kind of Tumor Progression up to 78 Months [throughout follow-up period, up to 78 months]: Any kind of tumor progression include intralesional progression, extralesional progression, or extrahepatic progression
• Progression Free Survival in Number of Months up to 78 Months [throughout follow-up period, up to 78 months]: Progression free survival is defined as the interval between the randomization date and the date of any kind of tumor progression or death from any cause;
• Overall Survival in Months up to 78 Months [throughout follow-up period, up to 78 months]: Overall survival Overall survival is 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;
• Adverse Event [Within 30 days after the first treatment]: Number of participants with the specific adverse event that occurred within 30 days after the first treatment
• Serious Adverse Event [Within 30 days after all treatments]: Serious adverse event that occurs within 30 days after all treatments

Sex: All, ages: 18 Years to any

Inclusion criteria

1. Written informed consent
2. Age above 18 years
3. HCC unsuitable for resection or ablation
4. Child-Pugh A cirrhosis
5. Eastern Cooperative Oncology Group performance score 0 or 1
6. BCLC A or 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 greater than or equal to 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
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

Participant flow

Outcome results

• Number of Paticipants With Complete Tumor Response After the First 3 Treatments (Primary), Count of participants, Participants: Suspension Group 35; Emulsion Group 18
• Number of Participants With Severe Adverse Events of All Treatment Procedures Occurring Within 30 Days of the Treatment (Primary), Count of participants, Participants: Suspension Group 2; Emulsion Group 7
• Number of Paticipants With Complete Tumour Response After the First Treatment (Secondary), Count of participants, Participants: Suspension Group 22; Emulsion Group 4
• Number of Participants With Complete or Partial Tumour Response at 6 Months (Secondary), Count of participants, Participants: Suspension Group 39; Emulsion Group 27
• Number of Participants With Intralesional Tumour Progression From Randomization Date up to 78 Months (Secondary), Count of participants, Participants: Suspension Group 5; Emulsion Group 17
• Number of Participants With Extralesional Tumour Progression From Randomization Date up to 78 Months (Secondary), Count of participants, Participants: Suspension Group 12; Emulsion Group 20
• Number of Participants With Extrahepatic Tumour Progression up to 78 Months (Secondary), Count of participants, Participants: Suspension Group 3; Emulsion Group 3
• Time Interval in Months From Randomization Date to Occurrence of Any Kind of Tumor Progression up to 78 Months (Secondary), Median, months: Suspension Group 24.6 (13.3 to 38.9); Emulsion Group 10.7 (7.5 to 14.1)
• Progression Free Survival in Number of Months up to 78 Months (Secondary), Median, months: Suspension Group 21.1 (14.3 to 38.9); Emulsion Group 10.4 (7.3 to 13.4)
• Overall Survival in Months up to 78 Months (Secondary), Median, months: Suspension Group 53.3 (40.5 to 80); Emulsion Group 36 (25.7 to 46.6)
• Adverse Event (Secondary), Count of participants, Participants: Suspension Group 30; Emulsion Group 32
• Serious Adverse Event (Secondary), Count of participants, Participants: Suspension 2; Emulsion 7

Adverse events

Time frame: Up to 78 months after randomization

Serious adverse events by term

Other adverse events by term

Limitations and caveats: The number of subjects was relatively small, although the power of study was 85%. Using CT in assessing tumor response in the presence of intratumoral ethiodized oil may suffer a higher risk of missing minute tumors hidden among the ethiodized oil cast and over-diagnosing complete tumor response, however, the study outcomes were unlikely significantly affected, because viable tumors that were missed would have been captured at the study endpoint of intralesional tumor progression.

• Results publication: Yu SCH, Chan L, Lee KF, Cho CCM, Hui EP, Chu CCM, Cheung SYS, Lok HT, Li L, Wong JKT, Wong JC, Yuen TY, Yu PSM, Wong SSM, Wong HL, Ho CHCH, Mo F, Yeo WMM. Ethiodized Oil-based Transarterial Chemoembolization for Hepatocellular Carcinoma: Randomized Clinical Trial of Anhydrous Cisplatin Suspension versus Cisplatin Emulsion. Radiology. 2025 Nov;317(2):e242982. doi: 10.1148/radiol.242982. PMID 41288481

• Study Protocol (PDF, 2016-07-16)
• Statistical Analysis Plan (PDF, 2016-07-16)
• Informed Consent Form (PDF, 2016-07-16)

• Simon Yu, Principal investigator, DIIR, CUHK, Hong Kong