The aim of the study was to evaluate the safety and efficacy of using the new formulation (Lipiodol-cisplatin suspension) for TACE in the treatment of HCC as compared to the conventional formulation (Lipiodol-cisplatin emulsion). This is a prospective, parallel-group, open-label randomized, phase III study that is conducted in accordance to the Declaration of Helsinki and international standards of Good Clinical Practice, and approved by the institutional review board. Eligible patients were randomized into either a treatment arm of Lipiodol-cisplatin suspension or a control arm of Lipiodol-cisplatin emulsion with a 1:1 ratio.

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 Assuming 10 subjects to be withdrawn from the study or lost to follow-up, the final sample size is estimated to be 80.

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

Up to 78 months after randomization

Details of "Adverse events" are being reported under secondary endpoints. "All-cause mortality", details of "Serious Adverse Events", and "Other Adverse Events" are being reported here.

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.

The patients, doctors and other caretakers are not blinded to group allocation. Data collectors and analysts who assessed the study outcome and radiologists who assessed tumor response are blinded to group allocation.