Hepatocellular Carcinoma
Conditions
Brief summary
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.
Detailed description
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 Assuming 10 subjects to be withdrawn from the study or lost to follow-up, the final sample size is estimated to be 80.
Interventions
PROCEDURELipiodol-based transarterial chemoembolization
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.
Sponsors
Chinese University of Hong Kong
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Investigator, Outcomes Assessor)
Masking description
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.
Intervention model description
prospective, multi-center, parallel-group, open-label, phase III randomized control trial
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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. |
| 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 |
| 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; |
| 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 |
Countries
Hong Kong
Participant flow
Recruitment details
Recruitment period: September 2016 to August 2022 Recruitment took place in the surgery and oncology clinics of three general hospitals including Prince of Wales Hospital, United Christian Hospital and Tuen Mun Hospital in Hong Kong
Pre-assignment details
Of all 2772 new HCC patients who attended the three hospitals from September 2016 to August 2022, 862 patients who refused or were considered unsuitable for liver resection or ablation were screened, 782 patients were excluded due to failing to meet the eligibility criteria (97%) or having declined to participate (3%).
Participants by arm
| Arm | Count |
|---|---|
| Suspension Group Received TACE using suspension formulation | 39 |
| Emulsion Group Received TACE using emulsion formulation | 38 |
| Total | 77 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 2 | 1 |
Baseline characteristics
| Characteristic | Emulsion Group | Total | Suspension Group |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 24 Participants | 50 Participants | 26 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants | 27 Participants | 13 Participants |
| Age, Continuous | 68 years | 68 years | 70 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 38 Participants | 77 Participants | 39 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Hong Kong | 38 participants | 77 participants | 39 participants |
| Sex: Female, Male Female | 5 Participants | 18 Participants | 13 Participants |
| Sex: Female, Male Male | 33 Participants | 59 Participants | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 10 / 39 | 16 / 38 |
| other Total, other adverse events | 39 / 39 | 38 / 38 |
| serious Total, serious adverse events | 2 / 39 | 7 / 38 |
Outcome results
Primary
Number of Participants With Severe Adverse Events of All Treatment Procedures Occurring 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.
Time frame: within 30 days of the treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Suspension Group | Number of Participants With Severe Adverse Events of All Treatment Procedures Occurring Within 30 Days of the Treatment | 2 Participants |
| Emulsion Group | Number of Participants With Severe Adverse Events of All Treatment Procedures Occurring Within 30 Days of the Treatment | 7 Participants |
Primary
Number of Paticipants With Complete Tumor Response After the First 3 Treatments
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.
Time frame: Within 6 months after randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Suspension Group | Number of Paticipants With Complete Tumor Response After the First 3 Treatments | 35 Participants |
| Emulsion Group | Number of Paticipants With Complete Tumor Response After the First 3 Treatments | 18 Participants |
Secondary
Adverse Event
Number of participants with the specific adverse event that occurred within 30 days after the first treatment
Time frame: Within 30 days after the first treatment
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Suspension Group | Adverse Event | Fever | 30 Participants |
| Suspension Group | Adverse Event | Abdominal pain | 25 Participants |
| Suspension Group | Adverse Event | bilirubin elevation | 32 Participants |
| Suspension Group | Adverse Event | Nausea | 14 Participants |
| Suspension Group | Adverse Event | Vomiting | 13 Participants |
| Suspension Group | Adverse Event | albumin depression | 33 Participants |
| Suspension Group | Adverse Event | Alkaline phosphatase elevation | 31 Participants |
| Suspension Group | Adverse Event | Alanine aminotransferase | 39 Participants |
| Emulsion Group | Adverse Event | Alanine aminotransferase | 33 Participants |
| Emulsion Group | Adverse Event | Vomiting | 10 Participants |
| Emulsion Group | Adverse Event | bilirubin elevation | 37 Participants |
| Emulsion Group | Adverse Event | Abdominal pain | 26 Participants |
| Emulsion Group | Adverse Event | Alkaline phosphatase elevation | 33 Participants |
| Emulsion Group | Adverse Event | Fever | 32 Participants |
| Emulsion Group | Adverse Event | albumin depression | 30 Participants |
| Emulsion Group | Adverse Event | Nausea | 8 Participants |
Secondary
Number of Participants With Complete or Partial Tumour Response at 6 Months
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
Time frame: At 6 months after the first treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Suspension Group | Number of Participants With Complete or Partial Tumour Response at 6 Months | 39 Participants |
| Emulsion Group | Number of Participants With Complete or Partial Tumour Response at 6 Months | 27 Participants |
Secondary
Number of Participants With Extrahepatic Tumour Progression up to 78 Months
Extrahepatic tumor progression is defined as occurrence of venous invasion by tumor or extrahepatic tumor metastasis;
Time frame: throughout follow-up period, up to 78 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Suspension Group | Number of Participants With Extrahepatic Tumour Progression up to 78 Months | 3 Participants |
| Emulsion Group | Number of Participants With Extrahepatic Tumour Progression up to 78 Months | 3 Participants |
Secondary
Number of Participants With Extralesional Tumour Progression From Randomization Date up to 78 Months
Extralesional tumor progression is defined as occurrence of new tumor at a new site of the liver;
Time frame: throughout follow-up period, up to 78 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Suspension Group | Number of Participants With Extralesional Tumour Progression From Randomization Date up to 78 Months | 12 Participants |
| Emulsion Group | Number of Participants With Extralesional Tumour Progression From Randomization Date up to 78 Months | 20 Participants |
Secondary
Number of Participants With Intralesional Tumour Progression From Randomization Date 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;
Time frame: throughout follow-up period, up to 78 months
Population: 2 participants excluded from analysis in each group since the patients received liver resection
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Suspension Group | Number of Participants With Intralesional Tumour Progression From Randomization Date up to 78 Months | 5 Participants |
| Emulsion Group | Number of Participants With Intralesional Tumour Progression From Randomization Date up to 78 Months | 17 Participants |
Secondary
Number of Paticipants With Complete Tumour Response 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.
Time frame: At 3 months after the first treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Suspension Group | Number of Paticipants With Complete Tumour Response After the First Treatment | 22 Participants |
| Emulsion Group | Number of Paticipants With Complete Tumour Response After the First Treatment | 4 Participants |
Secondary
Overall Survival in Months 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;
Time frame: throughout follow-up period, up to 78 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Suspension Group | Overall Survival in Months up to 78 Months | 53.3 months |
| Emulsion Group | Overall Survival in Months up to 78 Months | 36 months |
Secondary
Progression Free Survival in Number of Months 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;
Time frame: throughout follow-up period, up to 78 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Suspension Group | Progression Free Survival in Number of Months up to 78 Months | 21.1 months |
| Emulsion Group | Progression Free Survival in Number of Months up to 78 Months | 10.4 months |
Secondary
Serious Adverse Event
Serious adverse event that occurs within 30 days after all treatments
Time frame: Within 30 days after all treatments
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Suspension Group | Serious Adverse Event | 2 Participants |
| Emulsion Group | Serious Adverse Event | 7 Participants |
Secondary
Time Interval in Months From Randomization Date to Occurrence of Any Kind of Tumor Progression up to 78 Months
Any kind of tumor progression include intralesional progression, extralesional progression, or extrahepatic progression
Time frame: throughout follow-up period, up to 78 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Suspension Group | Time Interval in Months From Randomization Date to Occurrence of Any Kind of Tumor Progression up to 78 Months | 24.6 months |
| Emulsion Group | Time Interval in Months From Randomization Date to Occurrence of Any Kind of Tumor Progression up to 78 Months | 10.7 months |