Liver Cancer
Conditions
Keywords
adult primary hepatocellular carcinoma, localized unresectable adult primary liver cancer
Brief summary
RATIONALE: Radiofrequency ablation uses a high-frequency, electric current to kill tumor cells. CT-, MRI-, or ultrasound-guided radiofrequency ablation may be an effective treatment for liver cancer and cirrhosis. PURPOSE: This phase II trial is studying how well radiofrequency ablation works in treating patients with liver cancer and cirrhosis.
Detailed description
OBJECTIVES: Primary * Determine the 18-month successful disease control rate, defined as no identifiable liver tumor by CT scan, in patients with hepatocellular carcinoma and cirrhosis treated with solitary or repetitive percutaneous radiofrequency ablation (RFA). Secondary * Correlate tumor size, MELD score, and the number of RFA treatments (solitary or repetitive) with the 18-month successful disease control rate in patients treated with this procedure. * Determine the local and remote intrahepatic and extrahepatic tumor recurrence rates in patients treated with this procedure. * Correlate local and remote intrahepatic and extrahepatic tumor recurrence rates with the 18-month successful disease control rate in patients treated with this procedure. * Correlate tumor size with the local disease control rate in patients treated with this procedure. * Correlate solitary or repetitive RFA with or without local/regional tumor control with the development of extrahepatic tumor in these patients. * Determine the local tumor eradication rate, as determined by examination of whole liver specimens or CT scan, in patients treated with this procedure. OUTLINE: This is a multicenter study. Patients are stratified according to hepatic dysfunction using the MELD score (\< 15 vs 15-25 vs \> 25). Patients undergo placement of an ablation electrode percutaneously into the tumor(s) by CT scan, MRI, or ultrasound guidance. Patients then undergo percutaneous radiofrequency ablation (RFA) directly to the tumor(s) for 12 minutes. Patients undergo CT scan of the liver within 1 week after RFA treatment and then every 3 months for up to 18 months. Patients with residual or recurrent intrahepatic tumor(s) detectable on the 3-month or subsequent CT scan undergo repeat RFA as is technically feasible and clinically indicated for up to 15 months after initial RFA treatment. After completion of study treatment, patients are followed at 1 day, 1 week, 1 month, and then every 3 months for up to 18 months. PROJECTED ACCRUAL: A total of 40 patients will be accrued for this study.
Interventions
DEVICEradiofrequency ablation
Sponsors
National Cancer Institute (NCI)
American College of Radiology Imaging Network
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Diagnosis of hepatocellular carcinoma (HCC), meeting 1 of the following criteria: * Histologically confirmed HCC * Discrete non-biopsied hepatic tumors, meeting 1 of the following criteria: * Hypervascular tumor \> 2 cm by 2 imaging studies * Hypervascular tumor \> 2 cm by a single imaging study AND alpha-fetoprotein ≥ 400 ng/mL * Discrete non-biopsied hypervascular hepatic tumors by 2 consecutive imaging studies (e.g., CT scan or MRI) with documented tumor growth \> 1 cm in diameter * Histologically confirmed cirrhosis OR typical findings of cirrhosis (i.e., nodular liver, splenomegaly, varices, or ascites) by CT scan and/or MRI scan * Single hepatic tumor \> 3.0 cm but ≤ 5.0 cm in diameter OR 3 or fewer hepatic tumors ≤ 3.0 cm in diameter * No excessive intrahepatic tumor burden (i.e., \> 3 hepatic tumors OR a single hepatic tumor \> 5 cm OR more than 3 vague hypervascular nodules \> 1 cm) * Tumor(s) ≥ 1 cm from the main, right, and left portal veins and hollow viscera * No hepatic or portal vein tumor invasion * Tumor(s) \> 1 cm treatable by percutaneous radiofrequency ablation * No extrahepatic tumor * Not a surgical candidate due to any of the following reasons: * Tumor in an unresectable location * Comorbid disease * Insufficient hepatic reserve PATIENT CHARACTERISTICS: Age * 18 and over Performance status * Zubrod 0-2 Life expectancy * Not specified Hematopoietic * No uncorrectable coagulopathy Hepatic * Not specified Renal * Creatinine ≤ 2.0 mg/dL Other * Not pregnant * Negative pregnancy test * Fertile patients must use effective contraception * No active symptomatic bacterial or fungal infection that is newly diagnosed and/or requires treatment * No absolute contraindication to IV iodinated contrast (i.e., history of significant contrast reaction not mitigated by appropriate premedication) PRIOR CONCURRENT THERAPY: Biologic therapy * Not specified Chemotherapy * No prior or concurrent chemotherapy for HCC * No prior or concurrent chemoembolization for HCC Endocrine therapy * Not specified Radiotherapy * No prior or concurrent radiotherapy for HCC Surgery * No prior choledochoenteric anastomosis * No prior sphincterotomy of duodenal papilla Other * No prior or concurrent cryoablation for HCC * No other prior or concurrent therapy for HCC * At least 7 days since prior aspirin * At least 24 hours since prior ibuprofen * At least 12 hours since prior low molecular weight heparin preparations
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants With Successful Control of Disease at 18 Months | 18 months after start of therapy | Outcome is positive (success) if alive and no disease is observed by CT at 18 months post start of therapy Outcome is negative if the patient was deceased or disease was observed by CT at 18 months post start of therapy Success rate it the fraction of eligible patients who were alive and disease free at 18 months. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Effect of Tumor Size on Successful Control of Disease at 18 Months | 18 months after start of therapy | Outcome is positive (success) if alive and no disease is observed by CT at 18 months post start of therapy Outcome is negative if the patient was deceased or disease was observed by CT at 18 months post start of therapy Success rate it the fraction of eligible patients who were alive and disease free at 18 months. Tumor size is a continuous variable as measured at imaging. |
| Local Tumor Recurrence (Control) Rates | 18 months after start of therapy | local tumor control rate is defined as a tumor that was ablated and was not seen again within the 18 month period |
| Impact of Tumor Size on Local Control Rates | 18 months after start of therapy | Lesion level local control is defined as a success if a tumor is ablated and does not recur in 18 mo. |
| Number of Participants With Success in Those Who Received Solitary vs Repetitive Radiofrequency Ablation | 18 months after start of therapy | this outcome measures the impact of Solitary vs repetitive radiofrequency ablation on success. Success is defined as the number of patients centrally determined to be alive and tumor-free 18 months after start of therapy, corrected for repetitive RFA. |
| Local Tumor Eradication Rate by Examination of Liver Via Autopsy or Transplant vs That Determined by CT Scan | 18 months after start of therapy | the primary outcome was evidence of existing tumor on pathologic review of the liver at the time or transplant or autopsy within the 18 month observational period. This outcome was compared to the CT HCC detection. |
| Remote Tumor Occurrence Rates | 18 months after start of therapy | remote tumor occurrence rate is defined as a new intrahepatic tumor that developed remote from the ablation site within the 18 month period |
| Development of Extra-hepatic Tumor | 18 months after start of therapy | Whether or not extrahepatic tumors were seen at 18months post ablation will be compared with the number of RFA sessions. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Patients patients with cirrhosis undergoing solitary or repetitive percutaneous radiofrequency ablation (RFA) treatment sessions for the treatment of HCC. | 45 |
| Total | 45 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| 12 Months Post Ablation | Death | 1 |
| 12 Months Post Ablation | non-protocol Treatment | 1 |
| 12 Months Post Ablation | Transplant | 1 |
| 12 Months Post Ablation | Withdrawal by Subject | 1 |
| 15 Months Post Ablation | Death | 1 |
| 15 Months Post Ablation | Non-Protocol Treatment | 1 |
| 15 Months Post Ablation | Transplant | 5 |
| 15 Months Post Ablation | Withdrawal by Subject | 1 |
| 18 Months Post Ablation | ExtraHepatic tumor | 1 |
| 18 Months Post Ablation | Non-Protocol Treatment | 3 |
| 18 Months Post Ablation | Transplant | 1 |
| 18 Months Post Ablation | Withdrawal by Subject | 1 |
| 3 Months Post Ablation | Non-Protocol Treatment | 2 |
| 3 Months Post Ablation | Transplant | 1 |
| 6 Months Post Ablation | Death | 2 |
| 6 Months Post Ablation | Transplant | 6 |
| 6 Months Post Ablation | Withdrawal by Subject | 2 |
| 9 Months Post Ablation | Death | 1 |
| 9 Months Post Ablation | Transplant | 1 |
| Baseline | Ineligible | 6 |
Baseline characteristics
| Characteristic | All Patients |
|---|---|
| Age, Continuous | 62 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 15 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 28 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 7 Participants |
| Race (NIH/OMB) White | 31 Participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 3 / 45 |
| other Total, other adverse events | 26 / 45 |
| serious Total, serious adverse events | 5 / 45 |
Outcome results
Primary
Proportion of Participants With Successful Control of Disease at 18 Months
Outcome is positive (success) if alive and no disease is observed by CT at 18 months post start of therapy Outcome is negative if the patient was deceased or disease was observed by CT at 18 months post start of therapy Success rate it the fraction of eligible patients who were alive and disease free at 18 months.
Time frame: 18 months after start of therapy
Population: Patients not reaching 18mo were considered failures
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eligible Patients | Proportion of Participants With Successful Control of Disease at 18 Months | .18 proportion of participants |
Comparison: logistic regression was used to estimate the success rate95% CI: [0.091, 0.317]
Comparison: logistic regression model after specifying site as cluster (using GEE approach).95% CI: [0.136, 0.252]
Secondary
Development of Extra-hepatic Tumor
Whether or not extrahepatic tumors were seen at 18months post ablation will be compared with the number of RFA sessions.
Time frame: 18 months after start of therapy
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Eligible Patients | Development of Extra-hepatic Tumor | 1-RFA | 2 Participants |
| Eligible Patients | Development of Extra-hepatic Tumor | Multiple RFA | 4 Participants |
| Repetitive Ablation | Development of Extra-hepatic Tumor | 1-RFA | 25 Participants |
| Repetitive Ablation | Development of Extra-hepatic Tumor | Multiple RFA | 14 Participants |
Secondary
Effect of Tumor Size on Successful Control of Disease at 18 Months
Outcome is positive (success) if alive and no disease is observed by CT at 18 months post start of therapy Outcome is negative if the patient was deceased or disease was observed by CT at 18 months post start of therapy Success rate it the fraction of eligible patients who were alive and disease free at 18 months. Tumor size is a continuous variable as measured at imaging.
Time frame: 18 months after start of therapy
Population: 8 participants has successful control at 18mo; 37 participants did not.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eligible Patients | Effect of Tumor Size on Successful Control of Disease at 18 Months | Successful Control mean size | 2.80 centimeters | Standard Deviation 0.85 |
| Eligible Patients | Effect of Tumor Size on Successful Control of Disease at 18 Months | Failure mean size | 3.32 centimeters | Standard Deviation 1.26 |
Comparison: Effect of tumor size in the multivariate model with response:18 mo success/failure; covariates: tumor size,repeated RFA, local tumor recurrence, remote tumor occurrence, and age and gender.p-value: 0.022195% CI: [-1.6894, -0.1308]Generlaized Estimating Equations
Secondary
Impact of Tumor Size on Local Control Rates
Lesion level local control is defined as a success if a tumor is ablated and does not recur in 18 mo.
Time frame: 18 months after start of therapy
Population: local tumor control rate (No Recurrence) is defined as a tumor that was ablated and was not seen again
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eligible Patients | Impact of Tumor Size on Local Control Rates | No Recurrance | 2.4833 cm | Standard Deviation 0.999 |
| Eligible Patients | Impact of Tumor Size on Local Control Rates | Recurrance | 2.9417 cm | Standard Deviation 0.8622 |
Comparison: the mean tumor size in the two groups, recurred and non recurred tumors, will be compared using a t-test assuming H0: recur=non-recurrp-value: 0.06t-test, 2 sided
Secondary
Local Tumor Eradication Rate by Examination of Liver Via Autopsy or Transplant vs That Determined by CT Scan
the primary outcome was evidence of existing tumor on pathologic review of the liver at the time or transplant or autopsy within the 18 month observational period. This outcome was compared to the CT HCC detection.
Time frame: 18 months after start of therapy
Population: 14 cases (13 transplanted cases and 1 deceased case) had pathology available for review, representing 16 specimens (12 tumors in 14 livers))
| Arm | Measure | Category | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Eligible Patients | Local Tumor Eradication Rate by Examination of Liver Via Autopsy or Transplant vs That Determined by CT Scan | CT negative (not seen) | 3 specimen |
| Eligible Patients | Local Tumor Eradication Rate by Examination of Liver Via Autopsy or Transplant vs That Determined by CT Scan | CT Positive (seen) | 1 specimen |
| Repetitive Ablation | Local Tumor Eradication Rate by Examination of Liver Via Autopsy or Transplant vs That Determined by CT Scan | CT negative (not seen) | 11 specimen |
| Repetitive Ablation | Local Tumor Eradication Rate by Examination of Liver Via Autopsy or Transplant vs That Determined by CT Scan | CT Positive (seen) | 1 specimen |
95% CI: [0, 0.38]
Comparison: Specificity95% CI: [0.194, 0.994]
Secondary
Local Tumor Recurrence (Control) Rates
local tumor control rate is defined as a tumor that was ablated and was not seen again within the 18 month period
Time frame: 18 months after start of therapy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eligible Patients | Local Tumor Recurrence (Control) Rates | 0.51 percentage recurring |
Secondary
Number of Participants With Success in Those Who Received Solitary vs Repetitive Radiofrequency Ablation
this outcome measures the impact of Solitary vs repetitive radiofrequency ablation on success. Success is defined as the number of patients centrally determined to be alive and tumor-free 18 months after start of therapy, corrected for repetitive RFA.
Time frame: 18 months after start of therapy
Population: of the 45 participants, 35 had single ablate therapy while 10 received multiple RFA sessions.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Eligible Patients | Number of Participants With Success in Those Who Received Solitary vs Repetitive Radiofrequency Ablation | Success | 5 Participants |
| Eligible Patients | Number of Participants With Success in Those Who Received Solitary vs Repetitive Radiofrequency Ablation | Failure | 30 Participants |
| Repetitive Ablation | Number of Participants With Success in Those Who Received Solitary vs Repetitive Radiofrequency Ablation | Success | 3 Participants |
| Repetitive Ablation | Number of Participants With Success in Those Who Received Solitary vs Repetitive Radiofrequency Ablation | Failure | 7 Participants |
Comparison: logistic regression was used to estimate the success rate95% CI: [0.091, 0.317]
Comparison: multivariate logistic regression model was fit using GEEs to correct for site clustering effects, in which, the response variable was success/failure at 18 months and the covariates were tumor size, whether or not a patient received repeated RFA, whether or not a local tumor recurrence occurred, whether or not a remote tumor occurrence occurred, and two common confounding factors - age and genderp-value: 0.000495% CI: [-5.9056, -1.6769]Generlaized estimating equations
Secondary
Remote Tumor Occurrence Rates
remote tumor occurrence rate is defined as a new intrahepatic tumor that developed remote from the ablation site within the 18 month period
Time frame: 18 months after start of therapy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eligible Patients | Remote Tumor Occurrence Rates | 0.53 percent occuring |
Post Hoc
Rate of Successful Control of Disease at 18 Months, Including Transplants
Outcome is positive (success) if the participant received a liver transplant or no diseaseis was observed by CT at 18 months after start of therapy Success rate it the fraction of eligible patients who are successes at 18 months.
Time frame: 18 months after start of therapy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eligible Patients | Rate of Successful Control of Disease at 18 Months, Including Transplants | 0.51 proportion of successes to eligible |
p-value: 0.0001McNemar