Child-Pugh Class A, Child-Pugh Class B, Recurrent Hepatocellular Carcinoma
Conditions
Brief summary
This randomized phase III trial studies how well transarterial chemoembolization (TACE) works compared to stereotactic body radiation therapy (SBRT) or stereotactic ablative radiation therapy (SABR) in patients with liver cancer that remain after attempts to remove the cancer have been made (residual) or has come back (recurrent). TACE is a minimally invasive, image-guided treatment procedure that uses a catheter to deliver both chemotherapy medication and embolization materials into the blood vessels that lead to the tumors. SBRT or SABR may be able to send radiation directly to the tumor and cause less damage to normal liver tissue. It is not yet known whether TACE is more effective than SBRT or SABR in treating patients with persistent or recurrent liver cancer who have undergone initial TACE.
Detailed description
PRIMARY OBJECTIVES: I. To determine the freedom from local progression (FFLP) of TACE versus (vs) SABR in patients with persistent hepatocellular carcinoma (HCC) after TACE. SECONDARY OBJECTIVES: I. To determine the progression-free survival (PFS) of TACE vs SABR in patients with persistent HCC after initial TACE. II. To determine the overall survival (OS) of TACE vs SABR for persistent HCC. III. To determine the toxicities associated with TACE or SABR for persistent HCC. OUTLINE: Patients are randomized to 1 of 2 treatment arms. Arm I: Patients undergo TACE. ARM II: Beginning within 2 weeks of the radiation set-up scan and within 4 weeks of fiducial seed implantation (if applicable), patients undergo image guided SBRT 3 fractions within 1 week or 5 fractions within 2 weeks. After completion of study treatment, patients are followed up for 1-2 weeks, 1, 3, 6, 12, and 18 months, and every 6 months up to 3 years.
Interventions
RADIATIONStereotactic Body Radiation Therapy
Undergo SBRT
PROCEDURETransarterial Chemoembolization
Undergo TACE
DRUGembolic agent
. Acceptable embolic agents include: * Gelatin sponge (gelfoam) * Polyvinyl alcohol (PVA) particles * Microspheres / Embolic beads
DRUGlipiodol
Sponsors
National Cancer Institute (NCI)
Stanford University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Confirmed hepatocellular carcinoma (HCC) by one of the following: * Histopathology * One radiographic technique that confirms a lesion \>= 1 cm with arterial hypervascularization with washout on delayed phase * Radiographic evidence of persistent, progressive, or recurrent disease in an area previously treated with TACE and determined from 3 months after initial TACE; this evaluation should be within 6 weeks of date of study eligibility * Unifocal liver tumors not to exceed 7.5 cm in greatest axial dimension; multifocal lesions will be restricted to lesions that can be treated within a single target volume within the same liver segment and to an aggregate of 10 cm as long as the dose constraints to normal tissue can be met * Eastern Clinical Oncology Group (ECOG) performance status 0, 1 or 2 * Patients with liver disease classified as Child Pugh class A or B, with score =\< 9 ((within 4 weeks of treatment) * Life expectancy \>= 6 months * Ability of the research subject or authorized legal representative to understand and have the willingness to sign a written informed consent document
Exclusion criteria
* Prior radiotherapy to the upper abdomen * Prior radioembolization to the liver * Prior radiofrequency ablation (RFA) to index lesion * Liver transplant * Active gastrointestinal bleed within 2 weeks of study enrollment * Ascites refractory to medical therapy (mild to moderate ascites is allowed) * Women who are pregnant or breastfeeding * Administration of chemotherapy within the last 1 month * Extrahepatic metastases * Participation in another concurrent treatment protocol * Prior history of malignancy other than HCC, dermatologic basal cell or squamous cell carcinoma
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a Local Progression Event | Up to 12 months | Local progression event: occurring in the treated hepatic lesion. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Extra Hepatic PFS for Patients With Tumors Smaller Than 3 cm and Greater Than 3 cm Per Treatment Group | At 18 months | Extra hepatic PFS within each subgroup will be summarized by cumulative incidence function estimators adjusted for the competing risk of death or regional or distant progression. |
| Median FFLP for Patients With Tumors Smaller Than 3 cm and With Tumors Greater Than 3 cm Per Treatment Group | At 18 months | FFLP within each subgroup will be summarized by cumulative incidence function estimators adjusted for the competing risk of death or regional or distant progression. |
| Median OS | Time from randomization until death from any cause, assessed up to 3 years | Overall survival will be summarized using Kaplan-Meier curves and medians with 95% confidence intervals calculated using Greenwood's formula. Log rank tests will be used to compare treatment groups. Cox proportional hazard models will be used to estimate hazard ratios between treatment groups and to assess other risk factors, in particular the effect of tumor size and the impact of the different institutions. |
| Median OS for Patients With Tumors Smaller Than 3 cm and Greater Than 3 cm Per Treatment Group | At 18 months | Within each subgroup OS will be summarized using Kaplan-Meier curves and medians with 95% confidence intervals calculated using Greenwood's formula. |
| Number of Participants With Disease Progression or Death | Randomization through 3 years | Including local, regional, or distant progression events, or death. Local progression event: occurring in the treated tumor. Regional progression event: occurring in the same part of the body as the treated tumor. Distant progression event: occurring outside the region of the body where the treated tumor is located. |
| Comparison of Median Freedom From Extra Hepatic Progression | Up to 16 weeks | The time to freedom from extra hepatic progression will be estimated by competing risk models with death as a competing risk. Risk factors such as tumor size and institution will be tested in a multivariate Cox regression model adjusting for the competing risks. |
| The Impact of Elevated Serum Alpha-Fetoprotein Level (AFP) on Freedom From Local Progression (FFLP) | Up to 18 months | The impact of elevated AFP level on time to event endpoints will be evaluated both in terms of the initial AFP level and on-study levels in a Cox proportional hazards model. |
| The Impact of Elevated Serum Alpha-Fetoprotein Level (AFP) on Progression-free Survival (PFS) | Up to 18 months | The impact of elevated AFP level on time to event endpoints will be evaluated both in terms of the initial AFP level and on-study levels in a Cox proportional hazards model. |
| The Impact of Elevated Serum Alpha-Fetoprotein Level (AFP) on Extra Hepatic PFS | Up to 18 months | The impact of elevated AFP level on time to event endpoints: FFLP, PFS, extra hepatic PFS and OS will be evaluated both in terms of the initial AFP level and on-study levels in a Cox proportional hazards model. |
| The Impact of Elevated Serum Alpha-Fetoprotein Level (AFP) on Overall Survival (OS) | Up to 18 months | The impact of elevated AFP level on time to event endpoints will be evaluated both in terms of the initial AFP level and on-study levels in a Cox proportional hazards model. |
| Number of Participants With Disease Progression or Death by Tumor Size (<= 3 cm and > 3 cm) Per Treatment Group | Randomization through 18 months | Including local, regional, or distant progression events, or death. Local progression event: occurring in the treated tumor. Regional progression event: occurring in the same part of the body as the treated tumor. Distant progression event: occurring outside the region of the body where the treated tumor is located. |
Countries
Japan, United States
Participant flow
Pre-assignment details
13 participants signed informed consent, 12 were randomized to a study arm.
Participants by arm
| Arm | Count |
|---|---|
| Transarterial Chemoembolization (TACE) Patients undergo TACE using an embolic agent. | 4 |
| Stereotactic Body Radiation Therapy (SBRT) Patients undergo image-guided SBRT. | 6 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 2 | 0 |
Baseline characteristics
| Characteristic | Transarterial Chemoembolization (TACE) | Stereotactic Body Radiation Therapy (SBRT) | Total |
|---|---|---|---|
| Age, Continuous | 69.9 years STANDARD_DEVIATION 6.25 | 67.7 years STANDARD_DEVIATION 7.15 | 68.6 years STANDARD_DEVIATION 6.54 |
| Elevated Serum Alpha-Fetoprotein (AFP) | 0 Participants | 3 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 5 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 1 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 0 Participants | 2 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 | 2 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) White | 1 Participants | 1 Participants | 2 Participants |
| Region of Enrollment Japan | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment United States | 3 Participants | 6 Participants | 9 Participants |
| Sex: Female, Male Female | 0 Participants | 4 Participants | 4 Participants |
| Sex: Female, Male Male | 4 Participants | 2 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 3 / 6 |
| other Total, other adverse events | 6 / 6 | 6 / 6 |
| serious Total, serious adverse events | 0 / 6 | 1 / 6 |
Outcome results
Primary
Number of Participants With a Local Progression Event
Local progression event: occurring in the treated hepatic lesion.
Time frame: Up to 12 months
Population: Participants who received treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Transarterial Chemoembolization (TACE) | Number of Participants With a Local Progression Event | 0 Participants |
| Stereotactic Body Radiation Therapy (SBRT) | Number of Participants With a Local Progression Event | 0 Participants |
Secondary
Comparison of Median Freedom From Extra Hepatic Progression
The time to freedom from extra hepatic progression will be estimated by competing risk models with death as a competing risk. Risk factors such as tumor size and institution will be tested in a multivariate Cox regression model adjusting for the competing risks.
Time frame: Up to 16 weeks
Population: Participants who received treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Transarterial Chemoembolization (TACE) | Comparison of Median Freedom From Extra Hepatic Progression | NA months |
| Stereotactic Body Radiation Therapy (SBRT) | Comparison of Median Freedom From Extra Hepatic Progression | NA months |
Secondary
Median Extra Hepatic PFS for Patients With Tumors Smaller Than 3 cm and Greater Than 3 cm Per Treatment Group
Extra hepatic PFS within each subgroup will be summarized by cumulative incidence function estimators adjusted for the competing risk of death or regional or distant progression.
Time frame: At 18 months
Population: Participants who received treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Transarterial Chemoembolization (TACE) | Median Extra Hepatic PFS for Patients With Tumors Smaller Than 3 cm and Greater Than 3 cm Per Treatment Group | NA months |
| Stereotactic Body Radiation Therapy (SBRT) | Median Extra Hepatic PFS for Patients With Tumors Smaller Than 3 cm and Greater Than 3 cm Per Treatment Group | NA months |
Secondary
Median FFLP for Patients With Tumors Smaller Than 3 cm and With Tumors Greater Than 3 cm Per Treatment Group
FFLP within each subgroup will be summarized by cumulative incidence function estimators adjusted for the competing risk of death or regional or distant progression.
Time frame: At 18 months
Population: Participants who received treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Transarterial Chemoembolization (TACE) | Median FFLP for Patients With Tumors Smaller Than 3 cm and With Tumors Greater Than 3 cm Per Treatment Group | NA months |
| Stereotactic Body Radiation Therapy (SBRT) | Median FFLP for Patients With Tumors Smaller Than 3 cm and With Tumors Greater Than 3 cm Per Treatment Group | NA months |
Secondary
Median OS
Overall survival will be summarized using Kaplan-Meier curves and medians with 95% confidence intervals calculated using Greenwood's formula. Log rank tests will be used to compare treatment groups. Cox proportional hazard models will be used to estimate hazard ratios between treatment groups and to assess other risk factors, in particular the effect of tumor size and the impact of the different institutions.
Time frame: Time from randomization until death from any cause, assessed up to 3 years
Population: Participants who received treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Transarterial Chemoembolization (TACE) | Median OS | NA months |
| Stereotactic Body Radiation Therapy (SBRT) | Median OS | NA months |
Secondary
Median OS for Patients With Tumors Smaller Than 3 cm and Greater Than 3 cm Per Treatment Group
Within each subgroup OS will be summarized using Kaplan-Meier curves and medians with 95% confidence intervals calculated using Greenwood's formula.
Time frame: At 18 months
Population: Participants who received treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Transarterial Chemoembolization (TACE) | Median OS for Patients With Tumors Smaller Than 3 cm and Greater Than 3 cm Per Treatment Group | NA months |
| Stereotactic Body Radiation Therapy (SBRT) | Median OS for Patients With Tumors Smaller Than 3 cm and Greater Than 3 cm Per Treatment Group | NA months |
Secondary
Number of Participants With Disease Progression or Death
Including local, regional, or distant progression events, or death. Local progression event: occurring in the treated tumor. Regional progression event: occurring in the same part of the body as the treated tumor. Distant progression event: occurring outside the region of the body where the treated tumor is located.
Time frame: Randomization through 3 years
Population: Participants who received treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Transarterial Chemoembolization (TACE) | Number of Participants With Disease Progression or Death | 1 Participants |
| Stereotactic Body Radiation Therapy (SBRT) | Number of Participants With Disease Progression or Death | 3 Participants |
Secondary
Number of Participants With Disease Progression or Death by Tumor Size (<= 3 cm and > 3 cm) Per Treatment Group
Including local, regional, or distant progression events, or death. Local progression event: occurring in the treated tumor. Regional progression event: occurring in the same part of the body as the treated tumor. Distant progression event: occurring outside the region of the body where the treated tumor is located.
Time frame: Randomization through 18 months
Population: Participants who receive treatment
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Transarterial Chemoembolization (TACE) | Number of Participants With Disease Progression or Death by Tumor Size (<= 3 cm and > 3 cm) Per Treatment Group | <= 3 cm | 1 Participants |
| Stereotactic Body Radiation Therapy (SBRT) | Number of Participants With Disease Progression or Death by Tumor Size (<= 3 cm and > 3 cm) Per Treatment Group | <= 3 cm | 2 Participants |
| Stereotactic Body Radiation Therapy (SBRT) | Number of Participants With Disease Progression or Death by Tumor Size (<= 3 cm and > 3 cm) Per Treatment Group | > 3 cm | 1 Participants |
Secondary
The Impact of Elevated Serum Alpha-Fetoprotein Level (AFP) on Extra Hepatic PFS
The impact of elevated AFP level on time to event endpoints: FFLP, PFS, extra hepatic PFS and OS will be evaluated both in terms of the initial AFP level and on-study levels in a Cox proportional hazards model.
Time frame: Up to 18 months
Population: Participants who received treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Transarterial Chemoembolization (TACE) | The Impact of Elevated Serum Alpha-Fetoprotein Level (AFP) on Extra Hepatic PFS | NA months |
| Stereotactic Body Radiation Therapy (SBRT) | The Impact of Elevated Serum Alpha-Fetoprotein Level (AFP) on Extra Hepatic PFS | NA months |
Secondary
The Impact of Elevated Serum Alpha-Fetoprotein Level (AFP) on Freedom From Local Progression (FFLP)
The impact of elevated AFP level on time to event endpoints will be evaluated both in terms of the initial AFP level and on-study levels in a Cox proportional hazards model.
Time frame: Up to 18 months
Population: Participants who received treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Transarterial Chemoembolization (TACE) | The Impact of Elevated Serum Alpha-Fetoprotein Level (AFP) on Freedom From Local Progression (FFLP) | NA months |
| Stereotactic Body Radiation Therapy (SBRT) | The Impact of Elevated Serum Alpha-Fetoprotein Level (AFP) on Freedom From Local Progression (FFLP) | NA months |
Secondary
The Impact of Elevated Serum Alpha-Fetoprotein Level (AFP) on Overall Survival (OS)
The impact of elevated AFP level on time to event endpoints will be evaluated both in terms of the initial AFP level and on-study levels in a Cox proportional hazards model.
Time frame: Up to 18 months
Population: Participants who received treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Transarterial Chemoembolization (TACE) | The Impact of Elevated Serum Alpha-Fetoprotein Level (AFP) on Overall Survival (OS) | NA months |
| Stereotactic Body Radiation Therapy (SBRT) | The Impact of Elevated Serum Alpha-Fetoprotein Level (AFP) on Overall Survival (OS) | NA months |
Secondary
The Impact of Elevated Serum Alpha-Fetoprotein Level (AFP) on Progression-free Survival (PFS)
The impact of elevated AFP level on time to event endpoints will be evaluated both in terms of the initial AFP level and on-study levels in a Cox proportional hazards model.
Time frame: Up to 18 months
Population: Participants who received treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Transarterial Chemoembolization (TACE) | The Impact of Elevated Serum Alpha-Fetoprotein Level (AFP) on Progression-free Survival (PFS) | NA months |
| Stereotactic Body Radiation Therapy (SBRT) | The Impact of Elevated Serum Alpha-Fetoprotein Level (AFP) on Progression-free Survival (PFS) | NA months |