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Transarterial Chemoembolization Compared With Stereotactic Body Radiation Therapy or Stereotactic Ablative Radiation Therapy in Treating Patients With Residual or Recurrent Liver Cancer Undergone Initial Transarterial Chemoembolization

Primary Purpose

Child-Pugh Class A, Child-Pugh Class B, Recurrent Hepatocellular Carcinoma

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Stereotactic Body Radiation Therapy
Transarterial Chemoembolization
embolic agent
lipiodol
Sponsored by
Stanford University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Child-Pugh Class A

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Stanford University, School of Medicine
  • Hokkaido University Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Arm I (TACE)

Arm II (SBRT)

Arm Description

Patients undergo TACE.

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.

Outcomes

Primary Outcome Measures

Median FFLP
The time to freedom from local progression will be estimated by competing risk models with death and regional or distant progression as competing risks. Risk factors such as tumor size and institution will be tested in a multivariate Cox regression model adjusting for the competing risks.

Secondary Outcome Measures

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.
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.
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.
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.
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.
Median PFS
Progression free 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 PFS for patients with tumors smaller than 3 cm and greater than 3 cm per treatment group
Within each subgroup PFS will be summarized using Kaplan-Meier curves and medians with 95% confidence intervals calculated using Greenwood's formula.
Serum Alpha-Fetoprotein level (AFP)
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.

Full Information

First Posted
April 5, 2016
Last Updated
August 23, 2023
Sponsor
Stanford University
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT02762266
Brief Title
Transarterial Chemoembolization Compared With Stereotactic Body Radiation Therapy or Stereotactic Ablative Radiation Therapy in Treating Patients With Residual or Recurrent Liver Cancer Undergone Initial Transarterial Chemoembolization
Official Title
International Randomized Study of Transarterial Chemoembolization (TACE) Versus Stereotactic Body Radiotherapy (SBRT) / Stereotactic Ablative Radiotherapy (SABR) for Residual or Recurrent Hepatocellular Carcinoma After Initial TACE
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Completed
Study Start Date
February 27, 2016 (Actual)
Primary Completion Date
December 31, 2022 (Actual)
Study Completion Date
December 31, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Stanford University
Collaborators
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Child-Pugh Class A, Child-Pugh Class B, Recurrent Hepatocellular Carcinoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
13 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm I (TACE)
Arm Type
Active Comparator
Arm Description
Patients undergo TACE.
Arm Title
Arm II (SBRT)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Radiation
Intervention Name(s)
Stereotactic Body Radiation Therapy
Other Intervention Name(s)
SBRT
Intervention Description
Undergo SBRT
Intervention Type
Procedure
Intervention Name(s)
Transarterial Chemoembolization
Other Intervention Name(s)
TACE
Intervention Description
Undergo TACE
Intervention Type
Drug
Intervention Name(s)
embolic agent
Intervention Description
. Acceptable embolic agents include: Gelatin sponge (gelfoam) Polyvinyl alcohol (PVA) particles Microspheres / Embolic beads
Intervention Type
Drug
Intervention Name(s)
lipiodol
Primary Outcome Measure Information:
Title
Median FFLP
Description
The time to freedom from local progression will be estimated by competing risk models with death and regional or distant progression as competing risks. 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 12 months
Secondary Outcome Measure Information:
Title
Comparison of median freedom from extra hepatic progression
Description
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
Title
Median extra hepatic PFS for patients with tumors smaller than 3 cm and greater than 3 cm per treatment group
Description
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
Title
Median FFLP for patients with tumors smaller than 3 cm and with tumors greater than 3 cm per treatment group
Description
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
Title
Median OS
Description
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
Title
Median OS for patients with tumors smaller than 3 cm and greater than 3 cm per treatment group
Description
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
Title
Median PFS
Description
Progression free 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 or any progression including local, regional or distant progression, assessed up to 3 years
Title
Median PFS for patients with tumors smaller than 3 cm and greater than 3 cm per treatment group
Description
Within each subgroup PFS will be summarized using Kaplan-Meier curves and medians with 95% confidence intervals calculated using Greenwood's formula.
Time Frame
At 18 months
Title
Serum Alpha-Fetoprotein level (AFP)
Description
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Daniel Chang
Organizational Affiliation
Stanford University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Stanford University, School of Medicine
City
Palo Alto
State/Province
California
ZIP/Postal Code
94304
Country
United States
Facility Name
Hokkaido University Hospital
City
Sapporo
State/Province
Hokkaido
ZIP/Postal Code
060-8648
Country
Japan

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Transarterial Chemoembolization Compared With Stereotactic Body Radiation Therapy or Stereotactic Ablative Radiation Therapy in Treating Patients With Residual or Recurrent Liver Cancer Undergone Initial Transarterial Chemoembolization

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