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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

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

Intervention / Treatment
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* Radiation: Stereotactic Body Radiation Therapy
* Procedure: Transarterial Chemoembolization
* Drug: embolic agent
* Drug: lipiodol


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm I (TACE)<br>Patients undergo TACE. | Procedure: Transarterial Chemoembolization<br>* Undergo TACE<br>* Other names: TACE;Drug: embolic agent<br>* . Acceptable embolic agents include: Gelatin sponge (gelfoam) Polyvinyl alcohol (PVA) particles Microspheres / Embolic beads<br>Drug: lipiodol<br> <br> |
| Experimental: Arm II (SBRT)<br>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. | Radiation: Stereotactic Body Radiation Therapy<br>* Undergo SBRT<br>* Other names: SBRT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to 16 weeks | 
| 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. | At 18 months | 
| 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. | At 18 months | 
| 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 from randomization until death from any cause, assessed up to 3 years | 
| 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. | At 18 months | 
| 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. | Time from randomization until death or any progression including local, regional or distant progression, assessed up to 3 years | 
| 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. | At 18 months | 
| 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. | Up to 18 months |