Stereotactic Body Radiation Therapy (SBRT) vs Trans-Arterial Chemoembolization (TACE) as Bridge to Transplant

Study Overview
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Brief Summary
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This study will compare stereotactic body radiation therapy (SBRT) to trans-arterial chemoembolization (TACE) as a bridging strategy for patients with HCC undergoing liver transplantation. We propose that SBRT will be associated with longer time intervals between initial treatment and the need for retreatment, compared to TACE, as a bridge to liver transplantation in subjects with HCC.

Detailed Description
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For patients with hepatocellular carcinoma (HCC) who are waiting for a liver transplant, local treatment of their disease has become the standard of care in an effort to decrease dropout rates and as a means of reducing tumor recurrence after transplantation. For patients undergoing local regional therapy as a bridge to transplantation, trans-arterial chemoembolization (TACE) is the most commonly utilized treatment. However, the best modality for patients undergoing treatment as a bridge to transplantation is unclear. A newer strategy for the treatment of HCC is stereotactic body radiation therapy (SBRT). This study will compare SBRT to TACE as a bridging strategy for patients with HCC undergoing liver transplantation.

Official Title
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A Randomized Multi-Center Phase III Study of Individualized Stereotactic Body Radiation Therapy (SBRT) Versus Trans-Arterial Chemoembolization (TACE) as a Bridge to Transplant in Hepatocellular Carcinoma.

Conditions
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HCC, Hepatocellular Carcinoma

Intervention / Treatment
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* Radiation: Stereotactic Body Radiation Therapy (SBRT)
* Procedure: Trans-Arterial Chemoembolization (TACE)
* Drug: Doxorubin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects with HCC are eligible for this trial. HCC is defined as having at least one of the following: Biopsy proven HCC or: A discrete hepatic tumor(s) as defined by the Barcelona (29) criteria for cirrhotic subjects, ≥2cm with arterial hypervascularity and venous or delayed phase washout on CT or MRI. Subjects are liver transplant candidates (actively awaiting organ transplant per transplant services in documentation), or, potential liver transplant candidates (at the discretion of the liver team and/or Principal Investigator) advised by liver transplant services as needing local treatment prior to liver transplant evaluation. Subjects must be within UCSF criteria (one solitary tumor smaller than 6.5 cm, or patients having 3 or fewer nodules, with the largest lesion being smaller than 4.5 cm or having a total tumor diameter less than 8.5 cm without vascular invasion) and eligible for potential liver transplant. Subjects must be eligible per standard of care for either TACE or SBRT procedures. Subjects must have a life expectancy of at least 12 weeks. Subjects must be 18 years of age or older. Adult subjects of all ages, both sexes and all races will be included in this study. Subjects must sign an informed consent form approved for this purpose by the Institutional Review Board (IRB) of record . Subjects must have a Child-Turcotte-Pugh (CTP) score ≤8. Patients must have adequate organ function within 2 weeks of enrollment. Bone marrow: Platelets ≥30,000/mm3 Renal: BUN ≤40 mg/dl; creatinine ≤2.0 mg/dl Hepatic: INR ≤ 1.5 or correctable by Vitamin K, unless anti-coagulated for another medical reason Bilirubin < 3.0 mg/dl (in the absence of obstruction or pre-existing disease of the biliary tract, e.g. primary sclerosing cholangitis). Patients uninvolved liver volume will be estimated and must be > 700ml. Patients must have a Zubrod performance status of ≤2. Exclusion Criteria: Subjects in a special category designated by the Public Health Service, Including subjects younger than 18, pregnant women, and prisoners. Refractory ascites that requires paracentesis for management. Known allergy to intravenous iodinated contrast agents unresponsive to prednisone pre-treatment. History of prior radiation to the liver. Evidence of metastatic disease. Presence of a Trans-jugular intra-hepatic porto-systemic shunt (TIPS).

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 |
| --- | --- |
| Other: Stereotactic Body Radiation Therapy (SBRT)<br>Radiation Therapy | Radiation: Stereotactic Body Radiation Therapy (SBRT)<br>* SBRT will be delivered in five total fractions, with at a minimum of one day between any two treatments. The entire treatment must be delivered within 15 total days.<br>* Other names: Radiation Therapy;|
| Other: Trans-Arterial Chemoembolization (TACE)<br>Procedure/Surgery - Chemoembolization Drug: Doxorubin | Procedure: Trans-Arterial Chemoembolization (TACE)<br>* First day will be administered and a second TACE will be administered after 4 weeks and subsequently if imaging is showing disease progression. Following each TACE procedure all patients will remain in hospital for observation<br>* Other names: Chemoembolization;Drug: Doxorubin<br>* This procedure will be completed with 2 vials of drug eluting beads each loaded with 50 mg of Doxorubin.<br>* Other names: Doxorubin bead therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To compare the duration of disease control in treated lesions when utilizing SBRT versus TACE as a bridging strategy for patients with HCC eligible for liver transplantation |  | 1 year post treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To compare participants with treatment-related adverse events as assessed by CTCAE v5.0 |  | At each treatment, 2 weeks post treatment, 2 months post treatment, 5 months post treatment, every 3 months until 24 months post treatment | 
| Number of further interventions |  | 2 weeks post treatment, 2 months post treatment, 5 months post treatment, every 3 months until 24 months post treatment | 
| Rate of pathological response of treated lesion(s) |  | Review of pathology report after liver transplant | 
| Rate of radiological response of treated lesion(s) |  | Baseline, 2 months post-treatment, 5 months post-treatment, every 3 months thereafter until 2 years post treatment | 
| To assess Quality of Life by Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) Questionnaire | A 45-item self-report instrument to measure health-related quality of life (HRQL) in patients with hepatobiliary cancers and is one of the most widely-used instruments in this clinical area. The FACT-Hep consists of the 27-item FACT-G, assesses HRQL, and the 18-item Hepatobiliary Subscale (HS), assesses disease-specific issues such as pain, appetite, and cramping. The FACT-G evaluates physical well-being, social/family well-being, emotional well-being, and functional well-being. Sections have a 7-day reference period and are scored from 0-4 (not at all to very much), with higher scores indicating better HRQL. Score ranges are 0-28 for physical well-being, 0-28 for social/family well-being, 0-24 for emotional well-being, 0-28 for functional well-being, and 0-72 for the HS. All subscale scores from the FACT-G and HS can be summed together to create a total FACT-Hep score, with a possible range of 0-180. The FACT-Hep takes approximately 10 minutes to complete. | Baseline, during treatment, 2 months post-treatment, 5 months post-treatment, every 3 months until 24 months post treatment | 
| To assess over survival |  | Baseline, during treatment, 2 months post-treatment, 5 months post-treatment, every 3 months until 24 months post treatment | 
| To assess 90 day Post-transplant morbidity |  | Disease status to be captured 90 days post-transplantation (+/- 2 weeks) | 
| To assess 90 day Post-transplant mortality |  | Survival status to be captured 90 days post-transplantation (+/- 2 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatocellular Carcinoma (HCC), Liver transplant, Bridge to transplant, Stereotactic body radiation therapy (SBRT), Trans-arterial chemoembolization (TACE)