Carcinoma, Hepatocellular, Hepatobiliary Neoplasm, Liver Carcinoma
Conditions
Brief summary
To determine the efficacy and toxicity of TACE combined with SBRT
Detailed description
Hepatocellular carcinoma (HCC) is the third most deadly cancer in the world. It is primarily seen in areas where hepatitis is endemic, such as Asia, but other risk factors include alcoholic cirrhosis. Outcome of this disease is poor, mostly due to the fact that \>80% of patients present with unresectable disease. Surgery or transplantation remain the only curative options. For the vast majority of patients who are unresectable, a variety of treatment options are available, including transarterial chemo-embolization (TACE), radiofrequency ablation, radioactive microspheres, microwave coagulation, laser-induced thermotherapy, and percutaneous alcohol injection, all of which have similar survival rates. Stereotactic body radiotherapy (SBRT) for unresectable HCC is a relatively new treatment option made available because of great improvements in diagnostic imaging and radiation delivery techniques. Although follow-up is limited, results show encouraging local control rates. Some investigators have combined TACE with fractionated radiotherapy as a means of intensifying local therapy, with some evidence of benefit. TACE remains the dominant mode of local therapy for unresectable HCC. However, recurrence rates are high. The recent randomized trial suggests that a combination of local therapy (TACE and radiofrequency ablation \[RFA\]) is superior to either therapy alone, providing proof of principle that combined local treatment is most likely more effective for HCC. Because SBRT is rapidly becoming an accepted local therapy for hepatic lesions, its role in treating HCC needs to be further defined. Studies combining TACE and external beam radiotherapy have shown encouraging results, so the logical next step is to combine TACE with SBRT, which delivers a radiobiologically more intensive dose of radiation. However, toxicity data are lacking, since this combination has not been previously reported. We propose to conduct a trial of trans-arterial chemo-embolization (TACE) and SBRT for unresectable HCC.
Interventions
PROCEDURETACE
Standard of Care
PROCEDURESBRT
Standard of Care
Sponsors
Stanford University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Inclusion - * Liver tumors treatable by SBRT not to exceed 10cm in greatest axial dimension. * 800 cc of uninvolved liver * Patients may have additional hepatic lesions if they are \<3cm and can be treated with TACE or RFA. * Age \> 18 years old * Albumin \> 2.4 g/dL. * Total bilirubin \< 3 mg/dL. * INR ≤ 1.5. * Creatinine \< 2.0 mg/dL. * Confirmed hepatocellular carcinoma by one of the following: * Histopathology * Two radiographic techniques (out of US, MRI, CT, Angiography) that confirm a lesion \>2 cm with arterial hypervascularization * One radiographic technique that confirms a lesion \>2 cm with arterial hypervascularization and an elevated AFP * Hepatic lesion in patients for whom surgical resection is not possible or would not result in an opportunity for cure * Tumor(s) \<10cm * Eastern Clinical Oncology Group performance status 0, 1 or 2 * No prior surgery, chemotherapy, or radiation for the current tumor * Patients placed on the liver transplant registry are eligible for this trial, but will be withdrawn from the protocol if they receive liver transplantation. * TACE done prior to study enrollment is allowed if there were no more than 3 procedures within an 18 week period and SBRT can begin within 12 weeks of the last TACE procedure. Exclusion - * Prior radiotherapy to the upper abdomen * Prior TACE, RFA, or liver transplant * Tumor(s) ≥ 10cm * Large esophageal varices without band ligation * Active GI bleed or within 2 weeks of study enrollment * Ascites refractory to medical therapy * Contraindication to receiving radiotherapy * Women who are pregnant * Administration of any systemic cytotoxic agents within the last 12 months * Presence of extrahepatic metastases * Participation in another concurrent treatment protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Freedom From Local Progression of TACE and SBRT at 12 Months | 12 months | Freedom from local progression is defined as the time from start of treatment until the first occurrence of local progression. Local progression is defined as progression in the treated lesion according to the RECIST criteria. Progression outside the treated lesion and/or death will be considered as competing risks. The data was analyzed in a competing risk model with death as a competing risk. The outcome reported is the cumulative incidence at 12 months. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To Determine the Progression-free Survival of TACE and SBRT at 18 Months | 18 months | Progression free survival is defined as the time from the start of treatment until the first progression or death. Progression will be defined as either local progression, disease occurring elsewhere in the liver, extrahepatic progression or clinical deterioration attributable to another underlying medical condition in the absence of clear radiographic findings of progressive disease. |
| To Determine the Overall Survival of TACE and SBRT at 18 Months | 18 months | Overall survival is defined as the time from the start of treatment until death from any cause. |
| Median Progression Free Survival | 18 months | Time to progression free survival is defined as the time from randomization until either death or progression of disease. The median survival was calculated using a Kaplan Meier algorithm. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Stereotactic Body Radiotherapy (SBRT) SBRT will be delivered on Varian's linear accelerator with On-Board Imaging (OBI) capabilities. The tumor will be tracked with the ethiodol material from the TACE procedure, and respiratory gating will be used to minimize motion due to respiration. Treatment will be given in either 3 or 5 fractions . SBRT will take place after the treatment planning and within 12 weeks of the last TACE procedure.
Doses: 45 Gy at 15 Gy/fraction , 36 Gy at 12 Gy/fraction, 45 Gy at 9 Gy/fraction, 40 Gy at 8 Gy/fraction
TACE: Standard of Care
SBRT: Standard of Care | 8 |
| Total | 8 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Physician Decision | 1 |
| Overall Study | Protocol Violation | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Stereotactic Body Radiotherapy (SBRT) |
|---|---|
| Age, Continuous | 67.1 years STANDARD_DEVIATION 11.8 |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 6 / 8 |
| serious Total, serious adverse events | 0 / 8 |
Outcome results
Primary
Freedom From Local Progression of TACE and SBRT at 12 Months
Freedom from local progression is defined as the time from start of treatment until the first occurrence of local progression. Local progression is defined as progression in the treated lesion according to the RECIST criteria. Progression outside the treated lesion and/or death will be considered as competing risks. The data was analyzed in a competing risk model with death as a competing risk. The outcome reported is the cumulative incidence at 12 months.
Time frame: 12 months
Population: All patients who completed treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SBRT and TACE | Freedom From Local Progression of TACE and SBRT at 12 Months | 0.286 proportion of participants |
Comparison: The data was analyzed in a competitive risk model with the cumulative incidence function as the estimator. Death and other progression were competitive risks.95% CI: [0.031, 0.636]
Secondary
Median Progression Free Survival
Time to progression free survival is defined as the time from randomization until either death or progression of disease. The median survival was calculated using a Kaplan Meier algorithm.
Time frame: 18 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| SBRT and TACE | Median Progression Free Survival | 12 months |
Secondary
To Determine the Overall Survival of TACE and SBRT at 18 Months
Overall survival is defined as the time from the start of treatment until death from any cause.
Time frame: 18 months
Population: All patients who completed treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SBRT and TACE | To Determine the Overall Survival of TACE and SBRT at 18 Months | 0.857 probability |
Secondary
To Determine the Progression-free Survival of TACE and SBRT at 18 Months
Progression free survival is defined as the time from the start of treatment until the first progression or death. Progression will be defined as either local progression, disease occurring elsewhere in the liver, extrahepatic progression or clinical deterioration attributable to another underlying medical condition in the absence of clear radiographic findings of progressive disease.
Time frame: 18 months
Population: All patients who completed the treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SBRT and TACE | To Determine the Progression-free Survival of TACE and SBRT at 18 Months | 0.400 survival probability at 18 months |
Comparison: The data was analyzed using the Kaplan Meier estimator.