Radiation Therapy With Sorafenib for TACE-Resistant Hepatocellular Carcinoma
To determine the maximum tolerated radiation dose with concurrent sorafenib for unresectable hepatocellular carcinoma that has not responded to transarterial chemoembolization.
Radiation: Conventional fractionation (2 Gy per day) external beam radiation therapy
|Study Design:||Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase I Study of Radiation Therapy With Concurrent Sorafenib for Hepatocellular Carcinoma Not Responding to Transarterial Chemoembolization|
- Maximum Tolerated Dose [ Time Frame: From date of enrollment until 3 months after completion of treatment. ] [ Designated as safety issue: Yes ]Maximum tolerated dose (MTD) will be determined by dose limiting toxicity (DLT) that is observed in either the acute (during treatment) or subacute (up to 3 months after treatment) setting. Acute DLT will be defined by grade 3-5 hepatic, gastrointestinal, dermatologic, hematologic, or pulmonary toxicity per Common Toxicity Criteria for Adverse Effects (CTCAE), v4.0. Subacute DLT will be defined by radiation induced liver disease (RILD) or grade 3-5 gastrointestinal, hematologic, or pulmonary toxicity per CTCAE, v4.0.
- Radiographic Response [ Time Frame: 1 & 3 months post-treatment. ] [ Designated as safety issue: No ]Evaluated by either contrast enhanced MRI (preferred) or CT.
- Patterns of Failure [ Time Frame: From date of enrollment until the date of first documented progression, last known folow-up, or date of death from any cause, whichever came first, assessed up to 10 years. ] [ Designated as safety issue: No ]Classified as local (in-field), regional (intrahepatic out-of-field), or distant (extrahepatic, which includes porta hepatic lymph nodes).
- Progression Free Survival [ Time Frame: From date of enrollment until the date of first documented progression, last known folow-up, or date of death from any cause, whichever came first, assessed up to 10 years. ] [ Designated as safety issue: No ]From date of enrollment until first local, regional, or distant failure following RT, last follow-up, or death from any cause.
- Overall Survival [ Time Frame: From date of enrollment until the date of last known folow-up or date of death from any cause, whichever came first, assessed up to 10 years. ] [ Designated as safety issue: No ]From date of enrollment until last follow-up or death.
- Health Related Quality of Life [ Time Frame: 1, 2, & 3 months post-treatment. ] [ Designated as safety issue: No ]FACT-Hep survey will be utilized to establish pre-treatment baseline and then compared to post-treatment evaluations at months 1, 2, and 3.
|Study Start Date:||June 2012|
|Estimated Study Completion Date:||June 2016|
|Estimated Primary Completion Date:||June 2015 (Final data collection date for primary outcome measure)|
|Experimental: Radiation therapy with concurrent sorafenib||
Sorafenib 400 mg PO bid will be started two weeks prior to initiation of radiation therapy (RT) and continue until the end of protocol specified radiation dose.
Other Names:Radiation: Conventional fractionation (2 Gy per day) external beam radiation therapy
Patients will be stratified by the maximum diameter of HCC in any plane (≤10 cm or >10 cm) based on post-TACE, contrast enhanced MRI or CT. If only 1 lesion is present, the maximum diameter of that lesion in any plane determines stratification. If >1 but ≤3 lesions are present, the sum of the maximum diameter in any plane of all the lesions determines stratification.
The MTD will be determined utilizing a standard 3 + 3 dose escalation scheme (4 Gy increase per bin). For lesions ≤10 cm, the starting RT dose bin will be 42 Gy and escalate to a pre-determined maximum of 62 Gy if no DLT's are experienced. For lesions >10 cm, the starting RT dose bin will be 40 Gy and escalate to a pre-determined maximum of 52 Gy if no DLT's are experienced.
In patients with unresectable hepatocellular carcinoma (HCC), transarterial chemoembolization (TACE) is first line therapy. Non-responders to TACE (i.e. stable or progressive disease) represent a poor prognosis population with limited options. Sorafenib is indicated for first line salvage therapy, however it only improves survival 2-3 months and just has a 2-3% response rate. Thus, sorafenib is merely a cytostatic agent that delays progression and does not cytoreduce disease.
Radiation therapy (RT) is a non-invasive treatment that can cytoreduce HCC with minimal morbidity using modern techniques. A meta-analysis and multiple retrospective series suggest TACE + RT improve survival when compared to TACE alone. Higher RT doses are similarly associated with increased survival due to improved local control. Paradoxically, some series suggest that RT can induce vascular endothelial growth factor (VEGF) expression which may stimulate HCC.
Pre-clinical data suggest that combining RT with concurrent sorafenib (a VEGF inhibitor) improves tumor control. However, clinical data is limited to case reports and safety has not been well characterized. Prior to determining if this combination can improve control of HCC in this poor prognosis population, the optimal radiation dose with concurrent sorafenib must be determined by a phase I dose escalation trial.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01618253
|United States, Wisconsin|
|Froedtert Memorial Lutheran Hospital|
|Milwaukee, Wisconsin, United States, 53226|
|Principal Investigator:||Beth A. Erickson-Wittmann, M.D.||Medical College of Wisconsin|