Phase II Study of Concurrent Sorafenib and Intensity-modulated Radiotherapy (IMRT) for Advanced Hepatocellular Carcinoma

Study Overview
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Brief Summary
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This is a single-arm phase II clinical trial to investigate the efficacy and toxicity of concurrent sorafenib and intensity-modulated radiotherapy (IMRT) for advanced hepatocellular carcinoma with portal vein or hepatic vein tumor thrombosis or lymph node involved. Eligibility patients will receive IMRT to hepatic primary tumor, vein tumor thrombosis, and metastasis lymph node with concurrently sorafenib with a dose of 400mg twice daily. Prescription of IMRT will be a conventional fraction dose of 2Gy to a total dose of 40 to 60Gy. Sorafenib will be maintained with a dose of 400mg twice daily after IMRT until disease progression, or unacceptable adverse events. Six months of sorafenib maintenance is recommended.

Detailed Description
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With the clinical application of three-dimensional conformal radiotherapy (3DCRT) and intensity modulated radiotherapy (IMRT), radiotherapy (RT) has shown important role in the treatment of hepatocellular carcinoma (HCC). Meta-analysis has demonstrated that transcatheter arterial chemoembolization (TACE) combined RT was more therapeutically beneficial than TACE alone. Especially for advanced disease with portal vein tumor thrombosis (PVTT), or hepatic vein tumor thrombosis, or lymph node involved, RT was more effective than other treatment methods. Previous studies had showed that RT could receive response rate of 50% to 60% for HCC with PVTT. But for those patients, high accidence of out RT field failure of liver and distance metastasis was found. Effective systemic therapy was necessary to advanced HCC. Based on two phase III trials, sorafenib was recommended as systemic therapy to advanced HCC. But tumor response rate of sorafenib alone was only 2.3-3% by RICIST criteria. More than half of patients was received survival benefit by maintaining in stable disease. It is feasible to improve survival by combining IMRT and sorafenib for advanced HCC with portal vein tumor thrombosis (PVTT), or hepatic vein tumor thrombosis, or lymph node involved. In addition, it was demonstrated that sorafenib could potentiate irradiation in HCC cell lines through inhibiting radiation-induced proliferation and DNA repair and promoting radiation-induced apoptosis.

Official Title
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Phase II Study of Concurrent Sorafenib and Intensity-modulated Radiotherapy (IMRT) for Advanced Hepatocellular Carcinoma

Conditions
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Hepatocellular Carcinoma, Radiotherapy, Sorafenib

Intervention / Treatment
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* Radiation: concurrent sorafenib and IMRT, followed sorafenib maintenance


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical or histologic diagnosis of Hepatocellular carcinoma (HCC) Aged between 18 and 80 years ECOG 0-1 Liver-GTV>700ml BCLC stage C, HCC with portal vein or hepatic vein tumor thrombosis or lymph node involved (LN involved can be included one treatment planning) Estimated life expectancy > 3 months Child-Pugh Score: A5-B8 Hepatic function: alanine transaminase (ALT) and aspartate transaminase (AST)≤ 1.5 times ULN; or ALT ≤ ULN and AST≤ 6 times ULN exclude possibility of heart disease Renal function: creatinine (CRE) and blood urea nitrogen (BUN)≤ 1.5 times ULN Blood routine examination: Hb≥80g/L, ANC≥1.0×109 /L, PLT≥40×109 /L Voluntary to participate and sign informed consent Exclusion Criteria: Had prior abdominal irradiation Had prior liver transplantation Had serious myocardial disease or renal failure Pregnant, breast feeding, or unwilling to use adequate contraception Known hypersensitivity to sorafenib

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sorafenib and IMRT<br>Concurrent sorafenib and IMRT, followed sorafenib maintenance for advanced hepatocellular carcinoma with portal vein or hepatic vein tumor thrombosis or lymph node involved | Radiation: concurrent sorafenib and IMRT, followed sorafenib maintenance<br>* IMRT 40-60Gy/20-30f; concurrent sorafenib 400mg bid po (it can be given to patients in four weeks before IMRT is applied, so that it can control disease during waiting for IMRT); maintenance sorafenib 400mg bid po until disease progress or unacceptable adverse events; six months is recommended but not mandatory.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MST | Median Survival Time (MST) was defined as the duration from the date of patient recruited to the date of death from any cause | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR | Overall Response Rate (ORR) was defined as the total of CR (Complete Response) and PR (Partial Response). CR and PR were assessed by independent reviewers according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. ORR evaluated in 1 to 3 months after the completion of IMRT. | Assessment in 1 to 3 months after IMRT | 
| TTP | Time to Progression (TTP) was defined as the duration from the date of patient recruited to the first progress at any site or the date of death | 24 months | 
| Rate of III-IV grade adverse events | Adverse events was evaluated during received protocol therapy according to CTCAE 4.03 | up to 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hepatocellular carcinoma, intensity-modulated radiotherapy, sorafenib, portal vein thrombosis, lymph node metastasis