Adjuvant Stereotactic Body Radiotherapy (SBRT) for Hepatocellular Carcinoma After Hepatectomy With Narrow Margin: a Prospective, Multi-center, Randomized Controlled, Open-labelled, Phase III Study

Study Overview
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Brief Summary
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Hepatocellular carcinoma (HCC) is the sixth prevalent malignancy worldwide. Although surgical excision is considered the standard treatment for resectable HCC, a high rate of postoperative recurrence was observed after partial hepatectomy, with a marginal recurrence rate up to 30%. Narrow margin resection may be the most appropriate procedure for centrally located HCC or HCC located near liver capsule because the premise for survival is the conservation of more normal liver parenchyma. Unfortunately, narrow margin resection has been reported to contribute to poor survival outcomes. However, no adjuvant therapy after hepatectomy is generally considered to be effective in reducing post-operative recurrence. Radiotherapy (RT) has been well used in many solid malignant tumors as an (neo)adjuvant to surgical treatment, including HCC. SBRT has shown encouraging rates of local control for HCC. Compared with standard fractionation radiation, SBRT can achieve more precise delivery of high-dose radiation beams to the lesion, obtaining a much smaller target volume. Meanwhile, it could be finished in a short period which can bring more convenience to patients. Recently, several study and randomized controlled trials revealed the survival benefit of adjuvant RT (IMRT and SBRT) in patients with HCC. A large-sample and high-quality multi-center, randomized controlled, prospective study is warranted to further confirm the efficacy of adjuvant radiotherapy in patients with narrow margin resection, considering the small sample size of above-mentioned studies.

Detailed Description
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Hepatocellular carcinoma (HCC) is the sixth prevalent malignancy worldwide. Although surgical excision is considered the standard treatment for resectable HCC, a high rate of postoperative recurrence was observed after partial hepatectomy, with a marginal recurrence rate up to 30%. Narrow margin resection may be the most appropriate procedure for centrally located HCC or HCC located near liver capsule because the premise for survival is the conservation of more normal liver parenchyma. Unfortunately, narrow margin resection has been reported to contribute to poor survival outcomes. However, no adjuvant therapy after hepatectomy is generally considered to be effective in reducing post-operative recurrence. Radiotherapy (RT) has been well used in many solid malignant tumors as an (neo)adjuvant to surgical treatment, including HCC. SBRT has shown encouraging rates of local control for HCC. Compared with standard fractionation radiation, SBRT can achieve more precise delivery of high-dose radiation beams to the lesion, obtaining a much smaller target volume. Meanwhile, it could be finished in a short period which can bring more convenience to patients. Recently, several study and randomized controlled trials revealed the survival benefit of adjuvant RT (IMRT and SBRT) in patients with HCC. A large-sample and high-quality multi-center, randomized controlled, prospective study is warranted to further confirm the efficacy of adjuvant radiotherapy in patients with narrow margin resection, considering the small sample size of above-mentioned studies.

Official Title
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Adjuvant Stereotactic Body Radiotherapy (SBRT) for Hepatocellular Carcinoma After Hepatectomy With Narrow Margin: a Prospective, Multicenter, Randomized Controlled, Open-labelled, Phase III Study

Conditions
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Hepatocellular Carcinoma, Narrow Margin, Adjuvant Stereotactic Body Radiotherapy, Hepatectomy

Intervention / Treatment
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* Radiation: stereotactic body radiation therapy
* Other: regular follow-up


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged ≥18 years; Confirmed diagnosis of HCC. The diagnosis can be established radiographically by the criteria of the American Association for the Study of the Liver (AASLD), or by histologic diagnosis from the core biopsy; Pathologically confirmed as narrow margin (the shortest distance from the edge of the tumor to the surface of liver transection <1cm) ; Child-Pugh class A and B7; ECOG (Eastern Cooperative Oncology Group) performance status 0 or 1; Willing to provide tissue from an excisional biopsy of a tumor lesion; For patients with active HBV: HBV DNA < 2000 IU/mL during screening, and have initiated anti-HBV treatment at least 7 days prior to SBRT and willingness to continue anti-HBV treatment during the study; Adequate organ and marrow function as defined below: 1)Marrow: absolute neutrophil count ≥1.5×109/L; platelets ≥50×109/L; hemoglobin ≥90g/L; 2)Liver: total bilirubin ≤3× institutional upper limit of normal (ULN); AST(aspartate aminotransferase) or ALT(alanine aminotransferase) ≤ 5× institutional ULN; albumin ≥29g/L; 3)Kidney: creatinine ≤ 1.5× institutional ULN or estimated glomerular filtration rate (GFR) ≥50 mL/min/1.73 m2 (according to the Cockcroft-Gault formula); 9. Women of childbearing potential must be willing to use a highly effective method of contraception for the course of the study through 30 days after radiotherapy. Female patient of childbearing potential should have a negative serum pregnancy test before 72h of her first treatment. Sexually active males must agree to use an adequate method of contraception starting with the treatment through 4 months after radiotherapy. Exclusion Criteria: Have received radiotherapy for the area to be treated in the past; Severe bleeding tendency or coagulation dysfunction within the previous 6 months; Extrahepatic metastasis; Known history of active Bacillus Tuberculosis (TB) Known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy, or in situ cervical cancer. Active infection requiring systemic therapy; Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy; Known psychiatric or substance abuse disorders ; Pregnant or breastfeeding; Known history of human immunodeficiency virus (HIV: HIV 1/2 antibodies); Received a live vaccine within 30 days before radiotherapy.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Interventional Model Description: Experimental: adjuvant stereotactic body radiation therapy after hepatectomy with narrow margin Control: regular follow-up after hepatectomy with narrow margin
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: adjuvant stereotactic body radiation therapy<br>adjuvant stereotactic body radiation therapy after hepatectomy with narrow margin | Radiation: stereotactic body radiation therapy<br>* adjuvant stereotactic body radiation therapy<br>|
| Active Comparator: regular follow-up<br>regular follow-up after hepatectomy with narrow margin | Other: regular follow-up<br>* regular follow-up<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| marginal recurrence rate | 1-year marginal recurrence rate | from date of enrollment to date of first documented marginal recurrence. Assessed up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | 3-year Overall survival | from date of enrollment to the date of death from any cause. Assessed up to 36 months | 
| Recurrence free survival | 3-year Recurrence free survival | from date of enrollment to the date of first documented recurrence. Assessed up to 36 months | 
| Time to Progress | from date of enrollment to the date of progress. Assessed up to 36 months | from date of enrollment to the date of progress. Assessed up to 36 months | 
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] | Incidence of Treatment-Emergent Adverse events (CTCAE v5.0) | 6 months after SBRT | 
| Quality of life by EORTC QLQ-C30 | Quality of life by EORTC QLQ-C30 | through study completion, an average of 3 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatocellular carcinoma, Narrow margin, Adjuvant Stereotactic Body Radiotherapy, Hepatectomy