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

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Hepatocellular Carcinoma; Hepatectomy; Narrow Margin; Adjuvant Stereotactic Body Radiotherapy
• Intervention / Treatment: Radiation: stereotactic body radiation therapy; Other: regular follow-up

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 140
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Yongjie Shui, MM; Phone Number: +8657187783521; Email: shui-yongjie@zju.edu.cn
• Study Contact Backup: Name: Lihong Liu, MM; Phone Number: +8657187783521; Email: lihong_liu@zju.edu.cn

Study Locations

• China
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310009
      • The Second Affiliated Hospital of Zhejiang University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Aged ≥18 years;
2. 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;
3. Pathologically confirmed as narrow margin (the shortest distance from the edge of the tumor to the surface of liver transection <1cm) ;
4. Child-Pugh class A and B7;
5. ECOG (Eastern Cooperative Oncology Group) performance status 0 or 1;
6. Willing to provide tissue from an excisional biopsy of a tumor lesion;
7. 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;
8. 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:

1. Have received radiotherapy for the area to be treated in the past;
2. Severe bleeding tendency or coagulation dysfunction within the previous 6 months;
3. Extrahepatic metastasis;
4. Known history of active Bacillus Tuberculosis (TB)
5. 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.
6. Active infection requiring systemic therapy;
7. Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy;
8. Known psychiatric or substance abuse disorders ;
9. Pregnant or breastfeeding;
10. Known history of human immunodeficiency virus (HIV: HIV 1/2 antibodies);
11. Received a live vaccine within 30 days before radiotherapy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Second Affiliated Hospital, School of Medicine, Zhejiang University
• Investigators: Principal Investigator: Qichun Wei, MD/PhD, Zhejiang University; Principal Investigator: Weilin Wang, MD/PhD, Zhejiang University

Study record dates

Study Major Dates

• Study Start (Anticipated): March 1, 2023
• Primary Completion (Anticipated): December 1, 2025
• Study Completion (Anticipated): December 1, 2027

Study Registration Dates

• First Submitted: October 29, 2022
• First Submitted That Met QC Criteria: October 29, 2022
• First Posted (Actual): November 2, 2022

Study Record Updates

• Last Update Posted (Actual): February 17, 2023
• Last Update Submitted That Met QC Criteria: February 16, 2023
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: Hepatocellular carcinoma; Hepatectomy; Narrow margin; Adjuvant Stereotactic Body Radiotherapy
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular
• Other Study ID Numbers: 2022-0908

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No