Surgery Plus Systemic Therapy for Liver Cancer With Extrahepatic Metastases

Primary Tumor Resection Plus Systemic Therapy Versus Systemic Therapy Alone in Hepatocellular Carcinoma With Extrahepatic Metastases: A Multicenter Prospective Randomized Controlled Trial

This study will evaluate whether resection of the primary liver tumor, in addition to standard first-line systemic therapy, improves survival in patients with hepatocellular carcinoma that has spread outside the liver but still has a resectable primary intrahepatic tumor. Participants will be randomly assigned to receive either primary tumor resection followed by protocol-allowed first-line immune-based systemic therapy or systemic therapy alone. The primary outcome is overall survival. Secondary outcomes include progression-free survival, objective response rate, disease control rate, immune-related adverse events, postoperative complications, and quality of life.

Study Overview

• Status: Not yet recruiting
• Conditions: Hepatocellular Carcinoma (HCC); Metastasis
• Intervention / Treatment: Other: Protocol-Allowed First-Line Immune-Based Systemic Therapy; Procedure: Primary Tumor Resection

Detailed Description

This is a multicenter, prospective, open-label, randomized, parallel-group controlled trial in patients with hepatocellular carcinoma (HCC) with extrahepatic metastases whose primary intrahepatic tumor is considered resectable with curative intent (R0 intent). A total of 280 participants will be randomized in a 1:1 ratio to either primary tumor resection plus protocol-allowed first-line systemic therapy or systemic therapy alone.

Randomization will be performed using block randomization with a block size of 4 through a centralized system managed by an independent data management team. Stratification factors include maximum tumor diameter (<5 cm vs. >=5 cm), category of systemic therapy (immunotherapy plus anti-angiogenic therapy vs. immunotherapy plus targeted therapy), and liver function status (Child-Pugh A vs. B7).

All participants will receive guideline-concordant first-line immune-based systemic therapy. Preferred regimens include PD-1/PD-L1 inhibitor plus anti-angiogenic therapy. PD-1 inhibitor plus multikinase targeted therapy is allowed when anti-angiogenic therapy is contraindicated or not feasible. The use of more than one PD-1/PD-L1 agent in combination is not permitted. Optional hepatic arterial infusion chemotherapy (HAIC) may be used according to clinical need in either arm and will be recorded for exploratory and adjusted analyses.

In the experimental arm, participants will undergo resection of the primary liver tumor before systemic therapy. The surgical goal is R0 resection, and the procedure may be anatomic or non-anatomic hepatectomy based on tumor location, liver reserve, and operative risk. Systemic therapy will be initiated after adequate postoperative recovery. In the control arm, participants will receive systemic therapy alone. If a participant in the control arm later becomes a candidate for surgery, such surgery will be recorded as an unplanned intervention, but the participant will remain in the originally assigned group for the primary intention-to-treat analysis.

Tumor response will be assessed by contrast-enhanced CT or MRI according to RECIST version 1.1. Imaging will be performed every 6 weeks through week 54 and every 9 weeks thereafter until disease progression or treatment discontinuation. To preserve comparability of response assessment between the two arms, lesions planned for resection in the experimental arm will not be selected as target lesions at baseline.

The primary endpoint is overall survival. Secondary endpoints include progression-free survival, objective response rate, disease control rate, postoperative complications of Clavien-Dindo grade II or higher, incidence of immune-related adverse events, and change in quality of life measured by the EORTC QLQ-C30 questionnaire.

• Study Type: Interventional
• Enrollment (Estimated): 280
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Zhao Huang, M.D; Phone Number: +86 13006378908; Email: huangzhao@tjh.tjmu.edu.cn

Study Locations

• China
  • Hubei
    • Wuhan, Hubei, China, 430030
      • Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age 18 to 75 years
• Hepatocellular carcinoma confirmed by imaging and/or histology according to AASLD or EASL criteria
• Resectable primary intrahepatic tumor with expected R0 resection
• ECOG performance status 0 to 1
• At least one measurable extrahepatic metastatic lesion according to RECIST version 1.1
• Child-Pugh class A or stable Child-Pugh B7
• Written informed consent and willingness to comply with study follow-up and data collection

Exclusion Criteria:

• Prior systemic therapy for hepatocellular carcinoma, including immunotherapy, targeted therapy, or chemotherapy
• Decompensated or clinically unstable liver disease, including refractory ascites, recurrent hepatic encephalopathy, active gastrointestinal bleeding, or - Child-Pugh class greater than B7
• Major bleeding risk or clinically significant coagulation abnormality, including recent gastrointestinal bleeding or untreated/high-risk gastroesophageal varices
• Active autoimmune disease or long-term systemic immunosuppressive therapy
• Active severe infection, including uncontrolled bacterial or fungal infection, uncontrolled hepatitis B virus replication without appropriate antiviral treatment, or active tuberculosis
• Uncontrolled central nervous system metastases
• Uncontrolled cardiovascular disease, including poorly controlled hypertension, recent myocardial infarction, unstable angina, stroke, or major thrombotic event
• Significant proteinuria or renal dysfunction considered unsuitable for study treatment
• Another active malignancy, except for selected low-risk malignancies allowed by the investigator and ethics committee
• Pregnancy or breastfeeding
• Known severe hypersensitivity to study-related drugs
• Poor compliance, psychiatric or cognitive disorder preventing study participation, or any other condition judged by the investigator to make the participant unsuitable for the trial

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
Active Comparator: Systemic Therapy Alone; Participants receive protocol-allowed first-line immune-based systemic therapy without planned primary tumor resection. Optional HAIC may be used according to clinical need and will be recorded. Unplanned surgery after randomization will be recorded but will not change the original group assignment for the primary analysis.	Other: Protocol-Allowed First-Line Immune-Based Systemic Therapy; Guideline-concordant first-line immune-based systemic therapy. Preferred regimens include PD-1/PD-L1 inhibitor plus anti-angiogenic therapy. PD-1 inhibitor plus multikinase targeted therapy is allowed when anti-angiogenic therapy is contraindicated or not feasible. Concurrent use of more than one PD-1/PD-L1 agent is not permitted.
Experimental: Primary Tumor Resection Plus Systemic Therapy; Participants undergo resection of the primary intrahepatic tumor with curative intent (R0 intent) followed by protocol-allowed first-line immune-based systemic therapy after adequate postoperative recovery. Optional HAIC may be used according to clinical need and will be recorded.	Other: Protocol-Allowed First-Line Immune-Based Systemic Therapy; Guideline-concordant first-line immune-based systemic therapy. Preferred regimens include PD-1/PD-L1 inhibitor plus anti-angiogenic therapy. PD-1 inhibitor plus multikinase targeted therapy is allowed when anti-angiogenic therapy is contraindicated or not feasible. Concurrent use of more than one PD-1/PD-L1 agent is not permitted.; Procedure: Primary Tumor Resection; Surgical resection of the primary liver tumor with curative intent (R0 intent), using anatomic or non-anatomic hepatectomy as appropriate based on tumor location, liver reserve, and operative risk.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Overall survival is defined as the time from randomization to death from any cause.	From randomization until death from any cause, assessed up to 60 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival	Progression-free survival is defined as the time from randomization to disease progression according to RECIST version 1.1 or death from any cause, whichever occurs first.	From randomization until radiographic disease progression or death, assessed up to 60 months
Objective Response Rate	Objective response rate is defined as the proportion of participants with a best overall response of complete response or partial response according to RECIST version 1.1. In the experimental arm, lesions planned for resection are not selected as baseline target lesions.	Assessed from randomization through disease progression, up to 60 months
Disease Control Rate	Disease control rate is defined as the proportion of participants with complete response, partial response, or stable disease according to RECIST version 1.1.	Assessed from randomization through disease progression, up to 60 months

Collaborators and Investigators

• Sponsor: Tongji Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): April 30, 2026
• Primary Completion (Estimated): April 30, 2026
• Study Completion (Estimated): April 30, 2031

Study Registration Dates

• First Submitted: April 12, 2026
• First Submitted That Met QC Criteria: April 12, 2026
• First Posted (Actual): April 17, 2026

Study Record Updates

• Last Update Posted (Actual): April 17, 2026
• Last Update Submitted That Met QC Criteria: April 12, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Hepatocellular Carcinoma; Immunotherapy; Systemic Therapy; Primary Tumor Resection; Extrahepatic Metastases
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Digestive System Neoplasms; Digestive System Diseases; Liver Diseases; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Liver Neoplasms; Neoplastic Processes; Carcinoma; Pathological Conditions, Signs and Symptoms; Carcinoma, Hepatocellular; Neoplasm Metastasis
• Other Study ID Numbers: EHMS-101

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