Hepatocellular Carcinoma (HCC), Metastasis
Conditions
Keywords
Hepatocellular Carcinoma, Extrahepatic Metastases, Primary Tumor Resection, Systemic Therapy, Immunotherapy
Brief summary
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.
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.
Interventions
PROCEDUREPrimary 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.
OTHERProtocol-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.
Sponsors
Tongji Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
This is an open-label trial because the intervention includes surgery and cannot be masked to participants or investigators.
Intervention model description
Participants are randomized in a 1:1 ratio to receive either primary tumor resection plus protocol-allowed first-line immune-based systemic therapy or protocol-allowed first-line immune-based systemic therapy alone.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | From randomization until death from any cause, assessed up to 60 months | Overall survival is defined as the time from randomization to death from any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival | From randomization until radiographic disease progression or death, assessed up to 60 months | 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. |
| Objective Response Rate | Assessed from randomization through disease progression, up to 60 months | 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. |
| Disease Control Rate | Assessed from randomization through disease progression, up to 60 months | Disease control rate is defined as the proportion of participants with complete response, partial response, or stable disease according to RECIST version 1.1. |
Countries
China
Contacts
CONTACTZhao Huang, M.D
Outcome results
None listed