HAIC vs. TACE Combined With Sintilimab and Bevacizumab for Intermediate HCC (Beyond Up-To-Seven)

Hepatic Arterial Infusion Chemotherapy Plus Sintilimab and Bevacizumab Versus Transarterial Chemoembolization Plus Sintilimab and Bevacizumab for Intermediate-Stage Hepatocellular Carcinoma Beyond the Up-To-Seven Criteria：A Prospective, Randomized, Controlled Trial

The purpose of this prospective, randomized, multicenter, controlled clinical study is to evaluate the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) compared to transarterial chemoembolization (TACE) when both are combined with sintilimab and bevacizumab for patients with intermediate-stage hepatocellular carcinoma (HCC). Specifically, the trial focuses on patients with a high tumor burden that exceeds the Up-To-Seven criteria.While TACE is the standard treatment for BCLC stage B HCC, its effectiveness is often limited in patients with extensive intrahepatic tumor loads. This study investigates whether the combination of FOLFOX-HAIC and systemic therapy (sintilimab plus bevacizumab) provides better local control and survival outcomes than the combination of TACE and the same systemic therapy.

Experimental Group: Patients receive FOLFOX-HAIC (up to 4 cycles in the first 16 weeks) combined with sintilimab and bevacizumab. Control Group: Patients receive on-demand TACE (up to 4 cycles in the first 16 weeks) combined with sintilimab and bevacizumab. Primary Objective: To compare Progression-Free Survival (PFS) between the two arms as evaluated by mRECIST. Enrollment: A total of 300 patients will be randomized at a 1:1 ratio to the treatment groups. The study aims to provide high-level clinical evidence for optimizing treatment strategies for this specific subgroup of HCC patients.

Inclusion Criteria:

• Diagnosis: Histologically or cytologically confirmed hepatocellular carcinoma (HCC), or patients with cirrhosis meeting the American Association for the Study of Liver Diseases (AASLD) clinical diagnostic criteria for HCC.
• Age: ≥ 18 years old.
• Performance Status: ECOG performance status score of 0.
• Prior Treatment: No prior systemic anti-tumor therapy or transarterial interventional therapy for HCC.
• Tumor Stage and Burden: Barcelona Clinic Liver Cancer (BCLC) Stage B, unsuitable for radical surgery and/or local therapy (such as ablation).
• Up-To-Seven Criteria: Tumor burden exceeding the Up-To-Seven criteria, defined as the sum of the size of the largest intrahepatic tumor (in cm) and the number of tumors being greater than 7.
• Tumor Distribution: Bilobar multifocal tumors.
• Measurable Disease: At least one measurable lesion with arterial phase enhancement on CT/MRI.
• Vascular Status: Patent portal vein with no evidence of portal vein tumor thrombus.
• Extrahepatic Status: No extrahepatic metastasis.
• Variceal Risk: No risk of variceal bleeding; esophagogastroduodenoscopy (EGD) within 6 months shows no gastroesophageal varices or active ulcers.
• Liver Function: Child-Pugh Grade A.
• Hematology: Platelets > 75 × 10⁹/L; White Blood Cells > 3.0 × 10⁹/L; Neutrophils > 1.5 × 10⁹/L.
• Biochemistry: Serum bilirubin ≤ 1.5 × upper limit of normal (ULN); Transaminases ≤ 3 × ULN; Serum creatinine < 1.5 × ULN.
• Physical Findings: No ascites
• Albumin ≥ 30 g/L.
• Coagulation: Normal coagulation function.
• Expectancy: Expected survival > 3 months.
• Consent: Signed written informed consent and willingness/ability to comply with follow-up until death, study completion, or termination.

Exclusion Criteria:

• Histology: Known histology/cytology of fibrolamellar HCC, sarcomatoid HCC, or components of cholangiocarcinoma.
• Medical History: History of hepatic encephalopathy or liver transplantation.
• Effusions: Clinically symptomatic pleural effusion, ascites, or pericardial effusion requiring drainage.
• Viral Hepatitis: Active Hepatitis B (HBV DNA > 2000 IU/ml or 10⁴ copies/ml) or Hepatitis C (HCV RNA > 10³ copies/ml); co-infection with both HBsAg and anti-HCV positive. (Eligible if levels drop below these criteria after nucleoside antiviral therapy) .
• Cardiovascular (Past 12 Months): Myocardial infarction, severe/unstable angina, coronary artery bypass grafting, congestive heart failure, cerebrovascular accident (including transient ischemic attack), or pulmonary embolism.
• Ongoing Cardiac Issues: Arrhythmia ≥ Grade 2 (NCI-CTCAE); QTc prolongation (Male > 450 ms, Female > 470 ms).
• Bleeding Risk: History of gastrointestinal bleeding within 6 months or clear bleeding tendency (e.g., high-risk varices, active GI ulcer, persistent positive fecal occult blood).
• Hypertension: Uncontrollable hypertension (SBP > 140 mmHg or DBP > 90 mmHg despite optimal treatment); history of hypertensive crisis or hypertensive encephalopathy.
• Organ Failure: Renal failure requiring hemodialysis or peritoneal dialysis; severe dysfunction of other major organs.
• Second Malignancy: History of other malignancies within 3 years prior to screening (except those with negligible risk of metastasis/death such as treated cervical cancer in situ, non-melanoma skin cancer, or localized prostate cancer).
• CNS Involvement: Known or new evidence of brain or leptomeningeal lesions. Coagulation Disorders: Hemophilia or bleeding tendency; currently taking therapeutic doses of coumarin derivatives (e.g., warfarin).
• Pregnancy/Lactation: Pregnant or breastfeeding females; women of childbearing potential must have a negative pregnancy test within 7 days prior to enrollment.
• Other History: Prior organ transplant; known HIV infection; active tuberculosis; allergy to chemotherapy drugs.
• Autoimmune Diseases: Active or history of autoimmune diseases (e.g., myasthenia gravis, myositis, autoimmune hepatitis, SLE, rheumatoid arthritis, IBD, etc.).
• General Compliance: Any serious acute/chronic physical or mental illness, or laboratory abnormalities that increase study risk or interfere with interpretation of results.
• Non-compliance: History of significant non-compliance with medical protocols or inability to provide reliable informed consent.