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

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.