Overview

This study is conducted to evaluate the efficacy, prognosis, adverse effects, and factors for predicting therapeutic effects and clinical prognosis of combined therapy of hepatic artery infusion chemotherapy (HAIC), tyrosine kinase inhibitor/ anti-VEGF antibody, and anti-PD-1/ PD-L1 antibody for advanced hepatocellular carcinoma which initially unsuitable for the radical therapy, including resection, transplantation, or ablation. Factors are collected in preoperative routine blood examination, preoperative radiological imaging and pathological examination.

Eligibility

Inclusion Criteria:

1. Age ≥ 18 years old;
2. Diagnosis of HCC is according to the American Association for the Study of Liver Diseases or European Association for the Study of the Liver guidelines of HCC management;
3. at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or mRESIST criteria;
4. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1;
5. Hepatocellular carcinoma (HCC) was assessed as not suitable for radical resection, liver transplant, or ablation treatment after the assessment of a multidisciplinary team because either: (1) R0 resection was not feasible; (2) remnant liver volume was less than 30% in patients who did not have cirrhosis or 40% in patients with cirrhosis, or the results of an indocyanine green test were higher than 15%; (3) patients had Barcelona Clinic Liver Cancer (BCLC) stage B and beyond Up-to-seven criteria; or (4) patients had BCLC stage C.
6. Portal vein involvement (Chen's groups A and B, or Cheng's type I-III) is allowed: Chen's group A1 or Cheng's type I, tumor thrombus is involved in segmental or sectoral branches of the portal vein or above; Chen's group A2 or Cheng's type II, involvement of the first branch of portal vein; Chen's group B or Cheng's type III, involvement of the main portal vein.
7. Hepatic vein invasion (VV1 to VV2) were allowed. Patients with tumor thrombus in inferior vena cava (VV3 type, Sakamoto type 1) can be included; However, patients with inferior vena cava tumor thrombus exceeding the diaphragmatic plane (Sakamoto type II) and reaching the right atrium (Sakamoto type III) cannot be included in the study;
8. Patients with extrahepatic oligometastasis is allowed: extrahepatic oligometastasis was defined as up to three metastatic lesions in up to two organs with the largest diameter of 3 cm
9. Child-Pugh liver function class A-B7
10. No prior transplantation, TACE, or radioembolization to the liver was allowed. Prior locoregional therapies, such as surgical resection, radiotherapy, radiofrequency ablation, percutaneous ethanol injection or cryoablation, are allowed if the disease have progressed since prior treatment. Local therapy must have been completed at least 4 weeks prior to the baseline scan.
11. Adequate organ and marrow function, as defined below:

        (1) Hemoglobin≥80 g/L; (2) Absolute neutrophil count ≥1.5 ×10^9/L; (3) Platelet count ≥50
        ×10^9/L; (4) Total bilirubin < 51 μmol/L; (5) Alanine transaminase (ALT) and
        aminotransferase (AST)≤5×ULN; (6) Albumin ≥28 g/L; (7) INR ≤1.6; (8) Serum creatinine < 110
        μmol/L.
        Exclusion Criteria:
          1. Prior invasive malignancy within 2 years except for noninvasive malignancies such as
             cervical carcinoma in situ, in situ prostate cancer, non-melanomatous carcinoma of the
             skin, lobular or ductal carcinoma in situ of the breast that has been surgically cured
          2. Severe, active and uncontrolled co-morbidity including but not limited to:
        (1) Persistent or activity (except the HBV and HCV) infection; (2) symptoms of congestive
        heart failure and uncontrolled diabetes; (3) uncontrolled hypertension, systolic
        pressure≥160 mmHg or diastolic pressure≥100 mmHg despite anti-hypertension medications≤28
        days before randomization or first dose of drug; (4) unstable angina; (5) uncontrolled
        arrhythmias; (6) active ILD; (7) severe chronic GI disease accompanied by diarrhea; (8)
        compliance with requirements may limit the research, resulted in significant increase risk
        of AE or influence Subjects provided psychiatric/social problem status on their ability to
        provide written informed consent; (9) A history of active primary immunodeficiency or human
        immunodeficiency virus; (10) Active or previous records of autoimmune disease or
        inflammatory diseases, including inflammatory bowel disease (e.g., colitis or Crohn's
        disease], diverticulitis, except [diverticulosis], systemic lupus erythematosus (SLE),
        sarcoidosis syndrome or Wegener syndrome (e.g., granulomatous vasculitis, gray's disease,
        rheumatoid arthritis, the pituitary gland inflammation and uveitis]); (11) A history of
        hepatic decompensation, including refractory ascites, gastrointestinal bleeding, or hepatic
        encephalopathy.
        3. Known to produce allergic or hypersensitive reactions to any study drug or any excipient
        thereof.
        4. Significant clinical gastrointestinal bleeding or a potential risk of bleeding was
        identified by the investigator during the 30 days prior to study entry.
        5. Tumors of the central nervous system, including metastatic brain tumors. 6. Pregnant
        women or breast-feeding patients. 7. Has received anti-tumor system therapy for HCC.
        Non-anti-tumor purpose combined hormone therapy (e.g., hormone replacement therapy) is
        excluded.
        8. Is currently using, or has used an immunosuppressive drug within 14 days prior to the
        first dose of the investigational drug. This standard has the following exceptions: (1)
        intranasal, inhaled, topical or topical steroids. (e.g., intraarticular); (2) Systemic
        corticosteroid therapy not exceeding 10 mg/ day of prednisone; (3) prophylactic use of
        steroids for hypersensitivity. (e.g., CT scan pretherapy medication).
        9. A live attenuated vaccine was administered within 30 days prior to the first
        administration of the study drug. Note: If enrolled, patients shall not receive live
        attenuated vaccine within 30 days of receiving study drug therapy and after the last
        administration of study drug.
        10. Extrahepatic vascular involvement or thrombosis: superior mesenteric vein (Cheng's type
        IV), or with inferior vena cava tumor thrombus exceeding the diaphragmatic plane (Sakamoto
        type II) or reaching the right atrium (Sakamoto type III) cannot be included in the study.