Hepatic arterial infusion chemotherapy versus systemic therapy for advanced hepatocellular carcinoma: a systematic review and meta-analysis

Introduction To investigate the effects of hepatic arterial infusion chemotherapy (HAIC) with or without systemic chemotherapy compared to systemic chemotherapy alone in patients with locally advanced hepatocellular carcinoma (HCC). Methods Following a registered protocol (PROSPERO 2023 CRD42023386780 Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023386780), a comprehensive search was performed using reputable databases and registries up to December 26, 2022, with no language, publication date, or status restrictions. Only randomized controlled trials (RCTs) investigating the effects of HAIC with or without systemic chemotherapy versus systemic therapy alone were included. The primary outcomes were overall survival (OS), progression-free survival (PFS), and adverse events. The secondary outcomes included the objective response rate (ORR) and disease control rate (DCR). A random-effects model was used, and the certainty of the evidence was rated using GRADE. Results Seven RCTs involving 1,010 patients were included. All trials utilized sorafenib as the comparator. Five trials (690 patients) compared HAIC plus sorafenib to sorafenib alone, while two trials (320 patients) compared HAIC to sorafenib. The results indicate that HAIC, with or without sorafenib, may increase OS, PFS, and ORR compared with sorafenib alone. HAIC may enhance DCR, but the evidence is very uncertain. Adverse events were comparable between HAIC plus sorafenib and sorafenib alone. However, adverse events might be decreased in HAIC alone. Discussion HAIC with or without systemic chemotherapy may improve survival outcomes and response rates of patients with HCC. Since the current body of evidence is moderate to very low, more robust randomized trials are needed to confirm the efficacy of HAIC. Systematic Review Registration https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=386780, identifier CRD42023386780.

therapies or have progressed following locoregional therapy such as surgical resection, percutaneous hepatic arterial embolization, radiofrequency ablation, and percutaneous interventional therapy (3) At least one tumor lesion meeting measurable disease criteria as determined by RECIST v1.1.Lesions previously treated with local therapy, such as radiation therapy, hepatic arterial embolization, radiofrequency ablation, and percutaneous interventional therapy should not be selected unless progression is noted at baseline, in which case, these lesions would be considered as non-target lesions (4) Current cirrhotic status of Child-Pugh class A-B, with no encephalopathy (5) Ascites controlled by diuretics is permitted in this study (6) Availability of a representative tumor tissue specimen (archival tumor tissue is allowed) at pre-screening (7) Eastern Cooperative Oncology Group Scale for Assessment of Patient Performance Status ≤ 2 (8) Both men and women enrolled in this trial must use adequate barrier birth control measures during the course of the trial and 4 weeks after the completion of trial (9) Adequate bone marrow, liver and renal function as assessed by central lab by means of the following laboratory requirements from samples within 7 days prior to procedure: Hemoglobin > 100g/L, Absolute neutrophil count >3.0 ×109/L, Neutrophil count > 1.5 ×10 9 /L, Platelet count ≥ 50.0 ×10 9 /L, Total bilirubin < 51 μmol/L, Alanine transaminase (ALT) and aminotransferase (AST) < 5 x upper limit of normal, Albumin > 28 g/L, Prothrombin time (PT)international normalized ratio (INR) < 2.3, or PT < 6 seconds above control, Serum creatinine < 110 μmol/L (10) Willing and able to comply with scheduled visits, treatment plan and laboratory tests.

Exclusion criteria:
(1) refractory pleural effusion or ascites (2)  Treatment was divided into 28-day cycles.All patients in both groups were treated with 400 mg sorafenib orally twice daily on days 1-28.In the hepatic arterial infusion chemotherapy combination therapy group, cisplatin was administered at a dose of 20 mg/m² per day on days 1 and 8 and fluorouracil was administered at a dose of 330 mg/m² per day on days 1-5 and 8-12 of every 28-day cycle, followed by 2 weeks off treatment.

Control; Sorafenib
All patients in both groups were treated with 400 mg sorafenib orally twice daily on days 1-28.

Outcomes
Primary  /L; platelet count ≥100×10 9 /L; alanine aminotransferase and aspartate aminotransferase levels 2.5-fold or less of the upper limit of normal serum total bilirubin level two fold or less of the upper limit of normal serum creatinine level 1.5-fold or less of the upper limit of normal; and serum albumin level ≥30 g/L).

Exclusion criteria:
(1) Have had prior chemotherapy with Oxaliplatin or Fluorouracil or Sorafenib.
(2) receiving any other investigational agents (3) have a diagnosis of hepatic encephalopathy (4) have a diagnosis of sclerosing cholangitis (5) have a diagnosis of Gilbert's disease (6) have clinical ascites (7) have any uncontrolled concurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled diabetes mellitus and hypertension, or psychiatric illness/social situations that would limit compliance with study requirements (8) other malignancy except localized basal cell or squamous cell skin cancer in the past 5 years (2) Previous local therapy completed less than 4 weeks prior to the dosing and, if present any related acute toxicity > grade 1.
(4) any other malignancies within the last 3 years before study start.
(5) History of HCC tumor rupture (6) severe encephalopathy (7) Patients with known active bleeding (e.g. from GI ulcers, esophageal varices) within 2 months prior to baseline/screening visit or with history or evidence of inherited bleeding diathesis or coagulopathy (8) Clinically significant (CTC grade 3 or 4) venous or arterial thrombotic disease within past 6 months.
(12) Clinically significant third space fluid accumulation (i.e., ascites requiring tapping despite use of diuretic or pleural effusion that either required tapping or is associated with shortness of breath).
(13) Patients who have undergone major surgical procedure, open biopsy, or significant traumatic injury within 4 weeks of the start of protocol treatment.( 14) History of a bone marrow or solid organ transplant.
(15) Use of biologic response modifiers, such as G-colony stimulating factor (CSF), within 3 weeks prior to start of study drug.(G-CSF and other hematopoietic growth factors may be used in the management of acute toxicity such as febrile neutropenia when clinically indicated or at the discretion of the investigator; however, they may not be substituted for a required dose reduction).
(16) Subjects taking chronic erythropoietin are permitted provided no dose adjustment is undertaken within 1 month prior to the study or during the study.
(17) Any other condition that would, in the Investigator's judgment, contraindicate patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures, e.g., infection/inflammation, intestinal obstruction, unable or unwilling to swallow medication, social/ psychological issues, etc.
(19) Known history of human immunodeficiency virus (HIV) seropositivity.HIV testing is not required as part of this study.
(20) Patients who have received any other investigational agents within a period of time that is less than the cycle length used for that treatment or equal to 4 weeks (whichever is shorter) prior to starting study drug and recovered from any side effects to grade 1 or less.
(21) Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test.
(22) Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 7 days after permanently discontinuing HAIF and/or sorafenib treatment.
(23) Highly effective contraception methods include: Total abstinence (when this is in line with the preferred and usual lifestyle of the patient.Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment.In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.Male sterilization (at least 6 months prior to screening).For female patients on the study the vasectomized male partner should be the sole partner for that patient.Combination of any two of the following (a+b or a+c, or b+c): Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception.Placement of an intrauterine device or intrauterine system.Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment.Women are considered postmenopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g.age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago.In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.Sexually active males unless they use a condom during intercourse while receiving treatment and for 7 days after stopping study treatment and should not father a child in this period.A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid.Subjects unable to suffer the discomfort of the HAI procedure (e.g.pain, claustrophobia, noise).Any contraindication for sorafenib, oxaliplatin, leucovorin, or fluorouracil administration.Any agents which could affect the absorption or pharmacokinetics of the study drugs.Known or suspected allergy to the investigational agents or any agent given in association with this study.

Intervention
Experimental; HAIC-FO After the biopsy, each patient received an artery catheter procedure guided by digital subtraction angiography.
Control ; Sorafenib standard prescription of 400 mg sorafenib orally twice daily

Outcomes
Primary outcomes;  OS Secondary outcomes;  PFS  intrahepatic tumor PFS