Study Design and Population
The study was approved by the Ethics Committee of Zhongshan Hospital, Fudan University, and was conducted according to the guidelines of the Declaration of Helsinki. The electronic medical records of TKI-intolerant HCC patients who underwent MWA-TACE combined with PD-1 inhibitor (MTP) or MWA-TACE alone (MT) from January 2019 to June 2021 were reviewed. Diagnosis of HCC was based on non-invasive criteria in accordance with the European Association for the Study of Liver or American Association for the Study of Liver Disease guidelines[5, 16]. The multidisciplinary team recommended the treatment strategy of MWA-TACE combined with or without PD-1 inhibitor.
Inclusion criteria for this study were as follows: (a) patients with HCC who were intolerance to TKI such as sorafenib or lenvatinib, (b) Child-Pugh class A or B, (c) Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, (d) patients underwent at least one session of MWA-TACE combined with PD-1 inhibitor in our institution. Patients were excluded from the study if they (a) had incomplete medical records, (b) had serious comorbidities including hepatic encephalopathy, refractory ascites, and esophageal variceal bleeding, (c) had a history of malignant tumors in addition to HCC.
MWA-TACE Procedure
MWA and TACE were performed simultaneously in the study. At first, hepatic angiography was conducted to evaluate the tumor size, location, number, and arterial blood supply. Then, a commercially available water-cooled microwave system (VISON-CHINA MEDICAL DEVICES R&D CENTER, USA) was used to perform MWA. After administration of local anesthesia, one or two antennae were inserted into the tumor via ultrasound guidance. The position of the antennae, power output setting and ablation time were determined based on the tumor size, number, and distance from vulnerable structures (gallbladder, diaphragm, or gastrointestinal tract). The ablation procedure was repeated until the hyperechoic region overlapped with the tumor area under ultrasound guidance. The needle track was coagulated to prevent bleeding or tumor seeding. Afterward, arteriography was performed again to evaluate the residual tumor stain and ablative results. Subsequently, superselective catheterization of residual tumor blood supply was performed. The emulsion of chemotherapeutic agents (10-30mg epirubicin or 20-50 mg lobaplatin) and 5-10 mL lipiodol were administered via tumor-feeding artery. Finally, embolization was performed with blank microspheres or gelatin sponge particles until arterial flow stasis under X-ray.
PD-1 Inhibitor Administration
The PD-1 inhibitors including Camrelizumab, Pembrolizumab and Sintilimab injection were used in this study. The administration was injected intravenously at a dose of 200 mg once every three weeks after MWA-TACE. The interruption and discontinuation of PD-1 inhibitor administration depended on the patient's status and the severity of drug toxicity.
Follow-up
The deadline for follow-up was December 31, 2021. All patients underwent regular follow-up at 4-6 weeks after treatment. The contents mainly included detailed medical records, laboratory tests, and dynamic CT or MRI. During follow-up, MWA-TACE and PD-1 inhibitor would be repeated if the residual or recurrent tumor was visible on dynamic CT or MRI. The treatment strategy was discontinued and changed when intolerable toxicity occurred. The subsequent treatment, such as radiotherapy, iodine-125 seed brachytherapy, hepatic artery infusion chemotherapy (HAIC), or best supportive care, was determined by the multidisciplinary team.
Assessment
Overall survival (OS) and progression-free survival (PFS) were recorded and compared between the MTP group and MT group. OS was defined as the period from the initial treatment to death or the last follow-up. PFS was defined as the period from the initial combination therapy until the time of radiological progression or death.
The safety of all patients who underwent MWA and synchronous TACE was assessed by using the Society of Interventional Radiology classification system[17]. A major complication was defined as an event that resulted in substantial morbidity and disability, which increased the level of care, led to hospital admission, or substantially lengthened the hospital stay. All other complications were considered minor. Symptoms of postembolization syndrome (such as abdominal pain, fever without any infection focus, nausea and vomiting) were expected. Therefore, they were not documented separately. AEs related to PD-1 inhibitor were recorded and assessed according to the National Cancer Institute Common Terminology Criteria, version 5.0.
Tumor response was evaluated according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria[18]. The objective response rate (ORR) was defined as the percentage of the sum of complete response (CR) and partial response (PR). The disease control rate (DCR) was expressed as the percentage of the sum of CR, PR, and stable disease (SD). Intrahepatic targeted tumor response only referred to changes in tumors inside the liver after treatment. And overall tumor response evaluated changes in all tumors, including liver and extrahepatic tumors.
Statistical analysis
Statistical analyses were performed using SPSS version 25.0 and GraphPad Prism version 8.0. Continuous variables were expressed as mean ± standard deviation, and categorical variables were expressed as numbers and percentages. The independent sample t test, Person χ2, continuity correction and Fisher’s exact test were used to compare the differences between the MTP group and MT group. Survival curves for OS and PFS were performed using the Kaplan-Meier method. Univariate analyses were performed to identify the predictive factors of survival using the log-rank test. Variables with a P value less than 0.10 in the univariate analysis were entered into the multivariate analysis using Cox proportional hazard regression model. All analyses were two-tailed. A P value less than 0.05 was considered significant.