The Safety and Efficacy of Transarterial Chemoembolization (TACE) + Lenvatinib +Programmed Cell Death Protein 1 (PD-1) Antibody in the Conversion-resection of Advanced Unresectable Hepatocellular Carcinoma:a Multicenter Prospective Cohort Study

Hepatocellular carcinoma (hepatocellular carcinoma,HCC,) accounts for 85% to 90% of primary liver cancer. Worldwide, there are more than 700000 new cases of liver cancer every year, 55% of which are concentrated in China, which is the fourth most common malignant tumor and the third leading cause of death in China. More importantly, the onset of liver cancer is hidden, and 70% to 80% of patients with liver cancer are in the middle and advanced stage when they are first diagnosed, so they lose the opportunity for surgical treatment. Therefore, liver cancer seriously affects the life and health of the people. For these unresectable middle and advanced liver cancer, that is, Barcelona stage (barcelona clinic liver cancer,BCLC) stage C, BCLC and the European Association for the study of liver Diseases ((European Association for the Study of Liver Diseases)) recommended transarterial chemoembolization (transarterial chemoembolization,TACE) and systematic treatment, respectively. However, a number of clinical studies have shown that the prognosis of patients with advanced liver cancer who underwent surgical resection is significantly better than that of TACE or systemic therapy alone. Therefore, how to convert unresectable liver cancer into resectable liver cancer has always been a hot issue in clinical research.

Hepatectomy is to reduce the tumor load and tumor stage through some or several treatments, so that unresectable liver cancer can become resectable liver cancer and tumor resection. There are two purposes of translational therapy: one is that translational therapy can reduce tumor size, reduce tumor stage and improve its biological characteristics; the other is that translational therapy can select tumors with good biological characteristics. In 1977, Shafer et al reported that a single unresectable hepatoblastoma was successfully resected after radiotherapy and chemotherapy, and first mentioned the concept of liver cancer transformation therapy. Subsequently, sitzmann, Tang and fan reported the use of 131I or 90Y labeled anti ferritin antibody, TACE and TACE in the treatment of unresectable liver cancer. Finally, 8% to 18% of HCC patients underwent transformation resection. To be sure, the combination of multiple ways of transformation therapy can improve the success rate of transformation and prolong the survival of patients. But these studies are retrospective, the sample size is small, and the treatment plan is lack of unity. In addition, with the continuous emergence of targeted drugs and immune checkpoint blocking therapy (such as programmed death receptor-1, PD-1), the treatment mode of liver cancer has changed, and the success rate of transformation and resection may also be improved. Therefore, a prospective clinical study is urgently needed to explore the safety and effectiveness of hepatectomy in the new era of molecular targeted drugs and immunotherapy.

The treatment of liver cancer transformation includes local treatment and systemic therapy. The former includes TACE, transcatheter embolization, radiofrequency ablation, percutaneous alcohol injection, etc., among which TACE is the most commonly used local treatment. Fan and other scholars analyzed 65 patients with TACE after operation for liver cancer: the diameter of median tumor decreased from 9.9cm to 3.7cm, 35.9% (14/39) patients recovered AFP level, and the 1-year, 3-year and 5-year survival rate of patients were 80%, 65% and 56%, respectively. However, the pathological findings showed that 83.1% (54/65) of the tumors still failed to complete necrosis. Obviously, TACE is difficult to achieve complete necrosis of tumor as a non radical treatment. Moreover, the lack of 4 blood damage caused by TACE can induce the up regulation of related molecules (such as vascular endothelial growth factor (VEGF) which can promote the growth, invasion and metastasis of tumor. Therefore, TACE combined with antiangiogenic drugs can theoretically inhibit the angiogenesis and tumor growth induced by TACE, and TACE can reduce tumor effect or permit sensitization of antiangiogenic drugs. Solafeni and lumbotinib are first-line systemic therapy drugs for advanced liver cancer patients approved by FDA and CFDA. As a multi-target receptor tyrosine kinase inhibitor (TKI), they mainly inhibit VEGF receptor-1,2,3, FGF receptor-1,2,3,4, PDGFR α, RET and kit, thus inhibiting the proliferation of tumor cells, inducing apoptosis and playing an anti angiogenesis role. However, compared with solafeni, the binding of lumbotini with target molecules has stronger affinity. Based on an open label, multicenter, phase III non inferior effect clinical study, the results showed that the median survival time (13.6 months vs. 12.3 months) of the patients with liver cancer was the same as that of solafeni group, but the progression time (9.2 months vs. 3.6 months) and objective remission rate (24.1% vs. 9.2%) were better than those in the solafeni group. Therefore, TACE combined with lumbotinib may have better clinical outcomes.

Immune checkpoint blocking therapy may enhance the immune response induced by local treatment. TACE and other local treatment can make the body produce immune response. Local treatment leads to tumor cell death, apoptosis (non-cell necrosis) induces specific immunity of tumor, such as the release of calcium net protein and other endoplasmin on the cell surface, ATP secretion during the apoptosis and foaming stage, and the release of high mobility group box associated with cell death of non-histone chromatin group 1 1. HMGB1) promotes the collection, activation and entry of dendritic cells into the tumor microenvironment. The tumor antigen of tumor cells is phagocyted and the best antigen is presented to T cells. This process is called immunogenic cell death (ICD). Adriamycin (epirubicin, doxorubicin) as the most commonly used chemotherapeutic agent of TACE can enhance the immunogenicity of ICD. Therefore, TACE has been shown to promote ICD and induce tumor associated antigen-specific reactions. Ni Quanfa et al. Found that the levels of CD3 +, CD4 +, CD4 + / CD8 + increased significantly at 3 and 4 weeks after TACE treatment. Liao Juan and other researchers found that TACE can correct the low immune function of patients with HCC and make them partially recover. Kazumasa hiroishi and others studied 20 patients with HCC receiving TACE and RFA respectively. 80% of patients produced tumor specific antibody and cd8+ immune response one month later. Lakshmana ayaru et al. Found that APF specific CD4 + T cells increased after HCC embolization. Immune checkpoint blockade refers to blocking the inhibitory receptors or ligands on the surface of T cells, such as PD-1 / PD-L1, CTLA4 and Vista, to partially reverse T cell failure and improve tumor T cell response. This innovative treatment has been verified in a variety of solid tumors. Sangro et al. Showed that local treatment combined with immune checkpoint blocking therapy is safe and effective in patients with liver cancer. Moreover, TACE combined with immune checkpoint blocking therapy can further enhance the anti-tumor immunity without overlapping toxicity. Subsequently, a large number of clinical trials, such as nct03572582, nct03383458, nct03397654, were carried out worldwide to evaluate the efficacy of local treatment combined with immune checkpoint blocking therapy in patients with liver cancer.

In conclusion, current studies have shown that transformation therapy can benefit patients with unresectable HCC, but there are still some problems, such as low success rate of transformation, limited treatment options and so on. However, the new first-line drug for liver cancer is synergistic with TACE, and immune checkpoint blocking therapy may enhance the immune response induced by TACE. Therefore, this study is to compare the success rate of TACE combined with lenvastinib and sindilimab in the treatment of advanced unresectable liver cancer, and to explore the feasibility of the combined regimen in the treatment of liver cancer.