In this case, we report a case of advanced HCC with APS undergoing multidisciplinary treatment including interventional treatment, apatinib and camrelizumab. To the best of our knowledge, such case has not been previously documented.
HCC combined with APS is a common phenomenon in clinical practice. APS has been reported in 28.8–63.2% of HCC cases[2]. Severe APS aggravates the complications of portal hypertension, diminish the efficacy and safety of TACE, and even promote lung metastases. Portal hypertension arising from APS leads to rupture of gastroesophageal varices, which is a life-threatening complication in cirrhotic patients with a 6-week mortality as high as 20%[3]. Therefore, it is essential to treat severe APS for these patients. Endovascular embolization remains the treatment of choice. Several studys suggested that TACE with various embolic agents such as coil, ethanol, polyvinyl alcohol, and gelatin sponge is an effective treatment[4, 5]. Herein, we use coil combined with gelatin sponge or polyvinyl alcohol to embolize the severe APS. Subsequently, routine TACE was performed if there were residual tumor feeders after embolization. Unfortunately, APS was relieved but resistant to two TACE procedures. For the treatment of esophagogastric varices bleeding as a result of portal hypertension, endoscopic treatment is the standard treatment and has been tried in multiple studies with some degree of success. However, in our case, endoscopic treatment was usually insufficient to eradicate the varices and fail to control the esophagogastric varices bleeding, while TIPS can be used as a second-line therapy and it was proven to be efficacious and safe in the treatment of esophagogastric varices bleeding[6]. TIPS reduce the hepatic venous pressure gradient, which results in portal venous decompression and variceal bleeding control. In the presented case, we performed TIPS in combination with endovascular embolization of the APS to decrease portal hypertension. After TIPS creation and APS embolization, the portal pressure decreased from 50 cm H2O to 40 cm H2O. The patient remained stable for the rest of the hospital course with no signs of recurrent bleeding. The result suggested that our treatment strategy was effective and produced no major complications.
In patients with BCLC stage B, palliative locoregional treatments such as TACE remain the gold standard for therapy. However, it is recommended to initiate systemic therapy if no response is observed after 1 or 2 sessions of TACE, or progression with extrahepatic spread[7]. In the present case, the patient was initially treated with interventional treatment alone. Unfortunately, not only the tumor and the APS were not controlled, but also extrahepatic metastasis emerged. Under this condition, the treatment strategy then to move from locoregional treatment to systemic therapy. Therefore, we performed multidisciplinary treatment including molecular targeted therapy and immunotherapy.
Angiogenesis is mediated by vascular endothelial growth factor (VEGF) and act as an important role in the process of tumor growth, invasion, and metastasis. VEGF combines with VEGF receptor could activate the downstream signals, thereby stimulate the proliferation of vascular endothelium. It is plausible that blockage of VEGFR-2 could be a promising strategy to inhibit tumor induced angiogenesis. Therefore, drugs for the VEGFR anti-angiogenic pathway are being increasingly used for treatment. Apatinib (HENGRUI MEDICINE Co, Ltd. Jiangsu, China) is a novel and highly selective VEGFR-2 tyrosine kinase inhibitor and is the first generation of oral antiangiogenesis drug. Previous studies have suggested that apatinib shows promising clinical efficacy against a variety of solid tumors[8, 9]. Molecular targeted therapy has been a hot topic in multidisciplinary therapy of HCC. However, there is little data about apatinib in treating with HCC. For this case, we attempted to administrate him molecular targeted therapy with apatinib. We prescribed him apatinib 250 mg once daily. The patient showed stable condition of intrahepatic mass and a gradual decrease in AFP after apatinib therapy. Unfortunately, he suffered hematemesis and we had to stop the medicine.
Recently, cancer immunotherapies have attracted much attention as potential clinical treatments, particularly for patients with late-stage disease. A major breakthrough was the development of antibodies that targeting negative regulators of T-cell activation, named immune checkpoints. Immune checkpoint therapy mainly includes programmed cell death-ligand 1 (PD-L1) and programmed cell death protein-1 (PD-1) inhibitors. Tumor cells express PD-L1, which interact with PD-1 receptors, which prevent cytotoxic T cells from destroying tumor cells. Immune checkpoint inhibitors restore the cytotoxic T cell’s ability to destroy tumor cells by blocking the PD-1 receptor. Moreover, the specific inhibition of the PD-1 checkpoint significantly increased the antitumor efficacy of T cell. Thus, anti-cancer immunity can be enhanced by antibodies that block the PD-1/PD-L1 interaction. Immune checkpoint inhibitors have been extensively studied in multiple tumors, including HCC [10–12]. These trials showed significant potentiality of PD-1/PD-L1 inhibitor in treating HCC. Camrelizumab (HENGRUI MEDICINE Co, Ltd. Jiangsu, China) is a monoclonal antibody that inhibits PD-1 immune checkpoint signaling. In a recent trial, 32 of 217 (14.7%) patients with previously treated advanced HCC experienced objective response with tolerable adverse effects, and the 6-month overall survival probability was 74.4%[13]. In this case, the patient exhibited a promising clinical response with camrelizumab therapy. After administration of camrelizumab, stable condition of intrahepatic mass, a notable decrease in the number and size of the lung lesions and a significant decline in AFP levels, were observed (Fig. 3 and Fig. 4). We speculated that two or more cycles of camrelizumab treatment was significantly associated with objective response. Considering the promising evidence from the camrelizumab trial study, China National Medical Products Administration officially approved camrelizumab as second-line treatment for advanced HCC patients.
Notably, recent clinical data revealed that immunotherapy combined with molecular target therapy might develop synergetic effects. Lijun Liang et al.[14] reported that patients who received PD-1 blockade-activated multiple antigen-specific cellular therapy in combination with apatinib showed a significant improvement in progression-free survival and a stronger change in the circulating T cells. Those patients also tended to exhibit longer overall survival, even though the difference was not statistically significant. The promising results may be due to a normalization of the tumor microenvironment. Angiogenesis and immunosuppression constitute the tumor microenvironment, while VEGF/VEGFR pathway take an important role in the regulation of tumor microenvironment immune status. Apart from antiangiogenic properties of apatinib, the inhibition of VEGFR2 also has immunomodulatory effects mediated via reducing the number and function of regulatory T cells and myeloid-derived suppression cells, and enhancing dendritic cells maturation and effector T cells mobilization, activation, and infiltration, thereby resulting in the reprogramming of the immunosuppressive tumor microenvironment into an immunostimulatory microenvironment, ultimately reducing their immunosuppressive effects and suppressing tumor growth. Therefore, although apatinib administration was interrupted in our case, it is reasonable to hypothesize that the tumor microenvironment was changed by apatinib, enabling greater responses to the immune checkpoint blockade, as described above. Taken together, synergism between immunotherapy and molecular target therapy forms the rationale for the development of combined camrelizumab and apatinib therapy. Camrelizumab alone or in combination with apatinib may also be a likely first-line treatment option in treating with advanced HCC. However, the expensive cost of camrelizumab with no medical insurance reimbursement limits the utilization.