Bile duct cancer is a malignant tumor with high malignancy, rapid development and easy metastasis. According to the site of bile duct cancer, it can be divided into two types: intrahepatic bile duct cancer and extrahepatic bile duct cancer. In the past decades, the incidence of bile duct cancer in China and Southeast Asia has been increasing year by year due to the increase of bile duct stones, bile duct inflammation, smoking, obesity, diabetes and the prevalence of hepatitis B in China. Surgical resection is the treatment of choice for intrahepatic or extrahepatic cholangiocarcinoma. However, early stage of cholangiocarcinoma is usually asymptomatic, so when many patients get diagnosed, the tumor has already metastasized and cannot be resected, and even if surgical resection can be done, recurrence after surgery is still frequent and once it recurs, secondary resection is difficult. For advanced bile duct cancer that cannot be removed surgically, how should it be treated? 1.Systemic chemotherapy According to the domestic and international standards of bile duct cancer treatment, the main treatment strategy for advanced bile duct cancer that cannot be surgically resected is systemic chemotherapy, which can be combined with radiotherapy, interventional and other local treatment methods. At present, the first-line chemotherapy strategy for cholangiocarcinoma is gemcitabine combined with cisplatin or oxaliplatin, which has certain efficacy in advanced cholangiocarcinoma that cannot be removed by surgery. Gemcitabine combined with platinum is the standard first-line treatment for cholangiocarcinoma, but there is still a lack of standard back-line treatment after the progression of chemotherapy. 2.Targeted therapy Currently, most solid tumors have corresponding targeted drugs to choose from. However, for cholangiocarcinoma, there is no targeted drug for cholangiocarcinoma indications in China. Because the targeted therapy for bile duct cancer is still in the clinical trial stage. When we encounter patients with poor chemotherapy efficacy or unwilling to undergo systemic chemotherapy in our daily treatment, we will recommend them to participate in clinical trials related to bile duct cancer, so that they can use the latest international targeted drugs for free in the first time. Of course, there are many patients with bile duct cancer who are not eligible for clinical trials due to various reasons, they can choose to undergo genetic testing for tumor targets and individually select the suitable targeted drugs for their treatment. There is another good news to tell you about the targeted therapy for bile duct cancer. On April 17 this year, the U.S. Food and Drug Administration (FDA) officially approved Incyte’s FGFR2 inhibitor pemigatinib for the treatment of patients with locally advanced or metastatic cholangiocarcinoma carrying FGFR2 fusions or rearrangements who have received prior treatment, which is also the first targeted therapy for cholangiocarcinoma approved by the FDA. The approval was based on excellent data from the FIGHT-202 clinical study in bile duct cancer, the results of which were published in The Lancet Oncology. The clinical study data showed that the objective remission rate (percentage of tumor shrinkage or disappearance) of Pemigatinib for patients with FGFR2 fusion/rearrangement exceeded 30%, and the disease control rate exceeded 80%, with rapid onset of action and long-lasting effect. Of course, at this stage, Pemigatinib is not yet available in China because the new drug has not yet been approved by the Chinese FDA to be marketed in China. Immunotherapy Tumor immunotherapy is an emerging anti-tumor treatment method in recent years, especially immunotherapy represented by immune checkpoint inhibitors (PD-1, PD-L1, CTL4) for various solid tumors is widely carried out in clinical research, and bile duct cancer is no exception. It was found through basic research that about 9% of cholangiocarcinoma cells have tumor cells expressing PD-L1 expression and 46% of patients have intra-tumor PD-L1 positive inflammatory cell aggregates, so immunotherapy represented by PD-1 or PD-L1 may play an important role in the systemic treatment of cholangiocarcinoma. Genetic testing revealed that patients with tumor MSI-H (microsatellite instability type) were 5-13% in extrahepatic cholangiocarcinoma and 10% in intrahepatic cholangiocarcinoma, and patients with this subtype were very effective against PD-1 antibodies. Therefore, it is important to genetically test patients with cholangiocarcinoma to determine if they are microsatellite unstable. Since most patients are patients with subtypes that are not MSI-H, single agent treatment with PD-1 antibodies for cholangiocarcinoma is not effective. Therefore, combination therapies for bile duct cancer, such as PD-1 antibody and first-line chemotherapy in combination, and PD-1 antibody and targeted drugs in combination, are being explored clinically. Whether immunotherapy represented by PD-1 can achieve similar effect as hepatocellular carcinoma in cholangiocarcinoma is being clinically validated. 4.Local interventional or ablative treatment in liver Patients with bile duct cancer confined to the liver, which cannot be operated due to the combination of cirrhosis and other chronic underlying diseases, can be considered for tumor interventional treatment or ablative surgery. Both liver tumor interventional therapy and ablation therapy are minimally invasive treatment methods for localized liver. For early stage intrahepatic bile duct cancer less than 3 cm, ablative therapy can achieve comparable effect with surgical resection, and patients have better prognosis and significantly prolonged survival. For patients with large tumor load or multiple tumors, interventional therapy can be performed to embolize the blood vessels of the tumor and inject chemotherapeutic drugs into the tumor vessels to improve the treatment efficiency and slow down the development of the disease. 5.Radiotherapy For patients with combined lymph node metastasis, bone metastasis or lung metastasis, radiotherapy for local metastatic lesions on the basis of systemic treatment (such as chemotherapy and targeted immunotherapy) can achieve better results, especially for patients with bone metastasis, which can relieve the pain caused by bone metastasis and prevent pathological fracture or nerve compression in the future. Summary The treatment of inoperable advanced cholangiocarcinoma is currently based on a combination of chemotherapy, targeted immunotherapy and local therapy. Although patients with cholangiocarcinoma have a poor prognosis, aggressive combination therapy can still improve the quality of life and prolong survival time.