Gallbladder cancer is one of the common malignant tumors in gastrointestinal tract, accounting for 8.5% of gastrointestinal tract cancers, ranking fifth or sixth, and its incidence is increasing year by year. Since there is no specific clinical manifestation of gallbladder cancer, patients with gallbladder cancer often have no special symptoms in the early stage, and most of the gallbladder cancers found clinically are in the middle and late stages and progress rapidly, with high misdiagnosis rate, low radical resection rate and poor prognosis. The 5-year survival rate of gallbladder cancer in Europe and America is only 5%-13% after surgery, and the 5-year survival rate of curative resection in Japan is only 26.4% according to the survey of the Japanese Society of Biliary Surgery. In this paper, we discuss and study the feasibility and importance of chemotherapy treatment and other comprehensive adjuvant treatment methods for gallbladder cancer. Current status of chemotherapy for gallbladder cancer Gallbladder cancer is a malignant disease with short survival period, high mortality rate and very difficult treatment. At present, the overall treatment level of gallbladder cancer is not satisfactory, and the 5-year survival rate is less than 5%, mainly because of the delay in diagnosis, and patients with early lesions can survive for a long time after treatment. Although there is still no specific theoretical basis to prove the chemotherapy regimen that can effectively treat gallbladder cancer. However, for patients with intermediate and advanced stages of gallbladder cancer, especially for those who cannot be cured by surgery, chemotherapy can prolong patients’ survival time and improve their quality of life. The main chemotherapeutic drugs in clinical use at this stage are alkylating agents, biomodulators, antimetabolites, botanicals, hormones and so on. Combination chemotherapy based on fluorouracil Fluorouracil (fluorouracil, 5-FU, 5-fluorouracil) has been recognized as an important drug for the treatment of gastrointestinal tumors, inhibiting thymine synthase, blocking DNA synthesis, and even causing abnormalities in RNA at high concentrations. Adriamycin (doxorubicin, Doxorubicin) acts on topoisomerase, truncating DNA strands or inserting directly between DNA nucleobase pairs to affect the transcription process by blocking mRNA synthesis. Mitomycin (MMC) is a cell cycle non-specific drug that depolymerizes DNA and blocks DNA replication. According to relevant statistics, the single-agent response rate of fluorouracil in the treatment of gastric, colorectal and esophageal cancers is about 20%, and the median effective response period is about 6 months. The efficiency and patient survival rates of single-agent chemotherapy are often inferior to those of combination chemotherapy, and a common combination chemotherapy regimen is the FAM regimen (5-FU, doxorubicin and mitomycin C). The literature on fluorouracil-based combination chemotherapy regimens has been extensive in recent decades, and their experimental approaches as well as findings vary widely. Some reports suggest that fluorouracil-based FAM regimens have promising results for gallbladder cancer, with remission rates of more than 30%. In a multicenter study by Takada et al, a FAM regimen of 5-FU 200 mg/m2, doxorubicin 15 mg/m2, and mitomycin C 15 mg/m 2 was administered to 42 patients and showed a 50% control rate of gallbladder cancer in the FAM chemotherapy group. In addition, a report on a prospective randomized controlled study of 112 patients with stage II-IV surgically resected gallbladder cancer, 69 of whom were treated with 5-fluorouracil and MMC chemotherapy and 43 of whom received surgery only as a control, showed a significantly higher 5-year survival rate of 26% in the FAM chemotherapy group compared with 14.4% in the control group (P=0.0367). -Puhalla also suggested that postoperative chemotherapy with a combination of 5 fluorouracil, mitomycin, and formyl tetrahydrofolate may also prolong postoperative survival in patients with intermediate to advanced gallbladder cancer. In a retrospective analysis of 21 patients with gallbladder cancer who were treated with external beam radiation therapy (EBRT) and 5-fluorouracil chemotherapy after surgical resection, Kresl showed that Patients with gallbladder cancer who underwent radical resection followed by extracorporeal radiotherapy and chemotherapy had a 5-year survival rate of 64%, which was significantly higher than the 5-year survival rate of those patients who underwent surgery only (33%). Combination chemotherapy based on gemcitabine and platinum Gemcitabine (gemcitabine) is a representative of the newer antitumor drugs, which are cell cycle-specific antimetabolites that inhibit ribonucleotide reductase, bind DNA competitively with deoxycytidine triphosphate, and are useful in a variety of solid tumors, including pancreatic tumors and non-small cell non-cancer. Cisplatin (cisplatin) is a cell cycle non-specific drug that inhibits the DNA replication process in cancer cells. At the same time, the RNA in telomeres and telomerase is rich in this AG repeat sequence, so it is thought that the telomere site may be one of the targets for cisplatin to act. Cisplatin is often used in combination with 5-fluorouracil and gemcitabine, which have strong broad-spectrum anticancer effects. Castro et al. treated 5 patients with gemcitabine alone and 3 of them were in remission, with remission rate up to 60% and overall survival of 6.3-16 months.Castro et al. treated gallbladder cancer with the combination of gemcitabine and other drugs and the results showed that the 5-year survival rate of patients was also considerable. Verderame treated four patients with gemcitabine 1g/m2 on days 1,8,15 and found that three of them were stable and one had a partial response after three courses of treatment, and all patients had pain relief and a median period of progression of 10.7 months. The adverse effects of gemcitabine, mainly myelosuppression, skin mucosal reactions and peripheral edema, were minor and of short duration and generally resolved with routine treatment. malik et al. treated 11 patients with gallbladder cancer with gemcitabine and cisplatin (GP regimen), of which 8 were given gemcitabine plus cisplatin and 3 were given gemcitabine alone, and showed that 1 case (9%) Misra et al. reported a 55% overall effectiveness of the gemcitabine plus cisplatin regimen in the treatment of advanced gallbladder cancer. The GERCOR research center in France treated 46 patients with biliary tumors with oxaliplatin plus gemcitabine (GEMOX) regimen, and the results of the study showed that the GEMOX regimen was effective and well tolerated in the treatment of biliary tumors. Since 1995, CEF (Cisplatin+Epirubicin+5-FU) combination chemotherapy regimen has been confirmed by many clinical trials at home and abroad, which has a considerable response rate (19%-50%) and prolonged median survival time (2.7-9.0 months) for chemotherapy of intermediate to advanced gallbladder cancer, and the feasibility of CEF regimen has been reported to various degrees. Furuse et al. reported on a multicenter, phase II trial conducted by the National Cancer Center, Kanagawa Cancer Center, and Aichi Cancer Center Hospital to evaluate the efficacy and safety of S-1 (tegeo) in 40 patients with intermediate to advanced bile duct cancer. The lower 95% confidence interval (C.I.) was 20% higher than the expected response rate, which was 20% according to JSCT criteria. In addition, the design of this multicenter, phase II trial study also allowed for an assessment of S-1 effectiveness according to RECIST criteria. The results showed that 1 patient achieved CR (complete remission) and 12 patients achieved PR (partial remission), for a response rate of 32.5% (95% C.I., 18.6-49.1%). Although one patient achieved PR according to JSCT criteria and SD (stable disease) according to RECIST criteria, the high concordance between the 35% response rate achieved according to JSCT criteria and the 32.5% response rate achieved according to RECIST criteria reinforces the high effectiveness of S-1 in patients with intermediate to advanced gallbladder cancer. In addition, Lubner SJ et al. reported on a multicenter, phase II trial conducted by the Karmanos Cancer Institute in Detroit, the National University Hospital of Singapore, the Royal Prince Alfred Hospital in Sydney, and the Sir Charles Gairdner Hospital in Perth, in which the response of 49 patients with unresectable cholangiocarcinoma of the gallbladder was evaluated by the combination of bevacizumab (every two weeks) and erlotinib (once daily) The combination of bevacizumab and erlotinib (daily) was used to evaluate the response and safety of 49 patients with unresectable bile duct cancer. According to RECIST criteria, 6 of 49 patients (12%) achieved CR or PR (95% C.I., 6-27%), 25 (51%) achieved SD status, with few grade III and IV toxicities (4), mainly rash, and a median overall survival (OS) of 9.9 months and median time to progression (TTP) of 4.4 months. All these demonstrate the high efficacy and safety of bevacizumab and erlotinib combination chemotherapy in patients with gallbladder cancer. Nevertheless, there is still a lack of large randomized controlled studies on chemotherapy for advanced gallbladder cancer at home and abroad, and there are few multicenter and large sample clinical studies on chemotherapy for biliary tract malignancies internationally. The multicenter clinical trial was held in Changchun. This multicenter clinical trial used growth inhibitor combined with conventional chemotherapy regimen (5-FU/EPI/CP/LV). Based on the current severe clinical background, this clinical trial was highlighted in the meeting, and the solid in vivo and in vitro trials conducted by our general surgery team some time ago were fully recognized. During the meeting, experts from 31 clinical centers across China had a lively discussion on chemotherapy regimens, enrollment criteria and evaluation criteria. They actively interacted with our research team, discussed and exchanged in-depth on the corresponding contents, and further improved this new protocol. The meeting finally decided to enroll 260 patients with advanced gallbladder cancer in 31 clinical centers across China from 2010 to 2011, using a randomized controlled approach to provide a credible evidence-based basis for clinical application. New technologies and methods for the treatment of gallbladder cancer Since radical surgery is highly traumatic, with many complications, poor prognosis and high mortality, and there is no recognized chemotherapy regimen that can effectively control gallbladder cancer, comprehensive adjuvant therapy, with decades of experience, plays an important role in improving patients’ condition, prolonging their survival time and improving their survival quality, and is an inevitable choice based on today’s basic research and clinical treatment. It is an inevitable choice based on the level of basic research and clinical treatment today. On the basis of various imaging and pathological diagnoses, adjuvant therapy is an important part of improving the efficiency and remission rate. Currently, the main adjuvant treatments are: selective perfusion chemotherapy, embolization chemotherapy, systemic thermotherapy, immunotherapy, Chinese medicine treatment, and gene therapy and photodynamic therapy (PDT), which are still under further research. Selective perfusion chemotherapy In recent years, some experts and scholars have proposed many new solutions to the treatment of gallbladder cancer, which have been quite effective through scientific experiments and clinical treatment, among which the more common one is selective perfusion chemotherapy, especially for those patients with suspected liver metastasis or residual tumor during surgery, regional arterial perfusion chemotherapy is currently the most used. The remission rate and efficiency of arterial infusion chemotherapy are higher than those of systemic chemotherapy. (4) for unresectable gallbladder cancer patients, arterial perfusion therapy can effectively inhibit tumor growth, improve patients’ systemic symptoms, prolong patients’ survival and improve their survival quality; (6) compared with systemic chemotherapy, it has less toxic side effects. Regional perfusion chemotherapy is mostly chosen for hepatic artery perfusion. Cantory et al. used cisplatin, epirubicin and 5-fluorouracil to administer hepatic artery perfusion chemotherapy to 30 patients with unresectable gallbladder and bile duct cancer, and the results showed that the efficiency was 40%, the 1-year survival rate was 54%, and the 2-year survival rate was 20%, and the occurrence of adverse reactions and toxic side effects were mild. Selective embolization therapy Since the growth of tumor depends on the formation of tumor neovascularization, the blood supply of tumor can be blocked by embolizing the blood supply artery of tumor, resulting in tumor ischemia and hypoxia, to achieve the purpose of inhibiting tumor growth and promoting tumor cell necrosis and apoptosis. Several embolic agents are commonly used in clinical practice, such as gelatin sponge, iodine oil emulsion, etc. Each embolic agent has its own advantages as well as shortcomings. Considering the different nature of the lesion, the different embolization sites and the differences in the size of embolized vessels and collateral circulation, the choice of embolic agents needs to be more careful. At present, the more widely used procedure is percutaneous modified Seldingers femoral artery puncture, in which a catheter is placed into the target artery of the corresponding organ tumor and the appropriate embolic agent is selected for injection. Clinically, for patients with advanced gallbladder cancer, due to their susceptibility to liver metastasis, selective hepatic artery placement chemoembolization (TACE) is performed, with mitomycin (MMC), epiaminomycin (EADM) and 5-fluorouracil (5-FU) selected as the chemotherapeutic agents, and 400g/L iodized oil 10mL-20mL and gelatin sponge particles are used as the embolic agent. It allows its particles to fully enter into the capillary bed of liver, which plays the role of local chemotherapy and temporarily blocking the tumor diffusion pathway. The treatment efficiency of primary foci of gallbladder cancer is 72%, which provides a feasible treatment pathway for patients with unresectable mid- to late-stage gallbladder cancer with liver metastasis. Whole-body warming therapy Surgical treatment of gallbladder cancer, radiotherapy and chemotherapy all have deficiencies and shortcomings to a certain extent, which can reduce the whole body resistance of patients to different degrees, thus affecting their prognosis. Therefore, therapies such as thermo-therapy and immunotherapy, which are combined with radiotherapy and chemotherapy, have been developed to a certain extent. In recent years, the rapid development of science and technology has provided clinicians with the possibility of using thermotherapy to treat malignant tumors. A lot of experimental data shows that when the temperature is maintained at 43℃, it can cause damage to most tumor cells and inhibit their proliferation, while ensuring that normal cells and tissue proteins are not damaged. acts on the immune system to increase the immunity of the body. The effect of heat therapy alone is often unsatisfactory. Currently, heat therapy is mostly used in combination with radiotherapy and chemotherapy, such as intraperitoneal thermal perfusion (IPHP), in which the anticancer agent mitomycin (MMC) is added to the perfusate to improve the anticancer effect. Recently, a hospital in Japan treated patients with biliary tract malignancies by combining heat therapy with radiotherapy, and the results showed that the efficiency could reach 50%. Therefore, as a means of treating malignant tumors without adverse effects and with high efficiency, warm heat therapy plays its unique anti-cancer role and is used in combination with surgical treatment, radiotherapy and chemotherapy for the comprehensive treatment of patients with gallbladder malignant tumors. Immunotherapy As a part of biological treatment, immunotherapy has a strong effect on killing tumor cells, consolidating treatment effect, preventing, delaying and reducing cancer recurrence and metastasis by increasing the number of immune cells and improving the immunity of the body. At the same time, the rejection reaction and toxic side effects of immunotherapy are relatively weak, which is generally applicable to most patients. At present, biological immunotherapy for cancer mainly includes: non-specific immune enhancers, infusion of various lymphokines and anti-tumor antibodies, non-specific secondary immunotherapy, and tumor immune vaccines. According to current domestic and foreign research, dendritic cell (DC) vaccines and cytokine induced killing of cancer cells are more effective and have a broader application prospect. In recent years, DC cells have become a hot spot of attention in the field of biotherapeutics today. In the beginning of this century, vaccine regimens accounted for more than 30% of the clinical experience in biologic therapy in the United States, among which DC vaccines are considered to have high research value and therapeutic effects. Zhang Kun et al. reported that the fusion of DC with gastric cancer cells SGC7901 slowed down the growth of tumor and inhibited the division and proliferation of tumor cells. Zhu Liming et al. single-collected peripheral blood mononuclear cells from patients to grow DCs in vitro, made DC vaccine after sensitization with antigen, and then infused back into patients to treat various types of advanced malignant tumors, and the results showed that patients tolerated well and the clinical treatment effectiveness was high. In addition, IL-2 was one of the first cytokines studied for tumor over-the-top immunotherapy. IL-2 promotes the proliferation of CTL and NK cells that kill tumor cells while promoting the proliferation of T cells. Although IL-2 can play a role in elevating CD3+ cells in in vitro experiments, the effect in clinical application is not satisfactory, which is related to the low local concentration of IL-2 in tumors. The combined application of arterial perfusion and immunotherapy (IFN/IL-2) to unresectable gastrointestinal tumors by He Jianmiao et al. allows chemotherapeutic drugs and immune agents to reach higher concentrations locally in the tumor, which can improve the therapeutic effect. However, it should not be overlooked that the application of high-dose IL-2 for immunotherapy to improve the response rate of tumor treatment has not been accompanied by a significant improvement in its overall survival rate, and there is a risk of causing serious autoimmune disease. Herbal therapy Many of the chemotherapeutic agents used in the treatment of gallbladder cancer are of natural origin, or derived from synthetic drugs. These drugs are often applied in combination in different strengths, with increased efficacy as the dose of the drug increases, and also with the potential to overcome to some extent the resistance of malignant tumor cells. At the same time, the increase of chemotherapy drug dose will inevitably lead to the increase of adverse reactions as well as drug resistance, and chemotherapy drugs will become insensitive to gallbladder cancer. To reduce the side effects of chemotherapy and improve the therapeutic effect, we can combine chemotherapy with adjuvant therapy of traditional Chinese medicine, which can directly inhibit the proliferation of cancer cells, induce apoptosis and differentiation of cancer cells, and at the same time reduce the toxic side effects of chemotherapy drugs and improve the immunity of the body, so that patients can tolerate the treatment and improve their quality of life. In the 1960s, it was recognized that ginseng has certain inhibitory effect on certain malignant tumors. After a lot of research, it was proved that the active component of ginseng’s anti-tumor effect is ginsenoside (GS), and more than 40 kinds of ginsenoside monomer components have been isolated. It was found that ginsenosides can promote apoptosis and inhibit proliferation of tumor cells. The effect of GS-Rg3 on the growth inhibition rate of human hepatocellular carcinoma cells (SMMC-721) was analyzed by MTT method, and the morphological characteristics of apoptosis were observed by electron microscopy. anti-tumor drug. In addition, ginsenoside-Rg3 also inhibited tumor cell adhesion, invasion and metastasis. Experimental studies on the effect of GS-Rg3 on the intracellular Ca2+ concentration of ascites liver tumor cells MM1 showed that the addition of lysolecithin to the cell suspension immediately increased the intracellular Ca2+ concentration; however, when MM1 cells were pretreated with GS-Rg3, the peak Ca2+ concentration caused by lysolecithin disappeared. Thus, GS-Rg3 inhibited the monolayer cell infiltration of cancer cells by dose-dependently inhibiting the rise of intracellular Ca2+ caused by LPA. In addition to ginsenosides, there are many herbal medicines that exhibit strong antitumor effects. Telomerase has reverse transcriptase activity and is generally difficult to find in normally differentiated somatic cells. However, for the majority of tumor cells, telomerase can be reactivated under appropriate conditions, causing most tumor cells to replicate and proliferate, leading to cell immortalization. Sun et al. used allicin on human gastric cancer SGC-7901 cells and showed that telomerase activity was inhibited and apoptotic cell necrosis occurred. Gene therapy With the rapid development of molecular biology research, gene therapy for tumors is gradually developing as a new means of tumor treatment. In recent years, gene therapy has also conducted some relevant researches in the treatment of biliary tract malignant tumors, such as oncogene therapy and suicide gene combined with radiation therapy, which are expected to bring new development and breakthrough in the treatment of biliary tract tumors. Some studies have shown that p53 and p16 gene mutations exist in biliary tract malignant tumors, so the corresponding tumor cells can be transfected with p53 and p16 oncogenes to inhibit tumor proliferation and induce tumor apoptosis. Huang et al. used nude mice subcutaneously transplanted with human cholangiocarcinoma QBC939 cells and applied the combination by injecting recombinant adenovirus Ad-P16 into the tumor cells, followed immediately by subperitoneal injection of cisplatin. The results showed that the combined application of the two resulted in significantly higher tumor growth inhibition (62.6%) than that of the control group treated alone (30% and 41%), indicating that the p16 gene could increase the sensitivity of QBC939 cells to cisplatin. Oncogenes not only reduce the amount of chemotherapeutic drugs and alleviate toxic side effects, but also increase the sensitivity to chemotherapeutic drugs, which is a more effective approach in gene therapy for biliary tract malignancies. Some studies have shown that targeted therapy can be performed by pharmacogenetic transfer of an exogenous gene from a retroviral vector into the cell with varying degrees of radiotherapy. Viral vectors with this gene are expressed only in specific tissues or tumor cells and not in normal cells. The main genes commonly used are the thymidine deoxynucleotide (TK) gene and the cytosine deoxygenase (CD) gene. For example, cytosine deaminase converts the harmless 5-fluorocytosine (5-FC) into the cytotoxic 5-fluorocytosine. Pederson et al. introduced an adenoviral vector carrying the CD gene into the cholangiocarcinoma cell line SK-chA-1, along with 5-FC. The results showed that it was effective in treating patients with cholangiocarcinoma. Sikora et al. designed a “chimeric minigene” by linking an enzyme gene downstream of the promoter of the erbB2 gene, which enhances the promoter activity of erbB2 in breast cancer cells. The enhanced promoter activity can lead to overexpression of erbB2 in breast cancer cells. At this point, the drug 5-FC is injected into the cells and transformed into 5-FU, which inhibits DNA and RNA synthesis and causes tumor cell death. When 5-FC was given to cells containing this chimeric gene but without erbB2 expression, there was no drug precursor activity at this time either. This new strategy of gene therapy is adopted for different diseases such as tumors. Currently, the main issues in the field of gene therapy are efficacy and safety. Scientists involved in the field of gene therapy worldwide are constantly working on improving gene introduction systems and vectors, and new ideas, techniques and methods are emerging. With the progress and completion of the Human Genome Project, the discovery and isolation of new locus control regions, specific promoters, isolators, introns, enhancers, etc. will certainly drive gene therapy forward. Photodynamic therapy As a new technology for tumor treatment, photodynamic therapy has been approved by governmental drug authorities in many developed countries such as Europe and America, and has become a new conventional treatment in more and more hospitals, with deepening clinical applications. In the past 20 years, photosensitive drugs have been used in photodynamic clinical treatment, and tens of thousands of patients have been treated in the world, including malignant tumors of various histological types in almost all parts of the human body. Chen Huohui et al. treated 117 patients with dysphagia symptoms with PDT. The photosensitizer Photofrin was slowly injected intravenously before treatment, and the tumor was irradiated with red light laser of wavelength 630 nm under gastroscopy 36-48 h later. The results of clinical efficacy evaluation were 16 cases of healing, 73 cases of significant effect, 21 cases of progression and 7 cases of ineffectiveness. Shang Liqun et al. compared the responsiveness of drug-resistant and non-drug-resistant lung cancer cell lines to rhodopsin-photodynamic therapy, and whether there was any difference between the responsiveness of drug-resistant tumor cells to rhodopsin-photodynamic therapy and chemotherapy drugs. It was found that there was no significant difference in the phototoxic effect of dextran-photodynamic therapy on drug-resistant and non-drug-resistant cells, and that dextran-photodynamic therapy had a significant phototoxic effect on drug-resistant tumor cells, and its effect on killing cisplatin-resistant tumor cells was significantly better than that of chemotherapeutic drugs that had developed resistance. This study also suggests that photodynamic therapy with photosensitizing drugs may open a new pathway for the treatment of drug-resistant tumors. In a study by J. Fang et al. demonstrating the clinical efficacy and safety of the novel photosensitizer CDHS 801, it was found that the tumor necrophage rate and area were significantly higher in the 27 case treatment group than in the control group.