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OBJECTIVE To evaluate the cost-effectiveness of pembrolizumab combined with chemotherapy versus placebo combined with chemotherapy in the first-line treatment of advanced or unresectable biliary tract carcinoma （BTC） from the perspective of China’s health system. METHODS A partitioned survival model was constructed based on the KEYNOTE-966 study data. The simulation period was 21 days， and the simulation time was the patient’s whole life. Using quality-adjusted life year （QALY） as the output indicator， the cost-utility analysis method was used to evaluate the cost-effectiveness of the two schemes mentioned above. Univariate and probabilistic sensitivity analyses were performed to verify the results of the basic analysis， and to explore the cost-effectiveness under the scenario of drug donation scheme. RESULTS The basic analysis showed that both the cost and effectiveness of the pembrolizumab group were higher than those of the placebo group， and the incremental cost-effectiveness ratio （ICER） was 3 909 359.78 yuan/QALY， which was higher than the willingness-to-pay （WTP） threshold of 3 times 2022 gross domestic product （GDP） per capita （257 094 yuan）， indicating no cost-effectiveness. The results of univariate sensitivity analysis showed that the utility discount rate， the utility value of progression-free survival （PFS） status， the cost discount rate， and the cost of pembrolizumab had a great influence on ICER. Probabilistic sensitivity analysis verified the robustness of the results of basic analysis， and concluded that when the WTP threshold was greater than 1 500 000 yuan/QALY， the pembrolizumab group became cost-effective. The results of the scenario analysis showed that considering the drug donation scheme of pembrolizumab for low-income people， although its treatment cost was significantly reduced， it was still not cost-effective. CONCLUSIONS At the WTP threshold of 3 times China’s GDP per capita in 2022， pembrolizumab combined with chemotherapy is not cost-effective compared with placebo combined with chemotherapy for advanced or unresectable BTC.
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Background: Biliary tract carcinoma is highly fatal and one of the commonest cancers in Bangladesh. Chemotherapy is the mainstay of treatment as it is present in an advanced stage. Gemcitabine-Cisplatin association has been a standard of care for first-line regimens in advanced biliary tract cancer. Nevertheless, the Gemcitabine-Oxaliplatin regimen is frequently preferred. There has been no nationwide study to compare the effectiveness of these two platinum groups. Therefore, this study compared the efficacy and toxicities of Gemcitabine-Cisplatin (Gem-Cis) with Gemcitabine-Oxaliplatin (GEMOX) combination chemotherapy for the treatment of ABTC.Material & Methods:In this quasi-experimental study, a total number of eighty patients (40 patients in arm A and 40 patients in arm B), who had histopathologically or cytopathological proven ABTC with no history of previous treatment were included. The study has done between the periods of January 2019 to June 2020. The patients received Gemcitabine (1000 mg/m2 i.v. on day 1 and day 8) plus Cisplatin (25 mg/m2 i.v. on day 1 and 8) every 3 weeks for 6 cycles in Arm A. In another group, Gemcitabine (1000 mg/m2 i.v. on day 1) plus Oxaliplatin (100 mg/m2 i.v. on day 2) every 2 weeks for 6 cycles in Arm B was given. All the patients were followed up according to the set follow-up criteria up to 6 weeks after completion of treatment.Results:At the end of the treatment, Response rates (CR+PR+SD) were analyzed. No patient from both the arms showed Complete Response (CR). 37.5% and 45% of patients of the Arm A and Arm B groups showed Partial Response (PR) respectively. Meanwhile, 45% and 40% of patients from Arm A and B showed Stable Disease (SD) respectively. P-value was 0.410 (>0.05). Seven patients (17%) in Arm A and six patients (15%) in Arm B developed Progressive disease (PD). The most common treatment-related grade 3 toxicities were more experienced in the Arm A group. For Arm A versus Arm B that were as follows: neutropenia (15% versus 5%), anemia (15% versus 8%), thrombocytopenia (10% versus 2.5%), nausea (10% versus 5%), vomiting (5%versus 2.5%), peripheral neuropathy (0% versus 15%) and renal toxicity (7.5% versus 0%). For none of them, the p-value was <0.05 except for neutropenia, anemia, thrombocytopenia, renal toxicity, and peripheral neuropathy in which the p-value was 0.042, 0.001, 0.014, 0.0001, and 0.00001 respectively. For both Arms, there were no treatment-related Grade 4 toxicities.Conclusion:The study exhibited that treatment with the Gemcitabine-Oxaliplatin regimen was well tolerated, less toxic, and convenient with similar effectiveness compared to the Gemcitabine-Cisplatin regimen in loco regional control of advanced biliary tract cancer.
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Background: Biliary tract carcinoma is highly fatal and one of the commonest cancers in Bangladesh. Chemotherapy is the mainstay of treatment as it is present in an advanced stage. Gemcitabine-Cisplatin association has been a standard of care for first-line regimens in advanced biliary tract cancer. Nevertheless, the Gemcitabine-Oxaliplatin regimen is frequently preferred. There has been no nationwide study to compare the effectiveness of these two platinum groups. Therefore, this study compared the efficacy and toxicities of Gemcitabine-Cisplatin (Gem-Cis) with Gemcitabine-Oxaliplatin (GEMOX) combination chemotherapy for the treatment of ABTC.Material & Methods:In this quasi-experimental study, a total number of eighty patients (40 patients in arm A and 40 patients in arm B), who had histopathologically or cytopathologically proven ABTC with no history of previous treatment were included. The study has done between the periods of January 2019 to June 2020. The patients received Gemcitabine (1000 mg/m2 i.v. on day 1 and day 8) plus Cisplatin (25 mg/m2i.v. on day 1 and 8) every 3 weeks for 6 cycles in Arm A. In another group, Gemcitabine (1000 mg/m2 i.v. on day 1) plus Oxaliplatin (100 mg/m2 i.v. on day 2) every 2 weeks for 6 cycles in Arm B was given. All the patients were followed up according to the set follow-up criteria up to 6 weeks after completion of treatment.Results:At the end of the treatment, Response rates (CR+PR+SD) were analyzed. No patient from both the arms showed Complete Response (CR). 37.5% and 45% of patients of the Arm A and Arm B groups showed Partial Response (PR) respectively. Meanwhile, 45% and 40% of patients from Arm A and B showed Stable Disease (SD) respectively. P-value was 0.410 (>0.05). Seven patients (17%) in Arm A and six patients (15%) in Arm B developed Progressive disease (PD). The most common treatment-related grade 3 toxicities were more experienced in the Arm A group. For Arm A versus Arm B that were as follows: neutropenia (15% versus 5%), anemia (15% versus 8%), thrombocytopenia (10% versus 2.5%), nausea (10% versus 5%), vomiting (5%versus 2.5%), peripheral neuropathy (0% versus 15%) and renal toxicity (7.5% versus 0%). For none of them, the p-value was <0.05 except for neutropenia, anemia, thrombocytopenia, renal toxicity, and peripheral neuropathy in which the p-value was 0.042, 0.001, 0.014, 0.0001, and 0.00001 respectively. For both Arms, there were no treatment-related Grade 4 toxicities.Conclusion:The study exhibited that treatment with Gemcitabine-Oxaliplatin regimen was well tolerated, less toxic, and convenient with similar effectiveness compared to Gemcitabine-Cisplatin regimen in loco regional control of advanced biliary tract cancer.
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Objective:To evaluate the efficacy of chemotherapy for advanced biliary tract carcinoma and the factors that influence sur-vival. Methods:A total of 91 cases of advanced biliary tract carcinoma from January 2010 to April 2015 were enrolled in our study. The patients' characteristics, chemotherapy regimens, and effects were analyzed. Results:We enrolled 56 males and 35 females with a me-dian age of 57 years. A total of 90 patients were assessable for their responses to first-line chemotherapy. A total of 69 patients re-ceived the GP regimen, whereas 21 patients received some other regimens. The disease control rate (DCR), median progression free survival (mPFS), and median overall survival (mOS) were 68.1%versus 52.4%, 5.10 months versus 2.50 months (P=0.025), and 13.00 months versus 7.20 months, respectively. Only 31 patients received S-1 based regimens, and 12 patients received some other regi-mens as second-line chemotherapy. The DCR, median PFS, and median OS showed no statistical differences. Only four patients re-ceived S-1 based regimen plus bevacizumab as second-line chemotherapy (median PFS 5.3 months;median OS 7 months). Hematologi-call toxicity was the most common side effect in the first-line GP regimen. The side effects of the S-1 based chemotherapy regimen was relatively less. Conclusion:The GP regimen is an effective first-line chemotherapy for advanced biliary tract carcinoma, whereas S-1 ap-pears as an effective second-line chemotherapy drug. Bevacizumab-based regimens may be effective and require further validation.
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Objective:To investigate and compare the effects of oxaliplatin combined with gemcitabine administered in a fixed dose rate and that administered in a more standard infusion in advanced biliary tract cancer patients on chemotherapeutic efficacy, toxicities, and survival time. Methods:A total of 93 cancer patients were recruited from February 1, 2010 to December 12, 2012 in the First Hospital of Huai'an City Affiliated Nanjing Medical College. Those recruited were either newly diagnosed unresectable advanced biliary tract cancer patients by percutaneous liver biopsy or relapse or metastatic biliary tract cancer patients after operation. The patients were randomly divided into two groups. The first group was the study group in which the patients received chemotherapy with gemcitabine in a fixed dose rate of 10 mg/m2 per minute combined with oxaliplatin regimens. The other group was the control group in which the patients received chemotherapy with gemcitabine in a more standardized infusion within 30 min combined with oxaliplatin regimens. Each patient received four cycles, with at least two cycles of chemotherapy with GEMOX regimens every 21 d, with follow-up until death. The chemotherapeutic efficacy was evaluated. Toxicities were documented after each cycle. Results:The clinical characteristics of the two groups were well balanced before chemotherapy (P>0.05). The response rate (RR) and clinical benefit response of the study group were higher than those of the control group (P0.05). Conclusion:Gemcitabine in a fixed dose rate combined with oxaliplatin regimens is a feasible and effective scheme in treating advanced biliary tract cancer patients. RR is higher and OS and TTP are longer under this scheme. Non-hematological toxicities are also well tolerated. However, hematological toxicity is distinguished. These results guide us to be prudent in utilizing this regimen. The investigation of the value of gemcitabine in a fixed dose rate combined with oxaliplatin in treating advanced biliary tract cancer patients is worth pursuing in future clinical trials.
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Objective:To evaluate the distribution of lymph nodes metastases(LNM) in upper and middle abdomen from primarybiliary tract carcinoma and the imaging features of metastatic lymph nodes on contrast spiral CT scanning.Methods:A retrospective study was performed,consisting of 41 cases of biliary tract carcinoma(24 cases of extrahepatic cholangiocarcinoma and 17 cases of gallbladder cancer),with upper and middle abdominal LNM identified by surgically and pathological procedure.All patients underwent CT scanning with intravenous contrast-enhancement on single-slice or 16-slice spiral CT.According to the LN location,upper and middle abdominal LN was classified as eight sites in this study as follows:porta hepatis,hepatoduodenal ligament,gastrohepatic ligament,gastrocolic ligament,gastrosplenic ligament,celiac,superior mesenteric and paraaortic area.Anatomic distribution and CT appearances of metastatic LN were observed.Results:(1)The incidence of LNM in each site from biliary tract carcinoma was:19.5%(8/41)in porta hepatis,90.2%(37/41)in hepatoduodenal ligament,22%(9/41)in gastrohepatic ligament,63.4%(26/41)in celiac,39%(16/41)in superior mesenteric and 48.8%(20/41) in paraaortic area respectively.Hepatoduodenal ligament lymphonode was the most common site of LNM from primary biliary tract carcinoma.The patients with gallbladder carcinoma had more LN sites involved than extrahepatic cholangiocarcinoma.(2)The MSAD(Maximum Short Axis Diameter)of metastatic LN varied from 1.4 to 4.8 cm.The density of most of metastatic nodes was hypoattenuation or iso-attenuation,and necrosis of metastatic LN was found in 69% sites and occurred more frequently in metastatic LN with MSAD ≥2.5 cm.Necrosis of metastatic LN could be categorized as 3 types:no obvious necrosis was found(type 1,31%);the volume of necrosis region was less than 1/2 in metastatic LN(type 2,24.1%);the volume of necrosis region was more than 1/2 in metastatic LN(type 3,44.8%).Conclusion:Distribution of LNM is determined by the lymphatic drainage route of biliary tract.The patients with gallbladder carcinoma have more LN sites involved than extrahepatic cholangiocarcinoma.Hypoattenuation or iso-attenuation compared with crura of diaphragm,heterogeneous enhancement,incomplete patterns of necrosis,is the image feature of upper and middle abdominal metastatic lymph nodes from biliary tract carcinoma on spiral CT scanning with bolus intravenous contrast-enhancement.
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Hypermethylation of the promoter region is an important mean for the transcriptional repression of a number of cancer-associated genes, and over-expression and/or increased activity of DNA methyltransferase are considered to be the main cause of promoter hypermethylation. In order to further explore the epigenetic mechanism of tumor suppressor gene RASSF1A inactivation,5-aza-2'-deoxycytidine (5-Aza-CdR), a DNA methyltransferase inhibitor, was used to treat the human biliary tract carcinoma cell line QBC-939 at the concentration of 5 μmol/L for 24 h in this study. After the chemical intervention with 5-Aza-CdR, the methylation status in the promoter region of RASSF1A gene was detected by methylation specific PCR (MS-PCR), and the expression alteration of RASSF1A mRNA and protein were observed by RT-PCR and Western Blot respectively. Following the treatment with 5-Aza-CdR, methylaiton status in the promoter region of RASSF1A gene was reversed from methylation to unmethylation. A 280 bp DNA band which represented RASS1FA expression at transcriptional level and a 40 kDa (1kDa=0.9921 ku) protein band which represented RASSF1A expression at protein level were detected by RT-PCR and Western Blot respectively in the experimental group cells and there were no corresponding bands in the control group cells. The experimental results suggest that 5-Aza-CdR can induce demethylation in the promoter region of RASSF1A. It can also reverse epigenetic transcriptional silencing caused by DNA methylation and induce the re-expression of RASSF1A in QBC-939. This study also suggest that the mechanism of RASSF1A inactivation is very closely related to the methylation of the promoter region, which may provide a new epigenetic understanding for tumor related gene inactivation and the pathogenesis of biliary tract carcinoma.
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Hypermethylation of the promoter region is one of the major mechanism of tumor suppressor gene inactivation. In order to provide a research tool for the study on the function of MBD1gene in DNA methylation and tumorigenesis, antisense MBD1 gene eukaryotic expression plasmid was constructed and transfected into human biliary tract carcinoma cell line QBC-939 to observe its effect on the expression of MBD1 mRNA and protein by using RT-PCR and FCM respectively. Following the transfection, the mRNA level of MBD1 gene decreased from 0. 912±0. 022 to 0. 215±0.017, and the protein level of MBD1 gene also decreased from (80.19±5.05) % to (35.11±4.05)%. There were very significant differences in the expression both at the transcription and post-transcription levels of MBD1 gene between non-tranfection group and the antisense MBD1 gene eukary otic expression plasmid transfection group (P＜0.01). It was suggested that transfection with the antisense MBD1 gene eukaryotic expression plasmid can significantly reduce the expression level of MBD1 gene in QBC-939, and this study may provide a valid tool for the investigation of the function of MBD1 gene and its role in biliary tract carcinoma.
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Carcinomas of the biliary tract are known to be more common in East Asia than in Western countries, but their exact histopathological characteristics and tumorigenesis are not well elucidated. To examine the histological and immunohistochemical characteristics of the biliary tract carcinomas according to their anatomical sites and to elucidate their tumorigenesis, we performed histological review and immunohistochemical study in a total of 135 cases of biliary tract carcinomas; 24 intrahepatic bile duct, 34 gallbladder, 51 common bile duct, and 26 periampullary carcinomas. Precancerous lesions were associated with 5 (20.8%) cases of intrahepatic duct carcinomas (dysplasia 5), 7 (20.6%) cases of gallbladder carcinomas (adenoma 5, dysplasia 2), 10 (19.6%) cases of common bile duct carcinomas (adenoma 7, dysplasia 3), and 2(7.7%)cases of periampullary carcinomas (adenoma 2). Immunohistochemically, c-erbB-2 expression in gallbladder carcinoma (21/34, 62%) was significantly higher than that of intrahepatic (8/24, 33%). Ki-67 indices were higher in common bile duct carcinomas (19%) than those of intrahepatic bile duct (14%) or periampullary carcinomas (12%). Overexpression of p53 gene product in the periampullary carcinomas (20/22, 77%) was higher than that of intrahepatic (12/24, 50%) or common bile duct carcinoma (26/51, 51%). In the precancerous lesions the c-erbB-2 expression was present in 29% of the gallbladder, 20% of the intrahepatic, 10% of the common bile duct precancerous lesions and none of the 2 cases of adenomas in the periampullary region. The p53 overexpression in the precancerous lesions was frequent, ranging from 43% to 60%. These results suggest that a mechanism involving p53 gene mutation and c-erbB-2 gene activation is present in the tumorigenesis in a significant number of the biliary tract carcinomas and they may be the early events in the tumorigenesis of the biliary tract carcinomas.
Subject(s)
Adenoma , Bile Ducts, Intrahepatic , Biliary Tract , Carcinogenesis , Common Bile Duct , Asia, Eastern , Gallbladder , Genes, erbB-2 , Genes, p53ABSTRACT
Objective To investigate the effects of the tumor suppressor gene PTEN in growing inhibition and down-regulating mTOR in cholangiocarcinoma QBC939 cells in vitro.Methods QBC939 cells were transfected with plasmids wild-type PTEN and C124S-PTEN in vitro.After transfection,the expression of the PTEN and phosphorylation of AKT and mTOR was detected by Western blot.Flow cytometry was used to analyze apoptosis and cell cycle of the transfected cells.Results Compared with the control,the expression of phosphorylation AKT was decreased and mTOR were down-regulated respectively when transfected with the wild-type PTEN.However,after transfection with mutation-type PTEN,the level of PTEN in the cells by increased,but phosphorylation AKT level and mTOR expression had no significant change.Conclusions PTEN can be actived by phosphorylated AKT.Actived AKT decreased the mTOR which led to tumor cells apoptosis and regulation of the tumor cell cycle.In the pathway of signal transmission of PI3K/AKT/PTEN/mTOR,PTEN and mTOR are closely related through phosphorylation of AKT.