Chemotherapy For Gallbladder Cancer Research Articles

Impact of ABCB1 and ABCG2 Transporter in Outcome of Gallbladder Cancer

BackgroundGallbladder cancer (GBC) is a biologically aggressive malignancy requiring appropriate biomarkers to improve its outcome. Role of ABC transporters (ABCB1 and ABCG2) has been linked to cancer aggressiveness, tumorigenesis and multidrug resistance. Herein, we studied the prognostic implication of ABCB1 and ABCG2 in GBC. MethodsFresh tissue (tumour & normal) samples collected from 54 patients who underwent R0 resection, were analysed for mRNA and protein expression of ABCB1 and ABCG2 by quantitative Real-Time PCR and western blotting respectively in this prospective study. The molecular findings were correlated with clinical-pathological parameters using χ2 and fisher exact test. The molecular changes in ABCB1 and ABCG2 was analysed for predicting overall survival (OS), disease free survival (DFS) and response to chemotherapy using Kaplan Meier log rank test and Cox regression multivariate analysis. ResultsThe mean age of the cohort was 50 ±13.2 with 26 (48.1%) patients had early stage gallbladder cancer (GBC). Overexpression of ABCB1 and ABCG2 was noted in 32/54(59%) and 40/54 (74%) cases respectively. The protein expression of ABCB1(P-glycoprotein) and ABCG2 (BCRP) was higher in 27/54 (50%) and 37/54 (59%) cases respectively. The mean OS and DFS was 20.7 ±11.5 and 19.3 ± 12.2 months at median follow up 24 months. The TNM stage, lymph node metastasis, and presence of gallstone were significant factors for predicting OS and DFS on multivariate analysis. Both ABCB1 and ABCG2 did not show any significant correlation with OS and DFS with similar incidence of late death and recurrence among over-expression and down-expression. Sub- group comparison suggests that change in expression pattern of ABCB1 and ABCG2 may not affect response to chemotherapy in GBC. ConclusionAltered expression of ABCB1 and ABCG2 may not be a useful prognostic marker for survival or response to chemotherapy in GBC. Presently, histo-pathological characteristics and associated gallstones are the important predictors for survival and recurrence in GBC.

Role of Peri-operative Chemotherapy in Stage II (pT2N0) Gallbladder Cancers

BackgroundEvidence for adjuvant chemotherapy in gallbladder cancer (GBC) is conflicting, with a postulated beneficial effect reported in T2 stage or higher, and node-positive tumours. This study aims to assess the survival benefit of peri-operative chemotherapy in stage II (pT2N0) GBCs. MethodsA retrospective analysis of stage II GBCs who underwent curative surgical resection was done. Patients receiving neo-adjuvant therapy (NACT) prior to resection of the gallbladder primary were excluded. Primary endpoint was disease-free survival, and outcomes of patients who received chemotherapy were compared to those who did not. Survival curves were plotted using a Kaplan–Meier analysis and difference between the survival curves was analysed using a log-rank test. ResultsTwo hundred seventy-six patients of stage II GBC were included, of whom 188 (68.1%) received chemotherapy and 88 (31.8%) did not. Forty-one (21.8%) patients received chemotherapy in the neo-adjuvant setting. There was no significant difference in the survival of patients who did and did not receive chemotherapy (5-year DFS 67.8% vs 66%, p = 0.795). There was no significant difference in the survival of patients who received chemotherapy in the adjuvant or neo-adjuvant setting (5-year DFS 66.4% vs 71.8%, p = 0.541). There was no statistically significant difference in the survival of patients with high-risk histologic features and who did and did not receive chemotherapy (3-year DFS 72.4% vs 56%; p = 0.379). ConclusionsRoutine use of chemotherapy, either in the adjuvant or neo-adjuvant setting, offers no survival advantage in stage II (pT2N0) gallbladder cancers.

Cytoreductive Surgery and HIPEC for Regionally Advanced Gallbladder Cancer: a Case Report

Gallbladder cancer is a rare cancer, associated with an extremely poor prognosis. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy is not commonly performed in gallbladder cancer; however, case series have shown prolonged survival time with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in gallbladder cancer and no increase in morbidity compared to cytoreductive surgery without hyperthermic intraperitoneal chemotherapy. We present a case of gallbladder cancer with peritoneal metastases in a 60-year-old male who was successfully treated with complete cytoreductive surgery and hyperthermic intraperitoneal chemotherapy and survived for 4 years following diagnosis.

Chemotherapy for gallbladder cancer

Chemotherapy for gallbladder cancer

Tumor location and concurrent liver resection, impact survival in T2 gallbladder cancer: a meta-analysis of the literature.

Aim of doing this review was to give a uniform consensus on prognostic impact of tumor location (hepatic vs peritoneal), liver resection and adjuvant chemotherapy in gall bladder cancer and, to compare them with previous well-studied factors of survival. We systematically review PubMed, Scopus and Cochrane for relevant articles with no date restrictions, language was restricted to English. Those articles were included that had provided Hazard ratio (HR) of survival for T2 gall bladder cancer. We identified nine retrospective studies published between 2014 and 2020 with 2345 patients. Meta-analysis showed that T2b (hepatic) cancers had higher odds of mortality (HR 3.16 [2.11, 4.74], I2 = 0%). Liver resection was associated with significantly higher odds of 5-year overall survival only in T2b (2.20 [1.33, 3.63], I2 = 67%), adjuvant chemotherapy was not associated with any significant decrease in mortality risk (0.98 [0.83-1.16]. I2 = 20%). Hepatic sided gall bladder tumors carry higher odds for mortality and recurrence. T2a tumors can be managed without hepatic resection. To risk stratify patients we also formulated a scoring system for mortality risk.

High infiltration of mast cells is associated with improved response to adjuvant chemotherapy in gallbladder cancer.

Recent studies have reported that tumor‐infiltrating mast cells (TIM) play an important role in tumor regression, but the effect of TIM in gallbladder cancer (GBC) remains unclear. The present study aims to investigate the prognostic value of TIM in GBC patients and its responsiveness to gemcitabine‐based adjuvant chemotherapy (ACT). A total of 298 GBC patients from Zhongshan Hospital were recruited for this study. TIM infiltration was measured by immunohistochemical staining. Accumulation of TIM is significantly associated with prolonged overall survival in GBC patients. The benefit from gemcitabine‐based ACT was superior among patients with high infiltration of TIM with GBC. Multivariate analysis identified TIM infiltration as an independent prognostic factor for overall survival. A heatmap showed that TIM‐activated gene signatures were positively correlated with CD8+ T cells' gene signatures. Gene set enrichment analysis (GSEA) suggested that TIM was related to multiple T cell‐related processes and signaling pathways, including the interferon gamma signaling pathway and the leukocyte migration signaling pathway. It was confirmed that CD8+ T cell infiltration was positively correlated with high TIM infiltration in tissue microarray (TMA), suggesting that TIM infiltration was linked to the immune surveillance in GBC. TIM can be used as an independent prognostic factor and a predictor of therapeutic response of gemcitabine‐based ACT in GBC patients, which may mediate immune surveillance by recruiting and activating CD8+ T cells in GBC.

Low immune index correlates with favorable prognosis but with reduced benefit from chemotherapy in gallbladder cancer.

Use of immune index is a new potential approach for cancer classification and prediction. To investigate the status and clinical effect of immune index in gallbladder cancer (GBC), 238 GBC patients from Zhongshan Hospital affiliated to Fudan University were involved in the present study, including 113 patients in a training set and 125 patients in a validation set. Five immune cells (macrophages, neutrophils, regulatory T cells, cytotoxic T cells and mast cells) were selected based on a literature review and the immune index for each patient was calculated using the LASSO regression. A low immune index (<1) was defined as immunotype A and a high immune index (≥1) was defined as immunotype B. The 5‐year overall survival rate for immunotype A was higher than that for immunotype B in the training set and the validation set (70.0% vs 37.0%, P < 0.001; 68.9% vs 47.5%, P = 0.002; respectively). Moreover, the immune index showed higher prediction efficiency compared with all the single immune cells which we selected. When combined with the immune index, the areas under the curve (AUC) of the TNM staging system in both sets were elevated from 0.677 to 0.787 and from 0.631 to 0.694, respectively. Interestingly, gemcitabine‐based chemotherapy only benefits stage II patients of immunotype B and stage III patients of both immunotype A and immunotype B (P = 0.015, P = 0.030, P = 0.011, respectively) but does not work in stage II patients of immunotype A (P = .307). Taken together, the immune index could effectively predict prognosis and the benefits of gemcitabine‐based chemotherapy and might improve on the TNM staging system.

Second-line chemotherapy for gallbladder cancer.

450 Background: The standard treatment for patients with gallbladder cancer is a combination of gemcitabine and cisplatin based on ABC-02 trial. However, there are no guidelines regarding treatment after first-line therapy. We retrospectively analyzed the efficacy and overall survival of different second-line regimens. Methods: We identified 203 patients with advanced gallbladder cancer who received palliative treatment between January 2000 and December 2015 at Mayo Clinic, Rochester. RECIST criteria was used to assess response. Results: 68 patients received second-line chemotherapy. Median age was 63 years (range: 32-86) and majority were males (60.6%). The median time from the diagnosis to the start of the second line chemotherapy was 8 (1-120) months. The most common used second-line chemotherapy were FOLFOX (14), gemcitabine alone (10), single agent fluoropyrimidine (11), gemcitabine with capecitabine (5), and capecitabine with oxaliplatin (4). There were 30 patients that received 5-fluorouracil based regimens, 20 patients received gemcitabine-based regimen, 3 patients received taxane-based regimen, and 15 patients received other types of chemotherapy. Median progression free survival and overall survival was 2.1 (1.8-2.7) and 16.7 (13.2-21.3) months respectively. There were 10 (52%), 11 (37%), 2 (67%), 5 (33%) with partial response and stable disease in 5-fluorouracil-based, gemcitabine-based, taxane-based, and others, respectively. There were no difference in PFS, with median PFS of 2.5, 2.0, 2.8 and 2.3 months, respectively (p=0.43). The overall survival were 15.7 (8.9-40.2), 15.0 (10.7-21.3), 40.3 (22.0-47.0), and 20.4 (9.2-30.7) months, respectively (p=0.83). There were 27 patients that received single agent chemotherapy and 41 patients that received combined regimen. There were 17 (42%) patients and 13 (48%) patients with partial response or stable disease in single and combined regimen. There were no differences in progression free survival and overall survival between single and multi agent chemotherapy. Conclusions: In this largest single institution study, second-line chemotherapy regimens for gallbladder cancer provided benefit in select patients and there is an urgent need to develop more active therapeutic regimens.

Neoadjuvant chemotherapy in gallbladder cancer – outcome of 112 patients from Tata Memorial Centre

Neoadjuvant chemotherapy in gallbladder cancer – outcome of 112 patients from Tata Memorial Centre

Neoadjuvant chemotherapy for gall bladder cancer: Does it increase resectability?

406 Background: Surgery is the treatment of choice for patients with carcinoma gall bladder patients (GBC). However, most of the patients are metastatic at the time of diagnosis with only a fraction of patients deemed non metastatic. Many are locally advanced either infilterating liver, orinvolving adjacent other organs. Studies with gemcitabine for metastatic biliary tract cancers have shown promising results. Extrapolating these results to locally advanced GBC might improve the outcomes in these otherwise poor risk patients. Methods: Patients with locally advanced GBC from January 2013 to June 2014 who were considered borderline resectable on cross sectional imaging were planned for preoperative gemcitabine based chemotherapy to downsize the tumor and make them resectable. Gemcitabine and cisplatin based chemotherapy was given to all these patients and evaluated after 3 cycles. Those who became resectable were taken up for surgery and rest were given additional three cycles of chemotherapy. Results: 840 patients of GBC were seen in the out patient department since January 2013. Of these, 40 patients with locally advanced GBC were considered for neoadjuvant chemotherapy (Gemcitabine and cisplatin). However, only 22 patients actually received neoadjuvant chemotherapy. Out of these 22 patients, 4 are still receiving chemotherapy. Of 18 patients who completed there chemotherapy schedule, 2 patients lost to follow up after receiving 3 cycles of chemotherapy. 15 patients (83.3%%) had good radiological response to chemotherapy and were advised surgery. One patient had no radiological response. 3 patients refused surgery inspite of good radiological response. 13 patients (including the patient who did not have radiological response) underwent surgery. Out of 13 patients, 4 patients had metastatic disease intraoperatively. 9 out of 16 patients (56.25%) underwent R0 resection. Conclusions: Best surgical outcomes are seen with those undergoing RO resection. Neoadjuvant chemotherapy can downsize the tumor in approximately 50% of the patients leading to R0 resection. Neoadjuvant chemotherapy should be considered in locally advanced GBC with the aim of increasing the resectablility in these patients.

Chemotherapy for gallbladder cancer

Chemotherapy for gallbladder cancer

Comprehensive management of gallbladder cancer

Gallbladder cancer is the most common malignancy of biliary tract with a very poor prognosis. The therapeutic strategy of gallbladder cancer has been improved in some aspects. Identifying the accurate stage is the basis of surgical treatment. Radical resection is the only choice of treatment which provides patients long survival. For most patients in T1a stage, simple cholecystectomy is adequate, but dissection of hepatoduodenal ligament should be added when the lesions located in neck and duct of gallbladder. Patients in T1b stage often need radical cholecystectomy. Radical cholecystectomy with Ⅳb and Ⅴ segmentectomy and lymphadenectomy of N2 nodes should be performed to patients in T2 stage. Extended right lobe resection can improve the prognosis of selected T3 and T4 patients.The effect of chemotherapy for gallbladder cancer remains unsatisfactory, and current chemotherapeutic regimens were based on 5-FU, gemcitabine or S-1. The effect of a new chemotherapeutic sensitization scheme with continuous infusion of somatostatin,epirubicin 5-FU/CF and cisplatin is under research, and the preliminary results are promising. Radiation shows some benefits to patients with gallbladder cancer, but its effects are still uncertain. Key words: Gallbladder neoplasms; Surgical treatment; Chemotherapy; Radiotherapy

The effect and safety of new chemotherapy regimen for advanced gallbladder carcinoma： an open multicenter randomized controled trial

Comprehensive therapy is the leading method to improve the overall survival for patients with advanced gallbladder cancer, especially the study of new chemotherapy regimen are on demand.From 2010 to 2011, a phase Ⅲ study of new chemotherapy regimen in the treatment of advanced gallbladder carcinoma would be undertaken nationwide to assess the clinical outcome and safety, in 31 clinical centers led by the department of General Surgery of Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, and a total of 260 patients would be accrued for this study.Chemotherapy consists of 2 regimes, conventional regime（cisplatin, epirubicin, and 5-fluorouracil, leucovorin）and new regime（conventional regime plus somatostatin）.At present, the study has been approved by Clinical Trial Registration Platform of National Institutes of Health in U.S.A., and more than 30 patients are rolling in the study.The clinical trial could provide the high-quality evidence of EBM（evdence based medicine）for the chemotherapy of advanced gallbladder caner, and it will be one of the important components in the large-scale clinical study of chemotherapy for the advanced gallbladder cancer in China and worldwide. Key words: Advanced gallbladder carcinoma; Chemotherapy regimen; Somatostatin

Genetic Alteration of Keap1 Confers Constitutive Nrf2 Activation and Resistance to Chemotherapy in Gallbladder Cancer

Biliary tract cancer (BTC) is a highly malignant tumor, and identification of effective therapeutic targets to improve prognosis is urgently required. Oncogenic activation of survival genes is important for cancer cells to overcome oxidative stresses induced by their microenvironments that include chronic inflammation or exposure to anticancer drugs. We attempted to examine whether deregulation of Nrf2, a master transcriptional factor of various cytoprotective genes against oxidative stress, plays a role in the carcinogenesis of BTC. We screened genetic alteration of Keap1, a negative regulator of Nrf2, in BTC including tumors originated from gallbladder and extra- and intrahepatic bile ducts. Functional analysis of cancer-related mutant Keap1 in Nrf2 repression and the association between Nrf2 activation and resistance to 5-fluorouracil (5-FU) were investigated. Recurrent (in 1/11 cell lines and 6/53 primary tumors) Keap1 gene alterations were observed in BTC and were especially frequent (4/13, 30.7%) in gallbladder cancer (GBC). These alterations led to a considerable loss of Nrf2 repression activity, caused constitutive activation of Nrf2, and promoted cell proliferation. Down-regulation of Nrf2 activity by either Keap1 complementation or Nrf2 short interference RNA increased sensitivity to 5-FU in Keap1-altered BTC cells. Keap1 mutation occurs frequently in GBC. Aberrant Nrf2 activation provoked by Keap1 alteration is one of the molecular mechanisms for chemotherapeutic resistance in GBC and will be a novel therapeutic target as an enhancer of sensitivity to 5-FU-based regimens.

Chemotherapy in gallbladder cancer: Improving survival

15140 Background: Since 1999 we had been studying the effect of chemotherapy in gallbladder cancer, a disease frequent in low economical income area of the world, orphan of research, traditionally considered chemotherapy-resistant. Previous studies included 5- FU regimen and communicated response rate of 10–26 %, and no changes on survival. We first conducted a phase II study with gemcitabine (Gem), and later, another study (with support of GOCCHI) using Gem and cisplatin (C). Since 2001 we had treated patients out of clinical trial. We compare median survival observed in all series. Methods: Patients file of both 2 phase II studies and clinical record of all patients treated out of clinical trial were retrieved and median survival was calculated. The both phase two trials had a similar population, and inclusion criteria, both were multicenters. The third cohort is a one center experience. The regimens used were: Gem 1,000 mg/m2 on days 1,8 and 15 every 28 days (first trial), Gem 1,250 mg/m2+C 35 mg/m2 on the 1 and 8 days every 21 days (second trial), only maximum 6 courses were planned. The third group, most frequently, received Gem 1.000 mg/m2 (10mg/m2/min)+C 40 mg/m2 days 1 and 8 every 21 days, until disease progression and/or toxicity; second line chemotherapy was allowed. Among whole group 7 pts, who had significant response, underwent a surgical resection. Survival was also calculated and comparison is included. The toxicity was evaluated every 2 weeks and response was assessed every two cycles using CT scan. Overall survival was calculated from beginning of chemotherapy until death or last follow up. Survival analysis was also done using Kaplan Meier’s tables Results: For Gem monotherapy (26 pts) median survival was 30 weeks, for Gem+C (44 pts) median survival was 28 weeks. For third group (29 pts) median survival was 56 weeks. Until now, for the 7 pts who underwent a surgical resection median survival is 92 weeks, with one pt alive, without evidence of disease, at 112 weeks of follow up Conclusions: Both regimens showed better efficacy than 5-FU based chemotherapy, the combination did not show better survival. The third group has better median survival, probable due to the use of second line therapies. Combining chemotherapy + surgical resection may be a better treatment for some few, well selected patients. No significant financial relationships to disclose.

Gallbladder cancer

Gallbladder cancer (GBC) is the most common malignancy of the biliary tract and the fifth most common gastrointestinal (GI) cancer. In addition to global inter-country variations in incidence, large racial and ethnic variations have been noted within countries. High incidence rates of GBC have been described in North India, for example. Despite the fact that the precise etiology of GBC is poorly understood, a strong association between GBC and cholelithiasis exists. Most GBC presents clinically as advanced disease with unfavorable prognosis and poor response to treatment. A small but increasing proportion of cases of incidental GBC detected during or after cholecystectomy is also being seen. Such patients are generally in an earlier stage of disease and are potentially more curable by a completion radical cholecystectomy, which is especially indicated for patients whose disease is stage pT1b or beyond. Radical surgery is the mainstay of curative intent treatment for GBC. When feasible, extended or radical cholecystectomy is the standard treatment for resectable GBC. Patients with advanced stage III or IV disease may undergo more complex, high-risk, and morbid extended resections such as hepatopancreaticoduodenectomy. We believe that these procedures should be performed only in selected patients at centers specializing in these resections. Patients not fit for such major resection or found unresectable on imaging or exploration are usually offered palliative treatment. This may be in the form of surgical palliation (eg, palliative bypass for gastric outlet, bowel, or biliary tract obstruction), endoscopic biliary stenting (for obstructive jaundice), or palliative chemotherapy. Chemotherapy for GBC is generally used in the palliative setting. Gemcitabine, cisplatin, 5-fluorouracil, mitomycin, and capecitabine are some of the effective agents. We have reported gratifying overall response rates of 55% with the combination of gemcitabine and cisplatin in patients with advanced GBC. Patients with advanced GBC and jaundice who undergo stenting followed by chemotherapy show response and survival rates similar to those who present without jaundice.

Population pharmacokinetic analysis of the microemulsion formulation of cyclosporin A (Neoral®) in renal transplant patients

Gallbladder cancer is an asymptomatic disease in the early stage and no therapeutic measure is available except surgical intervention. The prognosis for patients with advanced,i.e., unresectable or metastatic disease is dismal, with median survival usually being less than 6 months if not treated with chemotherapy. To date, chemotherapy for gallbladder cancer has been limited by the absence of agents with effective cytotoxic activity. Thalidomide has been shown to have antiangiogenic and immunomodulatory effects, including the inhibition of vascular endothelial growth factor, basic fibroblast growth factor and tumor necrosis factor alpha. Celecoxib is a potent selective COX-2 inhibitor. The reported biological consequences of COX-2 up-regulation include inhibition of apoptosis, increased metastatic potential and promotion of angiogenesis. These events may contribute to cell transformation and tumor progression. Antiangiogenesis represents a significant new strategy for cancer treatment. Therefore,it is important to accept a wide range of different inhibitors such as thalidomide and selective COX-2 inhibitors with conventional cytotoxic agents. Here we show a case of unresectable gallbladder cancer with remarkable improvement in CA19-9 and prolongation of life.

Chemotherapy for gallbladder cancer

Chemotherapy for gallbladder cancer

Combination with chemotherapy enhances efficacy of E1 double-mutant adnovirus for gene therapy of gallbladder cancer

Advanced gallbladder cancer (GBC) is one of the most difficult cancers to be cured by cmT~nt therapies and new treatments, such as gene therapy, are necessary, but little has been studied Recent studies have introduced E1B mntam adenoviruses fad) focusing on tmnor-specific replication, and clinical results have been promising. We have constructed AxdAdB-3, a E1 double-mutant Ad with a mutant EIA and E1B-55kD deletion and reported on its efficacy for GBC as well as enhanced safety m normal cells. ALMS: We aimed to study the combined effects of this Ad and chemotherapy with 5-fluoronracil (5-FU) on GBC in vivo, METHODS: We compared the replication and the cytopathic effects of AxdAdB-3 in several lines of GBC and prima~y normal cells with those of wild-t3~?e Ad The efficacy in vivo was examined in nude mice with subcataneously implanted or intraperitoneally disseminated GBC Mice were separated into the following groups; contrd, Ad monotherapy, 5-FU monotherapy, and combination therapy of Ad and 5-FU. Ad was intratumorally injected ~br subeutaneons xenografis and intraperitoneally injected for disseminated GBC with or wtdmut intraperitoneal injection of 5FU. RESULTS: Axcka-dB-3 replicated and caused oncolysis as efficient]y as wild-type Ad in several GBC cell lines, whereas it replicated much less effectively in normal cells and had only' a mild cytopathic eitect unlike wild-type Ad in vitro. Furthermore, cytotoxicity of Ax&a-dB-3 in normal cells was milder than AxE1AdB, a E1B55kD deleted Ad. AxdAdB-3 significantly suppressed the growth of subeutaneous GBC xenogmfis and also showed eft~:ctiveness in the treatment of peritoneaily disseminated GBC with significantly prolonged survival Combination therapy with 5-FU further regressed the subcutaneous GBC xenografts and significantly prolonged the survival of mice with disseminated GBC. CONCLUSIONS: E1 double-mntant Ad effectively and selectively replicated and caused oncolysis in GBC in vitro and in vivo with reduced negative eflects on normal cells, Combination therapy wifh 5-FU further enhanced its efficacy in vivo, suggesting a synergistic therapeutic effects of the virotherapy and chemotherapy for GBC.