Treatment Of Advanced Gallbladder Cancer Research Articles

Evolving Paradigms in the Systemic Treatment of Advanced Gallbladder Cancer: Updates in Year 2022.

Simple SummaryGallbladder cancer is distinct type of biliart tract cancer that is rare, aggressive and with limited treatment options aside from surgical resection. As of now in year 2022, systemic chemotherapy remains as the mainstay treatment option for patients with advanced staged gallbladder cancer. Despite decades of scientific research, new treatment options have been struggling to succeed. Furthermore, almost all clinical studies on gallbladder cancer have included other tyes of biliary tract cancers, raising the need to specifically inspect the outcomes of these clinical trial regimens on gallbladder cancer. In this article, we summarized all seminal literature and the most recent advances in scientific discoveries and clinical trials on gallbladder cancer. We provide a succinct update on current understanding, treatment landscape and therapeutic challenges in gallbladder cancer, as well as future prospects in the management of this disease.Gallbladder cancer (GBC) is a biological, anatomical, and clinically distinct subset of biliary tract cancers (BTC), which also include extra- and intra-hepatic cholangiocarcinoma. The advent of next-generation sequencing (NGS) clearly shows that GBC is genetically different from cholangiocarcinoma. Although GBC is a relatively rare cancer, it is highly aggressive and carries a grave prognosis. To date, complete surgical resection remains the only path for cure but is limited to patients with early-stage disease. The majority of the patients are diagnosed at an advanced, inoperable stage when systemic treatment is administered as an attempt to enable surgery or for palliation. Gemcitabine and platinum-based chemotherapies have been the main treatment modality for unresectable, locally advanced, and metastatic gallbladder cancer. However, over the past decade, the treatment paradigm has evolved. These include the introduction of newer chemotherapeutic strategies after progression on frontline chemotherapy, incorporation of targeted therapeutics towards driver mutations of genes including HER2, FGFR, BRAF, as well as approaches to unleash host anti-tumor immunity using immune checkpoint inhibitors. Notably, due to the rarity of BTC in general, most clinical trials included both GBC and cholangiocarcinomas. Here, we provide a review on the pathogenesis of GBC, past and current systemic treatment options focusing specifically on GBC, clinical trials tailored towards its genetic mutations, and emerging treatment strategies based on promising recent clinical studies.

Hepatic Arterial Infusion Chemotherapy with Oxaliplatin and 5-Fluorouracil for Advanced Gallbladder Cancer.

The aim of this study was to assess the safety and efficacy of hepatic arterial infusion chemotherapy (HAIC) with oxaliplatin and 5-fluorouracil for patients with advanced gallbladder cancer (GBC). Twenty-six patients with advanced GBC, who underwent HAIC with oxaliplatin and 5-fluorouracil from January 2012 to July 2019, were enrolled in this retrospective study. The HAIC regimen consisted of infusions of oxaliplatin at 40mg/m2 for 2h, followed by 5-fluorouracil at 800mg/m2 for 22h on days 1-3 every 3-4weeks. A maximum of six cycles of HAIC were applied for tumor control patients followed by maintenance with oral capecitabine or S-1. Overall survival (OS), progression-free survival (PFS), tumor response, and adverse events were investigated. Six of the 26 patients (23.1%) had failed systemic chemotherapy, 8/26 (30.8%) patients had failed various local therapies, and 9/26 (34.6%) patients had contraindications to systemic chemotherapy. The median OS was 13.5months, and the median PFS was 10.0months. The overall response rate was 69.2% (18/26), and disease control rate was 92.3% (24/26). Carcinoembryonic antigen (CEA) ≥ 10U/ml (p = 0.003) and carbohydrate antigen 19-9 (CA19-9) ≥ 200U/ml (p = 0.000) were independent risk factors for decreased survival. The most frequent Grade 3 or 4 treatment-related adverse event was liver dysfunction (4, 15.4%). HAIC with oxaliplatin and 5-fluorouracil is an acceptable and well-tolerated treatment for advanced gallbladder cancer even for patients in whom systemic chemotherapy had failed or is contraindicated. Level 2, Observation Study with Dramatic Effect.

Is combination chemotherapy of cisplatin and gemcitabine in the first-line treatment of advanced gallbladder cancer the right choice? A study in indian patients from the gangetic belt

Background: Owing to presentation at advanced stage, most of the time, gallbladder carcinoma is nonresectable. Nonsurgical palliative procedures such as stenting help in a limited number of patients. Although anecdotal Western data are present, combination chemotherapy data from Indian scenario are scanty. The present study was carried out with an aim to evaluate the response to first-line chemotherapy with cisplatin and gemcitabine in Indian patients with advanced gallbladder carcinoma. This observational study was conducted in the Departments of Oncology at the Army Command Hospital (Central Command), Lucknow, between April 2013 and May 2016. All patients presenting to this center with histologically proven advanced carcinoma of gallbladder were screened for eligibility for inclusion in the study. Patients and Methods: No prior approach for sample size calculation was followed owing to rarity of disease. Hence, all the patients falling in the sampling frame were included in the study. Power analysis was done post hoc. A total of 60 patients falling in sampling frame and completing 6 months of treatment protocol were enrolled in the study. Statistical Analysis Used: Chi-square test and independent samples t-test were used to compare and evaluate the data. P

Treatment of advanced gallbladder cancer: A SEER-based study.

PurposeThe treatment of advanced gallbladder cancer (GBC) remains controversial. Therefore, the purpose of this study was to explore treatment choices for advanced GBC.MethodsWe identified four different treatments from the surveillance, epidemiology, and end results (SEER) database: surgery, chemotherapy (CT), surgery and chemotherapy (Surgery + CT), and no surgery/no chemotherapy (No surgery/No CT). Kaplan‐Meier method and Cox proportional hazards regression method were used to determine the risk factors for overall survival (OS) and cancer‐specific survival (CSS). In addition, patients in AJCC stages III and IV stage were matched with 1:1 propensity score matching (PSM) for diagnosis age, race, marital status, histological type, tumor grade, and treatment pattern to decrease the possibility of selection bias.ResultsA total of 288 AJCC stage III patients and 4239 AJCC stage IV patients with advanced GBC were identified from the SEER database between 2004 and 2015. Treatment pattern was an independent risk factor for patients with advanced GBC. For all patient, AJCC stage III patients and AJCC stage IV patients, “Surgery + CT” treatment minimized the OS and CSS in advanced GBC patients. In addition, after the PSM analysis, the “Surgery + CT” treatment still significantly decreased patient OS and CSS.Conclusions“Surgery + CT” treatment can provide survival benefits for patients with advanced GBC. In addition, “Surgery + CT” treatment was not fully utilized and may further improve the survival rate of GBC patients.

Mo1417 – Adjuvant Treatment for Advanced Gallbladder Cancer; Does External Beam Radiation Therapy Play a Role?

Mo1417 – Adjuvant Treatment for Advanced Gallbladder Cancer; Does External Beam Radiation Therapy Play a Role?

Long non-coding RNA GBCDRlnc1 induces chemoresistance of gallbladder cancer cells by activating autophagy

BackgroundGallbladder cancer is the most common biliary tract malignancy and not sensitive to chemotherapy. Autophagy is an important factor prolonging the survival of cancer cells under chemotherapeutic stress. We aimed to investigate the role of long non-coding RNAs (lncRNAs) in autophagy and chemoresistance of gallbladder cancer cells.MethodsWe established doxorubicin (Dox)-resistant gallbladder cancer cells and used microarray analysis to compare the expression profiles of lncRNAs in Dox-resistant gallbladder cancer cells and their parental cells. Knockdown or exogenous expression of lncRNA combined with in vitro and in vivo assays were performed to prove the functional significance of lncRNA. The effects of lncRNA on autophagy were assessed by stubRFP-sensGFP-LC3 and western blot. We used RNA pull-down and mass spectrometry analysis to identify the target proteins of lncRNA.ResultsThe drug-resistant property of gallbladder cancer cells is related to their enhanced autophagic activity. And we found a lncRNA ENST00000425894 termed gallbladder cancer drug resistance-associated lncRNA1 (GBCDRlnc1) that serves as a critical regulator in gallbladder cancer chemoresistance. Furthermore, we discovered that GBCDRlnc1 is upregulated in gallbladder cancer tissues. Knockdown of GBCDRlnc1, via inhibiting autophagy at initial stage, enhanced the sensitivity of Dox-resistant gallbladder cancer cells to Dox in vitro and in vivo. Mechanically, we identified that GBCDRlnc1 interacts with phosphoglycerate kinase 1 and inhibits its ubiquitination in Dox-resistant gallbladder cancer cells, which leads to the down-regulation of autophagy initiator ATG5-ATG12 conjugate.ConclusionsOur findings established that the chemoresistant driver GBCDRlnc1 might be a candidate therapeutic target for the treatment of advanced gallbladder cancer.

The role of neoadjuvant chemotherapy or chemoradiotherapy for advanced gallbladder cancer - A systematic review

Abstract Background Neoadjuvant chemotherapy for advanced gallbladder cancer (GBC) has recently been proposed as an alternative to adjuvant chemotherapy, with potential increase in resectability rate and overall survival. Aim To undertake a systematic review and critical appraisal of available literature on the use of neoadjuvant chemotherapy (NACT) or chemoradiotherapy (NACRT) in the treatment of advanced GBC. Methods Systematic review carried out in line with the Meta-analysis Of Observational Studies in Epidemiology guidelines. Primary outcomes were clinical benefit rate (CBR) of neoadjuvant therapy, defined as percentage of complete response, partial response and stable disease, resectability rate and R0 resection. Secondary outcomes were overall and disease-free survival. Results 8 studies met the inclusion criteria (n = 474), of which 398 (84.0%) received NACT and 76 (16.0%) received NACRT. 133 of 434 patients (30.6%) had progressive disease despite NACT or NACRT. The CBR was 66.6%. 17% of the patients who responded to chemotherapy did not proceed to surgery. 50.4% of the patients were considered suitable for surgical resection, of which 191 (40.3%) underwent curative resection. The R0 rate for the whole cohort was 35.4%. Overall survival ranged from 18.5 to 50.1 months for those who underwent curative resection versus 5.0–10.8 months for non-resected group. Conclusions There is insufficient data to support the routine use of NACT or NACRT in advanced GBC, as this has only benefited a third of whole cohort, who eventually achieved a R0 resection. Future studies should be in the form of randomized controlled trials to investigate the role of neoadjuvant therapy in advanced GBC.

Successful curative resection after chemotherapy for initially unresectable advanced gallbladder cancer with rectal metastasis:a case report

A 42-year-old male was referred to our hospital with bloody feces and lower back pain. He was diagnosed with unresectable gallbladder cancer with rectal metastasis (T3aN1M1, Stage IVB). The patient was administered gemcitabine plus cisplatin (GC). After nine courses of GC, computed tomography showed regression of the tumor and the patient's tumor marker levels had decreased. Therefore, curative resection was performed. Ten months after the operation, recurrence was observed in the rectal margin and GC was restarted. Because the total dose of cisplatin was 1040mg, we stopped cisplatin and continued to administer only gemcitabine (at the same dose). A follow-up examination 2 years after the operation showed no evidence of recurrence. Conversion therapy might be an effective multidisciplinary treatment for advanced gallbladder cancer that is initially unresectable. Herein, we report the case of a patient with advanced gallbladder cancer and rectal metastasis who was successfully treated by curative resection after chemotherapy;we also review the relevant literature.

Clinical application of hepatopancreatoduodenectomy in treatment of advanced gallbladder cancer

Clinical application of hepatopancreatoduodenectomy in treatment of advanced gallbladder cancer

Surgical treatment of advanced gallbladder cancer.

Radical lymph node dissection in surgery for advanced gallbladder cancer is controversial. The purpose of this study is to evaluate the different extent of lymph node dissection for N2 stage gallbladder cancer patients. A retrospective analysis was made of 60 patients with N2 stage who underwent standard regional lymphadenectomy (SRLN) and extended regional lymphadenectomy (ERLN). Between September 2000 and June 2011, 60 advanced gallbladder cancer patients with N2 stage of lymph node metastasis were included in this study. The curative effects with different extent of lymphadenctomy for lymph node N2 stage of gallbladder cancer patients were compared. The median survival time was 34.83 months in the SRLN group and 30.28 months in the ERLN group. There was no significant difference of survival rate between SRLN and ERLN group (P=0.51). Postoperative major morbidity and mortality rates were 64.3% and 7.14% in the SRLN group, 81.3% and 9.34% in the ERLN group, respectively. Moreover, the number of positive lymph nodes and chemotherapy were found to correlate with survival on univariate analyses (P<0.05). For advanced gallbladder patients with N2 stage lymph node metastasis, ERLN cannot provide a significant survival benefit over SRLN and the rate of morbidity and mortality in ERLN is exceptionally high. ERLN therefore should not be considered in the advanced gallbladder cancers with N2 stage.

MTOR/P70S6K signaling pathway as a potential target for advanced gallbladder cancer therapy.

242 Background: Gallbladder cancer (GBC) is a highly malignant tumor usually diagnosed at advanced stages and characterized by a poor prognosis. Effective therapeutic strategies are urgently needed to improve the prognosis of GBC patients. Our objective was to analyze the expression of mTOR/p70S6K pathway in primary tumors and GBC cell lines, and to evaluate the effect of mTOR inhibitors in in vitro and in vivo models of GBC. Methods: The expression of mTOR/p70S6K signaling pathway components was examined by immunohistochemistry in primary tumors and chronic cholecystitis (CC), and by Western blot in eight GBC cell lines. The in vitro effect of mTOR inhibitors (LY294002, Rapamycin, Everolimus and AZD8055) on cell viability and migration was assessed by MTS and Transwell chamber assays. The therapeutic effect of Rapamycin was evaluated in subcutaneous tumor models (NOD/SCID mice). Treatment started when tumor volumes had reached 100mm3. Animals (G-415 and TGBC-2TKB xenografts) were randomly divided (n=5 per group) and treated with Polietilenglicol solution as vehicle and 10mg/kg of Rapamycin, daily IP injection (5 days/week for 3 weeks). Mice were sacrificed 30 days after treatment and tumors were dissected and measured. Tumor volume was calculated as π/6 × (large diameter) × (small diameter)2. Results: Our findings indicate that mTOR/p70S6K pathway is frequently activated in GBC (&gt;60% of tumors showed high expression of phospho-mTOR and phospho-p70S6K, compared to CC). GBC patients whose tumors overexpressed phospho-mTOR had a poorer prognosis (p=0.02). G-415 and TGBC-2TKB cells showed a constitutive activation of this pathway and the treatment with different mTOR inhibitors significantly reduced their viability and migration capacity (p&lt;0.001). In subcutaneous tumor models, treatment with Rapamycin significantly reduced the weight and tumor volume compared with the control group (p&lt;0.001). Conclusions: mTOR/p70S6K signaling pathway is frequently activated in gallbladder cancer tissues and cells lines, which suggest that this pathway is a potential therapeutic target for the treatment of advanced GBC, using Rapamycin or other specific inhibitors. Supported by FONDECYT 1090171 and DIUFRO DI11-0039.

Evaluation of two modified ECF regimens in the treatment of advanced gallbladder cancer

Gallbladder cancer is a rare disease and it is associated with a poor clinical outcome and survival. A standard therapy for it has not been established yet. The aim of this study is to evaluate efficacy and safety of two modified ECF regimens in advanced gallbladder cancer patients. Clinical data of 38 patients with advanced gallbladder cancer treated with modified ECF regimen were reviewed retrospectively. Of them, 21 patients received an epirubicin, cisplatin, and 5-FU/LV combination therapy. Seventeen patients received a chemotherapy of epirubicin, cisplatin, and capecitabine. Partial response was achieved in fourteen (36.84%) patients with a median duration of 5 months (range, 3-13 months), while stable disease was achieved in eight patients (21.05%). The median time to progression was 4.0 months (95% CI, 3.62-4.58 months). And the median overall survival was 9.8 months (95% CI, 7.26-12.34 months). Responders demonstrated better survival than non-responders (median survival time: 16 vs. 6.9 months, P = 0.008). The median survival time for epirubicin-, cisplatin- and capecitabine-treated patients was 9.2 versus 8.9 months for epirubicin-, cisplatin- and 5-FU/LV-treated patients. There was no statistical difference between both treatment groups in terms of survival time (P = 0.769). Regimen-related toxicity resulted in at least one treatment delay or dosage reduction in 63.2 and 34.2% patients, respectively. There were no chemotherapy-related deaths during the study. Modified ECF regimen with epirubicin, cisplatin and 5-FU/LV or substituting capecitabine for 5-FU/LV is still a potentially effective therapeutic chemotherapy for patients with advanced gallbladder cancer, and toxicity was manageable. There was no remarkable difference in efficacy between the two regimens.

Successful treatment of advanced gallbladder cancer with an anticancer drug S-1: assessment based on intratumoral gene

While surgical resection is the most effective treatment for gallbladder cancer, most of these cancers are not resectable at the time of diagnosis, and therefore, chemotherapy serves as the primary therapy in many cases. However, to date, there is no standard chemotherapy for this cancer. We report a case of advanced gallbladder cancer for which the anticancer drug S-1 was effective. The patient was a 53-year-old woman who presented with a huge ovarian tumor. On workup, all abdominal images revealed the presence of advanced gallbladder cancer that had invaded the liver. Because the gallbladder formed a relatively hard and swollen mass involving the omentum, as revealed during exploration, the surgical resection of the gallbladder was not possible at that time, and only hysterectomy and bilateral salpingo-oophorectomy were performed. She started on the anticancer drug S-1 just after this operation. S-1 is a prodrug of 5-fluorouracil (5-FU), and contains 5-chloro-2-4-dihydroxypyridine (CDHP), an inhibitor of dihydropyrimidine dehydrogenase (DPD) that rapidly degrades 5-FU. Eight months after the first operation, radical cholecystectomy was performed. Pathologically, the tumor was diagnosed as an adenocarcinoma of the gallbladder, and no evidence of liver invasion was found. Intratumoral gene expression analysis of the resected gallbladder revealed significantly elevated DPD expression. We suggest that the rapid degradation of 5-FU mediated by this high DPD in our patient was significantly blocked by the CDHP in S-1, and that the efficacy of 5-FU was consequently maintained at the maximum level.

Extrahepatic bile duct resection: Standard treatment for advanced gallbladder cancer?

Journal of Surgical OncologyVolume 94, Issue 4 p. 269-270 Guest Editorial Extrahepatic bile duct resection: Standard treatment for advanced gallbladder cancer? Eddie K. Abdalla MD, Corresponding Author Eddie K. Abdalla MD [email protected] Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TexasAssistant Professor, Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 444, Houston, Texas 77030-4009. Fax: 713-745-1921.Search for more papers by this authorJean-Nicolas Vauthey MD, Jean-Nicolas Vauthey MD Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TexasSearch for more papers by this author Eddie K. Abdalla MD, Corresponding Author Eddie K. Abdalla MD [email protected] Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TexasAssistant Professor, Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 444, Houston, Texas 77030-4009. Fax: 713-745-1921.Search for more papers by this authorJean-Nicolas Vauthey MD, Jean-Nicolas Vauthey MD Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TexasSearch for more papers by this author First published: 17 August 2006 https://doi.org/10.1002/jso.20586Citations: 4AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article.Citing Literature Volume94, Issue415 September 2006Pages 269-270 RelatedInformation

Chemotherapy in the Treatment of Advanced Gallbladder Cancer

Objective: To clarify the role of chemotherapy for advanced gallbladder cancer (GBC). Methods: We reviewed 89 GBC patients: 21 admitted before 1997 were treated with a combination of cisplatin, epirubicin, and 5-fluorouracil (CEF); 25, admitted subsequently, received a combination of 5-fluorouracil, doxorubicin and mitomycin (FAM), and the remaining 43, ineligible for these trials, received supportive care. We investigated the relation between pretreatment clinical variables and long-term survival in these 89 subjects, and analyzed whether chemotherapy could favor longer survival. Results: There were no significant differences in survival time between the chemotherapy groups, whereas the response rate to the CEF regimen was 4-fold higher than to the FAM regimen (32 vs. 8%). Subgroup analysis suggested that chemotherapy favored longer survival in patients with a performance status (PS) of 0 or 1, but not in patients with a PS of 2. Cox regression analysis suggested a significant hazard reduction by chemotherapy in patients with a PS of 0 or 1, but not in patients with a PS of 2. Conclusions: GBC patients with poor PS should not be treated with chemotherapy at present. It is essential to design good clinical trials and develop more effective chemotherapy regimens.

A MEK inhibitor (U0126) prolongs survival in nude mice bearing human gallbladder cancer cells with K-ras mutation: Analysis in a novel orthotopic inoculation model

Most cases of gallbladder cancer are found at an advanced stage accompanied by invasion to the liver, metastases to the lymph nodes and distant organs, and peritoneal dissemination. Then, the treatment for advanced gallbladder cancer is often ineffective, and the prognosis of this disease is poor. The specific aim of this study was to establish a model system for developing new therapeutic strategies, such as molecular target therapy, for human advanced gallbladder cancer. We used a human gallbladder cancer cell line, NOZ with K-ras mutation in this experiment. Then, we established a novel orthotopic inoculation model for gallbladder cancer by using NOZ cells in nude mice. Mitogen-activated protein kinase (MAPK) in NOZ cells was constitutively activated, and the activation of MAPK provided autonomous proliferation of NOZ cells. All of the mice orthotopically inoculated by NOZ cells developed tumors at the gallbladder. Direct invasion into the liver, and bloody ascites were observed. Metastases to the mediastinal lymph nodes were also recognized in all of the mice examined. Moreover, most of the mice showed lung metastases. Survival duration was 29-50 days after inoculation. Nude mice with NOZ tumor at gallbladder were treated by an intraperitoneal injection of a MAPK kinase inhibitor U0126 (25 micro mole/kg) twice a week. U0126 (p=0.0110, one-way ANOVA) significantly prolonged the survival duration of the mice with NOZ gallbladder tumor. Our orthotopic inoculation model is useful for developing new therapeutic strategies, such as molecular target therapy for advanced gallbladder cancer.