Chronic inflammation and gallbladder cancer

Gallbladder cancer (GBC) is the most common biliary tract malignancy with an extremely poor prognosis. Epidemiological data have demonstrated that chronic inflammation resulting from infection of gallbladder or gallstones predispose individuals to GBC. Recent studies have begun to elucidate molecular mechanisms underlying the development of GBC in the setting of chronic inflammation. It is possible that persistently local inflammatory reactions may contribute to the development and progression of GBC through inducing genetic alterations, and subsequent promoting survival and proliferation of mutated sells, inhibiting apoptosis, stimulating angiogenesis and metastasis. This article reviews the current understanding of the involvement of chronic inflammation in gallbladder tumorigenesis.     

A genetic model for gallbladder carcinogenesis and its dissemination

Gallbladder cancer, although regarded as the most common malignancy of the biliary tract, continues to be associated with a dismal overall survival even in the present day. While complete surgical removal of the tumour offers a good chance of cure, only a fraction of the patients are amenable to curative surgery owing to their delayed presentation. Moreover, the current contribution of adjuvant therapies towards prolonging survival is marginal, at best. Thus, understanding the biology of the disease will not only enable a better appreciation of the pathways of progression but also facilitate the development of an accurate genetic model for gallbladder carcinogenesis and dissemination. This review provides an updated, evidence-based model of the pathways of carcinogenesis in gallbladder cancer and its dissemination. The model proposed could serve as the scaffolding for elucidation of the molecular mechanisms involved in gallbladder carcinogenesis. A better understanding of the pathways involved in gallbladder tumorigenesis will serve to identify patients at risk for the cancer (and who thus could be offered prophylactic cholecystectomy) as well as aid oncologists in planning the most suitable treatment for a particular patient, thereby setting us on the vanguard of transforming the current treatment paradigm for gallbladder cancer.     

胆道肿瘤:过去、现在和未来(英文)

Tumors of the biliary tract (gallbladder tumors, cholangiocarcinomas and ampullary carcinomas) are low incidence tumors with poor prognosis. The five-year overall survival is 50% for stage Ⅰ, 30% stage Ⅱ, 10% stage Ⅲ and 0% stage Ⅳ. Treatment is based on surgery for potentially resectable tumors. Chemotherapy and chemo-radiotherapy is the treatment of choice when surgery is not amenable, however it has not achieved encouraging results. These patients use to have very few symptoms, which is the reason for the delay in diagnosis and the poor prognosis. They frequently develop biliary obstruction: obstructive jaundice, right upper quadrant pain and weight loss. Ampullary carcinomas are frequently related to steatorrhea due to malabsorption. The most effective chemotherapy drugs used in monotherapy are 5FU (response rate 20%) and gemcitabine (response rate of 13%-60%), so they have been selected for further development in multiple phase Ⅱ clinical trials to explore their efficacy and safety in combination with other agents. In a phase Ⅲ clinical trial, combination of gemcitabine and cisplatin has been selected as the schedule of choice. Target therapies are also being developed in this malignancy. The present work reviews the most current knowledge of the pathogenesis, diagnosis and natural history of biliary tract tumors. Further, review of surgery, current adjuvant treatment and therapies for unresectable and advanced disease is provided. The most recent understanding for target therapies and molecular biology is also summarized.     

Surgery in combination with systemic chemotherapy is associated with improved survival in stage IV gallbladder cancer

BackgroundGallbladder cancer (GBC) is the most common biliary malignancy frequently metastatic at diagnosis with poor prognosis. While surgery remains the standard for early-stage GBC, the role of surgery in patients with metastatic gastrointestinal cancers is expanding due to improvements in systemic therapies. We sought to evaluate the survival of patients with stage IV GBC undergoing surgery in an era of improved multi-agent systemic therapy.MethodsA retrospective review of the National Cancer Database was performed. Patients with stage IV GBC who underwent systemic therapy were included. Patients who received radiation therapy, palliative therapy or had missing survival data were excluded. Univariable and multivariable analysis was performed.Results4,145 patients were identified between 2004 and 2016. Mean age was 69. Surgery combined with systemic therapy predicted improved median survival compared with chemotherapy alone (11.1mo versus 6.8mo, HR 0.65, p < 0.001). Additionally, receipt of treatment after 2011 predicted improved survival (HR 0.86, p < 0.001). Patients treated with multi-agent chemotherapy in combination with surgery were associated with the greatest hazard ratio benefit (0.40, p < 0.001) versus single agent therapy alone.ConclusionPatients with stage IV gallbladder cancer treated with a combination of surgery and chemotherapy are associated with an improved overall survival compared to chemotherapy alone. Patients receiving care during the more recent era demonstrated improved survival. These results support a role for surgery in selected patients with stage IV gallbladder cancer receiving chemotherapy.     

Comparison of Clinical Outcomes of Incidental and Non-Incidental Gallbladder Cancers: A Single-Center Cross-Sectional Study

Background: Gallbladder cancer (GBC) is a rare malignancy characterized by high invasiveness and poorsurvival. In a nation-wide cancer survey, the age-standardized incidence rate of GBC was the highest in JejuIsland compared to 15 other provinces in Korea. The purpose of this study was to compare the clinical outcomesof GBC according to the nature of diagnosis, that is, incidental versus non-incidental. Materials and Methods:Consecutive patients who were newly diagnosed with GBC at the Digestive Disease Center and Department ofInternal Medicine, Cheju Halla General Hospital, between November 2008 and November 2011, were enrolledand divided into 2 groups: incidental gallbladder cancer (IGBC) and non-incidental gallbladder cancer (NIGBC).Clinical outcomes were retrospectively compared between the two groups. Results: Seventy-nine patientswere enrolled and analyzed in our study. Thirty-three (41.8%) and 46 (58.2%) were identified as IGBC andNIGBC, respectively. The proportions of patients with gallstone disease, gallbladder polyp, and cholecystectomywere significantly different between the two groups. Additionally, the median survival rate was significantlyhigher for patients with IGBC than for those with NIGBC (11.4, 95% confidence interval, 5.6-13.7 vs 4.0, 95%confidence interval 3.03-5.96 months; p=0.01) during a median follow-up period of 5.7 months. Conclusions:Patients with IGBC showed better clinical prognosis than those with NIGBC. Therefore, patients with gallstonedisease or gallbladder polyps, major predictive risk factors for IGBC, should undergo advanced work-up forchelecystectomy.     

Current standards and future perspectives in adjuvant treatment for biliary tract cancers

Biliary tract cancer, including cholangiocarcinoma (CCA) and gallbladder cancer (GBC) are rare tumours with a rising incidence. Prognosis is poor, since most patients are diagnosed with advanced disease. Only ~20% of patients are diagnosed with early-stage disease, suitable for curative surgery. Despite surgery performed with potentially-curative intent, relapse rates are high, with around 60–70% of patients expected to have disease recurrence. Most relapses occur in the form of distant metastases, with a predominance of liver spread. In view of high tumour recurrence, adjuvant strategies have been explored for many years, in the form of radiotherapy, chemo-radiotherapy and chemotherapy. Historically, few randomised trials were available, which included a variety of additional tumours (e.g. pancreatic and ampullary tumours); most evidence relied on phase II and retrospective studies, with no high-quality evidence available to define the real benefit derived from adjuvant strategies.Since 2017, three randomised phase III clinical trials have been reported; all recruited patients with resected biliary tract cancer (CCA and GBC) who were randomised to observation alone, or chemotherapy in the form of gemcitabine (BCAT study; included patients diagnosed with extrahepatic CCA only), gemcitabine and oxaliplatin (PRODIGE-12/ACCORD-18; included patients diagnosed with CCA and GBC) or capecitabine (BILCAP; included patients diagnosed with CCA and GBC). While gemcitabine-based chemotherapy failed to show an impact on patient outcome (relapse-free survival (RFS) or overall survival (OS)), the BILCAP study showed a benefit from adjuvant capecitabine in terms of OS (pre-planned sensitivity analysis in the intention-to-treat population and in the per-protocol analysis), with confirmed benefit in terms of RFS. Based on the BILCAP trial, international guidelines recommend adjuvant capecitabine for a period of six months following potentially curative resection of CCA as the current standard of care for resected CCA and GBC. However, BILCAP failed to show OS benefit in the intention-to-treat (non-sensitivity analysis) population (primary end-point), and this finding, as well as some inconsistencies between studies has been criticised and has led to confusion in the biliary tract cancer medical community.This review summarises the adjuvant field in biliary tract cancer, with evidence before and after 2017, and comparison between the latest randomised phase III studies. Potential explanations are presented for differential findings, and future steps are explored.     

Current Management of Gallbladder Carcinoma

Gallbladder cancer (GBC) represents the most common and aggressive type among the biliary tree cancers (BTCs). Complete surgical resection offers the only chance for cure; however, only 10% of patients with GBC present with early‐stage disease and are considered surgical candidates. Among those patients who do undergo “curative” resection, recurrence rates are high. There are no established adjuvant treatments in this setting. Patients with unresectable or metastatic GBC have a poor prognosis. There has been a paucity of randomized phase III data in this field. A recent report demonstrated longer overall survival with gemcitabine in combination with cisplatin than with gemcitabine alone in patients with advanced or metastatic BTCs. Molecularly targeted agents are under development. In this review, we attempt to discuss the current status and key issues involved in the management of GBC.     

Gallbladder cancer: a subtype of biliary tract cancer which is a current challenge in China

Biliary tract cancers, broadly described as malignancies that arise from the biliary tract epithelia, are usually divided into two major clinical phenotypes: cholangiocarcinoma and gallbladder cancer, differing in etiopathogenesis, risk factors, and perhaps molecular and genetic signatures. Atypical symptoms and lack of tumor biomarkers make it difficult to diagnose in early stages. At the time of presentation, few patients are candidates for potentially curative surgical resection. We here assessed and compared features of a total of 150 cases divided into extra- and intrahepatic cholangiocarcinomas and gallbladder cancers (GBC). Althought there were no significant differences in serum tumour marker levels, GBC patients had the poorest prognosis. Furthermore, gallbladder cancer respond poorly to chemotherapy or radiation therapy and approximately half of untreated patients died within 10 months. Therefore, treatment for patients with gallbladder cancer is still in challenge. Outcomes and survival of these patients had improved little over the past three decades - a period in which new successful treatments have greatly contributed to the prolonged patient survival for many other cancers.     

Genetic aberrations in gallbladder cancer

Gallbladder carcinoma (GBC) is the most common type of biliary tract carcinoma and the third commonest digestive tract malignancy in our region. Studies available in literature do not clearly define the molecular genetic mechanisms involved in the pathogenesis of GBC. Most of these studies are limited to protein expression analysis by immunohistochemistry and western blotting, and only a few have been done on mRNA (messenger RNA) and mutation analysis. This review aims to critically analyze all the available evidence on genetic aberrations in gallbladder carcinoma.     

A review of association of dietary factors in gallbladder cancer

Gallbladder cancer (GBC) is the prominent malignancy of hepato-biliary tract, being the fifth most common carcinoma for gastrointestinal tract in United States. Epidemiological studies world wide have implicated dietary factors in the development of gallbladder cancer. The ecological evidences indicate considerable geographic variation in the incidence of gallbladder cancer. However the variations in GBC incidence of different populations might be partly determined by their dietary variations. Higher intake of energy and carbohydrate possibly increase the risk of gallbladder cancer. Obesity plays an important role in the causation of GBC. Adequate intake of fruits and vegetables probably reduce the risk of GBC. This nutritional preventive effect against GBC could be attributed to high content of vitamins, carotenes and fibers. They can not be too emphatically stated as the sole determinants of GBC. It is apparently clear that a variety of essential nutrients can significantly modify the carcinogenic process. Furthermore, an attempt has been made to establish an association between dietary factors and the occurrence of gallbladder cancer.     

Adjuvant external beam radiation therapy with concurrent chemotherapy in the management of gallbladder carcinoma.

PURPOSE: This study was performed to evaluate the outcome of patients with gallbladder cancer who received postoperative concurrent chemotherapy and radiation therapy. METHODS AND MATERIALS: Curative resection followed by adjuvant combined modality therapy with external beam radiation therapy (EBRT) and chemotherapy was attempted in 21 consecutive gallbladder carcinoma (GBC) patients at the Mayo Clinic from 1985 through 1997. All patients received concurrent 5-fluorouracil during EBRT. EBRT fields encompassed the tumor bed and regional lymph nodes (median dose of 54 Gy in 1.8-2.0-Gy fractions). One patient received 15 Gy intraoperatively after EBRT. A retrospective analysis was performed for the end points of local control, distant failure, and overall survival. RESULTS: After maximal resection, 12 patients had no residual disease on pathologic evaluation, 5 had microscopic residual disease, and 4 had gross residual disease. One patient had Stage I disease, and 20 had Stage III-IV disease. With median follow-up of 5 years (range: 2.6-11.5 years), 5-year survival for the entire cohort was 33%. The 5-year survival rate of patients with Stage I-III disease was 65% vs. 0% for those with Stage IV disease (p < 0.02). For patients with no residual disease, 5-year survival was 64% vs. 0% for those with residual disease (p = 0.002). The median survival was 0.6, 1.4, and 5.1 years for patients with gross residual, microscopic residual, and no residual disease, respectively (p = 0.02). The 5-year local control rate for the entire cohort was 73%. Two-year local control rates were 0%, 80%, and 88% for patients with gross residual, microscopic residual, or no residual disease, respectively (p < 0.01). Five-year local control rates were 100% for the 6 patients who received total EBRT doses >54 Gy (microscopic residual, 3 patients; gross residual, 1 patient; negative but narrow margins, 2 patients) vs. 65% for the 15 who received a lower dose (3, gross residual; 2, microresidual; 10, negative margins). CONCLUSION: Patients with completely resected (negative margins) GBC followed by adjuvant EBRT plus 5-fluorouracil chemotherapy had a relatively favorable prognosis, with a 5-year survival rate of 64%. These results seem to be superior to historical surgical controls from the Mayo Clinic and other institutions, which report 5-year survival rates of approximately 33% with complete resection alone. Both tumor stage and extent of resection seemed to influence survival and local control. More aggressive measures using current cancer therapies and integration of new cancer treatment modalities will be required to favorably impact on the poor prognosis of patients with Stage IV or subtotally resected GBC. Additional investigation leading to earlier diagnosis is warranted, because most patients with GBC present with advanced disease.     

Clinicopathological Study of Gall Bladder Carcinoma with Special Reference to Gallstones: Our 8-year Experience from Eastern India

Gallbladder carcinoma (GBC) is the commonest cancer of the biliary tree and the most frequent cause of deathfrom biliary malignancies. The incidence of GBC shows prominent geographic, age, race, and gender-relateddifferences and is 4-7 times higher in patients with gallstones. This prompted us to study the clinicopathologicalaspects of the disease and the incidence of gallstones in gallbladder carcinoma patients, in this part of India. Inthis, combined retrospective (Jan 2004-March 2010) and prospective study (April 2010-Dec 2011) of eight years,198 patients of gallbladder carcinoma (50 males and 148 females), (range 28-82 years; mean 55 years) were studied.Most of the patients were poor and presented with abdominal pain and mass, with abnormal lab parameters.Gallstones were present in 86% of patients. Surgical exploration was performed in 130, with gallbladder resectionin 60 (including 7 incidental GBC). Adenocarcinoma (87.7%) was the commonest histological type. The studyindicates that GBC is common in our scenario. It is a disease of elderly females, has a strong association withgallstones and every cholecystectomy specimen should be examined histopathologically.     

Incidental gall bladder cancers: Are they truly incidental?

AIM: To seek and analyze features suggestive of gallbladder cancer (GBC) on preoperative imaging and intraoperative findings in patients diagnosed as having incidental GBC (IGBC).METHODS: The study was conducted on 79 patients of IGBC managed in our department over a 10-year period (2003-2012). Review of preoperative imaging and operative notes was done to ascertain any suspicion of malignancy-in-retrospect.RESULTS: Of the 79 patients, Ultrasound abdomen showed diffuse thickening, not suspicious of malignancy in 5 patients, and diffuse suspicious thickening was seen in 4 patients. Focal thickening suspicious of malignancy was present in 24 patients. Preoperative computed tomography/magnetic resonance imaging was done in 9 patients for suspicion of malignancy. In 5 patients, difficult Cholecystectomy was encountered due to dense/inflammatory adhesions. Intraoperative findings showed focal thickening of the gallbladder and a gallbladder mass in 9 and 17 patients respectively. On overall analysis, 37 patients had preoperative imaging or intraoperative findings suggestive of malignancy, which was either a missed GBC or an unsuspected/unexpected GBC. In 42 (53.2%) patients, there was no evidence suggestive of malignancy and was an unanticipated diagnosis.CONCLUSION: Our study highlights a potential and not-so-rare pitfall of Laparoscopic Cholecystectomy. A greater awareness of this clinical entity along with a high index of suspicion and a low threshold for conversion to open procedure, especially in endemic areas may avert avoidable patient morbidity and mortality.     

Chemotherapy in advanced biliary tract carcinoma: a pooled analysis of clinical trials

Owing to the lack of randomised controlled trials no standard of chemotherapy exists in the treatment of advanced biliary tract carcinoma. 5-fluorouracil or gemcitabine is recommended based on small and predominately phase II trials. The aim of this analysis was to analyse existing trials, even small and nonrandomised, and identify superior regimens. Chemotherapy trials published in English from 1985 to July 2006 were analysed as well as ASCO abstracts from 1999 to 2006. Response rate (RR=CR+PR), tumour control rate (TCR=CR+PR+SD), time to tumour progression (TTP), overall survival (OS), and toxicity were analysed. One hundred and four trials comprising 112 trial arms and 2810 patients, thereof 634 responders and 1368 patients with tumour control were analysed. Pooled RR and TCR were 22.6 and 57.3%, respectively. Significant correlations of RR and TCR with survival times were found. Subgroup analysis showed superior RRs for gallbladder carcinoma (GBC) compared with cholangiocarcinoma, but shorter OS for GBC. Furthermore, superior RRs and TCRs of gemcitabine and platinum containing regimens were found with highest RRs and TCRs in the combination subgroup. Based on published results of predominately phase II trials, gemcitabine combined with platinum compounds represents the provisional standard of chemotherapy in advanced biliary tract cancer, unless a new evidence-based standard has been defined.     

Correlation of nutritional parameters of gallbladder cancer patients

BACKGROUND AND OBJECTIVE: Gallbladder cancer (GBC) is a highly fatal disease with poor prognosis and 5-year survival <5%. Weight loss and nutritional deterioration are associated with adverse outcomes in terms of cancer prognosis. Protein-calorie malnutrition is the single most common secondary diagnosis in a patient with cancer, and is a direct consequence of the anorexia of malignancy and altered host metabolism induced by the tumor. The present study of nutritional assessment is of particular interest for it helps in better understanding the extent of malnutrition in patients of GBC. PATIENTS AND METHODS: A case-control study was designed comprising of 153 cases of GBC and 153 controls of gallstone disease (GSD). To assess the nutritional status of the GBC patients, anthropometric measurements such as height, weight, mid arm circumference, and skinfold thickness were recorded together with the biochemical parameters and their nutrient intake. RESULTS AND CONCLUSIONS: The present study showed that GBC influences the nutritional status of the patients. Forty-three percent of GBC patients were malnourished with low body mass index (BMI). A significant reduction in all the anthropometric measures was observed for GBC patients compared to those with GSD. GBC patients had significantly low hemoglobin and serum albumin levels compared to the control group. The hemoglobin levels in case and control groups were 10.87 g/dl (+/-1.81 SD) and 11.62 g/dl (+/-1.89 SD), respectively (P < 0.001). Intake of almost all the nutrients was far below the recommendations of Indian Council of Medical Research. GBC patients had anorexia and weight loss.     

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

BackgroundNeoadjuvant 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.AimTo 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.MethodsSystematic 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.Results8 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.ConclusionsThere 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.     

Updates on Gallbladder Cancer Management

Purpose of Review

We will review the current standard of care management for metastatic gallbladder cancer (GBC), recommendations for resection of incidentally or non-incidentally diagnosed GBC, and developments in preoperative risk stratification and adjuvant chemotherapy.

Recent Findings

Gemcitabine-cisplatin is the standard of care therapy for advanced-stage disease. Patients with incidentally diagnosed GBC should undergo re-resection for T1b, T2, or T3 disease. The presence of residual disease is associated with decreased survival. Diagnostic laparoscopy should be used in select patients to avoid unnecessary laparotomy. Major hepatectomy and common bile duct excision should only be performed in select cases. Current standard of care for adjuvant therapy includes 6 months of oral capecitabine.

Summary

Gallbladder cancer continues to carry high mortality rates due to its aggressive course and early spread. Recent developments in preoperative risk stratification, surgical resection, and chemotherapy have greatly shaped management of this malignancy in the current era.

     

Potential Therapeutic Targets for the Primary Gallbladder Carcinoma: Estrogen Receptors

Gallbladder carcinoma, the most frequent malignant neoplasm of the biliary tract system, has always been considered to feature late clinical presentation and diagnosis, limited treatment options and an extremely poor prognosis. In recent years, while the incidence of gallbladder cancer has appeared to be on the increase, the available treatment methods have not greatly improved survival of the affected patients. Thus, exploring new therapeutic targets for this devastating disease is an urgent matter at present. Epidemical studies have demonstrated that the incidence of gallbladder carcinoma exhibits a distinct gender bias, affecting females two to three times more than males, pointing to crucial roles of estrogen. It is well known that estrogen acts on target tissues by binding to estrogen receptors (ERs), which are mainly divided into three subtypes, ERα, ERβ and ERγ. ERα and ERβ appear to have overlapping but also unique even opposite biological effects. As important pathogenic mediators, ERs have been considered to relate to several kinds of tumors. In gallbladder carcinoma tissue, ERs have been shown to be positively expressed, and ERs expression levels are associated with differentiation and prognosis of this cancer. Nevertheless, the exact mechanisms of estrogen inducing growth of gallbladder carcinoma remain poorly understood. On the base of the current investigations, we deduce that estrogen participates in promotion of gallbladder carcinoma by influencing the formation of gallstones, stimulating angiogenesis, and promoting abnormal proliferation. Since ERs mediate the carcinogenic actions of estrogen in gallbladder, and therapy targeting ERs may provide new directions for gallbladder carcinoma. Therefore, it should be stressed that ERs are potential therapeutic targets for gallbladder carcinoma.