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Background: Immunotherapy has been shown to improve outcomes for patients with cancer. Biliary tract cancers are a group of lethal diseases, and immunotherapy is an exciting new strategy to treat patients in advanced stages. Role of immunotherapy in biliary cancers: Durvalumab, an anti-PD-L1 antibody, is a new immunotherapy option for patients with advanced biliary cancers. In a randomized phase III trial, the combination of durvalumab and chemotherapy improved disease outcomes, including overall survival, in patients with advanced biliary cancers regardless of PD-L1 expression. Future perspective: Promising new combinations with new and potent antibodies or antiangiogenics are under development. Combinations with new immunotherapy agents targeting CTLA-4 or OX40 can enhance T-cell activation and improve outcomes compared with single anti-PD-1/PD-L1 agents. Furthermore, ctDNA is being used as an alternative to tissue genomic analysis and can be used to identify actionable targets. In this review, we will discuss the most important studies involving immunotherapy in biliary cancers as well as future perspectives in the field.
New treatment strategies for advanced biliary cancers with chemoimmunotherapy combinations have been shown to lead to better tumor responses and overall survival compared with chemotherapy alone. The combination of durvalumab, cisplatin and gemcitabine may become a new standard of care for advanced disease despite the modest improvement in median overall survival of less than 2 months. Promising combinations with anti-CTLA-4 antibodies or antiangiogenics are underway with the objective of improvement in survival. Although multiple combinations are available with the potential to establish a new standard of care, concerns regarding toxicities should also be evaluated. In this review, we will discuss the most important studies involving immunotherapy in biliary cancers as well as future perspectives in the field.
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Neoplasias do Sistema Biliar , Humanos , Imunoterapia , Ensaios Clínicos Fase III como Assunto , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Bile duct tumors are comprised of tumors that originate from both intrahepatic and extrahepatic bile ducts and gallbladder tumors. These are aggressive tumors and chemotherapy is still the main treatment for advanced-stage disease and most of these cases have a poor overall survival. Strategies are aimed at treatments with better outcomes and less toxicity which makes immunotherapy an area of ââsignificant importance. Recent Food and Drug Administration approvals of immune checkpoint inhibitors (ICI) for agnostic tumors based on biomarkers such as microsatellite instability-high and tumor mutation burden-high are important steps in the treatment of patients with advanced bile duct tumors. Despite limited responses with isolated checkpoint inhibitors in later lines of systemic treatment in advanced disease, drug combination strategies have been demonstrating encouraging results to enhance ICI efficacy.
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Pancreatic cancer and biliary tract cancer have a poor prognosis. In recent years, the development of new diagnostic techniques has enabled the identification of the main genetic alterations involved in the development of these tumours. Multiple studies have assessed the ability of certain biomarkers, such as BRCA in pancreatic cancer, IDH1 or FGFR2 in biliary tract cancer and microsatellite instability or NTRK fusions in an agnostic tumour fashion, to predict response to treatment.In this consensus, a group of experts selected by the Spanish Society of Medical Oncology (SEOM) and the Spanish Society of Pathology (SEAP) reviewed the role played by these mutations in the process of carcinogenesis and their clinical implications. As a result, this article proposes a series of recommendations to optimize the determination of these biomarkers to help standardize the diagnosis and treatment of these tumours.
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Neoplasias do Sistema Biliar , Neoplasias Pancreáticas , Neoplasias do Sistema Biliar/diagnóstico , Neoplasias do Sistema Biliar/genética , Biomarcadores Tumorais/genética , Consenso , Humanos , Oncologia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Neoplasias PancreáticasRESUMO
Resumen Introducción y objetivos: El ultrasonido endoscópico con punción-aspiración con aguja fina (USE-PAAF) en lesiones neoplásicas biliopancreáticas suele tener un rendimiento alto, que depende de características de la lesión; aspectos técnicos de la USE-PAAF y la experiencia del endoscopista. De los factores menos estudiados es la presencia de patólogo en sala. Se plantea la realización de USE-PAAF con patólogo en sala para disminuir el número de pases, la tasa de muestras inadecuadas y la necesidad de repetir el procedimiento. Material y métodos: Estudio observacional, retrospectivo, con recolección prospectiva de enero de 2018 a junio de 2019, en pacientes adultos sometidos a USE-PAAF. Las muestras obtenidas fueron extendidas y evaluadas en salas de endoscopia por médico patólogo con coloración Diff-Quick y cuando se obtenía una muestra suficiente se enviaba en frasco con formol para bloque celular o biopsias. Resultados: Se realizaron 48 USE-PAAF biliopancreáticas en individuos con una edad mediana de 64 años. Las indicaciones más frecuentes fueron punciones por masa o pseudomasa pancreática (71 % de casos); Se diagnosticaron 35 malignidades (77 % correspondientes a adenocarcinoma, y 14 % a tumores neuroendocrinos). La mediana de tamaño de lesiones fue de 28 mm; el número de pases promedio fue de 3. Se obtuvieron resultados diagnósticos en 89 % frente a 11 % de falsos negativos. Se presentó 1 complicación menor (2,1 %), que fue dolor abdominal. Conclusiones: La USE-PAAF con patólogo en sala tiene alto rendimiento diagnóstico, con escasos resultados falsos negativos. Se requiere una mediana de pases menor, que podría minimizar los riesgos del procedimiento y la necesidad de repetir la prueba.
Abstract Introduction: Endoscopic ultrasound with fine-needle aspiration (EUS-FNA) of pancreatobiliary neoplastic lesions usually has a high performance that depends on the characteristics of the lesion, technical aspects, and expertise of the endoscopist. One of the least studied factors is rapid on-site evaluation with a pathologist in the room. Objective: To perform EUS-FNA with a pathologist in the endoscopy room to reduce the number of passes, the rate of inadequate samples and the need to repeat the procedure. Material and methods: Observational retrospective study with a prospective data collection approach from January 2018 to June 2019 of adult patients undergoing EUS-FNA. The samples obtained were spread and evaluated in endoscopy rooms by a pathologist with Diff-Quick stain, and when a sufficient sample was obtained, it was sent in a vial with formalin for cell block and/or biopsy. Results: 48 pancreatobiliary EUS-FNA were performed in individuals with a median age of 64 years. The most frequent indication was aspiration due to pancreatic mass (71%); 35 malignancies were diagnosed (77% were adenocarcinomas and 14% were neuroendocrine tumors). The median size of the lesions was 28mm, and the average number of passes was 3. Diagnostic results were obtained in 89% vs. 11% of false negatives. There was 1 minor complication (2.1%), which was abdominal pain. Conclusions: EUS-FNA with an in-room pathologist has a high diagnostic performance, with few false negative results. Also, a lower median number of passes is required, minimizing the risks of the procedure and the need for repeating it.
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Humanos , Masculino , Feminino , Doenças dos Ductos Biliares , Ductos Biliares Intra-Hepáticos , Doença de Caroli , Ultrassom , Dor Abdominal , Colangite , DiagnósticoRESUMO
Pancreatic cancer (PC) and biliary tract cancer (BTC) are both aggressive and highly fatal malignancies. Nowadays we have a profound knowledge about the molecular landscape of these neoplasms and this has allowed new therapeutic options. Surgery is the only potentially curative therapy in both cancers, but disease recurrence is frequent. In PC, adjuvant treatment with mFOLFIRINOX has improved overall survival (OS) and in BTC adjuvant treatment with capecitabine seems to improve OS and relapse-free survival. Concomitant radio-chemotherapy could also be considered following R1 surgery in both neoplasms. Neoadjuvant treatment represents the best option for achieving an R0 resection in borderline PC. Upfront systemic chemotherapy is the treatment of choice in unresectable locally advanced PC and BTC; then locoregional therapy could be considered after an initial period of at least 3-4 months of systemic chemotherapy. In metastatic PC, FOLFIRINOX or Gemcitabine plus nab-paclitaxel have improved OS compared with gemcitabine alone. In metastatic BTC, cisplatin plus gemcitabine constitute the standard treatment. Progress in the knowledge of molecular biology has enabled the identification of new targets for therapy with encouraging results that could in the future improve the survival and quality of life of patients with PC and BTC.
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Neoplasias do Sistema Biliar/terapia , Neoplasias Pancreáticas/terapia , Albuminas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Biliar/genética , Neoplasias do Sistema Biliar/patologia , Neoplasias do Sistema Biliar/cirurgia , Capecitabina/uso terapêutico , Quimiorradioterapia/métodos , Quimioterapia Adjuvante/métodos , Cisplatino/uso terapêutico , Fluoruracila/uso terapêutico , Humanos , Irinotecano/uso terapêutico , Leucovorina/uso terapêutico , Oncologia , Terapia Neoadjuvante/métodos , Estadiamento de Neoplasias , Oxaliplatina/uso terapêutico , Paclitaxel/uso terapêutico , Cuidados Paliativos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Qualidade de Vida , Sociedades Médicas , EspanhaRESUMO
The most common malignancy of the biliary tract, gallbladder cancer (GBC) often has a dismal prognosis. The aggressive nature of the tumor, delayed diagnosis at advanced stages of the disease, and lack of effective treatment options are some of the factors that contribute to a poor outcome. Early detection and accurate assessment of disease burden is critical to optimize management and improve long-term survival, as well as identify patients for adjuvant therapy and clinical trials. With recent advances in the understanding of the molecular pathogenesis of GBC, several specific diagnostic and biomarkers have been proposed as being of diagnostic and prognostic importance. Indeed, identification of novel diagnostic and prognostic markers has an important role in early diagnosis and development of targeted therapies among patients with GBC. Next-generation sequencing technology and genomewide data analysis have provided novel insight into understanding the molecular pathogenesis of biliary tract cancers, thereby identifying potential biomarkers for clinical use. We herein review available GBC biomarkers and the potential clinical implications in the management of GBC.
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Biomarcadores Tumorais/metabolismo , Neoplasias da Vesícula Biliar/diagnóstico , Neoplasias da Vesícula Biliar/terapia , Regulação Neoplásica da Expressão Gênica , Transdução de Sinais , Animais , Neoplasias da Vesícula Biliar/metabolismo , Humanos , PrognósticoRESUMO
Biliary tract cancer (BTC) is comprised of intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma (EHC) and gallbladder cancer (GBC). These tumors arise in the biliary epithelium, share histological characteristics and are associated with grim prognosis even when diagnosed at early stages. Moreover, its relatively low incidence in developed countries has precluded the development of clinical trials addressing specific differences among BTC subgroups in terms of their biology, treatment response and clinical outcomes. In this scenario, the development of effective treatment strategies for patients has been rather modest. To date, the combination of cisplatin plus gemcitabine remains as the standard first line therapy in advanced disease and after progression to this regimen there are limited treatment options. Next generation sequencing (NGS) studies have assessed the distribution of driver genes and potentially actionable genomic alterations among ICC, EHC and GBC. Here, we outline genomic differences among these subsets and describe key milestones in order to develop novel targeted drugs against BTCs. Although the early results of several studies are promising, international collaboration is critical to conduct adequately-powered trials, enrolling patients from high-incidence countries.
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Neoplasias do Sistema Biliar/genética , Genômica/métodos , Neoplasias do Sistema Biliar/patologia , Humanos , Prognóstico , Resultado do TratamentoRESUMO
BACKGROUND: Neuronal signaling has been implicated in the pathophysiology of multiple malignancies. In biliary tract cancers (BTCs), tumor cell expression of nerve growth factor (NGF) and its receptor neurotrophic tropomyosin receptor kinase (NTRK) has been reported in Asian patients and linked to inferior clinical outcome. Furthermore, NTRK fusions have emerged as a promising target in various cancers. Expression patterns of these markers in Caucasian patients remain unknown. METHODS: In this study, 106 patients with BTCs were included. Immunohistochemistry for pan-NTRK and NGF-beta was performed on > 90 samples of this cohort. Additionally, samples from two independent cohorts, incorporating 254 cases, were used to confirm the findings of the original cohort. RESULTS: While expression of pan-NTRK and NGF-beta was readily detectable in peri-tumoral nerves, these markers were not detectable in malignant epithelial cells in our cohort. CONCLUSIONS: In a large cohort of Caucasian patients with BTC, NTRK and NGF-beta were not detectable, underscoring potential differences between Caucasian and Asian patient populations.
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Neoplasias do Sistema Biliar/diagnóstico , Biomarcadores Tumorais/metabolismo , Fator de Crescimento Neural/metabolismo , Receptor trkA/metabolismo , População Branca/estatística & dados numéricos , Neoplasias do Sistema Biliar/etnologia , Neoplasias do Sistema Biliar/metabolismo , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos RetrospectivosRESUMO
Intrahepatic cholangiocarcinoma (ICC) is the second most prevalent primary liver neoplasm after hepatocellular carcinoma (HCC), corresponding to 10% to 15% of cases. Pathologies that cause chronic biliary inflammation and bile stasis are known predisposing factors for development of ICC. The incidence and cancer-related mortality of ICC is increasing worldwide. Most patients remain asymptomatic until advance stage, commonly presenting with a liver mass incidentally diagnosed. The only potentially curative treatment available for ICC is surgical resection. The prognosis is dismal for unresectable cases. The principle of the surgical approach is a margin negative hepatic resection with preservation of adequate liver remnant. Regional lymphadenectomy is recommended at time of hepatectomy due to the massive impact on outcomes caused by lymph node (LN) metastasis. Multicentric disease, tumor size, margin status and tumor differentiation are also important prognostic factors. Staging laparoscopy is warranted in high-risk patients to avoid unnecessary laparotomy. Exceedingly complex surgical procedures, such as major vascular, extrahepatic bile ducts and visceral resections, ex vivo hepatectomy and autotransplantation, should be implemented in properly selected patients to achieve negative margins. Neoadjuvant therapy may be used in initially unresectable lesions in order to downstage and allow resection. Despite optimal surgical management, recurrence is frustratingly high. Adjuvant chemotherapy with radiation associated with locoregional treatments should be considered in cases with unfavorable prognostic factors. Selected patients may undergo re-resection of tumor recurrence. Despite the historically poor outcomes of liver transplantation for ICC, highly selected patients with unresectable disease, especially those with adequate response to neoadjuvant therapy, may be offered transplant. In this article, we reviewed the current literature in order to highlight the most recent advances and recommendations for the surgical treatment of this aggressive malignancy.
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PURPOSE: To investigate the prevalence, related risk factors, and survival of intrahepatic cholangiocarcinoma in a Mexican population. MATERIAL AND METHODS: We conducted a cross-sectional study at Medica Sur Hospital in Mexico City with approval of the local research ethics committee. We found cases by reviewing all clinical records of in-patients between October 2005 and January 2016 who had been diagnosed with malignant liver tumors. Clinical characteristics and comorbidities were obtained to evaluate the probable risk factors and the Charlson index. The cases were staged based on the TNM staging system for bile duct tumors used by the American Joint Committee on Cancer and median patient survival rates were calculated using the Kaplan-Meier method. RESULTS: We reviewed 233 cases of hepatic cancer. Amongst these, hepatocellular carcinomas represented 19.3% (n = 45), followed by intrahepatic cholangiocarcinomas, which accounted for 7.7% (n = 18). The median age of patients with intrahepatic cholangiocarcinoma was 63 years, and most of them presented with cholestasis and intrahepatic biliary ductal dilation. Unfortunately, 89% (n = 16) of them were in an advanced stage and 80% had multicentric tumors. Median survival was 286 days among patients with advanced stage tumors (25th-75th interquartile range, 174-645 days). No correlation was found between the presence of comorbidities defined by the Charlson index, and survival. We evaluated the presence of definite and probable risk factors for the development of intrahepatic cholangiocarcinoma, that is, smoking, alcohol consumption, and primary sclerosing cholangitis. DISCUSSION: We found an overall prevalence of intrahepatic cholangiocarcinoma of 7.7%; unfortunately, these patients were diagnosed at advanced stages. Smoking and primary sclerosing cholangitis were the positive risk factors for its development in this population.
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Neoplasias dos Ductos Biliares/epidemiologia , Colangiocarcinoma/epidemiologia , Idoso , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/epidemiologia , Neoplasias dos Ductos Biliares/mortalidade , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/terapia , Colangiocarcinoma/mortalidade , Colangiocarcinoma/patologia , Colangiocarcinoma/terapia , Colangite Esclerosante/epidemiologia , Comorbidade , Estudos Transversais , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prevalência , Estudos Retrospectivos , Fatores de Risco , Fumar/efeitos adversos , Fumar/epidemiologia , Fatores de Tempo , Resultado do TratamentoRESUMO
Biliary tract cancer (BTC) is an uncommon and highly fatal malignancy. It is composed of three main different entities; Gall bladder carcinoma (GBC), intrahepatic cholangiocarcinoma (iCC) and extrahepatic cholangiocarcinoma (eCC) sharing different genetic, risk factors and clinical presentation. Multidetector-row computed tomography (MDCT) and magnetic resonance cholangio-pancreatography (MRCP) are the more important diagnostic techniques. Surgery is the only potentially curative therapy but disease recurrence is frequent. Treatment with chemotherapy, radiotherapy or both has not demonstrated survival benefit in the adjuvant setting. Cisplatin plus gemcitabine constitutes the gold standard in metastatic disease. New ongoing studies mainly in the adjuvant and neoadjuvant setting along with molecular research will hopefully help to improve survival and quality of life of this disease.
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Neoplasias do Sistema Biliar/diagnóstico , Neoplasias do Sistema Biliar/terapia , Guias de Prática Clínica como Assunto/normas , Ensaios Clínicos como Assunto , Terapia Combinada , Gerenciamento Clínico , Detecção Precoce de Câncer , Humanos , Oncologia , Estadiamento de Neoplasias , Prognóstico , Qualidade de Vida , Sociedades MédicasRESUMO
La diabetes mellitus se ha asociado con la presencia de algunos tipos de cáncer del tracto digestivo, sobre todo en los últimos años se ha relacionado con el cáncer de hígado, el páncreas y las vías biliares. Es por ello que se realizó el presente estudio retrospectivo con el objetivo de determinar la frecuencia del cáncer hepatobiliopancreático y su asociación con la presencia de diabetes en pacientes del Hospital Universitario de Maracaibo durante el periodo 2006-2012. Noventa y siete casos fueron registrados; con diagnóstico de neoplasias hepáticas malignas primarias (hepatocarcinoma-colangiocarcinoma intrahepático) 26,8%, Colangiocarcinomas extrahepáticos distales 21,6%, tumor de Klatskin 16,5%, cáncer de páncreas 10,3%, tumor periampular 5,2% y tumor de vesícula biliar 5,2%. En los pacientes diabéticos los tumores más frecuentes fueron el cáncer de páncreas y neoplasias hepáticas malignas primarias (94,8%, p<0,01). No se observó en el resto de los pacientes estudiados asociación significativa entre el diagnóstico de cáncer con la presencia de diabetes. Se necesitan estudios prospectivos con el fin de establecer los factores que pudieran influir en la génesis del cáncer en los pacientes diabéticos, tales como el tipo de tratamiento, alteraciones metabólicas y otros factores inflamatorios que pudiesen estar involucrados.
Diabetes mellitus has been associated with the presence of some types of cancer of the digestive tract, especially in recent years has been linked to cancer of the liver, pancreas and bile ducts. That is why we undertook the present retrospective study in order to determine the frequency of hepatobiliopancreatic cancer and its association with the presence of diabetes in patients at Maracaibo University Hospital during the period 2006-2012. 97 cases were reported, with a diagnosis of primary hepatic malignancies (hepatocellular carcinoma, intrahepatic cholangiocarcinoma) 26.8% 21.6% distal extrahepatic cholangiocarcinoma, Klatskin tumor 16.5% 10.3% pancreatic cancer, tumor periampullar 5,2% and gallbladder tumor 5.2%. In diabetic patients, the most common tumors were pancreatic cancer and primary hepatic malignancies (94.8%, p<0,01). It was not observed in the rest of the patients significant association between cancer diagnosis and the presence of diabetes. Prospective studies are needed in order to establish the factors that may influence the genesis of cancer in diabetic patients, such as the type of treatment, metabolic and inflammatory factors that may be involved.