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Reimann P, Mavroeidi IA, Burghofer J, Taghizadeh H, Webersinke G, Kasper S, Schreil G, Morariu D, Reichinger A, Baba HA, Kirchweger P, Schuler M, Djanani A, Prager GW, Rumpold H, Benda M, Schneider EM, Mink S, Winder T, Doleschal B. Exploring the impact of durvalumab on biliary tract cancer: insights from real-world clinical data. Cancer Immunol Immunother 2024; 73:251. [PMID: 39358611 PMCID: PMC11447177 DOI: 10.1007/s00262-024-03842-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Accepted: 09/20/2024] [Indexed: 10/04/2024]
Abstract
INTRODUCTION This study assesses the effectiveness of durvalumab with platinum and gemcitabine for biliary tract cancers (BTC). It aims to confirm the TOPAZ-1 trial results in a real-world context and explore the link between BTC molecular profiles and patient outcomes. METHODS A retrospective analysis was conducted on 102 BTC patients treated with durvalumab, platinum, and gemcitabine at five cancer centers in Austria and one in Germany from 2022 to 2024. Molecular profiling used targeted DNA and RNA assays. Clinical endpoints, including progression-free survival (PFS) and overall survival (OS), were assessed using log-rank tests and Cox regression, with correlations to second-line molecular-targeted therapies. RESULTS Among 102 patients, 60.8% had intrahepatic cholangiocarcinoma. The treatment achieved a disease control rate of 71.57% and an overall response rate of 35.11%. Median PFS was 6.51 months, and OS was 13.61 months. Patients under 65 had significantly better OS. Alterations in chromatin remodeling or homologous recombination repair genes were not predictive of survival benefit (HR: 0.45; p = 0.851 and HR: 1.63; p = 0.26, respectively). Patients with molecular-informed second-line therapy showed a trend toward survival benefit (HR: 0.23; p = 0.052). CONCLUSION This study confirms the phase 3 trial results of durvalumab with platinum and gemcitabine, providing a substantial real-world dataset with detailed molecular characterization. No specific patient subgroup showed a markedly better response to durvalumab based on conventional NGS panels. Further research is needed to explore the link between immunotherapy responses and molecular subgroups.
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Affiliation(s)
- Patrick Reimann
- Department of Internal Medicine II, Academic Teaching Hospital Feldkirch, Feldkirch, Austria
- Private University of the Principality of Liechtenstein, Triesen, Principality of Liechtenstein
| | - Ilektra-Antonia Mavroeidi
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany
- German Cancer Consortium (DKTK), Partner Site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, Essen, Germany
- Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Jonathan Burghofer
- Laboratory for Molecular Genetic Diagnostics, Ordensklinikum Linz, Linz, Austria
| | - Hossein Taghizadeh
- Department of Internal Medicine I, Universitätsklinikum St. Pölten, St. Pölten, Austria
| | - Gerald Webersinke
- Laboratory for Molecular Genetic Diagnostics, Ordensklinikum Linz, Linz, Austria
| | - Stefan Kasper
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany
- German Cancer Consortium (DKTK), Partner Site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, Essen, Germany
| | - Georg Schreil
- Department of Internal Medicine, State Hospital Pyhrn Eisenwurzen, Steyr, Austria
| | - Darius Morariu
- Department of Internal Medicine, State Hospital Wiener Neustadt, Wiener Neustadt, Austria
| | - Andreas Reichinger
- Department of Internal Medicine I for Hematology With Stem Cell Transplantation, Hemostaseology, and Medical Oncology, Ordensklinikum Linz, Linz, Austria
| | - Hideo Andreas Baba
- German Cancer Consortium (DKTK), Partner Site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, Essen, Germany
- Institute of Pathology, West German Cancer Center, University Hospital Essen, Essen, Germany
| | - Patrick Kirchweger
- Medical Faculty, Johannes Kepler University Linz, Linz, Austria
- Department of General and Visceral Surgery, Ordensklinikum Linz, Linz, Austria
- Gastrointestinal Cancer Center, Ordensklinikum Linz, Linz, Austria
| | - Martin Schuler
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany
- German Cancer Consortium (DKTK), Partner Site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, Essen, Germany
- National Center for Tumor Diseases (NCT) West, Campus Essen, Essen, Germany
| | - Angela Djanani
- Department of Internal Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Gerald W Prager
- Department of Medicine I, Division of Oncology, Medical University Vienna, Vienna, Austria
| | - Holger Rumpold
- Department of Internal Medicine I for Hematology With Stem Cell Transplantation, Hemostaseology, and Medical Oncology, Ordensklinikum Linz, Linz, Austria
- Medical Faculty, Johannes Kepler University Linz, Linz, Austria
- Gastrointestinal Cancer Center, Ordensklinikum Linz, Linz, Austria
| | - Magdalena Benda
- Department of Internal Medicine II, Academic Teaching Hospital Feldkirch, Feldkirch, Austria
- Private University of the Principality of Liechtenstein, Triesen, Principality of Liechtenstein
| | - Eva-Maria Schneider
- Department of Internal Medicine II, Academic Teaching Hospital Feldkirch, Feldkirch, Austria
| | - Sylvia Mink
- Private University of the Principality of Liechtenstein, Triesen, Principality of Liechtenstein
- Central Medical Laboratories, Feldkirch, Austria
| | - Thomas Winder
- Department of Internal Medicine II, Academic Teaching Hospital Feldkirch, Feldkirch, Austria
- University of Zurich, Zurich, Switzerland
| | - Bernhard Doleschal
- Department of Internal Medicine I for Hematology With Stem Cell Transplantation, Hemostaseology, and Medical Oncology, Ordensklinikum Linz, Linz, Austria.
- Medical Faculty, Johannes Kepler University Linz, Linz, Austria.
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Komiyama S, Okusaka T, Maruki Y, Ohba A, Nagashio Y, Kondo S, Hijioka S, Morizane C, Ueno H, Sukeda A, Mizui T, Takamoto T, Nara S, Ban D, Esaki M, Hiraoka N, Shimada K. Clinicopathological Findings and Treatment Outcomes of Patients with Primary Hepatobiliary Neuroendocrine Neoplasms: A Retrospective Single-institution Analysis. Intern Med 2024; 63:891-901. [PMID: 37612088 PMCID: PMC11045373 DOI: 10.2169/internalmedicine.2016-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Accepted: 07/11/2023] [Indexed: 08/25/2023] Open
Abstract
Objective Primary hepatobiliary neuroendocrine neoplasms (NENs) are rare tumors exhibiting several morphological and behavioral characteristics. Considering the lack of relevant data on this topic, we evaluated the clinicopathological features and treatment outcomes of patients with primary hepatobiliary NENs. Methods/Patients We examined 43 consecutive patients treated at the National Cancer Center Hospital with pathological diagnoses of primary hepatobiliary NEN between 1980 and 2016. Results Nine patients were diagnosed with neuroendocrine tumor (NET) G1, 9 with NET G2, and 25 with neuroendocrine carcinoma (NEC) based on the World Health Organization 2019 classification. Patients with NEC had primary sites across the hepatobiliary organs, although sites in patients with NET G1 and NET G2 only included the liver and ampulla of Vater. Patients with primary extrahepatic bile duct or ampulla of Vater NENs tended to be diagnosed earlier than patients with primary gallbladder NENs. The median survival times in the NET G1, NET G2, and NEC groups were 167.9, 97.4, and 11.1 months, respectively. A good performance status, absence of distant metastases, and low tumor grade were identified as independent predictors of a favorable prognosis. Conclusion The NET-to-NEC ratio and tumor stage distribution at the diagnosis differed depending on the primary site. Patients with G1 and G2 NETs who underwent surgical resection had good prognoses, whereas those with NEC exhibited more advanced disease and poorer prognoses. The performance status, staging classification, and tumor grade are important factors to consider when devising an appropriate treatment strategy and predicting the prognoses of patients with primary hepatobiliary NEN.
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Affiliation(s)
- Satoshi Komiyama
- Chemotherapy Department, Yokohama City University Medical Center, Japan
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Japan
| | - Takuji Okusaka
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Japan
| | - Yuta Maruki
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Japan
| | - Akihiro Ohba
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Japan
| | - Yoshikuni Nagashio
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Japan
| | - Shunsuke Kondo
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Japan
| | - Susumu Hijioka
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Japan
| | - Chigusa Morizane
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Japan
| | - Hideki Ueno
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Japan
| | - Aoi Sukeda
- Pathology and Clinical Laboratories, National Cancer Center Hospital, Japan
- Department of Anatomic Pathology, Tokyo Medical University, Japan
| | - Takahiro Mizui
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Japan
| | - Takeshi Takamoto
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Japan
| | - Satoshi Nara
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Japan
| | - Daisuke Ban
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Japan
| | - Minoru Esaki
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Japan
| | - Nobuyoshi Hiraoka
- Pathology and Clinical Laboratories, National Cancer Center Hospital, Japan
| | - Kazuaki Shimada
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Japan
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Islam MA, Barshetty MM, Srinivasan S, Dudekula DB, Rallabandi VPS, Mohammed S, Natarajan S, Park J. Identification of Novel Ribonucleotide Reductase Inhibitors for Therapeutic Application in Bile Tract Cancer: An Advanced Pharmacoinformatics Study. Biomolecules 2022; 12:biom12091279. [PMID: 36139117 PMCID: PMC9496582 DOI: 10.3390/biom12091279] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 09/05/2022] [Accepted: 09/08/2022] [Indexed: 11/28/2022] Open
Abstract
Biliary tract cancer (BTC) is constituted by a heterogeneous group of malignant tumors that may develop in the biliary tract, and it is the second most common liver cancer. Human ribonucleotide reductase M1 (hRRM1) has already been proven to be a potential BTC target. In the current study, a de novo design approach was used to generate novel and effective chemical therapeutics for BTC. A set of comprehensive pharmacoinformatics approaches was implemented and, finally, seventeen potential molecules were found to be effective for the modulation of hRRM1 activity. Molecular docking, negative image-based ShaEP scoring, absolute binding free energy, in silico pharmacokinetics, and toxicity assessments corroborated the potentiality of the selected molecules. Almost all molecules showed higher affinity in comparison to gemcitabine and naphthyl salicylic acyl hydrazone (NSAH). On binding interaction analysis, a number of critical amino acids was found to hold the molecules at the active site cavity. The molecular dynamics (MD) simulation study also indicated the stability between protein and ligands. High negative MM-GBSA (molecular mechanics generalized Born and surface area) binding free energy indicated the potentiality of the molecules. Therefore, the proposed molecules might have the potential to be effective therapeutics for the management of BTC.
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Affiliation(s)
- Md Ataul Islam
- 3BIGS Omicscore Private Limited, 909 Lavelle Building, Richmond Circle, Bangalore 560025, India
| | | | - Sridhar Srinivasan
- 3BIGS Omicscore Private Limited, 909 Lavelle Building, Richmond Circle, Bangalore 560025, India
| | - Dawood Babu Dudekula
- 3BIGS Omicscore Private Limited, 909 Lavelle Building, Richmond Circle, Bangalore 560025, India
| | | | - Sameer Mohammed
- 3BIGS Omicscore Private Limited, 909 Lavelle Building, Richmond Circle, Bangalore 560025, India
| | | | - Junhyung Park
- 3BIGS Co., Ltd., B-831, Geumgang Penterium IX Tower, Hwaseong 18469, Korea
- Correspondence:
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Abstract
Primary liver cancer (PLC) is a fatal disease that affects millions of lives worldwide. PLC is the leading cause of cancer-related deaths and the incidence rate is predicted to rise in the coming decades. PLC can be categorized into three major histological subtypes: hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), and combined HCC-ICC. These subtypes are distinct with respect to epidemiology, clinicopathological features, genetic alterations, and clinical managements, which are thoroughly summarized in this review. The state of treatment strategies for each subtype, including the currently approved drugs and the potential novel therapies, are also discussed.
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Affiliation(s)
- Mei Feng
- Translational Cancer Research Center, Peking University First Hospital, Beijing 100034, China
- Department of General Surgery, Peking University First Hospital, Beijing 100034, China
| | - Yisheng Pan
- Department of General Surgery, Peking University First Hospital, Beijing 100034, China
| | - Ruirui Kong
- Translational Cancer Research Center, Peking University First Hospital, Beijing 100034, China
| | - Shaokun Shu
- Translational Cancer Research Center, Peking University First Hospital, Beijing 100034, China
- Department of Biomedical Engineering, Peking University, Beijing 100871, China
- Peking University Cancer Hospital, Beijing 100142, China
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Lamarca A, Ross P, Wasan HS, Hubner RA, McNamara MG, Lopes A, Manoharan P, Palmer D, Bridgewater J, Valle JW. Advanced Intrahepatic Cholangiocarcinoma: Post Hoc Analysis of the ABC-01, -02, and -03 Clinical Trials. J Natl Cancer Inst 2020; 112:200-210. [PMID: 31077311 DOI: 10.1093/jnci/djz071] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 03/26/2019] [Accepted: 03/19/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The incidence of intrahepatic cholangiocarcinoma (iCCA) is increasing. The aim of the study was to provide reference survival data for patients with advanced iCCA treated with first-line cisplatin-gemcitabine chemotherapy (current standard of care). METHODS Individual data from patients with iCCA recruited into the prospective, random assignment Advanced Biliary Tract Cancer (ABC)-01, -02, and -03 studies were retrieved. The prevalence and survival of liver-only iCCA was also assessed. Survival analysis was performed using univariate and multivariable Cox regression. All statistical tests were two-sided. RESULTS Of 534 patients recruited into the ABC-01, -02, and -03 studies, 109 (20.4%) had iCCA. Most patients (n = 86, 78.9%) had metastatic disease at the time of recruitment; 52 patients (47.7%) had liver-only disease. Following random assignment, 66 (60.6%) iCCA patients received cisplatin and gemcitabine. The median progression-free and overall survival (OS) were 8.4 months (95% confidence interval [CI] = 5.9 to 8.9 months) and 15.4 months (95% CI = 11.1 to 17.9 months), respectively. Of these 66 patients, 34 patients (51.5%) had liver-only disease. Following chemotherapy, 30 (45.5%) and 21 (31.8%) were progression-free at 3 and 6 months from chemotherapy commencement, respectively. The median OS for patients with liver-only iCCA at diagnosis and after 3 and 6 months of chemotherapy was 16.7 months (95% CI = 8.7 to 20.2 months), 17.9 months (95% CI = 11.7 to 20.9 months), and 18.9 months (95% CI = 16.7 to 25.9 months), respectively. Multivariable analysis confirmed that iCCA had a longer OS compared with other non-iCCA biliary tract cancers (hazard ratio = 0.58, 95% CI = 0.35 to 0.95, P value = .03); liver-only iCCA patients also showed longer OS even though findings did not reach statistical significance (hazard ratio = 0.65, 95% CI = 0.36 to 1.19, P value = .16). CONCLUSIONS Patients diagnosed with advanced iCCA have a better OS compared with other biliary tract cancers; a similar trend was identified for patients diagnosed with liver-only iCCA. These findings are to be considered for future clinical trial design.
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Affiliation(s)
- Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK.,Division of Cancer Sciences, University of Manchester, Manchester, UK.,Cancer Research UK & UCL Cancer Centre, University College of London, London, UK
| | - Paul Ross
- Department of Medical Oncology, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Harpreet S Wasan
- Department of Medical Oncology, Imperial College Healthcare, London, UK
| | - Richard A Hubner
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK.,Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Mairéad G McNamara
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK.,Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Andre Lopes
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK.,Division of Cancer Sciences, University of Manchester, Manchester, UK.,Cancer Research UK & UCL Cancer Centre, University College of London, London, UK
| | - Prakash Manoharan
- Department of Radiology and Nuclear Medicine, The Christie NHS Foundation Trust, Manchester, UK
| | - Daniel Palmer
- Department of Medical Oncology, Clatterbridge Cancer Centre, Liverpool, UK
| | - John Bridgewater
- Department of Medical Oncology, UCL Cancer Institute, London, UK
| | - Juan W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK.,Division of Cancer Sciences, University of Manchester, Manchester, UK
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Chakrabarti S, Kamgar M, Mahipal A. Targeted Therapies in Advanced Biliary Tract Cancer: An Evolving Paradigm. Cancers (Basel) 2020; 12:2039. [PMID: 32722188 PMCID: PMC7465131 DOI: 10.3390/cancers12082039] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 07/21/2020] [Accepted: 07/23/2020] [Indexed: 12/18/2022] Open
Abstract
Biliary tract cancers (BTCs) are a heterogeneous group of adenocarcinomas that originate from the epithelial lining of the biliary tree. BTCs are characterized by presentation with advanced disease precluding curative surgery, rising global incidence, and a poor prognosis. Chemotherapy is the mainstay of the current treatment, which results in a median overall survival of less than one year, underscoring the need for novel therapeutic agents and strategies. Next-generation sequencing-based molecular profiling has shed light on the underpinnings of the complex pathophysiology of BTC and has uncovered numerous actionable targets, leading to the discovery of new therapies tailored to the molecular targets. Therapies targeting fibroblast growth factor receptor (FGFR) fusion, isocitrate dehydrogenase (IDH) mutations, the human epidermal growth factor receptor (HER) family, DNA damage repair (DDR) pathways, and BRAF mutations have produced early encouraging results in selected patients. Current clinical trials evaluating targeted therapies, as monotherapies and in combination with other agents, are paving the way for novel treatment options. Genomic profiling of cell-free circulating tumor DNA that can assist in the identification of an actionable target is another exciting area of development. In this review, we provide a contemporaneous appraisal of the evolving targeted therapies and the ongoing clinical trials that will likely transform the therapeutic paradigm of BTC.
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Affiliation(s)
- Sakti Chakrabarti
- Department of Hematology-Oncology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; (S.C.); (M.K.)
| | - Mandana Kamgar
- Department of Hematology-Oncology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; (S.C.); (M.K.)
| | - Amit Mahipal
- Department of Medical Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
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Lamarca A, Barriuso J, McNamara MG, Valle JW. Molecular targeted therapies: Ready for "prime time" in biliary tract cancer. J Hepatol 2020; 73:170-185. [PMID: 32171892 DOI: 10.1016/j.jhep.2020.03.007] [Citation(s) in RCA: 254] [Impact Index Per Article: 50.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 03/02/2020] [Accepted: 03/03/2020] [Indexed: 12/13/2022]
Abstract
The prognosis for patients with biliary tract cancers (cholangiocarcinoma and gallbladder cancer) is poor, while the incidence of these cancers is increasing. Most patients are diagnosed with advanced disease when treatment options are limited to palliative approaches, mainly focused on chemotherapy. In recent years, novel treatment targets of relevance to biliary tract cancers, mainly present in patients with intrahepatic cholangiocarcinoma, have been identified and are rapidly changing the field. These include fibroblast growth factor receptor (FGFR) fusions and isocitrate dehydrogenase (IDH)-1 and -2 mutations which are each present in around 10-20% of patients with intrahepatic cholangiocarcinoma. In addition, inhibition of other pathways/molecules is currently being explored, including human epidermal growth factor receptor (HER) family members, the Wnt pathway, neurotropic tyrosine kinase receptor (NTRK) fusions and BRAF mutations. The IDH1 inhibitor ivosidenib has already been tested in a phase III clinical trial in pretreated cholangiocarcinoma and showed benefit in terms of progression-free survival. Multiple FGFR inhibitors have consistently shown high response rates in phase II/III trials, especially for patients harbouring FGFR2 fusions. Herein, we provide an overview of the status of targeted therapies in biliary tract cancers, discussing the current clinical development of IDH and FGFR inhibitors in detail, as well as reviewing current caveats and future steps.
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Affiliation(s)
- Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK; Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
| | - Jorge Barriuso
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK; Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Mairéad G McNamara
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK; Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Juan W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK; Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
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8
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Iyer P, Chen MH, Goyal L, Denlinger CS. Targets for therapy in biliary tract cancers: the new horizon of personalized medicine. Chin Clin Oncol 2020; 9:7. [PMID: 32146818 PMCID: PMC8650725 DOI: 10.21037/cco.2019.12.11] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 12/05/2019] [Indexed: 12/18/2022]
Abstract
Biliary tract cancers (BTCs) are a set of molecularly distinct and heterogeneous diseases. While cytotoxic chemotherapy remains the current standard of care for treatment-naïve and treatment-refractory unresectable disease, recently identified mutations driving oncologic development offer opportunities for targeted therapy. Currently, alterations in the fibroblast growth factor receptor (FGFR), isocitrate dehydrogenase (IDH), v-Raf murine sarcoma viral oncogene homolog B (BRAF), DNA damage repair, and HER2 pathways have demonstrated promising new therapeutic avenues, among others, and various studies have demonstrated clinical activity with targeted tyrosine kinase inhibitors and/or antibodies. In this review, we will discuss the currently identified targets for therapy in BTCs and review currently available data regarding clinical development of treatment options in these molecularly distinct subsets.
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Affiliation(s)
- Pritish Iyer
- Fox Chase Cancer Center, Temple University Health System, Philadelphia, PA, USA
| | - Ming-Huang Chen
- Department of Oncology, Taipei Veteran's General Hospital, Taipei
| | - Lipika Goyal
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA
| | - Crystal S Denlinger
- Fox Chase Cancer Center, Temple University Health System, Philadelphia, PA, USA.
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9
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Abou-Alfa GK, Jarnagin W, El Dika I, D'Angelica M, Lowery M, Brown K, Ludwig E, Kemeny N, Covey A, Crane CH, Harding J, Shia J, O'Reilly EM. Liver and Bile Duct Cancer. ABELOFF'S CLINICAL ONCOLOGY 2020:1314-1341.e11. [DOI: 10.1016/b978-0-323-47674-4.00077-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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10
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Lamarca A, Frizziero M, McNamara MG, Valle JW. Clinical and Translational Research Challenges in Biliary Tract Cancers. Curr Med Chem 2020; 27:4756-4777. [PMID: 31971102 DOI: 10.2174/0929867327666200123090153] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 11/27/2019] [Accepted: 01/13/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Biliary Tract Cancers (BTC) are rare malignancies with a poor prognosis. There are many challenges encountered in treating these patients in daily practice as well as in clinical, translational and basic research. OBJECTIVE This review summarises the most relevant challenges in clinical and translational research in BTCs and suggests potential solutions towards an improvement in quality of life and outcomes of patients diagnosed with such malignancies. FINDINGS The main challenge is the low number of patients with BTCs, complicated by the aggressive natural behaviour of cancer and the lack of funding sources for research. In addition, the clinical characteristics of these patients and the specific cancer-related complications challenge clinical research and clinical trial recruitment. It is worth highlighting that BTCs are a group of different malignancies (cholangiocarcinoma, gallbladder cancer and ampullary cancer) rather than a unique homogeneous disease. These subgroups differ not only in molecular aspects, but also in clinical and demographic characteristics. In addition, tailored imaging and quality of life assessment are required to tackle some of the issues specific to BTCs. Finally, difficulties in tissue acquisition both in terms of biopsy size and inclusion of sufficient tumour within the samples, may adversely impact translational and basic research. CONCLUSION Increasing awareness among patients and clinicians regarding BTC and the need for further research and treatment development may address some of the main challenges in BTC research. International collaboration is mandatory to progress the field.
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Affiliation(s)
- Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Melissa Frizziero
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Mairéad G McNamara
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Juan W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom
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11
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Ueno T, Tsuchikawa T, Hatanaka KC, Hatanaka Y, Mitsuhashi T, Nakanishi Y, Noji T, Nakamura T, Okamura K, Matsuno Y, Hirano S. Prognostic impact of programmed cell death ligand 1 (PD-L1) expression and its association with epithelial-mesenchymal transition in extrahepatic cholangiocarcinoma. Oncotarget 2018; 9:20034-20047. [PMID: 29732001 PMCID: PMC5929444 DOI: 10.18632/oncotarget.25050] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Accepted: 03/21/2018] [Indexed: 12/31/2022] Open
Abstract
Extrahepatic cholangiocarcinoma (eCCA) has a poor prognosis. Although the possibility of immunotherapy has been studied, immune checkpoint molecules such as programmed death ligand 1 (PD-L1) in eCCA are not well understood. Epithelial-mesenchymal transition (EMT) has recently been shown to regulate PD-L1 expression. Our aims were to assess the clinicopathological significance of tumor-infiltrating lymphocytes (TILs) and tumor PD-L1 expression in eCCA and to compare these immune responses with EMT marker expression. In this retrospective study, we conducted immunohistochemical analyses for 117 patients with eCCA. We stained for CD4, CD8, Foxp3, and PD-L1 as markers reflecting local immune responses, and for E-cadherin, N-cadherin, vimentin, ZEB1, ZEB2, SNAIL, and TWIST as markers associated with EMT. High numbers of CD4+ and CD8+ TILs correlated with node-negative (P = 0.009 and P = 0.046, respectively) and low SNAIL expression (P = 0.016 and P = 0.022, respectively). High PD-L1 expression was associated with poor histopathological classification (P = 0.034), and low E-cadherin (P = 0.001), high N-cadherin (P = 0.044), high vimentin (P < 0.001) and high ZEB1 (P = 0.036) expression. Multivariate analysis showed that CD4+ TILs, PD-L1 expression and N-cadherin expression were independent prognostic factors (hazard ratio (HR) = 0.61; 95% confidence interval (CI) = 0.38-1.00; HR=4.27; 95% CI = 1.82-9.39; HR = 2.20; 95% CI = 1.18-3.92, respectively). These findings could help to identify potential biomarkers for predicting not only the prognosis, but also the therapeutic response to immunotherapy for eCCA.
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Affiliation(s)
- Takashi Ueno
- Department of Gastroenterological Surgery II, Division of Surgery, Faculty of Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
- Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Hokkaido, Japan
| | - Takahiro Tsuchikawa
- Department of Gastroenterological Surgery II, Division of Surgery, Faculty of Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Kanako C. Hatanaka
- Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Hokkaido, Japan
| | - Yutaka Hatanaka
- Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Hokkaido, Japan
| | - Tomoko Mitsuhashi
- Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Hokkaido, Japan
| | - Yoshitsugu Nakanishi
- Department of Gastroenterological Surgery II, Division of Surgery, Faculty of Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Takehiro Noji
- Department of Gastroenterological Surgery II, Division of Surgery, Faculty of Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Toru Nakamura
- Department of Gastroenterological Surgery II, Division of Surgery, Faculty of Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Keisuke Okamura
- Department of Gastroenterological Surgery II, Division of Surgery, Faculty of Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Yoshihiro Matsuno
- Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Hokkaido, Japan
| | - Satoshi Hirano
- Department of Gastroenterological Surgery II, Division of Surgery, Faculty of Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
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Abdel‐Rahman O, Elsayed Z, Elhalawani H. Gemcitabine-based chemotherapy for advanced biliary tract carcinomas. Cochrane Database Syst Rev 2018; 4:CD011746. [PMID: 29624208 PMCID: PMC6494548 DOI: 10.1002/14651858.cd011746.pub2] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Biliary tract cancers are a group of rare heterogeneous malignant tumours. They include intrahepatic and extrahepatic cholangiocarcinomas, gallbladder carcinomas, and ampullary carcinomas. Surgery remains the optimal modality of therapy leading to long-term survival for people diagnosed with resectable biliary tract carcinomas. Unfortunately, most people with biliary tract carcinomas are diagnosed with either unresectable locally-advanced or metastatic disease, and they are only suitable for palliative chemotherapy or supportive care. OBJECTIVES To assess the benefits and harms of intravenous administration of gemcitabine monotherapy or gemcitabine-based chemotherapy versus placebo, or no intervention, or other treatments (excluding gemcitabine) in adults with advanced biliary tract carcinomas. SEARCH METHODS We performed electronic searches in the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, LILACS, Science Citation Index Expanded, and Conference Proceedings Citation Index - Science up to June 2017. We also checked reference lists of primary original studies and review articles manually, for further related articles (cross-references). SELECTION CRITERIA Eligible studies include randomised clinical trials, irrespective of language or publication status, comparing intravenous administration of gemcitabine monotherapy or gemcitabine-based combination to placebo, to no intervention, or to treatments other than gemcitabine. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. We assessed risks of bias of the included trials using definitions of predefined bias risk domains, and presented the review results incorporating the methodological quality of the trials using GRADE. MAIN RESULTS We included seven published randomised clinical trials with 600 participants. All included trials were at high risk of bias, and we rated the evidence as very low quality. Cointerventions were equally applied in three trials (gemcitabine plus S-1 (a combination of tegafur, gimeracil, and oteracil) versus S-1 monotherapy; gemcitabine plus S-1 versus gemcitabine monotherapy versus S-1 monotherapy; and gemcitabine plus vandetanib versus gemcitabine plus placebo versus vandetanib monotherapy), while four trials compared gemcitabine plus cisplatin versus S-1 plus cisplatin; gemcitabine plus mitomycin C versus capecitabine plus mitomycin C; gemcitabine plus oxaliplatin versus chemoradiotherapy; and gemcitabine plus oxaliplatin versus 5-fluorouracil plus folinic acid versus best supportive care. The seven trials were conducted in India, Japan, France, China, Austria, South Korea, and Italy. The median age of the participants in the seven trials was between 50 and 60 years, and the male/female ratios were comparable in most of the trials. Based on these seven trials, we established eight comparisons. We could not perform all planned analyses in all comparisons because of insufficient data.Gemcitabine versus vandetanibOne three-arm trial compared gemcitabine versus vandetanib versus both drugs in combination. It reported no data for mortality, health-related quality of life, or tumour progression outcomes. We rated the increased risk of serious adverse events, anaemia, and overall response rate as very low-certainty evidence.Gemcitabine plus cisplatin versus S-1 plus cisplatinFrom one trial of 96 participants, we found very low-certainty evidence that gemcitabine can lower the risk of mortality at one year when used with cisplatin versus S-1 plus cisplatin (risk ratio (RR) 0.76, 95% confidence interval (CI) 0.58 to 0.98; P = 0.04; participants = 96). The trial did not report data for serious adverse events, quality of life, or tumour response outcomes. There is very low-certainty evidence that gemcitabine plus cisplatin combination leads to a higher risk of high-grade thrombocytopenia compared with S-1 plus cisplatin combination (RR 5.28, 95% CI 1.23 to 22.55; P = 0.02; participants = 96).Gemcitabine plus S-1 versus S-1From two trials enrolling 151 participants, we found no difference between the two groups in terms of risk of mortality at one year or risk of serious adverse events. Gemcitabine plus S-1 combination was associated with a higher overall response rate compared with S-1 alone (RR 2.46, 95% CI 1.27 to 4.75; P = 0.007; participants = 140; trials = 2; I2 = 0%; very low certainty of evidence). Neither of the trials reported data for health-related quality of life or time to progression of the tumour.Gemcitabine plus oxaliplatin versus 5-fluorouracil plus folinic acid versus best supportive careOne three-arm trial compared gemcitabine plus oxaliplatin versus 5-fluorouracil plus folinic acid versus best supportive care. It reported no data for serious adverse events, health-related quality of life, or tumour progression. We rated the evidence for mortality and for overall response rate as of very low certainty.Gemcitabine plus oxaliplatin versus 5-fluorouracil plus cisplatin plus radiotherapyOne trial of 34 participants compared gemcitabine plus oxaliplatin versus 5-fluorouracil plus cisplatin plus radiotherapy. It reported no data for quality of life, overall response rate, or tumour progression outcomes. We rated the evidence for mortality and serious adverse events as of very low certainty.Gemcitabine plus mitomycin C versus capecitabine plus mitomycin COne trial of 51 participants compared gemcitabine plus mitomycin C versus capecitabine plus mitomycin C. It reported no data for serious adverse events, quality of life, or tumour progression. We rated the evidence for mortality, overall response rate and thrombocytopenia as of very low certainty.We also identified three ongoing trials evaluating outcomes of interest for our review, which we can incorporate in future updates.For-profit bias: there was a high risk of for-profit bias in two trials (because of industry sponsorship) while there was a low risk of for-profit bias in another three trials, and unclear risk in two trials. AUTHORS' CONCLUSIONS In adults with advanced biliary tract carcinomas, the effects of gemcitabine or gemcitabine-based chemotherapy are uncertain on mortality and overall response compared with a range of inactive or active controls. The very low certainty of evidence is due to risk of bias, lack of information in the analyses and hence large imprecision, and possible publication bias. The confidence intervals do not rule out meaningful benefits or lack of effect of gemcitabine in all comparisons but one on mortality where gemcitabine plus cisplatin is compared with S-1 plus cisplatin. Gemcitabine-based regimens showed an increase in non-serious adverse events (particularly haematological toxicities). Further randomised clinical trials are mandatory, to further explore the best therapeutic options for adults with advanced biliary tract carcinomas.
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Affiliation(s)
- Omar Abdel‐Rahman
- University of Calgary and Tom Baker Cancer CenterDepartment of OncologyCalgaryAlbertaCanadaT2N 4N1
- Faculty of Medicine, Ain Shams UniversityClinical OncologyLofty Elsayed StreetCairoEgypt11335
| | - Zeinab Elsayed
- Faculty of Medicine, Ain Shams UniversityClinical OncologyLofty Elsayed StreetCairoEgypt11335
| | - Hesham Elhalawani
- The University of Texas MD Anderson Cancer CenterDepartment of Radiation Oncology1515 Holcombe BlvdHoustonTexasUSA77030
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13
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Trachu N, Sirachainan E, Larbcharoensub N, Rattanadech W, Detarkom S, Monnamo N, Kamprerasart K, MunTham D, Sukasem C, Reungwetwattana T. Molecular alterations and clinical prognostic factors for cholangiocarcinoma in Thai population. Onco Targets Ther 2017; 10:4955-4968. [PMID: 29066915 PMCID: PMC5644605 DOI: 10.2147/ott.s143982] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
This study explores genomic alterations in cholangiocarcinoma (CCC) tissues in Thai patients. We identified and reviewed the records of patients who had been diagnosed with CCC and for whom sufficient tumor samples for DNA and RNA extraction were available in our database. The specimens were explored for EGFR, KRAS, BRAF, and PIK3CA mutations and ROS1 translocation in 81 samples. Immunohistochemistry staining for HER2, ALK, and Ki-67 expression was tested in 74 samples. Prevalence of EGFR, KRAS, and PIK3CA mutations in this study was 21%, 12%, and 16%, respectively. No BRAF V600 mutation or ROS1 translocation was found. Patients with T790M mutation had a significantly longer overall survival (18.84 months) than those with the other types of EGFR mutations (4.08 months; hazard ratio [HR]: 0.26, P=0.038) and also had a significantly lower median Ki-67 (22.5% vs 80%, P=0.025). Furthermore, patients with PIK3CA mutations had a significantly longer median progression-free survival (15.87 vs 7.01 months; HR: 0.46, P=0.043). Strongly positive HER2 expression was found in only 1 patient, whereas ALK expression was not found. The presence of EGFR and/or PIK3CA mutations implies that targeted drugs may provide a feasible CCC treatment in the future.
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Affiliation(s)
- N Trachu
- Research Center, Faculty of Medicine Ramathibodi Hospital.,Molecular Medicine Program, Multidisciplinary Unit, Faculty of Science
| | - E Sirachainan
- Division of Medical Oncology, Department of Medicine
| | - N Larbcharoensub
- Division of Anatomical Pathology, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University
| | - W Rattanadech
- Division of Medical Oncology, Department of Medicine
| | - S Detarkom
- Division of Medical Oncology, Department of Medicine
| | - N Monnamo
- Research Center, Faculty of Medicine Ramathibodi Hospital
| | - K Kamprerasart
- Division of Anatomical Pathology, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University
| | - D MunTham
- Section for Mathematic, Faculty of Science and Technology, Rajamangala University of Technology Suvarnabhumi
| | - C Sukasem
- Division of Pharmacogenomics and Personalized Medicine, Department of Pathology.,Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC), Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
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14
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Valle JW, Lamarca A, Goyal L, Barriuso J, Zhu AX, Knittel G, Leeser U, van Oers J, Edelmann W, Heukamp LC, Reinhardt HC. New Horizons for Precision Medicine in Biliary Tract Cancers. Cancer Discov 2017. [PMID: 28818953 DOI: 10.1158/2159-8290] [Citation(s) in RCA: 163] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Biliary tract cancers (BTC), including cholangiocarcinoma and gallbladder cancer, are poor-prognosis and low-incidence cancers, although the incidence of intrahepatic cholangiocarcinoma is rising. A minority of patients present with resectable disease but relapse rates are high; benefit from adjuvant capecitabine chemotherapy has been demonstrated. Cisplatin/gemcitabine combination chemotherapy has emerged as the reference first-line treatment regimen; there is no standard second-line therapy. Selected patients may be suitable for liver-directed therapy (e.g., radioembolization or external beam radiation), pending confirmation of benefit in randomized studies. Initial trials targeting the epithelial growth factor receptor and angiogenesis pathways have failed to deliver new treatments. Emerging data from next-generation sequencing analyses have identified actionable mutations (e.g., FGFR fusion rearrangements and IDH1 and IDH2 mutations), with several targeted drugs entering clinical development with encouraging results. The role of systemic therapies, including targeted therapies and immunotherapy for BTC, is rapidly evolving and is the subject of this review.Significance: The authors address genetic drivers and molecular biology from a translational perspective, in an intent to offer a clear view of the recent past, present, and future of BTC. The review describes a state-of-the-art update of the current status and future directions of research and therapy in advanced BTC. Cancer Discov; 7(9); 943-62. ©2017 AACR.
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Affiliation(s)
- Juan W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, UK. .,Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester, UK
| | - Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, UK
| | - Lipika Goyal
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
| | - Jorge Barriuso
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, UK.,Faculty of Medical, Biological and Human Sciences, University of Manchester, Rumford Street, Manchester, UK
| | - Andrew X Zhu
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
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15
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Valle JW, Lamarca A, Goyal L, Barriuso J, Zhu AX. New Horizons for Precision Medicine in Biliary Tract Cancers. Cancer Discov 2017; 7:943-962. [PMID: 28818953 DOI: 10.1158/2159-8290.cd-17-0245] [Citation(s) in RCA: 438] [Impact Index Per Article: 54.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2017] [Revised: 05/24/2017] [Accepted: 07/10/2017] [Indexed: 02/06/2023]
Abstract
Biliary tract cancers (BTC), including cholangiocarcinoma and gallbladder cancer, are poor-prognosis and low-incidence cancers, although the incidence of intrahepatic cholangiocarcinoma is rising. A minority of patients present with resectable disease but relapse rates are high; benefit from adjuvant capecitabine chemotherapy has been demonstrated. Cisplatin/gemcitabine combination chemotherapy has emerged as the reference first-line treatment regimen; there is no standard second-line therapy. Selected patients may be suitable for liver-directed therapy (e.g., radioembolization or external beam radiation), pending confirmation of benefit in randomized studies. Initial trials targeting the epithelial growth factor receptor and angiogenesis pathways have failed to deliver new treatments. Emerging data from next-generation sequencing analyses have identified actionable mutations (e.g., FGFR fusion rearrangements and IDH1 and IDH2 mutations), with several targeted drugs entering clinical development with encouraging results. The role of systemic therapies, including targeted therapies and immunotherapy for BTC, is rapidly evolving and is the subject of this review.Significance: The authors address genetic drivers and molecular biology from a translational perspective, in an intent to offer a clear view of the recent past, present, and future of BTC. The review describes a state-of-the-art update of the current status and future directions of research and therapy in advanced BTC. Cancer Discov; 7(9); 943-62. ©2017 AACR.
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Affiliation(s)
- Juan W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, UK. .,Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester, UK
| | - Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, UK
| | - Lipika Goyal
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
| | - Jorge Barriuso
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, UK.,Faculty of Medical, Biological and Human Sciences, University of Manchester, Rumford Street, Manchester, UK
| | - Andrew X Zhu
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
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16
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Sahu S, Sun W. Targeted therapy in biliary tract cancers-current limitations and potentials in the future. J Gastrointest Oncol 2017; 8:324-336. [PMID: 28480071 PMCID: PMC5401865 DOI: 10.21037/jgo.2016.09.16] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2016] [Accepted: 08/17/2016] [Indexed: 12/12/2022] Open
Abstract
Biliary tract cancers (BTC)/Cholangiocarcinoma (CCA) is an aggressive biliary tract epithelial malignancy from varying locations within the biliary tree with cholangiocyte depreciation., including intrahepatic cholangiocarcinoma (iCCA) (iCCA), extrahepatic cholangiocarcinoma (eCCA) and gallbladder carcinoma (GBC). The disease is largely heterogeneous in etiology, epidemiology, and molecular profile. There are limited treatment options and low survival rates for those patients with advanced or metastatic disease. Systemic treatment is confined to cytotoxic chemotherapy with the combination of gemcitabine and cisplatin. Lack of a stereotype genetic signature makes difficult in identification of potential actionable target directly, which may also explain lack of obvious clinic benefit with target oriented agents from current studies. It is crucial to understand of BTC carcinogenesis, tumor-stroma interactions, and key molecular pathways, and herald to establish targeted, individualized therapies for the heterogeneous disease, and eventually to improve the survival and overall outcome of patients.
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Affiliation(s)
- Selley Sahu
- Division of Oncology, Department of Medicine Hematology, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15232, USA
| | - Weijing Sun
- Division of Oncology, Department of Medicine Hematology, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15232, USA
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17
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Kato A, Shimizu H, Ohtsuka M, Yoshitomi H, Furukawa K, Takayashiki T, Nakadai E, Kishimoto T, Nakatani Y, Yoshidome H, Miyazaki M. Downsizing Chemotherapy for Initially Unresectable Locally Advanced Biliary Tract Cancer Patients Treated with Gemcitabine Plus Cisplatin Combination Therapy Followed by Radical Surgery. Ann Surg Oncol 2015; 22 Suppl 3:S1093-9. [PMID: 26240009 DOI: 10.1245/s10434-015-4768-9] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2015] [Indexed: 01/22/2023]
Abstract
BACKGOUND We have treated patients with initially unresectable locally advanced biliary tract cancer (BTC) by administering gemcitabine and have found that surgical resection became feasible in some downsized patients. The aim of this study was to investigate the usefulness of downsizing combination chemotherapy using gemcitabine plus cisplatin to treat initially unresectable locally advanced BTC. METHODS The subjects of the study were 150 consecutive patients who were treated for BTC between October 2011 and April 2014. Downsizing chemotherapy was carried out for 39 patients (26.0 %) whose lesions were unresectable because of locally advanced BTC. RESULTS Reduction in tumor size with downsizing chemotherapy was seen in 18 patients, and surgical resection was performed in 10 of 39 patients (25.6 %). Median survival time in patients with surgical resection following downsizing chemotherapy and those with chemotherapy alone was 17.9 and 12.4 months, respectively (p = 0.0378). According to the historical comparison between gemcitabine and gemcitabine plus cisplatin chemotherapy, there is no significant difference in overall survival. However, there was a significant difference for the pathologic response rate (≥Grade III) to be higher in patients with gemcitabine plus cisplatin chemotherapy compared with gemcitabine monotherapy. CONCLUSIONS Preoperative downsizing chemotherapy with gemcitabine plus cisplatin provides longer survival by the conversion to the surgical resection in patients with initially unresectable locally advanced BTC. It may have the potential for disease eradication as a new multidisciplinary approach for initially unresectable locally advanced BTC.
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Affiliation(s)
- Atsushi Kato
- Department of General Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Hiroaki Shimizu
- Department of General Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Masayuki Ohtsuka
- Department of General Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Hideyuki Yoshitomi
- Department of General Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Katsunori Furukawa
- Department of General Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Tsukasa Takayashiki
- Department of General Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Eri Nakadai
- Department of General Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Takashi Kishimoto
- Department of Molecular Pathology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Yukio Nakatani
- Department of Diagnostic Pathology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Hiroyuki Yoshidome
- Department of General Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Masaru Miyazaki
- Department of General Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.
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18
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Liver Resection for Advanced Intrahepatic Cholangiocarcinoma: A Cost-Utility Analysis. World J Surg 2015; 39:2500-9. [DOI: 10.1007/s00268-015-3150-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Abdel-Rahman OM, Elsayed Z. Gemcitabine-based chemotherapy for advanced biliary tract carcinomas. Hippokratia 2015. [DOI: 10.1002/14651858.cd011746] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Affiliation(s)
- Omar M Abdel-Rahman
- Faculty of Medicine, Ain Shams University; Clinical Oncology; Lofty Elsayed Street Cairo Egypt 11335
| | - Zeinab Elsayed
- Faculty of Medicine, Ain Shams University; Clinical Oncology; Lofty Elsayed Street Cairo Egypt 11335
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20
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Spolverato G, Kim Y, Alexandrescu S, Popescu I, Marques HP, Aldrighetti L, Clark Gamblin T, Miura J, Maithel SK, Squires MH, Pulitano C, Sandroussi C, Mentha G, Bauer TW, Newhook T, Shen F, Poultsides GA, Wallis Marsh J, Pawlik TM. Is Hepatic Resection for Large or Multifocal Intrahepatic Cholangiocarcinoma Justified? Results from a Multi-Institutional Collaboration. Ann Surg Oncol 2014; 22:2218-25. [PMID: 25354576 DOI: 10.1245/s10434-014-4223-3] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND The role of surgical resection for patients with large or multifocal intrahepatic cholangiocarcinoma (ICC) remains unclear. This study evaluated the long-term outcome of patients who underwent hepatic resection for large (≥7 cm) or multifocal (≥2) ICC. METHODS Between 1990 and 2013, 557 patients who underwent liver resection for ICC were identified from a multi-institutional database. Clinicopathologic characteristics, operative details, and long-term survival data were evaluated. RESULTS Of the 557 patients, 215 (38.6 %) had a small, solitary ICC (group A) and 342 (61.4 %) had a large or multifocal ICC (group B). The patients in group B underwent an extended hepatectomy more frequently (16.9 vs. 30.4 %; P < 0.001). At the final pathology exam, the patients in group B were more likely to show evidence of vascular invasion (22.5 vs. 38.5 %), direct invasion of contiguous organs (6.5 vs. 12.9 %), and nodal metastasis (13.3 vs. 21.0 %) (all P < 0.05). Interestingly, the incidences of postoperative complications (39.3 vs. 46.8 %) and hospital mortality (1.1 vs. 3.7 %) were similar between the two groups (both P > 0.05). The group A patients had better rates for 5-year overall survival (OS) (30.5 vs. 18.7 %; P < 0.05) and disease-free survival (DFS) (22.6 vs. 8.2 %; P < 0.05) than the group B patients. For the patients in group B, the factors associated with a worse OS included more than three tumor nodules [hazard ratio (HR), 1.56], nodal metastasis (HR, 1.47), and poor differentiation (HR, 1.48). CONCLUSIONS Liver resection can be performed safely for patients with large or multifocal ICC. The long-term outcome for these patients can be stratified on the basis of a prognostic score that includes tumor number, nodal metastasis, and poor differentiation.
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Affiliation(s)
- Gaya Spolverato
- The Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Abstract
Cholangiocarcinoma is a challenge to manage; mortality rate is nearly as high as the incidence. Unless curative resection is performed, these tumours are rapidly fatal because they respond poorly to current therapies. Symptoms occur late in cholangiocarcinoma and curative resection can be performed in less than half of the patients. In non-resectable disease, endoprostheses insertion can relieve jaundice and improve quality of life, provided that tumour extension does not lead to diffuse intrahepatic stenoses of ductal system. However, tumour growth cannot be influenced and therefore, prognosis remains dismal. Despite the fact, that radiotherapy and chemotherapy could reduce tumour volume and growth, no survival advantage has yet been shown. Photodynamic therapy has been evaluated as an new additional, palliative option. A randomised trial comparing photodynamic therapy plus endoprostheses insertion versus endoprostheses insertion alone, indicates a considerably benefit on survival time, cholestasis and quality of life in large, advanced cholangiocarcinoma. Furthermore, few specific side effects occurred. Since photodynamic therapy is the first approach leading to an improvement of prognosis, it should be offered to patients with non-resectable cholangiocarcinoma.
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Affiliation(s)
- Maria-Anna Ortner
- Department for Gastroenterology and Hepatology, Chef de Clinique, Centre Hospitalier Universitaire Vaudois, Rue du Bugnon 46, Lausanne CH 1011, Switzerland
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Kasai K, Kooka Y, Suzuki Y, Suzuki A, Oikawa T, Ushio A, Kasai Y, Sawara K, Miyamoto Y, Oikawa K, Takikawa Y. Efficacy of hepatic arterial infusion chemotherapy using 5-fluorouracil and systemic pegylated interferon α-2b for advanced intrahepatic cholangiocarcinoma. Ann Surg Oncol 2014; 21:3638-45. [PMID: 24817369 DOI: 10.1245/s10434-014-3766-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2013] [Indexed: 01/14/2023]
Abstract
BACKGROUND Cholangiocarcinoma is categorized into intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC). The prognosis of ICC is far worse than that of ECC. In this pilot trial, the efficacy of hepatic arterial infusion chemotherapy (HAIC) using 5-fluorouracil (5-FU) combined with subcutaneous administration of pegylated interferon (PEG-IFN) α-2b in patients with advanced ICC was evaluated. METHODS The subjects were 20 advanced ICC patients treated using subcutaneous PEG-IFNα-2b (50-100 μg on day 1 of every week, for 4 weeks) and intra-arterial infusion of 5-FU (250 mg/day for 5 h on days 1-5 of every week, for 4 weeks). One treatment cycle lasted 4 weeks. Therapy was discontinued in patients with progressive disease (PD). For responses other than PD, treatment was repeated for ≥1 cycle. RESULTS The objective early response rate was 60.0 %. Cumulative survival rates were 71.6 % at 6 months, 53.7 % at 12 months, 28.6 % at 18 months, and 14.3 % at 24 months. Median survival time was 14.6 months. All adverse reactions were controllable by temporary suspension of treatment. Serious complications and treatment-related deaths were not observed. CONCLUSIONS The combination therapy of PEG-IFNα-2b and 5-FU for advanced ICC seems not to be worse than the results of the previous studies. Furthermore, most adverse effects are transient and well tolerated. Based on the present findings, this combination therapy may be useful for patients with advanced ICC as one of the therapeutic option.
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Affiliation(s)
- Kazuhiro Kasai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Iwate Medical University, Morioka, Iwate, Japan,
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Suyama K, Ikeda M, Suzuki E, Kojima M, Mitsunaga S, Shimizu S, Ohno I, Takahashi H, Okuyama H, Kuwahara A, Okusaka T, Furuse J. Early relapse of unresectable gallbladder cancer after discontinuation of gemcitabine monotherapy administered for 5 years in a patient who had complete response to the treatment. Case Rep Oncol 2013; 6:531-7. [PMID: 24348389 PMCID: PMC3843915 DOI: 10.1159/000356080] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
The tumor shrinkage effect of gemcitabine is considered to be limited in cases of advanced gallbladder cancer, and there are few reports of complete response to gemcitabine therapy in patients with this cancer. Therefore, the treatment continuation strategy in these patients, after a complete response has been achieved, still remains to be established. Here, we present the case of a 77-year-old patient with unresectable gallbladder cancer, who after showing complete response to gemcitabine monotherapy administered for 5 years, showed early relapse within only 11 months of discontinuation of the drug. Thus, it is necessary to establish a suitable treatment continuation strategy for patients who show complete response to gemcitabine treatment.
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Affiliation(s)
- Koichi Suyama
- Division of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan ; Department of Medical Oncology, Toranomon Hospital, Tokyo, Japan
| | - Masafumi Ikeda
- Division of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Eiichiro Suzuki
- Division of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan ; Department of Gastroenterology and Neghrology, Chiba University, Chiba, Japan
| | - Motohiro Kojima
- Division of Pathology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Shuichi Mitsunaga
- Division of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Satoshi Shimizu
- Division of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Izumi Ohno
- Division of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Hideaki Takahashi
- Division of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Hiroyuki Okuyama
- Division of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Akiko Kuwahara
- Division of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Takuji Okusaka
- Hepatobiliary and Pancreatic Oncology Division, National Cancer Center Hospital, Tokyo, Japan
| | - Junji Furuse
- Department of Internal Medicine, Medical Oncology, Kyorin University School of Medicine, Tokyo, Japan
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Yokoyama T, Yoshida H, Makino H, Maruyama H, Suzuki S, Matsutani T, Matsushita A, Hirakata A, Sasajima K, Uchida E. Efficacy and safety of gemcitabine monotherapy for patients with advanced biliary tract cancer. J NIPPON MED SCH 2013; 79:204-12. [PMID: 22791122 DOI: 10.1272/jnms.79.204] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
OBJECTIVE The aim of this study was to analyze the efficacy and feasibility of gemcitabine monotherapy in patients with unresectable advanced or recurrent biliary tract cancer (BTC). METHODS Six patients with unresectable advanced BTC and 12 patients with recurrent BTC received gemcitabine monotherapy. Gemcitabine (800-1,000 mg/m²) was administered intravenously over 30 minutes on days 1, 8, and 15 every 28 days. Disease and toxicity were assessed once a week in all patients until the completion of gemcitabine treatment. Computed tomographic/magnetic resonance imaging studies were done every 8 weeks during chemotherapy, and every 4 weeks if progressive disease was suspected. Tumor response was determined according to the Response Evaluation Criteria in Solid Tumors. Toxicity was assessed using the National Cancer Institute Common Toxicity Criteria version 2.0. The time to progression and survival time were also calculated. RESULTS In patients with unresectable BTC, the overall response rate and the median time to progression for patients with partial response or stable disease was 66.7% and 5.68 months, respectively. Clinical benefit was observed in 3 patients with stable disease (50%). The median survival time was 5.2 months. In patients with recurrent BTC, 4 patients (33%) obtained partial responses and 2 patients (17%) had stable disease. The median time to progression was 8.2 months. Six of 12 patients (50%) obtained clinical benefit. The median survival time for cancer of the intrahepatic bile duct, the extrahepatic bile duct, and the ampulla of Vater were 2.8 months, 8.5 months, and 10.7 months, respectively. No significant correlation between the survival time and the resectability of the initial procedure (R number) was detected. The survival time for patients with a performance status of 0 or 1 was significantly longer than that for patients with a performance status of 2 (P=0.0051). Neither grade 3/4 hematologic toxicity nor grade 3/4 nonhematologic toxicity was observed. No treatment-related deaths were observed. CONCLUSION Gemcitabine monotherapy may provide a more favorable prognosis in patients with advanced BTC than does best supportive care alone. Moreover, this regimen may represent a therapeutic option for the adjuvant setting in patients with BTC.
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Affiliation(s)
- Tadashi Yokoyama
- Surgery for Organ Function and Biological Regulation, Graduate School of Medicine, Nippon Medical School, Tama, Tokyo, Japan.
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Dodson RM, Weiss MJ, Cosgrove D, Herman JM, Kamel I, Anders R, Geschwind JFH, Pawlik TM. Intrahepatic cholangiocarcinoma: management options and emerging therapies. J Am Coll Surg 2013; 217:736-750.e4. [PMID: 23890842 DOI: 10.1016/j.jamcollsurg.2013.05.021] [Citation(s) in RCA: 120] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2013] [Revised: 05/23/2013] [Accepted: 05/24/2013] [Indexed: 12/14/2022]
Affiliation(s)
- Rebecca M Dodson
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
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Abstract
Cholangiocarcinoma (CCA) is a tumor of the bile ducts that usually presents with biliary obstruction and has a poor prognosis. The treatment of CCA is challenging as the tumor is usually diagnosed late and the treatments are not very effective except when complete surgical resection is possible. In carefully selected patients, liver transplant can be a curative therapy. In the majority of cases, complete surgical resection is not possible and palliation is the mainstay of treatment. Stenting, using plastic or metallic stents, allows for biliary drainage. Photodynamic therapy plays a role in palliation and might play a role in adjuvant or neoadjuvant therapy. While radiation and chemotherapy can be beneficial, newer ablative techniques and targeted chemotherapies are promising.
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Konishi M. Adjuvant chemotherapy for resectable biliary tract cancer: current status and future direction. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2013; 19:301-5. [PMID: 22262202 DOI: 10.1007/s00534-011-0499-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The prognosis of patients with biliary tract cancer remains unsatisfactory even with surgery owing to the high recurrence rate. Therefore, an effective adjuvant chemotherapy is required to prolong survival. A few randomized controlled trials in patients with limited biliary tract cancer have been reported, but the efficacy of adjuvant chemotherapy could not be clarified. To date, effective adjuvant chemotherapy with evidence has not been established, and the standard therapy for patients with resectable biliary tract cancer has only been surgical treatment. Recently, a number of newer toxic agents have been shown to induce response in patients with advanced biliary tract cancer. Moreover, the morbi-mortality rate of operation for this cancer has been decreasing owing to advances in operative techniques and perioperative management. Given this background, a number of adjuvant chemotherapy trials have been started using gemcitabine, capecitabine, S-1, and combination chemotherapy with platinum. The results of these trials will be reported in the near future. Overall, the important aspects of adjuvant chemotherapy for biliary tract cancer are to establish well-organized and active clinical trial study groups, to conduct well-designed multicenter randomized controlled trials, and to continue such trials without interruption in the future.
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Affiliation(s)
- Masaru Konishi
- Hepatobiliary Pancreatic Oncology Division, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa 277-8577, Japan.
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Kato A, Shimizu H, Ohtsuka M, Yoshidome H, Yoshitomi H, Furukawa K, Takeuchi D, Takayashiki T, Kimura F, Miyazaki M. Surgical resection after downsizing chemotherapy for initially unresectable locally advanced biliary tract cancer: a retrospective single-center study. Ann Surg Oncol 2012; 20:318-24. [PMID: 23149849 DOI: 10.1245/s10434-012-2312-8] [Citation(s) in RCA: 123] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2011] [Indexed: 02/06/2023]
Abstract
BACKGROUND Surgical resection is the only method for curative treatment of biliary tract cancer (BTC). Recently, an improved efficacy has been revealed in patients with initially unresectable locally advanced BTC to improve the prognosis by the advent of useful cancer chemotherapy. The aim of this study was to evaluate the effect of downsizing chemotherapy in patients with initially unresectable locally advanced BTC. METHODS Initially unresectable locally advanced cases were defined as those in which therapeutic resection could not be achieved even by proactive surgical resection. Gemcitabine was administered intravenously once a week for 3 weeks followed by 1 week's respite. Patients whose disease responded to chemotherapy were reevaluated to determine whether their tumor was resectable. RESULTS Chemotherapy with gemcitabine was provided to 22 patients with initially unresectable locally advanced BTC. Tumor was significantly downsized in nine patients, and surgical resection was performed in 8 (36.4%) of 22 patients. Surgical resection resulted in R0 resection in four patients and R1 resection in four patients. Patients who underwent surgical resection had a significantly longer survival compared with those unable to undergo surgery. CONCLUSIONS Preoperative chemotherapy enables the downsizing of initially unresectable locally advanced BTC, with radical resection made possible in a certain proportion of patients. Downsizing chemotherapy should be proactively carried out as a multidisciplinary treatment strategy for patients with initially unresectable locally advanced BTC with the aim of expanding the surgical indication.
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Affiliation(s)
- Atsushi Kato
- Department of General Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.
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Biliary tract carcinomas: from chemotherapy to targeted therapy. Crit Rev Oncol Hematol 2012; 85:136-48. [PMID: 22809696 DOI: 10.1016/j.critrevonc.2012.06.006] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2012] [Revised: 06/07/2012] [Accepted: 06/22/2012] [Indexed: 12/16/2022] Open
Abstract
Biliary tract carcinomas (BTC) are a group of tumours arising from the epithelial cells of intra- and extra-hepatic biliaryducts and the gallbladder, characterised by a poor prognosis. Surgery is the only curative procedure, but the risk of recurrence is high and furthermore, the majority of patients present with unresectable disease at the time of diagnosis. Systemic therapy is the mainstay of treatment for patients who present recurrent or metastatic disease. Progress has been made in the last decade to identify the most effective chemotherapy regimens, with the recent recommendation of the combination of gemcitabine-cisplatin as the standard schedule. Comprehension of the molecular basis of cholangiocarcinogenesis and tumour progression has recently led to the experimentation of targeted therapies in patients with BTC, demonstrating promising results. In this review we will discuss the clinical experience with systemic treatment for BTC, focusing on future directions with targeted therapies.
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Furuse J, Okusaka T, Bridgewater J, Taketsuna M, Wasan H, Koshiji M, Valle J. Lessons from the comparison of two randomized clinical trials using gemcitabine and cisplatin for advanced biliary tract cancer. Crit Rev Oncol Hematol 2010; 80:31-9. [PMID: 21094052 DOI: 10.1016/j.critrevonc.2010.10.009] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2010] [Revised: 10/04/2010] [Accepted: 10/14/2010] [Indexed: 01/07/2023] Open
Abstract
There had been no standard chemotherapy established for advanced biliary tract cancer (BTC) until 2009, when the combination of cisplatin and gemcitabine (GC) was adopted as a first line standard chemotherapy option based on the results from two randomized studies: ABC-02, a UK investigator-initiated trial and the largest randomized phase III study in this tumor type with 410 patients; and BT22, a Japanese, industry-sponsored, randomized phase II study with 83 patients. In this review, investigators from both studies collaborated to compare protocols, patient characteristics, and outcomes of both studies including sub-analyses of study results. Although both studies showed GC combination therapy to be more effective than monotherapy, a detailed comparison revealed disparities between efficacy and safety end-points between the studies, which did not necessarily arise from different populations but from differences in protocol design. This review provides clinicians with insights for advanced BTC clinical study design and interpretation of historical studies.
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Affiliation(s)
- Junji Furuse
- Department of Internal Medicine, Medical Oncology, Kyorin University School of Medicine, Shinkawa, Mitaka, Tokyo, Japan.
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Gruenberger B, Schueller J, Heubrandtner U, Wrba F, Tamandl D, Kaczirek K, Roka R, Freimann-Pircher S, Gruenberger T. Cetuximab, gemcitabine, and oxaliplatin in patients with unresectable advanced or metastatic biliary tract cancer: a phase 2 study. Lancet Oncol 2010; 11:1142-8. [PMID: 21071270 DOI: 10.1016/s1470-2045(10)70247-3] [Citation(s) in RCA: 184] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Patients with biliary tract cancer have a poor prognosis, and, until recently, no standard palliative chemotherapy has been defined. We aimed to investigate the efficacy and safety of cetuximab in combination with gemcitabine and oxaliplatin (GEMOX) for first-line treatment of biliary tract cancer. METHODS From Oct 1, 2006, to July 26, 2008, patients with unresectable locally advanced or metastatic biliary tract cancer were sequentially enrolled and treated at one centre in Austria. All patients received intravenous infusions of 500 mg/m(2) cetuximab on day 1, 1000 mg/m(2) gemcitabine on day 1, and 100 mg/m(2) oxaliplatin on day 2, every 2 weeks for 12 cycles. The primary outcome was overall response rate. Analysis was by intention to treat. Adverse reactions were assessed according to National Cancer Institute Common Toxicity Criteria. The study is completed and registered with ClinicalTrials.gov, number NCT01216345. FINDINGS 30 patients with median age of 68 years (IQR 62-73) were enrolled and included in the analysis. Objective response occurred in 19 patients (63%; 95% CI 56·2-69·8), of whom three (10%; 3·2-16·8) achieved complete response, and 16 (53%; 46·2-59·8) achieved partial response. Nine patients underwent potentially curative secondary resection after major response to therapy. Grade 3 adverse events were recorded in 13 patients: skin rash (n=4), peripheral neuropathy (n=4), thrombocytopenia (n=3), nausea (n=1), diarrhoea (n=1), and neutropenia (n=1); no grade 4 adverse events were recorded. INTERPRETATION Cetuximab plus GEMOX was well tolerated and had encouraging antitumour activity, leading to secondary resection in a third of patients. These findings warrant further study of cetuximab plus GEMOX in a large randomised trial.
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Affiliation(s)
- Birgit Gruenberger
- Department of Internal Medicine, Barmherzige Brueder Hospital Vienna, Vienna, Austria.
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Williams KJ, Picus J, Trinkhaus K, Fournier CC, Suresh R, James JS, Tan BR. Gemcitabine with carboplatin for advanced biliary tract cancers: a phase II single institution study. HPB (Oxford) 2010; 12:418-26. [PMID: 20662793 PMCID: PMC3028583 DOI: 10.1111/j.1477-2574.2010.00197.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Only recently has a standard chemotherapy regimen, gemcitabine plus cisplatin, been established for advanced biliary tract cancers (BTCs) based on a phase III randomized study. The aim of this phase II single-institution trial was to assess the efficacy and safety of gemcitabine combined with carboplatin in the first-line treatment of patients with advanced BTCs. METHODS Patients with histologically proven BTCs, including cholangiocarcinoma or gallbladder and ampullary carcinomas, were treated with a maximum of nine cycles of intravenous (i.v.) gemcitabine at 1000 mg/m(2) over 30 min on days 1 and 8 with i.v. carboplatin dosed at an area-under-the-curve (AUC) of 5 over 60 min on day 1 of a 21-day cycle. RESULTS A total of 48 patients with advanced BTCs (35 cholangiocarcinoma, 12 gallbladder and 1 ampullary cancer) were enrolled. A median of four cycles were administered (range: 1-9). The overall response rate for evaluable patients was 31.1%. Median progression-free survival, overall survival and 6-month survival rates are 7.8 months, 10.6 months and 85.4%, respectively. The most common grade 3-4 toxicities include neutropenia and thrombocytopenia. Grade 3 or 4 non-haematological toxicities were rare. CONCLUSIONS Gemcitabine combined with carboplatin has activity against advanced BTCs. Our results are comparable to other gemcitabine-platinum or gemcitabine-fluoropyrimidine combinations in advanced BTCs.
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Affiliation(s)
- Kerry J Williams
- Division of Medical Oncology, Washington University School of MedicineSaint Louis, MI, USA
| | - Joel Picus
- Division of Medical Oncology, Washington University School of MedicineSaint Louis, MI, USA
| | - Kim Trinkhaus
- Department of Biostatistics, Washington University School of MedicineSaint Louis, MI, USA
| | - Chloe C Fournier
- Division of Medical Oncology, Washington University School of MedicineSaint Louis, MI, USA
| | - Rama Suresh
- Division of Medical Oncology, Washington University School of MedicineSaint Louis, MI, USA
| | - Joan S James
- Division of Medical Oncology, Washington University School of MedicineSaint Louis, MI, USA
| | - Benjamin R Tan
- Division of Medical Oncology, Washington University School of MedicineSaint Louis, MI, USA
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Kohya N, Kitahara K, Miyazaki K. Rational therapeutic strategy for T2 gallbladder carcinoma based on tumor spread. World J Gastroenterol 2010; 16:3567-72. [PMID: 20653066 PMCID: PMC2909557 DOI: 10.3748/wjg.v16.i28.3567] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the adequacy of surgical treatment of T2 gallbladder carcinoma (GBCa) according to tumor spread in the subserosal layer.
METHODS: A series of 84 patients with GBCa were treated at Saga University Hospital, Japan between April 1989 and October 2008. The tumor stage was graded according to the TNM staging for GBCa from the American Joint Committee on Cancer Manual 6th edition. Tumor staging revealed 30 patients with T2 tumors. T2 GBCa was divided into three groups histologically by the extent of tumor spread in the subserosal layer, using a score of ss minimum (ss min), ss medium (ss med) or ss massive (ss mas).
RESULTS: For ss min GBCa, there was no positive pathological factor and patient survival was satisfactory with simple cholecystectomy, with or without extra-hepatic bile duct resection. For ss med GBCa, some pathological factors, h-inf (hepatic infiltration), ly (lymphatic invasion) and n (lymph node metastasis), were positive. For ss mas GBCa, there was a high incidence of positive pathological factors. The patient group with extra-hepatic bile duct resection with D2 lymph node dissection (BDR with D2) and those with S4a5 hepatectomy had significantly better survival rates.
CONCLUSION: We suggest that radical surgery is not necessary for ss min GBCa, and partial hepatectomy and BDR are necessary for both ss med and ss mas GBCa.
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Morise Z, Sugioka A, Tokoro T, Tanahashi Y, Okabe Y, Kagawa T, Takeura C. Surgery and chemotherapy for intrahepatic cholangiocarcinoma. World J Hepatol 2010; 2:58-64. [PMID: 21160974 PMCID: PMC2998957 DOI: 10.4254/wjh.v2.i2.58] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2009] [Revised: 01/14/2010] [Accepted: 01/21/2010] [Indexed: 02/06/2023] Open
Abstract
Cholangiocarcinoma, arising from bile duct epithelium, is categorized into intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC), including hilarcholangiocarcinoma. Recently, there has been a worldwide increase in the incidence and mortality from ICC. Complete surgical resection is the only approach to cure the patients with ICC. However, locoregional extension of these tumors is usually advanced with intrahepatic and lymph-node metastases at the time of diagnosis. Resectability rates are quite low and variable (18%-70%). The five-year survival rate after surgical resection was reported to be 20%-40%. Median survival time after ICC resection was 12-37.4 mo. Only a small number of ICC cases, accompanied with ECC, gall bladder carcinoma, and ampullary carcinoma, have been reported in the studies of chemotherapy due to the rarity of the disease. However, in some reports, significant anti-cancer effects were achieved with a response rate of up to 40% and a median survival of one year. Although recurrence rate after hepatectomy is high for the patients with ICC, the residual liver and the lung are the main sites of recurrence after tentative curative surgical resection. Several patients in our study had a long-term survival with repeated surgery and chemotherapy. Repeated surgery, combined with new effective regimens of chemotherapy, could benefit the survival of ICC patients.
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Affiliation(s)
- Zenichi Morise
- Zenichi Morise, Atsushi Sugioka, Takamasa Tokoro, Yoshinao Tanahashi, Yasuhiro Okabe, Tadashi Kagawa, Chinatsu Takeura, Department of Surgery, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi 470-1192, Japan
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Abstract
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.
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Affiliation(s)
- Andrew X Zhu
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA.
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Wiedmann M, Witzigmann H, Mössner J. Malignant Tumors. CLINICAL HEPATOLOGY 2010:1519-1566. [DOI: 10.1007/978-3-642-04519-6_62] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Matsutani T, Uchida E, Yokoyama T, Matsushita A, Matsuda A, Sasajima K. A case of unresectable gallbladder cancer responding to gemcitabine after metallic biliary stent implantation. J NIPPON MED SCH 2009; 76:253-7. [PMID: 19915309 DOI: 10.1272/jnms.76.253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
A 69-year-old woman with a chief complaint of jaundice was referred to our hospital. She underwent exploratory laparotomy under a diagnosis of advanced biliary tract cancer. Histological examination of a biopsy specimen of the gallbladder revealed adenocarcinoma. The tumor was unresectable because of invasion into a wide area of the hepatoduodenal ligament and liver bed. Retrograde transhepatic bile drainage tubes were inserted through the common bile duct into the right and left branches of the intrahepatic bile ducts. After metallic biliary stent implantation, gemcitabine (1,000 mg) was administered intravenously once a week for 2 weeks, followed by 1 week of rest. After 2 courses of chemotherapy, computed tomography showed significant reductions in the size of target tumors and serum CA19-9 levels had normalized. Tumor size was stable for more than 6 months. The patient has been able to maintain a good quality of life without any severe adverse effects of chemotherapy. Gemcitabine therapy after metallic biliary stent implantation might be safe and effective in patients with unresectable gallbladder cancer.
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Affiliation(s)
- Takeshi Matsutani
- Surgery for Organ Function and Biological Regulation, Graduate School of Medicine, Nippon Medical School, Department of Surgery, Nayagama Tama, Tokyo, Japan.
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Abbas G, Lindor KD. Cholangiocarcinoma in primary sclerosing cholangitis. J Gastrointest Cancer 2009; 40:19-25. [PMID: 19705300 DOI: 10.1007/s12029-009-9085-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2009] [Accepted: 08/12/2009] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Cholangiocarcinoma (CCA) is an aggressive and nearly always fatal tumor of the biliary tract. PURPOSE This review explores risk factors, epidemiology, current diagnostic approaches, and treatment of CCA arising in patients with primary sclerosing cholangitis (PSC). METHODS We review latest recommendations about screening strategies to enable the early detection of CCA in PSC, using CA 19-9 and ultrasound imaging, as well as fluorescent in situ hybridization techniques to enhance the accuracy of biliary cytology. We also review the emerging role of liver transplantation.
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Affiliation(s)
- Ghulam Abbas
- Division of Gastroenterology and Hepatology, Mayo Clinic, 20 First Street, SW, Rochester, MN 55905, USA
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Valle JW, Wasan H, Johnson P, Jones E, Dixon L, Swindell R, Baka S, Maraveyas A, Corrie P, Falk S, Gollins S, Lofts F, Evans L, Meyer T, Anthoney A, Iveson T, Highley M, Osborne R, Bridgewater J. Gemcitabine alone or in combination with cisplatin in patients with advanced or metastatic cholangiocarcinomas or other biliary tract tumours: a multicentre randomised phase II study - The UK ABC-01 Study. Br J Cancer 2009; 101:621-7. [PMID: 19672264 PMCID: PMC2736816 DOI: 10.1038/sj.bjc.6605211] [Citation(s) in RCA: 197] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2009] [Revised: 06/24/2009] [Accepted: 07/03/2009] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND We assessed the activity of gemcitabine (G) and cisplatin/gemcitabine (C/G) in patients with locally advanced (LA) or metastatic (M) (advanced) biliary cancers (ABC) for whom there is no standard chemotherapy. METHODS Patients, aged > or =18 years, with pathologically confirmed ABC, Karnofsky performance (KP) > or =60, and adequate haematological, hepatic and renal function were randomised to G 1000 mg m(-2) on D1, 8, 15 q28d (Arm A) or C 25 mg m(-2) followed by G 1000 mg m(-2) D1, 8 q21d (Arm B) for up to 6 months or disease progression. RESULTS In total, 86 patients (A/B, n=44/42) were randomised between February 2002 and May 2004. Median age (64/62.5 years), KP, primary tumour site, earlier surgery, indwelling biliary stent and disease stage (LA: 25/38%) are comparable between treatment arms. Grade 3-4 toxicity included (A/B, % patients) anaemia (4.5/2.4), leukopenia (6.8/4.8), neutropenia (13.6/14.3), thrombocytopenia (9.1/11.9), lethargy (9.1/28.6), nausea/vomiting (0/7.1) and anorexia (2.3/4.8). Responses (WHO criteria, % of evaluable patients: A n=31 vs B n=36): no CRs; PR 22.6 vs 27.8%; SD 35.5 vs 47.1% for a tumour control rate (CR+PR+SD) of 58.0 vs 75.0%. The median TTP and 6-month progression-free survival (PFS) (the primary end point) were greater in the C/G arm (4.0 vs 8.0 months and 45.5 vs 57.1% in arms A and B, respectively). CONCLUSION Both regimens seem active in ABC. C/G is associated with an improved tumour control rate, TTP and 6-month PFS. The study has been extended (ABC-02 study) and powered to determine the effect on overall survival and the quality of life.
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Affiliation(s)
- J W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UK.
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Sharma A, Mohanti B, Raina V, Shukla N, Pal S, Dwary A, Deo S, Sahni P, Garg P, Thulkar S, DattaGupta S, Rath G. A phase II study of gemcitabine and oxaliplatin (Oxigem) in unresectable gall bladder cancer. Cancer Chemother Pharmacol 2009; 65:497-502. [DOI: 10.1007/s00280-009-1055-0] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2009] [Accepted: 06/16/2009] [Indexed: 12/30/2022]
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Simultaneous blockade of the epidermal growth factor receptor/mammalian target of rapamycin pathway by epidermal growth factor receptor inhibitors and rapamycin results in reduced cell growth and survival in biliary tract cancer cells. Mol Cancer Ther 2009; 8:1547-56. [PMID: 19509244 DOI: 10.1158/1535-7163.mct-09-0003] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Pemetrexed and Gemcitabine for Biliary Tract and Gallbladder Carcinomas: a North Central Cancer Treatment Group (NCCTG) Phase I and II Trial, N9943. J Gastrointest Cancer 2008; 38:87-94. [DOI: 10.1007/s12029-008-9037-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2008] [Accepted: 07/01/2008] [Indexed: 11/26/2022]
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Furuse J. Postoperative adjuvant treatments for biliary tract cancer. ACTA ACUST UNITED AC 2008; 15:463-7. [DOI: 10.1007/s00534-008-1358-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2008] [Accepted: 04/07/2008] [Indexed: 02/06/2023]
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Kaufman M, Mehrotra B, Limaye S, White S, Fuchs A, Lebowicz Y, Nissel-Horowitz S, Thomas A. EGFR expression in gallbladder carcinoma in North America. Int J Med Sci 2008; 5:285-91. [PMID: 18825277 PMCID: PMC2556051 DOI: 10.7150/ijms.5.285] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2008] [Accepted: 09/19/2008] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Increased epidermal growth factor receptor (EGF receptor) expression has been noted in various cancers and has become a useful target for therapeutic interventions. Small studies from Asia and Australia have demonstrated EGFR over-expression in gallbladder cancer. We sought to evaluate the expression of EGFR in a series of 16 gallbladder cancer patients from North America. METHODS Using tumor registry data, we identified 16 patients diagnosed with gall bladder carcinoma at our medical center between the years of 1998 and 2005. We performed a retrospective review of these patients' charts, obtained cell blocks from pathology archives and stained for EGFR and Her2/neu. RESULTS Fifteen of sixteen patients were noted to over-express EGFR. Three were determined 1+, nine were 2+ and three were 3+. Eight patients had poorly differentiated adenocarcinoma, six had moderately differentiated and two had well-differentiated tumors. In this small series, there was a trend toward shorter survival and more poorly differentiated tumors in patients with greater intensity of EGFR expression. One patient was EGFR negative but 3+ for erb-2/Her 2-neu expression. No patient co-expressed EGFR and Her-2-neu. Median survival of patients in this series was 17 months. CONCLUSION In view of our observations confirming the over-expression of EGFR in our patient population in North America, and the recent success of EGFR targeted therapies in other solid tumors that over-express EGFR, it may now be appropriate to evaluate agents targeting this pathway either as single agents or in combination with standard chemotherapy.
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Affiliation(s)
- Matthew Kaufman
- Long Island Jewish Medical Center, Division of Hematology/Oncology, New Hyde Park, NY 11040, USA.
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Koeberle D, Saletti P, Borner M, Gerber D, Dietrich D, Caspar CB, Mingrone W, Beretta K, Strasser F, Ruhstaller T, Mora O, Herrmann R. Patient-reported outcomes of patients with advanced biliary tract cancers receiving gemcitabine plus capecitabine: a multicenter, phase II trial of the Swiss Group for Clinical Cancer Research. J Clin Oncol 2008; 26:3702-8. [PMID: 18669455 DOI: 10.1200/jco.2008.16.5704] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
PURPOSE To evaluate the effects of palliative chemotherapy with gemcitabine plus capecitabine (GemCap) on patient-reported outcomes measured using clinical benefit response (CBR) and quality-of-life (QOL) measures in patients with advanced biliary tract cancer. PATIENTS AND METHODS Patients had to manifest symptoms of advanced biliary tract cancer and have at least one of the following: impaired Karnofsky performance score (60 to 80), average analgesic consumption >or= 10 mg of morphine equivalents per day, and average pain intensity score of >or= 20 mm out of 100 mm. Treatment consisted of oral capecitabine 650 mg/m(2) twice daily on days 1 through 14 plus gemcitabine 1,000 mg/m(2) as a 30-minute infusion on days 1 and 8 every 3 weeks until progression. The primary end point was the number of patients categorized as having a CBR or stable CBR (SCBR) during the first three treatment cycles. RESULTS Forty-four patients were enrolled (bile duct cancer, n = 36; gallbladder cancers, n = 8). The main grade 3 or 4 adverse events included hematologic toxicity and fatigue. After three cycles, 36% of patients achieved a CBR, and 34% achieved an SCBR. Over the full course of treatment, 57% of patients achieved a CBR, and 18% achieved an SCBR. Improved QOL was observed in patients with a CBR or SCBR. The objective response rate was 25%. Median time to progression and overall survival times were 7.2 months and 13.2 months, respectively. CONCLUSION Chemotherapy with GemCap is well tolerated and effective and leads to a high CBR rate. Patient-reported outcomes are useful for evaluating the effects of palliative chemotherapy in patients with biliary tract cancer.
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Affiliation(s)
- Dieter Koeberle
- Department of Internal Medicine, Division Oncology/Hematology, Kantonsspital St Gallen, CH-9007 St Gallen, Switzerland.
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Affiliation(s)
- Boris Blechacz
- Miles and Shirley Fiterman Center for Digestive Diseases, Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic, Rochester, MN 55905, USA
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Furuse J, Takada T, Miyazaki M, Miyakawa S, Tsukada K, Nagino M, Kondo S, Saito H, Tsuyuguchi T, Hirata K, Kimura F, Yoshitomi H, Nozawa S, Yoshida M, Wada K, Amano H, Miura F. Guidelines for chemotherapy of biliary tract and ampullary carcinomas. ACTA ACUST UNITED AC 2008; 15:55-62. [PMID: 18274844 PMCID: PMC2794344 DOI: 10.1007/s00534-007-1280-z] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2007] [Accepted: 10/22/2007] [Indexed: 02/06/2023]
Abstract
Few randomized controlled trials (RCTs) with large numbers of patients have been conducted to date in patients with biliary tract cancer, and standard chemotherapy has not been established yet. In this article we review previous studies and clinical trials regarding chemotherapy for unresectable biliary tract cancer, and we present guidelines for the appropriate use of chemotherapy in patients with biliary tract cancer. According to an RCT comparing chemotherapy and best supportive care for these patients, survival was significantly longer and quality of life was significantly better in the chemotherapy group than in the control group. Thus, chemotherapy for patients with biliary tract cancer seems to be a significant treatment of choice. However, chemotherapy for patients with biliary tract cancer should be indicated for those with unresectable, locally advanced disease or distant metastasis, or for those with recurrence after resection. That is why making the diagnosis of unresectable disease should be done with greatest care. As a rule, pathological diagnosis, including cytology or histopathological diagnosis, is preferable. Chemotherapy is recommended in patients with a good general condition, because in patients with general deterioration, such as those with a performance status of 2 or 3 or those with insufficient biliary decompression, the benefit of chemotherapy is limited. As chemotherapy for unresectable biliary tract cancer, the use of gemcitabine or tegafur/gimeracil/oteracil potassium is recommended. As postoperative adjuvant chemotherapy, no effective adjuvant therapy has been established at the present time. It is recommended that further clinical trials, especially large multi-institutional RCTs (phase III studies) using novel agents such as gemcitabine should be performed as soon as possible in order to establish a standard treatment.
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Affiliation(s)
- Junji Furuse
- Hepatobiliary and Pancreatic Oncology Division, National Cancer Center Hospital East, Kashiwa-shi, Chiba, Japan
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Abstract
Cholangiocarcinoma is a primary hepatic malignancy originating from bile duct epithelium. It is the second most common primary hepatic neoplasia, and its incidence has increased within the last 3 decades. Although several risk factors have been identified, especially chronic biliary tract inflammation, most patients with cholangiocarcinoma have no identifiable risk factors. Recent developments in radiologic and molecular diagnostic methods have helped in the diagnosis of this disease. The only curative therapy is surgical resection or liver transplantation. For patients with advanced stage disease, survival remains limited. With growing understanding of the molecular and cellular etiology of this disease, new targeted therapies are being developed.
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Affiliation(s)
- Boris R A Blechacz
- Division of Gastroenterology and Hepatology, Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA
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