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1
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Zou RQ, Dai YS, Liu F, Yang SQ, Hu HJ, Li FY. Hepatobiliary organoid research: the progress and applications. Front Pharmacol 2025; 16:1473863. [PMID: 40008122 PMCID: PMC11850396 DOI: 10.3389/fphar.2025.1473863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Accepted: 01/20/2025] [Indexed: 02/27/2025] Open
Abstract
Organoid culture has emerged as a forefront technology in the life sciences field. As "in vitro micro-organs", organoids can faithfully recapitulate the organogenesis process, and conserve the key structure, physiological function and pathological state of the original tissue or organ. Consequently, it is widely used in basic and clinical studies, becoming important preclinical models for studying diseases and developing therapies. Here, we introduced the definition and advantages of organoids and described the development and advances in hepatobiliary organoids research. We focus on applying hepatobiliary organoids in benign and malignant diseases of the liver and biliary tract, drug research, and regenerative medicine to provide valuable reference information for the application of hepatobiliary organoids. Despite advances in research and treatment, hepatobiliary diseases including carcinoma, viral hepatitis, fatty liver and bile duct defects have still been conundrums of the hepatobiliary field. It is necessary and crucial to study disease mechanisms, establish efficient and accurate research models and find effective treatment strategies. The organoid culture technology shed new light on solving these issues. However, the technology is not yet mature, and many hurdles still exist that need to be overcome. The combination with new technologies such as CRISPR-HOT, organ-on-a-chip may inject new vitality into future development.
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Affiliation(s)
- Rui-Qi Zou
- Division of Biliary Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Research Center for Biliary Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yu-Shi Dai
- Division of Biliary Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Research Center for Biliary Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Fei Liu
- Division of Biliary Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Research Center for Biliary Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Si-Qi Yang
- Division of Biliary Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Research Center for Biliary Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Hai-Jie Hu
- Division of Biliary Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Research Center for Biliary Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Fu-Yu Li
- Division of Biliary Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Research Center for Biliary Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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2
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Neuzillet C, Decraecker M, Larrue H, Ntanda-Nwandji LC, Barbier L, Barge S, Belle A, Chagneau C, Edeline J, Guettier C, Huguet F, Jacques J, Le Bail B, Leblanc S, Lewin M, Malka D, Ronot M, Vendrely V, Vibert É, Bureau C, Bourliere M, Ganne-Carrie N, Blanc JF. Management of intrahepatic and perihilar cholangiocarcinomas: Guidelines of the French Association for the Study of the Liver (AFEF). Liver Int 2024; 44:2517-2537. [PMID: 38967424 DOI: 10.1111/liv.15948] [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: 12/29/2023] [Revised: 03/13/2024] [Accepted: 04/11/2024] [Indexed: 07/06/2024]
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is the second most common malignant primary liver cancer. iCCA may develop on an underlying chronic liver disease and its incidence is growing in relation with the epidemics of obesity and metabolic diseases. In contrast, perihilar cholangiocarcinoma (pCCA) may follow a history of chronic inflammatory diseases of the biliary tract. The initial management of CCAs is often complex and requires multidisciplinary expertise. The French Association for the Study of the Liver wished to organize guidelines in order to summarize the best evidence available about several key points in iCCA and pCCA. These guidelines have been elaborated based on the level of evidence available in the literature and each recommendation has been analysed, discussed and voted by the panel of experts. They describe the epidemiology of CCA as well as how patients with iCCA or pCCA should be managed from diagnosis to treatment. The most recent developments of personalized medicine and use of targeted therapies are also highlighted.
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Affiliation(s)
- Cindy Neuzillet
- GI Oncology, Medical Oncology Department, Institut Curie, Versailles Saint-Quentin University, Paris Saclay University, Saint-Cloud, France
| | - Marie Decraecker
- Oncology Digestive Unit, INSERM U1312, University Hospital of Bordeaux, Bordeaux, France
| | - Hélène Larrue
- Department of Hepatology, University Hospital, Toulouse III-Paul Sabatier University, Toulouse, France
| | | | - Louise Barbier
- New Zealand Liver Transplant Unit and HPB Surgery, Te Toka Tumai, University of Auckland, Auckland, New Zealand
| | - Sandrine Barge
- Centre Hospitalier Intercommunal Créteil-CHI Créteil, Créteil, France
| | - Arthur Belle
- Department of Gastroenterology and Digestive Oncology, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | | | - Julien Edeline
- Department of Medical Oncology, CLCC Eugène Marquis, COSS-UMR S1242, INSERM, Univ Rennes, Rennes, France
| | - Catherine Guettier
- Department of Pathology, APHP University Paris Saclay, Hôpital Bicetre, Paris, France
| | - Florence Huguet
- Radiation Oncology Department, Tenon Hospital, APHP-Sorbonne University, Paris, France
| | | | - Brigitte Le Bail
- Pathology Department, University Hospital of Bordeaux, Bordeaux, France
| | - Sarah Leblanc
- Gastroenterology Department, Private Hospital Jean Mermoz, Ramsay Santé, Lyon, France
| | - Maïté Lewin
- Service de Radiologie, AP-HP-Université Paris Saclay Hôpital Paul Brousse, Villejuif, France
| | - David Malka
- Medical Oncology Department, Institut Mutualiste Monsouris, Paris, France
| | - Maxime Ronot
- Department of Radiology, Beaujon Hospital, APHP Nord Clichy, University Paris Cité, CRI UMR, Paris, France
| | | | - Éric Vibert
- Centre Hepato-Biliaire, AP-HP-Université Paris Saclay Hôpital Paul Brousse, Villejuif, France
| | - Christophe Bureau
- Department of Hepatology, University Hospital, Toulouse III-Paul Sabatier University, Toulouse, France
| | | | | | - Jean-Frédéric Blanc
- Oncology Digestive Unit, INSERM U1312, University Hospital of Bordeaux, Bordeaux, France
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3
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Yuan F, Zhou H, Liu C, Wang Y, Quan J, Liu J, Li H, von Itzstein M, Yu X. Heparanase interacting BCLAF1 to promote the development and drug resistance of ICC through the PERK/eIF2α pathway. Cancer Gene Ther 2024; 31:904-916. [PMID: 38467765 DOI: 10.1038/s41417-024-00754-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 02/22/2024] [Accepted: 02/26/2024] [Indexed: 03/13/2024]
Abstract
Intrahepatic cholangiocarcinoma (ICC) is a primary epithelial carcinoma known for its aggressive nature, high metastatic potential, frequent recurrence, and poor prognosis. Heparanase (HPSE) is the only known endogenous β-glucuronidase in mammals. In addition to its well-established enzymatic roles, HPSE critically exerts non-catalytic function in tumor biology. This study herein aimed to investigate the non-enzymatic roles of HPSE as well as relevant regulatory mechanisms in ICC. Our results demonstrated that HPSE was highly expressed in ICC and promoted the proliferation of ICC cells, with elevated HPSE levels implicating a poor overall survival of ICC patients. Notably, HPSE interacted with Bcl-2-associated factor 1 (BCLAF1) to upregulate the expression of Bcl-2, which subsequently activated the PERK/eIF2α-mediated endoplasmic reticulum (ER) stress pathway to promote anti-apoptotic effect of ICC. Moreover, our in vivo experiments revealed that concomitant administration of gemcitabine and the Bcl-2 inhibitor navitoclax enhanced the sensitivity of ICC cells with highly expressed HPSE to chemotherapy. In summary, our findings revealed that HPSE promoted the development and drug resistance of ICC via its non-enzymatic function. Bcl-2 may be considered as an effective target with therapeutic potential to overcome ICC chemotherapy resistance induced by HPSE, presenting valuable insights into the development of novel therapeutic strategies against ICC.
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Affiliation(s)
- Fengyan Yuan
- Department of Basic Medical Sciences, School of Medicine, Hunan Normal University, Changsha, China
- Key Laboratory of Model Animals and Stem Cell Biology of Hunan Province, School of Medicine, Hunan Normal University, Changsha, China
- Research Center of Reproduction and Translational Medicine of Hunan Province, School of Medicine, Hunan Normal University, Changsha, China
| | - Huiqin Zhou
- Department of Basic Medical Sciences, School of Medicine, Hunan Normal University, Changsha, China
- Key Laboratory of Model Animals and Stem Cell Biology of Hunan Province, School of Medicine, Hunan Normal University, Changsha, China
- Research Center of Reproduction and Translational Medicine of Hunan Province, School of Medicine, Hunan Normal University, Changsha, China
| | - Chongyang Liu
- Department of Basic Medical Sciences, School of Medicine, Hunan Normal University, Changsha, China
- Key Laboratory of Model Animals and Stem Cell Biology of Hunan Province, School of Medicine, Hunan Normal University, Changsha, China
- Research Center of Reproduction and Translational Medicine of Hunan Province, School of Medicine, Hunan Normal University, Changsha, China
| | - Yi Wang
- Department of Basic Medical Sciences, School of Medicine, Hunan Normal University, Changsha, China
- Key Laboratory of Model Animals and Stem Cell Biology of Hunan Province, School of Medicine, Hunan Normal University, Changsha, China
- Research Center of Reproduction and Translational Medicine of Hunan Province, School of Medicine, Hunan Normal University, Changsha, China
| | - Jing Quan
- Department of Basic Medical Sciences, School of Medicine, Hunan Normal University, Changsha, China
- Key Laboratory of Model Animals and Stem Cell Biology of Hunan Province, School of Medicine, Hunan Normal University, Changsha, China
- Research Center of Reproduction and Translational Medicine of Hunan Province, School of Medicine, Hunan Normal University, Changsha, China
| | - Jie Liu
- Department of Basic Medical Sciences, School of Medicine, Hunan Normal University, Changsha, China
- Key Laboratory of Model Animals and Stem Cell Biology of Hunan Province, School of Medicine, Hunan Normal University, Changsha, China
- Research Center of Reproduction and Translational Medicine of Hunan Province, School of Medicine, Hunan Normal University, Changsha, China
| | - Hao Li
- Biliary Tract Surgery Laboratory, Department of Hepatobiliary Surgery, Hunan Provincial People's Hospital, the First Affiliated Hospital of Hunan Normal University, Changsha, China.
- Hunan Research Center of Biliary Disease, the First Affiliated Hospital of Hunan Normal University, Changsha, China.
- Key Laboratory of Biliary Disease Prevention and treatment, the First Affiliated Hospital of Hunan Normal University,, Changsha, China.
| | - Mark von Itzstein
- Institute for Glycomics, Griffith University, Gold Coast Campus, Southport, QLD, Australia.
| | - Xing Yu
- Department of Basic Medical Sciences, School of Medicine, Hunan Normal University, Changsha, China.
- Key Laboratory of Model Animals and Stem Cell Biology of Hunan Province, School of Medicine, Hunan Normal University, Changsha, China.
- Research Center of Reproduction and Translational Medicine of Hunan Province, School of Medicine, Hunan Normal University, Changsha, China.
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Fujinaga A, Hirashita T, Hirashita Y, Sakai K, Kawamura M, Masuda T, Endo Y, Ohta M, Murakami K, Inomata M. Glucose metabolic upregulation via phosphorylation of S6 ribosomal protein affects tumor progression in distal cholangiocarcinoma. BMC Gastroenterol 2023; 23:157. [PMID: 37193984 DOI: 10.1186/s12876-023-02815-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 05/09/2023] [Indexed: 05/18/2023] Open
Abstract
BACKGROUND The prognosis of distal cholangiocarcinoma (dCCA) remains poor; thus, the identification of new therapeutic targets is warranted. Phosphorylated S6 ribosomal protein indicates a mammalian target of rapamycin complex 1 (mTORC1) activity, and mTORC1 plays a central role in controlling cell growth and regulating glucose metabolism. We aimed to clarify the effect of S6 phosphorylation on tumor progression and the glucose metabolic pathway in dCCA. METHODS Thirty-nine patients with dCCA who underwent curative resection were enrolled in this study. S6 phosphorylation and the expression of GLUT1 were evaluated by immunohistochemistry, and their relationship with clinical factors was investigated. The effect of S6 phosphorylation on glucose metabolism with PF-04691502 treatment, an inhibitor of S6 phosphorylation, was examined in cancer cell lines by Western blotting and metabolomics analysis. Cell proliferation assays were performed with PF-04691502. RESULTS S6 phosphorylation and the expression of GLUT1 were significantly higher in patients with an advanced pathological stage. Significant correlations between GLUT1 expression, S6 phosphorylation, and SUV-max of FDG-PET were shown. In addition, cell lines with high S6 phosphorylation levels showed high GLUT1 levels, and the inhibition of S6 phosphorylation reduced the expression of GLUT1 on Western blotting. Metabolic analysis revealed that inhibition of S6 phosphorylation suppressed pathways of glycolysis and the TCA cycle in cell lines, and then, cell proliferation was effectively reduced by PF-04691502. CONCLUSION Upregulation of glucose metabolism via phosphorylation of S6 ribosomal protein appeared to play a role in tumor progression in dCCA. mTORC1 may be a therapeutic target for dCCA.
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Affiliation(s)
- Atsuro Fujinaga
- Department of Gastroenterological and Pediatric Surgery, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-Machi, Oita, 879-5593, Japan.
| | - Teijiro Hirashita
- Department of Gastroenterological and Pediatric Surgery, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-Machi, Oita, 879-5593, Japan
| | - Yuka Hirashita
- Department of Gastroenterology, Faculty of Medicine, Oita University, Oita, Japan
- Molecular Pathology, Faculty of Medicine, Oita University, Oita, Japan
| | - Kumiko Sakai
- Department of Division of Life Science Research, Faculty of Medicine, Oita University, Oita, Japan
| | - Masahiro Kawamura
- Department of Gastroenterological and Pediatric Surgery, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-Machi, Oita, 879-5593, Japan
| | - Takashi Masuda
- Department of Gastroenterological and Pediatric Surgery, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-Machi, Oita, 879-5593, Japan
| | - Yuichi Endo
- Department of Gastroenterological and Pediatric Surgery, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-Machi, Oita, 879-5593, Japan
| | - Masayuki Ohta
- Department of Gastroenterological and Pediatric Surgery, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-Machi, Oita, 879-5593, Japan
| | - Kazunari Murakami
- Department of Gastroenterology, Faculty of Medicine, Oita University, Oita, Japan
| | - Masafumi Inomata
- Department of Gastroenterological and Pediatric Surgery, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-Machi, Oita, 879-5593, Japan
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Bai XS, Zhou SN, Jin YQ, He XD. Combining of chemotherapy with targeted therapy for advanced biliary tract cancer: A systematic review and meta-analysis. World J Gastrointest Oncol 2022; 14:2061-2076. [PMID: 36310709 PMCID: PMC9611432 DOI: 10.4251/wjgo.v14.i10.2061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 09/04/2022] [Accepted: 09/14/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Targeted therapy (TT) has resulted in controversial efficacy as first-line treatment for biliary tract cancer (BTC). More efficacy comparisons are required to clarify the overall effects of chemotherapy (CT) combined with TT and CT alone on advanced BTC.
AIM To conduct a meta-analysis of the available evidence on the efficacy of CT combined with TT for advanced BTC.
METHODS The PubMed, EMBASE, ClinicalTrials, Scopus and Cochrane Library databases were systematically searched for relevant studies published from inception to August 2022. Only randomized clinical trials (RCTs) including comparisons between the combination of gemcitabine-based CT with TT and CT alone as first-line treatment for advanced BTC were eligible (PROSPERO-CRD42022313001). The odds ratios (ORs) for the objective response rate (ORR) and hazard ratios (HRs) for both progression-free survival (PFS) and overall survival (OS) were calculated and analyzed. Subgroup analyses based on different targeted agents, CT regimens and tumor locations were prespecified.
RESULTS Nine RCTs with a total of 1361 individuals were included and analyzed. The overall analysis showed a significant improvement in ORR in patients treated with CT + TT compared to those treated with CT alone (OR = 1.43, 95%CI: 1.11-1.86, P = 0.007) but no difference in PFS or OS. Similar trends were observed in the subgroup treated with agents targeting epidermal growth factor receptor (OR = 1.67, 95%CI: 1.17-2.37, P = 0.004) but not in the subgroups treated with agents targeting vascular endothelial growth factor receptor or mesenchymal-epithelial transition factor. Notably, patients who received a CT regimen of gemcitabine + oxaliplatin in the CT + TT arm had both a higher ORR (OR = 1.75, 95%CI: 1.20-2.56, P = 0.004) and longer PFS (HR = 0.83, 95%CI: 0.70-0.99, P = 0.03) than those in the CT-only arm. Moreover, patients with cholangiocarcinoma treated with CT + TT had significantly increased ORR and PFS (ORR, OR = 2.06, 95%CI: 1.27-3.35, PFS, HR = 0.79, 95%CI: 0.66-0.94).
CONCLUSION CT + TT is a potential first-line treatment for advanced BTC that leads to improved tumor control and survival outcomes, and highlighting the importance of CT regimens and tumor types in the application of TT.
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Affiliation(s)
- Xue-Song Bai
- Department of General Surgery, Peking Union Medical College Hospital, China Academy of Medical Science & Peking Union Medical College, Beijing 100730, China
| | - Sheng-Nan Zhou
- Department of General Surgery, Peking Union Medical College Hospital, China Academy of Medical Science & Peking Union Medical College, Beijing 100730, China
| | - Yi-Qun Jin
- Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
| | - Xiao-Dong He
- Department of General Surgery, Peking Union Medical College Hospital, China Academy of Medical Science & Peking Union Medical College, Beijing 100730, China
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Suppramote O, Prasopporn S, Aroonpruksakul S, Ponvilawan B, Makjaroen J, Suntiparpluacha M, Korphaisarn K, Charngkaew K, Chanwat R, Pisitkun T, Okada S, Sampattavanich S, Jirawatnotai S. The Acquired Vulnerability Caused by CDK4/6 Inhibition Promotes Drug Synergism Between Oxaliplatin and Palbociclib in Cholangiocarcinoma. Front Oncol 2022; 12:877194. [PMID: 35664774 PMCID: PMC9157389 DOI: 10.3389/fonc.2022.877194] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 04/12/2022] [Indexed: 11/16/2022] Open
Abstract
Cholangiocarcinoma (CCA) is one of the most difficult to treat cancers, and its nature of being largely refractory to most, if not all, current treatments results in generally poor prognosis and high mortality. Efficacious alternative therapies that can be used ubiquitously are urgently needed. Using acquired vulnerability screening, we observed that CCA cells that reprofile and proliferate under CDK4/6 inhibition became vulnerable to ribosomal biogenesis stress and hypersensitive to the anti-ribosome chemotherapy oxaliplatin. CCA cells overexpress the oncogenic ribosomal protein RPL29 under CDK4/6 inhibition in a manner that correlated with CDK4/6 inhibitor resistance. Depletion of RPL29 by small interfering RNAs (siRNAs) restored the sensitivity of CCA cells to CDK4/6 inhibition. Oxaliplatin treatment suppressed the RPL29 expression in the CDK4/6 inhibitor treated CCA cells and triggered RPL5/11-MDM2-dependent p53 activation and cancer apoptosis. In addition, we found that combination treatment with oxaliplatin and the CDK4/6 inhibitor palbociclib synergistically inhibited both parental and CDK4/6 inhibitor-resistant CCA, and prevented the emergence of CDK4/6 and oxaliplatin-resistant CCA. This drug combination also exerted suppressive and apoptosis effects on CCA in the in vitro 3-dimensional culture, patient-derived organoid, and in vivo xenograft CCA models. These results suggest the combination of the CDK4/6 inhibitor palbociclib and the anti-ribosome drug oxaliplatin as a potentially promising treatment for cholangiocarcinoma.
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Affiliation(s)
- Orawan Suppramote
- Siriraj Center of Research Excellence (SiCORE) for Systems Pharmacology, Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.,Princess Srisavangavadhana College of Medicine, Chulabhorn Royal Academy, Bangkok, Thailand
| | - Sunisa Prasopporn
- Siriraj Center of Research Excellence (SiCORE) for Systems Pharmacology, Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Satinee Aroonpruksakul
- Siriraj Center of Research Excellence (SiCORE) for Systems Pharmacology, Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Ben Ponvilawan
- Siriraj Center of Research Excellence (SiCORE) for Systems Pharmacology, Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Jiradej Makjaroen
- Center of Excellence in Systems Biology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Monthira Suntiparpluacha
- Siriraj Center of Research Excellence (SiCORE) for Systems Pharmacology, Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Krittiya Korphaisarn
- Division of Medical Oncology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Komgrid Charngkaew
- Department of Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Rawisak Chanwat
- Hepato-Pancreato-Biliary Surgery Unit, Department of Surgical Oncology, National Cancer Institute, Bangkok, Thailand
| | - Trairak Pisitkun
- Center of Excellence in Systems Biology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Seiji Okada
- Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan
| | - Somponnat Sampattavanich
- Siriraj Center of Research Excellence (SiCORE) for Systems Pharmacology, Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Siwanon Jirawatnotai
- Siriraj Center of Research Excellence (SiCORE) for Systems Pharmacology, Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
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7
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Fanale D, Corsini LR, Scalia R, Brando C, Cucinella A, Madonia G, Dimino A, Filorizzo C, Barraco N, Bono M, Fiorino A, Magrin L, Sciacchitano R, Perez A, Russo TDB, Pantuso G, Russo A, Bazan V. Can the tumor-agnostic evaluation of MSI/MMR status be the common denominator for the immunotherapy treatment of patients with several solid tumors? Crit Rev Oncol Hematol 2022; 170:103597. [PMID: 35033663 DOI: 10.1016/j.critrevonc.2022.103597] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 01/11/2022] [Accepted: 01/11/2022] [Indexed: 12/24/2022] Open
Abstract
Alterations in short-repetitive DNA sequences, known as microsatellite instability (MSI), can reflect deficiencies in Mismatch Repair (MMR) system which represents a major player in DNA integrity maintenance. The incidence of MSI-H/dMMR has been shown to be variable depending on the tumor type. Several studies confirmed that dMMR/MSI status, although less frequent than PD-L1 expression, may better predict response to immune-checkpoint inhibitors (ICIs) in patients with solid tumors. In October 2016, the FDA granted pembrolizumab as breakthrough therapy for the treatment of non-CRC, MSI-H/dMMR tumors, providing, for the first time, a tumor-agnostic indication. In the next future, the tissue-agnostic evaluation of MSI-H/dMMR could become the common denominator for the immunotherapy treatment of patients with different advanced solid tumors, in order to select patient subgroups which may benefit from this therapy. In this Review we provided an overview of the main clinical studies describing the association between MSI-H/dMMR tumors and immunotherapy response.
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Affiliation(s)
- Daniele Fanale
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127, Palermo, Italy
| | - Lidia Rita Corsini
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127, Palermo, Italy
| | - Raimondo Scalia
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127, Palermo, Italy
| | - Chiara Brando
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127, Palermo, Italy
| | - Alessandra Cucinella
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127, Palermo, Italy
| | - Giorgio Madonia
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127, Palermo, Italy
| | - Alessandra Dimino
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127, Palermo, Italy
| | - Clarissa Filorizzo
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127, Palermo, Italy
| | - Nadia Barraco
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127, Palermo, Italy
| | - Marco Bono
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127, Palermo, Italy
| | - Alessia Fiorino
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127, Palermo, Italy
| | - Luigi Magrin
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127, Palermo, Italy
| | - Roberta Sciacchitano
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127, Palermo, Italy
| | - Alessandro Perez
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127, Palermo, Italy
| | - Tancredi Didier Bazan Russo
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127, Palermo, Italy
| | - Gianni Pantuso
- Unit of Oncological Surgery, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127, Palermo, Italy
| | - Antonio Russo
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127, Palermo, Italy.
| | - Viviana Bazan
- Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, 90127, Palermo, Italy
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8
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Houben P, Schimmack S, Unterrainer C, Döhler B, Mehrabi A, Süsal C. Rare Malignant Indications for Liver Transplantation: A Collaborative Transplant Study Report. Front Surg 2021; 8:678392. [PMID: 34926560 PMCID: PMC8678034 DOI: 10.3389/fsurg.2021.678392] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 10/27/2021] [Indexed: 12/04/2022] Open
Abstract
Introduction: Hepatocellular carcinoma (HCC) is by far the leading malignant indication for liver transplantation (LT). Few other malignancies, including cholangiocellular carcinoma (CCC), metastases from neuroendocrine tumors (NET), and sarcomas of the liver (LSAR), also are commonly accepted indications for LT. However, there is limited information on their outcome after LT. Methods: Graft and patient survival in 14,623 LTs performed in patients with hepatocellular carcinoma, CCC, NET, and LSAR from 1988 to 2017 and reported to the Collaborative Transplant Study were analyzed. Results: The study group consisted of 13,862 patients who had HCC (94.8%), 498 (3.4%) who had CCC, 100 (0.7%) who had NET, and 163 (1.1%) who had LSAR. CCC patients showed a 5-year graft survival rate of 32.1%, strikingly lower than the 63.2% rate in HCC, 51.6% rate in NET, and 64.5% rate in LSAR patients (P < 0.001 for all vs. CCC). Multivariable Cox regression analysis revealed a significantly higher risk of graft loss and death due to cancer during the first five post-transplant years in CCC vs. HCC patients (HR 1.77 and 2.56; P < 0.001 for both). The same risks were increased also in NET and LSAR patients but did not reach statistical significance. Conclusion: Among patients with rare malignant indications for LT, CCC patients showed significantly impaired graft as well as patient survival compared to HCC patients. The observed differences might challenge traditional decision-making processes for LT indication and palliative treatment in specific hepatic malignancies.
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Affiliation(s)
- Philipp Houben
- Department of General, Visceral, and Transplant Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Simon Schimmack
- Department of General, Visceral, and Transplant Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | | | - Bernd Döhler
- Institute of Immunology, Heidelberg University Hospital, Heidelberg, Germany
| | - Arianeb Mehrabi
- Department of General, Visceral, and Transplant Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Caner Süsal
- Institute of Immunology, Heidelberg University Hospital, Heidelberg, Germany.,Transplant Immunology Research Center of Excellence, Koç Üniversitesi, Istanbul, Turkey
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9
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Zanetto A, Shalaby S, Gambato M, Germani G, Senzolo M, Bizzaro D, Russo FP, Burra P. New Indications for Liver Transplantation. J Clin Med 2021; 10:3867. [PMID: 34501314 PMCID: PMC8432035 DOI: 10.3390/jcm10173867] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 08/20/2021] [Accepted: 08/27/2021] [Indexed: 12/12/2022] Open
Abstract
Liver transplantation (LT) is an important therapeutic option for the treatment of several liver diseases. Modern LT is characterized by remarkable improvements in post-transplant patient survival, graft survival, and quality of life. Thanks to these great improvements, indications for LT are expanding. Nowadays, clinical conditions historically considered exclusion criteria for LT, have been considered new indications for LT, showing survival advantages for patients. In this review, we provide an updated overview of the principal newer indications for LT, with particular attention to alcoholic hepatitis, acute-on-chronic liver failure (ACLF), cholangiocarcinoma and colorectal cancer metastases.
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Affiliation(s)
| | | | | | | | | | | | | | - Patrizia Burra
- Multivisceral Transplant Unit, Department of Surgery Oncology and Gastroenterology, University of Padova, Via Giustiniani 2, 35128 Padova, Italy; (A.Z.); (S.S.); (M.G.); (G.G.); (M.S.); (D.B.); (F.P.R.)
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10
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Personeni N, Lleo A, Pressiani T, Colapietro F, Openshaw MR, Stavraka C, Pouptsis A, Pinato DJ, Rimassa L. Biliary Tract Cancers: Molecular Heterogeneity and New Treatment Options. Cancers (Basel) 2020; 12:E3370. [PMID: 33202975 PMCID: PMC7696875 DOI: 10.3390/cancers12113370] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 11/08/2020] [Accepted: 11/11/2020] [Indexed: 12/13/2022] Open
Abstract
Most patients with biliary tract cancer (BTC) are diagnosed with advanced disease, relapse rates are high in those undergoing surgery and prognosis remains poor, while the incidence is increasing. Treatment options are limited, and chemotherapy is still the standard of care in both adjuvant and advanced disease setting. In recent years, different subtypes of BTC have been defined depending on the anatomical location and genetic and/or epigenetic aberrations. Especially for intrahepatic cholangiocarcinoma (iCCA) novel therapeutic targets have been identified, including fibroblast growth factor receptor 2 gene fusions and isocitrate dehydrogenase 1 and 2 mutations, with molecularly targeted agents having shown evidence of activity in this subgroup of patients. Additionally, other pathways are being evaluated in both iCCA and other subtypes of BTC, alongside targeting of the immune microenvironment. The growing knowledge of BTC biology and molecular heterogeneity has paved the way for the development of new therapeutic approaches that will completely change the treatment paradigm for this disease in the near future. This review provides an overview of the molecular heterogeneity of BTC and summarizes new targets and emerging therapies in development. We also discuss resistance mechanisms, open issues, and future perspectives in the management of BTC.
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Affiliation(s)
- Nicola Personeni
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center-IRCCS, Rozzano, 20089 Milan, Italy; (N.P.); (T.P.)
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milan, Italy; (A.L.); (F.C.)
| | - Ana Lleo
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milan, Italy; (A.L.); (F.C.)
- Internal Medicine Center, Humanitas Clinical and Research Center-IRCCS, Rozzano, 20089 Milan, Italy
| | - Tiziana Pressiani
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center-IRCCS, Rozzano, 20089 Milan, Italy; (N.P.); (T.P.)
| | - Francesca Colapietro
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milan, Italy; (A.L.); (F.C.)
- Internal Medicine Center, Humanitas Clinical and Research Center-IRCCS, Rozzano, 20089 Milan, Italy
| | - Mark Robert Openshaw
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London W120HS, UK; (M.R.O.); (D.J.P.)
| | - Chara Stavraka
- Department of Medical Oncology, Guy’s and St Thomas’ NHS Foundation Trust, Great Maze Pond, London SE1 9RT, UK;
| | - Athanasios Pouptsis
- Department of Medical Oncology, “Euromedica” General Clinic, 54645 Thessaloniki, Greece;
| | - David James Pinato
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London W120HS, UK; (M.R.O.); (D.J.P.)
| | - Lorenza Rimassa
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center-IRCCS, Rozzano, 20089 Milan, Italy; (N.P.); (T.P.)
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milan, Italy; (A.L.); (F.C.)
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11
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Continuum of care for advanced biliary tract cancers. Clin Res Hepatol Gastroenterol 2020; 44:810-824. [PMID: 32586782 DOI: 10.1016/j.clinre.2020.05.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 05/24/2020] [Accepted: 05/27/2020] [Indexed: 02/07/2023]
Abstract
Biliary tract cancers (BTC) are a heterogeneous group of epithelial neoplasms, with a poor prognosis. Advanced BTC remains a challenging, non-curable disease. In this review, we provide an overview of the medical treatment options in advanced BTC and new strategies under development. Gemcitabine plus platinum chemotherapy is the standard first-line therapy in this setting. Recently, 5-fluorouracil, folinic acid plus oxaliplatin (FOLFOX) regimen became the only second-line therapy to be prospectively validated beyond failure of gemcitabine plus cisplatin combination in a phase III study, even though chemotherapy yielded modest survival improvement over best supportive care. Anti-epidermal growth factor receptor and antiangiogenic antibodies have not demonstrated any survival benefit in unselected patient populations. In recent years, knowledge about the molecular heterogeneity of BTC has considerably increased with the advent of large-scale genomic and transcriptomic analyses, opening up new perspectives for so-called personalised targeted therapies. Patients with BTC may be particularly good candidates for biomarker-driven strategies in clinical practice. Among current developments, the targeting of fibroblast growth factor receptor and isocitrate dehydrogenase gene alterations are the most promising avenues, and combination immunotherapies are under investigation.
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12
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Fostea RM, Fontana E, Torga G, Arkenau HT. Recent Progress in the Systemic Treatment of Advanced/Metastatic Cholangiocarcinoma. Cancers (Basel) 2020; 12:E2599. [PMID: 32932925 PMCID: PMC7565778 DOI: 10.3390/cancers12092599] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 08/23/2020] [Accepted: 09/08/2020] [Indexed: 02/07/2023] Open
Abstract
Cholangiocarcinomas (CCAs) comprise of a heterogeneous group of cancers arising in the biliary tract (intrahepatic or iCCA, perihilar or pCCA and distal or dCCA; the latter are known under the collective term of eCCA), each subtype having its own particularities in carcinogenesis, management and prognosis. The increasing incidence in recent decades, limited treatment options and high mortality rates, even in the early stages, have led to an imperious need for more in-depth understanding and development of tailored treatments for this type of aggressive tumour. The wide use of molecular profiling has increased the understanding of biology and identified key molecular drivers, for example, IDH1 mutations or FGFR2 fusions for iCCA, or BRAF mutations in eCCA. Most recently, the FDA approved pemigatinib, an FGFR inhibitor and ivosidenib, an IDH1 inhibitor, but even though progress has been made to better understand the mechanisms of tumorigenesis, genetic make-up, and tumour resistance to standard chemotherapy and targeted therapies, cholangiocarcinomas still represent an important challenge in the daily clinical practice of oncology. The purpose of this review is to highlight the recent progress in the systemic treatment of advanced/metastatic CCAs with a focus on targeted drugs and their biomarkers currently evaluated in early-phase clinical trials.
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Affiliation(s)
- Raluca Maria Fostea
- Drug Development Unit, Sarah Cannon Research Institute UK, 93 Harley Street, Marylebone, London W1G 6AD, UK; (R.M.F.); (E.F.); (G.T.)
| | - Elisa Fontana
- Drug Development Unit, Sarah Cannon Research Institute UK, 93 Harley Street, Marylebone, London W1G 6AD, UK; (R.M.F.); (E.F.); (G.T.)
| | - Gonzalo Torga
- Drug Development Unit, Sarah Cannon Research Institute UK, 93 Harley Street, Marylebone, London W1G 6AD, UK; (R.M.F.); (E.F.); (G.T.)
| | - Hendrik-Tobias Arkenau
- Drug Development Unit, Sarah Cannon Research Institute UK, 93 Harley Street, Marylebone, London W1G 6AD, UK; (R.M.F.); (E.F.); (G.T.)
- Cancer Institute, University College London, 72 Huntley Street, Bloomsbury, London WC1E 6DD, UK
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13
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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: 58] [Impact Index Per Article: 11.6] [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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14
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Jansen H, Pape UF, Utku N. A review of systemic therapy in biliary tract carcinoma. J Gastrointest Oncol 2020; 11:770-789. [PMID: 32953160 PMCID: PMC7475338 DOI: 10.21037/jgo-20-203] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 07/13/2020] [Indexed: 12/11/2022] Open
Abstract
Biliary tract carcinoma (BTC) has a poor prognosis and is increasing in incidence. Although surgery, chemotherapy and other treatment modalities have improved, surgery remains the only potential curative treatment and is appropriate for only those few patients who present with localized, resectable disease. However, for the majority of patients, unresectable disease is evident at diagnosis and about 95% of patients die within 10 years, despite the majority receiving chemotherapy. Long-term survival is significantly greater for patients with resected BTC compared to those with unresectable disease. In unresected disease, life expectancy is limited, with first-line gemcitabine/cisplatin (GEM/CIS) accepted as standard of care. Currently no standard second-line regimen which provides significant improvement of clinical outcomes exists for those who present with refractory disease or who relapse after first-line treatment. Of particular importance is establishing the impact of best supportive care (BSC) as a benchmark for survival outcomes to which the impact of treatment modalities can be compared. Survival outcome often differs significantly for patients with different prognostic factor profiles even when receiving the same therapy so that it can be difficult to predict which patient subgroup might benefit most from which therapy. Therefore, the influence of prognostic factors on survival under different therapies as well as under BSC needs to be further assessed in order to arrive at truly evidence-based, best therapeutic decisions for individual patients. Encouraging new research into the genomic landscape of BTC may help to further subdivide the BTC population into molecular-genetic clusters likely to be sensitive to different targeted therapy approaches leading to further improvements in survival. Consequently, an unmet need exists not only to develop new and more effective therapies for this devastating disease, but also to integrate original research findings into a more complex, dynamic, individualized therapeutic decision model to aid clinicians in making evidence-based, best therapeutic decisions for individual patients.
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Affiliation(s)
- Holger Jansen
- Campus Virchow & Mitte Charité, Institute f. Med. Immunologie, Berlin, Germany
| | - Ulrich-Frank Pape
- Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Germany
- Internal Medicine and Gastroenterology, Asklepios Klinik St. Georg, Asklepios Tumor Zentrum Hamburg, Germany
| | - Nalân Utku
- Campus Virchow & Mitte Charité, Institute f. Med. Immunologie, Berlin, Germany
- CellAct Pharma GmbH, Dortmund, Germany
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15
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Hand F, Hoti E. Contemporary role of liver transplantation for the treatment of cholangiocarcinoma. Expert Rev Gastroenterol Hepatol 2020; 14:475-481. [PMID: 32401554 DOI: 10.1080/17474124.2020.1765771] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Cholangiocarcinoma (CCA) is a dismal disease with limited management options. Surgical resection remains the only established treatment however, due to its inherent predilection to invade vascular structures, only a fraction of patients with CCA meet resection criteria at diagnosis. Furthermore, R0 margins, crucial to obtain optimum survival can often prove elusive. AREAS COVERED This review discusses the evolution of liver transplant for CCA, following its introduction in the 1990 s with less than exemplary outcomes. While transplantation is not standard of care, emerging data has suggested a crucial role in prolonging survival of those with CCA. Here we analyze the current role of orthotopic liver transplantation (OLT) in cirrhotic and non-cirrhotic patients, in the setting of both intrahepatic CCA and hilar CCA in order to establish whether this is a judicious use of a precious resource. EXPERT OPINION Liver transplant has a definite role in the treatment of CCA, as highlighted by ongoing clinical trials. A greater understanding of tumor biology coupled with results of current studies will help elucidate which patients will best benefit from OLT. While significant strides are being made to improve outcomes, this must be tempered with an understanding of the finite nature of liver grafts.
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Affiliation(s)
- Fiona Hand
- Department of Hepatobiliary and Liver Transplant Surgery, St. Vincent's, University Hospital , Dublin 4, Ireland
| | - Emir Hoti
- Department of Hepatobiliary and Liver Transplant Surgery, St. Vincent's, University Hospital , Dublin 4, Ireland
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16
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Massironi S, Pilla L, Elvevi A, Longarini R, Rossi RE, Bidoli P, Invernizzi P. New and Emerging Systemic Therapeutic Options for Advanced Cholangiocarcinoma. Cells 2020; 9:E688. [PMID: 32168869 PMCID: PMC7140695 DOI: 10.3390/cells9030688] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Revised: 02/28/2020] [Accepted: 02/28/2020] [Indexed: 02/05/2023] Open
Abstract
Cholangiocarcinoma (CCA) represents a disease entity that comprises a heterogeneous group of biliary malignant neoplasms, with variable clinical presentation and severity. It may be classified according to its anatomical location and distinguished in intrahepatic (iCCA), perihilar (pCCA), or distal (dCCA), each subtype implying distinct epidemiology, biology, prognosis, and strategy for clinical management. Its incidence has increased globally over the past few decades, and its mortality rate remains high due to both its biological aggressiveness and resistance to medical therapy. Surgery is the only potentially curative treatment and is the standard approach for resectable CCA; however, more than half of the patients have locally advanced or metastatic disease at presentation. For patients with unresectable CCA, the available systemic therapies are of limited effectiveness. However, the advances of the comprehension of the complex molecular landscape of CCA and its tumor microenvironment could provide new keys to better understand the pathogenesis, the mechanisms of resistance and ultimately to identify promising new therapeutic targets. Recently, clinical trials targeting isocitrate dehydrogenase (IDH)-1 mutations and fibroblast growth factor receptor (FGFR)-2 fusions, as well as immunotherapy showed promising results. All these new and emerging therapeutic options are herein discussed.
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Affiliation(s)
- Sara Massironi
- Division of Gastroenterology, San Gerardo Hospital, University of Milano-Bicocca School of Medicine, 20900 Monza, Italy; (A.E.); (P.I.)
| | - Lorenzo Pilla
- Division of Medical Oncology, San Gerardo Hospital, University of Milano-Bicocca School of Medicine, 20900 Monza, Italy; (L.P.); (R.L.); (P.B.)
| | - Alessandra Elvevi
- Division of Gastroenterology, San Gerardo Hospital, University of Milano-Bicocca School of Medicine, 20900 Monza, Italy; (A.E.); (P.I.)
| | - Raffaella Longarini
- Division of Medical Oncology, San Gerardo Hospital, University of Milano-Bicocca School of Medicine, 20900 Monza, Italy; (L.P.); (R.L.); (P.B.)
| | - Roberta Elisa Rossi
- Gastrointestinal and Hepato-Pancreatic Surgery and Liver Transplantation Unit, Fondazione IRCCS Istituto Nazionale Tumori (INT, National Cancer Institute) - Università degli Studi di Milano, 20100 Milan, Italy;
| | - Paolo Bidoli
- Division of Medical Oncology, San Gerardo Hospital, University of Milano-Bicocca School of Medicine, 20900 Monza, Italy; (L.P.); (R.L.); (P.B.)
| | - Pietro Invernizzi
- Division of Gastroenterology, San Gerardo Hospital, University of Milano-Bicocca School of Medicine, 20900 Monza, Italy; (A.E.); (P.I.)
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17
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Zheng WH, Yu T, Luo YH, Wang Y, Liu YF, Hua XD, Lin J, Ma ZH, Ai FL, Wang TL. Clinical efficacy of gemcitabine and cisplatin-based transcatheter arterial chemoembolization combined with radiotherapy in hilar cholangiocarcinoma. World J Gastrointest Oncol 2019; 11:489-498. [PMID: 31236199 PMCID: PMC6580316 DOI: 10.4251/wjgo.v11.i6.489] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Revised: 05/15/2019] [Accepted: 05/29/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Radical surgical resection is regarded as the best treatment for hepatic hilar cholangiocarcinoma. However, 60%-70% of patients have lost the chance of surgery at the time of diagnosis. Simple biliary stent or drainage tube placement may fail in a short time due to tumor invasion or overgrowth, bile accumulation, or biofilm formation. Effective palliative treatments to extend the effective drainage time are of great significance for improving the quality of life of patients and changing the prognosis of patients.
AIM To investigate the clinical efficacy of gemcitabine and cisplatin-based transcatheter arterial chemoembolization (TACE) combined with radiotherapy in hilar cholangiocarcinoma.
METHODS A retrospective analysis was conducted on patients clinically diagnosed with hilar cholangiocarcinoma from June 2014 to January 2017 at the Liaoning Provincial Cancer Hospital. Patients were evaluated by specialists, and those who were not suitable for surgery or unwilling to undergo surgery and met the inclusion criteria were included in the study. There were a total of 72 patients (34 males and 38 females) with an average age of 59.9 years (range, 40-72 years). According to percutaneous transhepatic biliary angiography and the patients’ wishes, stent implantation or biliary drainage tube implantation was used to relieve biliary obstruction. The patients were divided into either a control group or a combined treatment group according to their follow-up treatment. The control group consisted of a total of 35 patients who received simple biliary drainage tube placement and biliary stent implantation (7 patients with bilateral stents and 6 with a unilateral stent) and 22 patients receiving biliary drainage tube placement alone. The combined treatment group received TACE and extracorporeal radiotherapy after biliary drainage or biliary stent implantation and consisted of a total of 37 patients, including 21 patients receiving combined treatment after biliary stent placement (14 patients with bilateral stents and 7 with a unilateral stent) and 16 undergoing combined therapy after implanting the biliary drainage tube. In the combination treatment group, the TACE chemotherapy regimen employed gemcitabine and cisplatin, and the embolic agent was iodized oil. A particular dose was determined according to the patient's body surface area and the tumor staining indicated by DSA. In vitro radiotherapy was performed with intensity-modulated radiotherapy or three-dimensional conformal radiotherapy at an average dose of 48.3 Gy. Both groups were followed from stent implantation or drainage tube implantation until the patient quitted or died. The median length of follow-up observation was 13 mo. The differences in overall survival time and the effect of different jaundice reducing methods (single stent, double stent, or biliary drainage) on the patency time and survival time of biliary stents were compared between the two groups; the related factors affecting overall survival time were analyzed.
RESULTS The median survival time of the control group was 10.5 mo; the median survival time of patients with biliary stent implantation and those with percutaneous biliary drainage was 9.6 mo and 11.4 mo, respectively, and there was no statistically significant difference between them. The median survival time of the combined treatment group was 20.0 mo, which was significantly higher than that of the control group (P < 0.05). Among patients in the combined treatment group, the median survival time of patients who underwent biliary stent implantation and those who accepted percutaneous biliary drainage before the combination therapy was 19.5 mo and 20.1 mo, respectively, and there was no significant difference between them. In the combination treatment group, the mean time of median stent patency was 15.6 mo, which was significantly higher than that of the control group (7.0 mo; P < 0.05). The independent factors affecting survival time included age, whether to receive combination therapy, percutaneous biliary drainage tube implantation, and Bismuth-Corlette classification as type IV.
CONCLUSION Gemcitabine and cisplatin-based TACE combined with radiotherapy can prolong the survival of patients with hilar cholangiocarcinoma. Independent predictors of survival include selection of combination therapy, Bismuth-Corlette classification as type IV, selection of percutaneous biliary drainage tube implantation, and age.
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Affiliation(s)
- Wen-Heng Zheng
- Department of Medical Imaging, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang 110042, Liaoning Province, China
| | - Tao Yu
- Department of Medical Imaging, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang 110042, Liaoning Province, China
| | - Ya-Hong Luo
- Department of Medical Imaging, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang 110042, Liaoning Province, China
| | - Ying Wang
- Department of Medical Imaging, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang 110042, Liaoning Province, China
| | - Ye-Fu Liu
- Department of Hepatobiliary and Pancreatic Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang 110042, Liaoning Province, China
| | - Xiang-Dong Hua
- Department of Hepatobiliary and Pancreatic Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang 110042, Liaoning Province, China
| | - Jie Lin
- Department of General Surgery (VIP ward), Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang 110042, Liaoning Province, China
| | - Zuo-Hong Ma
- Department of Hepatobiliary and Pancreatic Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang 110042, Liaoning Province, China
| | - Fu-Lu Ai
- Department of General Surgery (VIP ward), Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang 110042, Liaoning Province, China
| | - Tian-Lu Wang
- Department of Radiotherapy, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang 110042, Liaoning Province, China
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18
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Adeva J, Sangro B, Salati M, Edeline J, La Casta A, Bittoni A, Berardi R, Bruix J, Valle JW. Medical treatment for cholangiocarcinoma. Liver Int 2019; 39 Suppl 1:123-142. [PMID: 30892822 DOI: 10.1111/liv.14100] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2019] [Revised: 03/10/2019] [Accepted: 03/12/2019] [Indexed: 02/13/2023]
Abstract
Most of the patients with cholangiocarcinoma (CCA) present with advanced (inoperable or metastatic) disease, and relapse rates are high in those undergoing potentially curative resection. Previous treatment nihilism of patients with advanced disease has been replaced by active clinical research with the advent of randomized clinical trials (RCTs) and a much greater effort at understanding molecular mechanisms underpinning CCA. Three RCTs have recently been reported evaluating adjuvant chemotherapy following curative resection; only one of these has the potential to change practice. The BILCAP study failed to meet its primary endpoint by intention-to-treat analysis; however, a survival benefit was seen in a preplanned sensitivity analysis (predominantly adjusting for lymph nodes status). This, along with the numerical difference in median overall survival has led to the uptake of adjuvant capecitabine by many clinicians. In patients with advanced disease, the only level 1 data available supports the use of cisplatin and gemcitabine for the first-line treatment of patients with advanced disease; there is no established second-line chemotherapy. Previous forays into targeted therapy have proven unfruitful (namely targeting the epithelial growth factor receptor and vascular endothelial growth factor pathways). An increasing number of genomic subtypes are being defined; for some of these on-target therapeutic options are under active investigation. The most developed are studies targeting IDH-1 (isocitrate dehydrogenase) mutations and FGFR-2 (fibroblast growth factor receptor) fusions, with promising early results. Several other pathways are under evaluation, along with early studies targeting the immune environment; these are too premature to change practice to date. These emerging treatments are discussed.
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Affiliation(s)
- Jorge Adeva
- Department of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Bruno Sangro
- Liver Unit and HPB Oncology Area, Clinica Universidad de Navarra-IDISNA and CIBEREHD, Pamplona, Spain
| | - Maximiliano Salati
- Department of Oncology, University Hospital of Modena and Reggio Emilia, Modena, Italy.,Division of Molecular Pathology, Institute of Cancer Research and Gastrointestinal Unit, Royal Marsden Hospital, London and Sutton, UK
| | - Julien Edeline
- Department of Medical Oncology, Centre Eugene Marquis, Rennes, France
| | - Adelaida La Casta
- Department of Medical Oncology, Hospital Universitario Donostia, Navarra, Spain
| | - Alessandro Bittoni
- Clinica Oncologica, Università Politecnica delle Marche, Ospedali Riuniti, Ancona, Italy
| | - Rosanna Berardi
- Clinica Oncologica, Università Politecnica delle Marche, Ospedali Riuniti, Ancona, Italy
| | - Jordi Bruix
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clinic Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Juan W Valle
- Division of Cancer Sciences, University of Manchester, Manchester, UK.,Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
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Wu CE, Chen MH, Yeh CN. mTOR Inhibitors in Advanced Biliary Tract Cancers. Int J Mol Sci 2019; 20:E500. [PMID: 30682771 PMCID: PMC6386826 DOI: 10.3390/ijms20030500] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2019] [Revised: 01/19/2019] [Accepted: 01/22/2019] [Indexed: 12/19/2022] Open
Abstract
Patients with advanced biliary tract cancers (BTCs), including cholangiocarcinoma (CCA), have poor prognosis so novel treatment is warranted for advanced BTC. In current review, we discuss the limitations of current treatment in BTC, the importance of mTOR signalling in BTC, and the possible role of mTOR inhibitors as a future treatment in BTC. Chemotherapy with gemcitabine-based chemotherapy is still the standard of care and no targeted therapy has been established in advanced BTC. PI3K/AKT/mTOR signaling pathway linking to several other pathways and networks regulates cancer proliferation and progression. Emerging evidences reveal mTOR activation is associated with tumorigenesis and drug-resistance in BTC. Rapalogs, such as sirolimus and everolimus, partially inhibit mTOR complex 1 (mTORC1) and exhibit anti-cancer activity in vitro and in vivo in BTC. Rapalogs in clinical trials demonstrate some activity in patients with advanced BTC. New-generation mTOR inhibitors against ATP-binding pocket inhibit both TORC1 and TORC2 and demonstrate more potent anti-tumor effects in vitro and in vivo, however, prospective clinical trials are warranted to prove its efficacy in patients with advanced BTC.
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Affiliation(s)
- Chao-En Wu
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou branch, Chang Gung University, Taoyuan 333, Taiwan.
| | - Ming-Huang Chen
- School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.
- Department of Oncology, Taipei Veterans General Hospital, Taipei 112, Taiwan.
| | - Chun-Nan Yeh
- Department of General Surgery and Liver Research Center, Chang Gung Memorial Hospital, Linkou branch, Chang Gung University, Taoyuan 333, Taiwan.
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20
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Gangi A, Shah J, Hatfield N, Smith J, Sweeney J, Choi J, El-Haddad G, Biebel B, Parikh N, Arslan B, Hoffe SE, Frakes JM, Springett GM, Anaya DA, Malafa M, Chen DT, Chen Y, Kim RD, Shridhar R, Kis B. Intrahepatic Cholangiocarcinoma Treated with Transarterial Yttrium-90 Glass Microsphere Radioembolization: Results of a Single Institution Retrospective Study. J Vasc Interv Radiol 2018; 29:1101-1108. [PMID: 30042074 DOI: 10.1016/j.jvir.2018.04.001] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Revised: 03/25/2018] [Accepted: 04/01/2018] [Indexed: 12/14/2022] Open
Abstract
PURPOSE To evaluate the efficacy and safety of transarterial yttrium-90 glass microsphere radioembolization in patients with unresectable intrahepatic cholangiocarcinoma (ICC). MATERIALS AND METHODS Retrospective review of 85 consecutive patients (41 men and 44 women; age, 73.4 ± 9.3 years) was performed. Survival data were analyzed by the Kaplan-Meier method, Cox regression models, and the log-rank test. RESULTS Median overall survival (OS) from diagnosis was 21.4 months (95% confidence interval [CI]: 16.6-28.4); median OS from radioembolization was 12.0 months (95% CI: 8.0-15.2). Seven episodes of severe toxicity occurred. At 3 months, 6.2% of patients had partial response, 64.2% had stable disease, and 29.6% had progressive disease. Median OS from radioembolization was significantly longer in patients with Eastern Cooperative Oncology Group (ECOG) scores of 0 and 1 than patients with an ECOG score of 2 (18.5 vs 5.5 months, P = .0012), and median OS from radioembolization was significantly longer in patients with well-differentiated histology than patients with poorly differentiated histology (18.6 vs 9.7 months, P = .012). Patients with solitary tumors had significantly longer median OS from radioembolization than patients with multifocal disease (25 vs. 6.1 months, P = .006). The absence of extrahepatic metastasis was associated with significantly increased median OS (15.2 vs. 6.8 months, P = .003). Increased time from diagnosis to radioembolization was a negative predictor of OS. The morphology of the tumor (mass-forming or infiltrative, hyper- or hypo-enhancing) had no effect on survival. Post-treatment increased cancer antigen 19-9 level, increased international normalized ratio, decreased albumin, increased bilirubin, increased aspartate aminotransferase, and increased Model for End-Stage Liver Disease score were significant predictors of decreased OS. CONCLUSIONS These data support the therapeutic role of radioembolization for the treatment of unresectable ICC with good efficacy and an acceptable safety profile.
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Affiliation(s)
- Alexandra Gangi
- Diagnostic Imaging and Interventional Radiology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612; Department of Surgery, Cedars Sinai Medical Center, Los Angeles, California
| | - Jehan Shah
- Diagnostic Imaging and Interventional Radiology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612
| | - Nathan Hatfield
- Diagnostic Imaging and Interventional Radiology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612
| | - Johnna Smith
- Diagnostic Imaging and Interventional Radiology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612
| | - Jennifer Sweeney
- Diagnostic Imaging and Interventional Radiology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612
| | - Junsung Choi
- Diagnostic Imaging and Interventional Radiology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612
| | - Ghassan El-Haddad
- Diagnostic Imaging and Interventional Radiology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612
| | - Benjamin Biebel
- Diagnostic Imaging and Interventional Radiology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612
| | - Nainesh Parikh
- Diagnostic Imaging and Interventional Radiology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612
| | - Bulent Arslan
- Diagnostic Imaging and Interventional Radiology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612; Vascular and Interventional Radiology, Rush University Medical Center, Chicago, Illinois
| | - Sarah E Hoffe
- Radiation Oncology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612
| | - Jessica M Frakes
- Radiation Oncology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612
| | - Gregory M Springett
- Gastrointestinal Oncology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612
| | - Daniel A Anaya
- Gastrointestinal Oncology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612
| | - Mokenge Malafa
- Gastrointestinal Oncology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612
| | - Dung-Tsa Chen
- Biostatistics and Bioinformatics, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612
| | - Yunyun Chen
- Biostatistics and Bioinformatics, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612
| | - Richard D Kim
- Gastrointestinal Oncology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612
| | - Ravi Shridhar
- Radiation Oncology, Florida Hospital Orlando, Orlando, Florida
| | - Bela Kis
- Diagnostic Imaging and Interventional Radiology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612.
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Kolarich AR, Shah JL, George TJ, Hughes SJ, Shaw CM, Geller BS, Grajo JR. Non-surgical management of patients with intrahepatic cholangiocarcinoma in the United States, 2004-2015: an NCDB analysis. J Gastrointest Oncol 2018; 9:536-545. [PMID: 29998019 DOI: 10.21037/jgo.2018.02.04] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Background Surgical resection is the standard of care for intrahepatic cholangiocarcinoma (ICC), but only a minority of patients are managed surgically. Other modalities, including external beam radiation (XRT), radiofrequency ablation (RFA), and radioactive implants (RIs) have been employed with significant heterogeneity of prognosis reported in the literature. The aim of this study was to evaluate the demographics of patients with ICC managed non-surgically and compare prognosis in patients managed surgically to those that underwent XRT, RFA, or RI. Methods All patients diagnosed with ICC from 2004 to 2015 in the National Cancer Database (NCDB) were reviewed. Patient demographics, treatments, and survival outcomes were analyzed. Results Of the 6,140 patients with ICC, 4,374 (71%) did not undergo surgery. Patients managed non-surgically were typically older, treated at community centers, more likely to have severe fibrosis or cirrhosis, and present with higher stage disease. The strongest association to receipt of XRT, RI, or RFA modalities was treatment at an academic center. Increased clinical stage was associated with decreased use of RFA; a significantly higher proportion of patients with stage IV disease were given no local therapy. RFA associated with a statistically significant survival benefit over no local therapy only in stage I disease (2.1 vs. 0.7 years, P=0.012) as well as XRT over no local therapy (1.7 vs. 0.7 years, P=0.009). No survival benefit was realized for any treatment in stage II disease. Patients with stage III disease had a survival benefit from XRT versus no local therapy (0.9 vs. 0.6 years, P=0.029) and RI over no local therapy (1.2 vs. 0.6 years, P=0.013). Patients with stage IV disease only demonstrated survival benefit from RI over no local therapy (0.9 vs. 0.3 years, P=0.014). Conclusions The majority of patients with ICC in the United States continue to be managed non-surgically. RFA was associated with improved survival only in stage I disease. XRT was associated with improved survival in stage I & III disease, while RI was associated with improved survival in stage III and IV disease.
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Affiliation(s)
| | - Jehan L Shah
- Department of Radiology, University of Florida College of Medicine, Gainesville, FL, USA
| | - Thomas J George
- Department of Medicine, University of Florida College of Medicine, Gainesville, FL, USA
| | - Steven J Hughes
- Department of Surgery, University of Florida College of Medicine, Gainesville, FL, USA
| | - Christiana M Shaw
- Department of Surgery, University of Florida College of Medicine, Gainesville, FL, USA
| | - Brian S Geller
- Department of Radiology, University of Florida College of Medicine, Gainesville, FL, USA
| | - Joseph R Grajo
- Department of Radiology, University of Florida College of Medicine, Gainesville, FL, USA
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Kis B, El-Haddad G, Sheth RA, Parikh NS, Ganguli S, Shyn PB, Choi J, Brown KT. Liver-Directed Therapies for Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma. Cancer Control 2018; 24:1073274817729244. [PMID: 28975829 PMCID: PMC5937250 DOI: 10.1177/1073274817729244] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (IHC) are primary liver cancers where all or most of the tumor burden is usually confined to the liver. Therefore, locoregional liver-directed therapies can provide an opportunity to control intrahepatic disease with minimal systemic side effects. The English medical literature and clinical trials were reviewed to provide a synopsis on the available liver-directed percutaneous therapies for HCC and IHC. Locoregional liver-directed therapies provide survival benefit for patients with HCC and IHC compared to best medical treatment and have lower comorbid risks compared to surgical resection. These treatment options should be considered, especially in patients with unresectable disease.
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Affiliation(s)
- Bela Kis
- 1 Department of Diagnostic Imaging and Interventional Radiology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Ghassan El-Haddad
- 1 Department of Diagnostic Imaging and Interventional Radiology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Rahul A Sheth
- 2 Department of Interventional Radiology, MD Anderson Cancer Center, Houston, TX, USA
| | - Nainesh S Parikh
- 1 Department of Diagnostic Imaging and Interventional Radiology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Suvranu Ganguli
- 3 Center for Image Guided Cancer Therapy, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Paul B Shyn
- 4 Department of Radiology, Abdominal Imaging and Intervention, Brigham and Women's, Boston, MA, USA
| | - Junsung Choi
- 1 Department of Diagnostic Imaging and Interventional Radiology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Karen T Brown
- 5 Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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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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Phase II study of everolimus (RAD001) monotherapy as first-line treatment in advanced biliary tract cancer with biomarker exploration: the RADiChol Study. Br J Cancer 2018. [PMID: 29527009 PMCID: PMC5931084 DOI: 10.1038/s41416-018-0021-1] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Background Advanced biliary tract cancers (BTCs) have a poor prognosis and limited treatment options. This exploratory phase II study aimed to evaluate the activity of the mTOR inhibitor everolimus in advanced BTC and explore prognostic biomarkers. Methods Patients with advanced BTCs, who had not received chemotherapy for advanced disease, were enroled to receive everolimus (10 mg daily). The primary endpoint was disease control rate (DCR) at 12 weeks. Secondary endpoints included overall response rate, progression-free survival (PFS), overall survival (OS) and adverse events. Activation status of the RAS and phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathways was assessed by DNA sequencing and immunohistochemistry on archival tumour tissue. Results The study enroled 27 patients and the DCR at 12 weeks was 48%. Median PFS was 5.5 months (95% confidence interval (CI): 2.1–10.0 months) and median OS was 9.5 months (95% CI: 5.5–16.6 months). DCR at 12 weeks was significantly worse for gall bladder carcinoma compared to other anatomical sites, and there was a trend towards a worsened PFS and OS. Treatment was well tolerated. KRAS (12%) and PIK3CA mutations (12%) were uncommon. Immunohistochemical staining for PI3K/AKT/mTOR pathways did not significantly correlate with outcome. Conclusion In unselected patients, everolimus demonstrated clinical activity as first-line monotherapy in advanced BTC.
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Sun XF, He ZK, Sun JP, Ge QX, Shen ED. The efficacy and safety of different pharmacological interventions for patients with advanced biliary tract cancer: A network meta-analysis. Oncotarget 2017; 8:100657-100667. [PMID: 29246010 PMCID: PMC5725052 DOI: 10.18632/oncotarget.20445] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Accepted: 07/25/2017] [Indexed: 01/02/2023] Open
Abstract
Biliary tract cancer (BTC) is the second common cancer in liver cancer. Chemotherapy is the mainstay of treatments for patients with advanced or metastatic disease, while fluorouracil (FU)-based and gemcitabine (GEM)-based treatments are most widely applied. This NMA aimed to figure out whether the addition of platinum (PLA) and target agents (TAR) can influence the efficacy and safety of standard chemotherapy. Network meta-analysis (NMA) was conducted based on the records from PubMed, Embase and Cochrane. Eligible data was extracted from available qualified trials and outcomes. Software R 3.2.3 and STATA 13.0 were used to conduct the Bayesian NMA, calculating odds ratios (ORs) and hazard ratios (HRs) with 95% credible interval (CrI) to evaluate different treatments.Almost all treatments were superior to best supportive care (BSC) and FU in terms of 1-OS, 2-OS and 1-PFS. GEM+PLA and GEM+PLA+TAR exhibited better efficacy than most treatments in 1-OS, 2-OS and 1-PFS, and yielded better results than BSC and GEM+FU in terms of 2-PFS. Most drug-containing treatments reported higher overall response rate (ORR) than BSC. GEM and GEM+FU were associated with a higher risk of neutropenia and thrombocytopenia compared to FU, FU+PLA and GEM+PLA. No statistical difference was detected in terms of nausea and vomiting.GEM+PLA and GEM+PLA+TAR were both efficacious and were associated with fewer adverse events. In conclusion, the addition of PLA can significantly improve the efficacy of FU and GEM-based treatments, and the addition of TAR to GEM+PLA can contribute to further improvement, but with a mild increase of adverse events.
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Affiliation(s)
- Xin-Fang Sun
- Department of Gastroenterology, Henan University Huaihe Hospital, Kaifeng, 475000, Henan, China
| | - Zhi-Kuan He
- Department of Gastroenterology, Henan University Huaihe Hospital, Kaifeng, 475000, Henan, China
| | - Jin-Ping Sun
- Department of Gastroenterology, Henan University Huaihe Hospital, Kaifeng, 475000, Henan, China
| | - Quan-Xing Ge
- Department of Gastroenterology, Henan University Huaihe Hospital, Kaifeng, 475000, Henan, China
| | - Er-Dong Shen
- Department of Oncology, The First People's Hospital of Yueyang, Yueyang, 414000, Hunan, China
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Blair AB, Murphy A. Immunotherapy as a treatment for biliary tract cancers: A review of approaches with an eye to the future. Curr Probl Cancer 2017; 42:49-58. [PMID: 29501212 DOI: 10.1016/j.currproblcancer.2017.10.004] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Revised: 09/07/2017] [Accepted: 10/27/2017] [Indexed: 01/04/2023]
Abstract
Biliary tract cancers (BTC) are aggressive malignancies associated with resistance to chemotherapy and poor prognostic rates. Therefore, novel treatment approaches are in need. Immunotherapy represents a promising breakthrough that uses a patient's immune system to target a tumor. This treatment approach has shown immense progress with positive results for selected cancers such as melanoma and nonsmall cell lung cancer. Initial preclinical data and preliminary clinical studies suggest encouraging mechanistic effects for immunotherapy in BTC offering the hope for an expanding therapeutic role for this disease. These approaches include targeted tumor antigen therapy via peptide and dendritic cell-based vaccines, allogenic cell adoptive immunotherapy, and the use of inhibitory agents targeting the immune checkpoint receptor pathway and multiple components of the tumor microenvironment. At this time demonstrating efficacy in larger clinical trials remains imperative. A multitude of ongoing trials aim to successfully translate mechanistic effects into antitumor efficacy and ultimately aim to incorporate immunotherapy into the routine management of BTC. With further research efforts, the optimization of dosing and therapeutic regimens, the identification of novel tumor antigens and a better understanding of alternative checkpoint pathway receptor expression may provide additional targets for rational combinatorial therapies which enhance the effects of immunotherapy and may offer hope for further advancing treatment options. Ultimately, the challenge remains to prospectively identify the subsets of patients with BTC who may respond to immunotherapy, and devising alternative strategies to sensitize those that do not with the hopes of improving outcomes for all with this deadly disease.
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Affiliation(s)
- Alex B Blair
- Department of Surgery, Johns Hopkins Hospital, Baltimore, MD; Department of Oncology, The Sidney Kimmel Cancer Center, Johns Hopkins Hospital, Baltimore, MD
| | - Adrian Murphy
- Department of Oncology, The Sidney Kimmel Cancer Center, Johns Hopkins Hospital, Baltimore, MD.
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Motoyama H, Kobayashi A, Yokoyama T, Shimizu A, Kitagawa N, Notake T, Fukushima K, Masuo H, Yoshizawa T, Miyagawa SI. Survival Benefits of Surgical Resection in Patients with Recurrent Biliary Tract Carcinoma. World J Surg 2017; 41:2817-2829. [DOI: 10.1007/s00268-017-4107-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
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28
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Zhuang X, Xiao YP, Tan LH, Wang LT, Cao Q, Qu GF, Xiao S, Duan HX. Efficacy and safety of chemotherapy with or without targeted therapy in biliary tract cancer: A meta-analysis of 7 randomized controlled trials. ACTA ACUST UNITED AC 2017; 37:172-178. [PMID: 28397047 DOI: 10.1007/s11596-017-1711-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2016] [Revised: 02/07/2017] [Indexed: 12/18/2022]
Abstract
The systematic treatment based on gemcitabine plus cisplatin is recommended as the current standard chemotherapy for unresectable or metastatic biliary tract cancers. However, the exact benefits from the recognized regime are still dismal. We thus elicit this study in an attempt to analyze whether targeted therapy coupled with various chemotherapy could produce improvement of survival benefits. The clinical trials were searched electronically from databases till July 2016 published in English and Chinese. Nine hundred and sixty-four patients from 7 trials were identified in our analysis. The overall analysis achieved a significantly higher overall response rate (ORR) among the patients treated with targeted drugs plus chemotherapy than chemotherapy alone (OR=1.87; 95% CI: 1.37-2.57; P=0.000), but failed in the overall progression-free survival (PFS) [mean difference (MD)=0.63; 95% CI:-0.45-1.72; P=0.26] and overall survival (OS) (MD=-0.67; 95% CI:-2.54-1.20; P=0.49). In the sub analysis, better ORR was obtained with the addition of EGFR (OR=1.75; 95% CI: 1.20-2.56; P=0.004) and VEGFR (OR=2.5; 95% CI: 1.28-4.87; P=0.007) targeted therapy. Furthermore, the sub analysis of EGFR target showed an significant improvement on PFS (MD=1.36; 95% CI: 0.29-2.43; P=0.01). No significant differences were observed in the incidences of neutropenia (OR=1.37; 95% CI: 0.89-2.12), thrombocytopenia (OR=1.40; 95% CI: 0.83-2.39), anemia (OR=1.21; 95% CI: 0.62-2.38), peripheral neuropathy (OR=1.52; 95% CI: 0.81-2.88), increased AST/ALT (OR=1.40; 95% CI: 0.82-2.39) as well as fatigue (OR=1.65; 95% CI: 0.96-2.84) in either of the treatment groups. In conclusion, better ORR associated with chemotherapy combined with targeted therapy (both targeting EGFR and VEGF) is found in the present meta-analysis without the cost of increased unacceptable toxicities, but regretfully not for the OS. The sub-analysis of targeting EGFR instead of VEGF obtains a superior PFS. Otherwise, there is no statistically significant difference in the overall PFS between the combination regime and chemotherapy alone. Given the paucity of favorable data, we need further studies to characterize optimal targeted agents to confirm the potential value to biliary tract cancer.
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Affiliation(s)
- Xin Zhuang
- Department of Oncology, Hunan Provincial People's Hospital, the First Affiliated Hospital of Hunan Normal University, Changsha, 410005, China
| | - Ya-Ping Xiao
- Department of Orthopedic Surgery, Affiliated Hospital of North China University of Science and Technology, Tangshan, 063000, China
| | - Ling-Hua Tan
- Department of Oncology, Hunan Provincial People's Hospital, the First Affiliated Hospital of Hunan Normal University, Changsha, 410005, China
| | - Lu-Ting Wang
- Department of Oncology, Hunan Provincial People's Hospital, the First Affiliated Hospital of Hunan Normal University, Changsha, 410005, China
| | - Qian Cao
- Department of Oncology, Hunan Provincial People's Hospital, the First Affiliated Hospital of Hunan Normal University, Changsha, 410005, China
| | - Gui-Fang Qu
- Department of Oncology, Hunan Provincial People's Hospital, the First Affiliated Hospital of Hunan Normal University, Changsha, 410005, China
| | - Shuang Xiao
- Department of Oncology, Hunan Provincial People's Hospital, the First Affiliated Hospital of Hunan Normal University, Changsha, 410005, China
| | - Hua-Xin Duan
- Department of Oncology, Hunan Provincial People's Hospital, the First Affiliated Hospital of Hunan Normal University, Changsha, 410005, China.
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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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Burkhart RA, Laheru DA, Herman JM, Pawlik TM. Multidisciplinary management and the future of treatment in cholangiocarcinoma. Expert Opin Orphan Drugs 2016. [DOI: 10.1517/21678707.2016.1130618] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
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Marret G, Neuzillet C, Rousseau B, Tournigand C. [Medical management of cholangiocarcinomas in 2015]. Bull Cancer 2016; 103:389-99. [PMID: 26922666 DOI: 10.1016/j.bulcan.2016.01.019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2015] [Revised: 01/11/2016] [Accepted: 01/19/2016] [Indexed: 12/21/2022]
Abstract
Cholangiocarcinoma is a rare malignancy carrying a poor prognosis. Most patients are diagnosed with advanced-stage disease and are then ineligible for surgical resection, which is the only potentially curative therapeutic modality. The aim of this article is to provide an up-to-date review of medical management of patients with cholangiocarcinoma. The benefit of adjuvant therapy in patients undergoing curative-intent surgery is under evaluation. Combination chemotherapy with gemcitabine and platinum is the standard first-line treatment for patients with advanced cholangiocarcinoma. Targeted agents are not currently recommended due to limited data on use in this setting. The role of second-line chemotherapy is not established in advanced cholangiocarcinoma. Identification of predictive and prognostic markers to select patients who could benefit from second-line therapy is a major issue. A better understanding of the biological and molecular mechanisms underlying the carcinogenesis and the phenotypic heterogeneity of cholangiocarcinoma may path the way of new therapeutic strategies.
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Affiliation(s)
- Grégoire Marret
- Assistance publique-Hôpitaux de Paris (AP-HP), université Paris Est Créteil (UPEC), hôpital Henri-Mondor, service d'oncologie médicale, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94000 Créteil, France
| | - Cindy Neuzillet
- Assistance publique-Hôpitaux de Paris (AP-HP), université Paris Est Créteil (UPEC), hôpital Henri-Mondor, service d'oncologie médicale, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94000 Créteil, France.
| | - Benoît Rousseau
- Assistance publique-Hôpitaux de Paris (AP-HP), université Paris Est Créteil (UPEC), hôpital Henri-Mondor, service d'oncologie médicale, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94000 Créteil, France
| | - Christophe Tournigand
- Assistance publique-Hôpitaux de Paris (AP-HP), université Paris Est Créteil (UPEC), hôpital Henri-Mondor, service d'oncologie médicale, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94000 Créteil, France
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32
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Peng Y, Sun HY, Wang ZC, Xu XD, Song JC, Gong ZJ. Fabrication of Alginate/Calcium Carbonate Hybrid Microparticles for Synergistic Drug Delivery. Chemotherapy 2015; 61:32-40. [DOI: 10.1159/000440645] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2015] [Accepted: 08/25/2015] [Indexed: 11/19/2022]
Abstract
A hybrid drug delivery system coloaded with different drugs for synergistic drug delivery was developed. Alginate/calcium carbonate (CaCO3) hybrid microparticles (MPs) were fabricated via a facile coprecipitation method under mild conditions without using any organic solvent and surfactant. Due to the incorporation of negatively charged alginate chains onto the surface, the obtained hybrid MPs with spherical morphology showed good colloidal stability in an aqueous solution. An antitumor drug (doxorubicin, DOX) and a drug resistance reversal agent (verapamil, VP) were coloaded in the hybrid MPs simultaneously to obtain dual-drug-loaded MPs (DOX/VP/MP). Due to the presence of inorganic CaCO3 (∼54 wt%), the drugs could be loaded in the hybrid MPs with high encapsulation efficiency and the drug release could be effectively sustained. The cell growth inhibition of the drug-loaded MPs was evaluated in HeLa cells. An in vitro study showed DOX/VP/MP exhibited higher cell growth inhibition as compared with DOX monodrug-loaded MPs (DOX/MP). These results suggest the hybrid MPs can potentially be used as a synergistic drug delivery platform for cancer chemotherapy.
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Zhao Q, Qian S, Zhu L, Qu XD, Zhang W, Yan ZP, Cheng JM, Liu QX, Liu R, Wang JH. Transcatheter arterial chemoembolization with gemcitabine and oxaliplatin for the treatment of advanced biliary tract cancer. Onco Targets Ther 2015; 8:595-600. [PMID: 25792843 PMCID: PMC4360827 DOI: 10.2147/ott.s79316] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Background The aim of this study was to determine the therapeutic efficacy and safety of transarterial chemoembolization (TACE) with gemcitabine and oxaliplatin in patients with advanced biliary tract cancer (BTC). Methods We retrospectively analyzed the outcomes for 65 patients with advanced BTC treated by TACE with gemcitabine 1,000 mg/m2 and oxaliplatin 100 mg/m2. Follow-up laboratory tests and computed tomography or magnetic resonance imaging were performed routinely to evaluate the response of the tumor to treatment. All patients were assessed for adverse effects. Results Of the 65 patients, 19 (29.2%) achieved a partial response, 36 (55.4%) showed stable disease, and ten (15.4%) showed progressive disease. The overall response rate was 29.2%. At the end of this study, five patients were still alive. The median overall survival was 12.0 months (95% confidence interval 8.5–15.5). There were no serious complications after TACE. Conclusion The disease control rate and overall survival in this retrospective study were consistent with those in previous reports. TACE with gemcitabine and oxaliplatin was well tolerated and highly effective in patients with advanced BTC.
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Affiliation(s)
- Qing Zhao
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Sheng Qian
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Liang Zhu
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Xu-Dong Qu
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Wei Zhang
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Zhi-Ping Yan
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Jie-Min Cheng
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Qing-Xin Liu
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Rong Liu
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Jian-Hua Wang
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
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