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Ramaswamy A, Bhargava P, Srinivas S, Kapoor A, Mishra BK, Gupta A, Mandavkar S, Kannan S, Chaugule D, Patil R, Parulekar M, Nashikkar C, Ankathi SK, Kaushal RK, Naughane D, Daddi A, Mer N, Shetty N, Ostwal V. Bevacizumab Erlotinib Switch Maintenance in Chemo-Responsive Advanced Gallbladder and Cholangiocarcinoma (BEER BTC): A Multicenter, Open-Label, Randomized, Phase II Trial. J Clin Oncol 2024; 42:3218-3227. [PMID: 39102628 DOI: 10.1200/jco.23.02420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 03/21/2024] [Accepted: 04/17/2024] [Indexed: 08/07/2024] Open
Abstract
PURPOSE Patients with chemotherapy-responsive advanced biliary tract cancers (BTCs) are usually observed after 6 months of gemcitabine-based therapy. There is limited prospective evidence for maintenance strategies after chemotherapy. METHODS This investigator-initiated, open-label, randomized, integrated phase II-III study enrolled adult patients with advanced BTC from two cancer centers in India. Patients with histologically confirmed advanced biliary tract adenocarcinoma who had at least disease stabilization after 6 months of gemcitabine-based chemotherapy were randomly assigned (1:1) to either active surveillance or switch maintenance, which was a combination of bevacizumab 5 mg/kg intravenous once every 21 days plus erlotinib 100 mg once daily. Both arms were continued until disease progression, unacceptable toxicity, or patient decision to withdraw. The primary end point of the phase II component of the trial was investigator-evaluated progression-free survival. This trial is registered with Clinical Trials Registry of India (CTRI/2019/05/019323I). RESULTS From May 2021 to November 2022, 98 patients were randomly assigned to active surveillance (n = 49) or bevacizumab-erlotinib (n = 49). A majority of patients had gallbladder cancer (80%). The median follow-up was 13.4 months. The median progression-free survival was 3.1 months (95% CI, 2.47 to 3.64) in the active surveillance group versus 5.3 months (95% CI, 3.53 to 7.04) in the bevacizumab-erlotinib group (hazard ratio, 0.51 [95% CI, 0.33 to 0·74]; P = .0013). The most common grade 3 class-specific adverse events associated with bevacizumab-erlotinib were acneiform rash 1 (2%) and oral stomatitis 1 (2%) with erlotinib and bleeding 1 (2%) with bevacizumab. CONCLUSION The combination of bevacizumab and erlotinib as switch maintenance improves progression-free survival with an acceptable safety profile compared with active surveillance in patients with advanced BTCs in this phase II study. The trial moves on to the phase III component to evaluate improvement in overall survival.
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Affiliation(s)
- Anant Ramaswamy
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Prabhat Bhargava
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Sujay Srinivas
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Akhil Kapoor
- Department of Medical Oncology, Homi Bhabha Cancer Hospital, Varanasi, India
| | - Bal Krishna Mishra
- Department of Medical Oncology, Homi Bhabha Cancer Hospital, Varanasi, India
| | - Anuj Gupta
- Department of Medical Oncology, Homi Bhabha Cancer Hospital, Varanasi, India
| | - Sarika Mandavkar
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Sadhana Kannan
- Department of Statistics, Advanced Centre for Treatment, Research and Education in Cancer, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Deepali Chaugule
- CRC, Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Rajshree Patil
- CRC, Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Manali Parulekar
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Chaitali Nashikkar
- Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Suman Kumar Ankathi
- Department of Radiology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Rajiv Kumar Kaushal
- Department of Pathology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Deepali Naughane
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Anuprita Daddi
- Department of Medicine, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Neha Mer
- CRC, Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Nitin Shetty
- Department of Radiology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Vikas Ostwal
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
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Esmail A, Badheeb M, Alnahar BW, Almiqlash B, Sakr Y, Al-Najjar E, Awas A, Alsayed M, Khasawneh B, Alkhulaifawi M, Alsaleh A, Abudayyeh A, Rayyan Y, Abdelrahim M. The Recent Trends of Systemic Treatments and Locoregional Therapies for Cholangiocarcinoma. Pharmaceuticals (Basel) 2024; 17:910. [PMID: 39065760 PMCID: PMC11279608 DOI: 10.3390/ph17070910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 07/03/2024] [Accepted: 07/05/2024] [Indexed: 07/28/2024] Open
Abstract
Cholangiocarcinoma (CCA) is a hepatic malignancy that has a rapidly increasing incidence. CCA is anatomically classified into intrahepatic (iCCA) and extrahepatic (eCCA), which is further divided into perihilar (pCCA) and distal (dCCA) subtypes, with higher incidence rates in Asia. Despite its rarity, CCA has a low 5-year survival rate and remains the leading cause of primary liver tumor-related death over the past 10-20 years. The systemic therapy section discusses gemcitabine-based regimens as primary treatments, along with oxaliplatin-based options. Second-line therapy is limited but may include short-term infusional fluorouracil (FU) plus leucovorin (LV) and oxaliplatin. The adjuvant therapy section discusses approaches to improve overall survival (OS) post-surgery. However, only a minority of CCA patients qualify for surgical resection. In comparison to adjuvant therapies, neoadjuvant therapy for unresectable cases shows promise. Gemcitabine and cisplatin indicate potential benefits for patients awaiting liver transplantation. The addition of immunotherapies to chemotherapy in combination is discussed. Nivolumab and innovative approaches like CAR-T cells, TRBAs, and oncolytic viruses are explored. We aim in this review to provide a comprehensive report on the systemic and locoregional therapies for CCA.
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Affiliation(s)
- Abdullah Esmail
- Section of GI Oncology, Houston Methodist Neal Cancer Center, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Mohamed Badheeb
- Department of Internal Medicine, Yale New Haven Health, Bridgeport Hospital, Bridgeport, CT 06610, USA
| | | | - Bushray Almiqlash
- Zuckerman College of Public Health, Arizona State University, Tempe, AZ 85287, USA;
| | - Yara Sakr
- Department of GI Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Ebtesam Al-Najjar
- Section of GI Oncology, Houston Methodist Neal Cancer Center, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Ali Awas
- Faculty of Medicine and Health Sciences, University of Science and Technology, Sanaa P.O. Box 15201-13064, Yemen
| | | | - Bayan Khasawneh
- Section of GI Oncology, Houston Methodist Neal Cancer Center, Houston Methodist Hospital, Houston, TX 77030, USA
| | | | - Amneh Alsaleh
- Department of Medicine, Desert Regional Medical Center, Palm Springs, CA 92262, USA
| | - Ala Abudayyeh
- Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Yaser Rayyan
- Department of Gastroenterology & Hepatology, Faculty of Medicine, The University of Jordan, Amman 11942, Jordan
| | - Maen Abdelrahim
- Section of GI Oncology, Houston Methodist Neal Cancer Center, Houston Methodist Hospital, Houston, TX 77030, USA
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Heumann P, Albert A, Gülow K, Tümen D, Müller M, Kandulski A. Current and Future Therapeutic Targets for Directed Molecular Therapies in Cholangiocarcinoma. Cancers (Basel) 2024; 16:1690. [PMID: 38730642 PMCID: PMC11083102 DOI: 10.3390/cancers16091690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 04/17/2024] [Accepted: 04/21/2024] [Indexed: 05/13/2024] Open
Abstract
We conducted a comprehensive review of the current literature of published data, clinical trials (MEDLINE; ncbi.pubmed.com), congress contributions (asco.org; esmo.org), and active recruiting clinical trains (clinicaltrial.gov) on targeted therapies in cholangiocarcinoma. Palliative treatment regimens were analyzed as well as preoperative and perioperative treatment options. We summarized the current knowledge for each mutation and molecular pathway that is or has been under clinical evaluation and discussed the results on the background of current treatment guidelines. We established and recommended targeted treatment options that already exist for second-line settings, including IDH-, BRAF-, and NTRK-mutated tumors, as well as for FGFR2 fusion, HER2/neu-overexpression, and microsatellite instable tumors. Other options for targeted treatment include EGFR- or VEGF-dependent pathways, which are known to be overexpressed or dysregulated in this cancer type and are currently under clinical investigation. Targeted therapy in CCA is a hallmark of individualized medicine as these therapies aim to specifically block pathways that promote cancer cell growth and survival, leading to tumor shrinkage and improved patient outcomes based on the molecular profile of the tumor.
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Affiliation(s)
- Philipp Heumann
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases University Hospital Regensburg Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany
| | | | | | | | | | - Arne Kandulski
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases University Hospital Regensburg Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany
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Toledo B, Deiana C, Scianò F, Brandi G, Marchal JA, Perán M, Giovannetti E. Treatment resistance in pancreatic and biliary tract cancer: molecular and clinical pharmacology perspectives. Expert Rev Clin Pharmacol 2024; 17:323-347. [PMID: 38413373 DOI: 10.1080/17512433.2024.2319340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Accepted: 02/12/2024] [Indexed: 02/29/2024]
Abstract
INTRODUCTION Treatment resistance poses a significant obstacle in oncology, especially in biliary tract cancer (BTC) and pancreatic cancer (PC). Current therapeutic options include chemotherapy, targeted therapy, and immunotherapy. Resistance to these treatments may arise due to diverse molecular mechanisms, such as genetic and epigenetic modifications, altered drug metabolism and efflux, and changes in the tumor microenvironment. Identifying and overcoming these mechanisms is a major focus of research: strategies being explored include combination therapies, modulation of the tumor microenvironment, and personalized approaches. AREAS COVERED We provide a current overview and discussion of the most relevant mechanisms of resistance to chemotherapy, target therapy, and immunotherapy in both BTC and PC. Furthermore, we compare the different strategies that are being implemented to overcome these obstacles. EXPERT OPINION So far there is no unified theory on drug resistance and progress is limited. To overcome this issue, individualized patient approaches, possibly through liquid biopsies or single-cell transcriptome studies, are suggested, along with the potential use of artificial intelligence, to guide effective treatment strategies. Furthermore, we provide insights into what we consider the most promising areas of research, and we speculate on the future of managing treatment resistance to improve patient outcomes.
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Affiliation(s)
- Belén Toledo
- Department of Health Sciences, University of Jaén, Jaén, Spain
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), Amsterdam, The Netherlands
| | - Chiara Deiana
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Fabio Scianò
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), Amsterdam, The Netherlands
- Lumobiotics GmbH, Karlsruhe, Germany
| | - Giovanni Brandi
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Juan Antonio Marchal
- Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, Granada, Spain
- Instituto de Investigación Sanitaria ibs. GRANADA, Hospitales Universitarios de Granada-Universidad de Granada, Granada, Spain
- Department of Human Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada, Spain
- Excellence Research Unit "Modeling Nature" (MNat), University of Granada, Granada, Spain
| | - Macarena Perán
- Department of Health Sciences, University of Jaén, Jaén, Spain
- Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, Granada, Spain
- Excellence Research Unit "Modeling Nature" (MNat), University of Granada, Granada, Spain
| | - Elisa Giovannetti
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), Amsterdam, The Netherlands
- Cancer Pharmacology Lab, Fondazione Pisana per la Scienza, Pisa, Italy
- Cancer Pharmacology Lab, Associazione Italiana per la Ricerca sul Cancro (AIRC) Start-Up Unit, Fondazione Pisana per la Scienza, University of Pisa, Pisa, Italy
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Sun Y, Gong J, Li Z, Han L, Sun D. Gallbladder cancer: surgical treatment, immunotherapy, and targeted therapy. Postgrad Med 2024; 136:278-291. [PMID: 38635593 DOI: 10.1080/00325481.2024.2345585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Accepted: 04/12/2024] [Indexed: 04/20/2024]
Abstract
Gallbladder cancer is a common type of biliary tract tumor. Optimal management for early stage cases typically involves radical excision as the primary treatment modality. Various surgical techniques, including laparoscopic, robotic, and navigational surgery, have demonstrated favorable clinical outcomes in radical gallbladder excision. Unfortunately, most patients are ineligible for surgical intervention because of the advanced stage of the disease upon diagnosis. Consequently, non-surgical interventions, such as chemotherapy, radiotherapy, immunotherapy, and targeted therapy, have become the mainstay of treatment for patients in advanced stages. This review focuses on elucidating various surgical techniques as well as advancements in immunotherapy and targeted therapy in the context of recent advancements in gallbladder cancer research.
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Affiliation(s)
- Yanjun Sun
- Department of General Surgery, The Armed Police Corps Hospital of Anhui, Hefei, China
| | - Junfeng Gong
- Department of General Surgery, The Armed Police Corps Hospital of Anhui, Hefei, China
| | | | - Lin Han
- Department of General Surgery, The Armed Police Corps Hospital of Anhui, Hefei, China
| | - Dengqun Sun
- Department of General Surgery, The Armed Police Corps Hospital of Anhui, Hefei, China
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Duan XP, Qin BD, Jiao XD, Liu K, Wang Z, Zang YS. New clinical trial design in precision medicine: discovery, development and direction. Signal Transduct Target Ther 2024; 9:57. [PMID: 38438349 PMCID: PMC10912713 DOI: 10.1038/s41392-024-01760-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 01/25/2024] [Accepted: 01/29/2024] [Indexed: 03/06/2024] Open
Abstract
In the era of precision medicine, it has been increasingly recognized that individuals with a certain disease are complex and different from each other. Due to the underestimation of the significant heterogeneity across participants in traditional "one-size-fits-all" trials, patient-centered trials that could provide optimal therapy customization to individuals with specific biomarkers were developed including the basket, umbrella, and platform trial designs under the master protocol framework. In recent years, the successive FDA approval of indications based on biomarker-guided master protocol designs has demonstrated that these new clinical trials are ushering in tremendous opportunities. Despite the rapid increase in the number of basket, umbrella, and platform trials, the current clinical and research understanding of these new trial designs, as compared with traditional trial designs, remains limited. The majority of the research focuses on methodologies, and there is a lack of in-depth insight concerning the underlying biological logic of these new clinical trial designs. Therefore, we provide this comprehensive review of the discovery and development of basket, umbrella, and platform trials and their underlying logic from the perspective of precision medicine. Meanwhile, we discuss future directions on the potential development of these new clinical design in view of the "Precision Pro", "Dynamic Precision", and "Intelligent Precision". This review would assist trial-related researchers to enhance the innovation and feasibility of clinical trial designs by expounding the underlying logic, which be essential to accelerate the progression of precision medicine.
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Affiliation(s)
- Xiao-Peng Duan
- Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Bao-Dong Qin
- Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Xiao-Dong Jiao
- Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Ke Liu
- Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Zhan Wang
- Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Yuan-Sheng Zang
- Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China.
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Mirza-Aghazadeh-Attari M, Afyouni S, Zandieh G, Yazdani Nia I, Mohseni A, Borhani A, Madani SP, Shahbazian H, Ansari G, Kim A, Kamel IR. Utilization of Radiomics Features Extracted From Preoperative Medical Images to Detect Metastatic Lymph Nodes in Cholangiocarcinoma and Gallbladder Cancer Patients: A Systemic Review and Meta-analysis. J Comput Assist Tomogr 2024; 48:184-193. [PMID: 38013233 DOI: 10.1097/rct.0000000000001557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2023]
Abstract
OBJECTIVES This study aimed to determine the methodological quality and evaluate the diagnostic performance of radiomics features in detecting lymph node metastasis on preoperative images in patients with cholangiocarcinoma and gallbladder cancer. METHODS Publications between January 2005 and October 2022 were considered for inclusion. Databases such as Pubmed/Medline, Scopus, Embase, and Google Scholar were searched for relevant studies. The quality of the methodology of the manuscripts was determined using the Radiomics Quality Score and Quality Assessment of Diagnostic Accuracy Studies 2. Pooled results with corresponding 95% confidence intervals (CIs) were calculated using the DerSimonian-Liard method (random-effect model). Forest plots were used to visually represent the diagnostic profile of radiomics signature in each of the data sets pertaining to each study. Fagan plot was used to determine clinical applicability. RESULTS Overall sensitivity was 0.748 (95% CI, 0.703-0.789). Overall specificity was 0.795 (95% CI, 0.742-0.839). The combined negative likelihood ratio was 0.299 (95% CI, 0.266-0.350), and the positive likelihood ratio was 3.545 (95% CI, 2.850-4.409). The combined odds ratio of the studies was 12.184 (95% CI, 8.477-17.514). The overall summary receiver operating characteristics area under the curve was 0.83 (95% CI, 0.80-0.86). Three studies applied nomograms to 8 data sets and achieved a higher pooled sensitivity and specificity (0.85 [0.80-0.89] and 0.85 [0.71-0.93], respectively). CONCLUSIONS The pooled analysis showed that predictive models fed with radiomics features achieve good sensitivity and specificity in detecting lymph node metastasis in computed tomography and magnetic resonance imaging images. Supplementation of the models with biological correlates increased sensitivity and specificity in all data sets.
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Affiliation(s)
| | - Shadi Afyouni
- From the Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Hospital
| | - Ghazal Zandieh
- From the Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Hospital
| | - Iman Yazdani Nia
- From the Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Hospital
| | - Alireza Mohseni
- From the Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Hospital
| | - Ali Borhani
- From the Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Hospital
| | - Seyedeh Panid Madani
- From the Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Hospital
| | - Haneyeh Shahbazian
- From the Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Hospital
| | - Golnoosh Ansari
- From the Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Hospital
| | - Amy Kim
- Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Ihab R Kamel
- From the Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Hospital
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Gupta A, Sahai P, Prasad M, Yadav HP, Srivastava G, Nakhro N, Kumar G, Sharma N. Treatment Response and Survival with Chemotherapy for Unresectable, Nonmetastatic Cholangiocarcinoma. Euroasian J Hepatogastroenterol 2024; 14:5-8. [PMID: 39022199 PMCID: PMC11249901 DOI: 10.5005/jp-journals-10018-1396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Accepted: 08/11/2023] [Indexed: 07/20/2024] Open
Abstract
Background and objectives Limited studies have dwelt upon the treatment of unresectable, nonmetastatic cholangiocarcinoma as a separate entity. Hence, the management protocols are not clearly defined for this subgroup of patients. We aimed to analyze patients treated for unresectable, nonmetastatic cholangiocarcinoma. Materials and methods We analyzed the treatment of patients with unresectable, nonmetastatic cholangiocarcinoma retrospectively. Results A total of 162 cases of cholangiocarcinoma were reported to our center from 2016 to 2019, out of which 54 were unresectable and nonmetastatic. Thirty patients opted for treatment and were the subjects of this study. Of 30 patients, 24 had hyperbilirubinemia, out of which 10 received chemotherapy after biliary drainage procedure. Out of 30 patients, a total of 16 patients had received chemotherapy, while 14 did not. Gemcitabine/Cisplatin was the first-line chemotherapy administered to 9 patients, whereas 5 received Gemcitabine/Capecitabine and 2 received single-agent gemcitabine. Partial response was documented in 6 patients, and 4 patients had stable disease. The median overall survival was 12.04 months in patients who had received chemotherapy and 6.02 months in those who did not receive chemotherapy (p = 0.005). The median progression-free survival was 6.53 months for patients who had received chemotherapy. The aHR for mortality with chemotherapy compared with no chemotherapy was 0.353 (95% CI: 0.154-0.807). Conclusion The study data demonstrate that gemcitabine combined with cisplatin- or capecitabine-based chemotherapy prolongs survival in patients with unresectable and nonmetastatic cholangiocarcinoma. In patients with cholangiocarcinoma associated with jaundice, biliary drainage procedure enables giving chemotherapy. Hyperbilirubinemia persisting despite drainage procedures portends poor prognosis and represents an unmet need. How to cite this article Gupta A, Sahai P, Prasad M, et al. Treatment Response and Survival with Chemotherapy for Unresectable, Nonmetastatic Cholangiocarcinoma. Euroasian J Hepato-Gastroenterol 2024;14(1):5-8.
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Affiliation(s)
- Ajay Gupta
- Department of Medical Oncology, Indraprastha Apollo Hospital, New Delhi, India
| | - Puja Sahai
- Department of Radiation Oncology, Institute of Liver and Biliary Sciences (ILBS), New Delhi, India
| | - Manya Prasad
- Department of Epidemiology, Institute of Liver and Biliary Sciences (ILBS), New Delhi, India
| | - Hanuman Prasad Yadav
- Department of Radiation Oncology, Institute of Liver and Biliary Sciences (ILBS), New Delhi, India
| | - Gagan Srivastava
- Department of Medical Oncology, Institute of Liver and Biliary Sciences (ILBS), New Delhi, India
| | - Nuneno Nakhro
- Department of Medical Oncology, Institute of Liver and Biliary Sciences (ILBS), New Delhi, India
| | - Guresh Kumar
- Department of Research, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Namita Sharma
- Department of Medical Oncology, Institute of Liver and Biliary Sciences (ILBS), New Delhi, India
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Myint KZ, Sueca-Comes M, Collier P, Balasubramanian B, Venkatraman S, Gordan J, Zaitoun AM, Mukherjee A, Arora A, Larbcharoensub N, Suriyonplengsaeng C, Wongprasert K, Janvilisri T, Gomez D, Grabowska AM, Tohtong R, Bates DO, Yacqub-Usman K. Preclinical evidence for anaplastic lymphoma kinase inhibitors as novel therapeutic treatments for cholangiocarcinoma. Front Oncol 2023; 13:1184900. [PMID: 38144528 PMCID: PMC10748508 DOI: 10.3389/fonc.2023.1184900] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Accepted: 11/06/2023] [Indexed: 12/26/2023] Open
Abstract
Introduction Bile duct cancer (cholangiocarcinoma, CCA) has a poor prognosis for patients, and despite recent advances in targeted therapies for other cancer types, it is still treated with standard chemotherapy. Anaplastic lymphoma kinase (ALK) has been shown to be a primary driver of disease progression in lung cancer, and ALK inhibitors are effective therapeutics in aberrant ALK-expressing tumors. Aberrant ALK expression has been documented in CCA, but the use of ALK inhibitors has not been investigated. Using CCA cell lines and close-to-patient primary cholangiocarcinoma cells, we investigated the potential for ALK inhibitors in CCA. Methods ALK, cMET, and ROS1 expression was determined in CCA patient tissue by immunohistochemistry and digital droplet polymerase chain reaction, and that in cell lines was determined by immunoblot and immunofluorescence. The effect on cell viability and mechanism of action of ALK, cMet, and ROS1 inhibitors was determined in CCA cell lines. To determine whether ceritinib could affect primary CCA cells, tissue was taken from four patients with biliary tract cancer, without ALK rearrangement, mutation, or overexpression, and grown in three-dimensional tumor growth assays in the presence or absence of humanized mesenchymal cells. Results ALK and cMet but not ROS were both upregulated in CCA tissues and cell lines. Cell survival was inhibited by crizotinib, a c-met/ALK/ROS inhibitor. To determine the mechanism of this effect, we tested c-Met-specific and ALK/ROS-specific inhibitors, capmatinib and ceritinib, respectively. Whereas capmatinib did not affect cell survival, ceritinib dose-dependently inhibited survival in all cell lines, with IC50 ranging from 1 to 9 µM and co-treatments with gemcitabine and cisplatin further sensitized cells, with IC50 ranging from IC50 0.60 to 2.32 µM. Ceritinib did not inhibit cMet phosphorylation but did inhibit ALK phosphorylation. ALK was not mutated in any of these cell lines. Only ceritinib inhibited 3D growth of all four patient samples below mean peak serum concentration, in the presence and absence of mesenchymal cells, whereas crizotinib and capmatinib failed to do this. Ceritinib appeared to exert its effect more through autophagy than apoptosis. Discussion These results indicate that ceritinib or other ALK/ROS inhibitors could be therapeutically useful in cholangiocarcinoma even in the absence of aberrant ALK/ROS1 expression.
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Affiliation(s)
- Kyaw Zwar Myint
- Graduate Program in Molecular Medicine, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Mireia Sueca-Comes
- Division of Cancer and Stem Cells, Biodiscovery Institute, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | - Pamela Collier
- Division of Cancer and Stem Cells, Biodiscovery Institute, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | - Brinda Balasubramanian
- Graduate Program in Molecular Medicine, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Simran Venkatraman
- Graduate Program in Molecular Medicine, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - John Gordan
- Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
| | - Abed M. Zaitoun
- Department of Pathology, Nottingham Universities National Health Service (NHS) Hospital Trust, Queens Medical Centre, Nottingham, United Kingdom
| | - Abhik Mukherjee
- Division of Cancer and Stem Cells, Biodiscovery Institute, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
- Department of Pathology, Nottingham Universities National Health Service (NHS) Hospital Trust, Queens Medical Centre, Nottingham, United Kingdom
| | - Arvind Arora
- Division of Cancer and Stem Cells, Biodiscovery Institute, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
- Department of Medical Oncology, Nottingham Universities National Health Service (NHS) Hospital Trust, Queens Medical Centre, Nottingham, United Kingdom
| | - Noppadol Larbcharoensub
- Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | | | - Kanokpan Wongprasert
- Department of Anatomy, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Tavan Janvilisri
- Graduate Program in Molecular Medicine, Faculty of Science, Mahidol University, Bangkok, Thailand
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Dhanny Gomez
- Department of Hepatobiliary and Pancreatic Surgery, and National Institute of Health Care Research (NIHR) Nottingham Digestive Disease Biomedical Research Unit, University of Nottingham, Nottingham, United Kingdom
| | - Anna M. Grabowska
- Division of Cancer and Stem Cells, Biodiscovery Institute, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | - Rutaiwan Tohtong
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - David O. Bates
- Division of Cancer and Stem Cells, Biodiscovery Institute, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | - Kiren Yacqub-Usman
- Division of Cancer and Stem Cells, Biodiscovery Institute, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
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10
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Peng M, Li H, Cao H, Huang Y, Yu W, Shen C, Gu J. Dual FGFR and VEGFR inhibition synergistically restrain hexokinase 2-dependent lymphangiogenesis and immune escape in intrahepatic cholangiocarcinoma. J Gastroenterol 2023; 58:908-924. [PMID: 37433897 PMCID: PMC10423168 DOI: 10.1007/s00535-023-02012-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 06/18/2023] [Indexed: 07/13/2023]
Abstract
BACKGROUND Therapies for cholangiocarcinoma are largely limited and ineffective. Herein, we examined the role of the FGF and VEGF pathways in regulating lymphangiogenesis and PD-L1 expression in intrahepatic cholangiocarcinoma (iCCA). METHODS The lymphangiogenic functions of FGF and VEGF were evaluated in lymphatic endothelial cells (LECs) and iCCA xenograft mouse models. The relationship between VEGF and hexokinase 2 (HK2) was validated in LECs by western blot, immunofluorescence, ChIP and luciferase reporter assays. The efficacy of the combination therapy was assessed in LECs and xenograft models. Microarray analysis was used to evaluate the pathological relationships of FGFR1 and VEGFR3 with HK2 in human lymphatic vessels. RESULTS FGF promoted lymphangiogenesis through c-MYC-dependent modulation of HK2 expression. VEGFC also upregulated HK2 expression. Mechanistically, VEGFC phosphorylated components of the PI3K/Akt/mTOR axis to upregulate HIF-1α expression at the translational level, and HIF-1α then bound to the HK2 promoter region to activate its transcription. More importantly, dual FGFR and VEGFR inhibition with infigratinib and SAR131675 almost completely inhibited lymphangiogenesis, and significantly suppressed iCCA tumor growth and progression by reducing PD-L1 expression in LECs. CONCLUSIONS Dual FGFR and VEGFR inhibition inhibits lymphangiogenesis through suppression of c-MYC-dependent and HIF-1α-mediated HK2 expression, respectively. HK2 downregulation decreased glycolytic activity and further attenuated PD-L1 expression. Our findings suggest that dual FGFR and VEGFR blockade is an effective novel combination strategy to inhibit lymphangiogenesis and improve immunocompetence in iCCA.
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Affiliation(s)
- Min Peng
- Department of Microbiology and Immunology, Medical School of Southeast University, Nanjing, 210009, Jiangsu, China
| | - Hui Li
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, China
| | - Huan Cao
- Center for Liver Transplantation, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yamei Huang
- Department of Pathology and Pathophysiology, Medical School of Southeast University, Nanjing, 210009, Jiangsu, China
| | - Weiping Yu
- Department of Pathology and Pathophysiology, Medical School of Southeast University, Nanjing, 210009, Jiangsu, China
| | - Chuanlai Shen
- Department of Microbiology and Immunology, Medical School of Southeast University, Nanjing, 210009, Jiangsu, China.
| | - Jinyang Gu
- Center for Liver Transplantation, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Department of Transplantation, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
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11
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Romanzi A, Villa E. Angiogenesis: the Yin and Yang in intrahepatic cholangiocarcinoma. HEPATOMA RESEARCH 2023. [DOI: 10.20517/2394-5079.2023.53] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
Abstract
The tumor microenvironment (TME) constitutes a complex structure comprising different cell types and soluble factors that surround the tumor and promote its progression. Primarily for its pivotal role in malignant growth, TME has become a potential therapeutic objective for developing new targeted therapy and a marker for assessing therapeutic response. In intrahepatic cholangiocarcinoma (iCCA), the second most common primary liver malignancy, TME has also gained a central role in understanding the mechanisms underlying tumor progression. In this review, we focused on the role of angiogenic factors and their pathway in iCCA and analyzed possible therapeutic and prognostic implications.
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12
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Gyoten K, Kuriyama N, Maeda K, Ito T, Hayasaki A, Fujii T, Iizawa Y, Tanemura A, Murata Y, Kishiwada M, Mizuno S. Safety and efficacy of neoadjuvant chemotherapy based on our resectability criteria for locally advanced perihilar cholangiocarcinoma. Langenbecks Arch Surg 2023; 408:261. [PMID: 37392289 DOI: 10.1007/s00423-023-03000-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 06/24/2023] [Indexed: 07/03/2023]
Abstract
PURPOSE Neoadjuvant chemotherapy (NAC) is not commonly used for perihilar cholangiocarcinoma (PHC). This study evaluated the safety and efficacy of NAC for PHC. METHODS Ninety-one PHC patients without metastases were treated at our department. Patients were classified as resectable (R), borderline resectable (BR), or locally advanced unresectable (LA). Upfront surgery (US) was performed for R-PHC patients without regional lymph node metastases (LNM) or those unable to tolerate NAC. The NAC regimen comprised two courses of gemcitabine-based chemotherapy for advanced PHC: R-PHC with LNM, BR, and LA. RESULTS US and NAC were performed on 32 and 59 patients, respectively. For US, 31 patients underwent curative intent surgery (upfront-CIS). NAC caused adverse effects in 10/59 (17%), allowed 36/59 (61%) to undergo curative intent surgery (NAC-CIS) without impairing liver function, and spared 23/59 (39%) from undergoing resection (NAC-UR). Overall survival was better in the upfront-CIS and NAC-CIS groups than in the NAC-UR group (MST: 74 vs 57 vs 17 months, p < 0.001). In 59 NAC patients, tumour size response occurred in 11/11 (100%) of R, 22/33 (66.7%) of BR, and 9/15 (60.0%) of LA patients. The un-resection rate was the highest in the LA group (27% [3/11] than in R, 30% [10/33] in BR, and 67% [10/15] in LA, p = 0.039). Multivariate analyses revealed that LA and age were independent risk factors for non-resection after NAC. CONCLUSION was safe and contributed to improving survival in advanced PHC patients. R-PHC was responsive to NAC, but LA remains a risk factor for non-resection through NAC.
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Affiliation(s)
- Kazuyuki Gyoten
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
| | - Naohisa Kuriyama
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.
| | - Koki Maeda
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
| | - Takahiro Ito
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
| | - Aoi Hayasaki
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
| | - Takehiro Fujii
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
| | - Yusuke Iizawa
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
| | - Akihiro Tanemura
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
| | - Yasuhiro Murata
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
| | - Masashi Kishiwada
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
| | - Shugo Mizuno
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
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13
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Zeng W, Mao R, Zhang Z, Chen X. Combination Therapies for Advanced Biliary Tract Cancer. J Clin Transl Hepatol 2023; 11:490-501. [PMID: 36643047 PMCID: PMC9817051 DOI: 10.14218/jcth.2022.00277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Revised: 08/09/2022] [Accepted: 08/18/2022] [Indexed: 01/18/2023] Open
Abstract
Biliary tract cancers (BTCs) are a group of malignant neoplasms that have recently increased in incidence and have a poor prognosis. Surgery is the only curative therapy. However, most patients are only indicated for palliative therapy because of advanced-stage disease at diagnosis and rapid progression. The current first-line treatment for advanced BTC is gemcitabine and cisplatin chemotherapy. Nonetheless, many patients develop resistance to this regimen. Over the years, few chemotherapy regimens have managed to improve the overall survival of patients. Accordingly, novel therapies such as targeted therapy have been introduced to treat this patient population. Extensive research on tumorigenesis and the genetic profiling of BTC have revealed the heterogenicity and potential target pathways, such as EGFR, VEGF, MEK/ERK, PI3K and mTOR. Moreover, mutational analysis has documented the presence of IDH1, FGFR2, HER2, PRKACA, PRKACB, BRAF, and KRAS gene aberrations. The emergence of immunotherapy in recent years has expanded the treatment landscape for this group of malignancies. Cancer vaccines, adoptive cell transfer, and immune checkpoint inhibitors have been extensively investigated in trials of BTC. Therefore, patient stratification and a combination of various therapies have become a reasonable and important clinical strategy to improve patient outcomes. This review elaborates the literature on combined treatment strategies for advanced BTC from the past few years and ongoing clinical trials to provide new inspiration for the treatment of advanced BTC.
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Affiliation(s)
- Weifeng Zeng
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei, China
- Hubei key laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Ruiqi Mao
- Clinic Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zhanguo Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei, China
- Hubei key laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Correspondence to: Zhanguo Zhang and Xiaoping Chen, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Huazhong University of Science and Technology, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, 1095 Jiefang Avenue, Wuhan, Hubei 430030, China. ORCID: https://orcid.org/0000-0002-4527-4975 (ZZ). Tel: +86-27-83663400, Fax: +86-27-83662851, E-mail: (ZZ) and (XC)
| | - Xiaoping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei, China
- Hubei key laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Correspondence to: Zhanguo Zhang and Xiaoping Chen, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Huazhong University of Science and Technology, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, 1095 Jiefang Avenue, Wuhan, Hubei 430030, China. ORCID: https://orcid.org/0000-0002-4527-4975 (ZZ). Tel: +86-27-83663400, Fax: +86-27-83662851, E-mail: (ZZ) and (XC)
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14
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Wang L, Tang K, Li X, Lu W. Anti-PD-1-based immunotherapy plus lenvatinib to treat advanced gallbladder cancer in the elderly: a case series and review of current literature. J Cancer Res Clin Oncol 2023; 149:941-950. [PMID: 35759010 DOI: 10.1007/s00432-022-04126-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Accepted: 06/08/2022] [Indexed: 11/30/2022]
Abstract
BACKGROUND Gallbladder cancer (GBC) is a rare malignant tumour of the bile duct. Due to the lack of typical clinical manifestations in the early stage, it is basically at an advanced stage when discovered. Radical resection remains the only curative therapy for patients with GBC. The resection rate is relatively low due to tumour invasion and metastasis, and the overall prognosis is poor. For most patients with unresectable lesions, chemotherapy has been the only recommended treatment for decades. Immunotherapy combined with TKIs (tyrosine kinase inhibitors) was proven to be effective in patients with hepatocellular carcinoma and cholangiocarcinoma. Some physicians have attempted to apply immunotherapy and TKIs combined with traditional chemotherapy in patients with advanced GBC. However, the outcomes were not clear because limited cases were reported. CASE PRESENTATION We present a case series of four elderly patients with advanced GBC who received tislelizumab and lenvatinib combined with chemotherapy. All four patients responded to this treatment approach. Tumour responses were better in Patient 1 (TMB-H, MSS), Patient 2 (low TMB, MSS), and Patient 3 (low TMB, MSI-H) than in Patient 4 (low TMB, MSS), in whom metastasis occurred during the later stage of treatment. CONCLUSION The combination of tislelizumab and lenvatinib may be a promising treatment for patients with advanced GBC. The efficacy and safety need further confirmation.
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Affiliation(s)
- Lantian Wang
- Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Kezhong Tang
- Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Xiawei Li
- Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Wenjie Lu
- Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
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15
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Guven DC, Yildirim HC, Chalabiyev E, Kus F, Yilmaz F, Yasar S, Akyildiz A, Aktas BY, Yalcin S, Dizdar O. Emerging treatment strategies in hepatobiliary cancer. Expert Rev Anticancer Ther 2023; 23:243-256. [PMID: 36803258 DOI: 10.1080/14737140.2023.2183844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/23/2023]
Abstract
INTRODUCTION There have been significant advances in the treatment of hepatobiliary cancers, especially for advanced-stage disease. However, data is limited for optimal therapy selection in the first line and sequencing of available options. AREAS COVERED This review covers the systemic treatment of hepatobiliary cancers with an emphasis on the advanced stage. The previously published and ongoing trials will be discussed to create an algorithm for the current practice and to give future perspectives on how the field could go forward. EXPERT OPINION While there is no standard-of-care option in the adjuvant treatment of hepatocellular cancer, capecitabine is the standard of care for biliary tract cancer. The efficacy of adjuvant gemcitabine and cisplatin and the added benefit of radiotherapy to chemotherapy are yet to be defined. For the advanced stage, immunotherapy-based combinations became the standard of care for both hepatocellular and biliary tract cancers. The molecularly targeted therapy has profoundly changed the second-line and later treatment for biliary tract cancers, while the optimal second-line treatment for advanced hepatocellular cancer is yet to be defined due to rapid advances in the first-line setting.
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Affiliation(s)
- Deniz Can Guven
- Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey
| | - Hasan Cagri Yildirim
- Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey
| | - Elvin Chalabiyev
- Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey
| | - Fatih Kus
- Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey
| | - Feride Yilmaz
- Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey
| | - Serkan Yasar
- Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey
| | - Arif Akyildiz
- Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey
| | - Burak Yasin Aktas
- Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey
| | - Suayib Yalcin
- Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey
| | - Omer Dizdar
- Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey
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16
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Yan X, Zou H, Lai Y, Ung COL, Hu H. Efficacy and Safety of First-Line Targeted Treatment and Immunotherapy for Patients with Biliary Tract Cancer: A Systematic Review and Meta-Analysis. Cancers (Basel) 2022; 15:39. [PMID: 36612035 PMCID: PMC9817514 DOI: 10.3390/cancers15010039] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Revised: 12/06/2022] [Accepted: 12/18/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Biliary tract cancer is one of the most aggressive and fatal tumours. Gemcitabine with cisplatin chemotherapy has long been the first-line treatment, but the prognosis is poor. In recent years, targeted treatment and immunotherapy have produced encouraging outcomes requiring a thorough review and meta-analysis. METHOD For this systematic review and meta-analysis, we searched four databases, starting from the inception dates of databases to 11 January 2022. This study comprised randomised clinical trials and cohort studies that used immunotherapy or targeted treatment as the first line of treatment for patients with biliary tract cancer. RESULTS From the 888 studies extracted, 33 trials were examined and found to meet the criteria. These included 3087 patients, 16 single-arm trials, 13 RCTs, one nRCT, a prospective single-arm pilot study, and a clinical setting in the real world. From 2010 to 2020, 33 studies were conducted using targeted treatment or immunologic therapies as first-line treatments for BTC patients, and 18 of those studies had positive outcomes. CONCLUSION This study demonstrates that immunotherapy combined with chemotherapy as first-line treatment can provide survival benefits by improving the objective response rate for patients with unresectable biliary tract cancer. The potential for combination therapy to become a new trend in clinical treatment is promising but needs further clinical evaluation.
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Affiliation(s)
- Xin Yan
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China
| | - Huimin Zou
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China
| | - Yunfeng Lai
- School of Public Health and Management, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Carolina Oi Lam Ung
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China
- Department of Public Health and Medicinal Administration, Faculty of Health Sciences, University of Macau, Macao SAR, China
| | - Hao Hu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China
- Department of Public Health and Medicinal Administration, Faculty of Health Sciences, University of Macau, Macao SAR, China
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17
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Sturm N, Schuhbaur JS, Hüttner F, Perkhofer L, Ettrich TJ. Gallbladder Cancer: Current Multimodality Treatment Concepts and Future Directions. Cancers (Basel) 2022; 14:5580. [PMID: 36428670 PMCID: PMC9688543 DOI: 10.3390/cancers14225580] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 11/07/2022] [Accepted: 11/08/2022] [Indexed: 11/16/2022] Open
Abstract
Gallbladder cancer (GBC) is the most common primary tumor site of biliary tract cancer (BTC), accounting for 0.6% of newly diagnosed cancers and 0.9% of cancer-related deaths. Risk factors, including female sex, age, ethnic background, and chronic inflammation of the gallbladder, have been identified. Surgery is the only curative option for early-stage GBC, but only 10% of patients are primary eligible for curative treatment. After neoadjuvant treatment, up to one-third of locally advanced GBC patients could benefit from secondary surgical treatment. After surgery, only a high-risk subset of patients benefits from adjuvant treatment. For advanced-stage GBC, palliative chemotherapy with gemcitabine and cisplatin is the current standard of care in line with other BTCs. After the failure of gemcitabine and cisplatin, data for second-line treatment in non-resectable GBC is poor, and the only recommended chemotherapy regimen is FOLFOX (5-FU/folinic acid and oxaliplatin). Recent advances with the PD-L1 inhibitor durvalumab open the therapy landscape for immune checkpoint inhibition in GBC. Meanwhile, targeted therapy approaches are a cornerstone of GBC therapy based on molecular profiling and new evidence of molecular differences between different BTC forms and might further improve the prognosis of GBC patients.
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Affiliation(s)
- Niklas Sturm
- Department of Internal Medicine I, Ulm University Hospital, 89081 Ulm, Germany
| | | | - Felix Hüttner
- Department of General and Visceral Surgery, Ulm University Hospital, 89081 Ulm, Germany
| | - Lukas Perkhofer
- Department of Internal Medicine I, Ulm University Hospital, 89081 Ulm, Germany
| | - Thomas Jens Ettrich
- Department of Internal Medicine I, Ulm University Hospital, 89081 Ulm, Germany
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18
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Andersen LB, Mahler MSK, Andersen RF, Jensen LH, Raunkilde L. The Clinical Impact of Methylated Homeobox A9 ctDNA in Patients with Non-Resectable Biliary Tract Cancer Treated with Erlotinib and Bevacizumab. Cancers (Basel) 2022; 14:4598. [PMID: 36230519 PMCID: PMC9558975 DOI: 10.3390/cancers14194598] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 09/15/2022] [Accepted: 09/17/2022] [Indexed: 11/24/2022] Open
Abstract
Methylated homeobox A9 (meth-HOXA9) is tumor specific and has been suggested as a prognostic biomarker in several types of cancer. ctDNA measured as meth-HOXA9 may be a valuable biomarker in the decision-making process about last-line treatment of biliary tract cancer (BTC). The aim of the study was to investigate the clinical impact of meth-HOXA9 in plasma from patients receiving erlotinib and bevacizumab for late-stage BTC and to investigate the treatment effect and adverse events. Droplet digital PCR was applied to detect meth-HOXA9 in 39 patients. Response rates were registered according to RECIST (1.1) and adverse events according to Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE (4.0)). Endpoints were progression-free survival (PFS), overall survival (OS), response rate, and toxicity. A significant difference in PFS and OS between patients with increasing and non-increasing meth-HOXA9 was detected after one treatment cycle, hazard ratio (HR) 12.4 (p < 0.0001) and HR 2.75 (p = 0.04), respectively. The most common adverse events of erlotinib were fatigue, pain, and rash, and those of bevacizumab were bleeding and wounds. This study found meth-HOXA9 to be negatively associated with survival in patients with late-stage BTC. Hence, meth-HOXA9 may guide early discontinuation of ineffective treatment.
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Affiliation(s)
- Line Bechsgaard Andersen
- Faculty of Health, University of Southern Denmark, 5000 Odense, Denmark
- Department of Oncology, Vejle Hospital, University Hospital of Southern Denmark, 7100 Vejle, Denmark
| | - Marit Sofie Kjær Mahler
- Faculty of Health, University of Southern Denmark, 5000 Odense, Denmark
- Department of Oncology, Vejle Hospital, University Hospital of Southern Denmark, 7100 Vejle, Denmark
| | - Rikke Fredslund Andersen
- Department of Biochemistry and Immunology, Vejle Hospital, University Hospital of Southern Denmark, 7100 Vejle, Denmark
| | - Lars Henrik Jensen
- Department of Oncology, Vejle Hospital, University Hospital of Southern Denmark, 7100 Vejle, Denmark
- Institute of Regional Health Research, University of Southern Denmark, 5000 Odense, Denmark
| | - Louise Raunkilde
- Department of Oncology, Vejle Hospital, University Hospital of Southern Denmark, 7100 Vejle, Denmark
- Institute of Regional Health Research, University of Southern Denmark, 5000 Odense, Denmark
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19
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Brown ZJ, Patwardhan S, Bean J, Pawlik TM. Molecular diagnostics and biomarkers in cholangiocarcinoma. Surg Oncol 2022; 44:101851. [PMID: 36126350 DOI: 10.1016/j.suronc.2022.101851] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 08/26/2022] [Accepted: 09/09/2022] [Indexed: 10/14/2022]
Abstract
Regardless of anatomic origin, cholangiocarcinoma is generally an aggressive malignancy with a relatively high case fatality. Surgical resection with curative intent remains the best opportunity to achieve meaningful long-term survival. Most patients present, however, with advanced disease and less than 20% of patients are candidates for surgical resection. Unfortunately, even patients who undergo resection have a 5-year survival that ranges from 20 to 40%. Biomarkers are indicators of normal, pathologic, or biologic responses to an intervention and can range from a characteristic (i.e., blood pressure reading which can detect hypertension) to specific genetic mutations or proteins (i.e., carcinoembryonic antigen level). Novel biomarkers and improved molecular diagnostics represent an attractive opportunity to improve detection as well as to identify novel therapeutic targets for patients with cholangiocarcinoma. We herein review the latest advances in molecular diagnostics and biomarkers related to the early detection and treatment of patients with cholangiocarcinoma.
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Affiliation(s)
- Zachary J Brown
- Department of Surgery, The State Wexner Medical Center, Columbus, OH, USA.
| | - Satyajit Patwardhan
- Dept of HPB Surgery and Liver Transplantation, Global Hospital, Mumbai, India
| | - Joal Bean
- Department of Surgery, The State Wexner Medical Center, Columbus, OH, USA
| | - Timothy M Pawlik
- Department of Surgery, The State Wexner Medical Center, Columbus, OH, USA.
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20
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Supradit K, Boonsri B, Duangdara J, Thitiphatphuvanon T, Suriyonplengsaeng C, Kangsamaksin T, Janvilisri T, Tohtong R, Yacqub-Usman K, Grabowska AM, Bates DO, Wongprasert K. Inhibition of serine/arginine-rich protein kinase-1 (SRPK1) prevents cholangiocarcinoma cells induced angiogenesis. Toxicol In Vitro 2022; 82:105385. [PMID: 35568131 DOI: 10.1016/j.tiv.2022.105385] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 03/31/2022] [Accepted: 05/09/2022] [Indexed: 11/22/2022]
Abstract
The serine/arginine-rich protein kinase-1 (SRPK1) is an enzyme that has an essential role in regulating numerous aspects of mRNA splicing. SRPK1 has been reported to be overexpressed in multiple cancers, suggesting it as a promising therapeutic target in oncology. No previous studies reported the role of SRPK1 in cholangiocarcinoma (CCA) cells. This study aimed to examine the expression of SRPK1 and the effects of SRPK1 inhibition on the viability and angiogenesis activity of CCA cells using a selective SRPK1 inhibitor, SPHINX31. Here, we demonstrate that SPHINX31 (0.3-10 μM) had no inhibitory effects on CCA cells' viability and proliferation. However, SPHINX31 decreased the mRNA expression of pro-angiogenic VEGF-A165a isoform. In addition, SPHINX31 attenuated SRSF1 phosphorylation and nuclear localization, and increased the ratio of VEGF-A165b/total VEGF-A proteins. Moreover, when HUVECs were grown in conditioned medium from SPHINX31-treated CCA cells, migration slowed, and tube formation decreased. The present study demonstrates that targeting SRPK1 in CCA cells effectively attenuates angiogenesis by suppressing pro-angiogenic VEGF-A isoform splicing. These findings suggest a potential therapeutic treatment using SRPK1 inhibitors for the inhibition of angiogenesis in cholangiocarcinoma.
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Affiliation(s)
- Kittiya Supradit
- Department of Anatomy, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Boonyakorn Boonsri
- Division of Health and Applied Sciences, Faculty of Science, Prince of Songkla University, Songkhla, Thailand
| | - Jinchutha Duangdara
- Department of Anatomy, Faculty of Science, Mahidol University, Bangkok, Thailand
| | | | | | - Thaned Kangsamaksin
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Tavan Janvilisri
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Rutaiwan Tohtong
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Kiren Yacqub-Usman
- Division of Cancer and Stem Cells, Centre for Cancer Sciences, Biodiscovery Institute, School of Medicine, University of Nottingham, United Kingdom
| | - Anna M Grabowska
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - David O Bates
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Kanokpan Wongprasert
- Department of Anatomy, Faculty of Science, Mahidol University, Bangkok, Thailand.
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21
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Miao H, Geng Y, Li Y, Tang S, Feng F, Li W, Li Y, Liu L, Zhang R, Qiu S, Wu Y, Wang Z, Wang Z, Shao Z, Liu K, Zou L, Yang M, Zhao Y, Chen C, Li Z, Zhang D, Peng P, Qiang X, Wu F, He Y, Chen L, Xiang D, Jiang X, Li M, Liu Y, Liu Y. Novel protein kinase inhibitor TT-00420 inhibits gallbladder cancer by inhibiting JNK/JUN-mediated signaling pathway. Cell Oncol 2022; 45:689-708. [DOI: 10.1007/s13402-022-00692-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/06/2022] [Indexed: 11/09/2022] Open
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22
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Midorikawa Y. Treatment of biliary tract carcinoma over the last 30 years. Biosci Trends 2022; 16:189-197. [PMID: 35732436 DOI: 10.5582/bst.2022.01267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Surgical resection could offer the only chance of a long-term cure for biliary tract carcinoma. However, only a small percentage of these patients can undergo surgery based on the progression of the disease. Most patients with biliary tract carcinoma receive palliative chemotherapy. Until 2010, patients with unresectable biliary tract carcinoma received fluorouracil (5-FU), gemcitabine (GEM), and cisplatin (CDDP)-based chemotherapies. The ABC-02 study established GEM with CDDP as the first-line therapy for patients with unresectable biliary tract carcinoma, and phase III studies indicated that several combinations of anti-cancer drugs such as GEM with S-1 benefited patients. In contrast, clinical studies on targeted therapy dosages for biliary tract carcinoma in the 2010s failed to corroborate the advantages of administering cancer treatment with or without other anticancer drugs. Due to the easy access to cancer panels, precision medicines (such as ivosidenib for IDH1 mutations, pemigatinib for FGFR2 fusions, and entrectinib and larotrectinib for NTRK fusions) were recently found to be effective in the treatment of patients with these genetic alterations. Moreover, many clinical studies on immune checkpoint inhibitors for advanced biliary tract carcinoma are currently underway and could provide more effective treatment options in the near future.
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Affiliation(s)
- Yutaka Midorikawa
- Department of General Surgery, National Center of Neurology and Psychiatry, Tokyo, Japan
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23
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Lee S, Shroff RT, Makawita S, Xiao L, Danner De Armas A, Bhosale P, Reddy K, Shalaby A, Raghav K, Pant S, Wolff RA, Javle M. Phase II Study of Ramucirumab in Advanced Biliary Tract Cancer Previously Treated By Gemcitabine-Based Chemotherapy. Clin Cancer Res 2022; 28:2229-2236. [PMID: 35312753 DOI: 10.1158/1078-0432.ccr-21-3548] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Revised: 12/06/2021] [Accepted: 03/18/2022] [Indexed: 11/16/2022]
Abstract
PURPOSE VEGF receptor-2 (VEGFR-2)-mediated angiogenesis contributes to pathogenesis of biliary tract cancers (BTC). We investigated ramucirumab, a mAb targeting VEGFR-2 for treatment of advanced, chemorefractory BTC. PATIENTS AND METHODS This is a phase II, single-arm trial for advanced, unresectable, pre-treated patients with BTC with ECOG 0/1, adequate liver, renal, and marrow functions. Ramucirumab was administered at 8 mg/kg, 2 weekly with restaging performed 8 weekly. Primary endpoint was progression-free survival (PFS). Secondary endpoints were overall response rate (ORR), disease control rate (DCR), overall survival (OS), and toxicity. Exploratory endpoints included correlation of tumor mutational status with PFS and OS. RESULTS 61 patients were enrolled: the median age was 58.5 years; 59 with stage IV disease; 62%, intrahepatic cholangiocarcinoma; 22%, gallbladder cancer; and 16%, extrahepatic cholangiocarcinoma. All received prior chemotherapy: 52% had 1 prior, and rest ≥2 prior lines. Median treatment duration was 10.1 weeks (range, 2.1-86). Median PFS was 3.2 months [95% confidence interval (CI), 2.1-4.8]; median OS, 9.5 months (95% CI, 5.8-13.6). One (1.7%) patient achieved partial response; 26 (43.3%), stable disease; and 25 (41.7%), disease progression; DCR, 45%. Median 6-month PFS and OS rates were 32% (95% CI, 0.22-0.46) and 58% (95% CI, 0.47-0.72). The majority of toxicities were grade 1 or 2; grade 3 proteinuria (1, 2%), hypertension (13, 22%), and pulmonary embolism (1, 2%), and grade 4 gastrointestinal bleeding (1, 2%) occurred. CONCLUSIONS Ramucirumab was well tolerated and resulted in PFS similar to that achieved with other chemotherapy regimens used historically for chemorefractory BTC.
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Affiliation(s)
- Sunyoung Lee
- Division of Cancer Medicine, Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Rachna T Shroff
- Division of Hematology and Oncology, Department of Medicine, University of Arizona College of Medicine, Tucson, Arizona
| | - Shalini Makawita
- Division of Hematology and Oncology, Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Lianchun Xiao
- Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Anaemy Danner De Armas
- Division of Cancer Medicine, Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Priya Bhosale
- Division of Diagnostic Imaging, Department of Abdominal Imaging, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Kavitha Reddy
- Division of Cancer Medicine, Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ahmed Shalaby
- Department of Diagnostic Radiology, University of Mississippi, Oxford, Mississippi
| | - Kanwal Raghav
- Division of Cancer Medicine, Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Shubham Pant
- Division of Cancer Medicine, Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Robert A Wolff
- Division of Cancer Medicine, Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Milind Javle
- Division of Cancer Medicine, Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
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24
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Gray S, Lamarca A, Edeline J, Klümpen HJ, Hubner RA, McNamara MG, Valle JW. Targeted Therapies for Perihilar Cholangiocarcinoma. Cancers (Basel) 2022; 14:1789. [PMID: 35406560 PMCID: PMC8997784 DOI: 10.3390/cancers14071789] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 03/29/2022] [Accepted: 03/30/2022] [Indexed: 11/16/2022] Open
Abstract
Perihilar cholangiocarcinoma (pCCA) is the anatomical sub-group of biliary tract cancer (BTC) arising between the second-order intrahepatic bile ducts and the cystic duct. Together with distal and intrahepatic cholangiocarcinoma (dCCA and iCCA; originating distal to, and proximal to this, respectively), gallbladder cancer (GBC) and ampulla of Vater carcinoma (AVC), these clinicopathologically and molecularly distinct entities comprise biliary tract cancer (BTC). Most pCCAs are unresectable at diagnosis, and for those with resectable disease, surgery is extensive, and recurrence is common. Therefore, the majority of patients with pCCA will require systemic treatment for advanced disease. The prognosis with cytotoxic chemotherapy remains poor, driving interest in therapies targeted to the molecular nature of a given patient's cancer. In recent years, the search for efficacious targeted therapies has been fuelled both by whole-genome and epigenomic studies, looking to uncover the molecular landscape of CCA, and by specifically testing for aberrations where established therapies exist in other indications. This review aims to provide a focus on the current molecular characterisation of pCCA, targeted therapies applicable to pCCA, and future directions in applying personalised medicine to this difficult-to-treat malignancy.
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Affiliation(s)
- Simon Gray
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Rd, Manchester M20 4BX, UK; (S.G.); (A.L.); (R.A.H.); (M.G.M.)
| | - Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Rd, Manchester M20 4BX, UK; (S.G.); (A.L.); (R.A.H.); (M.G.M.)
- Division of Cancer Sciences, University of Manchester, Oxford Rd, Manchester M13 9PL, UK
| | - Julien Edeline
- Centre Eugène Marquis, Av. de la Bataille Flandres Dunkerque-CS 44229, CEDEX, 35042 Rennes, France;
| | - Heinz-Josef Klümpen
- Department of Medical Oncology, Amsterdam University Medical Center, P.O. Box 7057, 1081 HV Amsterdam, The Netherlands;
| | - Richard A. Hubner
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Rd, Manchester M20 4BX, UK; (S.G.); (A.L.); (R.A.H.); (M.G.M.)
- Division of Cancer Sciences, University of Manchester, Oxford Rd, Manchester M13 9PL, UK
| | - Mairéad G. McNamara
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Rd, Manchester M20 4BX, UK; (S.G.); (A.L.); (R.A.H.); (M.G.M.)
- Division of Cancer Sciences, University of Manchester, Oxford Rd, Manchester M13 9PL, UK
| | - Juan W. Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Rd, Manchester M20 4BX, UK; (S.G.); (A.L.); (R.A.H.); (M.G.M.)
- Division of Cancer Sciences, University of Manchester, Oxford Rd, Manchester M13 9PL, UK
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25
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Brown ZJ, Hewitt DB, Pawlik TM. Biomarkers of intrahepatic cholangiocarcinoma: diagnosis and response to therapy. FRONT BIOSCI-LANDMRK 2022; 27:85. [PMID: 35345317 DOI: 10.31083/j.fbl2703085] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/31/2022] [Accepted: 02/10/2022] [Indexed: 01/03/2025]
Abstract
Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer behind hepatocellular carcinoma (HCC) and carries a dismal prognosis. Improved genetic analysis has paved the way for a better understanding of the distinct somatic genomic landscapes of ICC. The use of next generation sequencing has paved the way for more personalized medicine through identifying unique mutations which may prove to be therapeutic targets. The ability to identify biomarkers specific to ICC will assist in establishing a diagnosis, monitoring response to therapy, as well as assist in identifying novel therapies and personalized medicine. Herein, we discuss potential biomarkers for ICC and how these markers can assist in diagnosis, monitor response to therapy, and potentially identify novel interventions for the treatment of ICC.
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Affiliation(s)
- Zachary J Brown
- Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - D Brock Hewitt
- Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Timothy M Pawlik
- Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
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26
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Hu ZI, Lim KH. Evolving Paradigms in the Systemic Treatment of Advanced Gallbladder Cancer: Updates in Year 2022. Cancers (Basel) 2022; 14:1249. [PMID: 35267556 PMCID: PMC8909874 DOI: 10.3390/cancers14051249] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Revised: 02/15/2022] [Accepted: 02/25/2022] [Indexed: 02/01/2023] Open
Abstract
Gallbladder cancer (GBC) is a biological, anatomical, and clinically distinct subset of biliary tract cancers (BTC), which also include extra- and intra-hepatic cholangiocarcinoma. The advent of next-generation sequencing (NGS) clearly shows that GBC is genetically different from cholangiocarcinoma. Although GBC is a relatively rare cancer, it is highly aggressive and carries a grave prognosis. To date, complete surgical resection remains the only path for cure but is limited to patients with early-stage disease. The majority of the patients are diagnosed at an advanced, inoperable stage when systemic treatment is administered as an attempt to enable surgery or for palliation. Gemcitabine and platinum-based chemotherapies have been the main treatment modality for unresectable, locally advanced, and metastatic gallbladder cancer. However, over the past decade, the treatment paradigm has evolved. These include the introduction of newer chemotherapeutic strategies after progression on frontline chemotherapy, incorporation of targeted therapeutics towards driver mutations of genes including HER2, FGFR, BRAF, as well as approaches to unleash host anti-tumor immunity using immune checkpoint inhibitors. Notably, due to the rarity of BTC in general, most clinical trials included both GBC and cholangiocarcinomas. Here, we provide a review on the pathogenesis of GBC, past and current systemic treatment options focusing specifically on GBC, clinical trials tailored towards its genetic mutations, and emerging treatment strategies based on promising recent clinical studies.
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Affiliation(s)
| | - Kian-Huat Lim
- Division of Oncology, Department of Internal Medicine, Barnes-Jewish Hospital and The Alvin J. Siteman Comprehensive Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA;
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27
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Pavicevic S, Reichelt S, Uluk D, Lurje I, Engelmann C, Modest DP, Pelzer U, Krenzien F, Raschzok N, Benzing C, Sauer IM, Stintzing S, Tacke F, Schöning W, Schmelzle M, Pratschke J, Lurje G. Prognostic and Predictive Molecular Markers in Cholangiocarcinoma. Cancers (Basel) 2022; 14:1026. [PMID: 35205774 PMCID: PMC8870611 DOI: 10.3390/cancers14041026] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 02/09/2022] [Accepted: 02/09/2022] [Indexed: 02/05/2023] Open
Abstract
Cholangiocarcinoma (CCA) is the second most common primary liver cancer and subsumes a heterogeneous group of malignant tumors arising from the intra- or extrahepatic biliary tract epithelium. A rising mortality from CCA has been reported worldwide during the last decade, despite significant improvement of surgical and palliative treatment. Over 50% of CCAs originate from proximal extrahepatic bile ducts and constitute the most common CCA entity in the Western world. Clinicopathological characteristics such as lymph node status and poor differentiation remain the best-studied, but imperfect prognostic factors. The identification of prognostic molecular markers as an adjunct to traditional staging systems may not only facilitate the selection of patients who would benefit the most from surgical, adjuvant or palliative treatment strategies, but may also be helpful in defining the aggressiveness of the disease and identifying patients at high-risk for tumor recurrence. The purpose of this review is to provide an overview of currently known molecular prognostic and predictive markers and their role in CCA.
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Affiliation(s)
- Sandra Pavicevic
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Sophie Reichelt
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Deniz Uluk
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Isabella Lurje
- Department of Gastroenterology and Hepatology, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (C.E.); (F.T.)
| | - Cornelius Engelmann
- Department of Gastroenterology and Hepatology, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (C.E.); (F.T.)
| | - Dominik P. Modest
- Department of Hematology, Oncology and Cancer Immunology, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (D.P.M.); (U.P.); (S.S.)
| | - Uwe Pelzer
- Department of Hematology, Oncology and Cancer Immunology, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (D.P.M.); (U.P.); (S.S.)
| | - Felix Krenzien
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Nathanael Raschzok
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Christian Benzing
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Igor M. Sauer
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Sebastian Stintzing
- Department of Hematology, Oncology and Cancer Immunology, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (D.P.M.); (U.P.); (S.S.)
| | - Frank Tacke
- Department of Gastroenterology and Hepatology, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (C.E.); (F.T.)
| | - Wenzel Schöning
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Moritz Schmelzle
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Johann Pratschke
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Georg Lurje
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
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28
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Simbolo M, Bersani S, Vicentini C, Taormina SV, Ciaparrone C, Bagante F, Rusev B, Centonze G, Montresor M, Brunelli M, Pedron S, Mafficini A, Paolino G, Mattiolo P, Conci S, Milione M, Guglielmi A, Ruzzenente A, Scarpa A, Luchini C. Molecular characterization of extrahepatic cholangiocarcinoma: perihilar and distal tumors display divergent genomic and transcriptomic profiles. Expert Opin Ther Targets 2021; 25:1095-1105. [PMID: 34873971 DOI: 10.1080/14728222.2021.2013801] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Extrahepatic cholangiocarcinoma (ECC) is classified into two subtypes based on anatomic origin: distal extrahepatic (DECC) and perihilar (PHCC) cholangiocarcinoma. This study aimed to shed light on its genomic and transcriptomic profiles. RESEARCH DESIGN AND METHODS The genomic alterations of 99 ECC (47 PHCC and 52 DECC) were investigated by next-generation sequencing of 96 genes. A subgroup of cases, representative of each subtype, was further investigated using transcriptomic analysis. Bioinformatics tools were applied for clustering and pathway analysis and defining the immune composition of the tumor microenvironment. RESULTS PHCC had more frequent KRAS mutations (p = 0.0047), whereas TP53 mutations were more common in DECC (p = 0.006). Potentially actionable alterations included high-tumor mutational burden and/or microsatellite instability (7.1%), PI3KCA mutations (8.1%), and MYC (10.1%) and ERBB2 amplification (5.1%). The transcriptomic profiles showed the presence of three distinct clusters, which followed the anatomic origin and differed in immune microenvironment. DECC appeared to contain two distinct tumor subgroups, one enriched for druggable alterations and one lacking actionable opportunities. CONCLUSIONS This study provides new insights into the molecular landscape and the actionable alterations of ECC. Our findings represent a step toward improved ECC molecular taxonomy and therapeutic strategies for precision oncology.
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Affiliation(s)
- Michele Simbolo
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Samantha Bersani
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Caterina Vicentini
- ARC-Net Research Center, University and Hospital Trust of Verona, Verona, Italy
| | - Sergio V Taormina
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Chiara Ciaparrone
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Fabio Bagante
- Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, Unit of General and Hepatobiliary Surgery, University and Hospital Trust of Verona, Verona, Italy
| | - Borislav Rusev
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy.,ARC-Net Research Center, University and Hospital Trust of Verona, Verona, Italy
| | - Giovanni Centonze
- Pathology Unit, Foundation IRCCS, Istituto Nazionale Tumori, Milano, Italy
| | - Marina Montresor
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Matteo Brunelli
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Serena Pedron
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Andrea Mafficini
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy.,ARC-Net Research Center, University and Hospital Trust of Verona, Verona, Italy
| | - Gaetano Paolino
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Paola Mattiolo
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Simone Conci
- Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, Unit of General and Hepatobiliary Surgery, University and Hospital Trust of Verona, Verona, Italy
| | - Massimo Milione
- Pathology Unit, Foundation IRCCS, Istituto Nazionale Tumori, Milano, Italy
| | - Alfredo Guglielmi
- Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, Unit of General and Hepatobiliary Surgery, University and Hospital Trust of Verona, Verona, Italy
| | - Andrea Ruzzenente
- Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, Unit of General and Hepatobiliary Surgery, University and Hospital Trust of Verona, Verona, Italy
| | - Aldo Scarpa
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy.,ARC-Net Research Center, University and Hospital Trust of Verona, Verona, Italy
| | - Claudio Luchini
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy.,ARC-Net Research Center, University and Hospital Trust of Verona, Verona, Italy
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Sarantis P, Tzanetatou ED, Ioakeimidou E, Vallilas C, Androutsakos T, Damaskos C, Garmpis N, Garmpi A, Papavassiliou AG, Karamouzis MV. Cholangiocarcinoma: the role of genetic and epigenetic factors; current and prospective treatment with checkpoint inhibitors and immunotherapy. Am J Transl Res 2021; 13:13246-13260. [PMID: 35035673 PMCID: PMC8748131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 11/09/2021] [Indexed: 06/14/2023]
Abstract
Cholangiocarcinoma (CCA) represents 3% of all gastrointestinal cancers worldwide and is the second most common primary liver tumor after hepatocellular carcinoma. CCA is an aggressive tumor that involves the intrahepatic, perihilar and distal biliary tree, with a poor prognosis and an increasing incidence worldwide. Various genetic and epigenetic factors have been implicated in CCA development. Gene mutations involving apoptosis control and cell cycle evolution, histone modifications, methylation dysregulation and abnormal expression of non-coding RNA are the most important of these factors. Regarding treatment, surgical resection, cisplatin and gemcitabine have long been the most common treatment options, but 5-year survival (7-20%) is disappointing. For that reason, inhibitors and small molecules related to specific mutations and molecular pathways have been introduced. Among them, immunotherapy seems to be a promising treatment in CCA, with multiple regimens being under clinical trial studies. The combinatorial therapy of traditional CCA treatment with tyrosine kinase inhibitors and/or immunotherapy seem to be the future, depending on the molecular profile of each patient's tumor.
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Affiliation(s)
- Panagiotis Sarantis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens11527 Athens, Greece
| | - Eleftheria Dikoglou Tzanetatou
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens11527 Athens, Greece
| | - Evangelia Ioakeimidou
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens11527 Athens, Greece
| | - Christos Vallilas
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens11527 Athens, Greece
| | - Theodoros Androutsakos
- Pathophysiology Department, Medical School, National and Kapodistrian University of Athens11527 Athens, Greece
| | - Christos Damaskos
- N.S. Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens11527 Athens, Greece
- Renal Transplantation Unit, Laiko General Hospital11527 Athens, Greece
| | - Nikolaos Garmpis
- N.S. Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens11527 Athens, Greece
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens11527 Athens, Greece
| | - Anna Garmpi
- First Department of Propedeutic Internal Medicine, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens11527 Athens, Greece
| | - Athanasios G Papavassiliou
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens11527 Athens, Greece
| | - Michalis V Karamouzis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens11527 Athens, Greece
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Rimini M, Puzzoni M, Pedica F, Silvestris N, Fornaro L, Aprile G, Loi E, Brunetti O, Vivaldi C, Simionato F, Zavattari P, Scartozzi M, Burgio V, Ratti F, Aldrighetti L, Cascinu S, Casadei-Gardini A. Cholangiocarcinoma: new perspectives for new horizons. Expert Rev Gastroenterol Hepatol 2021; 15:1367-1383. [PMID: 34669536 DOI: 10.1080/17474124.2021.1991313] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Biliary tract cancer represents a heterogeneous group of malignancies characterized by dismal prognosis and scarce therapeutic options. AREA COVERED In the last years, a growing interest in BTC pathology has emerged, thus highlighting a significant heterogeneity of the pathways underlying the carcinogenesis process, from both a molecular and genomic point of view. A better understanding of these differences is mandatory to deepen the behavior of this complex disease, as well as to identify new targetable target mutations, with the aim to improve the survival outcomes. The authors decided to provide a comprehensive overview of the recent highlights on BTCs, with a special focus on the genetic, epigenetic and molecular alterations, which may have an interesting clinical application in the next future. EXPERT OPINION In the last years, the efforts resulted from international collaborations have led to the identification of new promising targets for precision medicine approaches in the BTC setting. Further investigations and prospective trials are needed, but the hope is that these new knowledge in cooperation with the new technologies and procedures, including bio-molecular and genomic analysis as well radiomic studies, will enrich the therapeutic armamentarium thus improving the survival outcomes in a such lethal and complex disease.
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Affiliation(s)
- Margherita Rimini
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy
| | - Marco Puzzoni
- Medical Oncology, University and University Hospital of Cagliari, Italy
| | - Federica Pedica
- Department of Pathology, San Raffaele Scientific Institute, Milan, Italy
| | - Nicola Silvestris
- Department of oncology, Instituto Di Ricovero E Cura a Carattere Scientifico (IRCCS) Istituto Tumori "Giovanni Paolo Ii" of Bari, Bari, Italy.,Department of Biomedical Sciences and Human Oncology, Aldo Moro University of Bari, Bari, Italy
| | - Lorenzo Fornaro
- Department of medical oncology, U.O. Oncologia Medica 2 Universitaria, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Giuseppe Aprile
- Department of Oncology, San Bortolo General Hospital, Azienda ULSS8 Berica, Vicenza, Italy
| | - Eleonora Loi
- Department of Biomedical Sciences, Unit of Biology and Genetics, University of Cagliari, Cagliari, Italy
| | - Oronzo Brunetti
- Department of oncology, Instituto Di Ricovero E Cura a Carattere Scientifico (IRCCS) Istituto Tumori "Giovanni Paolo Ii" of Bari, Bari, Italy
| | - Caterina Vivaldi
- Department of medical oncology, U.O. Oncologia Medica 2 Universitaria, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Francesca Simionato
- Department of Oncology, San Bortolo General Hospital, Azienda ULSS8 Berica, Vicenza, Italy
| | - Patrizia Zavattari
- Department of Biomedical Sciences, Unit of Biology and Genetics, University of Cagliari, Cagliari, Italy
| | - Mario Scartozzi
- Medical Oncology, University and University Hospital of Cagliari, Italy
| | - Valentina Burgio
- Department of Oncology, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | - Francesca Ratti
- Hepatobiliary Surgery Division, IRCCS San Raffaele and Vita-Salute University, Italy
| | - Luca Aldrighetti
- Hepatobiliary Surgery Division, IRCCS San Raffaele and Vita-Salute University, Italy
| | - Stefano Cascinu
- Department of Oncology, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
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Hewitt DB, Brown ZJ, Pawlik TM. Surgical management of intrahepatic cholangiocarcinoma. Expert Rev Anticancer Ther 2021; 22:27-38. [PMID: 34730474 DOI: 10.1080/14737140.2022.1999809] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
INTRODUCTION Intrahepatic cholangiocarcinoma (ICC) incidence continues to rise worldwide, and overall survival remains poor. Complete surgical resection remains the only opportunity for cure in patients with ICC yet only one-third of patients present with resectable disease. AREAS COVERED While the low incidence rate of ICC hinders accrual of patients to large, randomized control trials, larger database and long-term institutional studies provide evidence to guide surgical management of ICC. These studies demonstrate feasibility, safety, and efficacy of aggressive surgical management in appropriately selected patients with ICC. Recent advances in the management of ICC, with a focus on surgical considerations, are reviewed. EXPERT OPINION Historically, little progress has been made in the management of ICC with stagnant mortality rates and poor long-term outcomes. However, regionalization of care to centers with experienced multidisciplinary teams, advances in minimally invasive surgical techniques, discovery and development of targeted and immunotherapy agents, and combination locoregional and systemic therapies offer signs of progress in the management of ICC.
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Affiliation(s)
- D Brock Hewitt
- Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Zachary J Brown
- Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Timothy M Pawlik
- Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA
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Canale M, Monti M, Rapposelli IG, Ulivi P, Sullo FG, Bartolini G, Tiberi E, Frassineti GL. Molecular Targets and Emerging Therapies for Advanced Gallbladder Cancer. Cancers (Basel) 2021; 13:5671. [PMID: 34830826 PMCID: PMC8616432 DOI: 10.3390/cancers13225671] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Revised: 11/09/2021] [Accepted: 11/10/2021] [Indexed: 01/07/2023] Open
Abstract
Biliary tract cancers (BTCs), for their low incidence, have been often considered together. Gallbladder cancer (GBC) is the most common biliary tract malignancy, characterized by late diagnosis and poor prognosis, and although it is considered a rare tumor in western countries, other areas of the world show considerable incidence rates. In 2010, results from the large phase III ABC-02 clinical trial on GBC identified the gemcitabine and cisplatin combination as the most effective first-line regimen for both GBC and other BTCs. Since then, various systemic therapies have proven active in BTCs in both first- and second-line settings. Molecular profiling has highlighted important genetic differences between GBC and other BTCs, opening new ways for targeted therapy in advanced disease where standard chemotherapies show marginal benefit. Genome-wide data analysis have shown that GBC molecular landscape offer possible strategies for precision medicine approaches, and a better molecular understanding of the GBC is needed to better stratify patients for treatment. In this review, we discuss the molecular targetable agents for GBC, including the results that emerged by clinical trials exploring new treatment strategies.
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Affiliation(s)
- Matteo Canale
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (M.C.); (P.U.)
| | - Manlio Monti
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (I.G.R.); (F.G.S.); (G.B.); (E.T.); (G.L.F.)
| | - Ilario Giovanni Rapposelli
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (I.G.R.); (F.G.S.); (G.B.); (E.T.); (G.L.F.)
| | - Paola Ulivi
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (M.C.); (P.U.)
| | - Francesco Giulio Sullo
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (I.G.R.); (F.G.S.); (G.B.); (E.T.); (G.L.F.)
| | - Giulia Bartolini
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (I.G.R.); (F.G.S.); (G.B.); (E.T.); (G.L.F.)
| | - Elisa Tiberi
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (I.G.R.); (F.G.S.); (G.B.); (E.T.); (G.L.F.)
| | - Giovanni Luca Frassineti
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (I.G.R.); (F.G.S.); (G.B.); (E.T.); (G.L.F.)
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Aimar G, Paratore C, Zichi C, Marino D, Sperti E, Caglio A, Gamba T, De Vita F, Di Maio M. A review of molecularly targeted therapy in biliary tract carcinoma: what is the next step? EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2021; 2:448-464. [PMID: 36045702 PMCID: PMC9400771 DOI: 10.37349/etat.2021.00056] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 09/14/2021] [Indexed: 12/13/2022] Open
Abstract
Patients with unresectable biliary tract carcinomas (BTCs) have a poor prognosis with a median overall survival of fewer than 12 months following systemic chemotherapy. In recent years, the identification of distinct molecular alterations with corresponding targeted therapies is modifying this therapeutic algorithm. The aim of this review is to present an overview of targeted therapy for BTCs, describing published available data and potential future challenges in ongoing trials. From clinicaltrials.gov online database all ongoing trials for BTCs (any stage) was examinated in July 2021, and data regarding study design, disease characteristics and type of treatments were registered. Oncogenic-driven therapy (targeted therapy) was investigated in 67 trials. According to research, 15 ongoing trials (22.4%) are investigating fibroblast growth factor (FGF) receptor (FGFR)-inhibitors in BTCs. Three (18.7%) are open-label randomized multicenter phase 3 trials, 8 (50%) are single-arm phase two trials, and 4 (25%) are phase one studies. Twelve (17.9%) clinical trials dealt with isocitrate dehydrogenase (IDH) 1/2 targeting therapy either in combination with cisplatin (Cis) and gemcitabine (Gem) as first-line treatment for BTCs or in monotherapy in patients with IDH1 mutant advanced malignancies, including cholangiocarcinoma (CCA). Nine (13.4%) clinical trials tested human epidermal growth factor receptor (HER) 2 targeting therapy. Four (44.4%) studies are phase I trials, two (22.2%) are phase I/II trials, and three (33.3%) phase II trials. Rare molecular alterations in BTCs, such as anaplastic lymphoma kinase (ALK), c-ros oncogene1 receptor tyrosine kinase (ROS1), and v-RAF murine sarcoma viral oncogene homologue B1 (BRAF), are also under investigation in a few trials. Forty-four clinical trials (17.2%) are investigating not oncogenic-driven multitarget therapy like multireceptor tyrosin kinase inhibitors and antiangiogenetic agents. In conclusion, this review shows that BTCs management is experiencing important innovations, especially in biomarker-based patient selection and in the new emerging therapeutic approach. Many ongoing trials could answer questions regarding the role of molecular inhibitors leading to new therapeutic frontiers for molecular subcategories of BTCs.
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Affiliation(s)
- Giacomo Aimar
- Department of Oncology, University of Turin, Division of Medical Oncology, Ordine Mauriziano Hospital, Via Magellano 1, 10128 Turino, Italy
| | - Chiara Paratore
- Department of Oncology, University of Turin, Division of Medical Oncology, Ordine Mauriziano Hospital, Via Magellano 1, 10128 Turino, Italy
| | - Clizia Zichi
- Department of Oncology, University of Turin, Division of Medical Oncology, Ordine Mauriziano Hospital, Via Magellano 1, 10128 Turino, Italy
| | - Donatella Marino
- Department of Oncology, University of Turin, Division of Medical Oncology, Ordine Mauriziano Hospital, Via Magellano 1, 10128 Turino, Italy
| | - Elisa Sperti
- Department of Oncology, University of Turin, Division of Medical Oncology, Ordine Mauriziano Hospital, Via Magellano 1, 10128 Turino, Italy
| | - Andrea Caglio
- Department of Oncology, University of Turin, Division of Medical Oncology, Ordine Mauriziano Hospital, Via Magellano 1, 10128 Turino, Italy
| | - Teresa Gamba
- Department of Oncology, University of Turin, Division of Medical Oncology, Ordine Mauriziano Hospital, Via Magellano 1, 10128 Turino, Italy
| | - Francesca De Vita
- Department of Oncology, University of Turin, Division of Medical Oncology, Ordine Mauriziano Hospital, Via Magellano 1, 10128 Turino, Italy
| | - Massimo Di Maio
- Department of Oncology, University of Turin, Division of Medical Oncology, Ordine Mauriziano Hospital, Via Magellano 1, 10128 Turino, Italy
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Wang Y, Chen T, Li K, Mu W, Liu Z, Shi A, Liu J, Zhao W, Lian S, Huang S, Pan C, Zhang Z. Recent Advances in the Mechanism Research and Clinical Treatment of Anti-Angiogenesis in Biliary Tract Cancer. Front Oncol 2021; 11:777617. [PMID: 34778094 PMCID: PMC8581488 DOI: 10.3389/fonc.2021.777617] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 10/11/2021] [Indexed: 12/25/2022] Open
Abstract
Biliary tract cancers (BTCs), including cholangiocarcinoma (CCA) and gallbladder cancer (GC), are malignancies originating from the biliary tract with poor prognosis. In the early stage of BTCs, surgery is the only choice for cure. Unfortunately, most patients with BTC are diagnosed at an advanced stage and lose the opportunity for surgery. For many advanced solid tumors, antiangiogenic therapy has achieved encouraging results. While most clinical studies on antiangiogenic therapy in advanced BTCs have shown an excellent disease control rate (DCR), the improvement in overall survival (OS) is controversial. Understanding how the relevant signaling molecules influence the angiogenic response and the functional interaction is necessary for the formulation of new treatment regimens and the selection of enrolled patients. In this review, we aim to summarize and discuss the latest advances in antiangeogenesis for BTCs, mainly focusing on the molecular mechanism of angiogenesis in BTCs and the therapeutic effects from clinical trials. Furthermore, the horizon of antiangiogenesis for BTCs is highlighted.
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Affiliation(s)
- Yue Wang
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Tianli Chen
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Kangshuai Li
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Wentao Mu
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Zengli Liu
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Anda Shi
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jialiang Liu
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Wei Zhao
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Shuo Lian
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Shaohui Huang
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Chang Pan
- Department of Emergency, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Zongli Zhang
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
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Ioffe D, Phull P, Dotan E. Optimal Management of Patients with Advanced or Metastatic Cholangiocarcinoma: An Evidence-Based Review. Cancer Manag Res 2021; 13:8085-8098. [PMID: 34737637 PMCID: PMC8558827 DOI: 10.2147/cmar.s276104] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Accepted: 09/18/2021] [Indexed: 12/13/2022] Open
Abstract
Cholangiocarcinomas are rare tumors originating at any point along the biliary tree. These tumors often pose significant challenges for diagnosis and treatment, and often carry a poor prognosis. However, in recent years, studies have identified significant molecular heterogeneity with up to 50% of tumors having detectable mutations, leading to the guideline recommendations for molecular testing as part of the diagnostic workup for these tumors. In addition, better classification of these tumors and understanding of their biology has led to new drugs being approved for treatment of this resistant tumor. This manuscript will provide a comprehensive review of the epidemiology, risk factors, diagnostic approach, molecular classification, and treatment options for patients with advanced cholangiocarcinomas.
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Affiliation(s)
- Dina Ioffe
- Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Pooja Phull
- Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Efrat Dotan
- Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
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Vignone A, Biancaniello F, Casadio M, Pesci L, Cardinale V, Ridola L, Alvaro D. Emerging Therapies for Advanced Cholangiocarcinoma: An Updated Literature Review. J Clin Med 2021; 10:4901. [PMID: 34768421 PMCID: PMC8584870 DOI: 10.3390/jcm10214901] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 10/19/2021] [Accepted: 10/22/2021] [Indexed: 12/14/2022] Open
Abstract
Cholangiocarcinoma is a group of malignancies with poor prognosis. Treatments for the management of advanced-stage cholangiocarcinoma are limited, and the 5-year survival rate is estimated to be approximately 5-15%, considering all tumor stages. There is a significant unmet need for effective new treatment approaches. The present review is provided with the aim of summarizing the current evidence and future perspectives concerning new therapeutic strategies for cholangiocarcinoma. The role of targeted therapies and immunotherapies is currently investigational in cholangiocarcinoma. These therapeutic options might improve survival outcomes, as shown by the promising results of several clinical trials illustrated in the present review. The co-presence of driver mutations and markers of susceptibility to immunotherapy may lead to rational combination strategies and clinical trial development. A better understanding of immunologically based therapeutic weapons is needed, which will lead to a form of a precision medicine strategy capable of alleviating the clinical aggressiveness and to improve the prognosis of cholangiocarcinoma.
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Affiliation(s)
- Anthony Vignone
- Department of Translational and Precision Medicine, Sapienza University of Rome, Viale dell’Università 37, 00185 Rome, Italy; (M.C.); (L.P.); (L.R.); (D.A.)
| | - Francesca Biancaniello
- Department of Translational and Precision Medicine, Sapienza University of Rome, Viale dell’Università 37, 00185 Rome, Italy; (M.C.); (L.P.); (L.R.); (D.A.)
| | - Marco Casadio
- Department of Translational and Precision Medicine, Sapienza University of Rome, Viale dell’Università 37, 00185 Rome, Italy; (M.C.); (L.P.); (L.R.); (D.A.)
| | - Ludovica Pesci
- Department of Translational and Precision Medicine, Sapienza University of Rome, Viale dell’Università 37, 00185 Rome, Italy; (M.C.); (L.P.); (L.R.); (D.A.)
| | - Vincenzo Cardinale
- Department of Medical-Surgical and Biotechnologies Sciences, Polo Pontino, Sapienza University of Rome, Corso della Repubblica 79, 04100 Latina, Italy;
| | - Lorenzo Ridola
- Department of Translational and Precision Medicine, Sapienza University of Rome, Viale dell’Università 37, 00185 Rome, Italy; (M.C.); (L.P.); (L.R.); (D.A.)
| | - Domenico Alvaro
- Department of Translational and Precision Medicine, Sapienza University of Rome, Viale dell’Università 37, 00185 Rome, Italy; (M.C.); (L.P.); (L.R.); (D.A.)
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Das C, Mukhopadhyay M, Subba S, Saha AK, Mukhopadhyay B. Role of EGFR and HER-2/NEU Expression in Gall Bladder Carcinoma (GBC). J Lab Physicians 2021; 13:29-35. [PMID: 34103877 PMCID: PMC8164917 DOI: 10.1055/s-0041-1726561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
Abstract
Background Gall bladder carcinoma (GBC) is the most common malignancy of the biliary tract. Being known for its geographical and racial variations, and compared with the global statistics, its incidence is higher in the Indian subcontinent, mainly in the northern and eastern regions, accounting for 80 to 95% of cases. Aims and Objectives This study was conducted to evaluate the clinic-pathological spectrum and expression of EGFR and HER-2/NEU in GBCs and to understand their relation to prognosis, paving the way for targeted therapies for better treatment outcomes and patient survival. Materials and Methods This is a prospective study performed in a tertiary care hospital in 30 resected specimens of GBC cases recorded in our Department of Pathology from November 2017 to November 2019. Clinical history including the radiological reports and demographic parameters were included in the study pro forma. Immunohistochemical (IHC) staining for EGFR and HER-2/NEU was performed on all the selected cases. Clinicopathologic parameters like age, sex, histologic type, perineural, and lymphovascular invasion were compared and correlated with EGFR and HER-2/NEU status. Results Expression of EGFR was found in 93.33% of cases, which showed a highly significant correlation with histological tumor type ( p = 0.000). HER-2/NEU expression was found in 56.66% of cases, which also showed a significant correlation with histological tumour type ( p = 0.021). We found most of the cases with strong EGFR immunoreactivity (3+) were poorly differentiated tumors and most of the cases showing weak immunoreactivity for EGFR (1+) were well-differentiated. Conversely, in case of HER-2/NEU immunoreactivity, strong staining (3+) was seen in well-differentiated tumors and weak staining (1+) in poorly differentiated tumors. A significant correlation was also found between EGFR and HER-2/NEU expression ( p = 0.000) and between cholelithiasis and EGFR expression ( p = 0 .033). Conclusion EGFR is expressed in most cases of GBC. Its expression is more in poorly differentiated carcinomas as compared to the well-differentiated carcinomas, whereas HER-2/NEU expression is more in well-differentiated carcinomas. Therefore, they may serve as independent prognostic factors and also as targets for molecular therapy in GBCs.
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Affiliation(s)
- Chhanda Das
- Department of Pathology, IPGME&R, Kolkata, India
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The Emerging Role of Immunotherapy in Intrahepatic Cholangiocarcinoma. Vaccines (Basel) 2021; 9:vaccines9050422. [PMID: 33922362 PMCID: PMC8146949 DOI: 10.3390/vaccines9050422] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/18/2021] [Accepted: 04/20/2021] [Indexed: 12/17/2022] Open
Abstract
Biliary tract cancer, and intrahepatic cholangiocarcinoma (iCC) in particular, represents a rather uncommon, highly aggressive malignancy with unfavorable prognosis. Therapeutic options remain scarce, with platinum-based chemotherapy is being considered as the gold standard for the management of advanced disease. Comprehensive molecular profiling of tumor tissue biopsies, utilizing multi-omics approaches, enabled the identification of iCC’s intratumor heterogeneity and paved the way for the introduction of novel targeted therapies under the scope of precision medicine. Yet, the unmet need for optimal care of patients with chemo-refractory disease or without targetable mutations still exists. Immunotherapy has provided a paradigm shift in cancer care over the past decade. Currently, immunotherapeutic strategies for the management of iCC are under intense research. Intrinsic factors of the tumor, including programmed death-ligand 1 (PD-L1) expression and mismatch repair (MMR) status, are simply the tip of the proverbial iceberg with regard to resistance to immunotherapy. Acknowledging the significance of the tumor microenvironment (TME) in both cancer growth and drug response, we broadly discuss about its diverse immune components. We further review the emerging role of immunotherapy in this rare disease, summarizing the results of completed and ongoing phase I–III clinical trials, expounding current challenges and future directions.
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Rimini M, Casadei-Gardini A. Angiogenesis in biliary tract cancer: targeting and therapeutic potential. Expert Opin Investig Drugs 2021; 30:411-418. [PMID: 33491502 DOI: 10.1080/13543784.2021.1881479] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Introduction: Biliary Tract Cancer (BTC) is a heterogeneous group of malignant neoplasms with a complex molecular pathogenesis. The prognosis of metastatic disease is dramatically dismal and therapeutic options are scarce. Systemic chemotherapy is the gold standard for the metastatic disease. However, because of the disappointing results with conventional chemotherapy, investigators have turned to new biological therapeutic options targeting the main molecular pathways, neo-angiogenesis, involved in the disease pathogenesis.Areas covered: This paper examines the rationale of using antiangiogenic therapies in this setting, evaluates the therapeutic implications, and highlights ongoing studies and future perspectives. A Pubmed systematic review of preclinical and clinical data was performed which enabled the composition of this paper.Expert opinion: Amore in-depth understanding of the interplay between the neo-angiogenesis pathways, and the microenvironment will could propel the design new therapeutic strategies. Nowadays, the combination of antiangiogenic drugs and immune check-point inhibitors looks promising, but further, more comprehensive data are necessary to gain afuller picture. In an era of novel technologies and techniques, which includes radiomics, the challenge is to identify the biomarkers of response to antiangiogenic drugs which will permit the selection of patients that are more likely to respond to antiangiogenic therapies.
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Affiliation(s)
- Margherita Rimini
- Department of Oncology and Hematology, Division of Oncology, University Hospital Modena, Modena, Italy
| | - Andrea Casadei-Gardini
- School of Medicine, Vita-Salute San Raffaele University, Milan, Italy.,Unit of Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
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Sutherland M, Ahmed O, Zaidi A, Ahmed S. Current progress in systemic therapy for biliary tract cancers. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2021; 29:1094-1107. [PMID: 33735541 DOI: 10.1002/jhbp.939] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 12/30/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND Biliary tract cancers (BTCs) are heterogeneous cancers that include cancers of the bile duct and gallbladder. Although they are relatively uncommon, most patients with BTC are diagnosed at advanced-stage disease with high mortality rates. Recently, systemic therapy options for patients with BTC have evolved. This paper reviews recent advancements in systemic therapy and the results of key clinical trials in BTC. METHODS A literature search in PubMed and Google Scholar was performed using keywords related to BTC and systemic therapy. Studies that were presented in major international cancer research conferences were also included. RESULTS The evidence shows that adjuvant capecitabine has been associated with a lower relapse rate in early-stage BTC. In unselected patients with advanced BTC, combination chemotherapy is a standard treatment option. However, with a better understanding of the molecular profile of BTC, there has been a shift toward targeted agents in BTC that have shown promising responses. The evolving data also support the evolving role of immunotherapy in patients with deficient DNA mismatch repair or PD-L1-positive BTC. DISCUSSION Systemic treatment options for BTC have improved. The future identification of new targets, novel compounds, and predictive markers is a key step toward the use of personalized medicine in BTC.
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Affiliation(s)
| | - Osama Ahmed
- Saskatoon Cancer Center, Saskatchewan Cancer Agency, University of Saskatchewan, Saskatoon, SK, Canada
| | - Adnan Zaidi
- Saskatoon Cancer Center, Saskatchewan Cancer Agency, University of Saskatchewan, Saskatoon, SK, Canada
| | - Shahid Ahmed
- Saskatoon Cancer Center, Saskatchewan Cancer Agency, University of Saskatchewan, Saskatoon, SK, Canada
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Rahnemai-Azar AA, Pawlik TM. Cholangiocarcinoma: shedding light on the most promising drugs in clinical development. Expert Opin Investig Drugs 2021; 30:419-427. [PMID: 33645382 DOI: 10.1080/13543784.2021.1897103] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Introduction: Cholangiocarcinoma (CCA) is a diverse group of fatal malignancies arising from the biliary tract. Surgical resection with negative margin offers the only potentially curative option. The majority of patients present at locally advanced or metastatic stages, when surgical resection is not feasible, highlighting the significance of systemic therapy. Given the limited effectiveness of traditional chemotherapy regimens in CCA, many investigators have focused on developing novel molecular therapies targeting key aberrant signaling pathways.Areas covered: We present the main genomic aberrations known to play a key role in cholangiocarcinogenesis and discuss promising targeted therapies in clinical development.In October of 2020, a review of the English literature was performed utilizing PubMed and Web of Science databases for the keywords of 'cholangiocarcinoma', 'biliary tract cancer', and 'targeted therapy'.Expert opinion: Unfortunately, despite encouraging results in preclinical studies, the outcome of clinical trials with established targeted therapies like anti-EGFR medications have been discouraging. Currently, agents targeting FGFR2 fusion and IDH1/2 mutations hold great promise for improving the management of CCA. Future studies focused on enhancing our understanding of key aberrant signaling pathways of cholangiocarcinogenesis and the design of homogeneous and biomarker-driven cohorts are key elements of establishing precision medicine in CCA.
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Affiliation(s)
- Amir A Rahnemai-Azar
- Division of Surgical Oncology, Department of Surgery, Arrowhead Regional Cancer Center, California University of Science and Medicine, Colton, CA, USA
| | - Timothy M Pawlik
- Department of Surgery, The Ohio State University Wexner Medical Center, The James Comprehensive Cancer Center, Columbus, OH, USA
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Perego G, Burgio V, Nozza R, Longobardo G, Bernecich M, Luciani A, Petrelli F. Is there any place for novel agents in treating biliary tract cancer? Med Oncol 2021; 38:19. [PMID: 33543377 DOI: 10.1007/s12032-021-01463-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 01/09/2021] [Indexed: 10/22/2022]
Abstract
Biliary tract cancer is an uncommon cancer in developed countries. In localized stages, surgery is the cornerstone of treatment with curative purpose. Conversely in advanced stages, chemotherapy with platinum-gemcitabine combination is the standard of care. Biliary tract cancers are a biologically heterogeneous group of malignancies, which perhaps explains the failure of targeted therapies in unselected patient populations to demonstrate benefit in advanced disease, although there are promises in selected populations (e.g. PD1/PD-L1 positive, BRAFV600E-mutated or IDH1-mutant). In view of the limited benefit of second line therapies in metastatic biliary tract cancer, various targeted agents have been tested in progressive disease. Furthermore, several ongoing trials are using next-generation sequencing of multiple genes to identify molecular abnormalities in the tumors of patients with refractory cancers that may potentially be used in pretreated disease (e.g. FGFR or IDH genes). Immunotherapy with immune checkpoint inhibitors may be interesting for patients whose tumors have programmed cell death 1 ligand 1 (PD-L1) overexpression. Ongoing and future trials will further advance our knowledge toward the optimal treatment strategy for the management of biliary tract cancer in its different stages, starting from metastatic and then reaching early stages of disease. We here provided an overview of these novel treatment strategies for advanced biliary tract cancers not amenable of curative treatment modalities.
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Affiliation(s)
| | | | - Renata Nozza
- School of Hospital Pharmacy, University of Milan, Milan, Italy
| | | | - Marco Bernecich
- School of Hospital Pharmacy, University of Milan, Milan, Italy
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Sarkis Y, Al Soueidy A, Kourie HR. Will advanced cholangiocarcinoma become a targetable malignancy? Crit Rev Oncol Hematol 2021; 159:103233. [PMID: 33482346 DOI: 10.1016/j.critrevonc.2021.103233] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 12/15/2020] [Accepted: 01/16/2021] [Indexed: 02/08/2023] Open
Abstract
Cholangiocarcinoma and biliary tract cancers are rare but aggressive tumors that are characterized by an heterogenous molecular and genetic footprint. Genetic aberrations such as FGFR2 fusion and ErBb2 amplification are common in those cancers. Recent studies aimed at exploring the efficacy and benefit of targeted therapy in the treatment of advanced cholangiocarcinoma. Many promising drugs exist and warrant additional investigations. This review will summarize available results and highlight therapeutic strategies incorporated in clinical trials.
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Affiliation(s)
- Yara Sarkis
- Hematology-Oncology Department, Faculty of Medicine, Saint Joseph University of Beirut, Lebanon.
| | - Amine Al Soueidy
- Hematology-Oncology Department, Faculty of Medicine, Saint Joseph University of Beirut, Lebanon
| | - Hampig Raphael Kourie
- Hematology-Oncology Department, Faculty of Medicine, Saint Joseph University of Beirut, Lebanon
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Balasubramanian B, Venkatraman S, Myint KZ, Janvilisri T, Wongprasert K, Kumkate S, Bates DO, Tohtong R. Co-Clinical Trials: An Innovative Drug Development Platform for Cholangiocarcinoma. Pharmaceuticals (Basel) 2021; 14:ph14010051. [PMID: 33440754 PMCID: PMC7826774 DOI: 10.3390/ph14010051] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Revised: 01/01/2021] [Accepted: 01/07/2021] [Indexed: 12/18/2022] Open
Abstract
Cholangiocarcinoma (CCA), a group of malignancies that originate from the biliary tract, is associated with a high mortality rate and a concerning increase in worldwide incidence. In Thailand, where the incidence of CCA is the highest, the socioeconomic burden is severe. Yet, treatment options are limited, with surgical resection being the only form of treatment with curative intent. The current standard-of-care remains adjuvant and palliative chemotherapy which is ineffective in most patients. The overall survival rate is dismal, even after surgical resection and the tumor heterogeneity further complicates treatment. Together, this makes CCA a significant burden in Southeast Asia. For effective management of CCA, treatment must be tailored to each patient, individually, for which an assortment of targeted therapies must be available. Despite the increasing numbers of clinical studies in CCA, targeted therapy drugs rarely get approved for clinical use. In this review, we discuss the shortcomings of the conventional clinical trial process and propose the implementation of a novel concept, co-clinical trials to expedite drug development for CCA patients. In co-clinical trials, the preclinical studies and clinical trials are conducted simultaneously, thus enabling real-time data integration to accurately stratify and customize treatment for patients, individually. Hence, co-clinical trials are expected to improve the outcomes of clinical trials and consequently, encourage the approval of targeted therapy drugs. The increased availability of targeted therapy drugs for treatment is expected to facilitate the application of precision medicine in CCA.
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Affiliation(s)
- Brinda Balasubramanian
- Graduate Program in Molecular Medicine, Faculty of Science, Mahidol University, Bangkok 10400, Thailand; (B.B.); (S.V.); (K.Z.M.)
| | - Simran Venkatraman
- Graduate Program in Molecular Medicine, Faculty of Science, Mahidol University, Bangkok 10400, Thailand; (B.B.); (S.V.); (K.Z.M.)
| | - Kyaw Zwar Myint
- Graduate Program in Molecular Medicine, Faculty of Science, Mahidol University, Bangkok 10400, Thailand; (B.B.); (S.V.); (K.Z.M.)
| | - Tavan Janvilisri
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand;
| | - Kanokpan Wongprasert
- Department of Anatomy, Faculty of Science, Mahidol University, Bangkok 10400, Thailand;
| | - Supeecha Kumkate
- Department of Biology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand;
| | - David O. Bates
- Division of Cancer and Stem Cells, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK;
| | - Rutaiwan Tohtong
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand;
- Correspondence: ; Tel.: +66-2-201-5606
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O'Rourke CJ, Munoz-Garrido P, Andersen JB. Molecular Targets in Cholangiocarcinoma. Hepatology 2021; 73 Suppl 1:62-74. [PMID: 32304327 DOI: 10.1002/hep.31278] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 04/02/2020] [Accepted: 04/06/2020] [Indexed: 12/18/2022]
Abstract
Cholangiocarcinoma (CCA) encompasses a heterogeneous collection of malignancies for which diagnostic biomarkers are lacking and population screening is infeasible because of its status as a rare disease. Coupled with high postsurgical recurrence rates among the minority of patients diagnosed at resectable stages, systemic clinical management will inevitably be required for the majority of patients with CCA with recurrent and advanced disease. In this review, we discuss the therapeutic potential of different classes of molecular targets at various stages of development in CCA, including those targeted to the tumor epithelia (oncogenic, developmental, metabolic, epigenomic) and tumor microenvironment (angiogenesis, checkpoint regulation). Furthermore, we discuss the successes and failures of CCA-targeted therapies, emphasizing key lessons learned that should pave the way for future molecular target evaluation in this uncommon yet bona fide target-rich disease.
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Affiliation(s)
- Colm J O'Rourke
- Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Patricia Munoz-Garrido
- Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jesper B Andersen
- Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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46
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Wang M, Chen Z, Guo P, Wang Y, Chen G. Therapy for advanced cholangiocarcinoma: Current knowledge and future potential. J Cell Mol Med 2020; 25:618-628. [PMID: 33277810 PMCID: PMC7812297 DOI: 10.1111/jcmm.16151] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 10/21/2020] [Accepted: 11/22/2020] [Indexed: 01/07/2023] Open
Abstract
Cholangiocarcinoma (CCA) is a biliary epithelial tumour that can emerge at any point in the biliary tree. It is commonly classified based on its anatomical site of development into intrahepatic cholangiocarcinoma (ICC), perihilar cholangiocarcinoma (PCC) and distal cholangiocarcinoma (DCC), each of which is associated with varying patient demographics, molecular characteristics and treatment options. CCA patients have poor overall prognoses and 5‐year survival rates. Additionally, CCA is often diagnosed at an advanced stage, with surgical treatment restricted to early‐stage disease. Owing to an increase in the incidence of ICC, that of CCA is also on the rise, with a corresponding increase in the associated mortality, particularly in South America and Asia. Therefore, the development of an effective treatment is crucial to improve the survival of CCA patients. We aimed to systematically review the current understanding of advanced CCA treatment and discuss potential effective strategies.
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Affiliation(s)
- Mingxun Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Ziyan Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Pengyi Guo
- Department of Cardiothoracic Surgery, Ningbo Yinzhou NO.2 Hospital, Ningbo, China
| | - Yi Wang
- Department of Epidemiology and Biostatistics, Public Health and Management School, Wenzhou Medical University, Wenzhou, China
| | - Gang Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
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Rodrigues PM, Olaizola P, Paiva NA, Olaizola I, Agirre-Lizaso A, Landa A, Bujanda L, Perugorria MJ, Banales JM. Pathogenesis of Cholangiocarcinoma. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2020; 16:433-463. [PMID: 33264573 DOI: 10.1146/annurev-pathol-030220-020455] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Cholangiocarcinoma (CCA) encompasses a group of malignancies that can arise at any point in the biliary tree. Although considered a rare cancer, the incidence of CCA is increasing globally. The silent and asymptomatic nature of these tumors, particularly in their early stages, in combination with their high aggressiveness, intra- and intertumor heterogeneity, and chemoresistance, significantly compromises the efficacy of current therapeutic options, contributing to a dismal prognosis. During the last few years, increasing efforts have been made to unveil the etiologies and pathogenesis of these tumors and to develop more effective therapies. In this review, we summarize current findings in the field of CCA, mainly focusing on the mechanisms of pathogenesis, cells of origin, genomic and epigenetic abnormalities, molecular alterations, chemoresistance, and therapies.
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Affiliation(s)
- Pedro M Rodrigues
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; , .,National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Paula Olaizola
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
| | - Nuno A Paiva
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
| | - Irene Olaizola
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
| | - Alona Agirre-Lizaso
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
| | - Ana Landa
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
| | - Luis Bujanda
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; , .,National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Maria J Perugorria
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; , .,National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; , .,National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain.,Ikerbasque, Basque Foundation for Science, 48013 Bilbao, Spain
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Rao J, Xia J, Yang W, Wu C, Sha B, Zheng Q, Cheng F, Lu L. Complete response to immunotherapy combined with an antiangiogenic agent in multiple hepatic metastases after radical surgery for advanced gallbladder cancer: a case report. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:1609. [PMID: 33437808 PMCID: PMC7791255 DOI: 10.21037/atm-20-4420] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Most advanced gallbladder cancers (GBCa) are unresectable or metastatic once diagnosed, and even patients who undergo surgery have a high risk of recurrence and metastasis. Immunotherapy, especially immune checkpoint inhibitors (ICIs), combined with an antiangiogenic agent, is an emerging prospective treatment for GBCa. However, the efficacy and safety of this combination therapy have not yet been investigated. We report the case of a 70-year-old female patient with recurrent metastatic GBCa (stage IVB) after radical surgery. Immunohistochemical examination revealed that 10% of the tumor cells expressed programmed cell death protein-1 (PD-1) and programmed cell death receptor ligand 1 (PD-L1). Whole-exome sequencing showed cancer tissues with a low tumor mutational burden (TMB) and microsatellite stability (MSS). The patient received Camrelizumab (200 mg, every three weeks) and Apatinib (40 mg/d). The clinical and immunological responses were observed, and the patient achieved a complete response after five cycles. This is the first case describing the efficacy and safety of Camrelizumab plus Apatinib in a GBCa patient with weak PD-1 and PD-L1 expression, and low TMB and MSS. The treatment had a tolerable safety profile and a complete response in the patient. Also, we found that the cluster of differentiation (CD)16+CD56+natural killer (NK) cell ratio in peripheral blood was increased after the combined treatment. Immunotherapy with antiangiogenic drugs may be a potential treatment option for patients with recurrent GBC or GBCa.
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Affiliation(s)
- Jianhua Rao
- Hepatobiliary Center, the First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China
| | - Jinguo Xia
- Hepatobiliary Center, the First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China
| | - Wenjie Yang
- Hepatobiliary Center, the First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China
| | - Chen Wu
- Hepatobiliary Center, the First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China
| | - Bowen Sha
- Hepatobiliary Center, the First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China
| | - Qitong Zheng
- Hepatobiliary Center, the First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China
| | - Feng Cheng
- Hepatobiliary Center, the First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China
| | - Ling Lu
- Hepatobiliary Center, the First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China
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Han S, Lee SY, Wang WW, Tan YB, Sim RHZ, Cheong R, Tan C, Hopkins R, Connolly J, Shuen WH, Toh HC. A Perspective on Cell Therapy and Cancer Vaccine in Biliary Tract Cancers (BTCs). Cancers (Basel) 2020; 12:E3404. [PMID: 33212880 PMCID: PMC7698436 DOI: 10.3390/cancers12113404] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 11/04/2020] [Accepted: 11/10/2020] [Indexed: 02/07/2023] Open
Abstract
Biliary tract cancer (BTC) is a rare, but aggressive, disease that comprises of gallbladder carcinoma, intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma, with heterogeneous molecular profiles. Advanced disease has limited therapeutic options beyond first-line platinum-based chemotherapy. Immunotherapy has emerged as a viable option for many cancers with a similar unmet need. Therefore, we reviewed current understanding of the tumor immune microenvironment and recent advances in cellular immunotherapy and therapeutic cancer vaccines against BTC. We illustrated the efficacy of dendritic cell vaccination in one patient with advanced, chemorefractory, melanoma-associated antigen (MAGE)-positive gallbladder carcinoma, who was given multiple injections of an allogenic MAGE antigen-positive melanoma cell lysate (MCL)-based autologous dendritic cell vaccine combined with sequential anti-angiogenic therapy. This resulted in good radiological and tumor marker response and an overall survival of 3 years from diagnosis. We postulate the potential synergism of adding anti-angiogenic therapy, such as bevacizumab, to immunotherapy in BTC, as a rational scientific principle to positively modulate the tumor microenvironment to augment antitumor immunity.
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Affiliation(s)
- Shuting Han
- Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Crescent, Singapore 169610, Singapore; (S.H.); (S.Y.L.); (W.-W.W.); (R.C.); (C.T.); (W.H.S.)
| | - Suat Ying Lee
- Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Crescent, Singapore 169610, Singapore; (S.H.); (S.Y.L.); (W.-W.W.); (R.C.); (C.T.); (W.H.S.)
| | - Who-Whong Wang
- Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Crescent, Singapore 169610, Singapore; (S.H.); (S.Y.L.); (W.-W.W.); (R.C.); (C.T.); (W.H.S.)
| | - Yu Bin Tan
- Singapore Health Services, 31 Third Hospital Ave, #03-03 Bowyer Block C, Singapore 168753, Singapore; (Y.B.T.); (R.H.Z.S.)
| | - Rachel Hui Zhen Sim
- Singapore Health Services, 31 Third Hospital Ave, #03-03 Bowyer Block C, Singapore 168753, Singapore; (Y.B.T.); (R.H.Z.S.)
| | - Rachael Cheong
- Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Crescent, Singapore 169610, Singapore; (S.H.); (S.Y.L.); (W.-W.W.); (R.C.); (C.T.); (W.H.S.)
| | - Cherlyn Tan
- Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Crescent, Singapore 169610, Singapore; (S.H.); (S.Y.L.); (W.-W.W.); (R.C.); (C.T.); (W.H.S.)
| | - Richard Hopkins
- Institute of Molecular and Cell Biology (IMCB), A*STAR, 61 Biopolis Drive, Singapore 138673, Singapore; (R.H.); (J.C.)
| | - John Connolly
- Institute of Molecular and Cell Biology (IMCB), A*STAR, 61 Biopolis Drive, Singapore 138673, Singapore; (R.H.); (J.C.)
| | - Wai Ho Shuen
- Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Crescent, Singapore 169610, Singapore; (S.H.); (S.Y.L.); (W.-W.W.); (R.C.); (C.T.); (W.H.S.)
| | - Han Chong Toh
- Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Crescent, Singapore 169610, Singapore; (S.H.); (S.Y.L.); (W.-W.W.); (R.C.); (C.T.); (W.H.S.)
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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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