|
1
|
Zhang F, Zhao X, Wei J, Wu L. PathSynergy: a deep learning model for predicting drug synergy in liver cancer. Brief Bioinform 2025; 26:bbaf192. [PMID: 40273429 PMCID: PMC12021016 DOI: 10.1093/bib/bbaf192] [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: 12/25/2024] [Revised: 03/13/2025] [Accepted: 04/01/2025] [Indexed: 04/26/2025] Open
Abstract
Cancer is a major public health problem while liver cancer is the main cause of global cancer-related deaths. The previous study demonstrates that the 5-year survival rate for advanced liver cancer is only 30%. Few of the first-line targeted drugs including sorafenib and lenvatinib are available, which often develop resistance. Drug combination therapy is crucial for improving the efficacy of cancer therapy and overcoming resistance. However, traditional methods for discovering drug synergy are costly and time consuming. In this study, we developed a novel predicting model PathSynergy by integrating drug feature data, cell line data, drug-target interactions, and signaling pathways. PathSynergy combined the advantages of graph neural networks and pathway map mapping. Comparing with other baseline models, PathSynergy showed better performance in model classification, accuracy, and precision. Excitingly, six Food and Drug Administration (FDA)-approved drugs including pimecrolimus, topiramate, nandrolone_decanoate, fluticasone propionate, zanubrutinib, and levonorgestrel were predicted and validated to show synergistic effects with sorafenib or lenvatinib against liver cancer for the first time. In general, the PathSynergy model provides a new perspective to discover synergistic combinations of drugs and has broad application potential in the fields of drug discovery and personalized medicine.
Collapse
Affiliation(s)
- Fengyue Zhang
- Guangxi Key Laboratory of Special Biomedicine, School of Medicine, Guangxi University, No. 100, East Daxue Road, Xixiangtang District, Nanning 530004, Guangxi, China
| | - Xuqi Zhao
- Guangxi Key Laboratory of Special Biomedicine, School of Medicine, Guangxi University, No. 100, East Daxue Road, Xixiangtang District, Nanning 530004, Guangxi, China
| | - Jinrui Wei
- Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi Scientific Research Center of Traditional Chinese Medicine, Guangxi University of Chinese Medicine, No. 13 Wuhe Avenue, Nanning 530200, Guangxi, China
| | - Lichuan Wu
- Guangxi Key Laboratory of Special Biomedicine, School of Medicine, Guangxi University, No. 100, East Daxue Road, Xixiangtang District, Nanning 530004, Guangxi, China
| |
Collapse
|
|
2
|
Piñero F, Thompson M, Marín JI, Silva M. Lenvatinib as first-line therapy for recurrent hepatocellular carcinoma after liver transplantation: Is the current evidence applicable to these patients? World J Transplant 2020; 10:297-306. [PMID: 33312891 PMCID: PMC7708877 DOI: 10.5500/wjt.v10.i11.297] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 06/09/2020] [Accepted: 09/22/2020] [Indexed: 02/05/2023] Open
Abstract
Liver transplantation (LT) is one of the leading curative therapies for hepatocellular carcinoma (HCC). Despite recent optimization of transplant selection criteria, including alpha-feto protein, HCC recurrence after LT is still the leading cause of death in these patients. During the last decades, effective systemic treatments for HCC, including tyrosine kinase inhibitors and immunotherapy, have been approved. We describe the clinical scenario of a patient with recurrence of HCC five years after LT, who received lenvatinib as first-line systemic therapy to introduce systemic treatment options in this clinical setting. In this opinion review, we detail first and second-line systemic treatment options, focusing on those feasible for patients with recurrent HCC after LT. Several trials have evaluated new drugs to treat HCC patients in first and second-line therapy, but patients with recurrent HCC after LT have been excluded from these trials. Consequently, most of the evidence comes from observational retrospective studies. Whether tyrosine kinase inhibitors will remain the primary therapeutic approach in these patients, due to a relative contraindication for immunotherapy, may be clarified in the near future.
Collapse
Affiliation(s)
- Federico Piñero
- Hepatology and Liver Transplant Unit, Hospital Universitario Austral, Buenos Aires B1629HJ, Argentina
- Hospital Universitario Austral, Facultad de Ciencias Biomédicas, Universidad Austral, Buenos Aires B1629HJ, Argentina
- Latin American Liver Research Educational and Awareness Network (LALREAN), Buenos Aires B1629HJ, Argentina
| | - Marcos Thompson
- Hospital Universitario Austral, Facultad de Ciencias Biomédicas, Universidad Austral, Buenos Aires B1629HJ, Argentina
| | - Juan Ignacio Marín
- Hepatology and Liver Transplantation Unit, Hospital Pablo Tobón Uribe, Medellín 240, Colombia
| | - Marcelo Silva
- Hospital Universitario Austral, Facultad de Ciencias Biomédicas, Universidad Austral, Buenos Aires B1629HJ, Argentina
- Latin American Liver Research Educational and Awareness Network (LALREAN), Buenos Aires B1629HJ, Argentina
| |
Collapse
|
|
3
|
Fan G, Wei X, Xu X. Is the era of sorafenib over? A review of the literature. Ther Adv Med Oncol 2020; 12:1758835920927602. [PMID: 32518599 PMCID: PMC7252361 DOI: 10.1177/1758835920927602] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 04/27/2020] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most severe diseases worldwide. For the different stages of HCC, there are different clinical treatment strategies, such as surgical therapy for the early stage, and transarterial chemoembolization (TACE) and selective internal radiation therapy (SIRT) for intermediate-stage disease. Systemic treatment, which uses mainly targeted drugs, is the standard therapy against advanced HCC. Sorafenib is an important first-line therapy for advanced HCC. As a classically effective drug, sorafenib can increase overall survival markedly. However, it still has room for improvement because of the heterogeneity of HCC and acquired resistance. Scientists have reported the acquired sorafenib resistance is associated with the anomalous expression of certain genes, most of which are also related with HCC onset and development. Combining sorafenib with inhibitors targeting these genes may be an effective treatment. Combined treatment may not only overcome drug resistance, but also inhibit the expression of carcinoma-related genes. This review focuses on the current status of sorafenib in advanced HCC, summarizes the inhibitors that can combine with sorafenib in the treatment against HCC, and provides the rationale for clinical trials of sorafenib in combination with other inhibitors in HCC. The era of sorafenib in the treatment of HCC is far from over, as long as we find better methods of medication.
Collapse
Affiliation(s)
- Guanghan Fan
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine; NHC Key Laboratory of Combined Multi-organ Transplantation; Key Laboratory of the diagnosis and treatment of organ Transplantation, CAMS; Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, China
| | - Xuyong Wei
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine; NHC Key Laboratory of Combined Multi-organ Transplantation; Key Laboratory of the diagnosis and treatment of organ Transplantation, CAMS; Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, China
| | - Xiao Xu
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine; NHC Key Laboratory of Combined Multi-organ Transplantation; Key Laboratory of the diagnosis and treatment of organ Transplantation, CAMS; Key Laboratory of Organ Transplantation, Zhejiang Province, 79 QingChun Road, Hangzhou, 310003, China
| |
Collapse
|
|
4
|
Wang D, Jia W, Wang Z, Wen T, Ding W, Xia F, Zhang L, Wu F, Peng T, Liu B, Zhou C, Zheng Q, Miao X, Peng J, Huang Z, Dou K. Retrospective analysis of sorafenib efficacy and safety in Chinese patients with high recurrence rate of post-hepatic carcinectomy. Onco Targets Ther 2019; 12:5779-5791. [PMID: 31410023 PMCID: PMC6643495 DOI: 10.2147/ott.s168447] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Accepted: 01/17/2019] [Indexed: 02/05/2023] Open
Abstract
Background: There is no guideline recommendation for preventing hepatocellular carcinoma (HCC) recurrence after hepatic resection. Moreover, an unmet need exists on the effectiveness of sorafenib therapy in recurrent HCC. Purpose: We therefore assessed the efficacy and safety of sorafenib in Chinese HCC patients with high risk of recurrence. Patients and methods: Data were collected retrospectively from 15 Chinese research centers from January 1, 2012 to November 15, 2013, by chart reviews of patients with moderate-advanced HCC who received hepatic carcinectomy. The primary end point was recurrence-free survival rate at 1 year in patients with a high recurrence risk. Secondary end points included 1-year survival rate, time to recurrence and safety assessment. Results: A total of 209 high-risk patients (sorafenib, n=98; control, n=111) who underwent carcinectomy were analyzed. There was no significant difference in the proportion of patients with recurrence-free survival at 1 year between the sorafenib and control (70.43% vs 68.90%: χ2=0.007, P=0.934). One-year survival rate was significantly higher with sorafenib than observed with control (95.5% vs 83.35%; χ2=7.441, P=0.006). Time to recurrence between sorafenib and control groups was similar. Incidences of all the adverse events (AEs) were similar in both the groups and transaminase elevation was most common in both groups (20.37% vs 24.79%). Thrombocytopenia incidence was significantly lower with the sorafenib group than with control (1.85% vs 9.40%; P=0.015). Conclusion: Sorafenib may be considered as a feasible option in the treatment of HCC recurrence.
Collapse
Affiliation(s)
- Desheng Wang
- Department of Hepatobiliary Surgery, Xijing Hospital, Shaanxi, China
| | - Weridong Jia
- Department of Hepatobiliary Surgery, Anhui Provincial Hospital, Hefei, China
| | - Zhiming Wang
- Department of Hepatobiliary Surgery, Xiangya Hospital, Changsha, China
| | - Tianfu Wen
- Department of Hepatobiliary Surgery, West China Hospital, Chengdu, China
| | - Wei Ding
- Department of Hepatobiliary Surgery, Cancer Hospital of Xinjiang, Urumqi, China
| | - Feng Xia
- Department of Hepatobiliary Surgery, Southwest Hospital, Chongqing, China
| | - Ling Zhang
- Department of Hepatobiliary Surgery, Cancer Hospital of Henan, Zhengzhou, China
| | - Feixiang Wu
- Department of Hepatobiliary Surgery, Cancer Hospital of Guangxi Medical University, Nanning, China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Bin Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Cuncai Zhou
- Department of Hepatobiliary Surgery, Cancer Hospital of Jiangxi, Nanchang, China
| | - Qichang Zheng
- Department of Hepatobiliary Surgery, Wuhan Union Hospital, Wuhan, China
| | - Xiongying Miao
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Xiangya, Changsha, China
| | - Junping Peng
- Department of Hepatopancreatobiliary Surgery, Cancer Hospital of Sichuan, Chengdu, China
| | - Zhiyong Huang
- Department of Hepatobiliary Surgery, Wuhan Tongji Hospital, Wuhan, China
| | - Kefeng Dou
- Department of Hepatobiliary Surgery, Xijing Hospital, Shaanxi, China
| |
Collapse
|
|
5
|
Lee HW, Suh KS. Advancements of liver transplantation for hepatocellular carcinoma in Korea. Jpn J Clin Oncol 2016; 47:93-100. [DOI: 10.1093/jjco/hyw168] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2016] [Revised: 09/21/2016] [Accepted: 11/14/2016] [Indexed: 02/06/2023] Open
|
|
6
|
de'Angelis N, Landi F, Nencioni M, Palen A, Lahat E, Salloum C, Compagnon P, Lim C, Costentin C, Calderaro J, Luciani A, Feray C, Azoulay D. Role of Sorafenib in Patients With Recurrent Hepatocellular Carcinoma After Liver Transplantation. Prog Transplant 2016; 26:348-355. [PMID: 27555074 DOI: 10.1177/1526924816664083] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
CONTEXT The management of hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) is challenging, especially if it is not treatable by surgery or embolization. OBJECTIVES The present study aims to compare the survival rates of liver transplanted patients receiving sorafenib or best supportive care (BSC) for HCC recurrence not amenable to curative intent treatments. DESIGN This is a retrospective comparative study on a prospectively maintained database. PARTICIPANTS Liver transplanted patients with untreatable HCC recurrence receiving BSC (n = 18) until 2007 or sorafenib (n = 15) thereafter were compared. RESULTS No group difference was observed for demographic characteristics at the time of transplantation and at the time of HCC recurrence. On the explant pathology of the native liver, 81.2% patients were classified within the Milan criteria, and 53.1% presented with microvascular invasion. Hepatocellular carcinoma recurrence was diagnosed 17.8 months (standard deviation: 14.5) after LT, with 17 (53.1%) patients presenting with early recurrence (≤12 months). The 1-year survival from untreatable progression of HCC recurrence was 23.9% for the BSC and 60% for the sorafenib group ( P = .002). The type of treatment (sorafenib vs BSC) was the sole independent predictor of survival (hazard ratio: 2.98; 95% confidence interval: 1.09-8.1; P = .033). In the sorafenib group, 8 (53.3%) patients required dose reduction, and 2 (13.3%) patients discontinued the treatment due to intolerable side effects. CONCLUSION Sorafenib improves survival and is superior to the BSC in cases of untreatable posttransplant hepatocellular carcinoma recurrence.
Collapse
Affiliation(s)
- Nicola de'Angelis
- 1 Department of HPB Surgery and Liver Transplantation, Henri-Mondor Hospital, Université Paris Est-UPEC, Créteil, France
| | - Filippo Landi
- 1 Department of HPB Surgery and Liver Transplantation, Henri-Mondor Hospital, Université Paris Est-UPEC, Créteil, France
| | - Marco Nencioni
- 1 Department of HPB Surgery and Liver Transplantation, Henri-Mondor Hospital, Université Paris Est-UPEC, Créteil, France
| | - Anais Palen
- 1 Department of HPB Surgery and Liver Transplantation, Henri-Mondor Hospital, Université Paris Est-UPEC, Créteil, France
| | - Eylon Lahat
- 1 Department of HPB Surgery and Liver Transplantation, Henri-Mondor Hospital, Université Paris Est-UPEC, Créteil, France
| | - Chady Salloum
- 1 Department of HPB Surgery and Liver Transplantation, Henri-Mondor Hospital, Université Paris Est-UPEC, Créteil, France
| | - Philippe Compagnon
- 1 Department of HPB Surgery and Liver Transplantation, Henri-Mondor Hospital, Université Paris Est-UPEC, Créteil, France
| | - Chetana Lim
- 1 Department of HPB Surgery and Liver Transplantation, Henri-Mondor Hospital, Université Paris Est-UPEC, Créteil, France
| | - Charlotte Costentin
- 2 Department of Hepatology, Henri-Mondor Hospital, Université Paris Est-UPEC, Créteil, France
| | - Julien Calderaro
- 3 Department of Pathology, Henri-Mondor Hospital, Université Paris Est-UPEC, Créteil, France.,4 INSERM Unit UMR1162, Créteil, France
| | - Alain Luciani
- 5 Department of Radiology and Medical Imaging, Henri-Mondor Hospital, Université Paris Est-UPEC, Créteil, France.,6 INSERM Unit 955, Créteil, France
| | - Cyrille Feray
- 2 Department of Hepatology, Henri-Mondor Hospital, Université Paris Est-UPEC, Créteil, France.,6 INSERM Unit 955, Créteil, France
| | - Daniel Azoulay
- 1 Department of HPB Surgery and Liver Transplantation, Henri-Mondor Hospital, Université Paris Est-UPEC, Créteil, France.,6 INSERM Unit 955, Créteil, France
| |
Collapse
|
|
7
|
Gao JJ, Shi ZY, Xia JF, Inagaki Y, Tang W. Sorafenib-based combined molecule targeting in treatment of hepatocellular carcinoma. World J Gastroenterol 2015; 21:12059-12070. [PMID: 26576091 PMCID: PMC4641124 DOI: 10.3748/wjg.v21.i42.12059] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Revised: 07/28/2015] [Accepted: 09/14/2015] [Indexed: 02/06/2023] Open
Abstract
Sorafenib is the only and standard systematic chemotherapy drug for treatment of advanced hepatocellular carcinoma (HCC) at the current stage. Although sorafenib showed survival benefits in large randomized phase III studies, its clinical benefits remain modest and most often consist of temporary tumor stabilization, indicating that more effective first-line treatment regimens or second-line salvage therapies are required. The molecular pathogenesis of HCC is very complex, involving hyperactivated signal transduction pathways such as RAS/RAF/MEK/ERK and PI3K/AKT/mTOR and aberrant expression of molecules such as receptor tyrosine kinases and histone deacetylases. Simultaneous or sequential abrogation of these critical pathways or the functions of these key molecules involved in angiogenesis, proliferation, and apoptosis may yield major improvements in the management of HCC. In this review, we summarize the emerging sorafenib-based combined molecule targeting for HCC treatment and analyze the rationales of these combinations.
Collapse
|
|
8
|
de’Angelis N, Landi F, Carra MC, Azoulay D. Managements of recurrent hepatocellular carcinoma after liver transplantation: A systematic review. World J Gastroenterol 2015; 21:11185-11198. [PMID: 26494973 PMCID: PMC4607916 DOI: 10.3748/wjg.v21.i39.11185] [Citation(s) in RCA: 126] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2015] [Revised: 04/06/2015] [Accepted: 08/25/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the efficacy (survival) and safety of treatments for recurrent hepatocellular carcinoma (HCC) in liver transplantation (LT) patients.
METHODS: Literature search was performed on available online databases without a time limit until January 2015. Clinical studies describing survival after HCC recurrence in LT patients were retrieved for a full-text evaluation. A total of 61 studies were selected: 13 case reports, 41 retrospective case series, and 7 retrospective comparative studies.
RESULTS: Based on all included studies, the mean HCC recurrence rate was 16% of all LTs for HCC. A total of 1021 LT patients experienced HCC recurrence. The median time from LT to HCC recurrence was 13 mo (range 2-132 mo). The majority of patients (67%) presented with HCC extra-hepatic recurrences, involving lung, bone, adrenal gland, peritoneal lymph nodes, and rarely the brain. Overall survival after HCC recurrence was 12.97 mo. Surgical resection of localized HCC recurrence and Sorafenib for controlling systemic spread of HCC recurrence were associated with the higher survival rates (42 and 18 mo, respectively). However, Sorafenib, especially when combined with mTOR, was frequently associated with severe side effects that required dose reduction or discontinuation
CONCLUSION: Management of recurrent HCC in LT patients is challenging and associated with poor prognosis independently of the type of treatment.
Collapse
|
|
9
|
Park JG, Park SY, Lee HW. Complete remission of advanced hepatocellular carcinoma by radiofrequency ablation after sorafenib therapy. World J Gastroenterol 2015; 21:2568-2572. [PMID: 25741170 PMCID: PMC4342939 DOI: 10.3748/wjg.v21.i8.2568] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2014] [Revised: 10/18/2014] [Accepted: 11/11/2014] [Indexed: 02/07/2023] Open
Abstract
Sorafenib, a potent multikinase inhibitor, lead to a significant improvement in progression free survival and overall survival in patients with advanced hepatocellular carcinoma (HCC). Though sorafenib has proven its efficacy in advanced stage HCC, there are limited reports on the role of sorafenib allowing for curative treatment by down-staging. We herein report a case of advanced HCC with vascular invasion, which showed treatment response by sorafenib therapy as to allow for radiofrequency ablation as curative treatment. The patient was followed-up for 6 mo without recurrence with continued sorafenib therapy.
Collapse
|
|
10
|
Suh KS, Lee HW. Liver transplantation for advanced hepatocellular carcinoma: how far can we go? Hepat Oncol 2015; 2:19-28. [PMID: 30190984 DOI: 10.2217/hep.14.34] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Liver transplantation is one of the most effective treatment options for hepatocellular carcinoma. Although the Milan criteria have been widely used to identify suitable candidates for liver transplant with a good prognosis, many transplant centers have developed and actually used more expanded criteria. Living donor liver transplant (LDLT) is at the center of expansion of criteria because it is based on the personal relationship between a recipient and a donor. Asian LDLT centers have developed various expanded criteria for LDLT using tumor biologic markers as well as the size and number of the tumors. However, there is no consensus on the limit of the expansion of criteria. Here, we present our experience and opinion on LDLT for advanced hepatocellular carcinoma.
Collapse
Affiliation(s)
- Kyung-Suk Suh
- Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea.,Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea
| | - Hae Won Lee
- Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea.,Department of Surgery, Seoul National University Boramae Medical Center, Seoul, South Korea.,Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea.,Department of Surgery, Seoul National University Boramae Medical Center, Seoul, South Korea
| |
Collapse
|
|
11
|
Tan-Shalaby JL. Reproducible complete remission of advanced hepatocellular carcinoma with sorafenib in combination with clopidogrel. BMJ Case Rep 2014; 2014:bcr-2014-203962. [PMID: 25178887 DOI: 10.1136/bcr-2014-203962] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
We present a 57-year-old Caucasian man with hepatocellular carcinoma (HCC) twice achieving complete remission with reduced dose sorafenib. His initial diagnosis of HCC rapidly improved with sorafenib and he achieved a complete biochemical and radiographic response within 7 months. Remission lasted only 5 months but we noted that the timing of his relapse was immediately after he incidentally discontinued clopidogrel. It was restarted and within 5 months of restarting clopidogrel he once again achieved complete remission. The course of his remission was followed and temporal association of sorafenib remission with use of clopidogrel was observed.
Collapse
Affiliation(s)
- Jocelyn L Tan-Shalaby
- Section of Hematology Oncology, Veteran Affairs Medical Center, Pittsburgh, Pennsylvania, USA
| |
Collapse
|
|
12
|
Waghray A, Balci B, El-Gazzaz G, Kim R, Pelley R, Narayanan Menon KV, Estfan B, Romero-Marrero C, Aucejo F. Safety and efficacy of sorafenib for the treatment of recurrent hepatocellular carcinoma after liver transplantation. Clin Transplant 2013; 27:555-61. [PMID: 23758296 DOI: 10.1111/ctr.12150] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/02/2013] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Recurrent hepatocellular carcinoma (HCC) following liver transplantation (LT) carries a poor prognosis. The aim of our study was to assess the safety and efficacy of sorafenib in patients with recurrent HCC following LT. METHODS A prospectively maintained LT database was retrospectively analyzed for patients with recurrent HCC following LT between 2001 and 2011-34 patients. Patients were divided into two groups based on whether they were prescribed sorafenib (n = 17) or not prescribed sorafenib (n = 17). The primary endpoint was overall survival. RESULTS There were no significant differences between the two groups analyzed. Seventeen patients were on sorafenib for recurrent HCC, with a mean daily dose of ~444 mg. Mean duration of treatment was ~10 months. Side effects included: thrombocytopenia, diarrhea, rising transaminases, fatigue, hand-foot skin reaction, and nausea. Survival in the sorafenib vs. non-sorafenib group was greater at three-, six-, nine-, and 12-month intervals and overall survival. CONCLUSION Sorafenib can be well tolerated and safe in patients with recurrent HCC following LT and may be associated with a modest survival benefit. To our knowledge, this is the largest single-center retrospective analysis of patients prescribed sorafenib for recurrent HCC after LT.
Collapse
Affiliation(s)
- Abhijeet Waghray
- Hepatobiliary and Liver Transplant Surgery, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | | | | | | | | | | | | | | | | |
Collapse
|
|
13
|
Hong KH, Lim YJ. Recent update of gastrointestinal endoscope reprocessing. Clin Endosc 2013; 46:267-73. [PMID: 23767038 PMCID: PMC3678065 DOI: 10.5946/ce.2013.46.3.267] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2013] [Revised: 03/26/2013] [Accepted: 03/26/2013] [Indexed: 01/10/2023] Open
Abstract
As infection-related issues have become one of the most important concerns in endoscopy centers, proper reprocessing of endoscopes has attracted great interest. Compliance with established guidelines for reprocessing is critical to prevent pathogen transmission. However, hospital compliance with guidelines has not been satisfactory. To increase compliance, efforts have focused on developing new and more innovative disinfectants and an automated endoscope reprocessor. Reprocessing must be performed by appropriately trained personnel and regular monitoring of reprocessing is essential for quality assurance to improve compliance.
Collapse
Affiliation(s)
- Kyong Hee Hong
- Department of Internal Medicine, Dongguk University Ilsan Hospital, Dongguk University College of Medicine, Goyang, Korea
| | | |
Collapse
|
|
14
|
Adverse events affect sorafenib efficacy in patients with recurrent hepatocellular carcinoma after liver transplantation: experience at a single center and review of the literature. Eur J Gastroenterol Hepatol 2013; 25:180-6. [PMID: 23044808 DOI: 10.1097/meg.0b013e328359e550] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
AIMS The aim of this study was to assess the safety and efficacy of sorafenib, with or without everolimus, in the treatment of recurrent hepatocellular carcinoma (HCC) after an orthotopic liver transplantation (OLT). METHODS We reviewed the outcome of our consecutive cohort series of patients. Eleven patients (nine men) with recurrent HCC after OLT were treated. Four patients received cyclosporine plus sorafenib at a starting dose of 400 mg twice daily; seven received the combination of sorafenib (same dosage) and everolimus. Sorafenib was reduced or stopped according to the drug label. RESULTS The median time to recurrence was 12 months (range 2-66). The mean age at the start of treatment was 57 ± 9 years. Sorafenib was withdrawn because of intolerance or side-effects in four (36%) patients. Dose reduction because of adverse events or intolerance was required in 91% of patients after 26 ± 11 days from the start of treatment. The average length of treatment was 68 days (range 15-444). One patient died because of a massive gastrointestinal bleeding while receiving sorafenib and everolimus. The most frequent adverse events were fatigue (54%), skin toxicity (45%), and hypophosphatemia (36%). Two patients (18%) showed a radiological partial response, one (9%) had a stable disease, and six (54%) showed a progressive disease. None of the patients achieved a complete response. Treatment response could not be assessed in two (18%) patients. The overall median survival since the start of treatment was 5 months. One-year survival was 18%. CONCLUSION Sorafenib, with or without mammalian target of rapamycin inhibitors, is poorly tolerated and rarely effective in the treatment of recurrent HCC after OLT.
Collapse
|
|
15
|
Lerut J, Julliard O, Ciccarelli O, Lannoy V, Gofette P. Hepatocellular cancer and liver transplantation: a Western experience. Recent Results Cancer Res 2013; 190:127-144. [PMID: 22941018 DOI: 10.1007/978-3-642-16037-0_9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
Orthotopic liver transplantation is the preferred treatment option in patients with hepatocellular carcinoma developing in chronic liver disease. Unfortunately, based on classical transplantation criteria (Milan criteria), only a minority of patients with hepatocellular carcinoma are candidate to orthotopic liver transplantation. Major improvements in treatment strategy and surgical technique including the use of neoadjuvant locoregional therapies and progresses of post-transplant immunosuppressive treatment have contributed to safely expand transplantation criteria preserving acceptable surgical morbidity-mortality and good oncologic outcome. Further extension of transplantation criteria may have advantages including an increase in the number of transplant candidates and improvement of the prognosis of the disease and also disadvantages including an increase of surgical morbidity and deterioration of global oncologic outcome of orthotopic liver transplantation in hepatocellular carcinoma. In the future, identification of imaging or molecular prognostic markers could help to better define transplantation criteria.
Collapse
Affiliation(s)
- Jan Lerut
- Department of Imaging - Interventional Radiology, Université catholique de Louvain-UCL, Brussels, Belgium.
| | | | | | | | | |
Collapse
|
|
16
|
Nakano M, Tanaka M, Kuromatsu R, Nagamatsu H, Sakata K, Matsugaki S, Kajiwara M, Fukuizumi K, Tajiri N, Matsukuma N, Sakai T, Ono N, Yano Y, Koga H, Kurogi J, Takata A, Sumie S, Satani M, Yamada S, Niizeki T, Aino H, Iwamoto H, Torimura T, Sata M. Efficacy, safety, and survival factors for sorafenib treatment in Japanese patients with advanced hepatocellular carcinoma. Oncology 2012; 84:108-14. [PMID: 23147476 DOI: 10.1159/000342650] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2012] [Accepted: 08/10/2012] [Indexed: 12/17/2022]
Abstract
BACKGROUND Sorafenib, an oral multikinase inhibitor, was approved for the treatment of advanced hepatocellular carcinoma (HCC), but has not been adequately evaluated for safety and effectiveness in Japanese patients with advanced HCC. AIMS The purpose of this study was to prospectively assess the efficacy, safety, and risk factors for survival in patients with advanced HCC treated with sorafenib. METHODS Between May 2009 and December 2010, 96 Japanese patients with advanced HCC (76 male, 20 female, mean age: 70.4 years) were treated with sorafenib. Eighty-eight patients had Child-Pugh class A, and 8 patients had Child-Pugh class B liver cirrhosis. Barcelona Clinic Liver Cancer stage B and C were found in 64 and 32 patients, respectively. RESULTS Twelve patients demonstrated partial response to sorafenib therapy, 43 patients had stable disease, and 33 patients had progressive disease at the first radiologic assessment. The most frequent adverse events leading to discontinuation of sorafenib treatment were liver dysfunction (n = 8), hand-foot skin reaction (n = 7), and diarrhea (n = 4). The median survival time and time to progression were 11.6 and 3.2 months, respectively. By multivariate analysis, des-γ-carboxy prothrombin serum levels and duration of treatment were identified as independent risk factors for survival. CONCLUSIONS This study showed that sorafenib was safe and useful in Japanese patients with advanced HCC. In addition, this study demonstrated that sorafenib should be administered as a long-term treatment for advanced HCC regardless of therapeutic effect and dosage.
Collapse
Affiliation(s)
- Masahito Nakano
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
17
|
Finn RS. Current and Future Treatment Strategies for Patients with Advanced Hepatocellular Carcinoma: Role of mTOR Inhibition. Liver Cancer 2012; 1:247-56. [PMID: 24159589 PMCID: PMC3760459 DOI: 10.1159/000343839] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a common cancer that has the third highest cancer-related mortality rate worldwide. Although potentially curable by transplantation if detected early, the majority of cases are diagnosed at an advanced stage of disease for which limited treatment options are available. The only proven systemic therapy for advanced HCC is sorafenib, a multi-kinase inhibitor that has demonstrated modest efficacy and reasonable tolerability in patients with advanced HCC. Five years after the approval of sorafenib, no other agent has been proven to be beneficial in the first- or second-line setting in advanced HCC. While molecular studies have highlighted various potential targets in HCC, the mammalian target of rapamycin (mTOR) has emerged as an exciting target for cancer therapy including HCC. Laboratory data have linked the phosphatidylinositol 3-kinase/AKT/mTOR axis to various oncogenic processes, including survival and angiogenesis. Historically, mTOR inhibitors have been used for their immunosuppressive properties, but more recently they have been approved as anticancer agents. Retrospective HCC studies suggest that the inclusion of mTOR inhibition as part of an immunosuppressant regimen after transplantation may reduce HCC recurrence compared with other immunosuppressive agents such as calcineurin inhibitors. More recently, single-arm, phase I/II studies have shown that mTOR inhibitors also have activity as monotherapy in cases of recurrent HCC or de novo advanced HCC. This article will review the rationale for targeting the mTOR pathway in HCC, and the currently available clinical data supporting its development for HCC.
Collapse
Affiliation(s)
- Richard S. Finn
- *Richard S. Finn, MD, Division of Hematology/Oncology, David Geffen School of Medicine, University of California, Los Angeles, 10833 Le Conte Avenue, 11-0934 Factor Building, Los Angeles, CA 90095 (USA), Tel. +1 310 586 2091, E-mail
| |
Collapse
|
|
18
|
Welker MW, Bechstein WO, Zeuzem S, Trojan J. Recurrent hepatocellular carcinoma after liver transplantation - an emerging clinical challenge. Transpl Int 2012; 26:109-18. [PMID: 22994652 DOI: 10.1111/j.1432-2277.2012.01562.x] [Citation(s) in RCA: 110] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
In western countries, hepatocellular carcinoma (HCC) is a major reason for orthotopic liver transplantation (OLT) with estimated recurrence rates between 15% and 20%. This selective literature review addresses follow-up care after OLT in HCC and current treatment options. Recurrence prediction is based on pathological tumor stage, vascular invasion, serum alfafetoprotein levels, and histological differentiation, but further advances are expected by molecular profiling techniques. Lower levels of immunosuppressive agents are associated with a lower risk for HCC recurrence. Retrospective studies indicate that mammalian target of rapamycin (mTOR) inhibitors as immunosuppression reduce the risk of HCC recurrence. However, prospective studies supporting this potential advantage of mTOR inhibitors are still lacking, and higher rejection rates were reported for sirolimus after OLT in HCC. Prognosis is poor in recurrent HCC, a longer interval between OLT and recurrence and feasibility of surgical resection are associated with improved survival. Systemic treatment with sorafenib is the current standard of care in patients with advanced-stage HCC not suitable for locoregional therapy. After OLT, combination of an mTOR inhibitor with sorafenib is feasible and frequently used in clinical practice. As safety and efficacy data are still limited, close clinical monitoring is mandatory.
Collapse
Affiliation(s)
- Martin-Walter Welker
- Medizinische Klinik 1, Klinikum der Johann-Wolfgang Goethe-Universität, Frankfurt am Main, Germany
| | | | | | | |
Collapse
|
|
19
|
Staufer K, Fischer L, Seegers B, Vettorazzi E, Nashan B, Sterneck M. High toxicity of sorafenib for recurrent hepatocellular carcinoma after liver transplantation. Transpl Int 2012; 25:1158-64. [PMID: 22882364 DOI: 10.1111/j.1432-2277.2012.01540.x] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Treatment options of recurrent hepatocellular carcinoma (HCC) after liver transplantation are limited and data on systemic compounds for advanced tumor stages in transplant recipients are sparse. We retrospectively analyzed the toxicity, tolerability, and efficacy of sorafenib in combination with mTOR inhibitors (mTORi), or calcineurin inhibitors (CNI) in transplant recipients with recurrent HCC. In total, 20 of 92 patients transplanted for HCC within a 10-year time period, experienced tumor recurrence. In case of ineligibility for other treatment options, patients received sorafenib (n = 13). In addition, CNI were stopped and switched to mTORi in nine patients, whereas CNI were continued in four patients. Grade 3-4 adverse events were observed in 92% of all patients necessitating sorafenib discontinuation in 77%. The most common severe adverse events were acute hepatitis, diarrhea, hand-foot - skin reaction and bone marrow suppression. In patients receiving sorafenib/mTORi one patient achieved partial response, and four achieved stable disease. In this cohort of liver transplant recipients side effects prevented full dosing of sorafenib and necessitated discontinuation of sorafenib in the majority of patients, yet antitumor efficacy seemed promising in combination with mTORi.
Collapse
Affiliation(s)
- Katharina Staufer
- Hepatobiliary and Transplant Surgery, University Medical Centre Hamburg -Eppendorf, Hamburg, Germany.
| | | | | | | | | | | |
Collapse
|
|
20
|
Davis E, Wiesner R, Valdecasas J, Kita Y, Rossi M, Schwartz M. Treatment of recurrent hepatocellular carcinoma after liver transplantation. Liver Transpl 2011; 17 Suppl 2:S162-6. [PMID: 21688382 DOI: 10.1002/lt.22361] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Eric Davis
- Mount Sinai Medical Center, New York, NY 10029, USA
| | | | | | | | | | | |
Collapse
|
|
21
|
Gamstätter T, Weinmann A, Schadmand-Fischer S, Spies PR, Niederle IM, Schuchmann M, Galle PR, Wörns MA. AFP measurement in monitoring treatment response of advanced hepatocellular carcinoma to sorafenib: case report and review of the literature. ACTA ACUST UNITED AC 2011; 34:538-42. [PMID: 21985853 DOI: 10.1159/000332137] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND The multi-targeted tyrosine kinase inhibitor sorafenib was the first agent to demonstrate a significant improvement in overall survival in patients with advanced hepatocellular carcinoma (HCC). However, survival under sorafenib treatment is still lower than 1 year in most patients in clinical practice. Sorafenib rarely produces radiological tumor regression, pointing out limitations in using conventional radiological assessment of response to targeted therapy. Serial alpha-fetoprotein (AFP) measurement may be useful in monitoring treatment response in patients with advanced HCC undergoing systemic therapy; however, this approach is poorly defined for the case of sorafenib. CASE REPORT We herein report the case of a 48-year-old patient with advanced HCC presenting with normalization of highly elevated AFP levels after 5 months of reduced-dose sorafenib treatment, resulting in a sustained radiological and clinical response. CONCLUSIONS Complete response to sorafenib may be possible in a small subgroup of patients with advanced HCC, strongly depending on one or more of the targets inhibited by sorafenib. Serial AFP measurement may provide additional information in monitoring treatment response to sorafenib and should be evaluated in future clinical trials in advanced HCC.
Collapse
Affiliation(s)
- Thomas Gamstätter
- I. Medizinische Klinik und Poliklinik, Universitätsmedizin Mainz, Germany
| | | | | | | | | | | | | | | |
Collapse
|
|
22
|
Matsuda Y, Ichida T, Fukumoto M. Hepatocellular carcinoma and liver transplantation: clinical perspective on molecular targeted strategies. Med Mol Morphol 2011; 44:117-24. [PMID: 21922382 DOI: 10.1007/s00795-011-0547-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2011] [Accepted: 04/20/2011] [Indexed: 12/11/2022]
Abstract
Hepatocellular carcinoma (HCC) has an aggressive clinical course with frequent recurrence and metastasis. Orthotopic liver transplantation has been the only curative tool for unresectable HCC; therefore, recent advances in molecular targeted therapy may improve the prognosis of HCC. The multiple kinase inhibitor sorafenib and the macrolide antibiotic rapamycin are currently the most promising agents for treating unresectable HCC. A large population-based clinical trial revealed that sorafenib significantly prolonged the overall survival of HCC patients. However, subsequent clinical studies showed that sorafenib rarely reduced tumor volume and inadequately prolonged survival of patients with severe liver damage. To improve its therapeutic effect, the development of a predictive biomarker and a sorafenib-based combination is awaited. Another molecular targeting agent, rapamycin, has now been considered as a putative agent for preventing tumor recurrence in post-liver transplantation HCC patients, because it not only has immunosuppressive activity but also exerts an anti-tumor effect. In the near future, a combination of molecular targeting agents, such as sorafenib and rapamycin, may become a standard protocol for treating unresectable HCC. For specifying cases with more effective and less harmful modalities, further investigation in clinical and basic research to identify unexpected effects are needed.
Collapse
Affiliation(s)
- Yasunobu Matsuda
- Department of Medical Technology, Niigata University Graduate School of Health Sciences, 2-746 Asahimachi-dori, Niigata 951-8518, Japan.
| | | | | |
Collapse
|
|
23
|
Chok KSH, Chan SC, Cheung TT, Chan ACY, Fan ST, Lo CM. Late recurrence of hepatocellular carcinoma after liver transplantation. World J Surg 2011; 35:2058-2062. [PMID: 21597889 PMCID: PMC3152711 DOI: 10.1007/s00268-011-1146-z] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Long-term survival of patients with hepatocellular carcinoma (HCC) after liver transplantation is affected mainly by recurrence of HCC. There is the opinion that the chance of recurrence after 2 years post-transplantation is remote, and therefore lifelong surveillance is not justified because of limited resources. The aims of the present study were to determine the rate of late HCC recurrence (≥ 2 years after transplantation) and to compare the long-term patient survival outcomes between cases of early recurrence (<2 years after transplantation) and late recurrence. PATIENTS A total of 139 adult HCC patients having liver transplantation during the period from July 1994 to December 2007 were included in the analysis. The median follow-up period was 55 months. Thirty-two patients received deceased-donor grafts and 107 received living-donor grafts. RESULTS Hepatocellular carcinoma recurrence occurred in 24 (17.3%) patients, among them 22 (86%) had living-donor grafts and 7 (5%) developed late recurrence. Patients in the early recurrence group and patients in the late recurrence group had comparable demographics and disease pathology. The former group, when compared with the latter, had significantly worse overall survival at 3 years (13.3 versus 100%) and 5 years (6.67 versus 71.4%) (log-rank test; p < 0.001). CONCLUSIONS Both early recurrence and late recurrence of HCC after liver transplantation were not uncommon, mostly detected at a subclinical stage. Regular and long-term surveillance with imaging and blood tests is essential for early detection.
Collapse
Affiliation(s)
- Kenneth S H Chok
- Department of Surgery, The University of Hong Kong, 102 Pokfulam Road, Hong Kong, SAR, People's Republic of China.
| | | | | | | | | | | |
Collapse
|