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Rao S, Prince SP, Gaddipati S, Feun L, Ezenwajiaku N, Martin P, Jones PD. Looking Toward the Future: Emerging Therapies for Hepatocellular Carcinoma. Gastroenterol Hepatol (N Y) 2025; 21:286-297. [PMID: 40416920 PMCID: PMC12100529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/27/2025]
Abstract
Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related deaths worldwide. Despite the decreasing prevalence of hepatitis C, the burden of HCC is expected to rise owing to the increasing prevalence of metabolic syndrome and increased global alcohol consumption. Guideline-concordant screening with ultrasound every 6 months has been associated with increased rates of early-stage detection and receipt of curative treatment. However, most patients with cirrhosis do not undergo screening, with HCC often diagnosed only at an advanced stage when curative resection or ablation is not feasible. Systemic medical therapy is indicated in patients diagnosed with infiltrative or advanced HCC, or when early-stage disease progresses or recurs after resection, transplant, or other locoregional therapy. Sorafenib was approved as first-line therapy for HCC in 2007. Since 2017, there has been an exponential rate of approval of novel agents targeting HCC, including lenvatinib, regorafenib, and cabozantinib. Checkpoint inhibitors, including pembrolizumab, nivolumab, ipilimumab, and combination therapy with atezolizumab plus bevacizumab and durvalumab plus tremelimumab, have expanded treatment options. This article describes treatment for all HCC stages, with a brief discussion of locoregional therapy for context, as some emerging treatment regimens combine locoregional and systemic therapies. The article highlights approved systemic therapies that are guideline-endorsed and emerging therapies for advanced HCC.
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Affiliation(s)
- Sanjana Rao
- University of Miami/Jackson Health System Internal Medicine Residency, University of Miami Miller School of Medicine, Miami, Florida
| | - Sean-Patrick Prince
- University of Miami/Holy Cross Health Internal Medicine Program, Fort Lauderdale, Florida
| | - Sirisha Gaddipati
- University of Miami/Jackson Health System Internal Medicine Residency, University of Miami Miller School of Medicine, Miami, Florida
| | - Lynn Feun
- Department of Medicine, Division of Medical Oncology, University of Miami Miller School of Medicine, Miami, Florida
| | - Nkiruka Ezenwajiaku
- Department of Medicine, Division of Medical Oncology, University of Miami Miller School of Medicine, Miami, Florida
| | - Paul Martin
- Department of Medicine, Division of Digestive Health and Liver Diseases, University of Miami Miller School of Medicine, Miami, Florida
| | - Patricia D. Jones
- Department of Medicine, Division of Digestive Health and Liver Diseases, University of Miami Miller School of Medicine, Miami, Florida
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida
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Shen Y, Bai X, Zhang Q, Liang X, Jin X, Zhao Z, Song W, Tan Q, Zhao R, Jia W, Gu S, Shi G, Zheng Z, Wei G, Wang Y, Fang T, Li Y, Wang Z, Yang Z, Guo S, Lin D, Wei F, Wang L, Sun X, Qin A, Xie L, Qiu Y, Bao W, Rahimian S, Singh M, Murad Y, Shang J, Chu M, Huang M, Ding J, Chen W, Ye Y, Chen Y, Li X, Liang T. Oncolytic virus VG161 in refractory hepatocellular carcinoma. Nature 2025; 641:503-511. [PMID: 40108464 DOI: 10.1038/s41586-025-08717-5] [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: 06/19/2024] [Accepted: 01/30/2025] [Indexed: 03/22/2025]
Abstract
Hepatocellular carcinoma remains a life-threatening malignancy with limited therapeutic options following the failure of second-line treatments1,2. Oncolytic viruses selectively replicate in and lyse cancer cells, releasing neoantigens and stimulating systemic antitumour immunity3, offering a potential therapeutic option. Here we present the results of a multicentre phase 1 clinical trial evaluating VG161, an engineered oncolytic herpes simplex virus that expresses IL-12, IL-15, IL-15Rα and a PD-1-PD-L1-blocking fusion protein4, for safety and efficacy in patients with advanced liver cancer. VG161 was well tolerated, with no dose-limiting toxicities observed, and it demonstrated promising efficacy by reshaping the tumour immune microenvironment and re-sensitizing tumours that were previously resistant to systemic treatments. Notably, we also found that patients who had previously been sensitive to checkpoint inhibitor therapy showed enhanced efficacy with VG161 treatment. Furthermore, we developed an efficacy-prediction model based on differentially expressed genes, which successfully identified patients who were likely to benefit from VG161 and predicted prolonged overall survival. These findings position VG161 as a promising third-line therapeutic option for refractory hepatocellular carcinoma. This provides a new avenue for treatment and advances the field of oncolytic virus-based immunotherapies. ClinicalTrials.gov registration: NCT04806464 .
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Affiliation(s)
- Yinan Shen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
| | - Xueli Bai
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
| | - Qi Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
| | - Xingmei Liang
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xinyan Jin
- Department of Ultrasound Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zeda Zhao
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
| | - Wei Song
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
| | - Qian Tan
- Shanghai Virogin Biotech, Shanghai, China
| | | | - William Jia
- Shanghai Virogin Biotech, Shanghai, China
- Virogin Biotech Canada, Richmond, British Columbia, Canada
- CNBG-Virogin Biotech (Shanghai), Shanghai, China
| | - Shanzhi Gu
- Department of Interventional Radiology, Hunan Cancer Hospital, Changsha, China
| | - Guoming Shi
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
| | | | - Guyue Wei
- Department of Ultrasound Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Youlei Wang
- Key Laboratory for Drug Evaluation and Clinical Research of Zhejiang Province, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Tian Fang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yuwei Li
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
| | - Zijun Wang
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
| | - Zifan Yang
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
| | - Sida Guo
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
| | - Danni Lin
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
| | - Fang Wei
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
| | - Lei Wang
- Department of Radiotherapy, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaoli Sun
- Department of Radiotherapy, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Aijun Qin
- Shanghai Virogin Biotech, Shanghai, China
| | - Longshen Xie
- CNBG-Virogin Biotech (Shanghai), Shanghai, China
| | - Yeting Qiu
- Shanghai Virogin Biotech, Shanghai, China
| | | | - Shah Rahimian
- Virogin Biotech Canada, Richmond, British Columbia, Canada
| | - Manu Singh
- Virogin Biotech Canada, Richmond, British Columbia, Canada
| | - Yanal Murad
- Virogin Biotech Canada, Richmond, British Columbia, Canada
| | | | - Min Chu
- Shanghai Virogin Biotech, Shanghai, China
| | | | - Jun Ding
- Shanghai Virogin Biotech, Shanghai, China
- Virogin Biotech Canada, Richmond, British Columbia, Canada
| | - Wei Chen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yufu Ye
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yiwen Chen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
| | - Xiang Li
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
| | - Tingbo Liang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China.
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Patresan J, Patel H, Chandrasekaran K, Reynolds G. Current Treatment Paradigm and Approach to Advanced Hepatocellular Carcinoma. Cureus 2024; 16:e75471. [PMID: 39791050 PMCID: PMC11717138 DOI: 10.7759/cureus.75471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/09/2024] [Indexed: 01/12/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common forms of primary liver cancer worldwide. Herein, we present a review article that provides a broad overview of the current landscape of HCC, including the etiology, potential risk factors, and molecular pathways that can serve as potential therapeutic targets. The risk factors tend to vary depending on the geographic distribution; hepatitis B-induced cirrhosis and HCC occur more frequently in Asia and Sub-Saharan Africa, whereas metabolic disorders are the culprits in Western Europe and the Americas. The exact molecular alterations that drive hepatocarcinogenesis have yet to be elucidated; however, a complex interplay exists between oxidative stress and chronic inflammation. Diagnostic modalities such as tri-phasic MRI or CT also have distinct patterns for HCC, which aid significantly in diagnosis. Furthermore, the review aims to highlight treatment strategies, including transplantation, locoregional radiation therapies, and interventional radiological techniques such as chemotherapy or radioembolization. Finally, systemic therapies will be discussed, taking advantage of molecular pathways that influence cellular proliferation and survival as well as immunotherapy.
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Affiliation(s)
- John Patresan
- Hematology and Oncology, Roger Williams Medical Center, Boston University School of Medicine, Providence, USA
| | - Harsh Patel
- Gastroenterology and Hepatology, New York-Presbyterian Brooklyn Methodist Hospital, Weill Cornell Medicine, Brooklyn, USA
| | - Karthik Chandrasekaran
- Internal Medicine and Gastroenterology, New York-Presbyterian Brooklyn Methodist Hospital, Weill Cornell Medicine, Brooklyn, USA
| | - Griffin Reynolds
- Hematology and Oncology, Roger Williams Medical Center, Boston University School of Medicine, Providence, USA
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4
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Feng J, Bin JL, Liao XW, Wu Y, Tang Y, Lu PZ, Zhu GZ, Cui QR, Dan YY, Yang GH, Li LX, Deng JH, Peng T, Hooi SC, Zhou J, Lu GD. The prognostic role of ACSL4 in postoperative adjuvant TACE-treated HCC: implications for therapeutic response and mechanistic insights. J Exp Clin Cancer Res 2024; 43:306. [PMID: 39563427 PMCID: PMC11575417 DOI: 10.1186/s13046-024-03222-5] [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: 07/28/2024] [Accepted: 11/01/2024] [Indexed: 11/21/2024] Open
Abstract
BACKGROUND The response of hepatocellular carcinoma (HCC) to transarterial chemoembolization (TACE) treatment and its underlying mechanisms remain elusive. This study investigates the role of enzymes involved in fatty acid activation, specifically Acyl-CoA synthetase long chain 4 (ACSL4), in HCC patients treated with postoperative adjuvant TACE (PA-TACE) and in nutrient-deprived HCC cells. METHODS We examined the expression of ACSL4 and its family members in HCC clinical samples and cell lines. The clinical significance of ACSL4, particularly regarding the prognosis of patients treated with PA-TACE, was assessed using two independent HCC cohorts. We further explored the role of ACSL4 in glucose starvation-induced cell death in HCC cells and xenograft mouse models. RESULTS Among the family members, ACSL4 is the most up-regulated enzyme, associated with poor survival in HCC patients, particularly in post-recurrent TACE-treated patients in a Singapore cohort. ACSL4 is essential for HCC cell survival in response to glucose starvation, rather than to hypoxia or to the combination of hypoxia with doxorubicin or cisplatin. ACSL4-mediated arachidonic acid (AA) metabolism supports mitochondrial β-oxidation and energy production. CCAAT/enhancer binding protein α (CEBPA) transcriptionally regulates ACSL4 by binding 3 motifs (-623 to -613, -1197 to -1187 and -1745 to -1735) of ACSL4 upstream promoter region, enhancing its pro-survival effects. Furthermore, canagliflozin (Cana), a clinical-approved drug for type 2 diabetes, mimics glucose starvation and inhibits the growth of ACSL4-low xenograft tumors. Moreover, high ACSL4 or CEBPA expressions correlate with increased recurrence susceptibility after PA-TACE in the China-Guangxi HCC cohort. CONCLUSIONS The CEBPA-ACSL4 pathway is critical in protecting HCC cells from glucose starvation-induced cell death, suggesting that ACSL4 and CEBPA could serve as valuable prognostic indicators and potential therapeutic targets in the context of PA-TACE treatment for HCC.
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Affiliation(s)
- Ji Feng
- School of Public Health, Fudan University, 130 Dong-An Road, Shanghai, 200032, China
- Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning, Guangxi, 530021, China
- Key Laboratory of Basic Research On Regional Diseases (Guangxi Medical University), Education Department of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, 530021, China
| | - Jin-Lian Bin
- Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Xi-Wen Liao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning, Guangxi, 530021, China
| | - Yong Wu
- Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Yue Tang
- Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Pei-Zhi Lu
- Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Guang-Zhi Zhu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning, Guangxi, 530021, China
| | - Qian-Ru Cui
- Department of Physiology, School of Preclinical Medicine, Guangxi Medical University, 22 Shuangyong Road, Nanning, Guangxi, 530021, China
| | - Yock Young Dan
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Guo-Huan Yang
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Li-Xin Li
- Department of Hepato-Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Jing-Huan Deng
- Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning, Guangxi, 530021, China.
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education; Guangxi Key Laboratory of High-Incidence-Tumor Prevention & Treatment, (Guangxi Medical University), Nanning, Guangxi, 530021, China.
| | - Shing Chuan Hooi
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 2 Medical Drive MD9, Singapore, 117593, Singapore.
| | - Jing Zhou
- Department of Physiology, School of Preclinical Medicine, Guangxi Medical University, 22 Shuangyong Road, Nanning, Guangxi, 530021, China.
| | - Guo-Dong Lu
- School of Public Health, Fudan University, 130 Dong-An Road, Shanghai, 200032, China.
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education; Guangxi Key Laboratory of High-Incidence-Tumor Prevention & Treatment, (Guangxi Medical University), Nanning, Guangxi, 530021, China.
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5
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Hua R, Zhao K, Xu Z, Zheng Y, Wu C, Zhang L, Teng Y, Wang J, Wang M, Hu J, Chen L, Yuan D, Dong W, Cheng X, Xia Y. Stratifin-mediated activation of AKT signaling and therapeutic targetability in hepatocellular carcinoma progression. CELL INSIGHT 2024; 3:100178. [PMID: 39027058 PMCID: PMC11254524 DOI: 10.1016/j.cellin.2024.100178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 05/14/2024] [Accepted: 05/15/2024] [Indexed: 07/20/2024]
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide and presents a significant threat to human health. Despite its prevalence, the underlying regulatory mechanisms of HCC remain unclear. In this study, we integrated RNA-seq datasets, proteome dataset and survival analysis and unveiled Stratifin (SFN) as a potential prognostic biomarker for HCC. SFN knockdown inhibited HCC progression in cell cultures and mouse models. Conversely, ectopic expression of Sfn in primary mouse HCC model accelerated HCC progression. Mechanistically, SFN acted as an adaptor protein, activating AKT1 signaling by fostering the interaction between PDK1 and AKT1, with the R56 and R129 sites on SFN proving to be crucial for this binding. In the syngeneic implantation model, the R56A/R129A mutant of SFN inhibited Akt signaling activation and impeded HCC growth. Additionally, peptide inhibitors designed based on the binding motif of AKT1 to SFN significantly inhibited HCC progression. In summary, our findings establish that SFN promotes HCC progression by activating AKT signaling through the R56 and R129 binding sites. This discovery opens new avenues for a promising therapeutic strategy for the treatment of HCC.
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Affiliation(s)
- Rong Hua
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, TaiKang Center for Life and Medical Sciences, TaiKang Medical School, Wuhan University, Wuhan, China
| | - Kaitao Zhao
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, TaiKang Center for Life and Medical Sciences, TaiKang Medical School, Wuhan University, Wuhan, China
| | - Zaichao Xu
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, TaiKang Center for Life and Medical Sciences, TaiKang Medical School, Wuhan University, Wuhan, China
| | - Yingcheng Zheng
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, TaiKang Center for Life and Medical Sciences, TaiKang Medical School, Wuhan University, Wuhan, China
| | - Chuanjian Wu
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, TaiKang Center for Life and Medical Sciences, TaiKang Medical School, Wuhan University, Wuhan, China
| | - Lu Zhang
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, TaiKang Center for Life and Medical Sciences, TaiKang Medical School, Wuhan University, Wuhan, China
| | - Yan Teng
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, TaiKang Center for Life and Medical Sciences, TaiKang Medical School, Wuhan University, Wuhan, China
| | - Jingjing Wang
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, TaiKang Center for Life and Medical Sciences, TaiKang Medical School, Wuhan University, Wuhan, China
| | - Mengfei Wang
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, TaiKang Center for Life and Medical Sciences, TaiKang Medical School, Wuhan University, Wuhan, China
| | - Jiayu Hu
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, TaiKang Center for Life and Medical Sciences, TaiKang Medical School, Wuhan University, Wuhan, China
| | - Lang Chen
- Department of Immunology, TaiKang Medical School, Wuhan University, Wuhan, China
| | - Detian Yuan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Wei Dong
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei, China
- Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei, China
| | - Xiaoming Cheng
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, TaiKang Center for Life and Medical Sciences, TaiKang Medical School, Wuhan University, Wuhan, China
- Wuhan University Center for Pathology and Molecular Diagnostics, Zhongnan Hospital of Wuhan University, Wuhan, China
- Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China
- Hubei Jiangxia Laboratory, Wuhan, China
| | - Yuchen Xia
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, TaiKang Center for Life and Medical Sciences, TaiKang Medical School, Wuhan University, Wuhan, China
- Hubei Jiangxia Laboratory, Wuhan, China
- Pingyuan Laboratory, Henan, China
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Lang D, Agarwal R, Goff LW, Heumann TR. Contemporary Systemic Therapy Approaches for Unresectable Hepatocellular Carcinoma. ADVANCES IN ONCOLOGY 2024; 4:233-246. [PMID: 38882259 PMCID: PMC11178263 DOI: 10.1016/j.yao.2024.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/18/2024]
Affiliation(s)
- Daenielle Lang
- Division of Hematology/Oncology, Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Rajiv Agarwal
- Division of Hematology/Oncology, Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Laura W Goff
- Division of Hematology/Oncology, Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Thatcher R Heumann
- Division of Hematology/Oncology, Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
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7
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Lang D, Agarwal R, Brown SA, Borgmann AJ, Lockney NA, Goff LW, Heumann TR. Multidisciplinary Care and Multimodal Treatment Approaches for Unresectable Hepatocellular Carcinoma. ADVANCES IN ONCOLOGY 2024; 4:247-262. [PMID: 38882260 PMCID: PMC11178262 DOI: 10.1016/j.yao.2024.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/18/2024]
Affiliation(s)
- Daenielle Lang
- Division of Hematology/Oncology, Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Rajiv Agarwal
- Division of Hematology/Oncology, Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Sara A Brown
- Department Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Anthony J Borgmann
- Department of Interventional Radiology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Natalie A Lockney
- Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Laura W Goff
- Division of Hematology/Oncology, Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Thatcher R Heumann
- Division of Hematology/Oncology, Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
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8
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Zhang Y, Yao B, Guo Y, Huang S, Liu J, Zhang Y, Liang C, Huang J, Tang Y, Wang X. Sorafenib reduces the production of epoxyeicosatrienoic acids and leads to cardiac injury by inhibiting CYP2J in rats. Biochem Pharmacol 2024; 223:116169. [PMID: 38548244 DOI: 10.1016/j.bcp.2024.116169] [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: 01/15/2024] [Revised: 03/15/2024] [Accepted: 03/25/2024] [Indexed: 04/22/2024]
Abstract
Sorafenib, an important cancer drug in clinical practice, has caused heart problems such as hypertension, myocardial infarction, and thrombosis. Although some mechanisms of sorafenib-induced cardiotoxicity have been proposed, there is still more research needed to reach a well-established definition of the causes of cardiotoxicity of sorafenib. In this report, we demonstrate that sorafenib is a potent inhibitor of the CYP2J enzyme. Sorafenib significantly inhibited the production of epoxyeicosatrienoic acids (EETs) in rat cardiac microsomes. The in vivo experimental results also showed that after the administration of sorafenib, the levels of 11,12-EET and 14,15-EET in rat plasma were significantly reduced, which was similar to the results of CYP2J gene knockout. Sorafenib decreased the levels of EETs, leading to abnormal expression of mitochondrial fusion and fission factors in heart tissue. In addition, the expression of mitochondrial energy metabolism factors (Pgc-1α, Pgc-1β, Ampk, and Sirt1) and cardiac mechanism factors (Scn5a and Prkag2) was significantly reduced, increasing the risk of arrhythmia and heart failure. Meanwhile, the increase in injury markers Anp, CK, and CK-MB further confirmed the cardiotoxicity of sorafenib. This study is of great significance for understanding the cardiotoxicity of sorafenib, and is also a model for studying the cardiotoxicity of other drugs that inhibit CYP2J activity.
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Affiliation(s)
- Yanfang Zhang
- Changning Maternity and Infant Health Hospital and School of Life Sciences, Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, China
| | - Bingyi Yao
- Changning Maternity and Infant Health Hospital and School of Life Sciences, Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, China
| | - Yuanqing Guo
- Changning Maternity and Infant Health Hospital and School of Life Sciences, Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, China
| | - Shengbo Huang
- Changning Maternity and Infant Health Hospital and School of Life Sciences, Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, China
| | - Jie Liu
- Changning Maternity and Infant Health Hospital and School of Life Sciences, Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, China
| | - Yuanjin Zhang
- Changning Maternity and Infant Health Hospital and School of Life Sciences, Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, China
| | - Chenmeizi Liang
- Changning Maternity and Infant Health Hospital and School of Life Sciences, Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, China
| | - Junze Huang
- Changning Maternity and Infant Health Hospital and School of Life Sciences, Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, China
| | - Yu Tang
- Changning Maternity and Infant Health Hospital and School of Life Sciences, Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, China
| | - Xin Wang
- Changning Maternity and Infant Health Hospital and School of Life Sciences, Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, China.
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Chen W, Hu Z, Li G, Zhang L, Li T. The State of Systematic Therapies in Clinic for Hepatobiliary Cancers. J Hepatocell Carcinoma 2024; 11:629-649. [PMID: 38559555 PMCID: PMC10981875 DOI: 10.2147/jhc.s454666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Accepted: 03/16/2024] [Indexed: 04/04/2024] Open
Abstract
Hepatobiliary cancer (HBC) includes hepatocellular carcinoma and biliary tract carcinoma (cholangiocarcinoma and gallbladder carcinoma), and its morbidity and mortality are significantly correlated with disease stage. Surgery is the cornerstone of curative therapy for early stage of HBC. However, a large proportion of patients with HBC are diagnosed with advanced stage and can only receive systemic treatment. According to the results of clinical trials, the first-line and second-line treatment programs are constantly updated with the improvement of therapeutic effectiveness. In order to improve the therapeutic effect, reduce the occurrence of drug resistance, and reduce the adverse reactions of patients, the treatment of HBC has gradually developed from single-agent therapy to combination. The traditional therapeutic philosophy proposed that patients with advanced HBC are only amenable to systematic therapies. With some encouraging clinical trial results, the treatment concept has been revolutionized, and patients with advanced HBC who receive novel systemic combination therapies with multi-modality treatment (including surgery, transplant, TACE, HAIC, RT) have significantly improved survival time. This review summarizes the treatment options and the latest clinical advances of HBC in each stage and discusses future direction, in order to inform the development of more effective treatments for HBC.
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Affiliation(s)
- Weixun Chen
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People’s Republic of China
| | - Zhengnan Hu
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People’s Republic of China
| | - Ganxun Li
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People’s Republic of China
| | - Lei Zhang
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People’s Republic of China
| | - Tao Li
- Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, People’s Republic of China
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10
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Luo X, He X, Zhang X, Zhao X, Zhang Y, Shi Y, Hua S. Hepatocellular carcinoma: signaling pathways, targeted therapy, and immunotherapy. MedComm (Beijing) 2024; 5:e474. [PMID: 38318160 PMCID: PMC10838672 DOI: 10.1002/mco2.474] [Citation(s) in RCA: 29] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 12/26/2023] [Accepted: 12/29/2023] [Indexed: 02/07/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer with a high mortality rate. It is regarded as a significant public health issue because of its complicated pathophysiology, high metastasis, and recurrence rates. There are no obvious symptoms in the early stage of HCC, which often leads to delays in diagnosis. Traditional treatment methods such as surgical resection, radiotherapy, chemotherapy, and interventional therapies have limited therapeutic effects for HCC patients with recurrence or metastasis. With the development of molecular biology and immunology, molecular signaling pathways and immune checkpoint were identified as the main mechanism of HCC progression. Targeting these molecules has become a new direction for the treatment of HCC. At present, the combination of targeted drugs and immune checkpoint inhibitors is the first choice for advanced HCC patients. In this review, we mainly focus on the cutting-edge research of signaling pathways and corresponding targeted therapy and immunotherapy in HCC. It is of great significance to comprehensively understand the pathogenesis of HCC, search for potential therapeutic targets, and optimize the treatment strategies of HCC.
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Affiliation(s)
- Xiaoting Luo
- Department of Radiation OncologyZhuhai People's HospitalZhuhai Hospital Affiliated with Jinan UniversityZhuhaiChina
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and TreatmentZhuhai People's HospitalZhuhai Hospital Affiliated with Jinan UniversityZhuhaiChina
| | - Xin He
- Department of Radiation OncologyZhuhai People's HospitalZhuhai Hospital Affiliated with Jinan UniversityZhuhaiChina
| | - Xingmei Zhang
- Department of NeurobiologySchool of Basic Medical SciencesSouthern Medical UniversityGuangzhouChina
| | - Xiaohui Zhao
- Department of Radiation OncologyZhuhai People's HospitalZhuhai Hospital Affiliated with Jinan UniversityZhuhaiChina
| | - Yuzhe Zhang
- Department of Radiation OncologyZhuhai People's HospitalZhuhai Hospital Affiliated with Jinan UniversityZhuhaiChina
| | - Yusheng Shi
- Department of Radiation OncologyZhuhai People's HospitalZhuhai Hospital Affiliated with Jinan UniversityZhuhaiChina
| | - Shengni Hua
- Department of Radiation OncologyZhuhai People's HospitalZhuhai Hospital Affiliated with Jinan UniversityZhuhaiChina
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11
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Kang MK, Song JE, Jang SY, Kim BS, Chung WJ, Lee C, Park SY, Tak WY, Kweon YO, Hwang JS, Jang BK, Lee YR, Park JG, on behalf of Daegu-Gyeongbuk Liver Study Group (DGLSG). The Clinical Significance of Myosteatosis in Survival Outcomes in Patients with Hepatocellular Carcinoma Treated with Sorafenib. Cancers (Basel) 2024; 16:454. [PMID: 38275895 PMCID: PMC10814239 DOI: 10.3390/cancers16020454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 01/11/2024] [Accepted: 01/19/2024] [Indexed: 01/27/2024] Open
Abstract
The role of body composition parameters in sorafenib-treated hepatocellular carcinoma (HCC) patients is still not fully elucidated. Here, we aimed to evaluate the impact of computed tomography (CT)-based body composition parameters on the survival of such patients. In this multicenter study, we analyzed the data of 245 sorafenib-treated HCC patients from January 2008 to December 2019. Sarcopenia, visceral obesity, and myosteatosis were defined by using cross-sectional CT images at the third lumbar vertebra level. The effects of these parameters on overall survival (OS) and progression-free survival (PFS) were evaluated. The median age was 67.0 years (interquartile range: 61.0-78.0 year), and 211 patients (86.1%) were male. The median OS and PFS were 7.9 months and 4.8 months, respectively. Vascular invasion (hazard ratio (HR), 1.727; 95% confidence interval (CI), 1.258-2.371; p = 0.001), extrahepatic metastasis (HR, 1.401; 95% CI, 1.028-1.908; p = 0.033), alpha-fetoprotein level > 200 ng/mL (HR, 1.559; 95% CI, 1.105-2.201; p = 0.012), and myosteatosis (HR, 1.814; 95% CI, 1.112-2.960; p = 0.017) were associated with OS. Patient mortality was significantly higher in the group with two or more risk factors than in the group with fewer risk factors. In conclusion, myosteatosis may be a novel prognostic CT-based radiological biomarker in sorafenib-treated HCC patients.
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Affiliation(s)
- Min Kyu Kang
- Department of Internal Medicine, Yeungnam University Hospital, College of Medicine, Yeungnam University, Daegu 42415, Republic of Korea;
| | - Jeong Eun Song
- Department of Internal Medicine, Daegu Catholic University Hospital, School of Medicine, Daegu Catholic University, Daegu 42415, Republic of Korea; (J.E.S.); (B.S.K.); (C.L.)
| | - Se Young Jang
- Department of Internal Medicine, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea; (S.Y.J.); (S.Y.P.); (W.Y.T.); (Y.O.K.)
| | - Byung Seok Kim
- Department of Internal Medicine, Daegu Catholic University Hospital, School of Medicine, Daegu Catholic University, Daegu 42415, Republic of Korea; (J.E.S.); (B.S.K.); (C.L.)
| | - Woo Jin Chung
- Department of Internal Medicine, Keimyung University Dongsan Hospital, School of Medicine, Keimyung University, Daegu 42601, Republic of Korea; (W.J.C.); (J.S.H.); (B.K.J.)
| | - Changhyeong Lee
- Department of Internal Medicine, Daegu Catholic University Hospital, School of Medicine, Daegu Catholic University, Daegu 42415, Republic of Korea; (J.E.S.); (B.S.K.); (C.L.)
| | - Soo Young Park
- Department of Internal Medicine, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea; (S.Y.J.); (S.Y.P.); (W.Y.T.); (Y.O.K.)
| | - Won Young Tak
- Department of Internal Medicine, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea; (S.Y.J.); (S.Y.P.); (W.Y.T.); (Y.O.K.)
| | - Young Oh Kweon
- Department of Internal Medicine, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea; (S.Y.J.); (S.Y.P.); (W.Y.T.); (Y.O.K.)
| | - Jae Seok Hwang
- Department of Internal Medicine, Keimyung University Dongsan Hospital, School of Medicine, Keimyung University, Daegu 42601, Republic of Korea; (W.J.C.); (J.S.H.); (B.K.J.)
| | - Byoung Kuk Jang
- Department of Internal Medicine, Keimyung University Dongsan Hospital, School of Medicine, Keimyung University, Daegu 42601, Republic of Korea; (W.J.C.); (J.S.H.); (B.K.J.)
| | - Yu Rim Lee
- Department of Internal Medicine, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea; (S.Y.J.); (S.Y.P.); (W.Y.T.); (Y.O.K.)
| | - Jung Gil Park
- Department of Internal Medicine, Yeungnam University Hospital, College of Medicine, Yeungnam University, Daegu 42415, Republic of Korea;
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Han S, Kim DY, Lim HY, Yoon JH, Ryoo BY, Kim Y, Kim K, Kim BY, Yi SY, Kim DS, Cho DY, Yu J, Kim S, Park JW. Sorafenib for 9,923 Patients with Hepatocellular Carcinoma: An Analysis from National Health Insurance Claim Data in South Korea. Gut Liver 2024; 18:116-124. [PMID: 37334671 PMCID: PMC10791511 DOI: 10.5009/gnl220406] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 01/18/2023] [Accepted: 01/26/2023] [Indexed: 06/20/2023] Open
Abstract
Background/Aims Sorafenib is the standard of care in the management of advanced hepatocellular carcinoma (HCC). The purpose of this study was to investigate the characteristics, treatment patterns and outcomes of sorafenib among HCC patients in South Korea. Methods This population-based retrospective, single-arm, observational study used the Korean National Health Insurance database to identify patients with HCC who received sorafenib between July 1, 2008, and December 31, 2014. A total of 9,923 patients were recruited in this study. Results Among 9,923 patients, 6,669 patients (68.2%) received loco-regional therapy prior to sorafenib, and 1,565 patients (15.8%) received combination therapy with concomitant sorafenib; 2,591 patients (26.1%) received rescue therapy after sorafenib, and transarterial chemoembolization was the most common modality applied in 1,498 patients (15.1%). A total of 3,591 patients underwent rescue therapy after sorafenib, and the median overall survival was 14.5 months compared to 4.6 months in 7,332 patients who received supportive care after sorafenib. The mean duration of sorafenib administration in all patients was 105.7 days; 7,023 patients (70.8%) received an initial dose of 600 to 800 mg. The longest survival was shown in patients who received the recommended dose of 800 mg, subsequently reduced to 400 mg (15.0 months). The second longest survival was demonstrated in patients with a starting dose of 800 mg, followed by a dose reduction to 400-600 mg (9.6 months). Conclusions Real-life data show that the efficacy of sorafenib seems similar to that observed in clinical trials, suggesting that appropriate subsequent therapy after sorafenib might prolong patient survival.
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Affiliation(s)
- Sojung Han
- Department of Internal Medicine, Uijeongbu Eulji Medical Center, Eulji University College of Medicine, Uijeongbu, Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Ho Yeong Lim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jung-Hwan Yoon
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Baek-Yeol Ryoo
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Yujeong Kim
- Health Insurance Review and Assessment, Wonju, Korea
| | - Kookhee Kim
- Health Insurance Review and Assessment, Wonju, Korea
| | - Bo Yeon Kim
- Health Insurance Review and Assessment, Wonju, Korea
| | - So Young Yi
- Health Insurance Review and Assessment, Wonju, Korea
| | - Dong-Sook Kim
- Health Insurance Review and Assessment, Wonju, Korea
| | - Do-Yeon Cho
- Health Insurance Review and Assessment, Wonju, Korea
| | - Jina Yu
- Health Insurance Review and Assessment, Wonju, Korea
| | - Suhyun Kim
- Health Insurance Review and Assessment, Wonju, Korea
| | - Joong-Won Park
- Center for Liver and Pancreatobiliary Cancer, National Cancer Center, Goyang, Korea
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Yan J, Wen Y, Deng M, Ye B, Liu X, Zhang L. Transarterial Chemoembolization Plus Sorafenib versus Transarterial Chemoembolization Alone for Advanced Hepatocellular Carcinoma: An Umbrella Review of Meta-Analyses and Systematic Reviews. J Hepatocell Carcinoma 2023; 10:1723-1733. [PMID: 37817915 PMCID: PMC10561755 DOI: 10.2147/jhc.s429352] [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] [Received: 07/06/2023] [Accepted: 09/27/2023] [Indexed: 10/12/2023] Open
Abstract
BACKGROUND Sorafenib is the standard treatment for most cases of advanced hepatocellular carcinoma (HCC), based on Western and Eastern clinical guidelines. Thus, an increasing number of transarterial chemoembolization (TACE) plus sorafenib combination therapies have been used in clinical practice. In addition, several systematic reviews and meta-analyses have explored the efficacy and safety of the combination of TACE and sorafenib. Therefore, we performed an umbrella review to summarize and evaluate these evidence-based studies. METHODS PubMed, Embase, Cochrane Library, and Web of Science databases were searched up to June 1, 2023. All meta-analyses that evaluated the effect of TACE plus sorafenib on HCC were considered eligible. The quality of the included meta-analyses was evaluated by AMSTAR2 (A Measurement Tool to Assess Systematic Reviews). The quality of evidence per association provided in the meta-analyses was rated using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE). This study was registered with PROSPERO (Registration ID: CRD42023420417). RESULTS We included 12 meta-analyses, including randomized clinical trials, cohort studies, and observational studies. A total of 44 associations with overall survival, survival rate, time to disease progression, overall response rate, disease control rate, and adverse events were evaluated in this umbrella review. The quality of most associations ranged from low to very low, indicating that flaws were significant in the current meta-analyses. CONCLUSION This umbrella review identified beneficial associations between TACE and sorafenib combination therapy in advanced HCC. However, owing to the low certainty of the evidence, clinicians should interpret our results with caution when applying them in clinical practice, and high-quality studies are required in the future to confirm our results.
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Affiliation(s)
- Jingxin Yan
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, Xining, People’s Republic of China
- Qinghai Province Key Laboratory of Hydatid Disease Research, Xining, People’s Republic of China
| | - Yonghao Wen
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, Xining, People’s Republic of China
- Department of Postgraduate, Qinghai University, Xining, People’s Republic of China
| | - Manjun Deng
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, Xining, People’s Republic of China
- Qinghai Province Key Laboratory of Hydatid Disease Research, Xining, People’s Republic of China
| | - Bin Ye
- Department of General Surgery, Rongxian People’s Hospital, Zigong, People’s Republic of China
| | - Xinlian Liu
- Department of Pathology and Pathophysiology, Chengdu Medical College, Chengdu, People’s Republic of China
| | - Lushun Zhang
- Department of Pathology and Pathophysiology, Chengdu Medical College, Chengdu, People’s Republic of China
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Waked I, Alsammany S, Tirmazy SH, Rasul K, Bani-Issa J, Abdel-Razek W, Omar A, Shafik A, Eid S, Abdelaal A, Hosni A, Esmat G. Multidisciplinary consensus recommendations for management of hepatocellular carcinoma in Middle East and North Africa region. Liver Int 2023; 43:2062-2077. [PMID: 37553777 DOI: 10.1111/liv.15685] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 06/30/2023] [Accepted: 07/20/2023] [Indexed: 08/10/2023]
Abstract
Hepatocellular carcinoma (HCC) is a growing health concern projected to cross over a million cases worldwide by 2025. HCC presents a significant burden of disease in Middle East and North African (MENA) countries due to a high prevalence of risk factors such as hepatitis C and B infections and rising incidence of non-alcoholic steatohepatitis and non-alcoholic fatty liver disease. In August 2022, an advisory meeting consisting of experts from 5 MENA countries was convened in an attempt to provide consensus recommendations on HCC screening, early diagnosis, current treatment modalities and unmet medical needs in the region. Data were collected from a pre-meeting survey questionnaire and responses analysed and presented during the advisory meeting. This review summarizes the evidence discussed at the meeting and provides expert recommendations on the management of HCC. The 2022 update of Barcelona clinic liver cancer (BCLC) staging and treatment strategy and its implementation in the MENA region was extensively discussed. A key consensus of the expert panel was that multidisciplinary care is crucial to effective patient management that results in better clinical outcomes and overall survival of the patient. The panel recommended the use of predictive and early response biomarkers to guide clinicians in arriving at more effective therapeutic decisions. The experts also emphasized the role of robust screening/surveillance systems, population-based registries, effective referral pathways and standardization of guidelines to ensure the successful management of HCC in the region.
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Affiliation(s)
- Imam Waked
- Department of Medicine, National Liver Institute, Menoufia University, Shebin El-Kom, Egypt
| | - Sherif Alsammany
- Department of Medical Oncology, King Abdullah Medical City, Mecca, KSA
| | | | - Kakil Rasul
- Department of Medical Oncology, GI Unit, National Centre for Cancer Care and Research, Doha, Qatar
| | - Jafar Bani-Issa
- Department of Interventional Radiology, King Hussein Cancer Center, Amman, Jordan
| | - Wael Abdel-Razek
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Shebin El-Kom, Egypt
| | - Ashraf Omar
- Department of Endemic Medicine and Hepato-Gastroentrology, Cairo University, Cairo, Egypt
| | - Amr Shafik
- Department of Clinical Oncology, Ain Shams University, Cairo, Egypt
| | - Salem Eid
- Department of Medical Oncology, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Amr Abdelaal
- Department of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, Ain Shams University, Cairo, Egypt
| | - Ahmed Hosni
- Department of Diagnostic and Interventional Radiology, Cairo University, Cairo, Egypt
| | - Gamal Esmat
- Department of Endemic Medicine and Hepato-Gastroentrology, Cairo University, Cairo, Egypt
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Nguyen DT, Nguyen DH, Nguyen VTH. Sorafenib as first-line treatment for patients with primary hepatocellular carcinoma: an outcome evaluation. J Int Med Res 2023; 51:3000605231179928. [PMID: 37314298 DOI: 10.1177/03000605231179928] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/15/2023] Open
Abstract
OBJECTIVE To evaluate the clinical outcomes following first-line treatment with sorafenib in patients with primary hepatocellular carcinoma (HCC). METHODS This retrospective cohort study enrolled patients with primary HCC that had been treated with sorafenib. Their data were collected from the hospital medical records database at three time-points: after three cycles, after six cycles and at the end of the sorafenib treatment regimen. The starting dose was 800 mg/day sorafenib but this could be reduced to 600 mg/day or 400 mg/day if patients developed adverse events (AEs). RESULTS A total of 98 patients participated in the study. Of these, nine (9.2%) had a partial response, 47 patients (48.0%) had stable disease and 42 patients (42.9%) had progressive disease. The overall disease control rate was 57.1% (56 of 98 patients). Median progression-free survival for the overall cohort was 4.7 months. The most common AEs were hand-foot skin reaction (49 of 98 patients; 50.0%), fatigue (41 of 98 patients; 41.8%), appetite loss (39 of 98 patients; 39.8%) and hepatotoxicity/transaminitis (24 of 98 patients; 24.5%). The majority of the AEs were toxicity grades 1 and 2. CONCLUSION Sorafenib as a first-line treatment for primary HCC patients provided survival benefits and the AEs were well tolerated by patients.
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Affiliation(s)
- Dung Thi Nguyen
- Department of On-demand GI Medical Oncology, Hanoi Oncology Hospital, Hanoi, Vietnam
| | - Duong Hoang Nguyen
- Department of On-demand GI Medical Oncology, Hanoi Oncology Hospital, Hanoi, Vietnam
| | - Van Thi Hong Nguyen
- Department of On-demand GI Medical Oncology, Hanoi Oncology Hospital, Hanoi, Vietnam
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Lazzaro A, Hartshorn KL. A Comprehensive Narrative Review on the History, Current Landscape, and Future Directions of Hepatocellular Carcinoma (HCC) Systemic Therapy. Cancers (Basel) 2023; 15:cancers15092506. [PMID: 37173972 PMCID: PMC10177076 DOI: 10.3390/cancers15092506] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 04/18/2023] [Accepted: 04/24/2023] [Indexed: 05/15/2023] Open
Abstract
We provide a comprehensive review of current approved systemic treatment strategies for advanced hepatocellular carcinoma (HCC), starting with the phase III clinical trial of sorafenib which was the first to definitively show a survival benefit. After this trial, there was an initial period of little progress. However, in recent years, an explosion of new agents and combinations of agents has resulted in a markedly improved outlook for patients. We then provide the authors' current approach to therapy, i.e., "How We Treat HCC". Promising future directions and important gaps in therapy that persist are finally reviewed. HCC is a highly prevalent cancer worldwide and the incidence is growing due not only to alcoholism, hepatitis B and C, but also to steatohepatitis. HCC, like renal cell carcinoma and melanoma, is a cancer largely resistant to chemotherapy but the advent of anti-angiogenic, targeted and immune therapies have improved survival for all of these cancers. We hope this review will heighten interest in the field of HCC therapies, provide a clear outline of the current data and strategy for treatment, and sensitize readers to new developments that are likely to emerge in the near future.
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Affiliation(s)
- Alexander Lazzaro
- Department of Medicine, Boston Medical Center, Boston, MA 02118, USA
| | - Kevan L Hartshorn
- Section of Hematology Oncology, Boston University Chobanian and Avedisian School of Medicine, Boston Medical Center, Boston, MA 02118, USA
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Farasati Far B, Rabie D, Hemati P, Fooladpanjeh P, Faal Hamedanchi N, Broomand Lomer N, Karimi Rouzbahani A, Naimi-Jamal MR. Unresectable Hepatocellular Carcinoma: A Review of New Advances with Focus on Targeted Therapy and Immunotherapy. LIVERS 2023; 3:121-160. [DOI: 10.3390/livers3010011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Abstract
With an expected incidence of more than 1 million cases by 2025, liver cancer remains a problem for world health. With over 90% of cases, hepatocellular carcinoma (HCC) is the most prevalent kind of liver cancer. In this review, we presented the range of experimental therapeutics for patients with advanced HCC, the successes and failures of new treatments, areas for future development, the evaluation of dose-limiting toxicity in different drugs, and the safety profile in patients with liver dysfunction related to the underlying chronic liver disease. In addition to the unmet demand for biomarkers to guide treatment decisions and the burgeoning fields of immunotherapy and systemic therapy in hepatocellular carcinoma, the development of old and new drugs, including their failures and current advancements, has been reviewed. This review aims to evaluate the updated optimal clinical treatment of unresectable hepatocellular carcinomas in clinical practice, mainly through targeted therapy. Although surgical treatment can significantly enhance the survival probability of early and intermediate-stage patients, it is unsuitable for most HCC patients due to a lack of donors. Due to their severe toxicity, the few first-line anti-HCC drugs, such as sorafenib, are often reserved for advanced HCC patients for whom other therapies have failed. The second-line drugs are usually alternatives for patients with intolerance or resistance. Consequently, the ongoing growth of possible preclinical drugs and studies on miRNAs, lncRNAs, and numerous other signaling pathway targets for developing novel drugs may introduce additional treatment prospects for HCC.
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Affiliation(s)
- Bahareh Farasati Far
- Department of Chemistry, Iran University of Science and Technology, Tehran 1684613114, Iran
| | - Dorsa Rabie
- Faculty of Pharmaceutical Chemistry, Tehran Medical Sciences, Islamic Azad University, Tehran 193951495, Iran
| | - Parisa Hemati
- Faculty of Pharmaceutical Chemistry, Tehran Medical Sciences, Islamic Azad University, Tehran 193951495, Iran
| | - Parastoo Fooladpanjeh
- Faculty of Pharmaceutical Chemistry, Tehran Medical Sciences, Islamic Azad University, Tehran 193951495, Iran
| | - Neda Faal Hamedanchi
- Faculty of Medicine, Islamic Azad University, Tehran Medical Sciences Branch, Tehran 193951495, Iran
| | - Nima Broomand Lomer
- Faculty of Medicine, Guilan University of Medical Sciences, Rasht 4314637758, Iran
| | - Arian Karimi Rouzbahani
- Student Research Committee, Lorestan University of Medical Sciences, Khorramabad 6718773654, Iran
- USERN Office, Lorestan University of Medical Sciences, Khorramabad 6718773654, Iran
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18
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Korean Liver Cancer Association (KLCA) and National Cancer Center (NCC) Korea. 2022 KLCA-NCC Korea practice guidelines for the management of hepatocellular carcinoma. JOURNAL OF LIVER CANCER 2023; 23:1-120. [PMID: 37384024 PMCID: PMC10202234 DOI: 10.17998/jlc.2022.11.07] [Citation(s) in RCA: 80] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Accepted: 11/07/2022] [Indexed: 06/30/2023]
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the fourth most common cancer among men in South Korea, where the prevalence of chronic hepatitis B infection is high in middle and old age. The current practice guidelines will provide useful and sensible advice for the clinical management of patients with HCC. A total of 49 experts in the fields of hepatology, oncology, surgery, radiology, and radiation oncology from the Korean Liver Cancer Association-National Cancer Center Korea Practice Guideline Revision Committee revised the 2018 Korean guidelines and developed new recommendations that integrate the most up-to-date research findings and expert opinions. These guidelines provide useful information and direction for all clinicians, trainees, and researchers in the diagnosis and treatment of HCC.
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Affiliation(s)
- Korean Liver Cancer Association (KLCA) and National Cancer Center (NCC) Korea
- Corresponding author: KLCA-NCC Korea Practice Guideline Revision Committee (KPGRC) (Committee Chair: Joong-Won Park) Center for Liver and Pancreatobiliary Cancer, Division of Gastroenterology, Department of Internal Medicine, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang 10408, Korea Tel. +82-31-920-1605, Fax: +82-31-920-1520, E-mail:
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Tampaki M, Papatheodoridis GV, Cholongitas E. Management of Hepatocellular Carcinoma in Decompensated Cirrhotic Patients: A Comprehensive Overview. Cancers (Basel) 2023; 15:1310. [PMID: 36831651 PMCID: PMC9954723 DOI: 10.3390/cancers15041310] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 02/14/2023] [Accepted: 02/16/2023] [Indexed: 02/22/2023] Open
Abstract
Primary liver cancer is the sixth most common cancer and the fourth leading cause of cancer-related death. Hepatocellular carcinoma (HCC) accounts for 75% of primary liver cancer cases, mostly on the basis of cirrhosis. However, the data and therapeutic options for the treatment of HCC in patients with decompensated cirrhosis are rather limited. This patient category is often considered to be in a terminal stage without the possibility of a specific treatment except liver transplantation, which is restricted by several criteria and liver donor shortages. Systemic treatments may provide a solution for patients with Child Pugh class B or C since they are less invasive. Although most of the existing trials have excluded patients with decompensated cirrhosis, there are increasing data from real-life settings that show acceptable tolerability and satisfying efficacy in terms of response. The data on the administration of locoregional treatments in such patients are also limited, but the overall survival seems to be potentially prolonged when patients are carefully selected, and close adverse event monitoring is applied. The aim of this review is to analyze the existing data regarding the administration of treatments in decompensated patients with HCC, evaluate the effect of therapy on overall survival and highlight the potential risks in terms of tolerability.
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Affiliation(s)
- Maria Tampaki
- Academic Department of Gastroenterology, General Hospital of Athens “Laiko”, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - George V. Papatheodoridis
- Academic Department of Gastroenterology, General Hospital of Athens “Laiko”, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Evangelos Cholongitas
- First Department of Internal Medicine, General Hospital of Athens “Laiko”, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
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20
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Hasan I, Loho IM, Setiawan PB, Djumhana A, Purnomo HD, Siregar L, Gani RA, Sulaiman AS, Lesmana CRA. Indonesian consensus on systemic therapies for hepatocellular carcinoma. Asia Pac J Clin Oncol 2023; 19:263-274. [PMID: 35599455 DOI: 10.1111/ajco.13768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 01/25/2022] [Accepted: 01/27/2022] [Indexed: 01/20/2023]
Abstract
Hepatocellular carcinoma (HCC) is a deadly cancer with a rising incidence in the last 20 years. Most patients are diagnosed late when curative treatment is no longer feasible. With the background of chronic liver disease in most patients, the management of HCC becomes more complicated, in which well-preserved liver function is a prerequisite for locoregional or systemic therapies. In 2008, sorafenib became the first systemic agent proven to provide survival benefit for patients with advanced-stage HCC. For nearly a decade, no treatment has succeeded in providing better results than sorafenib. However, numerous advances in systemic therapies have emerged in the last 5 years to fulfill the unmet needs of effective therapeutic options. Several agents have been approved for clinical use after positive results in phase III clinical trials, including lenvatinib, regorafenib, cabozantinib, ramucirumab, and lastly immune checkpoint inhibitor atezolizumab in combination with bevacizumab, a monoclonal antibody targeting the vascular endothelial growth factor. With various options available, knowledge on the clinical evidence of each drug, their safety profile, as well as the patient characteristics and preferences become mandatory in clinical decision making. The objective of this consensus is to help clinicians, health-care workers, and policy makers in providing best clinical care for HCC patients.
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Affiliation(s)
- Irsan Hasan
- Hepatobiliary Division, Department of Internal Medicine, Cipto Mangunkusumo National General Hospital, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Imelda Maria Loho
- Department of Gastroentero-Hepatology, "Dharmais" National Cancer Center Hospital, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Poernomo Boedi Setiawan
- Division of Gastroentero-Hepatology, Department of Internal Medicine, Soetomo General Hospital, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Ali Djumhana
- Division of Gastroentero-Hepatology, Department of Internal Medicine, Hasan Sadikin General Hospital, Faculty of Medicine, Universitas Padjajaran, Bandung, Indonesia
| | - Hery Djagat Purnomo
- Division of Gastroentero-Hepatology, Department of Internal Medicine, Kariadi General Hospital, Faculty of Medicine, Universitas Diponegoro, Semarang, Indonesia
| | - Lianda Siregar
- Department of Gastroentero-Hepatology, "Dharmais" National Cancer Center Hospital, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Rino Alvani Gani
- Hepatobiliary Division, Department of Internal Medicine, Cipto Mangunkusumo National General Hospital, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Andri Sanityoso Sulaiman
- Hepatobiliary Division, Department of Internal Medicine, Cipto Mangunkusumo National General Hospital, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Cosmas Rinaldi Adithya Lesmana
- Hepatobiliary Division, Department of Internal Medicine, Cipto Mangunkusumo National General Hospital, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
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21
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Butt NUH, Baytas SN. Advancements in Hepatocellular Carcinoma: Potential Preclinical Drugs and their Future. Curr Pharm Des 2023; 29:2-14. [PMID: 36529919 DOI: 10.2174/1381612829666221216114350] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 10/12/2022] [Accepted: 10/27/2022] [Indexed: 12/23/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the foremost causes of tumor-affiliated demises globally. The HCC treatment has undergone numerous developments in terms of both drug and non-drug treatments. The United States Food and Drug Administration (FDA) has authorized the usage of a variety of drugs for the treatment of HCC in recent years, involving multi-kinase inhibitors (lenvatinib, regorafenib, ramucirumab, and cabozantinib), immune checkpoint inhibitors (ICIs) (pembrolizumab and nivolumab), and combination therapies like atezolizumab along with bevacizumab. There are currently over a thousand ongoing clinical and preclinical studies for novel HCC drugs, which portrays a competent setting in the field. This review discusses the i. FDA-approved HCC drugs, their molecular targets, safety profiles, and potential disadvantages; ii. The intrial agents/drugs, their molecular targets, and possible benefits compared to alternatives, and iii. The current and future status of potential preclinical drugs with novel therapeutic targets for HCC. Consequently, existing drug treatments and novel strategies with their balanced consumption could ensure a promising future for a universal remedy of HCC in the near future.
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Affiliation(s)
- Noor-Ul-Huda Butt
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330, Ankara, Turkiye
| | - Sultan Nacak Baytas
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330, Ankara, Turkiye
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22
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Hosseini K, Beirami SM, Forouhandeh H, Vahed SZ, Eyvazi S, Ramazani F, Tarhriz V, Ardalan M. The role of circadian gene timeless in gastrointestinal cancers. GENE REPORTS 2022. [DOI: 10.1016/j.genrep.2022.101722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022]
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23
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2022 KLCA-NCC Korea Practice Guidelines for the Management of Hepatocellular Carcinoma. Korean J Radiol 2022; 23:1126-1240. [PMID: 36447411 PMCID: PMC9747269 DOI: 10.3348/kjr.2022.0822] [Citation(s) in RCA: 80] [Impact Index Per Article: 26.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 10/28/2022] [Indexed: 11/18/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the fourth most common cancer among men in South Korea, where the prevalence of chronic hepatitis B infection is high in middle and old age. The current practice guidelines will provide useful and sensible advice for the clinical management of patients with HCC. A total of 49 experts in the fields of hepatology, oncology, surgery, radiology, and radiation oncology from the Korean Liver Cancer Association-National Cancer Center Korea Practice Guideline Revision Committee revised the 2018 Korean guidelines and developed new recommendations that integrate the most up-to-date research findings and expert opinions. These guidelines provide useful information and direction for all clinicians, trainees, and researchers in the diagnosis and treatment of HCC.
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24
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Damaskos C, Garmpis N, Dimitroulis D, Garmpi A, Psilopatis I, Sarantis P, Koustas E, Kanavidis P, Prevezanos D, Kouraklis G, Karamouzis MV, Marinos G, Kontzoglou K, Antoniou EA. Targeted Therapies for Hepatocellular Carcinoma Treatment: A New Era Ahead-A Systematic Review. Int J Mol Sci 2022; 23:14117. [PMID: 36430594 PMCID: PMC9698799 DOI: 10.3390/ijms232214117] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 11/10/2022] [Accepted: 11/11/2022] [Indexed: 11/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) remains one of the most common malignancies and the third cause of cancer-related death worldwide, with surgery being the best prognostic tool. Among the well-known causative factors of HCC are chronic liver virus infections, chronic virus hepatitis B (HBV) and chronic hepatitis virus C (HCV), aflatoxins, tobacco consumption, and non-alcoholic liver disease (NAFLD). There is a need for the development of efficient molecular markers and alternative therapeutic targets of great significance. In this review, we describe the general characteristics of HCC and present a variety of targeted therapies that resulted in progress in HCC therapy.
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Affiliation(s)
- Christos Damaskos
- Renal Transplantation Unit, Laiko General Hospital, 11527 Athens, Greece
- Nikolaos Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Nikolaos Garmpis
- Nikolaos Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Dimitrios Dimitroulis
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Anna Garmpi
- First Department of Propedeutic Internal Medicine, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Iason Psilopatis
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt—Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Panagiotis Sarantis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Evangelos Koustas
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Prodromos Kanavidis
- Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | | | - Gregory Kouraklis
- Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Michail V. Karamouzis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Georgios Marinos
- Department of Hygiene, Epidemiology and Medical Statistics, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Konstantinos Kontzoglou
- Nikolaos Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Efstathios A. Antoniou
- Nikolaos Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
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25
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Vogel A, Meyer T, Sapisochin G, Salem R, Saborowski A. Hepatocellular carcinoma. Lancet 2022; 400:1345-1362. [PMID: 36084663 DOI: 10.1016/s0140-6736(22)01200-4] [Citation(s) in RCA: 1130] [Impact Index Per Article: 376.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 05/31/2022] [Accepted: 06/15/2022] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma is one of the most common cancers worldwide and represents a major global health-care challenge. Although viral hepatitis and alcohol remain important risk factors, non-alcoholic fatty liver disease is rapidly becoming a dominant cause of hepatocellular carcinoma. A broad range of treatment options are available for patients with hepatocellular carcinoma, including liver transplantation, surgical resection, percutaneous ablation, and radiation, as well as transarterial and systemic therapies. As such, clinical decision making requires a multidisciplinary team that longitudinally adapts the individual treatment strategy according to the patient's tumour stage, liver function, and performance status. With the approval of new first-line agents and second-line agents, as well as the establishment of immune checkpoint inhibitor-based therapies as standard of care, the treatment landscape of advanced hepatocellular carcinoma is more diversified than ever. Consequently, the outlook for patients with hepatocellular carcinoma has improved. However, the optimal sequencing of drugs remains to be defined, and predictive biomarkers are urgently needed to inform treatment selection. In this Seminar, we present an update on the causes, diagnosis, molecular classification, and treatment of hepatocellular carcinoma.
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Affiliation(s)
- Arndt Vogel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
| | - Tim Meyer
- Research Department of Oncology, UCL Cancer Institute, University College London, Royal Free Hospital, London, UK
| | - Gonzalo Sapisochin
- Abdominal Transplant & HPB Surgical Oncology, University Health Network, University of Toronto, ON, Canada
| | - Riad Salem
- Department of Radiology, Northwestern University, Chicago, IL, USA
| | - Anna Saborowski
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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26
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2022 KLCA-NCC Korea practice guidelines for the management of hepatocellular carcinoma. Clin Mol Hepatol 2022; 28:583-705. [PMID: 36263666 PMCID: PMC9597235 DOI: 10.3350/cmh.2022.0294] [Citation(s) in RCA: 174] [Impact Index Per Article: 58.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 09/23/2022] [Indexed: 01/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the fourth most common cancer among men in South Korea, where the prevalence of chronic hepatitis B infection is high in middle and old age. The current practice guidelines will provide useful and sensible advice for the clinical management of patients with HCC. A total of 49 experts in the fields of hepatology, oncology, surgery, radiology, and radiation oncology from the Korean Liver Cancer Association-National Cancer Center Korea Practice Guideline Revision Committee revised the 2018 Korean guidelines and developed new recommendations that integrate the most up-to-date research findings and expert opinions. These guidelines provide useful information and direction for all clinicians, trainees, and researchers in the diagnosis and treatment of HCC.
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27
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A Review of Current and Emerging Therapies for Advanced Hepatocellular Carcinoma. Curr Oncol 2022; 29:6445-6462. [PMID: 36135076 PMCID: PMC9498097 DOI: 10.3390/curroncol29090507] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 09/04/2022] [Accepted: 09/05/2022] [Indexed: 11/18/2022] Open
Abstract
Hepatocellular carcinoma remains a leading cause of cancer-related deaths worldwide. Liver disease including cirrhosis and viral hepatitis remains among the leading causes of hepatocellular carcinoma and despite increased screening, many patients are diagnosed in the advanced stages precluding them from locoregional therapy. Therapeutic agents for advanced hepatocellular carcinoma were limited to Sorafenib for several years; however, with the emergence of molecular targeted therapies including tyrosine kinase inhibitors and vascular endothelial growth factor inhibitors, in addition to immunotherapies, the way hepatocellular carcinoma is treated has changed significantly. In this review, we summarize the key clinical trials that lead to the approval of these agents for systemic treatment of hepatocellular carcinoma and discuss the preferred sequence of treatment options as well as prospective studies for management of hepatocellular carcinoma.
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28
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Borde T, Nezami N, Laage Gaupp F, Savic LJ, Taddei T, Jaffe A, Strazzabosco M, Lin M, Duran R, Georgiades C, Hong K, Chapiro J. Optimization of the BCLC Staging System for Locoregional Therapy for Hepatocellular Carcinoma by Using Quantitative Tumor Burden Imaging Biomarkers at MRI. Radiology 2022; 304:228-237. [PMID: 35412368 PMCID: PMC9270683 DOI: 10.1148/radiol.212426] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Background Patients with intermediate- and advanced-stage hepatocellular carcinoma (HCC) represent a highly heterogeneous patient collective with substantial differences in overall survival. Purpose To evaluate enhancing tumor volume (ETV) and enhancing tumor burden (ETB) as new criteria within the Barcelona Clinic Liver Cancer (BCLC) staging system for optimized allocation of patients with intermediate- and advanced-stage HCC to undergo transarterial chemoembolization (TACE). Materials and Methods In this retrospective study, 682 patients with HCC who underwent conventional TACE or TACE with drug-eluting beads from January 2000 to December 2014 were evaluated. Quantitative three-dimensional analysis of contrast-enhanced MRI was performed to determine thresholds of ETV and ETB (ratio of ETV to normal liver volume). Patients with ETV below 65 cm3 or ETB below 4% were reassigned to BCLC Bn, whereas patients with ETV or ETB above the determined cutoffs were restratified or remained in BCLC Cn by means of stepwise verification of the median overall survival (mOS). Results This study included 494 patients (median age, 62 years [IQR, 56-71 years]; 401 men). Originally, 123 patients were classified as BCLC B with mOS of 24.3 months (95% CI: 21.4, 32.9) and 371 patients as BCLC C with mOS of 11.9 months (95% CI: 10.5, 14.8). The mOS of all included patients (including the BCLC B and C groups) was 15 months (95% CI: 12.3, 17.2). A total of 152 patients with BCLC C tumors were restratified into a new BCLC Bn class, in which the mOS was then 25.1 months (95% CI: 21.8, 29.7; P < .001). The mOS of the remaining patients (ie, BCLC Cn group) (n = 222; ETV ≥65 cm3 or ETB ≥4%) was 8.4 months (95% CI: 6.1, 11.2). Conclusion Substratification of patients with intermediate- and advanced-stage hepatocellular carcinoma according to three-dimensional quantitative tumor burden identified patients with a survival benefit from transarterial chemoembolization before therapy. © RSNA, 2022 Online supplemental material is available for this article.
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29
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Huang KW, Lee PC, Chao Y, Su CW, Lee IC, Lan KH, Chu CJ, Hung YP, Chen SC, Hou MC, Huang YH. Durable objective response to sorafenib and role of sequential treatment in unresectable hepatocellular carcinoma. Ther Adv Med Oncol 2022; 14:17588359221099401. [PMID: 35646162 PMCID: PMC9134461 DOI: 10.1177/17588359221099401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 04/21/2022] [Indexed: 11/16/2022] Open
Abstract
Background The response rate to sorafenib is limited for unresectable hepatocellular carcinoma (HCC). Little is known about the long-term outcomes of objective responders. The role of second-line therapies on the survival of sorafenib-responders is unclear. We aimed to delineate the long-term outcomes and the role of subsequent treatment after responding to sorafenib. Methods From September 2012 to December 2019, 922 patients who received sorafenib treatment for unresectable HCC were retrospectively reviewed. Of these, 21 (2.3%) achieved a complete response (CR) and 54 (5.9%) had a partial response (PR) based on mRECIST criteria. Factors associated with survivals were analyzed. Results During the median follow-up of 35.3 months, the median duration of response was 18.3 months (range: 2.3-45.5) for patients achieving CR and 10.0 months (range: 1.9-60.3) for PR. The median overall survival (OS) was 39.5 months [95% confidence interval (CI): 28.4-50.5] including values not yet estimable for CR and 25.8 months for PR. Patients who experienced treatment-related adverse events (TRAEs) had better median OS than those without (44.9 versus 18.1 months, p = 0.003). Eventually, 53 patients developed tumor progression; 30 patients received second-line systemic treatment including nivolumab (n = 8), regorafenib (n = 15), and chemotherapy (n = 7). Sorafenib-nivolumab sequential therapy provided the best median OS versus sorafenib-regorafenib and sorafenib-chemotherapy in these patients (55.8, 39.5, and 25.5 months), respectively. Conclusions The response is durable for advanced HCC patients with CR or PR to sorafenib. Subsequent immunotherapy seems to provide the best survival. This information is important for characterizing outcomes of sorafenib-responders and the choice of sequential treatment.
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Affiliation(s)
- Kuo-Wei Huang
- Division of Gastroenterology and Hepatology,
Department of Medicine, Taipei Veterans General Hospital, Taipei
- Department of Medicine, Taipei City Hospital
Yang-Ming branch, Taipei
| | - Pei-Chang Lee
- Division of Gastroenterology and Hepatology,
Department of Medicine, Taipei Veterans General Hospital, Taipei
- School of Medicine, National Yang Ming Chiao
Tung University, Taipei
| | - Yee Chao
- Department of Oncology, Taipei Veterans General
Hospital, Taipei
| | - Chien-Wei Su
- Division of Gastroenterology and Hepatology,
Department of Medicine, Taipei Veterans General Hospital, Taipei
- School of Medicine, National Yang Ming Chiao
Tung University, Taipei
| | - I-Cheng Lee
- Division of Gastroenterology and Hepatology,
Department of Medicine, Taipei Veterans General Hospital, Taipei
- School of Medicine, National Yang Ming Chiao
Tung University, Taipei
| | - Keng-Hsin Lan
- Division of Gastroenterology and Hepatology,
Department of Medicine Taipei Veterans General Hospital, Taipei
- Institute of Pharmacology, School of Medicine,
National Yang Ming Chiao Tung University, Taipei
| | - Chi-Jen Chu
- Division of Gastroenterology and Hepatology,
Department of Medicine, Taipei Veterans General Hospital, Taipei
- School of Medicine, National Yang Ming Chiao
Tung University, Taipei
| | - Yi-Ping Hung
- Department of Oncology, Taipei Veterans
General Hospital, Taipei
- School of Medicine, National Yang Ming Chiao
Tung University, Taipei
| | - San-Chi Chen
- Institute of Clinical Medicine, School of
Medicine, National Yang Ming Chiao Tung University, Taipei
- Department of Oncology, Taipei Veterans
General Hospital, Taipei
| | - Ming-Chih Hou
- Division of Gastroenterology and Hepatology,
Department of Medicine, Taipei Veterans General Hospital, Taipei
- School of Medicine, National Yang Ming Chiao
Tung University, Taipei
| | - Yi-Hsiang Huang
- Division of Gastroenterology and Hepatology,
Department of Medicine, Taipei Veterans General Hospital, Taipei
- Institute of Clinical Medicine, School of
Medicine, National Yang Ming Chiao Tung University, No.201, Sec. 2, Shipai
Road, Beitou District, 11217 Taipei
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30
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Famularo S, Donadon M, Cipriani F, Giuliante F, Ferri S, Celsa C, Ferrero A, Foschi FG, Baiocchi GL, Biasini E, Campani C, Valle RD, Pelizzaro F, Baroni GS, Raimondo G, Mega A, Chiarelli M, Maestri M, Gasbarrini A, Jovine E, Grazi GL, Rapaccini GL, Ruzzenente A, Morisco F, Sacco R, Memeo R, Crespi M, Antonucci A, Bernasconi DP, Romano F, Griseri G, Aldrighetti L, Torzilli G, Trevisani F. Hepatectomy Versus Sorafenib in Advanced Nonmetastatic Hepatocellular Carcinoma: A Real-life Multicentric Weighted Comparison. Ann Surg 2022; 275:743-752. [PMID: 35081572 DOI: 10.1097/sla.0000000000005373] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
OBJECTIVE The aim of the study was to compare SURG vs SOR regarding the OS and progression-free survival (PFS) in a real-world clinical scenario. BACKGROUND DATA The treatment for advanced nonmetastatic HCC belonging to the Barcelona Clinic Liver Cancer stage C (BCLC C) is still controversial. METHODS BCLC C patients without extrahepatic spread and tumoral invasion of the main portal trunk were considered. Surgical patients were obtained from the HE.RC.O.LE.S. Register, whereas sorafenib patients were obtained from the ITA.LI.CA register The inverse probability weighting (IPW) method was adopted to balance the confounders between the 2 groups. RESULTS Between 2008 and 2019, 478 patients were enrolled: 303 in SURG and 175 in SOR group. Eastern Cooperative Oncological Group Performance Status (ECOG-PS), presence of cirrhosis, steatosis, Child-Pugh grade, hepatitis B virus and hepatitis C virus, alcohol intake, collateral veins, bilobar disease, localization of the tumor thrombus, number of nodules, alpha-fetoprotein, age, and Charlson Comorbidity index were weighted by IPW to create two balanced pseudo-populations: SURG = 374 and SOR = 263. After IPW, 1-3-5 years OS was 83.6%, 68.1%, 55.9% for SURG, and 42.3%, 17.8%, 12.8% for SOR (P < 0.001). Similar trends were observed after subgrouping patients by ECOG-PS = 0 and ECOG-PS >0, and by the intrahepatic location of portal vein invasion. At Cox regression, sorafenib treatment (hazard ratio 4.436; 95% confidence interval 3.19-6.15; P < 0.001) and Charlson Index (hazard ratio 1.162; 95% confidence interval 1.06-1.27; P = 0.010) were the only independent predictors of mortality. PFS at 1-3-5 years were 65.9%, 40.3%, 24.3% for SURG and 21.6%, 3.5%, 2.9% for SOR (P = 0.007). CONCLUSIONS In BCLC C patients without extrahepatic spread but with intrahepatic portal invasion, liver resection, if feasible, was followed by better OS and PFS compared with sorafenib.
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Affiliation(s)
- Simone Famularo
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
- Department of Hepatobiliary and General Surgery, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
- School of Medicine and Surgery, University of Milan-Bicocca, Department of Surgery, San Gerardo Hospital, Monza, Italy
| | - Matteo Donadon
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
- Department of Hepatobiliary and General Surgery, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Federica Cipriani
- Hepatobiliary Surgery Division, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Felice Giuliante
- Hepatobiliary Surgery Unit, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Catholic University of the Sacred Heart, Rome, Italy
| | - Silvia Ferri
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Ciro Celsa
- Division of Gastroenterology and Hepatology, Department Promozione della Salute, Materno Infantile, Medicina Interna e Specialistica di Eccellenza (PROMISE), University of Palermo, Palermo, Italy
| | - Alessandro Ferrero
- Department of General and Oncological Surgery, Mauriziano Hospital "Umberto I," Turin, Italy
| | | | - Gian Luca Baiocchi
- Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Elisabetta Biasini
- Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Claudia Campani
- Internal Medicine and Hepatology Unit, Department of Experimental and Clinical Medicine, University of Firenze, Florence, Italy
| | | | - Filippo Pelizzaro
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, Padua University, Padua, Italy
| | | | - Giovanni Raimondo
- Division of Clinical and Molecular Hepatology, University of Messina, Messina, Italy
| | - Andrea Mega
- Division of Gastroenterology, Bolzano Regional Hospital, Bolzano, Italy
| | - Marco Chiarelli
- Department of Emergency and Robotic Surgery, ASST Lecco, Lecco, Italy
| | - Marcello Maestri
- Unit of General Surgery 1, University of Pavia and Foundation IRCCS Policlinico San Matteo, Pavia, Italy
| | - Antonio Gasbarrini
- Division of Internal Medicine and Gastroenterology, Policlinico Gemelli, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Elio Jovine
- Alma Mater Studiorum, University of Bologna, AOU Sant'Orsola Malpighi, IRCCS at Maggiore Hospital, Bologna, Italy
| | - Gian Luca Grazi
- Division of Hepatobiliarypancreatic Unit, IRCCS - Regina Elena National Cancer Institute, Rome, Italy
| | - Gian Ludovico Rapaccini
- Division of Internal Medicine and Gastroenterology, Complesso Integrato Columbus, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Andrea Ruzzenente
- Division of General and Hepatobiliary Surgery, Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, Verona, Italy
| | - Filomena Morisco
- Gastroenterology Unit, Department of Clinical Medicine and Surgery, University of Napoli "Federico II," Napoli, Italy
| | - Rodolfo Sacco
- Gastroenterology and Digestive Endoscopy Unit, Foggia University Hospital, Foggia, Italy
| | - Riccardo Memeo
- Department of Hepato-Pancreatic-Biliary Surgery, Miulli Hospital, Bari, Italy
| | | | | | - Davide P Bernasconi
- Center of Biostatistics for Clinical Epidemiology, School of Medicine and Surgery, University of Milan - Bicocca, Monza, Italy
| | - Fabrizio Romano
- School of Medicine and Surgery, University of Milan-Bicocca, Department of Surgery, San Gerardo Hospital, Monza, Italy
| | - Guido Griseri
- HPB Surgical Unit, San Paolo Hospital, Savona, Italy
| | - Luca Aldrighetti
- Hepatobiliary Surgery Division, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Guido Torzilli
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
- Department of Hepatobiliary and General Surgery, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Franco Trevisani
- IRCCS Azienda Ospedaliero-universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, Semeiotics Unit, Alma Mater Studiorum-University of Bologna, Bologna, Italy
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31
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Ostwal V, Ramaswamy A, Gota V, Bhargava PG, Srinivas S, Shriyan B, Jadhav S, Goel M, Patkar S, Mandavkar S, Naughane D, Daddi A, Nashikkar C, Shetty N, Ankathi SK, Banavali SD. Phase I Study Evaluating Dose De-escalation of Sorafenib with Metformin and Atorvastatin in Hepatocellular Carcinoma (SMASH). Oncologist 2022; 27:165-e222. [PMID: 35274724 PMCID: PMC8914502 DOI: 10.1093/oncolo/oyab008] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 01/14/2022] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND This phase I dose de-escalation study aimed to assess the tolerability, safety, pharmacokinetics (PK), and efficacy of sequentially decreasing doses of sorafenib in combination (SAM) with atorvastatin (A, 10 mg) and metformin (M, 500 mg BD) in patients with advanced hepatocellular carcinoma (HCC). METHODS Patients were enrolled in 1 of 4 sequential cohorts (10 patients each) of sorafenib doses (800 mg, 600 mg. 400 mg, and 200 mg) with A and M. Progression from one level to the next was based on prespecified minimum disease stabilization (at least 4/10) and upper limits of specific grade 3-5 treatment-related adverse events (TRAE). RESULTS The study was able to progress through all 4 dosing levels of sorafenib by the accrual of 40 patients. Thirty-eight (95%) patients had either main portal vein thrombosis or/and extra-hepatic disease. The most common grade 3-5 TRAEs were hand-foot-syndrome (grade 2 and grade 3) in 3 (8%) and transaminitis in 2 (5%) patients, respectively. The plasma concentrations of sorafenib peaked at 600 mg dose, and the concentration threshold of 2400 ng/mL was associated with higher odds of achieving time to exposure (TTE) concentrations >75% centile (odds ratio [OR] = 10.0 [1.67-44.93]; P = .01). The median overall survival for patients without early hepatic decompensation (n = 31) was 8.9 months (95% confidence interval [CI]: 3.2-14.5 months). CONCLUSION The SAM combination in HCC patients with predominantly unfavorable baseline disease characteristics showed a marked reduction in sorafenib-related side effects. Studies using sorafenib 600 mg per day in this combination along with sorafenib drug level monitoring can be evaluated in further trials.(Trial ID: CTRI/2018/07/014865).
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Affiliation(s)
- Vikas Ostwal
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Anant Ramaswamy
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Vikram Gota
- Department of Clinical Pharmacology, ACTREC, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Prabhat G Bhargava
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Sujay Srinivas
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Bharati Shriyan
- Department of Clinical Pharmacology, ACTREC, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Shraddha Jadhav
- Department of Clinical Pharmacology, ACTREC, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Mahesh Goel
- Gastrointestinal and HPB Surgery, Department of Surgical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Shraddha Patkar
- Gastrointestinal and HPB Surgery, Department of Surgical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Sarika Mandavkar
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Deepali Naughane
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Anuprita Daddi
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Chaitali Nashikkar
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Nitin Shetty
- Department of Radiodiagnosis, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Suman Kumar Ankathi
- Department of Radiodiagnosis, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Shripad D Banavali
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
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Jia G, Van Valkenburgh J, Chen AZ, Chen Q, Li J, Zuo C, Chen K. Recent advances and applications of microspheres and nanoparticles in transarterial chemoembolization for hepatocellular carcinoma. WILEY INTERDISCIPLINARY REVIEWS. NANOMEDICINE AND NANOBIOTECHNOLOGY 2022; 14:e1749. [PMID: 34405552 PMCID: PMC8850537 DOI: 10.1002/wnan.1749] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 07/22/2021] [Accepted: 07/28/2021] [Indexed: 12/15/2022]
Abstract
Transarterial chemoembolization (TACE) is a recommended treatment for patients suffering from intermediate and advanced hepatocellular carcinoma (HCC). As compared to the conventional TACE, drug-eluting bead TACE demonstrates several advantages in terms of survival, treatment response, and adverse effects. The selection of embolic agents is critical to the success of TACE. Many studies have been performed on the modification of the structure, size, homogeneity, biocompatibility, and biodegradability of embolic agents. Continuing efforts are focused on efficient loading of versatile chemotherapeutics, controlled sizes for sufficient occlusion, real-time detection intra- and post-procedure, and multimodality imaging-guided precise treatment. Here, we summarize recent advances and applications of microspheres and nanoparticles in TACE for HCC. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.
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Affiliation(s)
- Guorong Jia
- Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
- Department of Nuclear Medicine, Changhai Hospital of Shanghai, Shanghai, China
| | - Juno Van Valkenburgh
- Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Austin Z. Chen
- Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Quan Chen
- Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Jindian Li
- Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Changjing Zuo
- Department of Nuclear Medicine, Changhai Hospital of Shanghai, Shanghai, China
| | - Kai Chen
- Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
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Park D. Fenbendazole Suppresses Growth and Induces Apoptosis of Actively Growing H4IIE Hepatocellular Carcinoma Cells via p21-Mediated Cell-Cycle Arrest. Biol Pharm Bull 2022; 45:184-193. [PMID: 35110505 DOI: 10.1248/bpb.b21-00697] [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: 12/22/2022]
Abstract
Bendimidazole anthelmintics (BAs) have gained interest for their anticancer activity. The anticancer activity is mediated via multiple intracellular changes, which are not consistent under different conditions even in the same cells. We investigated the anticancer activity of fenbendazole (FZ, one of BAs) under two different growth conditions. The growth rate of H4IIE cells was dose-dependently decreased by FZ only in actively growing cells but not in fully confluent quiescent cells. Apoptosis-associated changes were also induced by FZ in actively growing cells. Markers of autophagy were not changed by FZ. The number of cells was markedly increased in sub-G1 phase but decreased in S- and G2/M phases by FZ. FZ up-regulated p21 (an inhibitor of cyclin-CDK) but suppressed the expression of cell cycle-promoting proteins (cyclin D1 and cyclin B1). FZ did not affect integrin αV or n-cadherin expression as well as cell migration. Glycolytic changes (glucose consumption and lactate production) and the generation of reactive oxygen species (ROS) were not affected by FZ. Although the activity of mitogen-activated protein kinases (MAPKs) was altered by FZ, the inhibition of MAPKs did not affect the pro-apoptotic activity of FZ. Taken together, FZ selectively suppressed the growth of cells via p21-mediated cell cycle arrest at G1/S and G2/M, and resulted in apoptosis only in actively growing cells but not in quiescent cells. Glucose metabolism, ROS generation, and MAPKs are unlikely targets of FZ at least in H4IIE rat hepatocellular carcinoma cells used in this study.
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Affiliation(s)
- Deokbae Park
- Department of Histology, School of Medicine, Institute of Medical Science, Jeju National University
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34
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Patidar Y, Chandel K, Condati NK, Srinivasan SV, Mukund A, Sarin SK. Transarterial Chemoembolization (TACE) Combined With Sorafenib versus TACE in Patients With BCLC Stage C Hepatocellular Carcinoma - A Retrospective Study. J Clin Exp Hepatol 2022; 12:745-754. [PMID: 35677519 PMCID: PMC9168730 DOI: 10.1016/j.jceh.2021.12.009] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Accepted: 12/14/2021] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVE Advanced-stage hepatocellular carcinoma is a heterogeneous group with limited treatment options. TACE has been advocated recently by various study groups. The purpose of this study was to evaluate if TACE in combination with sorafenib, as well as TACE alone, was safe and efficacious in treating BCLC stage C HCC. METHODS A retrospective evaluation of the clinical data of 78 patients with BCLC stage C HCC who received either TACE-sorafenib (TS) combination therapy or TACE monotherapy as their first treatment was done. The two groups were compared in terms of radiological tumor response 1 month after the intervention. The two groups were also compared in terms of time to progression (TTP), overall survival (OS), and adverse events. RESULTS The disease control rate (44.9% and 25.8%, respectively, P = 0.09) was higher in the TS combination group than in the TACE monotherapy group after 1 month of treatment. The TS combination group had significantly superior TTP and OS than the TACE group (TTP was 4.6 and 3.1 months, respectively, P = 0.001), and OS was 10.1 and 7.8 months, respectively, P < 0.001). The TACE-S group had a greater cumulative survival time at 6 months, 9 months, and 1 year than the TACE group (97.9%, 51.1%, 25.7% vs. 90.4%, 51.6%, and 0%, respectively). CONCLUSION TS combination therapy in advanced-stage (BCLC-C) HCC significantly improved disease control rate, TTP, and OS compared with TACE alone, without any significant increase in adverse reactions.
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Key Words
- ALT, Alanine aminotransferase
- AST, Aspartate aminotransferase
- BCLC, Barcelona-Clinic Liver Cancer
- CT, Computed tomography
- CTCAE, Common terminology criteria for adverse events
- CTP, Child–Turcotte–Pugh
- ECOG, Eastern Cooperative Group
- EHS, Extrahepatic spread
- HCC, Hepatocellular carcinoma
- MRI, Magnetic resonance imaging
- MVI, Macrovascular invasion
- OS, Overall survival
- PS, Performance status
- SPSS, Statistical Package for Social Sciences
- TACE
- TACE, Transarterial chemoembolisation
- TS, TACE-sorafenib
- TTP, Time to tumor progression
- hepatocellular carcinoma (HCC)
- m-RECIST, Modified Response Evaluation Criteria in Solid Tumors
- overall survival
- sorafenib
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Affiliation(s)
- Yashwant Patidar
- Department of Interventional Radiology, Institute of Liver and Biliary Sciences, New Delhi, India,Address for correspondence. Yashwant Patidar, Department of Interventional Radiology, Institute of Liver and Biliary Sciences, Pocket D-1, Vasant Kunj, New Delhi, 110070, India. Tel.: +9540950980.
| | - Karamvir Chandel
- Department of Interventional Radiology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Naveen K. Condati
- Department of Interventional Radiology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Shyam V. Srinivasan
- Department of Interventional Radiology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Amar Mukund
- Department of Interventional Radiology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Shiv K. Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
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An L, Liao H, Yuan K. Efficacy and Safety of Second-line Treatments in Patients with Advanced Hepatocellular Carcinoma after Sorafenib Failure: A Meta-analysis. J Clin Transl Hepatol 2021; 9:868-877. [PMID: 34966650 PMCID: PMC8666373 DOI: 10.14218/jcth.2021.00054] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 04/05/2021] [Accepted: 04/26/2021] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND AND AIMS In the last decade, several second-line therapies followed by sorafenib in patients with advanced hepatocellular carcinoma (HCC) have been reported. But the outcomes were different from each other. This meta-analysis aimed to evaluate the efficacy and safety of the second-line therapies followed by sorafenib in patients with advanced HCC. METHODS Embase (1974 to October 2019) and Ovid MEDLINE (1946 to October 2019) were searched for randomized clinical trials on second-line therapies followed by sorafenib in patients with advanced HCC. The quality of each study was assessed by the modified Jadad scale. Statistical analysis was carried out by RevMan5.3 software. Efficacy and safety were analyzed. Efficacy included overall survival (OS), disease control rate, time to progression, and progression-free survival. RESULTS Eight studies involving 3,173 patients were eligible. No difference in OS was found between the second-line treatment group and the control group (HR=0.87, 95% CI: 0.74-1.01, p=0.06). Disease control rate (relative risk (RR)=1.36, 95% CI: 1.16-1.60, p=0.0002), time to progression (HR=0.64, 95% CI: 0.51-0.81, p=0.0002) and progression-free survival (HR=0.60, 95% CI: 0.46-0.77, p<0.0001) were significantly improved by the second-line therapies. There was a slight difference in adverse events of any grade (RR=1.07, 95% CI: 1.00-1.14, p=0.03) between the two groups. CONCLUSIONS These second-line therapies followed by sorafenib may potentially improve the prognosis in patients with advanced HCC. Compared with other second-line therapies, regorafenib seemed to be more effective.
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Affiliation(s)
- Limin An
- Department of Liver Surgery & Liver Transplantation, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, China
| | - Haotian Liao
- Department of Liver Surgery & Liver Transplantation, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, China
| | - Kefei Yuan
- Department of Liver Surgery & Liver Transplantation, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, China
- Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Correspondence to: Kefei Yuan, Laboratory of Liver Surgery, West China Hospital, Sichuan University, 37 Guoxue lane, Wuhou District, Chengdu, Sichuan 610041, China. ORCID: https://orcid.org/0000-0003-4308-7743. Tel: +86-28-8542-2114, Fax: +86-28-8558-2944, E-mail:
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Circulating MicroRNA-21 As A Novel Noninvasive Biomarker for Hepatocellular Carcinoma Compared with Alpha Fetoprotein Gold Test. JOURNAL OF PURE AND APPLIED MICROBIOLOGY 2021. [DOI: 10.22207/jpam.15.4.75] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the greatest traditional kind of pre-eminent cancer worldwide, which happens mainly in chronic liver disease and cirrhotic patients. The available surveillance strategies for suspected HCC patients include serum alpha-fetoprotein (AFP) and liver imaging have been mainly recommended. However, the sensitivity and selectivity of these diagnostic strategies especially in the early stages of HCC have many obstacles. MicroRNAs (miRNAs) are non-coding RNAs that are 18–25 nucleotides in length. Plasma miRNAs may be a promising new biomarker for cancer detection and prognosis in the early stages. Assessment of Plasma MicroRNA-21 (miRNA-21) significance as a noninvasive Hepatocellular carcinoma marker compared with AFP gold standard test to improve HCC early diagnostic power. This is a prospective research project that included 90 patients in total, split into three classes., liver cirrhosis patients (LC) without any malignancies and (HCC) patients in addition to the healthy control group. Patients and controls were subjected to the clinical studies, routine investigations, imaging studies, and detection of plasma miRNA-21 & AFP. miRNA-21 showed a highly significant difference in the 3 studied groups. Control group with LC group, control group with HCC group, and LC group with HCC group P value (P 0.0001, P1 0.0001, P2 0.0001and P3 0.0001) respectively. Also, a highly significant difference was observed between pre-TACE and post-TACE miRNA-21 in the HCC group P value (0.0001). Circulating miRNA-21 may be used as a noninvasive co biomarker with AFP to increase HCC diagnostic accuracy in its early stages.
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HCC and Molecular Targeting Therapies: Back to the Future. Biomedicines 2021; 9:biomedicines9101345. [PMID: 34680462 PMCID: PMC8533575 DOI: 10.3390/biomedicines9101345] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 09/22/2021] [Accepted: 09/23/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of death from cancer in the world. Recently, the effectiveness of new antiviral therapies and the HBV vaccine have reduced HCC’s incidence, while non-alcoholic steato-hepatitis is an emerging risk factor. This review focuses on antiangiogenic molecules and immune checkpoint inhibitors approved for HCC treatment and possible future approaches. Sorafenib was the first drug approved for the treatment of advanced HCC (aHCC) and it has been shown to increase survival by a few months. Lenvatinib, a multikinase inhibitor, has shown non-inferiority in survival compared with sorafenib and an improvement in progression-free survival (PFS). The combination of atezolizumab (an anti-PDL1 antibody) and bevacizumab (an anti-VEGF antibody) was the first drug combination approved for HCC, demonstrating improved survival compared with sorafenib (19.2 vs. 13.4 months). As a second line of therapy, three regimens (regorafenib, cabozantinib, and ramucirumab) have been approved for the treatment of aHCC after progression on sorafenib according to guidelines. Furthermore, nivolumab, pembrolizumab, and nivolumab plus ipilimumab have been approved by the FDA (2017, 2018, and 2020, respectively). Finally, immune target therapy, cancer vaccines, and epigenetic drugs represent three new possible weapons for the treatment of HCC.
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Lee-Ying R, Ahmed O, Ahmed S, Ahmed S, Bathe OF, Brunet B, Dawson L, Davies J, Gordon V, Hebbard P, Kasnik J, Kim CA, Le D, Lee MKC, Lim H, McGhie JP, Mulder K, Park J, Renouf D, Tam V, Visser R, Wong RPW, Zaidi A, Doll C. Report from the 21st Annual Western Canadian Gastrointestinal Cancer Consensus Conference; Calgary, Alberta; 20-21 September 2019. Curr Oncol 2021; 28:3629-3648. [PMID: 34590606 PMCID: PMC8482207 DOI: 10.3390/curroncol28050310] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 09/18/2021] [Accepted: 09/18/2021] [Indexed: 12/12/2022] Open
Abstract
The 21st annual Western Canadian Gastrointestinal Cancer Consensus Conference (WCGCCC) was held in Calgary, Alberta, 20-21 September 2019. The WCGCCC is an interactive multi-disciplinary conference attended by health care professionals from across Western Canada (British Columbia, Alberta, Saskatchewan, and Manitoba) involved in the care of patients with gastrointestinal cancer. Surgical, medical, and radiation oncologists, pathologists, radiologists, and allied health care professionals such as dietitians and nurses participated in presentation and discussion sessions to develop the recommendations presented here. This consensus statement addresses current issues in the management of hepato-pancreato-biliary (HPB) cancers.
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Affiliation(s)
- Richard Lee-Ying
- Tom Baker Cancer Center, Alberta Health Service, Calgary, AB T2N 4N2, Canada; (V.T.); (C.D.)
| | - Osama Ahmed
- Saskatoon Cancer Center, Saskatchewan Cancer Agency, Saskatoon, SK S7N 4H4, Canada; (O.A.); (S.A.); (B.B.); (D.L.); (A.Z.)
| | - Shahid Ahmed
- Saskatoon Cancer Center, Saskatchewan Cancer Agency, Saskatoon, SK S7N 4H4, Canada; (O.A.); (S.A.); (B.B.); (D.L.); (A.Z.)
| | - Shahida Ahmed
- Department of Oncology, Cancer Care Manitoba, Winnipeg, MB R3E 0V9, Canada; (S.A.); (V.G.); (P.H.); (C.A.K.); (J.P.); (R.P.W.W.)
| | - Oliver F. Bathe
- Surgical Oncology, Arnie Charbonneau Cancer Institute, Calgary, AB T2N 4Z6, Canada;
| | - Bryan Brunet
- Saskatoon Cancer Center, Saskatchewan Cancer Agency, Saskatoon, SK S7N 4H4, Canada; (O.A.); (S.A.); (B.B.); (D.L.); (A.Z.)
| | - Laura Dawson
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada;
| | - Janine Davies
- Department of Oncology, British Columbia Cancer Agency, Vancouver, BC V5Z 4E6, Canada; (J.D.); (M.K.C.L.); (H.L.); (D.R.)
| | - Valerie Gordon
- Department of Oncology, Cancer Care Manitoba, Winnipeg, MB R3E 0V9, Canada; (S.A.); (V.G.); (P.H.); (C.A.K.); (J.P.); (R.P.W.W.)
| | - Pamela Hebbard
- Department of Oncology, Cancer Care Manitoba, Winnipeg, MB R3E 0V9, Canada; (S.A.); (V.G.); (P.H.); (C.A.K.); (J.P.); (R.P.W.W.)
| | - Jessica Kasnik
- Cross Cancer Institute, Alberta Health Services, Edmonton, AB T5G 1Z2, Canada; (J.K.); (K.M.)
| | - Christina A. Kim
- Department of Oncology, Cancer Care Manitoba, Winnipeg, MB R3E 0V9, Canada; (S.A.); (V.G.); (P.H.); (C.A.K.); (J.P.); (R.P.W.W.)
| | - Duc Le
- Saskatoon Cancer Center, Saskatchewan Cancer Agency, Saskatoon, SK S7N 4H4, Canada; (O.A.); (S.A.); (B.B.); (D.L.); (A.Z.)
| | - Michael K. C. Lee
- Department of Oncology, British Columbia Cancer Agency, Vancouver, BC V5Z 4E6, Canada; (J.D.); (M.K.C.L.); (H.L.); (D.R.)
| | - Howard Lim
- Department of Oncology, British Columbia Cancer Agency, Vancouver, BC V5Z 4E6, Canada; (J.D.); (M.K.C.L.); (H.L.); (D.R.)
| | - John Paul McGhie
- Department of Oncology, British Columbia Cancer Agency, Victoria, BC V8R 4S1, Canada;
| | - Karen Mulder
- Cross Cancer Institute, Alberta Health Services, Edmonton, AB T5G 1Z2, Canada; (J.K.); (K.M.)
| | - Jason Park
- Department of Oncology, Cancer Care Manitoba, Winnipeg, MB R3E 0V9, Canada; (S.A.); (V.G.); (P.H.); (C.A.K.); (J.P.); (R.P.W.W.)
| | - Daniel Renouf
- Department of Oncology, British Columbia Cancer Agency, Vancouver, BC V5Z 4E6, Canada; (J.D.); (M.K.C.L.); (H.L.); (D.R.)
| | - Vincent Tam
- Tom Baker Cancer Center, Alberta Health Service, Calgary, AB T2N 4N2, Canada; (V.T.); (C.D.)
| | - Robin Visser
- Department of Surgery, University of Manitoba, Winnipeg, MB R3E 0V9, Canada;
| | - Ralph P. W. Wong
- Department of Oncology, Cancer Care Manitoba, Winnipeg, MB R3E 0V9, Canada; (S.A.); (V.G.); (P.H.); (C.A.K.); (J.P.); (R.P.W.W.)
| | - Adnan Zaidi
- Saskatoon Cancer Center, Saskatchewan Cancer Agency, Saskatoon, SK S7N 4H4, Canada; (O.A.); (S.A.); (B.B.); (D.L.); (A.Z.)
| | - Corinne Doll
- Tom Baker Cancer Center, Alberta Health Service, Calgary, AB T2N 4N2, Canada; (V.T.); (C.D.)
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Kaibori M, Matsushima H, Ishizaki M, Kosaka H, Matsui K, Nakatani M, Kariya S, Yamaguchi T, Yoshida K, Yoshii K, Sekimoto M. The Impact of Sorafenib in Combination with Intermittent Hepatic Arterial Infusion Chemotherapy for Unresectable Hepatocellular Carcinoma with Major Vascular Invasion. Cancer Invest 2021; 40:81-89. [PMID: 34236269 DOI: 10.1080/07357907.2021.1952594] [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: 10/20/2022]
Abstract
The aim of the current study was to investigate the efficacy and safety of sorafenib and intermittent hepatic arterial infusion chemotherapy with cisplatin for unresectable hepatocellular carcinoma (HCC) with severe portal vein invasion. The antitumor effect was a complete response in 1 of 38 patients, a partial response in 12 patients, stable disease in 16 patients, and progressive disease in 9 patients, for a 34.2% response rate and a 76.3% disease control rate. This regimen had favorable efficacy and acceptable safety and may be feasible for unresectable HCC with severe portal vein invasion.
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Affiliation(s)
- Masaki Kaibori
- Department of Surgery, Kansai Medical University, Hirakata, Japan
| | | | | | - Hisashi Kosaka
- Department of Surgery, Kansai Medical University, Hirakata, Japan
| | - Kosuke Matsui
- Department of Surgery, Kansai Medical University, Hirakata, Japan
| | - Miyuki Nakatani
- Department of Radiology, Kansai Medical University, Hirakata, Japan
| | - Shuji Kariya
- Department of Radiology, Kansai Medical University, Hirakata, Japan
| | - Takashi Yamaguchi
- Department of Gastroenterology and Hepatology, Kansai Medical University, Hirakata, Japan
| | - Katsunori Yoshida
- Department of Gastroenterology and Hepatology, Kansai Medical University, Hirakata, Japan
| | - Kengo Yoshii
- Department of Mathematics and Statistics in Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Mitsugu Sekimoto
- Department of Surgery, Kansai Medical University, Hirakata, Japan
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Monteiro AR, Conde RS, Basto R, Sclafani F, Deleporte A, Hendlisz A, Dal Lago L. Targeted agents in older patients with gastrointestinal cancers - An overview. J Geriatr Oncol 2021; 12:1240-1252. [PMID: 34226158 DOI: 10.1016/j.jgo.2021.06.013] [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: 04/07/2021] [Revised: 06/12/2021] [Accepted: 06/25/2021] [Indexed: 12/24/2022]
Abstract
Targeted agents have been increasingly used in different malignancies and are associated with improved survival outcomes, including gastrointestinal cancers. Their use in the treatment of older patients is appealing given their favorable toxicity profile. In the last years, this subgroup of patients has been attracting increased interest given their representativeness and specific clinical needs. Nonetheless, the lack of data on efficacy and safety of standard treatments in older patients hinders proper evidence-based decision-making, leaving most therapeutic recommendations to be extrapolated from registration trials with low representation of older and frail patients. However, even if most decisions regarding the use of targeted agents in older patients with gastrointestinal cancer remain guided by subanalyses of large trials, data from recent older adult-specific trials are beginning to emerge, particularly in colorectal cancer. This review aims to summarize the existing evidence on treatment of older patients with gastrointestinal carcinomas (colon and rectum, stomach, esophagus, liver, and pancreas) with targeted agents (cetuximab, panitumumab, bevacizumab, ramucirumab, aflibercept, regorafenib, encorafenib, trastuzumab, sorafenib, lenvatinib, cabozantinib, erlotinib, olaparib), and place the evidence in a geriatric oncology perspective.
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Affiliation(s)
- Ana Raquel Monteiro
- Instituto Português de Oncologia de Coimbra Francisco Gentil, Department of Medical Oncology, Av. Bissaya Barreto 98, 3000-075 Coimbra, Portugal.
| | - Rita Saúde Conde
- Instituto Português de Oncologia de Lisboa Francisco Gentil, Department of Medical Oncology, Rua Professor Lima Basto, 1099-023 Lisboa, Portugal.
| | - Raquel Basto
- Instituto Português de Oncologia de Coimbra Francisco Gentil, Department of Medical Oncology, Av. Bissaya Barreto 98, 3000-075 Coimbra, Portugal.
| | - Francesco Sclafani
- Institut Jules Bordet, Department of Medicine, Blvd de Waterloo 121, 1000 Brussels, Belgium.
| | - Amélie Deleporte
- Institut Jules Bordet, Department of Medicine, Blvd de Waterloo 121, 1000 Brussels, Belgium.
| | - Alain Hendlisz
- Institut Jules Bordet, Department of Medicine, Blvd de Waterloo 121, 1000 Brussels, Belgium.
| | - Lissandra Dal Lago
- Institut Jules Bordet, Department of Medicine, Blvd de Waterloo 121, 1000 Brussels, Belgium.
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The novel immune-related genes predict the prognosis of patients with hepatocellular carcinoma. Sci Rep 2021; 11:10728. [PMID: 34021184 PMCID: PMC8139963 DOI: 10.1038/s41598-021-89747-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 04/09/2021] [Indexed: 02/04/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the main causes of cancer deaths globally. Immunotherapy is becoming increasingly important in the cure of advanced HCC. Thus it is essential to identify biomarkers for treatment response and prognosis prediction. We searched publicly available databases and retrieved 465 samples of genes from The Cancer Genome Atlas (TCGA) database and 115 tumor samples from Gene Expression Omnibus (GEO). Meanwhile, we used the ImmPort database to determine the immune-related genes as well. Weighted gene correlation network analysis, Cox regression analysis and least absolute shrinkage and selection operator (LASSO) analysis were used to identify the key immune related genes (IRGs) which are closely related to prognosis. Gene set enrichment analysis (GSEA) was implemented to explore the difference of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway between Immune high- and low-risk score groups. Finally, we made a prognostic nomogram including Immune-Risk score and other clinicopathologic factors. A total of 318 genes from prognosis related modules were identified through weighted gene co-expression network analysis (WGCNA). 46 genes were strongly linked to prognosis after univariate Cox analysis. We constructed a seven genes prognostic signature which showed powerful prediction ability in both training cohort and testing cohort. 16 significant KEGG pathways were identified between high- and low- risk score groups using GSEA analysis. This study identified and verified seven immune-related prognostic biomarkers for the patients with HCC, which have potential value for immune modulatory and therapeutic targets.
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Vogel A, Bathon M, Saborowski A. Advances in systemic therapy for the first-line treatment of unresectable HCC. Expert Rev Anticancer Ther 2021; 21:621-628. [PMID: 33499684 DOI: 10.1080/14737140.2021.1882855] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Introduction: Hepatocellular carcinoma (HCC) is one of the most common and deadliest cancers worldwide. In recent years, several drugs have been approved in first- and second-line setting. Currently, several phase-III trials are ongoing with combinations of checkpoint inhibitors, tyrosine kinase inhibitors (TKI) and anti-angiogenic antibodies, which will most likely increase therapeutic options in frontline therapy in the near future.Areas covered: This review summarizes the standard of care in first-line systemic therapy for patients with advanced HCC and provides an outlook on the most promising combinations currently tested in prospective trials.Expert opinion: The recent approval of novel substances has substantially changed the field of palliative treatment strategies in patients with advanced HCC. Immuno-oncology (IO)-based combination therapies will become the next standard of care in frontline HCC. The potent anti-tumor efficacy and good tolerability of these therapies will increase the use of upfront systemic therapy in patients with intermediate stage HCC.
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Affiliation(s)
- Arndt Vogel
- Department of Gastroenterology, Hepatology & Endokrinologie, Medizinische Hochschule Hannover, Hannover, Germany
| | - Melanie Bathon
- Department of Gastroenterology, Hepatology & Endokrinologie, Medizinische Hochschule Hannover, Hannover, Germany
| | - Anna Saborowski
- Department of Gastroenterology, Hepatology & Endokrinologie, Medizinische Hochschule Hannover, Hannover, Germany
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Li X, Wang Y, Ye X, Liang P. Locoregional Combined With Systemic Therapies for Advanced Hepatocellular Carcinoma: An Inevitable Trend of Rapid Development. Front Mol Biosci 2021; 8:635243. [PMID: 33928118 PMCID: PMC8076864 DOI: 10.3389/fmolb.2021.635243] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 02/09/2021] [Indexed: 12/12/2022] Open
Abstract
Despite the application of antiviral drugs and improved surveillance tools, the number of patients diagnosed with hepatocellular carcinoma (HCC) at an advanced stage and with a dismal prognosis is still on the rise. Systemic treatment with multiple multitargeted tyrosine kinase inhibitors (TKIs), such as sorafenib, has been a widely utilized approach for a decade. In addition, the use of a combination of TKIs with other types of compounds, including immune checkpoint inhibitors (ICIs) and antiangiogenic inhibitors, has shown efficacy in treating advanced HCC. However, the presence of intolerable adverse events, low disease response and control rates, and relative short overall survival of such combinatory therapies makes novel or optimized therapies for advance HCC urgently needed. Locoregional therapy (transarterial chemoembolization, and thermal ablation) can destroy primary tumors and decrease tumor burden and is widely used for HCC management. This type of treatment modality can result in local hypoxia and increased vascular permeability, inducing immunogenic effects by releasing tumor antigens from dying cancer cells and producing damage-associated molecular patterns that facilitate antiangiogenic therapy and antitumor immunity. The combination of systemic and locoregional therapies may further produce synergistic effects without overlapping toxicity that can improve prognoses for advanced HCC. In preliminary studies, several combinations of therapeutic modes exhibited promising levels of safety, feasibility, and antitumor effects in a clinical setting and have, thus, garnered much attention. This review aims to provide a comprehensive, up-to-date overview of the underlying mechanisms of combined systemic and locoregional therapies in the treatment of advanced HCC, commenting on both their current status and future direction.
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Affiliation(s)
- Xin Li
- Department of Interventional Ultrasound, Chinese PLA General Hospital, Beijing, China
| | - Yaxi Wang
- Department of Interventional Ultrasound, Chinese PLA General Hospital, Beijing, China
- Department of Ultrasound, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China
| | - Xin Ye
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Lung Cancer Institute, Jinan, China
| | - Ping Liang
- Department of Interventional Ultrasound, Chinese PLA General Hospital, Beijing, China
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Bert F, Stahmeyer JT, Parpalea AL, Rossol S. Non-Invasive Reliable Methods to Objectify the Positive Influence of Hepatitis C Virus Treatment on Liver Stiffness. Gastroenterology Res 2021; 14:31-40. [PMID: 33737997 PMCID: PMC7935613 DOI: 10.14740/gr1347] [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: 11/30/2020] [Accepted: 01/22/2021] [Indexed: 11/11/2022] Open
Abstract
Background Chronic active hepatitis C virus (HCV) infection is a major public health problem and causes liver fibrosis (LF) up to liver cirrhosis (LC). LF can be estimated by non-invasive, easy handling methods. With implementation of new HCV therapies, elimination rates of HCV are near 100%, resulting in less clinical complications and costs. The aim of our study was to evaluate the positive influence of HCV treatment on liver stiffness by non-invasive assessments of LF. Methods Sixty-two patients with HCV were treated with antiviral drug regimes. Serological fibrosis scores and ultrasound elastography (acoustic radiation force impulse and shear wave elasticity imaging (ARFI-SWEI)) were used for LF assessment on day 0 and 6 months after therapy. Results Antiviral treatment was successful in all cases. ARFI-SWEI measurements showed an improvement of all LF stages. Results of serological markers and scores were heterogeneous. Significant positive effects of treatment were seen for aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis-4 (FIB-4) scores, only. Further Pearson's coefficient showed moderate till very high correlations for ARFI-SWEI and FIB-4/APRI scores. Conclusion Today HCV therapy is able to cure HCV. Positive influences are improvement of LF stages. ARFI-SWEI, APRI and FIB-4 score are useful, easy handling tools to verify positive influence of HCV treatment on LF alone or in combination.
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Affiliation(s)
- Florian Bert
- Department of Internal Medicine, Krankenhaus Nordwest, Frankfurt/Main, Germany
| | - Jona Theodor Stahmeyer
- Institute for Epidemiology, Social Medicine and Health Systems Research, Medical School, Hannover, Germany
| | | | - Siegbert Rossol
- Department of Internal Medicine, Krankenhaus Nordwest, Frankfurt/Main, Germany
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Chen A, Li S, Yao Z, Hu J, Cao J, Topatana W, Juengpanich S, Yu H, Shen J, Chen M. Adjuvant transarterial chemoembolization to sorafenib in unresectable hepatocellular carcinoma: A meta-analysis. J Gastroenterol Hepatol 2021; 36:302-310. [PMID: 32652685 DOI: 10.1111/jgh.15180] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Revised: 06/11/2020] [Accepted: 07/04/2020] [Indexed: 12/26/2022]
Abstract
BACKGROUND AND AIM An increasing number of transarterial chemoembolization (TACE) plus sorafenib combination therapy has been applied for unresectable hepatocellular carcinoma (HCC). However, it remains controversial whether combination therapy is superior to sorafenib monotherapy. Therefore, we aimed to perform a meta-analysis to evaluate the efficacy and safety of the combination therapy of TACE plus sorafenib for unresectable HCC. METHODS This meta-analysis was based on the relative outcomes from a specific search of online databases between January 2008 and November 2019, and subgroup analyses were conducted to identify potential predictive factors. RESULTS A total of 3868 patients (TACE plus sorafenib vs sorafenib, 1181 vs 2687) were identified from nine studies, including one randomized controlled trial and eight retrospective cohort studies. The pooled results revealed that TACE plus sorafenib combination therapy significantly improves overall survival with the combined hazard ratio 0.74 (95% confidence interval [CI] = 0.66-0.84, P < 0.001), time to progression (hazard ratio = 0.73, 95%CI = 0.65-0.82, P < 0.001), and objective response rate (odds ratio = 2.19, 95% CI = 1.31-3.66, P = 0.003). Subgroup analysis indicated that patients who developed macrovascular invasion achieve significantly great overall survival (P for interaction = 0.001) with combination therapy, in contrast to nonmacrovascular invasion patients. In addition, no significant differences in adverse events were observed. CONCLUSION This meta-analysis demonstrated that TACE plus sorafenib combination therapy is superior to sorafenib monotherapy and should be recommended as an optimal treatment choice for unresectable HCC.
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Affiliation(s)
- Anxin Chen
- Nanshan School, Guangzhou Medical University, Guangzhou, China
| | - Shijie Li
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, China
| | - Zhiyuan Yao
- Nanshan School, Guangzhou Medical University, Guangzhou, China
| | - Jiahao Hu
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, China
| | - Jiasheng Cao
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, China
| | - Win Topatana
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, China
| | - Sarun Juengpanich
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, China
| | - Hong Yu
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, China
| | - Jiliang Shen
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, China
| | - Mingyu Chen
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, China.,Engineering Research Center of Cognitive Healthcare of Zhejiang Province, Hangzhou, China
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The identification and functional analysis of CD8+PD-1+CD161+ T cells in hepatocellular carcinoma. NPJ Precis Oncol 2020; 4:28. [PMID: 33145436 PMCID: PMC7599220 DOI: 10.1038/s41698-020-00133-4] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Accepted: 09/25/2020] [Indexed: 12/22/2022] Open
Abstract
Immunotherapy is a powerful therapeutic strategy for end-stage hepatocellular carcinoma (HCC). It is well known that T cells, including CD8+PD-1+ T cells, play important roles involving tumor development. However, their underlying phenotypic and functional differences of T cell subsets remain unclear. We constructed single-cell immune contexture involving approximate 20,000,000 immune cells from 15 pairs of HCC tumor and non-tumor adjacent tissues and 10 blood samples (including five of HCCs and five of healthy controls) by mass cytometry. scRNA-seq and functional analysis were applied to explore the function of cells. Multi-color fluorescence staining and tissue micro-arrays were used to identify the pathological distribution of CD8+PD-1+CD161 +/− T cells and their potential clinical implication. The differential distribution of CD8+ T cells subgroups was identified in tumor and non-tumor adjacent tissues. The proportion of CD8+PD1+CD161+ T cells was significantly decreased in tumor tissues, whereas the ratio of CD8+PD1+CD161− T cells was much lower in non-tumor adjacent tissues. Diffusion analysis revealed the distinct evolutionary trajectory of CD8+PD1+CD161+ and CD8+PD1+CD161− T cells. scRNA-seq and functional study further revealed the stronger immune activity of CD8+PD1+CD161+ T cells independent of MHC class II molecules expression. Interestingly, a similar change in the ratio of CD8+CD161+/ CD8+CD161− T cells was also found in peripheral blood samples collected from HCC cases, indicating their potential usage clinically. We here identified different distribution, function, and trajectory of CD8+PD-1+CD161+ and CD8+PD-1+CD161− T cells in tumor lesions, which provided new insights for the heterogeneity of immune environment in HCCs and also shed light on the potential target for immunotherapy.
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Hatanaka T, Kakizaki S, Nagashima T, Namikawa M, Ueno T, Tojima H, Takizawa D, Naganuma A, Arai H, Sato K, Harimoto N, Shirabe K, Uraoka T. Liver Function Changes in Patients with Hepatocellular Carcinoma Treated with Lenvatinib: Predictive Factors of Progression to Child-Pugh Class B, the Formation of Ascites and the Candidates for the Post-Progression Treatment. Cancers (Basel) 2020; 12:2906. [PMID: 33050527 PMCID: PMC7601832 DOI: 10.3390/cancers12102906] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 09/26/2020] [Accepted: 10/07/2020] [Indexed: 02/08/2023] Open
Abstract
The aim of this multicenter retrospective study was to assess the change in liver function in patients with hepatocellular carcinoma treated with lenvatinib. Among 139 consecutive patients receiving lenvatinib treatment between March 2018 and July 2019, 28 patients with Child-Pugh class B and one patient with inadequate patient information were excluded. Remaining 110 patients with Child-Pugh class A were analyzed. The median age of 110 patients was 73 years (IQR 66.7-80) and 88 patients (80.0%) were men. Child-Pugh score was 5 (CP5A) and 6 (CP6A) in 58 (52.7%) and 52 patients (47.3%), and ALBI grade was 1 and 2 in 38 (34.5%) and 72 patients (65.5%), respectively. The deterioration to Child-Pugh class B was found in 43 patients (39.1%) during the lenvatinib treatment. The favorable factors related to preserving liver function were significantly shown to be male, ALBI grade 1, CP5A and BCLC early or intermediate stage in the multivariate analysis. The formation of ascites was found in 32 patients (28.6%). The significant unfavorable factors associated with the formation of ascites were found to be low platelet count and CP6A. Among the 79 patients, there were 36 (45.6%) and 11 patients (13.9%) who fulfilled the criteria for candidate for the post-progression treatment and ramucirumab treatment, respectively. The predictive factors of the post-progression treatment were shown to be ALBI grade 1 and CP5A in multivariate analysis. In conclusion, male, ALBI grade 1, CP5A and BCLC early or intermediate stage were favorable factors related to sustaining liver function and the patients with ALBI grade 1 and CP5A were eligible for the post-progression treatment. Careful screening for ascites was needed in patients with low platelet count and CP6A.
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Affiliation(s)
- Takeshi Hatanaka
- Department of Gastroenterology, Gunma Saiseikai Maebashi Hospital, 564-1 Kamishindenmachi, Maebashi, Gunma 371-0821, Japan
| | - Satoru Kakizaki
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, 3-39-15 Showa, Maebashi, Gunma 371-8511, Japan; (S.K.); (H.T.); (K.S.); (T.U.)
- Department of Clinical Research, National Hospital Organization Takasaki General Medical Center, 36 Takamatsu-cho, Takasaki, Gunma 370-0829, Japan
| | - Tamon Nagashima
- Department of Gastroenterology, National Hospital Organization Shibukawa Medical Center, 383 Shirai, Shibukawa, Gunma 377-0280, Japan;
| | - Masashi Namikawa
- Department of Internal Medicine, Kiryu Kosei General Hospital, 6-6-3 Orihime-cho, Kiryu, Gunma 376-0024, Japan;
| | - Takashi Ueno
- Department of Internal Medicine, Isesaki Municipal Hospital, 12-1 Tsunatorihonmachi, Isesaki, Gunma 372-0817, Japan;
| | - Hiroki Tojima
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, 3-39-15 Showa, Maebashi, Gunma 371-8511, Japan; (S.K.); (H.T.); (K.S.); (T.U.)
| | - Daichi Takizawa
- Department of Gastroenterology, Maebashi Red Cross Hospital, 389-1 Asakuramachi, Maebashi, Gunma 371-0811, Japan; (D.T.); (H.A.)
| | - Atsushi Naganuma
- Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, 36 Takamatsu-cho, Takasaki, Gunma 370-0829, Japan;
| | - Hirotaka Arai
- Department of Gastroenterology, Maebashi Red Cross Hospital, 389-1 Asakuramachi, Maebashi, Gunma 371-0811, Japan; (D.T.); (H.A.)
| | - Ken Sato
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, 3-39-15 Showa, Maebashi, Gunma 371-8511, Japan; (S.K.); (H.T.); (K.S.); (T.U.)
| | - Norifumi Harimoto
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University Graduate School of Medicine, 3-39-15 Showa, Maebashi, Gunma 371-8511, Japan; (N.H.); (K.S.)
| | - Ken Shirabe
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University Graduate School of Medicine, 3-39-15 Showa, Maebashi, Gunma 371-8511, Japan; (N.H.); (K.S.)
| | - Toshio Uraoka
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, 3-39-15 Showa, Maebashi, Gunma 371-8511, Japan; (S.K.); (H.T.); (K.S.); (T.U.)
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Tak KY, Nam HC, Choi JY, Yoon SK, Kim CW, Kim HY, Lee SW, Lee HL, Chang UI, Song DS, Yang JM, Kwon JH, Yoo SH, Sung PS, Choi SW, Song MJ, Kim SH, Jang JW. Effectiveness of sorafenib dose modifications on treatment outcome of hepatocellular carcinoma: Analysis in real-life settings. Int J Cancer 2020; 147:1970-1978. [PMID: 32167170 DOI: 10.1002/ijc.32964] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 02/28/2020] [Accepted: 03/03/2020] [Indexed: 12/22/2022]
Abstract
Controlling adverse events (AEs) through dose reduction can enhance drug adherence and treatment response. Currently, there is no guide for sorafenib dosing. The aim of this study was to evaluate whether sorafenib dosing could affect treatment outcomes. A total of 782 hepatocellular carcinoma (HCC) patients treated with sorafenib were evaluated for sorafenib dosing and its modifications via medical records at baseline and regular follow-up. Study outcomes included progression-free survival (PFS), overall survival (OS), sorafenib duration, cumulative dose, AEs and drug discontinuation. The median patient survival was 7.7 months. Overall, 242 (30.9%) patients underwent dose reduction and 121 (17.5%) discontinued sorafenib due to AEs. In multivariate analysis, dose reduction was identified to be independently predictive of PFS and OS. The 800-to-400 mg/day group provided significantly better PFS than the 800 mg/day-maintained group or the 800-to-600 mg/day group. Likewise, the 800-to-400 mg/day group resulted in a significantly better OS than other dosing. However, dose reduction to 200 mg/day led to significantly worse PFS and OS. Hand-foot skin reaction and drug discontinuation due to AEs were higher in the 800-to-600 mg/day group than the 800-to-400 mg/day group. The 800-to-400 mg/day group had significantly longer treatment duration and higher cumulative dose than the 800 mg/day-maintained group. Sorafenib dose reduction can improve HCC survival and increase patient tolerance and adherence coupled with longer duration and higher cumulative dose. Dose reduction from 800 to 400 mg/day than to 600 mg/day is recommended when clinically warranted. However, dose reduction to 200 mg/day is not recommendable.
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Affiliation(s)
- Kwon Yong Tak
- Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, Seoul, South Korea
| | - Hee Chul Nam
- Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, Seoul, South Korea
| | - Jong Young Choi
- Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, Seoul, South Korea
| | - Seung Kew Yoon
- Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, Seoul, South Korea
| | | | - Hee Yeon Kim
- Uijeongbu St. Mary's Hospital, Seoul, South Korea
| | | | - Hae Lim Lee
- Bucheon St. Mary's Hospital, Seoul, South Korea
| | - U Im Chang
- St. Vincent's Hospital, Seoul, South Korea
| | | | - Jin Mo Yang
- Incheon St. Mary's Hospital, Seoul, South Korea
| | | | | | - Pil Soo Sung
- Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, Seoul, South Korea
| | | | | | | | - Jeong Won Jang
- Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, Seoul, South Korea
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Albrecht KC, Aschenbach R, Diamantis I, Eckardt N, Teichgräber U. Response rate and safety in patients with hepatocellular carcinoma treated with transarterial chemoembolization using 40-µm doxorubicin-eluting microspheres. J Cancer Res Clin Oncol 2020; 147:23-32. [PMID: 32880029 PMCID: PMC7810642 DOI: 10.1007/s00432-020-03370-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 08/19/2020] [Indexed: 12/22/2022]
Abstract
Purpose To evaluate the response rate and safety of superselective drug-eluting beats transarterial chemoembolization (DEB-TACE) with doxorubicin-loaded 40-µm microspheres in patients with hepatocellular carcinoma (HCC). Methods One hundred and forty-one treatments with doxorubicin-loaded 40-µm microspheres in 83 patients between 2012 and 2017 were retrospectively evaluated. Images of the treated lesions were analyzed before and after each treatment according to mRECIST (modified Response Evaluation Criteria in Solid Tumors). Therapy response (complete response [CR] + partial response [PR]) and disease control (CR + PR + stable disease [SD]) rates were determined, and the correlation between the longitudinal axis (longest diameter of the tumor) and volume was investigated using a newly developed software for systematic tumor response assessment. Additional endpoints were progression-free survival (PFS) and time to progression (TTP). Results In the target tumors, a therapy response rate of 63.1% and a disease control rate of 95.7% were achieved. There was a good correlation between the measurement of the longitudinal axis and volume of the measured lesion (r value, 0.954). The median PFS was 2.23 months, and the median TTP was 5.91 months. The serious adverse event rate (SAE) was 10.64%. Conclusion Superselective DEB-TACE with 40-µm sized Embozene Tandem™ can be considered an effective and safe treatment, given the number of procedure-related complications. Electronic supplementary material The online version of this article (10.1007/s00432-020-03370-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Katharina Carolin Albrecht
- Institut für Diagnostische und Interventionelle Radiologie, Universitätsklinikum Jena IDIR, Am Klinikum 1, 07747, Jena, Germany
| | - René Aschenbach
- Institut für Diagnostische und Interventionelle Radiologie, Universitätsklinikum Jena IDIR, Am Klinikum 1, 07747, Jena, Germany
| | - Ioannis Diamantis
- Institut für Diagnostische und Interventionelle Radiologie, Universitätsklinikum Jena IDIR, Am Klinikum 1, 07747, Jena, Germany
| | - Niklas Eckardt
- Institut für Diagnostische und Interventionelle Radiologie, Universitätsklinikum Jena IDIR, Am Klinikum 1, 07747, Jena, Germany
| | - Ulf Teichgräber
- Institut für Diagnostische und Interventionelle Radiologie, Universitätsklinikum Jena IDIR, Am Klinikum 1, 07747, Jena, Germany.
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Chen Z, Xie H, Hu M, Huang T, Hu Y, Sang N, Zhao Y. Recent progress in treatment of hepatocellular carcinoma. Am J Cancer Res 2020; 10:2993-3036. [PMID: 33042631 PMCID: PMC7539784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Accepted: 06/28/2020] [Indexed: 06/11/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide. In the past decade, there have been improvements in non-drug therapies and drug therapies for HCC treatment. Non-drug therapies include hepatic resection, liver transplantation, transarterial chemoembolization (TACE) and ablation. The former two surgical treatments are beneficial for patients with early and mid-stage HCC. As the first choice for non-surgical treatment, different TACE methods has been developed and widely used in combination therapy. Ablation has become an important alternative therapy for the treatment of small HCC or cases of unresectable surgery. Meanwhile, the drugs including small molecule targeted drugs like sorafenib and lenvatinib, monoclonal antibodies such as nivolumab are mainly used for the systematic treatment of advanced HCC. Besides strategies described above are recommended as first-line therapies due to their significant increase in mean overall survival, there are also potential drugs in clinical trials or under preclinical development. In addition, a number of potential preclinical surgical or adjuvant therapies are being studied, such as oncolytic virus, mesenchymal stem cells, biological clock, gut microbiome composition and peptide vaccine, all of which have shown different degrees of inhibition on HCC. With some potential anti-HCC drugs being reported, many promising therapeutic targets in related taxonomic signaling pathways including cell cycle, epigenetics, tyrosine kinase and so on that affect the progression of HCC have also been found. Together, the rational application of existing therapies and drugs as well as the new strategies will bring a bright future for the global cure of HCC in the coming decades.
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Affiliation(s)
- Zhiqian Chen
- West China School of Pharmacy, Sichuan UniversityChengdu 610041, China
| | - Hao Xie
- West China School of Pharmacy, Sichuan UniversityChengdu 610041, China
| | - Mingming Hu
- West China School of Pharmacy, Sichuan UniversityChengdu 610041, China
| | - Tianyi Huang
- West China School of Pharmacy, Sichuan UniversityChengdu 610041, China
| | - Yanan Hu
- West China School of Pharmacy, Sichuan UniversityChengdu 610041, China
| | - Na Sang
- Cancer Center, West China Hospital, West China Medical School, and Collaborative Innovation Center for Biotherapy, Sichuan UniversityChengdu 610041, China
| | - Yinglan Zhao
- West China School of Pharmacy, Sichuan UniversityChengdu 610041, China
- Cancer Center, West China Hospital, West China Medical School, and Collaborative Innovation Center for Biotherapy, Sichuan UniversityChengdu 610041, China
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