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Fu X, Guo Y, Zhang K, Cheng Z, Liu C, Ren Y, Miao L, Liu W, Jiang S, Zhou C, Su Y, Yang L. Prognostic impact of extracellular volume fraction derived from equilibrium contrast-enhanced CT in HCC patients receiving immune checkpoint inhibitors. Sci Rep 2025; 15:13643. [PMID: 40254627 PMCID: PMC12009984 DOI: 10.1038/s41598-025-97677-x] [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: 01/06/2025] [Accepted: 04/07/2025] [Indexed: 04/22/2025] Open
Abstract
This study aimed to investigate whether extracellular volume (ECV) fraction derived from equilibration contrast-enhanced computed tomography (CECT) affects prognosis in HCC patients receiving ICIs. This retrospective study ultimately included 211 HCC patients undergoing ICIs, of whom 60 were included in an internal validation to assess the reproducibility of the results. Baseline unenhanced and equilibrated CECT were used to measure CT values of the tumor, liver and aorta, which were combined with hematocrit to calculate the ECV fraction. Correlation analysis was used to investigate the association between tumor ECV and liver ECV fractions. The effects of clinical variables and ECV fraction on progression-free survival (PFS) and overall survival (OS) were evaluated using Cox proportional hazards models and Kaplan-Meier curves. Of these 151 patients, tumor ECV fraction positively correlated with liver ECV fraction. In the Lower tumor ECV group, PFS (5.6 vs. 7.6 months) and OS (10.5 vs. 15.5 months) were notably shorter than in the Higher tumor ECV group, while no significant differences were found between the Higher and Lower liver ECV groups. Furthermore, the multivariable Cox regression model demonstrated that higher tumor ECV fraction level was an independent protective factor for PFS and OS (all P < 0.001). Internal validation cohort preliminary demonstrated reproducibility of results. The tumor ECV fraction is expected to become a routine indicator before ICIs therapy for HCC patients in contrast to liver ECV fraction, contributing to their subsequent management.
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Affiliation(s)
- Xiaona Fu
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Yusheng Guo
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Kailu Zhang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Zhixuan Cheng
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Chanyuan Liu
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Yi Ren
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Lianwei Miao
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Weiwei Liu
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Shanshan Jiang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Chen Zhou
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China.
| | - Yangbo Su
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China.
| | - Lian Yang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China.
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Sun R, Wu C, Gou Y, Zhao Y, Huang P. Advancements in second-line treatment research for hepatocellular carcinoma. Clin Transl Oncol 2025; 27:837-857. [PMID: 39162977 DOI: 10.1007/s12094-024-03653-8] [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: 05/08/2024] [Accepted: 07/29/2024] [Indexed: 08/21/2024]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors, characterized by high incidence and mortality rates. Due to its insidious onset, most patients are diagnosed at an advanced stage, often missing the opportunity for surgical resection. Consequently, systemic treatments play a pivotal role. In recent years, an increasing number of drugs have been approved for first-line systemic treatment of HCC. However, their efficacy is limited, and some patients develop drug resistance after a period of treatment. For such patients, there is currently a lack of standard second-line systemic treatment options. This review summarizes the latest advancements in second-line systemic treatment research for HCC patients who have developed resistance to various first-line systemic treatments, aiming to provide more rational and personalized second-line treatment strategies.
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Affiliation(s)
- Ruirui Sun
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, No.1, Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, 400000, China
| | - Chenrui Wu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, No.1, Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, 400000, China
| | - Yang Gou
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, No.1, Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, 400000, China
| | - Yaowu Zhao
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, No.1, Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, 400000, China
| | - Ping Huang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, No.1, Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, 400000, China.
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3
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Liu X, Lu Y, Zhou W, Peng T, Zhou J, Bi H, Xia F, Chen X. Chinese Multidisciplinary Expert Consensus on Immune Checkpoint Inhibitor-Based Combination Therapy for Hepatocellular Carcinoma (2023 Edition). Liver Cancer 2024; 13:355-375. [PMID: 39114757 PMCID: PMC11305662 DOI: 10.1159/000535496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Accepted: 11/10/2023] [Indexed: 08/10/2024] Open
Abstract
Background Immune checkpoint inhibitor (ICI)-based combination therapy modalities for hepatocellular carcinoma (HCC) have achieved significant efficacy in clinical research and practice and have become the mainstay for the treatment of unresectable HCC. Summary To better help clinicians use combination immunotherapy drugs and regimens rationally, effectively, and safely, the editorial board facilitated a discussion with multidisciplinary experts in the field, adopted the "Delphi" consensus formation method, and finally revised and completed the "Chinese Multidisciplinary Expert Consensus on the Immune Checkpoint Inhibitors (ICIs)-Based Combination Therapy for Hepatocellular Carcinoma (2023 Edition)" on the basis of the 2021 edition. Key Messages This consensus primarily focuses on the principles and methods of clinical practice of combination therapy based on ICIs, aiming to summarize the recommendations for clinical application based on the latest research and expert experience and provide application guidance for clinicians.
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Affiliation(s)
- Xiufeng Liu
- Department of Medical Oncology of PLA Cancer Center, Jinling Hospital, Nanjing, China
| | - Yinying Lu
- Comprehensive Liver Cancer Center, 5th Medical Center of PLA General Hospital, Beijing, China
| | - Weiping Zhou
- Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Tao Peng
- Hepatobiliary Surgery Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Jie Zhou
- Division of Hepatobiliopancreatic Surgery and Liver Transplantation, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Huaqiang Bi
- Department of Hepatobiliary Surgery, The First Hospital Affiliated to Army Medical University, Chongqing, China
| | - Feng Xia
- Department of Hepatobiliary Surgery, The First Hospital Affiliated to Army Medical University, Chongqing, China
| | - Xiaoping Chen
- Department of Hepatobiliary Surgery, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
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4
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Liu X, Xia F, Chen Y, Sun H, Yang Z, Chen B, Zhao M, Bi X, Peng T, Ainiwaer A, Luo Z, Wang F, Lu Y, National Clinical Research Center for Infectious Diseases, Society of Hepatology, Beijing Medical Association, Translational Medicine Branch, China Association of Gerontology and Geriatrics. Chinese expert consensus on refined diagnosis, treatment, and management of advanced primary liver cancer (2023 edition). LIVER RESEARCH (BEIJING, CHINA) 2024; 8:61-71. [PMID: 39959878 PMCID: PMC11771258 DOI: 10.1016/j.livres.2024.05.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 05/10/2024] [Accepted: 05/13/2024] [Indexed: 11/25/2024]
Abstract
Hepatocellular carcinoma (HCC), commonly known as primary liver cancer, is a major cause of malignant tumors and cancer-related deaths in China, accounting for approximately 85% of all cancer cases in the country. Several guidelines have been used to diagnose and treat liver cancer. However, these guidelines provide a broad definition for classifying advanced liver cancer, with an emphasis on a singular approach, without considering treatment options for individual patients. Therefore, it is necessary to establish a comprehensive and practical expert consensus, specifically for China, to enhance the diagnosis and treatment of HCC using the Delphi method. The classification criteria were refined for Chinese patients with HCC, and the corresponding optimal treatment regimen recommendations were developed. These recommendations took into account various factors, including tumor characteristics, vascular tumor thrombus grade, distant metastasis, liver function status, portal hypertension, and the hepatitis B virus replication status of patients with primary HCC, along with treatment prognosis. The findings and recommendations provide detailed, scientific, and reasonable individualized diagnosis and treatment strategies for clinicians.
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Affiliation(s)
- Xiufeng Liu
- Department of Medical Oncology, Bayi Hospital Affiliated to Nanjing Chinese Medical University, Nanjing, Jiangsu, China
| | - Feng Xia
- Department of Hepatobiliary Surgery, Southwest Hospital, Army Medical University, Chongqing, China
| | - Yue Chen
- Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Huichuan Sun
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhengqiang Yang
- Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Bo Chen
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ming Zhao
- Department of Minimally Invasive Interventional Therapy, Liver Cancer Study and Service Group, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Xinyu Bi
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Aizier Ainiwaer
- Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Zhiwen Luo
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Fusheng Wang
- Senior Department of Infectious Diseases, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Yinying Lu
- Comprehensive Liver Cancer Center, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - National Clinical Research Center for Infectious Diseases
- Department of Medical Oncology, Bayi Hospital Affiliated to Nanjing Chinese Medical University, Nanjing, Jiangsu, China
- Department of Hepatobiliary Surgery, Southwest Hospital, Army Medical University, Chongqing, China
- Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Minimally Invasive Interventional Therapy, Liver Cancer Study and Service Group, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
- Senior Department of Infectious Diseases, The Fifth Medical Center of PLA General Hospital, Beijing, China
- Comprehensive Liver Cancer Center, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Society of Hepatology, Beijing Medical Association
- Department of Medical Oncology, Bayi Hospital Affiliated to Nanjing Chinese Medical University, Nanjing, Jiangsu, China
- Department of Hepatobiliary Surgery, Southwest Hospital, Army Medical University, Chongqing, China
- Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Minimally Invasive Interventional Therapy, Liver Cancer Study and Service Group, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
- Senior Department of Infectious Diseases, The Fifth Medical Center of PLA General Hospital, Beijing, China
- Comprehensive Liver Cancer Center, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Translational Medicine Branch
- Department of Medical Oncology, Bayi Hospital Affiliated to Nanjing Chinese Medical University, Nanjing, Jiangsu, China
- Department of Hepatobiliary Surgery, Southwest Hospital, Army Medical University, Chongqing, China
- Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Minimally Invasive Interventional Therapy, Liver Cancer Study and Service Group, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
- Senior Department of Infectious Diseases, The Fifth Medical Center of PLA General Hospital, Beijing, China
- Comprehensive Liver Cancer Center, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - China Association of Gerontology and Geriatrics
- Department of Medical Oncology, Bayi Hospital Affiliated to Nanjing Chinese Medical University, Nanjing, Jiangsu, China
- Department of Hepatobiliary Surgery, Southwest Hospital, Army Medical University, Chongqing, China
- Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Minimally Invasive Interventional Therapy, Liver Cancer Study and Service Group, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
- Senior Department of Infectious Diseases, The Fifth Medical Center of PLA General Hospital, Beijing, China
- Comprehensive Liver Cancer Center, The Fifth Medical Center of PLA General Hospital, Beijing, China
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5
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Zarlashat Y, Abbas S, Ghaffar A. Hepatocellular Carcinoma: Beyond the Border of Advanced Stage Therapy. Cancers (Basel) 2024; 16:2034. [PMID: 38893154 PMCID: PMC11171154 DOI: 10.3390/cancers16112034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 04/27/2024] [Accepted: 05/23/2024] [Indexed: 06/21/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the deadliest emergent health issue around the globe. The stronger oncogenic effect, proteins, and weakened immune response are precisely linked with a significant prospect of developing HCC. Several conventional systemic therapies, antiangiogenic therapy, and immunotherapy techniques have significantly improved the outcomes for early-, intermediate-, and advanced-stage HCC patients, giving new hope for effective HCC management and prolonged survival rates. Innovative therapeutic approaches beyond conventional treatments have altered the landscape of managing HCC, particularly focusing on targeted therapies and immunotherapies. The advancement in HCC treatment suggested by the Food and Drug Administration is multidimensional treatment options, including multikinase inhibitors (sorafenib, lenvatinib, regorafenib, ramucirumab, and cabozantinib) and immune checkpoint inhibitors (atezolizumab, pembrolizumab, durvalumab, tremelimumab, ipilimumab, and nivolumab), in monotherapy and in combination therapy to increase life expectancy of HCC patients. This review highlights the efficacy of multikinase inhibitors and immune checkpoint inhibitors in monotherapy and combination therapy through the analysis of phase II, and III clinical trials, targeting the key molecular pathways involved in cellular signaling and immune response for the prospective treatment of advanced and unresectable HCC and discusses the upcoming combinations of immune checkpoint inhibitors-tyrosine kinase inhibitors and immune checkpoint inhibitors-vascular endothelial growth factor inhibitors. Finally, the hidden challenges with pharmacological therapy for HCC, feasible solutions for the future, and implications of possible presumptions to develop drugs for HCC treatment are reported.
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Affiliation(s)
- Yusra Zarlashat
- Department of Biochemistry, Government College University Faisalabad, Faisalabad 38000, Pakistan;
| | - Shakil Abbas
- Gomal Center of Biotechnology and Biochemistry (GCBB), Gomal University, Dera Ismail Khan 29050, Pakistan;
| | - Abdul Ghaffar
- Department of Biochemistry, Government College University Faisalabad, Faisalabad 38000, Pakistan;
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6
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Wei H, Dong C, Li X. Treatment Options for Hepatocellular Carcinoma Using Immunotherapy: Present and Future. J Clin Transl Hepatol 2024; 12:389-405. [PMID: 38638377 PMCID: PMC11022065 DOI: 10.14218/jcth.2023.00462] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 01/22/2024] [Accepted: 01/25/2024] [Indexed: 04/20/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a common cancer, and the body's immune responses greatly affect its progression and the prognosis of patients. Immunological suppression and the maintenance of self-tolerance in the tumor microenvironment are essential responses, and these form part of the theoretical foundations of immunotherapy. In this review, we first discuss the tumor microenvironment of HCC, describe immunosuppression in HCC, and review the major biomarkers used to track HCC progression and response to treatment. We then examine antibody-based therapies, with a focus on immune checkpoint inhibitors (ICIs), monoclonal antibodies that target key proteins in the immune response (programmed cell death protein 1, anti-cytotoxic T-lymphocyte associated protein 4, and programmed death-ligand 1) which have transformed the treatment of HCC and other cancers. ICIs may be used alone or in conjunction with various targeted therapies for patients with advanced HCC who are receiving first-line treatments or subsequent treatments. We also discuss the use of different cellular immunotherapies, including T cell receptor (TCR) T cell therapy and chimeric antigen receptor (CAR) T cell therapy. We then review the use of HCC vaccines, adjuvant immunotherapy, and oncolytic virotherapy, and describe the goals of future research in the development of treatments for HCC.
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Affiliation(s)
- Hongbin Wei
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China
- The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Chunlu Dong
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China
- The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Xun Li
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China
- The First Hospital of Lanzhou University, Lanzhou, Gansu, China
- Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, Gansu, China
- Cancer Prevention and Treatment Center of Lanzhou University School of Medicine, Lanzhou, Gansu, China
- Hepatopancreatobiliary Surgery Institute of Gansu Province, Lanzhou, Gansu, China
- Clinical Research Center for General Surgery of Gansu Province, Lanzhou, Gansu, China
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7
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Liao C, Zhang G, Huang R, Zeng L, Chen B, Dai H, Tang K, Lin R, Huang Y. Inducing the Abscopal Effect in Liver Cancer Treatment: The Impact of Microwave Ablation Power Levels and PD-1 Antibody Therapy. Pharmaceuticals (Basel) 2023; 16:1672. [PMID: 38139799 PMCID: PMC10747918 DOI: 10.3390/ph16121672] [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: 10/18/2023] [Revised: 11/15/2023] [Accepted: 11/27/2023] [Indexed: 12/24/2023] Open
Abstract
Microwave ablation (MWA) is an effective treatment for liver cancer (LC), but its impact on distant tumors remains to be fully elucidated. This study investigated the abscopal effects triggered by MWA treatment of LC, at different power levels and with or without combined immune checkpoint inhibition (ICI). We established a mouse model with bilateral subcutaneous LC and applied MWA of varied power levels to ablate the right-sided tumor, with or without immunotherapy. Left-sided tumor growth was monitored to assess the abscopal effect. Immune cell infiltration and distant tumor neovascularization were quantified via immunohistochemistry, revealing insights into the tumor microenvironment and neovascularization status. Th1- and Th2-type cytokine concentrations in peripheral blood were measured using ELISA to evaluate systemic immunological changes. It was found that MWA alone, especially at lower power, promoted distant tumor growth. On the contrary, combining high-power MWA with anti-programmed death (PD)-1 therapy promoted CD8+ T-cell infiltration, reduced regulatory T-cell infiltration, upregulated a Th1-type cytokine (TNF-α) in peripheral blood, and inhibited distant tumor growth. In summary, combining high-power MWA with ICI significantly enhances systemic antitumor immune responses and activates the abscopal effect, offering a facile and robust strategy for improving treatment outcomes.
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Affiliation(s)
- Changli Liao
- Department of Interventional Radiology, The First Affiliated Hospital, Sun Yat-sen University, No.58 Zhongshan 2nd Road, Guangzhou 510080, China; (C.L.); (G.Z.); (L.Z.); (B.C.); (H.D.); (K.T.)
- Department of Interventional Therapy, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, No. 55 South Renmin Road, Section 4, Chengdu 610041, China
| | - Guiyuan Zhang
- Department of Interventional Radiology, The First Affiliated Hospital, Sun Yat-sen University, No.58 Zhongshan 2nd Road, Guangzhou 510080, China; (C.L.); (G.Z.); (L.Z.); (B.C.); (H.D.); (K.T.)
| | - Ruotong Huang
- Department of Metabolism, Digestion, and Reproduction, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK;
| | - Linyuan Zeng
- Department of Interventional Radiology, The First Affiliated Hospital, Sun Yat-sen University, No.58 Zhongshan 2nd Road, Guangzhou 510080, China; (C.L.); (G.Z.); (L.Z.); (B.C.); (H.D.); (K.T.)
| | - Bin Chen
- Department of Interventional Radiology, The First Affiliated Hospital, Sun Yat-sen University, No.58 Zhongshan 2nd Road, Guangzhou 510080, China; (C.L.); (G.Z.); (L.Z.); (B.C.); (H.D.); (K.T.)
| | - Haitao Dai
- Department of Interventional Radiology, The First Affiliated Hospital, Sun Yat-sen University, No.58 Zhongshan 2nd Road, Guangzhou 510080, China; (C.L.); (G.Z.); (L.Z.); (B.C.); (H.D.); (K.T.)
| | - Keyu Tang
- Department of Interventional Radiology, The First Affiliated Hospital, Sun Yat-sen University, No.58 Zhongshan 2nd Road, Guangzhou 510080, China; (C.L.); (G.Z.); (L.Z.); (B.C.); (H.D.); (K.T.)
| | - Run Lin
- Department of Interventional Radiology, The First Affiliated Hospital, Sun Yat-sen University, No.58 Zhongshan 2nd Road, Guangzhou 510080, China; (C.L.); (G.Z.); (L.Z.); (B.C.); (H.D.); (K.T.)
| | - Yonghui Huang
- Department of Interventional Radiology, The First Affiliated Hospital, Sun Yat-sen University, No.58 Zhongshan 2nd Road, Guangzhou 510080, China; (C.L.); (G.Z.); (L.Z.); (B.C.); (H.D.); (K.T.)
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8
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Bicer F, Kure C, Ozluk AA, El-Rayes BF, Akce M. Advances in Immunotherapy for Hepatocellular Carcinoma (HCC). Curr Oncol 2023; 30:9789-9812. [PMID: 37999131 PMCID: PMC10670350 DOI: 10.3390/curroncol30110711] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 10/28/2023] [Accepted: 10/31/2023] [Indexed: 11/25/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related deaths in the world. More than half of patients with HCC present with advanced stage, and highly active systemic therapies are crucial for improving outcomes. Immune checkpoint inhibitor (ICI)-based therapies have emerged as novel therapy options for advanced HCC. Only one third of patients achieve an objective response with ICI-based therapies due to primary resistance or acquired resistance. The liver tumor microenvironment is naturally immunosuppressive, and specific mutations in cell signaling pathways allow the tumor to evade the immune response. Next, gene sequencing of the tumor tissue or circulating tumor DNA may delineate resistance mechanisms to ICI-based therapy and provide a rationale for novel combination therapies. In this review, we discuss the results of key clinical trials that have led to approval of ICI-based therapy options in advanced HCC and summarize the ongoing clinical trials. We review resistance mechanisms to ICIs and discuss how immunotherapies may be optimized based on the emerging research of tumor biomarkers and genomic alterations.
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Affiliation(s)
- Fuat Bicer
- Division of Hematology Oncology, Department of Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45267, USA;
| | - Catrina Kure
- Department of Medicine, Northside Hospital-Gwinnett, Lawrenceville, GA 30046, USA;
| | - Anil A. Ozluk
- Division of Hematology Oncology, Department of Medicine, O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL 35233, USA; (A.A.O.); (B.F.E.-R.)
| | - Bassel F. El-Rayes
- Division of Hematology Oncology, Department of Medicine, O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL 35233, USA; (A.A.O.); (B.F.E.-R.)
| | - Mehmet Akce
- Division of Hematology Oncology, Department of Medicine, O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL 35233, USA; (A.A.O.); (B.F.E.-R.)
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9
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Laface C, Memeo R. Clinical Updates for Gastrointestinal Malignancies. J Pers Med 2023; 13:1424. [PMID: 37763191 PMCID: PMC10533174 DOI: 10.3390/jpm13091424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 09/20/2023] [Indexed: 09/29/2023] Open
Abstract
Gastrointestinal (GI) cancers include hepatobiliary tumors, pancreatic cancer (PC), neuroendocrine tumors of the gastrointestinal tract, small bowel carcinomas, gastric cancer (GC), anal canal cancer, primary gastric and intestinal lymphomas, gastrointestinal stromal tumors (GISTs) and the most frequent colorectal cancer (CRC) [...].
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Affiliation(s)
- Carmelo Laface
- Medical Oncology, Dario Camberlingo Hospital, 72021 Francavilla Fontana, Italy
| | - Riccardo Memeo
- Unit of Hepato-Pancreatic-Biliary Surgery, “F. Miulli” General Regional Hospital, 70021 Acquaviva Delle Fonti, Italy
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10
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Parveen S, Ahmad SN, Mir AW, Shah AH, Mir TA, Rasool Z, Bhat MY, Dar NA, Bhat GM. Etiology, clinical profile, and treatment pattern of hepatocellular carcinoma at a tertiary care center in North India: A retrospective observational study. CANCER RESEARCH, STATISTICS, AND TREATMENT 2023; 6:400-407. [DOI: 10.4103/crst.crst_37_23] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 08/07/2023] [Indexed: 01/04/2025] Open
Affiliation(s)
- Shaheena Parveen
- Department of Gastroenterology, Sher-i-Kashmir Institute of Medical Sciences, Soura, Srinagar, Jammu and Kashmir, India
| | - Syed Nisar Ahmad
- Department of Medical Oncology, Sher-i-Kashmir Institute of Medical Sciences, Soura, Srinagar, Jammu and Kashmir, India
| | - Abdul Wahid Mir
- Department of Surgical Oncology, Sher-i-Kashmir Institute of Medical Sciences, Soura, Srinagar, Jammu and Kashmir, India
| | - Altaf Hussain Shah
- Department of Gastroenterology, Sher-i-Kashmir Institute of Medical Sciences, Soura, Srinagar, Jammu and Kashmir, India
| | - Tariq Abdullah Mir
- Department of Gastroenterology, Sher-i-Kashmir Institute of Medical Sciences, Soura, Srinagar, Jammu and Kashmir, India
| | - Zubaida Rasool
- Department of Pathology, Sher-i-Kashmir Institute of Medical Sciences, Soura, Srinagar, Jammu and Kashmir, India
| | - Mohamad Younis Bhat
- Department of Surgical Gastroenterology, Sher-i-Kashmir Institute of Medical Sciences, Soura, Srinagar, Jammu and Kashmir, India
| | - Nazir Ahmad Dar
- Department of Statistics, Sher-i-Kashmir Institute of Medical Sciences, Soura, Srinagar, Jammu and Kashmir, India
| | - Gull Mohammad Bhat
- Department of Medical Oncology, Sher-i-Kashmir Institute of Medical Sciences, Soura, Srinagar, Jammu and Kashmir, India
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11
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Roessler D, Öcal O, Philipp AB, Markwardt D, Munker S, Mayerle J, Jochheim LS, Hammer K, Lange CM, Geier A, Seidensticker M, Reiter FP, De Toni EN, Ben Khaled N. Ipilimumab and nivolumab in advanced hepatocellular carcinoma after failure of prior immune checkpoint inhibitor-based combination therapies: a multicenter retrospective study. J Cancer Res Clin Oncol 2023; 149:3065-3073. [PMID: 35864269 PMCID: PMC10314839 DOI: 10.1007/s00432-022-04206-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Accepted: 07/09/2022] [Indexed: 10/17/2022]
Abstract
INTRODUCTION Immune checkpoint inhibitor (ICI)-based regimens are transforming the landscape of hepatocellular carcinoma (HCC) treatment. We describe the effect of combined ipilimumab and nivolumab in patients with advanced HCC after the failure of prior ICI-based combination treatments. METHODS The clinical course of patients with advanced HCC who received combined ipilimumab and nivolumab after prior ICI-based combination therapies was assessed. Progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR) per RECIST v1.1 and mRECIST, overall survival (OS), and safety were analyzed. RESULTS Of 109 patients treated with atezolizumab and bevacizumab or other ICI-based combination treatments, ten patients received subsequent therapy with ipilimumab and nivolumab. The majority of patients had Barcelona Clinic Liver Cancer (BCLC) Stage C (80%) HCC and a preserved liver function as defined by Child-Pugh A (80%). At a median follow-up of 15.3 months, ORR for ipilimumab and nivolumab was 30% with a DCR of 40%. Median PFS was 2.9 months and the median OS was 7.4 months. CONCLUSION This retrospective study demonstrates that combined ipilimumab and nivolumab can be effective and tolerable after prior ICI-based combination therapies and provides a rationale for the prospective clinical evaluation of this treatment sequencing.
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Affiliation(s)
- Daniel Roessler
- Department of Medicine II, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Bavaria, Germany.
- Bavarian Cancer Research Center (BZKF), Partner site Munich, Munich, Germany.
| | - Osman Öcal
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Alexander B Philipp
- Department of Medicine II, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Bavaria, Germany
| | - Daniel Markwardt
- Department of Medicine II, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Bavaria, Germany
| | - Stefan Munker
- Department of Medicine II, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Bavaria, Germany
| | - Julia Mayerle
- Department of Medicine II, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Bavaria, Germany
- Bavarian Cancer Research Center (BZKF), Partner site Munich, Munich, Germany
| | - Leonie S Jochheim
- Department for Gastroenterology and Hepatology, University Hospital Essen, University Duisburg-Essen, Duisburg, Germany
| | - Katharina Hammer
- Department of Medicine II, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Bavaria, Germany
| | - Christian M Lange
- Department of Medicine II, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Bavaria, Germany
- Department for Gastroenterology and Hepatology, University Hospital Essen, University Duisburg-Essen, Duisburg, Germany
| | - Andreas Geier
- Division of Hepatology, Department of Medicine II, University Hospital Würzburg, Würzburg, Germany
| | - Max Seidensticker
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Florian P Reiter
- Division of Hepatology, Department of Medicine II, University Hospital Würzburg, Würzburg, Germany
| | - Enrico N De Toni
- Department of Medicine II, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Bavaria, Germany
| | - Najib Ben Khaled
- Department of Medicine II, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Bavaria, Germany
- German Cancer Consortium (DKTK), Partner site Munich, Munich, Germany
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12
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Ji JH, Ha SY, Lee D, Sankar K, Koltsova EK, Abou-Alfa GK, Yang JD. Predictive Biomarkers for Immune-Checkpoint Inhibitor Treatment Response in Patients with Hepatocellular Carcinoma. Int J Mol Sci 2023; 24:7640. [PMID: 37108802 PMCID: PMC10144688 DOI: 10.3390/ijms24087640] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 04/15/2023] [Accepted: 04/18/2023] [Indexed: 04/29/2023] Open
Abstract
Hepatocellular carcinoma (HCC) has one of the highest mortality rates among solid cancers. Late diagnosis and a lack of efficacious treatment options contribute to the dismal prognosis of HCC. Immune checkpoint inhibitor (ICI)-based immunotherapy has presented a new milestone in the treatment of cancer. Immunotherapy has yielded remarkable treatment responses in a range of cancer types including HCC. Based on the therapeutic effect of ICI alone (programmed cell death (PD)-1/programmed death-ligand1 (PD-L)1 antibody), investigators have developed combined ICI therapies including ICI + ICI, ICI + tyrosine kinase inhibitor (TKI), and ICI + locoregional treatment or novel immunotherapy. Although these regimens have demonstrated increasing treatment efficacy with the addition of novel drugs, the development of biomarkers to predict toxicity and treatment response in patients receiving ICI is in urgent need. PD-L1 expression in tumor cells received the most attention in early studies among various predictive biomarkers. However, PD-L1 expression alone has limited utility as a predictive biomarker in HCC. Accordingly, subsequent studies have evaluated the utility of tumor mutational burden (TMB), gene signatures, and multiplex immunohistochemistry (IHC) as predictive biomarkers. In this review, we aim to discuss the current state of immunotherapy for HCC, the results of the predictive biomarker studies, and future direction.
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Affiliation(s)
- Jun Ho Ji
- Division of Hematology and Oncology, Department of Internal Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon 51353, Republic of Korea
- Karsh Division of Gastroenterology and Hepatology, Comprehensive Transplant Center, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Sang Yun Ha
- Karsh Division of Gastroenterology and Hepatology, Comprehensive Transplant Center, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 03181, Republic of Korea
| | - Danbi Lee
- Karsh Division of Gastroenterology and Hepatology, Comprehensive Transplant Center, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
| | - Kamya Sankar
- Division of Medical Oncology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Ekaterina K. Koltsova
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Ghassan K. Abou-Alfa
- Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Weil Cornell Medicine, Cornell University, New York, NY 14853, USA
| | - Ju Dong Yang
- Karsh Division of Gastroenterology and Hepatology, Comprehensive Transplant Center, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
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13
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Mandlik DS, Mandlik SK, Choudhary HB. Immunotherapy for hepatocellular carcinoma: Current status and future perspectives. World J Gastroenterol 2023; 29:1054-1075. [PMID: 36844141 PMCID: PMC9950866 DOI: 10.3748/wjg.v29.i6.1054] [Citation(s) in RCA: 59] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 12/23/2022] [Accepted: 01/20/2023] [Indexed: 02/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the world’s deadliest and fastest-growing tumors, with a poor prognosis. HCC develops in the context of chronic liver disease. Curative resection, surgery (liver transplantation), trans-arterial chemoembolization, radioembolization, radiofrequency ablation and chemotherapy are common treatment options for HCC, however, they will only assist a limited percentage of patients. Current treatments for advanced HCC are ineffective and aggravate the underlying liver condition. Despite promising preclinical and early-phase clinical trials for some drugs, existing systemic therapeutic methods for advanced tumor stages remain limited, underlining an unmet clinical need. In current years, cancer immunotherapy has made significant progress, opening up new treatment options for HCC. HCC, on the other hand, has a variety of causes and can affects the body’s immune system via a variety of mechanisms. With the speedy advancement of synthetic biology and genetic engineering, a range of innovative immunotherapies, such as immune checkpoint inhibitors [anti-programmed cell death-1 (PD-1), anti-cytotoxic T lymphocyte antigen-4, and anti-PD ligand 1 cell death antibodies], therapeutic cancer vaccines, engineered cytokines, and adoptive cell therapy have all been used for the treatment of advanced HCC. In this review, we summarize the present clinical and preclinical landscape of immunotherapies in HCC, critically discuss recent clinical trial outcomes, and address future perspectives in the field of liver cancer.
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Affiliation(s)
- Deepa S Mandlik
- Department of Pharmacology, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
| | - Satish K Mandlik
- Department of Pharmaceutics, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
| | - Heena B Choudhary
- Department of Pharmacology, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
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14
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Gao B, Wang Y, Li C, Lu S. Estrogen-related genes influence immune cell infiltration and immunotherapy response in Hepatocellular Carcinoma. Front Immunol 2023; 14:1114717. [PMID: 36814910 PMCID: PMC9939443 DOI: 10.3389/fimmu.2023.1114717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 01/25/2023] [Indexed: 02/08/2023] Open
Abstract
Background Immunotherapy has been the first-line treatment option in advanced Hepatocellular Carcinoma(HCC); but now, there are no established molecular markers that can predict immunotherapy response. Estrogen has a crucial role in the development of a variety of liver illnesses, including liver fibrosis, Nonalcoholic fatty liver disease (NAFLD), and HCC. Nonetheless, the significance of estrogen-related genes in HCC immunotherapy and the underlying molecular mechanisms are not yet fully understood. Method In this study, we constructed a novel estrogen-related gene prognostic signature (ERGPS) by analyzing bulk RNA sequencing data from 365 HCC patients. Based on the median risk score, we divided 365 HCC patients into low- and high-risk groups. Tumor mutation burden (TMB), Microsatellite instability (MSI), T cell receptor (TCR) richness, B cell receptor (BCR) richness, single-nucleotide variants (SNV) Neoantigens, Cancer Testicular Antigens (CTA) scores, and Tumour Immune Dysfunction and Exclusion (TIDE) scores were used to evaluate the magnitude of immunotherapy response. Multiple external datasets validate the validity and robustness of the prognostic signature. Real-time quantitative polymerase chain reaction (qRT-PCR) was used to validate estrogen-related gene overexpression in HCC tissue samples. Results ERGPS is an independent risk factor affecting the prognosis of HCC patients and is superior to other clinical variables in predicting patient survival and immunotherapy response. Multiple independent external datasets confirmed the superior predictive efficacy of the prognostic signature. The prognostic signature was positively correlated with TMB score, MSI score, TCR richness, BCR richness, SNV Neoantigens score, CTA score, expression levels of immune checkpoint-related genes, and TIDE score. Patients with HCC in the high-risk group identified by the prognostic signature were likely to be more responsive to immunotherapy and more suitable for immunotherapy. qRT-PCR confirmed that estrogen-related genes of the construct signature were highly expressed in HCC tumor tissues. Conclusion Estrogen-related genes are overexpressed in HCC tissues. Our novel prognostic signature can accurately predict not only the prognosis but also the immunotherapy response of HCC patients. In the future, prognostic signatures will be a useful tool for clinicians to screen patients with HCC who are suitable for immunotherapy.
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Affiliation(s)
- Biao Gao
- Nankai University School of Medicine, Nankai University, Tianjin, China,Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital, Beijing, China
| | - Yafei Wang
- Nankai University School of Medicine, Nankai University, Tianjin, China,Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital, Beijing, China
| | - Chonghui Li
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital, Beijing, China,Institute of Hepatobiliary Surgery, Chinese PLA General Hospital, Beijing, China,*Correspondence: Chonghui Li, ; Shichun Lu,
| | - Shichun Lu
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital, Beijing, China,Institute of Hepatobiliary Surgery, Chinese PLA General Hospital, Beijing, China,*Correspondence: Chonghui Li, ; Shichun Lu,
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15
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Laface C, Ranieri G, Maselli FM, Ambrogio F, Foti C, Ammendola M, Laterza M, Cazzato G, Memeo R, Mastrandrea G, Lioce M, Fedele P. Immunotherapy and the Combination with Targeted Therapies for Advanced Hepatocellular Carcinoma. Cancers (Basel) 2023; 15:654. [PMID: 36765612 PMCID: PMC9913568 DOI: 10.3390/cancers15030654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 01/11/2023] [Accepted: 01/17/2023] [Indexed: 01/24/2023] Open
Abstract
One of the most important abilities of a tumor is to establish a state of immunosuppression inside the tumor microenvironment. This is made possible through numerous mechanisms of tumor immune escape that have been identified in experimental studies during the last decades. In addition, the hepatic microenvironment is commonly oriented towards a state of immune tolerance because the liver receives blood from the hepatic arteries and portal veins containing a variety of endogenous antigens. Therefore, the hepatic microenvironment establishes an autoimmune tolerance, preventing an autoimmune reaction in the liver. On this basis, hepatic tumor cells may escape the immune system, avoiding being recognized and destroyed by immune cells. Moreover, since the etiology of Hepatocellular Carcinoma (HCC) is often related to cirrhosis, and hepatitis B or C, this tumor develops in the context of chronic inflammation. Thus, the HCC microenvironment is characterized by important immune cell infiltration. Given these data and the poor prognosis of advanced HCC, different immunotherapeutic strategies have been developed and evaluated for these patients. In this review, we describe all the clinical applications of immunotherapy for advanced HCC, from the drugs that have already been approved to the ongoing clinical trials.
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Affiliation(s)
- Carmelo Laface
- Medical Oncology, Dario Camberlingo Hospital, 72021 Francavilla Fontana, Italy
| | | | | | - Francesca Ambrogio
- Section of Dermatology, Department of Biomedical Science and Human Oncology, University of Bari, 70124 Bari, Italy
| | - Caterina Foti
- Section of Dermatology, Department of Biomedical Science and Human Oncology, University of Bari, 70124 Bari, Italy
| | - Michele Ammendola
- Department of Health Science, General Surgery, Medicine School of Germaneto, Magna Graecia University, 88100 Catanzaro, Italy
| | - Marigia Laterza
- Division of Cardiac Surgery, University of Bari, 70124 Bari, Italy
| | - Gerardo Cazzato
- Department of Emergency and Organ Transplantation, Pathology Section, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy
| | - Riccardo Memeo
- Unit of Hepato-Pancreatic-Biliary Surgery, “F. Miulli” General Regional Hospital, 70021 Acquaviva Delle Fonti, Italy
| | | | - Marco Lioce
- IRCCS Istituto Tumori “Giovanni Paolo II”, 70124 Bari, Italy
| | - Palma Fedele
- Medical Oncology, Dario Camberlingo Hospital, 72021 Francavilla Fontana, Italy
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16
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Hepatocellular Carcinoma: Current Therapeutic Algorithm for Localized and Advanced Disease. JOURNAL OF ONCOLOGY 2022; 2022:3817724. [PMID: 36624801 PMCID: PMC9825221 DOI: 10.1155/2022/3817724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 12/16/2022] [Accepted: 12/19/2022] [Indexed: 01/02/2023]
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer in patients with liver cirrhosis of various etiologies. In recent years, there has been an advance in the knowledge of molecular mechanisms and a better staging definition of patients which has allowed the development of new therapies that have entered the therapeutic workup of these patients. Deep information on molecular drivers of HCC contributed to the development of targeted therapies with remarkable benefits. The novel strategies of targeting immune evasion using immune checkpoint inhibitors and CAR-T and TCR-T therapeutics have also shown promising results. For advanced diseases, the therapeutic algorithm has been recently updated, thanks to the efficacy of combining immunotherapy and antiangiogenic therapy in the first-line setting, and new drugs, both as single-agents or combinations, are currently under investigation.
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17
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Ahn JC, Lauzon M, Luu M, Noureddin M, Ayoub W, Kuo A, Sundaram V, Kosari K, Nissen N, Gong J, Hendifar A, Roberts LR, Abou-Alfa GK, Singal AG, Yang JD. Racial and ethnic disparities in early treatment with immunotherapy for advanced HCC in the United States. Hepatology 2022; 76:1649-1659. [PMID: 35429171 DOI: 10.1002/hep.32527] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 03/29/2022] [Accepted: 04/04/2022] [Indexed: 12/26/2022]
Abstract
BACKGROUND AND AIMS Immunotherapy has emerged as an effective treatment for patients with advanced-stage HCC. We aimed to investigate the efficacy of immunotherapy for advanced HCC in a nationwide cohort and racial and ethnic disparities in access to immunotherapy. APPROACH AND RESULTS We used the US National Cancer Database to identify patients with tumor-node-metastasis stage 3 or 4 HCC between 2017 and 2018. We performed multivariable Cox regression to identify factors associated with overall survival (OS) and logistic regression to identify factors associated with receipt of immunotherapy. Of the 3,990 patients treated for advanced HCC, 3,248 (81.4%) patients received chemotherapy and 742 (18.6%) patients received immunotherapy as a first-line treatment. Immunotherapy was associated with improved OS compared with chemotherapy (adjusted HR: 0.76, 95% CI: 0.65-0.88) after adjusting for covariates. There were racial and ethnic disparities in access to immunotherapy, with Hispanic (adjusted OR [aOR]: 0.63, 95% CI: 0.46-0.83) and Black patients (aOR: 0.71, 95% CI: 0.54-0.89) less likely to receive immunotherapy compared with White patients. There was a significant interaction between race-ethnicity and facility type, with higher disparity observed in nonacademic centers (interaction p = 0.004). CONCLUSIONS Immunotherapy was associated with improved OS compared with chemotherapy in advanced HCC. There are significant disparities in early access to immunotherapy, likely due to differential access to clinical trials and experimental therapies. A comprehensive approach to monitoring and eliminating racial-ethnic disparities in the management of advanced HCC is urgently needed.
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Affiliation(s)
- Joseph C Ahn
- Division of Gastroenterology and HepatologyMayo ClinicRochesterMinnesotaUSA
| | - Marie Lauzon
- 22494Biostatistics and Bioinformatics Research CenterCedars-Sinai Medical CenterLos AngelesCaliforniaUSA
| | - Michael Luu
- 22494Biostatistics and Bioinformatics Research CenterCedars-Sinai Medical CenterLos AngelesCaliforniaUSA
| | - Mazen Noureddin
- 22494Comprehensive Transplant CenterCedars-Sinai Medical CenterLos AngelesCaliforniaUSA.,22494Karsh Division of Gastroenterology and HepatologyCedars-Sinai Medical CenterLos AngelesCaliforniaUSA
| | - Walid Ayoub
- 22494Comprehensive Transplant CenterCedars-Sinai Medical CenterLos AngelesCaliforniaUSA.,22494Karsh Division of Gastroenterology and HepatologyCedars-Sinai Medical CenterLos AngelesCaliforniaUSA
| | - Alexander Kuo
- 22494Comprehensive Transplant CenterCedars-Sinai Medical CenterLos AngelesCaliforniaUSA.,22494Karsh Division of Gastroenterology and HepatologyCedars-Sinai Medical CenterLos AngelesCaliforniaUSA
| | - Vinay Sundaram
- 22494Comprehensive Transplant CenterCedars-Sinai Medical CenterLos AngelesCaliforniaUSA.,22494Karsh Division of Gastroenterology and HepatologyCedars-Sinai Medical CenterLos AngelesCaliforniaUSA
| | - Kambiz Kosari
- 22494Comprehensive Transplant CenterCedars-Sinai Medical CenterLos AngelesCaliforniaUSA.,22494Samuel Oschin Comprehensive Cancer InstituteCedars-Sinai Medical CenterLos AngelesCaliforniaUSA.,22494Department of SurgeryCedars-Sinai Medical CenterLos AngelesCaliforniaUSA
| | - Nicholas Nissen
- 22494Comprehensive Transplant CenterCedars-Sinai Medical CenterLos AngelesCaliforniaUSA.,22494Samuel Oschin Comprehensive Cancer InstituteCedars-Sinai Medical CenterLos AngelesCaliforniaUSA.,22494Department of SurgeryCedars-Sinai Medical CenterLos AngelesCaliforniaUSA
| | - Jun Gong
- 22494Samuel Oschin Comprehensive Cancer InstituteCedars-Sinai Medical CenterLos AngelesCaliforniaUSA
| | - Andrew Hendifar
- 22494Samuel Oschin Comprehensive Cancer InstituteCedars-Sinai Medical CenterLos AngelesCaliforniaUSA
| | - Lewis R Roberts
- Division of Gastroenterology and HepatologyMayo ClinicRochesterMinnesotaUSA
| | - Ghassan K Abou-Alfa
- Department of MedicineMemorial Sloan Kettering Cancer CenterNew YorkNew YorkUSA.,Department of MedicineWeill Medical College at Cornell UniversityNew YorkNew YorkUSA
| | - Amit G Singal
- Harold C. Simmons Comprehensive Cancer CenterUT Southwestern Medical CenterDallasTexasUSA.,Division of Digestive and Liver DiseasesUT Southwestern Medical CenterDallasTexasUSA
| | - Ju Dong Yang
- 22494Comprehensive Transplant CenterCedars-Sinai Medical CenterLos AngelesCaliforniaUSA.,22494Karsh Division of Gastroenterology and HepatologyCedars-Sinai Medical CenterLos AngelesCaliforniaUSA.,22494Samuel Oschin Comprehensive Cancer InstituteCedars-Sinai Medical CenterLos AngelesCaliforniaUSA
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18
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Storandt MH, Mahipal A, Tella SH, Kommalapati A, Jin Z. Systemic Therapy in Advanced Hepatocellular Carcinoma: Patient Selection and Key Considerations. J Hepatocell Carcinoma 2022; 9:1187-1200. [PMID: 36471742 PMCID: PMC9719284 DOI: 10.2147/jhc.s365002] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 11/04/2022] [Indexed: 08/30/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. Most patients with HCC have advanced disease at initial diagnosis, and sorafenib has been the only systemic treatment option for more than a decade in patients with advanced, unresectable HCC. However, there has been a dramatic change in the treatment algorithm in the last several years, given new drug approvals in the field. Most importantly, the combination of atezolizumab and bevacizumab has demonstrated clinically meaningful benefits in terms of response rate, progression-free survival, and overall survival compared to sorafenib in the first-line setting. Recently a phase III trial showed that the combination of durvalumab with a single dose of tremelimumab improved overall survival compared to sorafenib, while durvalumab monotherapy was found to be noninferior to sorafenib, making it an attractive alternative single agent in selected patient populations. As immunotherapy makes its way into the therapeutic landscape of HCC, other novel targeted therapies, such as lenvatinib, cabozantinib, ramucirumab, and regorafenib, have also been approved by regulatory authorities for treatment of advanced, unresectable HCC. This review article focuses on the first-line systemic treatment options for HCC while addressing some of the most important questions aimed at optimization of HCC treatment.
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Affiliation(s)
| | - Amit Mahipal
- Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA
| | | | | | - Zhaohui Jin
- Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA
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19
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Anderson TS, Wooster AL, Piersall SL, Okpalanwaka IF, Lowe DB. Disrupting cancer angiogenesis and immune checkpoint networks for improved tumor immunity. Semin Cancer Biol 2022; 86:981-996. [PMID: 35149179 PMCID: PMC9357867 DOI: 10.1016/j.semcancer.2022.02.009] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/11/2022] [Accepted: 02/05/2022] [Indexed: 01/27/2023]
Abstract
Immune checkpoint inhibitors (ICIs) have advanced the field of cancer immunotherapy in patients by sustaining effector immune cell activity within the tumor microenvironment. However, the approach in general is still faced with issues related to ICI response duration/resistance, treatment eligibility, and safety, which indicates a need for further refinements. As immune checkpoint upregulation is inextricably linked to cancer-induced angiogenesis, newer clinical efforts have demonstrated the feasibility of disrupting both tumor-promoting networks to mediate enhanced immune-driven protection. This review focuses on such key evidence stipulating the necessity of co-applying ICI and anti-angiogenic strategies in cancer patients, with particular interest in highlighting newer engineered antibody approaches that may provide theoretically superior multi-pronged and safe therapeutic combinations.
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Affiliation(s)
- Trevor S Anderson
- Department of Immunotherapeutics and Biotechnology, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX, 79601, United States
| | - Amanda L Wooster
- Department of Immunotherapeutics and Biotechnology, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX, 79601, United States
| | - Savanna L Piersall
- Department of Immunotherapeutics and Biotechnology, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX, 79601, United States
| | - Izuchukwu F Okpalanwaka
- Department of Immunotherapeutics and Biotechnology, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX, 79601, United States
| | - Devin B Lowe
- Department of Immunotherapeutics and Biotechnology, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX, 79601, United States.
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20
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Qin LX. Immunotherapy for hepatobiliary malignancies: Progress and prospective. Hepatobiliary Pancreat Dis Int 2022; 21:409-412. [PMID: 36117110 DOI: 10.1016/j.hbpd.2022.09.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Accepted: 08/31/2022] [Indexed: 02/05/2023]
Affiliation(s)
- Lun-Xiu Qin
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China.
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21
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Zhu Y, Qin LX. Strategies for improving the efficacy of immunotherapy in hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int 2022; 21:420-429. [PMID: 35977874 DOI: 10.1016/j.hbpd.2022.08.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 08/02/2022] [Indexed: 02/05/2023]
Abstract
Primary liver cancer, mainly hepatocellular carcinoma (HCC), is the sixth most diagnosed cancer and third leading cause of cancer-related death globally. Recently, immunotherapies such as immune checkpoint inhibitors (ICIs) have made great progress in the systemic treatment of HCC. However, anti-PD-1 therapy with pembrolizumab or nivolumab as a single agent did not meet their predefined end points of overall survival in the KEYNOTE-240 and CheckMate 459 trials. It is urgent to understand the immunological rationale and explore novel ways to improve the efficacy of immunotherapy. The combination of ICIs with other therapies, such as tyrosine kinase inhibitors (TKIs), monoclonal antibodies, or local therapy, has been demonstrated to improve overall response rate and survival. In addition, modulating tumor microenvironment is a potential way to overcome the primary and secondary resistance to immunotherapies. In this review, we summarized the latest findings in the immune microenvironment, the mechanisms of their synergistic effects when combined with anti-VEGF agents or TKIs, as well as other kinds of immune treatment.
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Affiliation(s)
- Ying Zhu
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai 200040, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Lun-Xiu Qin
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai 200040, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
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22
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D’Alessio A, Fulgenzi CAM, Nishida N, Schönlein M, von Felden J, Schulze K, Wege H, Gaillard VE, Saeed A, Wietharn B, Hildebrand H, Wu L, Ang C, Marron TU, Weinmann A, Galle PR, Bettinger D, Bengsch B, Vogel A, Balcar L, Scheiner B, Lee P, Huang Y, Amara S, Muzaffar M, Naqash AR, Cammarota A, Personeni N, Pressiani T, Sharma R, Pinter M, Cortellini A, Kudo M, Rimassa L, Pinato DJ. Preliminary evidence of safety and tolerability of atezolizumab plus bevacizumab in patients with hepatocellular carcinoma and Child-Pugh A and B cirrhosis: A real-world study. Hepatology 2022; 76:1000-1012. [PMID: 35313048 PMCID: PMC9790703 DOI: 10.1002/hep.32468] [Citation(s) in RCA: 163] [Impact Index Per Article: 54.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 02/25/2022] [Accepted: 03/10/2022] [Indexed: 12/31/2022]
Abstract
BACKGROUND AND AIMS Atezolizumab plus bevacizumab (AtezoBev) is the standard of care for first-line treatment of unresectable HCC. No evidence exists as to its use in routine clinical practice in patients with impaired liver function. APPROACH AND RESULTS In 216 patients with HCC who were consecutively treated with AtezoBev across 11 tertiary centers, we retrospectively evaluated treatment-related adverse events (trAEs) graded (G) according to Common Terminology Criteria for Adverse Events v5.0, including in the analysis all patients treated according to label (n = 202, 94%). We also assessed overall survival (OS), progression-free survival (PFS), overall response (ORR), and disease control rates (DCR) defined by Response Evaluation Criteria in Solid Tumors v1.1. Disease was mostly secondary to viral hepatitis, namely hepatitis C (n = 72; 36%) and hepatitis B infection (n = 35, 17%). Liver function was graded as Child-Pugh (CP)-A in 154 patients (76%) and CP-B in 48 (24%). Any grade trAEs were reported by 143 patients (71%), of which 53 (26%) were G3 and 3 (2%) G4. Compared with CP-A, patients with CP-B showed comparable rates of trAEs. Presence and grade of varices at pretreatment esophagogastroduodenoscopy did not correlate with bleeding events. After a median follow-up of 9.0 months (95% CI, 7.8-10.1), median OS was 14.9 months (95% CI, 13.6-16.3), whereas median PFS was 6.8 months (95% CI, 5.2-8.5). ORR and DCR were respectively 25% and 73%, with no difference across CP classes. CONCLUSIONS This study confirms reproducible safety and efficacy of AtezoBev in routine practice. Patients with CP-B reported similar tolerability compared with CP-A, warranting prospective evaluation of AtezoBev in this treatment-deprived population.
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Affiliation(s)
- Antonio D’Alessio
- Department of Surgery & CancerImperial College LondonHammersmith HospitalLondonUK
- Department of Biomedical SciencesHumanitas UniversityPieve Emanuele, MilanItaly
| | - Claudia Angela Maria Fulgenzi
- Department of Surgery & CancerImperial College LondonHammersmith HospitalLondonUK
- Division of Medical OncologyPoliclinico Universitario Campus Bio‐MedicoRomeItaly
| | - Naoshi Nishida
- Department of Gastroenterology and HepatologyKindai University Faculty of MedicineOsakaJapan
| | - Martin Schönlein
- Department of Oncology, Hematology and Bone Marrow Transplantation with Section of PneumologyUniversity Medical Center Hamburg‐EppendorfHamburgGermany
| | - Johann von Felden
- Department of MedicineUniversity Medical Center Hamburg‐EppendorfHamburgGermany
| | - Kornelius Schulze
- Department of MedicineUniversity Medical Center Hamburg‐EppendorfHamburgGermany
| | - Henning Wege
- Department of MedicineUniversity Medical Center Hamburg‐EppendorfHamburgGermany
| | | | - Anwaar Saeed
- Division of Medical OncologyDepartment of MedicineKansas University Cancer CenterKansas CityKansasUSA
| | - Brooke Wietharn
- Division of Medical OncologyDepartment of MedicineKansas University Cancer CenterKansas CityKansasUSA
| | - Hannah Hildebrand
- Division of Medical OncologyDepartment of MedicineKansas University Cancer CenterKansas CityKansasUSA
| | - Linda Wu
- Division of Hematology/OncologyDepartment of MedicineTisch Cancer InstituteMount Sinai HospitalNew YorkNew YorkUSA
| | - Celina Ang
- Division of Hematology/OncologyDepartment of MedicineTisch Cancer InstituteMount Sinai HospitalNew YorkNew YorkUSA
| | - Thomas U. Marron
- Division of Hematology/OncologyDepartment of MedicineTisch Cancer InstituteMount Sinai HospitalNew YorkNew YorkUSA
| | | | | | - Dominik Bettinger
- Department of Medicine II (Gastroenterology, Hepatology, Endocrinology and Infectious Diseases)Faculty of MedicineFreiburg University Medical CenterUniversity of FreiburgFreiburgGermany
| | - Bertram Bengsch
- Department of Medicine II (Gastroenterology, Hepatology, Endocrinology and Infectious Diseases)Faculty of MedicineFreiburg University Medical CenterUniversity of FreiburgFreiburgGermany
- University of FreiburgSignalling Research Centres BIOSS and CIBSSFreiburgGermany
- German Cancer Consortium (DKTK), partner siteFreiburgGermany
| | | | - Lorenz Balcar
- Division of Gastroenterology & HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Bernhard Scheiner
- Division of Gastroenterology & HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Pei‐Chang Lee
- Division of Gastroenterology and HepatologyDepartment of MedicineTaipei Veterans General HospitalTaipeiTaiwan
| | - Yi‐Hsiang Huang
- Division of Gastroenterology and HepatologyDepartment of MedicineTaipei Veterans General HospitalTaipeiTaiwan
- Institute of Clinical MedicineSchool of MedicineNational Yang Ming Chiao Tung UniversityTaipeiTaiwan
| | - Suneetha Amara
- Division of Hematology/OncologyEast Carolina UniversityGreenvilleNorth CarolinaUSA
| | - Mahvish Muzaffar
- Division of Hematology/OncologyEast Carolina UniversityGreenvilleNorth CarolinaUSA
| | - Abdul Rafeh Naqash
- Division of Hematology/OncologyEast Carolina UniversityGreenvilleNorth CarolinaUSA
- Medical Oncology/TSET Phase 1 ProgramStephenson Cancer CenterUniversity of OklahomaNormanOklahomaUSA
| | - Antonella Cammarota
- Department of Biomedical SciencesHumanitas UniversityPieve Emanuele, MilanItaly
- Medical Oncology and Hematology UnitHumanitas Cancer CenterIRCCS Humanitas Research HospitalRozzanoMilanItaly
| | - Nicola Personeni
- Department of Biomedical SciencesHumanitas UniversityPieve Emanuele, MilanItaly
- Medical Oncology and Hematology UnitHumanitas Cancer CenterIRCCS Humanitas Research HospitalRozzanoMilanItaly
| | - Tiziana Pressiani
- Medical Oncology and Hematology UnitHumanitas Cancer CenterIRCCS Humanitas Research HospitalRozzanoMilanItaly
| | - Rohini Sharma
- Department of Surgery & CancerImperial College LondonHammersmith HospitalLondonUK
| | - Matthias Pinter
- Division of Gastroenterology & HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Alessio Cortellini
- Department of Surgery & CancerImperial College LondonHammersmith HospitalLondonUK
| | - Masatoshi Kudo
- Department of Gastroenterology and HepatologyKindai University Faculty of MedicineOsakaJapan
| | - Lorenza Rimassa
- Department of Biomedical SciencesHumanitas UniversityPieve Emanuele, MilanItaly
- Medical Oncology and Hematology UnitHumanitas Cancer CenterIRCCS Humanitas Research HospitalRozzanoMilanItaly
| | - David J. Pinato
- Department of Surgery & CancerImperial College LondonHammersmith HospitalLondonUK
- Division of OncologyDepartment of Translational MedicineUniversity of Piemonte OrientaleNovaraItaly
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23
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Yao J, Zhu X, Wu Z, Wei Q, Cai Y, Zheng Y, Hu X, Hu H, Zhang X, Pan H, Zhong X, Han W. Efficacy and safety of PD-1 inhibitor combined with antiangiogenic therapy for unresectable hepatocellular carcinoma: A multicenter retrospective study. Cancer Med 2022; 11:3612-3622. [PMID: 35403359 PMCID: PMC9554456 DOI: 10.1002/cam4.4747] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 03/01/2022] [Accepted: 04/01/2022] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Immunotherapy-antiangiogenesis combination therapy has achieved excellent survival outcomes in hepatocellular carcinoma (HCC) in clinical trials. However, the combination therapy for HCC outside clinical trials is not well studied, and predictive factors are lacking. Here, we retrospectively analyzed the efficacy and safety of immunotherapy-antiangiogenesis combination therapy in unresectable HCC patients in a real-world setting. METHODS We conducted a four-center, retrospective study of unresectable HCC patients who received the combination of programmed death 1 (PD-1) inhibitor and antiangiogenic agent between April 2018 and July 2021 in China. RESULTS In total, 136 patients were enrolled in the cohort. The objective response rate (ORR) and disease control rate (DCR) were 38.0% and 81.8%, respectively. The median time to progression (TTP), progression-free survival (PFS), and overall survival (OS) were 7.2, 7.3, and 19.6 months, respectively. The multivariate analysis indicated that ECOG performance status score (PS) 2 was a significantly independent negative factor of ORR. Moreover, ECOG PS 2, peritoneum metastasis and previous immunotherapy were found to be independent negative predictors of PFS. A shorter OS was associated with ECOG PS 2, peritoneum metastasis, the presence of previous immunotherapy, Child-Pugh stage B, and high alpha-fetoprotein (AFP) concentration. One hundred and twenty-five patients (91.9%) reported adverse events (AEs) with any grade. CONCLUSION We elucidated the efficacy and safety of immunotherapy-antiangiogenesis combination therapy and identified potential predictors for response and survival in a real-world cohort of patients with unresectable HCC.
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Affiliation(s)
- Junlin Yao
- Department of Medical Oncology, Sir Run Run Shaw Hospital, College of MedicineZhejiang UniversityHangzhouZhejiangChina
| | - Xudong Zhu
- Department of Medical Oncology, The First Affiliated Hospital, College of MedicineZhejiang UniversityHangzhouZhejiangChina
| | - Zhiheng Wu
- Department of Medical Oncology, Sir Run Run Shaw Hospital, College of MedicineZhejiang UniversityHangzhouZhejiangChina
| | - Qing Wei
- Department of Medical OncologyCancer Hospital of the University of Chinese Academy of SciencesZhejiang Cancer HospitalHangzhouZhejiangChina
| | - Yibo Cai
- Department of Colorectal SurgeryCancer Hospital of University of Chinese Academy of SciencesZhejiang Cancer HospitalHangzhouZhejiangChina
| | - Yu Zheng
- Department of Medical Oncology, Sir Run Run Shaw Hospital, College of MedicineZhejiang UniversityHangzhouZhejiangChina
| | - Xinyu Hu
- Department of Medical Oncology, Sir Run Run Shaw Hospital, College of MedicineZhejiang UniversityHangzhouZhejiangChina
- Present address:
Shaoxing Shangyu Hospital of Traditional Chinese MedicineShangyuZhejiangChina
| | - Hong Hu
- Department of Medical Oncology, Sir Run Run Shaw Hospital, College of MedicineZhejiang UniversityHangzhouZhejiangChina
| | - Xiangyu Zhang
- Department of General Surgery, Sir Run Run Shaw Hospital, College of MedicineZhejiang UniversityHangzhouZhejiangChina
| | - Hongming Pan
- Department of Medical Oncology, Sir Run Run Shaw Hospital, College of MedicineZhejiang UniversityHangzhouZhejiangChina
| | - Xian Zhong
- Department of Medical Oncology, The Second Affiliated Hospital, College of MedicineZhejiang UniversityHangzhouZhejiangChina
| | - Weidong Han
- Department of Medical Oncology, Sir Run Run Shaw Hospital, College of MedicineZhejiang UniversityHangzhouZhejiangChina
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24
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Cammarota A, Zanuso V, Pressiani T, Personeni N, Rimassa L. Assessment and Monitoring of Response to Systemic Treatment in Advanced Hepatocellular Carcinoma: Current Insights. J Hepatocell Carcinoma 2022; 9:1011-1027. [PMID: 36128575 PMCID: PMC9482774 DOI: 10.2147/jhc.s268293] [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: 05/31/2022] [Accepted: 08/22/2022] [Indexed: 11/23/2022] Open
Abstract
Advanced hepatocellular carcinoma (HCC) management has become more complex as novel therapies have been proven effective. After sorafenib, the approval of other multikinase inhibitors (MKIs) and immune checkpoints inhibitors (ICIs) has considerably increased the number of systemic therapies available. Therefore, careful assessment and monitoring of response to systemic treatment are essential to identify surrogate endpoints of overall survival (OS) in clinical trials and reliable tools to gauge treatment benefit in clinical practice. Progression-free survival (PFS) and objective response rate (ORR) are early informative parameters of efficacy that are not influenced by further lines of therapy. However, none of them has shown sufficient surrogacy to be recommended in place of OS in phase 3 trials. With such a wealth of therapeutic options, the prime intent of tumor assessments is no longer limited to identifying progressive disease to spare ineffective treatments to non-responders. Indeed, the early detection of responders could also help tailor treatment sequencing. Tumor assessment relies on the Response Evaluation Criteria for Solid Tumors (RECIST), which are easy to interpret - being based on dimensional principles - but could misread the activity of targeted agents. The HCC-specific modified RECIST (mRECIST), considering both the MKI-induced biological modifications and some of the cirrhosis-induced liver changes, better capture tumor response. Yet, mRECIST could not be considered a standard in advanced HCC. Further prognosticators including progression patterns, baseline and on-treatment liver function deterioration, and baseline alpha-fetoprotein (AFP) levels and AFP response have been extensively evaluated for MKIs. However, limited information is available for patients receiving ICIs and regarding their predictive role. Finally, there is increasing interest in incorporating novel imaging techniques which go beyond sizes and novel serum biomarkers in the advanced HCC framework. Hopefully, multiparametric models grouping dimensional and functional radiological parameters with biochemical markers will most precisely reflect treatment response.
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Affiliation(s)
- Antonella Cammarota
- Department of Biomedical Sciences, Humanitas University, Milan, Pieve Emanuele, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Milan, Rozzano, Italy
| | - Valentina Zanuso
- Department of Biomedical Sciences, Humanitas University, Milan, Pieve Emanuele, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Milan, Rozzano, Italy
| | - Tiziana Pressiani
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Milan, Rozzano, Italy
| | - Nicola Personeni
- Department of Biomedical Sciences, Humanitas University, Milan, Pieve Emanuele, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Milan, Rozzano, Italy
| | - Lorenza Rimassa
- Department of Biomedical Sciences, Humanitas University, Milan, Pieve Emanuele, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Milan, Rozzano, Italy
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25
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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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26
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Sidali S, Trépo E, Sutter O, Nault J. New concepts in the treatment of hepatocellular carcinoma. United European Gastroenterol J 2022; 10:765-774. [PMID: 35975347 PMCID: PMC9486494 DOI: 10.1002/ueg2.12286] [Citation(s) in RCA: 64] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 07/25/2022] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death and occurs mainly in the context of chronic liver disease at cirrhosis stage. The Barcelona Clinic Liver Cancer classification, first established in 1999, is the most commonly used staging system for HCC in Western countries that link tumor burden, liver function and performance status with prognosis and therapeutic management. Since the first publication of this classification, it has been implemented in several clinical guidelines and recent major therapeutic advances in the management of HCC have modified the therapeutic landscape of HCC. Accordingly, an updated version was recently published in 2022, incorporating an expert clinical decision-making component and the concept of treatment stage migration. This update also introduces the positive results of recent randomized clinical trials, and introduces atezolizumab/bevacizumab (A/B) as a first-line combination regimen for patients with advanced HCC. Finally, the complexity of the management of patients with HCC highlights the need for a multidisciplinary approach including input from hepatology, surgery, radiology, medical oncology, and radiation oncology.
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Affiliation(s)
- Sabrina Sidali
- Université de ParisHôpitaux de Paris, Hôpital BeaujonService D’HépatologieDMU DIGESTClichyFrance
- Centre de Recherche des CordeliersSorbonne UniversitéInsermUniversité de ParisFunctional Genomics of Solid TumorsEquipe Labellisée Ligue Nationale Contre le CancerLabex OncoImmunologyParisFrance
| | - Eric Trépo
- Department of Gastroenterology, Hepatopancreatology and Digestive OncologyCUB Hôpital ErasmeUniversité Libre de BruxellesBrusselsBelgium
- Laboratory of Experimental GastroenterologyUniversité Libre de BruxellesBrusselsBelgium
| | - Olivier Sutter
- Interventional Radiology UnitHôpital AvicenneHôpitaux Universitaires Paris‐Seine‐Saint‐DenisAssistance‐Publique Hôpitaux de ParisBobignyFrance
| | - Jean‐Charles Nault
- Centre de Recherche des CordeliersSorbonne UniversitéInsermUniversité de ParisFunctional Genomics of Solid TumorsEquipe Labellisée Ligue Nationale Contre le CancerLabex OncoImmunologyParisFrance
- Liver UnitHôpital AvicenneHôpitaux Universitaires Paris‐Seine‐Saint‐DenisAssistance‐Publique Hôpitaux de ParisBobignyFrance
- Unité de Formation et de Recherche Santé Médecine et Biologie HumaineUniversité Paris 13Communauté D’Universités et Etablissements Sorbonne Paris CitéParisFrance
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27
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Ozeki Y, Kanogawa N, Ogasawara S, Ogawa K, Ishino T, Nakagawa M, Fujiwara K, Unozawa H, Iwanaga T, Sakuma T, Fujita N, Kojima R, Kanzaki H, Koroki K, Kobayashi K, Nakamura M, Kiyono S, Kondo T, Saito T, Nakagawa R, Suzuki E, Ooka Y, Nakamoto S, Muroyama R, Tawada A, Chiba T, Arai M, Kato J, Ikeda JI, Takiguchi Y, Kato N. Liver biopsy technique in the era of genomic cancer therapies: a single-center retrospective analysis. Int J Clin Oncol 2022; 27:1459-1466. [PMID: 35704154 DOI: 10.1007/s10147-022-02195-9] [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: 10/29/2021] [Accepted: 05/22/2022] [Indexed: 11/05/2022]
Abstract
BACKGROUND With the evolution of personalized medicine in the field of oncology, which includes optimal treatment selection using next-generation sequencing-based companion diagnostic systems and tumor-agnostic treatments according to common biomarkers, a liver tumor biopsy technique that can obtain a sufficient specimen volume must be established. The current study aimed to evaluate the safety and availability of a liver tumor biopsy technique with multiple puncture sites made using a coaxial introducer needle and embolization with gelatin sponge particles. METHODS Patients with primary or metastatic liver cancer who underwent liver tumor biopsies with puncture tract embolization using gelatin sponge (Spongel®) from October 2019 to September 2020 were included in the study. The complication and diagnostic rates were evaluated, and whether the specimen volume was sufficient for Foundation® CDx was investigated. RESULTS In total, 96 patients were enrolled in this analysis. The median total number of puncture times per patient was 3 (range 1-8). The pathological diagnostic rate was 79.2%. Using the FoundationOne® CDx, specimens with a sufficient volume required for genomic medicine were collected in 84.9% of patients. The incidence rate of bleeding was 4.2% (n = 4), and only one patient presented with major bleeding requiring transfusion. CONCLUSIONS Liver biopsy with puncture tract embolization using a gelatin sponge may be safe and effective for collecting specimens with a volume sufficient for modern cancer treatments.
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Affiliation(s)
- Yusuke Ozeki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan
| | - Naoya Kanogawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan
| | - Sadahisa Ogasawara
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan.
- Translational Research and Development Center, Chiba University Hospital, Chiba, Japan.
| | - Keita Ogawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan
| | - Takamasa Ishino
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan
| | - Miyuki Nakagawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan
| | - Kisako Fujiwara
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan
| | - Hidemi Unozawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan
| | - Terunao Iwanaga
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan
| | - Takafumi Sakuma
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan
| | - Naoto Fujita
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan
| | - Ryuta Kojima
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan
| | - Hiroaki Kanzaki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan
| | - Keisuke Koroki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan
| | - Kazufumi Kobayashi
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan
- Translational Research and Development Center, Chiba University Hospital, Chiba, Japan
| | - Masato Nakamura
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan
| | - Soichiro Kiyono
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan
| | - Takayuki Kondo
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan
| | - Tomoko Saito
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan
| | - Ryo Nakagawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan
| | - Eiichiro Suzuki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan
| | - Yoshihiko Ooka
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan
| | - Shingo Nakamoto
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan
| | - Ryosuke Muroyama
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan
| | - Akinobu Tawada
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan
- Department of Medical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tetsuhiro Chiba
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan
| | - Makoto Arai
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan
- Department of Medical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Jun Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan
| | - Jun-Ichiro Ikeda
- Department of Diagnostic Pathology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Yuichi Takiguchi
- Department of Medical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Naoya Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan
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Abou-Alfa GK, Lau G, Kudo M, Chan SL, Kelley RK, Furuse J, Sukeepaisarnjaroen W, Kang YK, Van Dao T, De Toni EN, Rimassa L, Breder V, Vasilyev A, Heurgué A, Tam VC, Mody K, Thungappa SC, Ostapenko Y, Yau T, Azevedo S, Varela M, Cheng AL, Qin S, Galle PR, Ali S, Marcovitz M, Makowsky M, He P, Kurland JF, Negro A, Sangro B. Tremelimumab plus Durvalumab in Unresectable Hepatocellular Carcinoma. NEJM EVIDENCE 2022; 1:EVIDoa2100070. [PMID: 38319892 DOI: 10.1056/evidoa2100070] [Citation(s) in RCA: 607] [Impact Index Per Article: 202.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2024]
Abstract
BACKGROUND: A single, high priming dose of tremelimumab (anti-cytotoxic T lymphocyte–associated antigen 4) plus durvalumab (anti–programmed cell death ligand-1), an infusion regimen termed STRIDE (Single Tremelimumab Regular Interval Durvalumab), showed encouraging clinical activity and safety in a phase 2 trial of unresectable hepatocellular carcinoma. METHODS: In this global, open-label, phase 3 trial, the majority of the patients we enrolled with unresectable hepatocellular carcinoma and no previous systemic treatment were randomly assigned to receive one of three regimens: tremelimumab (300 mg, one dose) plus durvalumab (1500 mg every 4 weeks; STRIDE), durvalumab (1500 mg every 4 weeks), or sorafenib (400 mg twice daily). The primary objective was overall survival for STRIDE versus sorafenib. Noninferiority for overall survival for durvalumab versus sorafenib was a secondary objective. RESULTS: In total, 1171 patients were randomly assigned to STRIDE (n=393), durvalumab (n=389), or sorafenib (n=389). The median overall survival was 16.43 months (95% confidence interval [CI], 14.16 to 19.58) with STRIDE, 16.56 months (95% CI, 14.06 to 19.12) with durvalumab, and 13.77 months (95% CI, 12.25 to 16.13) with sorafenib. Overall survival at 36 months was 30.7%, 24.7%, and 20.2%, respectively. The overall survival hazard ratio for STRIDE versus sorafenib was 0.78 (96.02% CI, 0.65 to 0.93; P=0.0035). Overall survival with durvalumab monotherapy was noninferior to sorafenib (hazard ratio, 0.86; 95.67% CI, 0.73 to 1.03; noninferiority margin, 1.08). Median progression-free survival was not significantly different among all three groups. Grade 3/4 treatment-emergent adverse events occurred for 50.5% of patients with STRIDE, 37.1% with durvalumab, and 52.4% with sorafenib. CONCLUSIONS: STRIDE significantly improved overall survival versus sorafenib. Durvalumab monotherapy was noninferior to sorafenib for patients with unresectable hepatocellular carcinoma. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT03298451.)
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MESH Headings
- Humans
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/mortality
- Carcinoma, Hepatocellular/pathology
- Liver Neoplasms/drug therapy
- Liver Neoplasms/mortality
- Liver Neoplasms/pathology
- Male
- Antibodies, Monoclonal/therapeutic use
- Antibodies, Monoclonal/administration & dosage
- Antibodies, Monoclonal/adverse effects
- Female
- Middle Aged
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antibodies, Monoclonal, Humanized/administration & dosage
- Antibodies, Monoclonal, Humanized/adverse effects
- Aged
- Sorafenib/therapeutic use
- Sorafenib/administration & dosage
- Sorafenib/adverse effects
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Antineoplastic Combined Chemotherapy Protocols/adverse effects
- Adult
- Antineoplastic Agents, Immunological/therapeutic use
- Antineoplastic Agents, Immunological/adverse effects
- Antineoplastic Agents, Immunological/administration & dosage
- Aged, 80 and over
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Affiliation(s)
- Ghassan K Abou-Alfa
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York
- Weill Medical College, Cornell University, New York
| | - George Lau
- Humanity and Health Clinical Trial Center, Humanity and Health Medical Group, Hong Kong Special Administrative Region, China
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Stephen L Chan
- State Key Laboratory of Translational Oncology, Department of Clinical Oncology, Sir Yue-Kong Pao Center for Cancer, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Robin Kate Kelley
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco
| | - Junji Furuse
- Department of Medical Oncology, Kyorin University Faculty of Medicine, Mitaka, Japan
| | | | - Yoon-Koo Kang
- Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Tu Van Dao
- Cancer Research and Clinical Trials Center, Department of Optimal Therapy, National Cancer Hospital, Hanoi, Vietnam
| | - Enrico N De Toni
- Department of Medicine II, University Hospital, Ludwig Maximilian University Munich, Munich, Germany
| | - Lorenza Rimassa
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan
- Humanitas Cancer Center, Istituto di Ricovero e Cura a Carattere Scientifico Humanitas Research Hospital, Rozzano, Milan
| | - Valeriy Breder
- Chemotherapy Department No. 17, N.N. Blokhin Russian Cancer Research Center, Moscow
| | - Alexander Vasilyev
- Department of Oncology, Railway Clinical Hospital, St. Petersburg, Russia
| | - Alexandra Heurgué
- Department of Hepato-Gastroenterology, Robert-Debré Hospital, Reims, France
| | - Vincent C Tam
- Department of Oncology, Tom Baker Cancer Centre, University of Calgary, Calgary, Alberta, Canada
| | - Kabir Mody
- Division of Hematology/Oncology, Department of Medicine, Mayo Clinic, Jacksonville, FL
| | | | - Yuriy Ostapenko
- Department of Minimally Invasive and Endoscopic Surgery, Interventional Radiology, National Cancer Institute, Kiev, Ukraine
| | - Thomas Yau
- Queen Mary Hospital, Pok Fu Lam, Hong Kong Special Administrative Region, China
| | - Sergio Azevedo
- Unidade de Pesquisa em Oncologia Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | - María Varela
- Liver Unit, Hospital Universitario Central de Asturias, Universidad de Oviedo, Instituto Universitario de Oncología del Principado de Asturias-Obra Social Cajastur, Instituto de Investigación Sanitaria del Principado de Asturias, Fundación para la Investigación y la Innovación Biosanitaria del Principado de Asturia, Oviedo, Spain
| | - Ann-Lii Cheng
- National Taiwan University Cancer Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Shukui Qin
- People's Liberation Army Cancer Center, Nanjing Bayi Hospital, Nanjing, China
| | | | | | | | | | | | | | | | - Bruno Sangro
- Liver Unit and Hepato-pancreato-Biliary Oncology Area, Clínica Universidad de Navarra and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Pamplona, Spain
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29
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Sharma R, Pillai A, Marron TU, Fessas P, Saeed A, Jun T, Dharmapuri S, Szafron D, Naqash AR, Gampa A, Wang Y, Khan U, Muzaffar M, Lee CJ, Lee PC, Bulumulle A, Paul S, Bettinger D, Hildebrand H, Yehia M, Pressiani T, Kaseb A, Huang YH, Ang C, Kudo M, Nishida N, Personeni N, Rimassa L, Pinato DJ. Patterns and outcomes of subsequent therapy after immune checkpoint inhibitor discontinuation in HCC. Hepatol Commun 2022; 6:1776-1785. [PMID: 35481940 PMCID: PMC9234627 DOI: 10.1002/hep4.1927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 12/10/2021] [Accepted: 12/12/2021] [Indexed: 11/18/2022] Open
Abstract
The availability of immune checkpoint inhibitors (ICIs) for the management of advanced hepatocellular cancer (HCC) has changed the treatment paradigm. There are emerging questions regarding the efficacy of subsequent anticancer therapies. The primary aim of this retrospective, multicenter study was to examine the types of anticancer treatment received after ICIs and to assess the impact on post-ICI survival. We established an international consortium of 11 tertiary-care referral centers located in the USA (n = 249), Europe (n = 74), and Asia (n = 97), and described patterns of care following ICI therapy. The impact of subsequent therapy on overall survival (OS) was estimated using the Kaplan-Meier method and presented with a 95% confidence interval (CI). A total of 420 patients were treated with ICIs for advanced HCC after one line of systemic therapy (n = 371, 88.8%): 31 (8.8%) had died, 152 (36.2%) received best supportive care (BSC) following ICIs, and 163 patients (38.8%) received subsequent anticancer therapy. Tyrosine kinase inhibitors (TKIs, n = 132, 80.9%), in particular sorafenib (n = 49, 30.0%), were the most common post-ICI therapy followed by external beam radiotherapy (n = 28, 17.2%), further immunotherapy (n = 21, 12.9%), locoregional therapy (n = 23, 14.1%), chemotherapy (n = 9, 5.5%), and surgery (n = 6, 3.6%). Receipt of post-ICI therapy was associated with longer median OS compared with those who had received BSC (12.1 vs. 3.3 months; hazard ratio [HR]: 0.4 (95% CI: 2.7-5.0). No difference in OS was noted in those patients who received TKI before ICIs compared with those who received ICIs followed by TKI. Conclusion: Post-ICI therapy is associated with OS in excess of 12 months, suggesting a role for therapeutic sequencing. OS from TKI therapy was similar to that reported in registration studies, suggesting preserved efficacy following ICIs.
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Affiliation(s)
- Rohini Sharma
- Department of Surgery & CancerImperial College LondonHammersmith HospitalLondonUK
| | - Anjana Pillai
- Section of Gastroenterology, Hepatology and NutritionThe University of Chicago MedicineChicagoIllinoisUSA
| | - Thomas Urban Marron
- Department of MedicineDivision of Hematology/OncologyTisch Cancer InstituteMount Sinai HospitalNew YorkNew YorkUSA
| | - Petros Fessas
- Department of Surgery & CancerImperial College LondonHammersmith HospitalLondonUK
| | - Anwaar Saeed
- Division of Medical OncologyGI Oncology ProgramKansas University Cancer CentreKansas CityKansasUSA
| | - Tomi Jun
- Department of MedicineDivision of Hematology/OncologyTisch Cancer InstituteMount Sinai HospitalNew YorkNew YorkUSA
| | - Sirish Dharmapuri
- Department of MedicineDivision of Hematology/OncologyTisch Cancer InstituteMount Sinai HospitalNew YorkNew YorkUSA
| | - David Szafron
- Department of MedicineBaylor College of MedicineHoustonTexasUSA
| | - Abdul Rafeh Naqash
- Division of Cancer Treatment and DiagnosisNational Cancer InstituteBethesdaMarylandUSA
| | - Anuhya Gampa
- Section of Gastroenterology, Hepatology and NutritionThe University of Chicago MedicineChicagoIllinoisUSA
| | - Yinghong Wang
- Department of GastroenterologyHepatology & NutritionThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - Uqba Khan
- Department of medicineLincoln Medical CenterWeill Cornell/New York Presbyterian HospitalNew YorkNew YorkUSA
| | - Mahvish Muzaffar
- Division of Hematology/ OncologyEast Carolina UniversityGreenvilleNorth CarolinaUSA
| | - Chieh-Ju Lee
- Division of Gastroenterology and HepatologyDepartment of MedicineTaipei Veterans General HospitalTaipeiTaiwan
| | - Pei-Chang Lee
- Division of Gastroenterology and HepatologyDepartment of MedicineTaipei Veterans General HospitalTaipeiTaiwan
| | - Anushi Bulumulle
- Division of Hematology/ OncologyEast Carolina UniversityGreenvilleNorth CarolinaUSA
| | - Sonal Paul
- New York Presbyterian Brooklyn Methodist HospitalNew YorkNew YorkUSA
| | - Dominic Bettinger
- Department of Medicine IIFaculty of MedicineMedical Center University of FreiburgUniversity of FreiburgFreiburgGermany.,Berta-Ottenstein ProgrammeFaculty of MedicineMedical Center University of FreiburgUniversity of FreiburgFreiburgGermany
| | - Hannah Hildebrand
- Division of Medical OncologyGI Oncology ProgramKansas University Cancer CentreKansas CityKansasUSA
| | - Mohammed Yehia
- Department of Gastrointestinal Medical OncologyThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - Tiziana Pressiani
- Medical Oncology and Hematology UnitHumanitas Cancer CenterHumanitas Clinical and Research Center - IRCCSRozzano, MilanItaly
| | - Ahmed Kaseb
- Department of Gastrointestinal Medical OncologyThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - Yi-Hsiang Huang
- Division of Gastroenterology and HepatologyDepartment of MedicineTaipei Veterans General HospitalTaipeiTaiwan
| | - Celina Ang
- Department of MedicineDivision of Hematology/OncologyTisch Cancer InstituteMount Sinai HospitalNew YorkNew YorkUSA
| | - Masatoshi Kudo
- Department of Gastroenterology and HepatologyKindai University Faculty of MedicineOsaka-sayama, OsakaJapan
| | - Naoshi Nishida
- Department of Gastroenterology and HepatologyKindai University Faculty of MedicineOsaka-sayama, OsakaJapan
| | - Nicola Personeni
- Medical Oncology and Hematology UnitHumanitas Cancer CenterHumanitas Clinical and Research Center - IRCCSRozzano, MilanItaly.,Department of Biomedical SciencesHumanitas UniversityPieve Emanuele, MilanItaly
| | - Lorenza Rimassa
- Medical Oncology and Hematology UnitHumanitas Cancer CenterHumanitas Clinical and Research Center - IRCCSRozzano, MilanItaly.,Department of Biomedical SciencesHumanitas UniversityPieve Emanuele, MilanItaly
| | - David James Pinato
- Department of Surgery & CancerImperial College LondonHammersmith HospitalLondonUK
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30
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Labadie KP, Hamlin DK, Kenoyer A, Daniel SK, Utria AF, Ludwig AD, Kenerson HL, Li L, Sham JG, Chen DL, Orozco JJ, Yeung RS, Orvig C, Li Y, Wilbur DS, Park JO. Glypican-3-Targeted 227Th α-Therapy Reduces Tumor Burden in an Orthotopic Xenograft Murine Model of Hepatocellular Carcinoma. J Nucl Med 2022; 63:1033-1038. [PMID: 34772791 PMCID: PMC9258570 DOI: 10.2967/jnumed.121.262562] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 10/08/2021] [Indexed: 01/03/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a significant cause of morbidity and mortality worldwide, with limited therapeutic options for advanced disease. Targeted α-therapy is an emerging class of targeted cancer therapy in which α-particle-emitting radionuclides, such as 227Th, are delivered specifically to cancer tissue. Glypican-3 (GPC3) is a cell surface glycoprotein highly expressed on HCC. In this study, we describe the development and in vivo efficacy of a 227Th-labeled GPC3-targeting antibody conjugate (227Th-octapa-αGPC3) for treatment of HCC in an orthotopic murine model. Methods: The chelator p-SCN-Bn-H4octapa-NCS (octapa) was conjugated to a GPC3-targeting antibody (αGPC3) for subsequent 227Th radiolabeling (octapa-αGPC3). Conditions were varied to optimize radiolabeling of 227Th. In vitro stability was evaluated by measuring the percentage of protein-bound 227Th by γ-ray spectroscopy. An orthotopic athymic Nu/J murine model using HepG2-Red-FLuc cells was developed. Biodistribution and blood clearance of 227Th-octapa-αGPC3 were evaluated in tumor-bearing mice. The efficacy of 227Th-octapa-αGPC3 was assessed in tumor-bearing animals with serial measurement of serum α-fetoprotein at 23 d after injection. Results: Octapa-conjugated αGPC3 provided up to 70% 227Th labeling yield in 2 h at room temperature. In the presence of ascorbate, at least 97.8% of 227Th was bound to αGPC3-octapa after 14 d in phosphate-buffered saline. In HepG2-Red-FLuc tumor-bearing mice, highly specific GPC3 targeting was observed, with significant 227Th-octapa-αGPC3 accumulation in the tumor over time and minimal accumulation in normal tissue. Twenty-three days after treatment, a significant reduction in tumor burden was observed in mice receiving a 500 kBq/kg dose of 227Th-octapa-αGPC3 by tail-vein injection. No acute off-target toxicity was observed, and no animals died before termination of the study. Conclusion:227Th-octapa-αGPC3 was observed to be stable in vitro; maintain high specificity for GPC3, with favorable biodistribution in vivo; and result in significant antitumor activity without significant acute off-target toxicity in an orthotopic murine model of HCC.
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Affiliation(s)
- Kevin P. Labadie
- Department of Surgery, University of Washington, Seattle, Washington
| | - Donald K. Hamlin
- Department of Radiation Oncology, University of Washington, Seattle, Washington
| | - Aimee Kenoyer
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Sara K. Daniel
- Department of Surgery, University of Washington, Seattle, Washington
| | - Alan F. Utria
- Department of Surgery, University of Washington, Seattle, Washington
| | - Andrew D. Ludwig
- Department of Surgery, University of Washington, Seattle, Washington
| | - Heidi L. Kenerson
- Department of Surgery, University of Washington, Seattle, Washington
| | - Lily Li
- Life Sciences Division, TRIUMF, and Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, Vancouver, British Columbia, Canada
| | - Jonathan G. Sham
- Department of Surgery, University of Washington, Seattle, Washington
| | - Delphine L. Chen
- Department of Radiology, University of Washington, Seattle, Washington
| | - Johnnie J. Orozco
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Raymond S. Yeung
- Department of Surgery, University of Washington, Seattle, Washington
| | - Chris Orvig
- Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, Vancouver, British Columbia, Canada
| | - Yawen Li
- Department of Radiation Oncology, University of Washington, Seattle, Washington
| | - D. Scott Wilbur
- Department of Radiation Oncology, University of Washington, Seattle, Washington
| | - James O. Park
- Department of Surgery, University of Washington, Seattle, Washington
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31
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Koustas E, Trifylli EM, Sarantis P, Papadopoulos N, Karapedi E, Aloizos G, Damaskos C, Garmpis N, Garmpi A, Papavassiliou KA, Karamouzis MV, Papavassiliou AG. Immunotherapy as a Therapeutic Strategy for Gastrointestinal Cancer-Current Treatment Options and Future Perspectives. Int J Mol Sci 2022; 23:6664. [PMID: 35743107 PMCID: PMC9224428 DOI: 10.3390/ijms23126664] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 06/12/2022] [Accepted: 06/14/2022] [Indexed: 12/12/2022] Open
Abstract
Gastrointestinal (GI) cancer constitutes a highly lethal entity among malignancies in the last decades and is still a major challenge for cancer therapeutic options. Despite the current combinational treatment strategies, including chemotherapy, surgery, radiotherapy, and targeted therapies, the survival rates remain notably low for patients with advanced disease. A better knowledge of the molecular mechanisms that influence tumor progression and the development of optimal therapeutic strategies for GI malignancies are urgently needed. Currently, the development and the assessment of the efficacy of immunotherapeutic agents in GI cancer are in the spotlight of several clinical trials. Thus, several new modalities and combinational treatments with other anti-neoplastic agents have been identified and evaluated for their efficiency in cancer management, including immune checkpoint inhibitors, adoptive cell transfer, chimeric antigen receptor (CAR)-T cell therapy, cancer vaccines, and/or combinations thereof. Understanding the interrelation among the tumor microenvironment, cancer progression, and immune resistance is pivotal for the optimal therapeutic management of all gastrointestinal solid tumors. This review will shed light on the recent advances and future directions of immunotherapy for malignant tumors of the GI system.
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Affiliation(s)
- Evangelos Koustas
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (E.K.); (E.-M.T.); (P.S.); (K.A.P.)
- First Department of Internal Medicine, 417 Army Share Fund Hospital, 11521 Athens, Greece; (N.P.); (E.K.); (G.A.)
| | - Eleni-Myrto Trifylli
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (E.K.); (E.-M.T.); (P.S.); (K.A.P.)
- First Department of Internal Medicine, 417 Army Share Fund Hospital, 11521 Athens, Greece; (N.P.); (E.K.); (G.A.)
| | - Panagiotis Sarantis
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (E.K.); (E.-M.T.); (P.S.); (K.A.P.)
| | - Nikolaos Papadopoulos
- First Department of Internal Medicine, 417 Army Share Fund Hospital, 11521 Athens, Greece; (N.P.); (E.K.); (G.A.)
| | - Eleni Karapedi
- First Department of Internal Medicine, 417 Army Share Fund Hospital, 11521 Athens, Greece; (N.P.); (E.K.); (G.A.)
| | - Georgios Aloizos
- First Department of Internal Medicine, 417 Army Share Fund Hospital, 11521 Athens, Greece; (N.P.); (E.K.); (G.A.)
| | - Christos Damaskos
- ‘N.S. Christeas’ Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
- Renal Transplantation Unit, ‘Laiko’ General Hospital, 11527 Athens, Greece
| | - Nikolaos Garmpis
- Second Department of Propaedeutic Surgery, ‘Laiko’ General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Anna Garmpi
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Kostas A. Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (E.K.); (E.-M.T.); (P.S.); (K.A.P.)
| | - Michalis V. Karamouzis
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (E.K.); (E.-M.T.); (P.S.); (K.A.P.)
| | - Athanasios G. Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (E.K.); (E.-M.T.); (P.S.); (K.A.P.)
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32
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Verset G, Borbath I, Karwal M, Verslype C, Van Vlierberghe H, Kardosh A, Zagonel V, Stal P, Sarker D, Palmer DH, Vogel A, Edeline J, Cattan S, Kudo M, Cheng AL, Ogasawara S, Daniele B, Chan SL, Knox JJ, Qin S, Siegel AB, Chisamore M, Hatogai K, Wang A, Finn RS, Zhu AX. Pembrolizumab Monotherapy for Previously Untreated Advanced Hepatocellular Carcinoma: Data from the Open-Label, Phase II KEYNOTE-224 Trial. Clin Cancer Res 2022; 28:2547-2554. [PMID: 35421228 PMCID: PMC9784157 DOI: 10.1158/1078-0432.ccr-21-3807] [Citation(s) in RCA: 63] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 01/27/2022] [Accepted: 04/11/2022] [Indexed: 01/07/2023]
Abstract
PURPOSE KEYNOTE-224 cohort 1 demonstrated that pembrolizumab was efficacious and tolerable in patients with advanced hepatocellular carcinoma (HCC) previously treated with sorafenib. We report results from KEYNOTE-224 (NCT02702414) cohort 2, which enrolled patients with advanced HCC and no prior systemic therapy. PATIENTS AND METHODS KEYNOTE-224 was an open-label, multicountry phase II trial. Eligible patients in cohort 2 had advanced HCC not amenable or refractory to locoregional therapy and not previously treated with systemic therapy. Patients received pembrolizumab 200 mg intravenously every 3 weeks for ≤2 years. Primary endpoint was objective response rate (ORR) by central imaging review per RECIST v1.1. Secondary endpoints included duration of response (DOR), disease control rate (DCR), time to progression (TTP), progression-free survival (PFS), overall survival (OS), and safety/tolerability. RESULTS Between September 4, 2018, and February 20, 2019, 51 patients were allocated in cohort 2. The median time from the first dose to data cutoff (January 19, 2021) was 27 months (range, 23-29). ORR was 16% [95% confidence interval (CI), 7-29] and was similar across key subgroups. Median DOR was 16 months (range, 3-24+), and DCR was 57%. The median PFS was 4 months (95% CI, 2-8), and median TTP was 4 months (95% CI, 3-9). Median OS was 17 months (95% CI, 8-23). Grade ≥3 treatment-related adverse events occurred in 16% of patients. CONCLUSIONS In patients with advanced HCC with no prior systemic therapy, pembrolizumab provided durable antitumor activity, promising OS, and had a safety profile consistent with previous observations. These findings support further evaluation of pembrolizumab-based regimens for HCC.
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Affiliation(s)
- Gontran Verset
- Gastrointestinal Oncology Unit, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
| | - Ivan Borbath
- Cliniques Universitaires Saint-Luc and Université Catholique de Louvain, Brussels, Belgium
| | | | - Chris Verslype
- Digestive Oncology, Department of Oncology, University Hospital Leuven, Belgium
| | | | - Adel Kardosh
- Oregon Health & Science University, Knight Cancer Institute, Portland, Oregon
| | - Vittorina Zagonel
- Oncology Unit 1, Istituto Oncologico Veneto, IOV, IRCCS, Padua, Italy
| | - Per Stal
- Karolinska Institutet, Stockholm, Sweden
| | - Debashis Sarker
- School of Cancer and Pharmaceutical Sciences, King's College London, London, United Kingdom
| | - Daniel H. Palmer
- Cancer Research UK Liverpool Experimental Cancer Medicine Centre, University of Liverpool, Liverpool, United Kingdom
| | - Arndt Vogel
- Department of Gastroenterology, Hepatology, and Endocrinology, Medizinische Hochschule, Hannover, Germany
| | - Julien Edeline
- Department of Medical Oncology, Centre Eugène Marquis, Rennes, France
| | - Stephane Cattan
- Department of Medical Oncology and Gastroenterology, Hôpital Claude Huriez, Centre Hospitalier Régional Universitaire de Lille, Lille, France
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Ann-Lii Cheng
- Department of Medical Oncology, National Taiwan University Cancer Center, and Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
| | - Sadahisa Ogasawara
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | | | - Stephen L. Chan
- Department of Clinical Oncology, State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Jennifer J. Knox
- Department of Medical Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada
| | - Shukui Qin
- Cancer Centre of Jinling Hospital, Nanjing University of Chinese Medicine, Nanjing, China
| | | | | | | | - Anran Wang
- Merck & Co., Inc., Kenilworth, New Jersey
| | - Richard S. Finn
- Department of Medicine, University of California, Los Angeles, California
| | - Andrew X. Zhu
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts
- Jiahui International Cancer Center, Jiahui Health, Shanghai, China
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Foerster F, Gairing SJ, Ilyas SI, Galle PR. Emerging immunotherapy for HCC: A guide for hepatologists. Hepatology 2022; 75:1604-1626. [PMID: 35253934 PMCID: PMC9117522 DOI: 10.1002/hep.32447] [Citation(s) in RCA: 157] [Impact Index Per Article: 52.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 01/31/2022] [Accepted: 01/31/2022] [Indexed: 12/12/2022]
Abstract
HCC is one of the most common cancers worldwide, and the third leading cause of cancer-related death globally. HCC comprises nearly 90% of all cases of primary liver cancer. Approximately half of all patients with HCC receive systemic therapy during their disease course, particularly in the advanced stages of disease. Immuno-oncology has been paradigm shifting for the treatment of human cancers, with strong and durable antitumor activity in a subset of patients across a variety of malignancies including HCC. Immune checkpoint inhibition with atezolizumab and bevacizumab, an antivascular endothelial growth factor neutralizing antibody, has become first-line therapy for patients with advanced HCC. Beyond immune checkpoint inhibition, immunotherapeutic strategies such as oncolytic viroimmunotherapy and adoptive T-cell transfer are currently under investigation. The tumor immune microenvironment of HCC has significant immunosuppressive elements that may affect response to immunotherapy. Major unmet challenges include defining the role of immunotherapy in earlier stages of HCC, evaluating combinatorial strategies that use targeting of the immune microenvironment plus immune checkpoint inhibition, and identifying treatment strategies for patients who do not respond to the currently available immunotherapies. Herein, we review the rationale, mechanistic basis and supporting preclinical evidence, and available clinical evidence for immunotherapies in HCC as well as ongoing clinical trials of immunotherapy.
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Affiliation(s)
- Friedrich Foerster
- Department of Medicine I, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany
| | - Simon Johannes Gairing
- Department of Medicine I, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany
| | - Sumera Irie Ilyas
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Peter Robert Galle
- Department of Medicine I, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany
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Guven DC, Stephen B, Sahin TK, Cakir IY, Erul E, Aksoy S. The efficacy of immune checkpoint inhibitors in rare tumors: A systematic review of published clinical trials. Crit Rev Oncol Hematol 2022; 174:103700. [PMID: 35533815 DOI: 10.1016/j.critrevonc.2022.103700] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 04/22/2022] [Accepted: 05/02/2022] [Indexed: 02/08/2023] Open
Abstract
The immune checkpoint inhibitors (ICIs) entered treatment algorithms in most tumors. However, the data on the efficacy is limited in rare tumors with no phase III studies. We systemically reviewed the clinical trials evaluating the ICI efficacy in rare tumors and included a total of 47 clinical trials in this review. The ICIs demonstrated over 30% response rates in Merkel cell carcinoma and squamous cell carcinoma of the skin and became the standard of care. Additionally, the ICI efficacy was promising in thymic epithelial tumors and gestational trophoblastic neoplasia. In contrast, the ICI efficacy is limited in most sarcomas, germ cell tumors and low-grade neuroendocrine tumors. The ICI efficacy seemed to be improved with combinations targeting tumor microenvironment in sarcomas. The available evidence on ICI efficacy in rare tumors denote a need for better patient selection and novel combination strategies to improve outcomes.
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Affiliation(s)
- Deniz Can Guven
- Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey.
| | - Bettzy Stephen
- Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, USA
| | - Taha Koray Sahin
- Department of Internal Medicine, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Ibrahim Yahya Cakir
- Department of Internal Medicine, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Enes Erul
- Department of Internal Medicine, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Sercan Aksoy
- Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey
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Chandok N, Sirpal S, Yoshida EM. Checkpoint inhibition in hepatocellular carcinoma: Outsmarting the Squid Game. CANADIAN LIVER JOURNAL 2022; 5:165-168. [PMID: 35991480 PMCID: PMC9236585 DOI: 10.3138/canlivj-2022-0012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Accepted: 04/06/2022] [Indexed: 01/04/2025]
Affiliation(s)
- Natasha Chandok
- Division of Gastroenterology, William Osler Health System, Brampton, Ontario, Canada
| | - Sanjeev Sirpal
- Department of Emergency Medicine, Fleury Hospital, Montreal, Quebec, Canada
| | - Eric M Yoshida
- Division of Gastroenterology, University of British Columbia, Vancouver, British Columbia, Canada
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36
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Kang SM, Khalil L, El-Rayes BF, Akce M. Rapidly Evolving Landscape and Future Horizons in Hepatocellular Carcinoma in the Era of Immuno-Oncology. Front Oncol 2022; 12:821903. [PMID: 35433430 PMCID: PMC9008732 DOI: 10.3389/fonc.2022.821903] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 03/08/2022] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a serious global health problem as one of the leading causes of cancer-related death worldwide. Systemic therapy for advanced HCC has progressed with the development of molecular targeted agents, however survival benefits remain modest. More recently, immune checkpoint inhibitors (ICI) have emerged and exhibited promising therapeutic benefits in a subset of patients. Physiologically, the intrinsic microenvironment in the liver is immunosuppressive, which represents a major obstacle for effective immune therapies in primary and secondary liver malignancies. For this reason, combination therapies that can overcome immune inhibitory mechanisms and enhance the immune response are a rationale approach for drug development in HCC. A recent example is the combination of the anti-PD-L1 antibody (atezolizumab) and anti-VEGF-A antibody (bevacizumab), which has shown significant improvement in survival as compared to standard of care in the first-line treatment for HCC. Other immunotherapy approaches including cancer vaccines and adoptive cell therapy are also under investigation. This review summarizes the key trials leading to our current HCC treatment options and provides an overview of future immune-based strategies in development.
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Affiliation(s)
| | | | | | - Mehmet Akce
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, United States
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Cammarota A, Zanuso V, D'Alessio A, Pressiani T, Bozzarelli S, Personeni N, Rimassa L. The dual checkpoint blockade in unresectable hepatocellular carcinoma: Opportunities emerging in clinical trials. Expert Opin Investig Drugs 2022; 31:425-435. [PMID: 35152830 DOI: 10.1080/13543784.2022.2042253] [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: 12/30/2022]
Abstract
INTRODUCTION To prevent damage from an immune response against autoantigens and toxins originating from the gut, the liver promotes an immune-tolerant milieu providing fertile ground for immune escape of cancer cells. Therefore, the use and evaluation of immune checkpoint inhibitors (ICIs) in hepatocellular carcinoma (HCC) is a treatment rationale. AREA COVERED In this article, we discuss the role of the dual ICIs blockade in advanced HCC, covering the biological basis for their combination, their mechanism of action, and the results of the early phase studies testing nivolumab plus ipilimumab and durvalumab plus tremelimumab. Furthermore, we provide the results of the phase III HIMALAYA trial and an overview of the ongoing trials investigating the dual ICIs in different disease stages. EXPERT OPINION The potential approval of the dual ICIs blockade strategies for advanced HCC will set the entry of antiangiogenic-free options, expanding the proportion of patients eligible for a first-line treatment. However, it will pose a series of clinical challenges with a sizeable proportion of patients, namely Child-Pugh B, elderly, and immunocompromised patients, still marginalized. Also, given the rate of disease progression, identifying reliable predictive biomarkers is crucial to inform treatment choice and sequences. Finally, the compelling response rate of such combinations is paving the way for their evaluation in earlier stages.
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Affiliation(s)
- Antonella Cammarota
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Milan, Italy.,Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Valentina Zanuso
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Milan, Italy.,Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Antonio D'Alessio
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Milan, Italy.,Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, W120HS, United Kingdom
| | - Tiziana Pressiani
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Silvia Bozzarelli
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Nicola Personeni
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Milan, Italy.,Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Lorenza Rimassa
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Milan, Italy.,Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
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Awosika J, Sohal D. A narrative review of systemic treatment options for hepatocellular carcinoma: state of the art review. J Gastrointest Oncol 2022; 13:426-437. [PMID: 35284102 PMCID: PMC8899752 DOI: 10.21037/jgo-21-274] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 12/14/2021] [Indexed: 06/23/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is an aggressive cancer that typically develops in the setting of underlying cirrhosis of the liver. HCC commonly presents in advanced stages and if eligible orthotopic liver transplantation (OLT) and surgical resection/ablation remain as the only curative options. Prior to 2007, no systemic therapy was available that demonstrated an improvement in survival. Underlying cirrhosis and poor synthetic hepatic function provides a major challenge into effective systemic options contributing to the poor success of cytotoxic chemotherapy in HCC. The first drug to achieve clinical success was sorafenib despite the underwhelming overall survival of 3 months. Since then, other targeted therapies have shown modest benefit as well. Most recently, immunotherapy advances have come to the forefront in the management of HCC and combination therapy with immunotherapy and monoclonal antibodies have now surpassed sorafenib as first line treatment. This article will review the various approved and emerging therapies that have had a significant clinical impact and highlight the future directions and ongoing research that will hopefully translate into better outcomes in the treatment approach of advanced HCC.
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Liu JKH, Irvine AF, Jones RL, Samson A. Immunotherapies for hepatocellular carcinoma. Cancer Med 2022; 11:571-591. [PMID: 34953051 PMCID: PMC8817091 DOI: 10.1002/cam4.4468] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 10/29/2021] [Accepted: 11/02/2021] [Indexed: 12/21/2022] Open
Abstract
Cases of hepatocellular carcinoma (HCC) are rapidly rising. This is particularly the case in the Western world, as a result of increasing rates of chronic liver disease, secondary to lifestyle-associated risk factors and the lack of an established screening programme for the general population. Traditionally, radical/curative treatment options for HCC, including liver transplantation and surgical resection are reserved for the minority of patients, presenting with an early stage cancer. For patients with advanced disease, Sorafenib and Lenvatinib were, until recently, the only licensed systemic treatments, and provided only limited survival benefits at the cost of a multitude of potential side effects. Recent scientific advances in the field of cancer immunotherapy have renewed significant interest in advanced HCC, in order to fulfil this apparent area of unmet clinical need. This has led to the success and recent regulatory approval of an Atezolizumab/Bevacizumab combination for the first-line treatment of advanced HCC following results from the IMbrave150 clinical trial in 2019, with further immune checkpoint inhibitors currently undergoing testing in advanced clinical trials. Furthermore, other cancer immunotherapies, including chimeric antigen receptor T-cells, dendritic cell vaccines and oncolytic viruses are also in early stage clinical trials, for the treatment of advanced HCC. This review will summarise the major approaches that have been and are currently in development for the systemic treatment of advanced HCC, their advantages, drawbacks, and predictions of where this revolutionary treatment field will continue to travel for the foreseeable future.
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Affiliation(s)
- Justin K. H. Liu
- Leeds Institute of Medical Research at St James's (LIMR)School of MedicineFaculty of Medicine and HealthUniversity of LeedsSt James's University HospitalLeedsUK
| | - Andrew F. Irvine
- Leeds Institute of Medical Research at St James's (LIMR)School of MedicineFaculty of Medicine and HealthUniversity of LeedsSt James's University HospitalLeedsUK
| | - Rebecca L. Jones
- Leeds Liver UnitSt James's University HospitalLeeds Teaching Hospitals NHS TrustLeedsUK
| | - Adel Samson
- Leeds Institute of Medical Research at St James's (LIMR)School of MedicineFaculty of Medicine and HealthUniversity of LeedsSt James's University HospitalLeedsUK
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40
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Immunotherapy—another breakthrough in gastrointestinal malignancies. MEMO - MAGAZINE OF EUROPEAN MEDICAL ONCOLOGY 2022. [DOI: 10.1007/s12254-021-00785-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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41
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Cammarota A, Zanuso V, D’Alessio A, Pressiani T, Personeni N, Rimassa L. Cabozantinib plus atezolizumab for the treatment of advanced hepatocellular carcinoma: Shedding light on the preclinical rationale and clinical trials. Expert Opin Investig Drugs 2022; 31:401-413. [DOI: 10.1080/13543784.2022.2032641] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Antonella Cammarota
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Milan,Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Valentina Zanuso
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Milan,Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Antonio D’Alessio
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Milan,Italy
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospitalc, London, W120HS, United Kingdom
| | - Tiziana Pressiani
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Nicola Personeni
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Milan,Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Lorenza Rimassa
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Milan,Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
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42
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Argemi J, Ponz-Sarvise M, Sangro B. Immunotherapies for hepatocellular carcinoma and intrahepatic cholangiocarcinoma: Current and developing strategies. Adv Cancer Res 2022; 156:367-413. [PMID: 35961706 DOI: 10.1016/bs.acr.2022.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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43
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Decraecker M, Toulouse C, Blanc JF. Is There Still a Place for Tyrosine Kinase Inhibitors for the Treatment of Hepatocellular Carcinoma at the Time of Immunotherapies? A Focus on Lenvatinib. Cancers (Basel) 2021; 13:6310. [PMID: 34944930 PMCID: PMC8699782 DOI: 10.3390/cancers13246310] [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: 11/14/2021] [Revised: 12/12/2021] [Accepted: 12/14/2021] [Indexed: 02/08/2023] Open
Abstract
The systemic treatment of hepatocellular carcinoma is changing rapidly. Three main classes of treatment are now available. Historically, multi-targeted tyrosine kinase inhibitors (TKIs) (sorafenib and lenvatinib as first-line; regorafenib and cabozantinib as second-line) were the first to show an improvement in overall survival (OS). Anti-vascular endothelial growth factor (anti-VEGF) antibodies can be used in first-line (bevacizumab) or second-line (ramucirumab) combination therapy. More recently, immuno-oncology (IO) has profoundly changed therapeutic algorithms, and the combination of atezolizumab-bevacizumab is now the first-line standard of care. Therefore, the place of TKIs needs to be redefined. The objective of this review was to define the place of TKIs in the therapeutic algorithm at the time of IO treatment in first-line therapy, with a special focus on lenvatinib that exhibits one of the higher anti-tumoral activity among TKI in HCC. We will discuss the place of lenvatinib in first line (especially if there is a contra-indication to IO) but also after failure of atezolizumab and bevacizumab. New opportunities for lenvatinib will also be presented, including the use at an earlier stage of the disease and combination with IOs.
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Affiliation(s)
- Marie Decraecker
- Department of Oncology, Hospital Haut Leveque-CHU Bordeaux, Avenue Magellan, 33604 Pessac, France; (C.T.); (J.-F.B.)
| | - Caroline Toulouse
- Department of Oncology, Hospital Haut Leveque-CHU Bordeaux, Avenue Magellan, 33604 Pessac, France; (C.T.); (J.-F.B.)
| | - Jean-Frédéric Blanc
- Department of Oncology, Hospital Haut Leveque-CHU Bordeaux, Avenue Magellan, 33604 Pessac, France; (C.T.); (J.-F.B.)
- INSERM U1053, BaRITOn, University Victor Segalen, 146 Rue Léo Saignat, 33000 Bordeaux, France
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Zheng LL, Tao CC, Tao ZG, Zhang K, Wu AK, Wu JX, Rong WQ. Research progress regarding programmed cell death 1/programmed cell death ligand 1 inhibitors combined with targeted therapy for treating hepatocellular carcinoma. World J Gastrointest Surg 2021; 13:1136-1148. [PMID: 34754383 PMCID: PMC8554719 DOI: 10.4240/wjgs.v13.i10.1136] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 06/27/2021] [Accepted: 08/30/2021] [Indexed: 02/06/2023] Open
Abstract
In recent years, a number of targeted therapeutic agents have achieved success in phase III trials in patients with advanced hepatocellular carcinoma (HCC), including sorafenib, lenvatinib, and regorafenib. Immunotherapy is considered to be an effective treatment for advanced HCC. Immune checkpoint inhibitors targeting programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) are important antitumor immunotherapy agents that represent breakthroughs in the treatment of advanced HCC. However, treating advanced HCC is still a great challenge, and the need for new treatments remains urgent. This review briefly summarizes the research progress in the use of PD-1/PD-L1 inhibitors combined with targeted therapy for treating HCC.
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Affiliation(s)
- Lin-Lin Zheng
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Chang-Cheng Tao
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Zong-Gui Tao
- Department of Imaging, Jinan City People's Hospital, Shandong First Medical University, Jinan 271199, Shandong Province, China
| | - Kai Zhang
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - An-Ke Wu
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Jian-Xiong Wu
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Wei-Qi Rong
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
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45
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Chu PY, Chan SH. Cure the Incurable? Recent Breakthroughs in Immune Checkpoint Blockade for Hepatocellular Carcinoma. Cancers (Basel) 2021; 13:5295. [PMID: 34771459 PMCID: PMC8582442 DOI: 10.3390/cancers13215295] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 10/20/2021] [Accepted: 10/20/2021] [Indexed: 12/12/2022] Open
Abstract
HCC usually arises from a chronic inflammation background, driven by several factors including fatty liver, HBV/HCV viral infection and metabolic syndrome. Systemic treatment for advanced HCC remains disappointing due to its strong resistance to chemotherapy and even to tyrosine kinase inhibitors (TKIs). Recently, the use of ICI therapy has revolutionized the systemic treatment of advanced HCC. For the first time, clinical trials testing ICIs, anti-CTLA-4 and anti-PD1/PDL1 reported a survival benefit in patients with sorafenib resistance. However, it took four more years to find the right combination regimen to use ICI in combination with the anti-angiogenic agent bevacizumab to substantially prolong overall survival (OS) of patients with advanced HCC after sorafenib. This review provides a comprehensive history of ICI therapy in HCC, up-to-date information on the latest ICI clinical trials, and discusses the recent development of novel ICIs that would potentially lead to a new checkpoint blockade therapy for advanced HCC.
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Affiliation(s)
- Pei-Yi Chu
- National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan;
- College of Medicine, National Chung Hsing University, Taichung 402, Taiwan
- Department of Pathology, Show Chwan Memorial Hospital, Changhua 500, Taiwan
- School of Medicine, College of Medicine, Fu Jen Catholic University, Taipei 242, Taiwan
- Department of Health Food, Chung Chou University of Science and Technology, Changhua 510, Taiwan
| | - Shih-Hsuan Chan
- Graduate Institute of Integrated Medicine, China Medial University, Taichung 402, Taiwan
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Liu HT, Jiang MJ, Deng ZJ, Li L, Huang JL, Liu ZX, Li LQ, Zhong JH. Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: Current Progresses and Challenges. Front Oncol 2021; 11:737497. [PMID: 34745958 PMCID: PMC8570111 DOI: 10.3389/fonc.2021.737497] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Accepted: 10/08/2021] [Indexed: 01/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumor in the world and its incidence is increasing in many countries. In recent years, with the deepening understanding of the immune and pathological mechanisms of HCC, immunotherapy based on the regulation of tumor immune microenvironment has become a new treatment choice for patients with HCC. Immune checkpoint inhibitors (ICIs) targeting programmed death protein-1, programmed death protein-ligand-1, or cytotoxic T-lymphocyte-associated antigen 4 are the most widely used. Instead of general immune-enhancing therapies, ICIs can reactivate anti-tumor immune responses by disrupting co-inhibitory T cell signaling. In this review, the research progress and existing problems of ICIs in the treatment of HCC in recent years are reviewed.
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Affiliation(s)
| | | | | | | | | | | | | | - Jian-Hong Zhong
- Hepatobiliary Surgery Department, Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Guangxi Medical University Cancer Hospital, Nanning, China
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47
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Lawal G, Xiao Y, Rahnemai-Azar AA, Tsilimigras DI, Kuang M, Bakopoulos A, Pawlik TM. The Immunology of Hepatocellular Carcinoma. Vaccines (Basel) 2021; 9:vaccines9101184. [PMID: 34696292 PMCID: PMC8538643 DOI: 10.3390/vaccines9101184] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 09/20/2021] [Accepted: 10/08/2021] [Indexed: 12/13/2022] Open
Abstract
Liver cancer is the third leading cause of cancer death worldwide. Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver. Liver resection or transplantation offer the only potentially curative options for HCC; however, many patients are not candidates for surgical resection, either due to presentation at advanced stages or poor liver function and portal hypertension. Liver transplantation is also limited to patients with certain characteristics, such as those that meet the Milan criteria (one tumor ≤ 5 cm, or up to three tumors no larger than 3 cm, along with the absence of gross vascular invasion or extrahepatic spread). Locoregional therapies, such as ablation (radiofrequency, ethanol, cryoablation, microwave), trans-arterial therapies like chemoembolization (TACE) or radioembolization (TARE), and external beam radiation therapy, have been used mainly as palliative measures with poor prognosis. Therefore, emerging novel systemic treatments, such as immunotherapy, have increasingly become popular. HCC is immunogenic, containing infiltrating tumor-specific T-cell lymphocytes and other immune cells. Immunotherapy may provide a more effective and discriminatory targeting of tumor cells through induction of a tumor-specific immune response in cancer cells and can improve post-surgical recurrence-free survival in HCC. We herein review evidence supporting different immunomodulating cell-based technology relative to cancer therapy in vaccines and targeted therapies, such as immune checkpoint inhibitors, in the management of hepatocellular carcinoma among patients with advanced disease.
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Affiliation(s)
- Gbemisola Lawal
- Division of Surgical Oncology, Department of Surgery, Arrowhead Regional Cancer Center, California University of Science and Medicine, Colton, CA 92324, USA; (G.L.); (A.A.R.-A.)
| | - Yao Xiao
- Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China; (Y.X.); (M.K.)
| | - Amir A. Rahnemai-Azar
- Division of Surgical Oncology, Department of Surgery, Arrowhead Regional Cancer Center, California University of Science and Medicine, Colton, CA 92324, USA; (G.L.); (A.A.R.-A.)
| | - Diamantis I. Tsilimigras
- Department of Surgery, The Ohio State Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH 43210, USA;
- Correspondence: ; Tel.: +1-215-987-9177
| | - Ming Kuang
- Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China; (Y.X.); (M.K.)
| | - Anargyros Bakopoulos
- Department of Surgery, Attikon University Hospital, University of Athens, 12462 Athens, Greece;
| | - Timothy M. Pawlik
- Department of Surgery, The Ohio State Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH 43210, USA;
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48
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Pathak S, Sonbol MB. Second-Line Treatment Options for Hepatocellular Carcinoma: Current Landscape and Future Direction. J Hepatocell Carcinoma 2021; 8:1147-1158. [PMID: 34584898 PMCID: PMC8464222 DOI: 10.2147/jhc.s268314] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 08/31/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma is a leading cause of mortality worldwide, and its incidence is rising. The last few years have witnessed a proliferation of available systemic therapeutic options, with the approval of multiple agents, including immune checkpoint inhibitors and drugs targeting vascular endothelial growth factor, such as cabozantinib, regorafenib, and ramucirumab. Most recently, the combination of atezolizumab plus bevacizumab has resulted in the longest overall survival yet known in hepatocellular carcinoma, therefore changing the preferred first-line treatment from the previous options of sorafenib and lenvatinib. The aim of this review is to summarize the available clinical data for the current second-line systemic treatment options and the future perspectives in the treatment landscape of hepatocellular carcinoma.
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Affiliation(s)
- Surabhi Pathak
- Hematology-Oncology, King’s Daughters Medical Center, Ashland, KY, USA
| | - Mohamad Bassam Sonbol
- Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic Cancer Center, Phoenix, AZ, USA
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49
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Greten TF, Abou-Alfa GK, Cheng AL, Duffy AG, El-Khoueiry AB, Finn RS, Galle PR, Goyal L, He AR, Kaseb AO, Kelley RK, Lencioni R, Lujambio A, Mabry Hrones D, Pinato DJ, Sangro B, Troisi RI, Wilson Woods A, Yau T, Zhu AX, Melero I. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of hepatocellular carcinoma. J Immunother Cancer 2021; 9:e002794. [PMID: 34518290 PMCID: PMC8438858 DOI: 10.1136/jitc-2021-002794] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/02/2021] [Indexed: 12/11/2022] Open
Abstract
Patients with advanced hepatocellular carcinoma (HCC) have historically had few options and faced extremely poor prognoses if their disease progressed after standard-of-care tyrosine kinase inhibitors (TKIs). Recently, the standard of care for HCC has been transformed as a combination of the immune checkpoint inhibitor (ICI) atezolizumab plus the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab was shown to offer improved overall survival in the first-line setting. Immunotherapy has demonstrated safety and efficacy in later lines of therapy as well, and ongoing trials are investigating novel combinations of ICIs and TKIs, in addition to interventions earlier in the course of disease or in combination with liver-directed therapies. Because HCC usually develops against a background of cirrhosis, immunotherapy for liver tumors is complex and oncologists need to account for both immunological and hepatological considerations when developing a treatment plan for their patients. To provide guidance to the oncology community on important concerns for the immunotherapeutic care of HCC, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel of experts to develop a clinical practice guideline (CPG). The expert panel drew on the published literature as well as their clinical experience to develop recommendations for healthcare professionals on these important aspects of immunotherapeutic treatment for HCC, including diagnosis and staging, treatment planning, immune-related adverse events (irAEs), and patient quality of life (QOL) considerations. The evidence- and consensus-based recommendations in this CPG are intended to give guidance to cancer care providers treating patients with HCC.
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Affiliation(s)
- Tim F Greten
- Thoracic and GI Malignancies Branch, National Cancer Institute, Bethesda, Maryland, USA
| | - Ghassan K Abou-Alfa
- Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Weill Medical College at Cornell University, New York, New York, USA
| | - Ann-Lii Cheng
- Department of Medical Oncology, National Taiwan University Cancer Center and National Taiwan University Hospital, Taipei, Taiwan
| | - Austin G Duffy
- The Mater Hospital/University College Dublin, Dublin, Ireland
| | - Anthony B El-Khoueiry
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA
| | - Richard S Finn
- David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
| | | | - Lipika Goyal
- Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Aiwu Ruth He
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia, USA
| | - Ahmed O Kaseb
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Robin Kate Kelley
- Department of Medicine (Hematology/Oncology), UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California, USA
| | - Riccardo Lencioni
- Department of Radiology, University of Pisa School of Medicine, Pisa, Italy
- Miami Cancer Institute, Miami, Florida, USA
| | - Amaia Lujambio
- Oncological Sciences Department, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Donna Mabry Hrones
- Thoracic and GI Malignancies Branch, National Cancer Institute, Bethesda, Maryland, USA
| | - David J Pinato
- Department of Surgery & Cancer, Imperial College London, London, UK
| | - Bruno Sangro
- Clinica Universidad de Navarra-Instituto de Investigación Sanitaria de Navarra (IDISNA), Pamplona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | | | - Andrea Wilson Woods
- Blue Faery: The Adrienne Wilson Liver Cancer Association, Birmingham, Alabama, USA
| | - Thomas Yau
- Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong
| | - Andrew X Zhu
- Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts, USA
- Jiahui Health, Jiahui International Cancer Center, Shanghai, China
| | - Ignacio Melero
- Clinica Universidad de Navarra-Instituto de Investigación Sanitaria de Navarra (IDISNA), Pamplona, Spain
- Foundation for Applied Medical Research (FIMA), Pamplona, Spain
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Madrid, Spain
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50
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D'Alessio A, Cammarota A, Zanuso V, Pressiani T, Personeni N, Rimassa L. Atezolizumab plus bevacizumab for unresectable or metastatic hepatocellular carcinoma. Expert Rev Anticancer Ther 2021; 21:927-939. [PMID: 34167423 DOI: 10.1080/14737140.2021.1948329] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Introduction: The treatment of unresectable hepatocellular carcinoma (HCC) has radically changed after the approval of the combination of atezolizumab plus bevacizumab as first-line treatment. A strong preclinical rationale exists to support the combination of bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody (mAb), and atezolizumab, an anti-programmed death ligand 1 mAb. The efficacy of the combination was first assessed in the phase Ib GO30140 study, and the combination was then proven superior to the prior standard of care, sorafenib, in the phase III IMbrave150 trial.Areas covered: This article focuses on the mechanism of action of atezolizumab and bevacizumab, their synergistic action, and the two clinical trials leading to approval. We also collected the body of post-hoc analyses and meta-analyses to help guide the decision-making process in terms of patient selection and subsequent treatments.Expert opinion: Atezolizumab plus bevacizumab are the current standard of care for first-line treatment of unresectable or metastatic HCC and treatment-naïve patient should be treated with the combination, unless contraindications to the drugs. Since all the available agents for further lines of treatment have been approved for sorafenib-pretreated patients, prospective trials, post-hoc analyses, and real-world data assessing valid treatment sequencing are strongly needed.
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Affiliation(s)
- Antonio D'Alessio
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, (Milan), Italy.,Medical Oncology and Hematology Unit,Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, (Milan), Italy
| | - Antonella Cammarota
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, (Milan), Italy.,Medical Oncology and Hematology Unit,Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, (Milan), Italy
| | - Valentina Zanuso
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, (Milan), Italy.,Medical Oncology and Hematology Unit,Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, (Milan), Italy
| | - Tiziana Pressiani
- Medical Oncology and Hematology Unit,Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, (Milan), Italy
| | - Nicola Personeni
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, (Milan), Italy.,Medical Oncology and Hematology Unit,Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, (Milan), Italy
| | - Lorenza Rimassa
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, (Milan), Italy.,Medical Oncology and Hematology Unit,Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, (Milan), Italy
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