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1
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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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Zheng J, Wang S, Xia L, Sun Z, Chan KM, Bernards R, Qin W, Chen J, Xia Q, Jin H. Hepatocellular carcinoma: signaling pathways and therapeutic advances. Signal Transduct Target Ther 2025; 10:35. [PMID: 39915447 PMCID: PMC11802921 DOI: 10.1038/s41392-024-02075-w] [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: 05/21/2024] [Revised: 09/18/2024] [Accepted: 11/14/2024] [Indexed: 02/09/2025] Open
Abstract
Liver cancer represents a major global health concern, with projections indicating that the number of new cases could surpass 1 million annually by 2025. Hepatocellular carcinoma (HCC) constitutes around 90% of liver cancer cases and is primarily linked to factors incluidng aflatoxin, hepatitis B (HBV) and C (HCV), and metabolic disorders. There are no obvious symptoms in the early stage of HCC, which often leads to delays in diagnosis. Therefore, HCC patients usually present with tumors in advanced and incurable stages. Several signaling pathways are dis-regulated in HCC and cause uncontrolled cell propagation, metastasis, and recurrence of HCC. Beyond the frequently altered and therapeutically targeted receptor tyrosine kinase (RTK) pathways in HCC, pathways involved in cell differentiation, telomere regulation, epigenetic modification and stress response also provide therapeutic potential. Investigating the key signaling pathways and their inhibitors is pivotal for achieving therapeutic advancements in the management of HCC. At present, the primary therapeutic approaches for advanced HCC are tyrosine kinase inhibitors (TKI), immune checkpoint inhibitors (ICI), and combination regimens. New trials are investigating combination therapies involving ICIs and TKIs or anti-VEGF (endothelial growth factor) therapies, as well as combinations of two immunotherapy regimens. The outcomes of these trials are expected to revolutionize HCC management across all stages. Here, we provide here a comprehensive review of cellular signaling pathways, their therapeutic potential, evidence derived from late-stage clinical trials in HCC and discuss the concepts underlying earlier clinical trials, biomarker identification, and the development of more effective therapeutics for HCC.
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Affiliation(s)
- Jiaojiao Zheng
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Siying Wang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Lei Xia
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Zhen Sun
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Kui Ming Chan
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, PR China
| | - René Bernards
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
- Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Wenxin Qin
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Jinhong Chen
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, PR China.
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
| | - Haojie Jin
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
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Raghav A, Jeong GB. Phase I-IV Drug Trials on Hepatocellular Carcinoma in Asian Populations: A Systematic Review of Ten Years of Studies. Int J Mol Sci 2024; 25:9286. [PMID: 39273237 PMCID: PMC11395253 DOI: 10.3390/ijms25179286] [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: 06/06/2024] [Revised: 08/02/2024] [Accepted: 08/07/2024] [Indexed: 09/15/2024] Open
Abstract
Despite advances in the treatment of hepatocellular carcinoma (HCC) over the last few decades, treatment opportunities for patients with HCC remain limited. HCC is the most common form of liver cancer, accounting for approximately 90% of all cases worldwide. Moreover, apart from the current pharmacological interventions, hepatic resection and liver transplantation are the mainstay curative approaches for patients with HCC. This systematic review included phase I, II, III, and IV clinical trials (CTs) and randomized controlled trials (RCTs) on current treatments for patients with HCC in Asian populations (2013-2023). A total of 427 articles were screened, and 184 non-duplicate publications were identified. After screening the titles and abstracts, 96 publications were excluded, and another 28 were excluded after full-text screening. The remaining 60 eligible RCTs/CTs were finally included. A total of 60 clinical trials fulfilled our inclusion criteria with 36 drugs used as monotherapy or combination therapy for HCC. Most studies used sorafenib alone or in combination with any of the treatment regimens. Lenvatinib or atezolizumab with bevacizumab was used for HCC after initial sorafenib treatment. Eighteen studies compared the efficacy of sorafenib with that of other drugs, including lenvatinib, cabozantinib, tepotinib, tigatuzumab, linifanib, erlotinib, resminostat, brivanib, tislelizumab, selumetinib, and refametinib. This study provides comprehensive insights into effective treatment interventions for HCC in Asian populations. The overall assessment indicates that sorafenib, used alone or in combination with atezolizumab and bevacizumab, has been the first treatment choice in the past decade to achieve better outcomes in patients with HCC in Asian populations.
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Affiliation(s)
- Alok Raghav
- Department of Anatomy and Cell Biology, College of Medicine, Gachon University, 155 Getbeol-ro, Yeonsu-gu, Incheon 21999, Republic of Korea
| | - Goo Bo Jeong
- Department of Anatomy and Cell Biology, College of Medicine, Gachon University, 155 Getbeol-ro, Yeonsu-gu, Incheon 21999, Republic of Korea
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4
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Payo-Serafín T, Méndez-Blanco C, Fernández-Palanca P, Martínez-Geijo J, Reviejo M, Ortiz-de-Urbina JJ, González-Gallego J, Marin JJG, Mauriz JL, San-Miguel B. Risk versus Benefit of Tyrosine Kinase Inhibitors for Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Clin Pharmacol Ther 2024; 116:328-345. [PMID: 38803056 DOI: 10.1002/cpt.3312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 05/06/2024] [Indexed: 05/29/2024]
Abstract
Although the treatment landscape has rapidly evolved over the last years, hepatocellular carcinoma (HCC) is one of the most lethal cancers. With recent advances, both immunotherapy and tyrosine kinase inhibitors (TKIs)-based chemotherapy constitute the standard treatment for advanced HCC. A systematic search of randomized clinical trials employing TKIs was performed in 17 databases, obtaining 25 studies evaluating the prognosis, tumor response, and presence of adverse events (AEs) related to TKIs in HCC. Overall effect sizes were estimated for the hazard ratios (HR) and odds ratios (OR) with 95% confidence interval (CI), either extracted or calculated with the Parmar method, employing STATA 16. Heterogeneity was assessed by Chi-square-based Q-test and inconsistency (I2) statistic; source of heterogeneity by meta-regression and subgroup analysis; and publication bias by funnel plot asymmetry and Egger's test. The research protocol was registered in PROSPERO (CRD42023397263). Meta-analysis revealed a correlation between survival and tumor response parameters and TKI treatment vs. placebo, despite detecting high heterogeneity. Combined TKI treatment showed a significantly better objective response rate (ORR) with no heterogeneity, whereas publication bias was only detected with time to progression (TTP). Few gastrointestinal and neurological disorders were associated with TKI treatment vs. placebo or with combined treatment. However, a higher number of serious AEs were related to TKI treatment vs. sorafenib alone. Results show positive clinical benefits from TKI treatment, supporting the approval and maintenance of TKI-based therapy for advanced HCC, while establishing appropriate strategies to maximize efficacy and minimize toxicity.
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Affiliation(s)
- Tania Payo-Serafín
- Institute of Biomedicine (IBIOMED), Universidad de León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Carolina Méndez-Blanco
- Institute of Biomedicine (IBIOMED), Universidad de León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Paula Fernández-Palanca
- Institute of Biomedicine (IBIOMED), Universidad de León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Jennifer Martínez-Geijo
- Institute of Biomedicine (IBIOMED), Universidad de León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - María Reviejo
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Experimental Hepatology and Drug Targeting (HEVEPHARM), IBSAL, University of Salamanca, Salamanca, Spain
| | - Juan José Ortiz-de-Urbina
- Institute of Biomedicine (IBIOMED), Universidad de León, León, Spain
- Pharmacy Service, Complejo Asistencial Universitario de León (CAULE), Hospital of León, León, Spain
| | - Javier González-Gallego
- Institute of Biomedicine (IBIOMED), Universidad de León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Jose J G Marin
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Experimental Hepatology and Drug Targeting (HEVEPHARM), IBSAL, University of Salamanca, Salamanca, Spain
| | - José L Mauriz
- Institute of Biomedicine (IBIOMED), Universidad de León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Beatriz San-Miguel
- Institute of Biomedicine (IBIOMED), Universidad de León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
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Marin JJG, Macias RIR, Asensio M, Romero MR, Temprano AG, Pereira OR, Jimenez S, Mauriz JL, Di Giacomo S, Avila MA, Efferth T, Briz O. Strategies to enhance the response of liver cancer to pharmacological treatments. Am J Physiol Cell Physiol 2024; 327:C11-C33. [PMID: 38708523 DOI: 10.1152/ajpcell.00176.2024] [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: 03/25/2024] [Revised: 04/26/2024] [Accepted: 04/26/2024] [Indexed: 05/07/2024]
Abstract
In contrast to other types of cancers, there is no available efficient pharmacological treatment to improve the outcomes of patients suffering from major primary liver cancers, i.e., hepatocellular carcinoma and cholangiocarcinoma. This dismal situation is partly due to the existence in these tumors of many different and synergistic mechanisms of resistance, accounting for the lack of response of these patients, not only to classical chemotherapy but also to more modern pharmacological agents based on the inhibition of tyrosine kinase receptors (TKIs) and the stimulation of the immune response against the tumor using immune checkpoint inhibitors (ICIs). This review summarizes the efforts to develop strategies to overcome this severe limitation, including searching for novel drugs derived from synthetic, semisynthetic, or natural products with vectorial properties against therapeutic targets to increase drug uptake or reduce drug export from cancer cells. Besides, immunotherapy is a promising line of research that is already starting to be implemented in clinical practice. Although less successful than in other cancers, the foreseen future for this strategy in treating liver cancers is considerable. Similarly, the pharmacological inhibition of epigenetic targets is highly promising. Many novel "epidrugs," able to act on "writer," "reader," and "eraser" epigenetic players, are currently being evaluated in preclinical and clinical studies. Finally, gene therapy is a broad field of research in the fight against liver cancer chemoresistance, based on the impressive advances recently achieved in gene manipulation. In sum, although the present is still dismal, there is reason for hope in the non-too-distant future.
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Affiliation(s)
- Jose J G Marin
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Rocio I R Macias
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Maitane Asensio
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Marta R Romero
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Alvaro G Temprano
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
| | - Olívia R Pereira
- Centro de Investigação de Montanha (CIMO), Laboratório Associado para a Sustentabilidade e Tecnologia em Regiões de Montanha (SusTEC), Instituto Politécnico de Bragança, Bragança, Portugal
- Research Centre for Active Living and Wellbeing (LiveWell), Instituto Politécnico de Bragança, Bragança, Portugal
| | - Silvia Jimenez
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
- Servicio de Farmacia Hospitalaria, Hospital de Salamanca, Salamanca, Spain
| | - Jose L Mauriz
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
- Institute of Biomedicine (IBIOMED), University of Leon, Leon, Spain
| | - Silvia Di Giacomo
- Department of Food Safety, Nutrition and Veterinary Public Health, National Institute of Health, Rome, Italy
| | - Matias A Avila
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
- Hepatology Laboratory, Solid Tumors Program, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Instituto de Investigaciones Sanitarias de Navarra (IdisNA), Pamplona, Spain
| | - Thomas Efferth
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany
| | - Oscar Briz
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
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6
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Becht R, Kiełbowski K, Wasilewicz MP. New Opportunities in the Systemic Treatment of Hepatocellular Carcinoma-Today and Tomorrow. Int J Mol Sci 2024; 25:1456. [PMID: 38338736 PMCID: PMC10855889 DOI: 10.3390/ijms25031456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 01/22/2024] [Accepted: 01/23/2024] [Indexed: 02/12/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Liver cirrhosis, hepatitis B, hepatitis C, and non-alcoholic fatty liver disease represent major risk factors of HCC. Multiple different treatment options are available, depending on the Barcelona Clinic Liver Cancer (BCLC) algorithm. Systemic treatment is reserved for certain patients in stages B and C, who will not benefit from regional treatment methods. In the last fifteen years, the arsenal of available therapeutics has largely expanded, which improved treatment outcomes. Nevertheless, not all patients respond to these agents and novel combinations and drugs are needed. In this review, we aim to summarize the pathway of trials investigating the safety and efficacy of targeted therapeutics and immunotherapies since the introduction of sorafenib. Furthermore, we discuss the current evidence regarding resistance mechanisms and potential novel targets in the treatment of advanced HCC.
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Affiliation(s)
- Rafał Becht
- Department of Clinical Oncology, Chemotherapy and Cancer Immunotherapy, Pomeranian Medical University in Szczecin, 71-252 Szczecin, Poland; (R.B.); (K.K.)
| | - Kajetan Kiełbowski
- Department of Clinical Oncology, Chemotherapy and Cancer Immunotherapy, Pomeranian Medical University in Szczecin, 71-252 Szczecin, Poland; (R.B.); (K.K.)
| | - Michał P. Wasilewicz
- Liver Unit, Department of Gastroenterology, Pomeranian Medical University in Szczecin, 71-252 Szczecin, Poland
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Requeijo C, Bracchiglione J, Meza N, Acosta-Dighero R, Salazar J, Santero M, Meade AG, Quintana MJ, Rodríguez-Grijalva G, Selva A, Solà I, Urrútia G, Bonfill Cosp X. Anticancer Drugs Compared to No Anticancer Drugs in Patients with Advanced Hepatobiliary Cancer: A Mapping Review and Evidence Gap Map. Clin Epidemiol 2023; 15:1069-1085. [PMID: 38025841 PMCID: PMC10644842 DOI: 10.2147/clep.s431498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Accepted: 10/14/2023] [Indexed: 12/01/2023] Open
Abstract
Introduction Despite being commonly recommended, the impact of anticancer drugs (ACDs) on patient-important outcomes beyond survival for advanced hepatobiliary cancers (HBCs) may not have been sufficiently assessed. We aim to identify and map the evidence regarding ACDs versus best supportive care (BSC) for advanced HBCs, considering patient-centered outcomes. Methods In this mapping review, we included systematic reviews, randomized controlled trials, quasi-experimental, and observational studies comparing ACDs (chemotherapy, immunotherapy, biological/targeted therapy) versus BSC for advanced HBCs. We searched MEDLINE (PubMed), EMBASE (Ovid), Cochrane Library, Epistemonikos, PROSPERO and clinicaltrials.gov for eligible studies. Two reviewers performed the screening and data extraction processes. We developed evidence maps for each type of cancer. Results We included 87 studies (60 for advanced liver cancer and 27 for gallbladder or bile duct cancers). Most of the evidence favored ACDs for survival outcomes, and BSC for toxicity. We identified several evidence gaps for non-survival outcomes, including quality of life or quality of end-of-life care. Discussion Patient-important outcomes beyond survival in advanced HBCs are insufficiently assessed by the available evidence. Future studies need to address these gaps to better inform decision-making processes.
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Affiliation(s)
- Carolina Requeijo
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
| | - Javier Bracchiglione
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
- Interdisciplinary Centre for Health Studies (CIESAL), Valparaiso University, Viña del Mar, Chile
- CIBER of Epidemiology and Public Health (CIBERESP), Barcelona, Spain
| | - Nicolás Meza
- Interdisciplinary Centre for Health Studies (CIESAL), Valparaiso University, Viña del Mar, Chile
| | - Roberto Acosta-Dighero
- Interdisciplinary Centre for Health Studies (CIESAL), Valparaiso University, Viña del Mar, Chile
| | - Josefina Salazar
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
| | - Marilina Santero
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
| | - Adriana-G Meade
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
| | - María Jesús Quintana
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
- CIBER of Epidemiology and Public Health (CIBERESP), Barcelona, Spain
- Autonomous University of Barcelona, Barcelona, Spain
| | | | - Anna Selva
- CIBER of Epidemiology and Public Health (CIBERESP), Barcelona, Spain
- Clinical Epidemiology and Cancer Screening, Parc Taulí Hospital Universitari, Parc Taulí Research and Innovation Institute Foundation (I3PT-CERCA), Autonomous University of Barcelona, Sabadell, Spain
| | - Ivan Solà
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
- CIBER of Epidemiology and Public Health (CIBERESP), Barcelona, Spain
| | - Gerard Urrútia
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
- CIBER of Epidemiology and Public Health (CIBERESP), Barcelona, Spain
| | - Xavier Bonfill Cosp
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
- CIBER of Epidemiology and Public Health (CIBERESP), Barcelona, Spain
- Autonomous University of Barcelona, Barcelona, Spain
| | - On behalf of Appropriateness of Systemic Oncological Treatments for Advanced Cancer (ASTAC) Research Group
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
- Interdisciplinary Centre for Health Studies (CIESAL), Valparaiso University, Viña del Mar, Chile
- CIBER of Epidemiology and Public Health (CIBERESP), Barcelona, Spain
- Autonomous University of Barcelona, Barcelona, Spain
- Clinical Epidemiology and Cancer Screening, Parc Taulí Hospital Universitari, Parc Taulí Research and Innovation Institute Foundation (I3PT-CERCA), Autonomous University of Barcelona, Sabadell, Spain
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8
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Jiang H, Liao J, Wang L, Jin C, Mo J, Xiang S. The multikinase inhibitor axitinib in the treatment of advanced hepatocellular carcinoma: the current clinical applications and the molecular mechanisms. Front Immunol 2023; 14:1163967. [PMID: 37325670 PMCID: PMC10264605 DOI: 10.3389/fimmu.2023.1163967] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Accepted: 05/22/2023] [Indexed: 06/17/2023] Open
Abstract
Advanced hepatocellular carcinoma (HCC) is a formidable public health problem with limited curable treatment options. Axitinib, an oral tyrosine kinase inhibitor, is a potent and selective second-generation inhibitor of vascular endothelial growth factor receptor (VEGFR) 1, 2, and 3. This anti-angiogenic drug was found to have promising activity in various solid tumors, including advanced HCC. At present, however, there is no relevant review article that summarizes the exact roles of axitinib in advanced HCC. In this review, 24 eligible studies (seven studies in the ClinicalTrials, eight experimental studies, and nine clinical trials) were included for further evaluation. The included randomized or single-arm phase II trials indicated that axitinib could not prolong the overall survival compared to the placebo for the treatment of advanced HCC, but improvements in progression free survival and time to tumor progression were observed. Experimental studies showed that the biochemical effects of axitinib in HCC might be regulated by its associated genes and affected signaling cascades (e.g. VEGFR2/PAK1, CYP1A2, CaMKII/ERK, Akt/mTor, and miR-509-3p/PDGFRA). FDA approved sorafenib combined with nivolumab (an inhibitor of PD-1/PD-L1) as the first line regimen for the treatment of advanced HCC. Since both axitinib and sorafenib are tyrosine kinase inhibitors as well as the VEGFR inhibitors, axitinib combined with anti-PDL-1/PD-1 antibodies may also exhibit tremendous potential in anti-tumoral effects for advanced HCC. The present review highlights the current clinical applications and the molecular mechanisms of axitinib in advanced HCC. To move toward clinical applications by combining axitinib and other treatments in advanced HCC, more studies are still warranted in the near future.
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Affiliation(s)
- Hao Jiang
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, China
| | - Jian Liao
- Department of Nephrology, Jiaxing Hospital of Traditional Chinese Medicine, Jiaxing, Zhejiang, China
| | - Liezhi Wang
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, China
| | - Chong Jin
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, China
| | - Jinggang Mo
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, China
| | - Sheng Xiang
- Department of General Surgery, Tiantai People’s Hospital, Taizhou, Zhejiang, China
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Zhang T, Gu J, Wang X, Lu Y, Cai K, Li H, Nie Y, Chen X, Wang J. A novel liver zonation phenotype-associated molecular classification of hepatocellular carcinoma. Front Immunol 2023; 14:1140201. [PMID: 36936935 PMCID: PMC10017747 DOI: 10.3389/fimmu.2023.1140201] [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: 01/08/2023] [Accepted: 02/20/2023] [Indexed: 03/06/2023] Open
Abstract
Background Liver zonation is a unique phenomenon in which the liver exhibits distinct functions among hepatocytes along the radial axis of the lobule. This phenomenon can cause the sectionalized initiation of several liver diseases, including hepatocellular carcinoma (HCC). However, few studies have explored the zonation features of HCC. Methods Four single-cell RNA sequencing datasets were used to identify hepatocyte-specific zonation markers. Integrative analysis was then performed with a training RNA-seq cohort (616 HCC samples) and an external validating microarray cohort (285 HCC samples) from the International Cancer Genome Consortium, The Cancer Genome Atlas, Gene Expression Omnibus, and EMBL's European Bioinformatics Institute for clustering using non-negative matrix factorization consensus clustering based on zonation genes. Afterward, we evaluated the prognostic value, clinical characteristics, transcriptome and mutation features, immune infiltration, and immunotherapy response of the HCC subclasses. Results A total of 94 human hepatocyte-specific zonation markers (39 central markers and 55 portal markers) were identified for the first time. Subsequently, three subgroups of HCC, namely Cluster1, Cluster2, and Cluster3 were identified. Cluster1 exhibited a non-zonational-like signature with the worst prognosis. Cluster2 was intensively associated with a central-like signature and exhibited low immune infiltration and sensitivity toward immune blockade therapy. Cluster3 was intensively correlated with a portal-like signature with the best prognosis. Finally, we identified candidate therapeutic targets and agents for Cluster1 HCC samples. Conclusion The current study established a novel HCC classification based on liver zonation signature. By classifying HCC into three clusters with non-zonational-like (Cluster1), central-like (Cluster2), and portal-like (Cluster3) features, this study provided new perspectives on the heterogeneity of HCC and shed new light on delivering precision medicine for HCC patients.
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Affiliation(s)
- Tao Zhang
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jian Gu
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xinyi Wang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yaoyao Lu
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kailin Cai
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huili Li
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yingli Nie
- Department of Dermatology, Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiangdong Chen
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiliang Wang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Bracchiglione J, Rodríguez-Grijalva G, Requeijo C, Santero M, Salazar J, Salas-Gama K, Meade AG, Antequera A, Auladell-Rispau A, Quintana MJ, Solà I, Urrútia G, Acosta-Dighero R, Bonfill Cosp X. Systemic Oncological Treatments versus Supportive Care for Patients with Advanced Hepatobiliary Cancers: An Overview of Systematic Reviews. Cancers (Basel) 2023; 15:cancers15030766. [PMID: 36765723 PMCID: PMC9913533 DOI: 10.3390/cancers15030766] [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: 11/25/2022] [Revised: 01/14/2023] [Accepted: 01/18/2023] [Indexed: 01/28/2023] Open
Abstract
BACKGROUND The trade-off between systemic oncological treatments (SOTs) and UPSC in patients with primary advanced hepatobiliary cancers (HBCs) is not clear in terms of patient-centred outcomes beyond survival. This overview aims to assess the effectiveness of SOTs (chemotherapy, immunotherapy and targeted/biological therapies) versus UPSC in advanced HBCs. METHODS We searched for systematic reviews (SRs) in PubMed, EMBASE, the Cochrane Library, Epistemonikos and PROSPERO. Two authors assessed eligibility independently and performed data extraction. We estimated the quality of SRs and the overlap of primary studies, performed de novo meta-analyses and assessed the certainty of evidence for each outcome. RESULTS We included 18 SRs, most of which were of low quality and highly overlapped. For advanced hepatocellular carcinoma, SOTs showed better overall survival (HR = 0.62, 95% CI 0.55-0.77, high certainty for first-line therapy; HR = 0.85, 95% CI 0.79-0.92, moderate certainty for second-line therapy) with higher toxicity (RR = 1.18, 95% CI 0.87-1.60, very low certainty for first-line therapy; RR = 1.58, 95% CI 1.28-1.96, low certainty for second-line therapy). Survival was also better for SOTs in advanced gallbladder cancer. No outcomes beyond survival and toxicity could be meta-analysed. CONCLUSION SOTs in advanced HBCs tend to improve survival at the expense of greater toxicity. Future research should inform other patient-important outcomes to guide clinical decision making.
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Affiliation(s)
- Javier Bracchiglione
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain
- Interdisciplinary Centre for Health Studies (CIESAL), Universidad de Valparaíso, Viña del Mar 46383, Chile
- CIBER Epidemiología y Salud Pública (CIBERESP), 28029 Madrid, Spain
| | - Gerardo Rodríguez-Grijalva
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain
| | - Carolina Requeijo
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain
- Correspondence:
| | - Marilina Santero
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain
| | - Josefina Salazar
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain
| | - Karla Salas-Gama
- CIBER Epidemiología y Salud Pública (CIBERESP), 28029 Madrid, Spain
- Quality, Process and Innovation Direction, Valld’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain
| | - Adriana-Gabriela Meade
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain
| | - Alba Antequera
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain
| | - Ariadna Auladell-Rispau
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain
| | - María Jesús Quintana
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain
- CIBER Epidemiología y Salud Pública (CIBERESP), 28029 Madrid, Spain
- Departament de Pediatria, d’Obstetrícia i Ginecologia, i Medicina Preventiva i Salut Pública, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain
| | - Ivan Solà
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain
- CIBER Epidemiología y Salud Pública (CIBERESP), 28029 Madrid, Spain
- Departament de Pediatria, d’Obstetrícia i Ginecologia, i Medicina Preventiva i Salut Pública, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain
| | - Gerard Urrútia
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain
- CIBER Epidemiología y Salud Pública (CIBERESP), 28029 Madrid, Spain
- Departament de Pediatria, d’Obstetrícia i Ginecologia, i Medicina Preventiva i Salut Pública, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain
| | - Roberto Acosta-Dighero
- Interdisciplinary Centre for Health Studies (CIESAL), Universidad de Valparaíso, Viña del Mar 46383, Chile
| | - Xavier Bonfill Cosp
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain
- CIBER Epidemiología y Salud Pública (CIBERESP), 28029 Madrid, Spain
- Departament de Pediatria, d’Obstetrícia i Ginecologia, i Medicina Preventiva i Salut Pública, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain
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11
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Damaskos C, Garmpis N, Dimitroulis D, Garmpi A, Psilopatis I, Sarantis P, Koustas E, Kanavidis P, Prevezanos D, Kouraklis G, Karamouzis MV, Marinos G, Kontzoglou K, Antoniou EA. Targeted Therapies for Hepatocellular Carcinoma Treatment: A New Era Ahead-A Systematic Review. Int J Mol Sci 2022; 23:ijms232214117. [PMID: 36430594 PMCID: PMC9698799 DOI: 10.3390/ijms232214117] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 11/10/2022] [Accepted: 11/11/2022] [Indexed: 11/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) remains one of the most common malignancies and the third cause of cancer-related death worldwide, with surgery being the best prognostic tool. Among the well-known causative factors of HCC are chronic liver virus infections, chronic virus hepatitis B (HBV) and chronic hepatitis virus C (HCV), aflatoxins, tobacco consumption, and non-alcoholic liver disease (NAFLD). There is a need for the development of efficient molecular markers and alternative therapeutic targets of great significance. In this review, we describe the general characteristics of HCC and present a variety of targeted therapies that resulted in progress in HCC therapy.
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Affiliation(s)
- Christos Damaskos
- Renal Transplantation Unit, Laiko General Hospital, 11527 Athens, Greece
- Nikolaos Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Correspondence: ; Tel.: +30-694-846-7790
| | - Nikolaos Garmpis
- Nikolaos Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Dimitrios Dimitroulis
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Anna Garmpi
- First Department of Propedeutic Internal Medicine, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Iason Psilopatis
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt—Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Panagiotis Sarantis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Evangelos Koustas
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Prodromos Kanavidis
- Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | | | - Gregory Kouraklis
- Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Michail V. Karamouzis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Georgios Marinos
- Department of Hygiene, Epidemiology and Medical Statistics, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Konstantinos Kontzoglou
- Nikolaos Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Efstathios A. Antoniou
- Nikolaos Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
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12
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Liu P, Zhu Z, Ma J, Wei L, Han Y, Shen E, Tan X, Chen Y, Cai C, Guo C, Peng Y, Gao Y, Liu Y, Huang Q, Gao L, Li Y, Jiang Z, Wu W, Liu Y, Zeng S, Li W, Feng Z, Shen H. Prognostic stratification based on m5C regulators acts as a novel biomarker for immunotherapy in hepatocellular carcinoma. Front Immunol 2022; 13:951529. [PMID: 36159831 PMCID: PMC9505913 DOI: 10.3389/fimmu.2022.951529] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 08/22/2022] [Indexed: 12/24/2022] Open
Abstract
Background Immunotherapy is a promising anti-cancer strategy in hepatocellular carcinoma (HCC). However, a limited number of patients can benefit from it. There are currently no reliable biomarkers available to find the potential beneficiaries. Methylcytosine (m5C) is crucial in HCC, but its role in forecasting clinical responses to immunotherapy has not been fully clarified. Methods In this study, we analyzed 371 HCC patients from The Cancer Genome Atlas (TCGA) database and investigated the expression of 18 m5C regulators. We selected 6 differentially expressed genes (DEGs) to construct a prognostic risk model as well as 2 m5C-related diagnostic models. Results The 1-, 3-, and 5-year area under the curve (AUC) of m5C scores for the overall survival (OS) was 0.781/0.762/0.711, indicating the m5C score system had an ideal distinction of prognostic prediction for HCC. The survival analysis showed that patients with high-risk scores present a worse prognosis than the patients with low-risk scores (p< 0.0001). We got consistent results in 6 public cohorts and validated them in Xiangya real-world cohort by quantitative real-time PCR and immunohistochemical (IHC) assays. The high-m5C score group was predicted to be in an immune evasion state and showed low sensitivity to immunotherapy, but high sensitivity to chemotherapy and potential targeted drugs and agents, such as sepantronium bromide (YM-155), axitinib, vinblastine and docetaxel. Meanwhile, we also constructed two diagnostic models to distinguish HCC tumors from normal liver tissues or liver cirrhosis. Conclusion In conclusion, our study helps to early screen HCC patients and select patients who can benefit from immunotherapy. Step forwardly, for the less likely beneficiaries, this study provides them with new potential targeted drugs and agents for choice to improve their prognosis.
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Affiliation(s)
- Ping Liu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, China
| | - Ziqing Zhu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, China
| | - Jiayao Ma
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, China
| | - Le Wei
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, China
| | - Ying Han
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, China
| | - Edward Shen
- Department of Life Science, McMaster University, Hamilton, ON, Canada
| | - Xiao Tan
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
| | - Yihong Chen
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, China
| | - Changjing Cai
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, China
| | - Cao Guo
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, China
| | - Yinghui Peng
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, China
| | - Yan Gao
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, China
| | - Yongting Liu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, China
| | - Qiaoqiao Huang
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, China
| | - Le Gao
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, China
| | - Yin Li
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, China
| | - Zhaohui Jiang
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, China
| | - Wantao Wu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, China
| | - Yihan Liu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, China
| | - Shan Zeng
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Wei Li
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Wei Li, ; Ziyang Feng, ; Hong Shen,
| | - Ziyang Feng
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Wei Li, ; Ziyang Feng, ; Hong Shen,
| | - Hong Shen
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Wei Li, ; Ziyang Feng, ; Hong Shen,
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13
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Small Molecule Inhibitors for Hepatocellular Carcinoma: Advances and Challenges. Molecules 2022; 27:molecules27175537. [PMID: 36080304 PMCID: PMC9457820 DOI: 10.3390/molecules27175537] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 08/20/2022] [Accepted: 08/22/2022] [Indexed: 12/12/2022] Open
Abstract
According to data provided by World Health Organization, hepatocellular carcinoma (HCC) is the sixth most common cause of deaths due to cancer worldwide. Tremendous progress has been achieved over the last 10 years developing novel agents for HCC treatment, including small-molecule kinase inhibitors. Several small molecule inhibitors currently form the core of HCC treatment due to their versatility since they would be more easily absorbed and have higher oral bioavailability, thus easier to formulate and administer to patients. In addition, they can be altered structurally to have greater volumes of distribution, allowing them to block extravascular molecular targets and to accumulate in a high concentration in the tumor microenvironment. Moreover, they can be designed to have shortened half-lives to control for immune-related adverse events. Most importantly, they would spare patients, healthcare institutions, and society as a whole from the burden of high drug costs. The present review provides an overview of the pharmaceutical compounds that are licensed for HCC treatment and other emerging compounds that are still investigated in preclinical and clinical trials. These molecules are targeting different molecular targets and pathways that are proven to be involved in the pathogenesis of the disease.
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14
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Griffiths CD, Zhang B, Tywonek K, Meyers BM, Serrano PE. Toxicity Profiles of Systemic Therapies for Advanced Hepatocellular Carcinoma: A Systematic Review and Meta-analysis. JAMA Netw Open 2022; 5:e2222721. [PMID: 35849393 PMCID: PMC9295000 DOI: 10.1001/jamanetworkopen.2022.22721] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Accepted: 06/02/2022] [Indexed: 11/14/2022] Open
Abstract
Importance The recent development of targeted therapy and immunotherapy has made neoadjuvant therapy an attractive option for patients with hepatocellular carcinoma (HCC). However, surgeons are concerned that adverse effects of neoadjuvant therapy with these agents could lead to delayed or even cancelled surgeries. Objective To summarize the current evidence regarding toxicity profiles for tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) among patients with HCC. Data Sources Medline, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched from January 1990 and December 2021. Study Selection Single-group, placebo-controlled, and dual-agent clinical trials comparing TKIs and ICIs in patients with HCC were eligible for inclusion. Data Extraction and Synthesis Following the Preferred Reporting Items in Systematic Reviews and Meta-analysis guideline, 2 reviewers independently extracted data. A random-effects model was used. Main Outcomes and Measures The primary outcome was the proportion of patients with clinically significant liver-related adverse events. Secondary outcomes included the proportion of patients who experienced clinically relevant (grade 3 or higher) adverse events and significant adverse events (ie, those that were life threatening, required hospitalization, or prolonged disability) as well as the risk ratio (RR) of these complications. Results Overall, 30 studies with 12 921 patients were included. Patients had a mean (range) age of 62 (18-89) years; a mean (SD) 84% (3) were male; a mean (SD) 82% (16) had Barcelona Clinic Liver Cancer stage C HCC; and a mean (SD) 97% (6) had Childs A cirrhosis. Overall, 21% (95% CI, 16%-26%) of patients receiving TKIs had liver toxic effects compared with 28% (95% CI, 21%-35%) of patients receiving ICIs. Severe adverse events occurred in 46% (95% CI, 40%-51%) of patients receiving TKIs compared with 24% (95% CI, 13%-35%) of patients receiving ICIs. Compared with patients receiving sorafenib, other TKIs were associated with similar rates of liver toxic effects (RR, 1.06; 95% CI, 0.92-1.24) but higher rates of severe adverse events (RR, 1.24; 95% CI, 1.07-1.44). Comparing ICIs with sorafenib, there were similar rates of liver toxic effects (RR, 1.10; 95% CI, 0.86-1.40) and severe adverse events (RR, 1.19; 95% CI, 0.95-1.50). Conclusions and Relevance In this systematic review and meta-analysis, serious adverse events were lower with ICIs than with TKIs, while liver toxic effects were similar. Combination therapy with novel ICIs is an appealing option in trials of neoadjuvant therapy for patients with HCC, requiring evaluation in preoperative trials.
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Affiliation(s)
| | - Betty Zhang
- Department of Anesthesia, University of Ottawa, Ottawa, Ontario, Canada
| | - Kasia Tywonek
- Department of Surgery, McMaster University, Hamilton, Ontario, Canada
| | - Brandon M. Meyers
- Department of Oncology, McMaster University, Hamilton, Ontario, Canada
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
| | - Pablo E. Serrano
- Department of Surgery, McMaster University, Hamilton, Ontario, Canada
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
- Division of General Surgery, Juravinski Hospital, Hamilton, Ontario, Canada
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15
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Brown ZJ, Hewitt DB, Pawlik TM. Experimental drug treatments for hepatocellular carcinoma: Clinical trial failures 2015 to 2021. Expert Opin Investig Drugs 2022; 31:693-706. [PMID: 35580650 DOI: 10.1080/13543784.2022.2079491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) is a major health problem worldwide with limited systemic therapy options. Since the approval of sorafenib in 2008, no systemic therapy has provided a sustained/robust/survival benefit for patients with advanced HCC until recently. Many initially promising therapies have been trialed, but survival outcomes remained stagnant. As such, knowledge concerning previous treatment failures may help guide further areas of study, as well inform future therapeutic approaches. AREA COVERED This article reviews recent advances in the treatment of HCC. Despite some recent success, many systemic and locoregional therapies have failed to produce significant improvements in outcome. These treatment failures are examined and insight into pathways for future success are discussed. EXPERT OPINION Combination atezolizumab and bevacizumab has changed the landscape of systemic treatment for patients with HCC when it became the first therapy after demonstrating improve outcomes over sorafenib. Clinical trials in patients with advanced HCC have inherent difficulty with challenges to determine if a patient's declining liver function is secondary to disease progression, worsening cirrhosis, or drug toxicity, which may skew results. As we gain more knowledge of underlying genetic alterations behind the pathophysiology of the development of HCC, molecular markers may be identified to assist in predicting which patients would respond to a specific therapy.
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16
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Wang C, Lv Y, Sha Z, Zhang J, Wu J, Qi Y, Guo Z. Dicer Enhances Bevacizumab-Related Inhibition of Hepatocellular Carcinoma via Blocking the Vascular Endothelial Growth Factor Pathway. J Hepatocell Carcinoma 2022; 8:1643-1653. [PMID: 35004391 PMCID: PMC8721026 DOI: 10.2147/jhc.s327258] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 12/22/2021] [Indexed: 12/12/2022] Open
Abstract
Purpose Vascular endothelial growth factor (VEGF) family members contribute greatly to the development and angiogenesis of hypervascular hepatocellular carcinoma (HCC). We have previously shown that Dicer inhibited HCC growth. In this study, we aimed to determine the relationship between Dicer and VEGF in HCC. Methods Gain-of-function studies were performed to determine the effect of different treatments on the proliferation, migration, and invasion of HCC cells. Expression of VEGF-A in xenograft tumor tissues was analysed using Western blotting, and that of CD31 using immunohistochemical analysis. Results We found that Dicer inhibited proliferation, migration and invasion of HCC cells by suppressing VEGF-A expression. Interestingly, VEGF-A165, which is the most prominent VEGF-A isoform, counteracted Dicer-induced inhibition of HCC cells. In addition, a monoclonal anti-VEGF antibody (bevacizumab) enhanced Dicer-induced inhibition of HCC in vitro and in vivo. Further, immunohistochemical analysis of CD31 indicated bevacizumab and Dicer synergized to reduce tumor microvessel density. Conclusion Our data demonstrated that Dicer enhanced bevacizumab-related inhibition of HCC cell via the VEGF pathway; therefore, Dicer in coordination with bevacizumab may provide another potential approach for HCC therapy.
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Affiliation(s)
- Cuiju Wang
- Department of Gynaecology Ultrasound, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China
| | - Yalei Lv
- Department of Medical Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China
| | - Ziyue Sha
- Department of Immunology and Rheumatology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China
| | - Jingjing Zhang
- Department of Immunology and Rheumatology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China
| | - Jianhua Wu
- Animal Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China
| | - Yixin Qi
- Breast Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China
| | - Zhanjun Guo
- Department of Immunology and Rheumatology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China
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Kudo M, Montal R, Finn RS, Castet F, Ueshima K, Nishida N, Haber PK, Hu Y, Chiba Y, Schwartz M, Meyer T, Lencioni R, Llovet JM. Objective Response Predicts Survival in Advanced Hepatocellular Carcinoma treated with Systemic Therapies. Clin Cancer Res 2021; 28:3443-3451. [PMID: 34907081 DOI: 10.1158/1078-0432.ccr-21-3135] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/27/2021] [Accepted: 12/08/2021] [Indexed: 11/16/2022]
Abstract
PURPOSE Due to the increased number of sequential treatments used for advanced HCC, there is a need for surrogate endpoints of overall survival (OS). We analyze if objective response (OR) is an independent predictor and surrogate endpoint of OS. EXPERIMENTAL DESIGN A systematic review of randomized clinical trials (RCTs) in advanced HCC published between 2010 and 2020 was conducted to explore OS surrogacy of OR by RECIST and mRECIST. In parallel, RCTs exploring the impact of OR on OS in a time-dependent multivariate analysis were integrated in a meta-analysis. RESULTS Out of 65 RCTs identified in advanced HCC, we analyzed 34 studies including 14,056 patients that reported OS and OR by either RECIST (n=23), mRECIST (n=5) or both (n=6). When exploring surrogacy, the trial-level correlation between OR odds ratio and OS hazard ratio was R=0.677 by mRECIST and R=0.532 by RECIST. Meta-analysis of five RCT assessing predictors of survival in multivariate analysis found that patients with OR by mRECIST presented a pooled HR for OS of 0.44 (95% CI, 0.27-0.70, p<0.001) compared with non-responders. Responses to atezolizumab-bevacizumab had a greater impact on OS than tyrosine-kinase inhibitor responses. CONCLUSIONS OR-mRECIST is an independent predictor of OS in patients with advanced HCC. Although correlation of OR-mRECIST and OS is better than with OR-RECIST, the level of surrogacy is modest. Thus, it can be used as endpoint in proof-of-concept phase II trials, but the data does not support its use as a primary endpoint of phase III investigations assessing systemic therapies.
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Affiliation(s)
- Masatoshi Kudo
- Gastroenterology and Hepatology, Kindai University School of Medicine
| | - Robert Montal
- Medical Oncology, Hospital Universitari Arnau de Vilanova
| | | | - Florian Castet
- Translational Research in Hepatic Oncology, Liver Unit, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS)
| | - Kazuomi Ueshima
- Gastroenterology and Hepatology, Kindai University Faculty of Medicine
| | - Naoshi Nishida
- Gastroenterology and Hepatology, Kindai University Faculty of Medicine
| | | | | | - Yasutaka Chiba
- Department of Environmental Medicine and Behavioral Science, Kinki University School of Medicine
| | | | - Tim Meyer
- UCL Cancer Institute, University College London
| | | | - Josep M Llovet
- Translational Research in Hepatic Oncology, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, Universitat De Barcelona
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Early Changes in DCE-MRI Biomarkers May Predict Survival Outcomes in Patients with Advanced Hepatocellular Carcinoma after Sorafenib Failure: Two Prospective Phase II Trials. Cancers (Basel) 2021; 13:cancers13194962. [PMID: 34638446 PMCID: PMC8508238 DOI: 10.3390/cancers13194962] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 09/28/2021] [Accepted: 09/28/2021] [Indexed: 01/10/2023] Open
Abstract
Simple Summary In patients with advanced hepatocellular carcinoma, systemic therapy is recommended by most treatment guidelines. Sorafenib and lenvatinib are both 1st-line treatments for inoperable advanced HCC. Regorafenib, cabozantinib, and ramucirumab have been approved as 2nd-line targeted therapy in patients who show progression or do not tolerate sorafenib. However, there is a lack of imaging biomarkers for predicting survival outcomes in patients receiving 2nd-line targeted therapy after sorafenib failure. In this paper, we try to predict survival outcomes via early changes in the DCE-MRI biomarkers in participants with advanced HCC after 2nd-line targeted therapy following sorafenib failure, taking data from two different prospective clinical trials. We found that an early reduction in tumor perfusion detected by DCE-MRI biomarkers, especially on day 14, may predict survival outcomes in these participants. For the further clinical development of anti-angiogenic therapies, optimal participant selection with predictive biomarkers, such as DCE-MRI, is essential in order to improve treatment outcomes. Abstract In this paper, our main objective was to predict survival outcomes using DCE-MRI biomarkers in patients with advanced hepatocellular carcinoma (HCC) after progression from 1st-line sorafenib treatment in two prospective phase II trials. This study included 74 participants (men/women = 64/10, mean age 60 ± 11.8 years) with advanced HCC who received 2nd-line targeted therapy (n = 41 with lenalidomide in one clinical trial; n = 33 with axitinib in another clinical trial) after sorafenib failure from two prospective phase II studies. Among them, all patients underwent DCE-MRI at baseline, and on days 3 and 14 of treatment. The relative changes (Δ) in the DCE-MRI parameters, including ΔPeak, ΔAUC, and ΔKtrans, were derived from the largest hepatic tumor. The treatment response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). The Cox model was used to investigate the associations of the clinical variables and DCE-MRI biomarkers with progression-free survival (PFS) and overall survival (OS). The objective response rate (ORR) was 10.8% (8/74) and the disease control rate (DCR) was 58.1% (43/74). The median PFS and OS values were 1.9 and 7.8 months, respectively. On day 3 (D3), participants with high reductions in ΔPeak_D3 (hazard ratio (HR) 0.4, 95% confidence interval (CI) 0.17–0.93, p = 0.017) or ΔAUC_D3 (HR 0.51, 95% CI 0.25–1.04, p = 0.043) were associated with better PFS. On day 14, participants with high reductions in ΔPeak_D14 (HR 0.51, 95% CI 0.26–1.01, p = 0.032), ΔAUC_D14 (HR 0.54, 95% CI 0.33–0.9, p = 0.009), or ΔKtrans_D14 (HR 0.26, 95% CI 0.12–0.56, p < 0.001) had a higher PFS than those with lower reduction values. In addition, high reductions in ΔAUC_D14 (HR 0.53, 95% CI 0.32–0.9, p = 0.016) or ΔKtrans_D14 (HR 0.47, 95% CI 0.23–0.98, p = 0.038) were associated with a better OS. Among the clinical variables, ORR was associated with both PFS (p = 0.001) and OS (p = 0.005). DCR was associated with PFS (p = 0.002), but not OS (p = 0.089). Cox multivariable analysis revealed that ΔKtrans_D14 (p = 0.002) remained an independent predictor of PFS after controlling for ORR and DCR. An early reduction in tumor perfusion detected by DCE-MRI biomarkers, especially on day 14, may predict favorable survival outcomes in participants with HCC receiving 2nd-line targeted therapy after sorafenib failure.
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19
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Chen J, Wang J, Xie F. Comparative efficacy and safety for second-line treatment with ramucirumab, regorafenib, and cabozantinib in patients with advanced hepatocellular carcinoma progressed on sorafenib treatment: A network meta-analysis. Medicine (Baltimore) 2021; 100:e27013. [PMID: 34559096 PMCID: PMC8462645 DOI: 10.1097/md.0000000000027013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 12/22/2020] [Accepted: 08/05/2021] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND The present network meta-analysis was conducted to perform an indirect comparison among ramucirumab, regorafenib, and cabozantinib in patients with advanced hepatocellular carcinoma (HCC) progressed on sorafenib treatment. METHODS A systematic review through Medline, Embase, and Cochrane library was developed, with eligible randomized clinical trials been included. Hazard ratios (HRs) including progression-free survival (PFS), overall survival (OS), odds ratios of disease control rate (DCR), objective response rate (ORR), and adverse events were compared indirectly with network meta-analysis using random model in software STATA version 13.0. RESULTS A total of 4 randomized clinical trials including 2137 patients met the eligibility criteria and enrolled. Indirect comparisons showed that there was no statistical difference observed in the indirect comparison of PFS, OS, ORR, or DCR among agents of regorafenib, cabozantinib, and ramucirumab in advanced HCC patients with elevated α-fetoprotein (AFP) (400 ng/mL or higher). However, in patients with low-level AFP (lower than 400 ng/mL), regorafenib was the only agent associated with significant superiority in OS, compared with placebo (hazard ratio 0.67, 95% CI, 0.50-0.90). CONCLUSIONS The present network meta-analysis revealed that there might be no statistical difference observed in the indirect comparison of PFS, OS, ORR, or DCR among regorafenib, cabozantinib, or ramucirumab in advanced HCC patients with elevated AFP (400 ng/mL or higher). However, in patients with low-level AFP (lower than 400 ng/mL), regorafenib might be associated with significant superiority in OS, compared to placebo, which need further investigation in clinical practice.
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Affiliation(s)
- Jianxin Chen
- Department of Medical Oncology, Quzhou People′s Hospital, Quzhou, Zhejiang, China
| | - Junhui Wang
- Department of Radiation Oncology, Quzhou People′s Hospital, Quzhou, Zhejiang, China
| | - Fangwei Xie
- Department of Oncology, the 900th Hospital of Joint Logistics Support Forces of Chinese PLA, Fuzhou, China
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20
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Zhou W, Fang DL, He Y. Screening potential prognostic biomarkers for portal vein emboli in patients with hepatocellular carcinoma. J Gastrointest Oncol 2021; 12:1927-1938. [PMID: 34532139 DOI: 10.21037/jgo-21-433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 08/10/2021] [Indexed: 01/27/2023] Open
Abstract
Background The formation of portal vein tumor thrombus (PVTT) is closely related to the prognosis of patients with hepatocellular carcinoma (HCC). However, the mechanisms by which PVTTs form and the biomarkers involved are still little understood. Methods The Genome Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases were used to obtain transcriptome data from normal tissue, HCC tissue, primary tumors (PTs) of HCC, and paired PVTT tissue. Differentially expressed genes (DEGs) in PTs and PVTTs were analyzed. The differentially expressed immune genes were further investigated in terms of their prognostic significance, immune infiltration, function. Finally, we explored the relationship between risk scores and drug sensitivity based on the R package. Results In the two datasets, there were 458 DEGs identified in the PT and PVTT tissues, of which, 58 were immune-related genes. The differentially expressed immune genes may promote the progression of PVTT by participating in the regulation of non-cellular components such as the extracellular matrix, inflammatory factors, and chemokines. Furthermore, the immune genes KDR, AKT3, FCGR2B, KIAA1429, and TPT1 were correlated with the prognosis of HCC in patients with PVTT. Using this data, a model was constructed to predict the prognosis of patients, thus allowing for the identification of high- and low-risk patients. Conclusions This study demonstrated that immune-related genes may be involved in the regulation of the extracellular matrix and acellular components, and subsequently, in the formation of PVTT. These five genes KDR, AKT3, FCGR2B, KIAA1429, and TPT1 may be potential prognostic biomarkers and treatment targets for HCC patients with PVTT.
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Affiliation(s)
- Weijie Zhou
- Clinical Laboratory, Baise People's Hospital, Baise, China
| | - Da Lang Fang
- Department of Breast and Thyroid Surgery, the Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
| | - Yongfei He
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
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21
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Solimando AG, Susca N, Argentiero A, Brunetti O, Leone P, De Re V, Fasano R, Krebs M, Petracci E, Azzali I, Nanni O, Silvestris N, Vacca A, Racanelli V. Second-line treatments for Advanced Hepatocellular Carcinoma: A Systematic Review and Bayesian Network Meta-analysis. Clin Exp Med 2021; 22:65-74. [PMID: 34146196 PMCID: PMC8863772 DOI: 10.1007/s10238-021-00727-7] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Accepted: 05/24/2021] [Indexed: 12/30/2022]
Abstract
BACKGROUND & AIMS A plethora of second-line therapies have been recently introduced for hepatocellular carcinoma (HCC) treatment with promising results. A meta-analysis of second-line treatments for HCC has been performed to better tailor their use based on improved patient stratification and to identify the best available option. METHODS Pubmed, Scopus, Web of Science, and ClinicalTrials.gov were searched for randomized controlled trials evaluating second-line treatment for advanced HCC in patients already treated with sorafenib. The primary outcome was overall survival (OS). Secondary outcomes were progression-free survival (PFS) and drug withdrawal due to adverse events. Network meta-analyses were performed considering placebo as the basis for comparison in efficacy and safety analyses. Subgroup stratification considered gender, age, sorafenib-responsiveness and drug tolerability, viral infection, macrovascular invasion, HCC extrahepatic spread, performance status, and alpha-fetoprotein levels. RESULTS Fourteen phase II or III randomized controlled trials, involving 5,488 patients and 12 regimens, were included in the analysis. Regorafenib (hazard ratio (HR) = 0.63, 95% confidence interval (CI) = 0.50-0.79), cabozantinib (HR = 0.76, 95% CI = 0.63-0.92), and ramucirumab (HR = 0.82, 95% CI = 0.70-0.76) significantly prolonged OS compared with placebo. Cabozantinib (HR = 0.44, 95% CI = 0.36-0.52), regorafenib (HR = 0.46, 95% CI = 0.37-0.56), ramucirumab (HR = 0.54, 95% CI = 0.43-0.68), brivanib (HR = 0.56, 95% CI = 0.42-0.76), S-1 (HR = 0.60, 95% CI = 0.46-0.77), axitinib (HR = 0.62, 95% CI = 0.44-0.87), and pembrolizumab (HR = 0.72, 95% CI = 0.57-0.90) significantly improved PFS compared with placebo. None of the compared drugs deemed undoubtedly superior after having performed a patients' stratification. CONCLUSIONS The results of this network meta-analysis suggest the use of regorafenib and cabozantinib as second-line treatments in HCC.
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Affiliation(s)
- Antonio Giovanni Solimando
- Guido Baccelli Unit of Internal Medicine, Department of Biomedical Sciences and Human Oncology, School of Medicine, Aldo Moro University of Bari, Bari, Italy.,IRCCS Istituto Tumori Giovanni Paolo II of Bari, Bari, Italy
| | - Nicola Susca
- Guido Baccelli Unit of Internal Medicine, Department of Biomedical Sciences and Human Oncology, School of Medicine, Aldo Moro University of Bari, Bari, Italy
| | | | - Oronzo Brunetti
- IRCCS Istituto Tumori Giovanni Paolo II of Bari, Bari, Italy
| | - Patrizia Leone
- Guido Baccelli Unit of Internal Medicine, Department of Biomedical Sciences and Human Oncology, School of Medicine, Aldo Moro University of Bari, Bari, Italy
| | - Valli De Re
- Bio-Proteomics Facility, Department of Translational Research, Centro Di Riferimento Oncologico Di Aviano (CRO) IRCCS, Aviano, Italy
| | - Rossella Fasano
- IRCCS Istituto Tumori Giovanni Paolo II of Bari, Bari, Italy.,Department of Biomedical Sciences and Human Oncology, School of Medicine, Aldo Moro University of Bari, Bari, Italy
| | - Markus Krebs
- Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, Würzburg, Germany
| | - Elisabetta Petracci
- Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo Per Lo Studio E La Cura Dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Irene Azzali
- Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo Per Lo Studio E La Cura Dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Oriana Nanni
- Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo Per Lo Studio E La Cura Dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Nicola Silvestris
- IRCCS Istituto Tumori Giovanni Paolo II of Bari, Bari, Italy. .,Department of Biomedical Sciences and Human Oncology, School of Medicine, Aldo Moro University of Bari, Bari, Italy.
| | - Angelo Vacca
- Guido Baccelli Unit of Internal Medicine, Department of Biomedical Sciences and Human Oncology, School of Medicine, Aldo Moro University of Bari, Bari, Italy
| | - Vito Racanelli
- Guido Baccelli Unit of Internal Medicine, Department of Biomedical Sciences and Human Oncology, School of Medicine, Aldo Moro University of Bari, Bari, Italy.
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22
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Wang T, Zhang Q, Wang N, Liu Z, Zhang B, Zhao Y. Research Progresses of Targeted Therapy and Immunotherapy for Hepatocellular Carcinoma. Curr Med Chem 2021; 28:3107-3146. [PMID: 33050856 DOI: 10.2174/0929867327666201013162144] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 08/25/2020] [Accepted: 09/01/2020] [Indexed: 12/24/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, with nearly one million new cases and deaths every year. Owing to the complex pathogenesis, hidden early symptoms, rapidly developing processes, and poor prognosis, the morbidity and mortality of HCC are increasing yearly. With the progress being made in modern medicine, the treatment of HCC is no longer limited to traditional methods. Targeted therapy and immunotherapy have emerged to treat advanced and metastatic HCC in recent years. Since Sorafenib is the first molecular targeting drug against angiogenesis, targeted drugs for HCC are continually emerging. Moreover, immunotherapy plays a vital role in clinical trials. In particular, the application of immune checkpoint inhibitors, which have received increasing attention in the field of cancer treatment, is a possible research path. Interestingly, these two therapies generally complement each other at some stages of HCC, bringing new hope for patients with advanced HCC. In this paper, we discuss the research progress of targeted therapy and immunotherapy for HCC in recent years, which will provide a reference for the further development of drugs for HCC.
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Affiliation(s)
- Tao Wang
- Institute of Drug Discovery Technology, Ningbo University, Ningbo, Zhejiang 315211, China
| | - Qiting Zhang
- Institute of Drug Discovery Technology, Ningbo University, Ningbo, Zhejiang 315211, China
| | - Ning Wang
- Institute of Drug Discovery Technology, Ningbo University, Ningbo, Zhejiang 315211, China
| | - Ziqi Liu
- Department of Pharmacy, the PLA Rocket Force Characteristic Medical Center, Beijing 100088, China
| | - Bin Zhang
- Li Dak Sum Yip Yio Chin Kenneth Li Marine Biopharmaceutical Research Center, Department of Marine Pharmacy, College of Food and Pharmaceutical Sciences, Ningbo University, Ningbo, Zhejiang 315211, China
| | - Yufen Zhao
- Institute of Drug Discovery Technology, Ningbo University, Ningbo, Zhejiang 315211, China
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23
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Kudo M, Motomura K, Wada Y, Inaba Y, Sakamoto Y, Kurosaki M, Umeyama Y, Kamei Y, Yoshimitsu J, Fujii Y, Aizawa M, Robbins PB, Furuse J. Avelumab in Combination with Axitinib as First-Line Treatment in Patients with Advanced Hepatocellular Carcinoma: Results from the Phase 1b VEGF Liver 100 Trial. Liver Cancer 2021; 10:249-259. [PMID: 34239811 PMCID: PMC8237783 DOI: 10.1159/000514420] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 01/13/2021] [Indexed: 02/04/2023] Open
Abstract
INTRODUCTION Combining an immune checkpoint inhibitor with a targeted antiangiogenic agent may leverage complementary mechanisms of action for the treatment of advanced/metastatic hepatocellular carcinoma (aHCC). Avelumab is a human anti-PD-L1 IgG1 antibody with clinical activity in various tumor types; axitinib is a selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3. We report the final analysis from VEGF Liver 100 (NCT03289533), a phase 1b study evaluating safety and efficacy of avelumab plus axitinib in treatment-naive patients with aHCC. METHODS Eligible patients had confirmed aHCC, no prior systemic therapy, ≥1 measurable lesion, Eastern Cooperative Oncology Group performance status ≤1, and Child-Pugh class A disease. Patients received avelumab 10 mg/kg intravenously every 2 weeks plus axitinib 5 mg orally twice daily until progression, unacceptable toxicity, or withdrawal. Endpoints included safety and investigator-assessed objective response per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and modified RECIST (mRECIST) for HCC. RESULTS Twenty-two Japanese patients were enrolled and treated with avelumab plus axitinib. The minimum follow-up was 18 months as of October 25, 2019 (data cutoff). Grade 3 treatment-related adverse events (TRAEs) occurred in 16 patients (72.7%); the most common (≥3 patients) were hypertension (n = 11 [50.0%]), palmar-plantar erythrodysesthesia syndrome (n = 5 [22.7%]), and decreased appetite (n = 3 [13.6%]). No grade 4 TRAEs or treatment-related deaths occurred. Ten patients (45.5%) had an immune-related AE (irAE) of any grade; 3 patients (13.6%) had an infusion-related reaction (IRR) of any grade, and no grade ≥3 irAE and IRR were observed. The objective response rate was 13.6% (95% CI: 2.9-34.9%) per RECIST 1.1 and 31.8% (95% CI: 13.9-54.9%) per mRECIST for HCC. CONCLUSION Treatment with avelumab plus axitinib was associated with a manageable toxicity profile and showed antitumor activity in patients with aHCC.
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Affiliation(s)
- Masatoshi Kudo
- Faculty of Medicine, Kindai University, Osaka, Japan,*Masatoshi Kudo,
| | | | | | | | | | | | | | | | | | | | | | | | - Junji Furuse
- Faculty of Medicine, Kyorin University, Tokyo, Japan
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Yu B, Mamedov R, Fuhler GM, Peppelenbosch MP. Drug Discovery in Liver Disease Using Kinome Profiling. Int J Mol Sci 2021; 22:2623. [PMID: 33807722 PMCID: PMC7961955 DOI: 10.3390/ijms22052623] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 03/01/2021] [Accepted: 03/01/2021] [Indexed: 12/15/2022] Open
Abstract
The liver is one of the most important organs, playing critical roles in maintaining biochemical homeostasis. Accordingly, disease of the liver is often debilitating and responsible for untold human misery. As biochemical nexus, with kinases being master regulators of cellular biochemistry, targeting kinase enzymes is an obvious avenue for treating liver disease. Development of such therapy, however, is hampered by the technical difficulty of obtaining comprehensive insight into hepatic kinase activity, a problem further compounded by the often unique aspects of hepatic kinase activities, which makes extrapolations from other systems difficult. This consideration prompted us to review the current state of the art with respect to kinome profiling approaches towards the hepatic kinome. We observe that currently four different approaches are available, all showing significant promise. Hence we postulate that insight into the hepatic kinome will quickly increase, leading to rational kinase-targeted therapy for different liver diseases.
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Affiliation(s)
| | | | | | - Maikel P. Peppelenbosch
- Department of Gastroenterology and Hepatology, Erasmus MC—University Medical Center Rotterdam, 3015 CN Rotterdam, The Netherlands; (B.Y.); (R.M.); (G.M.F.)
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25
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Li H. Angiogenesis in the progression from liver fibrosis to cirrhosis and hepatocelluar carcinoma. Expert Rev Gastroenterol Hepatol 2021; 15:217-233. [PMID: 33131349 DOI: 10.1080/17474124.2021.1842732] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Introduction: Persistent inflammation and hypoxia are strong stimulus for pathological angiogenesis and vascular remodeling, and are also the most important elements resulting in liver fibrosis. Sustained inflammatory process stimulates fibrosis to the end-point of cirrhosis and sinusoidal portal hypertension is an important feature of cirrhosis. Neovascularization plays a pivotal role in collateral circulation formation of portal vein, mesenteric congestion, and high perfusion. Imbalance of hepatic artery and portal vein blood flow leads to the increase of hepatic artery inflow, which is beneficial to the formation of nodules. Angiogenesis contributes to progression from liver fibrosis to cirrhosis and hepatocellular carcinoma (HCC) and anti-angiogenesis therapy can improve liver fibrosis, reduce portal pressure, and prolong overall survival of patients with HCC. Areas covers: This paper will try to address the difference of the morphological characteristics and mechanisms of neovascularization in the process from liver fibrosis to cirrhosis and HCC and further compare the different efficacy of anti-angiogenesis therapy in these three stages. Expert opinion: More in-depth understanding of the role of angiogenesis factors and the relationship between angiogenesis and other aspects of the pathogenesis and transformation may be the key to enabling future progress in the treatment of patients with liver fibrosis, cirrhosis, and HCC.
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Affiliation(s)
- Hui Li
- Central Laboratory, Hospital of Chengdu University of Traditional Chinese Medicine , Chengdu, Sichuan Province, P. R. China
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26
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Wang W, Shui L, Liu Y, Zheng M. C-Kit, a Double-Edged Sword in Liver Regeneration and Diseases. Front Genet 2021; 12:598855. [PMID: 33603771 PMCID: PMC7884772 DOI: 10.3389/fgene.2021.598855] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 01/08/2021] [Indexed: 12/24/2022] Open
Abstract
Previous studies have reported an important role of c-kit in embryogenesis and adulthood. Activation of the SCF/KIT signal transduction pathway is customarily linked to cell proliferation, migration and survival thus influence hematopoiesis, pigmentation, and spermatogenesis. The role of c-kit in the liver is controversial, it is however argued that it is a double-edged sword in liver regeneration and diseases. First, liver c-kit+ cells, including oval cells, bile epithelial cells, and part of hepatocytes, participate in liver tissue repair by regenerating target cells according to the type of liver injury. At the same time, c-kit+ mast cells, act as immature progenitors in circulation, playing a critical role in liver fibrosis. Furthermore, c-kit is also a proto-oncogene. Notably, c-kit overexpression regulates gastrointestinal stromal tumors. Various studies have explored on c-kit and hepatocellular carcinoma, nevertheless, the intricate roles of c-kit in the liver are largely understudied. Herein, we extensively summarize previous studies geared toward providing hints for future clinical and basic research.
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Affiliation(s)
- Weina Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Liyan Shui
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Yanning Liu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Min Zheng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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Abstract
Hepatocellular carcinoma (HCC) is a lethal malignancy with poor prognosis. More than 80% of patients are diagnosed at an advanced stage, and most patients with HCC also have liver cirrhosis that complicates cancer management. No targeted treatment options currently exist outside genomics-based clinical trials. Multiple tyrosine kinase inhibitors (mTKIs) such as sorafenib, lenvatinib, cabozantinib, and regorafenib have been used to treat advanced hepatocellular carcinoma (aHCC). Immune checkpoint inhibitors including nivolumab and pembrolizumab have shown survival benefit. More recently, atezolizumab in combination with bevacizumab resulted in improved overall survival and progression-free survival, compared with sorafenib in patients with aHCC in the first-line setting. The combination of nivolumab with ipilimumab as an alternative in the treatment of patients treated with sorafenib has inspired various combination studies of immune checkpoint inhibitors. Currently, ongoing studies of systemic therapy consist of various immune-based combination therapies. Finally, there is no established adjuvant and neoadjuvant therapy although a few early phase studies show promising results. In this chapter, we summarize current approaches of systemic treatment in patients with liver cancer.
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Affiliation(s)
- Tarik Demir
- Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United States
| | - Sunyoung S Lee
- Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United States
| | - Ahmed O Kaseb
- Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United States.
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Yang KL, Chi MS, Ko HL, Huang YY, Huang SC, Lin YM, Chi KH. Axitinib in combination with radiotherapy for advanced hepatocellular carcinoma: a phase I clinical trial. Radiat Oncol 2021; 16:18. [PMID: 33472666 PMCID: PMC7819176 DOI: 10.1186/s13014-020-01742-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Accepted: 12/26/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND To investigate maximum tolerated dose (MTD) of axitinib, a selective vascular endothelial growth factor receptor 1-3 inhibitor, in combination with radiotherapy (RT) for advanced hepatocellular carcinoma (HCC). METHODS This phase I study followed the rule of traditional 3 + 3 design. Major eligibility included: (1) patients with advanced HCC unsuitable for surgery, radiofrequency ablation or transarterial chemoembolization, or who failed after prior local-regional treatment; (2) failure on sorafenib or no grant for sorafenib from health insurance system. Eligible patients with advanced HCC received axitinib for total 8 weeks during and after RT. Three cohorts with axitinib dose escalation were planned: 1 mg twice daily (level I), 2 mg twice daily (level II) and 3 mg twice daily (level III). The prescribed doses of RT ranged from 37.5 to 67.5 Gy in 15 fractions to liver tumor(s) and were determined based on an upper limit of mean liver dose of 18 Gy (intended isotoxic RT for normal liver). The primary endpoint was MTD of axitinib in combination with RT. The secondary endpoints included overall response rate (ORR), RT in-field response rate, acute and late toxicities, overall survival (OS) and progression free survival (PFS). RESULTS Total nine eligible patients received axitinib dose levels of 1 mg twice daily (n = 3), 2 mg twice daily (n = 3) and 3 mg twice daily (n = 3). Dose-limiting toxicity (DLT) did not occur in the 3 cohorts; the MTD was defined as 3 mg twice daily in this study. ORR was 66.7%, including 3 complete responses and 3 partial responses, at 3 months after treatment initiation. With a median follow-up of 16.6 months, median OS was not reached, 1-year OS was 66.7%, and median PFS was 7.4 months. CONCLUSIONS Axitinib in combination with RT for advanced HCC was well tolerated with an axitinib MTD of 3 mg twice daily in this study. The outcome analysis should be interpreted with caution due to the small total cohort. Trial registration ClinicalTrials.gov (Identifier: NCT02814461), Registered June 27, 2016-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02814461.
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Affiliation(s)
- Kai-Lin Yang
- Department of Radiation Therapy and Oncology, Shin Kong Wu Ho-Su Memorial Hospital, Shih-Lin District, No. 95, Wen-Chang Road, Taipei City, 111, Taiwan
- School of Medicine, Fu Jen Catholic University, No. 510, Chung-Cheng Road, Hsin-Chuang, New Taipei City, Taiwan
| | - Mau-Shin Chi
- Department of Radiation Therapy and Oncology, Shin Kong Wu Ho-Su Memorial Hospital, Shih-Lin District, No. 95, Wen-Chang Road, Taipei City, 111, Taiwan
| | - Hui-Ling Ko
- Department of Radiation Therapy and Oncology, Shin Kong Wu Ho-Su Memorial Hospital, Shih-Lin District, No. 95, Wen-Chang Road, Taipei City, 111, Taiwan
| | - Yi-Ying Huang
- Department of Radiation Therapy and Oncology, Shin Kong Wu Ho-Su Memorial Hospital, Shih-Lin District, No. 95, Wen-Chang Road, Taipei City, 111, Taiwan
| | - Su-Chen Huang
- Department of Radiation Therapy and Oncology, Shin Kong Wu Ho-Su Memorial Hospital, Shih-Lin District, No. 95, Wen-Chang Road, Taipei City, 111, Taiwan
| | - Yu-Min Lin
- School of Medicine, Fu Jen Catholic University, No. 510, Chung-Cheng Road, Hsin-Chuang, New Taipei City, Taiwan
- Division of Gastroenterology, Department of Internal Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei City, Taiwan
| | - Kwan-Hwa Chi
- Department of Radiation Therapy and Oncology, Shin Kong Wu Ho-Su Memorial Hospital, Shih-Lin District, No. 95, Wen-Chang Road, Taipei City, 111, Taiwan.
- Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, No. 155, Sec. 2, Linong Street, Beitou District, Taipei City, Taiwan.
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Progression-Free Survival Early Assessment Is a Robust Surrogate Endpoint of Overall Survival in Immunotherapy Trials of Hepatocellular Carcinoma. Cancers (Basel) 2020; 13:cancers13010090. [PMID: 33396833 PMCID: PMC7796103 DOI: 10.3390/cancers13010090] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Revised: 12/21/2020] [Accepted: 12/26/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Radiology-based outcomes, such as progression-free survival (PFS) and objective response rate (ORR), are used as surrogate endpoints in oncology trials. We aimed to assess the surrogacy relationship of PFS with overall survival (OS) in clinical trials of systemic therapies targeting advanced hepatocellular carcinoma (HCC) by novel meta-regression methods. METHODS A search of databases (PubMed, American Society of Clinical Oncology (ASCO), and European Society for Medical Oncology (ESMO) Meeting Libraries, Clinicaltrials.gov) for trials of systemic therapies for advanced HCC reporting both OS and PFS was performed. Individual patient data were extracted from PFS and OS Kaplan-Meier curves. Summary median PFS and OS data were obtained from random-effect model. The surrogate relationships of median PFS, first quartile (Q1), third quartile (Q3), and restricted mean survival time (RMST) for OS were evaluated by the coefficient of determination R2. Heterogeneity was explored by meta-regression. RESULTS We identified 49 trials, 11 assessing immune-checkpoint inhibitors (ICIs) and 38 multikinase inhibitors (MKIs). Overall, the correlation between median PFS and median OS was weak (R2 = 0.20. 95% Confidence Intervals [CI]-0.02;0.42). Surrogacy robustness varied between treatment classes and PFS endpoints. In ICI trials only, the correlations between Q1-PFS and Q1-OS and between 12-month PFS-RMST and 12-month OS-RMST were high (R2 = 0.89, 95%CI 0.78-0.98, and 0.80, 95% CI 0.63-0.96, respectively). Interaction p-values obtained by meta-regression confirmed the robustness of results. CONCLUSIONS In trials of systemic therapies for advanced HCC, the surrogate relationship of PFS with OS is highly variable depending on treatment class (ICI or MKI) and evaluation time-point. In ICI trials, Q1-PFS and 12-month PFS-RMST are robust surrogate endpoints for OS.
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Vanderborght B, Lefere S, Vlierberghe HV, Devisscher L. The Angiopoietin/Tie2 Pathway in Hepatocellular Carcinoma. Cells 2020; 9:cells9112382. [PMID: 33143149 PMCID: PMC7693961 DOI: 10.3390/cells9112382] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 10/23/2020] [Accepted: 10/27/2020] [Indexed: 02/07/2023] Open
Abstract
Due to the usually late diagnosis and lack of effective therapies, hepatocellular carcinoma (HCC), which poses a growing global health problem, is characterized by a poor prognosis. Angiogenesis plays an important role in HCC progression, and vascular endothelial growth factor (VEGF) and angiopoietins (Angs) are key drivers of HCC angiogenesis. VEGF-targeting strategies already represent an important component of today’s systemic treatment landscape of HCC, whereas targeting the Ang/Tie2 signaling pathway may harbor future potential in this context due to reported beneficial anticancer effects when targeting this pathway. In addition, a better understanding of the relation between Angs and HCC angiogenesis and progression may reveal their potential as predictive factors for post-treatment disease progression and prognosis. In this review, we give a comprehensive overview of the complex role of Ang/Tie2 signaling in HCC, pinpointing its potential value as biomarker and target for HCC treatments, aiding HCC diagnosis and therapy.
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Affiliation(s)
- Bart Vanderborght
- Department of Internal Medicine and Pediatrics, Department of Gastroenterology and Hepatology, Hepatology Research Unit, Ghent University, B-9000 Ghent, Belgium; (B.V.); (S.L.); (H.V.V.)
- Department of Basic and Applied Medical Sciences, Gut-Liver Immunopharmacology Unit, Ghent University, B-9000 Ghent, Belgium
| | - Sander Lefere
- Department of Internal Medicine and Pediatrics, Department of Gastroenterology and Hepatology, Hepatology Research Unit, Ghent University, B-9000 Ghent, Belgium; (B.V.); (S.L.); (H.V.V.)
- Department of Basic and Applied Medical Sciences, Gut-Liver Immunopharmacology Unit, Ghent University, B-9000 Ghent, Belgium
| | - Hans Van Vlierberghe
- Department of Internal Medicine and Pediatrics, Department of Gastroenterology and Hepatology, Hepatology Research Unit, Ghent University, B-9000 Ghent, Belgium; (B.V.); (S.L.); (H.V.V.)
| | - Lindsey Devisscher
- Department of Basic and Applied Medical Sciences, Gut-Liver Immunopharmacology Unit, Ghent University, B-9000 Ghent, Belgium
- Correspondence: ; Tel.: +32-9-332-56-65
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Alqahtani SA, Colombo M. Multikinase inhibitors to treat hepatocellular carcinoma failures to sorafenib-time has come for a better approach. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:1255. [PMID: 33178787 PMCID: PMC7607112 DOI: 10.21037/atm-2020-79] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Saleh A Alqahtani
- Liver Transplant Unit, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.,Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, MD, USA
| | - Massimo Colombo
- Center of Translational Research in Hepatology, Humanitas Hospital, Rozzano, Italy
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32
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Nouso K, Wakuta A, Kariyama K. Combination therapy of transcatheter arterial chemoembolization with axitinib for the treatment of inoperable hepatocellular carcinoma. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:1039. [PMID: 32953839 PMCID: PMC7475487 DOI: 10.21037/atm.2020.03.198] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Affiliation(s)
- Kazuhiro Nouso
- Department of Gastroenterology, Okayama City Hospital, Okayama, Japan
| | - Akiko Wakuta
- Department of Gastroenterology, Okayama City Hospital, Okayama, Japan
| | - Kazuya Kariyama
- Department of Gastroenterology, Okayama City Hospital, Okayama, Japan
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Ding F, Liu B, Wang Y. Risk of hand-foot skin reaction associated with vascular endothelial growth factor-tyrosine kinase inhibitors: A meta-analysis of 57 randomized controlled trials involving 24,956 patients. J Am Acad Dermatol 2020; 83:788-796. [PMID: 30991119 DOI: 10.1016/j.jaad.2019.04.021] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Revised: 04/07/2019] [Accepted: 04/10/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND Multiple randomized controlled trials have assessed hand-foot skin reaction (HFSR) caused by vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs). OBJECTIVE We performed a meta-analysis to determine the incidence and the relative risk (RR) of HFSR associated with these agents. METHODS Databases were searched for relevant studies. Statistical analyses were conducted to calculate the summary incidences, RR, and 95% confidence intervals (CIs) by using random-effects or fixed-effects models according to the heterogeneity of the included studies. RESULTS A total of 24,956 patients from 57 studies were included. The overall incidence of all-grade and high-grade HFSR associated with VEGFR-TKIs was 35.0% (95% CI, 28.6%-41.6%) and 9.7% (95% CI, 7.3%-12.3%), respectively. The use of VEGFR-TKIs significantly increased the risk of developing all-grade (RR, 5.09; 95% CI, 3.52-7.35; P < .001) and high-grade (RR, 9.42; 95% CI, 5.59-15.90; P < .001) HFSR. Subgroup analyses revealed that the risk of HFSR was significantly increased according to tumor type, VEGFR-TKI, trial phase, treatment regimen, and control therapy. No evidence of publication bias was observed. LIMITATION High heterogeneity in most studies. CONCLUSION High risk of HFSR is prone to develop in cancer patients receiving VEGFR-TKIs.
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Affiliation(s)
- Fengxia Ding
- Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, Chongqing, China; Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, China.
| | - Bo Liu
- Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, China; Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Yaping Wang
- Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, Chongqing, China; Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, China
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Lin Z, Chen B, Hung Y, Huang P, Shen Y, Shao Y, Hsu C, Cheng A, Lee R, Chao Y, Hsu C. A Multicenter Phase II Study of Second-Line Axitinib for Patients with Advanced Hepatocellular Carcinoma Failing First-Line Sorafenib Monotherapy. Oncologist 2020; 25:e1280-e1285. [PMID: 32271494 PMCID: PMC7485356 DOI: 10.1634/theoncologist.2020-0143] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Accepted: 02/18/2020] [Indexed: 12/24/2022] Open
Abstract
LESSONS LEARNED For patients with advanced hepatocellular carcinoma after failure of first-line sorafenib monotherapy, second-line axitinib provides modest efficacy with tolerable toxicity. The discrepant tumor responses and survival outcomes in trials using axitinib as salvage therapy highlight the importance of optimal patient selection with the aid of clinical biomarkers. BACKGROUND Multikinase inhibitors have been effective treatment for hepatocellular carcinoma (HCC). This multicenter phase II study explored the efficacy and safety of second-line axitinib for advanced HCC. METHODS Patients with advanced HCC and Child-Pugh A liver function, experiencing progression on first-line sorafenib monotherapy, were eligible. Axitinib 5 mg twice daily was given continuously with allowed dose escalation. Tumor assessment was performed according to RECIST version 1.1. The primary endpoint was rate of disease control. RESULTS From April 2011 to March 2016, 45 patients were enrolled. Thirty-seven patients (82%) tested positive for hepatitis B surface antigen. The disease control rate was 62.2%, and the response rate was 6.7%, according to RECIST criteria. Median progression-free survival (PFS) and overall survival (OS) were 2.2 months and 10.1 months, respectively. Treatment-related adverse events were compatible with previous reports of axitinib. CONCLUSION Second-line axitinib has moderate activity and acceptable toxicity for patients with advanced HCC after failing the first-line sorafenib monotherapy.
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Affiliation(s)
- Zhong‐Zhe Lin
- Department of Medical Oncology, National Taiwan University Cancer CenterTaipeiTaiwan
- Department of Oncology, National Taiwan University HospitalTaipeiTaiwan
- Department of Internal Medicine, National Taiwan University College of MedicineTaipeiTaiwan
| | - Bang‐Bin Chen
- Department of Radiology, National Taiwan University HospitalTaipeiTaiwan
| | - Yi‐Ping Hung
- Department of Oncology, Taipei Veterans General HospitalTaipeiTaiwan
| | - Po‐Hsiang Huang
- Department of Oncology, National Taiwan University HospitalTaipeiTaiwan
| | - Ying‐Chun Shen
- Department of Medical Oncology, National Taiwan University Cancer CenterTaipeiTaiwan
- Department of Oncology, National Taiwan University HospitalTaipeiTaiwan
- Graduate Institute of Oncology, National Taiwan University College of MedicineTaipeiTaiwan
| | - Yu‐Yun Shao
- Department of Oncology, National Taiwan University HospitalTaipeiTaiwan
- Graduate Institute of Oncology, National Taiwan University College of MedicineTaipeiTaiwan
| | - Chih‐Hung Hsu
- Department of Medical Oncology, National Taiwan University Cancer CenterTaipeiTaiwan
- Department of Oncology, National Taiwan University HospitalTaipeiTaiwan
- Graduate Institute of Oncology, National Taiwan University College of MedicineTaipeiTaiwan
| | - Ann‐Lii Cheng
- Department of Medical Oncology, National Taiwan University Cancer CenterTaipeiTaiwan
- Department of Oncology, National Taiwan University HospitalTaipeiTaiwan
- Department of Internal Medicine, National Taiwan University College of MedicineTaipeiTaiwan
- Graduate Institute of Oncology, National Taiwan University College of MedicineTaipeiTaiwan
| | - Rheun‐Chuan Lee
- Department of Radiology, Taipei Veterans General HospitalTaipeiTaiwan
| | - Yee Chao
- Department of Oncology, Taipei Veterans General HospitalTaipeiTaiwan
- School of Medicine, National Yang‐Ming UniversityTaipeiTaiwan
| | - Chiun Hsu
- Department of Medical Oncology, National Taiwan University Cancer CenterTaipeiTaiwan
- Department of Oncology, National Taiwan University HospitalTaipeiTaiwan
- Graduate Institute of Oncology, National Taiwan University College of MedicineTaipeiTaiwan
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35
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Park R, Eshrat F, Al-Jumayli M, Saeed A, Saeed A. Immuno-Oncotherapeutic Approaches in Advanced Hepatocellular Carcinoma. Vaccines (Basel) 2020; 8:E447. [PMID: 32784389 PMCID: PMC7563532 DOI: 10.3390/vaccines8030447] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 08/01/2020] [Accepted: 08/05/2020] [Indexed: 12/13/2022] Open
Abstract
Advanced hepatocellular carcinoma has limited treatment options, but there has been extensive growth recently with cabozantinib, regorafenib, lenvatinib, nivolumab, atezolizumab, and bevacizumab, which are some of the treatments that have received FDA approval just over the last three years. Because HCC tumor microenvironment is potentially immunogenic and typically characterized by inflammation, immunotherapy has been proposed as a potential novel therapeutic approach, which has prompted studies in advanced HCC patients investigating various immune-therapeutic strategies such as CAR-T cell therapy, checkpoint inhibitors, and onco-vaccines. The anti-PD-1 checkpoint inhibitors nivolumab and pembrolizumab have been FDA approved as a second line treatment in patients who progressed or are intolerant to Sorafenib. To build up on the success of PD-1 monotherapy, combinatorial regimens with PD-1/PD-L1 inhibitors plus VEGF targeted agents have shown positive results in various malignancies including HCC. The combination of atezolizumab plus bevacizumab is the new addition to the HCC treatment armamentarium following a pivotal study that demonstrated an improvement in OS over frontline sorafenib. Other novel immune-based approaches and oncolytic viruses are in the early phases of clinical evaluation. These innovative approaches enhance the intensity of cancer-directed immune responses and will potentially impact the outlook of this aggressive disease.
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Affiliation(s)
- Robin Park
- MetroWest Medical Center, Tufts University School of Medicine, Framingham, MA 01702, USA;
| | - Fariha Eshrat
- Department of Medicine, Division of Medical Oncology, Kansas University Cancer Center, Kansas City, KS 66160, USA; (F.E.); (M.A.-J.)
| | - Mohammed Al-Jumayli
- Department of Medicine, Division of Medical Oncology, Kansas University Cancer Center, Kansas City, KS 66160, USA; (F.E.); (M.A.-J.)
| | - Azhar Saeed
- Department of Pathology and Laboratory Medicine, Kansas University Medical Center, Kansas City, KS 66160, USA;
| | - Anwaar Saeed
- Department of Medicine, Division of Medical Oncology, Kansas University Cancer Center, Kansas City, KS 66160, USA; (F.E.); (M.A.-J.)
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Benson AB, D'Angelica MI, Abbott DE, Abrams TA, Alberts SR, Anaya DA, Anders R, Are C, Brown D, Chang DT, Cloyd J, Covey AM, Hawkins W, Iyer R, Jacob R, Karachristos A, Kelley RK, Kim R, Palta M, Park JO, Sahai V, Schefter T, Sicklick JK, Singh G, Sohal D, Stein S, Tian GG, Vauthey JN, Venook AP, Hammond LJ, Darlow SD. Guidelines Insights: Hepatobiliary Cancers, Version 2.2019. J Natl Compr Canc Netw 2020; 17:302-310. [PMID: 30959462 DOI: 10.6004/jnccn.2019.0019] [Citation(s) in RCA: 188] [Impact Index Per Article: 37.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The NCCN Guidelines for Hepatobiliary Cancers provide treatment recommendations for cancers of the liver, gallbladder, and bile ducts. The NCCN Hepatobiliary Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel's discussion and updated recommendations regarding systemic therapy for first-line and subsequent-line treatment of patients with hepatocellular carcinoma.
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Affiliation(s)
- Al B Benson
- 1Robert H. Lurie Comprehensive Cancer Center of Northwestern University
| | | | | | | | | | | | - Robert Anders
- 7The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
| | | | | | | | - Jordan Cloyd
- 11The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute
| | | | - William Hawkins
- 12Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine
| | | | - Rojymon Jacob
- 14University of Alabama at Birmingham Comprehensive Cancer Center
| | | | - R Kate Kelley
- 16UCSF Helen Diller Family Comprehensive Cancer Center
| | - Robin Kim
- 17Huntsman Cancer Institute at the University of Utah
| | | | - James O Park
- 19University of Washington/Seattle Cancer Care Alliance
| | | | | | | | | | - Davendra Sohal
- 24Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute
| | | | - G Gary Tian
- 26St. Jude Children's Research Hospital/The University of Tennessee Health Science Center
| | | | - Alan P Venook
- 16UCSF Helen Diller Family Comprehensive Cancer Center
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Dong Y, Liu TH, Yau T, Hsu C. Novel systemic therapy for hepatocellular carcinoma. Hepatol Int 2020; 14:638-651. [PMID: 32661949 DOI: 10.1007/s12072-020-10073-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Accepted: 07/01/2020] [Indexed: 12/11/2022]
Abstract
Systemic therapy for hepatocellular carcinoma (HCC) used to be limited to patients with advanced diseases and multi-kinase inhibitors targeting tumor angiogenesis the major approach of developing new treatment options. In the past 3 years, new data from trials of both molecular targeted therapy and immune checkpoint inhibitors (ICI) provided many new options of first- and second-line treatment for advanced HCC. Most notably, combination of ICI targeting the program cell death-1 (PD-1) pathway with other novel agents or conventional anti-cancer therapy may further improve treatment efficacy in different clinical settings. In this paper updated data of clinical trials of systemic therapy in the first- and second-line settings for advanced HCC were reviewed and the following issues were discussed: (1) lessons of trial design learned from positive and negative trials; (2) the balance between efficacy and safety in clinical practice; and (3) impact on future multi-disciplinary management of HCC.
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Affiliation(s)
- Yawen Dong
- Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China
| | - Tsung-Hao Liu
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Oncology, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, 10002, Taiwan
| | - Thomas Yau
- Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China.
| | - Chiun Hsu
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan. .,Department of Oncology, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, 10002, Taiwan.
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38
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Nakano M, Kuromatsu R, Niizeki T, Okamura S, Iwamoto H, Shimose S, Shirono T, Noda Y, Kamachi N, Koga H, Torimura T. Primary Treatment with Molecular-Targeted Agents for Hepatocellular Carcinoma: A Propensity Score-matching Analysis. Hepatol Commun 2020; 4:1218-1228. [PMID: 32766480 PMCID: PMC7395064 DOI: 10.1002/hep4.1535] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 04/13/2020] [Accepted: 04/28/2020] [Indexed: 12/22/2022] Open
Abstract
Sorafenib and lenvatinib, as molecular-targeted agents, constitute effective primary treatment options for advanced hepatocellular carcinoma (HCC). However, the choice of optimal primary treatment agent remains controversial. Here, we aimed to assess the respective outcomes between these agents as primary treatment in patients with advanced HCC through use of propensity score-matching analysis (PSMA). We enrolled 670 consecutive patients who were diagnosed with advanced HCC and received sorafenib (n = 524) or lenvatinib (n = 146) as the primary treatment among 18 participating institutions between May 2009 and October 2019. To reduce confounding, we used PSMA regarding seven variables related to advanced HCC prognosis, resulting in the selection of 292 patients (n = 146 for each agent). Following PSMA, no significant difference was observed in the outcome of overall survival time between patients treated with sorafenib or lenvatinib (median survival time 15.3 or 14.9 months, respectively; P = 0.2358). Patients treated with lenvatinib exhibited significantly greater therapeutic effects (response rate: 5% and 31%; disease control rate: 46% and 69% for sorafenib and lenvatinib, respectively; P < 0.0001), but showed significantly lower probability of transition to secondary treatment (sorafenib, 60%; lenvatinib, 45%; P < 0.0269) and higher any adverse events rate (sorafenib, 86%; lenvatinib, 95%; P = 0.0207). Conclusion: As a primary molecular-targeted agent-based treatment for advanced HCC, our findings suggested that sorafenib is generally appropriate as it offers significantly lower frequency of adverse events and higher probability of transition to secondary treatment, in consideration of the enhanced postprogression survival mediated by sequential treatment. Alternatively, lenvatinib affords a significantly higher therapeutic effect and should be used when immediate tumor reduction is required.
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Affiliation(s)
- Masahito Nakano
- Division of Gastroenterology Department of Medicine Kurume University School of Medicine Kurume Japan
| | - Ryoko Kuromatsu
- Division of Gastroenterology Department of Medicine Kurume University School of Medicine Kurume Japan
| | - Takashi Niizeki
- Division of Gastroenterology Department of Medicine Kurume University School of Medicine Kurume Japan
| | - Shusuke Okamura
- Division of Gastroenterology Department of Medicine Kurume University School of Medicine Kurume Japan
| | - Hideki Iwamoto
- Division of Gastroenterology Department of Medicine Kurume University School of Medicine Kurume Japan
| | - Shigeo Shimose
- Division of Gastroenterology Department of Medicine Kurume University School of Medicine Kurume Japan
| | - Tomotake Shirono
- Division of Gastroenterology Department of Medicine Kurume University School of Medicine Kurume Japan
| | - Yu Noda
- Division of Gastroenterology Department of Medicine Kurume University School of Medicine Kurume Japan
| | - Naoki Kamachi
- Division of Gastroenterology Department of Medicine Kurume University School of Medicine Kurume Japan
| | - Hironori Koga
- Division of Gastroenterology Department of Medicine Kurume University School of Medicine Kurume Japan
| | - Takuji Torimura
- Division of Gastroenterology Department of Medicine Kurume University School of Medicine Kurume Japan
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Zhang W, Feng LJ, Teng F, Li YH, Zhang X, Ran YG. Incidence and risk of proteinuria associated with newly approved vascular endothelial growth factor receptor tyrosine kinase inhibitors in cancer patients: an up-to-date meta-analysis of randomized controlled trials. Expert Rev Clin Pharmacol 2020; 13:311-320. [PMID: 32105149 DOI: 10.1080/17512433.2020.1734450] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Objective: We performed a meta-analysis to quantify the overall incidence and risk of proteinuria associated with five newly approved VEGFR-TKIs (regorafenib, vandetanib, cabozantinib, lenvatinib, axitinib) in cancer patients.Methods: Pubmed, Embase, ASCO abstracts, and ESMO abstracts were searched to identify relevant studies. Overall incidence rates, relative risk (RR), and 95% confidence intervals (CI) were estimated using random or fixed effects models according to the heterogeneity of included studies.Results: A total of 9,446 patients from 20 RCTs were included for the meta-analysis. The use of newly approved VEGFR-TKIs was associated with an increased risk of all-grade (RR 2.35, 95% CI 1.69-3.27, P < 0.001) and high-grade (RR 3.70, 95% CI 2.09-6.54, P < 0.001) proteinuria. On subgroup analysis, lenvatinib, axitinib, and vandetanib significantly increased the risk of all-grade proteinuria, and lenvatinib was associated with an increased risk of high-grade proteinuria. In addition, the risk of developing high-grade proteinuria events was significant for patients with hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC), but not for patients with colorectal cancer (CRC) and thyroid cancer (TC).Conclusion: Treatment with newly approved VEGFR-TKIs significantly increases the risk of developing proteinuria events in cancer patients, especially for patients treated with lenvatinib.
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Affiliation(s)
- Wei Zhang
- Department of Pathology, Shanghai Tenth People`s Hospital, Tongji University, School of Medicine, Shanghai, China
| | - Li-Jin Feng
- Department of Pathology, Shanghai Tenth People`s Hospital, Tongji University, School of Medicine, Shanghai, China
| | - Fei Teng
- Department of Radiotherapy, Affiliated Hospital of Hebei University, Baoding, China
| | - Yan-Hong Li
- Department of Radiotherapy, Affiliated Hospital of Hebei University, Baoding, China
| | - Xi Zhang
- Department of Radiotherapy, Affiliated Hospital of Hebei University, Baoding, China
| | - Yu-Ge Ran
- Department of Radiotherapy, Affiliated Hospital of Hebei University, Baoding, China
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Wang H, Rao B, Lou J, Li J, Liu Z, Li A, Cui G, Ren Z, Yu Z. The Function of the HGF/c-Met Axis in Hepatocellular Carcinoma. Front Cell Dev Biol 2020; 8:55. [PMID: 32117981 PMCID: PMC7018668 DOI: 10.3389/fcell.2020.00055] [Citation(s) in RCA: 97] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Accepted: 01/22/2020] [Indexed: 12/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, leading to a large global cancer burden. Hepatocyte growth factor (HGF) and its high-affinity receptor, mesenchymal epithelial transition factor (c-Met), are closely related to the onset, progression, and metastasis of multiple tumors. The HGF/c-Met axis is involved in cell proliferation, movement, differentiation, invasion, angiogenesis, and apoptosis by activating multiple downstream signaling pathways. In this review, we focus on the function of the HGF/c-Met axis in HCC. The HGF/c-Met axis promotes the onset, proliferation, invasion, and metastasis of HCC. Moreover, it can serve as a biomarker for diagnosis and prognosis, as well as a therapeutic target for HCC. In addition, it is closely related to drug resistance during HCC treatment.
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Affiliation(s)
- Haiyu Wang
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Benchen Rao
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jiamin Lou
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jianhao Li
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhenguo Liu
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ang Li
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Guangying Cui
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhigang Ren
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zujiang Yu
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Chen S, Cao Q, Wen W, Wang H. Targeted therapy for hepatocellular carcinoma: Challenges and opportunities. Cancer Lett 2019; 460:1-9. [PMID: 31207320 DOI: 10.1016/j.canlet.2019.114428] [Citation(s) in RCA: 162] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 05/15/2019] [Accepted: 06/05/2019] [Indexed: 12/24/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, which ranks as the sixth of cancer-related death. Despite the emergence of targeted therapy, advanced-stage HCC remains largely incurable due to low response rate and therapeutic resistance. In this review, we mainly focused on the current progression of multi-kinase inhibitors and immunotherapies in the treatment of HCC. We highlight the mechanism underlying the ineffectiveness of these targeted therapies, including oncogenic alterations in driver genes and downstream pathways, high heterogeneity of HCC, and the mutual interaction of tumor microenvironment that promotes therapeutic resistance. We also discussed how these previous studies suggested for future therapeutic strategies. Besides, the complexity of HCC heterogeneity and cancer revolution need to be recognized in personalized therapy. Establishment of a drug screening system and identification of biomarkers of response is also in urgent need to overcome drug resistance. Meanwhile, a combination of targeted therapies could also be explored as a promising strategy in the future.
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Affiliation(s)
- Shuzhen Chen
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China; National Center for Liver Cancer, Second Military Medical University, Shanghai, 201805, China
| | - Qiqi Cao
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China
| | - Wen Wen
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China; National Center for Liver Cancer, Second Military Medical University, Shanghai, 201805, China.
| | - Hongyang Wang
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China; National Center for Liver Cancer, Second Military Medical University, Shanghai, 201805, China.
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Moehler M, Heo J, Lee HC, Tak WY, Chao Y, Paik SW, Yim HJ, Byun KS, Baron A, Ungerechts G, Jonker D, Ruo L, Cho M, Kaubisch A, Wege H, Merle P, Ebert O, Habersetzer F, Blanc JF, Rosmorduc O, Lencioni R, Patt R, Leen AM, Foerster F, Homerin M, Stojkowitz N, Lusky M, Limacher JM, Hennequi M, Gaspar N, McFadden B, De Silva N, Shen D, Pelusio A, Kirn DH, Breitbach CJ, Burke JM. Vaccinia-based oncolytic immunotherapy Pexastimogene Devacirepvec in patients with advanced hepatocellular carcinoma after sorafenib failure: a randomized multicenter Phase IIb trial (TRAVERSE). Oncoimmunology 2019; 8:1615817. [PMID: 31413923 PMCID: PMC6682346 DOI: 10.1080/2162402x.2019.1615817] [Citation(s) in RCA: 96] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Revised: 04/15/2019] [Accepted: 04/19/2019] [Indexed: 02/07/2023] Open
Abstract
Pexastimogene devacirepvec (Pexa-Vec) is a vaccinia virus-based oncolytic immunotherapy designed to preferentially replicate in and destroy tumor cells while stimulating anti-tumor immunity by expressing GM-CSF. An earlier randomized Phase IIa trial in predominantly sorafenib-naïve hepatocellular carcinoma (HCC) demonstrated an overall survival (OS) benefit. This randomized, open-label Phase IIb trial investigated whether Pexa-Vec plus Best Supportive Care (BSC) improved OS over BSC alone in HCC patients who failed sorafenib therapy (TRAVERSE). 129 patients were randomly assigned 2:1 to Pexa-Vec plus BSC vs. BSC alone. Pexa-Vec was given as a single intravenous (IV) infusion followed by up to 5 IT injections. The primary endpoint was OS. Secondary endpoints included overall response rate (RR), time to progression (TTP) and safety. A high drop-out rate in the control arm (63%) confounded assessment of response-based endpoints. Median OS (ITT) for Pexa-Vec plus BSC vs. BSC alone was 4.2 and 4.4 months, respectively (HR, 1.19, 95% CI: 0.78–1.80; p = .428). There was no difference between the two treatment arms in RR or TTP. Pexa-Vec was generally well-tolerated. The most frequent Grade 3 included pyrexia (8%) and hypotension (8%). Induction of immune responses to vaccinia antigens and HCC associated antigens were observed. Despite a tolerable safety profile and induction of T cell responses, Pexa-Vec did not improve OS as second-line therapy after sorafenib failure. The true potential of oncolytic viruses may lie in the treatment of patients with earlier disease stages which should be addressed in future studies. ClinicalTrials.gov: NCT01387555
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Affiliation(s)
- M Moehler
- First Department of Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - J Heo
- College of Medicine, Pusan National University and Medical Research Institute, Pusan National University Hospital, Busan, Republic of Korea
| | - H C Lee
- Asan Medical Center, University of Ulsan College of Medicine, Ulsan, Republic ofKorea
| | - W Y Tak
- School of Medicine, Kyungpook National University Medical Center, Daegu, Republic of Korea
| | - Y Chao
- Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - S W Paik
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - H J Yim
- Department of Internal Medicine, Korea University Ansan Hospital, Ansan-si, Republic of Korea
| | - K S Byun
- Department of Internal Medicine, Korea UniversityCollege of Medicine, Seoul, Republic of Korea
| | - A Baron
- Department of Medicine, California Pacific Medical Center, San Francisco, CA, USA
| | - G Ungerechts
- Department of Medical Oncology, National Center for Tumor Diseases (NCT) and Heidelberg University Hospital, Heidelberg, Germany
| | - D Jonker
- The Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada
| | - L Ruo
- Department of Surgery, Juravinski Hospital and Cancer Centre, McMaster University, Hamilton, Canada
| | - M Cho
- Department of Internal Medicine, Pusan National University Yangsan Hospital, Busan, Republic of Korea
| | - A Kaubisch
- Department of Medicine, Montefiore Medical Center, New York, NY, USA
| | - H Wege
- Department of Medicine, Gastroenterology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - P Merle
- Hepatology Unit, Croix-Rousse Hospital, Lyon, France
| | - O Ebert
- Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University, Munich, Germany
| | - F Habersetzer
- Pôle Hépato-Digestif, Hôpitaux Universitaires de Strasbourg, INSERM 1110, IHU de Strasbourg and Université de Strasbourg, Strasbourg, France
| | - J F Blanc
- Hepato-Gastroenterology and Digestive Oncology Department, CHU Bordeaux, Bordeaux, France
| | | | - R Lencioni
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - R Patt
- Rad-MD, New York, NY, USA
| | - A M Leen
- Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
| | - F Foerster
- First Department of Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - M Homerin
- Medical Affairs, Transgene S.A., Illkirch-Graffenstaden, France
| | - N Stojkowitz
- Clinical Operations, Transgene S.A., 400 Bd Gonthier d'Andernach, Parc d'Innovation, 67405 Illkirch-Graffenstaden, France
| | - M Lusky
- Program Management, Transgene S.A., 400 Bd Gonthier d'Andernach, Parc d'Innovation, 67405 Illkirch-Graffenstaden, France
| | - J M Limacher
- Medical Affairs, Transgene S.A., 400 Bd Gonthier d'Andernach, Parc d'Innovation, 67405 Illkirch-Graffenstaden, France
| | - M Hennequi
- Biostatistics, Transgene S.A., 400 Bd Gonthier d'Andernach, Parc d'Innovation, 67405 Illkirch-Graffenstaden, France
| | - N Gaspar
- Clinical Assays, SillaJen Inc., San Francisco, CA, USA
| | - B McFadden
- Analytical Development and Quality Control, SillaJen Inc., San Francisco, CA, USA
| | - N De Silva
- Clinical, SillaJen Inc., San Francisco, CA, USA
| | - D Shen
- Clinical, SillaJen Inc., San Francisco, CA, USA
| | - A Pelusio
- Clinical, SillaJen Inc., San Francisco, CA, USA
| | - D H Kirn
- SillaJen Inc., San Francisco, CA, USA
| | | | - J M Burke
- Clinical, SillaJen Inc., San Francisco, CA, USA
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Second-line Treatments of Advanced Hepatocellular Carcinoma: Systematic Review and Network Meta-Analysis of Randomized Controlled Trials. J Clin Gastroenterol 2019; 53:251-261. [PMID: 30575632 DOI: 10.1097/mcg.0000000000001160] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Advanced hepatocellular carcinoma (HCC) constitutes the second leading cause of cancer-related deaths. First-line therapy is either sorafenib or lenvatinib. Several treatment options have been recently added to the second-line treatment of advanced HCC. The aim of this network meta-analysis of randomized controlled trials was to compare the second-line treatments of advanced HCC. METHODS Network meta-analyses were computed for overall survival (OS), progression-free survival, rates of grade 3 to 5 adverse events, and for treatment discontinuation due to adverse events. OS was considered to be the primary outcome of this study, and everolimus was chosen to be the common comparator for efficacy analyses and placebo for safety analyses. Subgroup analyses were computed for OS in patients with hepatitis B, patients with hepatitis C, Asian patients, patients with macrovascular invasion, and patients with extrahepatic metastases. RESULTS Thirteen randomized controlled trials including 5076 patients and evaluating 11 agents were found to be eligible. Regorafenib [hazard ratio (HR)=0.60, 95% confidence interval (CI)=0.44-0.81] and cabozantinib (HR=0.72, 95% CI=0.55-0.95) were found to significantly prolong OS compared with everolimus. The effect of regorafenib on OS tended to be conserved across patient subgroups. Regorafenib was also found to significantly prolong progression-free survival (HR=0.46, 95% CI=0.35-0.62) and significantly increase the rates of grade 3 to 5 adverse events (odds ratios=3.18, 95% CI=2.22-4.54) and treatment discontinuation due to adverse events (odds ratios=2.67, 95% CI=1.21-5.87). CONCLUSIONS This network meta-analysis concludes that, based on current evidence, regorafenib could be the agent of choice in the second-line treatment of HCC, with cabozantinib as a possible alternative for sorafenib-intolerant patients.
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Systemic Management for Advanced Hepatocellular Carcinoma: A Review of the Molecular Pathways of Carcinogenesis, Current and Emerging Therapies, and Novel Treatment Strategies. Dig Dis Sci 2019; 64:1016-1029. [PMID: 30887150 DOI: 10.1007/s10620-019-05582-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) arises from a number of cirrhosis-related and non-cirrhosis-related exposures and is one of the leading causes of cancer-related deaths worldwide. Achieving a durable cure currently relies on either resection or transplantation, but since most patients will be diagnosed with inoperable disease, there is great interest in achieving more effective systemic therapies. At a molecular level, HCC is heterogeneous, but initial treatment strategies, including the use of multi-targeted tyrosine kinase inhibitors and checkpoint inhibitors, have been fairly homogenous, depending on general host factors and overall tumor burden rather than specific molecular signatures. Over the past 2 decades, however, there has been significant success in identifying key molecular targets, including driver mutations involving the telomerase reverse transcriptase, p53, and beta-catenin genes, and significant work is now being devoted to translating these discoveries into the development of robust and well-tolerated targeted therapies. Furthermore, multi-modal therapies have also begun to emerge, harnessing possible synergism amongst a variety of different treatment classes. As the findings of these landmark trials become available over the next several years, the landscape of the systemic management of advanced HCC will change significantly.
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45
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Gong X, Qin S. Study progression of anti-angiogenetic therapy and its combination with other agents for the treatment of advanced hepatocellular carcinoma. Hepatobiliary Surg Nutr 2018; 7:466-474. [PMID: 30652091 PMCID: PMC6295396 DOI: 10.21037/hbsn.2018.11.04] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2018] [Accepted: 10/31/2018] [Indexed: 01/24/2023]
Abstract
Hepatocellular carcinoma (HCC) is a common malignancy worldwide and is especially prevalent in the Chinese population. Treatment of advanced HCC has posed a considerable challenge to clinicians and highly effective therapies remain elusive. Angiogenesis contributes greatly to the pathogenesis, invasion and metastasis of HCC. Therefore, anti-angiogenesis therapy could be instrumental to the treatment of HCC. In recent years, several anti-angiogenesis drugs have generated significant outcomes in a few key clinical studies, and in this light, anti-angiogenesis therapy has become a critical aspect of comprehensive treatment of HCC. In this article, to provide a reference for clinicians, we review these advances and discuss the future direction of development.
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Affiliation(s)
- Xinlei Gong
- Department of Medical Oncology, PLA Cancer Center of Bayi Hospital Affiliated to Nanjing University of Chinese Medicine, Nanjing 210002, China
| | - Shukui Qin
- Department of Medical Oncology, PLA Cancer Center of Bayi Hospital Affiliated to Nanjing University of Chinese Medicine, Nanjing 210002, China
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Li J, Gu J. Cardiovascular Toxicities with Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors in Cancer Patients: A Meta-Analysis of 77 Randomized Controlled Trials. Clin Drug Investig 2018; 38:1109-1123. [DOI: 10.1007/s40261-018-0709-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
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Li X, Wan J, Wu Z, Tu J, Hu Y, Wu S, Lou L. Fatal adverse events with molecular targeted agents in the treatment of advanced hepatocellular carcinoma: a meta-analysis of randomized controlled trials. DRUG DESIGN DEVELOPMENT AND THERAPY 2018; 12:3043-3049. [PMID: 30271119 PMCID: PMC6151100 DOI: 10.2147/dddt.s151241] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Aims Concerns have increased about the risk of fatal adverse events (FAEs) associated with molecular targeted agents (MTAs) in the treatment of advanced hepatocellular carcinoma (HCC). The purpose of this study is to investigate the overall incidence and risk of FAEs in advanced HCC with administration of MTAs by using a meta-analysis of available clinical trials. Materials and methods Electronic databases were searched for relevant articles before March 2017. Eligible studies were selected according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. Pooled incidence, Peto ORs and 95% CIs were calculated according to the heterogeneity of selected studies. Results A total of 4,716 HCC participants from 10 randomized controlled trials (RCTs) were finally considered for this meta-analysis. The pooled incidence of death due to MTAs was 2.1% (95% CI 1.6%–2.8%) with a Peto OR of 1.79 (95% CI 1.07–3.01; p=0.027) in comparison with controlled groups. Subgroup analysis according to biological agents showed that brivanib treatment in HCC patients significantly increased the risk of developing FAEs (Peto OR 3.97; 95% CI 1.17–13.51; p=0.028) but not for sorafenib (Peto OR 1.78; 95% CI 0.54–5.89; p=0.34) and other MTAs (Peto OR 1.43; 95% CI 0.75–2.76; p=0.28). Sensitive analysis showed that the pooled results were influenced by removing each single trial. The most common causes of FAEs were hepatic failure (22.2%) and hemorrhage (13.3%), respectively. Conclusion Clinicians should be aware of the risks of FAEs during the administration of MTAs in advanced HCC patients, especially for patients with abnormal liver function. However, the use of sorafenib remains justified in its approved indications due to their potential survival benefits and limited toxicities.
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Affiliation(s)
- Xiaofei Li
- Department of Infectious Diseases, Yiwu Central Hospital, Yiwu, China,
| | - Jia Wan
- The First Hospital of Nanchang, Nanchang, China
| | - Zhenping Wu
- Gastroenterology Department, Jinhua Central Hospital, Jinhua, China
| | - Juncai Tu
- Department of Infectious Diseases, Yiwu Central Hospital, Yiwu, China,
| | - Yongtao Hu
- Department of Infectious Diseases, Yiwu Central Hospital, Yiwu, China,
| | - Shuang Wu
- Department of Infectious Diseases, Yiwu Central Hospital, Yiwu, China,
| | - Lianqing Lou
- Department of Infectious Diseases, Yiwu Central Hospital, Yiwu, China,
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Emerging therapies in advanced hepatocellular carcinoma. Exp Hematol Oncol 2018; 7:17. [PMID: 30087805 PMCID: PMC6076403 DOI: 10.1186/s40164-018-0109-6] [Citation(s) in RCA: 82] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Accepted: 07/30/2018] [Indexed: 12/14/2022] Open
Abstract
Background Prognosis is very poor for advanced HCC patients partially due to lack of effective systemic treatment. Sorafenib was the only approved agent for advanced HCC since 2007 until recent breakthroughs. In this article, we will review the newer approved and promising agents in the treatment of advanced HCC in the first line setting and beyond progression. Main body The Food and Drug Administration approved sorafenib as it demonstrated 3 months overall survival benefit compared to placebo in the first line setting over 10 years ago. Multiple single agent and combination therapies have been studied but failed to show benefit. Chemotherapy has limited role in patients with advanced HCC given poor hepatic reserve due to underlying cirrhosis. A new era of treatment for advanced HCC arrived recently with exciting data presented for lenvatinib, regorafenib, cabozantinib, nivolumab, ramucirumab and several other promising clinical trials. Conclusion Advanced HCC patients are difficult to treat with poor outcomes. After initial approval of sorafenib in 2007, we recently have multiple new agents that showed benefit and promising activity, and are set to change the landscape of HCC treatment.
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Eatrides J, Wang E, Kothari N, Kim R. Role of Systemic Therapy and Future Directions for Hepatocellular Carcinoma. Cancer Control 2018; 24:1073274817729243. [PMID: 28975834 PMCID: PMC5937243 DOI: 10.1177/1073274817729243] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is an aggressive tumor that often arises in the setting of liver cirrhosis. Although early-stage disease is often amenable for surgical resection, transplant, or locoregional therapies, many patients are diagnosed at an advanced stage or have poor liver reserve. Systemic therapy is the mainstay of treatment for these patients. At present, the only approved therapy for the treatment of advanced disease is the tyrosine multikinase inhibitor sorafenib. Candidacy for treatment is based on liver reserve. Novel agents for the treatment of this disease are urgently needed. In this article, we review systemic therapy trials and upcoming data for the treatment of HCC.
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Affiliation(s)
- Jennifer Eatrides
- 1 Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | - Emilie Wang
- 1 Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | - Nishi Kothari
- 1 Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | - Richard Kim
- 1 Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
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Kudo M, Kang YK, Park JW, Qin S, Inaba Y, Assenat E, Umeyama Y, Lechuga MJ, Valota O, Fujii Y, Martini JF, Williams JA, Obi S. Regional Differences in Efficacy, Safety, and Biomarkers for Second-Line Axitinib in Patients with Advanced Hepatocellular Carcinoma: From a Randomized Phase II Study. Liver Cancer 2018; 7:148-164. [PMID: 29888205 PMCID: PMC5985413 DOI: 10.1159/000484620] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND An unmet need exists for treatment of patients with advanced hepatocellular carcinoma (HCC) who progress on or are intolerant to sorafenib. A global randomized phase II trial (ClinicalTrial.gov No. NCT01210495) of axitinib, a vascular endothelial growth factor receptor 1-3 inhibitor, in combination with best supportive care (BSC) did not prolong overall survival (OS) over placebo/BSC, but showed improved progression-free survival in some patients. Subgroup analyses were conducted to identify potential predictive/prognostic factors. METHODS The data from this phase II study were analyzed for the efficacy and safety of axitinib/BSC in patients from Asia versus non-Asia versus Asian subgroups (Japan, Korea, or mainland China/Hong Kong/Taiwan) and predictive/prognostic values of baseline microRNAs and serum soluble proteins, using the Cox proportional hazards model. RESULTS Of 202 patients, 78 were from non-Asia and 124 from Asia (37 Japanese, 36 Korean, and 51 Chinese). No significant differences in OS were found between axitinib/BSC and placebo/BSC in non-Asians, Asians, or Asian subgroups. However, in an exploratory analysis, axitinib/BSC showed favorable OS in Asians, especially Japanese, when patients intolerant to prior antiangiogenic therapy were excluded from the data set. Axitinib/BSC was well tolerated by non-Asians and Asians alike. The presence of 4 circulating microRNAs, including miR-5684 and miR-1224-5p, or a level lower than or equal to the median protein level of stromal cell-derived factor 1 at baseline was significantly associated with longer OS in axitinib/BSC-treated Asians or non-Asians. CONCLUSIONS Axitinib/BSC did not prolong survival over placebo/BSC in non-Asians, Asians, or Asian subgroups, but favorable OS with axitinib/BSC was observed in a subset of Japanese patients. A patient population that excludes sorafenib-intolerant patients might potentially be more suitable for clinical trials of new agents in advanced HCC. Since these results are very preliminary, further investigation is warranted. The potential predictive/prognostic value of several baseline microRNAs and soluble proteins identified in this study would require validation in prospective studies on a large cohort of patients.
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Affiliation(s)
- Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Yoon-Koo Kang
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Joong-Won Park
- Center for Liver Cancer, National Cancer Center, Goyang, Republic of Korea
| | - Shukui Qin
- Department of Medical Oncology, Nanjing Bayi Hospital, Nanjing, China
| | - Yoshitaka Inaba
- Department of Diagnostic and Interventional Radiology, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Eric Assenat
- Department of Medical Oncology, Hôpital Saint Eloi, Montpellier, France
| | | | | | | | | | | | | | - Shuntaro Obi
- Department of Hepatology, Sasaki Foundation Kyoundo Hospital, Tokyo, Japan
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