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Ren T, Huang Y. Recent advancements in improving the efficacy and safety of chimeric antigen receptor (CAR)-T cell therapy for hepatocellular carcinoma. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:1433-1446. [PMID: 39316087 DOI: 10.1007/s00210-024-03443-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 09/08/2024] [Indexed: 09/25/2024]
Abstract
The liver is one of the most frequent sites of primary malignancies in humans. Hepatocellular carcinoma (HCC) is one of the most prevalent solid tumors with poor prognosis. Current treatments showed limited efficacy in some patients, and, therefore, alternative strategies, such as immunotherapy, cancer vaccines, adoptive cell therapy (ACT), and recently chimeric antigen receptors (CAR)-T cells, are developed to offer better efficacy and safety profile in patients with HCC. Unlike other ACTs like tumor-infiltrating lymphocytes (TILs), CAR-T cells are equipped with engineered CAR receptors that effectively identify tumor antigens and eliminate cancer cells without major histocompatibility complex (MHC) restriction. This process induces intracellular signaling, leading to T lymphocyte recruitment and subsequent activation of other effector cells in the tumor microenvironment (TME). Until today, novel approaches have been used to develop more potent CAR-T cells with robust persistence, specificity, trafficking, and safety. However, the clinical application of CAR-T cells in solid tumors is still challenging. Therefore, this study aims to review the advancement, prospects, and possible avenues of CAR-T cell application in HCC following an outline of the CAR structure and function.
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Affiliation(s)
- Tuo Ren
- Department of Interventional Radiology, The First Affiliated Hospital, Sun Yat-Sen University, No.58 Zhongsahn 2nd Road, Guangzhou, Guangdong, 510080, China
| | - Yonghui Huang
- Department of Interventional Radiology, The First Affiliated Hospital, Sun Yat-Sen University, No.58 Zhongsahn 2nd Road, Guangzhou, Guangdong, 510080, China.
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Shao Y, Pu W, Su R, Wang Y, Yin S, Zhong H, Han L, Yu H. Autocrine and paracrine LIF signals to collaborate sorafenib-resistance in hepatocellular carcinoma and effects of Kanglaite Injection. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 136:156262. [PMID: 39580996 DOI: 10.1016/j.phymed.2024.156262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 09/22/2024] [Accepted: 11/13/2024] [Indexed: 11/26/2024]
Abstract
BACKGROUND Sorafenib (SFN) is the first-line medicine for advanced hepatocellular carcinoma (HCC). However, Sorafenib resistance is a main challenge of therapeutic efficacy, and the mechanisms have not been fully clarified. PURPOSE The purpose of this study was to investigate the therapeutic potential and mechanism of action of LIF in modulating the microenvironment of SFN resistance as well as Kanglaite Injection (KLTI) in ameliorating SFN resistance in HCC and to guide future research directions for drug combination for HCC. METHODS Established SFN-resistance HCC cell line was used to study the relationship between resistance and immunosuppression in HCC-tumor microenvironment (TME). In vivo macrophage and natural killer (NK) cells depletion were achieved by clodronate liposomes (CL) and anti-NK1.1. In vitro multiple cell co-culture systems were used to determine the effects of KLTI on SFN-resistant. Likewise, flow cytometry, qRT-PCR, Western blot, and immunohistochemistry analysis were performed for further mechanistic investigation. RESULTS Tumor associated-macrophages (TAMs) and NK cells mediated SFN-resistance in murine HCC. In the case of SFN resistance, the paracrine-leukemia inhibitory factor (LIF) by M2-like TAMs increased and potently suppressed NK cells proliferation and cytotoxicity, which finally inducing NK cells exhaustion and malignancy of HCC metastasis. Meanwhile, SFN resistance led to the increased autocrine-LIF of tumor cells, and further promoted the protective autophagy and activation of the acquired drug-resistant pathway PI3K/Akt/mTOR. KLTI could ameliorate the resistance of tumor immune microenvironment (TIME) and enhance the sensitivity of HCC to SFN by regulating LIF and macrophage-NK cell interaction. CONCLUSIONS Our findings verify the therapeutic effects of targeting LIF in SFN-resistance, uncover the potential mechanism for the increased sensitivity to SFN and sought to elucidate how this intervention might contribute to overcoming SFN resistance. KLTI is a promising immunomodulatory drug by regulating LIF and macrophage-NK cell interaction, which could be a potential combination partner for HCC treatment.
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Affiliation(s)
- Yingying Shao
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China; School of Medicine, Nankai University, Tianjin 300071, PR China
| | - Weiling Pu
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China; Haihe Laboratory of Modern Chinese Medicine, Tianjin 301617, PR China
| | - Ranran Su
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China; Haihe Laboratory of Modern Chinese Medicine, Tianjin 301617, PR China
| | - Yu Wang
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China; Haihe Laboratory of Modern Chinese Medicine, Tianjin 301617, PR China
| | - Shuangshuang Yin
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China; Haihe Laboratory of Modern Chinese Medicine, Tianjin 301617, PR China
| | - Hao Zhong
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China; Haihe Laboratory of Modern Chinese Medicine, Tianjin 301617, PR China
| | - Lifeng Han
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China; Haihe Laboratory of Modern Chinese Medicine, Tianjin 301617, PR China; Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China
| | - Haiyang Yu
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China; Haihe Laboratory of Modern Chinese Medicine, Tianjin 301617, PR China; Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China.
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Yamamoto M, Terashima T, Yamashita T, Seki A, Nakagawa H, Nio K, Shimakami T, Takatori H, Arai K, Mizukoshi E, Honda M, Takeuchi S, Yamashita T. Successful second-line treatment with cabozantinib for hepatocellular carcinoma harboring cytoplasmic mesenchymal-epithelial transition factor amplification. Hepatol Res 2024; 54:315-319. [PMID: 37817425 DOI: 10.1111/hepr.13975] [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: 06/01/2023] [Revised: 09/27/2023] [Accepted: 10/08/2023] [Indexed: 10/12/2023]
Abstract
A 72-year-old man with metastatic hepatocellular carcinoma previously received first-line systemic therapy with atezolizumab plus bevacizumab. His disease was judged to be progressing 5 months after treatment initiation. Comprehensive genomic profiling revealed cytoplasmic mesenchymal-epithelial transition factor amplification. On the basis of an expert panel's recommendation, he received cabozantinib as second-line therapy. The tumors shrank markedly and continued to shrink 6 months after treatment. Comprehensive genomic profiling could provide useful information for selecting effective second-line treatments for patients with hepatocellular carcinoma after first-line immunotherapy.
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Affiliation(s)
- Makoto Yamamoto
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan
| | - Takeshi Terashima
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan
| | - Tatsuya Yamashita
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan
| | - Akihiro Seki
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan
| | - Hidetoshi Nakagawa
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan
| | - Kouki Nio
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan
| | - Tetsuro Shimakami
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan
| | - Hajime Takatori
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan
| | - Kuniaki Arai
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan
| | - Eishiro Mizukoshi
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan
| | - Masao Honda
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan
| | - Shinji Takeuchi
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Taro Yamashita
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan
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Gao Y, Li Y, Liu Z, Dong Y, Yang S, Wu B, Xiao M, Chen C, Wen Y, Chen L, Jiang H, Yao Y. AHSA1 Regulates Hepatocellular Carcinoma Progression via the TGF-β/Akt-Cyclin D1/CDK6 Pathway. J Hepatocell Carcinoma 2023; 10:2021-2036. [PMID: 38022728 PMCID: PMC10640837 DOI: 10.2147/jhc.s407680] [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: 02/08/2023] [Accepted: 10/24/2023] [Indexed: 12/01/2023] Open
Abstract
Background Activator of heat shock protein 90 (HSP90) ATPase Activity 1 (AHSA1) regulates proliferation, apoptosis, migration, and invasion of osteosarcoma and hepatocellular carcinoma (HCC). However, the novel mechanism of AHSA1 in the tumor biology of hepatocellular carcinoma (HCC) remains unclear. Methods We analyzed AHSA1 expression in 85 pairs of clinical samples of HCC and the Cancer Genome Atlas database. The role of AHSA1 in HCC was proved by cell proliferation, colony formation, migration, cell cycle analysis in vitro, xenograft models and tumor metastasis assay in vivo, and bioinformatics. Results High AHSA1 expression was demonstrated in HCC and associated with invasive depth, clinical stage, and poor overall survival of patients. Univariate Cox analysis confirmed that AHSA1 was an independent prognostic factor for patients with HCC. Meanwhile, AHSA1 upregulation promoted cell proliferation, colony formation, and cell migration in vitro and tumor cell proliferation and metastasis of HCC cells in vivo. AHSA1 upregulation increased the cell cycle transition from G1 to S phase by increasing the expression of cyclinD1, cyclinD3, and cyclin-dependent kinase 6(CD). Transforming growth factor beta 1 (TGF-β1)-induced protein kinase B (Akt) signaling regulated the expression of downstream targets, including cyclinD1. AHSA1 expression was closely correlated with the expression of TGF-β, Akt, cyclinD1, cyclinD3, and CDK6 using the Gene Expression Profiling Interactive Analysis database. AHSA1 upregulation participated in HCC progression by regulating TGF-β/Akt-cyclinD1/CDK6 signaling. Conclusion AHSA1 might serve as a biomarker for predicting the clinical outcome of patients with HCC. It is vital in tumor metastasis and disease progression of HCC and may facilitate the development of clinical intervention strategies against HCC.
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Affiliation(s)
- Yanjun Gao
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China
- Hubei Provincial Research Center for Precision Medicine of Cancer, Wuhan, 430200, People’s Republic of China
| | - Yingge Li
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China
- Hubei Provincial Research Center for Precision Medicine of Cancer, Wuhan, 430200, People’s Republic of China
| | - Zheming Liu
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China
- Hubei Provincial Research Center for Precision Medicine of Cancer, Wuhan, 430200, People’s Republic of China
| | - Yi Dong
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China
- Hubei Provincial Research Center for Precision Medicine of Cancer, Wuhan, 430200, People’s Republic of China
| | - Siqi Yang
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China
- Hubei Provincial Research Center for Precision Medicine of Cancer, Wuhan, 430200, People’s Republic of China
| | - Bin Wu
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China
- Department of Oncology, Huang-Gang Central Hospital, Huanggang, 438000, People’s Republic of China
| | - Mengxia Xiao
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China
- Department of Oncology, Yichun People’s Hospital, Yichun, 336000, People’s Republic of China
| | - Chen Chen
- Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China
| | - Yingmei Wen
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China
- Hubei Provincial Research Center for Precision Medicine of Cancer, Wuhan, 430200, People’s Republic of China
| | - Lei Chen
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China
| | - Haijuan Jiang
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, People’s Republic of China
| | - Yi Yao
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China
- Hubei Provincial Research Center for Precision Medicine of Cancer, Wuhan, 430200, People’s Republic of China
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Yang XA, Jin R, Zhang LM, Ying DJ. Global trends of targeted therapy for hepatocellular carcinoma: A bibliometric and visualized study from 2008 to 2022. Medicine (Baltimore) 2023; 102:e34932. [PMID: 37653818 PMCID: PMC10470737 DOI: 10.1097/md.0000000000034932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 07/25/2023] [Accepted: 08/04/2023] [Indexed: 09/02/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is an exceedingly prevalent malignancy with an exceptionally poor prognosis. Targeted therapy is an effective treatment option for patients with advanced HCC. However, there have been no bibliometric analyses of targeted therapies for HCC. METHODS This study aimed to assess the current status and future directions of targeted therapy for HCC to provide future scholars with clearer research contents and popular themes. Methods: Literature on targeted therapy for HCC from 2008 to 2022 was obtained from the Web of Science (WoS) and assessed using bibliometric methodology. Additionally, the VOS viewer was applied in the visualization study to conduct bibliographic coupling, co-authorship, co-citation, and co-occurrence analyses of publications. RESULTS A total of 10,779 papers were subsequently selected. Over the past 15 years, there has been a progressive increase in the number of publications on an annualized basis. China released the most publications in the field, whereas the United States had the highest H-index. Cancers published the most papers. Fudan University had the greatest sway in this area. Studies could be divided into 5 clusters: "Gene and expression research," "Mechanism study," "Nanoparticle study," "Targeted drug research," and "Clinical study." CONCLUSIONS In the upcoming years, more papers on targeted therapy for HCC are expected to be released, demonstrating the potential for this topic to flourish. Particularly, "Clinical study" is the following trendy topic in this field. Other research subfields may likewise exhibit a continuous tendency towards balanced development.
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Affiliation(s)
- Xuan-Ang Yang
- Health Science Center, Ningbo University, Ningbo, Zhejiang Province, China
| | - Rong Jin
- Health Science Center, Ningbo University, Ningbo, Zhejiang Province, China
| | - Lei-Ming Zhang
- Health Science Center, Ningbo University, Ningbo, Zhejiang Province, China
| | - Dong-Jian Ying
- The Affiliated Lihuili Hospital of Ningbo University, Ningbo, Zhejiang Province, China
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Zhou Z, Xu X, Sun M, Liu Y, Liu Q, Chen C, Yin Y. Conversion therapy for massive hepatocellular carcinoma: A case report and literature review. Clin Case Rep 2023; 11:e7533. [PMID: 37323266 PMCID: PMC10264960 DOI: 10.1002/ccr3.7533] [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: 04/23/2023] [Revised: 05/08/2023] [Accepted: 05/28/2023] [Indexed: 06/17/2023] Open
Abstract
KEY CLINICAL MESSAGE For potentially resectable HCC, a more aggressive conversion therapy strategy (high-intensity combined with multiple treatment modalities) can be used. ABSTRACT Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide. The best treatment for HCC is radical surgical resection, but 70%-80% of patients are ineligible for surgery. Although conversion therapy is an established treatment strategy for various solid tumors, there is no uniform protocol for treating HCC. In this case, we present a 69-year-old male patient diagnosed with massive HCC with Barcelona clinical liver cancer (BCLC) stage B. Because of the insufficient volume of the future liver remnant, we believed radical surgical resection was temporarily impossible. Therefore, the patient received conversion therapy, including four cycles of transcatheter arterial embolization (TAE) and hepatic arterial infusion chemotherapy (HAIC-Folfox), lenvatinib (8 mg orally once a day), and tislelizumab (an anti-PD-1 antibody, 200 mg intravenously once every 3 weeks). Fortunately, the patient achieved a good treatment response (smaller lesions and improved liver function) and underwent radical surgery finally. There was no clinical evidence of recurrence at 6 months of follow-up. For potentially resectable HCC, this case reveals that a more aggressive conversion therapy strategy (high-intensity combined with multiple treatment modalities) can be used.
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Affiliation(s)
- Zheyu Zhou
- Department of General Surgery, Nanjing Drum Tower HospitalChinese Academy of Medical Sciences & Peking Union Medical College, Graduate School of Peking Union Medical CollegeNanjingChina
- Department of Hepatobiliary SurgeryThe Affiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjingChina
| | - Xiaoliang Xu
- Department of General SurgeryThe First Affiliated Hospital of Anhui Medical UniversityHefeiChina
| | - Meiling Sun
- Department of Hepatobiliary SurgeryThe Affiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjingChina
| | - Yang Liu
- Department of Hepatobiliary SurgeryThe Affiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjingChina
| | - Qiaoyu Liu
- Department of General SurgeryThe First Affiliated Hospital of Anhui Medical UniversityHefeiChina
| | - Chaobo Chen
- Department of Hepatobiliary SurgeryThe Affiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjingChina
- Department of General SurgeryXishan People's Hospital of Wuxi CityWuxiChina
| | - Yin Yin
- Department of General SurgeryThe First Affiliated Hospital of Anhui Medical UniversityHefeiChina
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Mandlik DS, Mandlik SK, Choudhary HB. Immunotherapy for hepatocellular carcinoma: Current status and future perspectives. World J Gastroenterol 2023; 29:1054-1075. [PMID: 36844141 PMCID: PMC9950866 DOI: 10.3748/wjg.v29.i6.1054] [Citation(s) in RCA: 59] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 12/23/2022] [Accepted: 01/20/2023] [Indexed: 02/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the world’s deadliest and fastest-growing tumors, with a poor prognosis. HCC develops in the context of chronic liver disease. Curative resection, surgery (liver transplantation), trans-arterial chemoembolization, radioembolization, radiofrequency ablation and chemotherapy are common treatment options for HCC, however, they will only assist a limited percentage of patients. Current treatments for advanced HCC are ineffective and aggravate the underlying liver condition. Despite promising preclinical and early-phase clinical trials for some drugs, existing systemic therapeutic methods for advanced tumor stages remain limited, underlining an unmet clinical need. In current years, cancer immunotherapy has made significant progress, opening up new treatment options for HCC. HCC, on the other hand, has a variety of causes and can affects the body’s immune system via a variety of mechanisms. With the speedy advancement of synthetic biology and genetic engineering, a range of innovative immunotherapies, such as immune checkpoint inhibitors [anti-programmed cell death-1 (PD-1), anti-cytotoxic T lymphocyte antigen-4, and anti-PD ligand 1 cell death antibodies], therapeutic cancer vaccines, engineered cytokines, and adoptive cell therapy have all been used for the treatment of advanced HCC. In this review, we summarize the present clinical and preclinical landscape of immunotherapies in HCC, critically discuss recent clinical trial outcomes, and address future perspectives in the field of liver cancer.
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Affiliation(s)
- Deepa S Mandlik
- Department of Pharmacology, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
| | - Satish K Mandlik
- Department of Pharmaceutics, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
| | - Heena B Choudhary
- Department of Pharmacology, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
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Xiu Z, Li Y, Fang J, Han J, Li S, Li Y, Yang X, Song G, Li Y, Jin N, Zhu Y, Zhu G, Sun L, Li X. Inhibitory Effects of Esculetin on Liver Cancer Through Triggering NCOA4 Pathway-Mediation Ferritinophagy in vivo and in vitro. J Hepatocell Carcinoma 2023; 10:611-629. [PMID: 37069958 PMCID: PMC10105581 DOI: 10.2147/jhc.s395617] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 01/18/2023] [Indexed: 04/19/2023] Open
Abstract
Objective To explore the effects of Esculetin on liver cancer and explore potential mechanisms of Esculetin-inducing cells death. Methods Esculetin's effects on the proliferation, migration and apoptosis of HUH7 and HCCLM3 cells were detected by using CCK8, crystal violet staining, wound healing, TranswellTM and Annexin V-FITC/PI. Flow cytometry, fluorescence staining, Western blot, T-AOC, DPPH radical scavenging assay, hydroxyl radical's inhibitory capability and GSH test were used to examine the esculetin's effects on the ROS level, the oxidation-related substances and proteins' expression in hepatoma cells. In vivo experiment was performed by xenograft model. Ferrostatin-1 was used to determine the death way of hepatoma cells induced by esculetin. Live cell probe, Western blot, Fe2+ content, MDA, HE staining, Prussian blue staining and immunohistochemistry were used to examine the ferritinophagy-related phenomenon induced by esculetin in hepatoma cells. The relationship between esculetin and NCOA4-mediated ferritinophagy was confirmed through gene silence and overexpression, immunofluorescence staining and Western blot. Results Esculetin suppressed the proliferation, migration and apoptosis of HUH7 and HCCLM3 cells significantly, influenced the oxidative stress level, altered the autophagy and iron metabolism levels in cells, and produced a ferritinophagy-related phenomena. Esculetin increased the levels of cellular lipid peroxidation and reactive oxygen species. In vivo, esculetin could decrease tumour volume, promote LC3 and NCOA4 expressions, suppresse hydroxyl radical's inhibiting capacity and GSH, increase Fe2+ and MDA levels, decrease antioxidant proteins expression in tumour tissue. In addition, Esculetin could also increase the iron deposition of tumour tissues, promote ferritinophagy, and induce tumours' ferroptosis. Conclusion Esculetin has an inhibitory effect on liver cancer in vivo and in vitro through triggering NCOA4 pathway-mediation ferritinophagy.
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Affiliation(s)
- Zhiru Xiu
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, People’s Republic of China
| | - Yiquan Li
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, People’s Republic of China
| | - Jinbo Fang
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, People’s Republic of China
| | - Jicheng Han
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, People’s Republic of China
| | - Shanzhi Li
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, People’s Republic of China
| | - Yaru Li
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, People’s Republic of China
- Medical College, Yanbian University, Yanji, People’s Republic of China
| | - Xia Yang
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, People’s Republic of China
| | - Gaojie Song
- Medical College, Jiujiang· University, Jiujiang, People’s Republic of China
| | - Yue Li
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, People’s Republic of China
| | - Ningyi Jin
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, People’s Republic of China
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, People’s Republic of China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, People’s Republic of China
| | - Yilong Zhu
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, People’s Republic of China
| | - Guangze Zhu
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, People’s Republic of China
| | - Lili Sun
- Department of Head and Neck Surgery, Tumor Hospital of Jilin Province, Changchun, People’s Republic of China
- Correspondence: Lili Sun; Xiao Li, Boshuo Road, 1035, Jingyue Economic & Technological Development Zone, Changchun, Jilin, 130122, People’s Republic of China, Tel +86-431-86985923, Fax +86-431-87985861, Email ;
| | - Xiao Li
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, People’s Republic of China
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, People’s Republic of China
- College of Life Sciences, Shandong Normal University, Jinan, People’s Republic of China
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Li X, Sun X, Wang B, Li Y, Tong J. Oncolytic virus-based hepatocellular carcinoma treatment: Current status, intravenous delivery strategies, and emerging combination therapeutic solutions. Asian J Pharm Sci 2023; 18:100771. [PMID: 36896445 PMCID: PMC9989663 DOI: 10.1016/j.ajps.2022.100771] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 10/24/2022] [Accepted: 12/04/2022] [Indexed: 12/30/2022] Open
Abstract
Current treatments for advanced hepatocellular carcinoma (HCC) have limited success in improving patients' quality of life and prolonging life expectancy. The clinical need for more efficient and safe therapies has contributed to the exploration of emerging strategies. Recently, there has been increased interest in oncolytic viruses (OVs) as a therapeutic modality for HCC. OVs undergo selective replication in cancerous tissues and kill tumor cells. Strikingly, pexastimogene devacirepvec (Pexa-Vec) was granted an orphan drug status in HCC by the U.S. Food and Drug Administration (FDA) in 2013. Meanwhile, dozens of OVs are being tested in HCC-directed clinical and preclinical trials. In this review, the pathogenesis and current therapies of HCC are outlined. Next, we summarize multiple OVs as single therapeutic agents for the treatment of HCC, which have demonstrated certain efficacy and low toxicity. Emerging carrier cell-, bioengineered cell mimetic- or nonbiological vehicle-mediated OV intravenous delivery systems in HCC therapy are described. In addition, we highlight the combination treatments between oncolytic virotherapy and other modalities. Finally, the clinical challenges and prospects of OV-based biotherapy are discussed, with the aim of continuing to develop a fascinating approach in HCC patients.
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Affiliation(s)
- Xinguo Li
- The First Hospital of China Medical University, Shenyang 110001, China
| | - Xiaonan Sun
- The 4th People's Hospital of Shenyang, Shenyang 110031, China
| | - Bingyuan Wang
- The First Hospital of China Medical University, Shenyang 110001, China
| | - Yiling Li
- The First Hospital of China Medical University, Shenyang 110001, China
| | - Jing Tong
- The First Hospital of China Medical University, Shenyang 110001, China
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Hu L, Zheng Y, Lin J, Shi X, Wang A. Comparison of the effects of lenvatinib and sorafenib on survival in patients with advanced hepatocellular carcinoma: A systematic review and meta-analysis. Clin Res Hepatol Gastroenterol 2023; 47:102061. [PMID: 36473632 DOI: 10.1016/j.clinre.2022.102061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Accepted: 12/02/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM The first-line systemic therapy for advanced hepatocellular carcinoma (HCC) involves the use of sorafenib and lenvatinib. The present meta-analysis attempted to compare the therapeutic safety and effectiveness of the two drugs in advanced HCC. METHODS The library databases of Cochrane, Embase, PubMed, and Web of Science were systematically searched to identify eligible studies comparing the long-term outcomes of sorafenib and lenvatinib use in advanced HCC patients. Overall survival (OS) was considered the primary endpoint, whereas the progression-free survival (PFS), severe adverse events (AEs), objective response rate (ORR), and disease control rate (DCR) were considered the secondary endpoints. RESULTS The present systematic review included 8 nonrandomized studies and 1 randomized controlled trial, comprising a total of 1, 914 cases. OS in patients receiving lenvatinib was better than that in patients receiving sorafenib [hazard ratio (HR): 1.23; 95% confidence interval (CI): 1.04-1.45]. Additionally, patients who received lenvatinib exhibited better PFS, ORR, and DCR (HR: 0.89, 95% CI: 0.79-0.99), [odds ratio (OR: 7.50, 95% CI: 4.43-12.69)], (OR: 7.50, 95% CI: 4.43-12.69), but higher incidences of AEs than those receiving sorafenib (OR: 1.28, 95% CI: 1.08-1.53). CONCLUSION Lenvatinib is superior to sorafenib in treating unresectable HCC patients.
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Affiliation(s)
- Lingbo Hu
- Department of Hepatopancreatobiliary Surgery, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Zhejiang, China; Department of Hepatopancreatobiliary Surgery, Enze Hospital, Taizhou Enze Medical Center (Group), Zhejiang, China
| | - Yu Zheng
- Department of Rehabilitation Medicine, the First Affiliated Hospital of Nanjing Medical University, Jiangsu, China
| | - Jiangyin Lin
- Department of Blood Purification, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Zhejiang, China
| | - Xingpeng Shi
- Department of Hepatopancreatobiliary Surgery, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Zhejiang, China; Department of Hepatopancreatobiliary Surgery, Enze Hospital, Taizhou Enze Medical Center (Group), Zhejiang, China
| | - Aidong Wang
- Department of Hepatopancreatobiliary Surgery, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Zhejiang, China; Department of Hepatopancreatobiliary Surgery, Enze Hospital, Taizhou Enze Medical Center (Group), Zhejiang, China.
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11
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Persano M, Casadei-Gardini A, Burgio V, Scartozzi M, Cascinu S, Rimini M. Five years of lenvatinib in hepatocellular carcinoma: are there any predictive and/or prognostic factors? Expert Rev Anticancer Ther 2023; 23:19-27. [PMID: 36472371 DOI: 10.1080/14737140.2023.2156340] [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: 12/12/2022]
Abstract
INTRODUCTION Lenvatinib was the first drug approved in 2017 for first-line treatment of hepatocarcinoma (HCC) after 10 years of Sorafenib as exclusive standard of care. The therapeutic armamentarium has recently expanded following the approval of atezolizumab plus bevacizumab. AREAS COVERED Numerous studies have been conducted during the past 5 years on Lenvatinib use in real-world settings in an effort to determine prognostic and predictive factors of Lenvatinib efficacy. In order to choose the most effective therapeutic approach, it may be helpful to summarize these results in this review. EXPERT OPINION A subgroup that appears to benefit most from Lenvatinib therapy are patients with non-viral cirrhosis. This aspect is of great importance today considering the increase in NASH prevalence. Also, a significant proportion of BCLC B patients appear to respond well to Lenvatinib therapy. The biological heterogeneity highlighted in HCC patients, along with the growing number of therapeutic options, makes the identification of stratification tools able to define which patients are more likely to respond to a treatment rather than another one of crucial interest. Further investigation deepening the biological pathways underlying HCC carcinogenesis are of particular interest in order to pave the way for precision medicine even for HCC patients.
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Affiliation(s)
- Mara Persano
- Medical Oncology, University Hospital of Cagliari, Milan, Italy
| | - Andrea Casadei-Gardini
- Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | - Valentina Burgio
- IRCCS San Raffaele Scientific Institute Hospital, Department of Oncology, Vita-Salute San Raffaele University, Milan, Italy
| | - Mario Scartozzi
- Medical Oncology, University Hospital of Cagliari, Milan, Italy
| | - Stefano Cascinu
- Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | - Margherita Rimini
- IRCCS San Raffaele Scientific Institute Hospital, Department of Oncology, Vita-Salute San Raffaele University, Milan, Italy
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12
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Wang J, Wu R, Sun JY, Lei F, Tan H, Lu X. An overview: Management of patients with advanced hepatocellular carcinoma. Biosci Trends 2022; 16:405-425. [PMID: 36476621 DOI: 10.5582/bst.2022.01109] [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: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) has constituted a significant health burden worldwide, and patients with advanced HCC, which is stage C as defined by the Barcelona Clinic Liver Cancer staging system, have a poor overall survival of 6-8 months. Studies have indicated the significant survival benefit of treatment based on sorafenib, lenvatinib, or atezolizumab-bevacizumab with reliable safety. In addition, the combination of two or more molecularly targeted therapies (first- plus second-line) has become a hot topic recently and is now being extensively investigated in patients with advanced HCC. In addition, a few biomarkers have been investigated and found to predict drug susceptibility and prognosis, which provides an opportunity to evaluate the clinical benefits of current therapies. In addition, many therapies other than tyrosine kinase inhibitors that might have additional survival benefits when combined with other therapeutic modalities, including immunotherapy, transarterial chemoembolization, radiofrequency ablation, hepatectomy, and chemotherapy, have also been examined. This review provides an overview on the current understanding of disease management and summarizes current challenges with and future perspectives on advanced HCC.
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Affiliation(s)
- Jincheng Wang
- The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu, China.,Graduate School of Biomedical Science and Engineering, Hokkaido University, Sapporo, Japan
| | - Rui Wu
- The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jin-Yu Sun
- The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Feifei Lei
- Department of Infectious Diseases, Liver Disease Laboratory, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - Huabing Tan
- Department of Infectious Diseases, Liver Disease Laboratory, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - Xiaojie Lu
- Department of General Surgery, Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
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13
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Luo J, Gao B, Lin Z, Fan H, Ma W, Yu D, Yang Q, Tian J, Yang X, Li B. Efficacy and safety of lenvatinib versus sorafenib in first-line treatment of advanced hepatocellular carcinoma: A meta-analysis. Front Oncol 2022; 12:1010726. [PMID: 36620586 PMCID: PMC9814719 DOI: 10.3389/fonc.2022.1010726] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 12/06/2022] [Indexed: 12/24/2022] Open
Abstract
Objective Lenvatinib and sorafenib are first-line oral multikinase inhibitors approved for the treatment of advanced hepatocellular carcinoma (HCC). However, the choice of the primary therapeutic agent among these two remains controversial. This meta-analysis aimed to estimate the efficacy and safety of lenvatinib and sorafenib in patients with advanced HCC. Methods PubMed, Cochrane Library, Web of Science, and Embase databases were searched for relevant research published up to June 30, 2022. After quality assessment and data extraction of the included studies, RevMan 5.3 software was used for analysis. Odds ratio (OR) and hazard ratio (HR) with a 95% confidence interval (CI) were calculated using a fixed-effects or random-effects model. Results Fifteen studies containing 3908 patients were included after final scrutiny. Our meta-analysis showed that there was no significant difference in overall survival (OS) between the lenvatinib and sorafenib groups (HR = 0.86; 95% CI: 0.72-1.02; p = 0.09); however, the progression-free survival (PFS) (HR = 0.63; 95% CI: 0.53-0.74; p < 0.00001), complete response (CR) (OR = 5.61; 95% CI: 2.71-11.64; p < 0.00001), partial response (PR) (OR = 4.62; 95% CI: 3.06-6.98; p < 0.00001), objective response rate (ORR) (OR = 5.61; 95% CI: 3.90-8.09; p < 0.00001), and disease control rate (DCR) (OR = 2.42; 95% CI: 1.79-3.28; p < 0.00001) in the lenvatinib group were significantly better than those in the sorafenib group. In terms of treatment safety, lenvatinib had similar incidences of any grade adverse events (AEs) (OR = 0.99; 95% CI: 0.47-2.09; p = 0.98) and grade ≥ 3 AEs (OR = 1.17, 95% CI; 1.00-1.37; p = 0.05) compared to sorafenib. Besides, lenvatinib was significantly associated with a higher incidence of hypertension, proteinuria, fatigue, decreased appetite, and weight loss, whereas sorafenib was associated with a higher incidence of diarrhea and hand-foot skin reaction (p < 0.05). Conclusion Given its potential survival benefit and good tolerability, lenvatinib is an appropriate and promising alternative to sorafenib as first-line systemic therapy in patients with advanced HCC. Systematic review registration https://www.crd.york.ac.uk/prospero/, identifier: CRD 42022327398.
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Affiliation(s)
- Jia Luo
- Department of Oncology and Hematology, People’s Hospital of Leshan, Leshan, China,*Correspondence: Jia Luo, ; Bo Li,
| | - Benjian Gao
- Department of General Surgery (Hepatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, China,Academician (Expert) Workstation of Sichuan Province, Luzhou, China
| | - Zhiyu Lin
- Department of Oncology and Hematology, People’s Hospital of Leshan, Leshan, China
| | - Hua Fan
- Department of Oncology and Hematology, People’s Hospital of Leshan, Leshan, China
| | - Wen Ma
- Department of Oncology and Hematology, People’s Hospital of Leshan, Leshan, China
| | - Danfei Yu
- Department of Oncology and Hematology, People’s Hospital of Leshan, Leshan, China
| | - Qian Yang
- Department of Oncology and Hematology, People’s Hospital of Leshan, Leshan, China
| | - Jing Tian
- Department of Oncology and Hematology, People’s Hospital of Leshan, Leshan, China
| | - Xiaoli Yang
- Department of General Surgery (Hepatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, China,Academician (Expert) Workstation of Sichuan Province, Luzhou, China
| | - Bo Li
- Department of General Surgery (Hepatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, China,Academician (Expert) Workstation of Sichuan Province, Luzhou, China,*Correspondence: Jia Luo, ; Bo Li,
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Li Q, Su T, Zhang X, Pan Y, Ma S, Zhang L, Zhang X, Gao X. A Real-World Study of Optimal Treatment with Anlotinib First-Line Therapy in Advanced Hepatocellular Carcinoma. Cancer Manag Res 2022; 14:3037-3046. [PMID: 36275784 PMCID: PMC9580834 DOI: 10.2147/cmar.s379911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 09/29/2022] [Indexed: 12/24/2022] Open
Abstract
Purpose To observe the efficacy and safety of anlotinib as a first-line treatment for patients with advanced hepatocellular carcinoma (aHCC) in a real-word environment, explore the optimal treatment regimen for patients with aHCC using anlotinib as a first-line treatment. Patients and Methods Data from 62 patients with aHCC who received anlotinib single-drug first-line therapy between February 2019 and November 2021. Patients received anlotinib monotherapy, which may be interrupted or discontinued or changed in the event of unacceptable or severe adverse events (AEs) or failure to inhibit tumor progression. The primary endpoint was progression-free survival (PFS) and the secondary endpoints were objective response rate(ORR), disease control rate (DCR), overall survival (OS), and safety. Results Among the 62 patients, in the best overall response assessment, there were 12 with complete response (CR; 19.4%), 17 with partial response (PR; 27.4%), 25 with stable disease (SD; 40.3%), and 8 with progressive disease (PD; 14.5%). The ORR and DCR were 46.8% and 87.1%, respectively. Among the 11 patients who received tyrosine kinase inhibitors (TKIs) combined with programmed death 1 (PD-1) inhibitors after disease progression, three (27.3%) had CR, one (9.1%) had PR, three (27.3%) had SD, and four (36.4%) had PD. Therefore, the ORR and DCR were 36.4% and 63.6%, respectively. The median PFS for anlotinib monotherapy was 7.37 months (95% confidence interval [CI]: 5.88–8.86) and the median OS did not reach. AEs occurred in 95.2% of patients during anlotinib monotherapy, with the most common being thrombocytopenia (51.6%). The incidence of grade ≥3 AEs was 38.7%. Conclusion Anlotinib is effective and well-tolerated as a first-line treatment for patients with aHCC. Treatment with TKIs and PD-1 inhibitors after disease progression has also shown preliminary efficacy and safety; therefore, sequential therapy with anlotinib-TKIs and PD-1 inhibitors may be an effective treatment for patients with aHCC.
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Affiliation(s)
- Qingqing Li
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou city, People’s Republic of China
| | - Tong Su
- Department of Medical, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou city, People’s Republic of China
| | - Xu Zhang
- Department of Hepatobiliary Pancreatic Surgery, Zhengzhou University People’s Hospital, Henan Provincial People’s Hospital, Zhengzhou city, People’s Republic of China
| | - Yanfeng Pan
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou city, People’s Republic of China,Correspondence: Yanfeng Pan, Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Jinshui District, Zhengzhou city, 450000, People’s Republic of China, Tel +8613938448759, Email
| | - Shengli Ma
- Department of Infectious Diseases, The People’s Hospital of Yongcheng, Yongcheng city, People’s Republic of China
| | - Lu Zhang
- Department of Infectious Diseases, The People’s Hospital of Yongcheng, Yongcheng city, People’s Republic of China
| | - Xianqiang Zhang
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou city, People’s Republic of China
| | - Xiaojuan Gao
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou city, People’s Republic of China
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15
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Zhang JX, Chen YX, Zhou CG, Liu J, Liu S, Shi HB, Zu QQ. Transarterial chemoembolization combined with lenvatinib versus transarterial chemoembolization combined with sorafenib for unresectable hepatocellular carcinoma: A comparative retrospective study. Hepatol Res 2022; 52:794-803. [PMID: 35698267 DOI: 10.1111/hepr.13801] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Revised: 05/31/2022] [Accepted: 06/03/2022] [Indexed: 12/15/2022]
Abstract
AIM Tyrosine kinase inhibitors target transarterial chemoembolization (TACE)-mediated vascular endothelial growth factor to inhibit tumor revascularization and to slow tumor progression. The present study aimed to compare the clinical outcomes of TACE combined with lenvatinib (TACE-lenvatinib) and TACE combined with sorafenib (TACE-sorafenib) in patients with unresectable hepatocellular carcinoma (HCC). METHODS The clinical data of patients diagnosed with unresectable HCC who received TACE-lenvatinib or TACE-sorafenib between January 2018 and April 2021 were retrospectively reviewed. The tumor response, progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were evaluated and compared between the two groups. RESULTS A total of 112 patients were enrolled and classified into the TACE-lenvatinib group (n = 53) and the TACE-sorafenib group (n = 59). The objective response rates of patients in the TACE-lenvatinib and TACE-sorafenib groups were 54.7% and 44.1%, respectively (p = 0.260), and the disease control rates (DCRs) were 81.1% and 61.0% (p = 0.020). The median PFS time was significantly longer in the TACE-lenvatinib group than in the TACE-sorafenib group (10.7 vs. 6.0 months; p = 0.002). The median OS time between the TACE-lenvatinib and TACE-sorafenib groups also showed a significant difference (30.5 vs. 20.5 months, p = 0.018). All treatment-related AEs and grade 3/4 AEs were comparable between the two groups (p > 0.05). CONCLUSION Compared to TACE-sorafenib, TACE-lenvatinib was associated with better DCR, PFS and OS outcomes in patients with unresectable HCC. In subgroups of Barcelona Clinic Liver Cancer B stage or TACE-refractory patients, TACE-lenvatinib also showed a trend of superiority.
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Affiliation(s)
- Jin-Xing Zhang
- Department of Interventional Radiology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Yu-Xing Chen
- Department of Interventional Radiology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Chun-Gao Zhou
- Department of Interventional Radiology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Jin Liu
- Department of Clinical Medicine Research Institution, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Sheng Liu
- Department of Interventional Radiology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Hai-Bin Shi
- Department of Interventional Radiology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Qing-Quan Zu
- Department of Interventional Radiology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
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16
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Efficacy of Transarterial Chemoembolization Combined with Molecular Targeted Agents for Unresectable Hepatocellular Carcinoma: A Network Meta-Analysis. Cancers (Basel) 2022; 14:cancers14153710. [PMID: 35954373 PMCID: PMC9367476 DOI: 10.3390/cancers14153710] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 07/20/2022] [Accepted: 07/27/2022] [Indexed: 12/09/2022] Open
Abstract
Simple Summary Liver cancer is the second most common cause of cancer-related death, with hepatocellular carcinoma (HCC) being the most prevalent subtype. Transarterial chemoembolization (TACE) in combination with different tyrosine kinase inhibitors (TKIs) has recently been widely used for unresectable HCC (uHCC). However, studies investigating different combinations of agents have shown inconsistent results. Thus, we conducted a network meta-analysis to assess and compare the response of different agents in an uHCC setting. According to our results, TACE plus lenvatinib provides optimal treatment for uHCC, with the highest ranking based on OS, PFS, and DCR rates and the second-best ranking based on ORR rates. Abstract Transarterial chemoembolization (TACE) combined with tyrosine kinase inhibitors (TKIs) is the mainstay treatment for unresectable hepatocellular carcinoma (uHCC). However, studies investigating different combinations of agents have shown inconsistent results. Here, we used network meta-analysis (NMA) to compare different agents across 41 studies (36 cohort studies and five RCTs) in 11,540 patients. Multiple RCTs and cohort studies were searched to evaluate TACE combined with different TKIs. Outcomes of interest included overall survival (OS), progression-free survival (PFS), and tumor response. NMA used a random-effects consistency model to pool evidence from direct and indirect comparisons. Hazard ratio (HR) and relative risks (RR) with 95% confidence intervals (CI) were analyzed. Further, heterogeneity and publication bias analyses were performed and agents were ranked. TACE plus lenvatinib provided the maximal OS (Rank probability: 0.7559), PFS (Rank probability: 0.8595), CR (Rank probability: 0.4179), and DCR (Rank probability: 0.3857). TACE plus anlotinib demonstrated the highest PR (p = 0.62649) and ORR (p = 0.51158). SD was more often associated with TACE plus sorafenib (Rank probability: 0.601685). TACE plus lenvatinib provides optimal treatment for uHCC based on the highest ranking of OS, PFS, and DCR rates. However, given the lack of statistically significant OS benefit, shared decision making should include other TKIs as acceptable alternatives.
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Yasui Y, Kurosaki M, Tsuchiya K, Hayakawa Y, Hasebe C, Abe M, Ogawa C, Joko K, Ochi H, Tada T, Nakamura S, Furuta K, Kimura H, Tsuji K, Kojima Y, Akahane T, Tamada T, Uchida Y, Kondo M, Mitsuda A, Izumi N. Real-World Data on Ramucirumab Therapy including Patients Who Experienced Two or More Systemic Treatments: A Multicenter Study. Cancers (Basel) 2022; 14:cancers14122975. [PMID: 35740647 PMCID: PMC9221496 DOI: 10.3390/cancers14122975] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Revised: 06/11/2022] [Accepted: 06/14/2022] [Indexed: 02/01/2023] Open
Abstract
Simple Summary Ramucirumab has been shown to be effective as a second-line agent after sorafenib in hepatocellular carcinoma (HCC) patients whose α-fetoprotein was ≥400 ng/mL. We performed a retrospective cohort study to investigate ramucirumab efficacy in a real-world setting. Progression-free survival (PFS) was consistent through treatment lines, modified albumin–bilirubin (mALBI) grade, Barcelona Clinic for Liver Cancer (BCLC) stage, and α-fetoprotein (AFP) level. By contrast, ascites was more frequently seen in mALBI 2b/3 patients and, therefore, should be carefully monitored. Abstract Background: The present study aimed to clarify the efficacy and safety of ramucirumab in a real-world setting, including patients who experienced two or more systemic treatments or whose hepatic reserve was deteriorated. Methods: In total, 79 patients with hepatocellular carcinoma (HCC) from 14 institutes throughout Japan were retrospectively analyzed. The response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and AEs were recorded according to the Common Terminology Criteria for AEs (CTCAE) version 5.0. Results: Median overall survival (OS) in the total cohort was 7.5 months (m). Median OS was 8.8 m in patients who were administered ramucirumab as a second-line treatment, while it was 7.3 m in third- or later-line treatment. Progression-free survival rates in the second- and third- or later-line therapies were 3.2 m and 3.2 m, respectively. The disease control rate (DCR) in the study was 43%. There were no statistically significant differences in DCR between the treatment courses. Regarding adverse events (AEs), the development of ascites was observed significantly more frequently in modified albumin–bilirubin (mALBI) 2b/3 patients than in mALBI 1/2a patients (54.5% vs. 25.0%, p = 0.03). Conclusions: Ramucirumab is useful as a second-line therapy and feasible as a third- or later-line treatment for HCC.
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Affiliation(s)
- Yutaka Yasui
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (Y.Y.); (M.K.); (K.T.); (Y.H.)
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (Y.Y.); (M.K.); (K.T.); (Y.H.)
| | - Kaoru Tsuchiya
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (Y.Y.); (M.K.); (K.T.); (Y.H.)
| | - Yuka Hayakawa
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (Y.Y.); (M.K.); (K.T.); (Y.H.)
| | - Chitomi Hasebe
- Department of Gastroenterology, Japanese Red Cross Asahikawa Hospital, Asahikawa 070-8530, Japan; (C.H.); (M.A.)
| | - Masami Abe
- Department of Gastroenterology, Japanese Red Cross Asahikawa Hospital, Asahikawa 070-8530, Japan; (C.H.); (M.A.)
| | - Chikara Ogawa
- Department of Gastroenterology, Takamatsu Red Cross Hospital, Takamatsu 760-0017, Japan;
| | - Kouji Joko
- Center for Liver-Biliary-Pancreatic Disease, Matsuyama Red Cross Hospital, Matsuyama 790-8524, Japan; (K.J.); (H.O.)
| | - Hironori Ochi
- Center for Liver-Biliary-Pancreatic Disease, Matsuyama Red Cross Hospital, Matsuyama 790-8524, Japan; (K.J.); (H.O.)
| | - Toshifumi Tada
- Department of Gastroenterology, Japanese Red Cross Society Himeji Hospital, Himeji 670-8540, Japan; (T.T.); (S.N.)
| | - Shinichiro Nakamura
- Department of Gastroenterology, Japanese Red Cross Society Himeji Hospital, Himeji 670-8540, Japan; (T.T.); (S.N.)
| | - Koichiro Furuta
- Department of Internal Medicine, Masuda Red Cross Hospital, Masuda 698-8501, Japan;
| | - Hiroyuki Kimura
- Department of Gastroenterology, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto 605-0981, Japan;
| | - Keiji Tsuji
- Department of Gastroenterology, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Hiroshima 730-8619, Japan;
| | - Yuji Kojima
- Department of Gastroenterology, Japanese Red Cross Ise Hospital, Ise 516-8512, Japan;
| | - Takehiro Akahane
- Department of Gastroenterology, Ishinomaki Red Cross Hospital, Ishinomaki 986-8522, Japan;
| | - Takashi Tamada
- Department of Gastroenterology, Takatsuki Red Cross Hospital, Takatsuki 569-1096, Japan;
| | - Yasushi Uchida
- Department of Gastroenterology, Matsue Red Cross Hospital, Matsue 690-8506, Japan;
| | - Masahiko Kondo
- Department of Gastroenterology, Otsu Red Cross Hospital, Otsu 520-8511, Japan;
| | - Akeri Mitsuda
- Department of Internal Medicine, Japanese Red Cross Tottori Hospital, Tottori 680-8517, Japan;
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan; (Y.Y.); (M.K.); (K.T.); (Y.H.)
- Correspondence:
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D'Avola D, Granito A, Torre-Aláez MDL, Piscaglia F. The importance of liver functional reserve in the non-surgical treatment of hepatocellular carcinoma. J Hepatol 2022; 76:1185-1198. [PMID: 34793869 DOI: 10.1016/j.jhep.2021.11.013] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 11/02/2021] [Accepted: 11/05/2021] [Indexed: 02/08/2023]
Abstract
The aim of any oncological treatment is not just to eliminate the tumour, but to maximise patient survival and quality of life. Since the liver has a vital function, any radical treatment that severely compromises liver function will result in a shortening of life expectancy, rather than a prolongation. Furthermore, even non-severe liver damage may prevent the delivery of further effective therapies. This is particularly important in the case of hepatocellular carcinoma (HCC), as it is associated with underlying cirrhosis in most patients - cirrhosis itself is not only a potentially lethal disease and independent prognostic factor in HCC, but it also makes liver function fragile. Accordingly, some information about liver dysfunction is included in most staging systems for HCC and can be used to guide the selection of treatments that the functional liver reserve can tolerate. Unfortunately, the prediction of functional damage to the liver in the case of antitumor treatments is very challenging and still suboptimal in any given patient. Moreover, while the assessment of functional reserve can now be used to avoid postoperative liver failure in the surgical setting, its use has been less well clarified for non-surgical therapies, which is of particular relevance today, as several lines of effective non-surgical treatments, including systemic therapies, have become available. The present article will a) critically review the implications of the assessment of liver functional reserve in patients with HCC, b) illustrate the available tools to assess liver functional reserve and c) discuss the role of functional assessment for each type of non-surgical therapy for HCC.
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Affiliation(s)
- Delia D'Avola
- Liver Unit, Internal Medicine Department, Clinica Universidad de Navarra, Pamplona and Madrid, Spain; Centro de Investigación Bio Medica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Pamplona, Spain
| | - Alessandro Granito
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy; Department of Medical and Surgical Sciences, University of Bologna, Italy
| | - Manuel de la Torre-Aláez
- Liver Unit, Internal Medicine Department, Clinica Universidad de Navarra, Pamplona and Madrid, Spain
| | - Fabio Piscaglia
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy; Department of Medical and Surgical Sciences, University of Bologna, Italy.
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19
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Li Q, Cao M, Yuan G, Cheng X, Zang M, Chen M, Hu X, Huang J, Li R, Guo Y, Ruan J, Chen J. Lenvatinib Plus Camrelizumab vs. Lenvatinib Monotherapy as First-Line Treatment for Unresectable Hepatocellular Carcinoma: A Multicenter Retrospective Cohort Study. Front Oncol 2022; 12:809709. [PMID: 35280760 PMCID: PMC8907842 DOI: 10.3389/fonc.2022.809709] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 01/26/2022] [Indexed: 12/11/2022] Open
Abstract
Background Combining an antiangiogenic agent with an anti-PD-1 agent is a promising strategy for unresectable hepatocellular carcinoma (HCC). Aims To explore the effectiveness and tolerability of lenvatinib plus camrelizumab vs. lenvatinib monotherapy as a first-line treatment for unresectable HCC. Methods This multicenter, retrospective cohort study included patients with unresectable HCC treated with oral lenvatinib 8 mg daily and intravenous camrelizumab 200 mg every 3 weeks (L+C group) or lenvatinib 12 mg or 8 mg daily (L group) in four Chinese centers between September 2018 and February 2020. Tumor response was evaluated according to RECIST 1.1 and mRECIST. The outcomes included objective response rate (ORR), overall survival (OS), 1-year OS rate, progression-free survival (PFS), and safety. Results By March 31, 2021, 92 patients were finally included, with 48 and 44 in the L+C and L groups, respectively. ORR was significantly higher in the L+C group than in the L group (RECIST 1.1: 37.5% vs. 13.6%, P=0.009; mRECIST: 41.7% vs. 20.5%, P=0.029). Median OS and 95% confidence interval (CI) was 13.9 (13.3-18.3) months in the L group and not reached in the L+C group (P=0.015). The 1-year survival rate was 79.2% and 56.8% in the L+C and L groups, respectively. Median PFS was 10.3 (6.6-14.0) months and 7.5 (5.7-9.3) months in the L+C and L groups, respectively (P=0.0098). Combined therapy vs. monotherapy was independently associated with a prolonged OS (hazard ratio=0.380, 95% CI=: 0.196-0.739, P=0.004) and a prolonged PFS (hazard ratio=0.454, 95%CI=0.282-0.731, P=0.001). The safety profile was comparable between the two groups. The most common adverse event in the L+C and L groups was loss of appetite (41.7% vs. 40.9%, P=0.941). Three patients in the L+C group and two in the L group terminated treatment owing to adverse events. Conclusion First-line lenvatinib plus camrelizumab showed better effectiveness than lenvatinib alone in patients with unresectable HCC.
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Affiliation(s)
- Qi Li
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Mengran Cao
- Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing University, Nanjing, China
| | - Guosheng Yuan
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiao Cheng
- Zengcheng Branch of Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Mengya Zang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ming Chen
- Department of Medical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaoyun Hu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jing Huang
- Zengcheng Branch of Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Rong Li
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yabing Guo
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jian Ruan
- Department of Medical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Jinzhang Chen
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
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20
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Liu B, Shang X, Shi JY, Cui GZ, Li X, Wang NY. Early Alpha-Fetoprotein Response Is Associated With Survival in Patients With HBV-Related Hepatocellular Carcinoma Receiving Lenvatinib. Front Oncol 2022; 12:807189. [PMID: 35251977 PMCID: PMC8893311 DOI: 10.3389/fonc.2022.807189] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 01/26/2022] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND/PURPOSE Lenvatinib is a first-line treatment for unresectable hepatocellular carcinoma (uHCC). We assessed the value of early alpha-fetoprotein (AFP) response for predicting clinical outcomes with lenvatinib treatment in patients with HBV-related uHCC and elevated AFP levels. METHODS This retrospective analysis included patients with HBV-related uHCC and baseline AFP levels ≥20 ng/ml who received lenvatinib for >1 month between November 2018 and May 2021. Early AFP response was defined as a >20% decrease in AFP serum level from baseline after 4 weeks of lenvatinib treatment. Radiological response (Response Evaluation Criteria in Solid Tumors v1.1), progression-free survival, and overall survival were assessed in AFP responders and non-responders. RESULTS Of the 46 patients analyzed, 30 (65.2%) were early AFP responders and 16 (34.8%) were non-responders. Compared to the non-responders, early AFP responders had a significantly higher objective response rate (34.5% vs 6.3%, p=0.0349), disease control rate (82.8% vs 50.0%; p=0.0203) and longer median progression-free survival (13.0 vs 7.0 months; HR, 0.464; 95% CI, 0.222-0.967; p=0.028). A subsequent multivariate analysis confirmed that early AFP response (HR, 0.387; 95% CI, 0.183-0.992; p=0.0154), Eastern Cooperative Oncology Group Performance Status of 0 (HR, 0.890; 95% CI, 0.811-0.976; p=0.0132) and Albumin-Bilirubin grade 1 (HR, 0.457; 95% CI, 0.269-0.963; p=0.0327) were independent prognostic factors for longer progression-free survival. CONCLUSION AFP is an important prognostic factor and a predictive biomarker for survival benefit with lenvatinib treatment in patients with HBV-related uHCC.
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Affiliation(s)
| | | | | | | | | | - Nan-Ya Wang
- The Cancer Center, First Hospital of Jilin University, Changchun, China
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Sho T, Morikawa K, Kubo A, Tokuchi Y, Kitagataya T, Yamada R, Shigesawa T, Kimura M, Nakai M, Suda G, Natsuizaka M, Ogawa K, Sakamoto N. Prospect of lenvatinib for unresectable hepatocellular carcinoma in the new era of systemic chemotherapy. World J Gastrointest Oncol 2021; 13:2076-2087. [PMID: 35070043 PMCID: PMC8713309 DOI: 10.4251/wjgo.v13.i12.2076] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 07/08/2021] [Accepted: 09/17/2021] [Indexed: 02/06/2023] Open
Abstract
The phase III clinical trial of the novel molecular targeted agent (MTA) lenvatinib for patients with advanced hepatocellular carcinoma (HCC) (REFLECT trial) found that lenvatinib was non-inferior to sorafenib in overall survival. Recently, the efficacy of multiple MTAs, including lenvatinib, in practice has been reported, and therapeutic strategies for Barcelona Clinic Liver Cancer (BCLC) intermediate stage HCC are undergoing major changes. Based on these results, lenvatinib could be recommended for patients with transcatheter arterial chemoembolization (TACE)-refractory, ALBI grade 1, within the up-to-seven criteria in the BCLC intermediate stage. Lenvatinib provides a more favorable outcome than TACE, even in cases with large or multinodular HCC beyond the up-to-seven criteria with Child-Pugh grade A. When patients meet the definitions of TACE-refractory or TACE-unsuitable, switching to systemic chemotherapy, including lenvatinib, is for favorable for preserving liver function. If initial treatment, including MTA, has a significant therapeutic effect and downstaging of HCC is obtained, additional TACE or surgical resection should be considered. Lenvatinib also has a therapeutic effect for poorly differentiated type and non-simple nodular type HCC thanks to the survival-prolonging effect of this drug. Furthermore, a significant therapeutic effect is expected in tumors with more than 50% liver involvement or main portal vein invasion, which have traditionally been considered to have a poor prognosis in patients. This suggests that at the start of lenvatinib treatment, HCC patients with ALBI grade 1 may be able to maintain liver functional reserve.
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Affiliation(s)
- Takuya Sho
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Hokkaido, Japan
| | - Kenichi Morikawa
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Hokkaido, Japan
| | - Akinori Kubo
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Hokkaido, Japan
| | - Yoshimasa Tokuchi
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Hokkaido, Japan
| | - Takashi Kitagataya
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Hokkaido, Japan
| | - Ren Yamada
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Hokkaido, Japan
| | - Taku Shigesawa
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Hokkaido, Japan
| | - Mugumi Kimura
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Hokkaido, Japan
| | - Masato Nakai
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Hokkaido, Japan
| | - Goki Suda
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Hokkaido, Japan
| | - Mitsuteru Natsuizaka
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Hokkaido, Japan
| | - Koji Ogawa
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Hokkaido, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Hokkaido, Japan
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22
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Catalano M, Casadei-Gardini A, Vannini G, Campani C, Marra F, Mini E, Roviello G. Lenvatinib: established and promising drug for the treatment of advanced hepatocellular carcinoma. Expert Rev Clin Pharmacol 2021; 14:1353-1365. [PMID: 34289756 DOI: 10.1080/17512433.2021.1958674] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 07/19/2021] [Indexed: 02/07/2023]
Abstract
INTRODUCTION : The evolving therapeutic landscape of advanced hepatocellular carcinoma (HCC) includes the increasing implementation of target-therapy and immunotherapy. Lenvatinib, a multi-target tyrosine kinase inhibitor (TKI), is an emerging first-line therapy for hepatocellular carcinoma. Its approval has changed the scenario of first-line therapies for advanced HCC, where just sorafenib proved clinical efficacy for over a decade. AREAS COVERED : The current evidence on the role of lenvatinib for patients with advanced HCC is reviewed in this article. Particularly, therapeutic mechanisms and clinical efficacy of lenvatinib are summarized and the management of adverse events is discussed. In addition, future perspectives on the emerging role of combine therapy for HCC are highlighted. EXPERT OPINION In the first line, lenvatinib was found to be non-inferior to sorafenib for overall survival, with significantly better progression-free survival and objective response rate. Immune checkpoint inhibitors (ICIs) are now part of HCC treatment, and recently the combination of atezolizumab plus bevacizumab has become the recommended standard of care first-line therapy for selected patients. The antitumor and immunomodulatory activities that lenvatinib shows in preclinical studies, and the positive outcomes achieved using a combination of lenvatinib plus ICIs, open new perspectives for advanced HCC treatment.
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Affiliation(s)
- Martina Catalano
- School of Human Health Sciences, University of Florence, Florence, Italy
| | - Andrea Casadei-Gardini
- Department of Medical Oncology, Università Vita-Salute, San Raffaele Hospital IRCCS, Milan, Italy
| | - Gianmarco Vannini
- School of Human Health Sciences, University of Florence, Florence, Italy
| | - Claudia Campani
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Fabio Marra
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
- Excellence Center for Research, Transfer snd High Education DenoTHE, Florence, Italy
| | - Enrico Mini
- Department of Health Sciences, University of Florence, Florence, Italy
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23
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Liu Z, Liu X, Liang J, Liu Y, Hou X, Zhang M, Li Y, Jiang X. Immunotherapy for Hepatocellular Carcinoma: Current Status and Future Prospects. Front Immunol 2021; 12:765101. [PMID: 34675942 PMCID: PMC8524467 DOI: 10.3389/fimmu.2021.765101] [Citation(s) in RCA: 90] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 09/20/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer with poor prognosis. Surgery, chemotherapy, and radiofrequency ablation are three conventional therapeutic options that will help only a limited percentage of HCC patients. Cancer immunotherapy has achieved dramatic advances in recent years and provides new opportunities to treat HCC. However, HCC has various etiologies and can evade the immune system through multiple mechanisms. With the rapid development of genetic engineering and synthetic biology, a variety of novel immunotherapies have been employed to treat advanced HCC, including immune checkpoint inhibitors, adoptive cell therapy, engineered cytokines, and therapeutic cancer vaccines. In this review, we summarize the current landscape and research progress of different immunotherapy strategies in the treatment of HCC. The challenges and opportunities of this research field are also discussed.
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Affiliation(s)
- Zhuoyan Liu
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Xuan Liu
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jiaxin Liang
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Yixin Liu
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Xiaorui Hou
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Meichuan Zhang
- R&D Department, Caleb BioMedical Technology Co. Ltd, Guangzhou, China
| | - Yongyin Li
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaotao Jiang
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
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24
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Yamamura K, Beppu T. Conversion surgery for hepatocellular carcinoma after multidisciplinary treatment including lenvatinib. Hepatol Res 2021; 51:1029-1030. [PMID: 34596312 DOI: 10.1111/hepr.13691] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Kensuke Yamamura
- Department of Surgery, Yamaga City Medical Center, Kumamoto, Japan
| | - Toru Beppu
- Department of Surgery, Yamaga City Medical Center, Kumamoto, Japan
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25
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Fu Z, Li X, Zhong J, Chen X, Cao K, Ding N, Liu L, Zhang X, Zhai J, Qu Z. Lenvatinib in combination with transarterial chemoembolization for treatment of unresectable hepatocellular carcinoma (uHCC): a retrospective controlled study. Hepatol Int 2021; 15:663-675. [PMID: 33877527 PMCID: PMC8286947 DOI: 10.1007/s12072-021-10184-9] [Citation(s) in RCA: 118] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 03/27/2021] [Indexed: 12/24/2022]
Abstract
PURPOSE To compare the efficacy and safety of combined treatment with lenvatinib and transarterial chemoembolization (TACE) versus TACE only in patients with unresectable hepatocellular carcinoma (uHCC). METHODS Of the 120 patients enrolled in this study, 60 patients received treatment with TACE only, and 60 patients received TACE plus lenvatinib. We retrospectively compared the clinical outcomes including overall survival (OS), progression-free survival (PFS), and tumor response between the two groups. Both PFS and tumor response were based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Adverse events were analyzed to assess the safety profiles. RESULTS The 1-year and 2-year OS rates were significantly higher in the TACE + lenvatinib group (88.4% and 79.8%) than that in the TACE group (79.2% and 49.2%, p = 0.047). A similar PFS benefit was observed in the TACE + lenvatinib group (1-y PFS rate: 78.4% vs. 64.7%, 2-y PFS rate: 45.5% vs. 38.0%, p < 0.001). The best overall objective response rate (ORR) was also better with TACE + lenvatinib treatment (ORR: 68.3% vs. 31.7%, p < 0.001) and disease control rate (DCR) numerically increased in the TACE + lenvatinib treatment (93.3% vs. 86.7%, p = 0.224). Patients' liver function remained comparable to baseline in the TACE + lenvatinib group. The most common adverse events were decreased albumin (55.0%), hypertension (48.3%) and decreased platelet count (46.7%) in the TACE + lenvatinib group. CONCLUSIONS Combination treatment with TACE and lenvatinib may significantly improve clinical outcomes over TACE monotherapy with a manageable safety profile for unresectable HCC. The efficacy of the combination treatment should be validated in prospective studies with a large sample size.
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Affiliation(s)
- Zhigang Fu
- Department II of Interventional Radiology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Xiaowei Li
- Department II of Interventional Radiology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Jiaming Zhong
- Department II of Interventional Radiology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Xiaoxia Chen
- Department II of Interventional Radiology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Kunkun Cao
- Department II of Interventional Radiology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Ning Ding
- Department II of Interventional Radiology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Li Liu
- Department II of Interventional Radiology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Xiaoli Zhang
- Department II of Interventional Radiology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Jian Zhai
- Department II of Interventional Radiology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China.
| | - Zengqiang Qu
- Department II of Interventional Radiology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China.
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26
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Casadei-Gardini A, Scartozzi M, Tada T, Yoo C, Shimose S, Masi G, Lonardi S, Frassineti LG, Nicola S, Piscaglia F, Kumada T, Kim HD, Koga H, Vivaldi C, Soldà C, Hiraoka A, Bang Y, Atsukawa M, Torimura T, Tsuj K, Itobayashi E, Toyoda H, Fukunishi S, Rimassa L, Rimini M, Cascinu S, Cucchetti A. Lenvatinib versus sorafenib in first-line treatment of unresectable hepatocellular carcinoma: An inverse probability of treatment weighting analysis. Liver Int 2021; 41:1389-1397. [PMID: 33547848 DOI: 10.1111/liv.14817] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 01/25/2021] [Accepted: 01/31/2021] [Indexed: 02/05/2023]
Abstract
PURPOSE Data from common clinical practice were used to generate balanced cohorts of patients receiving either sorafenib or lenvatinib, for unresectable hepatocellular carcinoma, with the final aim to investigate their declared equivalence. METHODS Clinical features of lenvatinib and sorafenib patients were balanced through inverse probability of treatment weighting (IPTW) methodology, which weights patients' characteristics and measured outcomes of each patient in both treatment arms. Overall survival was the primary endpoint and occurrence of adverse events was the secondary. RESULTS The analysis included 385 patients who received lenvatinib, and 555 patients who received sorafenib. In the unadjusted cohort, lenvatinib did not show a survival advantage over sorafenib (HR: 0.85, 95% CI 0.70-1.02). After IPTW adjustment, lenvatinib still not returned a survival advantage over sorafenib (HR: 0.82, 95% CI: 0.62-1.07) even in presence of balanced baseline characteristics. Lenvatinib provided longer survival than sorafenib in patients previously submitted to TACE (HR: 0.69), with PS of 0 (HR: 0.73) or without extrahepatic disease (HR: 0.69). CONCLUSION Present results confirmed randomized controlled trial in the real-life setting, but also suggests that in earlier stages some benefit can be expected.
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Affiliation(s)
- Andrea Casadei-Gardini
- Vita-Salute San Rafaele University, Milan, Italy
- Department of Medical Oncology, San Rafaele Scientifc Institute IRCCS, Milan, Italy
| | - Mario Scartozzi
- Department of Medical Oncology, University Hospital of Cagliari, Cagliari, Italy
| | - Toshifumi Tada
- Department of Internal Medicine, Japanese Red Cross Society Himeji Hospital, Himeji, Japan
| | - Changhoon Yoo
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Shigeo Shimose
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Gianluca Masi
- Department of Translational Research and New Surgical and Medical Technologies, University of Pisa, Pisa, Italy
| | - Sara Lonardi
- Medical Oncology Unit 1, Veneto Institute of Oncology IOV - IRCCS, Padova, Italy
| | - Luca Giovanni Frassineti
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Silvestris Nicola
- Medical Oncology Unit, IRCCS IstitutoTumori "Giovanni Paolo II" of Bari, Bari, Italy
- Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro", Bari, Italy
| | - Fabio Piscaglia
- Division of Internal Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Takashi Kumada
- Faculty of Nursing, Gifu Kyoritsu University, Ogaki, Japan
| | - Hyung-Don Kim
- Department of Internal Medicine, Japanese Red Cross Society Himeji Hospital, Himeji, Japan
| | - Hironori Koga
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Caterina Vivaldi
- Department of Translational Research and New Surgical and Medical Technologies, University of Pisa, Pisa, Italy
| | - Caterina Soldà
- Medical Oncology Unit 1, Veneto Institute of Oncology IOV - IRCCS, Padova, Italy
| | - Atsushi Hiraoka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan
| | - Yeonghak Bang
- Department of Internal Medicine, Japanese Red Cross Society Himeji Hospital, Himeji, Japan
| | - Masanori Atsukawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan
| | - Takuji Torimura
- Department of Internal Medicine, Japanese Red Cross Society Himeji Hospital, Himeji, Japan
| | - Kunihiko Tsuj
- Center of Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan
| | - Ei Itobayashi
- Department of Gastroenterology, Asahi General Hospital, Asahi, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Shinya Fukunishi
- Second Department of Internal Medicine, Osaka Medical College, Takatsuki, Japan
| | - Lorenza Rimassa
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Milan, Italy
| | | | - Stefano Cascinu
- Vita-Salute San Rafaele University, Milan, Italy
- Department of Medical Oncology, San Rafaele Scientifc Institute IRCCS, Milan, Italy
| | - Alessandro Cucchetti
- Division of Internal Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
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Wei F, Huang Q, He J, Luo L, Zeng Y. Lenvatinib Plus Camrelizumab versus Lenvatinib Monotherapy as Post-Progression Treatment for Advanced Hepatocellular Carcinoma: A Short-Term Prognostic Study. Cancer Manag Res 2021; 13:4233-4240. [PMID: 34079375 PMCID: PMC8166816 DOI: 10.2147/cmar.s304820] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 05/10/2021] [Indexed: 12/30/2022] Open
Abstract
OBJECTIVE Compared the outcomes between lenvatinib plus camrelizumab therapy and lenvatinib monotherapy as post-progression treatment for advanced hepatocellular carcinoma (HCC) with progressive disease (PD). PATIENTS AND METHODS A total of 48 advanced HCC patients were included in this retrospective study between June 2019 and March 2020. The patients were divided into the lenvatinib plus camrelizumab group (n=21) and the lenvatinib group (n=27). Primary endpoints were overall survival (OS) and progression-free survival (PFS), and secondary endpoints were the objective response rate (ORR) and adverse events (AEs). RESULTS The median follow-up time was 8.4 months. The median OS was not obtained. The median PFS of lenvatinib plus camrelizumab group was significantly longer than that of lenvatinib group (8.0 months vs 4.0 months, p=0.011). Compared with lenvatinib group, lenvatinib plus camrelizumab group had higher ORR (28.57% vs 7.41%) and disease control rate (DCR) (71.43% vs 51.85%). The most common adverse events (AEs) included hand-foot skin reaction, hypertensions and abnormal hepatic function damage. Overall, 23.81% and 25.93% of patients experienced grade ≥3AEs in the lenvatinib plus camrelizumab group and the lenvatinib group, respectively. CONCLUSION Lenvatinib plus camrelizumab as post-progression treatment is effective and safe for advanced hepatocellular carcinoma with PD.
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Affiliation(s)
- Fuqun Wei
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People’s Republic of China
| | - Qizhen Huang
- Department of Radiation Oncology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People’s Republic of China
| | - Jian He
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People’s Republic of China
| | - Liuping Luo
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People’s Republic of China
| | - Yongyi Zeng
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People’s Republic of China
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Kim S, Kim KH, Kim BK, Park JY, Ahn SH, Kim DY, Kim SU. Lenvatinib is independently associated with the reduced risk of progressive disease when compared with sorafenib in patients with advanced hepatocellular carcinoma. J Gastroenterol Hepatol 2021; 36:1317-1325. [PMID: 33217054 DOI: 10.1111/jgh.15355] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 10/08/2020] [Accepted: 11/14/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Recently, lenvatinib demonstrated non-inferiority to sorafenib in terms of overall survival (OS) in a randomized phase III study that was conducted at 154 sites in 20 countries. Here, we investigated treatment outcomes and safety of lenvatinib compared with sorafenib and identified independent predictors of poor outcomes, including shorter progression-free survival (PFS) and OS in Korean patients with unresectable hepatocellular carcinoma (HCC). METHODS Patients with advanced HCC treated with lenvatinib or sorafenib at Yonsei Liver Center, Severance Hospital, Yonsei University College of Medicine between October 2018 to October 2019 were considered eligible. Response evaluation was performed according to the modified Response Evaluation Criteria in Solid Tumors. RESULTS The lenvatinib arm had a significantly lower proportion of patients who received prior anti-HCC treatments (47.7% vs 78.7%; P < 0.001) than those in the sorafenib arm. Univariate analysis showed that ECOG 1 (vs 0), serum albumin, alpha-fetoprotein (AFP), previous anti-HCC treatments, and lenvatinib (vs sorafenib) were significant predictors of progressive disease (all P < 0.05). In the subsequent multivariate analysis, ECOG 1 (vs 0) (hazard ratio [HR] = 4.721, 95% confidence interval [CI] 1.371-16.259; P = 0.014), higher AFP level (HR = 1.000, 95% CI 1.000-1.000; P = 0.015), and lenvatinib treatment (vs sorafenib) (HR = 0.461, 95% CI 0.264-0.804; P = 0.006) independently predicted a higher probability of progressive disease. CONCLUSIONS Patients treated with lenvatinib demonstrated significantly longer PFS than those treated with sorafenib. Furthermore, no significant differences were observed in mortality rates between the two groups, which indicated that lenvatinib is non-inferior to sorafenib in terms of OS.
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Affiliation(s)
- Soojin Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Kyung Hyun Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
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Tomonari T, Sato Y, Tani J, Hirose A, Ogawa C, Morishita A, Tanaka H, Tanaka T, Taniguchi T, Okamoto K, Sogabe M, Miyamoto H, Muguruma N, Uchida K, Masaki T, Takayama T. Comparison of therapeutic outcomes of sorafenib and lenvatinib as primary treatments for hepatocellular carcinoma with a focus on molecular-targeted agent sequential therapy: A propensity score-matched analysis. Hepatol Res 2021; 51:472-481. [PMID: 33238074 DOI: 10.1111/hepr.13597] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 11/09/2020] [Accepted: 11/15/2020] [Indexed: 12/22/2022]
Abstract
AIM The optimal choice between sorafenib (SOR) or lenvatinib (LEN) as the first-line treatment for unresectable hepatocellular carcinoma (u-HCC) remains debatable. Using propensity score matching, this study compares the outcomes of SOR and LEN in the molecular-targeted agent (MTA) sequential treatment of u-HCC patients. METHODS This retrospective, multicenter, observational study recruited 137 u-HCC patients who underwent primary treatment with LEN (n = 52) or SOR (n = 85) between June 2017 and June 2020 after regorafenib was approved as the secondary treatment for u-HCC. Propensity score matching was used to reduce confounding, resulting in the selection of 104 patients (n = 52 for the SOR and LEN cohorts). RESULTS The median overall survival was 21.8 months for LEN and 20.4 months for SOR. LEN exhibited significantly greater therapeutic efficacy as compared to SOR (objective response rate: 3.8% [SOR] vs. 42.3% [LEN], p < 0.01; progression-free survival: 10 months [LEN] vs. 5.1 months [SOR], p < 0.01). No significant intergroup differences were noted in the rate of transition to secondary MTA treatments (SOR: 58.7%; LEN: 48.4%), adverse events (SOR: 86%; LEN: 95%), and maintenance of the Child-Pugh (CP) score during treatment. Compared to non-MTA treatments, secondary MTA treatment achieved a greater improvement in survival (4.3 vs. 2.8 months, p = 0.0047). Multivariate analysis demonstrated that the CP score (p < 0.01) and alpha-fetoprotein level (p < 0.01) were independent prognostic factors. CONCLUSIONS Both SOR and LEN treatments showed a clinically comparable therapeutic efficacy as the first-line treatments for u-HCC patients in an MTA sequential therapy.
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Affiliation(s)
- Tetsu Tomonari
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School of Medicine, Tokushima, Tokushima, Japan
| | - Yasushi Sato
- Department of Community Medicine for Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School of Medicine, Tokushima, Tokushima, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Kagawa University Graduate School of Medicine, Miki-cho, Kagawa, Japan
| | - Akira Hirose
- Department of Gastroenterology and Hepatology, Kochi University Graduate School of Medicine, Kochi, Kochi, Japan
| | - Chikara Ogawa
- Department of Gastroenterology and Hepatology, Takamatsu Red Cross Hospital, Takamatsu, Kagawa, Japan
| | - Akihiro Morishita
- Department of Gastroenterology and Neurology, Kagawa University Graduate School of Medicine, Miki-cho, Kagawa, Japan
| | - Hironori Tanaka
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School of Medicine, Tokushima, Tokushima, Japan
| | - Takahiro Tanaka
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School of Medicine, Tokushima, Tokushima, Japan
| | - Tatsuya Taniguchi
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School of Medicine, Tokushima, Tokushima, Japan
| | - Koichi Okamoto
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School of Medicine, Tokushima, Tokushima, Japan
| | - Masahiro Sogabe
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School of Medicine, Tokushima, Tokushima, Japan
| | - Hiroshi Miyamoto
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School of Medicine, Tokushima, Tokushima, Japan
| | - Naoki Muguruma
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School of Medicine, Tokushima, Tokushima, Japan
| | - Kazushige Uchida
- Department of Gastroenterology and Hepatology, Kochi University Graduate School of Medicine, Kochi, Kochi, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Kagawa University Graduate School of Medicine, Miki-cho, Kagawa, Japan
| | - Tetsuji Takayama
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School of Medicine, Tokushima, Tokushima, Japan
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Takahashi K, Kim J, Takahashi A, Hashimoto S, Doi M, Furuya K, Hashimoto R, Owada Y, Ogawa K, Ohara Y, Akashi Y, Hisakura K, Enomoto T, Shimomura O, Noguchi M, Oda T. Conversion hepatectomy for hepatocellular carcinoma with main portal vein tumour thrombus after lenvatinib treatment: A case report. World J Hepatol 2021; 13:384-392. [PMID: 33815680 PMCID: PMC8006080 DOI: 10.4254/wjh.v13.i3.384] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 01/31/2021] [Accepted: 03/10/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) accompanied by portal vein tumour thrombus (PVTT) presents an aggressive disease course, worsening liver function reserve, and a high recurrence rate. Clinical practice guidelines recommend systemic therapy as the first-line option for HCC with portal invasion. However, to achieve longer survival in these patients, the treatment strategy should be concluded with removal of the tumour by locoregional therapy. We experienced a case of initially unresectable HCC with main PVTT converted to radical hepatectomy after lenvatinib treatment. CASE SUMMARY A 59-year-old male with chronic hepatitis C infection visited our clinic as a regular post-surgery follow-up. Contrast-enhanced abdominal computed tomography revealed a liver mass diffusely located at the lateral segment with a massive PVTT extending from the umbilical portion to the main and contralateral third-order portal branches. With the diagnosis of unresectable HCC with Vp4 (main trunk/contralateral branch) PVTT, lenvatinib was started at 12 mg/d. The computed tomography taken 3 mo after starting lenvatinib showed regression of the PVTT, which had retreated to the contralateral first-order portal branch. He tolerated the full dose without major adverse effects. With cessation of lenvatinib for 7 d, radical left lobectomy and PVTT thrombectomy were conducted. The patient's postoperative course was uneventful. Microscopically, the primary lesion showed fibrotic changes, with moderately to poorly differentiated tumour cells surrounded by granulation tissues in some areas. The majority of the PVTT showed necrosis. He was alive without recurrence for 8 mo. CONCLUSION This is the first case of HCC with Vp4 PVTT in which radical conversion hepatectomy was succeeded after lenvatinib treatment.
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Affiliation(s)
- Kazuhiro Takahashi
- Department of Gastrointestinal and Hepatobiliary Pancreatic Surgery, University of Tsukuba, Tsukuba 3058575, Ibaraki, Japan.
| | - Jaejeong Kim
- Department of Gastrointestinal and Hepatobiliary Pancreatic Surgery, University of Tsukuba, Tsukuba 3058575, Ibaraki, Japan
| | - Amane Takahashi
- Department of Gastroenterological Surgery, Saitama Cancer Center, Saitama 3620806, Saitama, Japan
| | - Shinji Hashimoto
- Department of Gastrointestinal and Hepatobiliary Pancreatic Surgery, University of Tsukuba, Tsukuba 3058575, Ibaraki, Japan
| | - Manami Doi
- Department of Gastrointestinal and Hepatobiliary Pancreatic Surgery, University of Tsukuba, Tsukuba 3058575, Ibaraki, Japan
| | - Kinji Furuya
- Department of Gastrointestinal and Hepatobiliary Pancreatic Surgery, University of Tsukuba, Tsukuba 3058575, Ibaraki, Japan
| | - Ryosuke Hashimoto
- Department of Diagnostic Pathology, University of Tsukuba, Tsukuba 3058575, Ibaraki, Japan
| | - Yohei Owada
- Department of Gastrointestinal and Hepatobiliary Pancreatic Surgery, University of Tsukuba, Tsukuba 3058575, Ibaraki, Japan
| | - Koichi Ogawa
- Department of Gastrointestinal and Hepatobiliary Pancreatic Surgery, University of Tsukuba, Tsukuba 3058575, Ibaraki, Japan
| | - Yusuke Ohara
- Department of Gastrointestinal and Hepatobiliary Pancreatic Surgery, University of Tsukuba, Tsukuba 3058575, Ibaraki, Japan
| | - Yoshimasa Akashi
- Department of Gastrointestinal and Hepatobiliary Pancreatic Surgery, University of Tsukuba, Tsukuba 3058575, Ibaraki, Japan
| | - Katsuji Hisakura
- Department of Gastrointestinal and Hepatobiliary Pancreatic Surgery, University of Tsukuba, Tsukuba 3058575, Ibaraki, Japan
| | - Tsuyoshi Enomoto
- Department of Gastrointestinal and Hepatobiliary Pancreatic Surgery, University of Tsukuba, Tsukuba 3058575, Ibaraki, Japan
| | - Osamu Shimomura
- Department of Gastrointestinal and Hepatobiliary Pancreatic Surgery, University of Tsukuba, Tsukuba 3058575, Ibaraki, Japan
| | - Masayuki Noguchi
- Department of Diagnostic Pathology, University of Tsukuba, Tsukuba 3058575, Ibaraki, Japan
| | - Tatsuya Oda
- Department of Gastrointestinal and Hepatobiliary Pancreatic Surgery, University of Tsukuba, Tsukuba 3058575, Ibaraki, Japan
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Shigesawa T, Suda G, Kimura M, Maehara O, Tokuchi Y, Kubo A, Yamada R, Furuya K, Baba M, Kitagataya T, Suzuki K, Ohara M, Kawagishi N, Nakai M, Sho T, Natsuizaka M, Morikawa K, Ogawa K, Sakamoto N. Baseline serum angiopoietin-2 and VEGF levels predict the deterioration of the liver functional reserve during lenvatinib treatment for hepatocellular carcinoma. PLoS One 2021; 16:e0247728. [PMID: 33647018 PMCID: PMC7920365 DOI: 10.1371/journal.pone.0247728] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 02/12/2021] [Indexed: 12/12/2022] Open
Abstract
A deteriorated liver functional reserve during systemic therapy for unresectable hepatocellular carcinoma (HCC) causes poor patient outcomes. We aimed to identify predictive factors associated with the deterioration of Child-Pugh score at 8 weeks after lenvatinib initiation. Patients with adequate clinical data and baseline preserved serum samples available were included. Baseline fibroblast growth factor (FGF)19 and 21, angiopoietin (ANG)2, and vascular endothelial growth factor (VEGF) levels were evaluated. Thirty-seven patients were included, and 6, 15, 14, and 2 experienced complete response, partial response, stable disease, and progressive disease, respectively. Twenty-four (65%) and 13 (35%) patients showed a maintained/improved and deteriorated Child-Pugh-score, respectively. While baseline clinical data, treatment response, and laboratory data were similar between these two patient groups, baseline ANG2 and VEGF levels were significantly higher (P = 0.0017) and lower (P = 0.0231), respectively, in patients with deteriorated Child-Pugh score than in those without. Based on receiver operating characteristic curve analysis, cut-off values for ANG2 and VEGF were found to be 3,108 pg/mL and 514.9 pg/mL, respectively. Among patients with low VEGF and high ANG2, 89% (8/9) exhibited a deteriorated Child-Pugh score, whereas none of the patients (0/9) with high VEGF and low ANG2 did. The deterioration of the Child-Pugh score in patients with unresectable HCC who are treated with lenvatinib may be predictable based on combined baseline serum ANG2 and VEGF levels.
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Affiliation(s)
- Taku Shigesawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Goki Suda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
- * E-mail:
| | - Megumi Kimura
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Osamu Maehara
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Yoshimasa Tokuchi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Akinori Kubo
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Ren Yamada
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Ken Furuya
- Department of Gastroenterology and Hepatology, Japan Community Health Care Organization (JCHO) Hokkaido Hospital, Hokkaido, Japan
| | - Masaru Baba
- Department of Gastroenterology and Hepatology, Japan Community Health Care Organization (JCHO) Hokkaido Hospital, Hokkaido, Japan
| | - Takashi Kitagataya
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Kazuharu Suzuki
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Masatsugu Ohara
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Naoki Kawagishi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Masato Nakai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Takuya Sho
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Mitsuteru Natsuizaka
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Kenichi Morikawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Koji Ogawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
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Eguchi S, Hidaka M, Kugiyama T, Soyama A, Hara T, Nagakawa K, Adachi T, Tanaka T, Yoshimoto T, Hamada T, Matsushima H, Ito S, Kanetaka K. Changes in the Role and Mode of Liver Resection for Hepatocellular Carcinoma Over 20 Years: A Single-Center Analysis. World J Surg 2021; 45:1152-1158. [PMID: 33491142 DOI: 10.1007/s00268-020-05914-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/05/2020] [Indexed: 12/01/2022]
Abstract
INTRODUCTION The aim of this study was to analyze changes in characteristics of HCC and the modes of LR over 20 years in order to show the impact of those changes in the outcome of LR. In addition, BCLC staging was used to assess the limitations of this classification system and changes over the decade. PATIENTS AND METHODS In our department, 500 liver resections (LR) were performed for hepatocellular carcinoma (HCC) over the 20 years between January 2000 and February 2020. The 208 cases performed through 2009 were designated as Era 1, and the 292 cases between 2010 and February 2020 were termed Era 2. We analyzed changes in the characteristics of HCC and mode of LR (Study 1), and final outcomes of LR are shown according to the BCLC staging classifications and eras using data from the 5 years after LR (Study 2). RESULTS In Era 1, the mean age of the patients was 68, while in Era 2 the mean age was 71, which was significantly older than the patients in Era 1. HCC that developed from non-B, non-C liver cirrhosis was significantly increased in Era 2 (45%) as compared to that in Era 1 (34%). Laboratory data were all comparable between the eras in patients undergoing LR for HCC. The size and numbers of the HCC as well as tumor markers were similar between the eras. As to the mode of LR, although the extent of LR was similar between the eras, the laparoscopic method was significantly increased in Era 2. Blood loss was significantly lower in Era 2 (mean 519 g) than in Era 1 (1,085 g). Patient survival and recurrence-free survival (RFS) were similar between the two eras, while RFS at 5 years after LR was better in Era 2. Even in the BCLC A category, only patients with a single HCC less than 5 cm showed best results, while patients with HCC within the rest of BCLC A and BCLC B showed a dismal outcome. There was no difference in OS and RFS between the eras after stratification by BCLC. CONCLUSION There are conspicuous changes in the baseline characteristics and mode of LR over 20 years, which should be taken into account for patient care and informed consent for patients undergoing LR going forward.
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Affiliation(s)
- Susumu Eguchi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
| | - Masaaki Hidaka
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Tota Kugiyama
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Akihiko Soyama
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Takanobu Hara
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Kantoku Nagakawa
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Tomohiko Adachi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Takayuki Tanaka
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Tomoko Yoshimoto
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Takashi Hamada
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Hajime Matsushima
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Sinichiro Ito
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Kengo Kanetaka
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
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Hatanaka T, Naganuma A, Kakizaki S. Lenvatinib for Hepatocellular Carcinoma: A Literature Review. Pharmaceuticals (Basel) 2021; 14:36. [PMID: 33418941 PMCID: PMC7825021 DOI: 10.3390/ph14010036] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 01/01/2021] [Accepted: 01/03/2021] [Indexed: 12/11/2022] Open
Abstract
Lenvatinib, which is an oral multikinase inhibitor, showed non-inferiority to the sorafenib in terms of overall survival (OS) and a higher objective response rate (ORR) and better progression-free survival (PFS) in patients with hepatocellular carcinoma (HCC). A good liver function and Barcelona Clinic Liver Cancer (BCLC) intermediate stage were the key factors in achieving therapeutic efficacy. The management of adverse events plays an important role in continuing lenvatinib treatment. While sequential therapies contributed to prolonging overall survival, effective molecular targeted agents for the administration after lenvatinib have not been established. Repeated transcatheter arterial chemoembolization (TACE) was associated with a decline in the liver function and poor therapeutic response in BCLC intermediate patients. Recently, the Asia-Pacific Primary Liver Cancer Expert (APPLE) Consensus Statement proposed the criteria for TACE unsuitability. Upfront systemic therapy may be better for the BCLC intermediate stage HCC patients with a high tumor burden, while selective TACE will be recommended for obtaining a curative response in patients with a low tumor burden. This article reviews the therapeutic response, management of adverse events, post-progression treatment after Lenvatinib, and treatment strategy for BCLC intermediate stage HCC.
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Affiliation(s)
- Takeshi Hatanaka
- Department of Gastroenterology, Gunma Saiseikai Maebashi Hospital, 564-1 Kamishindenmachi, Maebashi, Gunma 371-0821, Japan
| | - Atsushi Naganuma
- Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, 36 Takamatsucho, Takasaki, Gunma 370-0829, Japan;
| | - Satoru Kakizaki
- Department of Clinical Research, National Hospital Organization Takasaki General Medical Center, 36 Takamatsucho, Takasaki, Gunma 370-0829, Japan;
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, 3-39-15 Showa, Maebashi, Gunma 371-8511, Japan
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Cheon J, Chon HJ, Bang Y, Park NH, Shin JW, Kim KM, Lee HC, Lee J, Yoo C, Ryoo BY. Real-World Efficacy and Safety of Lenvatinib in Korean Patients with Advanced Hepatocellular Carcinoma: A Multicenter Retrospective Analysis. Liver Cancer 2020; 9:613-624. [PMID: 33083284 PMCID: PMC7548882 DOI: 10.1159/000508901] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 05/23/2020] [Indexed: 02/04/2023] Open
Abstract
INTRODUCTION/OBJECTIVE Lenvatinib demonstrated efficacy and safety in patients with advanced hepatocellular carcinoma (HCC) in the randomized phase III REFLECT trial. Considering the discrepancies in patients between clinical trial data and daily practice, an account of practical experience is needed. METHODS We conducted a multicenter retrospective analysis in which 3 tertiary referral centers participated. A total of 92 patients with advanced HCC treated with lenvatinib between September 2018 and January 2020 were analyzed. RESULTS Lenvatinib was used as the first-line therapy for 67 (72.8%) patients, and for 25 (27.2%) patients previously treated with other systemic therapy including immune checkpoint inhibitors. At the time of initiation of lenvatinib, 74 (80.4%) and 18 (19.6%) patients were classified as Child-Pugh A and B, respectively. Thirty-five patients (38.0%) had extensive disease that would have excluded them from the REFLECT trial. In the Child-Pugh A group, the response rate graded according to the Response Evaluation Criteria in Solid Tumors v1.1 was 21.1%, median progression-free survival (PFS) was 4.6 (95% confidence interval [CI] 3.1-6.1) months, and overall survival (OS) was 10.7 (95% CI 4.8-16.5) months for patients treated with first-line lenvatinib (n = 57). With second- or later-line lenvatinib (n = 17), median PFS and OS were 4.1 (95% CI 3.1-5.1) and 6.4 (95% CI 5.1-7.7) months, respectively. In the Child-Pugh B group (n = 18), median PFS and OS were 2.6 (95% CI 0.6-4.6) and 5.3 (95% CI 2.0-8.5) months, respectively. The most common grade 3-4 toxicities were hyperbilirubinemia (n = 8; 8.7%), AST elevation (n = 6; 6.5%), and diarrhea (n = 5; 5.4%) across all study patients. CONCLUSIONS In this real-world study, lenvatinib was found to be well tolerated and effective in more heterogeneous HCC patient populations.
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Affiliation(s)
- Jaekyung Cheon
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea
| | - Hong Jae Chon
- Departments of Medical Oncology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Republic of Korea
| | - Yeonghak Bang
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Neung Hwa Park
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea
| | - Jung Woo Shin
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea
| | - Kang Mo Kim
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Han Chu Lee
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jooho Lee
- Departments of Gastroenterology and Hepatology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Republic of Korea
| | - Changhoon Yoo
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea,*Changhoon Yoo and Baek-Yeol Ryoo, Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505 (South Korea), and
| | - Baek-Yeol Ryoo
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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