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1
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Li W, Zhao B, Wang Q, Lu J, Wu X, Chen X. M2 macrophage exosomes promote resistance to sorafenib in hepatocellular carcinoma cells via miR-200c-3p. Int Immunopharmacol 2024; 139:112807. [PMID: 39068757 DOI: 10.1016/j.intimp.2024.112807] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 07/08/2024] [Accepted: 07/23/2024] [Indexed: 07/30/2024]
Abstract
OBJECTIVE Sorafenib is a chemotherapeutic agent used to treat hepatocellular carcinoma (HCC). However, its clinical response rates are often low. Tumour-associated macrophages (TAMs) have been implicated in tumour resistance. The relationship between TAMs-derived exosomes and primary resistance to sorafenib in hepatocellular carcinoma is unclear. METHODS The study analysed RNA-SEQ data from TCGA-LIHC to explore the relationship between TAMs and sorafenib IC50. THP-1-induced M2 macrophages were used as a model to investigate the relationship between M2 macrophage exosomes and primary resistance to sorafenib in hepatocellular carcinoma cells using apoptosis, colony generation, cell viability and dual luciferase. RESULTS M2 macrophage score and sorafenib IC50 were positively correlated in hepatocellular carcinoma patients, M2 macrophage exosomes promoted sorafenib resistance in hepatocellular carcinoma cells, and M2-exo-miR-200c-3p facilitated the development of sorafenib resistance in hepatocellular carcinoma cells by mediating the activation of PI3K/AKT. CONCLUSION We propose and demonstrate for the first time that M2 macrophage exosomes promote sorafenib resistance in hepatocellular carcinoma, providing a new perspective for the clinical treatment of hepatocellular carcinoma patients.
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Affiliation(s)
- Wenhua Li
- Shihezi University School of Medicine, Shihezi 832000, China; Key Laboratory for Prevention and Treatment of High Morbidity in Central Asia, National Health and Health Commission, Shihezi 832000, China
| | - Bin Zhao
- Shihezi University School of Medicine, Shihezi 832000, China; Key Laboratory for Prevention and Treatment of High Morbidity in Central Asia, National Health and Health Commission, Shihezi 832000, China
| | - Qianwen Wang
- Shihezi University School of Medicine, Shihezi 832000, China; Key Laboratory for Prevention and Treatment of High Morbidity in Central Asia, National Health and Health Commission, Shihezi 832000, China
| | - Junxia Lu
- Shihezi University School of Medicine, Shihezi 832000, China; Key Laboratory for Prevention and Treatment of High Morbidity in Central Asia, National Health and Health Commission, Shihezi 832000, China
| | - Xiangwei Wu
- Shihezi University School of Medicine, Shihezi 832000, China; The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi 832000, China; Key Laboratory for Prevention and Treatment of High Morbidity in Central Asia, National Health and Health Commission, Shihezi 832000, China.
| | - Xueling Chen
- Shihezi University School of Medicine, Shihezi 832000, China; Key Laboratory for Prevention and Treatment of High Morbidity in Central Asia, National Health and Health Commission, Shihezi 832000, China.
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2
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Yan G, Zhang K, Yan L, Zhang Y. Long-term survival outcomes following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal metastasis of hepatocellular carcinoma patients. World J Surg Oncol 2024; 22:144. [PMID: 38822337 PMCID: PMC11140955 DOI: 10.1186/s12957-024-03426-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Accepted: 05/24/2024] [Indexed: 06/02/2024] Open
Abstract
BACKGROUND Hepatocellular carcinoma with peritoneal metastasis (HCC-PM) has a poor outlook. Traditional treatments have limited effect on survival. The safety and efficacy of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) have been shown in other peritoneal cancers. This study evaluates the role of CRS + HIPEC in HCC-PM. METHODS A retrospective analysis of HCC-PM patients treated with CRS + HIPEC at Beijing Shijitan Hospital from March 2017 to December 2023 was conducted, assessing clinical features, severe adverse events (SAEs), and overall survival (OS) rates. RESULTS The study population comprised 10 HCC-PM patients who underwent CRS + HIPEC. The median peritoneal cancer index (PCI) was 25, and complete cytoreduction (CC0 ~ 1) was achieved in half of the patients. Three patients experienced SAEs within 30 days postoperatively. The 1-year, 3-year, and 5-year OS rates were recorded as 89.0%, 89.0%, and 21.0% respectively, with a median OS1 of 107.8 months and OS2 of 49.9 months. The median progression-free survival (PFS) was 5.0 months. CONCLUSION The application of CRS + HIPEC offers significant benefits to patients with HCC-PM. A selected group of patients may achieve prolonged PFS. Incorporating CRS + HIPEC into the treatment paradigm can thus be considered a strategic therapeutic option for patients with HCC-PM.
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Affiliation(s)
- Guojun Yan
- Department of Peritoneal Cancer Surgery, Beijing Shijitan Hospital, Capital Medical University, No. 10, Tieyi Road, Yangfangdian Street, Haidian District, Beijing, 100038, China
| | - Kai Zhang
- Department of Peritoneal Cancer Surgery, Beijing Shijitan Hospital, Capital Medical University, No. 10, Tieyi Road, Yangfangdian Street, Haidian District, Beijing, 100038, China
| | - Lijun Yan
- Department of Peritoneal Cancer Surgery, Beijing Shijitan Hospital, Capital Medical University, No. 10, Tieyi Road, Yangfangdian Street, Haidian District, Beijing, 100038, China
| | - Yanbin Zhang
- Department of Peritoneal Cancer Surgery, Beijing Shijitan Hospital, Capital Medical University, No. 10, Tieyi Road, Yangfangdian Street, Haidian District, Beijing, 100038, China.
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Wang Y, Deng B. Hepatocellular carcinoma: molecular mechanism, targeted therapy, and biomarkers. Cancer Metastasis Rev 2023; 42:629-652. [PMID: 36729264 DOI: 10.1007/s10555-023-10084-4] [Citation(s) in RCA: 83] [Impact Index Per Article: 41.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 01/16/2023] [Indexed: 02/03/2023]
Abstract
Hepatocellular carcinoma (HCC) is a common malignancy and one of the leading causes of cancer-related death. The biological process of HCC is complex, with multiple factors leading to the broken of the balance of inactivation and activation of tumor suppressor genes and oncogenes, the abnormal activation of molecular signaling pathways, the differentiation of HCC cells, and the regulation of angiogenesis. Due to the insidious onset of HCC, at the time of first diagnosis, less than 30% of HCC patients are candidates for radical treatment. Systematic antitumor therapy is the hope for the treatment of patients with middle-advanced HCC. Despite the emergence of new systemic therapies, survival rates for advanced HCC patients remain low. The complex pathogenesis of HCC has inspired researchers to explore a variety of biomolecular targeted therapeutics targeting specific targets. Correct understanding of the molecular mechanism of HCC occurrence is key to seeking effective targeted therapy. Research on biomarkers for HCC treatment is also advancing. Here, we explore the molecular mechanism that are associated with HCC development, summarize targeted therapies for HCC, and discuss potential biomarkers that may drive therapies.
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Affiliation(s)
- Yu Wang
- Department of Infectious Diseases, The First Hospital of China Medical University, 155 Nanjing North Street, Shenyang, 110001, Liaoning Province, China
| | - Baocheng Deng
- Department of Infectious Diseases, The First Hospital of China Medical University, 155 Nanjing North Street, Shenyang, 110001, Liaoning Province, China.
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Rattner JI, Kopciuk KA, Vogel HJ, Tang PA, Shapiro JD, Tu D, Jonker DJ, Siu LL, O'Callaghan CJ, Bathe OF. Clinical and metabolomic characterization of Brivanib-Induced hypertension in metastatic colorectal cancer. Cancer Med 2023; 12:16019-16031. [PMID: 37329221 PMCID: PMC10469666 DOI: 10.1002/cam4.6248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 05/16/2023] [Accepted: 06/03/2023] [Indexed: 06/18/2023] Open
Abstract
BACKGROUND Trials of tyrosine kinase inhibitors (TKI) have not demonstrated dramatic benefits in advanced colorectal cancer (CRC), and this may be a function of poor patient selection. TKI-induced hypertension is reportedly a surrogate marker for treatment benefit for some tumor types. Our objective was to determine whether hypertension was associated with benefit in the context of CRC treatment, and also to gain insight on the pathogenesis of TKI-induced hypertension by monitoring associated changes in the circulating metabolome. PATIENTS AND METHODS Clinical data were acquired from clinical trial patients with metastatic CRC randomized to cetuximab ± the TKI brivanib (N = 750). Outcomes were evaluated as a function of treatment-induced hypertension. For metabolomic studies, plasma samples were taken at baseline, as well as at 1, 4, and 12 weeks after treatment initiation. Samples were submitted to gas chromatography-mass spectrometry to identify treatment-related metabolomic changes associated with TKI-induced hypertension, compared to pre-treatment baseline. A model based on changes in metabolite concentrations was generated using orthogonal partial least squares discriminant analysis (OPLS-DA). RESULTS In the brivanib treated group, 95 patients had treatment-related hypertension within 12 weeks of initiating treatment. TKI-induced hypertension was not associated with a significantly higher response rate, nor was it associated with improved progression-free or overall survival. In metabolomic studies, 386 metabolites were identified. There were 29 metabolites that changed with treatment and distinguished patients with and without TKI-induced hypertension. The OPLS-DA model for brivanib-induced hypertension was significant and robust (R2 Y score = 0.89, Q2 Y score = 0.70, CV-ANOVA = 2.01 e-7). Notable metabolomic features previously reported in pre-eclampsia and associated with vasoconstriction were found. CONCLUSION TKI-induced hypertension was not associated with clinical benefit in metastatic CRC. We have identified changes in the metabolome that are associated with the development of worsening brivanib-induced hypertension that may be useful in future efforts of characterizing this toxicity.
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Affiliation(s)
- Jodi I. Rattner
- Cumming School of MedicineArnie Charbonneau Cancer Institute, University of CalgaryCalgaryAlbertaCanada
| | - Karen A. Kopciuk
- Department of Mathematics and Statistics, Faculty of ScienceUniversity of CalgaryCalgaryAlbertaCanada
| | - Hans J. Vogel
- Department Biological Sciences, Faculty of ScienceUniversity of CalgaryCalgaryAlbertaCanada
| | - Patricia A. Tang
- Cumming School of MedicineArnie Charbonneau Cancer Institute, University of CalgaryCalgaryAlbertaCanada
- Department of Surgery and Oncology, Cumming School of MedicineUniversity of CalgaryCalgaryAlbertaCanada
| | - Jeremy D. Shapiro
- Department of Medical OncologyCarbini HospitalMelbourneVictoriaAustralia
| | - Dongsheng Tu
- Department of Community Health & EpidemiologyQueens UniversityKingstonOntarioCanada
| | - Derek J. Jonker
- Division of Medical OncologyOttawa Hospital Cancer CentreOttawaOntarioCanada
| | - Lillian L. Siu
- Division of Medical Oncology and HematologyPrincess Margaret Cancer CentreTorontoOntarioCanada
| | - Chris J. O'Callaghan
- Department of Community Health & EpidemiologyQueens UniversityKingstonOntarioCanada
| | - Oliver F. Bathe
- Cumming School of MedicineArnie Charbonneau Cancer Institute, University of CalgaryCalgaryAlbertaCanada
- Department of Surgery and Oncology, Cumming School of MedicineUniversity of CalgaryCalgaryAlbertaCanada
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Zhang X, Cai L, Fang J, Chen F, Pan F, Zhang K, Huang Q, Huang Y, Li D, Lv L, Chen M, Yan R, Lai Y, Peng Y, Wu Z. Efficacy and safety of transarterial chemoembolization plus sorafenib in patients with recurrent hepatocellular carcinoma after liver transplantation. Front Oncol 2023; 12:1101351. [PMID: 36713526 PMCID: PMC9880524 DOI: 10.3389/fonc.2022.1101351] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 12/20/2022] [Indexed: 01/15/2023] Open
Abstract
Objectives To explore the benefit and safety of transarterial chemoembolization (TACE) in combination with sorafenib in patients with recurrent hepatocellular carcinoma (HCC) after orthotopic liver transplantation (OLT). Methods In this multi-center retrospective study, 106 patients with recurrent HCC after OLT were included. Fifty-two patients were treated with TACE plus sorafenib (TS group) and 54 were treated with TACE alone (TC group). Primary and secondary endpoints including overall survival (OS) and progression-free survival (PFS), and safety were assessed. Results The median OS (17 vs 10 months, P=0.035) and PFS (12 vs 6 months, P=0.004) in the TS group were longer than those in the TC group. On multivariate analysis, BCLC stage (HR [hazard ratio]=0.73 [95% CI, 0.27-0.99], P=0.036) and sorafenib medication (HR=2.26 [95% CI, 1.35-3.69], P=0.01) were identified as independent prognostic risk factors for OS. No severe adverse events related to sorafenib were noted in the TS group. Four patients discontinued sorafenib due to intolerance. Conclusion TACE in combination with sorafenib is a feasible regimen to improve the survival with mild toxicity in patients with recurrent HCC after OLT.
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Affiliation(s)
- Xia Zhang
- Department of Hepatobiliary Disease, the 900th Hospital of Joint Logistics Support Force, Fujian Medical University, Fuzhou, China
| | - Lirong Cai
- Department of Hepatobiliary Disease, the 900th Hospital of Joint Logistics Support Force, Fujian Medical University, Fuzhou, China
| | - Jian Fang
- Department of Hepatobiliary Disease, The Third People’s Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Fengsui Chen
- Department of Hepatobiliary Disease, the 900th Hospital of Joint Logistics Support Force, Fujian Medical University, Fuzhou, China
| | - Fan Pan
- Department of Hepatobiliary Surgery, the 900th Hospital of Joint Logistics Support Force, Fujian Medical University, Fuzhou, China
| | - Kun Zhang
- Department of Hepatobiliary Surgery, Xiang’an Hospital, Xiamen University, Xiamen, China
| | - Qian Huang
- Department of Hepatobiliary Surgery, the 900th Hospital of Joint Logistics Support Force, Fujian Medical University, Fuzhou, China
| | - Yuju Huang
- Department of Hepatobiliary Disease, the 900th Hospital of Joint Logistics Support Force, Fujian Medical University, Fuzhou, China
| | - Dongliang Li
- Department of Hepatobiliary Disease, the 900th Hospital of Joint Logistics Support Force, Fujian Medical University, Fuzhou, China
| | - Lizhi Lv
- Department of Hepatobiliary Surgery, the 900th Hospital of Joint Logistics Support Force, Fujian Medical University, Fuzhou, China
| | - Man Chen
- Department of Hepatobiliary Disease, the 900th Hospital of Joint Logistics Support Force, Fujian Medical University, Fuzhou, China
| | - Ruiying Yan
- Department of Hepatobiliary Disease, the 900th Hospital of Joint Logistics Support Force, Fujian Medical University, Fuzhou, China
| | - Yanhua Lai
- Department of Transplantation, People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, China,*Correspondence: Zhixian Wu, ; Yonghai Peng, ; Yanhua Lai,
| | - Yonghai Peng
- Department of Oncology, the 900th Hospital of Joint Logistics Support Force, Fujian Medica University, Fuzhou, China,*Correspondence: Zhixian Wu, ; Yonghai Peng, ; Yanhua Lai,
| | - Zhixian Wu
- Department of Hepatobiliary Disease, the 900th Hospital of Joint Logistics Support Force, Fujian Medical University, Fuzhou, China,*Correspondence: Zhixian Wu, ; Yonghai Peng, ; Yanhua Lai,
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He P, Wan H, Wan J, Jiang H, Yang Y, Xie K, Wu H. Systemic therapies in hepatocellular carcinoma: Existing and emerging biomarkers for treatment response. Front Oncol 2022; 12:1015527. [PMID: 36483039 PMCID: PMC9723250 DOI: 10.3389/fonc.2022.1015527] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 10/28/2022] [Indexed: 07/21/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common malignancy and the third most common cause of cancer-related death worldwide. Due to asymptomatic patients in the early stage, most patients are diagnosed at an advanced stage and lose the opportunity for radical resection. In addition, for patients who underwent procedures with curative intent for early-stage HCC, up to 70% of patients may have disease recurrence within 5 years. With the advent of an increasing number of systemic therapy medications, we now have more options for the treatment of HCC. However, data from clinical studies show that with different combinations of regimens, the objective response rate is approximately 40%, and most patients will not respond to treatment. In this setting, biomarkers for predicting treatment response are of great significance for precise treatment, reducing drug side effects and saving medical resources. In this review, we summarized the existing and emerging biomarkers in the literature, with special emphasis on the pathways and mechanism underlying the prediction value of those biomarkers for systemic treatment response.
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Affiliation(s)
- Penghui He
- Department of Liver Transplant Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Haifeng Wan
- Department of Liver Transplant Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Juan Wan
- Department of Pancreatitis Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Hanyu Jiang
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yu Yang
- Department of Abdominal Oncology, Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - Kunlin Xie
- Department of Liver Transplant Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Hong Wu
- Department of Liver Transplant Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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7
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Huang KW, Lee PC, Chao Y, Su CW, Lee IC, Lan KH, Chu CJ, Hung YP, Chen SC, Hou MC, Huang YH. Durable objective response to sorafenib and role of sequential treatment in unresectable hepatocellular carcinoma. Ther Adv Med Oncol 2022; 14:17588359221099401. [PMID: 35646162 PMCID: PMC9134461 DOI: 10.1177/17588359221099401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 04/21/2022] [Indexed: 11/16/2022] Open
Abstract
Background The response rate to sorafenib is limited for unresectable hepatocellular carcinoma (HCC). Little is known about the long-term outcomes of objective responders. The role of second-line therapies on the survival of sorafenib-responders is unclear. We aimed to delineate the long-term outcomes and the role of subsequent treatment after responding to sorafenib. Methods From September 2012 to December 2019, 922 patients who received sorafenib treatment for unresectable HCC were retrospectively reviewed. Of these, 21 (2.3%) achieved a complete response (CR) and 54 (5.9%) had a partial response (PR) based on mRECIST criteria. Factors associated with survivals were analyzed. Results During the median follow-up of 35.3 months, the median duration of response was 18.3 months (range: 2.3-45.5) for patients achieving CR and 10.0 months (range: 1.9-60.3) for PR. The median overall survival (OS) was 39.5 months [95% confidence interval (CI): 28.4-50.5] including values not yet estimable for CR and 25.8 months for PR. Patients who experienced treatment-related adverse events (TRAEs) had better median OS than those without (44.9 versus 18.1 months, p = 0.003). Eventually, 53 patients developed tumor progression; 30 patients received second-line systemic treatment including nivolumab (n = 8), regorafenib (n = 15), and chemotherapy (n = 7). Sorafenib-nivolumab sequential therapy provided the best median OS versus sorafenib-regorafenib and sorafenib-chemotherapy in these patients (55.8, 39.5, and 25.5 months), respectively. Conclusions The response is durable for advanced HCC patients with CR or PR to sorafenib. Subsequent immunotherapy seems to provide the best survival. This information is important for characterizing outcomes of sorafenib-responders and the choice of sequential treatment.
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Affiliation(s)
- Kuo-Wei Huang
- Division of Gastroenterology and Hepatology,
Department of Medicine, Taipei Veterans General Hospital, Taipei
- Department of Medicine, Taipei City Hospital
Yang-Ming branch, Taipei
| | - Pei-Chang Lee
- Division of Gastroenterology and Hepatology,
Department of Medicine, Taipei Veterans General Hospital, Taipei
- School of Medicine, National Yang Ming Chiao
Tung University, Taipei
| | - Yee Chao
- Department of Oncology, Taipei Veterans General
Hospital, Taipei
| | - Chien-Wei Su
- Division of Gastroenterology and Hepatology,
Department of Medicine, Taipei Veterans General Hospital, Taipei
- School of Medicine, National Yang Ming Chiao
Tung University, Taipei
| | - I-Cheng Lee
- Division of Gastroenterology and Hepatology,
Department of Medicine, Taipei Veterans General Hospital, Taipei
- School of Medicine, National Yang Ming Chiao
Tung University, Taipei
| | - Keng-Hsin Lan
- Division of Gastroenterology and Hepatology,
Department of Medicine Taipei Veterans General Hospital, Taipei
- Institute of Pharmacology, School of Medicine,
National Yang Ming Chiao Tung University, Taipei
| | - Chi-Jen Chu
- Division of Gastroenterology and Hepatology,
Department of Medicine, Taipei Veterans General Hospital, Taipei
- School of Medicine, National Yang Ming Chiao
Tung University, Taipei
| | - Yi-Ping Hung
- Department of Oncology, Taipei Veterans
General Hospital, Taipei
- School of Medicine, National Yang Ming Chiao
Tung University, Taipei
| | - San-Chi Chen
- Institute of Clinical Medicine, School of
Medicine, National Yang Ming Chiao Tung University, Taipei
- Department of Oncology, Taipei Veterans
General Hospital, Taipei
| | - Ming-Chih Hou
- Division of Gastroenterology and Hepatology,
Department of Medicine, Taipei Veterans General Hospital, Taipei
- School of Medicine, National Yang Ming Chiao
Tung University, Taipei
| | - Yi-Hsiang Huang
- Division of Gastroenterology and Hepatology,
Department of Medicine, Taipei Veterans General Hospital, Taipei
- Institute of Clinical Medicine, School of
Medicine, National Yang Ming Chiao Tung University, No.201, Sec. 2, Shipai
Road, Beitou District, 11217 Taipei
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Rapposelli IG, Tada T, Shimose S, Burgio V, Kumada T, Iwamoto H, Hiraoka A, Niizeki T, Atsukawa M, Koga H, Hirooka M, Torimura T, Iavarone M, Tortora R, Campani C, Lonardi S, Tamburini E, Piscaglia F, Masi G, Cabibbo G, Giuseppe Foschi F, Silletta M, Tsuji K, Ishikawa T, Takaguchi K, Kariyama K, Itobayashi E, Tajiri K, Shimada N, Shibata H, Ochi H, Yasuda S, Toyoda H, Fukunishi S, Ohama H, Kawata K, Tani J, Nakamura S, Nouso K, Tsutsui A, Nagano T, Tanaka T, Itokawa N, Okubo T, Arai T, Imai M, Joko K, Koizumi Y, Hiasa Y, Rimini M, Ratti F, Aldrighetti L, Cascinu S, Casadei-Gardini A. Adverse events as potential predictive factors of activity in patients with advanced hepatocellular carcinoma treated with lenvatinib. Liver Int 2021; 41:2997-3008. [PMID: 34250737 DOI: 10.1111/liv.15014] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 07/02/2021] [Accepted: 07/08/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIM Lenvatinib is a standard of care option in first-line therapy of advanced hepatocellular carcinoma (HCC). In the present study, we aim to identify, in patients with HCC treated with lenvatinib, a possible association between occurrence and grading of adverse events (AEs) and outcome. METHODS We performed a retrospective analysis of 606 Japanese and Italian patients treated with lenvatinib in first-line setting and investigated the possible correlation between the onset of AEs, toxicity grade (G) and outcome measures such as overall survival (OS) and progression-free survival (PFS). RESULTS The appearance of arterial hypertension G ≥ 2 independently predicted prolonged OS [hazard ratio (HR) 0.66, 95% confidence interval (CI) 0.46-0.93, P = .0188], whereas decreased appetite G ≥ 2 independently predicted decreased OS (HR 1.70, 95% CI 1.25-2.32, P = .0007) by multivariate analysis. Appearance of hand-foot skin reaction independently predicted prolonged PFS (HR 0.72, 95% CI 0.56-0.93, P = .0149), whereas decreased appetite G ≥ 2 predicted decreased PFS (HR 1.36, 95% CI 1.04-1.77, P = .0277). CONCLUSIONS Our main findings are that the occurrence of arterial hypertension G ≥ 2 is a predictor of longer survival, whereas decreased appetite G ≥ 2 predicts for a poor prognosis. A careful management of AEs under lenvatinib treatment for HCC is required, to improve patients' quality of life, minimize the need for treatment discontinuation and achieve optimal outcome.
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Affiliation(s)
- Ilario Giovanni Rapposelli
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori"-IRST, Meldola, Italy
| | - Toshifumi Tada
- Department of Internal Medicine, Japanese Red Cross Himeji Hospital, Himeji, Japan
| | - Shigeo Shimose
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Valentina Burgio
- Department of Medical Oncology, San Raffaele Scientific Institute IRCCS, Milan, Italy
| | - Takashi Kumada
- Faculty of Nursing, Gifu Kyoritsu University, Ogaki, Japan
| | - Hideki Iwamoto
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Atsushi Hiraoka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan
| | - Takashi Niizeki
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Masanori Atsukawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan
| | - Hironori Koga
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Masashi Hirooka
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Matsuyama, Japan
| | - Takuji Torimura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Massimo Iavarone
- Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy
| | | | - Claudia Campani
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy
| | - Sara Lonardi
- Early Phase Clinical Trial Unit, Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
- Medical Oncology Unit 1, Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Emiliano Tamburini
- Department of Medical Oncology, Card. G. Panico Hospital of Tricase, Tricase, Italy
| | - Fabio Piscaglia
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, Azienda Ospedaliero Universitaria di Bologna, Italy
| | - Gianluca Masi
- Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Giuseppe Cabibbo
- Department of Health Promotion, Mother & Child Care, Internal Medicine & Medical Specialties, PROMISE, Gastroenterology & Hepatology Unit, University of Palermo, Palermo, Italy
| | | | | | - Kunihiko Tsuji
- Center of Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan
| | - Toru Ishikawa
- Department of Gastroenterology, Saiseikai Niigata Hospital, Niigata, Japan
| | - Koichi Takaguchi
- Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Kazuya Kariyama
- Department of Gastroenterology, Okayama City Hospital, Okayama, Japan
| | - Ei Itobayashi
- Department of Gastroenterology, Asahi General Hospital, Asahi, Japan
| | - Kazuto Tajiri
- Department of Gastroenterology, Toyama University Hospital, Toyama, Japan
| | - Noritomo Shimada
- Division of Gastroenterology and Hepatology, Otakanomori Hospital, Kashiwa, Japan
| | - Hiroshi Shibata
- Department of Gastroenterology, Tokushima Prefectural Central Hospital, Tokushima, Japan
| | - Hironori Ochi
- Hepato-biliary Center, Matsuyama Red Cross Hospital, Matsuyama, Japan
| | - Satoshi Yasuda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, 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
| | - Hideko Ohama
- Second Department of Internal Medicine, Osaka Medical College, Takatsuki, Japan
| | - Kazuhito Kawata
- Hepatology Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Kagawa, Japan
| | - Shinichiro Nakamura
- Department of Internal Medicine, Japanese Red Cross Himeji Hospital, Himeji, Japan
| | - Kazuhiro Nouso
- Department of Gastroenterology, Okayama City Hospital, Okayama, Japan
| | - Akemi Tsutsui
- Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Takuya Nagano
- Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Takaaki Tanaka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan
| | - Norio Itokawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan
| | - Tomomi Okubo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan
| | - Taeang Arai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan
| | - Michitaka Imai
- Department of Gastroenterology, Saiseikai Niigata Hospital, Niigata, Japan
| | - Kouji Joko
- Hepato-biliary Center, Matsuyama Red Cross Hospital, Matsuyama, Japan
| | - Yohei Koizumi
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Matsuyama, Japan
| | - Yoichi Hiasa
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Matsuyama, Japan
| | - Margherita Rimini
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Francesca Ratti
- Hepatobiliary Surgery Division, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Luca Aldrighetti
- Hepatobiliary Surgery Division, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Stefano Cascinu
- Department of Medical Oncology, San Raffaele Scientific Institute IRCCS, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Andrea Casadei-Gardini
- Department of Medical Oncology, San Raffaele Scientific Institute IRCCS, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
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9
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Zhang H, Zhang E, Hu H. Role of Ferroptosis in Non-Alcoholic Fatty Liver Disease and Its Implications for Therapeutic Strategies. Biomedicines 2021; 9:biomedicines9111660. [PMID: 34829889 PMCID: PMC8615581 DOI: 10.3390/biomedicines9111660] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 11/05/2021] [Indexed: 12/14/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become the chronic liver disease with the highest incidence throughout the world, but its pathogenesis has not been fully elucidated. Ferroptosis is a novel form of programmed cell death caused by iron-dependent lipid peroxidation. Abnormal iron metabolism, lipid peroxidation, and accumulation of polyunsaturated fatty acid phospholipids (PUFA-PLs) can all trigger ferroptosis. Emerging evidence indicates that ferroptosis plays a critical role in the pathological progression of NAFLD. Because the liver is the main organ for iron storage and lipid metabolism, ferroptosis is an ideal target for liver diseases. Inhibiting ferroptosis may become a new therapeutic strategy for the treatment of NAFLD. In this article, we describe the role of ferroptosis in the progression of NAFLD and its related mechanisms. This review will highlight further directions for the treatment of NAFLD and the selection of corresponding drugs that target ferroptosis.
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Affiliation(s)
- Han Zhang
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100080, China;
| | - Enxiang Zhang
- Key Laboratory of Growth Regulation and Transformation Research of Zhejiang Province, School of Life Sciences, Westlake Institute for Advanced Study, Westlake University, Hangzhou 310024, China
- Correspondence: (E.Z.); (H.H.)
| | - Hongbo Hu
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100080, China;
- Correspondence: (E.Z.); (H.H.)
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10
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Fahmy A, Hopkins AM, Sorich MJ, Rowland A. Evaluating the utility of therapeutic drug monitoring in the clinical use of small molecule kinase inhibitors: a review of the literature. Expert Opin Drug Metab Toxicol 2021; 17:803-821. [PMID: 34278936 DOI: 10.1080/17425255.2021.1943357] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Introduction: Orally administered small molecule kinase inhibitors (KI) are a key class of targeted anti-cancer medicines that have contributed substantially to improved survival outcomes in patients with advanced disease. Since the introduction of KIs in 2001, there has been a building body of evidence that the benefit derived from these drugs may be further enhanced by individualizing dosing on the basis of concentration.Areas covered: This review considers the rationale for individualized KI dosing and the requirements for robust therapeutic drug monitoring (TDM). Current evidence supporting TDM-guided KI dosing is presented and critically evaluated, and finally potential approaches to address translational challenges for TDM-guided KI dosing and alternate approaches to support individualization of KI dosing are discussed.Expert opinion: Intuitively, the individualization of KI dosing through an approach such as TDM-guided dosing has great potential to enhance the effectiveness and tolerability of these drugs. However, based on current literature evidence it is unrealistic to propose that TDM-guided KI dosing should be routinely implemented into clinical practice.
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Affiliation(s)
- Alia Fahmy
- College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
| | - Ashley M Hopkins
- College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
| | - Michael J Sorich
- College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
| | - Andrew Rowland
- College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
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11
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Ghaziani TT, Dhanasekaran R. Recent Progress in Systemic Therapy for Hepatocellular Cancer (HCC). CURRENT TREATMENT OPTIONS IN GASTROENTEROLOGY 2021; 19:351-368. [PMID: 35530750 DOI: 10.1007/s11938-021-00346-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Purpose of Review The management of advanced hepatocellular (HCC) has drastically changed in the past few years with approval of several first line and second line systemic therapies. In this review we present an overview of the recent progress in the treatment of advanced HCC and discuss future perspectives. Recent Findings The phase 3 clinical trial IMBRAVE150 has recently shown the combination of an immune checkpoint inhibitor, atezolizumab, with an anti-angiogenic agent, bevacizumab, to be superior to sorafenib monotherapy for treatment-naive advanced HCC. Moreover, patients now have multiple options available in second-line therapy including targeted therapies like sorafenib, lenvatinib, regorafenib, cabozantinib, ramucirumab and immunotherapies like atezolizumab, and nivolumab either alone or combined with ipilimumab. Summary There has been tremendous recent progress in the management of advanced HCC. Combination therapy with atezolizumab-bevacizumab has recently become the standard first line of therapy for patients with advanced HCC. Additionally, immunotherapy agents are poised to play a significant role in the management of HCC either alone or in combination with molecular targeted therapies.
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Affiliation(s)
- T Tara Ghaziani
- Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA
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12
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Unfried JP, Sangro P, Prats-Mari L, Sangro B, Fortes P. The Landscape of lncRNAs in Hepatocellular Carcinoma: A Translational Perspective. Cancers (Basel) 2021; 13:2651. [PMID: 34071216 PMCID: PMC8197910 DOI: 10.3390/cancers13112651] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 05/24/2021] [Accepted: 05/25/2021] [Indexed: 02/07/2023] Open
Abstract
LncRNAs are emerging as relevant regulators of multiple cellular processes involved in cell physiology as well as in the development and progression of human diseases, most notably, cancer. Hepatocellular carcinoma (HCC) is a prominent cause of cancer-related death worldwide due to the high prevalence of causative factors, usual cirrhotic status of the tumor-harboring livers and the suboptimal benefit of locoregional and systemic therapies. Despite huge progress in the molecular characterization of HCC, no oncogenic loop addiction has been identified and most genetic alterations remain non-druggable, underscoring the importance of advancing research in novel approaches for HCC treatment. In this context, long non-coding RNAs (lncRNAs) appear as potentially useful targets as they often exhibit high tumor- and tissue-specific expression and many studies have reported an outstanding dysregulation of lncRNAs in HCC. However, there is a limited perspective of the potential role that deregulated lncRNAs may play in HCC progression and aggressiveness or the mechanisms and therapeutic implications behind such effects. In this review, we offer a clarifying landscape of current efforts to evaluate lncRNA potential as therapeutic targets in HCC using evidence from preclinical models as well as from recent studies on novel oncogenic pathways that show lncRNA-dependency.
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Affiliation(s)
- Juan Pablo Unfried
- Center for Applied Medical Research (CIMA), Department of Gene Therapy and Regulation of Gene Expression, Universidad de Navarra (UNAV), 31008 Pamplona, Spain; (L.P.-M.); (P.F.)
| | - Paloma Sangro
- Liver Unit, Clínica Universidad de Navarra (CUN), 31008 Pamplona, Spain;
| | - Laura Prats-Mari
- Center for Applied Medical Research (CIMA), Department of Gene Therapy and Regulation of Gene Expression, Universidad de Navarra (UNAV), 31008 Pamplona, Spain; (L.P.-M.); (P.F.)
| | - Bruno Sangro
- Liver Unit, Clínica Universidad de Navarra (CUN), 31008 Pamplona, Spain;
- Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain
- Liver and Digestive Diseases Networking Biomedical Research Centre (CIBERehd), 31008 Pamplona, Spain
| | - Puri Fortes
- Center for Applied Medical Research (CIMA), Department of Gene Therapy and Regulation of Gene Expression, Universidad de Navarra (UNAV), 31008 Pamplona, Spain; (L.P.-M.); (P.F.)
- Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain
- Liver and Digestive Diseases Networking Biomedical Research Centre (CIBERehd), 31008 Pamplona, Spain
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13
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Cersosimo RJ. Systemic targeted and immunotherapy for advanced hepatocellular carcinoma. Am J Health Syst Pharm 2021; 78:187-202. [PMID: 33211092 DOI: 10.1093/ajhp/zxaa365] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
PURPOSE The activity of targeted agents and immunotherapy in the management of advanced hepatocellular carcinoma (HCC) is reviewed. SUMMARY The first drug approved by the Food and Drug Administration for advanced HCC, sorafenib, was approved in 2007. Regorafenib, the second drug, was approved 10 years later. Six additional drugs have been approved since. Targeted agents and checkpoint inhibitors are the only agents approved for systemic therapy of advanced HCC. Sorafenib and lenvatinib are approved as first-line agents, with regorafenib, cabozantinib, ramucirumab, nivolumab (used alone or with ipilimumab), and pembrolizumab approved for patients who have received prior sorafenib therapy. Most patients in phase 3 studies had Child-Pugh class A cirrhosis, and data on the use of these agents in patients with more advanced hepatic dysfunction are limited. All of the targeted agents improve survival in patients with advanced disease. Median overall survival durations of up to 12.3 and 13.6 months were reported with use of sorafenib and lenvatinib, respectively, in phase 3 trials. Overall survival durations of 10.6, 10.2, and 9.2 months have been achieved with use of regorafenib, cabozantinib, and ramucirumab as second-line therapy after sorafenib. A median overall survival of 13.2 months was reported in 1 cohort of a dose-expansion study of nivolumab in which all patients received prior sorafenib therapy. Median survival durations of 12.9 months and 13.9 months were reported with use of pembrolizumab in patients with a history of sorafenib therapy. The most common adverse effects associated with targeted agents are dermatological effects, diarrhea, fatigue, and hypertension. Immune-mediated adverse effects are associated with checkpoint inhibitors. CONCLUSION Targeted agents and checkpoint inhibitors are the standard of therapy for patients who need systemic therapy for advanced HCC.
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Affiliation(s)
- Robert J Cersosimo
- School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, MA, and Veterans Affairs Medical Center, Boston, MA
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14
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Hsieh MH, Kao TY, Hsieh TH, Kao CC, Peng CY, Lai HC, Chuang PH, Kao JT. Prognostic roles of diabetes mellitus and hypertension in advanced hepatocellular carcinoma treated with sorafenib. PLoS One 2021; 15:e0244293. [PMID: 33382703 PMCID: PMC7775090 DOI: 10.1371/journal.pone.0244293] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Accepted: 12/08/2020] [Indexed: 12/09/2022] Open
Abstract
BACKGROUND & AIMS It remains limited whether diabetes mellitus (DM) and hypertension (HTN) affect the prognosis of advanced hepatocellular carcinoma (HCC) treated with sorafenib. Our study attempted to elucidate the roles of DM/HTN and the effects of diabetes medications among advanced HCC patients receiving sorafenib. METHODS From August 2012 to February 2018, 733 advanced HCC patients receiving sorafenib were enrolled at China Medical University, Taichung, Taiwan. According to the presence/absence of DM or HTN, they were divided into four groups: control [DM(-)/HTN(-), n = 353], DM-only [DM(+)/HTN(-), n = 91], HTN-only [DM(-)/HTN(+), n = 184] and DM+HTN groups [DM(+)/HTN(+), n = 105]. Based on the types of diabetes medications, there were three groups among DM patients (the combined cohort of DM-only and DM+HTN groups), including metformin (n = 63), non-metformin oral hypoglycemic agent (OHA) (n = 104) and regular insulin (RI)/neutral protamine hagedorn (NPH) groups (n = 29). We then assessed the survival differences between these groups. RESULTS DM-only and DM+HTN groups significantly presented longer overall survival (OS) than control group (control vs. DM-only, 7.70 vs. 11.83 months, p = 0.003; control vs. DM+HTN, 7.70 vs. 11.43 months, p = 0.008). However, there was no significant OS difference between control and HTN-only group (7.70 vs. 8.80 months, p = 0.111). Besides, all groups of DM patients showed significantly longer OS than control group (control vs. metformin, 7.70 vs. 12.60 months, p = 0.011; control vs. non-metformin OHA, 7.70 vs. 10.80 months, p = 0.016; control vs. RI/NPH, 7.70 vs. 15.20 months, p = 0.026). CONCLUSIONS Rather than HTN, DM predicts better prognosis in advanced HCC treated with sorafenib. Besides, metformin, non-metformin OHA and RI/NPH are associated with longer survival among DM-related advanced HCC patients receiving sorafenib.
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Affiliation(s)
- Ming-Han Hsieh
- Department of Medicine, School of Medicine, China Medical University, Taichung, Taiwan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Tzu-Yu Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Ting-Hui Hsieh
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Chun-Chi Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Cheng-Yuan Peng
- Department of Medicine, School of Medicine, China Medical University, Taichung, Taiwan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Hsueh-Chou Lai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Po-Heng Chuang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Jung-Ta Kao
- Department of Medicine, School of Medicine, China Medical University, Taichung, Taiwan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
- * E-mail:
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15
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Kulik L, da Fonseca LG, He AR, Rimola J, Wilson Woods A, Zöllner YF, Galle PR. Potential Impact of IMbrave150 Results in the Evolving Treatment Landscape of Advanced Hepatocellular Carcinoma: A Multidisciplinary Expert Opinion. J Hepatocell Carcinoma 2020; 7:423-433. [PMID: 33376711 PMCID: PMC7762763 DOI: 10.2147/jhc.s274930] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 11/10/2020] [Indexed: 12/22/2022] Open
Abstract
A virtual expert roundtable was convened on April 16, 2020, to discuss the evolving landscape of care for treating patients with advanced hepatocellular carcinoma (HCC) and discuss questions related to patient care and treatment selection. This commentary presents highlights from this discussion and provides an expert opinion about approaches to treatment for HCC in the Americas and the European Union. We anticipate that atezolizumab plus bevacizumab will become the standard of care for advanced HCC patients. However, this approach will make decisions regarding the sequencing of treatments for second-line therapies and beyond more challenging. Therapy will require individualization based on patient characteristics and preferences, while insurance coverage decisions and requirements may also impact the options that patients can access. Additional research regarding prognostic and predictive biomarkers is needed to help better identify optimal treatment approaches for specific patient populations. Multidisciplinary tumor boards will continue to play a critical role in guiding treatment selection for individual patients. Atezolizumab plus bevacizumab offers a promising new first-line therapeutic option for patients with advanced HCC, but more research is needed to optimize and individualize patient therapy.
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Affiliation(s)
| | | | | | - Jordi Rimola
- Radiology Department, Hospital Clínic de Barcelona, Barcelona, Catalonia, Spain
| | - Andrea Wilson Woods
- Blue Faery: The Adrienne Wilson Liver Cancer Association, Birmingham, AL, USA
| | - York F Zöllner
- Hamburg University of Applied Sciences, Competence Center Health, Hamburg, Germany
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16
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Winters AC, Bedier F, Saab S. Management of Side Effects of Systemic Therapies for Hepatocellular Carcinoma: Guide for the Hepatologist. Clin Liver Dis 2020; 24:755-769. [PMID: 33012457 DOI: 10.1016/j.cld.2020.07.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Historically, systemic treatment of advanced hepatocellular carcinoma was limited to the tyrosine kinase inhibitor sorafenib. With the recent approval of several new agents the armamentarium of treatment options available to providers and patients has expanded. Although these promising advances offer hope for patients with advanced hepatocellular carcinoma, they also present new and challenging adverse effects that threaten to limit their efficacy. Immunotherapy with checkpoint inhibitors introduce immune-related adverse events, which may affect a wide array of organ systems. With prompt recognition, however, common side effects of systemic therapies for hepatocellular carcinoma are predictable, manageable, and many improve with appropriate intervention.
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Affiliation(s)
- Adam C Winters
- Pfleger Liver Institute, 200 Medical Plaza Driveway, Suite 214, Los Angeles, CA 90095, USA
| | - Fatima Bedier
- Pfleger Liver Institute, 200 Medical Plaza Driveway, Suite 214, Los Angeles, CA 90095, USA
| | - Sammy Saab
- Pfleger Liver Institute, 200 Medical Plaza Driveway, Suite 214, Los Angeles, CA 90095, USA.
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17
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Shomura M, Okabe H, Sato E, Fukai K, Shiraishi K, Hirose S, Tsuruya K, Arase Y, Anzai K, Kagawa T. Hypothyroidism is a Predictive Factor for Better Clinical Outcomes in Patients with Advanced Hepatocellular Carcinoma Undergoing Lenvatinib Therapy. Cancers (Basel) 2020; 12:cancers12113078. [PMID: 33105621 PMCID: PMC7690372 DOI: 10.3390/cancers12113078] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 10/16/2020] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Patients with advanced hepatocellular carcinoma (HCC) undergoing molecular targeted therapy often experience non-negligible adverse events (AEs). Paradoxically, certain AEs are reportedly associated with a good prognosis. We aimed to identify factors predictive of treatment duration and overall survival (OS) in patients with HCC undergoing lenvatinib therapy. This study suggested that better baseline liver function was predictive of longer treatment duration and better prognosis in patients with advanced HCC treated with lenvatinib. Moreover, an AE of Grade 2/3 hypothyroidism was associated with a better prognosis in patients receiving lenvatinib treatment for advanced HCC. Continuing anticancer therapy with appropriate thyroid hormone replacement may contribute to longer survival. Abstract Patients with advanced hepatocellular carcinoma (HCC) undergoing molecular targeted therapy often experience non-negligible adverse events (AEs). Paradoxically, certain AEs are reportedly associated with a good prognosis. We aimed to identify factors predictive of treatment duration and overall survival (OS) in patients with HCC undergoing lenvatinib therapy. Forty-six consecutive patients with advanced HCC who received lenvatinib therapy from April 2018 to November 2019 were prospectively followed until November 2019. Treatment efficacy was assessed according to the modified Response Evaluation Criteria in Solid Tumors for 2–3 months after therapy initiation. The disease control rate (DCR) was defined as the percentage of patients with a complete response, partial response, or stable disease. The DCR was 65.2%, with a median survival of 10.2 months. Grade 2/3 hypoalbuminemia resulted in shorter treatment duration. Factors predictive of longer OS were a Child-Pugh score of 5 at baseline and the occurrence of Grade 2/3 hypothyroidism. Conversely, Grade 2/3 hypoalbuminemia was associated with a poorer prognosis. An AE of Grade 2/3 hypothyroidism was associated with a better prognosis in patients receiving lenvatinib treatment for advanced HCC. Continuing anticancer therapy with appropriate thyroid hormone replacement may contribute to longer OS.
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Affiliation(s)
- Masako Shomura
- Faculty of Nursing, Tokai University School of Medicine, 143 Shimokasuya Isehara City, Kanagawa 2591193, Japan; (H.O.); (E.S.)
- Correspondence: ; Tel.: +81-463-90-2035
| | - Haruka Okabe
- Faculty of Nursing, Tokai University School of Medicine, 143 Shimokasuya Isehara City, Kanagawa 2591193, Japan; (H.O.); (E.S.)
| | - Emi Sato
- Faculty of Nursing, Tokai University School of Medicine, 143 Shimokasuya Isehara City, Kanagawa 2591193, Japan; (H.O.); (E.S.)
| | - Kota Fukai
- Department of Preventive Medicine, Tokai University School of Medicine, 143 Shimokasuya Isehara City, Kanagawa 2591193, Japan;
| | - Koichi Shiraishi
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, 143 Shimokasuya Isehara City, Kanagawa 2591193, Japan; (K.S.); (S.H.); (K.T.); (Y.A.); (K.A.); (T.K.)
| | - Shunji Hirose
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, 143 Shimokasuya Isehara City, Kanagawa 2591193, Japan; (K.S.); (S.H.); (K.T.); (Y.A.); (K.A.); (T.K.)
| | - Kota Tsuruya
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, 143 Shimokasuya Isehara City, Kanagawa 2591193, Japan; (K.S.); (S.H.); (K.T.); (Y.A.); (K.A.); (T.K.)
| | - Yoshitaka Arase
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, 143 Shimokasuya Isehara City, Kanagawa 2591193, Japan; (K.S.); (S.H.); (K.T.); (Y.A.); (K.A.); (T.K.)
| | - Kazuya Anzai
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, 143 Shimokasuya Isehara City, Kanagawa 2591193, Japan; (K.S.); (S.H.); (K.T.); (Y.A.); (K.A.); (T.K.)
| | - Tatehiro Kagawa
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, 143 Shimokasuya Isehara City, Kanagawa 2591193, Japan; (K.S.); (S.H.); (K.T.); (Y.A.); (K.A.); (T.K.)
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18
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Lin Z, Chen B, Hung Y, Huang P, Shen Y, Shao Y, Hsu C, Cheng A, Lee R, Chao Y, Hsu C. A Multicenter Phase II Study of Second-Line Axitinib for Patients with Advanced Hepatocellular Carcinoma Failing First-Line Sorafenib Monotherapy. Oncologist 2020; 25:e1280-e1285. [PMID: 32271494 PMCID: PMC7485356 DOI: 10.1634/theoncologist.2020-0143] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Accepted: 02/18/2020] [Indexed: 12/24/2022] Open
Abstract
LESSONS LEARNED For patients with advanced hepatocellular carcinoma after failure of first-line sorafenib monotherapy, second-line axitinib provides modest efficacy with tolerable toxicity. The discrepant tumor responses and survival outcomes in trials using axitinib as salvage therapy highlight the importance of optimal patient selection with the aid of clinical biomarkers. BACKGROUND Multikinase inhibitors have been effective treatment for hepatocellular carcinoma (HCC). This multicenter phase II study explored the efficacy and safety of second-line axitinib for advanced HCC. METHODS Patients with advanced HCC and Child-Pugh A liver function, experiencing progression on first-line sorafenib monotherapy, were eligible. Axitinib 5 mg twice daily was given continuously with allowed dose escalation. Tumor assessment was performed according to RECIST version 1.1. The primary endpoint was rate of disease control. RESULTS From April 2011 to March 2016, 45 patients were enrolled. Thirty-seven patients (82%) tested positive for hepatitis B surface antigen. The disease control rate was 62.2%, and the response rate was 6.7%, according to RECIST criteria. Median progression-free survival (PFS) and overall survival (OS) were 2.2 months and 10.1 months, respectively. Treatment-related adverse events were compatible with previous reports of axitinib. CONCLUSION Second-line axitinib has moderate activity and acceptable toxicity for patients with advanced HCC after failing the first-line sorafenib monotherapy.
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Affiliation(s)
- Zhong‐Zhe Lin
- Department of Medical Oncology, National Taiwan University Cancer CenterTaipeiTaiwan
- Department of Oncology, National Taiwan University HospitalTaipeiTaiwan
- Department of Internal Medicine, National Taiwan University College of MedicineTaipeiTaiwan
| | - Bang‐Bin Chen
- Department of Radiology, National Taiwan University HospitalTaipeiTaiwan
| | - Yi‐Ping Hung
- Department of Oncology, Taipei Veterans General HospitalTaipeiTaiwan
| | - Po‐Hsiang Huang
- Department of Oncology, National Taiwan University HospitalTaipeiTaiwan
| | - Ying‐Chun Shen
- Department of Medical Oncology, National Taiwan University Cancer CenterTaipeiTaiwan
- Department of Oncology, National Taiwan University HospitalTaipeiTaiwan
- Graduate Institute of Oncology, National Taiwan University College of MedicineTaipeiTaiwan
| | - Yu‐Yun Shao
- Department of Oncology, National Taiwan University HospitalTaipeiTaiwan
- Graduate Institute of Oncology, National Taiwan University College of MedicineTaipeiTaiwan
| | - Chih‐Hung Hsu
- Department of Medical Oncology, National Taiwan University Cancer CenterTaipeiTaiwan
- Department of Oncology, National Taiwan University HospitalTaipeiTaiwan
- Graduate Institute of Oncology, National Taiwan University College of MedicineTaipeiTaiwan
| | - Ann‐Lii Cheng
- Department of Medical Oncology, National Taiwan University Cancer CenterTaipeiTaiwan
- Department of Oncology, National Taiwan University HospitalTaipeiTaiwan
- Department of Internal Medicine, National Taiwan University College of MedicineTaipeiTaiwan
- Graduate Institute of Oncology, National Taiwan University College of MedicineTaipeiTaiwan
| | - Rheun‐Chuan Lee
- Department of Radiology, Taipei Veterans General HospitalTaipeiTaiwan
| | - Yee Chao
- Department of Oncology, Taipei Veterans General HospitalTaipeiTaiwan
- School of Medicine, National Yang‐Ming UniversityTaipeiTaiwan
| | - Chiun Hsu
- Department of Medical Oncology, National Taiwan University Cancer CenterTaipeiTaiwan
- Department of Oncology, National Taiwan University HospitalTaipeiTaiwan
- Graduate Institute of Oncology, National Taiwan University College of MedicineTaipeiTaiwan
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Hu J, Zhou ZY, Ran HL, Yuan XC, Zeng X, Zhang ZY. Diagnosis of liver tumors by multimodal ultrasound imaging. Medicine (Baltimore) 2020; 99:e21652. [PMID: 32769936 PMCID: PMC7593067 DOI: 10.1097/md.0000000000021652] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 05/30/2020] [Accepted: 07/08/2020] [Indexed: 12/12/2022] Open
Abstract
To investigate the diagnostic value of multimodal ultrasound imaging composed of conventional ultrasonography (US), contrast-enhanced ultrasonography (CEUS), and shear wave elastography (SWE) for liver tumors.Between October 2017 and October 2019, US, CEUS, and SWE examinations of a total of 158 liver tumors in 136 patients at The First Affiliated Hospital of Nanchang University were performed. The histopathological or imaging diagnostic results were used as controls to evaluate the sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of US, CEUS, SWE, and multimodal ultrasound imaging, which combines these 3 modes, in the differential diagnosis of benign and malignant liver tumors.Among the 158 tumors, there were 64 benign tumors, including 55 cases of hepatic hemangioma, 3 cases of focal nodular hyperplasia of the liver, 4 cases of hepatic cyst, and 2 cases of focal nonuniform distribution of fat in the liver. There were 94 malignant tumors, including 32 cases of hepatocellular carcinoma, 22 cases of intrahepatic cholangiocellular carcinoma, 29 cases of metastatic liver cancer, and 11 cases of dysplastic nodules in cirrhotic liver. In the diagnosis of benign and malignant liver tumors, the sensitivity, specificity, accuracy, positive predictive value, and negative predictive value were 82.56%, 68.06%, 75.96%, 75.53%, and 76.56% for US; 92.39%, 86.36%, 89.87%, 90.43%, and 89.06% for CEUS; 87.14%, 76.81%, 82.91%, 82.98%, and 82.81% for SWE; and 97.85%, 95.38%, 96.83%, 96.81%, and 96.88% for multimodal ultrasound imaging, respectively. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value were all significantly higher for multimodal ultrasound imaging than those values for US, CEUS, and SWE (all P < .05). The areas under the receiver operating characteristic curve for US, CEUS, SWE, and multimodal ultrasound imaging in the diagnosis of benign and malignant liver tumors were 0.760, 0.897, 0.829, and 0.968, respectively.US, CEUS, and SWE all have diagnostic value in the diagnosis of benign and malignant liver tumors. Multimodal ultrasound imaging could significantly increase the accuracy of the diagnosis of benign and malignant liver tumors and has higher value for clinical application.
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Affiliation(s)
- Jia Hu
- Department of Medical Ultrasound, The First Affiliated Hospital of Nanchang University
| | - Zhi-Yu Zhou
- College of Traditional Chinese Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Hong-Ling Ran
- Department of Medical Ultrasound, The First Affiliated Hospital of Nanchang University
| | - Xin-Chun Yuan
- Department of Medical Ultrasound, The First Affiliated Hospital of Nanchang University
| | - Xi Zeng
- Department of Medical Ultrasound, The First Affiliated Hospital of Nanchang University
| | - Zhe-Yuan Zhang
- Department of Medical Ultrasound, The First Affiliated Hospital of Nanchang University
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Zhang W, Liu Y, Fu Y, Han W, Xu H, Wen L, Deng Y, Liu K. RETRACTED: Long non-coding RNA LINC00160 functions as a decoy of microRNA-132 to mediate autophagy and drug resistance in hepatocellular carcinoma via inhibition of PIK3R3. Cancer Lett 2020; 478:22-33. [PMID: 32067991 DOI: 10.1016/j.canlet.2020.02.014] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 01/16/2020] [Accepted: 02/12/2020] [Indexed: 02/07/2023]
Abstract
This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the authors. Following the publication of the above article, the authors found that “LINC00160 did not affect Atg5 and P65 protein expression in HCC cells, which was inconsistent with the result of this paper. Furthermore, we apologize to the readership of the Journal for any inconvenience caused.” Additionally, after publication, the journal was made aware of comments in relation to this article (https://pubpeer.com/publications/333AE65483683ADF50A723BE34AD62). The authors have not responded to our request to respond to these comments.
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Affiliation(s)
- Wei Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, 130021, PR China
| | - Yahui Liu
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, 130021, PR China
| | - Yu Fu
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, 130021, PR China
| | - Wei Han
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, 130021, PR China
| | - Hongji Xu
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, 130021, PR China
| | - Lijia Wen
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, 130021, PR China
| | - Yu Deng
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, 130021, PR China
| | - Kai Liu
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, 130021, PR China.
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Kim BH, Park JW, Kim JS, Lee SK, Hong EK. Stem Cell Markers Predict the Response to Sorafenib in Patients with Hepatocellular Carcinoma. Gut Liver 2020; 13:342-348. [PMID: 30600675 PMCID: PMC6529171 DOI: 10.5009/gnl18345] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Revised: 09/18/2018] [Accepted: 09/24/2018] [Indexed: 12/12/2022] Open
Abstract
Background/Aims Sorafenib remains the only approved molecular targeted agent for hepatocellular carcinoma (HCC); however, reliable biomarkers that predict its efficacy are still lacking. The aim of this study was to explore whether cancer stem cell (CSC) markers have a predictive role with regard to the sorafenib response in HCC patients. Methods We enrolled 47 patients with HCC for whom tumor samples obtained before starting sorafenib treatment were available. RNA was extracted from formalin-fixed, paraffin-embedded samples, and real-time polymerase chain reaction was used to quantify mRNA expression of the CSC genes EpCAM, CD13, CK8, CD24, CD44, CD90, CD133, SALL4, ALDH1A1, ALB, and AFP. Results Of 47 patients, 14.9% and 74.5% had vascular invasion and extrahepatic spread, respectively. Patients with low CD133 expression tended to have longer progression-free survival (PFS) than those with high CD133 expression (5.5 months vs 4.0 months), although without statistical significance. The expression levels of other markers were not associated with PFS. When examining markers in combination, patients with high CD133 and CD90 expression had shorter PFS rates than those with low expression (2.7 months vs 5.5 months; p=0.04). Patients with low CD133 and EpCAM expression demonstrated better PFS than those with high expression (7.0 months vs 4.2 months; p=0.04). Multivariable analysis indicated that an Eastern Cooperative Oncology Group performance status score of 1 and high CD133/CD90 expression were significantly associated with shorter PFS. Conclusions Overexpression of the CSC markers CD133 and CD90 in HCC was associated with poorer response to sorafenib. These two genes may serve as predictive biomarkers for sorafenib therapy.
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Affiliation(s)
- Bo Hyun Kim
- Center for Liver Cancer,Division of Clinical Research, Research Institute, National Cancer Center, Goyang, Korea.,Common Cancer Branch, Division of Clinical Research, Research Institute, National Cancer Center, Goyang, Korea
| | - Joong-Won Park
- Center for Liver Cancer,Division of Clinical Research, Research Institute, National Cancer Center, Goyang, Korea.,Common Cancer Branch, Division of Clinical Research, Research Institute, National Cancer Center, Goyang, Korea
| | - Jin Sook Kim
- Common Cancer Branch, Division of Clinical Research, Research Institute, National Cancer Center, Goyang, Korea
| | - Sook-Kyung Lee
- Common Cancer Branch, Division of Clinical Research, Research Institute, National Cancer Center, Goyang, Korea
| | - Eun Kyung Hong
- Center for Liver Cancer,Division of Clinical Research, Research Institute, National Cancer Center, Goyang, Korea
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As Clinical Markers, Hand-Foot-Skin Reaction and Diarrhea Can Predict Better Outcomes for Hepatocellular Carcinoma Patients Receiving Transarterial Chemoembolization plus Sorafenib. Can J Gastroenterol Hepatol 2019; 2019:2576349. [PMID: 31815114 PMCID: PMC6877904 DOI: 10.1155/2019/2576349] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Revised: 07/13/2019] [Accepted: 07/28/2019] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Combination therapy of transarterial chemoembolization plus sorafenib (TACE-S) has been proven to be safe and effective for hepatocellular carcinoma (HCC); however, this combination therapy is associated with a high incidence of adverse events (AEs). Our study focused on the relationships between AEs and treatment outcomes and aimed to discover AE-based clinical markers that can predict the survival benefits of combination treatment. METHODS From January 2010 to June 2014, a total of 235 HCC patients treated with TACE-S were retrospectively enrolled. Major sorafenib-related AEs were prospectively recorded, and their correlations with overall survival (OS) were analysed using time-dependent covariate Cox regression analyses. RESULTS The majority of the patients (200, 85.1%) were male, and the median age was 51 years old. After two years of follow-up, the median OS of the study population reached 12.4 months. In all, 218 patients (92.8%) presented at least one AE, and 174 (74.0%) suffered AEs ≥2 grade. Based on time-dependent multivariate analyses, the development of hand-foot skin reaction (HFSR) ≥2 grade (HR = 0.43, 95% CI: 0.32-0.58, P < 0.001) and diarrhoea ≥1 grade (HR = 0.72, 95% CI: 0.53-0.97, P=0.029) were identified as independent predictors of prolonged OS. Moreover, patients who developed both HFSR ≥2 grade and diarrhoea ≥1 grade achieved better outcomes than those patients who developed either or neither of these AEs (HR = 1.51, 95% CI: 1.11-2.06, P=0.009). CONCLUSIONS The development of HFSR ≥2 grade or diarrhoea ≥1 grade during TACE-S treatment indicated prolonged OS, and these AEs should be considered important clinical markers for predicting patient prognoses.
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ANGPT2 and NOS3 Polymorphisms and Clinical Outcome in Advanced Hepatocellular Carcinoma Patients Receiving Sorafenib. Cancers (Basel) 2019; 11:cancers11071023. [PMID: 31330833 PMCID: PMC6679015 DOI: 10.3390/cancers11071023] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 07/16/2019] [Accepted: 07/17/2019] [Indexed: 12/23/2022] Open
Abstract
Sorafenib represents the standard of care for advanced hepatocellular carcinoma (HCC), even though a large number of patients have reported limited efficacy. The aim of the present study was to evaluate the prognostic value of single-nucleotide polymorphisms on angiopoietin-2 (ANGPT2) and endothelial-derived nitric oxide synthase (NOS3) genes in 135 patients with advanced HCC receiving sorafenib. Eight ANGPT2 polymorphisms were analyzed by direct sequencing in relation to overall survival (OS) and progression-free survival (PFS). In univariate analysis, ANGPT2rs55633437 and NOS3 rs2070744 were associated with OS and PFS. In particular, patients with ANGPT2rs55633437 TT/GT genotypes had significantly lower median OS (4.66 vs. 15.5 months, hazard ratio (HR) 4.86, 95% CI 2.73–8.67, p < 0.001) and PFS (1.58 vs. 6.27 months, HR 4.79, 95% CI 2.73–8.35, p < 0.001) than those homozygous for the G allele. Moreover, patients with NOS3 rs2070744 TC/CC genotypes had significantly higher median OS (15.6 vs. 9.1 months, HR 0.65, 95% CI 0.44–0.97; p = 0.036) and PFS (7.03 vs. 3.5 months, HR 0.43, 95% CI 0.30–0.63; p < 0.001) than patients homozygous for the T allele. Multivariate analysis confirmed these polymorphisms as independent prognostic factors. Our results suggest that ANGPT2rs55633437 and NOS3 rs2070744 polymorphisms could identify a subset of HCC patients more resistant to sorafenib.
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Hatanaka T, Kakizaki S, Uehara D, Nagashima T, Ueno T, Namikawa M, Saito S, Hosonuma K, Suzuki H, Naganuma A, Takagi H, Sato K, Uraoka T. Impact of the Prognostic Nutritional Index on the Survival of Japanese Patients with Hepatocellular Carcinoma Treated with Sorafenib: A Multicenter Retrospective Study. Intern Med 2019; 58:1835-1844. [PMID: 30918170 PMCID: PMC6663544 DOI: 10.2169/internalmedicine.1594-18] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Objective The purpose of this multicenter retrospective study was to investigate the impact of the prognostic nutritional index (PNI) on the survival of Japanese patients with hepatocellular carcinoma (HCC) treated with sorafenib. Methods A total of 178 HCC patients from May 2009 to December 2015 at our affiliated hospitals was included in this study. The PNI was calculated as follows: 10×serum albumin (g/dL) +0.005×total lymphocyte count (per mm3). The patients were divided into two groups according to the cut-off value of the PNI and as calculated by a receiver operating characteristic curve analysis. Results The optimum cut-off value of the PNI was set at 46.8. We defined the 33 patients with a PNI≥46.8 as the PNI-high group and the 145 patients with a PNI<46.8 as the PNI-low group. The response rate was 20.0% in the PNI-high group and 8.1% in the PNI-low group, without any statistically significance (p=0.09). The duration of sorafenib therapy and the overall survival in the PNI-high group were significantly better than those in the PNI-low group. The PNI-high group was thus found to be a predictive factor associated with the duration of sorafenib therapy [hazard ratio (HR) 0.58; 95% confidence interval (CI) 0.39-0.87, p=0.008] and overall survival (HR 0.62; 95% CI 0.39-0.99, p=0.046) in a multivariate analysis. Conclusion The PNI is a simple and useful marker for predicting the survival of patients with HCC treated with sorafenib.
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Affiliation(s)
- Takeshi Hatanaka
- Department of Gastroenterology, Gunma Saiseikai Maebashi Hospital, Japan
| | - Satoru Kakizaki
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Japan
| | - Daisuke Uehara
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Japan
| | - Tamon Nagashima
- Department of Gastroenterology, Shibukawa Medical Center, National Hospital Organization, Japan
| | - Takashi Ueno
- Department of Internal Medicine, Isesaki Municipal Hospital, Japan
| | - Masashi Namikawa
- Department of Internal Medicine, Kiryu Kosei General Hospital, Japan
| | - Shuichi Saito
- Department of Gastroenterology, Tomioka General Hospital, Japan
| | | | - Hideyuki Suzuki
- Department of Internal Medicine, Haramachi Red Cross Hospital, Japan
| | - Atsushi Naganuma
- Department of Gastroenterology, Takasaki General Medical Center, National Hospital Organization, Japan
| | - Hitoshi Takagi
- Department of Gastroenterology and Hepatology, Kusunoki Hospital, Japan
| | - Ken Sato
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Japan
| | - Toshio Uraoka
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Japan
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Samie HAA, Saeed M, Faisal SM, Kausar MA, Kamal MA. Recent Findings on Nanotechnology-based Therapeutic Strategies Against Hepatocellular Carcinoma. Curr Drug Metab 2019; 20:283-291. [DOI: 10.2174/1389200220666190308134351] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2018] [Revised: 12/14/2018] [Accepted: 02/14/2019] [Indexed: 02/07/2023]
Abstract
Background:
Nanotechnology-based therapies are emerging as a promising new anticancer approach.
Early clinical studies suggest that nanoparticle-based therapeutics can show enhanced efficacy while reducing side
effects minimal, owing to targeted delivery and active intracellular uptake.
Methods:
To overcome the problems of gene and drug delivery, nanotechnology based delivery system gained interest
in the last two decades. Encouraging results from Nano formulation based drug delivery systems revealed that
these emerging restoratives can efficiently lead to more effective, targeted, selective and efficacious delivery of chemotherapeutic
agents to the affected target cells.
Results:
Nanotechnology not only inhibits targeted gene products in patients with cancer, but also taught us valuable
lessons regarding appropriate dosages and route of administrations. Besides, nanotechnology based therapeutics
holds remarkable potential as an effective drug delivery system. We critically highlight the recent findings on
nanotechnology mediated therapeutics strategies to combat hepatocellular carcinoma and discuss how nanotechnology
platform can have enhanced anticancer effects compared with the parent therapeutic agents they contain.
Conclusion:
In this review, we discussed the key challenges, recent findings and future perspective in the development
of effective nanotechnology-based cancer therapeutics. The emphasis here is focused on nanotechnology-based
therapies that are likely to affect clinical investigations and their implications for advancing the treatment of patients
with hepatocellular carcinoma.
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Affiliation(s)
- Hany A. Abdel Samie
- Department of Zoology, Faculty of Science, Menoufia University, Al Minufya, Egypt
| | - Mohd Saeed
- Department of Biology, College of Sciences, University of Hail, Hail, Saudi Arabia
| | - Syed Mohd Faisal
- Molecular Immunology Laboratory, Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh-202002, India
| | - Mohd Adnan Kausar
- Department of Biochemistry, College of Medicine, University of Hail, Saudi Arabia
| | - Mohammad A. Kamal
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
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Grieb BC, Goff LW, Goyal L, Denlinger CS. Evolving Landscape of Systemic Therapy for Hepatocellular Carcinoma: Breakthroughs, Toxicities, and Future Frontiers. Am Soc Clin Oncol Educ Book 2019; 39:248-260. [PMID: 31099615 DOI: 10.1200/edbk_237555] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The incidence and death rates of hepatocellular carcinoma (HCC) are rising. For more than a decade, the multikinase inhibitor sorafenib was the only U.S. Food and Drug Administration (FDA)-approved systemic therapy for HCC. However, since 2017, five additional agents have been approved in the first- or second-line setting. Although this represents an incredible victory for the field, there are no clear guidelines for agent selection on the basis of either patient or tumor characteristics. Here, we review the available systemic therapy options for advanced HCC and reported clinical data for each. We outline each agent's unique toxicity profile, potential impact on patient quality of life, monitoring recommendations, and supportive strategies. Last, we review molecular and immunologic classifications of HCC as well as preclinical data that may serve as a basis for future biomarker enriched clinical trials to enable precision oncology care in HCC.
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Affiliation(s)
- Brian C Grieb
- 1 Vanderbilt-Ingram Cancer Center and Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
| | - Laura W Goff
- 1 Vanderbilt-Ingram Cancer Center and Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
| | - Lipika Goyal
- 2 Department of Medicine, Massachusetts General Hospital Cancer Center, and Harvard Medical School, Boston, MA
| | - Crystal S Denlinger
- 3 Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA
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Rimassa L, Danesi R, Pressiani T, Merle P. Management of adverse events associated with tyrosine kinase inhibitors: Improving outcomes for patients with hepatocellular carcinoma. Cancer Treat Rev 2019; 77:20-28. [PMID: 31195212 DOI: 10.1016/j.ctrv.2019.05.004] [Citation(s) in RCA: 144] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Revised: 05/10/2019] [Accepted: 05/13/2019] [Indexed: 12/24/2022]
Abstract
Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer. Sorafenib, regorafenib, lenvatinib and cabozantinib are tyrosine kinase inhibitors (TKIs) that target, in part, vascular endothelial growth factor receptors, and are approved in various regions of the world for the treatment of advanced HCC. All these agents are associated with a range of adverse events (AEs) that can have a substantial impact on patients' health-related quality of life. Fatigue, diarrhoea, hand-foot skin reaction, nausea, vomiting, decreased appetite, hypertension and weight loss are among the most common AEs experienced with these four TKIs. In this review, we discuss strategies for the management of these AEs in patients with advanced HCC, with the aim of maximizing treatment benefits and minimizing the need for TKI treatment discontinuation. We also consider potential TKI-drug interactions and discuss the use of TKIs in patients with liver dysfunction or who have experienced tumour recurrence after liver transplantation. Use of appropriate AE management strategies and avoidance of contraindicated drugs should help patients with advanced HCC to achieve optimal outcomes with TKIs.
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Affiliation(s)
- Lorenza Rimassa
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center - IRCCS, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Romano Danesi
- Clinical Pharmacology and Pharmacogenetics Unit, Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 67, Pisa, Italy
| | - Tiziana Pressiani
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center - IRCCS, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Philippe Merle
- Department of Hepatology, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Université Lyon 1, 103 Grande rue de la Croix Rousse, Lyon, France.
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Chien SC, Chen CY, Cheng PN, Liu YS, Cheng HC, Chuang CH, Chang TT, Chiu HC, Lin YJ, Chiu YC. Combined Transarterial Embolization/Chemoembolization-Based Locoregional Treatment with Sorafenib Prolongs the Survival in Patients with Advanced Hepatocellular Carcinoma and Preserved Liver Function: A Propensity Score Matching Study. Liver Cancer 2019; 8:186-202. [PMID: 31192155 PMCID: PMC6547299 DOI: 10.1159/000489790] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Accepted: 04/26/2018] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Sorafenib is the standard treatment for patients with Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma (HCC). However, the treatment outcome is not satisfactory. We retrospectively analyzed whether adding transarterial embolization/chemoembolization (TA(C)E)-based locoregional therapy to sorafenib can further improve treatment efficacy. PATIENTS AND METHODS We included 147 BCLC stage C HCC patients with Child-Turcotte-Pugh class A liver function and treated with sorafenib for analysis. Through propensity score matching, we divided patients into the combined treatment group (n = 63; patients received TA(C)E-based locoregional treatment and sorafenib) and the sorafenib monotherapy group (n = 63). We analyzed the effects of patients' clinical and tumor-related factors on their overall survival (OS) and time to tumor progression. RESULTS The OS was better in the combined treatment group than in the sorafenib monotherapy group (419 vs. 223 days, p = 0.028). In the Cox regression model, combined treatment, a lower baseline α-fetoprotein (AFP) level < 400 ng/mL, tumors without main portal venous tumorous thrombosis, and age ≥60 years were identified as independent factors for OS. Subgroup analysis demonstrated that patients with a higher baseline AFP level > 400 ng/mL, age < 60 years, tumors with branched portal venous tumorous thrombosis only or without extrahepatic metastasis benefited the most from combined treatment. CONCLUSION Combining TA(C)E-based locoregional treatment with sorafenib resulted in better OS in patients with BCLC stage C HCC compared with sorafenib alone. TA(C)E-based locoregional treatment can be an adjunctive treatment to sorafenib for patients with advanced HCC and a satisfactory liver functional reserve.
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Affiliation(s)
- Shih-Chieh Chien
- Division of Gastroenterology and Hepatology, Department of Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chiung-Yu Chen
- Division of Gastroenterology and Hepatology, Department of Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Pin-Nan Cheng
- Division of Gastroenterology and Hepatology, Department of Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yi-Shan Liu
- Division of Gastroenterology and Hepatology, Department of Radiology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Hsiu-Chi Cheng
- Division of Gastroenterology and Hepatology, Department of Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chiao-Hsiung Chuang
- Division of Gastroenterology and Hepatology, Department of Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Ting-Tsung Chang
- Division of Gastroenterology and Hepatology, Department of Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Hong-Chi Chiu
- Division of Gastroenterology and Hepatology, Department of Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yih-Jyh Lin
- Division of Transplant surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yen-Cheng Chiu
- Division of Gastroenterology and Hepatology, Department of Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan,*Yen-Cheng Chiu, MD, Division of Gastroenterology and Hepatology, Department of Medicine, National Cheng Kung University Hospital, #138 Sheng-Li Road, Tainan 704 (Taiwan, ROC), E-Mail
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Autophagy as a molecular target for cancer treatment. Eur J Pharm Sci 2019; 134:116-137. [PMID: 30981885 DOI: 10.1016/j.ejps.2019.04.011] [Citation(s) in RCA: 254] [Impact Index Per Article: 42.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Revised: 04/04/2019] [Accepted: 04/05/2019] [Indexed: 12/22/2022]
Abstract
Autophagy is an evolutionarily conserved catabolic mechanism, by which eukaryotic cells recycle or degrades internal constituents through membrane-trafficking pathway. Thus, autophagy provides the cells with a sustainable source of biomolecules and energy for the maintenance of homeostasis under stressful conditions such as tumor microenvironment. Recent findings revealed a close relationship between autophagy and malignant transformation. However, due to the complex dual role of autophagy in tumor survival or cell death, efforts to develop efficient treatment strategies targeting the autophagy/cancer relation have largely been unsuccessful. Here we review the two-faced role of autophagy in cancer as a tumor suppressor or as a pro-oncogenic mechanism. In this sense, we also review the shared regulatory pathways that play a role in autophagy and malignant transformation. Finally, anti-cancer therapeutic agents used as either inhibitors or inducers of autophagy have been discussed.
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Lee SW, Lee TY, Yang SS, Tong CF, Yeh HZ, Chang CS. Sorafenib-Related Adverse Events in Predicting the Early Radiologic Responses of Hepatocellular Carcinoma. Gastroenterology Res 2019; 12:16-20. [PMID: 30834030 PMCID: PMC6396795 DOI: 10.14740/gr1109] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Accepted: 12/10/2018] [Indexed: 12/11/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) has a poor prognosis with low chemotherapeutic efficiency to medications except to sorafenib. Previous studies showed that adverse events (AEs) of sorafenib can predict therapy efficacy to HCC. The aim of the study is to evaluate the early efficacy and AEs of sorafenib therapy. Methods The database of HCC patients receiving sorafenib at Taichung Veterans General Hospital during the period from June 2012 to October 2016 was analyzed. All HCC cases were Barcelona Clinic Liver Cancer (BCLC) classification stage C. The early efficacy of sorafenib was classified according to the mRECIST criteria as either partial response (PR), stable disease (SD) or progressive disease (PD). Responses were recorded within 6 weeks after the start of sorafenib treatment. AEs were defined as the appearance of hand-foot skin reaction (HFSR), hypertension (HTN) and diarrhea. Exclusion criteria were poor performance status, poor drug compliance, discontinued follow-up or mortality occurring within 1 day after medication. Results From a total of 222 subjects, eight cases (3.6%) were classified as PR, 82 cases (36.9%) SD, and 132 cases (59.5%) PD. The PR group had the highest ratio of HFSR (62.4%) and hypertension (37.5%). Pooling cases of PR and SD together, the presence of HFSR adjusted odd ratio (aOR) 2.80, 95% confidence interval (CI) 1.52 - 5.16) and diarrhea (aOR 3.42, 95% CI 1.67 - 7.01) were good predictors of favorable responses to sorafenib therapy. Conclusions HFSR and diarrhea are good predictors of early therapy efficacy to the sorafenib treatment.
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Affiliation(s)
- Shou-Wu Lee
- Division of Gastroenterology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.,Department of Internal Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Teng-Yu Lee
- Division of Gastroenterology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.,Department of Internal Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Sheng-Shun Yang
- Division of Gastroenterology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.,Department of Internal Medicine, Yang-Ming University, Taipei, Taiwan
| | - Chun-Fang Tong
- Division of Gastroenterology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Hong-Zen Yeh
- Division of Gastroenterology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.,Department of Internal Medicine, Yang-Ming University, Taipei, Taiwan
| | - Chi-Sen Chang
- Division of Gastroenterology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.,Department of Internal Medicine, Chung Shan Medical University, Taichung, Taiwan
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Sun Y, Yang L, Hao X, Liu Y, Zhang J, Ning Z, Shi Y. Phase I dose-escalation study of chiauranib, a novel angiogenic, mitotic, and chronic inflammation inhibitor, in patients with advanced solid tumors. J Hematol Oncol 2019; 12:9. [PMID: 30642372 PMCID: PMC6332596 DOI: 10.1186/s13045-018-0695-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Accepted: 12/27/2018] [Indexed: 02/03/2023] Open
Abstract
Background Chiauranib is a novel orally active multi-target inhibitor that simultaneously inhibits the angiogenesis-related kinases (VEGFR2, VEGFR1, VEGFR3, PDGFRα, and c-Kit), mitosis-related kinase Aurora B, and chronic inflammation-related kinase CSF-1R. This phase I dose-escalation study was to determine the maximum tolerated dose (MTD), safety, pharmacokinetics, and preliminary antitumor activity of chiauranib in patients with refractory advanced solid tumor and lymphoma. Methods Eighteen patients were treated with continuous dosing of chiauranib from 10 to 65 mg once daily in a dose-escalation 3 + 3 design and evaluated in 28-day cycles. Pharmacokinetic profile of plasma chiauranib was analyzed in both single and multiple dose studies. Results Dose-limiting toxicity (DLT) as of grade 3 hypertension occurred in two patients at 65 mg/day, and one dose level below as MTD was 50 mg/day. The most common treatment-related adverse events included fatigue (61.1%), proteinuria (44.4%), hematuria (38.9%), hypothyroidism (38.9%), hypertriglyceridemia (33.3%), and hypertension (33.3%). A linear and dose-dependent pharmacokinetic profile of chiauranib was characterized with rapid absorption and slow elimination feature in both single and multiple dose studies. The accumulative exposure of chiauranib reached the steady state within 8 days and was approximately increased by twofold as those in the single dose study. No complete or partial response was observed, and 12 patients (66.7%) achieved stable disease (SD). Conclusions Chiauranib demonstrated an acceptable safety and favorable pharmacokinetic profile with potential antitumor activity. Several phase Ib/II clinical studies are currently under further investigation. Trial registration NCT, NCT02122809. Registered 25 April 2014
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Affiliation(s)
- Yongkun Sun
- Department of Medical Oncology, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Lin Yang
- Department of Medical Oncology, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Xuezhi Hao
- Department of Medical Oncology, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Yutao Liu
- Department of Medical Oncology, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Jinwen Zhang
- Shenzhen Chipscreen Biosciences Ltd., BIO-Incubator, Suit 2-601, Shenzhen Hi-Tech Industrial Park, Shenzhen, 518057, Guangdong, China
| | - Zhiqiang Ning
- Shenzhen Chipscreen Biosciences Ltd., BIO-Incubator, Suit 2-601, Shenzhen Hi-Tech Industrial Park, Shenzhen, 518057, Guangdong, China
| | - Yuankai Shi
- Department of Medical Oncology, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China.
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McNamara MG, Slagter AE, Nuttall C, Frizziero M, Pihlak R, Lamarca A, Tariq N, Valle JW, Hubner RA, Knox JJ, Amir E. Sorafenib as first-line therapy in patients with advanced Child-Pugh B hepatocellular carcinoma-a meta-analysis. Eur J Cancer 2018; 105:1-9. [PMID: 30384012 DOI: 10.1016/j.ejca.2018.09.031] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Revised: 09/09/2018] [Accepted: 09/26/2018] [Indexed: 01/10/2023]
Abstract
BACKGROUND Sorafenib has demonstrated survival benefit in first-line treatment of advanced hepatocellular carcinoma (HCC); utility of sorafenib in patients with advanced HCC and Child-Pugh B (CP-B) liver function remains a subject of debate. METHODS A systematic review identified studies using first-line sorafenib in patients with advanced HCC and CP-A/B liver function. Meta-regression analysis comprising linear regression was conducted to explore the association between the baseline factors and overall survival (OS). Differences between efficacy/safety and tolerability parameters were explored using meta-analysis. RESULTS Thirty studies (12 Asian) comprising 8678 patients (August 2002 - September 2012) were included (four randomised controlled trials, 26 cohort studies). Median age was 61 years and 83% were men. Hepatitis B/C status was positive in 35%/22%, respectively. The CP status was available for 8577 patients (99%); CP-A, 79% and CP-B, 19%. Median OS on sorafenib for entire cohort was 7.2 months; 8.8 months in CP-A and 4.6 months in CP-B. Multivariable meta-regression analysis showed significant negative association between OS and proportion of patients with the Eastern Cooperative Oncology Group performance status 2 (P = 0.04) and CP-B liver function (P = 0.001). Among four studies reporting multivariable comparison of the CP status, CP-B was associated with significantly worse OS (P < 0.001). There were no differences in the response rate to sorafenib between patients with CP-A (4.6%) and CP-B (4.2%) liver function. Safety and tolerability were similar; 35% of patients with CP-A/B liver function developed grade III/IV adverse events (P = 0.7). Meta-regression analysis showed similar rates of treatment discontinuation without progression (P = 0.31) and treatment-related death (P = 0.94) in patients with CP-B liver function. CONCLUSION CP-B liver function (versus CP-A) is associated with worse OS (but the similar response rate, safety and tolerability of first-line sorafenib, is unlikely to be clinically meaningful).
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Affiliation(s)
- Mairéad Geraldine McNamara
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, UK; University of Manchester, Division of Cancer Sciences, Manchester, M20 4BX, UK.
| | - Astrid E Slagter
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, UK; University of Amsterdam, the Netherlands
| | - Christina Nuttall
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, UK
| | - Melissa Frizziero
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, UK
| | - Rille Pihlak
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, UK; University of Manchester, Division of Cancer Sciences, Manchester, M20 4BX, UK
| | - Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, UK
| | - Noor Tariq
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, UK; University of Manchester, Division of Cancer Sciences, Manchester, M20 4BX, UK
| | - Juan W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, UK; University of Manchester, Division of Cancer Sciences, Manchester, M20 4BX, UK
| | - Richard A Hubner
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, UK
| | - Jennifer J Knox
- Department of Medical Oncology, Princess Margaret Cancer Centre/University of Toronto, 610 University Avenue, Toronto, Ontario, M5G 2M9, Canada
| | - Eitan Amir
- Department of Medical Oncology, Princess Margaret Cancer Centre/University of Toronto, 610 University Avenue, Toronto, Ontario, M5G 2M9, Canada
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Lee SW, Lee TY, Yang SS, Peng YC, Yeh HZ, Chang CS. Specific adverse events predict survival rates in a Chinese population diagnosed with hepatocellular carcinoma and treated with sorafenib. JGH OPEN 2018; 3:10-16. [PMID: 30834335 PMCID: PMC6386742 DOI: 10.1002/jgh3.12096] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Revised: 08/28/2018] [Accepted: 08/30/2018] [Indexed: 01/30/2023]
Abstract
Hepatocellular carcinoma (HCC) is associated with a poor prognosis and a low chemotherapeutic efficiency except for when sorafenib is administered. The aim of this study was to evaluate the efficacy and adverse events (AEs) of sorafenib therapy in a Chinese population diagnosed with HCC. Method Data for the subjects with HCC receiving sorafenib at Taichung Veterans General Hospital from June 2012 to October 2016 were evaluated. All enrolled cases belonged to the HCC Barcelona Clinic Liver Cancer (BCLC) classification stage C. The AEs were defined as appearances of hand–foot syndrome reaction (HFSR), hypertension (HTN), or diarrhea. The exclusion criteria included a poor performance status, lack of compliance to drugs, and loss of follow‐up within the following day. Results Of a total of 116 subjects enrolled, there were 43 (37.1%), 13 (11.2%), and 15 (12.9%) cases experiencing HFSR, HTN, and diarrhea, respectively. The cases with AE had both a longer time to progression (TTP) (HFSR 5.16 vs. 3.33 months, P = 0.003; HTN 6.62 vs. 3.68 months, P = 0.001; diarrhea 6.67 vs. 3.61 months, P = 0.001) and overall survival (OS) (HFSR 8.12 vs. 4.75 months, P = 0.001; HTN 9.08 vs. 5.61 months, P = 0.008; diarrhea 8.20 vs. 5.67 months, P = 0.042) than those without. More AEs were correlated with a longer TTP and OS. Conclusion The appearance of sorafenib AEs, including HFSR, HTN, and diarrhea, can predict a positive therapy efficacy to HCC.
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Affiliation(s)
- Shou-Wu Lee
- Division of Gastroenterology, Department of Internal Medicine Taichung Veterans General Hospital Taichung Taiwan.,Department of Internal Medicine Chung Shan Medical University Taichung Taiwan
| | - Teng-Yu Lee
- Division of Gastroenterology, Department of Internal Medicine Taichung Veterans General Hospital Taichung Taiwan.,Department of Internal Medicine Chung Shan Medical University Taichung Taiwan
| | - Sheng-Shun Yang
- Division of Gastroenterology, Department of Internal Medicine Taichung Veterans General Hospital Taichung Taiwan.,Department of Internal Medicine Yang-Ming University Taipei Taiwan
| | - Yen-Chun Peng
- Division of Gastroenterology, Department of Internal Medicine Taichung Veterans General Hospital Taichung Taiwan.,Department of Internal Medicine Yang-Ming University Taipei Taiwan
| | - Hong-Zen Yeh
- Division of Gastroenterology, Department of Internal Medicine Taichung Veterans General Hospital Taichung Taiwan.,Department of Internal Medicine Yang-Ming University Taipei Taiwan
| | - Chi-Sen Chang
- Division of Gastroenterology, Department of Internal Medicine Taichung Veterans General Hospital Taichung Taiwan.,Department of Internal Medicine Chung Shan Medical University Taichung Taiwan
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Peng L, Ye X, Hong Y, Zhang J, Dong Y, Zhao Q. Treatment-related toxicities of apatinib in solid tumors: a meta-analysis. Oncotarget 2018; 9:32262-32270. [PMID: 30181815 PMCID: PMC6114950 DOI: 10.18632/oncotarget.24215] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2017] [Accepted: 11/03/2017] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Apatinib is a novel small molecular drug targeting vascular endothelial growth factor receptor-2 (VEGFR-2), which is being studied in multiple tumor types. We performed a meta-analysis to quantify the overall incidence and risk of hypertension, proteinuria, and hand-foot-syndrome (HFS) in cancer patients receiving apatinib. RESULTS Altogether, 820 cancer patients from 7 prospective trials were included for the meta-analysis. The incidences of all-grade and high-grade hypertension were 45.4% and 9.7%. The incidences of all-grade and high-grade proteinuria were 45.1% and 3.7%. The incidences of all-grade and high-grade HFS were 35.9% and 8.6%. The RRs of all-grade hypertension, proteinuria and HFS of apatinib compared to placebo were increased (hypertension, RR = 6.53; proteinuria, RR = 2.62, and HFS, RR = 11.45). The RRs of developing high-grade hypertension and HFS were substantially higher than that of placebo (hypertension, RR = 7.73; HFS, RR = 7.23), but not for proteinuria (RR = 2.56, 95% CI: 0.57-11.52). MATERIALS AND METHODS Prospective phase II and III clinical trials of cancer patients receiving apatinib were searched and included. Summary incidences, relative risk (RR), and 95% confidence intervals (CI) were calculated by using either fixed or random effects models according to the heterogeneity of the studies. CONCLUSIONS Apatinib is generally well tolerated, and associated with increased risks of all-grade hypertension, proteinuria and HFS, and high-grade hypertension and HFS, but not high-grade proteinuria.
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Affiliation(s)
- Ling Peng
- Department of Thoracic Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Xianghua Ye
- Department of Radiotherapy, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Yun Hong
- Department of Pharmacy, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Junyan Zhang
- Bothwin Clinical Study Consultant, Bellevue, WA, USA
| | - Yongquan Dong
- Department of Respiratory Disease, Yinzhou No.2 Hospital, Ningbo, Zhejiang Province, China
| | - Qiong Zhao
- Department of Thoracic Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
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Wang E, Xia D, Bai W, Wang Z, Wang Q, Liu L, Wang W, Yuan J, Li X, Chen H, Lv Y, Niu J, He C, Guo W, Yin Z, Luo B, Han N, Wang Z, Yu T, Yuan X, Li K, Tie J, Li C, Cai H, Xia J, Fan D, Han G. Hand-foot-skin reaction of grade ≥ 2 within sixty days as the optimal clinical marker best help predict survival in sorafenib therapy for HCC. Invest New Drugs 2018; 37:401-414. [PMID: 30019101 DOI: 10.1007/s10637-018-0640-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2018] [Accepted: 07/09/2018] [Indexed: 12/31/2022]
Abstract
Background & Aims Sorafenib-related adverse events have been reported as clinical surrogates for treatment response in hepatocellular carcinoma (HCC); however, no consensus has been reached regarding the definition of responders. We evaluated the predictive abilities of different definitions for sorafenib response based on treatment-emergent adverse events, aiming to identify the most discriminatory one as a clinical marker. Methods From January 2010 to December 2014, 435 consecutive HCC patients treated with sorafenib were enrolled. Considering the type, severity and timing of adverse events, twelve different categories of sorafenib response were defined. By comparing their discriminatory abilities for survival, an indicative criterion was defined, the prognostic value of which was evaluated by time-dependent multivariate analysis, validated in various subsets and confirmed by landmark analysis. Results Using concordance (C)-index analysis and time-dependent receiver operating characteristic curves, the development of a hand-foot-skin reaction ≥ grade 2 within 60 days of sorafenib initiation (2HFSR60) showed the highest discriminating value. Based on this criterion, 161 (37.0%) sorafenib responders achieved decreased risk of death by 47% (adjusted HR 0.53, 95%CI 0.43-0.67, P < 0.001) and likelihood of progression by 26% (adjusted HR 0.74, 95%CI 0.58-0.96, P = 0.020) compared with non-responders. Notably, 2HFSR60 remained an effective discriminator among most subgroups and had superior predictive ability to previous definitions, even according to the landmark analysis. Conclusions Our study demonstrated that 2HFSR60, with the best discriminatory ability compared to currently available definitions of sorafenib-related adverse events, could be the optimal clinical marker to identify sorafenib responders with decreased risk of death by half.
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Affiliation(s)
- Enxin Wang
- Department of Liver Disease and Digestive Interventional Radiology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 15 West Changle Road, Xi'an, 710032, China
| | - Dongdong Xia
- Department of Liver Disease and Digestive Interventional Radiology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 15 West Changle Road, Xi'an, 710032, China
| | - Wei Bai
- Department of Liver Disease and Digestive Interventional Radiology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 15 West Changle Road, Xi'an, 710032, China
| | - Zhexuan Wang
- Department of Liver Disease and Digestive Interventional Radiology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 15 West Changle Road, Xi'an, 710032, China
| | - Qiuhe Wang
- Department of Liver Disease and Digestive Interventional Radiology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 15 West Changle Road, Xi'an, 710032, China
| | - Lei Liu
- Department of Liver Disease and Digestive Interventional Radiology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 15 West Changle Road, Xi'an, 710032, China
| | - Wenjun Wang
- Department of Liver Disease and Digestive Interventional Radiology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 15 West Changle Road, Xi'an, 710032, China
| | - Jie Yuan
- Department of Liver Disease and Digestive Interventional Radiology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 15 West Changle Road, Xi'an, 710032, China
| | - Xiaomei Li
- Department of Liver Disease and Digestive Interventional Radiology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 15 West Changle Road, Xi'an, 710032, China
| | - Hui Chen
- Department of Liver Disease and Digestive Interventional Radiology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 15 West Changle Road, Xi'an, 710032, China
| | - Yong Lv
- Department of Liver Disease and Digestive Interventional Radiology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 15 West Changle Road, Xi'an, 710032, China
| | - Jing Niu
- Department of Liver Disease and Digestive Interventional Radiology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 15 West Changle Road, Xi'an, 710032, China
| | - Chuangye He
- Department of Liver Disease and Digestive Interventional Radiology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 15 West Changle Road, Xi'an, 710032, China
| | - Wengang Guo
- Department of Liver Disease and Digestive Interventional Radiology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 15 West Changle Road, Xi'an, 710032, China
| | - Zhanxin Yin
- Department of Liver Disease and Digestive Interventional Radiology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 15 West Changle Road, Xi'an, 710032, China
| | - Bohan Luo
- Department of Liver Disease and Digestive Interventional Radiology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 15 West Changle Road, Xi'an, 710032, China
| | - Na Han
- Department of Liver Disease and Digestive Interventional Radiology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 15 West Changle Road, Xi'an, 710032, China
| | - Zhengyu Wang
- Department of Liver Disease and Digestive Interventional Radiology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 15 West Changle Road, Xi'an, 710032, China
| | - Tianlei Yu
- Department of Liver Disease and Digestive Interventional Radiology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 15 West Changle Road, Xi'an, 710032, China
| | - Xulong Yuan
- Department of Liver Disease and Digestive Interventional Radiology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 15 West Changle Road, Xi'an, 710032, China
| | - Kai Li
- Department of Liver Disease and Digestive Interventional Radiology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 15 West Changle Road, Xi'an, 710032, China
| | - Jun Tie
- Department of Liver Disease and Digestive Interventional Radiology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 15 West Changle Road, Xi'an, 710032, China
| | - Chanjuan Li
- Department of Medical Statistics, Fourth Military Medical University, Xi'an, China
| | - Hongwei Cai
- Information Center, School of Stomatology, Fourth Military Medical University, Xi'an, China
| | - Jielai Xia
- Department of Medical Statistics, Fourth Military Medical University, Xi'an, China
| | - Daiming Fan
- Department of Liver Disease and Digestive Interventional Radiology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 15 West Changle Road, Xi'an, 710032, China
- Xijing Hospital of Digestive Diseases & State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, China
| | - Guohong Han
- Department of Liver Disease and Digestive Interventional Radiology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 15 West Changle Road, Xi'an, 710032, China.
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Contratto M, Wu J. Targeted therapy or immunotherapy? Optimal treatment in hepatocellular carcinoma. World J Gastrointest Oncol 2018; 10:108-114. [PMID: 29770170 PMCID: PMC5952267 DOI: 10.4251/wjgo.v10.i5.108] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Revised: 03/14/2018] [Accepted: 04/10/2018] [Indexed: 02/05/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer mortality in the United States and the second leading cause of cancer mortality worldwide. Sorafenib is the only food and drug administration (FDA) approved as first line systemic treatment in HCC. Regorafenib and nivolumab are the only FDA approved second line treatment after progression on sorafenib. We will discuss all potential first and second line options in HCC. In addition, we also will explore sequencing treatment options in HCC, and examine biomarkers that can potentially predict benefits from treatments such as immune checkpoint inhibitor. This minireview summarizes potential treatments in HCC based on clinical trials that have been published in manuscript or abstract format from 1994-2018.
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Affiliation(s)
- Merly Contratto
- Division of Hematology and Oncology, Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016, United States
| | - Jennifer Wu
- Division of Hematology and Oncology, Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016, United States
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Małyszko J, Małyszko M, Kozlowski L, Kozlowska K, Małyszko J. Hypertension in malignancy-an underappreciated problem. Oncotarget 2018; 9:20855-20871. [PMID: 29755695 PMCID: PMC5945504 DOI: 10.18632/oncotarget.25024] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Accepted: 03/19/2018] [Indexed: 12/25/2022] Open
Abstract
Hypertension is one of the most common comorbidities in cancer patients with malignancy, in particular, in the elderly. On the other hand, hypertension is a long-term consequence of antineoplastic treatment, including both chemotherapy and targeted agents. Several chemotherapeutics and targeted drugs may be responsible for development or worsening of the hypertension. The most common side effect of anti-VEGF (vascular endothelial growth factor) treatment is hypertension. However, pathogenesis of hypertension in patients receiving this therapy appears to be associated with multiple pathways and is not yet fully understood. Development of hypertension was associated with improved antitumor efficacy in patients treated with anti-antiangiogenic drugs in some but not in all studies. Drugs used commonly as adjuvants such as steroids, erythropoietin stimulating agents etc, may also cause rise in blood pressure or exacerbate preexisiting hypertension. Hypotensive therapy is crucial to manage hypertension during certain antineoplastic treatment. The choice and dose of antihypertensive drugs depend upon the presence of organ dysfunction, comorbidities, and/or adverse effects. In addition, severity of the hypertension and the urgency of blood pressure control should also be taken into consideration. As there are no specific guidelines on the hypertension treatment in cancer patients we should follow the available guidelines to obtain the best possible outcomes and pay the attention to the individualization of the therapy according to the actual situation.
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Affiliation(s)
- Jolanta Małyszko
- 2nd Department of Nephrology and Hypertension with Dialysis Unit, Medical University in Bialystok, Bialystok, Poland
- Department of Nephrology, Dialysis and Internal Medicine, Warsaw Medical University, Warsaw, Poland
| | - Maciej Małyszko
- 2nd Department of Nephrology and Hypertension with Dialysis Unit, Medical University in Bialystok, Bialystok, Poland
| | - Leszek Kozlowski
- Department of Oncological Surgery, Regional Cancer Center, Bialystok, Poland
| | - Klaudia Kozlowska
- 2nd Department of Nephrology and Hypertension with Dialysis Unit, Medical University in Bialystok, Bialystok, Poland
| | - Jacek Małyszko
- 1st Department of Nephrology and Transplantology with Dialysis Unit, Medical University in Bialystok, Bialystok, Poland
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Chen YC, Chung CC, Lin YK, Chen YJ. Genetic and ethnic modulation of cardiovascular toxicity of vascular endothelial growth factor inhibitors. Ann Med 2018; 50:46-56. [PMID: 28929822 DOI: 10.1080/07853890.2017.1383629] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Vascular endothelial growth factor (VEGF) inhibitors, including monoclonal antibodies and tyrosine kinase inhibitors (TKIs), are important as anticancer treatments through curbing tumour angiogenesis and growth. VEGF inhibitors have significant cardiovascular effects. By blocking VEGF receptors, ligands, or signal pathways, VEGF inhibitors disturb the balance between vasodilation and vasoconstriction, undermine endothelial cell integrity, and activate cardiomyocyte apoptosis. VEGF inhibitors increase risks of hypertension, heart failure, thromboembolism and arrhythmia. Genetic and geographic studies showed that genetic polymorphisms likely play significant predictive or prognostic roles in cardiovascular toxicity associated with VEGF inhibitors. This review updates current understandings of VEGF inhibitors on cardiovascular toxicity, explores potential mechanisms, and clarifies whether genetic or ethnic factors contribute to their adverse effects. Key Messages VEGF inhibitors disturb the balance between vasodilation and vasoconstriction, undermine endothelial cell integrity and activate cardiomyocyte apoptosis. VEGF inhibitors increase risks of hypertension, heart failure, thromboembolism and arrhythmia. Genetic and geographic studies showed that genetic polymorphisms likely play significant predictive or prognostic roles in cardiovascular toxicity associated with VEGF inhibitors.
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Affiliation(s)
- Yen-Chou Chen
- a Division of Cardiovascular Medicine, Department of Internal Medicine , Wan Fang Hospital, Taipei Medical University , Taipei , Taiwan
| | - Cheng-Chih Chung
- a Division of Cardiovascular Medicine, Department of Internal Medicine , Wan Fang Hospital, Taipei Medical University , Taipei , Taiwan.,b Graduate Institute of Clinical Medicine, College of Medicine , Taipei Medical University , Taipei , Taiwan
| | - Yung-Kuo Lin
- a Division of Cardiovascular Medicine, Department of Internal Medicine , Wan Fang Hospital, Taipei Medical University , Taipei , Taiwan
| | - Yi-Jen Chen
- a Division of Cardiovascular Medicine, Department of Internal Medicine , Wan Fang Hospital, Taipei Medical University , Taipei , Taiwan.,b Graduate Institute of Clinical Medicine, College of Medicine , Taipei Medical University , Taipei , Taiwan
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Casadei Gardini A, Marisi G, Faloppi L, Scarpi E, Foschi FG, Iavarone M, Lauletta G, Corbelli J, Valgiusti M, Facchetti F, Della Corte C, Neri LM, Tamberi S, Cascinu S, Scartozzi M, Amadori D, Nanni O, Tenti E, Ulivi P, Frassineti GL. eNOS polymorphisms and clinical outcome in advanced HCC patients receiving sorafenib: final results of the ePHAS study. Oncotarget 2018; 7:27988-99. [PMID: 27058899 PMCID: PMC5053704 DOI: 10.18632/oncotarget.8569] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2016] [Accepted: 03/28/2016] [Indexed: 02/06/2023] Open
Abstract
Sorafenib may reduce endothelial nitric oxide synthase (eNOS) activity by inhibiting vascular endothelial growth factor receptors (VEGF-R), leading to a decrease in nitric oxide production. In the Italian multicenter ePHAS (eNOS polymorphisms in HCC and sorafenib) study, we analyzed the role of eNOS polymorphisms in relation to clinical outcome in patients with hepatocellular carcinoma (HCC) receiving sorafenib. Our retrospective study included a training cohort of 41 HCC patients and a validation cohort of 87 HCC patients, all undergoing sorafenib treatment. Three eNOS polymorphisms (eNOS -786T>C, eNOS VNTR 27bp 4a/b and eNOS+894G>T) were analyzed by direct sequencing or Real Time PCR in relation to progression-free survival (PFS) and overall survival (OS) (log-rank test). In univariate analysis, training cohort patients homozygous for eNOS haplotype (HT1:T-4b at eNOS-786/eNOS VNTR) had a lower median PFS (2.6 vs. 5.8 months, P < 0.0001) and OS (3.2 vs.14.6 months, P = 0.024) than those with other haplotypes. In the validation set, patients homozygous for HT1 had a lower median PFS (2.0 vs. 6.7 months, P < 0.0001) and OS (6.4 vs.18.0 months, P < 0.0001) than those with other haplotypes. Multivariate analysis confirmed this haplotype as the only independent prognostic factor. Our results suggest that haplotype HT1 in the eNOS gene may be capable of identifying a subset of HCC patients who are resistant to sorafenib.
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Affiliation(s)
- Andrea Casadei Gardini
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Giorgia Marisi
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Luca Faloppi
- Department of Medical Oncology, Azienda Ospedaliero Universitaria Ospedali Riuniti, Università Politecnica delle Marche, Ancona, Italy
| | - Emanuela Scarpi
- Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | | | - Massimo Iavarone
- A.M.&A. Migliavacca Center for Liver Disease, 1st Division of Gastroenterology, Fondazione IRCCS Ca' Granda Maggiore Hospital, University of Milan, Milan, Italy
| | - Gianfranco Lauletta
- Department of Biomedical Sciences and Human Oncology, Internal Medicine "G. Baccelli", University of Bari "A. Moro", Bari, Italy
| | - Jody Corbelli
- Department of Medical Oncology, Faenza Hospital, AUSL Romagna, Faenza, Italy
| | - Martina Valgiusti
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Floriana Facchetti
- A.M.&A. Migliavacca Center for Liver Disease, 1st Division of Gastroenterology, Fondazione IRCCS Ca' Granda Maggiore Hospital, University of Milan, Milan, Italy
| | - Cristina Della Corte
- A.M.&A. Migliavacca Center for Liver Disease, 1st Division of Gastroenterology, Fondazione IRCCS Ca' Granda Maggiore Hospital, University of Milan, Milan, Italy
| | - Luca Maria Neri
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Stefano Tamberi
- Department of Medical Oncology, Faenza Hospital, AUSL Romagna, Faenza, Italy
| | - Stefano Cascinu
- Department of Medical Oncology, Azienda Ospedaliero Universitaria Ospedali Riuniti, Università Politecnica delle Marche, Ancona, Italy
| | - Mario Scartozzi
- Department of Medical Oncology, University Hospital Cagliari, Cagliari, Italy
| | - Dino Amadori
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Oriana Nanni
- Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Elena Tenti
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Paola Ulivi
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Giovanni Luca Frassineti
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
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Casadei Gardini A, Scarpi E, Marisi G, Foschi FG, Donati G, Giampalma E, Faloppi L, Scartozzi M, Silvestris N, Bisulli M, Corbelli J, Gardini A, La Barba G, Veneroni L, Tamberi S, Cascinu S, Frassineti GL. Early onset of hypertension and serum electrolyte changes as potential predictive factors of activity in advanced HCC patients treated with sorafenib: results from a retrospective analysis of the HCC-AVR group. Oncotarget 2017; 7:15243-51. [PMID: 26893366 PMCID: PMC4924783 DOI: 10.18632/oncotarget.7444] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2015] [Accepted: 02/09/2016] [Indexed: 12/17/2022] Open
Abstract
Hypertension (HTN) is frequently associated with the use of angiogenesis inhibitors targeting the vascular endothelial growth factor pathway and appears to be a generalized effect of this class of agent. We investigated the phenomenon in 61 patients with advanced hepatocellular carcinoma (HCC) receiving sorafenib. Blood pressure and plasma electrolytes were measured on days 1 and 15 of the treatment. Patients with sorafenib-induced HTN had a better outcome than those without HTN (disease control rate: 63.4% vs. 17.2% (p=0.001); progression-free survival 6.0 months (95% CI 3.2-10.1) vs. 2.5 months (95% CI 1.9-2.6) (p<0.001) and overall survival 14.6 months (95% CI9.7-19.0) vs. 3.9 months (95% CI 3.1-8.7) (p=0.003). Sodium levels were generally higher on day 15 than at baseline (+2.38, p<0.0001) in the group of responders (+4.95, p <0.0001) compared to patients who progressed (PD) (+0.28, p=0.607). In contrast, potassium was lower on day 14 (−0.30, p=0.0008) in the responder group (−0.58, p=0.003) than in those with progressive disease (−0.06, p=0.500). The early onset of hypertension is associated with improved clinical outcome in HCC patients treated with sorafenib. Our data are suggestive of an activation of the renin-angiotensin system in patients with advanced disease who developed HTN during sorafenib treatment.
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Affiliation(s)
- Andrea Casadei Gardini
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Emanuela Scarpi
- Unit of Biostatistics and Clinical Trials, IRST IRCCS, Meldola, Italy
| | | | | | - Gabriele Donati
- Internal Medicine, Infermi Hospital, AUSL Romagna, Rimini, Italy
| | | | - Luca Faloppi
- Department of Medical Oncology, University Hospital of Ancona, Polytechnic University of Marche, Ancona, Italy
| | - Mario Scartozzi
- Departments of Medical Oncology, University Hospital Cagliari, Cagliari, Italy
| | - Nicola Silvestris
- Medical Oncology Unit, Cancer Institute Giovanni Paolo II, Bari, Italy
| | | | - Jody Corbelli
- Unit of Medical Oncology, Hospital of Faenza, AUSL Romagna, Faenza, Italy
| | - Andrea Gardini
- Department of General Surgery, Morgagni-Pierantoni Hospital, AUSL Romagna, Forlì, Italy
| | - Giuliano La Barba
- Department of General Surgery, Morgagni-Pierantoni Hospital, AUSL Romagna, Forlì, Italy
| | - Luigi Veneroni
- Department of General Surgery, Infermi Hospital, AUSL Romagna, Rimini, Italy
| | - Stefano Tamberi
- Departments of Medical Oncology, University Hospital Cagliari, Cagliari, Italy
| | - Stefano Cascinu
- Department of Medical Oncology, University Hospital of Ancona, Polytechnic University of Marche, Ancona, Italy
| | - Giovanni Luca Frassineti
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS, Meldola, Italy
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Díaz-González Á, Forner A, Rodríguez de Lope C, Varela M. New challenges in clinical research on hepatocellular carcinoma. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2017; 108:485-93. [PMID: 26653993 DOI: 10.17235/reed.2015.4012/2015] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
This is an updated review of screening, early diagnosis and treatment of hepatocellular carcinoma, focusing on the advancements occurred in the last years and highlighting the challenges in clinical research. Hepatocellular carcinoma (HCC) is nowadays the sixth most frequent cancer worldwide with up to 740,000 new cases diagnosed each year, and it is the third most prevalent cause of cancer-related-death worldwide (1). This neoplasm usually appears linked to an underlying liver disease, being one of the most relevant causes of death in patients diagnosed of liver cirrhosis (2,3). In the last years, important advancements in terms of diagnosis, staging and treatment of HCC, improving the management and outcome of the disease, have been made (4-7). Despite the fact that these improvements have absolutely changed natural history of HCC, there are several areas that still need further advancements. The aim of this document is to discuss some controversial aspects, which in our opinion constitute real challenges in clinical research of HCC.
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Affiliation(s)
- Álvaro Díaz-González
- Servicio de Hepatología. Hospital Clínic Barcelona, Unidad de Oncología Hepática (BCLC)
| | - Alejandro Forner
- Hospital Clínic Barcelona. Ciberehd, Unidad de Oncología Hepática (BCLC)
| | | | - María Varela
- Digestivo. Sección de Hepatología, Hospital Universitario Central de Asturias, España
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Dual inhibitors of hepatitis C virus and hepatocellular carcinoma: design, synthesis and docking studies. Future Sci OA 2017; 4:FSO252. [PMID: 29255624 PMCID: PMC5729604 DOI: 10.4155/fsoa-2017-0075] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 09/11/2017] [Indexed: 01/06/2023] Open
Abstract
Aim Simultaneous inhibition of hepatitis C virus (HCV) and hepatocellular carcinoma (HCC) may enhance anti-HCV effects and reduce resistance and side effects. Results/methodology Novel hybrid derivatives were designed and synthesized to exhibit dual activity against HCV and its associated major complication, HCC. The synthesized compounds were screened for their potential activity against HCV and HCC. Compounds 5f, 5j, 5l, 5p, 5q, 5r, 6c and 6d exhibited potential in vitro anticancer activity against HCC cell line HepG2, while compounds 5a, 5l, 5p and 5v showed in vitro anti-HCV activity. Docking studies suggested that the newly synthesized compounds could suppress HCC through VEGFR2 tyrosine kinase inhibition. Conclusion Compounds 5l and 5p exhibited dual activity against HCV and HCC in vitro.
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Treatment-related Hypertension as a Pharmacodynamic Biomarker for the Efficacy of Bevacizumab in Advanced Pancreas Cancer: A Pooled Analysis of 4 Prospective Trials of Gemcitabine-based Therapy With Bevacizumab. Am J Clin Oncol 2017; 39:614-618. [PMID: 25068471 DOI: 10.1097/coc.0000000000000108] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
PURPOSE Phase III studies of bevacizumab in advanced pancreas cancer (APCA) demonstrated no improvement in outcome. No validated biomarkers for bevacizumab efficacy exist. We evaluated bevacizumab-related hypertension (B-HTN) as a biomarker in APCA patients in a pooled analysis from 4 prospective clinical trials of gemcitabine-based therapy combined with bevacizumab. MATERIALS AND METHODS Data were collected from individual databases from 4 prospective, single-arm phase II trials. Patients were grouped according to B-HTN or no hypertension (HTN), and patients with HTN were further grouped according to highest Common Terminology Criteria for Adverse Events grade of HTN: grade 1-2 or grade 3-4. Clinical outcomes of overall survival, time to progression, overall response rate (ORR), and disease control rate (ORR+SD>16 wk) were compared. RESULTS A total of 163 patients with stage IV APCA and Eastern Cooperative Oncology Group 0-1 were included. Median age was 59 years (range, 33 to 85 y). Thirty-four patients had B-HTN, and 129 patients had no HTN. Prognostic factors were balanced between groups. Patients with any grade B-HTN had a significantly improved median overall survival (13.1 vs. 8.1 mo, P=0.0006), median time to tumor progression (7.6 vs. 5.5 mo, P=0.0074), ORR (47% vs. 16%, P=0.0001), and disease control rate (85% vs. 59%, P=0.004). There were no differences in outcomes according to HTN grade (1-2 [N=16] vs. 3-4 [N=18]). CONCLUSIONS APCA patients who develop any grade of B-HTN appear to derive benefit from bevacizumab. Additional investigation is needed to identify subgroups of patients who develop B-HTN and are more likely to benefit from bevacizumab.
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Validation of a Simple Scoring System to Predict Sorafenib Effectiveness in Patients with Hepatocellular Carcinoma. Target Oncol 2017; 12:795-803. [DOI: 10.1007/s11523-017-0522-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Le Grazie M, Biagini MR, Tarocchi M, Polvani S, Galli A. Chemotherapy for hepatocellular carcinoma: The present and the future. World J Hepatol 2017; 9:907-920. [PMID: 28824742 PMCID: PMC5545136 DOI: 10.4254/wjh.v9.i21.907] [Citation(s) in RCA: 144] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2017] [Revised: 06/20/2017] [Accepted: 07/03/2017] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver. Its relationship to chronic liver diseases, in particular cirrhosis, develops on a background of viral hepatitis, excessive alcohol intake or metabolic steatohepatitis, leads to a high incidence and prevalence of this neoplasia worldwide. Despite the spread of HCC, its treatment it’s still a hard challenge, due to high rate of late diagnosis and to lack of therapeutic options for advanced disease. In fact radical surgery and liver transplantation, the most radical therapeutic approaches, are indicated only in case of early diagnosis. Even local therapies, such as transarterial chemoembolization, find limited indications, leading to an important problem regarding treatment of advanced disease. In this situation, until terminal HCC occurs, systemic therapy is the only possible approach, with sorafenib as the only standard treatment available. Anyway, the efficacy of this drug is limited and many efforts are necessary to understand who could benefit more with this treatment. Therefore, other molecules for a targeted therapy were evaluated, but only regorafenib showed promising results. Beside molecular target therapy, also cytotoxic drugs, in particular oxaliplatin- and gemcitabine-based regimens, and immune-checkpoint inhibitors were tested with interesting results. The future of the treatment of this neoplasia is linked to our ability to understand its mechanisms of resistance and to find novel therapeutic targets, with the objective to purpose individualized approaches to patients affected by advanced HCC.
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Brose MS, Smit J, Lin CC, Pitoia F, Fellous M, DeSanctis Y, Schlumberger M, Tori M, Sugitani I. Timing of multikinase inhibitor initiation in differentiated thyroid cancer. Endocr Relat Cancer 2017; 24:237-242. [PMID: 28270435 PMCID: PMC5446590 DOI: 10.1530/erc-17-0016] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2017] [Accepted: 03/07/2017] [Indexed: 12/14/2022]
Abstract
There are limited treatment options for patients with radioactive iodine refractory, progressive differentiated thyroid cancer. Although there is consensus that multikinase inhibitor therapy should be considered in patients with progressive disease with considerable tumor load or symptomatic disease, uncertainty exists on the optimal timing to treat with a multikinase inhibitor, especially for asymptomatic patients. RIFTOS MKI is an international, prospective, open-label, multicenter, noninterventional study with the primary objective to compare the time to symptomatic progression from study entry in asymptomatic patients with radioactive iodine refractory, progressive differentiated thyroid cancer for whom there is a decision to initiate multikinase inhibitors at study entry (cohort 1) with those for whom there is a decision to not initiate multikinase inhibitors at study entry (cohort 2). Secondary endpoints are overall survival and progression-free survival, which will be compared between cohorts 1 and 2. Additional secondary endpoints are postprogression survival from time of symptomatic progression, duration of and response to each systemic treatment regimen and dosing of sorafenib throughout the treatment period. Asymptomatic, multikinase inhibitor-naive patients aged ≥18 years with histologically/cytologically documented differentiated thyroid cancer that is radioactive iodine refractory are eligible. Patients may receive any therapy for differentiated thyroid cancer, including sorafenib or other multikinase inhibitors if indicated and decided on by the treating physician. In total, 700 patients are estimated to be enrolled from >20 countries. Final analysis will be performed once the last enrolled patient has been followed up with for 24 months (ClinicalTrials.gov identifier: Nbib2303444).
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Affiliation(s)
- Marcia S Brose
- Department of Otorhinolaryngology: Head and Neck SurgeryAbramson Cancer Center of the University of Pennsylvania, Stellar-Chance Laboratories Mezzanine, Philadelphia, Pennsylvania, USA
| | - Johannes Smit
- Department of Internal MedicineRadboud University Nijmegen Medical Center, 463 General Internal Medicine, Nijmegen, Netherlands
| | - Chia-Chi Lin
- Department of OncologyNational Taiwan University Hospital, Taipei, Taiwan
| | - Fabian Pitoia
- Division of EndocrinologyHospital de Clínicas, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Marc Fellous
- Bayer HealthCare PharmaceuticalsWhippany, New Jersey, USA
| | | | - Martin Schlumberger
- Department of Nuclear Medicine and Endocrine OncologyInstitut Gustave Roussy and Université Paris Saclay, Villejuif, France
| | - Masayuki Tori
- Department of Endocrine SurgeryOsaka Police Hospital, Tennoujiku, Osaka, Japan
| | - Iwao Sugitani
- Department of Endocrine SurgeryNippon Medical School Graduate School of Medicine, Bunkyo-Ku, Tokyo, Japan
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Zhong BY, Ni CF, Chen L, Zhu HD, Teng GJ. Early Sorafenib-related Biomarkers for Combination Treatment with Transarterial Chemoembolization and Sorafenib in Patients with Hepatocellular Carcinoma. Radiology 2017; 284:583-592. [PMID: 28263701 DOI: 10.1148/radiol.2017161975] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Purpose To identify early biomarkers for the prediction of the therapeutic response in patients with hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE) and sorafenib (referred to as TACE plus sorafenib) and establish an effective prognostic nomogram. Materials and Methods The study was approved by the institutional ethics review boards at both participating centers. This retrospective study included all patients with HCC who underwent TACE plus sorafenib therapy between January 2010 and December 2013 at two institutions. On the basis of the overall survival (OS), early biomarkers were identified with univariate and multivariate analyses; then, a prognostic nomogram was established and internally validated by using the concordance c statistic. Results Ninety-seven patients (mean age, 55.0 years; range, 27-89 years) were included. Of these patients, 84 (86.6%) were men. The median OS was 25.7 months. After univariate and multivariate analyses, the onset of sorafenib-induced hypertension and/or dermatologic adverse events (AEs) (grade ≥2) within the first month of sorafenib initiation were demonstrated as independent predictors of OS. The median OS of patients with either of the two independent risk factors was 32.2 months, which was significantly longer than for those patients without (19.8 months; P = .005). Survival analyses showed that the earlier the AEs (sorafenib-related dermatologic AEs or hypertension) occurred, the better the outcome of the combination therapy. A prognostic nomogram was established and showed high accuracy of the nomogram with the c statistic of 0.73. Conclusion The early onset of hypertension and/or sorafenib-related dermatologic AEs are early biomarkers for the clinical prognosis of patients with HCC treated with TACE plus sorafenib. © RSNA, 2017.
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Affiliation(s)
- Bin-Yan Zhong
- From the Department of Radiology, Zhong-Da Hospital, Medical School, Southeast University, 87 Dingjiaqiao Road, Nanjing 210009, China (B.Y.Z., L.C., H.D.Z., G.J.T.); and Department of Interventional Radiology, First Affiliated Hospital of Soochow University, Suzhou, China (C.F.N.)
| | - Cai-Fang Ni
- From the Department of Radiology, Zhong-Da Hospital, Medical School, Southeast University, 87 Dingjiaqiao Road, Nanjing 210009, China (B.Y.Z., L.C., H.D.Z., G.J.T.); and Department of Interventional Radiology, First Affiliated Hospital of Soochow University, Suzhou, China (C.F.N.)
| | - Li Chen
- From the Department of Radiology, Zhong-Da Hospital, Medical School, Southeast University, 87 Dingjiaqiao Road, Nanjing 210009, China (B.Y.Z., L.C., H.D.Z., G.J.T.); and Department of Interventional Radiology, First Affiliated Hospital of Soochow University, Suzhou, China (C.F.N.)
| | - Hai-Dong Zhu
- From the Department of Radiology, Zhong-Da Hospital, Medical School, Southeast University, 87 Dingjiaqiao Road, Nanjing 210009, China (B.Y.Z., L.C., H.D.Z., G.J.T.); and Department of Interventional Radiology, First Affiliated Hospital of Soochow University, Suzhou, China (C.F.N.)
| | - Gao-Jun Teng
- From the Department of Radiology, Zhong-Da Hospital, Medical School, Southeast University, 87 Dingjiaqiao Road, Nanjing 210009, China (B.Y.Z., L.C., H.D.Z., G.J.T.); and Department of Interventional Radiology, First Affiliated Hospital of Soochow University, Suzhou, China (C.F.N.)
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Real-life experience with sorafenib for the treatment of hepatocellular carcinoma in HIV-infected patients. AIDS 2017; 31:89-95. [PMID: 27755109 DOI: 10.1097/qad.0000000000001293] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
OBJECTIVE To report the real-life results of sorafenib use in a cohort of HIV-infected patients with hepatocellular carcinoma (HCC). METHODS The GEHEP-002 cohort (ClinicalTrials.gov ID: NCT02785835) has recruited 302 HCC cases diagnosed in HIV-infected patients from 32 centers from Spain. RIS-HEP12 study included 44 (14%) cases that have received at least one dose of sorafenib. The overall survival after the start of treatment was the main efficacy outcome. Permanent discontinuation due to adverse events was the primary safety end point. RESULTS Reasons for sorafenib use are HCC recurrence after previous curative therapy (n = 7), progression following transarterial chemoembolization (n = 6) and first treatment against HCC (n = 31). Nineteen (43%) patients harbored Child-Pugh B cirrhosis. Barcelona-Clinic Liver Cancer stage was A 3 (7%), B 6 (14%), C 30 (68%) and D 5 (11%). All patients were on antiretroviral therapy (ART). The median (Q1-Q3) duration of sorafenib treatment was 70 (31-158) days. Median survival was 7.2 months, whereas the median (Q1-Q3) duration of overall survival after the start of treatment was 4 (2-9.7) months. Twenty-six (59%) patients had any grade adverse events and 19 (43%) suffered a decompensation. Discontinuation due to adverse events occurred in 17 (38.6%) patients. There were no modifications or discontinuations of ART. CD4 cell counts and HIV viral load remained stable. CONCLUSION The efficacy of sorafenib under real-life conditions in HIV-infected patients seems lower than that reported in the registration clinical trial. On the contrary, the tolerability of sorafenib appears to be similar to what is seen in patients without HIV infection. Sorafenib does not seem to modify the efficacy of ART.
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Risk of Hypertension With Sorafenib Use in Patients With Cancer: A Meta-Analysis From 20,494 Patients. Am J Ther 2017; 24:e81-e101. [DOI: 10.1097/mjt.0000000000000331] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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