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Jayabalan D, Dhakal S, Raguragavan A, Saxena A, Jeffrey GP, Calzadilla-Bertot L, Adams LA, Wallace MC. Hepatocellular Carcinoma and Health-Related Quality of Life: A Systematic Review of Outcomes From Systemic Therapies. Int J Hepatol 2025; 2025:1083642. [PMID: 40230581 PMCID: PMC11996279 DOI: 10.1155/ijh/1083642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2025] [Accepted: 03/20/2025] [Indexed: 04/16/2025] Open
Abstract
Aim: Poor outcomes in advanced hepatocellular carcinoma (HCC) coupled with potential significant treatment side effects underpin a strong rationale to assess health-related quality of life (HRQOL) in those treated with systemic therapies. This study is aimed at quantifying the effect of systemic therapies on HRQOL outcomes in HCC patients when compared to baseline or placebo, other systemic therapies, and transarterial radioembolisation (TARE). Methods: In May 2024, two independent reviewers searched PubMed, EMBASE, and Google Scholar for studies comparing postsystemic therapy HRQOL scores in adult patients with HCC to baseline or placebo, other systemic therapies, or to TARE. Narrative synthesis was used to synthesise results. Risk of bias was assessed using RoB 2 and ROBINS-I. This review was structured according to PRISMA guidelines and was prospectively registered in the PROSPERO register (CRD42024521699). Results: Twenty-nine studies with 10,472 patients using eight HRQOL instruments were included. Compared to baseline, patients on atezolizumab/bevacizumab and sorafenib both experienced significant declines in HRQOL, and lenvatinib nonsignificantly decreased HRQOL. HRQOL remained unchanged in patients on pembrolizumab or nivolumab. Atezolizumab/bevacizumab and lenvatinib both significantly delayed HRQOL deterioration compared to sorafenib. Compared to TARE, atezolizumab/bevacizumab delayed time-to-deterioration in HRQOL, whereas sorafenib had significantly worse HRQOL. Conclusion: Despite worsening HRQOL outcomes compared to baseline, the first-line agents atezolizumab/bevacizumab and lenvatinib had superior HRQOL outcomes in comparison to sorafenib. Sorafenib significantly worsened HRQOL compared to TARE. As the majority of included studies included sorafenib, which has been largely superseded by newer therapies, further trials evaluating HRQOL with these newer therapies are required.
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Affiliation(s)
- Dujinthan Jayabalan
- Department of Hepatology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
- Medical School, The University of Western Australia, Nedlands, Western Australia, Australia
| | - Sugam Dhakal
- Medical School, The University of Western Australia, Nedlands, Western Australia, Australia
| | - Aarohanan Raguragavan
- Medical School, The University of Western Australia, Nedlands, Western Australia, Australia
| | - Akshat Saxena
- Department of Cardiothoracic Surgery, Fiona Stanley Hospital, Murdoch, Western Australia, Australia
| | - Gary P. Jeffrey
- Department of Hepatology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
- Medical School, The University of Western Australia, Nedlands, Western Australia, Australia
| | - Luis Calzadilla-Bertot
- Department of Hepatology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
- Medical School, The University of Western Australia, Nedlands, Western Australia, Australia
| | - Leon A. Adams
- Department of Hepatology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
- Medical School, The University of Western Australia, Nedlands, Western Australia, Australia
| | - Michael C. Wallace
- Department of Hepatology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
- Medical School, The University of Western Australia, Nedlands, Western Australia, Australia
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Simmons DJ, Valerio SJ, Thomas DS, Healey MJ, Jiang Z, Levingston Mac Leod JM, Lin Y, Sah J. Incidence and Costs of Clinically Significant Events with Systemic Therapy in Patients with Unresectable Hepatocellular Carcinoma: A Retrospective Cohort Study. Adv Ther 2024; 41:1711-1727. [PMID: 38443649 PMCID: PMC10960903 DOI: 10.1007/s12325-024-02790-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Accepted: 01/15/2024] [Indexed: 03/07/2024]
Abstract
INTRODUCTION Systemic therapies have been associated with clinically significant events (CSEs) in patients with unresectable hepatocellular carcinoma (uHCC). We evaluated the incidence of CSEs (bleeding, clotting, encephalopathy, and portal hypertension), and their impact on healthcare resource utilization (HCRU) and costs, in patients with uHCC treated with first-line (1L) atezolizumab plus bevacizumab (A + B), lenvatinib (LEN), or sorafenib (SOR) in the USA. METHODS A retrospective cohort study was performed using medical/pharmacy claims from Optum® Clinformatics® Data Mart. Patients diagnosed with HCC who initiated 1L A + B between June 01, 2020 and December 31, 2020 or LEN/SOR between January 01, 2016 and May 31, 2020 were included. Outcomes included incidence rates of CSEs, HCRU, and costs. Subgroup analysis was performed in patients with no CSEs or ≥ 1 CSE. RESULTS In total, 1379 patients were selected (A + B, n = 271; LEN, n = 217; SOR, n = 891). Clotting (incidence rate per 100 patient-years [PY] 94.9) and bleeding (88.1 per 100 PY) were the most common CSEs in the A + B cohort. The most common CSEs in the LEN cohort were clotting (78.6 per 100 PY) and encephalopathy (66.3 per 100 PY). Encephalopathy (73.0 per 100 PY) and portal hypertension (72.3 per 100 PY) were the most common CSEs in the SOR cohort. Mean total all-cause healthcare costs per patient per month (PPPM) were $32,742, $35,623, and $29,173 in the A + B, LEN, and SOR cohorts, respectively. Mean total all-cause healthcare costs PPPM were higher in patients who had ≥ 1 CSE versus those who did not (A + B $34,304 versus $30,889; LEN $39,591 versus $30,621; SOR $31,022 versus $27,003). CONCLUSION Despite improved efficacy of 1L systemic therapies, CSEs remain a concern for patients with uHCC, as well as an economic burden to the healthcare system. Newer treatments that reduce the risk of CSEs, while improving long-term survival in patients with uHCC, are warranted.
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Affiliation(s)
- Daniel J Simmons
- AstraZeneca, 200 Orchard Ridge Drive, Gaithersburg, MD, 20878, USA.
| | | | | | - Marcus J Healey
- AstraZeneca, 200 Orchard Ridge Drive, Gaithersburg, MD, 20878, USA
| | - Zhuoxin Jiang
- AstraZeneca, 200 Orchard Ridge Drive, Gaithersburg, MD, 20878, USA
| | | | - Yian Lin
- AstraZeneca, South San Francisco, CA, USA
| | - Janvi Sah
- AstraZeneca, 200 Orchard Ridge Drive, Gaithersburg, MD, 20878, USA
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Agirrezabal I, Pereira Grillo Junior LS, Nasser F, Brennan VK, Bugano D, Galastri FL, Azeredo-da-Silva ALFD, Shergill S, da Motta-Leal-Filho JM. Cost-effectiveness of selective internal radiation therapy with Y-90 resin microspheres for intermediate- and advanced-stage hepatocellular carcinoma in Brazil. J Med Econ 2023; 26:731-741. [PMID: 37139828 DOI: 10.1080/13696998.2023.2210475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/05/2023]
Abstract
AimsHepatocellular carcinoma (HCC) is a severe condition with poor prognosis that places a significant burden on patients, caregivers, and healthcare systems. Selective internal radiation therapy (SIRT) is a treatment available to patients with HCC which addresses some of the limitations of alternative treatment options. A cost-effectiveness analysis was undertaken into the use of SIRT using Y-90 resin microspheres for the treatment of unresectable, intermediate- and late-stage HCC in Brazil.Materials and methodsA partitioned-survival model was developed, including a tunnel state for patients downstaged to receive treatments with curative intent. Sorafenib was the selected comparator, a common systemic treatment in Brazil and for which comparative evidence exists. Clinical data were extracted from published sources of pivotal trials, and effectiveness was measured in quality-adjusted life-years (QALYs) and life-years (LYs). The analysis was conducted from the Brazilian private payer perspective and a lifetime horizon was implemented. Comprehensive sensitivity analyses were conducted.ResultsLYs and QALYs were higher for SIRT with Y-90 resin microspheres versus sorafenib (0.27 and 0.20 incremental LYs and QALYs, respectively) and costs were slightly higher for SIRT (R$15,864). The base case incremental cost-effectiveness ratio (ICER) was R$77,602 per QALY. The ICER was mostly influenced by parameters defining the sorafenib overall survival curve and SIRT had a 73% probability of being cost-effective at a willingness-to-pay threshold of R$135,761 per QALY (three times the per-capita gross domestic product in Brazil). Overall, sensitivity analyses confirmed the robustness of the results indicating that SIRT with Y-90 resin microspheres is cost-effective compared with sorafenib.LimitationsA rapidly evolving treatment landscape in Brazil and worldwide, and the lack of local data for some variables were the main limitations.ConclusionsSIRT with Y-90 resin microspheres is a cost-effective option compared with sorafenib in Brazil.
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Affiliation(s)
- Ion Agirrezabal
- Sirtex Medical Europe GmbH, Joseph-Schumpeter-Allee 33, 53227 Bonn, Germany
| | - Luiz Sérgio Pereira Grillo Junior
- AFECC - Hospital Santa Rita de Cássia, Av. Mal. Campos, 1579 - Santa Cecilia, Vitória - ES, 29043-260, Brazil
- Unimed Vitória - Hospital Unimed Vitória, R. Marins Alvarino, 365 - Itararé, Vitória - ES, 29047-660, Brazil
| | - Felipe Nasser
- Department of Interventional Radiology, Hospital Israelita Albert Einstein, Av. Albert Einstein, 627, São Paulo, SP, 05652-900, Brazil
| | - Victoria K Brennan
- Sirtex Medical United Kingdom Ltd., Hill House, 1 Little New Street, London, EC4A 3TR, United Kingdom
| | - Diogo Bugano
- Centro de Oncologia do Hospital Israelita Albert Einstein, Rua Ruggero Fasano, s/n., Bloco A - 3° Subsolo, São Paulo, SP, 05653-120, Brazil
| | - Francisco Leonardo Galastri
- Department of Interventional Radiology, Hospital Israelita Albert Einstein, Av. Albert Einstein, 627, São Paulo, SP, 05652-900, Brazil
| | - André Luis F de Azeredo-da-Silva
- Department of Internal Medicine, Hospital de Clinicas de Porto Alegre, Brazil
- HTAnalyze Consultoria e Treinamento Ltda, Porto Alegre, Brazil
| | - Suki Shergill
- Sirtex Medical United Kingdom Ltd., Hill House, 1 Little New Street, London, EC4A 3TR, United Kingdom
| | - Joaquim Maurício da Motta-Leal-Filho
- Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina, Universidade de São Paulo, Av. Dr. Arnaldo, 251, Cerqueira Cesar, São Paulo, SP, 01246-000, Brazil
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Huang T, Qi H, Shen L, Wu Y, Song Z, Cao F, Liu Y, Xie L, Chen S, Tang T, Li H, Zhang Y, Feng L, Zhang H, Chen J, Fan W. Benefits of step-by-step debulking microwave ablation for huge unresectable hepatocellular carcinoma patients after transcatheter arterial chemoembolization refractoriness. Int J Hyperthermia 2022; 39:935-945. [PMID: 35853727 DOI: 10.1080/02656736.2022.2093413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022] Open
Abstract
OBJECTIVES To compare the safety and efficacy of step-by-step debulking Microwave Ablation (MWA) with Transarterial Chemoembolization (TACE) monotherapy for huge (≥10 cm in diameter) unresectable hepatocellular carcinoma (HCC) after TACE refractoriness. METHODS This is a multi-center retrospective study carried out on 599 patients with huge unresectable HCC who received TACE as first-line therapy at five hospitals from January 2009 to December 2018. A total of 103 patients with TACE refractoriness were divided into two cohorts: monthly step-by-step debulking MWA (n = 52) or continued TACE (n = 51). Overall survival (OS) and progression-free survival (PFS) after refractory TACE were evaluated. Residual liver and tumor volume were recorded for the MWA group. RESULTS Median follow-up period was 24.3 months and median OS and PFS were significantly longer in the MWA group than in the TACE group (OS 21.0 vs. 11.7 months, PFS 6.1 vs. 3.0 months, both p < 0.001). The one-, two-, and three-year OS rates in the MWA and TACE groups were 73.1%, 46.6%, and 37.2% versus 43.1%, 15.5%, and 2.9%, respectively. Furthermore, the 0.5-, 1-, and 2-year PFS rates in the MWA and TACE groups were 51.9%, 36.5%, and 25.0% versus 27.5%, 11.8%, and 0, respectively. Multivariate analyses confirmed that switching to debulking MWA treatment was an independent favorable prognostic factor for PFS and OS. In the MWA group, the average additions of residual liver volume/total liver volume were 7.7% ± 6.7%, 7.2% ± 10.2%, and 10.1% ± 8.8% after the first, second, and third MWA procedure. CONCLUSION Step-by-step debulking MWA can significantly improve long-term OS and PFS in patients with huge unresectable HCCs compared with repeated TACE after TACE refractoriness. Key PointThe debulking MWA therapy provides significantly longer OS and PFS than continued TACE for patients with huge unresectable HCCs after TACE-refractory, especially with complete tumor ablation.The most common complications were fever (48.1%) and pain (46.2%) in the MWA group. Two major complications (abdominal infection) were recorded in the MWA group, which recovered after symptomatic treatment.During the course of repeated MWAs, liver hyperplasia appeared mainly after the second MWA procedure and the average maximum increased RLV/TLV rate was 16.3%±12.7%.
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Affiliation(s)
- Tao Huang
- Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou, China
| | - Han Qi
- Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou, China
| | - Lujun Shen
- Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou, China
| | - Ying Wu
- Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou, China
| | - Ze Song
- Department of Oncology, the Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Fei Cao
- Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou, China
| | - Yin Liu
- Department of Oncology, Jinshazhou Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Lin Xie
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Shuanggang Chen
- Department of Oncology, Yue Bei people's Hospital, Shaoguan, China
| | - Tian Tang
- Department of Interventional Therapy, Hunan Cancer Hospital, Changsha, China
| | - Hailiang Li
- Department of Interventional Therapy, Henan Cancer Hospital, Zhengzhou, China
| | - Yanfang Zhang
- Department of Interventional Therapy, Shenzhen people's Hospital, Shenzhen, China
| | - Long Feng
- Department of Oncology, the Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Hao Zhang
- Center for Interventional Medicine, the Affiliated Hospital of Qingdao University, Qingdao, China
| | - Jin Chen
- Department of Radiology, the First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Weijun Fan
- Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou, China
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Serper M, Parikh ND, Thiele G, Ovchinsky N, Mehta S, Kuo A, Ho C, Kanwal F, Volk M, Asrani SK, Ghabril MS, Lake JR, Merriman RB, Morgan TR, Tapper EB. Patient-reported outcomes in HCC: A scoping review by the Practice Metrics Committee of the American Association for the Study of Liver Diseases. Hepatology 2022; 76:251-274. [PMID: 34990516 PMCID: PMC10648308 DOI: 10.1002/hep.32313] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 12/20/2021] [Accepted: 12/20/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND AND AIMS HCC is a leading cause of mortality in patients with advanced liver disease and is associated with significant morbidity. Despite multiple available curative and palliative treatments, there is a lack of systematic evaluation of patient-reported outcomes (PROs) in HCC. APPROACH AND RESULTS The American Association for the Study of Liver Diseases Practice Metrics Committee conducted a scoping review of PROs in HCC from 1990 to 2021 to (1) synthesize the evidence on PROs in HCC and (2) provide recommendations on incorporating PROs into clinical practice and quality improvement efforts. A total of 63 studies met inclusion criteria investigating factors associated with PROs, the relationship between PROs and survival, and associations between HCC therapy and PROs. Studies recruited heterogeneous populations, and most were cross-sectional. Poor PROs were associated with worse prognosis after adjusting for clinical factors and with more advanced disease stage, although some studies showed better PROs in patients with HCC compared to those with cirrhosis. Locoregional and systemic therapies were generally associated with a high symptom burden; however, some studies showed lower symptom burden for transarterial radiotherapy and radiation therapy. Qualitative studies identified additional symptoms not routinely assessed with structured questionnaires. Gaps in the literature include lack of integration of PROs into clinical care to guide HCC treatment decisions, unknown impact of HCC on caregivers, and the effect of palliative or supportive care quality of life and health outcomes. CONCLUSION Evidence supports assessment of PROs in HCC; however, clinical implementation and the impact of PRO measurement on quality of care and longitudinal outcomes need future investigation.
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Affiliation(s)
- Marina Serper
- Division of Gastroenterology and Hepatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
- Section of Gastroenterology, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania, USA
- Leonard Davis Institute of Health Economics, Philadelphia, Pennsylvania, USA
| | - Neehar D Parikh
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA
| | - Grace Thiele
- Division of Gastroenterology and Hepatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Nadia Ovchinsky
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital at Montefiore-Albert Einstein College of Medicine, Bronx, New York, USA
| | - Shivang Mehta
- Hepatology, Baylor All Saints, Fort Worth, Texas, USA
| | - Alexander Kuo
- Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Chanda Ho
- Department of Transplantation, California Pacific Medical Center, San Francisco, California, USA
| | - Fasiha Kanwal
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
- Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA
- Section of Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
| | - Michael Volk
- Division of Gastroenterology and Transplantation Institute, Loma Linda University, Loma Linda, California, USA
| | - Sumeet K Asrani
- Hepatology, Baylor University Medical Center, Dallas, Texas, USA
| | - Marwan S Ghabril
- Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - John R Lake
- Division of Gastroenterology, Hepatology and Nutrition, University of Minnesota, Minneapolis, Minnesota, USA
| | | | | | - Elliot B Tapper
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA
- Gastroenterology Section, VA Ann Arbor Healthcare System, Ann Arbor, Michigan, USA
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Wohlleber K, Heger P, Probst P, Engel C, Diener MK, Mihaljevic AL. Health-related quality of life in primary hepatic cancer: a systematic review assessing the methodological properties of instruments and a meta-analysis comparing treatment strategies. Qual Life Res 2021; 30:2429-2466. [PMID: 34283381 PMCID: PMC8405513 DOI: 10.1007/s11136-021-02810-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/23/2021] [Indexed: 11/25/2022]
Abstract
PURPOSE Patient-reported outcomes including health-related quality of life (HRQoL) are important oncological outcome measures. The validation of HRQoL instruments for patients with hepatocellular and cholangiocellular carcinoma is lacking. Furthermore, studies comparing different treatment options in respect to HRQoL are sparse. The objective of the systematic review and meta-analysis was, therefore, to identify all available HRQoL tools regarding primary liver cancer, to assess the methodological quality of these HRQoL instruments and to compare surgical, interventional and medical treatments with regard to HRQoL. METHODS A systematic literature search was conducted in MEDLINE, the Cochrane library, PsycINFO, CINAHL and EMBASE. The methodological quality of all identified HRQoL instruments was performed according to the COnsensus-based Standards for the selection of health status Measurements INstruments (COSMIN) standard. Consequently, the quality of reporting of HRQoL data was assessed. Finally, wherever possible HRQoL data were extracted and quantitative analyses were performed. RESULTS A total of 124 studies using 29 different HRQoL instruments were identified. After the methodological assessment, only 10 instruments fulfilled the psychometric criteria and could be included in subsequent analyses. However, quality of reporting of HRQoL data was insufficient, precluding meta-analyses for 9 instruments. CONCLUSION Using a standardized methodological assessment, specific HRQoL instruments are recommended for use in patients with hepatocellular and cholangiocellular carcinoma. HRQoL data of patients undergoing treatment of primary liver cancers are sparse and reporting falls short of published standards. Meaningful comparison of established treatment options with regard to HRQoL was impossible indicating the need for future research.
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Affiliation(s)
- Kerstin Wohlleber
- Department of General, Visceral and Transplant Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany
| | - Patrick Heger
- Department of General, Visceral and Transplant Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany
- The Study Centre of the German Surgical Society (SDGC), University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany
| | - Pascal Probst
- Department of General, Visceral and Transplant Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany
- The Study Centre of the German Surgical Society (SDGC), University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany
| | - Christoph Engel
- Institute for Medical Informatics, Statistics and Epidemiology (IMISE), University of Leipzig, Härtelstraße 16-18, 04107, Leipzig, Germany
| | - Markus K Diener
- Department of General, Visceral and Transplant Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany
- The Study Centre of the German Surgical Society (SDGC), University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany
| | - André L Mihaljevic
- Department of General, Visceral and Transplant Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
- The Study Centre of the German Surgical Society (SDGC), University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
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Health-related quality of life in locally advanced hepatocellular carcinoma treated by either radioembolisation or sorafenib (SARAH trial). Eur J Cancer 2021; 154:46-56. [PMID: 34243077 DOI: 10.1016/j.ejca.2021.05.032] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 05/17/2021] [Accepted: 05/23/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND The aim of this ancillary study of the SARAH trial is to compare health-related quality of life (HRQoL) in patients with locally advanced or inoperable hepatocellular carcinoma (HCC) treated with transarterial radioembolisation (TARE) or sorafenib. METHODS This study included randomised patients who received either TARE or at least one dose of sorafenib with no major deviation in the protocol and who had at least one QoL follow-up assessment in addition to the baseline evaluation. QoL was assessed from the date of randomisation using the European Organisation for Research and Treatment of Cancer QLQ-C30 questionnaire, until disease progression or other reasons for stopping study participation. Data were analysed using linear mixed and time-dependent models. RESULTS A total of 285 patients were included (122 and 163, in the TARE and sorafenib groups, respectively). Questionnaire completion rates were similar (77.5% versus 80.4%, in the TARE and sorafenib groups, respectively, p = 0.25). Longitudinal HRQoL analysis showed a significant treatment and time effects for fatigue and global health status, and significant treatment, time and treatment by time interaction effects for appetite loss, diarrhoea and social functioning. The median time to deterioration for the global health status was 3.9 months (95% confidence interval [CI] 3.7-4.3) versus 2.6 months (95% CI 2.0-3.0) in the TARE and sorafenib groups, respectively. CONCLUSIONS HRQoL was preserved longer with TARE than with sorafenib in locally advanced HCC. These data could be used to optimise management of patients with advanced or inoperable HCC.
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Outcomes in hepatocellular carcinoma patients undergoing sorafenib treatment: toxicities, cellular oxidative stress, treatment adherence, and quality of life. Anticancer Drugs 2021; 31:523-527. [PMID: 32107349 DOI: 10.1097/cad.0000000000000902] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The study of toxicities induced by sorafenib, as well as the identification of possible mechanisms and biomarkers of these toxicities, is important to improve the treatment and quality of life of hepatocellular carcinoma (HCC) patients. This study focused on toxicities, cellular oxidative stress, adherence, and quality of life of 11 patients with HCC treated with sorafenib. Dermatotoxicity, myelotoxicity, gastro toxicity, nephrotoxicity, pain, and fatigue were investigated. For oxidative stress analysis, the peripheral blood mononuclear cells were isolated and mitochondrial superoxide anion production was measured using MitoSOX Red test. Medication adherence was evaluated based on Morisky-Green and MedTake tests. Quality of life assessment was performed using EORTC QLQ C-30 and QLQ HCC18 questionnaires. The results showed that hand-foot syndrome (45.5%), thrombocytopenia (45.5%), diarrhea (54.5%), pain (54.5%), and fatigue (36.4%) were the most prevalent toxicities. A non-statistically significant change in the levels of superoxide anion was observed after the sorafenib treatment (Wilcoxon test, P = 0.4131). Moreover, 81.8% of patients had high adherence, 100% knew the correct indication of sorafenib, 81.8% knew the correct intake and drug regimen, and 36.4% knew the correct dose of antineoplastic. There was a significant worsening in the emotional and pain domains of quality of life after the sorafenib (Wilcoxon test, P = 0.0313 and P = 0.0313, respectively). A production of superoxide anion was not correlated with toxicities (Spearman's correlation and Mann-Whitney U tests, P > 0.05). This study suggests that oxidative stress might not be the mechanism of sorafenib toxicities.
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Henriksson M, Björnsson B, Sternby Eilard M, Lindell G, Strömberg C, Hemmingsson O, Isaksson B, Rizell M, Sandström P. Treatment patterns and survival in patients with hepatocellular carcinoma in the Swedish national registry SweLiv. BJS Open 2019; 4:109-117. [PMID: 32011814 PMCID: PMC6996573 DOI: 10.1002/bjs5.50226] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Accepted: 08/22/2019] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Consistent data on clinical features, treatment modalities and long-term survival in patients with hepatocellular carcinoma (HCC) using nationwide quality registers are lacking. This study aimed to describe treatment patterns and survival outcomes in patients diagnosed with HCC using a national maintained database. METHODS Characteristics and treatment patterns in patients diagnosed with HCC and registered in the national register of liver and bile duct tumours (SweLiv) between 2009 and 2016 were reviewed. Overall survival (OS) was estimated using Kaplan-Meier analysis and the log rank test to compare subgroups for clinical features, treatment modalities and outcomes according to the year of treatment. RESULTS A total of 3376 patients with HCC were registered over 8 years, 246 (7·3 per cent) of whom underwent transplantation. Some 501 (14·8 per cent) and 390 patients (11·6 per cent) had resection and ablation as primary treatment. Transarterial chemoembolization and systemic sorafenib treatment were intended in 476 (14·1 per cent) and 426 patients (12·6 per cent) respectively; the remaining 1337 (39·6 per cent) were registered but referred for best supportive care (BSC). The 5-year survival rate was approximately 75 per cent in the transplantation group. Median OS was 4·6 (i.q.r. 2·0 to not reached) years after resection and 3·1 (2·3-6·7) years following ablation. In patients referred for palliative treatment, median survival was 1·4 (0·8-2·9), 0·5 (0·3-1·2) and 0·3 (0·1-1·0) years for the TACE, sorafenib and BSC groups respectively (P < 0·001). Median survival was 0·9 years for the total HCC cohort in 2009-2012, before publication of the Swedish national treatment programme, increasing to 1·4 years in 2013-2016 (P < 0·001). CONCLUSION The survival outcomes reported were in line with previous results from smaller cohorts. The introduction of national guidelines may have contributed to improved survival among patients with HCC in Sweden.
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Affiliation(s)
- M Henriksson
- Centre for Medical Technology Assessment, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden
| | - B Björnsson
- Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
| | - M Sternby Eilard
- Department of Transplantation and Liver Surgery, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - G Lindell
- Department of Surgery, Skåne University Hospital, Lund University, Lund, Sweden
| | - C Strömberg
- Department of Clinical Science, Intervention and Technology, Division of Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - O Hemmingsson
- Department of Surgical and Perioperative Sciences, Umeå University, Umeå, Sweden
| | - B Isaksson
- Department of Surgery, Akademiska Hospital, University of Uppsala, Uppsala, Sweden
| | - M Rizell
- Department of Transplantation and Liver Surgery, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - P Sandström
- Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
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10
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Wehling C, Hornuss D, Schneider P, Springfeld C, Hoffmann K, Chang DH, Naumann P, Mieth M, Longerich T, Kratochwil C, Mehrabi A, Gauss A, Weiss KH, Pfeiffenberger J. Impact of interventions and tumor stage on health-related quality of life in patients with hepatocellular carcinoma. J Cancer Res Clin Oncol 2019; 145:2761-2769. [PMID: 31428932 DOI: 10.1007/s00432-019-03005-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Accepted: 08/13/2019] [Indexed: 02/06/2023]
Abstract
PURPOSE This study aims to examine the health-related quality of life in patients with hepatocellular carcinoma. METHODS 181 patients attending a tertiary center outpatient clinic were interviewed and completed the short form 36 (SF36) questionnaire. The SF36 was used to assess health-related QoL. Cross-sectional analyses by group (age, gender, clinical scores, systemic, and local interventions) as well sequel questionnaires were conducted. RESULTS Participants included were 79% (143/181) men [mean age at first SF36: 63.8 (± 12.3; 18.4-85.8) years]. Barcelona Clinic Liver Cancer (BCLC) stadium C was associated with significantly lower SF36 total scores, and elevated initial alpha-fetoprotein (AFP) concentrations were associated with lower SF36 functional and mental health sum scores throughout the course of the third questionnaire. Patients treated with sorafenib had within the sub-dimension scores a significantly lower result for role limitations due to physical health compared to patients without sorafenib treatment. Patients who underwent a transarterial chemoembolization (TACE) had within the sub-dimension scores a significantly higher result for control of pain compared to patients without TACE. Kaplan-Meier analysis revealed significant survival benefits for patients who underwent any intervention at the first SF36 (mean survival in years 4.3 vs. 1.6; P < 0.01) as well as for patients who underwent hepatic resection (mean survival in years 6.3 vs. 2.7; P < 0.0001). CONCLUSION Advanced tumor stages marked by BCLC stadium C and elevated initial AFP concentrations were associated with lower SF36 total scores and functional sum scores, respectively. During the course of sorafenib treatment, the sub-dimensional score for role limitations due to physical health decreased significantly, whereas TACE performance was associated with a significant improvement of the control of body pain.
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Affiliation(s)
- Cyrill Wehling
- Department of Internal Medicine IV, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
- Liver Cancer Center Heidelberg LCCH, Heidelberg, Germany
| | - Daniel Hornuss
- Department of Internal Medicine IV, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
- Liver Cancer Center Heidelberg LCCH, Heidelberg, Germany
| | - Pasquale Schneider
- Department of Internal Medicine IV, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
| | - Christoph Springfeld
- Department of Internal Medicine VI, National Center for Tumor Diseases, Heidelberg University Hospital, Im Neuenheimer Feld 460, 69120, Heidelberg, Germany
- Liver Cancer Center Heidelberg LCCH, Heidelberg, Germany
| | - Katrin Hoffmann
- Department of Visceral and Transplant Surgery, Heidelberg University Hospital, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany
- Liver Cancer Center Heidelberg LCCH, Heidelberg, Germany
| | - De-Hua Chang
- Department of Interventional Radiology, Heidelberg University Hospital, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany
- Liver Cancer Center Heidelberg LCCH, Heidelberg, Germany
| | - Patrick Naumann
- Department of Radio-Oncology, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany
- Liver Cancer Center Heidelberg LCCH, Heidelberg, Germany
| | - Markus Mieth
- Department of Visceral and Transplant Surgery, Heidelberg University Hospital, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany
- Liver Cancer Center Heidelberg LCCH, Heidelberg, Germany
| | - Thomas Longerich
- Department of Pathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
- Liver Cancer Center Heidelberg LCCH, Heidelberg, Germany
| | - Clemens Kratochwil
- Department of Nuclear Medicine, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany
- Liver Cancer Center Heidelberg LCCH, Heidelberg, Germany
| | - Arianeb Mehrabi
- Department of Visceral and Transplant Surgery, Heidelberg University Hospital, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany
- Liver Cancer Center Heidelberg LCCH, Heidelberg, Germany
| | - Annika Gauss
- Department of Internal Medicine IV, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
| | - Karl Heinz Weiss
- Department of Internal Medicine IV, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
- Liver Cancer Center Heidelberg LCCH, Heidelberg, Germany
| | - Jan Pfeiffenberger
- Department of Internal Medicine IV, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
- Liver Cancer Center Heidelberg LCCH, Heidelberg, Germany.
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11
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Bettinger D, Pinato DJ, Schultheiss M, Sharma R, Rimassa L, Pressiani T, Burlone ME, Pirisi M, Kudo M, Park JW, Buettner N, Neumann-Haefelin C, Boettler T, Abbasi-Senger N, Alheit H, Baus W, Blanck O, Gerum S, Guckenberger M, Habermehl D, Ostheimer C, Riesterer O, Tamihardja J, Grosu AL, Thimme R, Brunner TB, Gkika E. Stereotactic Body Radiation Therapy as an Alternative Treatment for Patients with Hepatocellular Carcinoma Compared to Sorafenib: A Propensity Score Analysis. Liver Cancer 2019; 8:281-294. [PMID: 31602371 PMCID: PMC6738268 DOI: 10.1159/000490260] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Accepted: 05/20/2018] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND AND AIMS Stereotactic body radiation therapy (SBRT) has emerged as a safe and effective treatment for patients with hepatocellular carcinoma (HCC), but its role in patients with advanced HCC is not yet defined. In this study, we aim to assess the efficacy and safety of SBRT in comparison to sorafenib treatment in patients with advanced HCC. METHODS We included 901 patients treated with sorafenib at six tertiary centers in Europe and Asia and 122 patients treated with SBRT from 13 centers in Germany and Switzerland. Medical records were reviewed including laboratory parameters, treatment characteristics and development of adverse events. Propensity score matching was performed to adjust for differences in baseline characteristics. The primary endpoint was overall survival (OS) and progression-free survival. RESULTS Median OS of SBRT patients was 18.1 (10.3-25.9) months compared to 8.8 (8.2-9.5) in sorafenib patients. After adjusting for different baseline characteristics, the survival benefit for patients treated with SBRT was still preserved with a median OS of 17.0 (10.8-23.2) months compared to 9.6 (8.6-10.7) months in sorafenib patients. SBRT treatment of intrahepatic lesions in patients with extrahepatic metastases was also associated with improved OS compared to patients treated with sorafenib in the same setting (17.0 vs. 10.0 months, p = 0.012), whereas in patients with portal vein thrombosis there was no survival benefit in patients with SBRT. CONCLUSIONS In this retrospective comparative study, SBRT showed superior efficacy in HCC patients compared to patients treated with sorafenib.
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Affiliation(s)
- Dominik Bettinger
- Department of Medicine II, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany,Berta-Ottenstein Programme, Faculty of Medicine, University of Freiburg, Freiburg, Germany,*Dr. Dominik Bettinger, Medical Center – University of Freiburg, Department of Medicine II, Hugstetter Strasse 55, DE–79106 Freiburg (Germany), E-Mail
| | - David J. Pinato
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, United Kingdom
| | - Michael Schultheiss
- Department of Medicine II, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Rohini Sharma
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, United Kingdom
| | - Lorenza Rimassa
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, Milan, Italy
| | - Tiziana Pressiani
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, Milan, Italy
| | - Michela E. Burlone
- Department of Translational Medicine, Università degli Studi del Piemonte Orientale “A. Avogadro,”, Novara, Italy
| | - Mario Pirisi
- Department of Translational Medicine, Università degli Studi del Piemonte Orientale “A. Avogadro,”, Novara, Italy
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University School of Medicine, Osakasayama, Japan
| | - Joong Won Park
- Center for Liver Cancer, National Cancer Center Hospital, Goyang, Republic of Korea
| | - Nico Buettner
- Department of Medicine II, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Christoph Neumann-Haefelin
- Department of Medicine II, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Tobias Boettler
- Department of Medicine II, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Nasrin Abbasi-Senger
- Department of Radiation Oncology, Friedrich-Schiller University Jena, Jena, Germany
| | | | - Wolfgang Baus
- Department of Radiation Oncology, University Hospital of Cologne, Cologne, Germany
| | - Oliver Blanck
- Department of Radiation Oncology, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Sabine Gerum
- Department of Radiation Oncology, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Mathias Guckenberger
- Department of Radiation Oncology, University Hospital of Zurich, Zurich, Switzerland
| | - Daniel Habermehl
- Institute of Innovative Radiotherapy, Department of Radiation Science, Helmholtz Zentrum Munich, Munich, Germany,Department of Radiation Oncology, Klinikum Rechts der Isar, TU Munich, Munich, Germany
| | - Christian Ostheimer
- Department of Radiation Oncology, Martin Luther University Halle Wittenberg, Halle an der Saale, Germany
| | - Oliver Riesterer
- Department of Radiation Oncology, University Hospital of Zurich, Zurich, Switzerland
| | - Jörg Tamihardja
- Department of Radiation Oncology, University Hospital of Würzburg, Würzburg, Germany
| | - Anca-Ligia Grosu
- Department of Radiation Oncology, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany,German Cancer Consortium (DKTK), Partner Site Freiburg, Freiburg, Germany,German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Robert Thimme
- Department of Medicine II, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Thomas Baptist Brunner
- German Cancer Consortium (DKTK), Partner Site Freiburg, Freiburg, Germany,German Cancer Research Center (DKFZ), Heidelberg, Germany,Department of Radiotherapy, University of Magdeburg, Magdeburg, Germany
| | - Eleni Gkika
- Department of Radiation Oncology, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
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Li D, Sedano S, Allen R, Gong J, Cho M, Sharma S. Current Treatment Landscape for Advanced Hepatocellular Carcinoma: Patient Outcomes and the Impact on Quality of Life. Cancers (Basel) 2019; 11:E841. [PMID: 31216701 PMCID: PMC6627588 DOI: 10.3390/cancers11060841] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 06/12/2019] [Accepted: 06/14/2019] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer mortality worldwide. Heterogeneity of clinical conditions contributes to the complex management of care for patients with advanced HCC. Recently, the treatment landscape for advanced HCC has expanded rapidly, with the additional FDA approvals of several oral tyrosine kinase inhibitors (lenvatinib, regorafenib, and cabozantinib), as well as immunotherapies such as immune check point inhibitors (nivolumab and pembrolizumab) and the monoclonal IgG1 antibody, ramucirumab. This expansion has generated a need for novel treatment sequencing strategies in this patient population. In light of these developments, an evaluation of the impact of FDA-approved therapeutics on patient-centered outcomes such as health-related quality of life (HRQoL) is warranted. An increased understanding of HRQoL in patients included in advanced HCC clinical trials could potentially help physician decision-making for treatment sequencing in patients with advanced HCC.
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Affiliation(s)
- Daneng Li
- Department of Medical Oncology, City of Hope Comprehensive Cancer Center and Beckman Research Institute, Duarte, CA 91010, USA.
| | - Sabrina Sedano
- Department of Medical Oncology, City of Hope Comprehensive Cancer Center and Beckman Research Institute, Duarte, CA 91010, USA.
| | - Rebecca Allen
- Department of Medical Oncology, City of Hope Comprehensive Cancer Center and Beckman Research Institute, Duarte, CA 91010, USA.
| | - Jun Gong
- Department of Gastrointestinal Malignancies, Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA 90048, USA.
| | - May Cho
- Department of Internal Medicine, UC Davis Comprehensive Cancer Center, Sacramento, CA 95817, USA.
| | - Sunil Sharma
- Division of Clinical Sciences, Translational Genomics Research Institute, Phoenix, AZ 85004, USA.
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13
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Status of antiviral therapeutics against rabies virus and related emerging lyssaviruses. Curr Opin Virol 2019; 35:1-13. [PMID: 30753961 DOI: 10.1016/j.coviro.2018.12.009] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2018] [Revised: 12/19/2018] [Accepted: 12/20/2018] [Indexed: 12/19/2022]
Abstract
Rabies virus (RABV) constitutes a major social and economic burden associated with 60 000 deaths annually worldwide. Although pre-exposure and post-exposure treatment options are available, they are efficacious only when initiated before the onset of clinical symptoms. Aggravating the problem, the current RABV vaccine does not cross-protect against the emerging zoonotic phylogroup II lyssaviruses. A requirement for an uninterrupted cold chain and high cost of the immunoglobulin component of rabies prophylaxis generate an unmet need for the development of RABV-specific antivirals. We discuss desirable anti-RABV drug profiles, past efforts to address the problem and inhibitor candidates identified, and examine how the rapidly expanding structural insight into RABV protein organization has illuminated novel druggable target candidates and paved the way to structure-aided drug optimization. Special emphasis is given to the viral RNA-dependent RNA polymerase complex as a promising target for direct-acting broad-spectrum RABV inhibitors.
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14
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Chau I, Peck-Radosavljevic M, Borg C, Malfertheiner P, Seitz JF, Park JO, Ryoo BY, Yen CJ, Kudo M, Poon R, Pastorelli D, Blanc JF, Chung HC, Baron AD, Okusaka T, Bowman L, Cui ZL, Girvan AC, Abada PB, Yang L, Zhu AX. Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib: Patient-focused outcome results from the randomised phase III REACH study. Eur J Cancer 2017; 81:17-25. [PMID: 28591675 DOI: 10.1016/j.ejca.2017.05.001] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Accepted: 05/02/2017] [Indexed: 01/05/2023]
Abstract
PURPOSE To report patient-focused outcomes as measured by quality of life (QoL) and performance status (PS) in REACH, a phase III placebo-controlled randomised study, assessing ramucirumab in advanced hepatocellular carcinoma (HCC) patients who received prior sorafenib. METHODS Eligible patients had advanced HCC, Child-Pugh A, PS 0 or 1 and prior sorafenib. Patients received ramucirumab (8 mg/kg) or placebo (1:1) on day 1 of a 2-week cycle. QoL was assessed by FACT Hepatobiliary Symptom Index (FHSI)-8 and EuroQoL (EQ-5D) at baseline; cycles 4, 10, and 16; and end of treatment. PS was assessed at baseline, each cycle, and end of treatment. Deterioration in FHSI-8 was defined as a ≥3-point decrease from baseline and PS deterioration was defined as a change of ≥2. Both intention-to-treat and pre-specified subgroup of patients with baseline serum alpha-fetoprotein (AFP) ≥400 ng/mL were assessed. RESULTS There were 565 patients randomised to ramucirumab and placebo. Compliance with FHSI and EQ-5D was high and similar between groups. In the ITT population, deterioration in FHSI-8, EQ-5D, and PS was similar between ramucirumab and placebo. In patients with baseline AFP ≥400 ng/mL, ramucirumab significantly reduced deterioration in FHSI-8 at the end of treatment compared with placebo (P = 0.0381), and there was a trend towards a delay in the deterioration of symptoms in FHSI-8 (HR 0.690; P = 0.054) and PS (HR 0.642; P = 0.057) in favour of ramucirumab. CONCLUSIONS We report one of the most comprehensive data sets of QoL and symptom burden in patients undergoing systemic therapy for advanced HCC. Ramucirumab was associated with no worsening of QoL. In patients with baseline AFP ≥400 ng/mL, the significant survival benefit observed in patients treated with ramucirumab was coupled with a trend in patient-focused outcome benefits. CLINICAL TRIAL REGISTRATION NCT01140347.
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Affiliation(s)
- Ian Chau
- Royal Marsden Hospital, London and Surrey, United Kingdom.
| | | | | | | | | | - Joon Oh Park
- Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | | | - Chia-Jui Yen
- National Cheng Kung University Hospital, Tainan, Taiwan
| | - Masatoshi Kudo
- Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan
| | | | | | - Jean-Frederic Blanc
- Hepato-Gastroenterology and Digestive Oncology Unit, Centre Medico-chirurgical Magellan, CHU Bordeaux, France
| | - Hyun Cheol Chung
- Yonsei Cancer Center, Yonsei University Health System, Seoul, Republic of Korea
| | - Ari D Baron
- Sutter Health California Pacific Medical Center, San Francisco, CA, USA
| | | | - L Bowman
- Eli Lilly and Company, Indianapolis, IN, USA
| | | | | | | | - Ling Yang
- Eli Lilly and Company, Bridgewater, NJ, USA
| | - Andrew X Zhu
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA
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15
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Li L, Yeo W. Value of quality of life analysis in liver cancer: A clinician’s perspective. World J Hepatol 2017; 9:867-883. [PMID: 28804570 PMCID: PMC5534362 DOI: 10.4254/wjh.v9.i20.867] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Revised: 04/10/2017] [Accepted: 05/24/2017] [Indexed: 02/06/2023] Open
Abstract
Health related quality of life (HRQOL) is increasingly recognized as an important clinical parameter and research endpoint in patients with hepatocellular carcinoma (HCC). HRQOL in HCC patients is multifaceted and affected by medical factor which encompasses HCC and its complications, oncological and palliative treatment for HCC, underlying liver disease, as well as the psychological, social or spiritual reaction to the disease. Many patients presented late with advanced disease and limited survival, plagued with multiple symptoms, rendering QOL a very important aspect in their general well being. Various instruments have been developed and validated to measure and report HRQOL in HCC patients, these included general HRQOL instruments, e.g., Short form (SF)-36, SF-12, EuroQoL-5D, World Health Organization Quality of Life Assessment 100 (WHOQOL-100), World Health Organization Quality of Life Assessment abbreviated version; general cancer HRQOL instruments, e.g., the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30, Functional Assessment of Cancer Therapy (FACT)-General, Spitzer Quality of Life Index; and liver-cancer specific HRQOL instruments, e.g., EORTC QLQ-HCC18, FACT-Hepatobiliary (FACT-Hep), FACT-Hep Symptom Index, Trial Outcome Index. Important utilization of HRQOL in HCC patients included description of symptomatology and HRQOL of patients, treatment endpoint in clinical trial, prognostication of survival, benchmarking of palliative care service and health care valuation. In this review, difficulties regarding the use of HRQOL data in research and clinical practice, including choosing a suitable instrument, problems of missing data, data interpretation, analysis and presentation are examined. Potential solutions are also discussed.
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16
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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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17
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Shomura M, Kagawa T, Okabe H, Shiraishi K, Hirose S, Arase Y, Tsuruya K, Takahira S, Mine T. Longitudinal alterations in health-related quality of life and its impact on the clinical course of patients with advanced hepatocellular carcinoma receiving sorafenib treatment. BMC Cancer 2016; 16:878. [PMID: 27835949 PMCID: PMC5106792 DOI: 10.1186/s12885-016-2908-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Accepted: 10/28/2016] [Indexed: 12/19/2022] Open
Abstract
Background This study aimed to identify the health-related quality of life (HRQOL) domains associated with prognosis by assessing longitudinal alterations in HRQOL in patients with advanced hepatocellular carcinoma receiving sorafenib. Methods We prospectively assessed HRQOL by administering the SF-36 questionnaire 3-monthly to consecutive patients with advanced hepatocellular carcinoma receiving sorafenib. We evaluated the impact of HRQOL on their overall survival and duration of treatment with sorafenib using Cox's proportional hazards model. Results There were 54 participants: 42 (78 %) were male, the median age was 71 years, 24 (44 %) had hepatitis C virus infection, 33 (61 %) had Child-Pugh scores of 5, and 30 (56 %) had TNM stage IV hepatocellular carcinoma. The median overall survival and treatment duration were 9 and 5 months, respectively, and 40 patients (74 %) died. Thirteen patients receiving sorafenib over a 1-year period maintained all domain scores >40, without a significant decline during the treatment period. In contrast, physical functioning, physical role, and vitality scores declined continuously and significantly in the year before death (in the 40 patients who died). Previous curative treatment and physical functioning scores ≥40 at baseline were significantly associated with longer overall survival by multivariate analysis. Social functioning scores ≥40, absence of vascular invasion, and lower DCP value were significant predictors of longer treatment duration. Conclusions HRQOL was not significantly impaired in those patients who were able to complete a 1-year course of sorafenib treatment. Baseline physical functioning scores ≥40 and social functioning scores ≥40 were significantly associated with longer overall survival and longer treatment duration, respectively. Thus, HRQOL could be a valuable marker to predict the clinical course of patients with advanced hepatocellular carcinoma receiving sorafenib. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2908-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Masako Shomura
- Department of Nursing, Tokai University School of Health Sciences, Isehara, Kanagawa, Japan. .,, 143 Shimokasuya, Isehara-city, Kanagawa, 259-1193, Japan.
| | - Tatehiro Kagawa
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | - Haruka Okabe
- Department of Nursing, Tokai University School of Health Sciences, Isehara, Kanagawa, Japan
| | - Koichi Shiraishi
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | - Shunji Hirose
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | - Yoshitaka Arase
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | - Kota Tsuruya
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | - Sachiko Takahira
- University of Nagasaki Department of Nursing, Nagasaki, Nagasaki, Japan
| | - Tetsuya Mine
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan
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Gadaleta-Caldarola G, Infusino S, Divella R, Ferraro E, Mazzocca A, De Rose F, Filippelli G, Abbate I, Brandi M. Sorafenib: 10 years after the first pivotal trial. Future Oncol 2016; 11:1863-80. [PMID: 26161924 DOI: 10.2217/fon.15.85] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Sorafenib is an oral multikinase inhibitor with anticancer activity against a wide spectrum of cancers. It is currently approved for the treatment of patients with hepatocellular carcinoma, advanced renal cell carcinoma or progressive, locally advanced or metastatic differentiated thyroid carcinoma. In this review, we present a number of studies that investigated the efficacy and safety of sorafenib in these settings. We also discuss the perspectives on the use of this molecule, including the role of sorafenib as comparator for the development of new drugs, the combination of sorafenib with additional therapies (such as transarterial chemoembolization for hepatocellular carcinoma) and the use of this treatment in several other advanced refractory solid tumors.
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Affiliation(s)
- Gennaro Gadaleta-Caldarola
- Medical Oncology Unit, 'Mons. R Dimiccoli' Hospital, Viale Ippocrate, 15, 76121 Barletta, Asl BAT, Italy
| | - Stefania Infusino
- Medical Oncology Unit, 'S Francesco di Paola' Hospital, Via Promintesta, 87027 Paola, ASP, Cosenza, Italy
| | - Rosa Divella
- Laboratory of Clinical and Experimental Pathology - National Cancer Institute 'Giovanni Paolo II', Viale Orazio Flacco 65, 70124, Bari, Italy
| | - Emanuela Ferraro
- Department of Internal Medicine & Clinical Specialties, University of Rome 'La Sapienza', Policlinico Umberto I, Viale del Policlinico, 155, 00161 Roma, Italy
| | - Antonio Mazzocca
- Interdisciplinary Department of Medicine, University of Bari School of Medicine, Piazza G Cesare, 11,70124 Bari, Italy, National Institute for Digestive Diseases, IRCCS 'Saverio De Bellis', Via Turi 27, 70013, Castellana Grotte, Bari, Italy
| | | | - Gianfranco Filippelli
- Medical Oncology Unit, 'S Francesco di Paola' Hospital, Via Promintesta, 87027 Paola, ASP, Cosenza, Italy
| | - Ines Abbate
- Laboratory of Clinical and Experimental Pathology - National Cancer Institute 'Giovanni Paolo II', Viale Orazio Flacco 65, 70124, Bari, Italy
| | - Mario Brandi
- Medical Oncology Unit, 'Mons. R Dimiccoli' Hospital, Viale Ippocrate, 15, 76121 Barletta, Asl BAT, Italy
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Gallo M, Michelon F, Castiglione A, Felicetti F, Viansone AA, Nervo A, Zichi C, Ciccone G, Piovesan A, Arvat E. Sorafenib treatment of radioiodine-refractory advanced thyroid cancer in daily clinical practice: a cohort study from a single center. Endocrine 2015; 49:726-34. [PMID: 25414068 DOI: 10.1007/s12020-014-0481-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2014] [Accepted: 11/12/2014] [Indexed: 12/13/2022]
Abstract
Treatment options for recurrent or metastatic differentiated thyroid cancer (DTC) refractory to radioactive iodine (RAI) are inadequate. Multitargeted kinase inhibitors have recently shown promising results in phase 2-3 studies. This retrospective study aimed to document our clinical experience on the effects of sorafenib in the setting of daily clinical practice. Retrospective study evaluating the efficacy and safety of sorafenib in a cohort of patients consecutively treated with sorafenib at a single center. Twenty patients with advanced RAI-refractory thyroid carcinoma were enrolled (March 2011-March 2014). Patients generally started with 400 mg of sorafenib twice daily, tapering the dose in case of side effects. Radiological response and toxicity were measured during follow-up, together with safety parameters. CT scans were performed by a single experienced radiologist every 3-4 months. Five patients stopped sorafenib within 90 days due to severe toxicities. Median progression-free survival was 248 days. Five patients had a partial response (PR), achieved in all cases within 3 months, whereas 5 had stable disease (SD) at 12 months. Durable response rate (PR plus SD) for at least 6 months was 50 %, among those who received sorafenib for at least 3 months. Commonest adverse events included skin toxicity, gastrointestinal and constitutional symptoms. In our cohort of patients with advanced RAI-refractory thyroid carcinoma, sorafenib confirmed antitumor activity leading to SD or PR in the majority of cases, at the expense of clinically relevant side effects. More effective and tolerable agents are still needed in the treatment of RAI-refractory DTC.
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Affiliation(s)
- Marco Gallo
- Oncological Endocrinology Unit, Department of Medical Sciences, AOU Città della Salute e della Scienza di Torino, University of Turin, Via Genova 3, 10126, Turin, Italy,
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20
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Berk V, Kaplan MA, Tonyali O, Buyukberber S, Balakan O, Ozkan M, Demirci U, Ozturk T, Bilici A, Tastekin D, Ozdemir N, Unal OU, Oflazoglu U, Turkmen E, Erdogan B, Uyeturk U, Oksuzoglu B, Cinkir HY, Yasar N, Gumus M. Efficiency and side effects of sorafenib therapy for advanced hepatocellular carcinoma: a retrospective study by the anatolian society of medical oncology. Asian Pac J Cancer Prev 2015; 14:7367-9. [PMID: 24460304 DOI: 10.7314/apjcp.2013.14.12.7367] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Inoperable and metastatic hepatocellular carcinoma (HCC) is associated with a poor prognosis and low chemotherapeutic efficiency. Sorafenib is an oral multi-kinase inhibitor exerting its effects via the RAF/ MEK/ERK pathway, vascular endothelial growth factor receptor (VEGFR) and platelet derived growth factor receptor beta (PDGFR-β) tyrosine kinases. Randomized studies have shown a significant contribution of sorafenib to life expectancy and quality of life of cancer patients. The aim of the present study is to evaluate the efficacy and side effects of sorafenib therapy in Turkey. MATERIALS AND METHODS Data for 103 patients (82 males, 21 females) receiving sorafenib therapy in 13 centers from February 2008 to December 2012 were evaluated. Median age was 61 years and median ECOG performance status was 1 (range: 0-2). 60 patients (58%) had hepatitis B, 15 patients (15%) had hepatitis C infection and 12 patients (12%) had a history of alcohol consumption. All of the patients had Child scores meeting the utilization permit of the drug in our country (Child A). RESULTS A total of 571 cycles of sorafenib therapy were administered with a median of four per patient. Among the evaluable cases, there was partial response in 15 (15%), stable disease in 52 (50%), and progressive disease in 36 (35%). Median progression-free survival was 18 weeks and median overall survival was 48 weeks. The dose was reduced only in 6 patients and discontinued in 2 patients due to grade 3-4 toxicity, 18 patients (17%) suffering hand-foot syndrome, 7 (7%) diarrhea, and 2 (2%) vomiting. CONCLUSIONS This retrospective study demonstrated better efficacy of sorafenib therapy in patients with advanced HCC compared to the literature while progression-free survival and overall survival findings were comparable. The side effect rates indicate that the drug was tolerated well. In conclusion, among the available treatment options, sorafenib is an efficient and tolerable agent in patients with inoperable or metastatic HCC.
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Affiliation(s)
- Veli Berk
- Department of Medical Oncology, Erciyes University Faculty of Medicine, Turkey E-mail :
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Peng S, Zhao Y, Xu F, Jia C, Xu Y, Dai C. An updated meta-analysis of randomized controlled trials assessing the effect of sorafenib in advanced hepatocellular carcinoma. PLoS One 2014; 9:e112530. [PMID: 25460347 PMCID: PMC4251972 DOI: 10.1371/journal.pone.0112530] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2014] [Accepted: 10/06/2014] [Indexed: 12/15/2022] Open
Abstract
Background The efficacy of sorafenib in the treatment of advanced hepatocellular carcinoma (HCC) remains controversial. Therefore, we conducted a meta-analysis to evaluate the efficacy and safety of sorafenib for treating patients with advanced HCC. Methods The PubMed, Embase, and Web of Science databases were searched. Eligible studies were randomized controlled trials (RCTs) that assessed sorafenib therapy in patients with advanced HCC. The outcomes included overall survival (OS), time to progression (TTP), overall response rate (ORR), and toxicities. Hazard ratio (HR) and risk ratio (RR) were used for the meta-analysis and were expressed with 95% confidence intervals (CIs). Results Seven RCTs, with a total of 3807 patients, were included in this meta-analysis. All patients received sorafenib alone, or with other chemotherapeutic regimens. Pooled estimates showed that sorafenib improved the OS (HR = 0.74, 95% CI: 0.61, 0.90; P = 0.002), or TTP outcomes (HR = 0.69, 95% CI: 0.55, 0.86; P = 0.001). Subgroup analysis revealed that sorafenib was more effective in the patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 1–2 (HR = 0.77, 95% CI: 0.60, 1.0; P = 0.05), or macroscopic vascular invasion (MVI), and/or extrahepatic spread (EHS) (HR = 0.65, 95% CI: 0.46, 0.93; P = 0.02), in terms of OS. Patients who received sorafenib did not have a higher ORR (RR = 0.85, 95% CI: 0.65, 1.11; P = 0.10). In addition, there was a slight increase in toxicity in the sorafenib group. Conclusion Treatment with sorafenib significantly improved OS and TTP in patients with advanced HCC. Additional large-scale, well-designed RCTs are needed to evaluate the efficacy of sorafenib-based therapy in the treatment of advanced HCC.
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Affiliation(s)
- Songlin Peng
- Department of Hepatobiliary Surgery, The Affiliated Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Yang Zhao
- Department of Hepatobiliary Surgery, The Affiliated Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Feng Xu
- Department of Hepatobiliary Surgery, The Affiliated Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Changjun Jia
- Department of Hepatobiliary Surgery, The Affiliated Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Yongqing Xu
- Department of Hepatobiliary Surgery, The Affiliated Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Chaoliu Dai
- Department of Hepatobiliary Surgery, The Affiliated Shengjing Hospital of China Medical University, Shenyang 110004, China
- * E-mail:
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22
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MR imaging in hepatocellular carcinoma: correlations between MRI features and molecular marker VEGF. Med Oncol 2014; 31:313. [DOI: 10.1007/s12032-014-0313-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2014] [Accepted: 10/29/2014] [Indexed: 01/18/2023]
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Huang X, Qin J, Lu S. Kanglaite stimulates anticancer immune responses and inhibits HepG2 cell transplantation‑induced tumor growth. Mol Med Rep 2014; 10:2153-9. [PMID: 25119060 DOI: 10.3892/mmr.2014.2479] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2013] [Accepted: 04/25/2014] [Indexed: 11/05/2022] Open
Abstract
Previous studies revealed that Kanglaite (KLT) exhibits antitumor and immunomodulatory activities. In the present study, we show that KLT treatment stimulated the immune response by increasing the number of T cells and natural killer (NK) cells in the blood of hepatocellular carcinoma (HCC) patients. Experiments in tumor-bearing mice were further designed in order to explore the effects of KLT on the immune system and the underlying molecular mechanisms. The results showed that KLT improves the tumor cell transplantation-induced reduction in the serum level of the cytokines IFN‑γ and IL‑2, and rescues the levels of CD4+ T cells in host mice. These events enhanced the cytotoxic activities of natural killer and CD8+ T cells against the hepatic HepG2 cancer cells. KLT administration further increased the mRNA level of certain nuclear factor κB (NF‑κB)‑responsive genes in CD4+ cells. The chromatin immunoprecipitation assay showed that KLT increases the association of the NF-κB p65 subunit to the promoter regions of interleukin (IL)-2- and B-cell lymphoma (Bcl)-2-encoding genes in CD4+ T cells. Our study demonstrated that KLT is the main active ingredient of coix seed exhibiting anticancer and immunomodulatory properties. Induction of NF-κB‑mediated gene transcription in CD4+ T cells is involved in the immunomodulatory activity of KLT.
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Affiliation(s)
- Xinli Huang
- Center of Liver Transplantation, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Liver Transplantation, Ministry of Health, Nanjing 210029, P.R. China
| | - Jianjie Qin
- Center of Liver Transplantation, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Liver Transplantation, Ministry of Health, Nanjing 210029, P.R. China
| | - Sen Lu
- Center of Liver Transplantation, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Liver Transplantation, Ministry of Health, Nanjing 210029, P.R. China
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Horwitz E, Stein I, Andreozzi M, Nemeth J, Shoham A, Pappo O, Schweitzer N, Tornillo L, Kanarek N, Quagliata L, Zreik F, Porat RM, Finkelstein R, Reuter H, Koschny R, Ganten T, Mogler C, Shibolet O, Hess J, Breuhahn K, Grunewald M, Schirmacher P, Vogel A, Terracciano L, Angel P, Ben-Neriah Y, Pikarsky E. Human and mouse VEGFA-amplified hepatocellular carcinomas are highly sensitive to sorafenib treatment. Cancer Discov 2014; 4:730-43. [PMID: 24687604 DOI: 10.1158/2159-8290.cd-13-0782] [Citation(s) in RCA: 152] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
UNLABELLED Death rates from hepatocellular carcinoma (HCC) are steadily increasing, yet therapeutic options for advanced HCC are limited. We identify a subset of mouse and human HCCs harboring VEGFA genomic amplification, displaying distinct biologic characteristics. Unlike common tumor amplifications, this one seems to work via heterotypic paracrine interactions; stromal VEGF receptors (VEGFR), responding to tumor VEGF-A, produce hepatocyte growth factor (HGF) that reciprocally affects tumor cells. VEGF-A inhibition results in HGF downregulation and reduced proliferation, specifically in amplicon-positive mouse HCCs. Sorafenib-the first-line drug in advanced HCC-targets multiple kinases, including VEGFRs, but has only an overall mild beneficial effect. We found that VEGFA amplification specifies mouse and human HCCs that are distinctly sensitive to sorafenib. FISH analysis of a retrospective patient cohort showed markedly improved survival of sorafenib-treated patients with VEGFA-amplified HCCs, suggesting that VEGFA amplification is a potential biomarker for HCC response to VEGF-A-blocking drugs. SIGNIFICANCE Using a mouse model of inflammation-driven cancer, we identified a subclass of HCC carrying VEGFA amplification, which is particularly sensitive to VEGF-A inhibition. We found that a similar amplification in human HCC identifies patients who favorably responded to sorafenib-the first-line treatment of advanced HCC-which has an overall moderate therapeutic efficacy.
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Affiliation(s)
- Elad Horwitz
- Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Ilan Stein
- Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, GermanyAuthors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Mariacarla Andreozzi
- Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Julia Nemeth
- Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Avivit Shoham
- Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Orit Pappo
- Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Nora Schweitzer
- Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Luigi Tornillo
- Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Naama Kanarek
- Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Luca Quagliata
- Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Farid Zreik
- Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Rinnat M Porat
- Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Rutie Finkelstein
- Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Hendrik Reuter
- Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Ronald Koschny
- Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Tom Ganten
- Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Carolin Mogler
- Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Oren Shibolet
- Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Jochen Hess
- Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, GermanyAuthors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, GermanyAuthors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University
| | - Kai Breuhahn
- Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Myriam Grunewald
- Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Peter Schirmacher
- Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Arndt Vogel
- Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Luigi Terracciano
- Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Peter Angel
- Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Yinon Ben-Neriah
- Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Eli Pikarsky
- Authors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, GermanyAuthors' Affiliations:The Lautenberg Center for Immunology; Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University;Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem; Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Institute of Pathology, University Hospital Basel, Basel, Switzerland; Division of Signal Transduction and Growth Control (A100), Division of Molecular Genetics (B060), and Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; Institute of Pathology, University Hospital Heidelberg; Departments of Otolaryngology, Head and Neck Surgery and Internal Medicine, University Hospital Heidelberg, Heidelberg; and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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Hu BG, Liu LP, Chen GG, Ye CG, Leung KKC, Ho RLK, Lin MC, Lai PBS. Therapeutic efficacy of improved α-fetoprotein promoter-mediated tBid delivered by folate-PEI600-cyclodextrin nanopolymer vector in hepatocellular carcinoma. Exp Cell Res 2014; 324:183-91. [PMID: 24726886 DOI: 10.1016/j.yexcr.2014.04.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2014] [Revised: 04/02/2014] [Accepted: 04/04/2014] [Indexed: 12/24/2022]
Abstract
SNPs in human AFP promoter are associated with serum AFP levels in hepatocellular carcinoma (HCC), suggesting that AFP promoter variants may generate better transcriptional activities while retaining high specificity to AFP-producing cells. We sequenced human AFP promoters, cloned 15 different genotype promoters and tested their reporter activities in AFP-producing and non-producing cells. Among various AFP variant fragments tested, EA4D exhibited the highest reporter activity and thus was selected for the further study. EA4D was fused with tBid and coupled with nano-particle vector (H1) to form pGL3-EA4D-tBid/H1. pGL3-EA4D-tBid/H1 could express a high level of tBid while retain the specificity to AFP-producing cells. In a HCC tumor model, application of pGL3-EA4D-tBid/H1 significantly inhibited the growth of AFP-producing-implanted tumors with minimal side-effects, but had no effect on non-AFP-producing tumors. Furthermore, pGL3-EA4D-tBid/H1 could significantly sensitize HCC cells to sorafenib, an approved anti-HCC agent. Collectively, pGL3-EA4D-tBid/H1, a construct with the AFP promoter EA4D and the novel H1 delivery system, can specifically target and effectively suppress the AFP-producing HCC. This new therapeutic tool shows little toxicity in vitro and in vivo and it should thus be safe for further clinical tests.
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Affiliation(s)
- Bao-guang Hu
- Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China; Department of Gastrointestinal Surgery, the Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong, China
| | - Li-ping Liu
- Department of Hepatobiliary and Pancreas Department of Hepatobiliary Surgery, the Second Clinical Medical College of Jinan University (Shenzhen People׳s Hospital), Shenzhen, Guangdong Province, China
| | - George G Chen
- Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China.
| | - Cai Guo Ye
- Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China
| | - Kevin K C Leung
- Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China
| | - Rocky L K Ho
- Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China
| | - Marie C Lin
- Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China
| | - Paul B S Lai
- Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China
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26
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Inghilesi AL, Gallori D, Antonuzzo L, Forte P, Tomcikova D, Arena U, Colagrande S, Pradella S, Fani B, Gianni E, Boni L, Laffi G, Costanzo FD, Marra F. Predictors of survival in patients with established cirrhosis and hepatocellular carcinoma treated with sorafenib. World J Gastroenterol 2014; 20:786-794. [PMID: 24574751 PMCID: PMC3921487 DOI: 10.3748/wjg.v20.i3.786] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2013] [Revised: 08/08/2013] [Accepted: 08/29/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate in greater detail the efficacy and safety of sorafenib for the treatment of hepatocellular carcinoma (HCC) in patients with established cirrhosis.
METHODS: From October 2009 to July 2012 patients with an established diagnosis of cirrhosis and HCC treated with sorafenib were consecutively enrolled. According to the Barcelona Clinic Liver Cancer (BCLC) classification, patients were in the advanced stage (BCLC-C) or in the intermediate stage (BCLC-B) but unfit or unresponsive to other therapeutic strategies. Treatment was evaluated performing a 4-phase computed tomography or magnetic resonance imaging scan every 2-3 mo, and analyzed according to the modified Response Evaluation Criteria in Solid Tumors. Sorafenib was administered at 800 mg/d, until radiological progression or occurrence of unacceptable adverse events (AEs). Univariate and multivariate analyses identified predictors of 16-wk clinical benefit and overall survival.
RESULTS: Forty-four patients were enrolled, 15 had intermediate HCC and 14 a Child-Pugh score of B7. AEs caused treatment interruption in 19 patients (43%), and median treatment duration was shorter in this subset (5 wk vs 19 wk, P < 0.001) and in the BCLC-C subgroup (13 wk vs 40 wk, P = 0.015). No significant differences in the reason for treatment interruption or in treatment duration were found comparing patients in Child-Pugh class A vs B or in patients older or younger than 70 years. After 16 wk of treatment, 18 patients (41%) had stable disease or partial response. Patients with viral infection or BCLC-C were at higher risk of disease progression. ECOG, extrahepatic spread, macrovascular invasion, alpha-fetoprotein or alkaline phosphatase levels at admission were independent predictors of overall survival.
CONCLUSION: In patients with cirrhosis and HCC treated with sorafenib, AEs are a common cause of early treatment withdrawal. Vascular invasion and extrahepatic spread condition early response to treatment and survival. Baseline biochemical parameters may be helpful to identify patients at higher risk of shorter overall survival.
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27
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Huynh TT, Rao YK, Lee WH, Chen HA, Le TDQ, Tzeng DTW, Wang LS, Wu ATH, Lin YF, Tzeng YM, Yeh CT. Destruxin B inhibits hepatocellular carcinoma cell growth through modulation of the Wnt/β-catenin signaling pathway and epithelial-mesenchymal transition. Toxicol In Vitro 2014; 28:552-61. [PMID: 24434019 DOI: 10.1016/j.tiv.2014.01.002] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2013] [Revised: 12/29/2013] [Accepted: 01/02/2014] [Indexed: 02/06/2023]
Abstract
The aberrant activation of Wnt/β-catenin signaling plays an important role in the carcinogenesis and progression of hepatocellular carcinoma (HCC). Therefore, the Wnt/β-catenin signaling molecules are attractive candidates for the development of targeted therapies for this disease. The present study showed that destruxin B (DB) inhibits the proliferation and induces the apoptosis of HCC cells by decreasing the protein expression of anti-apoptotic Bcl-2 and Bcl-xL and increasing the expression of the proapoptotic protein Bax. More importantly, DB also attenuates Wnt-signaling in HCC cells by downregulating β-catenin, Tcf4, and β-catenin/Tcf4 transcriptional activity, which results in the decreased expression of β-catenin target genes, such as cyclin D1, c-myc, and survivin. Furthermore, DB affects the migratory and invasive abilities of Sk-Hep1 cells through the suppression of markers of the epithelial-mesenchymal transition (EMT). A synergistic anti-proliferative and migratory effect was achieved using the combination of DB and sorafenib in Sk-Hep1 cells. In conclusion, DB acts as a novel Wnt/β-catenin inhibitor and reduces the aggressiveness and invasive potential of HCC by altering the cells' EMT status and mobility. DB in combination with sorafenib may be considered for future clinical use for the management of metastatic HCC.
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Affiliation(s)
- Thanh-Tuan Huynh
- Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan; Department of Neurosurgery, University of Medicine and Pharmacy, Ho Chi Minh City, Viet Nam
| | - Yerra Koteswara Rao
- Institute of Biochemical Sciences and Technology, Chaoyang University of Technology, Taichung, Taiwan
| | - Wei-Hwa Lee
- Department of Pathology, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan
| | - Hsin-An Chen
- Departments of Surgery, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan
| | - T Do-Quyen Le
- Department of Hepatitis, Cho Ray Hospital, Ho Chi Minh City, Viet Nam
| | - David T W Tzeng
- Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung, Taiwan
| | - Liang-Shun Wang
- Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan; Division of Thoracic Surgery, Department of Surgery, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan
| | - Alexander T H Wu
- The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Yuh-Feng Lin
- Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan
| | - Yew-Min Tzeng
- Institute of Biochemical Sciences and Technology, Chaoyang University of Technology, Taichung, Taiwan.
| | - Chi-Tai Yeh
- Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan; Departments of Surgery, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan; Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
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