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Zhao M, Shao T, Yin Y, Fang H, Shao H, Tang W. Adverse Event Costs and Cost-Effectiveness Analyses of Anticancer Drugs: A Systematic Review. JAMA Netw Open 2025; 8:e2512455. [PMID: 40423968 PMCID: PMC12117467 DOI: 10.1001/jamanetworkopen.2025.12455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 03/25/2025] [Indexed: 05/28/2025] Open
Abstract
Importance Accurately quantifying adverse event (AE) costs is essential for cost-effectiveness analyses (CEAs) of anticancer drugs. Misestimates in AE costs may significantly affect cost-effectiveness conclusions. Objective To assess whether AE cost quantification in anticancer drug CEAs accurately reflects the true cost of AEs and to evaluate whether replacing AE costs with actual values affects cost-effectiveness conclusions. Evidence Review A systematic search of PubMed, Web of Science, and Tufts CEA databases was conducted from October 24 to December 1, 2023, with an additional search from November 4 to 10, 2024, for English-language CEAs and claims-based studies examining AE costs for anticancer drugs published between January 2003 and December 2023. Claims-based AE costs were considered to represent actual values. AE costs were compared in absolute terms and as a proportion of total medical costs. Impact of replacing CEA AE cost estimates with actual values for incremental cost-effectiveness ratios (ICERs) was examined at thresholds of $100 000 and $150 000 per quality-adjusted life year (QALY). AE cost differences between CEA estimates and actual values and their impact on ICERs were the main outcomes. Findings The sample included 11 claims-based US studies with 34 022 patients and 102 US payer-perspective CEAs. AE cost estimates in CEAs were consistently lower than actual values, with a median difference of 9.73% (IQR, 5.15%-27.22%; P = .002) in proportion of total medical costs and of $17 201 (IQR, $13 365-$48 970; P = .03) in absolute costs. Adjusting AE costs led to an ICER change of $42 656 per QALY, altering cost-effectiveness conclusions in 8 of 17 cases (47.1%). Among the 102 CEAs, 41 (40.2%) did not report AE types; of the remaining 61 (59.8%), 48 (78.7%) focused on treatment-related AEs instead of all-cause AEs. Of all CEAs, 79 (77.5%) considered grade 3 or higher AEs, ignoring grades 1 and 2. Only 13 studies (12.7%) accounted for AE-related dose reductions or interruptions, 87 (85.3%) did not consider postprogression AE costs, and 77 (82.8%) assumed AEs occurred only in the first treatment cycle. Substantial variability was observed in both drug AE and unit AE costs across studies. Conclusions and Relevance In this systematic review of AE costs in oncology CEAs, AE costs were frequently underestimated, potentially altering cost-effectiveness conclusions. Key problems included incomplete AE inclusion, inaccurate AE cost estimates, overlooked long-term AEs, and unaccounted dose modifications. Best practices and standardized guidelines should be established to improve AE cost quantification in oncology CEAs.
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Affiliation(s)
- Mingye Zhao
- Department of Pharmacoeconomics, School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, Jiangsu, China
- Center for Pharmacoeconomics and Outcomes Research, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Taihang Shao
- JC School of Public Health and Primary Care, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Yue Yin
- Department of Pharmacoeconomics, School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, Jiangsu, China
- Center for Pharmacoeconomics and Outcomes Research, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Hongshu Fang
- Department of Pharmacoeconomics, School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, Jiangsu, China
- Center for Pharmacoeconomics and Outcomes Research, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Hanqiao Shao
- Department of Pharmacoeconomics, School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, Jiangsu, China
- Center for Pharmacoeconomics and Outcomes Research, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Wenxi Tang
- Department of Pharmacoeconomics, School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, Jiangsu, China
- Center for Pharmacoeconomics and Outcomes Research, China Pharmaceutical University, Nanjing, Jiangsu, China
- Department of Public Affairs Management, School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, Jiangsu, China
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Cheng S, Li B, Tang L, Liu S, Xiao J. Tremelimumab plus durvalumab versus sorafenib in first-line treatment of unresectable hepatocellular carcinoma: a cost-effectiveness analysis from the US payer perspective. BMJ Open 2025; 15:e090992. [PMID: 40306910 PMCID: PMC12049948 DOI: 10.1136/bmjopen-2024-090992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Accepted: 04/11/2025] [Indexed: 05/02/2025] Open
Abstract
OBJECTIVE In a recently published 4-year overall survival (OS) update from the phase III clinical trial named HIMALAYA (NCT03298451), single tremelimumab plus regular interval durvalumab (a regimen termed STRIDE) demonstrated significantly improved OS compared with sorafenib in the first-line setting of unresectable hepatocellular carcinoma (uHCC). Although dual immunotherapy represents a novel treatment option for uHCC, the economic implications of these high-priced drugs require further exploration. This study aimed to evaluate the cost-effectiveness of STRIDE in uHCC to inform first-line treatment decisions and help allocate medical resources most effectively. DESIGN Using a partitioned survival model, we conducted a cost-effectiveness analysis comparing STRIDE to sorafenib in the first-line treatment of uHCC. Clinical information was gathered from the phase III HIMALAYA trial. Costs and health state utilities data were derived from previous literature. Uncertainty of the model was assessed through one-way sensitivity analysis and probabilistic sensitivity analysis. OUTCOME MEASURES Total costs, life years, quality-adjusted life years (QALYs), incremental QALYs and incremental cost-effectiveness ratio (ICER). SETTING US payer perspective. PARTICIPANTS 393 participants in the STRIDE group and 389 participants in the sorafenib group who were diagnosed with uHCC and had no previous systemic treatment. INTERVENTIONS Single-dose tremelimumab plus monthly durvalumab (STRIDE) versus sorafenib. RESULTS Treatment with STRIDE provided an additional 0.51 QALYs at an incremental total cost of United States dollar ($)9812. The ICER of STRIDE was $19 239 per QALY compared with sorafenib, which falls below the willingness-to-pay threshold of $150 000 per QALY. Sensitivity analyses indicated that our results were robust to the variation ranges of key inputs. CONCLUSION In this economic evaluation comparing two first-line systemic therapies for uHCC patients, STRIDE was cost-effective compared with sorafenib from a US payer perspective. Our study is the first to demonstrate that immunotherapy can provide both survival benefits and economic viability in uHCC.
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MESH Headings
- Female
- Humans
- Male
- Antibodies, Monoclonal/economics
- Antibodies, Monoclonal/therapeutic use
- Antibodies, Monoclonal, Humanized/economics
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antibodies, Monoclonal, Humanized/administration & dosage
- Antineoplastic Combined Chemotherapy Protocols/economics
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/mortality
- Carcinoma, Hepatocellular/economics
- Cost-Benefit Analysis
- Cost-Effectiveness Analysis
- Liver Neoplasms/drug therapy
- Liver Neoplasms/mortality
- Liver Neoplasms/economics
- Quality-Adjusted Life Years
- Sorafenib/economics
- Sorafenib/therapeutic use
- Sorafenib/administration & dosage
- United States
- Clinical Trials, Phase III as Topic
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Affiliation(s)
- Shuqiao Cheng
- Department of Pharmacy, Xiangya Hospital Central South University, Changsha, Hunan, China
| | - Bin Li
- Department of Oncology, Xiangya Hospital Central South University, Changsha, Hunan, China
| | - Lanhua Tang
- Department of Oncology, Xiangya Hospital Central South University, Changsha, Hunan, China
| | - Shao Liu
- Department of Pharmacy, Xiangya Hospital Central South University, Changsha, Hunan, China
| | - Jian Xiao
- Department of Pharmacy, Xiangya Hospital Central South University, Changsha, Hunan, China
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Xiong X, Guo JJ. Cost Effectiveness of Tremelimumab Plus Durvalumab for Unresectable Hepatocellular Carcinoma in the USA. PHARMACOECONOMICS 2025; 43:271-282. [PMID: 39546248 DOI: 10.1007/s40273-024-01453-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 10/29/2024] [Indexed: 11/17/2024]
Abstract
BACKGROUND Treating unresectable hepatocellular carcinoma (uHCC) is challenging. Clinical trials have shown that Single Tremelimumab Regular Interval Durvalumab (STRIDE) offers clinical benefits as a first-line treatment for uHCC, but its cost effectiveness remains unknown in the USA. OBJECTIVE We aimed to assess the cost effectiveness of STRIDE (tremelimumab plus durvalumab) versus sorafenib and durvalumab monotherapy as the first-line treatment for uHCC in the USA. METHODS A partitioned survival model was constructed to assess the cost effectiveness of STRIDE compared to sorafenib and durvalumab monotherapy as the first-line treatment for uHCC from the US societal perspective. The time horizon was 48 months with 1-month cycles. Seven parametric survival functions replicated survival curves from clinical trials, with the best-fitting model used to calculate survival probabilities. Costs, health utilities, and adverse events were included, with quality-adjusted life-years (QALYs) as the primary effectiveness measure. Both costs and effectiveness were discounted at 3%. In the base-case analysis, the incremental cost-effectiveness ratio was compared to a willingness-to-pay threshold of $150,000 per QALY gained. Deterministic and probabilistic sensitivity analyses were conducted to examine the uncertainty of the model. RESULTS In the base-case analysis, STRIDE was cost effective compared to sorafenib, with an incremental cost-effectiveness ratio of $97,995.51 per QALY gained, based on a willingness-to-pay threshold of $150,000 per QALY gained. However, STRIDE was not cost effective compared to durvalumab monotherapy at the same threshold, with an incremental cost-effectiveness ratio of $754,408.92 per QALY gained. Deterministic sensitivity analyses were consistent with the base-case analysis. A probabilistic sensitivity analysis indicated that STRIDE was more likely to be cost effective than sorafenib and durvalumab monotherapy when the willingness-to-pay exceeded $101,000 and $713,000, respectively. CONCLUSIONS The STRIDE regimen appears to be cost effective compared to sorafenib but not compared to durvalumab for first-line uHCC treatment in the USA. However, durvalumab has not yet been approved for uHCC in the USA. Future research should focus on long-term data and economic evaluations of other recommended biologics.
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MESH Headings
- Humans
- Cost-Benefit Analysis
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/economics
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/mortality
- Liver Neoplasms/drug therapy
- Liver Neoplasms/economics
- Liver Neoplasms/pathology
- Liver Neoplasms/mortality
- United States
- Quality-Adjusted Life Years
- Antibodies, Monoclonal, Humanized/economics
- Antibodies, Monoclonal, Humanized/administration & dosage
- Sorafenib/economics
- Sorafenib/administration & dosage
- Antibodies, Monoclonal/administration & dosage
- Antibodies, Monoclonal/economics
- Antineoplastic Combined Chemotherapy Protocols/economics
- Antineoplastic Combined Chemotherapy Protocols/administration & dosage
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Antineoplastic Combined Chemotherapy Protocols/adverse effects
- Models, Economic
- Cost-Effectiveness Analysis
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Affiliation(s)
- Xiaomo Xiong
- Division of Pharmacy Practice and Administrative Sciences, James L. Winkle College of Pharmacy, University of Cincinnati Academic Health Center, 3255 Eden Ave, Cincinnati, OH, 45267, USA.
| | - Jeff Jianfei Guo
- Division of Pharmacy Practice and Administrative Sciences, James L. Winkle College of Pharmacy, University of Cincinnati Academic Health Center, 3255 Eden Ave, Cincinnati, OH, 45267, USA
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Gong H, Ong SC, Li F, Shen Y, Weng Z, Zhao K, Jiang Z, Wang M. Cost-effectiveness of immune checkpoint inhibitors as a first-line therapy for advanced hepatocellular carcinoma: a systematic review. HEALTH ECONOMICS REVIEW 2024; 14:48. [PMID: 38967718 PMCID: PMC11225220 DOI: 10.1186/s13561-024-00526-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 06/25/2024] [Indexed: 07/06/2024]
Abstract
Since 2017, immune checkpoint inhibitors (ICIs) have been available for the treatment of advanced hepatocellular carcinoma (HCC) or unresectable HCC, but their adoption into national medical insurance programs is still limited. Cost-effectiveness evidence can help to inform treatment decisions. This systematic review aimed to provide a critical summary of economic evaluations of ICIs as a treatment for advanced HCC and identify key drivers (PROSPERO 2023: CRD42023417391). The databases used included Scopus, Web of Science, PubMed, Embase, and Cochrane Central. Economic evaluations of ICIs for the treatment of advanced HCC were included. Studies were screened by two people. Of the 898 records identified, 17 articles were included. The current evidence showed that ICIs, including atezolizumab plus bevacizumab, sintilimab plus bevacizumab/bevacizumab biosimilar, nivolumab, camrelizumab plus rivoceranib, pembrolizumab plus lenvatinib, tislelizumab, durvalumab, and cabozantinib plus atezolizumab, are probably not cost-effective in comparison with tyrosine kinase inhibitors or other ICIs. The most influential parameters were price of anticancer drugs, hazard ratios for progression-free survival and overall survival, and utility for health statest. Our review demonstrated that ICIs were not a cost-effective intervention in advanced HCC. Although ICIs can significantly enhance the survival of patients with advanced HCC, decision-makers should consider the findings of economic evaluations and affordability before adoption of new therapies.
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Affiliation(s)
- Hongyu Gong
- Incubation Center for Scientific and Technological Achievements, Kunming Medical University, Chunrong west road 1168, Kunming City, China
- School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 USM Penang, Penang City, Malaysia
| | - Siew Chin Ong
- School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 USM Penang, Penang City, Malaysia.
| | - Fan Li
- Incubation Center for Scientific and Technological Achievements, Kunming Medical University, Chunrong west road 1168, Kunming City, China
- Yunnan Drug Policy Research Center, Kunming Medical University, Kunming, China
| | - Yan Shen
- Gastroenterology Oncology, Yunnan Cancer Hospital, Kunzhou Road 519, Kunming City, China
| | - Zhiying Weng
- School of Pharmaceutical Science &Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Chunrong west road 1168, Kunming City, China
| | - Keying Zhao
- School of Public Health, Kunming Medical University, Chunrong West Road 1168, Kunming City, China
| | - Zhengyou Jiang
- School of Management, Universiti Sains Malaysia, 11800 USM Penang, Penang City, Malaysia
| | - Meng Wang
- Physical Examination Center, Kunming Center for Disease Prevention and Control, Xichang Road 126, Kunming City, China
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Njei B, Yi I, Strazzabosco M. Cost-effectiveness analysis: The missing factor in the management of HCC. Clin Liver Dis (Hoboken) 2024; 23:e0178. [PMID: 38860130 PMCID: PMC11164007 DOI: 10.1097/cld.0000000000000178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Accepted: 03/08/2024] [Indexed: 06/12/2024] Open
Affiliation(s)
- Basile Njei
- Liver Center, Digestive Disease Section, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA
- Department of Internal Medicine, Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut, USA
| | - Irvin Yi
- Liver Center, Digestive Disease Section, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA
- Department of Internal Medicine, Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut, USA
| | - Mario Strazzabosco
- Liver Center, Digestive Disease Section, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA
- Department of Internal Medicine, Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut, USA
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6
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Zou H, Xue Y, Chen X, Lai Y, Yao D, Ung COL, Hu H. Comparative analysis of disease modelling for health economic evaluations of systemic therapies in advanced hepatocellular carcinoma. PLoS One 2023; 18:e0292239. [PMID: 37796814 PMCID: PMC10553296 DOI: 10.1371/journal.pone.0292239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Accepted: 09/14/2023] [Indexed: 10/07/2023] Open
Abstract
BACKGROUND The objective of this study was to systematically analyse methodological and structural assumptions utilised in model-based health economic evaluations of systemic advanced hepatocellular carcinoma (HCC) therapies, discuss the existing challenges, and develop methodological recommendations for future models in advanced HCC. METHODS We performed literature searches using five databases (Embase, PubMed, Web of Science, Econlit, and CNKI) up to December 4, 2022. Technology appraisals from Canada, England, Australia, and the United States were also considered. Model-based full economic evaluations of systemic advanced HCC therapies in English or Chinese met the eligibility criteria. The reporting quality was assessed by using the Consolidated Health Economic Evaluation Reporting Standards 2022 checklist. RESULTS Of 12,863 records retrieved, 55 were eligible for inclusion. Markov model (n = 29, 53%) and partitioned survival model (n = 27, 49%) were the most commonly used modelling techniques. Most studies were based on health-state-driven structure (n = 51, 93%), followed by treatment-line-driven structure (n = 2, 4%) and combination structure (n = 1, 2%). Only three studies (5%) adopted external real-world data to extrapolate the overall survival or calibrate the extrapolation. Few studies reported the assumptions of transition probabilities. Utility modelling approaches were state-based (n = 51, 93%) and time-to-death (n = 1, 2%). Only 13 studies (24%) reported five types of model validation. Economic evaluation results of specific treatment strategies varied among studies. CONCLUSIONS Disease modelling for health economic evaluations of systemic therapies in advanced HCC has adopted various modelling approaches and assumptions, leading to marked uncertainties in results. By proposing methodological recommendations, we suggest that future model-based studies for health economic evaluation of HCC therapies should follow good modelling practice guidelines and improve modelling methods to generate reliable health and economic evidence.
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Affiliation(s)
- Huimin Zou
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China
| | - Yan Xue
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China
| | - Xianwen Chen
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China
| | - Yunfeng Lai
- School of Public Health and Management, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Dongning Yao
- Department of Drug Regulatory Science and Pharmacoeconomics, School of Pharmacy, Nanjing Medical University, Nanjing, China
| | - Carolina Oi Lam Ung
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China
- Centre for Pharmaceutical Regulatory Sciences, University of Macau, Macao SAR, China
- Department of Public Health and Medicinal Administration, Faculty of Health Sciences, University of Macau, Macao SAR, China
| | - Hao Hu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China
- Centre for Pharmaceutical Regulatory Sciences, University of Macau, Macao SAR, China
- Department of Public Health and Medicinal Administration, Faculty of Health Sciences, University of Macau, Macao SAR, China
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Li Y, Liang X, Li H, Chen X. Atezolizumab plus bevacizumab versus nivolumab as first‐line treatment for advanced or unresectable hepatocellular carcinoma: A cost‐effectiveness analysis. Cancer 2022; 128:3995-4003. [DOI: 10.1002/cncr.34457] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 06/22/2022] [Accepted: 07/08/2022] [Indexed: 12/16/2022]
Affiliation(s)
- Yan Li
- Department of Pharmacy Guangxi Academy of Medical Sciences and People's Hospital of Guangxi Zhuang Autonomous Region Nanning Guangxi People's Republic of China
| | - Xueyan Liang
- Department of Pharmacy Guangxi Academy of Medical Sciences and People's Hospital of Guangxi Zhuang Autonomous Region Nanning Guangxi People's Republic of China
| | - Huijuan Li
- Department of Pharmacy Guangxi Academy of Medical Sciences and People's Hospital of Guangxi Zhuang Autonomous Region Nanning Guangxi People's Republic of China
| | - Xiaoyu Chen
- Department of Pharmacy Guangxi Academy of Medical Sciences and People's Hospital of Guangxi Zhuang Autonomous Region Nanning Guangxi People's Republic of China
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Yuen SC, Amaefule AQ, Kim HH, Owoo BV, Gorman EF, Mattingly TJ. A Systematic Review of Cost-Effectiveness Analyses for Hepatocellular Carcinoma Treatment. PHARMACOECONOMICS - OPEN 2022; 6:9-19. [PMID: 34427897 PMCID: PMC8807829 DOI: 10.1007/s41669-021-00298-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 08/08/2021] [Indexed: 05/05/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is associated with significant financial burden for patients and payers. The objective of this study was to review economic models to identify, evaluate, and compare cost-effectiveness estimates for HCC treatments. METHODS A systematic search of the PubMed, Embase, and Cochrane Library databases to identify economic evaluations was performed and studies that modeled treatments for HCC reporting costs and cost effectiveness were included. Risk of bias was assessed qualitatively, considering costing approach, reported study perspective, and funding received. Intervention costs were adjusted to 2021 US dollars for comparison. For studies reporting quality-adjusted life-years (QALYs), we conducted analyses stratified by comparison type to assess cost effectiveness at the time of the analysis. RESULTS A total of 27 studies were included. Non-curative versus non-curative therapy comparisons were used in 20 (74.1%) studies, curative versus curative comparisons were used in 5 (18.5%) studies, and curative versus non-curative comparisons were used in 2 (7.4%) studies. Therapy effectiveness was estimated using a QALY measure in 20 (74.1%) studies, while 7 (25.9%) studies only assessed life-years gained (LYG). A health sector perspective was used in 26 (96.3%) of the evaluations, with only 1 study including costs beyond this perspective. Median intervention cost was $53,954 (range $4550-$4,760,835), with a median incremental cost of $6546 (range - $72,441 to $1,279,764). In cost-utility analyses, 11 (55%) studies found the intervention cost effective using a $100,000/QALY threshold at the time of the study, with an incremental cost-effectiveness ratio (ICER) ranging from - $1,176,091 to $1,152,440 when inflated to 2021 US dollars. CONCLUSION The majority of HCC treatments were found to be cost effective, but with significant variation and with few studies considering indirect costs. Standards for value assessment for HCC treatments may help improve consistency and comparability.
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Affiliation(s)
- Sydney C Yuen
- University of Maryland School of Pharmacy, 220 Arch Street, 12th Floor, Baltimore, MD, 21201, USA
| | - Adaeze Q Amaefule
- University of Maryland School of Pharmacy, 220 Arch Street, 12th Floor, Baltimore, MD, 21201, USA
| | - Hannah H Kim
- University of Maryland School of Pharmacy, 220 Arch Street, 12th Floor, Baltimore, MD, 21201, USA
| | - Breanna-Verissa Owoo
- University of Maryland School of Pharmacy, 220 Arch Street, 12th Floor, Baltimore, MD, 21201, USA
| | - Emily F Gorman
- Health Sciences and Human Services Library, University of Maryland, Baltimore, MD, USA
| | - T Joseph Mattingly
- University of Maryland School of Pharmacy, 220 Arch Street, 12th Floor, Baltimore, MD, 21201, USA.
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Williams SJ, Rilling WS, White SB. Quality of Life and Cost Considerations: Y-90 Radioembolization. Semin Intervent Radiol 2021; 38:482-487. [PMID: 34629718 DOI: 10.1055/s-0041-1735570] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Objective Transarterial radioembolization (TARE) offers a minimally invasive and safe treatment option for primary and metastatic hepatic malignancies. The benefits of TARE are manifold including prolonged overall survival, low associated morbidities, and improved time to progression allowing prolonged treatment-free intervals. The rapid development of new systemic therapies including immunotherapy has radically changed the treatment landscape for primary and metastatic liver cancer. Given the current climate, it is critical for interventional oncologists to understand the benefits of TARE relative to these other therapies. Therefore, this report aims to review quality-of-life outcomes and the cost comparisons of TARE as compared with systemic therapies.
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Affiliation(s)
- Stephen J Williams
- Division of Vascular and Interventional Radiology, Department of Radiology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - William S Rilling
- Division of Vascular and Interventional Radiology, Department of Radiology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Sarah B White
- Division of Vascular and Interventional Radiology, Department of Radiology, Medical College of Wisconsin, Milwaukee, Wisconsin
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Su D, Wu B, Shi L. Cost-effectiveness of Atezolizumab Plus Bevacizumab vs Sorafenib as First-Line Treatment of Unresectable Hepatocellular Carcinoma. JAMA Netw Open 2021; 4:e210037. [PMID: 33625508 PMCID: PMC7905498 DOI: 10.1001/jamanetworkopen.2021.0037] [Citation(s) in RCA: 115] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
IMPORTANCE Treatment with atezolizumab plus bevacizumab may prolong overall survival among patients with unresectable hepatocellular carcinoma. However, to our knowledge, the cost-effectiveness of using this high-priced therapy for this indication is currently unknown. OBJECTIVE To evaluate the cost-effectiveness of atezolizumab plus bevacizumab to treat unresectable hepatocellular carcinoma from the US payer perspective. DESIGN, SETTING, AND PARTICIPANTS This economic evaluation used a partitioned survival model consisting of 3 discrete health states to assess the cost-effectiveness of treatment of hepatocellular carcinoma with atezolizumab plus bevacizumab vs sorafenib. The characteristics of patients in the model were similar to patients in a phase 3, open-label randomized clinical trial (IMbrave150) who had unresectable hepatocellular carcinoma and had not previously received systemic treatment. Key clinical data were generated from the IMbrave150 trial conducted between March 15, 2018, and January 30, 2019, and cost and health preference data were collected from the literature. MAIN OUTCOMES AND MEASURES Costs, quality-adjusted life-years (QALYs), incremental cost-utility ratios, incremental net health benefits, and incremental net monetary benefits were calculated for the 2 treatment strategies. Subgroup, 1-way sensitivity, and probabilistic sensitivity analyses were performed. RESULTS Treatment of hepatocellular carcinoma with atezolizumab plus bevacizumab added 0.530 QALYs and resulted in an incremental cost of $89 807 compared with sorafenib therapy, which had an incremental cost-utility ratio of $169 223 per QALY gained. The incremental net health benefit was -0.068 QALYs, and the incremental net monetary benefit was -$10 202 at a willingness-to-pay threshold of $150 000/QALY. The probabilistic sensitivity analysis indicated that treatment with atezolizumab plus bevacizumab achieved a 35% probability of cost-effectiveness at a threshold of $150 000/QALY. One-way sensitivity analysis revealed that the results were most sensitive to the hazard ratio of overall survival. The subgroup analysis found that treatment with atezolizumab plus bevacizumab was associated with preferred incremental net health benefits in several subgroups, including patients with hepatitis B and C. CONCLUSIONS AND RELEVANCE Atezolizumab plus bevacizumab treatment is unlikely to be a cost-effective option compared with sorafenib for patients with unresectable hepatocellular carcinoma. Reducing the prices of atezolizumab and bevacizumab may improve cost-effectiveness. The economic outcomes also may be improved by tailoring treatments based on individual patient factors.
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Affiliation(s)
- Dan Su
- Department of Pharmacy, The First Affiliated Hospital of University of Science and Technology of China, Hefei, Anhui, China
| | - Bin Wu
- Medical Decision and Economic Group, Department of Pharmacy, Ren Ji Hospital, South Campus, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Lizheng Shi
- Department of Global Health Management and Policy, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana
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Aly A, Ronnebaum S, Patel D, Doleh Y, Benavente F. Epidemiologic, humanistic and economic burden of hepatocellular carcinoma in the USA: a systematic literature review. Hepat Oncol 2020; 7:HEP27. [PMID: 32774837 PMCID: PMC7399607 DOI: 10.2217/hep-2020-0024] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 07/01/2020] [Indexed: 12/24/2022] Open
Abstract
AIM To describe the epidemiologic, humanistic and economic burdens of hepatocellular carcinoma (HCC) in the USA. MATERIALS & METHODS Studies describing the epidemiology and economic burden from national cohorts, any economic models, or any humanistic burden studies published 2008-2018 were systematically searched. RESULTS HCC incidence was 9.5 per 100,000 person-years in most recent data, but was ∼100-times higher among patients with hepatitis/cirrhosis. Approximately a third of patients were diagnosed with advanced disease. Patients with HCC experienced poor quality of life. Direct costs were substantial and varied based on underlying demographics, disease stage and treatment received. Between 25-77% of patients did not receive surgical, locoregional or systemic treatment. CONCLUSION Better treatments are needed to extend survival and improve quality of life for patients with HCC.
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Affiliation(s)
| | | | - Dipen Patel
- Pharmerit – an OPEN Health Company, Bethesda, MD 20814, USA
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12
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Poojari R, Sawant AV, Kini S, Srivastava R, Panda D. Antihepatoma activity of multifunctional polymeric nanoparticles via inhibition of microtubules and tyrosine kinases. Nanomedicine (Lond) 2020; 15:381-396. [PMID: 31990235 DOI: 10.2217/nnm-2019-0349] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Accepted: 12/10/2019] [Indexed: 12/19/2022] Open
Abstract
Aim: Synthesis of poly-L-lactic acid nanoparticles comprising of microtubule-inhibitor docetaxel and tyrosine kinase inhibitor sorafenib (PLDS NPs) for hepatoma treatment. Materials & methods: PLDS NPs were prepared by the emulsion solvent evaporation method and the anticancer activity was evaluated in Huh7 hepatoma cells. Results: Real-time imaging of quantum dots incorporating poly-L-lactic acid nanoparticles showed a rapid internalization of the nanoparticles in Huh7 cells. PLDS NPs exerted stronger antiproliferative, apoptotic and antiangiogenic effects than free single drug counterparts. They strongly promoted microtubule bundling, multinucleation and increased mitotic index in Huh7 cells. They also inhibited the expression of pERK1/2, pAKT and cyclin D1. Conclusion: We developed a single-nanoscale platform for dual drug delivery and high-sensitivity quantum dots imaging for hepatoma treatment. [Formula: see text].
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Affiliation(s)
- Radhika Poojari
- Department of Biosciences & Bioengineering, Indian Institute of Technology Bombay, Mumbai, 400076, India
| | - Avishkar V Sawant
- Department of Biosciences & Bioengineering, Indian Institute of Technology Bombay, Mumbai, 400076, India
| | - Sudarshan Kini
- Department of Biosciences & Bioengineering, Indian Institute of Technology Bombay, Mumbai, 400076, India
- Nitte University Centre for Science Education & Research, Nitte (Deemed to be University), Paneer Campus, Deralakatte, Mangaluru, 575018, India
| | - Rohit Srivastava
- Department of Biosciences & Bioengineering, Indian Institute of Technology Bombay, Mumbai, 400076, India
| | - Dulal Panda
- Department of Biosciences & Bioengineering, Indian Institute of Technology Bombay, Mumbai, 400076, India
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Likhitsup A, Parikh ND. Economic Implications of Hepatocellular Carcinoma Surveillance and Treatment: A Guide for Clinicians. PHARMACOECONOMICS 2020; 38:5-24. [PMID: 31573053 DOI: 10.1007/s40273-019-00839-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
The incidence of hepatocellular carcinoma (HCC) is increasing worldwide, with significant morbidity and associated costs. Treatment allocation depends on the stage of diagnosis; however, resource utilization can be significant across all stages. We aimed to summarize the available data on the cost effectiveness of surveillance of and treatments for HCC in the context of current treatment guidelines. We performed a focused review of studies investigating the economic burden and cost effectiveness of HCC surveillance treatment modalities published between January 2000 and January 2019. The overall economic burden of HCC is increasing in the USA and in several countries worldwide due to its rising incidence and the proliferation of therapies. Liver transplantation is a cost-effective strategy for early-stage HCC treatment in selected patients. In settings where liver transplantation is not available or in patients awaiting transplant, ablative or locoregional therapies are cost effective with increases in quality-adjusted life-years. First-line therapy with sorafenib for advanced stage HCC is cost effective in the treatment of compensated cirrhosis. The cost effectiveness of recently approved systemic therapies for advanced HCC require further investigation. Existing studies have shown that guideline-recommended surveillance techniques and several available therapies for the treatment of HCC are cost effective; however, there are limitations in the literature, including reliance on suboptimal modeling with incomplete/simplified model structure or inadequate inputs. With increasing therapeutic options in patients with HCC, understanding their relative value is critical in designing HCC treatment algorithms.
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Affiliation(s)
- Alisa Likhitsup
- Division of Gastroenterology and Hepatology, University of Missouri, Kansas City, MO, USA
| | - Neehar D Parikh
- Division of Gastroenterology and Hepatology, University of Michigan, 1500 E. Medical Center Dr., Ann Arbor, MI, 48109, USA.
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Supplementary Sorafenib Therapies for Hepatocellular Carcinoma-A Systematic Review and Meta-Analysis: Supplementary Sorafenib for Liver Cancer. J Clin Gastroenterol 2019; 53:486-494. [PMID: 30939505 DOI: 10.1097/mcg.0000000000001175] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the third deadliest cancer worldwide. Sorafenib is considered a supplementary treatment to surgical or locoregional therapies for improving outcomes. We evaluated the efficacy of sorafenib as a supplementary therapy for HCC. METHODS We conducted a meta-analysis including 11 randomized controlled trials. Patients with HCC and studies in which sorafenib was administered alone and compared with placebo or those in which sorafenib was administered in combination with another treatment and compared with that treatment alone were included. The overall effects (OEs) on overall survival and time to progression were pooled as hazard ratios. RESULTS The OEs of sorafenib as a first-line therapy versus placebo for unresectable HCC were 0.62 [95% confidence interval (CI): 0.50-0.77] and 0.58 (95% CI: 0.47-0.70), respectively. The OEs of sorafenib as a second-line therapy versus placebo for progressive HCC were 0.73 (95% CI: 0.47-1.13) and 0.54 (95% CI: 0.30-0.97), respectively. The OEs of sorafenib as an adjuvant therapy versus placebo for early HCC were 1.00 (95% CI: 0.76-1.30) and 0.89 (95% CI: 0.74-1.08), respectively. The OEs of sorafenib combined with transarterial chemoemboliztion (TACE) versus placebo combined with TACE were 0.80 (95% CI: 0.54-1.21) and 0.85 (95% CI: 0.70-1.04), respectively. The OEs of sorafenib as an adjuvant to TACE versus placebo as an adjuvant to TACE for intermediate HCC were 1.06 (95% CI: 0.69-1.64) and 0.65 (95% CI: 0.31-1.36), respectively. CONCLUSIONS Sorafenib was effective as a first-line therapy for unresectable HCC, but it was ineffective as a second-line or adjuvant therapy. Sorafenib did not increase the efficacy of TACE.
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Soto-Perez-de-Celis E, Aguiar PN, Cordón ML, Chavarri-Guerra Y, Lopes GDL. Cost-Effectiveness of Cabozantinib in the Second-Line Treatment of Advanced Hepatocellular Carcinoma. J Natl Compr Canc Netw 2019; 17:669-675. [DOI: 10.6004/jnccn.2018.7275] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Accepted: 01/16/2019] [Indexed: 11/17/2022]
Abstract
Background: Treatment options are limited for patients with advanced hepatocellular carcinoma (HCC) that progresses after treatment with sorafenib. Cabozantinib, an oral small molecule inhibitor of multiple tyrosine kinase receptors, recently showed improved overall survival (OS) compared with placebo in sorafenib-pretreated patients with advanced HCC in the CELESTIAL trial. This study assessed the cost-effectiveness of cabozantinib for second-line treatment of patients with advanced HCC from a US healthcare system perspective. Patients and Methods: Cost and utility data were extracted from the CELESTIAL trial and used to determine the cost-effectiveness of cabozantinib compared with placebo plus best supportive care. The main outcome of this study was the incremental cost-effectiveness ratio (ICER), expressed as cost per quality-adjusted life year (QALY) gained by using cabozantinib compared with placebo plus best supportive care in sorafenib-pretreated HCC. Results: In the base-case analysis using data from the CELESTIAL trial, the incremental QALY and ICER were 0.067 and $1,040,675 for cabozantinib compared with placebo and best supportive care. OS reported in the CELESTIAL trial (hazard ratio, 0.76; 95% CI, 0.63–0.92) had the strongest association with the ICER. In one-way sensitivity analyses, there were no scenarios in which cabozantinib was cost-effective. In a cost-threshold analysis, cabozantinib would have to be priced at least $50 per pill to be cost-effective considering a willingness to pay of $100,000 per QALY. Although the CELESTIAL trial demonstrated that cabozantinib improves OS compared with placebo in patients with HCC that progresses after treatment with sorafenib, our analysis shows that cabozantinib is not a cost-effective therapy in this scenario. Conclusions: At current costs, cabozantinib is not cost-effective for second-line therapy of HCC in the United States.
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Affiliation(s)
- Enrique Soto-Perez-de-Celis
- aDepartment of Geriatrics, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Pedro N. Aguiar
- bCentro de Estudos e Pesquisa de Hematologia e Oncologia, Faculdade de Medicina do ABC, Santo André, Brazil
| | - Mónica L. Cordón
- cDepartment of Hemato-Oncology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico; and
| | - Yanin Chavarri-Guerra
- cDepartment of Hemato-Oncology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico; and
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Seyhoun I, Hajighasemlou S, Ai J, Hosseinzadeh F, Mirmoghtadaei M, Seyhoun SM, Parseh B, Abdolahi S, Ghazvinian Z, Shadnoush M, Verdi J. Novel Combination of Mesenchymal Stem Cell-Conditioned Medium with Sorafenib Have Synergistic Antitumor Effect of Hepatocellular Carcinoma Cells. Asian Pac J Cancer Prev 2019; 20:263-267. [PMID: 30678447 PMCID: PMC6485565 DOI: 10.31557/apjcp.2019.20.1.263] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Objective: Hepatocellular carcinoma (HCC) is the most common liver malignancy. Sorafenib is the first-line systemic treatment for advanced HCCs. However, due to safety concerns, researchers are now looking for ways to boost the efficacy of the medication. One approach for reducing toxicity is combining sorafenib with other agents so that a lower dose of sorafenib is required. Mesenchymal stromal cells (MSCs) can have an inhibitory effect on HCC tumor growth. Mesenchymal Stem Cell-Conditioned Medium (MSC-CM) is the substance extracted from MSC culture and contains most of the potential cytokines secreted by MSCs. We, therefore, anticipated a synergistic Antitumor Effect of sorafenib in Combination with MSC-CM. In this study, we used HepG2 as our target cell lines. Methods: HepG2 cells were treated with sorafenib alone and with sorafenib + MSC-CM. CCK-8 assay was used to evaluate and compare the inhibition of cell growth between the two groups with different treatments. Results: The combination treatment of cell lines with sorafenib and MSC-CM had significantly reduced the values of IC50 compared to the use of sorafenib alone (3.4 vs. 2.7 respectively). Conclusion: This study suggests that a combination of sorafenib with MSC-CM can synergistically suppress the growth of HCC cells.
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Affiliation(s)
- Iman Seyhoun
- Tissue Engineering and Applied cell Sciences,Tehran University of Medical Sciences,Tehran, Iran. ,
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Cost-effectiveness of Sorafenib for Treatment of Advanced Hepatocellular Carcinoma in India. J Clin Exp Hepatol 2019; 9:468-475. [PMID: 31516263 PMCID: PMC6728525 DOI: 10.1016/j.jceh.2018.10.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2018] [Accepted: 10/23/2018] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Majority of patients of hepatocellular carcinoma (HCC) in India present in advanced stages, when curative treatment options are limited. We undertook this study to assess the cost-effectiveness of treating advanced HCC patients with sorafenib compared with best supportive care (BSC). METHODS A Markov model was parameterized to model the lifetime costs and consequences of treating advanced HCC patients with sorafenib versus BSC using a societal perspective. Cost of routine care, diagnostics, management of complications in both the arms and management of adverse effects of sorafenib treatment were considered. A probabilistic sensitivity analysis was undertaken to assess the effect of parameter uncertainty. RESULTS The incremental cost and benefit gained by treating HCC using sorafenib was Indian rupees 94,182 ($1459) and 0.19 quality adjusted life years (QALYs) per patient, implying an incremental cost of Indian rupees 507,520 ($7861) per QALY gained. CONCLUSIONS Sorafenib is not cost-effective for use in advanced hepatocellular carcinoma treatment in India.
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Key Words
- BCLC, Barcelona Clinic Liver Cancer
- BSC, Best Supportive Care
- CEAC, Cost-Effectiveness Acceptability Curve
- CGHS, Central Government Health Scheme
- GDP, Gross Domestic Product
- HBV, Hepatitis B Viral
- HCC, Hepatocellular Carcinoma
- ICER, Incremental Cost-Effectiveness Ratio
- ICU, Intensive Care Unit
- INASL, Indian National Association for Study of Liver
- INR, Indian National Rupees
- LY, Life Year
- PD, Progressive Disease
- PFS, Progression Free State
- PSA, Probabilistic Sensitivity Analysis
- QALY, Quality Adjusted Life Year
- QOL, Quality of Life
- RCC, Renal Cell Carcinoma
- TTSP, Time to Symptomatic Progression
- UGIE, Upper Gastrointestinal Endoscopy
- USD, US Dollars
- cancer
- cost effectiveness analysis
- hepatocellular carcinoma
- sorafenib
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18
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Qin S, Kruger E, Tan SC, Cheng S, Wang N, Liang J. Cost-effectiveness analysis of FOLFOX4 and sorafenib for the treatment of advanced hepatocellular carcinoma in China. COST EFFECTIVENESS AND RESOURCE ALLOCATION 2018; 16:29. [PMID: 30087583 PMCID: PMC6076412 DOI: 10.1186/s12962-018-0112-0] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Accepted: 07/23/2018] [Indexed: 12/20/2022] Open
Abstract
Objectives Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths globally. In China, sorafenib and oxaliplatin plus infusional-fluorouracil/leucovorin (FOLFOX4) are approved for the systemic treatment of advanced HCC. This study compared the cost-effectiveness of these therapies from a healthcare system perspective and a patient perspectives. Methods A Markov model was constructed using overall and progression-free survival rates and adverse event (AE) rate from two randomized controlled studies of advanced HCC patients from Asia: EACH for FOLFOX4 and ORIENTAL for sorafenib. The patients in the Markov model were followed until death, the length of each Markov cycle was 1 month, and the survival was adjusted for quality-adjusted life years (QALYs). Direct medical costs included costs of therapies, AE treatment, general ward and tests. Costs were derived from published sources, interviews with oncologists and hospital data from China. One-way and probabilistic sensitivity analyses (PSA) were performed to test the robustness of the results. Results From the healthcare system perspective, FOLFOX4 dominated sorafenib with lower therapy costs (FOLFOX4: US$ 6972; sorafenib: US$ 12,289), lower direct medical costs (FOLFOX4: US$ 8428; sorafenib: US$ 12,798), and higher QALYs (FOLFOX4: 0.42; sorafenib: 0.38) per patient. This result was robust according to comprehensive one-way sensitivity analyses. According to the PSA, at the cost-effectiveness threshold for China (3 × GDP, US$ 22,073), FOLFOX4 should be chosen in 63.9% of simulations. From the patient perspective, FOLFOX4 also dominated sorafenib. Conclusions The study results indicate that FOLFOX4 dominates sorafenib because it appears to provide higher effectiveness with significantly lower costs in treating Chinese advanced HCC patients.
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Affiliation(s)
- Shukui Qin
- Department of Medical Oncology, People's Liberation Army Cancer Center, Eight One Hospital, Nanjing, China
| | - Eliza Kruger
- Economics and Outcomes, Real World Evidence, IMS Health, San Francisco, USA
| | - Seng Chuen Tan
- Economics and Outcomes, Real World Evidence, IMS Health, Singapore, Singapore
| | - Shuqun Cheng
- 4Department of Hepatic Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Nanya Wang
- 5Cancer Center, First Hospital of Jilin University, Jilin, China
| | - Jun Liang
- 6Department of Medical Oncology, Peking University Cancer Hospital, Peking University International Hospital, No. 1 Life Garden Road, Zhongguancun Life Science Park, Changping District, Beijing, 102206 China
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19
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Chen S, Peng Z, Wei M, Liu W, Dai Z, Wang H, Mei J, Cheong M, Zhang H, Kuang M. Sorafenib versus Transarterial chemoembolization for advanced-stage hepatocellular carcinoma: a cost-effectiveness analysis. BMC Cancer 2018; 18:392. [PMID: 29621988 PMCID: PMC5887167 DOI: 10.1186/s12885-018-4308-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Accepted: 03/26/2018] [Indexed: 12/14/2022] Open
Abstract
Background Sorafenib and transarterial chemoembolization (TACE) might both provide survival benefit for advanced hepatocellular carcinoma (HCC). Adopting either as a first-line therapy carries major cost and resource implications. We aimed to estimate the cost-effectiveness of sorafenib and TACE in advanced HCC. Methods A Markov model was constructed in a hypothetical cohort of patients aged 60 years with advanced HCC and Child-Pugh A/B cirrhosis over a 2-year time frame. Three strategies (full or dose-adjusted sorafenib and TACE) were compared in two cost settings: China and the USA. Transition probabilities, utility and costs were extracted from systematic review of 27 articles. Sensitivity analysis and Monte Carlo analysis were conducted. Results Full and dose-adjusted sorafenib respectively produced 0.435 and 0.482 quality-adjusted life years (QALYs) while TACE produced 0.375 QALYs. The incremental cost-effectiveness ratio (ICER) of full-dose sorafenib versus TACE was $101,028.83/QALY in China whereas full-dose sorafenib is a dominant strategy (ICER of -$1,014,507.20/ QALY) compared with TACE in the USA. Compared to full-dose sorafenib, dose-adjusted sorafenib was the dominant strategy with the negative ICERs in both China (−$132,238.94/QALY) and the USA (−$230,058.09/QALY). However, dose-adjusted sorafenib is not available currently, so full-dose sorafenib should be compared with TACE. As the acceptability curves shown, full-dose sorafenib was the optimal strategy at the accepted thresholds of WTP in these two countries. Specifically, full-dose sorafenib was the cost-effective treatment compared with TACE if a WTP was set above $21,670 in the USA, whereas in China, TACE could be more favorable than full-dose sorafenib if a WTP was set below $10,473. Conclusions Dose-adjusted sorafenib may be cost-effective compared to full-dose sorafenib or TACE for advanced HCC patients. However, when confining the comparisons between full-dose sorafenib and TACE, full-dose sorafenib was cost-effective for these patients, under the accepted thresholds of WTP. Electronic supplementary material The online version of this article (10.1186/s12885-018-4308-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Shuling Chen
- Division of Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China
| | - Zhenwei Peng
- Department of Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China.,Clinical Research Unit, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China
| | - Mengchao Wei
- Department of Liver Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China
| | - Weifeng Liu
- Department of Anesthesiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China
| | - Zihao Dai
- Department of Liver Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China
| | - Haibo Wang
- Clinical Research Unit, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China
| | - Jie Mei
- Clinical Research Unit, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China
| | - Mingfong Cheong
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
| | - Hanmei Zhang
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
| | - Ming Kuang
- Division of Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China. .,Department of Liver Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China.
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Li S, Dai W, Mo W, Li J, Feng J, Wu L, Liu T, Yu Q, Xu S, Wang W, Lu X, Zhang Q, Chen K, Xia Y, Lu J, Zhou Y, Fan X, Xu L, Guo C. By inhibiting PFKFB3, aspirin overcomes sorafenib resistance in hepatocellular carcinoma. Int J Cancer 2017; 141:2571-2584. [PMID: 28857200 DOI: 10.1002/ijc.31022] [Citation(s) in RCA: 81] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Revised: 08/01/2017] [Accepted: 08/10/2017] [Indexed: 01/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the few cancers with a continuous increase in incidence and mortality. Drug resistance is a major problem in the treatment of HCC. In this study, two sorafenib-resistant HCC cell lines and a nude mouse subcutaneously tumor model were used to explore the possible mechanisms leading to sorafenib resistance, and to investigate whether aspirin could increase the sensitivity of hepatoma cells to sorafenib. The combination of aspirin and sorafenib resulted in a synergistic antitumor effect against liver tumors both in vitro and in vivo. High glycolysis and PFKFB3 overexpression occupied a dominant position in sorafenib resistance, and can be targeted and overcome by aspirin. Aspirin plus sorafenib induced apoptosis in tumors without inducing weight loss, hepatotoxicity or inflammation. Our results suggest that aspirin overcomes sorafenib resistance and their combination may be an effective treatment approach for HCC.
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Affiliation(s)
- Sainan Li
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Weiqi Dai
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Wenhui Mo
- Department of Gastroenterology, Minhang Hospital, Fudan University, Shanghai, China
| | - Jingjing Li
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jiao Feng
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Liwei Wu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Tong Liu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Qiang Yu
- Department of Gastroenterology, Shanghai Tenth Hospital, School of Clinical Medicine of Nanjing Medical University, Shanghai, China
| | - Shizan Xu
- Department of Gastroenterology, Shanghai Tenth Hospital, School of Clinical Medicine of Nanjing Medical University, Shanghai, China
| | - Wenwen Wang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xiya Lu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Qinghui Zhang
- Department of Clinical Laboratory, Kunshan First People's Hospital Affiliated to Jiangsu University, Kunshan, JiangSu, China
| | - Kan Chen
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yujing Xia
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jie Lu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yingqun Zhou
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xiaoming Fan
- Department of Gastroenterology, Jinshan Hospital of Fudan University, Jinshan, Shanghai, China
| | - Ling Xu
- Department of Gastroenterology, Shanghai Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chuanyong Guo
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
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21
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Liang Y, Chen J, Yu Q, Ji T, Zhang B, Xu J, Dai Y, Xie Y, Lin H, Liang X, Cai X. Phosphorylated ERK is a potential prognostic biomarker for Sorafenib response in hepatocellular carcinoma. Cancer Med 2017; 6:2787-2795. [PMID: 29030911 PMCID: PMC5727337 DOI: 10.1002/cam4.1228] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2017] [Revised: 09/07/2017] [Accepted: 09/11/2017] [Indexed: 12/20/2022] Open
Abstract
Sorafenib, the only approved drug for hepatocellular carcinoma, acts as a remarkable inhibitor of Raf serine‐threonine kinases. However, Sorafenib is expensive, and clinical experience shows that it is not an effective treatment for many patients. Previous study has demonstrated that phosphorylated ERK (pERK) is a key downstream component in the RAF/MEK/ERK signaling pathway. Here, we investigate whether pERK is a useful biomarker for treating HCC with Sorafenib. In vitro cell viability assays showed that the efficacy of Sorafenib was distinctly different according to the level of pERK. Furthermore, in established patient‐derived xenografts from HCC specimens, we found that the growth rate of tumors with high levels of pERK was significantly decreased by Sorafenib treatment. Taken together, pERK is a potential biomarker for the sensitivity to Sorafenib in treating HCC.
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Affiliation(s)
- Yuelong Liang
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, China
| | - Jiang Chen
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, China
| | - Qingsong Yu
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, China
| | - Tong Ji
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, China
| | - Bin Zhang
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, China
| | - Junjie Xu
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, China
| | - Yi Dai
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, China
| | - Yangyang Xie
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, China
| | - Hui Lin
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, China
| | - Xiao Liang
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, China
| | - Xiujun Cai
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, China
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Thein HH, Qiao Y, Zaheen A, Jembere N, Sapisochin G, Chan KKW, Yoshida EM, Earle CC. Cost-effectiveness analysis of treatment with non-curative or palliative intent for hepatocellular carcinoma in the real-world setting. PLoS One 2017; 12:e0185198. [PMID: 29016627 PMCID: PMC5634563 DOI: 10.1371/journal.pone.0185198] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Accepted: 09/07/2017] [Indexed: 12/31/2022] Open
Abstract
Hepatocellular carcinoma (HCC) presentation is heterogeneous necessitating a variety of therapeutic interventions with varying efficacies and associated prognoses. Poor prognostic patients often undergo non-curative palliative interventions including transarterial chemoembolization (TACE), sorafenib, chemotherapy, or purely supportive care. The decision to pursue one of many palliative interventions for HCC is complex and an economic evaluation comparing these interventions has not been done. This study evaluates the cost-effectiveness of non-curative palliative treatment strategies such as TACE alone or TACE+sorafenib, sorafenib alone, and non-sorafenib chemotherapy compared with no treatment or best supportive care (BSC) among patients diagnosed with HCC between 2007 and 2010 in a Canadian setting. Using person-level data, we estimated effectiveness in life years and quality-adjusted life years (QALYs) along with total health care costs (2013 US dollars) from the health care payer’s perspective (3% annual discount). A net benefit regression approach accounting for baseline covariates with propensity score adjustment was used to calculate incremental net benefit to generate incremental cost-effectiveness ratio (ICER) and uncertainty measures. Among 1,172 identified patients diagnosed with HCC, 4.5%, 7.9%, and 5.6%, received TACE alone or TACE+sorafenib, sorafenib, and non-sorafenib chemotherapy clone, respectively. Compared with no treatment or BSC (81.9%), ICER estimates for TACE alone or TACE+sorafenib was $6,665/QALY (additional QALY: 0.47, additional cost: $3,120; 95% CI: -$18,800-$34,500/QALY). The cost-effectiveness acceptability curve demonstrated that if the relevant threshold was $50,000/QALY, TACE alone or TACE+sorafenib, non-sorafenib chemotherapy, and sorafenib alone, would have a cost-effectiveness probability of 99.7%, 46.6%, and 5.5%, respectively. Covariates associated with the incremental net benefit of treatments are age, sex, comorbidity, and cancer stage. Findings suggest that TACE with or without sorafenib is currently the most cost-effective active non-curative palliative treatment approach to HCC. Further research into new combination treatment strategies that afford the best tumor response is needed.
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Affiliation(s)
- Hla-Hla Thein
- Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
- Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada
- * E-mail:
| | - Yao Qiao
- Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
| | - Ahmad Zaheen
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Nathaniel Jembere
- Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
| | - Gonzalo Sapisochin
- Multi-Organ Transplant, Division of General Surgery, University Health Network, University of Toronto, Toronto, Canada
| | - Kelvin K. W. Chan
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
- Canadian Centre for Applied Research in Cancer Control (ARCC), Toronto, Ontario, Canada
| | - Eric M. Yoshida
- University of British Columbia, Division of Gastroenterology, Vancouver, BC, Canada
| | - Craig C. Earle
- Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada
- Canadian Centre for Applied Research in Cancer Control (ARCC), Toronto, Ontario, Canada
- Ontario Institute for Cancer Research, Toronto, Ontario, Canada
- Cancer Care Ontario, Toronto, Ontario, Canada
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23
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Melatonin enhances sorafenib actions in human hepatocarcinoma cells by inhibiting mTORC1/p70S6K/HIF-1α and hypoxia-mediated mitophagy. Oncotarget 2017; 8:91402-91414. [PMID: 29207653 PMCID: PMC5710933 DOI: 10.18632/oncotarget.20592] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2017] [Accepted: 08/09/2017] [Indexed: 12/29/2022] Open
Abstract
The antiangiogenic effects of sustained sorafenib treatment in hepatocellular carcinoma (HCC) lead to the occurrence of hypoxia-mediated drug resistance resulting in low therapy efficiency and negative outcomes. Combined treatments with coadjuvant compounds to target the hypoxia-inducible factor-1α (HIF-1α) represent a promising therapeutic approach through which sorafenib efficiency may be improved. Melatonin is a well-documented oncostatic agent against different cancer types. Here, we evaluated whether melatonin could enhance sorafenib cytotoxicity and overcome the hypoxia-mediated resistance mechanisms in HCC. The pharmacological melatonin concentration (2 mM) potentiated the oncostatic effects of sorafenib (5 μM) on Hep3B cells even under hypoxia. Melatonin downregulated the HIF-1α protein synthesis through the inhibition of the mammalian target of rapamycin complex 1 (mTORC1)/ribosomal protein S6 kinase beta-1 (p70S6K)/ribosomal protein S6 (RP-S6) pathway, although the indole enhanced Akt phosphorylation by the mTORC1/C2 negative feedback. Furthermore, melatonin and sorafenib coadministration reduced the HIF-1α-mitophagy targets expression, impaired autophagosome formation and subsequent mitochondria and lysosomes colocalization. Together, our results indicate that melatonin improves the Hep3B sensitivity to sorafenib, preventing HIF-1α synthesis to block the cytoprotective mitophagy induced by the hypoxic microenvironment, an important element of the multifactorial mechanisms responsible for the chemotherapy failure.
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24
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Parikh ND, Singal AG, Hutton DW. Cost effectiveness of regorafenib as second-line therapy for patients with advanced hepatocellular carcinoma. Cancer 2017; 123:3725-3731. [DOI: 10.1002/cncr.30863] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2017] [Revised: 05/05/2017] [Accepted: 05/10/2017] [Indexed: 01/23/2023]
Affiliation(s)
- Neehar D. Parikh
- Department of Internal Medicine; University of Michigan; Ann Arbor Michigan
| | - Amit G. Singal
- Department of Internal Medicine; University of Texas Southwestern; Dallas Texas
| | - David W. Hutton
- University of Michigan School of Public Health; Ann Arbor Michigan
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25
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Tunissiolli NM, Castanhole-Nunes MMU, Biselli-Chicote PM, Pavarino ÉC, da Silva RF, da Silva RDCMA, Goloni-Bertollo EM. Hepatocellular Carcinoma: a Comprehensive Review of
Biomarkers, Clinical Aspects, and Therapy. Asian Pac J Cancer Prev 2017; 18:863-872. [PMID: 28545181 PMCID: PMC5494234 DOI: 10.22034/apjcp.2017.18.4.863] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a cause of several deaths related to cancer worldwidely. In early stage, curative treatments such as surgical resection, liver transplant and local ablation can improve the patient ´s survival. However, the disease is detected in advanced stage; moreover some available therapies are restricted to palliative care and local treatment. Early detections of HCC and adequate therapy are crucial to increase survival as well as to improve the patient´s quality of life. Therefore, researchers have been investigating molecular biomarkers with high sensibility and reliability as Golgi 73 protein (GP73), Glypican-3 (GPC3), Osteopontin (OPN), microRNAs and others. MicroRNAs can regulate important pathways on carcinogenesis, as tumor angiogenesis and progression. So, they can be considered as possible markers of prognosis in HCC, and therapeutic target for this tumor type. In this review, we discuss the recent advances related to the cause (highlighting the main risk factors), treatment, biomarkers, clinic aspects, and outcome in hepatocellular carcinoma.
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Affiliation(s)
- Nathalia Martines Tunissiolli
- Research Unit of Genetics and Molecular Biology (UPGEM), São José do Rio Preto Medical School (FAMERP), São José do Rio Preto- SP, Brazil
- Liver Tumors Study Group (GETF),São Jose do Rio Preto Medical
School (FAMERP), Sao Jose do Rio Preto- SP, Brazil.
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26
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Colagrande S, Inghilesi AL, Aburas S, Taliani GG, Nardi C, Marra F. Challenges of advanced hepatocellular carcinoma. World J Gastroenterol 2016; 22:7645-7659. [PMID: 27678348 PMCID: PMC5016365 DOI: 10.3748/wjg.v22.i34.7645] [Citation(s) in RCA: 128] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Revised: 07/06/2016] [Accepted: 08/08/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is an aggressive malignancy, resulting as the third cause of death by cancer each year. The management of patients with HCC is complex, as both the tumour stage and any underlying liver disease must be considered conjointly. Although surveillance by imaging, clinical and biochemical parameters is routinely performed, a lot of patients suffering from cirrhosis have an advanced stage HCC at the first diagnosis. Advanced stage HCC includes heterogeneous groups of patients with different clinical condition and radiological features and sorafenib is the only approved treatment according to Barcelona Clinic Liver Cancer. Since the introduction of sorafenib in clinical practice, several phase III clinical trials have failed to demonstrate any superiority over sorafenib in the frontline setting. Loco-regional therapies have also been tested as first line treatment, but their role in advanced HCC is still matter of debate. No single agent or combination therapies have been shown to impact outcomes after sorafenib failure. Therefore this review will focus on the range of experimental therapeutics for patients with advanced HCC and highlights the successes and failures of these treatments as well as areas for future development. Specifics such as dose limiting toxicity and safety profile in patients with liver dysfunction related to the underlying chronic liver disease should be considered when developing therapies in HCC. Finally, robust validated and reproducible surrogate end-points as well as predictive biomarkers should be defined in future randomized trials.
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27
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Youssef MM, Tolba MF, Badawy NN, Liu AW, El-Ahwany E, Khalifa AE, Zada S, Abdel-Naim AB. Novel combination of sorafenib and biochanin-A synergistically enhances the anti-proliferative and pro-apoptotic effects on hepatocellular carcinoma cells. Sci Rep 2016; 6:30717. [PMID: 27470322 PMCID: PMC4965826 DOI: 10.1038/srep30717] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2015] [Accepted: 07/06/2016] [Indexed: 02/08/2023] Open
Abstract
Sorafenib (SOR) is the first-line treatment for hepatocellular carcinoma (HCC). However, its use is hindered by the recently expressed safety concerns. One approach for reducing SOR toxicity is to use lower doses in combination with other less toxic agents. Biochanin-A (Bio-A), a promising isoflavone, showed selective toxicity to liver cancer cells. We postulated that combining SOR and Bio-A could be synergistically toxic towards HCC cells. We further evaluated the underlying mechanism. Cytotoxicity assay was performed to determine the IC50 of Bio-A and SOR in HepG2, SNU-449 and Huh-7 cells. Then, combination index in HepG2 was evaluated using Calcusyn showing that the concurrent treatment with lower concentrations of SOR and Bio-A synergistically inhibited cell growth. Our combination induced significant arrest in pre-G and G0/G1 cell cycle phases and decrease in cyclin D1 protein level. Concomitantly, SOR/Bio-A reduced Bcl-2/Bax ratio. Furthermore, this co-treatment significantly increased caspase-3 & -9 apoptotic markers, while decreased anti-apoptotic and proliferative markers; survivin and Ki-67, respectively. Active caspase-3 in HepG2, SNU-449 and Huh-7 confirmed our synergism hypothesis. This study introduces a novel combination, where Bio-A synergistically enhanced the anti-proliferative and apoptotic effects of SOR in HCC cells, which could serve as a potential effective regimen for treatment.
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Affiliation(s)
- Mohieldin M Youssef
- The American University in Cairo, New Cairo, 11835 Egypt.,Okinawa Institute of Science and Technology Graduate University, OIST, Okinawa, 904-0495 Japan
| | - Mai F Tolba
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Ain-Shams University, Cairo, 11566 Egypt
| | - Noha N Badawy
- The American University in Cairo, New Cairo, 11835 Egypt
| | - Andrew W Liu
- Okinawa Institute of Science and Technology Graduate University, OIST, Okinawa, 904-0495 Japan
| | - Eman El-Ahwany
- Immunology Department, Theodor-Bilharz Research Institute (TBRI), Giza, 12411 Egypt
| | - Amani E Khalifa
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Ain-Shams University, Cairo, 11566 Egypt
| | - Suher Zada
- The American University in Cairo, New Cairo, 11835 Egypt
| | - Ashraf B Abdel-Naim
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Ain-Shams University, Cairo, 11566 Egypt
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28
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Leung HWC, Liu CF, Chan ALF. Cost-effectiveness of sorafenib versus SBRT for unresectable advanced hepatocellular carcinoma. Radiat Oncol 2016; 11:69. [PMID: 27193904 PMCID: PMC4870794 DOI: 10.1186/s13014-016-0644-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Accepted: 05/05/2016] [Indexed: 12/23/2022] Open
Abstract
OBJECTIVE Stereotactic body radiotherapy (SBRT) has been shown to improve overall survival in patients with advanced hepatocellular carcinoma. This study aimed to assess the cost-effectiveness of SBRT compared to sorafenib which is the only drug for advanced hepatocellular carcinoma. METHODS A Markov decision-analytic model was performed to compare the cost-effectiveness of SBRT and sorafenib for unresectable advanced hepatocellular carcinoma. Patients transitioned between three health states: stable disease, progression disease and death. We calculated the data on cost from the perspective of our National Health Insurance Bureau. Sensitivity analyses were conducted to determine the impact of several variables. RESULTS The incremental cost effectiveness ratio (ICER) for sorafenib compared to SBRT was NT$3,788,238 per quality-adjusted life year gained (cost/QALY), which was higher than the willingness to pay threshold of Taiwan according to WHO's guideline. One-way sensitivity analysis revealed that the utility of progression disease for the sorafenib treatment, utility of progression free survival for SBRT, utility of progression free survival for sorafenib, utility of PFS to progression disease for SBRT and transition probability of progression disease to dead for SBRT were the most sensitive parameters in all cost scenarios. The Monte-Carlo simulation demonstrated that the probability of cost-effectiveness at a willingness to pay threshold of NT$ 2,213,145 per QALY was 100 % and 0 % chance for SBRT and sorafenib. CONCLUSION This study indicated that SBRT for advanced hepatocellular carcinoma is cost-effective at a willingness to pay threshold as defined by WHO guideline in Taiwan.
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Affiliation(s)
- Henry W C Leung
- Department of Radiation Therapy, An Nan Hospital, China medical University, No. 66, Sec. 2, Changhe Rd., Annan Dist., Tainan, Taiwan.,Department of Nursing, Min-Hwei College of Health Care management, No.111 6, Sec 2, Zongshan E. Rd., Liuying Township, Tainan City, 736, Taiwan
| | - Chung-Feng Liu
- Department of Information Management, Chia Nan University of Pharmacy & Science, No. 60, Sec 1, Erren Rd., Rende Dist., Tainan City, 71710, Taiwan
| | - Agnes L F Chan
- Department of Pharmacy, An-Nan Hospital, China Medical University, 1. No. 66, Sec. 2, Changhe Rd., Annan Dist., Tainan, Taiwan.
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29
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Hsiao WD, Peng CY, Chuang PH, Lai HC, Cheng KS, Chou JW, Chen YY, Yu CJ, Feng CL, Su WP, Chen SH, Kao JT. Evaluation of dose-efficacy of sorafenib and effect of transarterial chemoembolization in hepatocellular carcinoma patients: a retrospective study. BMC Gastroenterol 2016; 16:50. [PMID: 27117280 PMCID: PMC4847248 DOI: 10.1186/s12876-016-0464-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2015] [Accepted: 04/15/2016] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Transarterial chemoembolization (TACE) and sorafenib are the therapeutic standard for intermediate and advanced stage hepatocellular carcinoma (HCC) patients respectively. High costs with adverse events (AE) of sorafenib might limit sorafenib dosage, further affecting therapeutic response. To attain greatest benefit, we evaluated the efficacy of different doses and effect of TACE during and after sorafenib discontinuation in patients representing Child-Pugh Classification Class A with venous or extra-hepatic invasion. METHODS A total 156 patients met the criteria and were divided into Groups I (n = 52) accepting 800 mg/day; II (n = 58) accepting 800 mg/day and reduced to 400 mg/day owing to AE; and III (n = 46) accepting 400 mg/day. TACE was performed during and after sorafenib discontinuation and therapeutic response bimonthly to four-monthly was rated thereafter. RESULTS Median duration of sorafenib treatment and patients' survival were 4.00 ± 0.45 and 7.50 ± 1.44 months in all cases; 2.50 ± 0.90 and 5.00 ± 1.10 months in Group I; 5.50 ± 1.27 and 16.50 ± 1.86 months in Group II; 4.00 ± 0.94 and 6.50 ± 2.49 months in Group III. Group II presented the best response and survival benefit (p = 0.010 and p = 0.011 respectively). Child-Pugh Classification score 5 (Hazard Ratio = 0.492, p = 0.049), absent AE (3.423, p = 0.015), tumor numbers ≤ 3 (0.313, p = 0.009), sorafenib duration ≤ 1 cycle (3.694, p = 0.004), and absent TACE (3.197, p = 0.008) significantly correlated with patient survival. TACE benefit appeared in separate and total cases during (p = 0.002, p = 0.595, p = 0.074, p = 0.002 respectively) and after discontinuation of sorafenib administration (p = 0.001, p = 0.034, p = 0.647, p = 0.001 respectively). CONCLUSIONS Low-dosage sorafenib not only appeared tolerable and lowered economic pressure but also provided satisfactory results. TACE benefited patient's survival during and after sorafenib discontinuation.
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Affiliation(s)
- Wang-De Hsiao
- Division of Hepato-Gastroenterology, Department of Internal Medicine, China Medical University Hospital, No. 2, Yuh-Der Road, Taichung, 404, Taiwan
| | - Cheng-Yuan Peng
- School of Medicine, China Medical University, Taichung, Taiwan
- Division of Hepato-Gastroenterology, Department of Internal Medicine, China Medical University Hospital, No. 2, Yuh-Der Road, Taichung, 404, Taiwan
| | - Po-Heng Chuang
- Division of Hepato-Gastroenterology, Department of Internal Medicine, China Medical University Hospital, No. 2, Yuh-Der Road, Taichung, 404, Taiwan
| | - Hsueh-Chou Lai
- Division of Hepato-Gastroenterology, Department of Internal Medicine, China Medical University Hospital, No. 2, Yuh-Der Road, Taichung, 404, Taiwan
| | - Ken-Sheng Cheng
- Division of Hepato-Gastroenterology, Department of Internal Medicine, China Medical University Hospital, No. 2, Yuh-Der Road, Taichung, 404, Taiwan
| | - Jen-Wei Chou
- Division of Hepato-Gastroenterology, Department of Internal Medicine, China Medical University Hospital, No. 2, Yuh-Der Road, Taichung, 404, Taiwan
| | - Yang-Yuan Chen
- School of Medicine, China Medical University, Taichung, Taiwan
- Division of Hepato-Gastroenterology, Department of Internal Medicine, China Medical University Hospital, No. 2, Yuh-Der Road, Taichung, 404, Taiwan
| | - Cheng-Ju Yu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, China Medical University Hospital, No. 2, Yuh-Der Road, Taichung, 404, Taiwan
| | - Chun-Lung Feng
- Division of Hepato-Gastroenterology, Department of Internal Medicine, China Medical University Hospital, No. 2, Yuh-Der Road, Taichung, 404, Taiwan
| | - Wen-Pang Su
- Division of Hepato-Gastroenterology, Department of Internal Medicine, China Medical University Hospital, No. 2, Yuh-Der Road, Taichung, 404, Taiwan
| | - Sheng-Hung Chen
- Division of Hepato-Gastroenterology, Department of Internal Medicine, China Medical University Hospital, No. 2, Yuh-Der Road, Taichung, 404, Taiwan
| | - Jung-Ta Kao
- School of Medicine, China Medical University, Taichung, Taiwan.
- Division of Hepato-Gastroenterology, Department of Internal Medicine, China Medical University Hospital, No. 2, Yuh-Der Road, Taichung, 404, Taiwan.
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30
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Grimm D, Lieb J, Weyer V, Vollmar J, Darstein F, Lautem A, Hoppe-Lotichius M, Koch S, Schad A, Schattenberg JM, Wörns MA, Weinmann A, Galle PR, Zimmermann T. Organic Cation Transporter 1 (OCT1) mRNA expression in hepatocellular carcinoma as a biomarker for sorafenib treatment. BMC Cancer 2016; 16:94. [PMID: 26872727 PMCID: PMC4751638 DOI: 10.1186/s12885-016-2150-3] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Accepted: 02/08/2016] [Indexed: 01/05/2023] Open
Abstract
Background The polyspecific organ cation transporter 1 (OCT1) is one of the most important active influx pumps for drugs like the kinase inhibitor sorafenib. The aim of this retrospective study was the definition of the role of intratumoral OCT1 mRNA expression in hepatocellular carcinoma (HCC) as a biomarker in systemic treatment with sorafenib. Methods OCT1 mRNA expression levels were determined in biopsies from 60 primary human HCC by real time PCR. The data was retrospectively correlated with clinical parameters. Results Intratumoral OCT1 mRNA expression is a significant positive prognostic factor for patients treated with sorafenib according to Cox regression analysis (HR 0.653, 95 %-CI 0.430-0.992; p = 0.046). Under treatment with sorafenib, a survival benefit could be shown using the lower quartile of intratumoral OCT1 expression as a cut-off. Macrovascular invasion (MVI) was slightly more frequent in patients with low OCT1 mRNA expression (p = 0.037). Treatment-induced AFP response was not associated with intratumoral OCT1 mRNA expression levels (p = 0.633). Conclusions This study indicates a promising role for intratumoral OCT1 mRNA expression as a prognostic biomarker in therapeutic algorithms in HCC. Further prospective studies are warranted on this topic.
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Affiliation(s)
- Daniel Grimm
- 1st Department of Medicine, University Medical Center Mainz, Langenbeckstr. 1, Mainz, 55131, Germany.
| | - Jonas Lieb
- 1st Department of Medicine, University Medical Center Mainz, Langenbeckstr. 1, Mainz, 55131, Germany.
| | - Veronika Weyer
- University Medical Center Mainz, Institute of Medical Biostatistics, Epidemiology and Informatics, Obere Zahlbacher Str. 69, Mainz, 55131, Germany.
| | - Johanna Vollmar
- 1st Department of Medicine, University Medical Center Mainz, Langenbeckstr. 1, Mainz, 55131, Germany.
| | - Felix Darstein
- 1st Department of Medicine, University Medical Center Mainz, Langenbeckstr. 1, Mainz, 55131, Germany.
| | - Anja Lautem
- Department of General-, Visceral- and Transplantation Surgery, University Medical Center Mainz, Langenbeckstr. 1, Mainz, 55131, Germany.
| | - Maria Hoppe-Lotichius
- Department of General-, Visceral- and Transplantation Surgery, University Medical Center Mainz, Langenbeckstr. 1, Mainz, 55131, Germany.
| | - Sandra Koch
- 1st Department of Medicine, University Medical Center Mainz, Langenbeckstr. 1, Mainz, 55131, Germany.
| | - Arno Schad
- Department of Pathology, University Medical Center Mainz, Langenbeckstr. 1, Mainz, 55131, Germany.
| | - Jörn M Schattenberg
- 1st Department of Medicine, University Medical Center Mainz, Langenbeckstr. 1, Mainz, 55131, Germany.
| | - Marcus A Wörns
- 1st Department of Medicine, University Medical Center Mainz, Langenbeckstr. 1, Mainz, 55131, Germany.
| | - Arndt Weinmann
- 1st Department of Medicine, University Medical Center Mainz, Langenbeckstr. 1, Mainz, 55131, Germany.
| | - Peter R Galle
- 1st Department of Medicine, University Medical Center Mainz, Langenbeckstr. 1, Mainz, 55131, Germany.
| | - Tim Zimmermann
- 1st Department of Medicine, University Medical Center Mainz, Langenbeckstr. 1, Mainz, 55131, Germany.
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McMahon B, Block J, Block T, Cohen C, Evans AA, Hosangadi A, London WT, Sherman M. Hepatitis-Associated Liver Cancer: Gaps and Opportunities to Improve Care. J Natl Cancer Inst 2015; 108:djv359. [PMID: 26626106 DOI: 10.1093/jnci/djv359] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2015] [Accepted: 10/22/2015] [Indexed: 02/07/2023] Open
Abstract
The global burden of hepatocellular carcinoma (HCC; primary liver cancer) is increasing. HCC is often unaccompanied by clear symptomatology, causing patients to be unaware of their disease. Moreover, effective treatment for those with advanced disease is lacking. As such, effective surveillance and early detection of HCC are essential. However, current screening and surveillance guidelines are not being fully implemented. Some at-risk populations fall outside of the guidelines, and patients who are screened are often not diagnosed at an early enough stage for treatment to be effective. From March 17 to 19, 2015, the Hepatitis B Foundation sponsored a workshop to identify gaps and limitations in current approaches to the detection and treatment of HCC and to define research priorities and opportunities for advocacy. In this Commentary, we summarize areas for further research and action that were discussed throughout the workshop to improve the recognition of liver disease generally, improve the recognition of liver cancer risk, and improve the recognition that screening for HCC makes a life-saving difference. Participants agreed that primary prevention of HCC relies on prevention and treatment of viral hepatitis and other underlying etiologies. Earlier diagnosis (secondary prevention) needs to be substantially improved. Areas for attention include increasing practitioner awareness, better definition of at-risk populations, and improved performance of screening approaches (ultrasound, biomarkers for detection, risk stratification, targeted therapies). The heterogeneous nature of HCC makes it unlikely that a single therapeutic agent will be universally effective. Medical management will benefit from the development of new, targeted treatment approaches.
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Affiliation(s)
- Brian McMahon
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage, AK (BM); Hepatitis B Foundation, Doylestown, PA (JB); Baruch S. Blumberg Institute and Hepatitis B Foundation, Doylestown, PA (TB); Hepatitis B Foundation, Doylestown, PA (CC); Drexel University School of Public Health, Philadelphia, PA (AAE); Hepatitis B Foundation, Doylestown, PA (AH); Fox Chase Cancer Center, Philadelphia, PA (WTL); University of Toronto, Toronto, Canada (MS)
| | - Joan Block
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage, AK (BM); Hepatitis B Foundation, Doylestown, PA (JB); Baruch S. Blumberg Institute and Hepatitis B Foundation, Doylestown, PA (TB); Hepatitis B Foundation, Doylestown, PA (CC); Drexel University School of Public Health, Philadelphia, PA (AAE); Hepatitis B Foundation, Doylestown, PA (AH); Fox Chase Cancer Center, Philadelphia, PA (WTL); University of Toronto, Toronto, Canada (MS).
| | - Timothy Block
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage, AK (BM); Hepatitis B Foundation, Doylestown, PA (JB); Baruch S. Blumberg Institute and Hepatitis B Foundation, Doylestown, PA (TB); Hepatitis B Foundation, Doylestown, PA (CC); Drexel University School of Public Health, Philadelphia, PA (AAE); Hepatitis B Foundation, Doylestown, PA (AH); Fox Chase Cancer Center, Philadelphia, PA (WTL); University of Toronto, Toronto, Canada (MS)
| | - Chari Cohen
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage, AK (BM); Hepatitis B Foundation, Doylestown, PA (JB); Baruch S. Blumberg Institute and Hepatitis B Foundation, Doylestown, PA (TB); Hepatitis B Foundation, Doylestown, PA (CC); Drexel University School of Public Health, Philadelphia, PA (AAE); Hepatitis B Foundation, Doylestown, PA (AH); Fox Chase Cancer Center, Philadelphia, PA (WTL); University of Toronto, Toronto, Canada (MS)
| | - Alison A Evans
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage, AK (BM); Hepatitis B Foundation, Doylestown, PA (JB); Baruch S. Blumberg Institute and Hepatitis B Foundation, Doylestown, PA (TB); Hepatitis B Foundation, Doylestown, PA (CC); Drexel University School of Public Health, Philadelphia, PA (AAE); Hepatitis B Foundation, Doylestown, PA (AH); Fox Chase Cancer Center, Philadelphia, PA (WTL); University of Toronto, Toronto, Canada (MS)
| | - Anu Hosangadi
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage, AK (BM); Hepatitis B Foundation, Doylestown, PA (JB); Baruch S. Blumberg Institute and Hepatitis B Foundation, Doylestown, PA (TB); Hepatitis B Foundation, Doylestown, PA (CC); Drexel University School of Public Health, Philadelphia, PA (AAE); Hepatitis B Foundation, Doylestown, PA (AH); Fox Chase Cancer Center, Philadelphia, PA (WTL); University of Toronto, Toronto, Canada (MS)
| | - W Thomas London
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage, AK (BM); Hepatitis B Foundation, Doylestown, PA (JB); Baruch S. Blumberg Institute and Hepatitis B Foundation, Doylestown, PA (TB); Hepatitis B Foundation, Doylestown, PA (CC); Drexel University School of Public Health, Philadelphia, PA (AAE); Hepatitis B Foundation, Doylestown, PA (AH); Fox Chase Cancer Center, Philadelphia, PA (WTL); University of Toronto, Toronto, Canada (MS)
| | - Morris Sherman
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage, AK (BM); Hepatitis B Foundation, Doylestown, PA (JB); Baruch S. Blumberg Institute and Hepatitis B Foundation, Doylestown, PA (TB); Hepatitis B Foundation, Doylestown, PA (CC); Drexel University School of Public Health, Philadelphia, PA (AAE); Hepatitis B Foundation, Doylestown, PA (AH); Fox Chase Cancer Center, Philadelphia, PA (WTL); University of Toronto, Toronto, Canada (MS)
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Gahr S, Mayr C, Kiesslich T, Illig R, Neureiter D, Alinger B, Ganslmayer M, Wissniowski T, Fazio PD, Montalbano R, Ficker JH, Ocker M, Quint K. The pan-deacetylase inhibitor panobinostat affects angiogenesis in hepatocellular carcinoma models via modulation of CTGF expression. Int J Oncol 2015; 47:963-970. [PMID: 26202945 DOI: 10.3892/ijo.2015.3087] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Accepted: 06/08/2015] [Indexed: 02/07/2023] Open
Abstract
Post-translational modifications of chromatin components are significantly involved in the regulation of tumor suppressor gene and oncogene expression. Connective tissue growth factor (CTGF) is an epigenetically regulated growth factor with functions in angiogenesis and cell-matrix interactions and plays a pivotal role in hepatocellular carcinoma (HCC). The pharmacologic inhibition of histone and protein deacetylases represents a new approach to interfere with pathways of apoptosis and angiogenesis. We investigated the effect of the pan-deacetylase inhibitor panobinostat (LBH589) on human HCC cell lines HepG2 (p53wt) and Hep3B (p53null) and in a subcutaneous xenograft model and explored the influence on angiogenesis. Specimens were characterized by quantitative real-time PCR. Protein was separated for western blotting against CTGF, VEGF, VEGF receptor-1 (VEGFR-1/FLT-1), VEGF receptor-2 (VEGFR-2/KDR), MAPK and phospho-MAPK. In vivo, HepG2 cells were xenografted to NMRI mice and treated with daily i.p. injections of 10 mg/kg panobinostat. After 1, 7 and 28 days, real-time PCR was performed. Immunohistochemistry and western blotting were examined after 28 days. An increased significant expression of CTGF was only seen after 24 h treatment with 0.1 µM panobinostat in HepG2 cells and Hep3B cells, whereas after 72 h treatment CTGF expression clearly decreased. In the xenografts, treatment with panobinostat showed a minimal CTGF expression after 1 day and 4 weeks, respectively. In vitro as well as in vivo, VEGF was not affected by panobinostat treatment at any time. In conclusion, panobinostat influences extracellular signaling cascades via CTGF-dependent pathways.
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Affiliation(s)
- Susanne Gahr
- Department of Medicine 1, University Hospital Erlangen, Erlangen, Germany
| | - Christian Mayr
- Laboratory for Tumour Biology and Experimental Therapies, Paracelsus Medical University, Salzburg, Austria
| | - Tobias Kiesslich
- Laboratory for Tumour Biology and Experimental Therapies, Paracelsus Medical University, Salzburg, Austria
| | - Romana Illig
- Institute of Pathology, Salzburger Landeskliniken, Paracelsus Private Medical University, Salzburg, Austria
| | - Daniel Neureiter
- Institute of Pathology, Salzburger Landeskliniken, Paracelsus Private Medical University, Salzburg, Austria
| | - Beate Alinger
- Institute of Pathology, Salzburger Landeskliniken, Paracelsus Private Medical University, Salzburg, Austria
| | - Marion Ganslmayer
- Department of Medicine 1, University Hospital Erlangen, Erlangen, Germany
| | - Till Wissniowski
- Department of Medicine 1, University Hospital Erlangen, Erlangen, Germany
| | - Pietro Di Fazio
- Institute for Surgical Research, Phillips University Marburg, Marburg, Germany
| | - Roberta Montalbano
- Institute for Surgical Research, Phillips University Marburg, Marburg, Germany
| | - Joachim H Ficker
- Klinikum Nuernberg, Department of Respiratory Medicine, Allergology and Sleep Medicine, Nuremberg, Germany
| | - Matthias Ocker
- Department of Medicine 1, University Hospital Erlangen, Erlangen, Germany
| | - Karl Quint
- Department of Medicine 1, University Hospital Erlangen, Erlangen, Germany
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Cabibbo G, Petta S, Maida M, Cammà C. Sorafenib for Hepatocellular Carcinoma: From Randomized Controlled Trials to Clinical Practice. Dig Dis 2015; 33:668-674. [PMID: 26398633 DOI: 10.1159/000438477] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Hepatocellular carcinoma is a challenging malignancy of global importance. It is the sixth most common solid malignancy and the third leading cause of cancer-related death, worldwide. Curative treatments at early stages include liver transplantation, resection and percutaneous ablation, while transarterial chemoembolization can improve survival in patients with intermediate tumor stage. Patients with mild, related symptoms and/or macrovascular invasion or extrahepatic spread are classified under the advanced stage. The standard of care in this group is sorafenib, an inhibitor of Raf kinase and vascular endothelial growth factor receptor, whose effectiveness has been proven by 2 recent randomized controlled trials (RCTs). The aim of this brief review is to highlight the main concerns and pitfalls and to analyze the recent data of literature regarding the efficacy and the management of sorafenib therapy from RCTs to real practice.
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Affiliation(s)
- Giuseppe Cabibbo
- Section of Gastroenterology, DIBIMIS, University of Palermo, Palermo, Italy
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Takeda H, Nishikawa H, Osaki Y, Tsuchiya K, Joko K, Ogawa C, Taniguchi H, Orito E, Uchida Y, Izumi N. Clinical features associated with radiological response to sorafenib in unresectable hepatocellular carcinoma: a large multicenter study in Japan. Liver Int 2015; 35:1581-9. [PMID: 24836552 DOI: 10.1111/liv.12591] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2014] [Accepted: 05/12/2014] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS There have been no established predictive factors of responders to sorafenib in patients with unresectable hepatocellular carcinoma (HCC). This study aimed to investigate the factors predicting a good response to sorafenib in Japanese patients with HCC. METHODS A total of 465 patients with unresectable HCC in the Japanese Red Cross Liver Study Group were treated with sorafenib between January 2008 and August 2013, and 316 patients with sufficient clinical data were analysed. To determine the factors predicting a good response, the relationships between radiological response and the following clinicopathological factors were analysed: age, gender, performance status, liver function, tumour status and decrease in serum alpha-foetoprotein (AFP) level after 1 month. RESULTS This study included 259 males and 57 females with a median age of 70 years (range, 37-90 years), of which 191 (60.4%) were classified as Barcelona Clinic Liver Cancer stage C, and 271 (85.8%) had Child-Pugh class A liver function. The median overall survival time was 307 days and progression-free survival time was 109 days. According to the modified Response Evaluation Criteria In Solid Tumours, four patients achieved a complete response, 51 achieved a partial response, 136 had stable disease and 125 had progressive disease. Multivariate analysis identified female gender (P = 0.003) and decreased serum AFP level after 1 month (P = 0.042) as independent predictors of a complete or partial response. CONCLUSION Our results suggest female gender and a decrease in serum AFP level are independent predictors of good response to sorafenib.
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Affiliation(s)
- Haruhiko Takeda
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
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Smieliauskas F, Chien CR, Shen C, Geynisman DM, Shih YCT. Cost-effectiveness analyses of targeted oral anti-cancer drugs: a systematic review. PHARMACOECONOMICS 2014; 32:651-680. [PMID: 24821281 DOI: 10.1007/s40273-014-0160-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
BACKGROUND Over the last 15 years, a paradigm shift in oncology has led to the approval of dozens of targeted oral anti-cancer medications (OAMs), which have become the standard of care for certain cancers. While more convenient for patients than infused drugs, the possibility of non-adherence and the frequently high costs of targeted OAMs have proven controversial. OBJECTIVE Our objective was to perform the first comprehensive review of cost-effectiveness analyses (CEAs) of targeted OAMs. METHODS A literature search in PubMed, The Cochrane Library, and the Health Technology Assessment (HTA) reports published by the National Institute for Health Research HTA Programme in the UK was performed, covering articles published in the 5 years prior to 30 September 2013. Our inclusion criteria were peer-reviewed English-language full-text original research articles with a primary focus on CEA related to targeted OAMs. We categorized these articles by treatment setting (i.e. cancer site/type, line of therapy, and treatment and comparator) and synthesized information from the articles into summary tables. RESULTS We identified 41 CEAs covering nine of the 18 targeted OAMs approved by the US FDA as of December 2012. These medications were studied in seven cancers, most often as second-line therapy for advanced-stage patients. In over half of treatment settings where a targeted OAM was compared with treatment that was not a targeted OAM, targeted OAMs were considered cost effective. Limitations in interpreting these findings include the risk of bias due to author conflicts of interest, cross-country variation, and difficulties in generalizing clinical trial evidence to community practice. CONCLUSIONS Several types of cost-effectiveness studies remain under-represented in the literature on targeted OAMs, including those for follow-on indications approved after the initial indication for a drug and for off-label indications, head-to-head comparisons of targeted OAMs with other targeted OAMs and targeted intravenous therapies, and studies that adopt a perspective other than the payer's. Keeping up with the increasing number of approved targeted OAMs will also prove an important challenge for economic evaluation.
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Kreissl MC, Jacob C, Führer D, Karges W, Luster M, Lux MP, Mann K, Mittendorf T, Schott M, Spitzweg C, Schmoll HJ. Best supportive care from the conservative/non-surgical perspective and its costs in the treatment of patients with advanced medullary thyroid cancer: results of a Delphi panel. Oncol Res Treat 2014; 37:316-22. [PMID: 24903762 DOI: 10.1159/000362613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2013] [Accepted: 03/26/2014] [Indexed: 11/19/2022]
Abstract
BACKGROUND Medullary thyroid cancer (MTC) is a rare tumor entity. The contents of best supportive care (BSC) have not been defined in advanced MTC. The objective of this work is to describe the epidemiology, the treatment patterns with respect to symptom management, as well as palliative treatment and associated costs. METHOD A Delphi panel with 9 clinical experts experienced in treating MTC was conducted to obtain details on the epidemiology of MTC and to gain insights into the therapeutic options considered for BSC in advanced MTC in Germany. Unit costs were applied to the described resources from the perspective of the German National Healthcare System in 2011. RESULTS The annual incidence of MTC in Germany was estimated at about 220. 32% of all patients were estimated to have aggressive/symptomatic MTC, with an estimated mean survival of 36.7 months (median: 36 months). The core element of BSC is relief of symptoms to maintain quality of life. The total mean cost of BSC per patient/year was estimated at € 9,248, lifetime cost at € 28,283. CONCLUSION There was consistent agreement within the panel on the epidemiology of MTC and on the structure of the provided therapeutic measures for BSC in advanced MTC, also defining the management of symptoms as a crucial goal of treatment.
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Affiliation(s)
- Michael C Kreissl
- Department of Nuclear Medicine, University Hospital of Wuerzburg, Germany
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Abstract
The multikinase inhibitor sorafenib, which inhibits targets related to tumor cell proliferation and angiogenesis, was the first systemic agent to demonstrate a significant improvement in the overall survival for patients with advanced hepatocellular carcinoma (HCC) in two large randomized controlled Phase III trials. Together with its manageable safety profile (mainly diarrhea, hand-foot skin reaction and fatigue), sorafenib was approved for the treatment of patients with (unresectable) HCC in 2007. Since then, sorafenib has been established as the standard of care in Child-Pugh A patients with advanced HCC or in those ineligible for or after failure of locoregional therapies in the intermediate stage of the disease. This article summarizes current knowledge and future perspectives regarding the use of sorafenib in patients with HCC.
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Affiliation(s)
- Marcus Alexander Wörns
- First Department of Internal Medicine, University Medical Center of the Johannes Gutenberg University, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Peter Robert Galle
- First Department of Internal Medicine, University Medical Center of the Johannes Gutenberg University, Langenbeckstrasse 1, 55131 Mainz, Germany
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Niemeyer DJ, Simo KA, Iannitti DA, McKillop IH. Ablation therapy for hepatocellular carcinoma: past, present and future perspectives. Hepat Oncol 2013; 1:67-79. [PMID: 30190942 DOI: 10.2217/hep.13.8] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, and is most commonly found in the setting of liver cirrhosis. Treatment of HCC must consider both the tumors present, as well as the remaining dysfunctional liver that both hinders treatment and can produce additional HCC over time. Ablation is an evolving part of the multimodality treatment approach to HCC that can effectively destroy tumors while preserving surrounding liver parenchyma. New technologies have made ablation an indispensable tool in the treatment of all stages of HCC. This review presents the history, present technologies and future potential of ablation in the treatment of HCC.
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Affiliation(s)
- David J Niemeyer
- Department of Surgery, Division of Hepatopancreaticobiliary Surgery, Carolinas Medical Center, 1000 Blythe Boulevard, Charlotte, NC 28203, USA
| | - Kerri A Simo
- Department of Surgery, Division of Hepatopancreaticobiliary Surgery, Carolinas Medical Center, 1000 Blythe Boulevard, Charlotte, NC 28203, USA
| | - David A Iannitti
- Department of Surgery, Division of Hepatopancreaticobiliary Surgery, Carolinas Medical Center, 1000 Blythe Boulevard, Charlotte, NC 28203, USA
| | - Iain H McKillop
- Department of Surgery, Division of Hepatopancreaticobiliary Surgery, Carolinas Medical Center, 1000 Blythe Boulevard, Charlotte, NC 28203, USA
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Canavan C, Eisenburg J, Meng L, Corey K, Hur C. Ultrasound elastography for fibrosis surveillance is cost effective in patients with chronic hepatitis C virus in the UK. Dig Dis Sci 2013; 58:2691-704. [PMID: 23720196 PMCID: PMC4067701 DOI: 10.1007/s10620-013-2705-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2013] [Accepted: 04/24/2013] [Indexed: 02/06/2023]
Abstract
BACKGROUND Chronic hepatitis C (HCV) is a significant risk factor for cirrhosis and subsequently hepatocellular carcinoma (HCC). HCV patients with cirrhosis are screened for HCC every 6 months. Surveillance for progression to cirrhosis and consequently access to HCC screening is not standardized. Liver biopsy, the usual test to determine cirrhosis, carries a significant risk of morbidity and associated mortality. Transient ultrasound elastography (fibroscan) is a non-invasive test for cirrhosis. PURPOSE This study assesses the cost effectiveness of annual surveillance for cirrhosis in patients with chronic HCV and the effect of replacing biopsy with fibroscan to diagnose cirrhosis. METHOD A Markov decision analytic model simulated a hypothetical cohort of 10,000 patients with chronic HCV initially without fibrosis over their lifetime. The cirrhosis surveillance strategies assessed were: no surveillance; current practice; fibroscan in current practice with biopsy to confirm cirrhosis; fibroscan completely replacing biopsy in current practice (definitive); annual biopsy; annual fibroscan with biopsy to confirm cirrhosis; annual definitive fibroscan. RESULTS Our results demonstrate that annual definitive fibroscan is the optimal strategy to diagnose cirrhosis. In our study, it diagnosed 20 % more cirrhosis cases than the current strategy, with 549 extra patients per 10,000 accessing screening over a lifetime and, consequently, 76 additional HCC cases diagnosed. The lifetime cost is £98.78 extra per patient compared to the current strategy for 1.72 additional unadjusted life years. Annual fibroscan surveillance of 132 patients results in the diagnosis one additional HCC case over a lifetime. The incremental cost-effectiveness ratio for an annual definitive fibroscan is £6,557.06/quality-adjusted life years gained. CONCLUSION Annual definitive fibroscan may be a cost-effective surveillance strategy to identify cirrhosis in patients with chronic HCV, thereby allowing access of these patients to HCC screening.
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Affiliation(s)
- C Canavan
- Division of Epidemiology and Public Health, Nottingham University, Clinical Sciences Building, City Hospital Campus, Hucknall Road, Nottingham, NG5 1PB, UK.
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Cho JY, Paik YH, Lim HY, Kim YG, Lim HK, Min YW, Gwak GY, Choi MS, Lee JH, Koh KC, Paik SW, Yoo BC. Clinical parameters predictive of outcomes in sorafenib-treated patients with advanced hepatocellular carcinoma. Liver Int 2013; 33:950-7. [PMID: 23601249 DOI: 10.1111/liv.12168] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2012] [Accepted: 02/28/2013] [Indexed: 12/19/2022]
Abstract
BACKGROUND Sorafenib is an orally active multikinase inhibitor approved for the treatment of advanced hepatocellular carcinoma (HCC). However, clinical parameters that may predict the treatment outcomes in sorafenib-treated advanced HCC patients remains unknown. METHODS A total of 99 advanced (BCLC C) HCC patients treated with sorafenib as an initial treatment modality from January 2007 to December 2011 were retrospectively reviewed. Overall survival was the primary endpoint for the analysis. Various clinical parameters including tumour stage and adverse effects to sorafenib were analysed. Univariate and multivariate analysis were carried out to identify clinical parameters predictive of the effect of sorafenib. RESULTS There were 86 males and 13 females included in this study, with a median age of 53 years. The median overall survival was 91 days. Sixty-nine patients had Child-Pugh class A cirrhosis and 30 patients had Child-Pugh class B cirrhosis. Hepatitis B virus was the predominant cause of HCC (75.8%). Noted adverse effects were hand-foot syndrome, diarrhoea, fatigue, abdominal pain, nausea and stomatitis. The presence of hand-foot syndrome and diarrhoea and the absence of portal vein thrombosis and lymph node metastasis predicted a better overall survival in the multivariate analysis. Excluding the absence of lymph node metastasis, the same parameters were associated with a longer radiological time to progression. CONCLUSION Advanced HCC patients treated with sorafenib who experienced hand-foot syndrome and diarrhoea showed better overall survival than patients without these side effects. These side effects may be used as clinical parameters predictive of sorafenib response in patients with HCC.
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Affiliation(s)
- Ju-Yeon Cho
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Gahr S, Wissniowski T, Zopf S, Strobel D, Pustowka A, Ocker M. Combination of the deacetylase inhibitor panobinostat and the multi-kinase inhibitor sorafenib for the treatment of metastatic hepatocellular carcinoma - review of the underlying molecular mechanisms and first case report. J Cancer 2012; 3:158-165. [PMID: 22514558 PMCID: PMC3328781 DOI: 10.7150/jca.4211] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2012] [Accepted: 03/29/2012] [Indexed: 12/11/2022] Open
Abstract
Advanced hepatocellular carcinoma still represents an unmet medical need that has only a limited overall survival despite the introduction of the multi-kinase inhibitor sorafenib. Recently, inhibitors of histone and other protein deacetylases have been established as novel therapeutic approaches to cancer diseases. We here review the molecular rationale for combining these two novel targeted therapies and report a patient with metastasized hepatocellular carcinoma who showed a partial remission of primary and metastatic lesions for five months after a combination therapy with sorafenib and the orally available pan-deacetylase inhibitor panobinostat.
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Affiliation(s)
- Susanne Gahr
- 1. Department of Medicine 1, University Hospital Erlangen, Erlangen, Germany
- 2. Klinikum Nuremberg Nord, Department of Pneumology, Nuremberg, Germany
| | - Till Wissniowski
- 1. Department of Medicine 1, University Hospital Erlangen, Erlangen, Germany
- 3. Division of Gastroenterology, University Hospital Marburg, Marburg, Germany
| | - Steffen Zopf
- 1. Department of Medicine 1, University Hospital Erlangen, Erlangen, Germany
| | - Deike Strobel
- 1. Department of Medicine 1, University Hospital Erlangen, Erlangen, Germany
| | | | - Matthias Ocker
- 1. Department of Medicine 1, University Hospital Erlangen, Erlangen, Germany
- 5. Institute for Surgical Research, Philipps University Marburg, Marburg, Germany
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Guy J, Kelley RK, Roberts J, Kerlan R, Yao F, Terrault N. Multidisciplinary management of hepatocellular carcinoma. Clin Gastroenterol Hepatol 2012; 10:354-62. [PMID: 22083023 DOI: 10.1016/j.cgh.2011.11.008] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2011] [Revised: 10/31/2011] [Accepted: 11/02/2011] [Indexed: 12/14/2022]
Abstract
Hepatocellular carcinoma is a leading cause of death in patients with cirrhosis. Management algorithms continually are increasing in sophistication and involve application of single and multimodality treatments, including liver transplantation, hepatic resection, ablation, transarterial chemoembolization, radioembolization, and systemic chemotherapy. These treatments have been shown to increase survival times. As many as 75% of patients with limited-stage disease who are given curative therapies survive 5 years, whereas less than 20% of untreated patients survive 1 year. Treatment can be optimized based on the patient's tumor stage, hepatic reserve, and functional status. However, because of the heterogeneity in presentation among patients, a multidisciplinary approach is required to treat hepatocellular carcinoma, involving hepatologists, surgeons, interventional radiologists, and oncologists. We present each specialist's viewpoint on controversies and advances in the management of hepatocellular carcinoma.
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Affiliation(s)
- Jennifer Guy
- Department of Medicine, University of California San Francisco, San Francisco, California, USA.
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Brown RL, de Souza JA, Cohen EEW. Thyroid cancer: burden of illness and management of disease. J Cancer 2011; 2:193-9. [PMID: 21509149 PMCID: PMC3079916 DOI: 10.7150/jca.2.193] [Citation(s) in RCA: 132] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2011] [Accepted: 03/24/2011] [Indexed: 01/05/2023] Open
Abstract
OBJECTIVE The incidence of thyroid cancer, the most common endocrine malignancy, has increased dramatically in the last fifty years. This article will review the standard approach to thyroid cancer treatment as well as novel therapies under investigation. We will also address potential cost considerations in the management of thyroid cancer. STUDY DESIGN A comprehensive literature search was performed. METHODS Review article. RESULTS The high prevalence of thyroid cancer and the availability of novel therapies for patients with metastatic disease have potential economic implications that have not been well-studied. Because many patients likely have very low morbidity from their cancers, better tools to identify the lowest risk patients are needed in order to prevent overtreatment. Improved risk stratification should include recognizing patients who are unlikely to benefit from radioactive iodine therapy after initial surgery and identifying those with indolent and asymptomatic metastatic disease that are unlikely to benefit from novel therapies. In patients with advanced incurable disease, randomized-controlled studies to assess the efficacy of novel agents are needed to determine if the costs associated with new agents are warranted. CONCLUSIONS Health care costs associated with the increased diagnosis of thyroid cancer remain unknown but are worthy of further research.
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Affiliation(s)
- Rebecca L. Brown
- Department of Medicine, The University of Chicago, Chicago, IL 60637, USA
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Beljanski V, Lewis CS, Smith CD. Antitumor activity of sphingosine kinase 2 inhibitor ABC294640 and sorafenib in hepatocellular carcinoma xenografts. Cancer Biol Ther 2011; 11:524-34. [PMID: 21258214 DOI: 10.4161/cbt.11.5.14677] [Citation(s) in RCA: 85] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The balance between the pro-apoptotic lipids ceramide and sphingosine and the pro-survival lipid sphingosine 1-phosphate (S1P) is termed the "sphingosine rheostat". Two isozymes, sphingosine kinase 1 and 2 (SK1 and SK2), are responsible for phosphorylation of pro-apoptotic sphingosine to form pro-survival S1P. We have previously reported the antitumor properties of an SK2 selective inhibitor, ABC294640, alone or in combination with the multikinase inhibitor sorafenib in mouse models of kidney carcinoma and pancreatic adenocarcinoma. Here we evaluated the combined antitumor effects of the aforementioned drug combination in two mouse models of hepatocellular carcinoma. Although combining the SK2 inhibitor, ABC294640, and sorafenib in vitro only afforded additive drug-drug effects, their combined antitumor properties in the mouse model bearing HepG2 cells mirrored effects previously observed in animals bearing kidney carcinoma and pancreatic adenocarcinoma cells. Combining ABC294640 and sorafenib led to a decrease in the levels of phosphorylated ERK in SK-HEP-1 cells, indicating that the antitumor effect of this drug combination is likely mediated through a suppression of the MAPK pathway in hepatocellular models. We also measured levels of S1P in the plasma of mice treated with two different doses of ABC294640 and sorafenib. We found decreases in the levels of S1P in plasma of mice treated daily with 100 mg/kg of ABC294640 for 5 weeks, and this decrease was not affected by co-administration of sorafenib. Taken together, these data support combining ABC294640 and sorafenib in clinical trials in HCC patients. Furthermore, monitoring levels of S1P may provide a pharmacodynamic marker of ABC294640 activity.
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Affiliation(s)
- Vladimir Beljanski
- Drug Discovery Core; Hollings Cancer Center, Medical University of South Carolina, Charleston, USA
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