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Xu M, Zhou SR, Li YL, Zhang CH, Liao DZ, Wang XL. Efficacy of sorafenib combined with transarterial chemoembolization in the treatment of advanced hepatocellular carcinoma: A meta-analysis. World J Gastrointest Oncol 2025; 17:98927. [PMID: 39958535 PMCID: PMC11756001 DOI: 10.4251/wjgo.v17.i2.98927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 11/22/2024] [Accepted: 12/10/2024] [Indexed: 01/18/2025] Open
Abstract
BACKGROUND The combination of sorafenib with transarterial chemoembolization (TACE) is being investigated for its potential to improve outcomes in advanced hepatocellular carcinoma (HCC). AIM To evaluate the efficacy of this combined treatment strategy in enhancing overall survival (OS) and progression-free survival (PFS) compared to monotherapies. METHODS A systematic review was conducted following the PRISMA guidelines. A comprehensive search was performed across PubMed, EMBASE, Web of Science, and the Cochrane Library up to May 8, 2024. Studies were included if they compared sorafenib plus TACE to sorafenib alone or TACE alone in adults with advanced HCC. Primary outcomes were OS, PFS, response rates, and safety profiles. Data extraction and quality assessment were independently performed by two reviewers. Heterogeneity was assessed using the I² statistic, and a random-effects model was applied for pooling data. Sensitivity analysis and publication bias assessment were also conducted. RESULTS A total of twelve studies involving 1174 patients met the inclusion criteria. Significant heterogeneity was observed for both OS (I² = 72.6%, P < 0.001) and PFS (I² = 83.7%, P < 0.001). The combined treatment of sorafenib with TACE significantly improved OS [hazard ratio (HR) = 0.60, 95% confidence interval (CI): 0.44-0.76] and PFS (HR = 0.54, 95%CI: 0.38-0.69). Sensitivity analysis confirmed the robustness of these findings. Funnel plots and Egger's test indicated no significant publication bias. CONCLUSION Sorafenib combined with TACE significantly enhances both OS and PFS in patients with advanced HCC compared to monotherapy. This combination therapy represents a promising approach to improving clinical outcomes in advanced liver cancer.
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Affiliation(s)
- Mei Xu
- Department of Oncology, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, Sichuan Province, China
| | - Si-Rui Zhou
- Department of Oncology, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, Sichuan Province, China
| | - Ya-Ling Li
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan Province, China
| | - Chen-Hao Zhang
- Department of Breast and Thyroid Surgery, The First People's Hospital of Yibin, Yibin 644000, Sichuan Province, China
| | - Da-Zhong Liao
- Department of Oncology, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, Sichuan Province, China
| | - Xiao-Li Wang
- Department of Oncology, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, Sichuan Province, China
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Arendt N, Kopsida M, Khaled J, Sjöblom M, Heindryckx F. Gastrointestinal side effects in hepatocellular carcinoma patients receiving transarterial chemoembolization: a meta-analysis of 81 studies and 9495 patients. Ther Adv Med Oncol 2025; 17:17588359251316663. [PMID: 39926261 PMCID: PMC11806495 DOI: 10.1177/17588359251316663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Accepted: 01/14/2025] [Indexed: 02/11/2025] Open
Abstract
Background Transarterial chemoembolization (TACE) is a widely used treatment for hepatocellular carcinoma (HCC), combining targeted chemotherapy and embolization. While effective, TACE can be associated with significant gastrointestinal (GI) side effects, impacting a patient's quality of life. Objectives Quantify the prevalence of key GI complications (diarrhea, nausea, GI toxicity, abdominal pain) following TACE. Design Systematic review was performed following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, focusing on studies that reported side effects of TACE. Studies not involving cTACE or drug-eluting bead TACE (DEB-TACE), non-HCC studies, meta-analyses or systematic reviews, and inaccessible publications were excluded. Data sources and methods A PubMed search for clinical and randomized trials was conducted. Extracted data included study identifiers, demographics, TACE details, and GI side effect prevalences. The Mixed Methods Appraisal Tool assessed study quality and bias. Results The analysis included data from 81 studies with 121 individual study arms and 9495 patients. Diarrhea was reported in 38 studies, with a mean prevalence of 23.46% (2.5; 95% confidence interval (CI): 18.39-28.544) and a weighted prevalence of 23.5%. Nausea was most frequently reported, mentioned in 67 studies, with a mean prevalence of 34.66% (2.4; 95% CI: 29.89-39.44) and a weighted prevalence of 32.5%. Abdominal pain was reported in 59 studies, with the highest mean prevalence of 48.07% (2.9; 95% CI: 42.20-53.93) and a weighted prevalence of 46.1%. GI toxicity was reported in 32 studies, with a mean prevalence of 8.85% (1.4; 95% CI: 5.99-11.70) and a weighted prevalence of 9.9%. DEB-TACE generally led to slightly higher rates of nausea, diarrhea, abdominal pain, and GI toxicity compared to conventional TACE. The type of chemotherapy agent influenced prevalence of GI-side effects, with high prevalences observed for agents such as zinostatin and cisplatin. Conclusion This meta-analysis synthesizes current evidence on managing GI side effects in TACE. Standardizing reporting and developing effective management strategies are crucial to improving patient outcomes.
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Affiliation(s)
- Nathalie Arendt
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Maria Kopsida
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Jaafar Khaled
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Markus Sjöblom
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Femke Heindryckx
- Department of Medical Cell Biology, Uppsala University, Husargatan 3, Uppsala 75431, Sweden
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Zarlashat Y, Mushtaq H, Pham L, Abbas W, Sato K. Advancements in Immunotherapeutic Treatments for Hepatocellular Carcinoma: Potential of Combination Therapies. Int J Mol Sci 2024; 25:6830. [PMID: 38999940 PMCID: PMC11241106 DOI: 10.3390/ijms25136830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Revised: 06/16/2024] [Accepted: 06/17/2024] [Indexed: 07/14/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and a significant global health burden, with increasing incidence rates and limited treatment options. Immunotherapy has become a promising approach due to its ability to affect the immune microenvironment and promote antitumor responses. The immune microenvironment performs an essential role in both the progression and the development of HCC, with different characteristics based on specific immune cells and etiological factors. Immune checkpoint inhibitors, including programmed death-1/programmed death-ligand 1 inhibitors (pembrolizumab, nivolumab, and durvalumab) and cytotoxic T lymphocyte antigen-4 inhibitors (tremelimumab and ipilimumab), have the potential to treat advanced HCC and overcome adverse effects, such as liver failure and chemoresistance. Phase II and phase III clinical trials highlight the efficacy of pembrolizumab and nivolumab, respectively, in advanced HCC patients, as demonstrated by their positive effects on overall survival and progression-free survival. Tremelimumab has exhibited modest response rates, though it does possess antiviral activity. Thus, it is still being investigated in ongoing clinical trials. Combination therapies with multiple drugs have demonstrated potential benefits in terms of survival and tumor response rates, improving patient outcomes compared to monotherapy, especially for advanced-stage HCC. This review addresses the clinical trials of immunotherapies for early-, intermediate-, and advanced-stage HCC. Additionally, it highlights how combination therapy can significantly enhance overall survival, progression-free survival, and objective response rate in advanced-stage HCC, where treatment options are limited.
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Affiliation(s)
- Yusra Zarlashat
- Department of Biochemistry, Government College University Faisalabad, Faisalabad 38000, Pakistan
| | - Hassan Mushtaq
- Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering-C (NIBGE), Faisalabad 38000, Pakistan
- Pakistan Institute of Engineering and Applied Sciences (PIEAS), Islamabad 45650, Pakistan
| | - Linh Pham
- Department of Science and Mathematics, Texas A&M University-Central Texas, Killeen, TX 76549, USA
| | - Wasim Abbas
- Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering-C (NIBGE), Faisalabad 38000, Pakistan
- Pakistan Institute of Engineering and Applied Sciences (PIEAS), Islamabad 45650, Pakistan
| | - Keisaku Sato
- Department of Medicine, Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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Zarlashat Y, Abbas S, Ghaffar A. Hepatocellular Carcinoma: Beyond the Border of Advanced Stage Therapy. Cancers (Basel) 2024; 16:2034. [PMID: 38893154 PMCID: PMC11171154 DOI: 10.3390/cancers16112034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 04/27/2024] [Accepted: 05/23/2024] [Indexed: 06/21/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the deadliest emergent health issue around the globe. The stronger oncogenic effect, proteins, and weakened immune response are precisely linked with a significant prospect of developing HCC. Several conventional systemic therapies, antiangiogenic therapy, and immunotherapy techniques have significantly improved the outcomes for early-, intermediate-, and advanced-stage HCC patients, giving new hope for effective HCC management and prolonged survival rates. Innovative therapeutic approaches beyond conventional treatments have altered the landscape of managing HCC, particularly focusing on targeted therapies and immunotherapies. The advancement in HCC treatment suggested by the Food and Drug Administration is multidimensional treatment options, including multikinase inhibitors (sorafenib, lenvatinib, regorafenib, ramucirumab, and cabozantinib) and immune checkpoint inhibitors (atezolizumab, pembrolizumab, durvalumab, tremelimumab, ipilimumab, and nivolumab), in monotherapy and in combination therapy to increase life expectancy of HCC patients. This review highlights the efficacy of multikinase inhibitors and immune checkpoint inhibitors in monotherapy and combination therapy through the analysis of phase II, and III clinical trials, targeting the key molecular pathways involved in cellular signaling and immune response for the prospective treatment of advanced and unresectable HCC and discusses the upcoming combinations of immune checkpoint inhibitors-tyrosine kinase inhibitors and immune checkpoint inhibitors-vascular endothelial growth factor inhibitors. Finally, the hidden challenges with pharmacological therapy for HCC, feasible solutions for the future, and implications of possible presumptions to develop drugs for HCC treatment are reported.
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Affiliation(s)
- Yusra Zarlashat
- Department of Biochemistry, Government College University Faisalabad, Faisalabad 38000, Pakistan;
| | - Shakil Abbas
- Gomal Center of Biotechnology and Biochemistry (GCBB), Gomal University, Dera Ismail Khan 29050, Pakistan;
| | - Abdul Ghaffar
- Department of Biochemistry, Government College University Faisalabad, Faisalabad 38000, Pakistan;
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Liu H, Wang C, Wang R, Cao H, Cao Y, Huang T, Lu Z, Xiao H, Hu M, Wang H, Zhao J. New insights into mechanisms and interventions of locoregional therapies for hepatocellular carcinoma. Chin J Cancer Res 2024; 36:167-194. [PMID: 38751435 PMCID: PMC11090796 DOI: 10.21147/j.issn.1000-9604.2024.02.06] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Accepted: 04/07/2024] [Indexed: 05/18/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is responsible for a significant number of cancer-related deaths worldwide and its incidence is increasing. Locoregional treatments, which are precision procedures guided by imaging to specifically target liver tumors, play a critical role in the management of a substantial portion of HCC cases. These therapies have become an essential element of the HCC treatment landscape, with transarterial chemoembolization (TACE) being the treatment of choice for patients with intermediate to advanced stages of the disease. Other locoregional therapies, like radiofrequency ablation, are highly effective for small, early-stage HCC. Nevertheless, the advent of targeted immunotherapy has challenged these established treatments. Tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) have shown remarkable efficacy in clinical settings. However, their specific uses and the development of resistance in subsequent treatments have led clinicians to reevaluate the future direction of HCC therapy. This review concentrates on the distinct features of both systemic and novel locoregional therapies. We investigate their effects on the tumor microenvironment at the molecular level and discuss how targeted immunotherapy can be effectively integrated with locoregional therapies. We also examine research findings from retrospective studies and randomized controlled trials on various combined treatment regimens, assessing their validity to determine the future evolution of locoregional therapies within the framework of personalized, comprehensive treatment.
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Affiliation(s)
- Hanyuan Liu
- Department of General surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing 210019, China
| | - Chunmei Wang
- Department of Oncology, Sir Run Run Hospital, Nanjing Medical University, Nanjing 211166, China
| | - Ruiqiang Wang
- School of Public Health, China Medical University, Shenyang 110122, China
| | - Hengsong Cao
- Department of General surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing 210019, China
| | - Yongfang Cao
- Department of General surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing 210019, China
| | - Tian Huang
- Hepatobiliary/Liver Transplantation Center, the First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Transplantation, Chinese Academy of Medical Sciences, Nanjing 210024, China
| | - Zhengqing Lu
- Hepatobiliary/Liver Transplantation Center, the First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Transplantation, Chinese Academy of Medical Sciences, Nanjing 210024, China
| | - Hua Xiao
- Department of General surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing 210019, China
| | - Mengcheng Hu
- Department of Gastroenterology, the Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing 211103, China
| | - Hanjin Wang
- Department of General surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing 210019, China
| | - Jun Zhao
- Department of Nuclear Medicine, the Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Changzhou 213001, China
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Li D, Zhang C, Yang K, Ma Z, Ma L, Cheng C, Xu L, Wan S. The long-term efficacy and safety of apatinib are inferior to sorafenib in the first-line treatment of advanced hepatocellular carcinoma: A systematic review and meta-analysis. Medicine (Baltimore) 2024; 103:e36865. [PMID: 38241568 PMCID: PMC10798748 DOI: 10.1097/md.0000000000036865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Accepted: 12/14/2023] [Indexed: 01/21/2024] Open
Abstract
BACKGROUND Apatinib, a novel tyrosine kinase inhibitor independently developed by China, has been widely used in the treatment of advanced hepatocellular carcinoma (HCC) in recent years. For more than a decade, sorafenib has been the classic first-line treatment option for patients with advanced HCC. However, the results of clinical studies comparing the efficacy and safety of these 2 drugs are still controversial. Therefore, the aim of this meta-analysis is to evaluate the efficacy and safety of apatinib versus sorafenib as first-line treatment for advanced HCC. METHODS Up to August 14, 2023, the databases of PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, China National Knowledge Infrastructure, and Wanfang were searched, and clinical studies of experimental group (apatinib or apatinib plus transarterial chemoembolization [TACE]) versus control group (sorafenib or sorafenib plus TACE) in the first-line treatment of advanced HCC were included. Two researchers evaluated the quality of the included studies and extracted the data. Revman 5.4 software was used for meta-analysis. RESULTS A total of 12 studies involving 1150 patients were included. Five studies are apatinib alone versus sorafenib alone, and the other 7 studies are apatinib plus TACE versus sorafenib plus TACE. The results of the meta-analysis showed that compared with sorafenib alone, apatinib could improve (OR = 3.06, 95%CI: 1.76-5.31), had no advantage in improving DCR (OR = 1.52, 95%CI: 0.86-2.68) and prolonging PFS (HR = 1.35, 95%CI: 0.94-1.96), and was significantly worse in prolonging OS (HR = 1.43, 95%CI: 1.08-1.88). Similarly, apatinib plus TACE was inferior to sorafenib plus TACE in prolonging OS (HR = 1.15, 95%CI: 1.03-1.28), although it improved ORR (OR = 1.49, 95%CI: 1.03-2.16). In terms of adverse drug events, the overall incidence of adverse events, and the incidence of drug reduction and discontinuation in the experimental group were significantly higher than those in the control group (P < .05). The incidence of hypertension, proteinuria, and oral mucositis in the experimental group was significantly higher than that in the control group (P < .05). CONCLUSION In the setting of first-line treatment of advanced HCC, apatinib has improved short-term efficacy (ORR) compared with sorafenib, but the safety and long-term efficacy of apatinib are inferior to sorafenib.
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Affiliation(s)
- Dailong Li
- Department of Oncology, General Hospital of The Yangtze River Shipping, Wuhan, Hubei, China
| | - Chunzhen Zhang
- Department of Critical Care Medicine, The First College of Clinical Medicine Science, China Three Gorges University and Yichang Central People’s Hospital, Yichang, Hubei, China
| | - Kui Yang
- Department of Oncology, General Hospital of The Yangtze River Shipping, Wuhan, Hubei, China
| | - Zhiwei Ma
- Department of Oncology, General Hospital of The Yangtze River Shipping, Wuhan, Hubei, China
| | - Lili Ma
- Department of Oncology, General Hospital of The Yangtze River Shipping, Wuhan, Hubei, China
| | - Chunlai Cheng
- Department of Oncology, General Hospital of The Yangtze River Shipping, Wuhan, Hubei, China
| | - Lu Xu
- Department of Radiation Oncology and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Sha Wan
- Department of Anatomy, College of Basic Medicine, Guilin Medical University, Guilin, China
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Hu L, Lin J, Shi X, Wang A. Efficacy of transarterial therapy combined with first-line tyrosine kinase inhibitors for unresectable hepatocellular carcinoma: a network meta-analysis. World J Surg Oncol 2023; 21:208. [PMID: 37475030 PMCID: PMC10360255 DOI: 10.1186/s12957-023-03098-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Accepted: 07/12/2023] [Indexed: 07/22/2023] Open
Abstract
BACKGROUND Transarterial therapies, including transarterial chemoembolization (TACE), hepatic arterial infusion chemotherapy (HAIC), and selective internal radiation therapy, combined with first-line tyrosine kinase inhibitors (TKIs) are considered the standard therapy for unresectable hepatocellular carcinoma. However, inconsistent results have been reported in various studies assessing different combinations of targeted agents. METHODS A network meta-analysis (NMA) was performed by including 23 randomized controlled trials (RCTs) with 6175 patients to investigate the efficiency of transarterial therapies in combination with different TKIs. Outcomes of interest included overall survival (OS), progression-free survival (PFS), time to progression (TTP), and tumor objective response rate (ORR). A random-effects consistency model was used in this Bayesian NMA. Hazard ratio and odd risks with a 95% credible interval were calculated and agents were ranked based on ranking probability. RESULTS HAIC showed maximal OS and TTP and TACE plus lenvatinib showed maximal PFS, ORR, and disease control rate (DCR). HAIC and TACE plus lenvatinib were ranked highest based on their respective parameters, which were OS for HAIC and PFS, ORR, and DCR for TACE plus lenvatinib. CONCLUSION HAIC and TACE plus lenvatinib were relatively better choice for unresectable hepatocellular carcinoma. However, owing to the lack of statistically significant OS benefits among most agents, other agents should be considered as potential alternatives for unresectable hepatocellular carcinoma.
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Affiliation(s)
- Lingbo Hu
- Department of Hepatopancreatobiliary Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Zhejiang, China
- Department of Hepatopancreatobiliary Surgery, Enze Hospital, Taizhou Enze Medical Center (Group), Zhejiang, China
| | - Jiangying Lin
- Department of Blood Purification, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Zhejiang, China
| | - Xingpeng Shi
- Department of Hepatopancreatobiliary Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Zhejiang, China
- Department of Hepatopancreatobiliary Surgery, Enze Hospital, Taizhou Enze Medical Center (Group), Zhejiang, China
| | - Aidong Wang
- Department of Hepatopancreatobiliary Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Zhejiang, China.
- Department of Hepatopancreatobiliary Surgery, Enze Hospital, Taizhou Enze Medical Center (Group), Zhejiang, China.
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Dong H, Ge D, Qu B, Zhu P, Wu Q, Wang T, Wang J, Li Z. Transarterial chemoembolization with or without multikinase inhibitors for patients with unresectable hepatocellular carcinoma: a systematic review and meta-analysis of randomized controlled trials. Front Oncol 2023; 13:1139025. [PMID: 37361570 PMCID: PMC10285094 DOI: 10.3389/fonc.2023.1139025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 05/23/2023] [Indexed: 06/28/2023] Open
Abstract
Background Randomized controlled trials (RCTs) testing the combination therapy of transarterial chemoembolization (TACE) plus multikinase inhibitor (MKI) in patients with unresectable hepatocellular carcinoma (HCC) have yielded inconsistent results. Methods In this work, a systematic review and meta-analysis was performed to compare the TACE+MKI combination therapy versus TACE monotherapy in HCC patients with time to progression (TTP) adopted as primary outcome. Results A total of 10 RCTs comprising 2837 patients receiving combination therapy (TACE plus sorafenib, brivanib, orantinib or apatinib) were included. TACE+MKI significantly prolonged TTP (hazard ratio [HR] 0.74, 95% CI 0.62-0.89, p=0.001) versus TACE monotherapy. Subgroup analysis suggested MKI administration before TACE might be preferable to post-TACE MKI for TTP. TACE+MKI also increased objective response rate (ORR) (risk ratio [RR] 1.17, 95% CI 1.03-1.32, p=0.01), but failed to improve overall survival (OS) (HR 0.98, 95% CI 0.86-1.13, p=0.82) and progression-free survival (PFS) (HR 0.75, 95% CI 0.50-1.12, p=0.16). The incidence of any adverse event (AE) did not significantly differ between TACE+MKI and TACE groups (RR 1.17, 95% CI 0.96-1.42, p=0.01), while serious AEs showed significant difference (RR 1.41, 95% CI 1.26-1.59, p<0.0001). Nevertheless, these AEs showing significant difference were mainly associated with MKI toxicities rather than TACE. Conclusions TACE+MKI combination therapy improved TTP and ORR but not OS and PFS in patients with unresectable HCC. Further high-quality trials are needed to verify these clinical benefits, and our findings could be very informative for future trial design.
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Affiliation(s)
- Han Dong
- Department of Nursing, Huaian Hospital of Huaian City, Huaian, China
| | - Dongfang Ge
- President’s Office of Huaian Hospital of Huaian City, Huaian, China
| | - Biao Qu
- Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei, China
| | - Ping Zhu
- Department of Endocrinology, Huaian Hospital of Huaian City, Huaian, China
| | - Qibiao Wu
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau, Macau SAR, China
| | - Tianyun Wang
- Department of Endocrinology, Huaian Hospital of Huaian City, Huaian, China
- Department of Pharmacy, Huaian Hospital of Huaian City, Huaian, China
| | - Jue Wang
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau, Macau SAR, China
| | - Zheng Li
- College of Health Sciences, School of Life Sciences, Jiangsu Normal University, Xuzhou, China
- State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China
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Wong JK, Lim HJ, Tam VC, Burak KW, Dawson LA, Chaudhury P, Abraham RJ, Meyers BM, Sapisochin G, Valenti D, Samimi S, Ramjeesingh R, Mujoomdar A, Martins I, Dixon E, Segedi M, Liu DM. Clinical consensus statement: Establishing the roles of locoregional and systemic therapies for the treatment of intermediate-stage hepatocellular carcinoma in Canada. Cancer Treat Rev 2023; 115:102526. [PMID: 36924644 DOI: 10.1016/j.ctrv.2023.102526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 02/12/2023] [Accepted: 02/14/2023] [Indexed: 03/06/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) a leading cause of cancer mortality worldwide and approximately one-third of patients present with intermediate-stage disease. The treatment landscape of intermediate-stage HCC is rapidly evolving due to developments in local, locoregional and systemic therapies. Treatment recommendations focused on this heterogenous disease stage and that take into account the Canadian reality are lacking. To address this gap, a pan-Canadian group of experts in hepatology, transplant, surgery, radiation therapy, nuclear medicine, interventional radiology, and medical oncology came together to develop consensus recommendations on management of intermediate-stage HCC relevant to the Canadian context. METHODS A modified Delphi framework was used to develop consensus statements with strengths of recommendation and supporting levels of evidence graded using the AHA/ACC classification system. Tentative consensus statements were drafted based on a systematic search and expert input in a series of iterative feedback cycles and were then circulated via online survey to assess the level of agreement. RESULTS & CONCLUSION The pre-defined ratification threshold of 80 % agreement was reached for all statements in the areas of multidisciplinary treatment (n = 4), intra-arterial therapy (n = 14), biologics (n = 5), radiation therapy (n = 3), surgical resection and transplantation (n = 7), and percutaneous ablative therapy (n = 4). These generally reflected an expansion in treatment options due to developments in previously established or emergent techniques, introduction of new and more active therapies and increased therapeutic flexibility. These developments have allowed for greater treatment tailoring and personalization as well as a paradigm shift toward strategies with curative intent in a wider range of disease settings.
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Affiliation(s)
- Jason K Wong
- University of Calgary, 2500 University Dr NW, Calgary, AB T2N 1N4, Canada.
| | - Howard J Lim
- BC Cancer Agency, 600 West 10th Avenue, Vancouver, BC V5Z 4E6, Canada.
| | - Vincent C Tam
- Tom Baker Cancer Centre, University of Calgary, 1331 29 St NW, Calgary, AB T2N 4N2, Canada.
| | - Kelly W Burak
- University of Calgary, 2500 University Dr NW, Calgary, AB T2N 1N4, Canada.
| | - Laura A Dawson
- Princess Margaret Cancer Centre, University of Toronto, 610 University Ave, Toronto, ON M5G 2C1, Canada.
| | | | - Robert J Abraham
- Department of Diagnostic Radiology, Dalhousie University, 6299 South St, Halifax, NS B3H 4R2, Canada.
| | - Brandon M Meyers
- Juravinski Cancer Centre, 699 Concession St, Hamilton, ON L8V 5C2, Canada.
| | | | - David Valenti
- McGill University, 845 Rue Sherbrooke O, Montréal, QC H3A 0G4, Canada.
| | - Setareh Samimi
- Hopital Sacre-Coeur de Montreal, University of Montreal, 5400 Boul Gouin O, Montréal, QC H4J 1C5, Canada.
| | - Ravi Ramjeesingh
- Department of Medicine, Dalhousie University, 6299 South St, Halifax, NS B3H 4R2, Canada.
| | - Amol Mujoomdar
- Western University, 1151 Richmond Street, London, ON N6A 5B9, Canada.
| | - Ilidio Martins
- Kaleidoscope Strategic, Inc. 1 King Street W, Suite 4800 - 117, Toronto, ON M5H 1A1, Canada.
| | - Elijah Dixon
- University of Calgary, 2500 University Dr NW, Calgary, AB T2N 1N4, Canada.
| | - Maja Segedi
- Department of Surgery, Vancouver General Hospital, Jim Pattison Pavilion, 899 W 12th Ave, Vancouver, BC V5Z 1M9, Canada.
| | - David M Liu
- School of Biomedical Engineering, University of British Columbia, 2329 West Mall Vancouver, BC V6T 1Z4, Canada.
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Chen WT, Lin SM, Lee WC, Wu TJ, Lin CC, Shen CH, Chang ML, Lin CL, Yeh CT. GALNT14 genotype-guided chemoembolization plus sorafenib therapy in hepatocellular carcinoma: a randomized trial. Hepatol Int 2022; 16:148-158. [PMID: 34982369 DOI: 10.1007/s12072-021-10283-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 12/06/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND GALNT14-rs9679162 "TT" genotype is associated with favorable clinical outcomes in hepatocellular carcinoma (HCC) treated by transarterial chemoembolization (TACE). We investigated whether patients with GALNT14-rs9679162 "non-TT" unfavorable genotype benefited from chemoembolization plus sorafenib combination therapy. METHODS Intermediate stage HCC patients were recruited for GALNT14-rs9679162 genotyping before TACE. Patients with "TT" genotype received only TACE, labeled as TT (TACE) group. Patients with "non-TT" genotype ("GG" or "GT") were randomized to receive either TACE alone, labeled as Non-TT (TACE) group, or TACE plus sorafenib, labeled as Non-TT (TACE + Sora) group. The latter group received sorafenib 400 mg daily plus TACE. RESULTS From October 2015 to April 2019, 103 HCC patients scheduled to receive chemoembolization were screened. Of them, 84 met inclusion criteria and were assigned to TT (TACE) (n = 25), Non-TT (TACE) (n = 30) and Non-TT (TACE + Sora) (n = 29) groups according to their GALNT14 genotypes. Repeated TACE sessions were performed on-demand and patients were followed until November 2020. It was found that TT (TACE) and Non-TT (TACE + Sora) patients had shorter time-to-complete response compared with that in Non-TT (TACE) patients (p < 0.001 and 0.009, respectively). These two groups also had longer time-to-TACE progression (p < 0.001 and 0.006, respectively) and longer progression-free survival (p = 0.001 and 0.021, respectively). However, TT (TACE) patients harbored longer overall survival compared with those in non-TT (TACE + Sora) and non-TT (TACE) patients (p = 0.028, < 0.001, respectively). CONCLUSION Combination of sorafenib and TACE for "non-TT" patients partially overcame the genetic disadvantage on treatment outcomes in terms of time-to-complete response, time-to-TACE progression and progression-free survival. TRIAL REGISTRATION ClinicalTrials.gov NCT02504983.
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Affiliation(s)
- Wei-Ting Chen
- Liver Research Center, Linko Chang Gung Memorial Hospital, Chang Gung Memorial Hospital, Linkou Branch, 5, Fu-Shin Street, Taoyuan, 333, Taiwan
| | - Shi-Ming Lin
- Liver Research Center, Linko Chang Gung Memorial Hospital, Chang Gung Memorial Hospital, Linkou Branch, 5, Fu-Shin Street, Taoyuan, 333, Taiwan
| | - Wei-Chen Lee
- Division of Liver and Transplantation Surgery, Linko Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Ting-Jung Wu
- Division of Liver and Transplantation Surgery, Linko Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Chen-Chun Lin
- Liver Research Center, Linko Chang Gung Memorial Hospital, Chang Gung Memorial Hospital, Linkou Branch, 5, Fu-Shin Street, Taoyuan, 333, Taiwan
| | - Chien-Heng Shen
- Department of Gastroenterology and Hepatology, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Ming-Ling Chang
- Liver Research Center, Linko Chang Gung Memorial Hospital, Chang Gung Memorial Hospital, Linkou Branch, 5, Fu-Shin Street, Taoyuan, 333, Taiwan
| | - Chih-Lang Lin
- Department of Gastroenterology and Hepatology, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Chau-Ting Yeh
- Liver Research Center, Linko Chang Gung Memorial Hospital, Chang Gung Memorial Hospital, Linkou Branch, 5, Fu-Shin Street, Taoyuan, 333, Taiwan.
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Dai Y, Jiang H, Jiang H, Zhao S, Zeng X, Sun R, Zheng R. Optimal timing of combining sorafenib with trans-arterial chemoembolization in patients with hepatocellular carcinoma: A meta-analysis. Transl Oncol 2021; 14:101238. [PMID: 34628285 PMCID: PMC8515486 DOI: 10.1016/j.tranon.2021.101238] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 09/30/2021] [Accepted: 10/02/2021] [Indexed: 01/10/2023] Open
Abstract
Sorafenib in combination with TACE can prolong survival in patients with hepatocellular carcinoma. Compared with TACE + placebo / alone, the combination of TACE and sorafenib can significantly improve the efficacy and safety of hepatocellular carcinoma. The timing of sorafenib combined with TACE may be a statistical difference in terms of survival and adverse events. Background The combination therapy of trans-arterial chemoembolization (TACE) and sorafenib were proved to be one of the effective methods for intermediate and advanced hepatocellular carcinoma (HCC). Although it has been confirmed that the combination therapy can prolong survival for advanced HCC effectively, the therapeutic efficacy and safety are still controversial and the clinical value has not been determined. This meta-analysis aims to evaluate the efficacy and safety of combination therapy and discuss the optimal timing of combination for better clinical benefits. Data sources PubMed, EMBASE, the Cochrane Library, MEDLINE, and Web of Science were systematically reviewed to search for relevant studies published before May 15, 2021. Studies comparing the efficacy and safety of TACE + sorafenib with TACE + placebo / alone were adopted. Two reviewers independently extracted study outcomes. The data were analyzed through fixed/random-effect meta-analysis models with Review Manager (Version 5. 3) software. Results 7 randomized controlled trials (RCTs) were included with 1464 patients with unresectable HCC (734 in TACE + sorafenib group and 730 in TACE + placebo or alone group). Meta-analysis showed that objective response rate (ORR) and disease control rate (DCR) were slightly improved in TACE + sorafenib group (ORR: risk ratio = 1.24; 95% confidence interval: 1.08–1.42; P = 0.002; DCR: risk ratio = 1.09; 95% confidence interval: 1.01–1.18; P = 0.02). The combination therapy obviously improved time to progression (TTP) (hazard ratio: 0.73; 95% confidence interval: 0.55–0.96; P = 0.03) and progression-free survival (PFS) (hazard ratio 0.62; 95% confidence interval: 0.52–0.73, P < 0.00001) but not overall survival (OS) (hazard ratio: 0.93; 95% confidence interval: 0.59–1.46; P = 0.75) or time to untreatable progression (TTUP) (hazard ratio: 0.76; 95% confidence interval: 0.31–1.89; P = 0.56). In addition, the incidence of adverse reactions (AEs) in combination group were higher than TACE + placebo / alone group. Furthermore, the subgroup analysis showed that the heterogeneity of TTP was notably decreased (pre-TACE: P = 0.12, I2 = 48%; post-TACE: P = 0.58, I2 = 0%), and the hazard ratio was 0.59 (95% confidence interval: 0.51–0.68; P < 0.00001) in pre-TACE subgroup which indicated that combination before TACE significantly prolonged TTP but not in combination after TACE (hazard ratio: 0.88; 95% confidence interval: 0.62–1.24; P = 0.46). In term of AEs, sensitivity analysis indicated that the risk ratio for hand-foot skin reaction, diarrhea, rash/desquamation, and hypertension was 7.41, 2.58, 2.14, 1.55 in pre-TACE subgroup respectively and was 11.34, 3.26, 3.61, 4.11 in post-TACE subgroup respectively (All P < 0.05). Conclusion The combination of TACE and sorafenib significantly can improve TTP and PFS, and reduce the level of risk of adverse reactions of unresectable HCC, especially in the combination before TACE.
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Affiliation(s)
- Yanmei Dai
- Department of Radiology, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province 150086, China
| | - Huijie Jiang
- Department of Radiology, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province 150086, China.
| | - Hao Jiang
- Department of Radiology, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province 150086, China
| | - Sheng Zhao
- Department of Radiology, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province 150086, China
| | - Xu Zeng
- Department of Radiology, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province 150086, China
| | - Ran Sun
- Department of Radiology, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province 150086, China
| | - Ruoshui Zheng
- Department of Radiology, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province 150086, China
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12
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Gupta S, Khan S, Kawka M, Gujjuri R, Chau I, Starling N, Cunningham D, Jiao LR, Gall T. Clinical utility of clonal origin determination in managing recurrent hepatocellular carcinoma. Expert Rev Gastroenterol Hepatol 2021; 15:1159-1167. [PMID: 34402366 DOI: 10.1080/17474124.2021.1967144] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
INTRODUCTION Recurrence is the driving factor for reduced long-term survival in patients following resected hepatocellular carcinoma (HCC). Extensive research efforts have been conducted to understand the molecular processes precipitating disease recurrence. Modern genomic techniques have identified two distinct mechanisms for recurrent HCC (RHCC): Intrahepatic metastasis (IM-HCC); and multicentric origin (MO-HCC). Medline, EMBASE and Cochrane library were methodically searched for primary research articles in English with the aim of appraising existing literature on the identification of clonal origin of RHCC and its potential clinical utility. AREAS COVERED Molecular and next-generation sequencing techniques, when applied to clonal origin identification, yield superior accuracy than traditional clinicopathological criteria. Despite various treatment modalities, no optimal therapy has yet been identified for treating clonally differentiated RHCC. Patients with MO-HCC appear to experience improved long-term survival following re-treatment compared to their IM-HCC counterparts (91.7% vs 22.9% 5-year survival, p < 0.001). However, cautious interpretation is advised as heterogeneous classification criteria and small sample sizes restrict the generalizability of such findings. EXPERT OPINION Improved identification of clonal origin in RHCC may facilitate further research on RHCC treatment strategies and enable the development of novel therapeutic targets, potentially leading to individualized treatment approaches in the future.
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Affiliation(s)
- Shubham Gupta
- Department of Medicine, Imperial College London, South Kensington Campus, London, UK
| | - Sikandar Khan
- Department of Medicine, Imperial College London, South Kensington Campus, London, UK
| | - Michal Kawka
- Department of Medicine, Imperial College London, South Kensington Campus, London, UK
| | - Rohan Gujjuri
- Department of Medicine, Imperial College London, South Kensington Campus, London, UK
| | - Ian Chau
- Department Of Oncology And Surgery, The Royal Marsden Hospital, London, UK
| | - Naureen Starling
- Department Of Oncology And Surgery, The Royal Marsden Hospital, London, UK
| | - David Cunningham
- Department Of Oncology And Surgery, The Royal Marsden Hospital, London, UK
| | - Long R Jiao
- Department of Medicine, Imperial College London, South Kensington Campus, London, UK.,Department Of Oncology And Surgery, The Royal Marsden Hospital, London, UK
| | - Tamara Gall
- Department of Medicine, Imperial College London, South Kensington Campus, London, UK.,Department Of Oncology And Surgery, The Royal Marsden Hospital, London, UK
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Meyers BM, Knox JJ, Cosby R, Beecroft JR, Chan KKW, Coburn N, Feld JJ, Jonker D, Mahmud A, Ringash J. Non-surgical management of advanced hepatocellular carcinoma: A systematic review by Cancer Care Ontario. CANADIAN LIVER JOURNAL 2021; 4:257-274. [PMID: 35992253 PMCID: PMC9202767 DOI: 10.3138/canlivj-2020-0039] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Accepted: 01/23/2021] [Indexed: 08/12/2023]
Abstract
Background Hepatocellular carcinoma (HCC) is a global health problem, accounting for 4.7% of all new cancer cases and 8.2% of all cancer deaths worldwide in 2018. Resection and transplantation are the only modalities that offer a cure for HCC; however, most patients are diagnosed at an advanced stage, precluding these curative treatments. A number of local (ie, ablative therapies) and/or local-regional therapies (ie, chemo-embolization) are used and followed by systemic therapy for advanced or progressive disease. Other treatments are available, but their efficacy compared with these standards is not well known. Methods Literature searches (1/2000 to 1/2020 or 1/2005 to 1/2020, depending on the specific systematic review question) were conducted, including MEDLINE, Embase and the Cochrane Database of Systematic Reviews. Results Over 30,000 articles were identified. In total, 49 studies were included in the systematic review. Conclusions There is no evidence to support the addition of sorafenib to any local or regional therapy. First-line systemic therapy options for unresectable or metastatic HCC include sorafenib, lenvatinib, and atezolizumab + bevacizumab. Regorafenib or cabozantinib provide survival benefits when given as second-line treatment.
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Affiliation(s)
- Brandon M Meyers
- Juravinski Cancer Centre, Department of Oncology, McMaster University, Hamilton, Ontario, Canada
| | | | - Roxanne Cosby
- Program in Evidence-Based Care, Department of Oncology, McMaster University, Hamilton, Ontario, Canada
| | - JR Beecroft
- Mount Sinai Hospital, Department of Medical Imaging, Toronto, Ontario, Canada
| | - Kelvin KW Chan
- Sunnybrook Odette Cancer Centre, Toronto, Ontario, Canada
| | - Natalie Coburn
- Sunnybrook Odette Cancer Centre, Toronto, Ontario, Canada
| | - Jordan J Feld
- Toronto General Hospital Research Institute, Toronto, Ontario, Canada
| | - Derek Jonker
- Ottawa Hospital Cancer Centre, Ottawa, Ontario, Canada
| | - Aamer Mahmud
- Cancer Centre of Southeastern Ontario, Kingston, Ontario, Canada
| | - Jolie Ringash
- Princess Margaret Cancer Centre, Toronto, Ontario, Canada
- Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada
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14
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Shao YY, Wang SY, Lin SM. Management consensus guideline for hepatocellular carcinoma: 2020 update on surveillance, diagnosis, and systemic treatment by the Taiwan Liver Cancer Association and the Gastroenterological Society of Taiwan. J Formos Med Assoc 2021; 120:1051-1060. [PMID: 33199101 DOI: 10.1016/j.jfma.2020.10.031] [Citation(s) in RCA: 82] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 09/28/2020] [Accepted: 10/30/2020] [Indexed: 02/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality in Taiwan. The Taiwan Liver Cancer Association and the Gastroenterological Society of Taiwan had established a management consensus guideline in 2016. The current recommendations focus on updating critical issues regarding the management of HCC, including surveillance, diagnosis, and systemic treatment. For surveillance, the updated guideline suggests the role of dynamic computed tomography or magnetic resonance imaging and contrast-enhanced ultrasound (CEUS) in selected patients. For diagnosis, this update incorporates CEUS and recognizes the role of gadoxetic acid-enhanced magnetic resonance imaging. For systemic therapy, the updated guideline summarizes the multiple choices of targeted therapy, immune checkpoint inhibitors, and the combination of both. Through this update of the management consensus guideline, patients with HCC can benefit from receiving optimal diagnostic and therapeutic modalities.
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Affiliation(s)
- Yu-Yun Shao
- Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan; Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
| | - Shen-Yung Wang
- Division of Gastroenterology and Hepatology, Department of Medicine, MacKay Memorial Hospital, Taipei, Taiwan
| | - Shi-Ming Lin
- Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan; Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan; Division of Gastroenterology and Hepatology, Department of Medicine, MacKay Memorial Hospital, Taipei, Taiwan.
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15
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Yang J, Eresen A, Scotti A, Cai K, Zhang Z. Combination of NK-based immunotherapy and sorafenib against hepatocellular carcinoma. Am J Cancer Res 2021; 11:337-349. [PMID: 33575075 PMCID: PMC7868752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Accepted: 12/07/2020] [Indexed: 06/12/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most frequent malignancy of the liver, which is considered the fourth leading cause of cancer-related death in the United States. Liver transplant and surgical resection are curative treatments for HCC, but only 10-15% of HCC patients are eligible candidates. The FDA-approved sorafenib is a multi-kinase inhibitor systemic therapy for advanced HCC that extends the overall survival by over 3 months when compared with placebo. Adoptive transfer of Natural Killer (NK) cells holds great promise for clinical cancer treatment. However, only limited clinical benefit has been achieved in cancer patients. Therefore, there is currently considerable interest in development of the combination of sorafenib and NK cells for the treatment of HCC patients. However, the mechanism of how sorafenib affects the function of NK cells remains to be comprehensively clarified. In this paper, we will discuss NK cell-based immunotherapies that are currently under preclinical and clinical investigation and its potential combination with sorafenib for improving the survival of HCC patients.
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Affiliation(s)
- Jia Yang
- Department of Radiology, Feinberg School of Medicine, Northwestern UniversityChicago, IL, 60611, USA
| | - Aydin Eresen
- Department of Radiology, Feinberg School of Medicine, Northwestern UniversityChicago, IL, 60611, USA
| | - Alessandro Scotti
- Department of Radiology, University of Illinois at ChicagoChicago, IL, 60612, USA
- Department of Bioengineering, University of Illinois at ChicagoChicago, IL, 60612, USA
| | - Kejia Cai
- Department of Radiology, University of Illinois at ChicagoChicago, IL, 60612, USA
- Department of Bioengineering, University of Illinois at ChicagoChicago, IL, 60612, USA
| | - Zhuoli Zhang
- Department of Radiology, Feinberg School of Medicine, Northwestern UniversityChicago, IL, 60611, USA
- Robert H. Lurie Comprehensive Cancer Center of Northwestern UniversityChicago, IL, 60611, USA
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Yao W, Xue M, Lu M, Wang Y, Zhao Y, Wu Y, Fan W, Li J. Diffuse Recurrence of Hepatocellular Carcinoma After Liver Resection: Transarterial Chemoembolization (TACE) Combined With Sorafenib Versus TACE Monotherapy. Front Oncol 2021; 10:574668. [PMID: 33425729 PMCID: PMC7793644 DOI: 10.3389/fonc.2020.574668] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Accepted: 11/13/2020] [Indexed: 12/26/2022] Open
Abstract
This study aims to compare the effectiveness and complications of transarterial chemoembolization (TACE) combined with sorafenib (S-TACE) and TACE monotherapy in HCC patients with diffuse recurrence (DR). This retrospective study was approved by our hospital ethics committee, and all patients provided informed consent. We retrospectively enrolled 356 DR patients from January 2005 to December 2014, who underwent either S-TACE or TACE monotherapy. Treatment complications, overall survival (OS) and progression-free survival (PFS) were evaluated. Survival curves were constructed using the Kaplan-Meier method and compared using a log-rank test. Our results found a significant difference between S-TACE and TACE monotherapy in the PFS and OS of HCC patients with early diffuse recurrence (EDR) (p=0.011 and 0.049, respectively). Patients with late diffuse recurrence (LDR) who underwent S-TACE had longer OS (median 24.0 vs. 16.0 months; p=0.044) compared with those in the TACE monotherapy group. Subgroup analysis revealed that S-TACE therapy resulted in higher OS of EDR patients with tumors > 5 cm and HBV-DNA >100 (p=0.036 and 0.035, respectively), compared with patients given TACE monotherapy. S-TACE therapy also resulted in better OS in LDR patients with AFP≥400 ng/ml, AFP<400 ng/ml, TB<28 g/L, TB>28 g/L, and a maximum tumor diameter < 5 cm (p=<0.001, 0.042, <0.001, <0.001, and <0.001, respectively). The rate of major complications in patients who underwent S-TACE was not significantly different to those who underwent TACE monotherapy (33.5% vs. 28.2%, p= 0.69). Overall, patients given S-TACE had better OS in both EDR and LDR patients, but only EDR patients had better PFS.
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Affiliation(s)
- Wang Yao
- Department of Interventional Oncology, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Miao Xue
- Department of Interventional Oncology, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Mingjian Lu
- Department of Radiology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
| | - Yu Wang
- Department of Interventional Oncology, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Yue Zhao
- Department of Interventional Oncology, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Yanqin Wu
- Department of Interventional Oncology, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Wenzhe Fan
- Department of Interventional Oncology, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Jiaping Li
- Department of Interventional Oncology, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
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Wang J, Feng L, Zhang L. Combining cellular immunotherapy was an optional choice for unresectable advanced HCC: A systematic review and meta-analysis. Clin Res Hepatol Gastroenterol 2021; 45:101440. [PMID: 32709504 DOI: 10.1016/j.clinre.2020.04.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 04/24/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND The efficacy of cellular immunotherapy in advanced hepatocellular carcinoma (HCC) was controversial. This study was conducted to compare the effectiveness of combining cellular immunotherapy with that of incurable treatment alone. METHODS The Ovid Medline, Embase, Cochrane Library and Pubmed were systematically searched due to January 8th 2020. The keywords include "immunotherapy", "HCC" and study type. Treatment response was evaluated and progression-free survival (PFS) and overall survival (OS) were calculated using hazard ratio (HR) and 95% confidence interval (CI). RESULTS A total of 19 studies with 1275 patients were included in the meta-analysis. The median complete response rate (CR) was 19% in combining cellular immunotherapy comparing to 9% in the control group (RR=0.55, P=0.003). No significant difference was found in partial response and stable disease (RR=1.06 and 0.78, P>0.05, respectively). The progression disease rate was higher in the non-cellular immunotherapy group (31%) compared to the cellular immunotherapy group (RR=2.20, P=0.002). Patients treating with cellular immunotherapy had a better OS and PFS compared to those without cellular immunotherapy (HR=0.52 and 0.63, P<0.001). In the subgroup analysis, the only CIK infusion therapy and combined DC with CIK perfusion therapy patients had a better OS (HR=0.52 and 0.49, P<0.001 and P=0.002, respectively). CONCLUSION Our results suggested that combining use of cellular immunotherapy in advanced HCC could increase the complete response rate, and thereafter extend the progression-free and overall survival rate. Subgroup analysis suggested that combining use of CIK and DC or using CIK alone could provide the benefit in survival outcome.
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Affiliation(s)
- Jing Wang
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao 266003 Shandong, People's Republic of China.
| | - Lingxin Feng
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao 266003 Shandong, People's Republic of China
| | - Linwei Zhang
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao 266003 Shandong, People's Republic of China
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Cheng Z, He L, Guo Y, Song Y, Song S, Zhang L. The combination therapy of transarterial chemoembolisation and sorafenib is the preferred palliative treatment for advanced hepatocellular carcinoma patients: a meta-analysis. World J Surg Oncol 2020; 18:243. [PMID: 32917226 PMCID: PMC7488414 DOI: 10.1186/s12957-020-02017-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 08/31/2020] [Indexed: 12/13/2022] Open
Abstract
Background To compare the efficacy of three types of palliative therapy for advanced hepatocellular carcinoma (HCC), including transarterial chemoembolisation (TACE) monotherapy, sorafenib alone and their combination. Methods The databases of PubMed, Embase and Cochrane Library were retrieved. The odds ratio (OR) with its 95% confidence interval (CI) was used to investigate the binary variables, and the standardised mean difference (SMD) with its 95% CI was employed to evaluate the continuous variables. All statistical tests were performed by using Stata/SE, version 12.0. Results Thirty-one clinical studies, containing 5125 unique cases of patients with advanced HCC, were included. There were significant improvements in overall survival (OS) (pooled SMD = 2.54; 95% CI 1.74–3.34) and time to progression (TTP) (pooled SMD = 2.49; 95% CI 0.87–4.12) of the patients after receiving the combination therapy of TACE and sorafenib, compared to TACE monotherapy, and the OS in the combined treatment cohort was also longer than that in the sorafenib-alone cohort (pooled SMD = 2.92; 95% CI 1.72–4.13). The combination therapy group in comparison to the TACE group benefited a significantly increased overall response rate (ORR) (pooled OR = 2.61; 95% CI 1.43–4.77), 1-year (pooled OR = 2.96; 95% CI 1.71–5.14) and 2-year (pooled OR = 1.64; 95% CI 1.18–2.28) survival rates and reduced disease progression rate (DPR) (pooled OR = 0.47; 95% CI 0.33–0.68); in parallel, the ORR in the group was also significantly higher than that in the sorafenib-alone group (pooled OR = 3.62; 95% CI 1.28–10.22), although without a difference in the DPR (pooled OR = 0.28; 95% CI 0.05–1.48). In addition, we discovered that the 1-year (pooled OR = 1.39; 95% CI 0.84–2.29) and 2-year (pooled OR = 1.70; 95% CI 0.69–4.18) survival rates in the TACE monotherapy cohort were not significantly different to those in the sorafenib-alone cohort. Conclusion The combination therapy is more effective than monotherapy in improving the prognostic outcomes of patients with advanced HCC. Therefore, we recommend it as the preferred treatment intervention for those patients.
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Affiliation(s)
- Zhoujing Cheng
- Department of Gastroenterology, The Second Hospital of Anhui Medical University, No.678 Furong Road, Jingkai District, Hefei, Anhui Province, China
| | - Lin He
- Breast Center B ward, The Affiliated Hospital of Qingdao University, Shandong Province, Qingdao, China
| | - Yingjie Guo
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Shandong Province, Qingdao, China
| | - Yuhua Song
- Breast Center B ward, The Affiliated Hospital of Qingdao University, Shandong Province, Qingdao, China
| | - Shasha Song
- Department of Gastroenterology, The Second Hospital of Anhui Medical University, No.678 Furong Road, Jingkai District, Hefei, Anhui Province, China
| | - Lijiu Zhang
- Department of Gastroenterology, The Second Hospital of Anhui Medical University, No.678 Furong Road, Jingkai District, Hefei, Anhui Province, China.
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19
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Lee SW, Tung CF, Peng YC, Lien HC, Chang CS. Therapeutic benefits of combined sorafenib for intermediate hepatocellular carcinoma unresponsive to transarterial chemoembolization in a Chinese population. J Dig Dis 2020; 21:462-467. [PMID: 32472590 DOI: 10.1111/1751-2980.12911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 05/06/2020] [Accepted: 05/26/2020] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Transarterial chemoembolization (TACE) is the treatment modality for intermediate, or Barcelona Clinic Liver Cancer stage B, hepatocellular carcinoma (HCC), but its beneficial effect on outcomes is still unsatisfactory. This study aimed to assess the outcomes of combined TACE and sorafenib for patients with intermediate HCC. METHODS Patients with intermediate HCC who were receiving TACE alone (the monotherapy group), or combined TACE and sorafenib (the combined therapy group) from January 2013 to June 2018 were enrolled. RESULTS Altogether 64 patients were enrolled, of whom 34 were assigned to the monotherapy group and 30 to the combined therapy group. A prolonged time-to-progression (TTP) (mean 14.46 mo vs 6.39 mo, P = 0.001) was noted in the combined therapy group compared with the monotherapy group. Overall survival (OS) (mean 18.96 mo vs15.44 mo, P = 1.000) between the two groups did not differ significantly. After adjustment, there were no significant differences in the 12-18 month mortality rate between the two groups. CONCLUSION Patients with intermediate HCC receiving combined TACE and sorafenib had a better TTP, but not OS, than those receiving TACE alone.
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Affiliation(s)
- Shou Wu Lee
- Division of Gastroenterology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan Province, China.,Department of Internal Medicine, Chung Shan Medical University, Taichung, Taiwan Province, China
| | - Chun Fang Tung
- Division of Gastroenterology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan Province, China.,Department of Internal Medicine, YangMing University, Taipei, Taiwan Province, China
| | - Yen Chun Peng
- Division of Gastroenterology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan Province, China.,Department of Internal Medicine, YangMing University, Taipei, Taiwan Province, China
| | - Han Chung Lien
- Division of Gastroenterology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan Province, China.,Department of Internal Medicine, YangMing University, Taipei, Taiwan Province, China
| | - Chi Sen Chang
- Division of Gastroenterology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan Province, China.,Department of Internal Medicine, Chung Shan Medical University, Taichung, Taiwan Province, China
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20
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Xie Y, Tian H, Xiang H. Is transcatheter arterial chemoembolization plus sorafenib better than chemoembolization plus placebo in the treatment of hepatocellular carcinoma? TUMORI JOURNAL 2020; 107:292-303. [PMID: 32729385 DOI: 10.1177/0300891620945029] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
OBJECTIVE To evaluate the efficacy and safety of transcatheter arterial chemoembolization (TACE) plus sorafenib compared with TACE plus placebo for hepatocellular carcinoma (HCC) using meta-analytical techniques. METHODS A search of PubMed, EMBASE, and Cochrane Library databases were done from inception to December 27, 2019. Published trials including a treatment group receiving TACE + sorafenib and a control group receiving TACE + placebo with data for at least 1-year survival or tumor response or time to progression were included. RESULTS Our study suggested that there was no evidence that TACE plus sorafenib was associated with a lower risk of disease progression compared with TACE plus placebo for treatment of HCC (hazard ratio 0.94 [95% confidence interval (CI), 0.84-1.05]), and no significant difference for treatment of HCC compared with TACE plus placebo in terms of 0.5-, 1-, 1.5-, and 2-year survival rates (risk ratio [RR] 1.01 [95% CI, 0.97-1.05]; RR 1.00 [95% CI, 0.92-1.08], RR 1.04 [95% CI, 0.89-1.23], RR 0.98 [95% CI, 0.72-1.34], respectively). The meta-analysis also showed that TACE + sorafenib seemed to have no significant difference for treatment of HCC compared with TACE + placebo in terms of complete response, partial response, stable disease, progressive disease, overall response rate, and disease control rate. There was an increased incidence of fatigue of grade 3/4 and elevation of aspartate aminotransferase and alanine aminotransferase of grade 3/4 in patients receiving TACE plus sorafenib compared with those receiving TACE plus placebo. CONCLUSIONS There is no additive benefit of TACE plus sorafenib compared to TACE plus placebo for HCC.
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Affiliation(s)
- Yong Xie
- Department of Interventional Radiology and Vascular Surgery, The First Affiliated Hospital of Hunan Normal University, Changsha, China
| | - Huan Tian
- Department of Radiology, The Second Affiliated Hospital of Hebei Medical University, Shijiazhuang, China
| | - Hua Xiang
- Department of Interventional Radiology and Vascular Surgery, The First Affiliated Hospital of Hunan Normal University, Changsha, China
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21
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Meyers BM, Knox J, Cosby R, Beecroft JR, Chan KKW, Coburn N, Feld J, Jonker D, Mahmud A, Ringash J. Nonsurgical management of advanced hepatocellular carcinoma: a clinical practice guideline. ACTA ACUST UNITED AC 2020; 27:e106-e114. [PMID: 32489260 DOI: 10.3747/co.27.5891] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Background Practice guidelines based on a systematic review of the literature regarding the nonsurgical management of hepatocellular carcinoma (hcc) in North America are lacking. Resection and transplantation are the foundations for cure of hcc; however, most patients are diagnosed at an advanced stage, precluding those curative treatments. A number of local or regional therapies are used and are followed by systemic therapy for advanced or progressive disease. Other treatments are available, but their efficacy, compared with those standards, is not well known. Methods First, systematic review questions were developed. Literature searches of the medline, embase, and Cochrane library databases (January 2000 to July 2018 or January 2005 to July 2018 depending on the question) were conducted; in addition, abstracts from the 2018 annual meeting of the American Society of Clinical Oncology were reviewed. A practice guideline was drafted that was then scrutinized by internal and external reviewers. Results Seventy-seven studies were included in the guideline: no guidelines, two systematic reviews, and seventy-five primary studies published in full (including one pooled analysis). Five recommendations were developed. Conclusions There is no evidence for or against the use of local or regional interventions other than transarterial chemoembolization for the treatment of intermediate- or advanced-stage hcc. Furthermore, there is no evidence to support the addition of sorafenib to any local or regional therapy. Sorafenib or lenvatinib are recommended for first-line systemic treatment of intermediate-stage hcc. Regorafenib or cabozantinib provide survival benefits when given as second-line treatment. Antiviral treatment is recommended in individuals with advanced hcc who are positive for the hepatitis B surface antigen.
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Affiliation(s)
- B M Meyers
- Juravinski Cancer Centre, Department of Oncology, McMaster University, Hamilton, ON
| | - J Knox
- Princess Margaret Cancer Centre, Toronto, ON
| | - R Cosby
- Program in Evidence-Based Care, Department of Oncology, McMaster University, Hamilton, ON
| | - J R Beecroft
- Department of Medical Imaging, Mount Sinai Hospital, and University Health Network, Toronto, ON
| | - K K W Chan
- Sunnybrook Odette Cancer Centre, Toronto, ON
| | - N Coburn
- Sunnybrook Odette Cancer Centre, Toronto, ON
| | - J Feld
- Toronto General Hospital Research Institute, Toronto, ON
| | - D Jonker
- The Ottawa Hospital Cancer Centre, Ottawa, ON
| | - A Mahmud
- Cancer Centre of Southeastern Ontario, Kingston, ON
| | - J Ringash
- Princess Margaret Cancer Centre, Toronto, ON.,Department of Radiation Oncology, University of Toronto, Toronto, ON
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Li H, Li S, Geng J, Zhao S, Tan K, Yang Z, Feng D, Liu L. Efficacy evaluation of the combination therapy of sorafenib and transarterial chemoembolization for unresectable HCC: a systematic review and meta-analysis of comparative studies. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:540. [PMID: 32411763 PMCID: PMC7214895 DOI: 10.21037/atm.2020.02.115] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Background Sorafenib and transarterial chemoembolization (TACE) are the standard treatments recommended by guidelines for unresectable hepatocellular carcinoma (HCC). Although previous studies have shown the combination therapy of sorafenib and TACE to be safe, there is no consensus regarding its efficacy. This systematic review and meta-analysis, which was based on the findings of comparative clinical trials, was conducted to provide up-to-date and comprehensive information about the efficacy of combination therapy versus TACE monotherapy in unresectable HCC. Methods Multiple databases were systematically reviewed to screen studies through particular inclusion criteria. Hazard ratio (HR) with 95% confidence intervals (95% CIs) was collected and analyzed by Revman 5.3 in a fixed or random effects meta-analysis model. Adverse events (AEs) were also evaluated. Results This review ultimately included 14 comparative studies focused on combination therapy versus TACE monotherapy. Of these: 5 studies conducted TACE plus sorafenib versus TACE with placebo; 9 studies provided overall survival (OS) in combination groups which ranged from 10.3 to 29.7 months; and 10 studies provided time to progression (TTP) in combination groups which ranged from 2.6 to 10.8 months. The disease control rate (DCR) in combination groups ranged from 9.7% to 89.2% in 7 of the studies. After performing a random effects meta-analysis model, our study showed that OS (HR =0.65, 95% CI: 0.54-0.79, P<0.0001) and TTP (HR =0.72, 95% CI: 0.59-0.88, P=0.001) have been significantly improved in the combination therapy group when compared with the TACE monotherapy group. AEs mainly included hand-foot skin reaction (HFSR), fatigue and diarrhea and the majority of these were in grade 1 or grade 2. Conclusions Combination therapy has significant advantages over TACE monotherapy in terms of improving TTP and OS.
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Affiliation(s)
- Huichen Li
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China
| | - Songlun Li
- Department of Blood Transfusion, Tangdu Hospital, The Fourth Military Medical University, Xi'an 710038, China
| | - Jie Geng
- Teaching and Research Section of Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China
| | - Shoujie Zhao
- Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China
| | - Kai Tan
- Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China
| | - Zhenyu Yang
- Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China
| | - Dayun Feng
- Department of Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China
| | - Lei Liu
- Department of Gastroenterology, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China
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23
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Ding W, Tan Y, Qian Y, Xue W, Wang Y, Jiang P, Xu X. First-line targ veted therapies of advanced hepatocellular carcinoma: A Bayesian network analysis of randomized controlled trials. PLoS One 2020; 15:e0229492. [PMID: 32134981 PMCID: PMC7058293 DOI: 10.1371/journal.pone.0229492] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Accepted: 02/07/2020] [Indexed: 02/07/2023] Open
Abstract
PURPOSE A variety of targeted drug were developed and proved effective and safe in clinical trials. Our study aims to compare the efficacies and safety of different targeted drugs in advanced hepatocellular carcinoma (HCC) for first-line treatment using a Bayesian network meta-analysis approach. METHODS PubMed, Embase, and Cochrane library were searched for randomized controlled trials (RCTs) of advanced HCC patients that treated with different targeted drugs. Time to progress (TTP), overall survival (OS) and progress-free survival (PFS) were calculated as hazard ratios (HRs). Objective response rate (ORR) and the proportion of Grade 3-5 adverse events (G3-5AE) were expressed as odds ratios (ORs). We pooled study-specific HRs and ORs using Bayesian network meta-analyses, and ranked first-line drugs by the surface under the cumulative ranking curve (SUCRA). RESULTS A total of 22 RCTs with 9288 patients were enrolled. Brivanib, linifanib, lenvatinib and sorafenib showed a significant improvement on TTP compared to placebo (HR range, 0.45-0.72). Sunitinib (HR = 1.99) and nintedanib (HR = 2.17) showed a significant decline on TTP compared to lenvatinib. Vandetanib (HR = 0.44) and sorafenib (HR = 0.73) showed a significant improvement on OS compared to placebo. There was no significant difference in PFS, ORR and G3-5AE across different drugs. According to cluster rank analysis, vandetanib was the drug with both more effective (OS) and more secure (G3-5AE) compared to Sor followed by nintedanib. CONCLUSIONS This network meta-analysis shows that vandetanib, linifanib, lenvatinib and nintedanib potentially may be the best substitution of sorafenib against advanced HCC as first-line targeted drugs. Vandetanib seems to be the best choise with low quality of evidence. For better survival, novel targeted treatment options for HCC are sorely needed.
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Affiliation(s)
- Wei Ding
- Department of General Surgery, Wujin Hospital Affiliated with Jiangsu University, Changzhou, China
- The Wujin Clinical College of Xuzhou Medical University, Changzhou, China
| | - Yulin Tan
- Department of General Surgery, Wujin Hospital Affiliated with Jiangsu University, Changzhou, China
- The Wujin Clinical College of Xuzhou Medical University, Changzhou, China
| | - Yan Qian
- Department of Respiration, Changzhou Second People’s Hospital Affiliated to Nanjing Medical University, Changzhou, China
| | - Wenbo Xue
- Department of General Surgery, Wujin Hospital Affiliated with Jiangsu University, Changzhou, China
- The Wujin Clinical College of Xuzhou Medical University, Changzhou, China
| | - Yibo Wang
- Department of General Surgery, Wujin Hospital Affiliated with Jiangsu University, Changzhou, China
- The Wujin Clinical College of Xuzhou Medical University, Changzhou, China
| | - Peng Jiang
- Department of General Surgery, Wujin Hospital Affiliated with Jiangsu University, Changzhou, China
- The Wujin Clinical College of Xuzhou Medical University, Changzhou, China
| | - Xuezhong Xu
- Department of General Surgery, Wujin Hospital Affiliated with Jiangsu University, Changzhou, China
- The Wujin Clinical College of Xuzhou Medical University, Changzhou, China
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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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Sayan M, Yegya-Raman N, Greco SH, Gui B, Zhang A, Chundury A, Grandhi MS, Hochster HS, Kennedy TJ, Langan RC, Malhotra U, Rustgi VK, Shah MM, Spencer KR, Carpizo DR, Nosher JL, Jabbour SK. Rethinking the Role of Radiation Therapy in the Treatment of Unresectable Hepatocellular Carcinoma: A Data Driven Treatment Algorithm for Optimizing Outcomes. Front Oncol 2019; 9:345. [PMID: 31275846 PMCID: PMC6591511 DOI: 10.3389/fonc.2019.00345] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Accepted: 04/15/2019] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the second most common cause of cancer death worldwide, with a majority of HCC patients not suitable for curative therapies. Approximately 70% of initially diagnosed patients cannot undergo surgical resection or transplantation due to locally advanced disease, poor liver function/underlying cirrhosis, or additional comorbidities. Local therapeutic options for patients with unresectable HCC, who are not suitable for thermal ablation, include transarterial embolization (bland, chemoembolization, radioembolization) and/or external beam radiation therapy (EBRT). Regarding EBRT specifically, technological advancements provide a means for safe and effective radiotherapy delivery in a wide spectrum of HCC patients. In multiple prospective studies, EBRT delivery in a variety of different fractionation schemes or in combination with transcatheter arterial chemoembolization (TACE) demonstrate improved outcomes, particularly with combination therapy. The Barcelona Clinic Liver Cancer classification provides a framework for treatment selection; however, given the growing complexity of treatment strategies, this classification system tends to simplify decision-making. In this review, we discuss the current literature regarding unresectable HCC and propose a modified treatment algorithm that emphasizes the role of radiation therapy for Child-Pugh score A or B patients with ≤3 nodules measuring >3 cm, multinodular disease or portal venous thrombosis.
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Affiliation(s)
- Mutlay Sayan
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, United States
| | - Nikhil Yegya-Raman
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, United States
| | - Stephanie H. Greco
- Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, United States
| | - Bin Gui
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, United States
| | - Andrew Zhang
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, United States
| | - Anupama Chundury
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, United States
| | - Miral S. Grandhi
- Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, United States
| | - Howard S. Hochster
- Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ, United States
| | - Timothy J. Kennedy
- Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, United States
| | - Russell C. Langan
- Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, United States
| | - Usha Malhotra
- Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ, United States
| | - Vinod K. Rustgi
- Division of Gastroenterology and Hepatology, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, United States
| | - Mihir M. Shah
- Division of Surgical Oncology, Department of Surgery, Emory University School of Medicine, Atlanta, GA, United States
| | - Kristen R. Spencer
- Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ, United States
| | - Darren R. Carpizo
- Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, United States
| | - John L. Nosher
- Department of Radiology, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, United States
| | - Salma K. Jabbour
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, United States
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Peng Z, Chen S, Xiao H, Wang Y, Li J, Mei J, Chen Z, Zhou Q, Feng S, Chen M, Qian G, Peng S, Kuang M. Microvascular Invasion as a Predictor of Response to Treatment with Sorafenib and Transarterial Chemoembolization for Recurrent Intermediate-Stage Hepatocellular Carcinoma. Radiology 2019; 292:237-247. [PMID: 31135299 DOI: 10.1148/radiol.2019181818] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Background The evidence of combining sorafenib with transarterial chemoembolization (TACE) for intermediate-stage recurrent hepatocellular carcinoma (HCC) is limited. Patient responses to this treatment varied because of the heterogeneous nature of intermediate-stage recurrent HCC, making it important to identify patients who are most likely to benefit from this combination therapy. Purpose To compare sorafenib administered in combination with TACE versus TACE alone in the treatment of recurrent intermediate-stage HCC after initial hepatectomy and to determine the relationship of microvascular invasion (MVI) to survival. Materials and Methods In this retrospective multicenter study, 3652 consecutive patients were found to have intrahepatic recurrences after initial hepatectomy of primary HCC from January 2010 to December 2016. Of these, 260 patients with intermediate-stage recurrent HCC underwent combination treatment with sorafenib and TACE or TACE alone. Overall survival (OS) and progression-free survival (PFS) were compared between these two treatments according to MVI status by using log-rank tests. Results A total of 128 patients were administered combination therapy (mean age, 55 years ± 7.6 [standard deviation]; 107 men) and 132 patients were administered TACE alone (mean age, 56 years ± 8.3; 110 men). The 5-year OS and PFS were higher in the combination group than in the TACE group (OS: 38.9% vs 20.5%, respectively, P = .01; PFS, 37.5% vs 18.7%, respectively, P = .003). For patients with MVI-positive lesions, the median OS and PFS after combination treatment (n = 55) were longer than those after TACE alone (n = 72; OS: 17.2 months vs 12.1 months, respectively, P = .02; PFS: 17.0 months vs 11.0 months, respectively, P = .02). Multivariable analysis showed that tumor number, MVI status, and treatment allocation were significant predictors of OS and PFS, whereas tumor size was a prognostic factor for PFS. Conclusion Patients with recurrent intermediate-stage hepatocellular carcinoma and lesions positive for microvascular invasion (MVI) had longer survival times by using a combined treatment of sorafenib with transarterial chemoembolization (TACE) compared with TACE alone; patients with MVI-negative lesions did not show survival benefit from combined therapy. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Malloy in this issue.
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Affiliation(s)
- Zhenwei Peng
- From the Clinical Trials Unit (Z.P., J.M., Q.Z., S.P.), Department of Oncology (Z.P.), Division of Interventional Ultrasound (S.C., M.K.), Departments of Gastroenterology (H.X., S.P.), Interventional Oncology (Y.W., J.L.), Liver Surgery (Z.C., M.K.), and Radiology (S.F.), The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China; Department of Hepatobiliary Surgery, Cancer Centre of Sun Yat-sen University, Guangzhou, China (M.C.); and Department of Minimal Invasion Therapy, The Affiliated Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Guangzhou, China (G.Q.)
| | - Shuling Chen
- From the Clinical Trials Unit (Z.P., J.M., Q.Z., S.P.), Department of Oncology (Z.P.), Division of Interventional Ultrasound (S.C., M.K.), Departments of Gastroenterology (H.X., S.P.), Interventional Oncology (Y.W., J.L.), Liver Surgery (Z.C., M.K.), and Radiology (S.F.), The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China; Department of Hepatobiliary Surgery, Cancer Centre of Sun Yat-sen University, Guangzhou, China (M.C.); and Department of Minimal Invasion Therapy, The Affiliated Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Guangzhou, China (G.Q.)
| | - Han Xiao
- From the Clinical Trials Unit (Z.P., J.M., Q.Z., S.P.), Department of Oncology (Z.P.), Division of Interventional Ultrasound (S.C., M.K.), Departments of Gastroenterology (H.X., S.P.), Interventional Oncology (Y.W., J.L.), Liver Surgery (Z.C., M.K.), and Radiology (S.F.), The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China; Department of Hepatobiliary Surgery, Cancer Centre of Sun Yat-sen University, Guangzhou, China (M.C.); and Department of Minimal Invasion Therapy, The Affiliated Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Guangzhou, China (G.Q.)
| | - Yu Wang
- From the Clinical Trials Unit (Z.P., J.M., Q.Z., S.P.), Department of Oncology (Z.P.), Division of Interventional Ultrasound (S.C., M.K.), Departments of Gastroenterology (H.X., S.P.), Interventional Oncology (Y.W., J.L.), Liver Surgery (Z.C., M.K.), and Radiology (S.F.), The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China; Department of Hepatobiliary Surgery, Cancer Centre of Sun Yat-sen University, Guangzhou, China (M.C.); and Department of Minimal Invasion Therapy, The Affiliated Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Guangzhou, China (G.Q.)
| | - Jiaping Li
- From the Clinical Trials Unit (Z.P., J.M., Q.Z., S.P.), Department of Oncology (Z.P.), Division of Interventional Ultrasound (S.C., M.K.), Departments of Gastroenterology (H.X., S.P.), Interventional Oncology (Y.W., J.L.), Liver Surgery (Z.C., M.K.), and Radiology (S.F.), The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China; Department of Hepatobiliary Surgery, Cancer Centre of Sun Yat-sen University, Guangzhou, China (M.C.); and Department of Minimal Invasion Therapy, The Affiliated Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Guangzhou, China (G.Q.)
| | - Jie Mei
- From the Clinical Trials Unit (Z.P., J.M., Q.Z., S.P.), Department of Oncology (Z.P.), Division of Interventional Ultrasound (S.C., M.K.), Departments of Gastroenterology (H.X., S.P.), Interventional Oncology (Y.W., J.L.), Liver Surgery (Z.C., M.K.), and Radiology (S.F.), The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China; Department of Hepatobiliary Surgery, Cancer Centre of Sun Yat-sen University, Guangzhou, China (M.C.); and Department of Minimal Invasion Therapy, The Affiliated Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Guangzhou, China (G.Q.)
| | - Zebin Chen
- From the Clinical Trials Unit (Z.P., J.M., Q.Z., S.P.), Department of Oncology (Z.P.), Division of Interventional Ultrasound (S.C., M.K.), Departments of Gastroenterology (H.X., S.P.), Interventional Oncology (Y.W., J.L.), Liver Surgery (Z.C., M.K.), and Radiology (S.F.), The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China; Department of Hepatobiliary Surgery, Cancer Centre of Sun Yat-sen University, Guangzhou, China (M.C.); and Department of Minimal Invasion Therapy, The Affiliated Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Guangzhou, China (G.Q.)
| | - Qian Zhou
- From the Clinical Trials Unit (Z.P., J.M., Q.Z., S.P.), Department of Oncology (Z.P.), Division of Interventional Ultrasound (S.C., M.K.), Departments of Gastroenterology (H.X., S.P.), Interventional Oncology (Y.W., J.L.), Liver Surgery (Z.C., M.K.), and Radiology (S.F.), The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China; Department of Hepatobiliary Surgery, Cancer Centre of Sun Yat-sen University, Guangzhou, China (M.C.); and Department of Minimal Invasion Therapy, The Affiliated Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Guangzhou, China (G.Q.)
| | - Shiting Feng
- From the Clinical Trials Unit (Z.P., J.M., Q.Z., S.P.), Department of Oncology (Z.P.), Division of Interventional Ultrasound (S.C., M.K.), Departments of Gastroenterology (H.X., S.P.), Interventional Oncology (Y.W., J.L.), Liver Surgery (Z.C., M.K.), and Radiology (S.F.), The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China; Department of Hepatobiliary Surgery, Cancer Centre of Sun Yat-sen University, Guangzhou, China (M.C.); and Department of Minimal Invasion Therapy, The Affiliated Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Guangzhou, China (G.Q.)
| | - Minshan Chen
- From the Clinical Trials Unit (Z.P., J.M., Q.Z., S.P.), Department of Oncology (Z.P.), Division of Interventional Ultrasound (S.C., M.K.), Departments of Gastroenterology (H.X., S.P.), Interventional Oncology (Y.W., J.L.), Liver Surgery (Z.C., M.K.), and Radiology (S.F.), The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China; Department of Hepatobiliary Surgery, Cancer Centre of Sun Yat-sen University, Guangzhou, China (M.C.); and Department of Minimal Invasion Therapy, The Affiliated Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Guangzhou, China (G.Q.)
| | - Guojun Qian
- From the Clinical Trials Unit (Z.P., J.M., Q.Z., S.P.), Department of Oncology (Z.P.), Division of Interventional Ultrasound (S.C., M.K.), Departments of Gastroenterology (H.X., S.P.), Interventional Oncology (Y.W., J.L.), Liver Surgery (Z.C., M.K.), and Radiology (S.F.), The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China; Department of Hepatobiliary Surgery, Cancer Centre of Sun Yat-sen University, Guangzhou, China (M.C.); and Department of Minimal Invasion Therapy, The Affiliated Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Guangzhou, China (G.Q.)
| | - Sui Peng
- From the Clinical Trials Unit (Z.P., J.M., Q.Z., S.P.), Department of Oncology (Z.P.), Division of Interventional Ultrasound (S.C., M.K.), Departments of Gastroenterology (H.X., S.P.), Interventional Oncology (Y.W., J.L.), Liver Surgery (Z.C., M.K.), and Radiology (S.F.), The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China; Department of Hepatobiliary Surgery, Cancer Centre of Sun Yat-sen University, Guangzhou, China (M.C.); and Department of Minimal Invasion Therapy, The Affiliated Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Guangzhou, China (G.Q.)
| | - Ming Kuang
- From the Clinical Trials Unit (Z.P., J.M., Q.Z., S.P.), Department of Oncology (Z.P.), Division of Interventional Ultrasound (S.C., M.K.), Departments of Gastroenterology (H.X., S.P.), Interventional Oncology (Y.W., J.L.), Liver Surgery (Z.C., M.K.), and Radiology (S.F.), The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China; Department of Hepatobiliary Surgery, Cancer Centre of Sun Yat-sen University, Guangzhou, China (M.C.); and Department of Minimal Invasion Therapy, The Affiliated Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Guangzhou, China (G.Q.)
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Tajiri K, Futsukaichi Y, Kobayashi S, Nagata K, Yasumura S, Takahara T, Minemura M, Yasuda I. Efficacy of on-demand intrahepatic arterial therapy in combination with sorafenib for advanced hepatocellular carcinoma. Onco Targets Ther 2019; 12:2205-2214. [PMID: 30988625 PMCID: PMC6441463 DOI: 10.2147/ott.s191741] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
PURPOSE The purpose of this study was to evaluate the effectiveness and tolerability of "on-demand" combination therapy with sorafenib and hepatic arterial treatments, such as transarterial chemoembolization and hepatic arterial infusion chemotherapy, in patients with hepatocellular carcinoma (HCC). PATIENTS AND METHODS Eighty consecutive patients with advanced HCC, 58 administered sorafenib monotherapy and 22 administered on-demand combination therapy, were retrospectively evaluated. RESULTS The disease control rate was significantly higher in the combination group than in the monotherapy group (86.3% vs 51.7%, p=0.01). Elevated alanine aminotransferase levels were significantly more frequent in the combination group (40.9% vs 12.1%, p=0.01), but it was tolerable. Progression-free survival (180 vs 45 days, p=0.045) and overall survival (983 vs 452 days, p=0.004) were significantly longer in the combination group, as was the duration of sorafenib treatment (367 vs 66 days, p<0.001). Multivariate analysis showed that hepatitis C virus infection, disease control, and combination therapy were positive independent prognostic factors for survival, whereas alpha-fetoprotein >400 ng/mL was negatively prognostic. In patients receiving combination therapy, male sex, hepatitis B virus infection, performance status deterioration, Barcelona clinic liver cancer-B, and major vascular invasion were prognostic of survival. CONCLUSION On-demand combination therapy was tolerated and may be a therapeutic option for patients with advanced HCC.
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Affiliation(s)
- Kazuto Tajiri
- Department of Gastroenterology, Toyama University Hospital, Toyama, Japan,
| | - Yuka Futsukaichi
- Department of Gastroenterology, Toyama University Hospital, Toyama, Japan,
| | - Saito Kobayashi
- Department of Gastroenterology, Toyama University Hospital, Toyama, Japan,
| | - Kohei Nagata
- Department of Gastroenterology, Toyama University Hospital, Toyama, Japan,
| | - Satoshi Yasumura
- Department of Gastroenterology, Toyama University Hospital, Toyama, Japan,
| | - Terumi Takahara
- Department of Gastroenterology, Toyama University Hospital, Toyama, Japan,
| | - Masami Minemura
- Department of Gastroenterology, Toyama University Hospital, Toyama, Japan,
| | - Ichiro Yasuda
- Department of Gastroenterology, Toyama University Hospital, Toyama, Japan,
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Jin PP, Shao SY, Wu WT, Zhao XY, Huang BF, Fu QH, Que RS, Hu QD. Combination of transarterial chemoembolization and sorafenib improves outcomes of unresectable hepatocellular carcinoma: an updated systematic review and meta-analysis. Jpn J Clin Oncol 2018; 48:1058-1069. [PMID: 30272196 DOI: 10.1093/jjco/hyy138] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Accepted: 09/18/2018] [Indexed: 12/28/2022] Open
Affiliation(s)
- Piao-Piao Jin
- Department of Gastroenterology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Shi-Yi Shao
- Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Wang-Teng Wu
- Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xin-Yu Zhao
- Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Bing-Feng Huang
- Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qi-Han Fu
- Department of Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Ri-Sheng Que
- Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qi-Da Hu
- Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Li L, Zhao W, Wang M, Hu J, Wang E, Zhao Y, Liu L. Transarterial chemoembolization plus sorafenib for the management of unresectable hepatocellular carcinoma: a systematic review and meta-analysis. BMC Gastroenterol 2018; 18:138. [PMID: 30180810 PMCID: PMC6124009 DOI: 10.1186/s12876-018-0849-0] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2017] [Accepted: 07/23/2018] [Indexed: 12/22/2022] Open
Abstract
Background Transarterial chemoembolization (TACE) is the recommended treatment for hepatocellular carcinoma (HCC) patients at Barcelona Clinic Liver Cancer (BCLC) B-stage, whereas sorafenib is an orally administered small molecule target drug for BCLC C-stage. This updated systemic review and meta-analysis focuses on identifying the efficacy of the combination of TACE with sorafenib, which remains controversial despite years of exploration. Methods PubMed, EMBASE, Scopus and the Cochrane Library were systematically reviewed to search for studies published from January 1990 to May 2017. Studies focusing on the efficacy of combination therapy for unresectable HCC were eligible. The hazard ratio (HR) with 95% confidence intervals (95% CIs) for time to progression (TTP), overall survival (OS), disease control rate (DCR) and aetiology were collected. The data were then analysed through fixed/random effects meta-analysis models with STATA 13.0. The incidence and severity of treatment-related adverse events (AEs) were also evaluated. Results Twenty-seven studies were included. Thirteen non-comparative studies reported median OS (ranging from 18.5 to 20.4 months), median TTP (ranging from 7 to 13.9 months) and DCR (ranging from 18.4 to 95%). Fourteen comparative studies provided median OS (ranging from 7.0 to 29.7 months) and median TTP (ranging from 2.6 to 10.2 months). Five comparative studies provided DCR (ranging from 32 to 97.2%). Forest plots showed that combination therapy significantly improved TTP (HR = 0.66, 95% CI 0.50–0.81, P = 0.002) rather than OS (HR = 0.63, 95% CI 0.55–0.71, P = 0.058), compared to TACE alone. DCR increased significantly in the combination therapy group (OR = 2.93, 95% CI 1.59–5.41, P = 0.005). Additional forest plots were drawn and no significant differences were observed with regard to survival outcome among various aetiologies. Forest plots for separate analysis of regions showed the HR for TTP was 0.62 (95% CI 0.45–0.79, P = 0.002) in the Asian countries group, and 0.82 (95% CI 0.59–1.05, P = 0.504)) in western countries. The HR for OS was 0.61 (95% CI 0.48–0.75, P = 0.050) in the Asian countries group and was 0.88 (95% CI 0.56–1.20, P = 0.845) in western countries. These data may indicate positive TTP outcome in Asian patients but not in European patients while no positive findings regarding OS were observed in either region. The most common AEs included fatigue, hand-foot skin reaction, diarrhoea and hypertension. Conclusions Combination therapy may benefit unresectable HCC patients in terms of prolonged TTP and DCR. More well-designed studies are needed to investigate its superiority for OS. Electronic supplementary material The online version of this article (10.1186/s12876-018-0849-0) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Lin Li
- Department of Gastroenterology, Tangdu Hospital, Military Medical University of PLA Airforce (Fourth Military Medical University), 1 Xinsi Road, Xi'an, 710038, China
| | - Wenzhuo Zhao
- Department of Gastroenterology, Tangdu Hospital, Military Medical University of PLA Airforce (Fourth Military Medical University), 1 Xinsi Road, Xi'an, 710038, China
| | - Mengmeng Wang
- Department of Drug and Equipment, Aeromedicine Identification and Training Centre of Air Force, Lintong District, Xi'an, China
| | - Jie Hu
- Department of Liver Disease and Digestive Interventional Radiology, Xijing Hospital of Digestive Diseases, Military Medical University of PLA Airforce (Fourth Military Medical University), Xi'an, China
| | - Enxin Wang
- Department of Liver Disease and Digestive Interventional Radiology, Xijing Hospital of Digestive Diseases, Military Medical University of PLA Airforce (Fourth Military Medical University), Xi'an, China
| | - Yan Zhao
- Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, 710061, China.
| | - Lei Liu
- Department of Gastroenterology, Tangdu Hospital, Military Medical University of PLA Airforce (Fourth Military Medical University), 1 Xinsi Road, Xi'an, 710038, China. .,Cell Engineering Research Center and Department of Cell Biology, State Key Laboratory of Cancer Biology, Military Medical University of PLA Airforce), Xi'an, China.
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Feng F, Jiang Q, Jia H, Sun H, Chai Y, Li X, Rong G, Zhang Y, Li Z. Which is the best combination of TACE and Sorafenib for advanced hepatocellular carcinoma treatment? A systematic review and network meta-analysis. Pharmacol Res 2018; 135:89-101. [PMID: 29959032 DOI: 10.1016/j.phrs.2018.06.021] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Revised: 06/13/2018] [Accepted: 06/20/2018] [Indexed: 02/06/2023]
Abstract
The aim of this study was to assess the comparative efficacy and safety of combination therapy with transarterial chemoembolization (TACE) and Sorafenib for patients with advanced hepatocellular carcinoma (HCC) through a systematic review and network meta-analysis and identify the best combination of TACE and Sorafenib. We searched databases for publications prior to May 2018. The prespecified efficacy outcomes were the objective response rate, overall survival rate, and time to progression. adverse effects included dermatologic, gastrointestinal, and general disorders. Subgroup analyses, meta-regression, and a network meta-analysis regarding two types of outcomes by different chemotherapy agents in TACE (5-fluorouracil, Adriamycin, Platinum, mitomycin C, hydroxycamptothecin) were included. The study is registered with PROSPERO (CRD42018098541). For efficacy outcomes, subgroups which included 5-fluorouracil and hydroxycamptothecin ranked higher than other chemotherapy agents, while mitomycin C ranked the lowest. For advanced effects, the use of mitomycin C or 5-fluorouracil as the chemotherapy agent ranked higher, while hydroxycamptothecin ranked the lowest. Therefore, we excluded 5-Fu and Mitomycin C in subsequent studies. Additionally, in the evaluation of primary adverse effects by the network meta-analysis, Platinum ranked the highest while hydroxycamptothecin ranked the lowest. Therefore, we excluded Platinum this time. Furthermore, all types of Adriamycin are not same, and some studies included two types of Adriamycin. The network meta-analysis results showed that the TACE (hydroxycamptothecin + pirarubicin) +Sorafenib arm and TACE (hydroxycamptothecin + epirubicin) +Sorafenib arm had significant efficacy differences. In conclusion, for patients with advanced HCC, combination therapy with HCPT plus THP/EPI in TACE and Sorfenib may be used as a first-line treatment.
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Affiliation(s)
- Fan Feng
- School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, P.R. China
| | - Qiyu Jiang
- Research Center for Clinical and Translational Medicine, 302 Military Hospital of China, Beijing 100039, P.R. China
| | - Hui Jia
- The Comprehensive Liver Cancer Center, 302 Military Hospital of China, Beijing 100039, P.R. China
| | - Huiwei Sun
- Research Center for Clinical and Translational Medicine, 302 Military Hospital of China, Beijing 100039, P.R. China
| | - Yantao Chai
- Research Center for Clinical and Translational Medicine, 302 Military Hospital of China, Beijing 100039, P.R. China
| | - Xiaojuan Li
- Research Center for Clinical and Translational Medicine, 302 Military Hospital of China, Beijing 100039, P.R. China
| | - Guanghua Rong
- The Comprehensive Liver Cancer Center, 302 Military Hospital of China, Beijing 100039, P.R. China.
| | - Yingshi Zhang
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, P.R. China.
| | - Zhengping Li
- School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, P.R. China.
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Lei XF, Ke Y, Bao TH, Tang HR, Wu XS, Shi ZT, Lin J, Zhang ZX, Gu H, Wang L. Effect and safety of sorafenib in patients with intermediate hepatocellular carcinoma who received transarterial chemoembolization: A retrospective comparative study. World J Clin Cases 2018; 6:74-83. [PMID: 29774219 PMCID: PMC5955731 DOI: 10.12998/wjcc.v6.i5.74] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2018] [Revised: 03/04/2018] [Accepted: 03/20/2018] [Indexed: 02/05/2023] Open
Abstract
AIM To evaluate the safety and efficacy of sorafenib plus transarterial chemoembolization (TACE) treatment for intermediate hepatocellular carcinoma (HCC).
METHODS Sixty-seven patients with intermediate-stage [Barcelona Clinic liver cancer stage B (BCLC-B)] HCC who were treated with sorafenib plus TACE or TACE alone between 2009 and 2011 were included in the study. Follow-up was until 2014 or patient death. Two groups were defined in the experiment: The experimental group, treated with sorafenib plus TACE, and the control group, treated with standard TACE alone.
RESULTS The Kaplan-Meier survival analysis showed that the median overall survival (mOS) of the experimental group was 35.2 mo, while that of the control group was 22.0 mo (P < 0.05). Sorafenib plus TACE showed higher incidence rates of rash, hand-foot syndrome (HFS), and hypertension (P < 0.05) than TACE treatment alone.
CONCLUSION Sorafenib plus TACE treatment for BCLC-B HCC significantly prolonged the mOS of patients compared to TACE treatment alone. The most common toxicities with sorafenib were rash (31.6%), HFS (39.5%) and hypertension (31.6%), but there were no intolerable adverse events. The Cox multivariate analysis showed that the survival of patients with BCLC-B HCC depended on the Child-Pugh classification, tumor diameter, and treatment with sorafenib plus TACE compared to TACE alone.
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Affiliation(s)
- Xue-Fen Lei
- Department of Medical Oncology, The Second Affiliated Hospital of Kunming Medical University, Kunming 650101, Yunnan Province, China
| | - Yang Ke
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming 650101, Yunnan Province, China
| | - Tian-Hao Bao
- The Mental Health Center of Kunming Medical University, Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming 650101, Yunnan Province, China
| | - Hao-Ran Tang
- Department of Gastroenterological Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming 650101, Yunnan Province, China
| | - Xue-Song Wu
- Department of Gastroenterological Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming 650101, Yunnan Province, China
| | - Zhi-Tian Shi
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University; Kunming 650101, Yunnan Province, China
| | - Jie Lin
- Department of Medical Oncology, The Second Affiliated Hospital of Kunming Medical University, Kunming 650101, Yunnan Province, China
| | - Zhi-Xian Zhang
- Department of Medical Oncology, The Second Affiliated Hospital of Kunming Medical University, Kunming 650101, Yunnan Province, China
| | - Hou Gu
- Department of Medical Oncology, The Second Affiliated Hospital of Kunming Medical University, Kunming 650101, Yunnan Province, China
| | - Lin Wang
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University; Kunming 650101, Yunnan Province, China
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Ha Y, Lee D, Shim JH, Lim YS, Lee HC, Chung YH, Lee YS, Park SR, Ryu MH, Ryoo BY, Kang YK, Kim KM. Role of transarterial chemoembolization in relation with sorafenib for patients with advanced hepatocellular carcinoma. Oncotarget 2018; 7:74303-74313. [PMID: 27494871 PMCID: PMC5342054 DOI: 10.18632/oncotarget.11030] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2016] [Accepted: 07/19/2016] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND Although sorafenib is considered standard therapy for advanced hepatocellular carcinoma (HCC), actual treatments vary. We evaluated the effects of different treatment strategies on overall survival. METHODS A retrospective study of sorafenib-treated patients with advanced HCC was conducted. The primary outcome was overall survival. Prognostic factors were analyzed using multivariate Cox-proportional hazards model. RESULTS A total of 658 patients (mean age, 54.5 years; 83.3% male) were analyzed; 293, 129, and 236 patients were treated with sorafenib, a combination therapy of sorafenib and transarterial chemoembolization (TACE), and TACE followed by sorafenib, respectively. Overall, 51.2% of patients treated under the combination strategy had portal vein invasion, whereas 89.9% of patients receiving sorafenib monotherapy had distant metastasis. Median overall survival durations were comparable (11.8 months for sorafenib, 16.2 months for the combination therapy, and 13.5 months for TACE followed by sorafenib; P = 0.13). However, among portal vein invasion cases, combination (25.7 months, P = 0.002) and TACE followed by sorafenib (14.0 months, P = 0.030) treatments were associated with longer overall survival duration compared with than sorafenib monotherapy (5.5 months). In a multivariate model, sorafenib duration (hazard ratio [HR], 0.96, P < 0.001) and TACE (HR, 0.24, P < 0.001) along with Child-Pugh stage (HR, 1.83, P = 0.005) were associated with better survival. CONCLUSIONS In patients with portal vein invasion, TACE performed concurrently with or before sorafenib administration is associated with better survival.
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Affiliation(s)
- Yeonjung Ha
- Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Republic of Korea.,Department of Gastroenterology, CHA Bundang Medical Center, CHA University, Republic of Korea
| | - Danbi Lee
- Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Republic of Korea
| | - Ju Hyun Shim
- Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Republic of Korea
| | - Young-Suk Lim
- Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Republic of Korea
| | - Han Chu Lee
- Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Republic of Korea
| | - Young-Hwa Chung
- Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Republic of Korea
| | - Yung Sang Lee
- Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Republic of Korea
| | - Sook Ryun Park
- Department of Oncology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Republic of Korea
| | - Min-Hee Ryu
- Department of Oncology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Republic of Korea
| | - Baek-Yeol Ryoo
- Department of Oncology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Republic of Korea
| | - Yoon-Koo Kang
- Department of Oncology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Republic of Korea
| | - Kang Mo Kim
- Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Republic of Korea
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Ye SL, Yang J, Bie P, Zhang S, Chen X, Liu F, Liu L, Zhou J, Dou K, Hao C, Shao G, Xia Q, Chen Y, Yang J, Deng X, Liu Y, Yuan Y, Fu Z, Nakajima K, Lv Z. Safety assessment of sorafenib in Chinese patients with unresectable hepatocellular carcinoma: subgroup analysis of the GIDEON study. BMC Cancer 2018; 18:247. [PMID: 29499662 PMCID: PMC5834849 DOI: 10.1186/s12885-018-4144-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2016] [Accepted: 02/19/2018] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND This study aimed to investigate the safety of sorafenib for the treatment of unresectable hepatocellular carcinoma in Chinese patients. METHODS A subgroup of 345 Chinese patients from the international database of the Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib (GIDEON) study was included in this analysis. Safety assessment measures were adverse events (AEs) and serious adverse events (SAEs) graded using the National Cancer Institute Common Terminology Criteria version 3.0. RESULTS Of 331 evaluable patients, 98% started sorafenib at 800 mg/day. The median treatment duration was 22 weeks (range, 0.1-116 weeks), and median overall survival (OS) was 322 days (10.7 months). Approximately 50% of patients had at least one adverse event, and 6% had grade 3-4 adverse events. Drug-related adverse events were experienced by 29% of patients, and 3.6% had grade 3-4 drug-related adverse events. Overall, 23% of patients (n = 77) experienced serious adverse events, among which only 1 event was drug-related (0.3%). No differences in overall adverse events, serious adverse events, and deaths were observed between Child-Pugh A and Child-Pugh B patients. The most frequent drug-related adverse events were dermatological/skin (24%), hand-foot skin reaction (20%), gastrointestinal (11%), and diarrhea (11%). The majority of adverse events occurred within 30 days of beginning sorafenib. CONCLUSION Sorafenib has satisfactory efficacy and safety in Chinese Child-Pugh A and B patients with unresectable HCC using the recommended dosage of 800 mg/day, and the safety of sorafenib is not affected by liver function. Prophylaxis for gastrointestinal adverse events may help to decrease dose interruptions or discontinuation. TRIAL REGISTRATION ClinicalTrials.gov ; Identifier: NCT00812175. Date of registration: December 19, 2008.
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Affiliation(s)
- Sheng-Long Ye
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yixueyuan Rd, Shanghai, 200032, China.
| | - Jiamei Yang
- Department of Special Treatment, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Ping Bie
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Shuijun Zhang
- Department of General Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiaoping Chen
- Department of Surgery, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Fengyong Liu
- Department of Interventional Radiology, Chinese PLA General Hospital, Beijing, China
| | - Luming Liu
- Shanghai Cancer Center, Fudan University, Shanghai, China
| | - Jie Zhou
- Department of Hepatobiliary Surgery, Nanfang Hospital of Southern Medical University, Guangzhou, China
| | - Kefeng Dou
- Department of Hepatobiliary Surgery, Xijing Hospital, Xi'an, China
| | - Chunyi Hao
- Department of Hepato-Pancreato-Biliary Surgery, Beijing Cancer Hospital, Peking University, Beijing, China
| | - Guoliang Shao
- Department of Radiology, Zhejiang Cancer Hospital, Hangzhou, China
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yajin Chen
- Department of Hepatobiliary Surgery, Second Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Jijin Yang
- Department of Nuclear Medicine, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Xiaxing Deng
- Department of General Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yunpeng Liu
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, China
| | - Yunfei Yuan
- Department of Hepatobiliary, Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Zhiren Fu
- Department of Liver Transplantation, Shanghai Changzheng Hospital, Shanghai, China
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Rognoni C, Ciani O, Sommariva S, Tarricone R. Cost–effectiveness analysis of treatments involving radioembolization in intermediate-stage hepatocellular carcinoma. J Comp Eff Res 2018; 7:209-221. [DOI: 10.2217/cer-2017-0050] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Aim: We evaluated two treatment sequences, transarterial radioembolization followed by transarterial chemoembolization and possibly sorafenib (=TTS) versus transarterial radioembolization followed by sorafenib alone (=TS), to identify the most cost-effective pathway to treat intermediate-stage hepatocellular carcinoma from the Italian healthcare system perspective. Materials & methods: A Markov model was developed to project costs and health outcomes for TTS and TS over a lifetime horizon. Data available at three hospitals in Italy were collected. Healthcare resource utilization was derived from standard clinical protocols. Costs were obtained from official regional tariffs. Results & Conclusion: Taking into consideration 16 patients for TTS and 22 patients for TS pathways, the TTS sequence provided a dominant strategy in comparison to TS. Further evidence is desirable to confirm these results.
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Affiliation(s)
- Carla Rognoni
- Centre for Research on Health and Social Care Management (CERGAS), SDA Bocconi School of Management, Bocconi University, Via Roentgen 1, 20136, Milan, Italy
| | - Oriana Ciani
- Centre for Research on Health and Social Care Management (CERGAS), SDA Bocconi School of Management, Bocconi University, Via Roentgen 1, 20136, Milan, Italy
- Evidence Synthesis & Modelling for Health Improvement (ESMI), University of Exeter Medical School, South Cloisters, St Luke's Campus, Exeter, EX1 2LU, UK
| | - Silvia Sommariva
- Centre for Research on Health and Social Care Management (CERGAS), SDA Bocconi School of Management, Bocconi University, Via Roentgen 1, 20136, Milan, Italy
- Department of Community and Family Health, College of Public Health, University of South Florida, 3010 USF Banyan Circle Tampa, FL 33612, USA
| | - Rosanna Tarricone
- Centre for Research on Health and Social Care Management (CERGAS), SDA Bocconi School of Management, Bocconi University, Via Roentgen 1, 20136, Milan, Italy
- Department of Policy Analysis and Public Management, Bocconi University, Via Roentgen 1, 20136, Milan, Italy
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Kaplan DE, Mehta R, D'Addeo K, Gade TP, Taddei TH. Transarterial Chemoembolization within First 3 Months of Sorafenib Initiation Improves Overall Survival in Hepatocellular Carcinoma: A Retrospective, Multi-Institutional Study with Propensity Matching. J Vasc Interv Radiol 2018; 29:540-549.e4. [PMID: 29477619 DOI: 10.1016/j.jvir.2017.11.033] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Revised: 11/14/2017] [Accepted: 11/14/2017] [Indexed: 02/07/2023] Open
Abstract
PURPOSE The impact of transarterial chemoembolization after initiation of sorafenib (SOR) has not been prospectively compared with SOR alone in unresectable hepatocellular carcinoma (HCC). The objective of this study was to assess whether SOR + transarterial chemoembolization provides benefit over SOR alone in this setting. MATERIALS AND METHODS A retrospective cohort study with propensity matching using data from patients prescribed SOR for HCC at Veterans Health Administration hospitals from 2007 to 2015. The primary outcome was overall survival from the time of SOR prescription and stratified by receipt of transarterial chemoembolization within 90 days of SOR initiation. RESULTS A total of 4,896 patients received SOR for HCC, of whom 232 (4.7%) underwent transarterial chemoembolization within 90 days. Patients receiving transarterial chemoembolization + SOR were highly selected, being younger and with less significant hepatic dysfunction, earlier Barcelona Clinic Liver Cancer stage (P < .0001), and fewer tumors with lower rates of macrovascular invasion (MVI) and metastases (all P < .0001) than SOR-alone patients. In unadjusted analysis, SOR + transarterial chemoembolization was associated with reduced mortality (hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.53-0.71; P < .0001). After propensity matching, SOR + transarterial chemoembolization continued to show significant associations with reduced mortality with HR 0.75 (95% CI 0.62-0.92; P = .0005). Subgroup analysis suggests that the addition of transarterial chemoembolization to SOR improves outcomes in most patients, particularly those with Model for End-Stage Liver Disease score <15, platelets >50,000/μL, and >3 tumors with or without macrovascular invasion, without local invasion or metastases. CONCLUSIONS Patients with unresectable HCC started on systemic therapy with SOR appear to benefit from adjuvant transarterial chemoembolization. Optimal application of multimodal therapy in this setting should be prospectively investigated.
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Affiliation(s)
- David E Kaplan
- Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; Corporal Michael J. Crescenz VA Medical Center, 3900 Woodland Avenue, Bldg 21, Room A422, Philadelphia, PA 19014.
| | - Rajni Mehta
- Yale University School of Medicine, New Haven, Connecticut; VA Connecticut Healthcare System, West Haven, Connecticut
| | - Kathryn D'Addeo
- Yale University School of Medicine, New Haven, Connecticut; VA Connecticut Healthcare System, West Haven, Connecticut
| | - Terence P Gade
- Corporal Michael J. Crescenz VA Medical Center, 3900 Woodland Avenue, Bldg 21, Room A422, Philadelphia, PA 19014; Department of Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Tamar H Taddei
- Yale University School of Medicine, New Haven, Connecticut; VA Connecticut Healthcare System, West Haven, Connecticut
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Casadei Gardini A, Marisi G, Faloppi L, Scarpi E, Foschi FG, Iavarone M, Lauletta G, Corbelli J, Valgiusti M, Facchetti F, Della Corte C, Neri LM, Tamberi S, Cascinu S, Scartozzi M, Amadori D, Nanni O, Tenti E, Ulivi P, Frassineti GL. eNOS polymorphisms and clinical outcome in advanced HCC patients receiving sorafenib: final results of the ePHAS study. Oncotarget 2018; 7:27988-99. [PMID: 27058899 PMCID: PMC5053704 DOI: 10.18632/oncotarget.8569] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2016] [Accepted: 03/28/2016] [Indexed: 02/06/2023] Open
Abstract
Sorafenib may reduce endothelial nitric oxide synthase (eNOS) activity by inhibiting vascular endothelial growth factor receptors (VEGF-R), leading to a decrease in nitric oxide production. In the Italian multicenter ePHAS (eNOS polymorphisms in HCC and sorafenib) study, we analyzed the role of eNOS polymorphisms in relation to clinical outcome in patients with hepatocellular carcinoma (HCC) receiving sorafenib. Our retrospective study included a training cohort of 41 HCC patients and a validation cohort of 87 HCC patients, all undergoing sorafenib treatment. Three eNOS polymorphisms (eNOS -786T>C, eNOS VNTR 27bp 4a/b and eNOS+894G>T) were analyzed by direct sequencing or Real Time PCR in relation to progression-free survival (PFS) and overall survival (OS) (log-rank test). In univariate analysis, training cohort patients homozygous for eNOS haplotype (HT1:T-4b at eNOS-786/eNOS VNTR) had a lower median PFS (2.6 vs. 5.8 months, P < 0.0001) and OS (3.2 vs.14.6 months, P = 0.024) than those with other haplotypes. In the validation set, patients homozygous for HT1 had a lower median PFS (2.0 vs. 6.7 months, P < 0.0001) and OS (6.4 vs.18.0 months, P < 0.0001) than those with other haplotypes. Multivariate analysis confirmed this haplotype as the only independent prognostic factor. Our results suggest that haplotype HT1 in the eNOS gene may be capable of identifying a subset of HCC patients who are resistant to sorafenib.
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Affiliation(s)
- Andrea Casadei Gardini
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Giorgia Marisi
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Luca Faloppi
- Department of Medical Oncology, Azienda Ospedaliero Universitaria Ospedali Riuniti, Università Politecnica delle Marche, Ancona, Italy
| | - Emanuela Scarpi
- Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | | | - Massimo Iavarone
- A.M.&A. Migliavacca Center for Liver Disease, 1st Division of Gastroenterology, Fondazione IRCCS Ca' Granda Maggiore Hospital, University of Milan, Milan, Italy
| | - Gianfranco Lauletta
- Department of Biomedical Sciences and Human Oncology, Internal Medicine "G. Baccelli", University of Bari "A. Moro", Bari, Italy
| | - Jody Corbelli
- Department of Medical Oncology, Faenza Hospital, AUSL Romagna, Faenza, Italy
| | - Martina Valgiusti
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Floriana Facchetti
- A.M.&A. Migliavacca Center for Liver Disease, 1st Division of Gastroenterology, Fondazione IRCCS Ca' Granda Maggiore Hospital, University of Milan, Milan, Italy
| | - Cristina Della Corte
- A.M.&A. Migliavacca Center for Liver Disease, 1st Division of Gastroenterology, Fondazione IRCCS Ca' Granda Maggiore Hospital, University of Milan, Milan, Italy
| | - Luca Maria Neri
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Stefano Tamberi
- Department of Medical Oncology, Faenza Hospital, AUSL Romagna, Faenza, Italy
| | - Stefano Cascinu
- Department of Medical Oncology, Azienda Ospedaliero Universitaria Ospedali Riuniti, Università Politecnica delle Marche, Ancona, Italy
| | - Mario Scartozzi
- Department of Medical Oncology, University Hospital Cagliari, Cagliari, Italy
| | - Dino Amadori
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Oriana Nanni
- Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Elena Tenti
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Paola Ulivi
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Giovanni Luca Frassineti
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
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Prenner S, Kulik L. Hepatocellular Carcinoma. ZAKIM AND BOYER'S HEPATOLOGY 2018:668-692.e9. [DOI: 10.1016/b978-0-323-37591-7.00046-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Tovoli F, Negrini G, Benevento F, Faggiano C, Goio E, Granito A. Systemic treatments for hepatocellular carcinoma: challenges and future perspectives. Hepat Oncol 2018; 5:HEP01. [PMID: 30302192 PMCID: PMC6168042 DOI: 10.2217/hep-2017-0020] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Accepted: 01/16/2018] [Indexed: 02/07/2023] Open
Abstract
Sorafenib has been the only approved systemic treatment of hepatocellular carcinoma (HCC) for almost a decade. Recently, two new drugs showed positive results in two Phase III studies. The RESORCE trial identified regorafenib as a valid second-line treatment for patients progressing to sorafenib, the REFLECT trial showed that lenvatinib is noninferior to sorafenib as front-line treatment. Following these trials, the therapeutic scenario will be dominated by anti-VEGFR drugs, with three different molecules showing a proven anticancer activity. Some open problems still remain and different immunotherapy trials are underway, following promising preliminary results. In this review we analyze: the most recent advancements about patients treated with sorafenib; the results of RESORCE and REFLECT trials; and the ongoing Phase III clinical trials. Finally, we discuss how they could address the current problems and possibly reshape the future of the systemic treatments for HCC.
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Affiliation(s)
- Francesco Tovoli
- Department of Medical & Surgical Sciences, University of Bologna, S Orsola-Malpighi Hospital, Bologna, Italy
| | - Giulia Negrini
- Department of Medical & Surgical Sciences, University of Bologna, S Orsola-Malpighi Hospital, Bologna, Italy
| | - Francesca Benevento
- Department of Medical & Surgical Sciences, University of Bologna, S Orsola-Malpighi Hospital, Bologna, Italy
| | - Chiara Faggiano
- Department of Medical & Surgical Sciences, University of Bologna, S Orsola-Malpighi Hospital, Bologna, Italy
| | - Elisabetta Goio
- Department of Medical & Surgical Sciences, University of Bologna, S Orsola-Malpighi Hospital, Bologna, Italy
| | - Alessandro Granito
- Department of Medical & Surgical Sciences, University of Bologna, S Orsola-Malpighi Hospital, Bologna, Italy
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Abstract
Sorafenib (Nexavar®) is currently the only systemic agent approved for use in hepatocellular carcinoma (HCC). Its approval was based on the results of the pivotal SHARP and Sorafenib Asia-Pacific (AP) trials in Child-Pugh (CP) class A patients with advanced HCC, which showed significantly longer median overall survival (OS) and time to radiological progression (TTP) with sorafenib 400 mg twice daily than with placebo, with no significant between-group difference in the median time to symptomatic progression (TTSP). Subsequent results from real-world studies such as GIDEON also support the use of sorafenib in HCC, including in carefully selected CP class B patients, although the median OS achieved in these patients appears relatively short. Sorafenib has a well characterized tolerability and safety profile, with strategies available to prevent and manage adverse effects such as hand-foot skin reactions. In conclusion, sorafenib remains an important option for the treatment of HCC.
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Affiliation(s)
- Gillian M Keating
- Springer, Private Bag 65901, Mairangi Bay 0754, Auckland, New Zealand.
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Chan SL, Yeo W, Mo F, Chan AWH, Koh J, Li L, Hui EP, Chong CCN, Lai PBS, Mok TSK, Yu SCH. A phase 2 study of the efficacy and biomarker on the combination of transarterial chemoembolization and axitinib in the treatment of inoperable hepatocellular carcinoma. Cancer 2017; 123:3977-3985. [PMID: 28640364 DOI: 10.1002/cncr.30825] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Revised: 05/12/2017] [Accepted: 05/22/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND A surge of vascular endothelial growth factor (VEGF) after transarterial chemoembolization (TACE) may contribute to tumor progression. Axitinib is a potent antiangiogenic agent with main activity against VEGF receptors 1 to 3. To the authors' knowledge, its role in combination with TACE for the treatment of patients with inoperable hepatocellular carcinoma (HCC) is unclear. METHODS A phase 2 clinical trial (ClinicalTrials.gov identifier NCT01352728) was conducted to evaluate the combination treatment. Patients with inoperable HCC who were potential candidates for TACE initiated treatment with axitinib at a dose of 5 mg twice daily and were evaluated for the need for TACE every 8 weeks. Axitinib was withheld 24 hours before TACE, and resumed 24 hours afterward when fulfilling predefined criteria. Radiologic assessment was conducted every 8 weeks. The primary endpoint was the 2-year overall survival (OS) rate. RESULTS A total of 50 patients were recruited from March 2011 to April 2014. The mean age of the patients was 61.8 years, and 46 patients (92%) had hepatitis B infection. The Barcelona Clinic Liver Cancer stage B/C percentage was 76% (38 cases)/24% (12 cases). The 2-year OS rate was 43.7%, and the median OS was 18.8 months in the intention-to-treat population. Among the evaluable population (44 patients), 40.9% (18 patients) and 27.3% (12 patients) achieved complete and partial responses, respectively. Common grade 3 or above axitinib-related complications included hand-foot skin reaction (14%) and hypertension (24%). The presence of hypertension during treatment was found to be an independent prognosticator (hazard ratio, 0.563; P = .0073) suggestive of a contributory role of axitinib to efficacy. CONCLUSIONS The combination of axitinib and TACE was potentially efficacious for patients with inoperable HCC with a high radiologic response rate. Cancer 2017;123:3977-85. © 2017 American Cancer Society.
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Affiliation(s)
- Stephen L Chan
- State Key Laboratory of Oncology in South China, Hong Kong
- Sir YK Pao Center for Cancer, Department of Clinical Oncology, Hong Kong Cancer Institute and Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
| | - Winnie Yeo
- State Key Laboratory of Oncology in South China, Hong Kong
- Sir YK Pao Center for Cancer, Department of Clinical Oncology, Hong Kong Cancer Institute and Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong
| | - Frankie Mo
- State Key Laboratory of Oncology in South China, Hong Kong
- Sir YK Pao Center for Cancer, Department of Clinical Oncology, Hong Kong Cancer Institute and Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong
| | - Anthony W H Chan
- State Key Laboratory of Oncology in South China, Hong Kong
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong
| | - Jane Koh
- Sir YK Pao Center for Cancer, Department of Clinical Oncology, Hong Kong Cancer Institute and Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong
| | - Leung Li
- Sir YK Pao Center for Cancer, Department of Clinical Oncology, Hong Kong Cancer Institute and Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong
| | - Edwin P Hui
- State Key Laboratory of Oncology in South China, Hong Kong
- Sir YK Pao Center for Cancer, Department of Clinical Oncology, Hong Kong Cancer Institute and Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong
| | - Charing C N Chong
- Department of Surgery, The Chinese University of Hong Kong, Hong Kong
| | - Paul B S Lai
- Department of Surgery, The Chinese University of Hong Kong, Hong Kong
| | - Tony S K Mok
- State Key Laboratory of Oncology in South China, Hong Kong
- Sir YK Pao Center for Cancer, Department of Clinical Oncology, Hong Kong Cancer Institute and Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong
| | - Simon C H Yu
- Department of Imaging and Interventional Radiology, The Chinese University of Hong Kong, Hong Kong
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Zhao RC, Zhou J, Wei YG, Liu F, Chen KF, Li Q, Li B. Cost-effectiveness analysis of transcatheter arterial chemoembolization with or without sorafenib for the treatment of unresectable hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int 2017; 16:493-498. [PMID: 28992881 DOI: 10.1016/s1499-3872(17)60009-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Accepted: 01/25/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND Transcatheter arterial chemoembolization (TACE) and TACE in combination with sorafenib (TACE-sorafenib) have shown a significant survival benefit for the treatment of unresectable hepatocellular carcinoma (HCC). Adopting either as a first-line therapy carries major cost and resource implications. The objective of this study was to estimate the relative cost-effectiveness of TACE against TACE-sorafenib for unresectable HCC using a decision analytic model. METHODS A Markov cohort model was developed to compare TACE and TACE-sorafenib. Transition probabilities and utilities were obtained from systematic literature reviews, and costs were obtained from West China Hospital, Sichuan University, China. Survival benefits were reported in quality-adjusted life-years (QALYs). The incremental cost-effectiveness ratio (ICER) was calculated. Sensitive analysis was performed by varying potentially modifiable parameters of the model. RESULTS The base-case analysis showed that TACE cost $26 951 and yielded survival of 0.71 QALYs, and TACE-sorafenib cost $44 542 and yielded survival of 1.02 QALYs in the entire treatment. The ICER of TACE-sorafenib versus TACE was $56 745 per QALY gained, which was above threshold for cost-effectiveness in China. Sensitivity analysis revealed that the major driver of ICER was the cost post TACE-sorafenib therapy with stable state. CONCLUSION TACE is a more cost-effective strategy than TACE-sorafenib for the treatment of unresectable HCC.
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Affiliation(s)
- Rong-Ce Zhao
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jing Zhou
- Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yong-Gang Wei
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Fei Liu
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Ke-Fei Chen
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Qiu Li
- Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Bo Li
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu 610041, China.
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Zhuang L, Wen T, Xu M, Yang J, Wang W, Wu H, Zeng Y, Yan L, Wei Y, Li B. Sorafenib combined with hepatectomy in patients with intermediate-stage and advanced hepatocellular carcinoma. Arch Med Sci 2017; 13:1383-1393. [PMID: 29181069 PMCID: PMC5701699 DOI: 10.5114/aoms.2017.71066] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2015] [Accepted: 08/23/2016] [Indexed: 02/05/2023] Open
Abstract
INTRODUCTION Guidelines based on the Barcelona Clinic Liver Cancer (BCLC) classification system recommend that hepatic resection should be performed only in patients in BCLC stage A. Patients with stage B or stage C should receive palliative or no treatment. However, actual clinical practice varies, and a recent analysis of hepatocellular carcinoma (HCC) surgery outcomes in high volume surgical centers throughout the world concluded that hepatectomy can provide survival benefit for selected patients in all three BCLC stages. The aim of this study is to evaluate the efficacy and tolerability of adjuvant sorafenib after hepatic resection in patients with intermediate-stage and advanced HCC. MATERIAL AND METHODS In a retrospective case-control study involving 81 patients with intermediate/advanced HCC, 27 who received sorafenib 400 mg BID (median duration 7.33 months) following hepatic resection were compared with a matched group of 54 patients who received hepatic resection only. Overall survival (OS) and time to recurrence (TTR) were evaluated over a median follow-up time of 14.5 months. RESULTS The median OS was significantly longer in the surgery+sorafenib group than in the surgery-only group (18.6 vs. 11.9 months, respectively; p = 0.014). However, the median TTR did not differ significantly between the 2 groups (p = 0.291). CONCLUSIONS Sorafenib is effective as adjuvant therapy after liver resection in intermediate-stage and advanced HCC, and can be considered a viable treatment option following surgery in such patients.
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Affiliation(s)
- Lei Zhuang
- Department of Hepatic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Tianfu Wen
- Department of Hepatic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Mingqing Xu
- Department of Hepatic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Jiayin Yang
- Department of Hepatic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Wentao Wang
- Department of Hepatic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Hong Wu
- Department of Hepatic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Yong Zeng
- Department of Hepatic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Lvnan Yan
- Department of Hepatic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Yonggang Wei
- Department of Hepatic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Bo Li
- Department of Hepatic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
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Katsanos K, Kitrou P, Spiliopoulos S, Maroulis I, Petsas T, Karnabatidis D. Comparative effectiveness of different transarterial embolization therapies alone or in combination with local ablative or adjuvant systemic treatments for unresectable hepatocellular carcinoma: A network meta-analysis of randomized controlled trials. PLoS One 2017; 12:e0184597. [PMID: 28934265 PMCID: PMC5608206 DOI: 10.1371/journal.pone.0184597] [Citation(s) in RCA: 76] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2017] [Accepted: 08/26/2017] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The optimal transcatheter embolization strategy for patients with unresectable hepatocellular carcinoma (HCC) remains elusive. We conducted a systematic review and network meta-analysis (NMA) of different embolization options for unresectable HCC. METHODS Medical databases were searched for randomized controlled trials evaluating bland transarterial embolization (TAE), conventional TACE, drug-eluting bead chemoembolization (DEB-TACE), or transarterial radioembolization (TARE), either alone or combined with adjuvant chemotherapy, or local liver ablation, or external radiotherapy for unresectable HCC up to June 2017. Random effects Bayesian models with a binomial and normal likelihood were fitted (WinBUGS). Primary endpoint was patient survival expressed as hazard ratios (HR) and 95% credible intervals. An exponential model was used to fit patient survival curves. Safety and objective response were calculated as odds ratios (OR) and accompanying 95% credible intervals. Competing treatments were ranked with the SUCRA statistic. Heterogeneity-adjusted effective sample sizes were calculated to evaluate information size for each comparison. Quality of evidence (QoE) was assessed with the GRADE system adapted for NMA reports. All analyses complied with the ISPOR-AMCP-NCP Task Force Report for good practice in NMA. FINDINGS The network of evidence included 55 RCTs (12 direct comparisons) with 5,763 patients with preserved liver function and unresectable HCC (intermediate to advanced stage). All embolization strategies achieved a significant survival gain over control treatment (HR range, 0.42-0.76; very low-to-moderate QoE). However, TACE, DEB-TACE, TARE and adjuvant systemic agents did not confer any survival benefit over bland TAE alone (moderate QoE, except low in case of TARE). There was moderate QoE that TACE combined with external radiation or liver ablation achieved the best patient survival (SUCRA 86% and 96%, respectively). Estimated median survival was 13.9 months in control, 18.1 months in TACE, 20.6 months with DEB-TACE, 20.8 months with bland TAE, 30.1 months in TACE plus external radiotherapy, and 33.3 months in TACE plus liver ablation. TARE was the safest treatment (SUCRA 77%), however, all examined therapies were associated with a significantly higher risk of toxicity over control (OR range, 6.35 to 68.5). TACE, DEB-TACE, TARE and adjuvant systemic agents did not improve objective response over bland embolization alone (OR range, 0.85 to 1.65). There was clinical diversity among included randomized controlled trials, but statistical heterogeneity was low. CONCLUSIONS Chemo- and radio-embolization for unresectable hepatocellular carcinoma may improve tumour objective response and patient survival, but are not more effective than bland particle embolization. Chemoembolization combined with external radiotherapy or local liver ablation may significantly improve tumour response and patient survival rates over embolization monotherapies. Quality of evidence remains mostly low to moderate because of clinical diversity. SYSTEMATIC REVIEW REGISTRATION CRD42016035796 (http://www.crd.york.ac.uk/PROSPERO).
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Affiliation(s)
- Konstantinos Katsanos
- Department of Interventional Radiology, Patras University Hospital, School of Medicine, Rion, Greece
- Department of Interventional Radiology, Guy's and St. Thomas' Hospitals, NHS Foundation Trust, King's Health Partners, London, United Kingdom
| | - Panagiotis Kitrou
- Department of Interventional Radiology, Patras University Hospital, School of Medicine, Rion, Greece
| | - Stavros Spiliopoulos
- Department of Interventional Radiology, Attikon University Hospital, School of Medicine, Athens, Greece
| | - Ioannis Maroulis
- Department of Liver Surgery, Patras University Hospital, School of Medicine, Rion, Greece
| | - Theodore Petsas
- Department of Interventional Radiology, Patras University Hospital, School of Medicine, Rion, Greece
| | - Dimitris Karnabatidis
- Department of Interventional Radiology, Patras University Hospital, School of Medicine, Rion, Greece
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Ren Z, He S, Fan X, He F, Sang W, Bao Y, Ren W, Zhao J, Ji X, Wen H. Survival prediction model for postoperative hepatocellular carcinoma patients. Medicine (Baltimore) 2017; 96:e7902. [PMID: 28906371 PMCID: PMC5604640 DOI: 10.1097/md.0000000000007902] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
This study is to establish a predictive index (PI) model of 5-year survival rate for patients with hepatocellular carcinoma (HCC) after radical resection and to evaluate its prediction sensitivity, specificity, and accuracy.Patients underwent HCC surgical resection were enrolled and randomly divided into prediction model group (101 patients) and model evaluation group (100 patients). Cox regression model was used for univariate and multivariate survival analysis. A PI model was established based on multivariate analysis and receiver operating characteristic (ROC) curve was drawn accordingly. The area under ROC (AUROC) and PI cutoff value was identified.Multiple Cox regression analysis of prediction model group showed that neutrophil to lymphocyte ratio, histological grade, microvascular invasion, positive resection margin, number of tumor, and postoperative transcatheter arterial chemoembolization treatment were the independent predictors for the 5-year survival rate for HCC patients. The model was PI = 0.377 × NLR + 0.554 × HG + 0.927 × PRM + 0.778 × MVI + 0.740 × NT - 0.831 × transcatheter arterial chemoembolization (TACE). In the prediction model group, AUROC was 0.832 and the PI cutoff value was 3.38. The sensitivity, specificity, and accuracy were 78.0%, 80%, and 79.2%, respectively. In model evaluation group, AUROC was 0.822, and the PI cutoff value was well corresponded to the prediction model group with sensitivity, specificity, and accuracy of 85.0%, 83.3%, and 84.0%, respectively.The PI model can quantify the mortality risk of hepatitis B related HCC with high sensitivity, specificity, and accuracy.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Xuewen Ji
- Department of Laparoscopic Surgery of Liver
| | - Hao Wen
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, People's Republic of China
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Lee TY, Lin CC, Chen CY, Wang TE, Lo GH, Chang CS, Chao Y. Combination of transcatheter arterial chemoembolization and interrupted dosing sorafenib improves patient survival in early-intermediate stage hepatocellular carcinoma: A post hoc analysis of the START trial. Medicine (Baltimore) 2017; 96:e7655. [PMID: 28906355 PMCID: PMC5604624 DOI: 10.1097/md.0000000000007655] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND/OBJECTIVE The survival benefit of treatment for unresectable hepatocellular carcinoma (HCC) with transcatheter arterial chemoembolization (TACE) combined with sorafenib remains uncertain. We compared the survival of patients treated with TACE and sorafenib with that of patients treated with TACE alone. METHODS This was a post hoc analysis of the Study in Asia of the Combination of TACE with Sorafenib in Patients with HCC (START) trial. All patients who received TACE and interrupted dosing of sorafenib for early or intermediate-stage HCC in Taiwan from 2009 to 2010 were recruited into the TACE and sorafenib group. They were randomly matched 1:1 by age, sex, Child-Pugh score, tumor size, tumor number, and tumor stage with patients from Taichung Veterans General Hospital in Taiwan who received TACE alone and who fulfilled the selection criteria of the START trial during the same time period (control group). Patient survival [cumulative incidence and hazard ratio (HR)] of the 2 groups were analyzed and compared. RESULTS The baseline characteristics of the 36 patients in each group were similar. Tumor response rates were significantly better in the TACE and sorafenib group (P < .04). Overall survival of the TACE and sorafenib group was also significantly better than that of the control (TACE alone) group over the 2 years [78%, 95% confidence interval (95% CI) 64-91 vs 49, 95% CI 32-66; P = .012]. In the multivariate regression analysis, TACE and sorafenib was found to be independently associated with a decreased risk of mortality (HR 0.33, 95% CI 0.12-0.89; P = .015). Multivariate stratified analyses verified this association in each patient subgroup (all HR < 1.0). CONCLUSION With a high patient tolerance to an interrupted sorafenib dosing schedule, the combination of TACE with sorafenib was associated with improved overall survival in early-intermediate stage HCC when compared with treatment with TACE alone.
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Affiliation(s)
- Teng-Yu Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital
- Department of Medicine, Chung Shan Medical University, Taichung
| | - Chen-Chun Lin
- Division of Hepatology, Liver Research Unit, Department of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital–Chang Gung University, Linkou
| | - Chiung-Yu Chen
- National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan
| | | | - Gin-Ho Lo
- Department of Medical Research, E-Da Hospital, School of Medicine for International Students, I-Shou University, Kaohsiung
| | - Chi-Sen Chang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital
| | - Yee Chao
- Department of Oncology, Taipei Veterans General Hospital, National Yang-Ming University, Taipei, Taiwan
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Dendrimer-doxorubicin conjugates exhibit improved anticancer activity and reduce doxorubicin-induced cardiotoxicity in a murine hepatocellular carcinoma model. PLoS One 2017; 12:e0181944. [PMID: 28829785 PMCID: PMC5567696 DOI: 10.1371/journal.pone.0181944] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Accepted: 07/10/2017] [Indexed: 02/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the 2nd leading cause of cancer-related deaths every year globally. The most common form of treatment, hepatic arterial infusion (HAI), involves the direct injection of doxorubicin (DOX) into the hepatic artery. It is plagued with limited therapeutic efficacy and the occurrence of severe toxicities (e.g. cardiotoxicity). We aim to improve the therapeutic index of DOX delivered via HAI by loading the drug onto generation 5 (G5) poly(amidoamine) (PAMAM) dendrimers targeted to hepatic cancer cells via N-acetylgalactosamine (NAcGal) ligands. DOX is attached to the surface of G5 molecules via two different enzyme-sensitive linkages, L3 or L4, to achieve controllable drug release inside hepatic cancer cells. We previously reported on P1 and P2 particles that resulted from the combination of NAcGal-targeting with L3- or L4-DOX linkages, respectively, and showed controllable DOX release and toxicity towards hepatic cancer cells comparable to free DOX. In this study, we demonstrate that while the intratumoral delivery of free DOX (1 mg/kg) into HCC-bearing nod scid gamma (NSG) mice achieves a 2.5-fold inhibition of tumor growth compared to the saline group over 30 days, P1 and P2 particles delivered at the same DOX dosage achieve a 5.1- and 4.4-fold inhibition, respectively. Incubation of the particles with human induced pluripotent stem cell derived cardiomyocytes (hiPSC CMs) showed no effect on monolayer viability, apoptosis induction, or CM electrophysiology, contrary to the effect of free DOX. Moreover, magnetic resonance imaging revealed that P1- and P2-treated mice maintained cardiac function after intraperitoneal administration of DOX at 1 mg/kg for 21 days, unlike the free DOX group at an equivalent dosage, confirming that P1/P2 can avoid DOX-induced cardiotoxicity. Taken together, these results highlight the ability of P1/P2 particles to improve the therapeutic index of DOX and offer a replacement therapy for clinical HCC treatment.
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Ronald J, Nixon AB, Marin D, Gupta RT, Janas G, Chen W, Suhocki PV, Pabon-Ramos W, Sopko DR, Starr MD, Brady JC, Hurwitz HI, Kim CY. Pilot Evaluation of Angiogenesis Signaling Factor Response after Transcatheter Arterial Embolization for Hepatocellular Carcinoma. Radiology 2017; 285:311-318. [PMID: 28787261 DOI: 10.1148/radiol.2017162555] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Purpose To identify changes in a broad panel of circulating angiogenesis factors after bland transcatheter arterial embolization (TAE), a purely ischemic treatment for hepatocellular carcinoma (HCC). Materials and Methods This prospective HIPAA-compliant study was approved by the institutional review board. Informed written consent was obtained from all participants prior to entry into the study. Twenty-five patients (21 men; mean age, 61 years; range, 30-81 years) with Liver Imaging Reporting and Data System category 5 or biopsy-proven HCC and who were undergoing TAE were enrolled from October 15, 2014, through December 2, 2015. Nineteen plasma angiogenesis factors (angiopoietin 2; hepatocyte growth factor; platelet-derived growth factor AA and BB; placental growth factor; vascular endothelial growth factor A and D; vascular endothelial growth factor receptor 1, 2, and 3; osteopontin; transforming growth factor β1 and β2; thrombospondin 2; intercellular adhesion molecule 1; interleukin 6 [IL-6]; stromal cell-derived factor 1; tissue inhibitor of metalloproteinases 1; and vascular cell adhesion molecule 1 [VCAM-1]) were measured by using enzyme-linked immunosorbent assays at 1 day, 2 weeks, and 5 weeks after TAE and were compared with baseline levels by using paired Wilcoxon tests. Tumor response was assessed according to modified Response Evaluation Criteria in Solid Tumors (mRECIST). Angiogenesis factor levels were compared between responders and nonresponders by mRECIST criteria by using unpaired Wilcoxon tests. Results All procedures were technically successful with no complications. Fourteen angiogenesis factors showed statistically significant changes following TAE, but most changes were transient. IL-6 was upregulated only 1 day after the procedure, but showed the largest increases of any factor. Osteopontin and VCAM-1 demonstrated sustained upregulation at all time points following TAE. At 3-month follow-up imaging, 11 patients had responses to TAE (complete response, n = 6; partial response, n = 5) and 11 patients were nonresponders (stable disease, n = 9; progressive disease, n = 2). In nonresponders, the percent change in IL-6 on the day after TAE (P = .033) and the mean percent change in osteopontin after TAE (P = .024) were significantly greater compared with those of responders. Conclusion Multiple angiogenesis factors demonstrated significant upregulation after TAE. VCAM-1 and osteopontin demonstrated sustained upregulation, whereas the rest were transient. IL-6 and osteopontin correlated significantly with radiologic response after TAE. © RSNA, 2017.
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Affiliation(s)
- James Ronald
- From the Department of Radiology, Division of Vascular & Interventional Radiology (J.R., D.M., R.T.G., G.J., W.C., P.V.S., W.P.R., D.R.S., C.Y.K.), and Department of Medicine (A.B.N., M.D.S., J.C.B., H.I.H.), Duke University Medical Center, Box 3808 Duke University Medical Center, 2301 Erwin Road, Durham, NC 27710
| | - Andrew B Nixon
- From the Department of Radiology, Division of Vascular & Interventional Radiology (J.R., D.M., R.T.G., G.J., W.C., P.V.S., W.P.R., D.R.S., C.Y.K.), and Department of Medicine (A.B.N., M.D.S., J.C.B., H.I.H.), Duke University Medical Center, Box 3808 Duke University Medical Center, 2301 Erwin Road, Durham, NC 27710
| | - Daniele Marin
- From the Department of Radiology, Division of Vascular & Interventional Radiology (J.R., D.M., R.T.G., G.J., W.C., P.V.S., W.P.R., D.R.S., C.Y.K.), and Department of Medicine (A.B.N., M.D.S., J.C.B., H.I.H.), Duke University Medical Center, Box 3808 Duke University Medical Center, 2301 Erwin Road, Durham, NC 27710
| | - Rajan T Gupta
- From the Department of Radiology, Division of Vascular & Interventional Radiology (J.R., D.M., R.T.G., G.J., W.C., P.V.S., W.P.R., D.R.S., C.Y.K.), and Department of Medicine (A.B.N., M.D.S., J.C.B., H.I.H.), Duke University Medical Center, Box 3808 Duke University Medical Center, 2301 Erwin Road, Durham, NC 27710
| | - Gemini Janas
- From the Department of Radiology, Division of Vascular & Interventional Radiology (J.R., D.M., R.T.G., G.J., W.C., P.V.S., W.P.R., D.R.S., C.Y.K.), and Department of Medicine (A.B.N., M.D.S., J.C.B., H.I.H.), Duke University Medical Center, Box 3808 Duke University Medical Center, 2301 Erwin Road, Durham, NC 27710
| | - Willa Chen
- From the Department of Radiology, Division of Vascular & Interventional Radiology (J.R., D.M., R.T.G., G.J., W.C., P.V.S., W.P.R., D.R.S., C.Y.K.), and Department of Medicine (A.B.N., M.D.S., J.C.B., H.I.H.), Duke University Medical Center, Box 3808 Duke University Medical Center, 2301 Erwin Road, Durham, NC 27710
| | - Paul V Suhocki
- From the Department of Radiology, Division of Vascular & Interventional Radiology (J.R., D.M., R.T.G., G.J., W.C., P.V.S., W.P.R., D.R.S., C.Y.K.), and Department of Medicine (A.B.N., M.D.S., J.C.B., H.I.H.), Duke University Medical Center, Box 3808 Duke University Medical Center, 2301 Erwin Road, Durham, NC 27710
| | - Waleska Pabon-Ramos
- From the Department of Radiology, Division of Vascular & Interventional Radiology (J.R., D.M., R.T.G., G.J., W.C., P.V.S., W.P.R., D.R.S., C.Y.K.), and Department of Medicine (A.B.N., M.D.S., J.C.B., H.I.H.), Duke University Medical Center, Box 3808 Duke University Medical Center, 2301 Erwin Road, Durham, NC 27710
| | - David R Sopko
- From the Department of Radiology, Division of Vascular & Interventional Radiology (J.R., D.M., R.T.G., G.J., W.C., P.V.S., W.P.R., D.R.S., C.Y.K.), and Department of Medicine (A.B.N., M.D.S., J.C.B., H.I.H.), Duke University Medical Center, Box 3808 Duke University Medical Center, 2301 Erwin Road, Durham, NC 27710
| | - Mark D Starr
- From the Department of Radiology, Division of Vascular & Interventional Radiology (J.R., D.M., R.T.G., G.J., W.C., P.V.S., W.P.R., D.R.S., C.Y.K.), and Department of Medicine (A.B.N., M.D.S., J.C.B., H.I.H.), Duke University Medical Center, Box 3808 Duke University Medical Center, 2301 Erwin Road, Durham, NC 27710
| | - John C Brady
- From the Department of Radiology, Division of Vascular & Interventional Radiology (J.R., D.M., R.T.G., G.J., W.C., P.V.S., W.P.R., D.R.S., C.Y.K.), and Department of Medicine (A.B.N., M.D.S., J.C.B., H.I.H.), Duke University Medical Center, Box 3808 Duke University Medical Center, 2301 Erwin Road, Durham, NC 27710
| | - Herbert I Hurwitz
- From the Department of Radiology, Division of Vascular & Interventional Radiology (J.R., D.M., R.T.G., G.J., W.C., P.V.S., W.P.R., D.R.S., C.Y.K.), and Department of Medicine (A.B.N., M.D.S., J.C.B., H.I.H.), Duke University Medical Center, Box 3808 Duke University Medical Center, 2301 Erwin Road, Durham, NC 27710
| | - Charles Y Kim
- From the Department of Radiology, Division of Vascular & Interventional Radiology (J.R., D.M., R.T.G., G.J., W.C., P.V.S., W.P.R., D.R.S., C.Y.K.), and Department of Medicine (A.B.N., M.D.S., J.C.B., H.I.H.), Duke University Medical Center, Box 3808 Duke University Medical Center, 2301 Erwin Road, Durham, NC 27710
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Casadei Gardini A, Santini D, Aprile G, Silvestris N, Felli E, Foschi FG, Ercolani G, Marisi G, Valgiusti M, Passardi A, Puzzoni M, Silletta M, Brunetti O, Cardellino GG, Frassineti GL, Scartozzi M. Antiangiogenic agents after first line and sorafenib plus chemoembolization: a systematic review. Oncotarget 2017; 8:66699-66708. [PMID: 29029548 PMCID: PMC5630448 DOI: 10.18632/oncotarget.19449] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Accepted: 04/27/2017] [Indexed: 12/31/2022] Open
Abstract
Transarterial chemoembolization (TACE) is the standard treatment for intermediate stage, although the combination of TACE with sorafenib may theoretically benefit HCC patients in intermediate stage. Owing to the significant antiangiogenic effect of sorafenib and the limitation of TACE, it is rational to combine them. Though the strategy of combining TACE and sorafenib has been increasingly used in patients with unresectable HCC but the current evidence is controversial and its clinical role has not been determined yet. In first-line therapy, patients receiving sorafenib had increased overall survival and progression free survival. Therefore several antiangiogenic agents have entered clinical studies on HCC, many with negative results. This review discusses the current drug development for patients with HCC and role of TACE plus sorafenib.
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Affiliation(s)
- Andrea Casadei Gardini
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Daniele Santini
- Medical Oncology Department, University Campus Bio-Medico, Via Álvaro del Portillo, Rome, Italy
| | - Giuseppe Aprile
- Department of Medical Oncology, University Hospital, Udine, Italy
| | - Nicola Silvestris
- Medical Oncology Unit, National Cancer Research Centre, Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - Emanuele Felli
- Hôpital Hautepierre Service de Chirurgie Générale, Hépatique, Endocrinienne et Transplantation Université de Strasbourg, Strasbourg, France
| | | | - Giorgio Ercolani
- Department of General Surgery, Morgagni-Pierantoni Hospiatal, AUSL Romagna, Forli, Italy.,Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | | | - Martina Valgiusti
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Alessandro Passardi
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Marco Puzzoni
- Department of Medical Oncology, University Hospital Cagliari, Cagliari, Italy
| | - Marianna Silletta
- Medical Oncology Department, University Campus Bio-Medico, Via Álvaro del Portillo, Rome, Italy
| | - Oronzo Brunetti
- Medical Oncology Unit, National Cancer Research Centre, Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | | | - Giovanni Luca Frassineti
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Mario Scartozzi
- Department of Medical Oncology, University Hospital Cagliari, Cagliari, Italy
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Li J, Liu W, Zhu W, Wu Y, Wu B. Transcatheter hepatic arterial chemoembolization and sorafenib for hepatocellular carcinoma: a meta-analysis of randomized, double-blind controlled trials. Oncotarget 2017; 8:59601-59608. [PMID: 28938663 PMCID: PMC5601759 DOI: 10.18632/oncotarget.19334] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Accepted: 07/06/2017] [Indexed: 12/11/2022] Open
Abstract
We performed a meta-analysis of transcatheter hepatic arterial chemoembolization (TACE) combined with sorafenib for hepatocellular carcinoma (HCC), which included 4 double-blind, randomized controlled trials (RCTs) that investigated the effects of TACE combined with sorafenib (experimental groups) on time to disease progression (TTP), overall survival (OS), and various sorafenib-related adverse events, compared to those in the placebo (control) groups. A total of 877 HCC cases from 14 countries, including China and the USA, were included in our meta-analysis. The TTP increased significantly in the experimental groups (hazard ration [HR]: 0.82; 95% CI: 0.69–0.97; p = 0.02), but OS did not improve significantly (HR: 0.97; 95% CI: 0.72–1.29; p = 0.82), compared with the control groups. The risks of hand and foot skin reactions (HFSR), rash, fatigue, and diarrhea were significantly greater in the experimental groups (p < 0.05 for all), compared to those in the control groups, whereas the risk of nausea was statistically similar (p > 0.05). Among these, the risk of HFSR was highest (risk ratio [RR]: 5.93; 95% CI: 2.00–17.53; p = 0.001), and a subgroup analysis of studies that lacked significant heterogeneity in the HFSR data showed a higher risk of HFSR (RR: 10.96; 95% CI: 5.54–21.69; p < 0.05). In conclusion, although TACE plus sorafenib increases TTP, it does not improve OS. Therefore, the risk of the adverse events of TACE plus sorafenib should be considered as a potential therapeutic limitation.
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Affiliation(s)
- Jun Li
- Department of Gastroenterology, Chinese PLA General Hospital, Beijing 100853, China
| | - Wenhui Liu
- Department of Gastroenterology, Chinese PLA General Hospital, Beijing 100853, China
| | - Wenhua Zhu
- Department of Oncology, Chinese 309th Hospital of PLA, Beijing 100091, China
| | - Yinqiao Wu
- Department of Gastroenterology, Chinese PLA General Hospital, Beijing 100853, China
| | - Benyan Wu
- Department of Gastroenterology, Chinese PLA General Hospital, Beijing 100853, China
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Ziogas IA, Tsoulfas G. Evolving role of Sorafenib in the management of hepatocellular carcinoma. World J Clin Oncol 2017; 8:203-213. [PMID: 28638790 PMCID: PMC5465010 DOI: 10.5306/wjco.v8.i3.203] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2017] [Revised: 04/03/2017] [Accepted: 04/23/2017] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant diseases worldwide and comes third in cancer-related mortality. Although there is a broad spectrum of treatment options to choose from, only a few patients are eligible candidates to receive a curative therapy according to their stage of disease, and thus palliative treatment is implemented in the majority of the patients suffering from liver cancer. Sorafenib, a multikinase inhibitor, is the only currently approved agent for systemic therapy in patients with advanced stage HCC and early stage liver disease. It has been shown to improve the overall survival, but with various side effects, while its cost is not negligible. Sorafenib has been in the market for a decade and has set the stage for personalized targeted therapy. Its role during this time has ranged from monotherapy to neoadjuvant and adjuvant treatment with surgical resection, liver transplantation and chemoembolization or even in combination with other chemotherapeutic agents. In this review our aim is to highlight in depth the current position of Sorafenib in the armamentarium against HCC and how that has evolved over time in its use either as a single agent or in combination with other therapies.
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