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Liu J, Xia S, Zhang B, Mohammed DM, Yang X, Zhu Y, Jiang X. Small molecule tyrosine kinase inhibitors approved for systemic therapy of advanced hepatocellular carcinoma: recent advances and future perspectives. Discov Oncol 2024; 15:259. [PMID: 38960980 PMCID: PMC11222362 DOI: 10.1007/s12672-024-01110-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 06/18/2024] [Indexed: 07/05/2024] Open
Abstract
Liver cancer is the sixth most commonly diagnosed cancer and the third leading cause of cancer death in the world, and hepatocellular carcinoma (HCC) is the most common form of liver cancer. More than half of the HCC patients are diagnosed at an advanced stage and often require systemic therapy. Dysregulation of the activity of receptor tyrosine kinases (RTKs) is involved in the development and progress of HCC, RTKs are therefore the potential targets for systemic therapy of advanced HCC (aHCC). Currently, a total of six small molecule tyrosine kinase inhibitors (TKIs) have been approved for aHCC, including first-line sorafenib, lenvatinib, and donafenib, and second-line regorafenib, cabozantinib, and apatinib. These TKIs improved patients survival, which are associated with disease stage, etiology, liver function, tumor burden, baseline levels of alpha-fetoprotein, and treatment history. This review focuses on the clinical outcomes of these TKIs in key clinical trials, retrospective and real-world studies and discusses the future perspectives of TKIs for aHCC, with an aim to provide up-to-date evidence for decision-making in the treatment of aHCC.
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Affiliation(s)
- Jianzhong Liu
- Clinical Laboratory, Wuhan No.7 Hospital, Zhong Nan 2nd Road, Wuhan, 430071, China
| | - Shuai Xia
- Department of Biochemistry and Molecular Biology, Jining Medical University, Jining, 272067, Shandong, China
| | - Baoyi Zhang
- National Engineering Research Center for Nanomedicine, Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, Hubei, China
| | - Dina Mostafa Mohammed
- Nutrition and Food Sciences Department, National Research Centre, Dokki, Cairo, Egypt
| | - Xiangliang Yang
- National Engineering Research Center for Nanomedicine, Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, Hubei, China
| | - Yanhong Zhu
- National Engineering Research Center for Nanomedicine, Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, Hubei, China
| | - Xinnong Jiang
- National Engineering Research Center for Nanomedicine, Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, Hubei, China.
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Asano K, Kageyama K, Yamamoto A, Jogo A, Uchida-Kobayashi S, Sohgawa E, Murai K, Kawada N, Miki Y. Transcatheter Arterial Chemoembolization for Treatment-Naive Hepatocellular Carcinoma Has Different Treatment Effects Depending on Central or Peripheral Tumor Location. Liver Cancer 2023; 12:576-589. [PMID: 38058422 PMCID: PMC10697731 DOI: 10.1159/000530441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 03/27/2023] [Indexed: 12/08/2023] Open
Abstract
Introduction The purpose of this study was to evaluate the treatment efficacy of transcatheter arterial chemoembolization (TACE) for treatment-naive hepatocellular carcinoma (HCC) according to tumor location and burden. Methods Between 2010 and 2019, consecutive patients who underwent TACE as the first treatment were enrolled. Tumors were classified into two categories based on their location, as central or peripheral tumors. Tumors in the central zone, which is within 1 cm of the main trunk or the first branch of the portal vein, were classified as central tumors, while those located in the peripheral zone were classified as peripheral tumors. Patients were grouped according to the HCC location and up-to-7 criteria. Patients with central tumors were classified into the central arm and those with only peripheral tumors were classified into the peripheral arm. Patients within and beyond the up-to-7 criteria were classified into the up-to-7 in and up-to-7 out-groups, respectively. Local recurrence-free survival (LRFS) and progression-free survival (PFS) were compared per nodule (central tumor vs. peripheral tumor) and per patient (central arm vs. peripheral arm), respectively. The prognostic factors of LRFS and PFS were analyzed by univariate and multivariate analyses. Results A total of 174 treatment-naive patients with 352 HCCs were retrospectively enrolled. Ninety-six patients and 130 lesions were selected by propensity score matching. Median LRFS was longer for peripheral tumors than central tumors (not reached vs. 3.3 months, p < 0.001). Median PFS was 17.1 months (8.3-24.9) in the peripheral arm and up-to-7 in, 7.0 months (3.3-12.7) in the peripheral arm and up-to-7 out, 8.4 months (4.0-12.6) in the central arm and up-to-7 in, and 3.0 months (1.2-4.9) in the central arm and up-to-7 out-groups. The peripheral arm and up-to-7 in-groups had significantly longer PFS than the other three groups (p = 0.013, p = 0.015, p < 0.001, respectively). Multivariate analysis confirmed that the central zone and central arm were associated with high adjusted hazard ratios for tumor recurrence or death (2.87, p < 0.001; 2.89, p < 0.001, respectively). Conclusion Treatment-naive HCCs in the peripheral zone had a longer LRFS and PFS following TACE compared to those in the central zone.
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Affiliation(s)
- Kazuo Asano
- Department of Diagnostic and Interventional Radiology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Ken Kageyama
- Department of Diagnostic and Interventional Radiology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Akira Yamamoto
- Department of Diagnostic and Interventional Radiology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Atsushi Jogo
- Department of Diagnostic and Interventional Radiology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Sawako Uchida-Kobayashi
- Department of Premier Preventive Medicine, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Etsuji Sohgawa
- Department of Diagnostic and Interventional Radiology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Kazuki Murai
- Department of Diagnostic and Interventional Radiology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Norifumi Kawada
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Yukio Miki
- Department of Diagnostic and Interventional Radiology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
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Huang CT, Chu YL, Su TH, Huang SC, Tseng TC, Hsu SJ, Liao SH, Hong CM, Liu CH, Yang HC, Liu CJ, Chen PJ, Kao JH. Optimizing Survival Benefit by Surgical Resection by the Seven-Eleven Criteria in Barcelona Clinic Liver Cancer Stage A/B Hepatocellular Carcinoma beyond the Milan Criteria. Liver Cancer 2023; 12:539-549. [PMID: 38476293 PMCID: PMC10928811 DOI: 10.1159/000529143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Accepted: 01/11/2023] [Indexed: 03/14/2024] Open
Abstract
INTRODUCTION Optimal treatment of hepatocellular carcinoma (HCC) beyond the Milan criteria is in debate. We aimed to identify candidates for surgical resection (SR) in Barcelona Clinic Liver Cancer (BCLC)-A/B HCC beyond the Milan criteria with survival benefit. METHODS Patients with BCLC-A/B HCC beyond the Milan criteria at the National Taiwan University Hospital during 2005 and 2019 were screened, and those who received transarterial chemoembolization (TACE) or SR were consecutively included. The tumor burden was classified by the seven-eleven criteria into low (≤7), intermediate (7-11), or high (>11). Multivariable Cox proportional hazard regression analysis was used for outcome prediction. RESULTS Overall, 474 patients who received SR (n = 247) and TACE (n = 227) were enrolled. Patients who underwent SR were significantly younger with better liver reserve. There were 76 (31%) and 129 (57%) deaths in the SR and TACE groups after a median follow-up of 3.9 and 2.1 years, respectively. The seven-eleven criteria could distinguish median overall survival (OS) among low (n = 149), intermediate (n = 203), and high (n = 122) tumor burden groups (7.7 vs. 6.9 vs. 2.8 years, respectively, p < 0.001). Patients receiving SR had a significantly higher median OS compared with TACE in those with intermediate (8.2 vs. 2.6 years, p < 0.001) and high (5.6 vs. 1.5 years, p = 0.001) tumor burden. After adjustment for age, sex, and liver reserve, SR was predictive for better OS in intermediate (adjusted hazard ratio [aHR]: 0.45, 95% confidence interval [CI]: 0.27-0.75) and high tumor burden groups (aHR: 0.54, 95% CI: 0.32-0.92). The survival benefit of SR especially confines to patients within 3 tumors. CONCLUSIONS In patients with BCLC-A/B HCC beyond the Milan criteria with tumor burden beyond the up-to-7 criteria but within 3 tumors, SR has better OS than TACE and should be considered in resectable patients.
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Affiliation(s)
- Chian-Tzu Huang
- School of Medicine, College of Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | | | - Tung-Hung Su
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Shang-Chin Huang
- Department of Internal Medicine, National Taiwan University Hospital Bei-Hu Branch, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Tai-Chung Tseng
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Shih-Jer Hsu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Sih-Han Liao
- Section of Gastroenterology, Department of Internal Medicine, National Taiwan University Cancer Center, Taipei, Taiwan
| | - Chun-Ming Hong
- Division of Hospital Medicine, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Chen-Hua Liu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Hung-Chih Yang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Chun-Jen Liu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Pei-Jer Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Jia-Horng Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
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Liu J, Yan S, Zhang G, Yang L, Wei S, Yi P. A retrospective study of transarterial chemoembolization (TACE) combined with lenvatinib compared with TACE monotherapy for BCLC B2 stage hepatocellular carcinoma. Oncol Lett 2023; 26:507. [PMID: 37920437 PMCID: PMC10618929 DOI: 10.3892/ol.2023.14094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 09/25/2023] [Indexed: 11/04/2023] Open
Abstract
The present study aimed to compare the efficacy and safety of combination therapy with lenvatinib (Len) plus transarterial chemoembolization (TACE) and TACE alone in patients with Barcelona Clinic Liver Cancer (BCLC) B2 stage hepatocellular carcinoma (HCC). A total of 66 patients with BCLC B2 stage HCC were retrospectively reviewed in the present study, of which 34 patients received Len + TACE, while 32 patients received TACE alone between May 2018 and May 2020. Survival outcome, tumor response and adverse events (AEs) were compared between the two treatment groups. The 6-month, 1- and 2-year overall survival (OS) rates were significantly higher in the Len + TACE group (97.1, 85.3 and 76.3%, respectively) compared with those in the TACE group [(93.8, 81.1 and 45.4%, respectively); hazard ratio (HR), 0.395; 95% confidence interval (CI), 0.180-0.867; P=0.023], but no significant difference in progression-free survival rate was observed between the two groups (HR, 0.815; 95% CI, 0.437-1.520; P=0.510). Patients receiving Len + TACE demonstrated a higher objective response rate compared with those receiving TACE alone (64.7 vs. 34.4%; P=0.014). Therefore, Len + TACE combination therapy was associated with increased OS and tumor response compared with that of TACE monotherapy in patients with BCLC B2 stage HCC. However, large-scale, multicenter, prospective studies are needed to further confirm these results.
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Affiliation(s)
- Junning Liu
- Department of Hepato-Biliary-Pancreas II, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Shu Yan
- Department of Hepato-Biliary-Pancreas II, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Guangnian Zhang
- Department of Hepato-Biliary-Pancreas II, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Linfeng Yang
- Department of Hepato-Biliary-Pancreas II, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Song Wei
- Department of Hepato-Biliary-Pancreas II, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Pengsheng Yi
- Department of Hepato-Biliary-Pancreas II, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
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Kudo M. Current Therapeutic Strategies for Hepatocellular Carcinoma in Japan. Liver Cancer 2023; 12:497-509. [PMID: 38098744 PMCID: PMC10721236 DOI: 10.1159/000534304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Accepted: 09/25/2023] [Indexed: 12/17/2023] Open
Affiliation(s)
- Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
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Xie DY, Zhu K, Ren ZG, Zhou J, Fan J, Gao Q. A review of 2022 Chinese clinical guidelines on the management of hepatocellular carcinoma: updates and insights. Hepatobiliary Surg Nutr 2023; 12:216-228. [PMID: 37124695 PMCID: PMC10129899 DOI: 10.21037/hbsn-22-469] [Citation(s) in RCA: 81] [Impact Index Per Article: 40.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 01/05/2023] [Indexed: 03/06/2023]
Abstract
Significant improvements in the management of hepatocellular carcinoma (HCC) during the past three years have urged the timely update of clinical guidelines in China. In brief, aMAP score is newly recommended as an effective risk stratification tool to predict HCC occurrence especially for non-cirrhotic patients. Biomarker-based surveillance including 7 micro-RNA panel and GALAD score are advocated to assist early diagnosis. China liver cancer (CNLC) staging system proposed in the 2017 guideline continues to be the standard model for staging with modifications in the treatment allocations. Conversion therapies using multi-modal, high intensity strategies are advocated to facilitate subsequent resection for patients with technically unresectable CNLC stage Ia, Ib, IIa HCC, or technically resectable IIb, IIIa HCC. Super-selective transcatheter arterial chemoembolization (TACE) with the assistance of Cone-Beam CT if necessary is recommended to guarantee the efficacy of TACE. Hepatic arterial infusion chemotherapy (HAIC) using oxaliplatin, fluorouracil, and leucovorin (FOLFOX) regimen alone or in combination with systemic therapy is recommended for TACE-refractory patients or for patients with locally advanced HCC. The systemic treatments for HCC have evolved considerably since atezolizumab plus bevacizumab, and suntilimab plus bevacizumab analogue showing superior survival benefit to sorafenib, and donafenib with comparable efficacy with sorafenib are added to the first-line treatments. In addition to regorafenib, apatinib, camrelizumab and tislelizumab are added as the second-line systemic therapies for patients who progressed on sorafenib. Updates in the 2022 Barcelona Clinic Liver Cancer (BCLC) guidelines and Japanese Society of Hepatology (JSH) consensus statement are also introduced and compared with the 2022 Chinese guidelines.
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Affiliation(s)
- Di-Yang Xie
- Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, China
| | - Kai Zhu
- Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, China
| | - Zheng-Gang Ren
- Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, China
| | - Jian Zhou
- Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, China
- Institute of Biomedical Sciences, Fudan University, Shanghai, China
| | - Jia Fan
- Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, China
- Institute of Biomedical Sciences, Fudan University, Shanghai, China
| | - Qiang Gao
- Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, China
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Xiang Z, Li G, Mu L, Wang H, Zhou C, Yan H, Huang M. TACE Combined with Lenvatinib and Camrelizumab for Unresectable Multiple Nodular and Large Hepatocellular Carcinoma (>5 cm). Technol Cancer Res Treat 2023; 22:15330338231200320. [PMID: 37723998 PMCID: PMC10510362 DOI: 10.1177/15330338231200320] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 07/30/2023] [Accepted: 08/18/2023] [Indexed: 09/20/2023] Open
Abstract
BACKGROUND The incidence and mortality of hepatocellular carcinoma (HCC) had increased globally over the past decades. Previous studies found that transarterial chemoembolization (TACE) combined with lenvatinib had also shown efficacy in the unresectable HCC. We aimed to evaluate the safety and efficacy of TACE combined with lenvatinib and camrelizumab to treat unresectable multiple nodular and large HCC (>5 cm). MATERIALS AND METHODS Between November 2018 and June 2021, we retrospectively recruited 82 patients with unresectable multiple nodular and large HCC (BCLC stage B or C with a single nodular diameter of >5 cm). Of the patients who had not previously been treated, 33 patients received TACE + lenvatinib + camrelizumab (group A, TLC), and 49 patients treated with TACE + lenvatinib (group B, TLB) as the initial treatment. Related efficacy and safety results were recorded and assessed. RESULTS The median follow-up periods of groups A and B were 14.5 ± 7.9 months (range, 3-36) and 12.5 ± 8.2 months (range, 3-32), respectively (P = 0.799). The progression-free survival (PFS) of groups A and B was 9.4 months and 5.9 months (P < 0.01), respectively, and overall survival (OS) was significantly longer in group A (16.4 months vs 11.0 months, P < 0.01). In group A, the local response rate (LRR) and disease control rate (DCR) were 51.5% and 81.8%, respectively, which was higher than the corresponding 46.9% and 77.6% observed in group B (P = 0.233; 0.429). Patients with BCLC B stage had better PFS and OS (P < 0.05). The BCLC stage was an independent factor that affected PFS and OS. There were no massive bleeding or treatment-related deaths. CONCLUSIONS In patients with unresectable multiple nodular and large HCC (single nodular diameter of >5 cm), TACE combined with target therapy and immunotherapy is safe and effective.
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Affiliation(s)
- Zhanwang Xiang
- Department of Interventional Radiology, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Guohong Li
- Department of Radiology, Guangdong Second Provincial General Hospital, Guangdong Provincial Emergency Hospital, Middle, Guangzhou, China
| | - Luwen Mu
- Department of Interventional Radiology, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Haofan Wang
- Department of Interventional Radiology, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Churen Zhou
- Department of Interventional Radiology, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Huzheng Yan
- Department of Interventional Radiology, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Mingsheng Huang
- Department of Interventional Radiology, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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Giuffrida P, Celsa C, Antonucci M, Peri M, Grassini MV, Rancatore G, Giacchetto CM, Cannella R, Incorvaia L, Corsini LR, Morana P, La Mantia C, Badalamenti G, Brancatelli G, Cammà C, Cabibbo G. The Evolving Scenario in the Assessment of Radiological Response for Hepatocellular Carcinoma in the Era of Immunotherapy: Strengths and Weaknesses of Surrogate Endpoints. Biomedicines 2022; 10:2827. [PMID: 36359347 PMCID: PMC9687474 DOI: 10.3390/biomedicines10112827] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 11/02/2022] [Indexed: 08/30/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a challenging malignancy characterised by clinical and biological heterogeneity, independent of the stage. Despite the application of surveillance programs, a substantial proportion of patients are diagnosed at advanced stages when curative treatments are no longer available. The landscape of systemic therapies has been rapidly growing over the last decade, and the advent of immune-checkpoint inhibitors (ICIs) has changed the paradigm of systemic treatments. The coexistence of the tumour with underlying cirrhosis exposes patients with HCC to competing events related to tumour progression and/or hepatic decompensation. Therefore, it is relevant to adopt proper clinical endpoints to assess the extent of treatment benefit. While overall survival (OS) is the most accepted endpoint for phase III randomised controlled trials (RCTs) and drug approval, it is affected by many limitations. To overcome these limits, several clinical and radiological outcomes have been used. For instance, progression-free survival (PFS) is a useful endpoint to evaluate the benefit of sequential treatments, since it is not influenced by post-progression treatments, unlike OS. Moreover, radiological endpoints such as time to progression (TTP) and objective response rate (ORR) are frequently adopted. Nevertheless, the surrogacy between these endpoints and OS in the setting of unresectable HCC (uHCC) remains uncertain. Since most of the surrogate endpoints are radiology-based (e.g., PFS, TTP, ORR), the use of standardised tools is crucial for the evaluation of radiological response. The optimal way to assess the radiological response has been widely debated, and many criteria have been proposed over the years. Furthermore, none of the criteria have been validated for immunotherapy in advanced HCC. The coexistence of the underlying chronic liver disease and the access to several lines of treatments highlight the urgent need to capture early clinical benefit and the need for standardised radiological criteria to assess cancer response when using ICIs in mono- or combination therapies. Here, we review the most commonly used clinical and radiological endpoints for trial design, as well as their surrogacy with OS. We also review the criteria for radiological response to treatments for HCC, analysing the major issues and the potential future perspectives.
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Affiliation(s)
- Paolo Giuffrida
- Section of Gastroenterology & Hepatology, Department of Health Promotion Sciences Maternal and Infant Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, 90127 Palermo, Italy
| | - Ciro Celsa
- Section of Gastroenterology & Hepatology, Department of Health Promotion Sciences Maternal and Infant Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, 90127 Palermo, Italy
- Department of Surgical, Oncological, and Oral Sciences (Di.Chir.On.S.), University of Palermo, 90127 Palermo, Italy
| | - Michela Antonucci
- Section of Radiology, Department of Biomedicine, Neuroscience and Advanced Diagnostics (BiND), University of Palermo, 90127 Palermo, Italy
| | - Marta Peri
- Department of Surgical, Oncological, and Oral Sciences (Di.Chir.On.S.), University of Palermo, 90127 Palermo, Italy
| | - Maria Vittoria Grassini
- Section of Gastroenterology & Hepatology, Department of Health Promotion Sciences Maternal and Infant Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, 90127 Palermo, Italy
| | - Gabriele Rancatore
- Section of Gastroenterology & Hepatology, Department of Health Promotion Sciences Maternal and Infant Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, 90127 Palermo, Italy
| | - Carmelo Marco Giacchetto
- Section of Gastroenterology & Hepatology, Department of Health Promotion Sciences Maternal and Infant Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, 90127 Palermo, Italy
| | - Roberto Cannella
- Section of Radiology, Department of Biomedicine, Neuroscience and Advanced Diagnostics (BiND), University of Palermo, 90127 Palermo, Italy
| | - Lorena Incorvaia
- Department of Surgical, Oncological, and Oral Sciences (Di.Chir.On.S.), University of Palermo, 90127 Palermo, Italy
| | - Lidia Rita Corsini
- Department of Surgical, Oncological, and Oral Sciences (Di.Chir.On.S.), University of Palermo, 90127 Palermo, Italy
| | - Piera Morana
- Section of Gastroenterology & Hepatology, Department of Health Promotion Sciences Maternal and Infant Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, 90127 Palermo, Italy
| | - Claudia La Mantia
- Section of Gastroenterology & Hepatology, Department of Health Promotion Sciences Maternal and Infant Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, 90127 Palermo, Italy
| | - Giuseppe Badalamenti
- Department of Surgical, Oncological, and Oral Sciences (Di.Chir.On.S.), University of Palermo, 90127 Palermo, Italy
| | - Giuseppe Brancatelli
- Section of Radiology, Department of Biomedicine, Neuroscience and Advanced Diagnostics (BiND), University of Palermo, 90127 Palermo, Italy
| | - Calogero Cammà
- Section of Gastroenterology & Hepatology, Department of Health Promotion Sciences Maternal and Infant Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, 90127 Palermo, Italy
| | - Giuseppe Cabibbo
- Section of Gastroenterology & Hepatology, Department of Health Promotion Sciences Maternal and Infant Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, 90127 Palermo, Italy
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Su TH, Hsu SJ, Kao JH. Paradigm shift in the treatment options of hepatocellular carcinoma. Liver Int 2022; 42:2067-2079. [PMID: 34515412 DOI: 10.1111/liv.15052] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 08/31/2021] [Accepted: 09/03/2021] [Indexed: 01/27/2023]
Abstract
Hepatocellular carcinoma (HCC) is prevalent worldwide with suboptimal therapeutic outcomes. The advancement of therapeutic options and the development of new systemic therapies expand the armamentarium to tackle HCC. Treatment options should be provided based on the hierarchy of efficacy in a multidisciplinary perspective, instead of the traditional stage-guided scheme. In advanced HCC, lenvatinib has a comparable efficacy as sorafenib for the first-line therapy of HCC; while regorafenib, cabozantinib, and ramucirumab have been approved as second-line therapy after the failure of sorafenib. Immune checkpoint inhibitor therapy prolongs response rate and survival and enables long-term cure. Atezolizumab plus bevacizumab is superior to sorafenib as the first-line therapy for advanced HCC. Several emerging regimens by the combination of various systemic therapies are currently under clinical trials. Systemic therapy may be used in the neoadjuvant, adjuvant or even as initial therapy for intermediate-stage HCC. The paradigm shift of HCC treatment will improve patient outcomes.
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Affiliation(s)
- Tung-Hung Su
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Shih-Jer Hsu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Yunlin, Taiwan
| | - Jia-Horng Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.,Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
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10
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Singal AG, Nagar SP, Hitchens A, Davis KL, Iyer S. Real-world effectiveness of lenvatinib monotherapy in previously treated unresectable hepatocellular carcinoma in US clinical practice. Cancer Rep (Hoboken) 2022; 6:e1679. [PMID: 35822407 PMCID: PMC9875657 DOI: 10.1002/cnr2.1679] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 06/10/2022] [Accepted: 06/27/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Lenvatinib monotherapy was approved in the United States for first-line treatment of patients with unresectable hepatocellular carcinoma (uHCC) in 2018. This study assessed real-world treatment patterns and outcomes of lenvatinib beyond first-line systemic treatment in the United States. METHODS A retrospective study was conducted among US adults (≥18 years) with uHCC. Eligible patients initiated lenvatinib monotherapy as second- or later-line systemic therapy (2L-plus) from August 2018 to September 2019. Clinical outcomes included physician-reported best response, progression-free survival (PFS), and overall survival (OS). RESULTS Of 164 patients who received lenvatinib in 2L-plus, most (n = 133; 81.1%) received lenvatinib in 2 L. There were 109 patients (66.4%) who initiated lenvatinib after immunotherapy. At lenvatinib initiation, only 31.1% of patients had Child-Pugh class A, while half (49.4%) had Child-Pugh class B. Most patients had Barcelona Clinic Liver Cancer stage B (23.8%) or C (38.4%) uHCC. Median duration of lenvatinib treatment was 6.9 months, with 42.7% of patients still on treatment at the end of follow-up. Physician-reported best response was complete and partial response for 8.5% and 44.5% of patients, respectively. PFS and OS rate estimates from lenvatinib initiation at 12 months were 51.7% and 57.8%, respectively. Among patients treated after immunotherapy, complete and partial responses were 10.1% and 43.1%, respectively, and PFS and OS estimates from lenvatinib initiation at 12 months were 52.8% and 60.0%, respectively. CONCLUSION This retrospective study suggests clinical effectiveness of lenvatinib monotherapy in a real-world setting among previously treated patients with uHCC, including among those previously treated with immunotherapy.
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Affiliation(s)
- Amit G. Singal
- Department of Internal MedicineUT Southwestern Medical CenterDallasTexasUSA
| | | | - Abby Hitchens
- RTI Health SolutionsResearch Triangle ParkNorth CarolinaUSA
| | - Keith L. Davis
- RTI Health SolutionsResearch Triangle ParkNorth CarolinaUSA
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11
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Wang F, Numata K, Komiyama S, Miwa H, Sugimori K, Ogushi K, Moriya S, Nozaki A, Chuma M, Ruan L, Maeda S. Combination Therapy With Lenvatinib and Radiofrequency Ablation for Patients With Intermediate-Stage Hepatocellular Carcinoma Beyond Up-To-Seven Criteria and Child-Pugh Class A Liver function: A Pilot Study. Front Oncol 2022; 12:843680. [PMID: 35600400 PMCID: PMC9114706 DOI: 10.3389/fonc.2022.843680] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Accepted: 04/08/2022] [Indexed: 11/16/2022] Open
Abstract
Background The present study aimed to evaluate the efficacy and safety of combined lenvatinib (first-line systemic therapy) and radiofrequency ablation (RFA) therapy in patients with intermediate-stage hepatocellular carcinoma with beyond up-to-seven criteria and Child-Pugh Class A liver function (CP A B2-HCC). Methods Twenty-two patients with CP A B2-HCC were enrolled in the study. The patients had no history of systemic treatment. For the initial lenvatinib administration in this study, all of the patients had an adequate course of treatment (no less than two weeks) and were administered the recommended dose. Of them, 13 were treated by means of lenvatinib monotherapy (monotherapy group), while the 9 patients with no contraindication to RFA operation and who had consented to RFA received initial lenvatinib plus subsequent RFA (combination group). The clinical outcomes that were considered to evaluate the treatments included tumor response, prognosis (recurrence and survivals), and possible adverse events (serum liver enzymes and clinically visible complications). Results The combination group exhibited a higher object response rate (9/9, 100%) as best tumor response than the monotherapy group (10/13, 76.9%). Longer progression-free survival (PFS) (12.5 months) and overall survival (OS) (21.3) were demonstrated in the combination group than in the monotherapy group (PFS: 5.5 months; OS:17.1 months). The combination group achieved a higher PFS rate (1-year: 74.1%) and OS rate (2-year: 80%) than the monotherapy group (1-year PFS rate: 0%; 2-year OS rate: 25.6%; for PFS, p<0.001; for OS, p=0.022). The treatment strategy was the independent factor for PFS (HR: 18.215 for monotherapy, p =0.010), which was determined by Cox regression analysis, suggesting that a combination strategy may reduce tumor progression when compared to the use of lenvatinib alone. There were no statistically significant intergroup differences that were observed in terms of adverse events, with the exception of ALT elevation (p=0.007) in the combination group. Conclusion Our newly proposed combination therapy may potentially be effective and safe for CP A B2-HCC beyond up-to-seven criteria. A larger scale, multicenter, prospective study is warranted to confirm our findings.
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Affiliation(s)
- Feiqian Wang
- Ultrasound Department, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Gastroenterological Center of Yokohama City University Medical Center, Yokohama, Japan
| | - Kazushi Numata
- Gastroenterological Center of Yokohama City University Medical Center, Yokohama, Japan
| | - Satoshi Komiyama
- Gastroenterological Center of Yokohama City University Medical Center, Yokohama, Japan
- Chemotherapy Department of Yokohama City University Medical Center, Yokohama, Japan
| | - Haruo Miwa
- Gastroenterological Center of Yokohama City University Medical Center, Yokohama, Japan
| | - Kazuya Sugimori
- Gastroenterological Center of Yokohama City University Medical Center, Yokohama, Japan
| | - Katsuaki Ogushi
- Gastroenterological Center of Yokohama City University Medical Center, Yokohama, Japan
| | - Satoshi Moriya
- Gastroenterological Center of Yokohama City University Medical Center, Yokohama, Japan
| | - Akito Nozaki
- Gastroenterological Center of Yokohama City University Medical Center, Yokohama, Japan
| | - Makoto Chuma
- Gastroenterological Center of Yokohama City University Medical Center, Yokohama, Japan
| | - Litao Ruan
- Ultrasound Department, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Shin Maeda
- Division of Gastroenterology of Yokohama City University Graduate School of Medicine, Yokohama, Japan
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12
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Kuroda H, Oikawa T, Ninomiya M, Fujita M, Abe K, Okumoto K, Katsumi T, Sato W, Igarashi G, Iino C, Endo T, Tanabe N, Numao H, Fukuda S, Iijima K, Masamune A, Ohira H, Ueno Y, Takikawa Y. Objective Response by mRECIST to Initial Lenvatinib Therapy Is an Independent Factor Contributing to Deep Response in Hepatocellular Carcinoma Treated with Lenvatinib-Transcatheter Arterial Chemoembolization Sequential Therapy. Liver Cancer 2022; 11:383-396. [PMID: 35978602 PMCID: PMC9294936 DOI: 10.1159/000522424] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 02/02/2022] [Indexed: 02/04/2023] Open
Abstract
OBJECTIVE There is limited information regarding the benefits of Lenvatinib-transcatheter arterial chemoembolization (LEN-TACE) sequential therapy for unresectable hepatocellular carcinoma (u-HCC). We compared the efficacy and safety of LEN-TACE sequential therapy to LEN monotherapy and investigated the factors contributing to the LEN-TACE sequential therapy deep response. METHODS We enrolled a multicenter cohort of 247 patients with u-HCC treated with LEN between 2018 and 2020. Propensity score matching identified 63 matching pairs of patients with well-balanced characteristics. We retrospectively compared the clinical outcomes, including overall survival (OS), progression-free survival (PFS), and incidence of adverse events (AEs), between the LEN-TACE and LEN monotherapy groups. Additionally, we evaluated the tumor response, change in albumin-bilirubin (ALBI) score, factors affecting PFS and OS, and independent predictors contributing to the LEN-TACE sequential therapy deep response. In this study, at eight weeks after resumption of LEN after initial TACE, "deep response" was defined as achieving complete response or partial response (PR) on modified Response Evaluation Criteria in Solid Tumors (mRECIST), and at least a 30% decrease in the sum of diameters of target lesions, taking the baseline sum diameters as the reference. RESULTS The OS and PFS in the LEN-TACE group were significantly higher than those in the LEN monotherapy group (p = 0.002 and p = 0.037, respectively). The incidence of AEs related to LEN was not significantly different between the two groups. In LEN-TACE sequential therapy, the objective response rate was 61.9%, and the disease control rate was 74.6%, according to the mRECIST criteria. No significant change in the ALBI score was observed during sequential LEN-TACE therapy. Multivariable analyses revealed that deep response was independently associated with the outcome of the initial response to LEN by mRECIST: PR (odds ratio: 5.176, 95% confidence interval: 1.528-17.537, p < 0.001). CONCLUSIONS LEN-TACE sequential therapy may provide more clinical benefits than LEN monotherapy in u-HCC patients who responded to initial LEN treatment. Objective response according to mRECIST to initial LEN is an independent factor contributing to LEN-TACE sequential therapy deep response.
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Affiliation(s)
- Hidekatsu Kuroda
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Iwate, Japan,*Hidekatsu Kuroda,
| | - Takayoshi Oikawa
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Iwate, Japan
| | - Masashi Ninomiya
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Masashi Fujita
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Kazumichi Abe
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Kazuo Okumoto
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Tomohiro Katsumi
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Wataru Sato
- Department of Gastroenterology, Graduate School of Medicine, Akita University, Akita, Japan
| | - Go Igarashi
- Department of Gastroenterology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Chikara Iino
- Department of Gastroenterology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Tetsu Endo
- Department of Gastroenterology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Nobukazu Tanabe
- Department of Gastroenterology, National Hospital Organisation Sendai Medical Center, Sendai, Japan
| | - Hiroshi Numao
- Department of Gastroenterology, Aomori Prefectural Central Hospital, Aomori, Japan
| | - Shinsaku Fukuda
- Department of Gastroenterology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Katsunori Iijima
- Department of Gastroenterology, Graduate School of Medicine, Akita University, Akita, Japan
| | - Atsushi Masamune
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hiromasa Ohira
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Yoshiyuki Ueno
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Yasuhiro Takikawa
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Iwate, Japan
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13
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Precision Medicine for Hepatocellular Carcinoma: Clinical Perspective. J Pers Med 2022; 12:jpm12020149. [PMID: 35207638 PMCID: PMC8879044 DOI: 10.3390/jpm12020149] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Revised: 01/19/2022] [Accepted: 01/20/2022] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the major malignant diseases worldwide, characterized by growing incidence and high mortality rates despite apparent improvements in surveillance programs, diagnostic and treatment procedures, molecular therapies, and numerous research initiatives. Most HCCs occur in patients with liver cirrhosis, and the competing mortality risks from the tumor and the cirrhosis should be considered. Presently, previously identified risk factors, such as hepatitis virus infection, hepatic inflammation and fibrosis, and metabolic syndrome, may be used as chemoprevention targets. The application of precision medicine for HCC management challenges the one-size-fits-all concept; moreover, patients should no longer be treated entirely according to the histology of their tumor but based on molecular targets specific to their tumor biology. Next-generation sequencing emphasizes HCC molecular heterogeneity and aids our comprehension of possible vulnerabilities that can be exploited. Moreover, genetic sequencing as part of a precision medicine concept may work as a promising tool for postoperative cancer monitoring. The use of genetic and epigenetic markers to identify therapeutic vulnerability could change the diagnosis and treatment of HCC, which so far was based on Barcelona clinic liver cancer (BCLC) staging. In daily clinical practice, the shift from a stage-oriented to a therapeutic-oriented approach is needed to direct the choice of HCC treatment toward the potentially most effective option on an individual basis. The important factor in precision medicine is the promotion of patient management based on the individual approach, knowing that the final decision must be approved by a multidisciplinary expert team.
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Sümbül Taner A, Beşen AA. Recent advances in medical treatment of hepatocellular cancer. THERANOSTICS AND PRECISION MEDICINE FOR THE MANAGEMENT OF HEPATOCELLULAR CARCINOMA, VOLUME 3 2022:365-375. [DOI: 10.1016/b978-0-323-99283-1.00004-5] [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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Sho T, Morikawa K, Kubo A, Tokuchi Y, Kitagataya T, Yamada R, Shigesawa T, Kimura M, Nakai M, Suda G, Natsuizaka M, Ogawa K, Sakamoto N. Prospect of lenvatinib for unresectable hepatocellular carcinoma in the new era of systemic chemotherapy. World J Gastrointest Oncol 2021; 13:2076-2087. [PMID: 35070043 PMCID: PMC8713309 DOI: 10.4251/wjgo.v13.i12.2076] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 07/08/2021] [Accepted: 09/17/2021] [Indexed: 02/06/2023] Open
Abstract
The phase III clinical trial of the novel molecular targeted agent (MTA) lenvatinib for patients with advanced hepatocellular carcinoma (HCC) (REFLECT trial) found that lenvatinib was non-inferior to sorafenib in overall survival. Recently, the efficacy of multiple MTAs, including lenvatinib, in practice has been reported, and therapeutic strategies for Barcelona Clinic Liver Cancer (BCLC) intermediate stage HCC are undergoing major changes. Based on these results, lenvatinib could be recommended for patients with transcatheter arterial chemoembolization (TACE)-refractory, ALBI grade 1, within the up-to-seven criteria in the BCLC intermediate stage. Lenvatinib provides a more favorable outcome than TACE, even in cases with large or multinodular HCC beyond the up-to-seven criteria with Child-Pugh grade A. When patients meet the definitions of TACE-refractory or TACE-unsuitable, switching to systemic chemotherapy, including lenvatinib, is for favorable for preserving liver function. If initial treatment, including MTA, has a significant therapeutic effect and downstaging of HCC is obtained, additional TACE or surgical resection should be considered. Lenvatinib also has a therapeutic effect for poorly differentiated type and non-simple nodular type HCC thanks to the survival-prolonging effect of this drug. Furthermore, a significant therapeutic effect is expected in tumors with more than 50% liver involvement or main portal vein invasion, which have traditionally been considered to have a poor prognosis in patients. This suggests that at the start of lenvatinib treatment, HCC patients with ALBI grade 1 may be able to maintain liver functional reserve.
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Affiliation(s)
- Takuya Sho
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Hokkaido, Japan
| | - Kenichi Morikawa
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Hokkaido, Japan
| | - Akinori Kubo
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Hokkaido, Japan
| | - Yoshimasa Tokuchi
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Hokkaido, Japan
| | - Takashi Kitagataya
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Hokkaido, Japan
| | - Ren Yamada
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Hokkaido, Japan
| | - Taku Shigesawa
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Hokkaido, Japan
| | - Mugumi Kimura
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Hokkaido, Japan
| | - Masato Nakai
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Hokkaido, Japan
| | - Goki Suda
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Hokkaido, Japan
| | - Mitsuteru Natsuizaka
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Hokkaido, Japan
| | - Koji Ogawa
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Hokkaido, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Hokkaido, Japan
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Kang H, Lee HW. Current role of systemic therapy in transarterial chemotherapy refractory hepatocellular carcinoma patients. INTERNATIONAL JOURNAL OF GASTROINTESTINAL INTERVENTION 2021. [DOI: 10.18528/ijgii210046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Affiliation(s)
- Hansung Kang
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Hye Won Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
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Overview of lenvatinib as a targeted therapy for advanced hepatocellular carcinoma. Clin Exp Hepatol 2021; 7:249-257. [PMID: 34712825 PMCID: PMC8527338 DOI: 10.5114/ceh.2021.109312] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 06/06/2021] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide. Patients commonly present with advanced/unresectable HCC where several treatment options are not effective. In this review, the authors discuss the indications and usage of lenvatinib, a multikinase inhibitor, as first-line therapy for advanced/unresectable HCC, its mode of action, efficacy, drug reactions, response to treatment and adverse effects. Since its approval in 2007, sorafenib has been used as first-line therapy for unresectable HCC. In 2018, a phase III multinational REFLECT trial on subjects with unresectable HCC (Child-Pugh class A) demonstrated that lenvatinib was non-inferior compared to sorafenib for overall survival, with a controllable toxicity profile, leading to its approval. In addition, our review discusses studies that compare the safety and efficacy profile of lenvatinib especially in patients who have a decline in their liver function to Child-Pugh class B. A current real world analysis of lenvatinib approval for unresectable HCC worldwide is reported.
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Adaptation of lenvatinib treatment in patients with hepatocellular carcinoma and portal vein tumor thrombosis. Cancer Chemother Pharmacol 2021; 89:11-20. [PMID: 34628536 DOI: 10.1007/s00280-021-04359-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 09/27/2021] [Indexed: 12/22/2022]
Abstract
PURPOSE The aim of this study was to clarify the adaptation of lenvatinib treatment in patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombosis (PVTT). METHOD Fifty-three patients with HCC were treated with lenvatinib. Before and after treatment blood sampling, patients were examined by computed tomography and ultrasonography. In patients with portal trunk invasion (Vp4), the analysis focused on the degree of occlusion due to the tumor in the portal trunk. In patients without major PVTT {ie, invasion of the primary branch of the portal vein [Vp3] or Vp4}, portal blood flow volume was measured by Doppler analysis; however, Doppler analysis is difficult to perform in patients with major PVTT, so the time from administration of the contrast agent to when it reached the primary branch of the portal vein (portal vein arrival time) was evaluated with the contrast agent Sonazoid. RESULTS Patients with Vp4 had a significantly worse prognosis than patients with Vp3 and a significant increase in Child-Pugh score at 2 months. Patients with major PVTT had a poor prognosis if the degree of occlusion of the portal trunk was 70% or more. In patients without major PVTT, portal blood flow was significantly decreased after administration of lenvatinib; and in patients with major PVTT, the hepatic artery and portal vein arrival times were significantly increased. CONCLUSION Lenvatinib treatment should be avoided in patients with Vp4 with a high degree of portal trunk occlusion because of concerns about decreased portal blood flow.
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Su TH, Hsu SJ, Kao JH. Systemic therapy for hepatocellular carcinoma: New agents and therapeutic hierarchy. J Formos Med Assoc 2021; 121:451-453. [PMID: 34454796 DOI: 10.1016/j.jfma.2021.08.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 08/17/2021] [Indexed: 10/20/2022] Open
Affiliation(s)
- Tung-Hung Su
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Shih-Jer Hsu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Jia-Horng Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
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Hao J, Peng Q, Wang K, Yu G, Pan Y, Du X, Hu N, Zhang X, Qin Y, Li H. Antitumor Effect of Lenvatinib Combined with Alisertib in Hepatocellular Carcinoma by Targeting the DNA Damage Pathway. BIOMED RESEARCH INTERNATIONAL 2021; 2021:6613439. [PMID: 34337035 PMCID: PMC8324353 DOI: 10.1155/2021/6613439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 06/12/2021] [Accepted: 07/09/2021] [Indexed: 12/24/2022]
Abstract
METHODS Immunohistochemical staining, sequencing, and genetic analysis of liver cancer tissues were performed. The antitumor efficacy of single-agent or combination treatment was measured by cell counting kit-8 assay and colony formation assays. Their antiproliferative and apoptosis activity is evaluated by cell cycle analyses and wound healing assays. The DNA-related proteins were also measured by Western blotting and immunohistochemical staining. The HepG2 xenograft model was used to detect the effects of lenvatinib-alisertib on the antitumor activity. RESULTS AURKA was found to be upregulated in HCC tissues (77.3%, 17/22). Combined alisertib and lenvatinib treatment significantly enhanced the inhibition of proliferation and migration in HepG2 and Hep3B cell lines compared to single-agent treatments (all Ps < 0.01). Alisertib alone or in combination with lenvatinib demonstrated a significant increase in the percentage of super-G2 cells (lenvatinib 1 μM vs. lenvatinib 1 μM + alisertib 0.1 μM 8.84 ± 0.84 vs. 34.0 ± 1.54, P < 0.001). Discontinuous spindles and missegregated chromosomes in HCC cells treated with alisertib in combination with lenvatinib were observed. We further revealed that combined treatment inhibited the expression of DNA damage pathway proteins compared to those of single-agent treatments. In nude mice, combined administration of alisertib combined with lenvatinib significantly enhanced the suppression of tumor growth and induced apoptosis (all Ps < 0.01). CONCLUSIONS Our findings provide evidence for the possible use of alisertib in combination with lenvatinib in the treatment of HCC for better therapeutic outcomes.
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Affiliation(s)
- Jianwen Hao
- Department of Radiology, Tianjin Chest Hospital, Tianjin 300350, China
| | - Qizhen Peng
- Department of Radiology, Tungwah Hospital of Sun Yat-Sen University, Dongguan, 523000 Guangdong, China
| | - Keruo Wang
- Department of Diagnostics, Tianjin Medical University, Tianjin 300070, China
| | - Ge Yu
- Department of Hepatobiliary, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin Clinical Research Center for Cancer, Tianjin 300070, China
| | - Yi Pan
- Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin Clinical Research Center for Cancer, Tianjin 300070, China
| | - Xiaoling Du
- Department of Diagnostics, Tianjin Medical University, Tianjin 300070, China
| | - Na Hu
- Department of Diagnostics, Tianjin Medical University, Tianjin 300070, China
| | - Xuening Zhang
- Department of Radiology Second Hospital of Tianjin Medical University, Tianjin 300070, China
| | - Yu Qin
- Department of Diagnostics, Tianjin Medical University, Tianjin 300070, China
| | - Huikai Li
- Department of Hepatobiliary, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin Clinical Research Center for Cancer, Tianjin 300070, China
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21
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Deng H, Kan A, Lyu N, He M, Huang X, Qiao S, Li S, Lu W, Xie Q, Chen H, Lai J, Chen Q, Jiang X, Liu S, Zhang Z, Zhao M. Tumor-derived lactate inhibit the efficacy of lenvatinib through regulating PD-L1 expression on neutrophil in hepatocellular carcinoma. J Immunother Cancer 2021; 9:jitc-2020-002305. [PMID: 34168004 PMCID: PMC8231064 DOI: 10.1136/jitc-2020-002305] [Citation(s) in RCA: 97] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/23/2021] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Neutrophils play a controversial role in tumor development. The function of programmed cell death-1 ligand (PD-L1+) neutrophils, however, may inhibit the cytotoxicity of anti-tumor immunity. In this study, we elucidate the stimulators of PD-L1+ neutrophils in tumor microenvironment (TME) and explore the optimal combination to enhance the effect of lenvatinib by inhibiting PD-L1+ neutrophils in hepatocellular carcinoma. METHODS Neutrophil infiltration after lenvatinib treatment was examined with RNA sequencing and multicolor flow cytometry analysis in patient samples, subcutaneous and orthotopic mouse models. Neutrophils and T cells were isolated from peripheral blood and tumor tissues and purified with magnetic beads for cytotoxicity assay. Metabolites and cytokines were detected by a biochemical analyzer manufactured by Yellow Springs Instrument (YSI) and proteome profiler cytokines array. In vitro screening of pathway inhibitors was used to identify possible candidates that could reduce PD-L1+ neutrophil infiltration. Further in vivo assays were used for verification. RESULTS Lenvatinib increased neutrophil recruitment by inducing CXCL2 and CXCL5 secretion in TME. After entering TME, neutrophils polarized toward N2 phenotype. PD-L1 expression was simultaneously upregulated. Thus, lenvatinib efficacy on tumor cells hindered. The increasing PD-L1+ neutrophils positively corelated with a suppressive T cell phenotype. Further investigation indicated that JAK/STAT1 pathway activated by immune-cell-derived interferon γ and MCT1/NF-kB/COX-2 pathway activated by high concentrations of tumor-derived lactate could induce PD-L1+ neutrophils. The latter could be significantly inhibited by COX-2 inhibitor celecoxib. Further in vivo assays verified that Celecoxib decreased the survival of lactate-stimulated PD-L1+ neutrophil and promoted the antitumor effect of lenvatinib. CONCLUSIONS PD-L1+ neutrophils decrease T cell cytotoxicity. Tumor-derived lactate induces PD-L1 expression on neutrophils via MCT1/NF-κB/COX-2 pathway. Thus, COX-2 inhibitor could reduce PD-L1+ neutrophil and restore T cell cytotoxicity. This may provide a potent addition to lenvatinib.
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Affiliation(s)
- Haijing Deng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.,Minimally Invasive Interventional Division, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Anna Kan
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.,Department of Hepatic Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Ning Lyu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.,Minimally Invasive Interventional Division, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Meng He
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.,Minimally Invasive Interventional Division, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Xin Huang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.,Department of Pancreatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Shuang Qiao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Shaolong Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Wenhua Lu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Qiankun Xie
- Department of Radiation Oncology, Southern Hospital of Southern Medical University, Guangzhou, Guangdong, China
| | - Huiming Chen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Jinfa Lai
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.,Minimally Invasive Interventional Division, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Qifeng Chen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.,Minimally Invasive Interventional Division, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Xiongying Jiang
- Interventional Radiology Divison, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Shousheng Liu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.,VIP Region, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Zhenfeng Zhang
- Minimally Invasive Interventional Division, Guangzhou Medical University Second Affiliated Hospital, Guangzhou, Guangdong, China
| | - Ming Zhao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China .,Minimally Invasive Interventional Division, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
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22
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Kudo M, Kawamura Y, Hasegawa K, Tateishi R, Kariyama K, Shiina S, Toyoda H, Imai Y, Hiraoka A, Ikeda M, Izumi N, Moriguchi M, Ogasawara S, Minami Y, Ueshima K, Murakami T, Miyayama S, Nakashima O, Yano H, Sakamoto M, Hatano E, Shimada M, Kokudo N, Mochida S, Takehara T. Management of Hepatocellular Carcinoma in Japan: JSH Consensus Statements and Recommendations 2021 Update. Liver Cancer 2021; 10:181-223. [PMID: 34239808 PMCID: PMC8237791 DOI: 10.1159/000514174] [Citation(s) in RCA: 423] [Impact Index Per Article: 105.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 12/23/2020] [Indexed: 02/06/2023] Open
Abstract
The Clinical Practice Manual for Hepatocellular Carcinoma was published based on evidence confirmed by the Evidence-based Clinical Practice Guidelines for Hepatocellular Carcinoma along with consensus opinion among a Japan Society of Hepatology (JSH) expert panel on hepatocellular carcinoma (HCC). Since the JSH Clinical Practice Guidelines are based on original articles with extremely high levels of evidence, expert opinions on HCC management in clinical practice or consensus on newly developed treatments are not included. However, the practice manual incorporates the literature based on clinical data, expert opinion, and real-world clinical practice currently conducted in Japan to facilitate its use by clinicians. Alongside each revision of the JSH Guidelines, we issued an update to the manual, with the first edition of the manual published in 2007, the second edition in 2010, the third edition in 2015, and the fourth edition in 2020, which includes the 2017 edition of the JSH Guideline. This article is an excerpt from the fourth edition of the HCC Clinical Practice Manual focusing on pathology, diagnosis, and treatment of HCC. It is designed as a practical manual different from the latest version of the JSH Clinical Practice Guidelines. This practice manual was written by an expert panel from the JSH, with emphasis on the consensus statements and recommendations for the management of HCC proposed by the JSH expert panel. In this article, we included newly developed clinical practices that are relatively common among Japanese experts in this field, although all of their statements are not associated with a high level of evidence, but these practices are likely to be incorporated into guidelines in the future. To write this article, coauthors from different institutions drafted the content and then critically reviewed each other's work. The revised content was then critically reviewed by the Board of Directors and the Planning and Public Relations Committee of JSH before publication to confirm the consensus statements and recommendations. The consensus statements and recommendations presented in this report represent measures actually being conducted at the highest-level HCC treatment centers in Japan. We hope this article provides insight into the actual situation of HCC practice in Japan, thereby affecting the global practice pattern in the management of HCC.
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Affiliation(s)
- Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan,*Masatoshi Kudo,
| | | | - Kiyoshi Hasegawa
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Ryosuke Tateishi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kazuya Kariyama
- Department of Gastroenterology, Okayama City Hospital, Okayama, Japan
| | - Shuichiro Shiina
- Department of Gastroenterology, Juntendo University, Tokyo, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Gifu, Japan
| | - Yasuharu Imai
- Department of Gastroenterology, Ikeda Municipal Hospital, Osaka, Japan
| | - Atsushi Hiraoka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan
| | - Masafumi Ikeda
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Michihisa Moriguchi
- Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Sadahisa Ogasawara
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Yasunori Minami
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Kazuomi Ueshima
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Takamichi Murakami
- Department of Radiology, Kobe University Graduate School of Medicine, Hyogo, Japan
| | - Shiro Miyayama
- Department of Diagnostic Radiology, Fukui-ken Saiseikai Hospital, Fukui, Japan
| | - Osamu Nakashima
- Department of Clinical Laboratory Medicine, Kurume University Hospital, Kurume, Japan
| | - Hirohisa Yano
- Department of Pathology, Kurume University School of Medicine, Kurume, Japan
| | - Michiie Sakamoto
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Etsuro Hatano
- Department of Gastroenterological Surgery, Hyogo College of Medicine, Nishinomiya, Japan
| | - Mitsuo Shimada
- Department of Surgery, Tokushima University, Tokushima, Japan
| | - Norihiro Kokudo
- Department of Surgery, National Center for Global Health and Medicine, Tokyo, Japan
| | - Satoshi Mochida
- Department of Gastroenterology and Hepatology, Saitama Medical University, Saitama, Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
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23
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Singal AG, Nagar SP, Hitchens A, Davis KL, Iyer S. Real-world effectiveness of lenvatinib monotherapy among unresectable hepatocellular carcinoma patients in the USA. Future Oncol 2021; 17:2759-2768. [PMID: 33832339 DOI: 10.2217/fon-2021-0242] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Aim: This study evaluated the effectiveness of lenvatinib monotherapy for first-line treatment of unresectable hepatocellular carcinoma (uHCC) in a real-world setting. Materials & methods: This retrospective cohort study included patients who initiated lenvatinib monotherapy as first-line treatment for uHCC (n = 233). Clinical outcomes included provider-reported best response, progression-free survival (PFS) and overall survival (OS). PFS and OS were estimated using Kaplan-Meier methods. Results: Most patients (67.8%) were male. A total of 44.6% had Child-Pugh A and 39.1% had Child-Pugh B. Dose reductions were reported in 9%. Median PFS and OS were not reached. At 6 and 12 months, landmark PFS were 85.1 and 64.9%, respectively; landmark OS were 91.8 and 72.6%, respectively. Conclusion: These results affirm the clinical effectiveness of first-line lenvatinib monotherapy in uHCC.
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Affiliation(s)
- Amit G Singal
- Division of Digestive & Liver Disease, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Saurabh P Nagar
- Department of Health Economics, RTI Health Solutions, Research Triangle Park, NC 27709, USA
| | - Abby Hitchens
- Department of Health Economics, RTI Health Solutions, Research Triangle Park, NC 27709, USA
| | - Keith L Davis
- Department of Health Economics, RTI Health Solutions, Research Triangle Park, NC 27709, USA
| | - Shrividya Iyer
- Global Real World Evidence & US HEOR, Eisai, Inc., Woodcliff Lake, NJ 07677, USA
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24
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Parikh ND, Marshall A, Betts KA, Song J, Zhao J, Yuan M, Wu A, Huff KD, Kim R. Network meta-analysis of nivolumab plus ipilimumab in the second-line setting for advanced hepatocellular carcinoma. J Comp Eff Res 2021; 10:343-352. [PMID: 33442996 DOI: 10.2217/cer-2020-0236] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Aims: To compare the efficacy of nivolumab 1 mg/kg + ipilimumab 3 mg/kg with regorafenib 160 mg, cabozantinib 60 mg and nivolumab 3 mg/kg monotherapy for second-line treatment of advanced hepatocellular carcinoma. Materials & methods: Indirect comparison using network meta-analysis and propensity score weighting. Results: Nivolumab 1 mg/kg + ipilimumab 3 mg/kg had significantly higher objective response rate (median 31.2% [95% credible interval: 19.6-44.5%]) than cabozantinib (4.2% [2.0-6.5%]) and regorafenib (4.8% [1.1-8.3%]), and significantly longer overall survival (cabozantinib: hazard ratio: 0.46 [95% credible interval: 0.27-0.79]; regorafenib: 0.56 [0.32-0.97]). Nivolumab 1 mg/kg + ipilimumab 3 mg/kg had significantly better objective response rate (difference 21.0% [4.5-37.5%]) and overall survival (hazard ratio: 0.58 [0.35-0.96]) than nivolumab monotherapy. Conclusion: Nivolumab 1 mg/kg + ipilimumab 3 mg/kg had a superior efficacy versus cabozantinib 60 mg, regorafenib 160 mg and nivolumab 3 mg/kg monotherapy as second-line therapy for advanced hepatocellular carcinoma.
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Affiliation(s)
- Neehar D Parikh
- Division of Gastroenterology & Hepatology, University of Michigan, Ann Arbor, MI 48109, USA
| | | | | | - Jinlin Song
- Analysis Group Inc., Los Angeles, CA 90071, USA
| | - Jing Zhao
- Analysis Group Inc., Boston, MA 02199, USA
| | - Muhan Yuan
- Analysis Group Inc., Boston, MA 02199, USA
| | - Aozhou Wu
- Analysis Group Inc., Los Angeles, CA 90071, USA
| | | | - Richard Kim
- Department of Gastroenterology Oncology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
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25
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Charoenvisal C, Tanaka T, Nishiofuku H, Anai H, Sato T, Matsumoto T, Marugami N, Kichikawa K. Feasibility and Techniques of Securing 3D-Safety Margin in Superselective Transarterial Chemoembolization to Improve Local Tumor Control for Small Hepatocellular Carcinoma: An Intend-to-Treat Analysis. Liver Cancer 2021; 10:63-71. [PMID: 33708640 PMCID: PMC7923884 DOI: 10.1159/000512337] [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] [Received: 06/28/2020] [Accepted: 10/15/2020] [Indexed: 02/04/2023] Open
Abstract
INTRODUCTION The aim of this study was to investigate the technical success rate of obtaining 3D-safety margin in superselective conventional transarterial chemoembolization (cTACE) using 3D images for small hepatocellular carcinoma (HCC). METHODS Consecutive 48 HCC nodules (diameter, 1-3 cm) in 44 patients were intentionally treated by superselective cTACE in an attempt to achieve 3D-safety margin. Superselective CT during hepatic arteriography (CTHA) was obtained before cTACE. When negative 3D-safety margin was found, branches supplied into the margin area were detected by using a 3D workstation. The technical success rate to obtain 3D-safety margin was investigated by intend-to-treat analysis. Local tumor recurrence rate and adverse events were also evaluated. RESULT Nine of 48 tumors (18.8%) had 3D-safety margin in the initial superselective CTHA. After pulling back of the catheter and/or selection of another branch based on 3D images, 3D-safety margin was finally achieved in 45 (93.8%). There were 8 of 46 tumors (17.4%) with local recurrence after 5-year follow-up. Grade 3-4 of aspartate aminotransferase, alanine aminotransferase, and total bilirubin were found in 38.6, 36.4, and 2.3%, respectively. One portal vein thrombus and 3 biliary dilation or biloma were developed. CONCLUSION Superselective cTACE obtaining 3D-safety margin in small HCC was feasible with a high success rate by using 3D images, which could be tolerable and prevent local tumor recurrence.
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Affiliation(s)
- Ching Charoenvisal
- Department of Radiology, Nara Medical University, Kashihara, Japan,King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Toshihiro Tanaka
- Department of Radiology, Nara Medical University, Kashihara, Japan,*Toshihiro Tanaka, Department of Radiology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8522 (Japan),
| | | | - Hiroshi Anai
- Department of Radiology, Nara City Hospital, Nara, Japan
| | - Takeshi Sato
- Department of Radiology, Nara Medical University, Kashihara, Japan
| | | | - Nagaaki Marugami
- Department of Radiology, Nara Medical University, Kashihara, Japan
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26
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Hatanaka T, Naganuma A, Kakizaki S. Lenvatinib for Hepatocellular Carcinoma: A Literature Review. Pharmaceuticals (Basel) 2021; 14:36. [PMID: 33418941 PMCID: PMC7825021 DOI: 10.3390/ph14010036] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 01/01/2021] [Accepted: 01/03/2021] [Indexed: 12/11/2022] Open
Abstract
Lenvatinib, which is an oral multikinase inhibitor, showed non-inferiority to the sorafenib in terms of overall survival (OS) and a higher objective response rate (ORR) and better progression-free survival (PFS) in patients with hepatocellular carcinoma (HCC). A good liver function and Barcelona Clinic Liver Cancer (BCLC) intermediate stage were the key factors in achieving therapeutic efficacy. The management of adverse events plays an important role in continuing lenvatinib treatment. While sequential therapies contributed to prolonging overall survival, effective molecular targeted agents for the administration after lenvatinib have not been established. Repeated transcatheter arterial chemoembolization (TACE) was associated with a decline in the liver function and poor therapeutic response in BCLC intermediate patients. Recently, the Asia-Pacific Primary Liver Cancer Expert (APPLE) Consensus Statement proposed the criteria for TACE unsuitability. Upfront systemic therapy may be better for the BCLC intermediate stage HCC patients with a high tumor burden, while selective TACE will be recommended for obtaining a curative response in patients with a low tumor burden. This article reviews the therapeutic response, management of adverse events, post-progression treatment after Lenvatinib, and treatment strategy for BCLC intermediate stage HCC.
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Affiliation(s)
- Takeshi Hatanaka
- Department of Gastroenterology, Gunma Saiseikai Maebashi Hospital, 564-1 Kamishindenmachi, Maebashi, Gunma 371-0821, Japan
| | - Atsushi Naganuma
- Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, 36 Takamatsucho, Takasaki, Gunma 370-0829, Japan;
| | - Satoru Kakizaki
- Department of Clinical Research, National Hospital Organization Takasaki General Medical Center, 36 Takamatsucho, Takasaki, Gunma 370-0829, Japan;
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, 3-39-15 Showa, Maebashi, Gunma 371-8511, Japan
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27
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Hatanaka T, Kakizaki S, Nagashima T, Ueno T, Namikawa M, Tojima H, Takizawa D, Naganuma A, Arai H, Sato K, Harimoto N, Shirabe K, Uraoka T. A change in the timing for starting systemic therapies for hepatocellular carcinoma: the comparison of sorafenib and lenvatinib as the first-line treatment. Acta Gastroenterol Belg 2021; 84:65-72. [PMID: 33639695 DOI: 10.51821/84.1.109] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
AIM The aim of this retrospective multicenter study was to evaluate the differences in the timing for starting systemic therapies as the first-line treatment for hepatocellular carcinoma (HCC). METHODS A total of 375 patients with HCC treated with sorafenib from May 2009 to March 2018 and 56 patients treated with lenvatinib from March 2018 to November 2018 at our affiliated hospitals were included in this study. RESULTS The median ages of the sorafenib and lenvatinib groups were 71.0 (interquartile range [IQR]: 64.0-77.0) and 73.5 (IQR: 68.0 -80.0) years old, and 300 (80.0%) and 42 (75.0%) patients were men, respectively. The Barcelona Clinic Liver Cancer stage was early, intermediate and advanced in 39 patients (10.4%), 133 patients (35.5%) and 203 patients (54.1%) in the sorafenib group and 1 patient (1.8%), 17 patients (30.4%) and 38 patients (67.9%) in the lenvatinib group, respectively. In the analysis of intermediate HCC, patients who satisfied the criteria of TACE failure/refractoriness (P=0.017), those with ALBI grade 1 (P=0.040), and those with a serum AFP level < 200 ng/ml (P=0.027) were found more frequently in the lenvatinib group than in the sorafenib group, with statistical significance. The objective response rate (ORR) of lenvatinib was 34.8% in the overall patients and 46.7% in the intermediate-stage HCC patients, which was significantly higher than sorafenib (P=0.001, P=0.017). CONCLUSIONS The emergence of lenvatinib has encouraged physicians to start systemic chemotherapy earlier in intermediatestage HCC patients.
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Affiliation(s)
- T Hatanaka
- Department of Gastroenterology, Gunma Saiseikai Maebashi Hospital
| | - S Kakizaki
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine
| | - T Nagashima
- Department of Gastroenterology, National Hospital Organization Shibukawa Medical Center
| | - T Ueno
- Department of Internal Medicine, Isesaki Municipal Hospital
| | - M Namikawa
- Department of Internal Medicine, Kiryu Kosei General Hospital
| | - H Tojima
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine
| | - D Takizawa
- Department of Gastroenterology, Maebashi Red Cross Hospital
| | - A Naganuma
- Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center
| | - H Arai
- Department of Gastroenterology, Maebashi Red Cross Hospital
| | - K Sato
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine
| | - N Harimoto
- Department of General Surgical Science, Gunma University Graduate School of Medicine
| | - K Shirabe
- Department of General Surgical Science, Gunma University Graduate School of Medicine
| | - T Uraoka
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine
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28
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Kaneko S, Tsuchiya K, Yasui Y, Inada K, Kirino S, Yamashita K, Osawa L, Hayakawa Y, Sekiguchi S, Higuchi M, Takaura K, Maeyashiki C, Tamaki N, Takeguchi T, Takeguchi Y, Nakanishi H, Itakura J, Takahashi Y, Himeno Y, Kurosaki M, Izumi N. Early radiological response evaluation with response evaluation criteria in solid tumors 1.1 stratifies survival in hepatocellular carcinoma patients treated with lenvatinib. JGH Open 2020; 4:1183-1190. [PMID: 33319054 PMCID: PMC7731835 DOI: 10.1002/jgh3.12420] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 08/20/2020] [Accepted: 09/05/2020] [Indexed: 12/29/2022]
Abstract
Background and Aim Lenvatinib (LEN) has an antitumor effect with an early reduction in contrast enhancement for unresectable hepatocellular carcinoma (HCC). The aim of this study was to reveal the most useful radiological response evaluation for overall survival (OS) in patients treated with LEN. Methods Patients receiving LEN therapy (n = 80) were retrospectively recruited from April 2018 to January 2020. Enhanced computed tomography scans were performed at baseline and every 4-8 weeks. OS and radiological response were evaluated using response evaluation criteria in solid tumors (RECIST 1.1), modified RECIST (mRECIST), and Choi criteria. To be eligible for study, a minimal cumulative duration of LEN was 4 weeks. A total of 62 patients were included in the analysis. Results The median OS was 469 days. The RECIST 1.1, mRECIST, and Choi criteria identified 14 (22.5%), 30 (48.3%), and 33 (53.2%) patients with an objective response, respectively. In the univariate analysis, Child-Pugh class B, major vascular invasion, and high alpha-fetoprotein (>200) were statistically significant poor prognostic factors. Radiological response was a significantly better prognostic factor in each criterion (RECIST, mRECIST, and Choi). In the multivariate analysis, radiological response evaluated by RECIST (hazard ratio, 0.259; 95% confidence interval, 0.0723-0.928; P = 0.038) was an independent factor. Furthermore, only RECIST significantly stratified prognosis (P = 0.041) when limited to the first evaluation. Conclusion RECIST 1.1 was useful even as early therapeutic evaluation for HCC patients treated with LEN. Understanding the characteristics of radiological response over time may contribute to improving the prognosis of patients with HCC.
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Affiliation(s)
- Shun Kaneko
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Kaoru Tsuchiya
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Yutaka Yasui
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Kento Inada
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Sakura Kirino
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Koji Yamashita
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Leona Osawa
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Yuka Hayakawa
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Shuhei Sekiguchi
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Mayu Higuchi
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Kenta Takaura
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Chiaki Maeyashiki
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Nobuharu Tamaki
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | | | - Yuko Takeguchi
- Department of RadiologyMusashino Red Cross HospitalTokyoJapan
| | - Hiroyuki Nakanishi
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Jun Itakura
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Yuka Takahashi
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Yoshiro Himeno
- Department of RadiologyMusashino Red Cross HospitalTokyoJapan
| | - Masayuki Kurosaki
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Namiki Izumi
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
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Kudo M. Limited Impact of Anti-PD-1/PD-L1 Monotherapy for Hepatocellular Carcinoma. Liver Cancer 2020; 9:629-639. [PMID: 33442537 PMCID: PMC7768125 DOI: 10.1159/000512170] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 10/07/2020] [Indexed: 02/04/2023] Open
Affiliation(s)
- Masatoshi Kudo
- *Masatoshi Kudo, Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 337-2 Ohnohigashi, Osaka-Sayama 589-8511 (Japan),
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Kudo M. Recent Advances in Systemic Therapy for Hepatocellular Carcinoma in an Aging Society: 2020 Update. Liver Cancer 2020; 9:640-662. [PMID: 33442538 PMCID: PMC7768150 DOI: 10.1159/000511001] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 08/17/2020] [Indexed: 02/04/2023] Open
Abstract
Systemic therapy for hepatocellular carcinoma (HCC) has changed markedly since the introduction of the molecular targeted agent sorafenib in 2007. Sorafenib increased the available treatment options for patients with extrahepatic spread and vascular invasion and improved survival in patients with advanced HCC; however, various shortcomings such as low response rates and relatively high toxicity (e.g., hand-foot skin reaction) prompted concerted efforts aimed at developing new molecular targeted agents to provide more treatment options and second-line agents for patients with disease progression or intolerance to sorafenib. Despite many attempts to develop new drugs between 2007 and 2016, all first-line and second-line clinical trials conducted during this period failed. However, between 2017 and 2019, 4 drugs (lenvatinib as a first-line agent and regorafenib, cabozantinib, and ramucirumab as second-line agents) emerged in quick succession from clinical trials and became available for clinical use. In addition, nivolumab and pembrolizumab were approved as second-line agents after sorafenib. A recent phase III trial (IMbrave150) showed that combination immunotherapy with atezolizumab plus bevacizumab increases overall survival compared with sorafenib therapy; Food and Drug Agency already approved this combination therapy, and worldwide approval is expected soon. This review describes the recent advances in systemic therapy and the use of tyrosine kinase inhibitors (sorafenib, lenvatinib, regorafenib, and cabozantinib), monoclonal antibodies (ramucirumab and bevacizumab), and immune checkpoint inhibitors (nivolumab, pembrolizumab, and atezolizumab) in elderly patients and the similarity of their efficacy and safety profiles to those in the general population.
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Affiliation(s)
- Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
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31
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Minamiguchi K, Tanaka T, Nishiofuku H, Fukuoka Y, Taiji R, Matsumoto T, Saito N, Taguchi H, Marugami N, Hirai T, Kichikawa K. Comparison of embolic effect between water-in-oil emulsion and microspheres in transarterial embolization for rat hepatocellular carcinoma model. Hepatol Res 2020; 50:1297-1305. [PMID: 32822527 DOI: 10.1111/hepr.13561] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 07/26/2020] [Accepted: 08/10/2020] [Indexed: 02/08/2023]
Abstract
AIM To compare two different embolic materials, water-in-oil (W/O) emulsion followed by gelatin particles and microspheres in transarterial embolization (TAE), using a rat hepatocellular carcinoma model. METHODS Twenty rats bearing N1S1 cells were divided into the W/O emulsion group and Microsphere group. Water-in-oil emulsion was created by a glass membrane emulsification device. The tumor vascularity was measured by contrast-enhanced ultrasonography 24 h before and 10 min and 48 h after TAE. Tumor necrosis, hepatic infarction ratio surrounding the tumor, and locations of the embolic materials 48 h after TAE were assessed. The changes of serum liver enzymes were also evaluated. Statistical significance was determined by using either the Mann-Whitney U-test or Fisher's exact test. RESULTS The tumor vascularity 48 h after TAE was significantly higher in the Microsphere group (20.1 vs. 3.76%, P = 0.016). The overflow of Lipiodol into the portal veins surrounding the tumor was seen, whereas microspheres were seen only in the artery. The percentage of necrotic area and complete response ratio in the W/O emulsion group was significantly higher (99.9 vs. 87.6%, P = 0.029 and 87.5 vs. 28.6%, P = 0.041, respectively). Serum aspartate aminotransferase and serum alanine aminotransferase levels 48 h after TAE were significantly higher in the W/O emulsion group (P < 0.01). CONCLUSIONS The embolization using W/O emulsion followed by gelatin particles showed stronger antitumor effects with the occlusion of both the tumor feeding artery and the portal vein compared with microspheres, which occluded only the arteries.
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Affiliation(s)
| | - Toshihiro Tanaka
- Department of Radiology, Nara Medical University, Kashihara, Japan
| | | | - Yasushi Fukuoka
- Department of Radiology, Nara Medical University, Kashihara, Japan
| | - Ryosuke Taiji
- Department of Radiology, Nara Medical University, Kashihara, Japan
| | | | - Natsuhiko Saito
- Department of Radiology, Nara Medical University, Kashihara, Japan
| | - Hidehiko Taguchi
- Department of Radiology, Nara Medical University, Kashihara, Japan
| | - Nagaaki Marugami
- Department of Radiology, Nara Medical University, Kashihara, Japan
| | - Toshiko Hirai
- Department of Radiology, Nara Medical University, Kashihara, Japan
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Kudo M. Gd-EOB-DTPA-MRI Could Predict WNT/β-Catenin Mutation and Resistance to Immune Checkpoint Inhibitor Therapy in Hepatocellular Carcinoma. Liver Cancer 2020. [PMID: 33083276 DOI: 10.1159/000509554.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Affiliation(s)
- Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
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Aoki T, Kudo M, Ueshima K, Morita M, Chishina H, Takita M, Hagiwara S, Ida H, Minami Y, Tsurusaki M, Nishida N. Exploratory Analysis of Lenvatinib Therapy in Patients with Unresectable Hepatocellular Carcinoma Who Have Failed Prior PD-1/PD-L1 Checkpoint Blockade. Cancers (Basel) 2020; 12:E3048. [PMID: 33092011 PMCID: PMC7590172 DOI: 10.3390/cancers12103048] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 10/08/2020] [Indexed: 12/25/2022] Open
Abstract
Although programmed cell death protein 1 (PD-1)/PD-ligand 1 (PD-L1) blockade is effective in a subset of patients with hepatocellular carcinoma (HCC), its therapeutic response is still unsatisfactory. Alternatively, the potential impact of the lenvatinib in patients who showed tumor progression on PD-1/PD-L1 blockade is unknown. In this work, we evaluated the safety and efficacy of lenvatinib administration after PD-1/PD-L1 checkpoint blockade. The outcome and safety of lenvatinib administered after PD-1/PD-L1 blockade failure was analyzed retrospectively in 36 patients. Tumor growth was assessed every 4-8 weeks using modified Response Evaluation Criteria in Solid Tumors. The mean relative dose intensity of lenvatinib was 87.6% and 77.8% in patients receiving a starting dose of 8 (interquartile range (IQR), 77.5-100.0) mg and 12 (IQR, 64.4-100.0) mg, respectively. Since lenvatinib therapy initiation, the median progression-free survival was 10 months (95% confidence interval (CI): 8.3-11.8) and the median overall survival was 15.8 months (95% CI: 8.5-23.2). The objective response rate was 55.6%, and the disease control rate was 86.1%. No particular safety concerns were observed. Lenvatinib demonstrated considerable antitumor effects with acceptable safety in patients with progressive and unresectable HCC when administered right after PD-1/PD-L1 blockade failure.
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Affiliation(s)
- Tomoko Aoki
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511, Japan; (T.A.); (K.U.); (M.M.); (H.C.); (M.T.); (S.H.); (H.I.); (Y.M.); (N.N.)
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511, Japan; (T.A.); (K.U.); (M.M.); (H.C.); (M.T.); (S.H.); (H.I.); (Y.M.); (N.N.)
| | - Kazuomi Ueshima
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511, Japan; (T.A.); (K.U.); (M.M.); (H.C.); (M.T.); (S.H.); (H.I.); (Y.M.); (N.N.)
| | - Masahiro Morita
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511, Japan; (T.A.); (K.U.); (M.M.); (H.C.); (M.T.); (S.H.); (H.I.); (Y.M.); (N.N.)
| | - Hirokazu Chishina
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511, Japan; (T.A.); (K.U.); (M.M.); (H.C.); (M.T.); (S.H.); (H.I.); (Y.M.); (N.N.)
| | - Masahiro Takita
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511, Japan; (T.A.); (K.U.); (M.M.); (H.C.); (M.T.); (S.H.); (H.I.); (Y.M.); (N.N.)
| | - Satoru Hagiwara
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511, Japan; (T.A.); (K.U.); (M.M.); (H.C.); (M.T.); (S.H.); (H.I.); (Y.M.); (N.N.)
| | - Hiroshi Ida
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511, Japan; (T.A.); (K.U.); (M.M.); (H.C.); (M.T.); (S.H.); (H.I.); (Y.M.); (N.N.)
| | - Yasunori Minami
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511, Japan; (T.A.); (K.U.); (M.M.); (H.C.); (M.T.); (S.H.); (H.I.); (Y.M.); (N.N.)
| | - Masakatsu Tsurusaki
- Department of Radiology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511, Japan;
| | - Naoshi Nishida
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511, Japan; (T.A.); (K.U.); (M.M.); (H.C.); (M.T.); (S.H.); (H.I.); (Y.M.); (N.N.)
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Liu Z, Fu Z, Li G, Lin D. Downstaging of Recurrent Advanced Hepatocellular Carcinoma After Lenvatinib Treatment: Opportunities or Pitfalls? A Case Report. Onco Targets Ther 2020; 13:10267-10273. [PMID: 33116607 PMCID: PMC7568629 DOI: 10.2147/ott.s261521] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 08/18/2020] [Indexed: 12/24/2022] Open
Abstract
Background The majority of patients with hepatocellular carcinoma (HCC) are diagnosed at an advanced stage that excludes them from potentially curative surgical treatment. Lenvatinib is associated with a high objective response rate (ORR) (40.6%) in advanced HCC, indicating the potential for tumor downstaging and conversion to surgical intervention. We report the case of a patient with recurrent, advanced HCC who achieved a partial response and downstaging following third-line treatment with lenvatinib but missed the opportunity for conversion hepatectomy. Case Presentation A male Chinese patient aged 42 years presented with an obstructive liver lesion, revealed by CT imaging to be a single tumor in segments V and VIII of the liver, without macrovascular invasion. The patient had chronic hepatitis B infection, Barcelona Clinic Liver Cancer (BCLC) Stage A, normal liver function (Child-Pugh Score 5 and Grade A) and AFP level 4.45 ng/mL. The patient underwent a successful hepatectomy but experienced recurrence 14 months later. The recurrent tumor was detected at an early stage and the patient underwent successful radiofrequency ablation and transarterial chemoembolization. After a further 11 months, the patient experienced a second relapse characterized by multiple disseminated metastases in the left and right lobes of the liver and possible macrovascular invasion, equal to BCLC Stage B/C. The patient received lenvatinib and achieved a partial response with complete disappearance of a number of lesions, recovering to BCLC Stage A and becoming eligible for liver transplantation. However, the patient refused surgery and after 4 months experienced progressive disease. Conclusion Our case suggests that radical treatment, such as conversion hepatectomy or liver transplantation, should be undertaken quickly following downstaging and within the expected PFS time associated with lenvatinib. However, further studies are required to provide additional evidence for this treatment strategy.
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Affiliation(s)
- Zhaobo Liu
- Department of General Surgery, Beijing Youan Hospital, Capital Medical University, Beijing 100069, People's Republic of China
| | - Zhi Fu
- Department of General Surgery, Beijing Youan Hospital, Capital Medical University, Beijing 100069, People's Republic of China
| | - Guangming Li
- Department of General Surgery, Beijing Youan Hospital, Capital Medical University, Beijing 100069, People's Republic of China
| | - Dongdong Lin
- Department of General Surgery, Beijing Youan Hospital, Capital Medical University, Beijing 100069, People's Republic of China
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Influence of NOS3 rs2070744 genotypes on hepatocellular carcinoma patients treated with lenvatinib. Sci Rep 2020; 10:17054. [PMID: 33051476 PMCID: PMC7553969 DOI: 10.1038/s41598-020-73930-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 09/23/2020] [Indexed: 12/19/2022] Open
Abstract
We investigated whether or not nitric oxide synthase 3 (NOS3) rs2070744 genotypes can affect the response for lenvatinib treatment in patients with hepatocellular carcinoma (HCC). We evaluated the relation of the NOS3 rs2070744 genotypes to the tumor response, progression-free survival (PFS), and overall survival (OS) as the response for lenvatinib. We also examined the association between fibroblast growth factor receptor (FGFR) gene polymorphisms, a potential feature of lenvatinib, and the response. There were no significant differences between the studies for either PFS or OS, even though patients with the TT genotype had a longer mean PFS (hazard ratio [HR] 0.60; p = 0.069) and mean OS (HR 0.46; p = 0.075) than those with the TC/CC genotypes. However, patients with a single-nucleotide polymorphism (SNP) combination pattern of the NOS3 rs2070744 TC/CC and FGFR4 rs351855 CT/TT genotypes had a significantly shorter mean PFS (HR 2.56; p = 0.006) and mean OS (HR 3.36; p = 0.013) than those with the other genotypes. The NOS3 rs2070744 genotypes did not influence the clinical response. However, the SNP combination pattern of the NOS3 rs2070744 and FGFR4 rs351855 genotypes may be helpful as treatment effect predictors and prognostic factors for HCC patients treated with lenvatinib.
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36
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Saito N, Tanaka T, Nishiohuku H, Sato T, Masada T, Matsumoto T, Anai H, Sakaguchi H, Sueyoshi S, Marugami N, Kichikawa K. Transarterial- chemoembolization remains an effective therapy for intermediate-stage hepatocellular carcinoma with preserved liver function. Hepatol Res 2020; 50:1176-1185. [PMID: 32721060 DOI: 10.1111/hepr.13550] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 07/06/2020] [Accepted: 07/19/2020] [Indexed: 12/11/2022]
Abstract
AIM To evaluate outcomes as well as prognostic factors of transarterial chemoembolization (TACE) in intermediate-stage hepatocellular carcinoma (HCC) with preserved liver function to determine positioning of TACE. METHODS Of 158 treatment-naïve patients with intermediate-stage HCC who received initial TACE from February 2007 to January 2016, 113 patients met the following inclusion criteria: no combined therapy within 4 weeks after initial TACE, and Child-Pugh score under 7. Response rate and overall survival were evaluated. The prognostic factors were investigated in univariate and multivariate analyses using Cox proportional hazards models. The deterioration of liver function after repeated TACE was also evaluated. RESULTS The response rate was 92.7% (complete response, 63.3%; partial response, 29.4%). The median survival time was 45.2 months. Survival rates at 1, 2, and 3 years were 90.4%, 77.0%, and 60.8% respectively. Age ≥ 75 years (P = 0.022), serum α-fetoprotein level ≥ 200 ng/mL (P = .010), tumor number ≥ 11 (P = 0.008), and heterogeneous enhancement on dynamic computed tomography (P = 0.024) were poor prognostic factors. The deterioration rate of Child-Pugh score and albumin-bilirubin grade was 18.5% and 12.3%, respectively, after the first TACE, 15.6% and 5.1%, respectively, after the second TACE, and 14.5% and 11.1%, respectively, after the third TACE. CONCLUSION Superselective TACE can achieve high tumor response rates with prolonged overall survival for patients with intermediate-stage HCC with preserved liver function. Age, serum α-fetoprotein level, tumor number ≥ 11, and heterogeneous enhancement on dynamic computed tomography indicated significantly poor prognosis.
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Affiliation(s)
- Natsuhiko Saito
- Department of Radiology, IVR Center, Nara Medical University, Kashihara, Japan
| | - Toshihiro Tanaka
- Department of Radiology, IVR Center, Nara Medical University, Kashihara, Japan
| | - Hideyuki Nishiohuku
- Department of Radiology, IVR Center, Nara Medical University, Kashihara, Japan
| | - Takeshi Sato
- Department of Radiology, IVR Center, Nara Medical University, Kashihara, Japan
| | - Tetsuya Masada
- Department of Radiology, IVR Center, Nara Medical University, Kashihara, Japan
| | - Takeshi Matsumoto
- Department of Radiology, IVR Center, Nara Medical University, Kashihara, Japan
| | - Hiroshi Anai
- Department of Radiology, Nara City Hospital, Nara, Japan
| | | | - Satoru Sueyoshi
- Department of Radiology, Saiseikai Chuwa Hospital, Sakurai, Japan
| | - Nagaaki Marugami
- Department of Radiology, IVR Center, Nara Medical University, Kashihara, Japan
| | - Kimihiko Kichikawa
- Department of Radiology, IVR Center, Nara Medical University, Kashihara, Japan
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Kudo M. Gd-EOB-DTPA-MRI Could Predict WNT/β-Catenin Mutation and Resistance to Immune Checkpoint Inhibitor Therapy in Hepatocellular Carcinoma. Liver Cancer 2020; 9:479-490. [PMID: 33083276 PMCID: PMC7548850 DOI: 10.1159/000509554] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Accepted: 06/18/2020] [Indexed: 02/04/2023] Open
Affiliation(s)
- Masatoshi Kudo
- *Masatoshi Kudo, Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 337-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511 (Japan),
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38
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Kudo M, Kurosaki M, Ikeda M, Aikata H, Hiraoka A, Torimura T, Sakamoto N. Treatment of hepatocellular carcinoma during the COVID-19 outbreak: The Working Group report of JAMTT-HCC. Hepatol Res 2020; 50:1004-1014. [PMID: 32583525 PMCID: PMC7361293 DOI: 10.1111/hepr.13541] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 06/15/2020] [Accepted: 06/17/2020] [Indexed: 01/08/2023]
Abstract
This contingency guide was formulated on the premise that delivering standard treatment for hepatocellular carcinoma (HCC) has come under strain due to the coronavirus (COVID-19) pandemic. Measures required are likely to vary largely across regions and individual institutions, depending on the level of the strain imposed by the pandemic (e.g., number of inpatients infected with COVID-19 and the availability of resources, including personal protective equipment and inpatient beds). In addition, models suggest that the second and third waves of COVID-19 will occur before effective vaccines and medicines become widely available in Japan (expected time, 2-3 years). This guide should serve as a good reference for best practices in the management of HCC, which is in light of the possible risk of impending collapse of the healthcare system due to a surge in COVID-19 infections.
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Affiliation(s)
- Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Faculty of MedicineKindai University
| | - Masayuki Kurosaki
- Department of Gastroenterology and HepatologyMusashino Red Cross Hospital
| | - Masafumi Ikeda
- Department of Hepatobiliary and Pancreatic OncologyNational Cancer Center Hospital East
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health ScienceHiroshima University
| | - Atsushi Hiraoka
- Department of GastroenterologyEhime Prefectural Central Hospital
| | - Takuji Torimura
- Division of Gastroenterology, Department of MedicineKurume University School of Medicine
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Graduate School of MedicineHokkaido University
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Wang DX, Yang X, Lin JZ, Bai Y, Long JY, Yang XB, Seery S, Zhao HT. Efficacy and safety of lenvatinib for patients with advanced hepatocellular carcinoma: A retrospective, real-world study conducted in China. World J Gastroenterol 2020. [PMID: 32874058 DOI: 10.3748/wjg.v26.i30.4465.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Lenvatinib has become an indispensable part of treatment regimens for patients with advanced hepatocellular carcinoma (aHCC). Several recent real-world studies appear to have confirmed this; however, there are etiological differences. This necessitates further real-world studies of lenvatinib across diverse populations, such as in China. AIM To investigate the efficacy and safety of lenvatinib in a Chinese HCC patient population under real-world conditions. METHODS This is a retrospective and multiregional study involving patients with aHCC receiving lenvatinib monotherapy. Efficacy was assessed using the Response Evaluation Criteria in Solid Tumors version 1.1. Baseline characteristics and adverse events (AEs) were recorded throughout the entire study. RESULTS In total, 54 HCC patients treated with lenvatinib monotherapy were included for final analysis. The objective response rate was 22% (n = 12) with a progression-free survival (PFS) of 168 d; however, AEs occurred in 92.8% of patients. Multivariate analysis showed that the Barcelona Clinic Liver Cancer stage [hazard ratio (HR) 0.465; 95%CI: 0.23-0.93; P = 0.031], portal vein tumor thrombus (HR 0.38; 95%CI: 0.15-0.94; P = 0.037) and Child-Pugh classifications (HR 0.468; 95%CI: 0.22-0.97; P = 0.042) were significant factors affecting PFS. The sensitivity (56.7%) and specificity (83.3%) of decreasing serum biomarkers including alpha-fetoprotein were calculated in order to predict tumor size reduction. Gene sequencing also provided insights into potential gene mutation signatures related to the effect of lenvatinib. CONCLUSION Our findings confirm previous evidence from the phase III REFLECT study. The majority of patients in this Chinese sample were suffering from concomitant hepatitis B virus-related HCC. However, further analysis suggested that baseline characteristics, changes in serum biomarkers and gene sequencing may hold the key for predicting lenvatinib responses. Further large-scale prospective studies that incorporate more basic medical science measures should be conducted.
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Affiliation(s)
- Dong-Xu Wang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Xu Yang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Jian-Zhen Lin
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Yi Bai
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Jun-Yu Long
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Xiao-Bo Yang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Samuel Seery
- Department of Humanities, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Hai-Tao Zhao
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
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40
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Wang DX, Yang X, Lin JZ, Bai Y, Long JY, Yang XB, Seery S, Zhao HT. Efficacy and safety of lenvatinib for patients with advanced hepatocellular carcinoma: A retrospective, real-world study conducted in China. World J Gastroenterol 2020; 26:4465-4478. [PMID: 32874058 PMCID: PMC7438196 DOI: 10.3748/wjg.v26.i30.4465] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Revised: 04/25/2020] [Accepted: 07/04/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Lenvatinib has become an indispensable part of treatment regimens for patients with advanced hepatocellular carcinoma (aHCC). Several recent real-world studies appear to have confirmed this; however, there are etiological differences. This necessitates further real-world studies of lenvatinib across diverse populations, such as in China.
AIM To investigate the efficacy and safety of lenvatinib in a Chinese HCC patient population under real-world conditions.
METHODS This is a retrospective and multiregional study involving patients with aHCC receiving lenvatinib monotherapy. Efficacy was assessed using the Response Evaluation Criteria in Solid Tumors version 1.1. Baseline characteristics and adverse events (AEs) were recorded throughout the entire study.
RESULTS In total, 54 HCC patients treated with lenvatinib monotherapy were included for final analysis. The objective response rate was 22% (n = 12) with a progression-free survival (PFS) of 168 d; however, AEs occurred in 92.8% of patients. Multivariate analysis showed that the Barcelona Clinic Liver Cancer stage [hazard ratio (HR) 0.465; 95%CI: 0.23-0.93; P = 0.031], portal vein tumor thrombus (HR 0.38; 95%CI: 0.15-0.94; P = 0.037) and Child-Pugh classifications (HR 0.468; 95%CI: 0.22-0.97; P = 0.042) were significant factors affecting PFS. The sensitivity (56.7%) and specificity (83.3%) of decreasing serum biomarkers including alpha-fetoprotein were calculated in order to predict tumor size reduction. Gene sequencing also provided insights into potential gene mutation signatures related to the effect of lenvatinib.
CONCLUSION Our findings confirm previous evidence from the phase III REFLECT study. The majority of patients in this Chinese sample were suffering from concomitant hepatitis B virus-related HCC. However, further analysis suggested that baseline characteristics, changes in serum biomarkers and gene sequencing may hold the key for predicting lenvatinib responses. Further large-scale prospective studies that incorporate more basic medical science measures should be conducted.
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Affiliation(s)
- Dong-Xu Wang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Xu Yang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Jian-Zhen Lin
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Yi Bai
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Jun-Yu Long
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Xiao-Bo Yang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Samuel Seery
- Department of Humanities, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Hai-Tao Zhao
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
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Kudo M. A new era of systemic therapy for intermediate and advanced stage hepatocellular carcinoma. Hepatobiliary Surg Nutr 2020; 9:530-533. [PMID: 32832511 DOI: 10.21037/hbsn-20-420] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
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Deng H, Kan A, Lyu N, Mu L, Han Y, Liu L, Zhang Y, Duan Y, Liao S, Li S, Xie Q, Gao T, Li Y, Zhang Z, Zhao M. Dual Vascular Endothelial Growth Factor Receptor and Fibroblast Growth Factor Receptor Inhibition Elicits Antitumor Immunity and Enhances Programmed Cell Death-1 Checkpoint Blockade in Hepatocellular Carcinoma. Liver Cancer 2020; 9:338-357. [PMID: 32647635 PMCID: PMC7325120 DOI: 10.1159/000505695] [Citation(s) in RCA: 118] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Accepted: 12/28/2019] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND AND AIMS Combining anti-angiogenic therapy with immune checkpoint blockade with anti-programmed cell death-1 (PD-1) antibodies is a promising treatment for hepatocellular carcinoma (HCC). Tyrosine kinase inhibitors are well-known anti-angiogenic agents and offer potential for combination with anti-PD-1 antibodies. This study investigated the possible underlying immunomodulatory mechanisms of combined therapy. METHODS HCC tissue samples for RNA-sequencing (RNA-seq) were obtained from patients with differential prognoses following anti-PD-1 treatment. Recombinant basic fibroblast growth factor (bFGF) and vascular endothelial growth factor A (VEGFA) were used to stimulate T cells following lenvatinib or sorafenib treatment, respectively. T cell function was analyzed by flow cytometry and lactate dehydrogenase assay. In vivo experiments were conducted in murine H22 and Hepa 1-6 competent models of HCC. Local immune infiltration in the tumor microenvironment (TME) was assessed using multicolor flow cytometry. Gene regulation was evaluated by RNA-seq. Microvascular density was measured by immunohistochemistry, and PD-1 ligand (PD-L1) induction was quantified by western blot. RESULTS The baseline expression of VEGF and fibroblast growth factor (FGF) in patients with progressive disease was significantly higher than in patients achieving stable disease following anti-PD-1 treatment. VEGFA and bFGF significantly upregulated the expression of PD-1, cytotoxic T-lymphocyte-associated protein-4, and Tim-3 on T cells, while inhibiting the secretion of interferon gamma (IFNG) and granzyme B and suppressing T cell cytotoxicity. This immunosuppressive effect was reverted by lenvatinib but not sorafenib. Furthermore, dual lenvatinib/anti-PD-1 antibody therapy led to better antitumor effects than either sorafenib or fibroblast growth factor receptor (FGFR) inhibitor (BGJ398) in H22 murine models of HCC. Combined lenvatinib/anti-PD-1 treatment also led to long-term immune memory formation, while synergistically modulating the TME and enhancing the cytotoxic effect of T cells. Finally, lenvatinib inhibited PD-L1 expression on human umbilical vein endothelial cells, which improved the function of T cells. CONCLUSIONS Inhibition of vascular endothelial growth factor receptor and FGFR augmented the efficacy of anti-PD-1 antibodies. Combined lenvatinib/anti-PD-1 treatment appears to exert antitumor activity by synergistically modulating effector T cell function in the TME and by mutually regulating tumor vessel normalization.
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Affiliation(s)
- Haijing Deng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China,Division of Minimally Invasive Interventional, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Anna Kan
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China,Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Ning Lyu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China,Division of Minimally Invasive Interventional, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Luwen Mu
- Department of Vascular Interventional Radiology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yi Han
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Longzhong Liu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China,Department of Ultrasonics, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yanyu Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Youfa Duan
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Shuangye Liao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Shaolong Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Qiankun Xie
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China,VIP Region, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Tianxiao Gao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China,Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yanrong Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China,Division of Minimally Invasive Interventional, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Zhenfeng Zhang
- Department of Radiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Ming Zhao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China,Division of Minimally Invasive Interventional, Sun Yat-sen University Cancer Center, Guangzhou, China,*Prof. Ming Zhao, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060 (PR China),
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Kudo M. Better Efficacy of Ramucirumab in Japanese Patients than in the Global Population with Unresectable Hepatocellular Carcinoma. Liver Cancer 2020; 9:232-244. [PMID: 32884915 PMCID: PMC7443680 DOI: 10.1159/000507889] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 04/11/2020] [Indexed: 02/04/2023] Open
Affiliation(s)
- Masatoshi Kudo
- *Masatoshi Kudo, Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 337-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511 (Japan),
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Kudo M, Han KH, Ye SL, Zhou J, Huang YH, Lin SM, Wang CK, Ikeda M, Chan SL, Choo SP, Miyayama S, Cheng AL. A Changing Paradigm for the Treatment of Intermediate-Stage Hepatocellular Carcinoma: Asia-Pacific Primary Liver Cancer Expert Consensus Statements. Liver Cancer 2020; 9:245-260. [PMID: 32647629 PMCID: PMC7325125 DOI: 10.1159/000507370] [Citation(s) in RCA: 197] [Impact Index Per Article: 39.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Accepted: 03/11/2020] [Indexed: 02/04/2023] Open
Abstract
The Asia-Pacific Primary Liver Cancer Expert (APPLE) Consensus Statement on the treatment strategy for patients with intermediate-stage hepatocellular carcinoma (HCC) was established on August 31, 2019, in Sapporo, Hokkaido during the 10th Annual APPLE Meeting. This manuscript summarizes the international consensus statements developed at APPLE 2019. Transarterial chemoembolization (TACE) is the only guideline-recommended global standard of care for intermediate-stage HCC. However, not all patients benefit from TACE because intermediate-stage HCC is a heterogeneous disease in terms of tumor burden and liver function. Ten important clinical questions regarding this stage of HCC were raised, and consensus statements were generated based on high-quality evidence. In intermediate-stage HCC, preservation of liver function is as important as achieving a high objective response (OR) because the treatment goal is to prolong overall survival. Superselective conventional TACE (cTACE) is recommended as the first choice of treatment in patients eligible for effective (curative) TACE, whereas in patients who are not eligible, systemic therapy is recommended as the first choice of treatment. TACE is not indicated as the first-line therapy in TACE-unsuitable patients. Another important statement is that TACE should not be continued in patients who develop TACE failure/refractoriness in order to preserve liver function. Targeted therapy is the recommended first-line treatment for TACE-unsuitable patients. Especially, the drug, which can have higher OR rate, is preferred. Immunotherapy, transarterial radioembolization, TACE + targeted therapy or other modalities may be considered alternative options in TACE-unsuitable patients who are not candidates for targeted therapy. Better liver function, such as albumin-bilirubin grade 1, is an important factor for maximizing the therapeutic effect of systemic therapy.
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Affiliation(s)
- Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Kwang-Hyub Han
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sheng-Long Ye
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jian Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yi-Hsiang Huang
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Shi-Ming Lin
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou, Taiwan
- College of Medicine, Chang Gung University, Taoyuan City, Taiwan
| | - Chung-Kwe Wang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taipei City Hospital, Ren-Ai Branch and Kang Ning Hospital, Taipei, Taiwan
| | - Masafumi Ikeda
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa-shi, Japan
| | - Stephen Lam Chan
- Department of Clinical Oncology, State Key Laboratory of Translation Oncology, The Chinese University of Hong Kong, Hong Kong, China
| | - Su Pin Choo
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Shiro Miyayama
- Department of Diagnostic Radiology, Fukui-ken Saiseikai Hospital, Fukui, Japan
| | - Ann Lii Cheng
- Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Oncology, School of Medicine, National Taiwan University, Taipei, Taiwan
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Kuzuya T, Ishigami M, Ito T, Ishizu Y, Honda T, Ishikawa T, Fujishiro M. Favorable radiological antitumor response at 2 weeks after starting lenvatinib for patients with advanced hepatocellular carcinoma. Hepatol Res 2020; 50:374-381. [PMID: 31721363 DOI: 10.1111/hepr.13452] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2019] [Revised: 10/22/2019] [Accepted: 11/01/2019] [Indexed: 02/08/2023]
Abstract
AIM We aimed to investigate the radiological antitumor response at 2 weeks after starting lenvatinib for patients with advanced hepatocellular carcinoma in real-world practice. METHODS This retrospective study enrolled 40 patients who received lenvatinib. Radiological antitumor response was evaluated according to the modified Response Evaluation Criteria in Solid Tumors. RESULTS The objective response rate at 2 weeks and best overall response on confirmation of complete response, partial response (PR), and stable disease required (confirmed response) were 57.5% and 32.5%, respectively. Based on confirmed response, the overall survival rate was significantly longer in patients with an objective response rate than in those with stable disease or progressive disease after 12 months (73.2% and 54.2%, P = 0.0358). All 13 patients with an objective response rate on confirmed response were evaluated as PR at 2 weeks. The alpha-fetoprotein ratio at 2 weeks was a significant factor associated with PR of response rate at 2 weeks. The median relative dose intensity from 2 to 6 weeks was significantly lower than that from 0 to 2 weeks (69.6% vs. 100%, P < 0.0001). Stratified by the antitumor response at 6 weeks considering the image evaluation at 2 weeks, the median relative dose intensity from 2 to 6 weeks was significantly lower in patients with progressive disease than in those with PR or stable disease (45.2% vs. 72.6%, P = 0.0482). CONCLUSIONS The radiological antitumor response at 2 weeks was favorable. Information on a favorable visible therapeutic response very early after lenvatinib initiation can help patients maintain their motivation for treatment, and allow physicians to continue treatment effectively and safely.
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Affiliation(s)
- Teiji Kuzuya
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masatoshi Ishigami
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takanori Ito
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoji Ishizu
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takashi Honda
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tetsuya Ishikawa
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Mitsuhiro Fujishiro
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Hatanaka T, Kakizaki S, Nagashima T, Namikawa M, Tojima H, Shimada Y, Takizawa D, Naganuma A, Arai H, Sato K, Harimoto N, Shirabe K, Uraoka T. Analyses of objective response rate, progression-free survival, and adverse events in hepatocellular carcinoma patients treated with lenvatinib: A multicenter retrospective study. Hepatol Res 2020; 50:382-395. [PMID: 31760660 DOI: 10.1111/hepr.13460] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2019] [Revised: 10/20/2019] [Accepted: 11/04/2019] [Indexed: 12/12/2022]
Abstract
AIM The aim of this study was to investigate the predictive factors of objective response rate (ORR) and progression-free survival (PFS), and the correlation of albumin-bilirubin (ALBI) grade with decreased appetite and fatigue in hepatocellular carcinoma patients treated with lenvatinib. METHODS From March 2018 to December 2018, a total of 94 patients was included in this retrospective multicenter study. RESULTS The median age of all patients was 73 years (interquartile range 66-79.3 years), and approximately 78% patients were men. The ALBI grade was 1, 2, and 3 in 27 (28.7%), 64 (68.1%), and three patients (3.2%), respectively. The Barcelona Clinic Liver Cancer stage was early, intermediate, and advanced in one (1.1%), 22 (23.4%), and 71 patients (75.5%), respectively. Best radiological response was determined to complete response, partial response, stable disease, and progressive disease in 0 (0.0%), 24 (30.4%), 38 (48.1%), and 17 patients (21.5%), respectively, giving the ORR of 30.4%. The 3-, 6-, and 12-month PFS was calculated to be 78.7% (95% CI 70.3-87.1%), 46.7% (95% CI 36.1-57.3%), and 17.4% (95% CI 6.6-28.2%). Multivariate analysis showed that the Barcelona Clinic Liver Cancer intermediate stage was shown to be the only significant factor affecting the ORR (odds ratio 3.78, 95% CI 1.14-12.5, P = 0.030) and PFS (hazard ratio 0.49, 95% CI 0.26-0.94, P = 0.030). The incidence of all grades of decreased appetite and fatigue was significantly less in patients with ALBI grade 1 compared with ALBI grade 2 + 3. CONCLUSIONS The Barcelona Clinic Liver Cancer intermediate stage was the predictive factor affecting the ORR and PFS, and ALBI grade was a good predictive factor affecting the incidence of fatigue and decreased appetite.
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Affiliation(s)
- Takeshi Hatanaka
- Department of Gastroenterology, Gunma Saiseikai Maebashi Hospital
| | - Satoru Kakizaki
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine
| | - Tamon Nagashima
- Department of Gastroenterology, National Hospital Organization Shibukawa Medical Center
| | | | - Hiroki Tojima
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine
| | | | | | - Atsushi Naganuma
- Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center
| | - Hirotaka Arai
- Department of Gastroenterology, Maebashi Red Cross Hospital
| | - Ken Sato
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine
| | - Norifumi Harimoto
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University Graduate School of Medicine
| | - Ken Shirabe
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University Graduate School of Medicine
| | - Toshio Uraoka
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine
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Sho T, Suda G, Ogawa K, Kimura M, Shimazaki T, Maehara O, Shigesawa T, Suzuki K, Nakamura A, Ohara M, Umemura M, Kawagishi N, Natsuizaka M, Nakai M, Morikawa K, Furuya K, Baba M, Yamamoto Y, Kobayashi T, Meguro T, Saga A, Miyagishima T, Yokoo H, Kamiyama T, Taketomi A, Sakamoto N. Early response and safety of lenvatinib for patients with advanced hepatocellular carcinoma in a real-world setting. JGH Open 2020; 4:54-60. [PMID: 32055698 PMCID: PMC7008153 DOI: 10.1002/jgh3.12209] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Revised: 04/24/2019] [Accepted: 05/04/2019] [Indexed: 02/05/2023]
Abstract
BACKGROUND AND AIM Lenvatinib has been recently approved as a first-line systematic therapy for patients with advanced hepatocellular carcinoma (HCC) based on the results of the phase 3 clinical trial REFLECT. This trial excluded patients with a history of systemic chemotherapy, bile duct invasion, and Child-Pugh grade B. We aimed to investigate the efficacy and safety of lenvatinib for these patients and in the real-world setting. METHODS Among patients who were administered lenvatinib for advanced HCC between April and October 2018 in Hokkaido University Hospital and related hospitals, we evaluated those who were followed for more than 2 months and whose treatment response was evaluated via dynamic computed tomography at baseline and 2 months after treatment initiation. Meanwhile, patients were excluded if they had decompensated liver cirrhosis, were followed up less than 2 months, or were not evaluated at 2 months. Patients were also stratified according to compliance with the REFLECT inclusion criteria for further analysis. RESULTS A total of 41 patients were included; more than 50% did not meet the REFLECT inclusion criteria. In total, 5 (12.2%), 20 (48.8%), 12 (29.3%), and 4 (9.3%) showed complete response, partial response, stable disease, and progressive disease, respectively. The objective response rate was 61.2%. The objective response rate and disease control rate were similar between patients who did and did not meet the REFLECT inclusion criteria. Moreover, the safety profile was also similar between the two patient groups. CONCLUSION Lenvatinib showed high early response rate and tolerability in patients with advanced HCC. Favorable outcomes were similarly observed in patients who did not meet the REFLECT inclusion criteria.
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Affiliation(s)
- Takuya Sho
- Department of Gastroenterology and Hepatology, Graduate School of MedicineHokkaido UniversitySapporoJapan
| | - Goki Suda
- Department of Gastroenterology and Hepatology, Graduate School of MedicineHokkaido UniversitySapporoJapan
| | - Koji Ogawa
- Department of Gastroenterology and Hepatology, Graduate School of MedicineHokkaido UniversitySapporoJapan
| | - Megumi Kimura
- Department of Gastroenterology and Hepatology, Graduate School of MedicineHokkaido UniversitySapporoJapan
| | - Tomoe Shimazaki
- Department of Gastroenterology and Hepatology, Graduate School of MedicineHokkaido UniversitySapporoJapan
| | - Osamu Maehara
- Department of Gastroenterology and Hepatology, Graduate School of MedicineHokkaido UniversitySapporoJapan
| | - Taku Shigesawa
- Department of Gastroenterology and Hepatology, Graduate School of MedicineHokkaido UniversitySapporoJapan
| | - Kazuharu Suzuki
- Department of Gastroenterology and Hepatology, Graduate School of MedicineHokkaido UniversitySapporoJapan
| | - Akihisa Nakamura
- Department of Gastroenterology and Hepatology, Graduate School of MedicineHokkaido UniversitySapporoJapan
| | - Masatsugu Ohara
- Department of Gastroenterology and Hepatology, Graduate School of MedicineHokkaido UniversitySapporoJapan
| | - Machiko Umemura
- Department of Gastroenterology and Hepatology, Graduate School of MedicineHokkaido UniversitySapporoJapan
| | - Naoki Kawagishi
- Department of Gastroenterology and Hepatology, Graduate School of MedicineHokkaido UniversitySapporoJapan
| | - Mitsuteru Natsuizaka
- Department of Gastroenterology and Hepatology, Graduate School of MedicineHokkaido UniversitySapporoJapan
| | - Masato Nakai
- Department of Gastroenterology and Hepatology, Graduate School of MedicineHokkaido UniversitySapporoJapan
| | - Kenichi Morikawa
- Department of Gastroenterology and Hepatology, Graduate School of MedicineHokkaido UniversitySapporoJapan
| | - Ken Furuya
- Department of Gastroenterology and HepatologyJapan Community Health Care Organization, Hokkaido HospitalSapporoJapan
| | - Masaru Baba
- Department of Gastroenterology and HepatologyJapan Community Health Care Organization, Hokkaido HospitalSapporoJapan
| | | | | | | | | | | | - Hideki Yokoo
- Hokkaido University, Gastroenterological Surgery 1 Sapporo, Graduate School of MedicineHokkaido UniversitySapporoJapan
| | - Toshiya Kamiyama
- Hokkaido University, Gastroenterological Surgery 1 Sapporo, Graduate School of MedicineHokkaido UniversitySapporoJapan
| | - Akinobu Taketomi
- Hokkaido University, Gastroenterological Surgery 1 Sapporo, Graduate School of MedicineHokkaido UniversitySapporoJapan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Graduate School of MedicineHokkaido UniversitySapporoJapan
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Kariyama K, Nouso K, Wakuta A, Oonishi A, Toyoda H, Tada T, Hiraoka A, Tsuji K, Itobayashi E, Ishikawa T, Takaguchi K, Tsutsui A, Shimada N, Kumada T. Treatment of Intermediate-Stage Hepatocellular Carcinoma in Japan: Position of Curative Therapies. Liver Cancer 2020; 9:41-49. [PMID: 32071908 PMCID: PMC7024876 DOI: 10.1159/000502479] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2019] [Accepted: 08/02/2019] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Transcatheter arterial chemoembolization (TACE) is the standard therapy for intermediate-stage (IM) hepatocellular carcinoma (HCC). However, IM-HCC includes various clinical conditions, and various therapies were conducted in practice. In this study, we retrospectively analyzed the actually conducted treatments for IM-HCC and their efficacies to elucidate the treatment strategies suitable for IM-HCC. METHODS This study included 627 IM-HCC of 5,260 HCC from 9 hospitals. We examined the treatment strategies of these patients and analyzed the efficacy of each therapy with the Cox proportional hazard model and propensity score-matched analysis. RESULTS Liver resection, radiofrequency ablation (RFA), and TACE were performed in 165, 108, and 351 patients, respectively. Liver resection and RFA were preferably selected in cases of Barcelona Clinic Liver Cancer (BCLC)-B1/B2, and patient survival was significantly longer than in those treated with TACE (p< 0.0001). However, no beneficial effect of these active therapies was observed in cases of BCLC-B3/B4. Multivariate analysis revealed that surgical resection (hazard ratio = 0.384) and RFA (hazard ratio = 0.597) were negative risk factors for survival. Propensity score-matching analysis revealed that -survival of RFA-treated patients was longer than that of TACE-treated patients (p = 0.036). CONCLUSION RFA and surgical resection were effective for IM-HCC, particularly in BCLC-B1/B2 cases.
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Affiliation(s)
- Kazuya Kariyama
- aDepartment of Gastroenterology and Liver Disease Center, Okayama City Hospital, Okayama, Japan
| | - Kazuhiro Nouso
- aDepartment of Gastroenterology and Liver Disease Center, Okayama City Hospital, Okayama, Japan
| | - Akiko Wakuta
- aDepartment of Gastroenterology and Liver Disease Center, Okayama City Hospital, Okayama, Japan
| | - Ayano Oonishi
- aDepartment of Gastroenterology and Liver Disease Center, Okayama City Hospital, Okayama, Japan
| | - Hidenori Toyoda
- bDepartment of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Gifu, Japan
| | - Toshifumi Tada
- bDepartment of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Gifu, Japan
| | - Atsushi Hiraoka
- cGastroenterology Center, Ehime Prefectural Central Hospital, Ehime, Japan
| | - Kunihiko Tsuji
- dCenter of Gastroenterology, Teine Keijinkai Hospital, Hokkaido, Japan
| | - Ei Itobayashi
- eDepartment of Gastroenterology, Asahi General Hospital, Chiba, Japan
| | - Toru Ishikawa
- fDepartment of Gastroenterology, Saiseikai Niigata Daini Hospital, Niigata, Japan
| | - Koichi Takaguchi
- gDepartment of Hepatology, Kagawa Prefectural Central Hospital, Kagawa, Japan
| | - Akemi Tsutsui
- gDepartment of Hepatology, Kagawa Prefectural Central Hospital, Kagawa, Japan
| | - Noritomo Shimada
- hDepartment of Gastroenterology and Hepatology, Otakanomori Hospital, Chiba, Japan
| | - Takashi Kumada
- bDepartment of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Gifu, Japan
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Duan J, Wu Y, Liu J, Zhang J, Fu Z, Feng T, Liu M, Han J, Li Z, Chen S. Genetic Biomarkers For Hepatocellular Carcinoma In The Era Of Precision Medicine. J Hepatocell Carcinoma 2019; 6:151-166. [PMID: 31696097 PMCID: PMC6805787 DOI: 10.2147/jhc.s224849] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Accepted: 09/18/2019] [Indexed: 12/24/2022] Open
Abstract
Being one of the most lethal cancers that exhibit high levels of heterogeneity, hepatocellular carcinoma (HCC) is associated with diverse oncogenic pathways underpinned by varied driver genes. HCC can be induced by different etiological factors including virus infection, toxin exposure or metabolic disorders. Consequently, patients may display varied genetic profiles, and may respond differently to the treatments involving inhibition of target pathways. These DNA/RNA mutations, copy number variations, chromatin structural changes, aberrant expression of non-coding RNAs and epigenetic modifications were considered as biomarkers in the application of precision medication. To explore how genetic testing could contribute to early diagnosis, prognosis, treatment and postoperative monitoring of HCC, we conducted a systematic review of genetic markers associated with different pathologies. Moreover, we summarized on-going clinical trials for HCC treatment, including the trials for multiple kinase inhibitors and immune checkpoint blockade (ICB). The efficacy of ICB treatment in HCC is not as good as what was observed in lung cancer and melanoma, which might be due to the heterogeneity of the microenvironment of the liver.
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Affiliation(s)
- Jingxian Duan
- Department of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, People’s Republic of China
| | - Yuling Wu
- Department of Oncology, HaploX Biotechnology Co. Ltd, Shenzhen518000, People’s Republic of China
| | - Jikui Liu
- Department of Hepatobiliary and Pancreatic Surgery, Peking University Shenzhen Hospital, Shenzhen518036, People’s Republic of China
| | - Jiajia Zhang
- Department of Oncology, HaploX Biotechnology Co. Ltd, Shenzhen518000, People’s Republic of China
| | - Zhichao Fu
- Department of Oncology, HaploX Biotechnology Co. Ltd, Shenzhen518000, People’s Republic of China
| | - Tieshan Feng
- Department of Oncology, HaploX Biotechnology Co. Ltd, Shenzhen518000, People’s Republic of China
| | - Ming Liu
- Department of Oncology, HaploX Biotechnology Co. Ltd, Shenzhen518000, People’s Republic of China
| | - Jie Han
- Department of Oncology, HaploX Biotechnology Co. Ltd, Shenzhen518000, People’s Republic of China
| | - Zhicheng Li
- Department of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, People’s Republic of China
| | - Shifu Chen
- Department of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, People’s Republic of China
- Department of Oncology, HaploX Biotechnology Co. Ltd, Shenzhen518000, People’s Republic of China
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Kudo M. A New Treatment Option for Intermediate-Stage Hepatocellular Carcinoma with High Tumor Burden: Initial Lenvatinib Therapy with Subsequent Selective TACE. Liver Cancer 2019; 8:299-311. [PMID: 31768341 PMCID: PMC6872999 DOI: 10.1159/000502905] [Citation(s) in RCA: 106] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Accepted: 08/26/2019] [Indexed: 02/04/2023] Open
Affiliation(s)
- Masatoshi Kudo
- *Prof. Masatoshi Kudo, Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohnohigashi, Osaka-Sayama 589-8511 (Japan), E-Mail
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