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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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Li Z, Wang J, Zhao J, Leng Z. Regorafenib plus programmed death‑1 inhibitors vs. regorafenib monotherapy in second‑line treatment for advanced hepatocellular carcinoma: A systematic review and meta‑analysis. Oncol Lett 2024; 28:318. [PMID: 38807680 PMCID: PMC11130614 DOI: 10.3892/ol.2024.14451] [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: 01/25/2024] [Accepted: 04/24/2024] [Indexed: 05/30/2024] Open
Abstract
The present study compared the efficacy and safety of regorafenib plus programmed death-1 inhibitors (R-P) with regorafenib monotherapy as second-line therapies for advanced hepatocellular carcinoma (HCC). A systematic search of relevant literature published in PubMed, Embase, Web of Science and Cochrane Library databases until October 2023 was conducted. Two authors independently performed data extraction and screening using standardized protocols. Stata/MP 17.0 was used for the meta-analysis to evaluate the impact of R-P treatment on major outcome indicators, including overall survival, progression-free survival (PFS), tumor response and adverse reactions, in patients with advanced HCC. The results indicated that five cohort studies involving 444 patients with advanced HCC were included. The results revealed that R-P treatment improved overall survival [hazard ratio (HR), 0.61; 95% confidence interval (CI) 0.48-0.77; I2=0.0%; P=0.663] and PFS (HR, 0.51; 95% CI 0.41-0.63; I2=17.5%; P=0.303). Additionally, it increased the objective response rate (risk ratio, 2.33; 95% CI, 1.49-3.64; I2=0.0%; P=0.994) and disease control rate (HR, 1.40; 95% CI, 1.20-1.63; I2=0.0%; P=0.892) compared with those of regorafenib. However, R-P treatment was associated with an increased incidence of adverse events, such as hypothyroidism, thrombocytopenia and rash, compared with that in regorafenib. In conclusion, R-P is superior to regorafenib monotherapy in terms of survival benefits and tumor response.
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Affiliation(s)
- Zhao Li
- Department of Hepato-Biliary-Pancreas II, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Jie Wang
- Department of Hepato-Biliary-Pancreas II, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Jingbing Zhao
- Department of Hepato-Biliary-Pancreas II, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Zhengwei Leng
- Department of Hepato-Biliary-Pancreas II, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
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Liu S, Liu C, Wang Q, Liu Y, Wang D, Zhao G, Yu G. The second-line treatment of hepatocellular carcinoma with CalliSpheres drug-eluting bead transarterial chemoembolization combined with regorafenib: A safety and efficacy analysis. Ir J Med Sci 2024; 193:1215-1222. [PMID: 38300460 DOI: 10.1007/s11845-024-03611-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Accepted: 01/12/2024] [Indexed: 02/02/2024]
Abstract
BACKGROUND This study aimed to investigate the efficacy and safety of CalliSpheres drug-eluting beads transarterial chemoembolization (DEB-TACE) combined with regorafenib in the second-line treatment of unresectable hepatocellular carcinoma. METHODS A retrospective analysis was made of 34 patients with unresectable hepatocellular carcinoma (HCC) that had progressed after first-line treatment in Linyi Tumor Hospital from October 2019 to June 2021. These patients were divided into observation group (n = 15) and control group (n = 19) based on their treatment plans, who were respectively treated with regorafenib alone and regorafenib combined with DEB-TACE. The objective response rate (ORR) and the disease control rate (DCR) were evaluated by the modified Response Evaluation Criteria in Solid Tumors (mRECIST), and the progression-free survival (PFS) and the overall survival (OS) were calculated; the factors influencing PFS and OS of patients were analyzed by the Cox proportional hazards model; and the adverse reactions to the treatments were observed and recorded. RESULTS After 2 months of treatment, the ORR and the DCR of the observation group were 73.3% (11/15) and 86.7% (13/15) respectively, both higher than 10.5% (2/19) and 47.4% (9/19) of the control group. Their differences are statistically significant (P < 0.05). There were no statistically significant differences in the incidences of regorafenib-related adverse reactions including hand-foot skin reactions, fatigue, hypertension, diarrhea, and proteinuria between the two groups (P > 0.05). In the observation group, the main adverse reactions to DEB-TACE such as fever, pain, nausea, and vomiting were relieved after symptomatic treatment, and no serious complications such as ectopic embolization of CalliSpheres drug-eluting beads occurred. As of July 31, 2022, the median follow-up time was 12.5 months, and the average was (14.00 ± 5.69) months. The median PFS was 9 months in the observation group, and 6 months in the control group, presenting a statistically significant difference (P < 0.05), and the median OS was 18 months in the observation group, and 12 months in the control group, also presenting a statistically significant difference (P < 0.05). The results of monofactor prognostic analysis showed that Child grade, AFP level, and treatment method had an influence on the PFS and the OS of liver cancer patients receiving regorafenib second-line treatment (P < 0.05), and the results of multifactor prognostic analysis showed that child grade and treatment method independently influenced the PFS of patients, while treatment method independently influenced the OS of patients (P < 0.05). CONCLUSIONS DEB-TACE combined with regorafenib is safe and feasible in the treatment of unresectable HCC, with good efficacy and mild adverse reactions.
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Affiliation(s)
- Song Liu
- Dalian Medical University, No.9 Western Section, Lvshun South Street, Lvshun District, Dalian, 116044, Liaoning Province, China
- Department of Interventional Therapy, Linyi Cancer Hospital, No. 6 East Lingyuan Street, Linyi, 276000, Shandong Province, China
| | - Changqing Liu
- Dalian Medical University, No.9 Western Section, Lvshun South Street, Lvshun District, Dalian, 116044, Liaoning Province, China
- Department of General Surgery, Dalian Municipal Central Hospital, No. 826 Southwest Road, Shahekou District, Dalian, 116089, Liaoning Province, China
| | - Qingdong Wang
- Department of Interventional Therapy, Linyi Cancer Hospital, No. 6 East Lingyuan Street, Linyi, 276000, Shandong Province, China
| | - Ying Liu
- Hepatobiliary and Pancreatic Center, Beijing Tsinghua Chang geng Hospital, Changping District, Beijing, 102218, China
| | - Dong Wang
- Dalian Medical University, No.9 Western Section, Lvshun South Street, Lvshun District, Dalian, 116044, Liaoning Province, China.
- Department of General Surgery, Dalian Municipal Central Hospital, No. 826 Southwest Road, Shahekou District, Dalian, 116089, Liaoning Province, China.
| | - Guangsheng Zhao
- Minimally Invasive Interventional Diagnosis and Treatment Center, Affiliated Zhongshan Hospital of Dalian University, No.6 JieFang Street, Zhongshan District, Dalian, 116001, Liaoning Province, China.
| | - Guangji Yu
- Department of Interventional Therapy, Linyi Cancer Hospital, No. 6 East Lingyuan Street, Linyi, 276000, Shandong Province, China.
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Han S, Kim DY, Lim HY, Yoon JH, Ryoo BY, Kim Y, Kim K, Kim BY, Yi SY, Kim DS, Cho DY, Yu J, Kim S, Park JW. Sorafenib for 9,923 Patients with Hepatocellular Carcinoma: An Analysis from National Health Insurance Claim Data in South Korea. Gut Liver 2024; 18:116-124. [PMID: 37334671 PMCID: PMC10791511 DOI: 10.5009/gnl220406] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 01/18/2023] [Accepted: 01/26/2023] [Indexed: 06/20/2023] Open
Abstract
Background/Aims Sorafenib is the standard of care in the management of advanced hepatocellular carcinoma (HCC). The purpose of this study was to investigate the characteristics, treatment patterns and outcomes of sorafenib among HCC patients in South Korea. Methods This population-based retrospective, single-arm, observational study used the Korean National Health Insurance database to identify patients with HCC who received sorafenib between July 1, 2008, and December 31, 2014. A total of 9,923 patients were recruited in this study. Results Among 9,923 patients, 6,669 patients (68.2%) received loco-regional therapy prior to sorafenib, and 1,565 patients (15.8%) received combination therapy with concomitant sorafenib; 2,591 patients (26.1%) received rescue therapy after sorafenib, and transarterial chemoembolization was the most common modality applied in 1,498 patients (15.1%). A total of 3,591 patients underwent rescue therapy after sorafenib, and the median overall survival was 14.5 months compared to 4.6 months in 7,332 patients who received supportive care after sorafenib. The mean duration of sorafenib administration in all patients was 105.7 days; 7,023 patients (70.8%) received an initial dose of 600 to 800 mg. The longest survival was shown in patients who received the recommended dose of 800 mg, subsequently reduced to 400 mg (15.0 months). The second longest survival was demonstrated in patients with a starting dose of 800 mg, followed by a dose reduction to 400-600 mg (9.6 months). Conclusions Real-life data show that the efficacy of sorafenib seems similar to that observed in clinical trials, suggesting that appropriate subsequent therapy after sorafenib might prolong patient survival.
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Affiliation(s)
- Sojung Han
- Department of Internal Medicine, Uijeongbu Eulji Medical Center, Eulji University College of Medicine, Uijeongbu, Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Ho Yeong Lim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jung-Hwan Yoon
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Baek-Yeol Ryoo
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Yujeong Kim
- Health Insurance Review and Assessment, Wonju, Korea
| | - Kookhee Kim
- Health Insurance Review and Assessment, Wonju, Korea
| | - Bo Yeon Kim
- Health Insurance Review and Assessment, Wonju, Korea
| | - So Young Yi
- Health Insurance Review and Assessment, Wonju, Korea
| | - Dong-Sook Kim
- Health Insurance Review and Assessment, Wonju, Korea
| | - Do-Yeon Cho
- Health Insurance Review and Assessment, Wonju, Korea
| | - Jina Yu
- Health Insurance Review and Assessment, Wonju, Korea
| | - Suhyun Kim
- Health Insurance Review and Assessment, Wonju, Korea
| | - Joong-Won Park
- Center for Liver and Pancreatobiliary Cancer, National Cancer Center, Goyang, Korea
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Sun H, Yang H, Mao Y. Personalized treatment for hepatocellular carcinoma in the era of targeted medicine and bioengineering. Front Pharmacol 2023; 14:1150151. [PMID: 37214451 PMCID: PMC10198383 DOI: 10.3389/fphar.2023.1150151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 04/24/2023] [Indexed: 05/24/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a major global health burden, causing approximately 8.3 million deaths each year, and it is the third leading cause of cancer-related death worldwide, with a relative 5-year survival rate of around 18%. Due to the advanced stage of diagnosis in most patients, systemic treatment based on targeted therapy has become the only feasible option. Genomic studies have established a profile of molecular alterations in hepatocellular carcinoma with potentially actionable mutations, but these mutations have yet to be translated into clinical practice. The first targeted drug approved for systemic treatment of patients with advanced hepatocellular carcinoma was Sorafenib, which was a milestone. Subsequent clinical trials have identified multiple tyrosine kinase inhibitors, such as Lenvatinib, Cabozantinib, and Regorafenib, for the treatment of hepatocellular carcinoma, with survival benefits for the patient. Ongoing systemic therapy studies and trials include various immune-based combination therapies, with some early results showing promise and potential for new therapy plans. Systemic therapy for hepatocellular carcinoma is complicated by the significant heterogeneity of the disease and its propensity for developing drug resistance. Therefore, it is essential to choose a better, individualized treatment plan to benefit patients. Preclinical models capable of preserving in vivo tumor characteristics are urgently needed to circumvent heterogeneity and overcome drug resistance. In this review, we summarize current approaches to targeted therapy for HCC patients and the establishment of several patient-derived preclinical models of hepatocellular carcinoma. We also discuss the challenges and opportunities of targeted therapy for hepatocellular carcinoma and how to achieve personalized treatment with the continuous development of targeted therapies and bioengineering technologies.
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Affiliation(s)
| | - Huayu Yang
- *Correspondence: Huayu Yang, ; Yilei Mao,
| | - Yilei Mao
- *Correspondence: Huayu Yang, ; Yilei Mao,
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Li J, Jia Y, Shao C, Li Y, Song J. Clinical Efficacy and Safety of an Immune Checkpoint Inhibitor in Combination with Regorafenib Therapy as Second-Line Regimen for Patients with Unresectable Hepatocellular Carcinoma. Ther Clin Risk Manag 2023; 19:329-339. [PMID: 37041973 PMCID: PMC10083010 DOI: 10.2147/tcrm.s400079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 03/19/2023] [Indexed: 04/07/2023] Open
Abstract
Purpose This study aimed to evaluate the safety and efficacy of a combination of programmed death-1 (PD-1) inhibitor and regorafenib as second-line treatment for advanced hepatocellular carcinoma (HCC). Patients and Methods We retrospectively analyzed the data of 38 patients with unresectable HCC who were treated with PD-1 inhibitor in combination with regorafenib as a second⁃line therapy as well as the data of 32 patients treated with regorafenib only therapy as a control. The clinical data, previous treatment strategies, follow-up imaging results, and adverse events during follow-ups were recorded. The mRECIST Criteria were used to evaluate the treatment outcome of intrahepatic lesions, and the Kaplan-Meier method was used to evaluate survival time. Results Up to the last follow-up, the rego-PD-1 group had higher objective response rate (39.5% vs 15.6%, P = 0.028), longer progression-free survival (median 5.9 vs 4.6 months; P = 0.044), and better overall survival (OS) (median 14.5 vs 9.5 months; P = 0.041) than the regorafenib only group. Among the 38 patients in rego-PD-1 group, 1 patient (2.7%) achieved complete response, 14 patients (36.8%) achieved partial response, 14 patients (36.8%) achieved stable disease, and 9 patients (23.7%) achieved progressive disease. Among the 32 patients in regorafenib alone, 5 (15.6%) achieved partial response, 12 (37.5%) achieved stable disease, and 15 (46.9%) achieved progressive disease. Regorafenib alone, Child-Pugh B, and tumors >3 were independent prognostic factors for poor OS. The difference in the incidence of grade 3/4 adverse events between the two groups was not statistically significant (36.8% vs 28.1%; P = 0.439). Grade ≥3 treatment-related adverse events included hypertension and diarrhea. Conclusion PD-1 inhibitor combined with regorafenib is a promising regimen in treating patients with unresectable HCC owing to its safety and effectiveness as well as low incidence of serious adverse events with its use.
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Affiliation(s)
- Jinpeng Li
- Intervention Ward 1, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, People’s Republic of China
- Correspondence: Jinpeng Li, Intervention Ward 1, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, People’s Republic of China, Tel +86 531 67626412, Fax +86 531 67626411, Email
| | - Yuntao Jia
- Intervention Ward 1, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, People’s Republic of China
| | - Changdong Shao
- Qixia Hospital of Traditional Chinese Medicine Hospital, Qixia, Shandong, People’s Republic of China
| | - Yuanming Li
- Laizhou Hospital of Traditional Chinese Medicine, Laizhou, People’s Republic of China
| | - Jinlong Song
- Intervention Ward 1, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, People’s Republic of China
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Kim Y, Lee JS, Lee HW, Kim BK, Park JY, Kim DY, Ahn SH, Goh MJ, Kang W, Kim SU. Sorafenib versus nivolumab after lenvatinib treatment failure in patients with advanced hepatocellular carcinoma. Eur J Gastroenterol Hepatol 2023; 35:191-197. [PMID: 36574310 DOI: 10.1097/meg.0000000000002466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND AND AIM An optimal sequential anti-hepatocellular carcinoma (HCC) agent that can be used after failed lenvatinib treatment has not been established. Here, we compared the outcomes of sorafenib and nivolumab as second-line agents after failed lenvatinib treatment in patients with advanced HCC. METHODS Patients with advanced HCC who had received sorafenib or nivolumab as second-line agents after failed lenvatinib treatment were recruited from two Korean tertiary institutions between November 2018 and June 2020. RESULTS The median age of the 60 participants (52 treated with sorafenib and eight treated with nivolumab) at baseline was 56.8 years. The demographic, laboratory and tumor variables, as well as lenvatinib treatment duration, were similar between the two groups. The median durations of sorafenib and nivolumab treatment were 1.2 and 2.6 months, respectively ( P = 0.164). Twenty-four (40.0%) patients died during the follow-up period (median, 15.8 months). The median overall survival (OS) of the study population was 5.8 months. The median OS of patients treated with sorafenib was significantly longer than the median OS of patients treated with nivolumab (8.7 vs. 3.0 months; P = 0.046). Sorafenib treatment (vs. nivolumab) was independently associated with a lower risk of mortality (hazard ratio = 0.194; 95% confidence interval, 0.053-0.708; P = 0.013). Worse Eastern Cooperative Oncology Group performance status, larger maximal tumor size, lymph node metastases and higher total bilirubin levels were independently associated with increased mortality risk (all P < 0.05). CONCLUSIONS Lenvatinib-sorafenib sequential treatment resulted in significantly better survival did than lenvatinib-nivolumab sequential treatment in patients with advanced HCC. Larger studies are needed to validate our results.
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Affiliation(s)
- Yuna Kim
- Department of Internal Medicine
- Institute of Gastroenterology, Yonsei University College of Medicine
| | - Jae Seung Lee
- Department of Internal Medicine
- Institute of Gastroenterology, Yonsei University College of Medicine
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Hye Won Lee
- Department of Internal Medicine
- Institute of Gastroenterology, Yonsei University College of Medicine
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Beom Kyung Kim
- Department of Internal Medicine
- Institute of Gastroenterology, Yonsei University College of Medicine
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Jun Yong Park
- Department of Internal Medicine
- Institute of Gastroenterology, Yonsei University College of Medicine
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Do Young Kim
- Department of Internal Medicine
- Institute of Gastroenterology, Yonsei University College of Medicine
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine
- Institute of Gastroenterology, Yonsei University College of Medicine
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Myung Ji Goh
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine
| | - Wonseok Kang
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea
| | - Seung Up Kim
- Department of Internal Medicine
- Institute of Gastroenterology, Yonsei University College of Medicine
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
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Tu X, Yang J, Zheng Y, Liang C, Tao Q, Tang X, Liu Z, Jiang L, He Z, Xie F, Zheng Y. Immunotherapy combination with regorafenib for refractory hepatocellular carcinoma: A real-world study. Int Immunopharmacol 2022; 113:109401. [PMID: 36395672 DOI: 10.1016/j.intimp.2022.109401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 10/27/2022] [Accepted: 10/28/2022] [Indexed: 11/16/2022]
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Lim DH, Casadei-Gardini A, Lee MA, Lonardi S, Kim JW, Masi G, Chon HJ, Rimini M, Kim I, Cheon J, Hwang JE, Kang JH, Lim HY, Yoo C. Prognostic implication of serum AFP in patients with hepatocellular carcinoma treated with regorafenib. Future Oncol 2022; 18:3021-3030. [PMID: 35903991 DOI: 10.2217/fon-2022-0524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Background: This multicenter study investigated the predictive value of baseline AFP and on-treatment AFP response for survival in hepatocellular carcinoma (HCC) patients with regorafenib. Materials & methods: A total of 578 patients with HCC treated with regorafenib from 12 institutions in South Korea and Italy were included. Baseline AFP (cutoff, 400 ng/ml) and AFP response (20% reduction from baseline) were analyzed for overall survival (OS) and progression-free survival (PFS). Results: Baseline AFP below 400 ng/ml was a significant factor that was independently associated with longer OS and PFS. AFP response was also a significant factor independently associated with longer OS and PFS. Conclusion: Baseline AFP and AFP response may be used as prognostic factors for survival in HCC treated with regorafenib.
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Affiliation(s)
- Dong-Hoon Lim
- University of Ulsan College of Medicine, Seoul, 05505, South Korea
| | - Andrea Casadei-Gardini
- Vita-Salute San Raffaele University School of Medicine, Milan, 20132, Italy.,Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, 20132, Italy
| | - Myung Ah Lee
- Division of Hematology-Oncology, Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, 06591, South Korea
| | - Sara Lonardi
- Oncology Unit 3, Veneto Institute of Oncology IOV-IRCCS, Padua, 35128, Italy
| | - Jin Won Kim
- Division of Hematology-Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do, 13620, South Korea
| | - Gianluca Masi
- Department of Translational Research & New Technologies in Medicine & Surgery, University of Pisa, Pisa, 56126, Italy
| | - Hong Jae Chon
- Division of Hematology-Oncology, Department of Internal Medicine, Bundang CHA Hospital, Seongnam-si, Gyeonggi-do, 13496, South Korea
| | - Margherita Rimini
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, 20132, Italy
| | - Ilhwan Kim
- Division of Oncology, Department of Internal Medicine, Haeundae Paik Hospital, Inje University College of Medicine, Busan, 48108, South Korea
| | - Jaekyung Cheon
- Division of Hematology-Oncology, Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, 44033, South Korea
| | - Jun-Eul Hwang
- Division of Hematology-Oncology, Department of Internal Medicine, Chonnam National University Medical School, Gwangju, 61469, South Korea
| | - Jung Hun Kang
- Division of Hematology-Oncology, Department of Internal Medicine, Gyeongsang National University, Jinju, 52727, South Korea
| | - Ho Yeong Lim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, South Korea
| | - Changhoon Yoo
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea
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Ren SH, Cui ZL, Lang MR, Li Q, Zhang W, Fang F, Wu Q, Cui YL, Li HK, Chen P, Zhang Y, Song T. Efficacy and safety of sequential therapy with sorafenib and regorafenib for advanced hepatocellular carcinoma: a two-center study in China. J Gastrointest Oncol 2022; 13:1266-1277. [PMID: 35837206 PMCID: PMC9274072 DOI: 10.21037/jgo-22-397] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 06/09/2022] [Indexed: 10/21/2023] Open
Abstract
BACKGROUND Regorafenib is a standard 2nd-line treatment for patients with advanced hepatocellular carcinoma (HCC), but the efficacy and safety of sequential therapy with sorafenib and regorafenib among advanced HCC patients in China is not clear. METHODS This was a retrospective, two-center, cohort study of advanced HCC patients who received sequential therapy of sorafenib and regorafenib from October 2018 to April 2020 at 2 Chinese institutions. The patients were converted directly to regorafenib after failing to respond to sorafenib monotherapy. The patients underwent evaluations every 4-6 weeks to determine the efficacy and safety of the treatment according to physiological, laboratory, and radiological results. A radiological evaluation using computed tomography or magnetic resonance imaging scans was conducted. The outcomes included overall survival (OS) and progression-free survival (PFS). RESULTS A total of 43 patients received regorafenib as a 2nd-line treatment after sorafenib progression. Of these patients, 26 (60.5%) and 17 (39.5%) were diagnosed with Barcelona Clinic Liver Cancer (BCLC) stages B and C, respectively. The median PFS was 11.0 [95% confidence interval (CI): 5.8-16.2] months, and the median OS was 17.0 (95% CI: 12.8-21.2) months. Conversely, the most common toxicities were hand-foot skin reaction (48.8%), diarrhea (32.6%), and hypertension (14%). The most common grade 3-4 toxicities were hypoalbuminemia (4.7%), anemia (4.7%), and thrombocytopenia (4.7%). Alpha-fetoprotein (AFP) ≥400, alanine transaminase (ALT) ≥60 IU/L, and aspartate aminotransferase (AST) ≥60 IU/L before 2nd-line treatment were associated with PFS in the univariable analyses. The Cox proportional-hazards regression analysis showed that AFP [hazard ratio (HR) =0.225; 95% CI: 0.073-0.688; P=0.009], ALT (HR =0.195; 95% CI: 0.051-0.741; P=0.016), AST (HR =0.209; 95% CI: 0.063-0.697; P=0.011), and presence of extrahepatic metastasis (HR =0.074; 95% CI: 0.009-0.608; P=0.015) before 2nd-line treatment were independently associated with PFS. CONCLUSIONS The sequential therapy of sorafenib and regorafenib is well-tolerated and effective in advanced HCC patients after sorafenib progression based on our two-center real-world data. Patients with good liver function reserve and a high level of AFP before 2nd-line treatment may benefit from sequential treatment. These results still need further validation.
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Affiliation(s)
- Shao-Hua Ren
- Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- Tianjin’s Clinical Research Center for Cancer, Tianjin, China
| | - Zi-Lin Cui
- Department of Hepatobiliary Surgery, Tianjin First Central Hospital, Tianjin, China
| | - Meng-Ran Lang
- Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- Tianjin’s Clinical Research Center for Cancer, Tianjin, China
| | - Qiang Li
- Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- Tianjin’s Clinical Research Center for Cancer, Tianjin, China
| | - Wei Zhang
- Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- Tianjin’s Clinical Research Center for Cancer, Tianjin, China
| | - Feng Fang
- Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- Tianjin’s Clinical Research Center for Cancer, Tianjin, China
| | - Qiang Wu
- Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- Tianjin’s Clinical Research Center for Cancer, Tianjin, China
| | - Yun-Long Cui
- Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- Tianjin’s Clinical Research Center for Cancer, Tianjin, China
| | - Hui-Kai Li
- Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- Tianjin’s Clinical Research Center for Cancer, Tianjin, China
| | - Ping Chen
- Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- Tianjin’s Clinical Research Center for Cancer, Tianjin, China
| | - Yamin Zhang
- Department of Hepatobiliary Surgery, Tianjin First Central Hospital, Tianjin, China
| | - Tianqiang Song
- Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- Tianjin’s Clinical Research Center for Cancer, Tianjin, China
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11
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Kobayashi K, Ogasawara S, Takahashi A, Seko Y, Unozawa H, Sato R, Watanabe S, Moriguchi M, Morimoto N, Tsuchiya S, Iwai K, Inoue M, Ogawa K, Ishino T, Iwanaga T, Sakuma T, Fujita N, Kanzaki H, Koroki K, Nakamura M, Kanogawa N, Kiyono S, Kondo T, Saito T, Nakagawa R, Suzuki E, Ooka Y, Nakamoto S, Tawada A, Chiba T, Arai M, Kanda T, Maruyama H, Nagashima K, Kato J, Isoda N, Aramaki T, Itoh Y, Kato N. Evolution of Survival Impact of Molecular Target Agents in Patients with Advanced Hepatocellular Carcinoma. Liver Cancer 2022; 11:48-60. [PMID: 35222507 PMCID: PMC8820147 DOI: 10.1159/000519868] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 09/24/2021] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND AND AIMS The prognosis of patients with advanced hepatocellular carcinoma (HCC) is expected to improve as multiple molecular target agents (MTAs) are now available. However, the impact of the availability of sequential MTAs has not been fully verified yet. APPROACH AND RESULTS We retrospectively collected the data on the whole clinical course of 877 patients who received any MTAs as first-line systemic therapy for advanced HCC between June 2009 and March 2019. The study population was divided into 3 groups according to the date of first-line MTA administration (period 1: 2009-2012, n = 267; period 2: 2013-2016, n = 352; period 3: 2017-2019, n = 258). Then, we compared the number of MTAs used, overall survival (OS), and MTA treatment duration among the 3 groups. Analysis was also performed separately for advanced-stage and nonadvanced-stage HCC. The proportion of patients who received multiple MTAs was remarkably increased over time (1.1%, 10.2%, and 42.6% in periods 1, 2, and 3, respectively, p < 0.001). The median OS times were prolonged to 10.4, 11.3, and 15.2 months in periods 1, 2, and 3, respectively (p = 0.016). Similarly, the MTA treatment durations were extended (2.7, 3.2, and 6.6 months in periods 1, 2, and 3, respectively; p < 0.001). We confirmed that the correlation between OS and MTA treatment duration was strengthened (period 1: 0.395, period 2: 0.505, and period 3: 0.667). All these trends were pronounced in the patients with advanced-stage HCC but limited in the patients with nonadvanced-stage HCC. CONCLUSIONS The availability of multiple MTAs had steadily improved the prognosis of patients with advanced HCC patients, particularly advanced-stage HCC patients.
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Affiliation(s)
- Kazufumi Kobayashi
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
- Translational Research and Development Center, Chiba University Hospital, Chiba, Japan
| | - Sadahisa Ogasawara
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
- Translational Research and Development Center, Chiba University Hospital, Chiba, Japan
| | - Aya Takahashi
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yuya Seko
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Hidemi Unozawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Rui Sato
- Division of Interventional Radiology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Shunji Watanabe
- Division of Gastroenterology, Department of Medicine, Jichi Medical University, Tochigi, Japan
| | - Michihisa Moriguchi
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Naoki Morimoto
- Division of Gastroenterology, Department of Medicine, Jichi Medical University, Tochigi, Japan
| | - Satoshi Tsuchiya
- Division of Interventional Radiology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Kenji Iwai
- Division of Interventional Radiology, Shizuoka Cancer Center, Shizuoka, Japan
| | | | - Keita Ogawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Takamasa Ishino
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Terunao Iwanaga
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Takafumi Sakuma
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Naoto Fujita
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Hiroaki Kanzaki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Keisuke Koroki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Masato Nakamura
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Naoya Kanogawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Soichiro Kiyono
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Takayuki Kondo
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tomoko Saito
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Ryo Nakagawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Eiichiro Suzuki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Yoshihiko Ooka
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Shingo Nakamoto
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Akinobu Tawada
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
- Department of Medical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tetsuhiro Chiba
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Makoto Arai
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
- Department of Medical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tatsuo Kanda
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Hitoshi Maruyama
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Kengo Nagashima
- Research Center for Medical and Health Data Science, The Institute of Statistical Mathematics, Tokyo, Japan
- Biostatistics Unit, Clinical and Translational Research Center, Keio University Hospital, Tokyo, Japan
| | - Jun Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Norio Isoda
- Division of Gastroenterology, Department of Medicine, Jichi Medical University, Tochigi, Japan
| | - Takeshi Aramaki
- Division of Interventional Radiology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Yoshito Itoh
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Naoya Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
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12
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Xia J, Gelfond J, Arora SP. Second-line treatment with nivolumab, cabozantinib, regorafenib, or best supportive care in patients with advanced hepatocellular carcinoma: analysis at a Hispanic-majority NCI-designated cancer center. J Gastrointest Oncol 2021; 12:2943-2951. [PMID: 35070420 PMCID: PMC8748055 DOI: 10.21037/jgo-21-414] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 11/03/2021] [Indexed: 12/01/2023] Open
Abstract
BACKGROUND In the last four years, six regimens were approved by the Food and Drug Association as second-line therapies for advanced hepatocellular carcinoma (HCC). However, there are significant differences between real-world and clinical trial populations. We analyzed survival and toxicities among second-line therapies for HCC in our population. METHODS We performed a retrospective cohort study of patients with advanced HCC who received second-line therapies (tyrosine kinase inhibitor or TKI; immunotherapy or IO) or best supportive care (BSC) at a tertiary-referral cancer center serving the South Texas region. Progression-free survival (PFS) was determined, and adverse events were compared between therapies. RESULTS In our cohort, median age was 60 years (n=65), and 49 (75%) were Hispanic. 58 (89%) patients received second-line therapy. Child-Pugh (CP) score of cohort: A, 18%; B, 55%; C, 26%. Median PFS (mPFS) was 3.1 months with TKI (n=6), 3.3 months with IO (n=27), and 1.3 months with BSC (n=25). There was improved survival with IO compared to BSC [hazards ratio (HR) =0.31; 95% confidence interval (CI): 0.15-0.63; P=0.0014]. There was no significant difference comparing IO to TKI (HR =0.94; 95% CI: 0.31-2.86; P=0.92), but a trend to improved PFS with TKI when compared to BSC (HR =0.33; 95% CI: 0.10-1.04; P=0.058). TKI group had significantly more rash (P=0.01) and hand-foot syndrome (P<0.001) compared to IO and BSC. CONCLUSIONS Our Hispanic-majority cohort with varying liver dysfunction, including CP-B & C cirrhosis, were more likely to receive IO or BSC. Both second-line treatment groups, IO or TKI, demonstrated increased mPFS compared to BSC and were tolerable compared to BSC, with expected toxicity per class of drug.
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Affiliation(s)
| | - Jonathan Gelfond
- Mays Cancer Center, University of Texas Health San Antonio, San Antonio, TX, USA
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13
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Shimose S, Hiraoka A, Nakano M, Iwamoto H, Tanaka M, Tanaka T, Noguchi K, Aino H, Ogata K, Kajiwara M, Itano S, Yokokura Y, Yamaguchi T, Kawano H, Matsukuma N, Suga H, Niizeki T, Shirono T, Noda Y, Kamachi N, Okamura S, Kawaguchi T, Koga H, Torimura T. First-line sorafenib sequential therapy and liver disease etiology for unresectable hepatocellular carcinoma using inverse probability weighting: A multicenter retrospective study. Cancer Med 2021; 10:8530-8541. [PMID: 34693661 PMCID: PMC8633265 DOI: 10.1002/cam4.4367] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 10/04/2021] [Accepted: 10/06/2021] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND AND AIMS Sequential therapy with molecular-targeted agents (MTAs) is considered effective for unresectable hepatocellular carcinoma (HCC) patients. This study purposed to evaluate the efficacy of sequential therapy with sorafenib (SORA) as a first-line therapy and to investigate the therapeutic impact of SORA in nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steato hepatitis (NASH)-related HCC. METHODS We evaluated 504 HCC patients treated with SORA (Study-1). The times of administration for sorafenib from 2009 to 2015, 2016 to 2017, and 2018 and later were defined as the early-, mid-, and late-term periods, respectively. Among them, 180 HCC patients treated with SORA in addition to MTAs in the mid- and late-term periods were divided into groups based on disease etiology (NAFLD or NASH [n = 37] and viral or alcohol [n = 143]), and outcomes were compared after inverse probability weighting (IPW) (Study-2). RESULTS Overall survival (OS) of HCC patients who received sequential MTA therapy after first-line SORA was significantly longer. The median survival times (MST) were 12.6 versus 17.6 versus 17.4 months in the early-term group, mid-term group, and the later-time group (early vs. mid, p = 0.014, early vs. later. p = 0.045), respectively. (Study-1). In Study-2, there was no significant differences in OS between the Virus/alcohol group and the NAFLD/NASH group in patients who received sequential therapy (MST was 23.4 and 27.0 months p = 0.173, respectively). The NAFLD or NASH, female sex, albumin-bilirubin (ALBI) grade 2b, and major Vp (Vp3/Vp4) were significant factors for OS treated with SORA. CONCLUSIONS Sequential therapy with SORA as the first-line treatment improved the prognosis of unresectable HCC patients and was effective regardless of HCC etiology.
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Affiliation(s)
- Shigeo Shimose
- Division of GastroenterologyDepartment of MedicineKurume University School of MedicineKurumeFukuokaJapan
| | - Atsushi Hiraoka
- Gastroenterology CenterEhime Prefectural Central HospitalMatsuyamaJapan
| | - Masahito Nakano
- Division of GastroenterologyDepartment of MedicineKurume University School of MedicineKurumeFukuokaJapan
| | - Hideki Iwamoto
- Division of GastroenterologyDepartment of MedicineKurume University School of MedicineKurumeFukuokaJapan
- Iwamoto Internal Medical ClinicKitakyusyuJapan
| | | | - Takaaki Tanaka
- Gastroenterology CenterEhime Prefectural Central HospitalMatsuyamaJapan
| | | | - Hajime Aino
- Division of GastroenterologyDepartment of MedicineSocial Insurance Tagawa HospitalTagawaJapan
| | - Kei Ogata
- Department of GastroenterologyKurume University Medical CenterKurumeJapan
| | | | - Satoshi Itano
- Department of GastroenterologyKurume Central HospitalKurumeJapan
| | | | | | - Hiroshi Kawano
- Department of GastroenterologySt. Mary's HospitalKurumeJapan
| | - Norito Matsukuma
- Department of GastroenterologyKurume General HospitalKurumeJapan
| | - Hideya Suga
- Department of Gastroenterology and HepatologyYanagawa HospitalYanagawaJapan
| | - Takashi Niizeki
- Division of GastroenterologyDepartment of MedicineKurume University School of MedicineKurumeFukuokaJapan
| | - Tomotake Shirono
- Division of GastroenterologyDepartment of MedicineKurume University School of MedicineKurumeFukuokaJapan
| | - Yu Noda
- Division of GastroenterologyDepartment of MedicineKurume University School of MedicineKurumeFukuokaJapan
| | - Naoki Kamachi
- Division of GastroenterologyDepartment of MedicineKurume University School of MedicineKurumeFukuokaJapan
| | - Shusuke Okamura
- Division of GastroenterologyDepartment of MedicineKurume University School of MedicineKurumeFukuokaJapan
| | - Takumi Kawaguchi
- Division of GastroenterologyDepartment of MedicineKurume University School of MedicineKurumeFukuokaJapan
| | - Hironori Koga
- Division of GastroenterologyDepartment of MedicineKurume University School of MedicineKurumeFukuokaJapan
| | - Takuji Torimura
- Division of GastroenterologyDepartment of MedicineKurume University School of MedicineKurumeFukuokaJapan
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14
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Advances in locoregional therapy for hepatocellular carcinoma combined with immunotherapy and targeted therapy. J Interv Med 2021; 4:105-113. [PMID: 34805958 PMCID: PMC8562181 DOI: 10.1016/j.jimed.2021.05.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 05/11/2021] [Accepted: 05/13/2021] [Indexed: 12/11/2022] Open
Abstract
Locoregional therapies (LRTs) of hepatocellular carcinoma (HCC) represented by ablation and TACE has become the main means for the clinical treatment of unresectable HCC. Among these, TACE is used throughout the stage Ib to IIIb of HCC treatment. In recent years, immunotherapy led by immune checkpoint inhibitors has become a hot direction in clinical research. At the same time, targeted drugs such as Sorafenib and Apatinib have played an important role in the treatment and complementary therapy of advanced HCC, and their clinical application has been quite mature. HCC is the sixth most common malignant tumor in the world. When it comes to its treatment, different therapies have different indications, and their individual efficacies are not satisfactory, which makes the exploration of the use of combination therapy in HCC treatment become a new trend. In this paper, the status of the three therapies and the progress of their combined application are briefly reviewed.
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15
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Long HY, Huang TY, Xie XY, Long JT, Liu BX. Treatment strategies for hepatocellular carcinoma with extrahepatic metastasis. World J Clin Cases 2021; 9:5754-5768. [PMID: 34368295 PMCID: PMC8316954 DOI: 10.12998/wjcc.v9.i21.5754] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 04/20/2021] [Accepted: 05/25/2021] [Indexed: 02/06/2023] Open
Abstract
Extrahepatic metastasis (EHM) of hepatocellular carcinoma (HCC) has increasingly been seen due to improved survival with effective management of intrahepatic lesions. The presence of EHM indicates an advanced stage of HCC, for which systemic therapy serves as the standard treatment modality. Since the approval of Sorafenib as the first systemic agent in 2007, it took almost a decade to show its efficacy in both first and further lines of setting until the landscape of systemic drugs was finally expanded. Moreover, with inspiring results from immunotherapy trials in HCC, it appears that the introduction of immunotherapy may lead to an evolution in the portfolio of HCC treatment. Although the locoregional approach in the management of EHM is not recommended for advanced-stage HCC, efforts have been made to demonstrate its efficacy in symptom relief and potential benefit for overall survival. This review provides a summary of recent updates of the systemic agents in the treatment of advanced HCC, with an emphasis on aggressive locoregional management of EHM by various treatment modalities.
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Affiliation(s)
- Hai-Yi Long
- Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, Guangdong Province, China
| | - Tong-Yi Huang
- Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, Guangdong Province, China
| | - Xiao-Yan Xie
- Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, Guangdong Province, China
| | - Jian-Ting Long
- Department of Medical Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China
| | - Bao-Xian Liu
- Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, Guangdong Province, China
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16
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Yeh H, Chiang CC, Yen TH. Hepatocellular carcinoma in patients with renal dysfunction: Pathophysiology, prognosis, and treatment challenges. World J Gastroenterol 2021; 27:4104-4142. [PMID: 34326614 PMCID: PMC8311541 DOI: 10.3748/wjg.v27.i26.4104] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 03/17/2021] [Accepted: 06/16/2021] [Indexed: 02/06/2023] Open
Abstract
The population of patients with hepatocellular carcinoma (HCC) overlaps to a high degree with those for chronic kidney disease (CKD) and end-stage renal disease (ESRD). The degrees of renal dysfunction vary, from the various stages of CKD to dialysis-dependent ESRD, which often affects the prognosis and treatment choice of patients with HCC. In addition, renal dysfunction makes treatment more difficult and may negatively affect treatment outcomes. This study summarized the possible causes of the high comorbidity of HCC and renal dysfunction. The possible mechanisms of CKD causing HCC involve uremia itself, long-term dialysis status, immunosuppressive agents for postrenal transplant status, and miscellaneous factors such as hormone alterations and dysbiosis. The possible mechanisms of HCC affecting renal function include direct tumor invasion and hepatorenal syndrome. Finally, we categorized the risk factors that could lead to both HCC and CKD into four categories: Environmental toxins, viral hepatitis, metabolic syndrome, and vasoactive factors. Both CKD and ESRD have been reported to negatively affect HCC prognosis, but more research is warranted to confirm this. Furthermore, ESRD status itself ought not to prevent patients receiving aggressive treatments. This study then adopted the well-known Barcelona Clinic Liver Cancer guidelines as a framework to discuss the indicators for each stage of HCC treatment, treatment-related adverse renal effects, and concerns that are specific to patients with pre-existing renal dysfunction when undergoing aggressive treatments against CKD and ESRD. Such aggressive treatments include liver resection, simultaneous liver kidney transplantation, radiofrequency ablation, and transarterial chemoembolization. Finally, focusing on patients unable to receive active treatment, this study compiled information on the latest systemic pharmacological therapies, including targeted and immunotherapeutic drugs. Based on available clinical studies and Food and Drug Administration labels, this study details the drug indications, side effects, and dose adjustments for patients with renal dysfunction. It also provides a comprehensive review of information on HCC patients with renal dysfunction from disease onset to treatment.
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Affiliation(s)
- Hsuan Yeh
- Department of Nephrology, Chang Gung Memorial Hospital and Chang Gung University, Taipei 105, Taiwan
| | - Chun-Cheng Chiang
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Tzung-Hai Yen
- Department of Nephrology, Chang Gung Memorial Hospital and Chang Gung University, Taipei 105, Taiwan
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17
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Granito A, Forgione A, Marinelli S, Renzulli M, Ielasi L, Sansone V, Benevento F, Piscaglia F, Tovoli F. Experience with regorafenib in the treatment of hepatocellular carcinoma. Therap Adv Gastroenterol 2021; 14:17562848211016959. [PMID: 34104211 PMCID: PMC8165525 DOI: 10.1177/17562848211016959] [Citation(s) in RCA: 98] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Accepted: 04/20/2021] [Indexed: 02/06/2023] Open
Abstract
Regorafenib is a diphenylurea oral multikinase inhibitor, structurally comparable to sorafenib, which targets a variety of kinases implicated in angiogenic and tumor growth-promoting pathways. Regorafenib was the first agent to positively show significant survival advantage as a second-line therapy in patients with unresectable hepatocellular carcinoma (HCC) who had previously failed first-line treatment with sorafenib. Recent evidence has shown that its antitumor efficacy is due to a comprehensive spectrum of tumor neo-angiogenesis and proliferation inhibition and immunomodulatory effects on the tumor microenvironment, which plays a crucial role in tumor development. This review addresses the rationale and supporting evidence for regorafenib's efficacy in HCC that led to regorafenib's approval as a second-line therapy. In addition, we review proof from clinical practice studies that validate the RESORCE trial results. We discuss regorafenib's potential role in the newly emerging therapeutic strategy based on combination with immune checkpoint blockade and its possible extensibility to patient categories not enrolled in the registrative study.
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Affiliation(s)
- Alessandro Granito
- Department of Medical and Surgical Sciences, University of Bologna, S. Orsola-Malpighi Hospital, Via Albertoni 15, Bologna, 40138, Italy
- Division of Internal Medicine IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Antonella Forgione
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italia
| | - Sara Marinelli
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Matteo Renzulli
- Radiology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Luca Ielasi
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italia
| | - Vito Sansone
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italia
| | - Francesca Benevento
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italia
| | - Fabio Piscaglia
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italia
| | - Francesco Tovoli
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italia
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18
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Granito A, Marinelli S, Forgione A, Renzulli M, Benevento F, Piscaglia F, Tovoli F. Regorafenib Combined with Other Systemic Therapies: Exploring Promising Therapeutic Combinations in HCC. J Hepatocell Carcinoma 2021; 8:477-492. [PMID: 34079777 PMCID: PMC8165211 DOI: 10.2147/jhc.s251729] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 03/25/2021] [Indexed: 02/05/2023] Open
Abstract
Regorafenib was the first drug to demonstrate a survival benefit as a second-line agent after sorafenib failure in patients with unresectable hepatocellular carcinoma (HCC). Recent studies have shown that its mechanism of action is not only limited to its very broad spectrum of inhibition of angiogenesis, tumor proliferation, spread, and metastasis, but also to its immunomodulatory properties that have favorable effects on the very intricate role that the tumor microenvironment plays in carcinogenesis and tumor growth. In this review, we discuss rationale and evidence supporting regorafenib efficacy in HCC and that led to its approval as a second-line treatment, after sorafenib failure. We also discuss the evidence from clinical practice studies that confirm the results previously achieved in clinical trials. Finally, we analyze the potential role of regorafenib in emerging combined treatment approach with immunotherapy strategies using immune checkpoint blockade and its potential extension to patient categories not included in the registrative study.
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Affiliation(s)
- Alessandro Granito
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Sara Marinelli
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Antonella Forgione
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Matteo Renzulli
- Radiology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Francesca Benevento
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Fabio Piscaglia
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Francesco Tovoli
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
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19
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Naruto K, Kawaoka T, Amioka K, Ogawa Y, Chihiro K, Yoshikawa Y, Ando Y, Suehiro Y, Kosaka Y, Uchikawa S, Kodama K, Morio K, Fujino H, Murakami E, Nakahara T, Yamauchi M, Tsuge M, Hiramatsu A, Fukuhara T, Takaki S, Mori N, Tsuji K, Nonaka M, Hyogo H, Aisaka Y, Masaki K, Honda Y, Kohno H, Kohno H, Moriya T, Naeshiro N, Azakami T, Imamura M, Chayama K, Aikata H. Clinical Outcomes of 2nd- and 3rd-Line Regorafenib for Advanced Hepatocellular Carcinoma. Oncology 2021; 99:491-498. [PMID: 34000725 DOI: 10.1159/000515280] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Accepted: 02/15/2021] [Indexed: 11/19/2022]
Abstract
INTRODUCTION This study compared clinical outcomes of 2nd- and 3rd-line regorafenib in patients with unresectable hepatocellular carcinoma. METHODS In this retrospective cohort study, 48 patients were treated with regorafenib for unresectable hepatocellular carcinoma. Thirty-five and 13 patients were initiated on 2nd- and 3rd-line therapy, respectively. We assessed the responses to and safety of the therapy. RESULTS There were no statistically significant differences in clinical characteristics at the start of 2nd- or 3rd-line regorafenib therapy. The overall response rate of 2nd- and 3rd-line regorafenib was 20 and 8%, respectively. The disease control rate was 57 and 54%, respectively. Median overall survival (mOS) from the start of 2nd-line regorafenib was 17.5 months. mOS from the start of 3rd-line regorafenib was not obtained. Median progression-free survival of 2nd- and 3rd-line regorafenib was 4.9 and 2.3 months, respectively. mOS from 1st-line therapy with tyrosine kinase inhibitor plus sorafenib-regorafenib-lenvatinib was 29.5 months; that with lenvatinib-sorafenib-regorafenib was not obtained. Patients on 3rd-line therapy tended to have better Child-Pugh scores and tumor factors at the start of 1st-line therapy than other patients. CONCLUSION Patients on 2nd- and 3rd-line regorafenib showed favorable responses. Good Child-Pugh scores and tumor factors may be associated with a better response rate and OS.
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Affiliation(s)
- Kensuke Naruto
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kei Amioka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yutaro Ogawa
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kikukawa Chihiro
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yuki Yoshikawa
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yuwa Ando
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yosuke Suehiro
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yumi Kosaka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Shinsuke Uchikawa
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kenichiro Kodama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kei Morio
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hatsue Fujino
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Eisuke Murakami
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Masami Yamauchi
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Masataka Tsuge
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Akira Hiramatsu
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Takayuki Fukuhara
- Department of Gastroenterology, Hiroshima Red Cross Hospital and Atomic Bomb Survivors Hospital, Hiroshima, Japan
| | - Shintaro Takaki
- Department of Gastroenterology, Hiroshima Memorial Hospital, Hiroshima, Japan
| | - Nami Mori
- Department of Gastroenterology, Hiroshima Red Cross Hospital and Atomic Bomb Survivors Hospital, Hiroshima, Japan
| | - Keiji Tsuji
- Department of Gastroenterology, Hiroshima Red Cross Hospital and Atomic Bomb Survivors Hospital, Hiroshima, Japan
| | - Michihiro Nonaka
- Department of Gastroenterology, JA Hiroshima General Hospital, Hiroshima, Japan
| | - Hideyuki Hyogo
- Department of Gastroenterology, JA Hiroshima General Hospital, Hiroshima, Japan
| | - Yasuyuki Aisaka
- Department of Gastroenterology, JA Hiroshima General Hospital, Hiroshima, Japan
| | - Keiichi Masaki
- Department of Gastroenterology, Hiroshima City Asa Hospital, Hiroshima, Japan
| | - Yoji Honda
- Department of Gastroenterology, Hiroshima City Asa Hospital, Hiroshima, Japan
| | - Hirotaka Kohno
- Institute of Physical and Chemical Research (RIKEN) Center for Integrative Medical Sciences, Yokohama, Japan
| | - Hiroshi Kohno
- Institute of Physical and Chemical Research (RIKEN) Center for Integrative Medical Sciences, Yokohama, Japan
| | - Takashi Moriya
- Department of Gastroenterology, Chugoku Rosai Hospital, Hiroshima, Japan
| | - Noriaki Naeshiro
- Department of Gastroenterology, National Hospital Organization Kure Medical Center, Hiroshima, Japan
| | - Takahiro Azakami
- Department of Gastroenterology, National Hospital Organization Higashihiroshima Medical Center, Hiroshima, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.,Institute of Physical and Chemical Research (RIKEN) Center for Integrative Medical Sciences, Yokohama, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
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20
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Cerrito L, Santopaolo F, Monti F, Pompili M, Gasbarrini A, Ponziani FR. Advances in pharmacotherapeutics for hepatocellular carcinoma. Expert Opin Pharmacother 2021; 22:1343-1354. [PMID: 33637024 DOI: 10.1080/14656566.2021.1892074] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Although hepatocellular carcinoma (HCC) is the most frequent primary liver cancer, there are limited therapeutic options for the advanced stages. Sorafenib was the first tyrosine-kinase inhibitor (TKI) approved for unresectable HCC and remained the only effective choice for a decade. The horizon of systemic treatments drastically expanded in the latest years, opening new interesting possibilities. AREAS COVERED In this manuscript, the authors have analysed the recent advances in pharmacotherapy for HCC, discussing their mechanisms of action, the clinical efficacy and the safety profile of currently available first, second-and third-line treatments. The authors have also analysed the role of immune system modulators, in particular immune checkpoints inhibitors (ICIs), based on the limited data published so far. EXPERT OPINION The emergence of new targeted therapies, such as lenvatinib, have changed the landscape of HCC therapy. Tumor extension, differences in objective response rates and adverse events profiles should be considered to tailor the choice of the first-line agent. Sorafenib remains the most studied drug, with much real-world data available. The efficacy of second line therapies has only been proven in non-responder or sorafenib-intolerant patients. Unfortunately, studies directly comparing the second-line agents regorafenib, ramucirumab and cabozantinib are still lacking.
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Affiliation(s)
- Lucia Cerrito
- Internal Medicine, Gastroenterology And Hepatology, Fondazione Policlinico Universitario Agostino Gemelli Irccs, Università Cattolica Del Sacro Cuore, ROMA, ITALY
| | - Francesco Santopaolo
- Internal Medicine, Gastroenterology And Hepatology, Fondazione Policlinico Universitario Agostino Gemelli Irccs, Università Cattolica Del Sacro Cuore, ROMA, ITALY
| | | | - Maurizio Pompili
- Internal Medicine, Gastroenterology And Hepatology, Fondazione Policlinico Universitario Agostino Gemelli Irccs, Università Cattolica Del Sacro Cuore, ROMA, ITALY
| | - Antonio Gasbarrini
- Internal Medicine, Gastroenterology And Hepatology, Fondazione Policlinico Universitario Agostino Gemelli Irccs, Università Cattolica Del Sacro Cuore, ROMA, ITALY
| | - Francesca Romana Ponziani
- Internal Medicine, Gastroenterology And Hepatology, Fondazione Policlinico Universitario Agostino Gemelli Irccs, Università Cattolica Del Sacro Cuore, ROMA, ITALY
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21
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Li H. Angiogenesis in the progression from liver fibrosis to cirrhosis and hepatocelluar carcinoma. Expert Rev Gastroenterol Hepatol 2021; 15:217-233. [PMID: 33131349 DOI: 10.1080/17474124.2021.1842732] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Introduction: Persistent inflammation and hypoxia are strong stimulus for pathological angiogenesis and vascular remodeling, and are also the most important elements resulting in liver fibrosis. Sustained inflammatory process stimulates fibrosis to the end-point of cirrhosis and sinusoidal portal hypertension is an important feature of cirrhosis. Neovascularization plays a pivotal role in collateral circulation formation of portal vein, mesenteric congestion, and high perfusion. Imbalance of hepatic artery and portal vein blood flow leads to the increase of hepatic artery inflow, which is beneficial to the formation of nodules. Angiogenesis contributes to progression from liver fibrosis to cirrhosis and hepatocellular carcinoma (HCC) and anti-angiogenesis therapy can improve liver fibrosis, reduce portal pressure, and prolong overall survival of patients with HCC. Areas covers: This paper will try to address the difference of the morphological characteristics and mechanisms of neovascularization in the process from liver fibrosis to cirrhosis and HCC and further compare the different efficacy of anti-angiogenesis therapy in these three stages. Expert opinion: More in-depth understanding of the role of angiogenesis factors and the relationship between angiogenesis and other aspects of the pathogenesis and transformation may be the key to enabling future progress in the treatment of patients with liver fibrosis, cirrhosis, and HCC.
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Affiliation(s)
- Hui Li
- Central Laboratory, Hospital of Chengdu University of Traditional Chinese Medicine , Chengdu, Sichuan Province, P. R. China
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22
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Schipilliti FM, Garajová I, Rovesti G, Balsano R, Piacentini F, Dominici M, Gelsomino F. The Growing Skyline of Advanced Hepatocellular Carcinoma Treatment: A Review. Pharmaceuticals (Basel) 2021; 14:43. [PMID: 33429973 PMCID: PMC7827379 DOI: 10.3390/ph14010043] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 12/13/2020] [Accepted: 12/30/2020] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the main type of liver cancer. In the majority of cases, HCC is diagnosed at the advanced stage, leading to poor prognosis. In recent years, many efforts have been devoted to investigating potential new and more effective drugs and, indeed, the treatment armamentarium for advanced HCC has broadened tremendously, with targeted- and immune-therapies, and probably the combination of both, playing pivotal roles. Together with new established knowledge, many issues are emerging, with the role of neoadjuvant/adjuvant settings, the definition of the best transitioning time from loco-regional treatments to systemic therapy, the identification of potential predictive biomarkers, and radiomics being just some of the topics that will have to be further explored in the next future. Clearly, the current COVID-19 pandemic has influenced the management of HCC patients and some considerations about this topic will be elucidated.
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Affiliation(s)
- Francesca Matilde Schipilliti
- Oncology Unit, University Hospital of Modena and Reggio Emilia, Largo del Pozzo 71, 41125 Modena, Italy; (G.R.); (F.P.); (M.D.)
| | - Ingrid Garajová
- Medical Oncology Unit, University Hospital of Parma, Via Gramsci 14, 43126 Parma, Italy;
| | - Giulia Rovesti
- Oncology Unit, University Hospital of Modena and Reggio Emilia, Largo del Pozzo 71, 41125 Modena, Italy; (G.R.); (F.P.); (M.D.)
| | - Rita Balsano
- Medical Oncology Unit, University Hospital of Parma, Via Gramsci 14, 43126 Parma, Italy;
| | - Federico Piacentini
- Oncology Unit, University Hospital of Modena and Reggio Emilia, Largo del Pozzo 71, 41125 Modena, Italy; (G.R.); (F.P.); (M.D.)
| | - Massimo Dominici
- Oncology Unit, University Hospital of Modena and Reggio Emilia, Largo del Pozzo 71, 41125 Modena, Italy; (G.R.); (F.P.); (M.D.)
| | - Fabio Gelsomino
- Oncology Unit, University Hospital of Modena and Reggio Emilia, Largo del Pozzo 71, 41125 Modena, Italy; (G.R.); (F.P.); (M.D.)
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23
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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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24
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Chui AMN, Yau TCC, Cheung TT. An overview in management of hepatocellular carcinoma in Hong Kong using the Hong Kong Liver Cancer (HKLC) staging system. Glob Health Med 2020; 2:312-318. [PMID: 33330826 DOI: 10.35772/ghm.2020.01062] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 09/16/2020] [Accepted: 09/23/2020] [Indexed: 12/13/2022]
Abstract
In Hong Kong, liver cancer is the fifth most common cancer and the third most common cause of cancer deaths. The prevalence of hepatitis B is high in Hong Kong because of the high rate of hepatitis B virus infection, and chronic hepatitis B has remained the leading cause of hepatocellular carcinoma in the city, accounting for 80% of all cases in the period from 1992 to 2016. In view of the different etiologies of hepatocellular carcinoma around the world, a group of liver experts in Hong Kong developed the Hong Kong Liver Cancer staging system in order to provide more aggressive treatment guidance (predominantly a wider use of surgical resection) for Asian patients of hepatocellular carcinoma. In this article focussing on the Hong Kong Liver Cancer staging system, we briefly reviewed the screening criteria adopted in Hong Kong for liver resection, local ablation, transcatheter arterial chemoembolization, transcatheter arterial radioembolization, stereotactic body radiation therapy, and systemic therapy.
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Affiliation(s)
- Arnold Man Nok Chui
- Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
| | | | - Tan To Cheung
- Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China.,Department of Surgery, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
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25
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Kim HD, Bang Y, Lee MA, Kim JW, Kim JH, Chon HJ, Kang B, Kang MJ, Kim I, Cheon J, Hwang JE, Kang JH, Byeon S, Hong JY, Ryoo BY, Lim HY, Yoo C. Regorafenib in patients with advanced Child-Pugh B hepatocellular carcinoma: A multicentre retrospective study. Liver Int 2020; 40:2544-2552. [PMID: 32563213 DOI: 10.1111/liv.14573] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Revised: 06/11/2020] [Accepted: 06/12/2020] [Indexed: 12/18/2022]
Abstract
INTRODUCTION Regorafenib is an approved agent in patients with advanced hepatocellular carcinoma (HCC) who progressed on sorafenib, but little is known about its clinical outcomes in Child-Pugh B patients. We aimed to investigate the safety and effectiveness of regorafenib in Child-Pugh B HCC patients. METHODS This multicentre retrospective study included 59 patients with Child-Pugh B HCC who received regorafenib. Comparative analyses were performed with an independent cohort of Child-Pugh class A patients from the same registry (n = 440). RESULTS The median age was 58 years (range, 19-83). All patients had progression on prior sorafenib. Regorafenib was given as 2nd line, and 3rd-4th line systemic therapy in 37 (62.7%) and 22 (37.3%) patients respectively. Compared to Child-Pugh A cohort, grade 3-4 AEs were more common in the Child-Pugh B cohort (27.1% vs 14.1%, P = .017). The median progression-free survival (PFS) and overall survival (OS) were 1.8 and 4.6 months, respectively, and these were significantly poorer than the Child-Pugh A cohort (P = .008 and P < .001 respectively). Child-Pugh B patients with albumin-bilirubin (ALBI) grade 3 had a significantly higher frequency of increased bilirubin (P = .01 for any grade and P = .01 for grade 3-4) and showed significantly poorer OS (P = .021), compared to those with ALBI grade 1 or 2. CONCLUSION Regorafenib's poor clinical outcomes and increased frequency of severe adverse events lead us to discourage its use in the Child-Pugh B population. In particular, regorafenib should not be used in Child-Pugh B patients with ALBI grade 3.
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Affiliation(s)
- Hyung-Don Kim
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Yeonghak Bang
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Myung Ah Lee
- Division of Hematology-Oncology, Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea
| | - Jin Won Kim
- Division of Hematology-Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Jee Hyun Kim
- Division of Hematology-Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Hong Jae Chon
- Division of Hematology-Oncology, Department of Internal Medicine, Bundang CHA Hospital, Seongnam, Korea
| | - Beodeul Kang
- Division of Hematology-Oncology, Department of Internal Medicine, Bundang CHA Hospital, Seongnam, Korea
| | - Myoung Joo Kang
- Division of Oncology, Department of Internal Medicine, Inje University College of Medicine, Haeundae Paik Hospital, Busan, Korea
| | - Ilhwan Kim
- Division of Oncology, Department of Internal Medicine, Inje University College of Medicine, Haeundae Paik Hospital, Busan, Korea
| | - Jaekyung Cheon
- Division of Hematology-Oncology, Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Jun-Eul Hwang
- Division of Hematology-Oncology, Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea
| | - Jung Hun Kang
- Division of Hematology-Oncology, Department of Internal Medicine, Gyeongsang National University, Jinju, Korea
| | - Seonggyu Byeon
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jung Yong Hong
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Baek-Yeol Ryoo
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Ho Yeong Lim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Changhoon Yoo
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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26
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Yoo C, Byeon S, Bang Y, Cheon J, Kim JW, Kim JH, Chon HJ, Kang B, Kang MJ, Kim I, Hwang JE, Kang JH, Lee MA, Hong JY, Lim HY, Ryoo BY. Regorafenib in previously treated advanced hepatocellular carcinoma: Impact of prior immunotherapy and adverse events. Liver Int 2020; 40:2263-2271. [PMID: 32449588 DOI: 10.1111/liv.14496] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 04/15/2020] [Accepted: 04/25/2020] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS Regorafenib demonstrated a clinical benefit for patients with unresectable hepatocellular carcinoma (uHCC) in the phase III RESORCE trial. Considering the heterogeneity of uHCC and discrepancies in its characteristics between prospective trials and daily practice, real-life evidence is necessary. METHODS This multicentre, retrospective analysis was performed by the Korean Cancer Study Group. In total, 440 patients who received regorafenib between January 2017 and November 2019 were identified in nine tertiary referral hospitals in Korea. RESULTS All patients received prior sorafenib, and the median time-to-progression (TTP) on sorafenib was 3.9 months (range, 0.2-71.6). Regorafenib was used as the second, third and fourth to seventh lines of therapy in 305 (69.3%), 115 (26.1%) and 20 (4.5%) patients respectively. According to the RECIST v1.1, the overall response rate was 7.7% (n = 34), and the median progression-free survival (PFS) and overall survival (OS) were 3.2 (95% CI, 2.8-3.5) and 12.1 (95% CI, 9.7-14.5) months respectively. Immune checkpoint inhibitors (ICIs) were given in 115 patients (26.1%) prior to regorafenib. There were no differences in PFS and OS with regorafenib according to the prior use of ICIs (PFS, P = .61; OS, P = .63). The occurrence of hand-foot skin reaction (HFSR) was associated with a better OS (P < .001). CONCLUSIONS The real-life clinical outcomes of regorafenib for patients who progressed on prior systemic therapy including ICIs were consistent with the phase III trial results. HFSR was significantly associated with better OS with regorafenib.
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Affiliation(s)
- Changhoon Yoo
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Seonggyu Byeon
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Department of Internal Medicine, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Korea
| | - Yeonghak Bang
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jaekyung Cheon
- Division of Hematology-Oncology, Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Jin W Kim
- Division of Hematology-Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Jee H Kim
- Division of Hematology-Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Hong J Chon
- Division of Hematology-Oncology, Department of Internal Medicine, Bundang CHA Hospital, Seongnam, Korea
| | - Beodeul Kang
- Division of Hematology-Oncology, Department of Internal Medicine, Bundang CHA Hospital, Seongnam, Korea
| | - Myoung J Kang
- Division of Oncology, Department of Internal Medicine, Inje University College of Medicine, Haeundae Paik Hospital, Busan, Korea
| | - Ilhwan Kim
- Division of Oncology, Department of Internal Medicine, Inje University College of Medicine, Haeundae Paik Hospital, Busan, Korea
| | - Jun-Eul Hwang
- Division of Hematology-Oncology, Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea
| | - Jung H Kang
- Division of Hematology-Oncology, Department of Internal Medicine, Gyeongsang National University, Jinju, Korea
| | - Myung A Lee
- Division of Hematology-Oncology, Department of Internal Medicine, Seoul St. Mary's hospital, The Catholic University of Korea, Seoul, Korea
| | - Jung Y Hong
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ho Y Lim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Baek-Yeol Ryoo
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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27
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Huang A, Yang XR, Chung WY, Dennison AR, Zhou J. Targeted therapy for hepatocellular carcinoma. Signal Transduct Target Ther 2020; 5:146. [PMID: 32782275 PMCID: PMC7419547 DOI: 10.1038/s41392-020-00264-x] [Citation(s) in RCA: 470] [Impact Index Per Article: 94.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Revised: 07/10/2020] [Accepted: 07/15/2020] [Indexed: 02/06/2023] Open
Abstract
The last 3 years have seen the emergence of promising targeted therapies for the treatment of hepatocellular carcinoma (HCC). Sorafenib has been the mainstay of treatment for a decade and newer modalities were ineffective and did not confer any increased therapeutic benefit until the introduction of lenvatinib which was approved based on its non-inferiority to sorafenib. The subsequent success of regorafenib in HCC patients who progress on sorafenib treatment heralded a new era of second-line treatment and was quickly followed by ramucirumab, cabozantinib, and the most influential, immune checkpoint inhibitors (ICIs). Over the same period combination therapies, including anti-angiogenesis agents with ICIs, dual ICIs and targeted agents in conjunction with surgery or other loco-regional therapies, have been extensively investigated and have shown promise and provided the basis for exciting clinical trials. Work continues to develop additional novel therapeutic agents which could potentially augment the presently available options and understand the underlying mechanisms responsible for drug resistance, with the goal of improving the survival of patients with HCC.
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Affiliation(s)
- Ao Huang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xin-Rong Yang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wen-Yuan Chung
- Department of Hepatobiliary and Pancreatic Surgery, University Hospitals of Leicester NHS Trust, Leicester, UK
| | - Ashley R Dennison
- Department of Hepatobiliary and Pancreatic Surgery, University Hospitals of Leicester NHS Trust, Leicester, UK
| | - Jian Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China.
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China.
- Institute of Biomedical Sciences, Fudan University, Shanghai, China.
- State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China.
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28
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Lee MJ, Chang SW, Kim JH, Lee YS, Cho SB, Seo YS, Yim HJ, Hwang SY, Lee HW, Chang Y, Jang JY. Real-world systemic sequential therapy with sorafenib and regorafenib for advanced hepatocellular carcinoma: a multicenter retrospective study in Korea. Invest New Drugs 2020; 39:260-268. [PMID: 32749658 DOI: 10.1007/s10637-020-00977-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 07/28/2020] [Indexed: 12/29/2022]
Abstract
Background/Aims Regorafenib has been approved as a second-line systemic therapy for hepatocellular carcinoma (HCC) patients after the phase III RESORCE trial. This study analyzed real-world data to assess the clinical effectiveness and safety of regorafenib compared to the RESORCE trial. Methods This multicenter cohort study included HCC patients treated with regorafenib after sorafenib (n = 133). We evaluated the time to progression (TTP), progression-free survival (PFS), overall survival (OS), and safety in patients receiving regorafenib along with the predictors of prognosis. Results The median age was 60 years and 81.2% patients were men. Hepatitis B virus infection (68.4%) was the commonest etiology. Most patients were classified as Child-Pugh A (98.5%) and had extrahepatic metastasis (84%) and vascular invasion (45.1%). This study demonstrated similar characteristics apart from more frequent hepatitis B etiology and more vascular or extrahepatic involvement compared with the RESORCE trial. An objective response rate of 12.5% was obtained for response assessment (n = 112); the disease control rate was 34.8%. Thirty-eight patients died during follow-up. With regorafenib, the median OS, PFS, and TTP were 10.0, 2.7, and 2.6 months, respectively. In the exploratory analysis after sorafenib administration, the median OS was 25.8 months. The rate of response and survival were comparable to those in the RESORCE trial. Child-Pugh score > 5, alpha-fetoprotein > 400 ng/ml, and TTP for sorafenib ≥ median were independently associated with OS. Conclusions This real-word regorafenib study showed comparable effectiveness and safety to the RESORCE trial. Regorafenib improves the prognosis of patients with prolonged TTP during previous sorafenib therapy.
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Affiliation(s)
- Min Jin Lee
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Sung Won Chang
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Ji Hoon Kim
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea.
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Guro Hospital, Korea University College of Medicine, 97, Guro-Dong Gil, Guro-Dong, Guro-Ku, Seoul, 08308, Korea.
| | - Young-Sun Lee
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Sung Bum Cho
- Department of Gastroenterology and Hepatology, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, 264 Seoyang-ro, Hwasun-eup, Hwasun-gun, Jeollanam-do, Hwasun, 58128, Republic of Korea.
| | - Yeon Seok Seo
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Hyung Joon Yim
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Sang Youn Hwang
- Department of Internal Medicine and Gastrointestinal Cancer Center, Dongnam Institute of Radiological and Medical Sciences, Busan, Korea
| | - Hyun Woong Lee
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Young Chang
- Department of Internal Medicine, Soonchunhyang University College of Medicine Seoul Hospital, Seoul, Korea
| | - Jae Young Jang
- Department of Internal Medicine, Soonchunhyang University College of Medicine Seoul Hospital, Seoul, Korea
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29
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Komiyama S, Numata K, Ogushi K, Moriya S, Fukuda H, Chuma M, Maeda S. Therapeutic effects of regorafenib after sorafenib monotherapy with advanced hepatocellular carcinoma including Child-Pugh classification B: A retrospective observational study. Medicine (Baltimore) 2020; 99:e21191. [PMID: 32702881 PMCID: PMC7373530 DOI: 10.1097/md.0000000000021191] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
The therapeutic effect of regorafenib was previously demonstrated in patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh classification A (CP-A) whose disease progressed during sorafenib treatment in a phase III trial. However, treatment options are limited for patients with advanced HCC other than CP-A. In this study, we aimed to evaluate the therapeutic effect of regorafenib on advanced HCC patients including those with Child-Pugh classification B (CP-B).We retrospectively analyzed the medical records of 21 patients with advanced HCC who were treated with regorafenib after sorafenib monotherapy at our hospital from July 2017 to April 2018 and were followed up until September 2019. Patients were classified according to liver function and adverse events experienced during sorafenib treatment and were started on regorafenib with a pre-defined reduced starting dose along with a dose reduction and schedule change based on the judgement of the attending physician.At regorafenib initiation, 13 and 8 patients were classified as CP-A and CP-B, respectively. In all patients with CP-B, the starting dose of regorafenib was reduced, and the pre-defined starting-dose sets were applied to 17 (81%) patients. The median duration of regorafenib treatment in patients with CP-A and CP-B were 4.1 months and 2.0 months, respectively, with no significant difference. The median overall survival from regorafenib initiation (OS-r) and sorafenib initiation (OS-s) was 13.2 months and 30.9 months, respectively. In subgroup analysis, OS-r was 16.3 months in patients with CP-A and 10.1 months with CP-B with no significant difference (P = .44), whereas OS-r was 16.3 months in patients with modified albumin-bilirubin Grade 1/2a and 13.2 months in patients with Grade 2b, with no significant difference. There was no clear difference in the incidence rate of ≥grade 3 adverse events between CP-A and CP-B. OS-r and OS-s were significantly correlated.Even patients with impaired liver function achieved the desired therapeutic effects by safely reducing the starting dose of regorafenib according to both impaired liver function and adverse events during pretreatment. Regorafenib may be considered to be an effective treatment after sorafenib monotherapy in patients with impaired liver function.
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Affiliation(s)
- Satoshi Komiyama
- Gastroenterological Center
- Chemotherapy Department, Yokohama City University Medical Center
| | | | | | | | | | | | - Shin Maeda
- Department of Gastroenterology, Graduate School of Medicine, Yokohama City University, Yokohama, Kanagawa, Japan
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30
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Han S, Kim DY. Optimal sequence of systemic therapy after sorafenib failure in patients with hepatocellular carcinoma. Clin Mol Hepatol 2020; 26:305-308. [PMID: 32646205 PMCID: PMC7364361 DOI: 10.3350/cmh.2020.0096] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Accepted: 06/02/2020] [Indexed: 12/13/2022] Open
Affiliation(s)
- Sojung Han
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
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31
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Choi W, Choi J, Lee D, Shim JH, Lim Y, Lee HC, Chung Y, Lee Y, Park SR, Ryu M, Ryoo B, Lee SJ, Kim KM. Regorafenib Versus Nivolumab After Sorafenib Failure: Real-World Data in Patients With Hepatocellular Carcinoma. Hepatol Commun 2020; 4:1073-1086. [PMID: 32626838 PMCID: PMC7327222 DOI: 10.1002/hep4.1523] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 03/17/2020] [Accepted: 04/02/2020] [Indexed: 12/16/2022] Open
Abstract
Regorafenib and nivolumab are drugs approved for second-line treatment of patients with hepatocellular carcinoma (HCC) after sorafenib failure. However, the effectiveness of regorafenib and nivolumab following sorafenib has not been directly compared. This study retrospectively evaluated 373 patients with HCC who were treated with regorafenib (n = 223) or nivolumab (n = 150) after sorafenib failure between July 2017 and February 2019. Progression-free survival (PFS; hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.69-1.06; P = 0.150), time to progression (TTP; HR, 0.95; 95% CI, 0.77-1.19; P = 0.680), and overall survival (OS; HR, 0.83; 95% CI, 0.64-1.07; P = 0.154) did not differ significantly between groups of patients treated with regorafenib and nivolumab, findings consistently observed by multivariable-adjusted, propensity score-matched, and inverse probability treatment weighting (IPTW) analyses. However, the objective response rate was significantly higher in the nivolumab than in the regorafenib group (13.3% vs. 4.0%; P = 0.002). When the effectiveness of regorafenib and nivolumab was compared in nonprogressors to treatment, defined as patients who achieved complete response, partial response, or stable disease after first response evaluation, PFS (HR, 0.50; 95% CI, 0.33-0.75; P = 0.001), TTP (HR, 0.48; 95% CI, 0.31-0.73; P < 0.001), and OS (HR, 0.51; 95% CI, 0.31-0.87; P = 0.013) were significantly longer in the 59 nonprogressors to nivolumab than in the 104 nonprogressors to regorafenib, findings also observed by multivariable-adjusted and IPTW analyses. Conclusion: Survival outcomes in patients treated with regorafenib and nivolumab after sorafenib failure did not differ significantly. However, nivolumab may be more effective than regorafenib in nonprogressors.
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Affiliation(s)
- Won‐Mook Choi
- Department of GastroenterologyLiver CenterUniversity of Ulsan College of MedicineSeoulRepublic of Korea
| | - Jonggi Choi
- Department of GastroenterologyLiver CenterUniversity of Ulsan College of MedicineSeoulRepublic of Korea
| | - Danbi Lee
- Department of GastroenterologyLiver CenterUniversity of Ulsan College of MedicineSeoulRepublic of Korea
| | - Ju Hyun Shim
- Department of GastroenterologyLiver CenterUniversity of Ulsan College of MedicineSeoulRepublic of Korea
| | - Young‐Suk Lim
- Department of GastroenterologyLiver CenterUniversity of Ulsan College of MedicineSeoulRepublic of Korea
| | - Han Chu Lee
- Department of GastroenterologyLiver CenterUniversity of Ulsan College of MedicineSeoulRepublic of Korea
| | - Young‐Hwa Chung
- Department of GastroenterologyLiver CenterUniversity of Ulsan College of MedicineSeoulRepublic of Korea
| | - Young‐Sang Lee
- Department of GastroenterologyLiver CenterUniversity of Ulsan College of MedicineSeoulRepublic of Korea
| | - Sook Ryun Park
- Department of OncologyUniversity of Ulsan College of MedicineSeoulRepublic of Korea
| | - Min‐Hee Ryu
- Department of OncologyUniversity of Ulsan College of MedicineSeoulRepublic of Korea
| | - Baek‐Yeol Ryoo
- Department of OncologyUniversity of Ulsan College of MedicineSeoulRepublic of Korea
| | - So Jung Lee
- Department of RadiologyAsan Medical CenterUniversity of Ulsan College of MedicineSeoulRepublic of Korea
| | - Kang Mo Kim
- Department of GastroenterologyLiver CenterUniversity of Ulsan College of MedicineSeoulRepublic of Korea
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32
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Kirstein MM, Scheiner B, Marwede T, Wolf C, Voigtländer T, Semmler G, Wacker F, Manns MP, Hinrichs JB, Pinter M, Vogel A. Sequential systemic treatment in patients with hepatocellular carcinoma. Aliment Pharmacol Ther 2020; 52:205-212. [PMID: 32432799 DOI: 10.1111/apt.15789] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 03/18/2020] [Accepted: 04/22/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most lethal cancers. After many years of stagnation, there are now several systemic treatments available for patients with HCC. AIM To analyse the feasibility and efficacy of sequential systemic treatments in patients with HCC in clinical practice. METHODS In this multicentre study, patients who were treated with novel systemic therapies for HCC between 2014 and 2019 at two referral centres, Hannover Medical School, Germany, and Medical University of Vienna, Austria, were included. RESULTS Overall, 85 patients were included of which 76 patients (89.4%) received more than one and a maximum of five systemic treatment lines. The most common therapy sequence was sorafenib (n = 72; 84.7%) followed by regorafenib (n = 37; 48.7%), whereas 11 patients were initially treated with lenvatinib (12.9%). Other second-line treatments included pembrolizumab, nivolumab, cabozantinib and ramucirumab. Hepatic function deteriorated during sequential systemic treatment in 48.6% of the patients as defined by an increase in at least one Child-Pugh point. Median overall survival (mOS) from the start of first systemic treatment was 35 months for patients with sequential systemic treatment compared to 9 months for patients with one systemic treatment line (P < 0.001). Patients previously treated with surgical/locoregional therapies had a longer mOS compared to patients with initial systemic treatment (66 vs 25 months; P = 0.020). CONCLUSIONS Sequential systemic treatment is feasible and effective in selected patients with HCC in clinical practice. Our study underlines the critical importance of well-preserved liver function for successful administration of sequential systemic therapy.
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Affiliation(s)
- Martha M Kirstein
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
- Department of Medicine I, University Medical Center Schleswig-Holstein, Lübeck, Germany
| | - Bernhard Scheiner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Tristan Marwede
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Caroline Wolf
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Torsten Voigtländer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Georg Semmler
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Frank Wacker
- Institute for Diagnostic and Interventional Radiology, Hannover Medical School, Hannover, Germany
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Jan B Hinrichs
- Institute for Diagnostic and Interventional Radiology, Hannover Medical School, Hannover, Germany
| | - Matthias Pinter
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Arndt Vogel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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33
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Lee CH, Lee YB, Kim MA, Jang H, Oh H, Kim SW, Cho EJ, Lee KH, Lee JH, Yu SJ, Yoon JH, Kim TY, Kim YJ. Effectiveness of nivolumab versus regorafenib in hepatocellular carcinoma patients who failed sorafenib treatment. Clin Mol Hepatol 2020; 26:328-339. [PMID: 32460459 PMCID: PMC7364358 DOI: 10.3350/cmh.2019.0049n] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Accepted: 04/07/2020] [Indexed: 02/06/2023] Open
Abstract
Background/Aims Several treatment options are currently available for patients with hepatocellular carcinoma (HCC) failing previous sorafenib treatment. We aimed to compare the effectiveness of regorafenib and nivolumab in these patients. Methods Consecutive HCC patients who received regorafenib or nivolumab after failure of sorafenib treatment were included. Primary endpoint was overall survival (OS) and secondary endpoints were time to progression, tumor response rate, and adverse events. Inverse probability of treatment weighting (IPTW) using the propensity score was conducted to reduce treatment selection bias. Results Among 150 study patients, 102 patients received regorafenib and 48 patients received nivolumab. Median OS was 6.9 (95% confidence interval [CI], 3.0–10.8) months for regorafenib and 5.9 (95% CI, 3.7–8.1) months for nivolumab (P=0.77 by log-rank test). In multivariable analysis, nivolumab was associated with prolonged OS (vs. regorafenib: adjusted hazard ratio [aHR], 0.54; 95% CI, 0.30–0.96; P=0.04). Time to progression was not significantly different between groups (nivolumab vs. regorafenib: aHR, 0.82; 95% CI, 0.51–1.30; P=0.48). HRs were maintained after IPTW. Objective response rates were 5.9% and 16.7% in patients treated with regorafenib and nivolumab, respectively (P=0.04). Conclusions After sorafenib failure, the use of nivolumab may be associated with improved OS and better objective response rate as compared to using regorafenib.
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Affiliation(s)
- Cheol-Hyung Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Yun Bin Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Minseok Albert Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Heejoon Jang
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Hyunwoo Oh
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Sun Woong Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Eun Ju Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Kyung-Hun Lee
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.,Cancer Research Institute, Seoul National University, Seoul, Korea
| | - Jeong-Hoon Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Su Jong Yu
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Jung-Hwan Yoon
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Tae-You Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.,Cancer Research Institute, Seoul National University, Seoul, Korea
| | - Yoon Jun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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34
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Ogasawara S, Ooka Y, Koroki K, Maruta S, Kanzaki H, Kanayama K, Kobayashi K, Kiyono S, Nakamura M, Kanogawa N, Saito T, Kondo T, Suzuki E, Nakamoto S, Tawada A, Chiba T, Arai M, Kato J, Kato N. Switching to systemic therapy after locoregional treatment failure: Definition and best timing. Clin Mol Hepatol 2020; 26:155-162. [PMID: 31937081 PMCID: PMC7160341 DOI: 10.3350/cmh.2019.0021n] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Accepted: 11/22/2019] [Indexed: 12/11/2022] Open
Abstract
In patients with unresectable hepatocellular carcinoma (HCC) without both macrovascular invasion and extrahepatic metastasis, the initial treatment choice recommended is transarterial chemoembolization (TACE). Before sorafenib came into wide use, TACE had been pointlessly carried out repeatedly. It was in the early 2010s that the concept of TACE refractory was advocated. Two retrospective studies from Japan indicated that conversion from TACE to sorafenib the day after patients were deemed as TACE refractory improved overall survival compared with continued TACE, according to the definition by the Japan Society of Hepatology. Nowadays, phase 3 trials have shown clinical benefits of several novel molecular target agents. Compared with the era of sorafenib, sequential treatments with these molecular target agents have gradually prolonged patients' survival and have become major strategies in patients with HCC. Taking these together, conversion from TACE to systemic therapies at the time of TACE refractory, compared with before, may have a greater impact on survival and may be considered deeper in the decisions-making process in patients with unresectable HCC who are candidate for TACE. Up-to-date information on the concept of TACE refractory is summarized in this review. We believe that the survival of patients with unresectable HCC without both macrovascular invasion and extrahepatic metastasis may be dramatically improved by optimal timing of TACE refractory and switching to systemic therapies.
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Affiliation(s)
- Sadahisa Ogasawara
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
- Translational Research and Development Center, Chiba University Hospital, Chiba, Japan
| | - Yoshihiko Ooka
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Keisuke Koroki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Susumu Maruta
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Hiroaki Kanzaki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Kengo Kanayama
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Kazufumi Kobayashi
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
- Translational Research and Development Center, Chiba University Hospital, Chiba, Japan
| | - Soichiro Kiyono
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Masato Nakamura
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Naoya Kanogawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tomoko Saito
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Takayuki Kondo
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Eiichiro Suzuki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Shingo Nakamoto
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Akinobu Tawada
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
- Department of Medical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tetsuhiro Chiba
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Makoto Arai
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
- Department of Medical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Jun Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Naoya Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
- Translational Research and Development Center, Chiba University Hospital, Chiba, Japan
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Zhang CH, Li M, Lin YP, Gao Q. Systemic Therapy for Hepatocellular Carcinoma: Advances and Hopes. Curr Gene Ther 2020; 20:84-99. [PMID: 32600231 DOI: 10.2174/1566523220666200628014530] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 05/26/2020] [Accepted: 05/28/2020] [Indexed: 12/24/2022]
Abstract
The majority of patients with hepatocellular carcinoma (HCC) are diagnosed at an advanced stage that can only benefit from systemic treatments. Although HCC is highly treatmentresistant, significant achievements have been made in the molecular targeted therapy and immunotherapy of HCC. In addition to regorafenib, cabozantinib and ramucirumab were approved for the second- line targeted treatment by the FDA after disease progression on sorafenib. Nivolumab failed to demonstrate remarkable benefit in overall survival (OS) as first-line therapy, while pembrolizumab did not achieve pre-specified statistical significance in both OS and progression-free survival (PFS) as second-line treatment. Combinations of targeted agents, immune checkpoint inhibitors and other interventions showed favorable results. In this review, we summarized the progress of systemic therapy in HCC and discussed the future directions of the treatment of HCC.
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Affiliation(s)
- Chen-Hao Zhang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Ming Li
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - You-Pei Lin
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Qiang Gao
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
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Facciorusso A, Abd El Aziz MA, Sacco R. Efficacy of Regorafenib in Hepatocellular Carcinoma Patients: A Systematic Review and Meta-Analysis. Cancers (Basel) 2019; 12:36. [PMID: 31877664 PMCID: PMC7017079 DOI: 10.3390/cancers12010036] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Revised: 12/12/2019] [Accepted: 12/15/2019] [Indexed: 12/12/2022] Open
Abstract
Regorafenib showed promising results as a second-line agent after sorafenib failure in hepatocellular carcinoma patients. The aim of this meta-analysis was to evaluate the efficacy and safety of regorafenib in hepatocarcinoma patients. A computerized bibliographic search was performed on the main databases. The primary outcome was overall survival. Secondary outcomes were progression-free survival, tumor response, and the adverse events rate. Outcomes were pooled through a random-effects model and summary estimates were expressed in terms of median and 95% confidence interval or rates, as appropriate. One randomized-controlled trial and seven non-randomized studies with 809 patients were included. The great majority of recruited patients were in Child-Pugh A and ECOG 0 stage. Median overall survival was 11.08 months (9.46-12.71) and sensitivity analyses confirmed this finding, with a median survival ranging from 10.2 to 13.8 months. Duration of regorafenib therapy was 3.58 months, whereas median progression-free survival was 3.24 months (2.68-3.86). The pooled objective response rate was 10.1% (7.8%-12.5%) while the disease control rate was 65.5% (61.3%-69.7%) with no evidence of heterogeneity (I2 = 0%; Diarrhea, fatigue, and hand-foot skin reaction were the most frequent adverse events. The current meta-analysis shows that regorafenib represents a valuable and relatively safe therapeutic option in intermediate/advanced hepatocellular carcinomapatients who progress on sorafenib.
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Affiliation(s)
- Antonio Facciorusso
- Department of Medical Sciences, Section of Gastroenterology, University of Foggia, 71122 Foggia, Italy;
| | - Mohamed A. Abd El Aziz
- Department of Surgery, Faculty of Medicine, University of Arizona, Tucson, AZ 85719, USA; or
- Department of Surgery, Mayo Clinic, Rochester, MN 55905, USA
| | - Rodolfo Sacco
- Department of Medical Sciences, Section of Gastroenterology, University of Foggia, 71122 Foggia, Italy;
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Wang W, Tsuchiya K, Kurosaki M, Yasui Y, Inada K, Kirino S, Yamashita K, Sekiguchi S, Hayakawa Y, Osawa L, Okada M, Higuchi M, Takaura K, Maeyashiki C, Kaneko S, Tamaki N, Nakanishi H, Itakura J, Takahashi Y, Asahina Y, Enomoto N, Izumi N. Sorafenib-Regorafenib Sequential Therapy in Japanese Patients with Unresectable Hepatocellular Carcinoma-Relative Dose Intensity and Post-Regorafenib Therapies in Real World Practice. Cancers (Basel) 2019; 11:cancers11101517. [PMID: 31601010 PMCID: PMC6826625 DOI: 10.3390/cancers11101517] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2019] [Revised: 10/03/2019] [Accepted: 10/05/2019] [Indexed: 02/08/2023] Open
Abstract
Background: We aimed to explore the relative dose intensity (RDI) and post-regorafenib treatments in regorafenib therapy. Methods: The medical records of 38 patients treated with regorafenib between July 2017 and June 2019 at our institution were collected. The RDI of regorafenib for the first month (1M-RDI) was calculated. Results: The overall survival (OS) and progression-free survival (PFS) were 12.4 and 3.7 months. The objective response rate and disease control rate were 13.2% and 71.1%. The median total dose of regorafenib in the first month was 2080 mg (240–3360 mg), and the median 1M-RDI was 61.9% (7.1–100%). Patients with 1M-RDI ≥ 50% showed significantly longer OS and PFS than patients with 1M-RDI < 50% (HR 0.19, 95% CI 0.08–0.48, p = 0.0004 and HR 0.2, 95% CI 0.08–0.52, p = 0.0008). A 1M-RDI ≥ 50% (HR 0.18, 95% CI 0.06–0.55, p = 0.002) and hand–foot skin reaction (HR 0.03, 95% CI 0.008–0.16, p < 0.0001) were independently associated with OS. Post-regorafenib therapies were performed in 19 (86.4%) of 22 patients who had stopped regorafenib due to disease progression. Conclusion: A 1M-RDI ≥ 50% is clinically significant. Post-regorafenib therapies are commonly performed in real-world practice.
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Affiliation(s)
- Wan Wang
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1,Kyonan-cho, Musashino-shi, Tokyo 180-8610, Japan; (W.W.); (K.T.); (M.K.); (Y.Y.); (K.I.); (S.K.); (K.Y.); (S.S.); (Y.H.); (L.O.); (M.O.); (M.H.); (K.T.); (C.M.); (S.K.); (N.T.); (H.N.); (J.I.); (Y.T.)
| | - Kaoru Tsuchiya
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1,Kyonan-cho, Musashino-shi, Tokyo 180-8610, Japan; (W.W.); (K.T.); (M.K.); (Y.Y.); (K.I.); (S.K.); (K.Y.); (S.S.); (Y.H.); (L.O.); (M.O.); (M.H.); (K.T.); (C.M.); (S.K.); (N.T.); (H.N.); (J.I.); (Y.T.)
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1,Kyonan-cho, Musashino-shi, Tokyo 180-8610, Japan; (W.W.); (K.T.); (M.K.); (Y.Y.); (K.I.); (S.K.); (K.Y.); (S.S.); (Y.H.); (L.O.); (M.O.); (M.H.); (K.T.); (C.M.); (S.K.); (N.T.); (H.N.); (J.I.); (Y.T.)
| | - Yutaka Yasui
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1,Kyonan-cho, Musashino-shi, Tokyo 180-8610, Japan; (W.W.); (K.T.); (M.K.); (Y.Y.); (K.I.); (S.K.); (K.Y.); (S.S.); (Y.H.); (L.O.); (M.O.); (M.H.); (K.T.); (C.M.); (S.K.); (N.T.); (H.N.); (J.I.); (Y.T.)
| | - Kento Inada
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1,Kyonan-cho, Musashino-shi, Tokyo 180-8610, Japan; (W.W.); (K.T.); (M.K.); (Y.Y.); (K.I.); (S.K.); (K.Y.); (S.S.); (Y.H.); (L.O.); (M.O.); (M.H.); (K.T.); (C.M.); (S.K.); (N.T.); (H.N.); (J.I.); (Y.T.)
- Department of Gastroenterology and Hepatology, Tokyo Medical Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan;
| | - Sakura Kirino
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1,Kyonan-cho, Musashino-shi, Tokyo 180-8610, Japan; (W.W.); (K.T.); (M.K.); (Y.Y.); (K.I.); (S.K.); (K.Y.); (S.S.); (Y.H.); (L.O.); (M.O.); (M.H.); (K.T.); (C.M.); (S.K.); (N.T.); (H.N.); (J.I.); (Y.T.)
- Department of Gastroenterology and Hepatology, Tokyo Medical Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan;
| | - Koji Yamashita
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1,Kyonan-cho, Musashino-shi, Tokyo 180-8610, Japan; (W.W.); (K.T.); (M.K.); (Y.Y.); (K.I.); (S.K.); (K.Y.); (S.S.); (Y.H.); (L.O.); (M.O.); (M.H.); (K.T.); (C.M.); (S.K.); (N.T.); (H.N.); (J.I.); (Y.T.)
- First Department of internal Medicine, Faculty of Medicine, University of Yamanashi, Shimokato, Chuo, Yamanashi 409-3898, Japan;
| | - Shuhei Sekiguchi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1,Kyonan-cho, Musashino-shi, Tokyo 180-8610, Japan; (W.W.); (K.T.); (M.K.); (Y.Y.); (K.I.); (S.K.); (K.Y.); (S.S.); (Y.H.); (L.O.); (M.O.); (M.H.); (K.T.); (C.M.); (S.K.); (N.T.); (H.N.); (J.I.); (Y.T.)
- Department of Gastroenterology and Hepatology, Tokyo Medical Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan;
| | - Yuka Hayakawa
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1,Kyonan-cho, Musashino-shi, Tokyo 180-8610, Japan; (W.W.); (K.T.); (M.K.); (Y.Y.); (K.I.); (S.K.); (K.Y.); (S.S.); (Y.H.); (L.O.); (M.O.); (M.H.); (K.T.); (C.M.); (S.K.); (N.T.); (H.N.); (J.I.); (Y.T.)
- Department of Gastroenterology and Hepatology, Tokyo Medical Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan;
| | - Leona Osawa
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1,Kyonan-cho, Musashino-shi, Tokyo 180-8610, Japan; (W.W.); (K.T.); (M.K.); (Y.Y.); (K.I.); (S.K.); (K.Y.); (S.S.); (Y.H.); (L.O.); (M.O.); (M.H.); (K.T.); (C.M.); (S.K.); (N.T.); (H.N.); (J.I.); (Y.T.)
- First Department of internal Medicine, Faculty of Medicine, University of Yamanashi, Shimokato, Chuo, Yamanashi 409-3898, Japan;
| | - Mao Okada
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1,Kyonan-cho, Musashino-shi, Tokyo 180-8610, Japan; (W.W.); (K.T.); (M.K.); (Y.Y.); (K.I.); (S.K.); (K.Y.); (S.S.); (Y.H.); (L.O.); (M.O.); (M.H.); (K.T.); (C.M.); (S.K.); (N.T.); (H.N.); (J.I.); (Y.T.)
| | - Mayu Higuchi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1,Kyonan-cho, Musashino-shi, Tokyo 180-8610, Japan; (W.W.); (K.T.); (M.K.); (Y.Y.); (K.I.); (S.K.); (K.Y.); (S.S.); (Y.H.); (L.O.); (M.O.); (M.H.); (K.T.); (C.M.); (S.K.); (N.T.); (H.N.); (J.I.); (Y.T.)
- First Department of internal Medicine, Faculty of Medicine, University of Yamanashi, Shimokato, Chuo, Yamanashi 409-3898, Japan;
| | - Kenta Takaura
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1,Kyonan-cho, Musashino-shi, Tokyo 180-8610, Japan; (W.W.); (K.T.); (M.K.); (Y.Y.); (K.I.); (S.K.); (K.Y.); (S.S.); (Y.H.); (L.O.); (M.O.); (M.H.); (K.T.); (C.M.); (S.K.); (N.T.); (H.N.); (J.I.); (Y.T.)
| | - Chiaki Maeyashiki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1,Kyonan-cho, Musashino-shi, Tokyo 180-8610, Japan; (W.W.); (K.T.); (M.K.); (Y.Y.); (K.I.); (S.K.); (K.Y.); (S.S.); (Y.H.); (L.O.); (M.O.); (M.H.); (K.T.); (C.M.); (S.K.); (N.T.); (H.N.); (J.I.); (Y.T.)
- Department of Gastroenterology and Hepatology, Tokyo Medical Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan;
| | - Shun Kaneko
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1,Kyonan-cho, Musashino-shi, Tokyo 180-8610, Japan; (W.W.); (K.T.); (M.K.); (Y.Y.); (K.I.); (S.K.); (K.Y.); (S.S.); (Y.H.); (L.O.); (M.O.); (M.H.); (K.T.); (C.M.); (S.K.); (N.T.); (H.N.); (J.I.); (Y.T.)
- Department of Gastroenterology and Hepatology, Tokyo Medical Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan;
| | - Nobuharu Tamaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1,Kyonan-cho, Musashino-shi, Tokyo 180-8610, Japan; (W.W.); (K.T.); (M.K.); (Y.Y.); (K.I.); (S.K.); (K.Y.); (S.S.); (Y.H.); (L.O.); (M.O.); (M.H.); (K.T.); (C.M.); (S.K.); (N.T.); (H.N.); (J.I.); (Y.T.)
- First Department of internal Medicine, Faculty of Medicine, University of Yamanashi, Shimokato, Chuo, Yamanashi 409-3898, Japan;
| | - Hiroyuki Nakanishi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1,Kyonan-cho, Musashino-shi, Tokyo 180-8610, Japan; (W.W.); (K.T.); (M.K.); (Y.Y.); (K.I.); (S.K.); (K.Y.); (S.S.); (Y.H.); (L.O.); (M.O.); (M.H.); (K.T.); (C.M.); (S.K.); (N.T.); (H.N.); (J.I.); (Y.T.)
| | - Jun Itakura
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1,Kyonan-cho, Musashino-shi, Tokyo 180-8610, Japan; (W.W.); (K.T.); (M.K.); (Y.Y.); (K.I.); (S.K.); (K.Y.); (S.S.); (Y.H.); (L.O.); (M.O.); (M.H.); (K.T.); (C.M.); (S.K.); (N.T.); (H.N.); (J.I.); (Y.T.)
| | - Yuka Takahashi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1,Kyonan-cho, Musashino-shi, Tokyo 180-8610, Japan; (W.W.); (K.T.); (M.K.); (Y.Y.); (K.I.); (S.K.); (K.Y.); (S.S.); (Y.H.); (L.O.); (M.O.); (M.H.); (K.T.); (C.M.); (S.K.); (N.T.); (H.N.); (J.I.); (Y.T.)
| | - Yasuhiro Asahina
- Department of Gastroenterology and Hepatology, Tokyo Medical Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan;
| | - Nobuyuki Enomoto
- First Department of internal Medicine, Faculty of Medicine, University of Yamanashi, Shimokato, Chuo, Yamanashi 409-3898, Japan;
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1,Kyonan-cho, Musashino-shi, Tokyo 180-8610, Japan; (W.W.); (K.T.); (M.K.); (Y.Y.); (K.I.); (S.K.); (K.Y.); (S.S.); (Y.H.); (L.O.); (M.O.); (M.H.); (K.T.); (C.M.); (S.K.); (N.T.); (H.N.); (J.I.); (Y.T.)
- Correspondence: ; Tel.: +81-422-32-3111
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Guo T, Liu P, Yang J, Wu P, Chen B, Liu Z, Li Z. Evaluation of Targeted Agents for Advanced and Unresectable Hepatocellular Carcinoma: A Network Meta-Analysis. J Cancer 2019; 10:4671-4678. [PMID: 31528232 PMCID: PMC6746130 DOI: 10.7150/jca.32828] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2019] [Accepted: 06/12/2019] [Indexed: 02/07/2023] Open
Abstract
Objective: To evaluate different targeted anticancer agents for patients with advanced or unresectable hepatocellular carcinoma (HCC) based on network meta-analysis. Methods: Literature retrieval was conducted in globally recognized databases, namely, MEDLINE, PMC, EMBASE and Cochrane Central to find relevant randomized controlled trials (RCTs). Relative parametric data, including overall survival (OS), progression-free survival (PFS) and adverse event (AE), were quantitatively pooled and estimated based on the Bayesian theorem. The values of the surface under the cumulative ranking (SUCRA) probabilities regarding each parameter were calculated and ranked. Node-splitting analysis was performed to test the inconsistency of the main results, and publication bias was assessed by examining funnel-plot symmetry. Results: After a detailed review, 31 RCTs containing 20 different agents or combinations were finally included for network meta-analysis. For patients without previously systematic treatments, lenvatinib had the best clinical effects on OS (SUCRA, 0.22), and apatinib was superior regarding PFS (SUCRA, 0.41) and AE (SUCRA, 0.15). For patients who received previously targeted agents therapies, regorafenib exhibited the superior clinical effects on OS (SUCRA, 0.42) and PFS (SUCRA, 0.30), while codrituzumab showed the greatest safety benefit on AE (SUCRA, 0.75). Moreover, node-splitting analysis and funnel-plot symmetries illustrated no inconsistency or obvious publication bias in the current study. Conclusions: According to current evidence, lenvatinib and apatinib had superior clinical effects for patients without previously systematic treatments, and regorafenib seemed to be more suitable for patients with previously targeted agent therapies. However, our conclusions still need more statistical validations, and more high-quality trials are expected.
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Affiliation(s)
- Tao Guo
- Department of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, P.R. China
| | - Pengpeng Liu
- Department of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, P.R. China
| | - Jian Yang
- School of Nursing, Huanggang Polytechnic College, Huanggang, 438002, P.R. China
| | - Ping Wu
- Department of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, P.R. China
| | - Baiyang Chen
- Department of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, P.R. China
| | - Zhisu Liu
- Department of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, P.R. China
| | - Zhen Li
- Department of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, P.R. China
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Ogasawara S, Ooka Y, Itokawa N, Inoue M, Okabe S, Seki A, Haga Y, Obu M, Atsukawa M, Itobayashi E, Mizumoto H, Sugiura N, Azemoto R, Kanayama K, Kanzaki H, Maruta S, Maeda T, Kusakabe Y, Yokoyama M, Kobayashi K, Kiyono S, Nakamura M, Saito T, Suzuki E, Nakamoto S, Yasui S, Tawada A, Chiba T, Arai M, Kanda T, Maruyama H, Kato N. Sequential therapy with sorafenib and regorafenib for advanced hepatocellular carcinoma: a multicenter retrospective study in Japan. Invest New Drugs 2019; 38:172-180. [PMID: 31172442 DOI: 10.1007/s10637-019-00801-8] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2019] [Accepted: 05/28/2019] [Indexed: 02/08/2023]
Abstract
Background Conversion from sorafenib to regorafenib is primarily an evidence-based treatment strategy in patients with advanced hepatocellular carcinoma (HCC). This study aimed to assess the safety and efficacy of sequential therapy with sorafenib and regorafenib in patients with advanced HCC by analysis of outcomes in clinical practice with the aim to complement phase III findings. Methods The medical records of patients with advanced HCC receiving regorafenib were retrieved to collect data on sorafenib administration at seven Japanese institutions. Radiological responses and adverse events were evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1 and the Common Terminology Criteria for Adverse Events version 4.0, respectively. Results Before March 2018, 44 patients were administered regorafenib for advanced HCC. The median sorafenib treatment duration was 8.4 months. The most common adverse events were similar to those reported by the RESORCE trial. The median overall survival (OS) was 17.3 months (95% confidence interval [CI] 11.4-22.9), and 17 of 37 patients (45.9%) discontinued regorafenib and received sequential systemic therapy after regorafenib. These patients had significantly longer OS than those who were treated by the best supportive care or sub-optimal therapy (not reached versus 8.7 months [95% CI 5.8-11.7]; P < 0.001). Conclusion The results based on Japanese clinical practices verified the tolerability of regorafenib in advanced HCC. Major regorafenib-associated adverse events were similar to those related to sorafenib. OS was significantly longer than expected, which might be associated with the sequential systemic therapies after regorafenib, mainly lenvatinib.
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Affiliation(s)
- Sadahisa Ogasawara
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan. .,Translational Research and Development Center, Chiba University Hospital, Chiba, Japan.
| | - Yoshihiko Ooka
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Norio Itokawa
- Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Chiba, Japan
| | - Masanori Inoue
- Department of Gastroenterology, Asahi General Hospital, Asahi, Japan
| | - Shinichiro Okabe
- Department of Gastroenterology, Matsudo City General Hospital, Matsudo, Japan
| | - Atsuyoshi Seki
- Department of Gastroenterology, Funabashi Municipal Medical Center, Funabashi, Japan
| | - Yuki Haga
- Department of Gastroenterology, National Hospital Organization Chiba Medical Center, Chiba, Japan
| | - Masamichi Obu
- Department of Gastroenterology, Kimitsu Chuo Hospital, Kisarazu, Japan
| | - Masanori Atsukawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan
| | - Ei Itobayashi
- Department of Gastroenterology, Asahi General Hospital, Asahi, Japan
| | - Hideaki Mizumoto
- Department of Gastroenterology, Funabashi Municipal Medical Center, Funabashi, Japan
| | - Nobuyuki Sugiura
- Department of Gastroenterology, National Hospital Organization Chiba Medical Center, Chiba, Japan
| | - Ryosaku Azemoto
- Department of Gastroenterology, Kimitsu Chuo Hospital, Kisarazu, Japan
| | - Kengo Kanayama
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Hiroaki Kanzaki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Susumu Maruta
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Takahiro Maeda
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Yuko Kusakabe
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Masayuki Yokoyama
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Kazufumi Kobayashi
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.,Translational Research and Development Center, Chiba University Hospital, Chiba, Japan
| | - Soichiro Kiyono
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Masato Nakamura
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Tomoko Saito
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Eiichiro Suzuki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Shingo Nakamoto
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Shin Yasui
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Akinobu Tawada
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.,Department of Medical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tetsuhiro Chiba
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Makoto Arai
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.,Department of Medical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tatsuo Kanda
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.,Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Hitoshi Maruyama
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.,Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Naoya Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.,Translational Research and Development Center, Chiba University Hospital, Chiba, Japan
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