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Chuang CH, Chen CT, Hsu CH, Shao YY. Carry-over effect of immunotherapy in patients with advanced hepatocellular carcinoma. Cancer Immunol Immunother 2025; 74:208. [PMID: 40377687 DOI: 10.1007/s00262-025-04052-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2024] [Accepted: 04/10/2025] [Indexed: 05/18/2025]
Abstract
BACKGROUND Combination immunotherapy is the current standard for treating advanced hepatocellular carcinoma (HCC). The response elicited by upfront immune checkpoint inhibitors (ICIs) might influence the efficacy of salvage therapy, a phenomenon known as the carry-over effect. This effect is thought to stem from immune memory and sustained immune activation, providing extended protection against tumor progression and resulting in a durable response even after discontinuation of ICI. This study aimed to investigate the carry-over effect of first-line ICI therapy in patients with advanced HCC. METHODS Patients who received first-line ICI therapy for advanced HCC from December 2017 to December 2021 were included if they exhibited disease progression and received second-line systemic therapy. We analyzed the associations between clinical benefit (classified as complete, partial response and stable disease) of first-line ICI therapy, post-progression survival (PPS) and second-line progression-free survival (PFS). We used a historical cohort of patients receiving first-line multikinase inhibitor (MKI) for comparison. RESULTS A total of 137 patients were analyzed. We included 60 patients who received first-line ICI therapy, of which clinical benefit was detected in 46 (76.7%). Compared with patients without clinical benefit of first-line ICI therapy, patients with clinical benefit exhibited significantly longer PPS (median: 14.6 vs. 4.9 months, P = 0.024) and second-line PFS (median: 3.6 vs. 1.6 months, P = 0.027). In multivariate analysis, clinical benefit of first-line ICI therapy remained an independent predictor of PPS [hazard ratio (HR): 0.295, P = 0.005] and second-line PFS (HR: 0.484, P = 0.047). Conversely, clinical benefit was not associated with PPS among patients receiving first-line MKI therapy in both univariate and multivariate analysis in historical MKI cohort. CONCLUSIONS Clinical benefit of first-line ICI therapy was associated with PPS and second-line PFS in patients with advanced HCC, suggestive of the carry-over effect of ICI.
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Affiliation(s)
- Chien-Huai Chuang
- Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan
- Department of Oncology, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, 10002, Taiwan
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Ching-Tso Chen
- Department of Oncology, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, 10002, Taiwan
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan
- Department of Oncology, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu, Taiwan
| | - Chih-Hung Hsu
- Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan
- Department of Oncology, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, 10002, Taiwan
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Yu-Yun Shao
- Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan.
- Department of Oncology, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, 10002, Taiwan.
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.
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Colloca GA, Venturino A. Immune Checkpoint Inhibitors Affect Post-Progression Survival of Specific Patient Subgroups With Advanced Hepatocellular Carcinoma: A Study Cohorts' Analysis. J Dig Dis 2024; 25:655-663. [PMID: 40007104 DOI: 10.1111/1751-2980.13332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 01/11/2025] [Accepted: 01/15/2025] [Indexed: 02/27/2025]
Abstract
OBJECTIVES Immunotherapy-based regimens (IMBs), compared with tyrosine-kinase inhibitors (TKIs), improve the overall survival (OS) of patients with advanced hepatocellular carcinoma (aHCC). The aim of the study was to explore the interaction of prognostic factors with survival in study cohorts receiving IMB or TKI. METHODS A systematic search was performed and single arms of phase III trials including IMB or TKI were selected. Analysis of IMB and TKI cohorts was performed, and the relationship between progression-free survival (PFS) with OS was assessed. Finally, 13 variables were extracted, and their relationships with survival in the two groups were evaluated. RESULTS Thirty-three study cohorts were selected. Longer OS and post-progression survival (PPS) were evident in the group of IMB, while the relationship of PFS with OS was significant only in the TKI cohorts (β = 0.527, p = 0.007). Prognostic factors in the IMB cohorts did not report any significant relationship with OS, while among patients receiving TKIs, longer OS was documented with elder age (β = 0.577, p = 0.003) and good performance status (β = 0.500, p = 0.011). Conversely, in the IMB cohorts, PPS increased with hepatitis B virus (HBV) (β = 0.756, p = 0.030) and Barcelona Clinic Liver Classification (BCLC) stage (β = 0.898, p = 0.002). CONCLUSION In contrast to TKIs, IMBs improved the outcome of patients with aHCC by increasing PPS, particularly in patients with BCLC stage C and HBV-related hepatopathy, but the outcome improvement was lost in patients with hepatitis C virus-related liver disease.
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Komiyama S, Okusaka T, Maruki Y, Ohba A, Nagashio Y, Kondo S, Hijioka S, Morizane C, Ueno H, Sukeda A, Mizui T, Takamoto T, Nara S, Ban D, Esaki M, Hiraoka N, Shimada K. Clinicopathological Findings and Treatment Outcomes of Patients with Primary Hepatobiliary Neuroendocrine Neoplasms: A Retrospective Single-institution Analysis. Intern Med 2024; 63:891-901. [PMID: 37612088 PMCID: PMC11045373 DOI: 10.2169/internalmedicine.2016-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Accepted: 07/11/2023] [Indexed: 08/25/2023] Open
Abstract
Objective Primary hepatobiliary neuroendocrine neoplasms (NENs) are rare tumors exhibiting several morphological and behavioral characteristics. Considering the lack of relevant data on this topic, we evaluated the clinicopathological features and treatment outcomes of patients with primary hepatobiliary NENs. Methods/Patients We examined 43 consecutive patients treated at the National Cancer Center Hospital with pathological diagnoses of primary hepatobiliary NEN between 1980 and 2016. Results Nine patients were diagnosed with neuroendocrine tumor (NET) G1, 9 with NET G2, and 25 with neuroendocrine carcinoma (NEC) based on the World Health Organization 2019 classification. Patients with NEC had primary sites across the hepatobiliary organs, although sites in patients with NET G1 and NET G2 only included the liver and ampulla of Vater. Patients with primary extrahepatic bile duct or ampulla of Vater NENs tended to be diagnosed earlier than patients with primary gallbladder NENs. The median survival times in the NET G1, NET G2, and NEC groups were 167.9, 97.4, and 11.1 months, respectively. A good performance status, absence of distant metastases, and low tumor grade were identified as independent predictors of a favorable prognosis. Conclusion The NET-to-NEC ratio and tumor stage distribution at the diagnosis differed depending on the primary site. Patients with G1 and G2 NETs who underwent surgical resection had good prognoses, whereas those with NEC exhibited more advanced disease and poorer prognoses. The performance status, staging classification, and tumor grade are important factors to consider when devising an appropriate treatment strategy and predicting the prognoses of patients with primary hepatobiliary NEN.
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Affiliation(s)
- Satoshi Komiyama
- Chemotherapy Department, Yokohama City University Medical Center, Japan
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Japan
| | - Takuji Okusaka
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Japan
| | - Yuta Maruki
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Japan
| | - Akihiro Ohba
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Japan
| | - Yoshikuni Nagashio
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Japan
| | - Shunsuke Kondo
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Japan
| | - Susumu Hijioka
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Japan
| | - Chigusa Morizane
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Japan
| | - Hideki Ueno
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Japan
| | - Aoi Sukeda
- Pathology and Clinical Laboratories, National Cancer Center Hospital, Japan
- Department of Anatomic Pathology, Tokyo Medical University, Japan
| | - Takahiro Mizui
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Japan
| | - Takeshi Takamoto
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Japan
| | - Satoshi Nara
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Japan
| | - Daisuke Ban
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Japan
| | - Minoru Esaki
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Japan
| | - Nobuyoshi Hiraoka
- Pathology and Clinical Laboratories, National Cancer Center Hospital, Japan
| | - Kazuaki Shimada
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Japan
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Liu J, Yang L, Wei S, Li J, Yi P. Efficacy and safety of atezolizumab plus bevacizumab versus lenvatinib for unresectable hepatocellular carcinoma: a systematic review and meta-analysis. J Cancer Res Clin Oncol 2023; 149:16191-16201. [PMID: 37658861 DOI: 10.1007/s00432-023-05342-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Accepted: 08/24/2023] [Indexed: 09/05/2023]
Abstract
BACKGROUND Atezolizumab plus bevacizumab and lenvatinib are the current first-line systematic therapy for unresectable hepatocellular carcinoma (uHCC). However, the selection of initial treatment among the two therapies are controversial. This meta-analysis aims to compare efficacy and safety between atezolizumab plus bevacizumab and lenvatinib. METHODS We systematically searched for studies on atezolizumab plus bevacizumab and lenvatinib in the online databases PubMed, Embase, Web of Science and Cochrane Library. The outcome data including overall survival (OS), progression free survival (PFS), tumor response and adverse events (AEs), were independently extracted by two authors in a standardized way. RESULTS Eight retrospective cohort studies with 3690 patients (atezolizumab plus bevacizumab: 1680, lenvatinib: 2010) were included in the meta-analysis. The atezolizumab plus bevacizumab group had significant longer PFS [hazard ratio (HR) 0.76, 95% confidence intervals (CI) 0.65-0.88; I squared statistic (I2) = 0.0%, p = 0.590], compared with lenvatinib group but no significant difference in OS (HR 0.87, 95% CI 0.75-1.01; I2 = 0.0%, p = 0.597), objective response rate (ORR) [risk ratio (RR) 0.89, 95% CI 0.79-1.02; I2 = 19.3%, p = 0.283] and disease control rate (DCR) (RR 1.03, 95% CI 0.98-1.09; I2 = 0.0%, p = 0.467) among them. Moreover, patients receiving atezolizumab plus bevacizumab exhibited lower incidences of grade 3/4 AEs than those receiving lenvatinib (RR 0.65, 95% CI 0.51-0.83; I2 = 69.3%, p = 0.003). However, in non-viral patients group, lenvatinib delivered favorable outcomes in OS (HR 1.32, 95% CI 1.04-1.67; I2 = 0.0%, p = 0.380) compared with atezolizumab plus bevacizumab. CONCLUSION Atezolizumab plus bevacizumab provides potential advantage in efficacy and better safety than lenvatinib in the treatment of uHCC. Lenvatinib is an appropriate effective alternative to atezolizumab plus bevacizumab in patients without viral infecting.
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Affiliation(s)
- Junning Liu
- Department of Hepato-Biliary-Pancrease II, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, China
| | - Linfeng Yang
- Department of Hepato-Biliary-Pancrease II, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, China
| | - Song Wei
- Department of Hepato-Biliary-Pancrease II, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, China
| | - Jijiang Li
- Department of Hepato-Biliary-Pancrease II, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, China
| | - Pengsheng Yi
- Department of Hepato-Biliary-Pancrease II, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, China.
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Xu L, Chen L, Zhang B, Liu Z, Liu Q, Liang H, Chen Y, Chen X, Leng C, Zhang B. Alkaline phosphatase combined with γ-glutamyl transferase is an independent predictor of prognosis of hepatocellular carcinoma patients receiving programmed death-1 inhibitors. Front Immunol 2023; 14:1115706. [PMID: 36761721 PMCID: PMC9905229 DOI: 10.3389/fimmu.2023.1115706] [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: 12/04/2022] [Accepted: 01/09/2023] [Indexed: 01/27/2023] Open
Abstract
Background Immunotherapy plays an increasingly critical role in the systemic treatment of HCC. This current study aimed to establish a novel prognostic predictor of Programmed death 1 (PD-1) inhibitor therapy in hepatocellular carcinoma (HCC) independent of Child-Pugh grade. Methods Our study screened patients with HCC who received PD-1 inhibitors at Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology from January 2018 to December 2020. ALG grade was determined by the patient's serum ALP and GGT levels before the initiation of PD-1 inhibitors. The endpoints of our study were overall survival (OS) and progression free survival (PFS). Follow-up ended at May 31, 2022. Results Eighty- five patients (77 with Child-Pugh grade A, 8 with Child-Pugh grade B at baseline) were enrolled according to the inclusion criteria. Patients with Child-Pugh grade A achieved longer PFS and OS than those with Child-Pugh grade B. Patients with ALG grade 3 at baseline showed worse tumor response and poorer survival, and ALG grade could stratify patients with Child-Pugh grade A into subgroups with significantly different prognosis. Conclusions ALG grade, combining ALP and GGT, is a novel and readily available prognostic marker and the predictive effect of ALG grade on patient prognosis is independent of Child-Pugh grade.
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Affiliation(s)
- Lei Xu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Lin Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Bin Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zhichen Liu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Qiumeng Liu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Huifang Liang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yifa Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiaoping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China,Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China,*Correspondence: Xiaoping Chen, ; Chao Leng, ; Bixiang Zhang,
| | - Chao Leng
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China,*Correspondence: Xiaoping Chen, ; Chao Leng, ; Bixiang Zhang,
| | - Bixiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China,*Correspondence: Xiaoping Chen, ; Chao Leng, ; Bixiang Zhang,
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Personeni N, Pressiani T, Zanuso V, Casadei-Gardini A, D’Alessio A, Valgiusti M, Dadduzio V, Bergamo F, Soldà C, Rizzato MD, Giordano L, Santoro A, Rimassa L. Determinants of Treatment Benefit and Post-Treatment Survival for Patients with Hepatocellular Carcinoma Enrolled in Second-Line Trials after the Failure of Sorafenib Treatment. J Pers Med 2022; 12:1726. [PMID: 36294865 PMCID: PMC9604940 DOI: 10.3390/jpm12101726] [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: 09/29/2022] [Revised: 10/09/2022] [Accepted: 10/11/2022] [Indexed: 11/16/2022] Open
Abstract
Second-line treatments are standard care for advanced hepatocellular carcinoma (HCC) patients with preserved liver function who are intolerant of or progress on first-line therapy. However, determinants of treatment benefit and post-treatment survival (PTS) remain unknown. HCC patients previously treated with sorafenib and enrolled in second-line clinical trials were pooled according to the investigational treatment received and the subsequent regulatory approval: approved targeted agents and immune checkpoint inhibitors (AT) or other agents (OT) not subsequently approved. Univariate and multivariate analyses using Cox proportional hazards models established relationships among treatments received, clinical variables, and overall survival (OS) or PTS. For 174 patients (80 AT; 94 OT) analyzed, baseline factors for longer OS in multivariate analysis were second-line AT, absence of both portal vein thrombosis and extrahepatic spread (EHS). Treatment with AT (versus OT) was associated with significantly longer OS among patients with EHS (pinteraction = 0.005) and patients with low neutrophil-to-lymphocyte ratio (NLR; pinteraction = 0.032). Median PTS was 4.0 months (95% CI 2.8−5.3). At second-line treatment discontinuation, alpha-fetoprotein (AFP) levels <400 ng/dl, albumin-bilirubin (ALBI) grade 1, and enrolment onto subsequent trials independently predicted longer PTS. Treatment with AT, PVT, and EHS were prognostic factors for OS, while AFP, ALBI grade and enrolment onto a third-line trial were prognostic for PTS. Presence of EHS and low NLR were predictors of greater OS benefit from AT.
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Affiliation(s)
- Nicola Personeni
- Department of Biomedical Sciences, Humanitas University, 20072 Milan, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, 20089 Milan, Italy
| | - Tiziana Pressiani
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, 20089 Milan, Italy
| | - Valentina Zanuso
- Department of Biomedical Sciences, Humanitas University, 20072 Milan, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, 20089 Milan, Italy
| | - Andrea Casadei-Gardini
- Department of Oncology, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, 20132 Milan, Italy
| | - Antonio D’Alessio
- Department of Biomedical Sciences, Humanitas University, 20072 Milan, Italy
- Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK
| | - Martina Valgiusti
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “DinoAmadori”, 47014 Meldola, Italy
| | - Vincenzo Dadduzio
- Oncology 1 Unit, Veneto Institute of Oncology, IOV, IRCCS, 35128 Padua, Italy
| | - Francesca Bergamo
- Oncology 1 Unit, Veneto Institute of Oncology, IOV, IRCCS, 35128 Padua, Italy
| | - Caterina Soldà
- Oncology 1 Unit, Veneto Institute of Oncology, IOV, IRCCS, 35128 Padua, Italy
| | - Mario Domenico Rizzato
- Oncology 1 Unit, Veneto Institute of Oncology, IOV, IRCCS, 35128 Padua, Italy
- Department of Surgical, Oncological and Gastroenterological Sciences, University of Padua, 35122 Padua, Italy
| | - Laura Giordano
- Biostatistic Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Milan, Italy
| | - Armando Santoro
- Department of Biomedical Sciences, Humanitas University, 20072 Milan, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, 20089 Milan, Italy
| | - Lorenza Rimassa
- Department of Biomedical Sciences, Humanitas University, 20072 Milan, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, 20089 Milan, Italy
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Shao YY, Feng YH, Yen CJ, Yang TS, Shen YC, Chao Y, Chen JS, Su CY, Chen WJ, Hsiang HL, Hsu CH. Bevacizumab and atezolizumab as first-line therapy for advanced hepatocellular carcinoma: A Taiwanese subgroup analysis on efficacy and safety. J Formos Med Assoc 2022; 121:2430-2437. [PMID: 36153210 DOI: 10.1016/j.jfma.2022.09.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 07/03/2022] [Accepted: 09/04/2022] [Indexed: 11/16/2022]
Abstract
BACKGROUND The combination of bevacizumab and atezolizumab has been established as a standard first-line systemic treatment for unresectable hepatocellular carcinoma (HCC). We examined the treatment outcomes of patients in Taiwan who received the combination in 2 pivotal clinical trials. METHODS All patients who resided in Taiwan, were enrolled in the IMbrave150 and GO30140 studies, and received bevacizumab and atezolizumab as the first-line systemic therapy for unresectable HCC were included. We extracted and pooled anonymous raw data from the study records. RESULTS We enrolled 40 patients, with the median age of 62.5 years; 36 (90%) had Barcelona Clinic Liver Cancer stage C disease. The response rate was 37.5%, including 3 (7.5%) complete responses. The disease control rate was 85%. The median duration of response was 21.4 months (95% confidence interval [CI], 16.6-not estimable). The median progression-free survival (PFS) and overall survival (OS) were 8.6 (95% CI, 5.6-18.6) and 24.9 months (95% CI, 14.2-not estimable), respectively. The most common adverse events of all grades were proteinuria (50%) and hypertension (37.5%), the median onset of which were 157 and 127 days, respectively. Bevacizumab and atezolizumab treatment had to be interrupted in 20 (50%) and 13 (32.5%) patients, respectively. Among patients whose treatment duration was ≥6 months, 50% of them had to skip bevacizumab, but no signal of poorer PFS or OS was observed. CONCLUSION In Taiwanese patients with advanced HCC, the efficacy and safety outcomes of bevacizumab and atezolizumab treatment were generally consistent with the global intent-to-treat populations.
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Affiliation(s)
- Yu-Yun Shao
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan.
| | - Yin-Hsun Feng
- Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan
| | - Chia-Jui Yen
- Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Tsai-Sheng Yang
- Department of Hematology-Oncology, Linkou Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan
| | - Ying-Chun Shen
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan
| | - Yee Chao
- Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Jen-Shi Chen
- Department of Hematology-Oncology, Linkou Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan
| | - Ching-Yen Su
- Medical Division, Roche Products Ltd, Taipei, Taiwan
| | - Wei-Jen Chen
- Medical Division, Roche Products Ltd, Taipei, Taiwan
| | | | - Chih-Hung Hsu
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan
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Prognosis and treatment pattern of advanced hepatocellular carcinoma after failure of first-line atezolizumab and bevacizumab treatment. Hepatol Int 2022; 16:1199-1207. [PMID: 35986846 DOI: 10.1007/s12072-022-10392-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 07/08/2022] [Indexed: 11/04/2022]
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Meng L, Xu KX, Zhao MX, Li K, Zhu K, Yuan DW, Wang HN, Dai PG, Yan R. Nucleolar protein 6 promotes cell proliferation and acts as a potential novel prognostic marker for hepatocellular carcinoma. Chin Med J (Engl) 2021; 134:2611-2618. [PMID: 34561331 PMCID: PMC8577660 DOI: 10.1097/cm9.0000000000001655] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Background: Nucleolar protein 6 (NOL6) is a nucleolar RNA-associated protein that is highly conserved between species. It has been proved to be associated with the prognosis of liver cancer. However, the underlying mechanism has not been fully established. This study aimed to assess the relationship between NOL6 and liver cancer prognosis. Methods: We constructed an NOL6-short hairpin RNA (shRNA)-expressing lentivirus. Through viral transfection, cell growth assay and fluorescence-activated cell sorting, we evaluated the effect of shRNA-mediated NOL6 knockdown on the proliferation, colony formation, and apoptosis of hepatocellular carcinoma (HCC) cells. The relationship between NOL6 expression and HCC patient survival has been established through bioinformatics analysis. We also explored the downstream molecular regulatory network of NOL6 in HCC by performing an Ingenuity Pathway Analysis in the database. Results: Increased NOL6 expression was detected in HCC cells compared to normal controls; HCC patients with high NOL6 expression had poorer prognoses than those with low expression. NOL6 knockdown inhibited HCC cell proliferation, apoptosis, and colony formation. Also, MAPK8, CEBPA, and FOSL1 were selected as potential downstream genes of NOL6. Conclusions: NOL6 up-regulates HCC cell proliferation and affects downstream expression of related genes. Moreover, NOL6 is considered to be associated with poor prognosis in HCC patients.
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Affiliation(s)
- Lei Meng
- National Engineering Research Center for Miniaturized Detection Systems, The College of Life Sciences, Northwest University, Xi'an, Shaanxi 710069, China.,Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Kai-Xuan Xu
- National Engineering Research Center for Miniaturized Detection Systems, The College of Life Sciences, Northwest University, Xi'an, Shaanxi 710069, China
| | - Ming-Xi Zhao
- National Engineering Research Center for Miniaturized Detection Systems, The College of Life Sciences, Northwest University, Xi'an, Shaanxi 710069, China
| | - Kang Li
- Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Kun Zhu
- Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Da-Wei Yuan
- Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Hao-Nan Wang
- Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Peng-Gao Dai
- National Engineering Research Center for Miniaturized Detection Systems, The College of Life Sciences, Northwest University, Xi'an, Shaanxi 710069, China
| | - Rong Yan
- Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
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Eg5 as a Prognostic Biomarker and Potential Therapeutic Target for Hepatocellular Carcinoma. Cells 2021; 10:cells10071698. [PMID: 34359867 PMCID: PMC8303881 DOI: 10.3390/cells10071698] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 06/29/2021] [Accepted: 07/01/2021] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND The kinesin Eg5, a mitosis-associated protein, is overexpressed in many cancers. Here we explored the clinical significance of Eg5 in hepatocellular carcinoma (HCC). METHODS HCC tissues from surgical resection were collected. Total RNA was prepared from tumorous and nontumorous parts. Eg5 expression levels were correlated with overall survival (OS) and disease-free survival (DFS). In vitro efficacy of LGI-147, a specific Eg5 inhibitor, was tested in HCC cell lines. In vivo efficacy of Eg5 inhibition was investigated in a xenograft model. RESULTS A total of 108 HCC samples were included. The patients were divided into three tertile groups with high, medium, and low Eg5 expression levels. OS of patients with low Eg5 expression was better than that of patients with medium and high Eg5 expression (median, 155.6 vs. 75.3 vs. 57.7 months, p = 0.002). DFS of patients with low Eg5 expression was also better than that of patients with medium and high Eg5 expression (median, 126.3 vs. 46.2 vs. 39.4 months, p = 0.001). In multivariate analyses, the associations between Eg5 expression and OS (p < 0.001) or DFS remained (p < 0.001). LGI-147 reduced cell growth via cell cycle arrest and apoptosis and induced accumulation of abnormal mitotic cells. In the xenograft model, the tumor growth rate under LGI-147 treatment was significantly slower than under the control. CONCLUSION High Eg5 expression was associated with poor HCC prognosis. In vitro and in vivo evidence suggests that Eg5 may be a reasonable therapeutic target for HCC.
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Eligibility for Second-line Therapy in Patients With Advanced Hepatocellular Carcinoma. Am J Clin Oncol 2020; 43:788-791. [PMID: 32868523 DOI: 10.1097/coc.0000000000000754] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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12
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Feng D, Wang M, Hu J, Li S, Zhao S, Li H, Liu L. Prognostic value of the albumin-bilirubin grade in patients with hepatocellular carcinoma and other liver diseases. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:553. [PMID: 32411776 PMCID: PMC7214886 DOI: 10.21037/atm.2020.02.116] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
One of the most commonly used systems for grading liver function in hepatocellular carcinoma (HCC) patients is the Child-Pugh (CP) score. However, the CP scoring system is not without its shortcomings: for example, the cut-off values for the parameters are calculated arbitrarily and the assessment of ascites and hepatic encephalopathy is subjective. More recently, an alternative to traditional CP grade has emerged in the form of albumin-bilirubin (ALBI) grade. The predictive value provided for HCC patients by the ALBI grade is comparable to that of the CP grade; however, it can also surpass CP grade by greatly reducing subjectivity and further subdividing CP A patients into several different groups, thus improving the prognosis judgment and helping to inform clinicians’ optimal decision-making. The application of the ALBI grade into currently used HCC staging systems such as the Barcelona Clinic Liver Cancer (BCLC) staging system, the Cancer of the Liver Italian Program (CLIP) staging system, and the Japan Integrated Staging (JIS) score, etc., as well as newly produced systems like the ALBI-PLT grade, the ALBI and progression disease (ALBI-PD) grade and Modified Intermediate Stage of Liver Cancer (MICAN) criteria, greatly elevates prognostic power.
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Affiliation(s)
- Dayun Feng
- Department of surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China
| | - Mengmeng Wang
- Department of Drug and Equipment, Aeromedicine Identification and Training Centre of Air Force, Xi'an 710069, China
| | - Jie Hu
- Department of Clinical laboratory, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China
| | - Songlun Li
- Department of Blood Transfusion, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, China
| | - Shoujie Zhao
- Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China
| | - Huichen Li
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China
| | - Lei Liu
- Department of Gastroenterology, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China
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Kuzuya T, Ishigami M, Ito T, Ishizu Y, Honda T, Ishikawa T, Hirooka Y, Fujishiro M. Clinical characteristics and outcomes of candidates for second-line therapy, including regorafenib and ramucirumab, for advanced hepatocellular carcinoma after sorafenib treatment. Hepatol Res 2019; 49:1054-1065. [PMID: 31033165 DOI: 10.1111/hepr.13358] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Revised: 04/09/2019] [Accepted: 04/19/2019] [Indexed: 02/08/2023]
Abstract
AIM This study aimed to investigate the clinical characteristics and outcomes of candidates for second-line therapy, including regorafenib and ramucirumab, for advanced hepatocellular carcinoma (HCC) after sorafenib treatment. METHODS Of 122 patients, 103 were radiologically confirmed as progressive disease (PD) (sorafenib-refractory group), and 19 discontinued sorafenib therapy due to adverse events prior to radiologic PD (sorafenib-intolerant group). Patients in the sorafenib-refractory group were divided into two subgroups each, according to their eligibility for second-line treatment (second-line-in and -out group), regorafenib (RESORCE-in and -out group), or ramucirumab (REACH-2-in and -out group). RESULTS Patients included in the non-candidate group were those with α-fetoprotein level <400 ng/mL (n = 51, 49.5%), daily sorafenib dose <400 mg (n = 44, 42.7%), Child-Pugh B or C (n = 40, 38.8%), and Eastern Cooperative Oncology Group performance status score ≥2 (n = 24, 23.3%). The percentages of candidates were 57.3% for second-line, 35.0% for regorafenib, and 23.3% for ramucirumab. The median post-progression survival (PPS) was significantly longer for the second-line-in and the RESORCE-in groups than in the non-candidate groups (12.6 and 11.0 months vs. 3.0 and 6.1 months, respectively). The PPS was not significantly different between the REACH-2-in and -out groups. A significant predictor of candidates for second-line treatment at sorafenib initiation was a Child-Pugh score of 5 (A5). CONCLUSIONS Not all patients refractory to sorafenib were candidates for second-line therapy. A Child-Pugh score of A5 at sorafenib initiation was an important and favorable factor related to eligibility for second-line therapy and good outcomes.
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Affiliation(s)
- Teiji Kuzuya
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masatoshi Ishigami
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takanori Ito
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoji Ishizu
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takashi Honda
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tetsuya Ishikawa
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshiki Hirooka
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Mitsuhiro Fujishiro
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Liu TH, Shao YY, Lu LC, Shen YC, Hsu C, Lin ZZ, Hsu CH, Cheng AL. Considerations of heterogeneity in clinical trials for hepatocellular carcinoma. Expert Rev Gastroenterol Hepatol 2019; 13:615-621. [PMID: 31132887 DOI: 10.1080/17474124.2019.1621165] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Introduction: Clinical trials in hepatocellular carcinoma (HCC) exhibit a high degree of heterogeneity. These heterogeneities may lead to unexpected results among clinical trials. Area covered: In this review, we address the heterogeneity noted in early phase HCC trials, trials involving transarterial chemoembolization, and advanced HCC trials. Furthermore, we discuss possible methods to attenuate the detrimental effects of heterogeneity when conducting clinical trials. Expert opinion: Clinical trials in HCC exhibit an inherently high degree of heterogeneity because of various reasons: tumor heterogeneity, different cirrhotic backgrounds, various etiologies of cirrhosis, and geographical differences in practice and expertise. Such heterogeneity may cause imbalance among the enrolled patient population, premature withdrawal from the clinical trial, and variable response to the treatment. In addition, methodological heterogeneity also exists in designing trial protocol and response evaluation. All these factors may eventually lead to conflicting results among clinical trials. Accounting for these heterogeneities is important to foster the success of future trials. In recent years, significant progress with molecular targeted agents and immune checkpoint inhibitors was made in advanced HCC. These new agents are also being tested in clinical trials involving earlier stage HCC and will also face the challenge of these issues.
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Affiliation(s)
- Tsung-Hao Liu
- a Department of Internal Medicine , National Taiwan University Hospital Hsin-Chu Branch , Hsinchu , Taiwan.,b Department of Oncology , National Taiwan University Hospital , Taipei , Taiwan.,d Graduate Institute of Oncology , National Taiwan University College of Medicine , Taipei , Taiwan
| | - Yu-Yun Shao
- b Department of Oncology , National Taiwan University Hospital , Taipei , Taiwan.,d Graduate Institute of Oncology , National Taiwan University College of Medicine , Taipei , Taiwan.,e Department of Medical Oncology , National Taiwan University Cancer Center , Taipei , Taiwan
| | - Li-Chun Lu
- b Department of Oncology , National Taiwan University Hospital , Taipei , Taiwan.,d Graduate Institute of Oncology , National Taiwan University College of Medicine , Taipei , Taiwan.,e Department of Medical Oncology , National Taiwan University Cancer Center , Taipei , Taiwan
| | - Ying-Chun Shen
- b Department of Oncology , National Taiwan University Hospital , Taipei , Taiwan.,d Graduate Institute of Oncology , National Taiwan University College of Medicine , Taipei , Taiwan
| | - Chiun Hsu
- b Department of Oncology , National Taiwan University Hospital , Taipei , Taiwan.,d Graduate Institute of Oncology , National Taiwan University College of Medicine , Taipei , Taiwan
| | - Zhong-Zhe Lin
- b Department of Oncology , National Taiwan University Hospital , Taipei , Taiwan.,d Graduate Institute of Oncology , National Taiwan University College of Medicine , Taipei , Taiwan.,e Department of Medical Oncology , National Taiwan University Cancer Center , Taipei , Taiwan
| | - Chih-Hung Hsu
- b Department of Oncology , National Taiwan University Hospital , Taipei , Taiwan.,d Graduate Institute of Oncology , National Taiwan University College of Medicine , Taipei , Taiwan.,e Department of Medical Oncology , National Taiwan University Cancer Center , Taipei , Taiwan
| | - Ann-Lii Cheng
- b Department of Oncology , National Taiwan University Hospital , Taipei , Taiwan.,c Department of Internal Medicine , National Taiwan University Hospital , Taipei , Taiwan.,d Graduate Institute of Oncology , National Taiwan University College of Medicine , Taipei , Taiwan.,e Department of Medical Oncology , National Taiwan University Cancer Center , Taipei , Taiwan
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Raoul JL, Frenel JS, Raimbourg J, Gilabert M. Current options and future possibilities for the systemic treatment of hepatocellular carcinoma. Hepat Oncol 2019; 6:HEP11. [PMID: 31244990 PMCID: PMC6571544 DOI: 10.2217/hep-2019-0001] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Accepted: 02/14/2019] [Indexed: 01/10/2023] Open
Abstract
Most hepatocellular carcinoma patients could not benefit from or experience disease recurrence after curative treatments. In 2007 sorafenib demonstrated efficacy in first line treatment of advanced hepatocellular carcinoma. After a decade of negative trials, in early 2019 we now have another tyrosine kinase inhibitor available in first line, lenvatinib, three other targeted therapies in second line post-sorafenib (regorafenib, cabozantinib and ramucirumab) and promising data from two immunotherapies (nivolumab and pembrolizumab). Unfortunately, no biomarkers have been identified to help guide our choice. In this short review we summarize the results of these different therapies and propose a therapeutic algorithm based on subgroup analysis. It is most likely that we will not have head-to-head comparisons in second line trials.
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Affiliation(s)
- Jean-Luc Raoul
- Department of Medical Oncology, Institut de Cancérologie de l'Ouest, Nantes 44805 Saint-Herblain, France
| | - Jean-Sébastien Frenel
- Department of Medical Oncology, Institut de Cancérologie de l'Ouest, Nantes 44805 Saint-Herblain, France
| | - Judith Raimbourg
- Department of Medical Oncology, Institut de Cancérologie de l'Ouest, Nantes 44805 Saint-Herblain, France
| | - Marine Gilabert
- Department of Medical Oncology, Institut Paoli-Calmettes, Cedex 9, Marseille 13000, France
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Lu LC, Lee YH, Chang CJ, Shun CT, Fang CY, Shao YY, Liu TH, Cheng AL, Hsu CH. Increased Expression of Programmed Death-Ligand 1 in Infiltrating Immune Cells in Hepatocellular Carcinoma Tissues after Sorafenib Treatment. Liver Cancer 2019; 8:110-120. [PMID: 31019901 PMCID: PMC6465685 DOI: 10.1159/000489021] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2017] [Accepted: 04/06/2018] [Indexed: 02/04/2023] Open
Abstract
OBJECTIVE Programmed death-ligand 1 (PD-L1) expression in the tumor microenvironment (TME) has been reported to be related to prognosis in patients with hepatocellular carcinoma (HCC) after hepatectomy. The impact of sorafenib on PD-L1 expression in the TME of advanced HCC is unclear. PATIENTS AND METHODS Patients with HCC who received sorafenib for advanced disease at National Taiwan University Hospital, Taipei, Taiwan, and who had paired HCC tissues obtained before and after sorafenib treatment were included in the study group. HCC patients not treated with sorafenib who had paired primary and recurrent or metastatic tissues were identified as the reference group. The membrane PD-L1 staining, detected by immunohistochemistry (IHC) using SP142 antibody, was semiquantitatively scored in tumor cells (TCs) or tumor-infiltrating immune cells (ICs). Additional IHC assays were employed to characterize the PD-L1-expressing ICs. RESULTS Twenty-three advanced HCC patients with pre- and post-sorafenib paired HCC tissues were included in the study group. The median duration of sorafenib treatment was 4.3 months (range: 1.3-18.7). PD-L1 expression in ICs was significantly higher in post-sorafenib HCC tissues than in pre-sorafenib HCC tissues (pre-sorafenib vs. post-sorafenib IHC 0/1/2/3: 11/5/5/2 vs. 5/5/2/11, p = 0.016). However, PD-L1 expression in TCs was not significantly different between pre- and post-sorafenib tissues (IHC 0/1/2/3: 19/2/0/2 vs. 14/5/0/4, p = 0.094). In the reference group of 44 patients not treated with sorafenib, PD-L1 expression in ICs and TCs was not significantly different between the paired primary and metastatic HCC tissues. By performing IHC double staining with PD-L1 and CD68, we found the PD-L1-expressing ICs were mainly CD68-positive macrophages. PD-L1 expression levels of pre- and post-sorafenib tissues were not associated with patients' overall survival or duration of sorafenib treatment. CONCLUSIONS PD-L1 expression in ICs was significantly increased in post-sorafenib HCC tissues. The mechanisms and clinical significance of this observation warrants further investigation.
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Affiliation(s)
- Li-Chun Lu
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan,Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan,National Taiwan University Cancer Center, Taipei, Taiwan
| | - Yi-Hsuan Lee
- Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan
| | - Chun-Jung Chang
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chia-Tung Shun
- Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan,Department of Forensic Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Chih-Yeu Fang
- Department of Pathology, Wan Fan Hospital, Taipei Medical University, Taipei, Taiwan
| | - Yu-Yun Shao
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan,Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan,National Taiwan University Cancer Center, Taipei, Taiwan
| | - Tsung-Hao Liu
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan,Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu, Taiwan
| | - Ann-Lii Cheng
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan,Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan,Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan,National Taiwan University Cancer Center, Taipei, Taiwan
| | - Chih-Hung Hsu
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan,Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan,*Chih-Hung Hsu, MD, PhD, and Ann-Lii Cheng, MD, PhD, Department of Oncology, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei 10002 (Taiwan, ROC), E-Mail and
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17
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Lyu N, Kong Y, Mu L, Lin Y, Li J, Liu Y, Zhang Z, Zheng L, Deng H, Li S, Xie Q, Guo R, Shi M, Xu L, Cai X, Wu P, Zhao M. Hepatic arterial infusion of oxaliplatin plus fluorouracil/leucovorin vs. sorafenib for advanced hepatocellular carcinoma. J Hepatol 2018; 69:60-69. [PMID: 29471013 DOI: 10.1016/j.jhep.2018.02.008] [Citation(s) in RCA: 179] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Revised: 11/01/2017] [Accepted: 02/03/2018] [Indexed: 01/07/2023]
Abstract
BACKGROUND & AIMS To compare the overall survival (OS) and disease progression free survival (PFS) in patients with advanced hepatocellular carcinoma (Ad-HCC) who are undergoing hepatic arterial infusion (HAI) of oxaliplatin, fluorouracil/leucovorin (FOLFOX) treatment vs. sorafenib. METHODS This retrospective study was approved by the ethical review committee, and informed consent was obtained from all patients before treatment. HAI of FOLFOX (HAIF) was recommended as an alternative treatment option for patients who refused sorafenib. Of the 412 patients with Ad-HCC (376 men and 36 women) between Jan 2012 to Dec 2015, 232 patients were treated with sorafenib; 180 patients were given HAIF therapy. The median age was 51 years (range, 16-82 years). Propensity-score matched estimates were used to reduce bias when evaluating survival. Survival curves were calculated by performing the Kaplan-Meier method and compared by using the log-rank test and Cox regression models. RESULTS The median PFS and OS in the HAIF group were significantly longer than those in the sorafenib group (PFS 7.1 vs. 3.3 months [RECIST]/7.4 vs. 3.6 months [mRECIST], respectively; OS 14.5 vs. 7.0 months; p <0.001 for each). In the propensity-score matched cohorts (147 pairs), both PFS and OS in the HAIF group were longer than those in the sorafenib group (p <0.001). At multivariate analysis, HAIF treatment was an independent factor for PFS (hazard ratio [HR] 0.389 [RECIST]/0.402 [mRECIST]; p <0.001 for each) and OS (HR 0.129; p <0.001). CONCLUSION HAIF therapy may improve survival compared to sorafenib in patients with Ad-HCC. A prospective randomized trial is ongoing to confirm this finding. LAY SUMMARY We compared the hepatic arterial infusion of FOLFOX (a combination chemotherapy) with sorafenib (a tyrosine kinase inhibitor) in patients with advanced hepatocellular carcinoma, retrospectively. It was found that hepatic arterial infusion of FOLFOX therapy may improve both progression free and overall survival in patients with advanced hepatocellular carcinoma.
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Affiliation(s)
- Ning Lyu
- Minimally Invasive Interventional Division, Department of Medical Imaging and Interventional Radiology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yanan Kong
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Luwen Mu
- Minimally Invasive Interventional Division, Department of Medical Imaging and Interventional Radiology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Youen Lin
- Department of Interventional Radiology, Jieyang Affiliated Hospital, Sun Yat-sen University, Jieyang, China
| | - Jibin Li
- Department of Clinical Research, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yaru Liu
- Medical Imaging Division, Department of Medical Imaging and Interventional Radiology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Zhenfeng Zhang
- Medical Imaging Division, Department of Medical Imaging and Interventional Radiology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Lie Zheng
- Medical Imaging Division, Department of Medical Imaging and Interventional Radiology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Haijing Deng
- Minimally Invasive Interventional Division, Department of Medical Imaging and Interventional Radiology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Shaolong Li
- Minimally Invasive Interventional Division, Department of Medical Imaging and Interventional Radiology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Qiankun Xie
- Minimally Invasive Interventional Division, Department of Medical Imaging and Interventional Radiology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Rongping Guo
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Ming Shi
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Li Xu
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xiuyu Cai
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Peihong Wu
- Minimally Invasive Interventional Division, Department of Medical Imaging and Interventional Radiology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Ming Zhao
- Minimally Invasive Interventional Division, Department of Medical Imaging and Interventional Radiology, Sun Yat-sen University Cancer Center, Guangzhou, China.
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Kuzuya T, Ishigami M, Ishizu Y, Honda T, Hayashi K, Ishikawa T, Nakano I, Hirooka Y, Goto H. Prognostic Factors Associated with Postprogression Survival in Advanced Hepatocellular Carcinoma Patients Treated with Sorafenib Not Eligible for Second-Line Regorafenib Treatment. Oncology 2018; 95:91-99. [PMID: 29723866 DOI: 10.1159/000488453] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Accepted: 03/14/2018] [Indexed: 12/14/2022]
Abstract
OBJECTIVES The aim of this study was to investigate the prognostic factors associated with postprogression survival (PPS) in advanced hepatocellular carcinoma (HCC) patients treated with sorafenib, who were not eligible for second-line treatment with regorafenib. METHODS A total of 103 patients with radiological confirmation of progressive disease (PD) were enrolled. RESULTS The median PPS (n = 67) was 6.1 months. Significant and independent prognostic factors at initial radiological PD associated with good PPS were an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) score of 0, the absence of macrovascular invasion (MVI), and time to progression (TTP) ≥4 months. Upon scoring these three variables as good PPS factors, the median PPS in the good PPS score of 3 or 2 group (n = 38) was significantly longer than that in the good PPS score of 1 or 0 group (n = 29) (16.6 vs. 2.9 months; p < 0.0001, respectively). CONCLUSIONS An ECOG-PS score of 0, the absence of MVI, and TTP ≥4 months at first radiological confirmation of PD may be useful for predicting good PPS in patients with advanced HCC who do not meet the eligibility criteria for the RESORCE trial.
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19
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Tang Z, Peng H, Chen J, Liu Y, Yan S, Yu G, Chen Q, Tang H, Liu S. Rap1b enhances the invasion and migration of hepatocellular carcinoma cells by up-regulating Twist 1. Exp Cell Res 2018; 367:56-64. [PMID: 29559227 DOI: 10.1016/j.yexcr.2018.03.019] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Revised: 03/15/2018] [Accepted: 03/16/2018] [Indexed: 02/04/2023]
Abstract
Rap1b was found be dysregulated in several types of cancers. Previously, we have demonstrated that Rap1b affects proliferation, migration and invasion of hepatocellular carcinoma (HCC) cells. However, the definite function of Rap1b in HCC remains unknown. Here, we reported that Rap1b was significantly up-regulated in HCC tissues compared with the non-tumoral liver tissues. Overexpression of Rap1b promoted tumor growth and migration in vitro and tumor formation in vivo. Oppositely, inhibition of Rap1b suppressed the proliferation and migration of HCC cells. Mechanism study revealed that Rap1b could up-regulate Twist 1 expression by enhancing its promoter activity. We concluded that Rap1b increased Twist 1 expression by targeting its promoter activity to induce proliferation and migration of HCC cells.
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Affiliation(s)
- Zhenrong Tang
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, China
| | - Hong Peng
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, 1 Yi Xue Yuan Road, Chongqing, China
| | - Juan Chen
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, 1 Yi Xue Yuan Road, Chongqing, China
| | - Yuyang Liu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, 1 Yi Xue Yuan Road, Chongqing, China
| | - Shaoying Yan
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, 1 Yi Xue Yuan Road, Chongqing, China
| | - Gangfeng Yu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, 1 Yi Xue Yuan Road, Chongqing, China
| | - Qiuxu Chen
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, 1 Yi Xue Yuan Road, Chongqing, China
| | - Hua Tang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, 1 Yi Xue Yuan Road, Chongqing, China.
| | - Shengchun Liu
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, China.
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20
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Lee PC, Chen YT, Chao Y, Huo TI, Li CP, Su CW, Lee MH, Hou MC, Lee FY, Lin HC, Huang YH. Validation of the albumin-bilirubin grade-based integrated model as a predictor for sorafenib-failed hepatocellular carcinoma. Liver Int 2018; 38:321-330. [PMID: 28736952 DOI: 10.1111/liv.13527] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Accepted: 07/18/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC) but is challenging after treatment failure. Appropriate criteria for enrolling patients into second-line trials are still limited. In this study, we aimed to establish more objective criteria based on Albumin-Bilirubin (ALBI) grade to select patients with better post-progression survival (PPS) for second-line treatment. METHODS Consecutive 404 advanced HCC patients receiving sorafenib were retrospectively enrolled. All patients were in Child-Pugh class A and BCLC stage C with either portal vein invasion or extrahepatic metastasis at the beginning of sorafenib treatment. Radiological evaluation based on mRECIST criteria and clinical assessments with compliance were performed on schedule. RESULTS During the median follow-up period of 5.8 months, 310 patients developed progressive disease (PD) and 350 deaths occurred. The PD patients were randomized into derivation and validation cohorts by a 1:1 ratio. The independent predictors of poor PPS in derivation cohort were ALBI grade 3 at PD (hazard ratio [HR]=3.24, P = .002), new extrahepatic lesions (NEH) (HR=1.75, P = .011), and early PD within 4 months (HR=1.88, P = .037). ALBI-PD criteria were proposed by incorporating these three risk factors. In the validation cohort, PPS could be independently predicted by presence of early PD, NEH as well as ALBI grade 3 at PD. Patients within ALBI-PD criteria had significant longer median PPS than those beyond it even in Child-Pugh A (9.7 vs 4.9 months, P = .005) subpopulations. CONCLUSIONS The ALBI-PD criteria can differentiate PPS and stratify the patients with advanced HCC for the second-line trials or salvage therapy.
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Affiliation(s)
- Pei-Chang Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.,Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Yi-Tzen Chen
- Department of Nursing, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yee Chao
- Cancer Center, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Teh-Ia Huo
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.,Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Chung-Pin Li
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chien-Wei Su
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Mei-Hsuan Lee
- Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Ming-Chih Hou
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Fa-Yauh Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Han-Chieh Lin
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yi-Hsiang Huang
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.,Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
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21
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Trevisani F, Brandi G, Garuti F, Barbera MA, Tortora R, Casadei Gardini A, Granito A, Tovoli F, De Lorenzo S, Inghilesi AL, Foschi FG, Bernardi M, Marra F, Sacco R, Di Costanzo GG. Metronomic capecitabine as second-line treatment for hepatocellular carcinoma after sorafenib discontinuation. J Cancer Res Clin Oncol 2018; 144:403-414. [PMID: 29249005 DOI: 10.1007/s00432-017-2556-6] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Accepted: 12/08/2017] [Indexed: 02/07/2023]
Abstract
PURPOSE Metronomic capecitabine (MC) is a well-tolerated systemic treatment showing promising results in one retrospective study, as second-line therapy after sorafenib failure, in patients with hepatocellular carcinoma (HCC). METHODS 117 patients undergoing MC were compared to 112 patients, eligible for this treatment, but undergoing best supportive care (BSC) after sorafenib discontinuation for toxicity or HCC progression. The two groups were compared for demographic and clinical features. A multivariate regression analysis was conducted to detect independent prognostic factors. To balance confounding factors between the two groups, a propensity score model based on independent prognosticators (performance status, neoplastic thrombosis, causes of sorafenib discontinuation and pre-sorafenib treatment) was performed. RESULTS Patients undergoing MC showed better performance status, lower tumor burden, lower prevalence of portal vein thrombosis, and better cancer stage. Median (95% CI) post-sorafenib survival (PSS) was longer in MC than in BSC patients [9.5 (7.5-11.6) vs 5.0 (4.2-5.7) months (p < 0.001)]. Neoplastic thrombosis, cause of sorafenib discontinuation, pre-sorafenib treatment and MC were independent prognosticators. The benefit of capecitabine was confirmed in patients after matching with propensity score [PSS: 9.9 (6.8-12.9) vs. 5.8 (4.8-6.8) months, (p = 0.001)]. MC lowered the mortality risk by about 40%. MC achieved better results in patients who stopped sorafenib for adverse events than in those who progressed during it [PSS: 17.3 (10.5-24.1) vs. 7.8 (5.2-10.1) months, (p = 0.035)]. Treatment toxicity was low and easily manageable with dose modulation. CONCLUSIONS MC may be an efficient and safe second-line systemic therapy for HCC patients who discontinued sorafenib for toxicity or tumor progression.
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Affiliation(s)
- Franco Trevisani
- Department of Medical and Surgical Sciences, Medical Semeiotics, University of Bologna, via Albertoni 15, 40138, Bologna, Italy.
| | - Giovanni Brandi
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Francesca Garuti
- Department of Medical and Surgical Sciences, Medical Semeiotics, University of Bologna, via Albertoni 15, 40138, Bologna, Italy
| | - Maria Aurelia Barbera
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Raffaella Tortora
- Department of Transplantation, Liver Unit, Cardarelli Hospital, Naples, Italy
| | - Andrea Casadei Gardini
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Alessandro Granito
- Department of Medical and Surgical Sciences, Internal Medicine, University of Bologna, Bologna, Italy
| | - Francesco Tovoli
- Department of Medical and Surgical Sciences, Internal Medicine, University of Bologna, Bologna, Italy
| | - Stefania De Lorenzo
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Andrea Lorenzo Inghilesi
- Department of Clinical and Experimental Medicine, Internal Medicine and Hepatology, University of Florence, Florence, Italy
| | | | - Mauro Bernardi
- Department of Medical and Surgical Sciences, Medical Semeiotics, University of Bologna, via Albertoni 15, 40138, Bologna, Italy
| | - Fabio Marra
- Department of Clinical and Experimental Medicine, Internal Medicine and Hepatology, University of Florence, Florence, Italy
| | - Rodolfo Sacco
- Gastroenterology and Metabolic Diseases, University Hospital of Pisa, Pisa, Italy
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22
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Management consensus guideline for hepatocellular carcinoma: 2016 updated by the Taiwan Liver Cancer Association and the Gastroenterological Society of Taiwan. J Formos Med Assoc 2017; 117:381-403. [PMID: 29074347 DOI: 10.1016/j.jfma.2017.09.007] [Citation(s) in RCA: 81] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Revised: 08/16/2017] [Accepted: 09/13/2017] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality in Taiwan. To help clinical physicians to manage patients with HCC, the Taiwan Liver Cancer Association and the Gastroenterological Society of Taiwan produced the management consensus guideline for HCC. METHODS The recommendations focus on nine important issues on management of HCC, including surveillance, diagnosis, staging, surgery, local ablation, transarterial chemoembolization/transarterial radioembolization/hepatic arterial infusion chemotherapy, systemic therapy, radiotherapy, and prevention. RESULTS The consensus statements were discussed, debated and got consensus in each expert team. And then the statements were sent to all of the experts for further discussion and refinement. Finally, all of the experts were invited to vote for the statements, including the level of evidence and recommendation. CONCLUSION With the development of the management consensus guideline, HCC patients could benefit from the optimal therapeutic modality.
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23
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Shao YY, Chen BB, Ou DL, Lin ZZ, Hsu CH, Wang MJ, Cheng AL, Hsu C. Lenalidomide as second-line therapy for advanced hepatocellular carcinoma: exploration of biomarkers for treatment efficacy. Aliment Pharmacol Ther 2017; 46:722-730. [PMID: 28815645 DOI: 10.1111/apt.14270] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Revised: 07/05/2017] [Accepted: 07/26/2017] [Indexed: 12/21/2022]
Abstract
BACKGROUND Lenalidomide has immunomodulatory and anti-angiogenic effects and showed moderate anti-tumour efficacy in patients with. advanced hepatocellular carcinoma (HCC) AIM: To explore potential biomarkers of lenalidomide efficacy as second-line therapy for HCC. METHODS Eligible patients were diagnosed with advanced HCC, documented progression on sorafenib, and Child-Pugh class A liver function. Patients received 25 mg/day lenalidomide orally on days 1-21 every 4 weeks. The primary endpoint was 6 month progression-free survival rate. Early α-fetoprotein response was defined as a > 20% decline of α-fetoprotein levels from baseline within the first 4 weeks of treatment. Vascular response, evaluated using dynamic contrast-enhanced magnetic resonance imaging, was defined as a > 40% decline in Ktrans after 2 weeks of treatment. The percentage of peripheral blood lymphocyte subsets were also analysed. RESULTS Fifty-five patients were enrolled. The response rate was 13%, and the disease-control rate was 53%. The 6 month progression-free survival rate was 9.1%. The median progression-free and overall survival was 1.8 months and 8.9 months respectively. Early α-fetoprotein response was significantly associated with higher disease-control rate (76% vs 22%, P = .001) and longer progression-free survival (P = .020). Vascular response was not associated with any treatment outcomes. Patients with a high pre-treatment B cell percentage were more likely to have disease control (70% vs 36%, P = .010) and exhibited longer progression-free survival (P < .001) and overall survival (P = .042). CONCLUSIONS Lenalidomide exhibited moderate activity as second-line therapy for advanced HCC. Its immunomodulatory effects should be further explored (www.clinicaltrials.gov NCT01545804).
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Affiliation(s)
- Y-Y Shao
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.,National Taiwan University Cancer Center, Taipei, Taiwan.,Departments of Oncology, National Taiwan University Hospital, Taipei, Taiwan
| | - B-B Chen
- Department of Medical Imaging, National Taiwan University Hospital, Taipei, Taiwan
| | - D-L Ou
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.,National Taiwan University Cancer Center, Taipei, Taiwan
| | - Z-Z Lin
- Departments of Oncology, National Taiwan University Hospital, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - C-H Hsu
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.,National Taiwan University Cancer Center, Taipei, Taiwan.,Departments of Oncology, National Taiwan University Hospital, Taipei, Taiwan
| | - M-J Wang
- Departments of Oncology, National Taiwan University Hospital, Taipei, Taiwan
| | - A-L Cheng
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.,National Taiwan University Cancer Center, Taipei, Taiwan.,Departments of Oncology, National Taiwan University Hospital, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - C Hsu
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.,National Taiwan University Cancer Center, Taipei, Taiwan.,Departments of Oncology, National Taiwan University Hospital, Taipei, Taiwan
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24
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Lee HW, Kim HS, Kim SU, Kim DY, Kim BK, Park JY, Ahn SH, Jeon MY, Heo JY, Park SY, Lee YR, Jang SK, Lee SH, Jang SY, Tak WY, Han KH. Survival Estimates after Stopping Sorafenib in Patients with Hepatocellular Carcinoma: NEXT Score Development and Validation. Gut Liver 2017; 11:693-701. [PMID: 28651299 PMCID: PMC5593332 DOI: 10.5009/gnl16391] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Revised: 11/28/2016] [Accepted: 01/10/2017] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND/AIMS Limited information is available regarding patient survival after sorafenib discontinuation in patients with hepatocellular carcinoma (HCC). Thus, we developed and validated a novel survival prediction model. METHODS Clinical data from 409 patients with HCC who stopped taking sorafenib between September 2008 and February 2015 were reviewed. RESULTS In the training cohort, four factors were independent negative predictors of survival (p<0.05). Based on the β regression coefficient of each factor, we established the NEXT score (Survival after Stopping Nexavar Treatment), allocating 1 point each for an Eastern Cooperative Oncology Group score ≥2, Child-Pugh class B or C, serum sodium ≤135 mEq/L, and α-fetoprotein 〉400 ng/mL. Area under the receiver operating characteristic curve values to predict 1-, 3-, and 6-month survival rates were 0.805, 0.809, and 0.774, respectively, in the training cohort and 0.783, 0.728, and 0.673, respectively, in the validation cohort (n=137). When the training and validation cohorts were stratified into three risk groups (NEXT score 0 [low-risk] vs 1 to 2 [intermediate-risk] vs 3 to 4 [high-risk]), survival differed significantly between the groups (p＜0.05, log-rank test). CONCLUSIONS In patients with HCC, survival after stopping sorafenib is poor. However, risk estimates based on a new "NEXT score" may help predict survival and prognosis even in patients who discontinue sorafenib treatment.
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Affiliation(s)
- Hye Won Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul,
Korea
| | - Hyun Soo Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul,
Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul,
Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul,
Korea
- Liver Cirrhosis Clinical Research Center, Seoul,
Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul,
Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul,
Korea
- Liver Cirrhosis Clinical Research Center, Seoul,
Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul,
Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul,
Korea
- Liver Cirrhosis Clinical Research Center, Seoul,
Korea
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul,
Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul,
Korea
- Liver Cirrhosis Clinical Research Center, Seoul,
Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul,
Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul,
Korea
- Liver Cirrhosis Clinical Research Center, Seoul,
Korea
| | - Mi Young Jeon
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul,
Korea
| | - Ja Yoon Heo
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul,
Korea
| | - Soo Young Park
- Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu,
Korea
| | - Yu Rim Lee
- Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu,
Korea
| | - Sun Kyung Jang
- Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu,
Korea
| | - Su Hyun Lee
- Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu,
Korea
| | - Se Young Jang
- Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu,
Korea
| | - Won Young Tak
- Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu,
Korea
| | - Kwang-Hyub Han
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul,
Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul,
Korea
- Liver Cirrhosis Clinical Research Center, Seoul,
Korea
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25
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Ogasawara S, Chiba T, Ooka Y, Suzuki E, Maeda T, Yokoyama M, Wakamatsu T, Inoue M, Saito T, Kobayashi K, Kiyono S, Nakamura M, Nakamoto S, Yasui S, Tawada A, Arai M, Kanda T, Maruyama H, Yokosuka O, Kato N. Characteristics of patients with sorafenib-treated advanced hepatocellular carcinoma eligible for second-line treatment. Invest New Drugs 2017; 36:332-339. [PMID: 28891038 DOI: 10.1007/s10637-017-0507-3] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Accepted: 08/29/2017] [Indexed: 12/20/2022]
Abstract
Background Regorafenib has been investigated for its efficacy and safety as a second-line treatment in patients with advanced hepatocellular carcinoma (HCC). We assessed the characteristics of patients with HCC treated with sorafenib who might be eligible for second-line treatment in general and regorafenib in particular. Methods Patients with HCC treated with sorafenib were retrospectively analyzed. We defined second-line candidate patients as maintaining Child-Pugh A and ECOG-PS ≤1 at the time of sorafenib failure. We also defined regorafenib candidate patients as follows: 1) continuing sorafenib at the time of radiological progression, 2) maintaining Child-Pugh A and ECOG-PS ≤ 1 at the time of sorafenib failure, and 3) continuing sorafenib 400 mg or more without intolerable adverse events at least 20 days of the last 28 days of treatment. Results Of 185 patients, 130 (70%) and 69 (37%) were candidates for second-line treatment and regorafenib. Child-Pugh score 6 and ECOG-PS 1 at the time of starting sorafenib were significantly lower in both second-line treatment and regorafenib candidate patients. Moreover, hand-foot skin reaction and liver failure during sorafenib treatment were associated with significantly low and high probabilities, respectively, of both Child-Pugh score > 6 and ECOG-PS > 1 at the time of sorafenib failure. Conclusion Regorafenib candidate patients after sorafenib failure are limited, and generally fewer than those who are candidates for second-line treatment. A lower Child-Pugh score and a better ECOG-PS were predictors of eligibility for second-line therapy and regorafenib treatment in sorafenib-treated patients with advanced HCC patients.
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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
| | - Tetsuhiro Chiba
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.
| | - Yoshihiko Ooka
- 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
| | - Takahiro Maeda
- 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
| | - Toru Wakamatsu
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Masanori Inoue
- 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
| | - Kazufumi Kobayashi
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, 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
| | - 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
| | - Makoto Arai
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Tatsuo Kanda
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Hitoshi Maruyama
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Osamu Yokosuka
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Naoya Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
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26
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Choi SI, Yu A, Kim BH, Ko EJ, Park SS, Nam BH, Park JW. A model predicting survival of patients with recurrent or progressive hepatocellular carcinoma: the MORE score. J Gastroenterol Hepatol 2017; 32:651-658. [PMID: 27519171 DOI: 10.1111/jgh.13532] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/09/2016] [Indexed: 12/20/2022]
Abstract
BACKGROUND AND AIM Most prognostic models for hepatocellular carcinoma are based on data at the time of diagnosis. However, the disease frequently recurs or progresses after initial treatment, with changes in tumor burden and clinical status. Therefore, we developed a risk score model to predict survival of hepatocellular carcinoma patients at the time of disease recurrence or progression. METHODS Of 1972 patients newly diagnosed with hepatocellular carcinoma at the National Cancer Center, Korea, between January 2004 and December 2009, 1301 with recurrent or progressive disease were enrolled. They were randomly classified into a development (75%, n = 976) and a validation cohort (25%, n = 325). A survival prediction method was established in the development cohort using the multivariate Cox proportional hazards model, and its performance was evaluated on the validation cohort. RESULTS A model predicting survival of patients with recurrent or progressive hepatocellular carcinoma was developed using some known independent prognostic factors for overall survival: age, albumin, Model for End-Stage Liver Disease score, tumor burden, serum alpha-fetoprotein level, and presence of ascites. In addition, initial treatment modality and best response after initial treatment were also independent prognostic factors and were incorporated in the model. The C-statistics and χ2 statistics of this novel score for the validation cohort were 0.808 (95% CI: 0.781-0.834) and 4.408 for 3-year survival. CONCLUSIONS A new model to predict survival of patients with recurrent or progressive hepatocellular carcinoma was developed and validated. This model may be useful for planning subsequent treatments.
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Affiliation(s)
- Sang Il Choi
- Center for Liver Cancer, National Cancer Center, Goyang, South Korea
| | - Ami Yu
- Biometric Research Branch, National Cancer Center, Goyang, South Korea
| | - Bo Hyun Kim
- Center for Liver Cancer, National Cancer Center, Goyang, South Korea
| | - Eun Jeong Ko
- Center for Liver Cancer, National Cancer Center, Goyang, South Korea
| | - Soon Seob Park
- Center for Liver Cancer, National Cancer Center, Goyang, South Korea
| | - Byung-Ho Nam
- Biometric Research Branch, National Cancer Center, Goyang, South Korea
| | - Joong-Won Park
- Center for Liver Cancer, National Cancer Center, Goyang, South Korea
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27
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Casadei Gardini A, Foca F, Scartozzi M, Silvestris N, Tamburini E, Faloppi L, Brunetti O, Rudnas B, Pisconti S, Valgiusti M, Marisi G, Foschi FG, Ercolani G, Tassinari D, Cascinu S, Frassineti GL. Metronomic capecitabine versus best supportive care as second-line treatment in hepatocellular carcinoma: a retrospective study. Sci Rep 2017; 7:42499. [PMID: 28211921 PMCID: PMC5304169 DOI: 10.1038/srep42499] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 01/10/2017] [Indexed: 12/15/2022] Open
Abstract
Preliminary studies suggest that capecitabine may be safe and effective in HCC patients. The aim of this study was to retrospectively evaluate the safety and efficacy of metronomic capecitabine as second-line treatment. This multicentric study retrospectively analyzed data of HCC patients unresponsive or intolerant to sorafenib treatment with metronomic capecitabine or best supportive care (BSC).Median progression free survival was 3.1 months in patients treated with capecitabine (95%CI: 2.7-3.5). Median overall survival was 12.0 months (95% CI: 10.7-15.8) in patients receiving capecitabine, while 9.0 months (95% CI: 6.5-13.9) in patients receiving BSC. The result of univariate unweighted Cox regression model shows a 46% reduction in death risk for patients on capecitabine (95%CI: 0.357-0.829; p =0.005) compared to patients receiving BSC alone. After weighting for potential confounders, death risk remained essentially unaltered (45%; 95%CI: 0.354-0.883; p = 0.013). Metronomic capecitabine seems a safe second-line treatment for HCC patients in terms of management of adverse events, showing a potential anti-tumour activity which needs further evaluation in phase III studies.
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Affiliation(s)
- Andrea Casadei Gardini
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Flavia Foca
- Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Mario Scartozzi
- Department of Medical Oncology, University of Cagliari, Cagliari, Italy
| | - Nicola Silvestris
- Department of Medical Oncology, National Cancer Institute "Giovanni Paolo II", Bari, Italy
| | | | - Luca Faloppi
- Department of Medical Oncology, University of Cagliari, Cagliari, Italy
| | - Oronzo Brunetti
- Department of Medical Oncology, National Cancer Institute "Giovanni Paolo II", Bari, Italy
| | - Britt Rudnas
- Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Salvatore Pisconti
- Department of Onco-Ematology Medical Oncology, S.G. Moscati Hospital, Taranto, Italy
| | - Martina Valgiusti
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Giorgia Marisi
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | | | - Giorgio Ercolani
- Department of General Surgery, Morgagni-Pierantoni Hospital, Forlì, Italy.,Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | | | - Stefano Cascinu
- Department of Hematology and Oncology, University of Modena and Reggio Emilia, Modena, Italy
| | - Giovanni Luca Frassineti
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS, Meldola, Italy
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Raoul JL, Adhoute X, Gilabert M, Edeline J. How to assess the efficacy or failure of targeted therapy: Deciding when to stop sorafenib in hepatocellular carcinoma. World J Hepatol 2016; 8:1541-1546. [PMID: 28050234 PMCID: PMC5165267 DOI: 10.4254/wjh.v8.i35.1541] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Accepted: 11/02/2016] [Indexed: 02/06/2023] Open
Abstract
Sorafenib is thus far the only systemic treatment for hepatocellular carcinoma (HCC) based on the results of two randomized controlled trials performed in Western and in Eastern countries, despite a poor response rate (from 2% to 3.3%) following conventional evaluation criteria. It is now recognized that the criteria (European Association of the Study of the Liver criteria, modified response evaluation criteria in solid tumors) based on contrast enhanced techniques (computed tomography scan, magnetic resonance imaging) aimed to assess the evolution of the viable part of the tumor (hypervascularized on arterial phase) are of major interest to determine the efficacy of sorafenib and of most antiangiogenic drugs in patients with HCC. The role of alpha-fetoprotein serum levels remains unclear. In 2016, in accordance with the SHARP and the Asia-Pacific trials, sorafenib must be stopped when tolerance is poor despite dose adaptation or in cases of radiological and symptomatic progression. This approach will be different in cases of available second-line therapy trials. Some recent data (in renal cell carcinoma) revealed that despite progression in patients who received sorafenib, this drug can still decrease tumor progression compared to drug cessation. Then, before deciding to continue sorafenib post-progression or shift to another drug, knowing other parameters of post-progression survival (Child-Pugh class, Barcelona Clinic Liver Cancer, alpha-fetoprotein, post-progression patterns in particular, the development of extrahepatic metastases and of portal vein thrombosis) will be of major importance.
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Woo HY, Yoo SY, Heo J. New chemical treatment options in second-line hepatocellular carcinoma: what to do when sorafenib fails? Expert Opin Pharmacother 2016; 18:35-44. [PMID: 27849399 DOI: 10.1080/14656566.2016.1261825] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
INTRODUCTION There have been no therapies available for patients who experience disease progression after sorafenib treatment. Regorafenib inhibits multiple kinases involved in tumor proliferation and neoangiogenesis, which has produced a survival benefit in hepatocellular carcinoma (HCC) after sorafenib failure. Other active candidate agents are c-Met inhibitors and immune checkpoint inhibitors. Areas covered: This paper presents an updated summary of the preclinical and clinical experience with regorafenib, c-Met inhibitors (tivantinib, cabozantinib and tepotinib), and a checkpoint inhibitor (nivolumab, pembrolizumab) in HCC. The reported data were obtained from abstracts of international conferences and journal articles published up to August 2016 and found in a PubMed search. Expert opinion: Based on favorable data from preclinical and clinical trials, regorafenib, c-Met inhibitor, and checkpoint inhibitors are promising agents for HCC after sorafenib failure. However, further efforts to maximize the survival benefit and minimize adverse events of these drugs in the treatment of HCC are still necessary. Additionally, searching for predictors of good responders could allow these new drugs to be applied in personalized treatments of HCC.
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Affiliation(s)
- Hyun Young Woo
- a Department of Internal Medicine, College of Medicine , Pusan National University and Medical Research Institute, Pusan National University Hospital , Busan , Republic of Korea
| | - So Young Yoo
- b BIO-IT Foundry Technology Institute , Pusan National University , Busan , Republic of Korea.,c Research Institute for Convergence of Biomedical Science and Technology , Pusan National University Yangsan Hospital , Yangsan , Republic of Korea
| | - Jeong Heo
- a Department of Internal Medicine, College of Medicine , Pusan National University and Medical Research Institute, Pusan National University Hospital , Busan , Republic of Korea
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Kudo M, Trevisani F, Abou-Alfa GK, Rimassa L. Hepatocellular Carcinoma: Therapeutic Guidelines and Medical Treatment. Liver Cancer 2016; 6:16-26. [PMID: 27995084 PMCID: PMC5159738 DOI: 10.1159/000449343] [Citation(s) in RCA: 92] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Western and Eastern perspectives on therapeutic guidelines for hepatocellular carcinoma (HCC) have many commonalities but may also differ in certain aspects, as described in this article. In view of the limited therapeutic options for advanced HCC, evidence-based therapies are few, and thus there is a dependence on consensus-based guidelines. This article focuses on the Italian Association for the Study of the Liver guidelines and the Japanese approaches to therapy, while drawing attention to certain controversies from other academic bodies where applicable and appropriate.
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Affiliation(s)
- Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, OsakaSayama, Japan
| | - Franco Trevisani
- Semeiotic Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum − University of Bologna, Bologna, Italy
| | - Ghassan K Abou-Alfa
- Memorial Sloan Kettering Cancer Center, N.Y., USA
- Weill Cornell Medical College, N.Y., USA
| | - Lorenza Rimassa
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, Milan, Italy
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31
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Shao YY, Liu TH, Lee YH, Hsu CH, Cheng AL. Modified CLIP with objective liver reserve assessment retains prognosis prediction for patients with advanced hepatocellular carcinoma. J Gastroenterol Hepatol 2016; 31:1336-41. [PMID: 26860846 DOI: 10.1111/jgh.13312] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Revised: 01/04/2016] [Accepted: 02/03/2016] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM The Cancer of the Liver Italian Program (CLIP) score is a commonly used staging system for hepatocellular carcinoma (HCC) helpful with predicting prognosis of advanced HCC. CLIP uses the Child-Turcotte-Pugh (CTP) score to evaluate liver reserve. A new scoring system, the albumin-bilirubin (ALBI) grade, has been proposed as they objectively evaluate liver reserve. We examined whether the modification of CLIP with ALBI retained its prognosis prediction for patients with advanced HCC. METHODS We included patients who received first-line antiangiogenic therapy for advanced HCC. Liver reserve was assessed using CTP and ALBI scores, which were then incorporated into CLIP and ALBI-CLIP, respectively. To assess their efficacies of prognostic prediction, the Cox's proportional hazard model and concordance indexes were used. RESULTS A total of 142 patients were included; 137 of them were classified CTP A and 5 patients CTP B. Patients could be divided into four or five groups with different prognosis according to CLIP and ALBI-CLIP, respectively. Higher R(2) (0.249 vs 0.216) and lower Akaike information criterion (995.0 vs 1001.1) were observed for ALBI-CLIP than for CLIP in the Cox's model predicting overall survival. ALBI-CLIP remained an independent predictor for overall survival when CLIP and ALBI-CLIP were simultaneously incorporated in Cox's models allowing variable selection with adjustment for hepatitis etiology, treatment, and performance status. The concordance index was also higher for ALBI-CLIP than for CLIP (0.724 vs 0.703). CONCLUSIONS Modification of CLIP scoring with ALBI, which objectively assesses liver reserve, retains and might have improved prognosis prediction for advanced HCC.
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Affiliation(s)
- Yu-Yun Shao
- Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei City, Taiwan.,National Taiwan University Cancer Center, College of Medicine, National Taiwan University, Taipei City, Taiwan.,Department of Oncology, National Taiwan University Hospital, Taipei City, Taiwan
| | - Tsung-Hao Liu
- Department of Oncology, National Taiwan University Hospital, Taipei City, Taiwan
| | - Ying-Hui Lee
- Department of Oncology, National Taiwan University Hospital, Taipei City, Taiwan
| | - Chih-Hung Hsu
- Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei City, Taiwan.,Department of Oncology, National Taiwan University Hospital, Taipei City, Taiwan
| | - Ann-Lii Cheng
- Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei City, Taiwan.,National Taiwan University Cancer Center, College of Medicine, National Taiwan University, Taipei City, Taiwan.,Department of Oncology, National Taiwan University Hospital, Taipei City, Taiwan.,Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei City, Taiwan
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Shao YY, Hsu CH, Cheng AL. Predictive biomarkers of sorafenib efficacy in advanced hepatocellular carcinoma: Are we getting there? World J Gastroenterol 2015; 21:10336-10347. [PMID: 26420960 PMCID: PMC4579880 DOI: 10.3748/wjg.v21.i36.10336] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Revised: 05/26/2015] [Accepted: 08/31/2015] [Indexed: 02/06/2023] Open
Abstract
Sorafenib is the current standard treatment for advanced hepatocellular carcinoma (HCC), but its efficacy is modest with low response rates and short response duration. Predictive biomarkers for sorafenib efficacy are necessary. However, efforts to determine biomarkers for sorafenib have led only to potential candidates rather than clinically useful predictors. Studies based on patient cohorts identified the potential of blood levels of angiopoietin-2, hepatocyte growth factor, insulin-like growth factor-1, and transforming growth factor-β1 for predicting sorafenib efficacy. Alpha-fetoprotein response, dynamic contrast-enhanced magnetic resonance imaging, and treatment-related side effects may serve as early surrogate markers. Novel approaches based on super-responders or experimental mouse models may provide new directions in biomarker research. These studies identified tumor amplification of FGF3/FGF4 or VEGFA and tumor expression of phospho-Mapk14 and phospho-Atf2 as possible predictive markers that await validation. A group effort that considers various prognostic factors and proper collection of tumor tissues before treatment is imperative for the success of future biomarker research in advanced HCC.
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Kang YK, Yau T, Park JW, Lim HY, Lee TY, Obi S, Chan SL, Qin S, Kim RD, Casey M, Chen C, Bhattacharyya H, Williams JA, Valota O, Chakrabarti D, Kudo M. Randomized phase II study of axitinib versus placebo plus best supportive care in second-line treatment of advanced hepatocellular carcinoma. Ann Oncol 2015; 26:2457-63. [PMID: 26386123 DOI: 10.1093/annonc/mdv388] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Accepted: 09/10/2015] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The efficacy and safety of axitinib, a potent and selective vascular endothelial growth factor receptors 1-3 inhibitor, combined with best supportive care (BSC) was evaluated in a global, randomized, placebo-controlled phase II trial in patients with locally advanced or metastatic hepatocellular carcinoma (HCC). PATIENTS AND METHODS Patients with HCC and Child-Pugh Class A who progressed on or were intolerant to one prior antiangiogenic therapy were stratified by tumour invasion (presence/absence of extrahepatic spread and/or vascular invasion) and region (Asian/non-Asian) and randomized (2:1) to axitinib/BSC (starting dose 5 mg twice-daily) or placebo/BSC. The primary end point was overall survival (OS). RESULTS The estimated hazard ratio for OS was 0.907 [95% confidence interval (CI) 0.646-1.274; one-sided stratified P = 0.287] for axitinib/BSC (n = 134) versus placebo/BSC (n = 68), with the median (95% CI) of 12.7 (10.2-14.9) versus 9.7 (5.9-11.8) months, respectively. Results of prespecified subgroup analyses in Asian versus non-Asian patients or presence versus absence of tumour invasion were consistent with the overall population. Improvements favouring axitinib/BSC (P < 0.01) were observed in secondary efficacy end point analyses [progression-free survival (PFS), time to tumour progression (TTP), and clinical benefit rate (CBR)], and were retained among Asian patients in the prespecified subgroup analyses. Overall response rate did not differ significantly between treatments and patient-reported outcomes favoured placebo/BSC. Most common all-causality adverse events with axitinib/BSC were diarrhoea (54%), hypertension (54%), and decreased appetite (47%). Baseline serum analyses identified potential new prognostic (interleukin-6, E-selectin, interleukin-8, angiopoietin-2, migration inhibitory factor, and c-MET) or predictive (E-selectin and stromal-derived factor-1) factors for survival. CONCLUSIONS Axitinib/BSC did not improve OS over placebo/BSC in the overall population or in stratification subgroups. However, axitinib/BSC resulted in significantly longer PFS and TTP and higher CBR, with acceptable toxicity in patients with advanced HCC. TRIAL REGISTRATION ClinicalTrials.gov, NCT01210495.
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Affiliation(s)
- Y-K Kang
- Department of Oncology, Asan Medical Center, University of Ulsan, Seoul, Republic of Korea
| | - T Yau
- Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - J-W Park
- National Cancer Center/Center for Liver Cancer, Goyang-si
| | - H Y Lim
- Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University, Seoul, Republic of Korea
| | - T-Y Lee
- Division of Gastroenterology and Hepatology, Taichung Veterans General Hospital, Taichung, Taiwan
| | - S Obi
- Department of Hepatology, Sasaki Foundation Kyoundo Hospital, Tokyo, Japan
| | - S L Chan
- State Key Laboratory in Oncology of South China, Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong
| | - Sk Qin
- Nanjing Bayi Hospital, Nanjing, China
| | - R D Kim
- H. Lee Moffitt Cancer Center, Tampa
| | | | | | | | | | | | | | - M Kudo
- Department of Gastroenterology and Hepatology, Kinki University Hospital, Osaka, Japan
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Iavarone M, Cabibbo G, Biolato M, Della Corte C, Maida M, Barbara M, Basso M, Vavassori S, Craxì A, Grieco A, Cammà C, Colombo M. Predictors of survival in patients with advanced hepatocellular carcinoma who permanently discontinued sorafenib. Hepatology 2015; 62:784-791. [PMID: 25645399 DOI: 10.1002/hep.27729] [Citation(s) in RCA: 115] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2014] [Accepted: 01/13/2015] [Indexed: 12/21/2022]
Abstract
UNLABELLED Treatment with sorafenib of patients with advanced hepatocellular carcinoma is challenged by anticipated discontinuation due to tumor progression, liver decompensation, or adverse effects. While postprogression survival is clearly determined by the pattern of tumor progression, understanding the factors that drive prognosis in patients who discontinued sorafenib for any reason may help to improve patient management and second-line trial design. Patients consecutively admitted to three referral centers who were receiving best supportive care following permanent discontinuation of sorafenib for any reason were included. Postsorafenib survival (PSS) was calculated from the last day of treatment to death or last visit available. Two hundred and sixty patients were included in this prospective study, aged 67 years, 60% with hepatitis C, 51% Child-Pugh A, 83% performance status (PS) ≥1, 41% with macroscopic vascular invasion, and 38% with extrahepatic tumor spread. Overall, median PSS was 4.1 (3.3-4.9) months, resulting from 4.6 (3.3-5.7) months for 123 progressors, 7.3 (6.0-10.0) months in 77 with adverse effects, and 1.8 (1.6-2.4) months in 60 decompensated patients (P < 0.001). Postsorafenib survival was independently predicted by PS, prothrombin time, extrahepatic tumor spread, macrovascular invasion, and reason for discontinuation. Two hundred patients potentially eligible for second-line therapy had a PSS of 5.3 (4.6-7.1) months, which was dependent on reasons of discontinuation (P = 0.004), PS (P < 0.001), macrovascular invasion (P < 0.001), and extrahepatic metastases (P < 0.002). CONCLUSION Discontinuation due to adverse effects in the absence of macrovascular invasion, extrahepatic metastases, and deteriorated PS predicts the best PSS in compensated patients, thereby setting the stage for both improved patient counseling and selection for second-line therapy.
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Affiliation(s)
- Massimo Iavarone
- A.M.&A. Migliavacca Center for Liver Disease, 1st Division of Gastroenterology, Fondazione IRCCS Ca' Granda Maggiore Hospital, University of Milan, Milan, Italy
| | - Giuseppe Cabibbo
- Sezione di Gastroenterologia, DIBIMIS, University of Palermo, Palermo, Italy
| | - Marco Biolato
- Institute of Internal Medicine, School of Medicine, Catholic University of the Sacred Heart, Rome, Italy
| | - Cristina Della Corte
- A.M.&A. Migliavacca Center for Liver Disease, 1st Division of Gastroenterology, Fondazione IRCCS Ca' Granda Maggiore Hospital, University of Milan, Milan, Italy
| | - Marcello Maida
- Sezione di Gastroenterologia, DIBIMIS, University of Palermo, Palermo, Italy
| | | | - Michele Basso
- Institute of Internal Medicine, School of Medicine, Catholic University of the Sacred Heart, Rome, Italy
| | - Sara Vavassori
- A.M.&A. Migliavacca Center for Liver Disease, 1st Division of Gastroenterology, Fondazione IRCCS Ca' Granda Maggiore Hospital, University of Milan, Milan, Italy
| | - Antonio Craxì
- Sezione di Gastroenterologia, DIBIMIS, University of Palermo, Palermo, Italy
| | - Antonio Grieco
- Institute of Internal Medicine, School of Medicine, Catholic University of the Sacred Heart, Rome, Italy
| | - Carlo Cammà
- Sezione di Gastroenterologia, DIBIMIS, University of Palermo, Palermo, Italy
| | - Massimo Colombo
- A.M.&A. Migliavacca Center for Liver Disease, 1st Division of Gastroenterology, Fondazione IRCCS Ca' Granda Maggiore Hospital, University of Milan, Milan, Italy
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Porta C, Giglione P, Ferrari A, Reversi F, Liguigli W, Imarisio I, Ganini C. Tivantinib (ARQ197) in hepatocellular carcinoma. Expert Rev Anticancer Ther 2015; 15:615-622. [DOI: 10.1586/14737140.2015.1050383] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
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Granito A, Marinelli S, Terzi E, Piscaglia F, Renzulli M, Venerandi L, Benevento F, Bolondi L. Metronomic capecitabine as second-line treatment in hepatocellular carcinoma after sorafenib failure. Dig Liver Dis 2015; 47:518-522. [PMID: 25861840 DOI: 10.1016/j.dld.2015.03.010] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Revised: 02/27/2015] [Accepted: 03/10/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND No standard second-line treatments are available for hepatocellular carcinoma patients who fail sorafenib therapy. We assessed the safety and efficacy of metronomic capecitabine after first-line sorafenib failure. METHODS Retrospective analysis of consecutive hepatocellular carcinoma patients receiving metronomic capecitabine between January 2012 and November 2014. The primary end-point was safety, secondary end-point was efficacy, including time-to-progression and overall survival. RESULTS Twenty-six patients (80% Child-Pugh A, 80% Barcelona Clinic Liver Cancer stage C) received metronomic capecitabine (500 mg/bid). Median treatment duration was 3.2 months (range 0.6-31). Fourteen (53%) patients experienced at least one adverse event. The most frequent drug-related adverse events were bilirubin elevation (23%), fatigue (15%), anaemia (11%), lymphoedema (11%), and hand-foot syndrome (7.6%). Treatment was interrupted in 19 (73%) for disease progression, in 4 (15%) for liver deterioration, and in 1 (3.8%) for adverse event. Disease control was achieved in 6 (23%) patients. Median time-to-progression was 4 months (95% confidence interval 3.2-4.7). Median overall survival was 8 months (95% confidence interval 3.7-12.3). CONCLUSIONS Metronomic capecitabine was well tolerated in hepatocellular carcinoma patients who had been treated with sorafenib. Preliminary data show potential anti-tumour activity with long-lasting disease control in a subgroup of patients that warrants further evaluation in a phase III study.
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Affiliation(s)
- Alessandro Granito
- Department of Medical and Surgical Sciences, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy.
| | - Sara Marinelli
- Department of Medical and Surgical Sciences, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy
| | - Eleonora Terzi
- Department of Medical and Surgical Sciences, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy
| | - Fabio Piscaglia
- Department of Medical and Surgical Sciences, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy
| | - Matteo Renzulli
- Radiology Unit, Department of Digestive Diseases and Internal Medicine, S. Orsola-Malpighi Hospital, Bologna, Italy
| | - Laura Venerandi
- Department of Medical and Surgical Sciences, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy
| | - Francesca Benevento
- Department of Medical and Surgical Sciences, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy
| | - Luigi Bolondi
- Department of Medical and Surgical Sciences, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy
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Lee IC, Chen YT, Chao Y, Huo TI, Li CP, Su CW, Lin HC, Lee FY, Huang YH. Determinants of survival after sorafenib failure in patients with BCLC-C hepatocellular carcinoma in real-world practice. Medicine (Baltimore) 2015; 94:e688. [PMID: 25860213 PMCID: PMC4554055 DOI: 10.1097/md.0000000000000688] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Sorafenib may improve progression-free survival (PFS) and overall survival (OS) of advanced hepatocellular carcinoma (HCC). However, the survival benefit is short lived and survivals after progressive disease (PD) have not been well characterized. This study aimed to evaluate the survival predictors of OS and postprogression survival (PPS) in advanced HCC patients receiving sorafenib treatment. Consecutive 149 HCC patients receiving sorafenib under National Health Insurance were retrospectively enrolled. All patients fulfilled the reimbursement criteria: Barcelona Clinic Liver Cancer stage C HCC with macroscopic vascular invasion or extrahepatic metastasis (Mets), and Child-Pugh class A. Radiologic assessment was performed at a 2-month interval using modified Response Evaluation Criteria in Solid Tumors. Patients who maintained Eastern Cooperative Oncology Group ≤2 and Child-Pugh class A at PD were assumed to be candidates for second-line treatment. During the median follow-up period of 7.5 months (range, 1.1-18.5), PD developed in 120 (80.5%) patients and 96 (64.4%) deaths occurred. The median PFS, OS, and PPS were 2.5, 8.0, and 4.6 months, respectively. In general, patients with Mets only had better OS and PPS than those with portal vein invasion. Independent predictors of OS include baseline performance status (hazard ratio [HR] = 1.956), tumor size (HR = 1.597), alpha-fetoprotein (HR = 1.869), discontinuation of sorafenib due to liver function deterioration (LD) (HR = 6.142), or concurrent PD and LD (HR = 2.661) and PD within 4 months (HR = 5.164). Independent predictors of PPS include deteriorated performance status (HR = 7.680), deteriorated liver functions (HR = 5.603), bilirubin (HR = 2.114), early PD (HR = 6.109), and new extrahepatic lesion (HR = 1.804). In 46 candidates for second-line trials, development of new extrahepatic lesion independently predicts poorer PPS (HR = 3.669). In conclusion performance status, liver functions, early disease progression, and progression pattern are important determinants of survival after sorafenib failure. These factors should be considered in clinical practice and second-line trial designs for patients with sorafenib failure.
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Affiliation(s)
- I-Cheng Lee
- From the Division of Gastroenterology (I-CL, T-IH, C-PL, C-WS, H-CL, F-YL, Y-HH), Department of Medicine, Taipei Veterans General Hospital; Institute of Clinical Medicine (I-CL, Y-HH), National Yang-Ming University School of Medicine; Department of Nursing (Y-TC), Taipei Veterans General Hospital; Cancer Center (YC), Taipei Veterans General Hospital; and Institute of Pharmacology (T-IH), National Yang-Ming University School of Medicine, Taipei, Taiwan
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Rimassa L, Personeni N, Santoro A. Tivantinib for hepatocellular carcinoma. Expert Opin Orphan Drugs 2015. [DOI: 10.1517/21678707.2015.1009038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Abdel-Rahman O, Fouad M. Second line systemic therapy options for advanced hepatocellular carcinoma; a systematic review. Expert Rev Anticancer Ther 2015; 15:165-182. [DOI: 10.1586/14737140.2015.978295] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
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Bolos D, Finn RS. Systemic therapy in HCC: lessons from brivanib. J Hepatol 2014; 61:947-50. [PMID: 24972045 DOI: 10.1016/j.jhep.2014.06.019] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2014] [Revised: 06/11/2014] [Accepted: 06/18/2014] [Indexed: 01/29/2023]
Affiliation(s)
- David Bolos
- Department of Medicine, Division of Hematology/Oncology, Geffen School of Medicine at UCLA, USA
| | - Richard S Finn
- Department of Medicine, Division of Hematology/Oncology, Geffen School of Medicine at UCLA, USA.
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Kim BH, Park JW. Systemic therapy for hepatocellular carcinoma: why do we keep failing? Hepat Oncol 2014; 1:355-358. [PMID: 30190969 PMCID: PMC6095331 DOI: 10.2217/hep.14.23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Affiliation(s)
- Bo Hyun Kim
- Center for Liver Cancer, National Cancer Center, Goyang, Republic of Korea
| | - Joong-Won Park
- Center for Liver Cancer, National Cancer Center, Goyang, Republic of Korea
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Abstract
The antiangiogenic multikinase inhibitor sorafenib was the first systemic agent to demonstrate a significant improvement in the overall survival of patients with advanced hepatocellular carcinoma (HCC), thereby introducing molecularly-targeted therapy in a therapeutic field of unmet needs. However, survival benefits for patients on sorafenib treatment are modest in clinical practice and advancing the field is far more challenging than initially anticipated. Molecular and clinical heterogeneity diminishes signals of potential activity in unselected populations, and underlying liver cirrhosis seals the fate of many novel targeted agents by causing relevant toxicity and mortality. The failure of subsequent randomized controlled phase III trials underscores the urgent need to identify the driver targets and to develop matched active agents with manageable toxicities in specific phase I studies in patients with cirrhosis. Refinement of phase II-III trial designs with a biomarker-enriched patient-selection process and stratification according to prognostic baseline factors is indispensable to prevent another 5-year vain endeavour in systemic therapy of HCC.
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Germano D, Daniele B. Systemic therapy of hepatocellular carcinoma: Current status and future perspectives. World J Gastroenterol 2014; 20:3087-3099. [PMID: 24696596 PMCID: PMC3964381 DOI: 10.3748/wjg.v20.i12.3087] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2013] [Revised: 10/31/2013] [Accepted: 01/06/2014] [Indexed: 02/06/2023] Open
Abstract
The management of hepatocellular carcinoma (HCC) has substantially changed in the past few decades, the introduction of novel therapies (such as sorafenib) have improved patient survival. Nevertheless, HCC remains the third most common cause of cancer-related deaths worldwide. Decision-making largely relies on evidence-based criteria, as showed in the US and European clinical practice guidelines, which endorse five therapeutic recommendations:resection; transplantation; radiofrequency ablation; chemoembolization; and sorafenib. Many molecularly targeted agents that inhibit angiogenesis, epidermal growth factor receptor, and mammalian target of rapamycin are at different stages of clinical development in advanced HCC. Future research should continue to unravel the mechanism of hepatocarcinogenesis and to identify key relevant molecular targets for therapeutic intervention. Identification and validation of potential surrogate and predictive biomarkers hold promise to individualize patient’s treatment to maximize clinical benefit and minimize the toxicity and cost of targeted agents.
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Shao YY, Cheng AL, Hsu CH. Clinical Activity of Metronomic Chemotherapy in Liver Cancers. METRONOMIC CHEMOTHERAPY 2014:189-202. [DOI: 10.1007/978-3-662-43604-2_13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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