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Artusa F, Lamatsch S, Phan MD, Özdirik B, Berger H, Egerer M, Knorr‐Klocke J, Fischer J, Veelken R, van Bömmel F, Berg T, Kappert K, Tauber R, Puengel T, Engelmann C, Demir M, Tacke F, Mohr R. Soluble Urokinase Plasminogen Activator Receptor Predicts Survival and Hepatic Decompensation in Advanced Hepatocellular Carcinoma. Liver Int 2025; 45:e70121. [PMID: 40317602 PMCID: PMC12046945 DOI: 10.1111/liv.70121] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Revised: 04/01/2025] [Accepted: 04/22/2025] [Indexed: 05/07/2025]
Abstract
BACKGROUND AND AIMS The introduction of immune checkpoint inhibitor (ICI) based therapies has significantly improved the prognosis of patients with unresectable hepatocellular carcinoma (HCC). However, the variable treatment response and the uncertain benefit in patients with advanced liver cirrhosis emphasise the urgent need for prognostic and predictive biomarkers guiding patient selection. The soluble urokinase plasminogen activator receptor (suPAR) is strongly associated with inflammation, liver cirrhosis and various types of cancer. In this study, we investigated suPAR as a potential novel biomarker in patients with unresectable HCC. METHODS This multicenter retrospective study, conducted at three German tertiary care centers, included 90 patients with unresectable HCC and suPAR measurements prior to and during atezolizumab/bevacizumab therapy. Patients with liver cirrhosis without HCC (n = 235) and non-cirrhotic patients with other gastrointestinal tumours (n = 155) were selected as control cohorts. RESULTS Median suPAR levels were significantly higher in patients with liver cirrhosis compared to non-cirrhotic cancer patients. A strong association with parameters of liver function, but not with HCC characteristics, was observed. In patients with HCC receiving atezolizumab/bevacizumab, suPAR was the most accurate independent predictor of hepatic decompensation and overall survival (OS). In addition, suPAR was able to stratify the risk of hepatic decompensation within the different Child-Pugh classes. CONCLUSIONS SuPAR represents a promising novel biomarker in patients with HCC treated with ICI-based therapies and bears the potential to guide the selection of antitumoral systemic therapies in patients with advanced liver cirrhosis.
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Affiliation(s)
- Fabian Artusa
- Department of Hepatology and GastroenterologyCharité ‐ Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM)BerlinGermany
| | - Sven Lamatsch
- Department of Hepatology and GastroenterologyCharité ‐ Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM)BerlinGermany
| | - Minh Duc Phan
- Department of Hepatology and GastroenterologyCharité ‐ Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM)BerlinGermany
| | - Burcin Özdirik
- Department of Hepatology and GastroenterologyCharité ‐ Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM)BerlinGermany
| | - Hilmar Berger
- Department of Hepatology and GastroenterologyCharité ‐ Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM)BerlinGermany
| | - Mara Egerer
- Department of Hepatology and GastroenterologyCharité ‐ Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM)BerlinGermany
| | - Jana Knorr‐Klocke
- Department of Hepatology and GastroenterologyCharité ‐ Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM)BerlinGermany
| | - Janett Fischer
- Division of Hepatology, Department of Medicine IILeipzig University Medical CenterLeipzigGermany
| | - Rhea Veelken
- Division of Hepatology, Department of Medicine IILeipzig University Medical CenterLeipzigGermany
| | - Florian van Bömmel
- Division of Hepatology, Department of Medicine IILeipzig University Medical CenterLeipzigGermany
| | - Thomas Berg
- Division of Hepatology, Department of Medicine IILeipzig University Medical CenterLeipzigGermany
| | - Kai Kappert
- Institute of Diagnostic Laboratory Medicine, Clinical Chemistry and PathobiochemistryCharité ‐ Universitätsmedizin BerlinBerlinGermany
- Labor Berlin – Charité Vivantes GmbHBerlinGermany
| | - Rudolf Tauber
- Institute of Diagnostic Laboratory Medicine, Clinical Chemistry and PathobiochemistryCharité ‐ Universitätsmedizin BerlinBerlinGermany
- Labor Berlin – Charité Vivantes GmbHBerlinGermany
| | - Tobias Puengel
- Department of Hepatology and GastroenterologyCharité ‐ Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM)BerlinGermany
| | - Cornelius Engelmann
- Department of Hepatology and GastroenterologyCharité ‐ Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM)BerlinGermany
- Institute for Liver and Digestive HealthUniversity College LondonLondonUK
| | - Münevver Demir
- Department of Hepatology and GastroenterologyCharité ‐ Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM)BerlinGermany
| | - Frank Tacke
- Department of Hepatology and GastroenterologyCharité ‐ Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM)BerlinGermany
| | - Raphael Mohr
- Department of Hepatology and GastroenterologyCharité ‐ Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM)BerlinGermany
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Singal AG, Salem R, Pinato DJ, Pillai A. Advances in Locoregional and Systemic Treatments for Hepatocellular Carcinoma. Gastroenterology 2025:S0016-5085(25)00660-2. [PMID: 40320088 DOI: 10.1053/j.gastro.2025.03.047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2025] [Revised: 03/20/2025] [Accepted: 03/26/2025] [Indexed: 05/29/2025]
Abstract
Significant advances have occurred in the locoregional and systemic therapy landscape for hepatocellular carcinoma (HCC), with the most notable being the introduction of immune checkpoint inhibitor (ICI) combinations. ICI combinations have significantly improved the overall survival of patients with unresectable HCC, affording median survival over 2 years and long-term survival exceeding 5 years in a subset of patients. Accordingly, there has been increased interest in the earlier application of systemic therapies, including (neo)adjuvant therapy in the perioperative setting or in combination with intra-arterial therapies. However, recent data failed to demonstrate improved recurrence-free survival with use of adjuvant ICI therapy. Conversely, 2 trials showed improved progression-free survival when ICI therapies were combined with transarterial chemoembolization, although data regarding the impact on overall survival are still immature. These improved outcomes raise several new questions, including which patients with liver-localized HCC should receive systemic therapy, how should this be sequenced or combined with other available therapies, and how to manage those patients with marked responses, including consideration of liver transplantation. These questions are often determined on a case-by-case basis and best made in a multidisciplinary manner considering several factors, including tumor burden, degree of liver dysfunction, performance status, and patient's long-term goals of care.
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Affiliation(s)
- Amit G Singal
- Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas (UT) Southwestern Medical Center, Dallas Texas.
| | - Riad Salem
- Department of Radiology, Northwestern University, Chicago, Illinois
| | - David J Pinato
- Department of Surgery & Cancer, Imperial College London, London, United Kingdom; Department of Translational Medicine (DIMET), University of Piemonte Orientale, Novara, Italy
| | - Anjana Pillai
- Department of Internal Medicine, University of Chicago, Chicago, Illinois
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Biswas S, Samanta A. Immune therapies in intermediate-advanced unresectable hepatocellular carcinoma: Changing the therapeutic landscape. World J Gastroenterol 2025; 31:103267. [PMID: 40248376 PMCID: PMC12001191 DOI: 10.3748/wjg.v31.i14.103267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 03/13/2025] [Accepted: 03/19/2025] [Indexed: 04/11/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. A substantial proportion of patients are diagnosed with advanced or intermediate-advanced stage disease at presentation and are often ineligible for curative surgery. The mainstay of treatment of this unique intermediate-advanced stage patients who have a liver-limited disease but unresectable due to large tumor burden, number of lesions or technical difficulties, have traditionally been locoregional therapies. However, the response has not been satisfactory in the majority of patients. With the advent of immune therapies and the remarkable progress it has made over the past decade, the management of intermediate-advanced HCC has undergone a paradigm change. Till 2020, sorafenib, a multi-targeted inhibitor of vascular endothelial growth factor, platelet-derived growth factor and rapidly accelerated fibrosarcoma was the one approved immune therapy. However, since 2021, nine more drugs have been approved, based on studies showing improved survival in advanced-stage HCC patients. However, the challenge clinicians face now is to determine the best choice/combination of available drugs to achieve long-term success and survival while maintaining preserved liver function. In light of emerging literature concerning immune therapies, including the relevant randomized controlled trial by Han et al, this editorial aims to review the currently available treatment strategies for the intermediate-advanced stage HCC.
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Affiliation(s)
- Sagnik Biswas
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Arghya Samanta
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
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Salimi S, Liu K. Editorial: Variceal Bleeding in Patients Receiving Atezolizumab-Bevacizumab for Hepatocellular Carcinoma-Don't Ignore the Risk Factors! Aliment Pharmacol Ther 2025; 61:1404-1405. [PMID: 39957603 DOI: 10.1111/apt.70017] [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: 01/30/2025] [Revised: 01/30/2025] [Accepted: 01/30/2025] [Indexed: 02/18/2025]
Affiliation(s)
- Shirin Salimi
- AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
| | - Ken Liu
- AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia
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Chok KSH, Joeng TYT, Poon DMC. Proton beam therapy in the management of hepatocellular carcinoma. Expert Rev Gastroenterol Hepatol 2025; 19:495-504. [PMID: 40272863 DOI: 10.1080/17474124.2025.2495080] [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: 01/27/2025] [Accepted: 04/15/2025] [Indexed: 04/26/2025]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer. Photon radiotherapy shows efficacy in treating HCC but carries risks of high exit dose and radiation-induced liver disease. Additionally, HCCs with portal vein tumor thrombosis (PVTT) have a poor prognosis and are associated with higher risk of death. In recent years, proton beam therapy (PBT) has emerged as a novel treatment with the ability to downstage HCC for liver transplant (LT). AREAS COVERED This review will provide an overview of dosimetric benefits of PBT, efficacy of PBT in treating HCC, downstaging HCC-PVTT for LT, and a comparison of PBT with other non-surgical techniques. A search of PubMed until 3 September 2024 was conducted using free search and the following keywords: hepatocellular carcinoma, proton beam therapy, portal vein tumor thrombosis, local ablative therapy, trans-arterial chemoembolization, stereotactic body radiotherapy, Y-90 radioembolization. EXPERT OPINION Various clinical trials using PBT have shown promising tumor local control and overall survival rates. PBT is mostly safe and efficacious for downstaging HCC-PVTT for LT. PBT has also been shown to be non-inferior to various other treatment modalities. Future research should focus on combinations of PBT with other modalities.
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Affiliation(s)
- Kenneth S H Chok
- Department of Surgery, The Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Tiffany Y T Joeng
- Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Darren M C Poon
- Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Center for Cancer, Hong Kong Cancer Institute, The Chinese University of Hong Kong, Hong Kong, China
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Stella L, Pallozzi M, Cerrito L, Santopaolo F, Tovoli F, Hollande C, Sidali S, Stefanini B, Campani C, Pellegrini E, Cabibbo G, Marra F, Piscaglia F, Gasbarrini A, Pompili M, Bouattour M, Ponziani FR. Liver Decompensation in Patients With Hepatocellular Carcinoma Treated With Atezolizumab Plus Bevacizumab: A Real-life Study. Clin Gastroenterol Hepatol 2025:S1542-3565(25)00148-X. [PMID: 40020957 DOI: 10.1016/j.cgh.2024.12.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 11/25/2024] [Accepted: 12/23/2024] [Indexed: 03/03/2025]
Abstract
BACKGROUND & AIMS Atezolizumab plus bevacizumab (atezobeva) has changed the treatment landscape of advanced hepatocellular carcinoma, but its efficacy and safety in patients with impaired liver function are still debated. This study aimed to evaluate the prognostic impact of baseline liver function and liver decompensation during treatment on clinical outcomes. METHODS In this multicenter study, we included 247 patients with advanced or unresectable hepatocellular carcinoma treated with atezobeva. We analyzed data on survival, tumor progression, and liver decompensation and introduced time to decompensation as a new safety endpoint. RESULTS The reported overall survival (OS) was 18.30 months, time to progression 13.07 months, and progression-free survival (PFS) 9.83 months. Although OS was better in Child Pugh A compared with Child Pugh B patients (20.20 vs 9.83 months; P = .0008), no differences were observed in time to progression and treatment safety. Liver decompensation occurred in 63 patients (25.51%), specifically 27.89% Child Pugh A and 51.16% Child Pugh B patients; in 41.26% of patients, atezobeva was resumed after decompensation, achieving an OS comparable to those who never decompensated (20.87 vs 20.2 months; P = .77), and better than those who permanently stopped treatment (8.07 months; P = .02). Time to decompensation was similar for patients with albumin-bilirubin score 2 regardless of Child Pugh class, and the probability of recovery from decompensation was similar for Child Pugh A and B patients. CONCLUSION Atezobeva is effective in both Child Pugh A and B patients. The possibility to resume treatment after an episode of decompensation underscores the importance of integrated hepato-oncological management.
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Affiliation(s)
- Leonardo Stella
- Liver Unit, CEMAD - Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy
| | - Maria Pallozzi
- Liver Unit, CEMAD - Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy
| | - Lucia Cerrito
- Liver Unit, CEMAD - Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy
| | - Francesco Santopaolo
- Liver Unit, CEMAD - Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy
| | - Francesco Tovoli
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | | | - Sabrina Sidali
- Université de Paris, AP-HP, C, DMU DIGEST, Centre de Référence des Maladies Vasculaires du Foie, FILFOIE, ERN RARE-LIVER, Centre de Recherche sur l'inflammation, Inserm, Paris, France; Centre Hospitalier Universitaire Charles Nicolle, Hépato-Gastroentérologie, Rouen, France
| | - Bernardo Stefanini
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Claudia Campani
- Department of Experimental and Clinical Medicine, Internal Medicine and Hepatology Unit, University of Florence, Florence, Italy
| | - Elisa Pellegrini
- Medical Oncology Unit, Careggi University Hospital, Florence, Italy
| | - Giuseppe Cabibbo
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Mother and Child-Care, Internal Medicine and Medical Specialties PROMISE, University of Palermo, Palermo, Italy
| | - Fabio Marra
- Department of Experimental and Clinical Medicine, Internal Medicine and Hepatology Unit, University of Florence, Florence, Italy
| | - Fabio Piscaglia
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Antonio Gasbarrini
- Liver Unit, CEMAD - Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Maurizio Pompili
- Liver Unit, CEMAD - Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | | | - Francesca Romana Ponziani
- Liver Unit, CEMAD - Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy.
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Kim DH, Min EJ, Kim B, Choi JY, Jang JW, Sung PS, Han JW, Kim H, Choi JI. RECIST 1.1, mRECIST, and Choi criteria for evaluating treatment response and survival outcomes in hepatocellular carcinoma patients treated with atezolizumab plus bevacizumab. Eur Radiol 2025; 35:684-694. [PMID: 39080067 DOI: 10.1007/s00330-024-10986-z] [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: 03/19/2024] [Revised: 05/19/2024] [Accepted: 07/14/2024] [Indexed: 02/01/2025]
Abstract
OBJECTIVES We aimed to compare the early responder rates, defined as complete or partial responders, using response evaluation criteria in solid tumors (RECIST) 1.1, modified RECIST (mRECIST), and Choi criteria in advanced HCC patients treated with atezolizumab-bevacizumab (atezo-bev), and to correlate them with progression-free survival (PFS) and overall survival (OS). METHODS This retrospective study included advanced HCC patients treated with ≥ 3 cycles of atezo-bev. Two reviewers assessed responses using RECIST 1.1, mRECIST, and Choi criteria at 1st follow-up imaging. Kaplan-Meier curves with log-rank tests evaluated and compared PFS and OS. Cox proportional hazard models identified survival outcome predictors. Kappa statistics assessed inter-reader agreement. RESULTS We evaluated 77 patients (65 men; mean age, 62.8 ± 12.3 years). Choi's criteria revealed the highest early responders rate (53.2%), exceeding mRECIST (32.5-33.8%) and RECIST 1.1 (24.7-26.0%), with an excellent agreement in all criteria (κ, 0.85-0.95). Across criteria, a consistent number of patients progressed (23-26) and was associated with significantly poor OS (ps ≤ 0.049). Responders by any criteria showed longer PFS (ps ≤ 0.009), and 1-year OS (ps ≤ 0.01). Choi criteria linked to significantly better OS without landmark (p = 0.003), with 1-year OS rates at 76.9% for responders vs 38.1% for non-responders. Cox analysis identified responders by Choi criteria as a significant OS predictor. CONCLUSION Choi criteria identified more early responders than RECIST 1.1 and mRECIST, significantly correlating with improved OS. Choi criteria could be considered as a formal response assessment criterion for the emerging atezo-bev systemic treatment. CLINICAL RELEVANCE STATEMENT For atezo-bev treatment of advanced HCC, more comprehensive response criteria, such as Choi criteria, could be effective in identifying early responders and predicting survival outcomes along with RECIST 1.1 and mRECIST. KEY POINTS Choi criteria identified a higher rate of early responders compared to mRECIST and RECIST1.1 following atezo-bev treatment. Responders by all criteria had longer PFS and 1-year OS, and only those by Choi criteria experienced longer OS without landmark time. Choi criteria, with RECIST 1.1 and mRECIST, is an effective response assessment tool for atezo-bev treatment.
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Affiliation(s)
- Dong Hwan Kim
- Department of Radiology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Eun Jeong Min
- Department of Medical Life Science, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Bohyun Kim
- Department of Radiology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
| | - Jong Young Choi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul St. Mary's Hospital, Seoul, Republic of Korea
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jeong Won Jang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul St. Mary's Hospital, Seoul, Republic of Korea
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Pil Soo Sung
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul St. Mary's Hospital, Seoul, Republic of Korea
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Ji Won Han
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul St. Mary's Hospital, Seoul, Republic of Korea
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Hokun Kim
- Department of Radiology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Joon-Il Choi
- Department of Radiology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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Hwang SY, Danpanichkul P, Agopian V, Mehta N, Parikh ND, Abou-Alfa GK, Singal AG, Yang JD. Hepatocellular carcinoma: updates on epidemiology, surveillance, diagnosis and treatment. Clin Mol Hepatol 2025; 31:S228-S254. [PMID: 39722614 PMCID: PMC11925437 DOI: 10.3350/cmh.2024.0824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Revised: 11/08/2024] [Accepted: 12/20/2024] [Indexed: 12/28/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a major global burden, ranking as the third leading cause of cancer-related mortality. HCC due to chronic hepatitis B virus (HBV) or C virus (HCV) infection has decreased due to universal vaccination for HBV and effective antiviral therapy for both HBV and HCV, but HCC related to metabolic dysfunction-associated steatotic liver disease and alcohol-associated liver disease is increasing. Biannual liver ultrasonography and serum α-fetoprotein are the primary surveillance tools for early HCC detection among high-risk patients (e.g., cirrhosis, chronic HBV). Alternative surveillance tools such as blood-based biomarker panels and abbreviated magnetic resonance imaging (MRI) are being investigated. Multiphasic computed tomography or MRI is the standard for HCC diagnosis, but histological confirmation should be considered, especially when inconclusive findings are seen on cross-sectional imaging. Staging and treatment decisions are complex and should be made in multidisciplinary settings, incorporating multiple factors including tumor burden, degree of liver dysfunction, patient performance status, available expertise, and patient preferences. Early-stage HCC is best treated with curative options such as resection, ablation, or transplantation. For intermediate-stage disease, locoregional therapies are primarily recommended although systemic therapies may be preferred for patients with large intrahepatic tumor burden. In advanced-stage disease, immune checkpoint inhibitor-based therapy is the preferred treatment regimen. In this review article, we discuss the recent global epidemiology, risk factors, and HCC care continuum encompassing surveillance, diagnosis, staging, and treatments.
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Affiliation(s)
- Soo Young Hwang
- Department of Internal Medicine, University of Maryland Medical Center, Midtown Campus, Baltimore, Maryland, USA
| | - Pojsakorn Danpanichkul
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas, USA
| | - Vatche Agopian
- Dumont-UCLA Transplant and Liver Cancer Centers, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Neil Mehta
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, California, USA
| | - Neehar D. Parikh
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA
| | - Ghassan K. Abou-Alfa
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA
- Department of Medicine, Weill Medical College at Cornell University, New York, USA
- Trinity College Dublin, Dublin, Ireland
| | - Amit G. Singal
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Ju Dong Yang
- Karsh Division of Gastroenterology and Hepatology, Comprehensive Transplant Center, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
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Li X, Qin Z, Chen H, Chen D, Alimu N, Li D, Cheng X, Yan Q, Zhang L, Liu X, Zhou Z, Zhu J, Ma H, Pei X, Xu H, Huang J. Construction of a tumor immune microenvironment-related risk scoring model for prognosis of hepatocellular carcinoma. Int J Immunopathol Pharmacol 2025; 39:3946320251333975. [PMID: 40265593 PMCID: PMC12035210 DOI: 10.1177/03946320251333975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 03/25/2025] [Indexed: 04/24/2025] Open
Abstract
OBJECTIVE This study aims to develop a prognostic model for HCC based on TME-related factors. INTRODUCTION Hepatocellular carcinoma (HCC) is characterized by a poor prognosis, largely due to the complex and heterogeneous interactions between stromal and immune cells within the tumor microenvironment (TME). METHODS Genome and transcriptome data, as well as clinical information of HCC patients, were obtained from the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). The TME score was evaluated using the "ESTIMATE" R package. Differentially expressed genes (DEGs) associated with TME phenotype were analyzed using the LIMMA R-package. Survival outcomes were compared using Kaplan-Meier curves with log-rank test and Cox proportional hazards model. Protein-Protein Interaction (PPI) networks integrated with multivariate survival and LASSO analyses were utilized to identify TME-related hub genes for a risk score model. A nomogram predicting prognosis of HCC patients was developed through four independent cohorts. RESULTS The TME scores showed a negative correlation with tumor progression and survival in HCC patients. We identified 50 core genes with high connectivity in the PPI network, as along with 33 key DEGs associated with survival in HCC. Intersection analysis revealed six hub genes -CXCL8, CXCL1, CCR7, IL7R, MMP9, and CD69. The risk score based on these six TME-related hub genes was significantly associated with overall survival and clinicopathological characteristics of HCC patients. Furthermore, the nomogram demonstrated its ability to discriminate HCC patients from healthy individuals using peripheral blood mononuclear cells. CONCLUSION We have developed a TME-related risk scoring model for HCC patients and identified six hub gene panel that serve as a potential biomarker for personalized prognosis of immunotherapy and non-invasive diagnostics of HCC.
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Affiliation(s)
- Xinyi Li
- College of Life Sciences & Bioengineering, Beijing Jiaotong University, Beijing, China
| | - Zifan Qin
- College of Life Sciences & Bioengineering, Beijing Jiaotong University, Beijing, China
| | - Haozhi Chen
- College of Life Sciences & Bioengineering, Beijing Jiaotong University, Beijing, China
| | - Daichuan Chen
- College of Life Sciences & Bioengineering, Beijing Jiaotong University, Beijing, China
| | - Nafisa Alimu
- School of Stomatology, Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Duoduo Li
- College of Life Sciences & Bioengineering, Beijing Jiaotong University, Beijing, China
| | - Xiyu Cheng
- College of Life Sciences & Bioengineering, Beijing Jiaotong University, Beijing, China
| | - Qiong Yan
- College of Life Sciences & Bioengineering, Beijing Jiaotong University, Beijing, China
| | - Lishu Zhang
- College of Life Sciences & Bioengineering, Beijing Jiaotong University, Beijing, China
| | - Xingwei Liu
- College of Life Sciences & Bioengineering, Beijing Jiaotong University, Beijing, China
| | - Zitong Zhou
- College of Life Sciences & Bioengineering, Beijing Jiaotong University, Beijing, China
| | - Jiayi Zhu
- College of Life Sciences & Bioengineering, Beijing Jiaotong University, Beijing, China
| | - Hangqi Ma
- College of Life Sciences & Bioengineering, Beijing Jiaotong University, Beijing, China
| | - Xinyue Pei
- College of Life Sciences & Bioengineering, Beijing Jiaotong University, Beijing, China
| | - Hanli Xu
- College of Life Sciences & Bioengineering, Beijing Jiaotong University, Beijing, China
| | - Jiaqiang Huang
- College of Life Sciences & Bioengineering, Beijing Jiaotong University, Beijing, China
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10
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Marell P, Kournoutas I, Gile J, Peersen A, Shah P, Babiker H, Kankeu LF, Washburn L, Graham R, Truty M, Starlinger P, Halfdanarson T, Jin Z, Jatoi A, McWilliams R, Borad M, Bekaii-Saab TS, Mahipal A, Ou FS, Tran NH. Second-line therapies in advanced hepatocellular carcinoma following first-line atezolizumab and bevacizumab: multicenter single institution cohort experience. Oncologist 2024:oyae342. [PMID: 39674576 DOI: 10.1093/oncolo/oyae342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Accepted: 11/08/2024] [Indexed: 12/16/2024] Open
Abstract
BACKGROUND Atezolizumab plus bevacizumab (A/B) received FDA approval as the first-line therapy for patients with advanced hepatocellular carcinoma (HCC) in 2020. However, optimal subsequent treatment options are unclear. Here, we describe clinical outcomes of advanced HCC patients following first-line treatment with A/B. PATIENTS AND METHODS We conducted a multi-site analysis of patients with HCC treated with first-line A/B between January 2018 and December 2022 at Mayo Clinic. This study cohort included all patients receiving second-line systemic therapy after A/B. Median overall survival (OS) and time-to-treatment discontinuation (TTD) were estimated using the Kaplan-Meier method. Child Pugh (CP) scores are also described at diagnosis, prior to first line, and prior to second-line therapy. RESULTS Of the 342 patients who received A/B, 107 (31.3%) received second-line treatments including anti-VEGF therapy or immune checkpoint inhibitor (ICI) and were included in the final analysis. Median OS for all patients was 11.1 months from initiation of second-line therapy. Median OS was 10.7 months (95% CI: 7.2-12.8) and 15.7 months (95%CI: 6.8-NE) for those receiving anti-VEGF inhibitors and ICI ( P = .50). Median TTD for second-line therapies was 2.4 months (95% CI: 1.7-3.3) and 2.6 months (95% CI: 1.5-5.1) for anti-VEGF inhibitors and ICI, respectively (P = .87). In multivariate analyses, CP was significantly associated with survival. CONCLUSION Following first-line A/B treatment, there is no statistically significant difference in survival between ICI and anti-VEGF therapy, nor in time to treatment discontinuation. CP score remains an important prognostic tool.
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Affiliation(s)
- Paulina Marell
- Department of Medicine, Mayo Clinic, Rochester, MN, United States
| | | | - Jennifer Gile
- Department of Oncology, Mayo Clinic, Rochester, MN, United States
| | - Anina Peersen
- Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN, United States
| | - Priyanshi Shah
- Department of Oncology, Mayo Clinic, Rochester, MN, United States
| | - Hani Babiker
- Division of Hematology/Oncology, Department of Medicine, Mayo Clinic, Jacksonville, FL, United States
| | | | - Leslie Washburn
- Department of Oncology, Mayo Clinic, Rochester, MN, United States
| | - Rondell Graham
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
| | - Mark Truty
- Department of Surgery, Mayo Clinic, Rochester, MN, United States
| | | | | | - Zhaohui Jin
- Department of Oncology, Mayo Clinic, Rochester, MN, United States
| | - Aminah Jatoi
- Department of Oncology, Mayo Clinic, Rochester, MN, United States
| | | | - Mitesh Borad
- Division of Hematology/Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ, United States
| | - Tanios S Bekaii-Saab
- Division of Hematology/Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ, United States
| | - Amit Mahipal
- Department of Oncology, University Hospitals Seidman Cancer Center and Case Western Reserve University, Cleveland, OH, United States
| | - Fang-Shu Ou
- Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN, United States
| | - Nguyen H Tran
- Department of Oncology, Mayo Clinic, Rochester, MN, United States
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11
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Jahagirdar V, Rama K, Habeeb MF, Sharma M, Rao PN, Reddy DN, Singal AG, Kulkarni AV. Systemic Therapies for Hepatocellular Carcinoma in India. J Clin Exp Hepatol 2024; 14:101440. [PMID: 38975606 PMCID: PMC11225346 DOI: 10.1016/j.jceh.2024.101440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2024] [Accepted: 04/30/2024] [Indexed: 07/09/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality in India. This review explores the epidemiological trends and the landscape of systemic therapy for HCC in the Indian context, acknowledging the recent shift in etiology from viral hepatitis to lifestyle-associated factors. A comprehensive review of the literature was conducted, including data from the Global Cancer Observatory and the Indian Council of Medical Research, along with a critical analysis of various clinical trials. The article investigates systemic therapies in-depth, discussing their mechanisms, efficacy, and adaptation to Indian healthcare framework. Progression-free survival with a hazard ratio of ≤0.6 compared to sorafenib, overall survival of ∼16-19 months, and objective response rate of 20-30% are the defining thresholds for systemic therapy clinical trials. Systemic therapy for advanced HCC in India primarily involves the use of tyrosine kinase inhibitors such as sorafenib, lenvatinib, regorafenib, and cabozantinib, with sorafenib being the most commonly used drug for a long time. Monoclonal antibodies such as ramucirumab and bevacizumab and immune-checkpoint inhibitors, such as atezolizumab, nivolumab, and pembrolizumab, are expanding treatment horizons. Lenvatinib has emerged as a cost-effective alternative, and the combination of atezolizumab and bevacizumab has demonstrated superior outcomes in terms of overall survival and progression-free survival. Despite these advances, late-stage diagnosis and limited healthcare accessibility pose significant challenges, often relegating patients to palliative care. Addressing HCC in India demands an integrative approach that not only encompasses advancements in systemic therapy but also targets early detection and comprehensive care models. Future strategies should focus on enhancing awareness, screening for high-risk populations, and overcoming infrastructural disparities. Ensuring the judicious use of systemic therapies within the constraints of the Indian healthcare economy is crucial. Ultimately, a nuanced understanding of systemic therapeutic options and their optimal utilization will be pivotal in elevating the standard of HCC care in India.
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Affiliation(s)
- Vinay Jahagirdar
- Department of Internal Medicine, University of Missouri-Kansas City School of Medicine, Kansas City, USA
| | - Kaanthi Rama
- Gandhi Medical College & Hospital, Secunderabad, India
| | | | - Mithun Sharma
- Department of Hepatology, AIG Hospitals, Hyderabad, India
| | - Padaki N. Rao
- Department of Hepatology, AIG Hospitals, Hyderabad, India
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12
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Adhoute X, Gonzalez A, Levi-Strauss T, Mineur L, Pénaranda G, Sellier F, Toullec C, Pietri O, Castellani P, Tran A, Perrier H, Bourliere M, Anty R. Outcomes and safety of atezolizumab plus bevacizumab in the treatment of hepatocellular carcinoma: treatment prognosis and comparison with tyrosine kinase inhibitors in a French multicenter matched real-life study. Eur J Gastroenterol Hepatol 2024; 36:1329-1339. [PMID: 39083056 DOI: 10.1097/meg.0000000000002830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/27/2024]
Abstract
BACKGROUND AND AIMS The combination of atezolizumab plus bevacizumab (Atz/Bev) has radically changed the treatment strategy for advanced hepatocellular carcinoma (HCC) but raises questions. Our objectives were to determine survival outcomes and safety in a real-life multicenter French cohort, to investigate the on-treatment prognostic value of the bioinflammatory RECA score, and to perform a matched comparison with patients who previously received tyrosine kinase inhibitors (TKIs). METHODOLOGY A retrospective analysis of 109 consecutive patients enrolled from September 2020 to January 2023 and a post matched comparison with a TKI cohort ( n = 79) by the propensity score matching method. RESULTS The Atz/Bev population was mainly nonviral disease patients (69%) with Child-Pugh grade A (90%), performance status 0/1 (90%), and Barcelona Clinic Liver Cancer stage B (38%) or stage C (62%) classification. After a median follow-up of 6.5 months (3.6-11.7), overall survival (OS) was 13.0 (5.1-28.7) months. OS was independently associated with metastasis, increased alkaline phosphatase, and serum bilirubin levels. Treatment-related adverse events were reported in 78% of patients, mostly grade 1 or 2. The RECA score clearly revealed two different prognosis groups after three cycles. No difference in OS was observed after matching between sequential treatment with TKIs and Atz/Bev. CONCLUSION This real-life study highlights the importance of liver function when using Atz/Bev combination and the necessity of identifying predictive markers of response to HCC therapies. Our findings suggest a change in practices, with a marked proportion of intermediate stages, and support the on-treatment prognostic value of an inflammatory score.
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Affiliation(s)
- Xavier Adhoute
- Department of Gastroenterology and Hepatology, Hôpital Saint-Joseph, Marseille
| | - Alexia Gonzalez
- Department of Gastroenterology and Hepatology, Hôpital Saint-Joseph, Marseille
| | - Thomas Levi-Strauss
- Department of Gastroenterology and Hepatology, Hôpital Universitaire de l'Archet, Nice
| | - Laurent Mineur
- Department of Oncology, Institut Sainte-Catherine, Avignon
| | | | - Floriane Sellier
- Department of Gastroenterology and Hepatology, Hôpital Saint-Joseph, Marseille
| | | | - Olivia Pietri
- Department of Gastroenterology and Hepatology, Hôpital Saint-Joseph, Marseille
| | - Paul Castellani
- Department of Gastroenterology and Hepatology, Hôpital Saint-Joseph, Marseille
| | - Albert Tran
- Department of Gastroenterology and Hepatology, Hôpital Universitaire de l'Archet, Nice
| | - Hervé Perrier
- Department of Gastroenterology and Hepatology, Hôpital Saint-Joseph, Marseille
| | - Marc Bourliere
- Department of Gastroenterology and Hepatology, Hôpital Saint-Joseph, Marseille
| | - Rodolphe Anty
- Department of Gastroenterology and Hepatology, Hôpital Universitaire de l'Archet, Nice
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13
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Kaplan DE, Tan R, Xiang C, Mu F, Hernandez S, Ogale S, Li J, Lin Y, Shi L, Singal AG. Overall Survival in Real-World Patients with Unresectable Hepatocellular Carcinoma Receiving Atezolizumab Plus Bevacizumab Versus Sorafenib or Lenvatinib as First-Line Therapy: Findings from the National Veterans Health Administration Database. Cancers (Basel) 2024; 16:3508. [PMID: 39456602 PMCID: PMC11506031 DOI: 10.3390/cancers16203508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 09/27/2024] [Accepted: 10/10/2024] [Indexed: 10/28/2024] Open
Abstract
Background/Objectives: This study evaluated comparative overall survival (OS) of United States veterans with unresectable hepatocellular carcinoma (uHCC) receiving first-line (1L) atezolizumab plus bevacizumab vs. sorafenib or lenvatinib, overall and across racial and ethnic groups. Methods: In this retrospective study, patients with uHCC who initiated atezolizumab plus bevacizumab (post-2020) or sorafenib or lenvatinib (post-2018) were identified from the Veterans Health Administration National Corporate Data Warehouse (1 January 2017-31 December 2022). Patient characteristics were evaluated in the year prior to 1L treatment initiation. Kaplan-Meier and multivariable Cox regression methods were used to compare OS starting from treatment between cohorts, both overall and by race and ethnicity. Results: Among the 1874 patients included, 405 (21.6%) received 1L atezolizumab plus bevacizumab, 1016 (54.2%) received sorafenib, and 453 (24.2%) received lenvatinib, with a median follow-up time of 8.5, 7.6, and 8.2 months, respectively. Overall, patients receiving atezolizumab plus bevacizumab had longer unadjusted median OS (12.8 [95% CI: 10.6, 17.1] months) than patients receiving sorafenib (8.0 [7.1, 8.6] months) or lenvatinib (9.5 [7.8, 11.4] months; both log-rank p < 0.001). After adjustment, atezolizumab plus bevacizumab was associated with a reduced risk of death by 30% vs. sorafenib (adjusted HR: 0.70 [95% CI: 0.60, 0.82]) and by 26% vs. lenvatinib (0.74 [0.62, 0.88]; both p < 0.001). OS trends in the White, Black, and Hispanic patient cohorts were consistent with that of the overall population. Conclusions: Atezolizumab plus bevacizumab was associated with improved survival outcomes compared with sorafenib and lenvatinib in patients with uHCC, both overall and across racial and ethnic subgroups.
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Affiliation(s)
- David E. Kaplan
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Gastroenterology Section, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA 19104, USA
| | - Ruoding Tan
- Genentech, South San Francisco, CA 94080, USA; (R.T.); (S.H.); (S.O.)
| | - Cheryl Xiang
- Analysis Group Inc., Boston, MA 02199, USA; (C.X.); (F.M.); (J.L.)
| | - Fan Mu
- Analysis Group Inc., Boston, MA 02199, USA; (C.X.); (F.M.); (J.L.)
| | - Sairy Hernandez
- Genentech, South San Francisco, CA 94080, USA; (R.T.); (S.H.); (S.O.)
| | - Sarika Ogale
- Genentech, South San Francisco, CA 94080, USA; (R.T.); (S.H.); (S.O.)
| | - Jiayang Li
- Analysis Group Inc., Boston, MA 02199, USA; (C.X.); (F.M.); (J.L.)
| | - Yilu Lin
- Department of Health Policy and Management, Tulane University, New Orleans, LA 70118, USA; (Y.L.); (L.S.)
- New Orleans VA Medical Center, New Orleans, LA 70119, USA
| | - Lizheng Shi
- Department of Health Policy and Management, Tulane University, New Orleans, LA 70118, USA; (Y.L.); (L.S.)
- New Orleans VA Medical Center, New Orleans, LA 70119, USA
| | - Amit G. Singal
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA;
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14
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Chuma M, Uojima H, Toyoda H, Hiraoka A, Arase Y, Atsukawa M, Itokawa N, Okubo T, Tada T, Numata K, Morimoto M, Sugimori M, Nozaki A, Iwasaki S, Yasuda S, Koshiyama Y, Mishima Y, Tsuruya K, Tokoro C, Miura Y, Hidaka H, Kumada T, Kusano C, Kagawa T, Maeda S. Clinical significance of circulating biomarkers of immune-checkpoint molecules with atezolizumab plus bevacizumab therapy in unresectable hepatocellular carcinoma. Hepatol Int 2024; 18:1472-1485. [PMID: 38963640 DOI: 10.1007/s12072-024-10680-8] [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: 01/02/2024] [Accepted: 04/06/2024] [Indexed: 07/05/2024]
Abstract
BACKGROUND The aims of this study were to identify clinically significant biomarkers of a response to atezolizumab plus bevacizumab (ATZ + BV) therapy and to develop target strategies against unresectable hepatocellular carcinoma (u-HCC). METHOD We first investigated the potential of circulating tumor DNA (ctDNA) to serve as a biomarker for predicting the therapeutic outcome in 24 u-HCC patients treated with ATZ + BV therapy. Next, we analyzed levels of immune-related cytokines in blood samples from 134 u-HCC patients who received ATZ + BV. For this, serum immune-related molecules or cancer-immune cycle-related molecules that have been reported in HCC patient sera, namely CD274, LAG-3, CCL2, 4, 5, CXCL1, 9, 10, 12, 13, CX3CL1, CCR5, IFNγ and IL-6, 8 were measured using enzyme-linked immunosorbent assay. RESULTS More than 1% of variant read frequency (VRF) mutations were found in TP53, APC, PIK3CA and VHL, although with no correlation with treatment response. Among the 15 cytokines evaluated, CXCL9 and LAG-3 levels were significantly different between patients with objective response (OR), stable disease (SD), and progressive disease (PD) following ATZ + BV treatment. Receiver-operating characteristic curve analyses of CXCL9 (cut-off value: 419.1 pg/ml) and LAG-3 (cut-off value: 3736.3 pg/ml) indicated areas of 0.779 and 0.697, respectively, for differentiating PD from non-PD and OR from non-OR. In multivariate analysis of progression-free survival (PFS) and overall survival (OS), high serum CXCL9 (hazard ratio (HR) and 95% confidence interval (CI): 0.412 (0.251-0.677) (p = 0.0005) for PFS and 0.252 (0.125-0.508) (p = 0.0001) for OS), and low serum LAG-3 (HR and 95% CI 0.419 (0.249-0.705) (p = 0.0011) for PFS and 0.294 (0.140-0.617) (p = 0.0012) for OS) were independent positive predictive factors. CONCLUSION Although, as far as we examined, no ctDNA mutations in blood were found to be related to ATZ + BV treatment efficacy, serum CXCL9 and LAG-3 levels, which are related to the cancer-immune cycle, were associated with treatment efficacy and could be predictive markers of the efficacy of ATZ + BV treatment in HCC patients.
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Affiliation(s)
- Makoto Chuma
- Gastroenterological Center, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama, Kanagawa, Japan.
| | - Haruki Uojima
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Atsushi Hiraoka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan
| | - Yoshitake Arase
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Masanori Atsukawa
- Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Hospital, Tokyo, Japan
| | - Norio Itokawa
- Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Hospital, Tokyo, Japan
| | - Tomomi Okubo
- Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Japan
| | - Toshifumi Tada
- Department of Gastroenterology, Himeji Red Cross Hospital, Himeji, Japan
| | - Kazushi Numata
- Gastroenterological Center, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama, Kanagawa, Japan
| | - Manabu Morimoto
- Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Center Hospital, Yokohama, Japan
| | - Makoto Sugimori
- Gastroenterological Center, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama, Kanagawa, Japan
| | - Akito Nozaki
- Gastroenterological Center, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama, Kanagawa, Japan
| | - Shuichiro Iwasaki
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Japan
| | - Satoshi Yasuda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Yuichi Koshiyama
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Yusuke Mishima
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Kota Tsuruya
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Chikako Tokoro
- Division of Gastroenterology, Saiseikai Yokohamashi-Nanbu Hospital, Yokohama, Japan
| | - Yuki Miura
- Gastroenterology Division, Hadano Red Cross Hospital, Hadano, Japan
| | - Hisashi Hidaka
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Japan
| | - Takashi Kumada
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
- Faculty of Nursing, Gifu Kyoritsu University, Ogaki, Japan
| | - Chika Kusano
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Japan
| | - Tatehiro Kagawa
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Shin Maeda
- Department of Gastroenterology, Yokohama City University Hospital, Yokohama, Japan
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15
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Kulkarni AV, Kumaraswamy P, Menon B, Sekaran A, Rambhatla A, Iyengar S, Alla M, Venishetty S, Ramachandra SK, Premkumar GV, Sharma M, Rao PN, Reddy DN, Singal AG. Downstaging with atezolizumab-bevacizumab: a case series. JOURNAL OF LIVER CANCER 2024; 24:224-233. [PMID: 38797993 PMCID: PMC11449572 DOI: 10.17998/jlc.2024.05.12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 05/10/2024] [Accepted: 05/12/2024] [Indexed: 05/29/2024]
Abstract
BACKGROUNDS/AIMS Hepatocellular carcinoma (HCC) is generally diagnosed at an advanced stage, which limits curative treatment options for these patients. Locoregional therapy (LRT) is the standard approach to bridge and downstage unresectable HCC for liver transplantation (LT). Atezolizumab-bevacizumab (atezo-bev) can induce objective responses in nearly one-third of patients; however, the role and outcomes of downstaging using atezo-bev remains unknown. METHODS In this retrospective single-center study, we included consecutive patients between November 2020 and August 2023, who received atezo-bev with or without LRT and were subsequently considered for resection/LT after downstaging. RESULTS Of the 115 patients who received atezo-bev, 12 patients (10.4%) achieved complete or partial response and were willing to undergo LT; they (age, 58.5 years; women, 17%; Barcelona Clinic Liver Cancer stage system B/C, 5/7) had received 3-12 cycles of atezo- bev, and four of them had received prior LRT. Three patients died before LT, while three were awaiting LT. Six patients underwent curative therapies: four underwent living donor LT after a median of 79.5 days (range, 54-114) following the last atezo-bev dose, one underwent deceased donor LT 38 days after the last dose, and one underwent resection. All but one patient had complete pathologic response with no viable HCC. Three patients experienced wound healing complications, and one required re-exploration and succumbed to sepsis. After a median follow-up of 10 months (range, 4-30), none of the alive patients developed HCC recurrence or graft rejection. CONCLUSIONS Surgical therapy, including LT, is possible after atezo-bev therapy in well-selected patients after downstaging.
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Affiliation(s)
| | | | | | | | - Anuhya Rambhatla
- Department of Liver Transplant Anaesthesia, AIG Hospitals, Hyderabad, India
| | - Sowmya Iyengar
- Department of Hepatology, AIG Hospitals, Hyderabad, India
| | - Manasa Alla
- Department of Hepatology, AIG Hospitals, Hyderabad, India
| | | | | | - Giri V. Premkumar
- Department of Liver Transplant Anaesthesia, AIG Hospitals, Hyderabad, India
| | - Mithun Sharma
- Department of Hepatology, AIG Hospitals, Hyderabad, India
| | | | | | - Amit G. Singal
- Department of Medicine, UT Southwestern Medical Centre, Dallas, TX, USA
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16
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Lee CL, Freeman M, Burak KW, Moffat GT, O’Donnell CDJ, Ding PQ, Lyubetska H, Meyers BM, Gordon V, Kosyachkova E, Bucur R, Cheung WY, Knox JJ, Tam VC. Real-World Outcomes of Atezolizumab with Bevacizumab Treatment in Hepatocellular Carcinoma Patients: Effectiveness, Esophagogastroduodenoscopy Utilization and Bleeding Complications. Cancers (Basel) 2024; 16:2878. [PMID: 39199649 PMCID: PMC11352899 DOI: 10.3390/cancers16162878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 08/15/2024] [Accepted: 08/17/2024] [Indexed: 09/01/2024] Open
Abstract
The IMbrave150 trial established atezolizumab with bevacizumab (A+B) as standard care for hepatocellular carcinoma (HCC), recommending an esophagogastroduodenoscopy (EGD) within 6 months of treatment initiation to prevent bleeding from esophagogastric varices. The necessity of mandatory EGD for all patients remains unclear. We retrospectively analyzed 112 HCC patients treated with A+B at five Canadian cancer centers from 1 July 2020 to 31 August 2022. A+B was the first-line therapy for 90% of patients, with median overall survival at 20.3 months and progression-free survival at 9.6 months. There was no survival difference between patients with bleeding and those without. Before A+B, 71% (n = 79) of patients underwent an EGD within 6 months, revealing varices in 41% (n = 32) and requiring intervention in 19% (n = 15). The overall bleeding rate was 15% (n = 17), with GI-specific bleeding occurring in 5% (n = 17). In the EGD group, GI-specific bleeding was 6% (n = 5) while in the non-EGD group, it was 3% (n = 1). Non-GI bleeding was observed in 10% (n = 11) of patients. Outcomes for HCC patients treated with A+B in Canada were comparable to IMbrave150. There was no increase in GI bleeding in patients without pre-treatment EGD, possibly supporting a selective EGD approach.
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Affiliation(s)
- Cha Len Lee
- Princess Margaret Cancer Center, University of Toronto, Toronto, ON M5G1Z5, Canada (J.J.K.)
| | - Mark Freeman
- Tom Baker Cancer Center, University of Calgary, Calgary, AB T2N4N2, Canada (V.C.T.)
| | - Kelly W. Burak
- Liver Unit, Divisions of Gastroenterology & Hepatology and Transplant Medicine, Departments of Medicine and Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N4N2, Canada;
| | - Gordon T. Moffat
- Princess Margaret Cancer Center, University of Toronto, Toronto, ON M5G1Z5, Canada (J.J.K.)
| | - Conor D. J. O’Donnell
- Juravinski Cancer Center, Escarpment Cancer Research Institute, McMaster University, Hamilton, ON L8S4L8, Canada
| | - Philip Q. Ding
- Tom Baker Cancer Center, University of Calgary, Calgary, AB T2N4N2, Canada (V.C.T.)
| | - Hanna Lyubetska
- CancerCare Manitoba, University of Manitoba, Winnipeg, MB R3A1R9, Canada
| | - Brandon M. Meyers
- Juravinski Cancer Center, Escarpment Cancer Research Institute, McMaster University, Hamilton, ON L8S4L8, Canada
| | - Vallerie Gordon
- CancerCare Manitoba, University of Manitoba, Winnipeg, MB R3A1R9, Canada
| | - Ekaterina Kosyachkova
- Princess Margaret Cancer Center, University of Toronto, Toronto, ON M5G1Z5, Canada (J.J.K.)
| | - Roxana Bucur
- Princess Margaret Cancer Center, University of Toronto, Toronto, ON M5G1Z5, Canada (J.J.K.)
| | - Winson Y. Cheung
- Tom Baker Cancer Center, University of Calgary, Calgary, AB T2N4N2, Canada (V.C.T.)
| | - Jennifer J. Knox
- Princess Margaret Cancer Center, University of Toronto, Toronto, ON M5G1Z5, Canada (J.J.K.)
| | - Vincent C. Tam
- Tom Baker Cancer Center, University of Calgary, Calgary, AB T2N4N2, Canada (V.C.T.)
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17
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Rose S, Ashraf MU, Premkumar M. Adjuvant therapy in hepatocellular carcinoma: the IMbrave050 trial. Lancet 2024; 404:656-657. [PMID: 39153814 DOI: 10.1016/s0140-6736(24)00800-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 04/12/2024] [Indexed: 08/19/2024]
Affiliation(s)
- Sweta Rose
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Muhammad Uwais Ashraf
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Madhumita Premkumar
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India.
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18
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Shi Y, Taherifard E, Saeed A, Saeed A. MASLD-Related HCC: A Comprehensive Review of the Trends, Pathophysiology, Tumor Microenvironment, Surveillance, and Treatment Options. Curr Issues Mol Biol 2024; 46:5965-5983. [PMID: 38921027 PMCID: PMC11202630 DOI: 10.3390/cimb46060356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Revised: 06/07/2024] [Accepted: 06/11/2024] [Indexed: 06/27/2024] Open
Abstract
Hepatocellular carcinoma (HCC) represents a significant burden on global healthcare systems due to its considerable incidence and mortality rates. Recent trends indicate an increase in the worldwide incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) and a shift in the etiology of HCC, with MASLD replacing the hepatitis B virus as the primary contributor to new cases of HCC. MASLD-related HCC exhibits distinct characteristics compared to viral HCC, including unique immune cell profiles resulting in an overall more immunosuppressive or exhausted tumor microenvironment. Furthermore, MASLD-related HCC is frequently identified in older age groups and among individuals with cardiometabolic comorbidities. Additionally, a greater percentage of MASLD-related HCC cases occur in noncirrhotic patients compared to those with viral etiologies, hindering early detection. However, the current clinical practice guidelines lack specific recommendations for the screening of HCC in MASLD patients. The evolving landscape of HCC management offers a spectrum of therapeutic options, ranging from surgical interventions and locoregional therapies to systemic treatments, for patients across various stages of the disease. Despite ongoing debates, the current evidence does not support differences in optimal treatment modalities based on etiology. In this study, we aimed to provide a comprehensive overview of the current literature on the trends, characteristics, clinical implications, and treatment modalities for MASLD-related HCC.
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Affiliation(s)
- Yuming Shi
- Department of Medicine, Division of Hematology & Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA 15232, USA; (Y.S.); (E.T.)
| | - Erfan Taherifard
- Department of Medicine, Division of Hematology & Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA 15232, USA; (Y.S.); (E.T.)
| | - Ali Saeed
- Department of Medicine, Ochsner Lafayette General Medical Center, Lafayette, LA 70503, USA;
| | - Anwaar Saeed
- Department of Medicine, Division of Hematology & Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA 15232, USA; (Y.S.); (E.T.)
- UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA
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19
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Ruli TM, Pollack ED, Lodh A, Evers CD, Price CA, Shoreibah M. Immune Checkpoint Inhibitors in Hepatocellular Carcinoma and Their Hepatic-Related Side Effects: A Review. Cancers (Basel) 2024; 16:2042. [PMID: 38893164 PMCID: PMC11171072 DOI: 10.3390/cancers16112042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 05/24/2024] [Accepted: 05/27/2024] [Indexed: 06/21/2024] Open
Abstract
Primary liver cancer is one of the leading causes of cancer mortality worldwide, with hepatocellular carcinoma (HCC) being the most prevalent type of liver cancer. The prognosis of patients with advanced, unresectable HCC has historically been poor. However, with the emergence of immunotherapy, specifically immune checkpoint inhibitors (ICIs), there is reason for optimism. Nevertheless, ICIs do not come without risk, especially when administered in patients with HCC, given their potential underlying poor hepatic reserve. Given their novelty in the management of HCC, there are few studies to date specifically investigating ICI-related side effects on the liver in patients with underlying HCC. This review will serve as a guide for clinicians on ICIs' role in the management of HCC and their potential side effect profile. There will be a discussion on ICI-related hepatotoxicity, the potential for hepatitis B and C reactivation with ICI use, the potential for the development of autoimmune hepatitis with ICI use, and the risk of gastrointestinal bleeding with ICI use. As ICIs become more commonplace as a treatment option in patients with advanced HCC, it is imperative that clinicians not only understand the mechanism of action of such agents but also understand and are able to identify hepatic-related side effects.
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Affiliation(s)
- Thomas M. Ruli
- Internal Medicine Residency Program, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (E.D.P.); (A.L.); (C.A.P.)
| | - Ethan D. Pollack
- Internal Medicine Residency Program, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (E.D.P.); (A.L.); (C.A.P.)
| | - Atul Lodh
- Internal Medicine Residency Program, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (E.D.P.); (A.L.); (C.A.P.)
| | - Charles D. Evers
- Internal Medicine Residency Program, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (E.D.P.); (A.L.); (C.A.P.)
| | - Christopher A. Price
- Internal Medicine Residency Program, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (E.D.P.); (A.L.); (C.A.P.)
| | - Mohamed Shoreibah
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35233, USA;
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20
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Arima S, Kanda T, Totsuka M, Honda M, Kanezawa S, Sasaki-Tanaka R, Matsumoto N, Masuzaki R, Yamagami H, Ogawa M, Kogure H. Elderly patient with unresectable advanced‑stage hepatocellular carcinoma who received atezolizumab plus bevacizumab and achieved a complete response: A case report. MEDICINE INTERNATIONAL 2024; 4:23. [PMID: 38595809 PMCID: PMC11002835 DOI: 10.3892/mi.2024.147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Accepted: 03/13/2024] [Indexed: 04/11/2024]
Abstract
Hepatocellular carcinoma (HCC) is a common malignancy with a poor prognosis, particularly in patients with advanced-stage disease, elderly individuals and/or in those with poor liver function. Immune checkpoint inhibitor-containing therapies, such as atezolizumab, an anti-programmed death ligand-1 monoclonal antibody, plus bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody, may be effective and safe therapeutic options for elderly patients with advanced-stage HCC. The present study reports the case of a male patient his 80s who consumed alcohol with unresectable advanced-stage HCC who received combination therapy comprising atezolizumab plus bevacizumab for 6 months. The patient achieved a complete response despite the discontinuation of treatment due to nephrotoxicity. It is critical for patients with HCC and a Child-Pugh A grade to continue therapy for HCC, even if they are older. The development of more effective therapies is required for patients with advanced-stage HCC with a worse liver function than those with a Child-Pugh A grade. The case described in the present study demonstrates the need for obtaining further evidence regarding the efficacy and safety of the combination therapy including atezolizumab plus bevacizumab for elderly patients with advanced-stage HCC.
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Affiliation(s)
- Shuhei Arima
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo 137-8610, Japan
| | - Tatsuo Kanda
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo 137-8610, Japan
| | - Mai Totsuka
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo 137-8610, Japan
| | - Masayuki Honda
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo 137-8610, Japan
| | - Shini Kanezawa
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo 137-8610, Japan
| | - Reina Sasaki-Tanaka
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo 137-8610, Japan
| | - Naoki Matsumoto
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo 137-8610, Japan
| | - Ryota Masuzaki
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo 137-8610, Japan
| | - Hiroaki Yamagami
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo 137-8610, Japan
| | - Masahiro Ogawa
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo 137-8610, Japan
| | - Hirofumi Kogure
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo 137-8610, Japan
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21
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Zhang R, Wang F, You Z, Deng D, He J, Yan W, Quan J, Wang J, Yan S. Approved immune checkpoint inhibitors in hepatocellular carcinoma: a large-scale meta-analysis and systematic review. J Cancer Res Clin Oncol 2024; 150:82. [PMID: 38319412 PMCID: PMC10847200 DOI: 10.1007/s00432-023-05539-8] [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: 07/18/2023] [Accepted: 11/20/2023] [Indexed: 02/07/2024]
Abstract
A meta-analysis was performed to assess the benefits and safety profile of approved immune checkpoint inhibitors in hepatocellular carcinoma patients. Eligible studies were searched from Cochrane, Embase, and PubMed databases based on a well-established strategy. Following the exclusion of ineligible studies, 12 studies were included in this meta-analysis. Compared with control group, immune checkpoint inhibitors were associated with improved ORR (OR 3.03, 95% CI 2.26-4.05, P < 0.00001), SD (OR 0.77, 95% CI 0.62-0.95, P = 0.02), OS (HR 0.75, 95% CI 0.68-0.83, P < 0.00001), and PFS (HR 0.74, 95% CI 0.63-0.87, P < 0.0003). However, no significant differences were observed in DCR (OR 1.33, 95% CI 0.97-1.81, P = 0.07), PD (OR 0.90, 95% CI 0.67-1.21, P = 0.48), and all caused any-grade adverse events (OR 1.22, 95% CI 0.62-2.39, P = 0. 57), all caused ≥ grade 3 adverse events (OR 1.10, 95% CI 0.97-1.25, P = 0.14), treatment-related any-grade adverse events (OR 1.13, 95% CI 0.55-2.32, P = 0.73), and treatment-related ≥ grade 3 events (OR 0.82, 95% CI 0.34-1.97, P = 0.65) between the two groups. After subgroup analysis conducted, patients in the immune checkpoint inhibitor group compared with targeted drug group showed significant improvements in OS (HR 0.74, 95% CI 0.66-0.84, P < 0.00001) and PFS (HR 0.75, 95% CI 0.61-0.91, P = 0.004). Immune checkpoint inhibitors have demonstrated peculiar benefits in the treatment of HCC with an acceptable safety profile. Compared to targeted drugs, immune checkpoint inhibitors still offer advantages in the treatment of hepatocellular carcinoma. However, there is still considerable room for further improvement.
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Affiliation(s)
- Ruyi Zhang
- Department of Clinical Laboratory, First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guizhou, 550001, China
- Center for Eugenics Research, First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, 550001, China
| | - Fang Wang
- Center for Eugenics Research, First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, 550001, China
| | - Zhiyu You
- Department of Clinical Laboratory, First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guizhou, 550001, China
| | - Dongyang Deng
- Center for Eugenics Research, First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, 550001, China
| | - Jiangyan He
- Center for Eugenics Research, First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, 550001, China
| | - Wentao Yan
- Department of Clinical Laboratory, First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guizhou, 550001, China
| | - Jian Quan
- Department of Clinical Laboratory, Anshun Hospital of Guizhou Aviation Industry Group, Guizhou, 561099, China
| | - Jing Wang
- Department of Orthopedic, Kunming Hospital of Chinese Medicine, Kunming, 650051, China
| | - Shujuan Yan
- Department of Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Tianhe District, No.9 Jinsui Road, Zhujiang New Town, Guangzhou, 510623, People's Republic of China.
- Department of Prenatal Diagnosis Center, Guizhou Provincial People's Hospital, the Affiliated Hospital of Guizhou University, Guiyang, 550000, Guizhou Province, China.
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22
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Ruff SM, Pawlik TM. Emerging therapies targeting growth factors in hepatocellular carcinoma. Expert Opin Pharmacother 2024; 25:255-262. [PMID: 38591252 DOI: 10.1080/14656566.2024.2340714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2023] [Accepted: 03/01/2024] [Indexed: 04/10/2024]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) is a primary liver cancer that commonly arises in the background of chronic liver inflammation and/or cirrhosis. Chronic liver inflammation results in the production of different growth factors, remodeling of the microenvironment architecture into fibrosis, and eventually carcinogenesis. Overexpression of some growth factors has been associated with worse prognosis in patients with HCC. Targeted therapies against growth factors may disrupt cell signaling and the mechanisms that allow for cell survival (e.g. angiogenesis, proliferation, metastases). AREAS COVERED We herein review potential growth factor targets of HCC and the limited research that exists regarding targeted therapy of these ligands and their receptors. We performed an extensive literature search to investigate preclinical studies, clinical research, and clinical trials. EXPERT OPINION Systemic therapy for patients with HCC is continuing to evolve. Anti-angiogenic therapy holds the most promise among targeted therapy for growth factors among patients with HCC. Improving our understanding of growth factors in HCC will hopefully lead to the development of new targeted therapies and strategies for combination therapies with immune checkpoint inhibitors.
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Affiliation(s)
- Samantha M Ruff
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Timothy M Pawlik
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
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