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Fortuny M, García-Calonge M, Arrabal Ó, Sanduzzi-Zamparelli M, Castaño-García A, Cascos E, Mesa A, Piedra-Cerezal AM, Llarch N, Iserte G, Campos M, González M, Marsal A, Lorca R, Rodríguez M, Torres F, Varela M, Reig M. Cardiological adverse events in hepatocellular carcinoma patients receiving immunotherapy: Influence of comorbidities and clinical outcomes. Eur J Cancer 2025; 221:115404. [PMID: 40245453 DOI: 10.1016/j.ejca.2025.115404] [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: 01/22/2025] [Revised: 03/21/2025] [Accepted: 03/28/2025] [Indexed: 04/19/2025]
Abstract
INTRODUCTION Immunotherapy-based combinations have revolutionized the first-line treatment for advanced hepatocellular carcinoma (HCC), improving overall survival (OS). However, these therapies are associated with adverse events (AEs), particularly cardiological complications and major adverse cardiovascular events (MACE), which may adversely affect outcomes. The influence of comorbid conditions such as arterial hypertension (AHT) and type 2 diabetes mellitus (T2DM) on the incidence and prognosis of cardiological AEs in HCC patients remains understudied. METHODS This retrospective study included 109 HCC patients treated with atezolizumab-bevacizumab, tremelimumab-durvalumab, or durvalumab as first-line therapy at two Spanish medical centers from 2017-2023. Patients were stratified by comorbidities, AE incidence, and cardiological risk (CARDIOSOR scale). The primary endpoints were the incidence of treatment-modifying AEs and MACE, and their association with survival. RESULTS Among the cohort, 50.5 % experienced AEs of special interest (AESI), with 34 % considered immune-related (irAE). MACE occurred in 7.3 % of patients, including myocarditis (3.7 %). The CARDIOSOR scale identified a higher risk of MACE in patients with AHT, T2DM, or both (OR: 5.07, p = 0.034). Early cardiological AEs were independently associated with worse OS (HR: 3.38, p = 0.04). Patients with both AHT and T2DM exhibited higher rates of MACE (16.7 %) and treatment discontinuation (25.9 %). The CARDIOSOR scale effectively stratified patients into high-risk groups, correlating with increased MACE rates and poor survival outcomes. CONCLUSIONS Comorbid conditions, particularly AHT and T2DM, amplify the risk of MACE and influence treatment discontinuation. The CARDIOSOR scale is a valuable tool for personalized risk assessment, guiding tailored therapeutic strategies. Integrating cardiovascular risk management into HCC care is crucial for optimizing both oncological and cardiovascular outcomes.
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Affiliation(s)
- Marta Fortuny
- Barcelona Clinic Liver Cancer (BCLC) Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain; Liver Oncology Unit, Liver Unit, Hospital Clinic de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain; Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Marta García-Calonge
- Servicio de Digestivo, Sección de Hepatología, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Óscar Arrabal
- Biostatistics Unit, Medical School, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Marco Sanduzzi-Zamparelli
- Barcelona Clinic Liver Cancer (BCLC) Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain; Liver Oncology Unit, Liver Unit, Hospital Clinic de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Andrés Castaño-García
- Servicio de Digestivo, Sección de Hepatología, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Enric Cascos
- Cardiology Department, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Alicia Mesa
- Radiodiagnostic Department, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Ana María Piedra-Cerezal
- Servicio de Digestivo, Sección de Hepatología, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Neus Llarch
- Barcelona Clinic Liver Cancer (BCLC) Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain; Liver Oncology Unit, Liver Unit, Hospital Clinic de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain; Universitat de Barcelona, Barcelona, Spain
| | - Gemma Iserte
- Barcelona Clinic Liver Cancer (BCLC) Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain; Liver Oncology Unit, Liver Unit, Hospital Clinic de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Marta Campos
- Barcelona Clinic Liver Cancer (BCLC) Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain; Liver Oncology Unit, Liver Unit, Hospital Clinic de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Melina González
- Liver Oncology Unit, Liver Unit, Hospital Clinic de Barcelona, Barcelona, Spain
| | - Aida Marsal
- Barcelona Clinic Liver Cancer (BCLC) Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain; Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Rebeca Lorca
- Área del Corazón, Servicio de Cardiología, Hospital Universitario Central de Asturias, Spain; Universidad de Oviedo, Oviedo, Asturias, Spain; IUOPA, ISPA, FINBA, Oviedo, Spain; Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORs), Madrid, Spain
| | - Manuel Rodríguez
- Servicio de Digestivo, Sección de Hepatología, Hospital Universitario Central de Asturias, Oviedo, Spain; Universidad de Oviedo, Oviedo, Asturias, Spain; IUOPA, ISPA, FINBA, Oviedo, Spain
| | - Ferran Torres
- Biostatistics Unit, Medical School, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - María Varela
- Servicio de Digestivo, Sección de Hepatología, Hospital Universitario Central de Asturias, Oviedo, Spain; Universidad de Oviedo, Oviedo, Asturias, Spain; IUOPA, ISPA, FINBA, Oviedo, Spain.
| | - María Reig
- Barcelona Clinic Liver Cancer (BCLC) Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain; Liver Oncology Unit, Liver Unit, Hospital Clinic de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain; Universitat de Barcelona, Barcelona, Spain.
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Piscaglia F, Ikeda K, Cheng AL, Kudo M, Ikeda M, Breder V, Ryoo BY, Mody K, Ren M, Ramji Z, Sung MW. Association between treatment-emergent hypertension and survival with lenvatinib treatment for patients with hepatocellular carcinoma in the REFLECT study. Cancer 2024; 130:1281-1291. [PMID: 38261521 DOI: 10.1002/cncr.35185] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 11/13/2023] [Accepted: 11/17/2023] [Indexed: 01/25/2024]
Abstract
BACKGROUND Lenvatinib is approved as a first-line treatment for patients with unresectable and/or recurrent hepatocellular carcinoma (HCC). Lenvatinib achieved promising clinical benefits in REFLECT but was associated with clinically significant treatment-emergent hypertension (CSTE-HTN, a grouped term), a common class effect of tyrosine kinase inhibitors. This post hoc analysis assessed the impact of CSTE-HTN on the efficacy and safety of lenvatinib in HCC. METHODS Patients from REFLECT who received lenvatinib (n = 476) were stratified according to CSTE-HTN. Tumors were assessed by mRECIST. Overall survival (OS) and progression-free survival (PFS) were evaluated using landmark analyses at 4 and 8 weeks. RESULTS A total of 212 patients in the lenvatinib arm developed CSTE-HTN, and 264 did not. CSTE-HTN first occurred at 3.7 weeks (median); the worst grade CSTE-HTN occurred at 4.1 weeks (median). No patients had life-threatening CSTE-HTN and/or died due to CSTE-HTN. Median OS was numerically longer in patients with versus without CSTE-HTN (at 4 weeks: 16.3 vs. 11.6 months; hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.621-1.004; at 8 weeks: 13.5 vs. 11.6 months; HR, 0.87; 95% CI, 0.696-1.089). Median PFS was similar between patients with and without CSTE-HTN (at 4 weeks: 6.6 vs. 6.4 months; HR, 0.887; 95% CI, 0.680-1.157; at 8 weeks: 5.7 vs. 6.4 months; HR, 1.09; 95% CI, 0.84-1.41). Objective response rate was numerically higher in patients with (48.6%) versus without CSTE-HTN (34.5%). CONCLUSIONS In this retrospective analysis, CSTE-HTN was associated with improved OS but not PFS. CSTE-HTN did not impair the outcomes of patients with HCC treated with lenvatinib when detected early and managed appropriately.
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Affiliation(s)
- 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
| | | | - Ann-Lii Cheng
- National Taiwan University Hospital and National Taiwan University Cancer Center, Taipei, Taiwan
| | | | | | - Valery Breder
- N.N. Blokhin Russian Cancer Research Center, Moscow, Russia
| | - Baek-Yeol Ryoo
- Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | | | - Min Ren
- Eisai Inc, Nutley, New Jersey, USA
| | | | - Max W Sung
- Tisch Cancer Institute at Mount Sinai, New York, New York, USA
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Tutusaus A, Sanduzzi-Zamparelli M, Boix L, Rider P, Subías S, García de Frutos P, Colell A, Marí M, Reig M, Morales A. Induction of the Inflammasome Pathway by Tyrosine Kinase Inhibitors Provides an Actionable Therapeutic Target for Hepatocellular Carcinoma. Cancers (Basel) 2024; 16:1491. [PMID: 38672578 PMCID: PMC11048610 DOI: 10.3390/cancers16081491] [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: 02/27/2024] [Revised: 04/04/2024] [Accepted: 04/10/2024] [Indexed: 04/28/2024] Open
Abstract
During the last decade, tyrosine kinase inhibitors (TKIs) sorafenib and regorafenib have been standard systemic treatments for advanced hepatocellular carcinoma (HCC). Previous data associated sorafenib with inflammasome activation. However, the role of the inflammasome in sorafenib and regorafenib signaling has not been described in liver cancer patients. For this purpose, we analyzed inflammasome-related transcriptomic changes in a murine HCC model. Our data confirmed inflammasome activation after both TKI treatments, sharing a similar pattern of increased gene expression. According to human database results, transcriptional increase of inflammasome genes is associated with poorer prognosis for male liver cancer patients, suggesting a sex-dependent role for inflammasome activation in HCC therapy. In biopsies of HCC and its surrounding tissue, we detected durable increases in the inflammasome activation pattern after sorafenib or regorafenib treatment in male patients. Further supporting its involvement in sorafenib action, inflammasome inhibition (MCC950) enhanced sorafenib anticancer activity in experimental HCC models, while no direct in vitro effect was observed in HCC cell lines. Moreover, activated human THP-1 macrophages released IL-1β after sorafenib administration, while 3D Hep3B spheres displayed increased tumor growth after IL-1β addition, pointing to the liver microenvironment as a key player in inflammasome action. In summary, our results unveil the inflammasome pathway as an actionable target in sorafenib or regorafenib therapy and associate an inflammasome signature in HCC and surrounding tissue with TKI administration. Therefore, targeting inflammasome activation, principally in male patients, could help to overcome sorafenib or regorafenib resistance and enhance the efficacy of TKI treatments in HCC.
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Affiliation(s)
- Anna Tutusaus
- Department of Cell Death and Proliferation, IIBB-CSIC, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (A.T.); (P.R.); (P.G.d.F.); (A.C.); (M.M.)
- Barcelona Clinic Liver Cancer (BCLC) Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (M.S.-Z.); (L.B.)
| | - Marco Sanduzzi-Zamparelli
- Barcelona Clinic Liver Cancer (BCLC) Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (M.S.-Z.); (L.B.)
- Liver Unit, Hospital Clinic de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, CIBEREHD, ISCIII, 28029 Madrid, Spain
- Departament de Medicina, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain
| | - Loreto Boix
- Barcelona Clinic Liver Cancer (BCLC) Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (M.S.-Z.); (L.B.)
- Liver Unit, Hospital Clinic de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, CIBEREHD, ISCIII, 28029 Madrid, Spain
| | - Patricia Rider
- Department of Cell Death and Proliferation, IIBB-CSIC, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (A.T.); (P.R.); (P.G.d.F.); (A.C.); (M.M.)
- Departament de Biomedicina, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain
| | - Silvia Subías
- Department of Cell Death and Proliferation, IIBB-CSIC, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (A.T.); (P.R.); (P.G.d.F.); (A.C.); (M.M.)
| | - Pablo García de Frutos
- Department of Cell Death and Proliferation, IIBB-CSIC, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (A.T.); (P.R.); (P.G.d.F.); (A.C.); (M.M.)
- Unidad Asociada (IMIM), IIBB-CSIC, 08036 Barcelona, Spain
- CIBERCV, ISCIII, 28029 Madrid, Spain
| | - Anna Colell
- Department of Cell Death and Proliferation, IIBB-CSIC, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (A.T.); (P.R.); (P.G.d.F.); (A.C.); (M.M.)
- Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), ISCIII, 28029 Madrid, Spain
| | - Montserrat Marí
- Department of Cell Death and Proliferation, IIBB-CSIC, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (A.T.); (P.R.); (P.G.d.F.); (A.C.); (M.M.)
| | - María Reig
- Barcelona Clinic Liver Cancer (BCLC) Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (M.S.-Z.); (L.B.)
- Liver Unit, Hospital Clinic de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, CIBEREHD, ISCIII, 28029 Madrid, Spain
- Departament de Medicina, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain
| | - Albert Morales
- Department of Cell Death and Proliferation, IIBB-CSIC, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (A.T.); (P.R.); (P.G.d.F.); (A.C.); (M.M.)
- Barcelona Clinic Liver Cancer (BCLC) Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (M.S.-Z.); (L.B.)
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Fortuny M, Sanduzzi-Zamparelli M, Reig M. Systemic therapies in hepatocellular carcinoma: A revolution? United European Gastroenterol J 2024; 12:252-260. [PMID: 38267015 PMCID: PMC10954433 DOI: 10.1002/ueg2.12510] [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: 09/03/2023] [Accepted: 11/06/2023] [Indexed: 01/26/2024] Open
Abstract
The evolution in systemic therapies in hepatocellular carcinoma (HCC) signifies a strategy of high-cost, high-gain innovation that originated with sorafenib, despite its limited impact on tumor response. This strategic approach paved the way for the emergence of a second wave of the short-lived competitive advantage, exemplified by the incorporation of atezolizumab plus bevacizumab and tremelimumab plus durvalumab. In the context of safety concerns within the liver cancer domain, the IMBRAVE150 and HIMALAYA trials boldly incorporated bevacizumab and tremelimumab, respectively, demonstrating the continuation of the high-risk, high-reward innovation paradigm. This review delves into the strengths, weaknesses, opportunities, and threats analysis of systemic therapies in the field of HCC.
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Affiliation(s)
- Marta Fortuny
- Barcelona Clinic Liver Cancer (BCLC) Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Liver Oncology Unit, Liver Unit, Hospital Clinic de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Marco Sanduzzi-Zamparelli
- Barcelona Clinic Liver Cancer (BCLC) Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Liver Oncology Unit, Liver Unit, Hospital Clinic de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Maria Reig
- Barcelona Clinic Liver Cancer (BCLC) Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Liver Oncology Unit, Liver Unit, Hospital Clinic de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- Barcelona University, Barcelona, Spain
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Becht R, Kiełbowski K, Wasilewicz MP. New Opportunities in the Systemic Treatment of Hepatocellular Carcinoma-Today and Tomorrow. Int J Mol Sci 2024; 25:1456. [PMID: 38338736 PMCID: PMC10855889 DOI: 10.3390/ijms25031456] [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: 12/07/2023] [Revised: 01/22/2024] [Accepted: 01/23/2024] [Indexed: 02/12/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Liver cirrhosis, hepatitis B, hepatitis C, and non-alcoholic fatty liver disease represent major risk factors of HCC. Multiple different treatment options are available, depending on the Barcelona Clinic Liver Cancer (BCLC) algorithm. Systemic treatment is reserved for certain patients in stages B and C, who will not benefit from regional treatment methods. In the last fifteen years, the arsenal of available therapeutics has largely expanded, which improved treatment outcomes. Nevertheless, not all patients respond to these agents and novel combinations and drugs are needed. In this review, we aim to summarize the pathway of trials investigating the safety and efficacy of targeted therapeutics and immunotherapies since the introduction of sorafenib. Furthermore, we discuss the current evidence regarding resistance mechanisms and potential novel targets in the treatment of advanced HCC.
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Affiliation(s)
- Rafał Becht
- Department of Clinical Oncology, Chemotherapy and Cancer Immunotherapy, Pomeranian Medical University in Szczecin, 71-252 Szczecin, Poland; (R.B.); (K.K.)
| | - Kajetan Kiełbowski
- Department of Clinical Oncology, Chemotherapy and Cancer Immunotherapy, Pomeranian Medical University in Szczecin, 71-252 Szczecin, Poland; (R.B.); (K.K.)
| | - Michał P. Wasilewicz
- Liver Unit, Department of Gastroenterology, Pomeranian Medical University in Szczecin, 71-252 Szczecin, Poland
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Singal AG, Kudo M, Bruix J. Breakthroughs in Hepatocellular Carcinoma Therapies. Clin Gastroenterol Hepatol 2023; 21:2135-2149. [PMID: 36813012 PMCID: PMC10293061 DOI: 10.1016/j.cgh.2023.01.039] [Citation(s) in RCA: 60] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 12/22/2022] [Accepted: 01/23/2023] [Indexed: 02/24/2023]
Abstract
Several breakthroughs in hepatocellular carcinoma (HCC) therapy across tumor stages provide hope to improve its dismal prognosis. Although surgical and local ablative therapies have few significant changes in technique, an improved understanding of tumor biology has facilitated increase numbers of patients who are now eligible to undergo curative-intent procedures. Most notably, acceptable post-transplant outcomes can be achieved in well selected patients whose tumors are downstaged into Milan Criteria. Adjuvant therapy in patients at high risk of recurrence also significantly improves recurrence-free survival after resection or ablation. For patients with liver-localized disease who are not eligible for curative-intent procedures, transarterial chemoembolization (TACE) was historically the treatment modality of choice, regardless of tumor burden; however, there is now increased recognition of patients who are "TACE unsuitable" and may be better treated with systemic therapy. The greatest evolution in HCC treatment options has occurred with systemic therapy, where several new agents are now available in the first- and second-line setting, including immune checkpoint inhibitor combinations. Objective responses are observed in approximately 30% of patients and median survival is approaching 2 years. The availability of immune checkpoint inhibitors has renewed interest in combination therapies for earlier tumor stages, with several phase III trials ongoing. Considering increasing complexities of HCC care, requiring decisions between therapies delivered by different providers, multidisciplinary care is critical and is associated with improved clinical outcomes. In this review, we detail major breakthroughs in HCC therapy, how these breakthroughs can be applied in clinical practice, and remaining areas in need of further research.
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Affiliation(s)
- Amit G Singal
- Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, Texas.
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka Japan.
| | - Jordi Bruix
- Barcelona Clinic Liver Cancer Group, Liver Unit, August Pi i Sunyer Biomedical Research Institute, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Hospital Clinic, University of Barcelona, Barcelona, Spain.
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7
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Sapena V, Iavarone M, Boix L, Facchetti F, Guarino M, Sanduzzi Zamparelli M, Granito A, Samper E, Scartozzi M, Corominas J, Marisi G, Díaz A, Casadei-Gardini A, Gramantieri L, Lampertico P, Morisco F, Torres F, Bruix J, Reig M. Polymorphism AGT2 (rs4762) is involved in the development of dermatologic events: Proof-of-concept in hepatocellular carcinoma patients treated with sorafenib. World J Hepatol 2022; 14:1438-1458. [PMID: 36158918 PMCID: PMC9376774 DOI: 10.4254/wjh.v14.i7.1438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 01/24/2022] [Accepted: 07/06/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Dermatologic adverse events (DAEs) are associated with a better outcome in patients with hepatocellular carcinoma (HCC) irrespective of the therapeutic agent received. The exact mechanisms associated with the development of DAEs are unknown although several studies point to direct toxicity of tyrosine kinase inhibitors (TKIs) to the skin or an immune-mediated reaction triggered by the oncologic treatment. As is the case in other conditions, individual genetic variants may partially explain a higher risk of DAEs. AIM To evaluate the contribution of several gene variants to the risk of developing DAEs in HCC patients treated with TKIs. METHODS We first analyzed 27 single-nucleotide polymorphisms (SNPs) from 12 genes selected as potential predictors of adverse event (AE) development in HCC patients treated with sorafenib [Barcelona Clinic Liver Cancer 1 (BCLC1) cohort]. Three additional cohorts were analyzed for AGT1 (rs699) and AGT2 (rs4762) polymorphisms-initially identified as predictors of DAEs: BCLC2 (n = 79), Northern Italy (n = 221) and Naples (n = 69) cohorts, respectively. The relation between SNPs and DAEs and death were assessed by univariate and multivariate Cox regression models, and presented with hazard ratios and their 95% confidence intervals (95%CI). RESULTS The BCLC1 cohort showed that patients with arterial hypertension (AHT) (HR = 1.61; P value = 0.007) and/or AGT SNPs had an increased risk of DAEs. Thereafter, AGT2 (rs4762) AA genotype was found to be linked to a statistically significant increased probability of DAEs (HR = 5.97; P value = 0.0201, AA vs GG) in the Northern Italy cohort by multivariate analysis adjusted for BCLC stage, ECOG-PS, diabetes and AHT. The value of this genetic marker was externally validated in the cohort combining the BCLC1, BCLC2 and Naples cohorts [HR = 3.12 (95%CI: 1.2-8.14), P value = 0.0199, AGT2 (rs4762) AA vs AG genotype and HR = 2.73 (95%CI: 1.18-6.32) P value = 0.0188, AGT2 (rs4762) AA vs GG genotype]. None of the other gene variants tested were found to be associated with the risk of DAE development. CONCLUSION DAE development in HCC patients receiving TKIs could be explained by the AGT2 (rs4762) gene variant. If validated in other anti-oncogenic treatments, it might be considered a good prognosis marker.
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Affiliation(s)
- Víctor Sapena
- Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona 08036, Spain
- Universidad de Barcelona, Barcelona 08036, Spain
| | - Massimo Iavarone
- Division of Gastroenterology and Hepatology, Foundation Istituto di Ricovero e Cura a Carattere Scientifico di Natura Pubblica Ca' Granda Ospedale Maggiore Policlinico, Milano 20122, Italy
| | - Loreto Boix
- Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona 08036, Spain
| | - Floriana Facchetti
- Gastroenterology and Hepatology Unit, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico di Natura Pubblica Cà Granda Ospedale Maggiore Policlinico, University of Milan, Milan 20100, Italy
| | - Maria Guarino
- Department of Clinical Medicine and Surgery, Gastroenterology Unit, University of Naples "Federico II", Napoli 80100, Italy
| | - Marco Sanduzzi Zamparelli
- Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona 08036, Spain
- Universidad de Barcelona, Barcelona 08036, Spain
- Department of Clinical Medicine and Surgery, Gastroenterology and Hepatology, Federico II University of Naples, Naples 80131, Italy
| | - Alessandro Granito
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, Istituto di Ricovero e Cura a Carattere Scientifico di Natura Pubblica Azienda Ospedaliero-Universitaria di Bologna, Bologna 40139, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna 40139, Italy
| | - Esther Samper
- Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona 08036, Spain
| | - Mario Scartozzi
- Department of Medical Oncology, University of Cagliari, Cagliari 45698, Italy
| | - Josep Corominas
- Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona 08036, Spain
| | - Giorgia Marisi
- Biosciences Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico di Natura Pubblica, Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori", Meldola 47014, Italy
| | - Alba Díaz
- Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona 08036, Spain
- Universidad de Barcelona, Barcelona 08036, Spain
- Department of Pathology, Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona 08036, Spain
| | - Andrea Casadei-Gardini
- School of Medicine, Vita-Salute San Raffaele University, Milan 20132, Italy
- Unit of Oncology, Università Vita-Salute, Istituto di Ricovero e Cura a Carattere Scientifico di Natura Pubblica-San Raffaele Scientific Institute, Milan 20132, Italy
| | - Laura Gramantieri
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, Istituto di Ricovero e Cura a Carattere Scientifico di Natura Pubblica Azienda Ospedaliero, Bologna 40138, Italy
| | - Pietro Lampertico
- Division of Gastroenterology and Hepatology, Foundation Istituto di Ricovero e Cura a Carattere Scientifico di Natura Pubblica Ca' Granda Ospedale Maggiore Policlinico, Milano 20122, Italy
- Department of Pathophysiology and Transplantation, Colorectal Cancer "A. M. and A. Migliavacca" Center for Liver Disease, University of Milan, Milano 20122, Italy
| | - Filomena Morisco
- Department of Clinical Medicine and Surgery, Gastroenterology Unit, University of Naples Federico II, Naples 80131, Italy
| | - Ferran Torres
- Medical Statistics Core Facility, Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Hospital Clinic Barcelona, Barcelona 08036, Spain
- Biostatistics Unit, Faculty of Medicine, Universitat Autònoma de Barcelona, Cerdanyola 08193, Spain
| | - Jordi Bruix
- Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona 08036, Spain
- Universidad de Barcelona, Barcelona 08036, Spain
| | - María Reig
- Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona 08036, Spain
- Universidad de Barcelona, Barcelona 08036, Spain
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Khattak S, Rauf MA, Khan NH, Zhang QQ, Chen HJ, Muhammad P, Ansari MA, Alomary MN, Jahangir M, Zhang CY, Ji XY, Wu DD. Hydrogen Sulfide Biology and Its Role in Cancer. Molecules 2022; 27:3389. [PMID: 35684331 PMCID: PMC9181954 DOI: 10.3390/molecules27113389] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 04/27/2022] [Accepted: 05/01/2022] [Indexed: 02/07/2023] Open
Abstract
Hydrogen sulfide (H2S) is an endogenous biologically active gas produced in mammalian tissues. It plays a very critical role in many pathophysiological processes in the body. It can be endogenously produced through many enzymes analogous to the cysteine family, while the exogenous source may involve inorganic sulfide salts. H2S has recently been well investigated with regard to the onset of various carcinogenic diseases such as lung, breast, ovaries, colon cancer, and neurodegenerative disorders. H2S is considered an oncogenic gas, and a potential therapeutic target for treating and diagnosing cancers, due to its role in mediating the development of tumorigenesis. Here in this review, an in-detail up-to-date explanation of the potential role of H2S in different malignancies has been reported. The study summarizes the synthesis of H2S, its roles, signaling routes, expressions, and H2S release in various malignancies. Considering the critical importance of this active biological molecule, we believe this review in this esteemed journal will highlight the oncogenic role of H2S in the scientific community.
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Affiliation(s)
- Saadullah Khattak
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China; (S.K.); (N.H.K.); (Q.-Q.Z.); (H.-J.C.)
| | - Mohd Ahmar Rauf
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA;
| | - Nazeer Hussain Khan
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China; (S.K.); (N.H.K.); (Q.-Q.Z.); (H.-J.C.)
| | - Qian-Qian Zhang
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China; (S.K.); (N.H.K.); (Q.-Q.Z.); (H.-J.C.)
| | - Hao-Jie Chen
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China; (S.K.); (N.H.K.); (Q.-Q.Z.); (H.-J.C.)
| | - Pir Muhammad
- Henan-Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng 475004, China;
| | - Mohammad Azam Ansari
- Department of Epidemic Disease Research, Institute for Research & Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia;
| | - Mohammad N. Alomary
- National Centre for Biotechnology, King Abdulaziz City for Science and Technology (KACST), P.O. Box 6086, Riyadh 11442, Saudi Arabia;
| | - Muhammad Jahangir
- Department of Psychiatric and Mental Health, Central South University, Changsha 410078, China;
| | - Chun-Yang Zhang
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Department of General Thoracic Surgery, Hami Central Hospital, Hami 839000, China
| | - Xin-Ying Ji
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China; (S.K.); (N.H.K.); (Q.-Q.Z.); (H.-J.C.)
- Kaifeng Key Laboratory of Infection and Biological Safety, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China
| | - Dong-Dong Wu
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China; (S.K.); (N.H.K.); (Q.-Q.Z.); (H.-J.C.)
- School of Stomatology, Henan University, Kaifeng 475004, China
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9
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Determinants of Survival and Post-Progression Outcomes by Sorafenib–Regorafenib Sequencing for Unresectable Hepatocellular Carcinoma. Cancers (Basel) 2022; 14:cancers14082014. [PMID: 35454919 PMCID: PMC9030368 DOI: 10.3390/cancers14082014] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 04/06/2022] [Accepted: 04/14/2022] [Indexed: 02/08/2023] Open
Abstract
The predictors of response and survival in patients with hepatocellular carcinoma (HCC) receiving regorafenib remain unclear. This study aimed to delineate the determinants of response and survival after regorafenib and evaluate post-progression treatment and outcomes. We retrospectively enrolled 108 patients with unresectable HCC receiving regorafenib after sorafenib failure. Progression-free survival (PFS), overall survival (OS), post-progression survival (PPS) and post-progression treatments were evaluated. The median PFS, OS and PPS were 3.1, 13.1 and 10.3 months, respectively. Achieving disease control by prior sorafenib, early AFP reduction and hand-foot skin reaction (HFSR) were associated with significantly better radiologic responses. By multivariate analysis, the time to progression on prior sorafenib, HFSR and early AFP reduction were associated with PFS; ALBI grade, portal vein invasion, HFSR and early AFP reduction were associated with OS. ALBI grade at disease progression, main portal vein invasion, high tumor burden and next-line therapy were associated with PPS. The median PPS was 12 months in patients who received next-line therapy, and the PPS was comparable between patients who received next-line targeted agents and immunotherapy. In conclusion, survival outcomes of regorafenib for HCC have improved in the era of multi-line sequential therapy. Preserved liver function and next-line therapy are important prognostic factors after regorafenib failure.
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10
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Llovet JM, Pinyol R, Kelley RK, El-Khoueiry A, Reeves HL, Wang XW, Gores GJ, Villanueva A. Molecular pathogenesis and systemic therapies for hepatocellular carcinoma. NATURE CANCER 2022; 3:386-401. [PMID: 35484418 PMCID: PMC9060366 DOI: 10.1038/s43018-022-00357-2] [Citation(s) in RCA: 254] [Impact Index Per Article: 84.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 02/25/2022] [Indexed: 12/11/2022]
Abstract
Hepatocellular carcinoma (HCC) remains one of the most prevalent and deadliest cancers. The poor outcome associated with HCC is dramatically changing due to the advent of effective systemic therapies. Here we discuss the molecular pathogenesis of HCC, molecular classes and determinants of heterogeneity. In addition, effective single-agent and combination systemic therapies involving immunotherapies as standard of care are analyzed. Finally, we propose a flowchart of sequential therapies, explore mechanisms of resistance and address the need for predictive biomarkers.
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Affiliation(s)
- Josep M Llovet
- Liver Cancer Translational Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain.
- Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain.
| | - Roser Pinyol
- Liver Cancer Translational Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
| | - Robin K Kelley
- Helen Diller Cancer Center, University of California San Francisco, San Francisco, CA, USA
| | - Anthony El-Khoueiry
- Keck School of Medicine, USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA
| | - Helen L Reeves
- Newcastle University Translational and Clinical Research Institute and Newcastle University Centre for Cancer, Medical School, Newcastle Upon Tyne, UK
- Hepatopancreatobiliary Multidisciplinary Team, Newcastle upon Tyne NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK
| | - Xin Wei Wang
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
- Liver Cancer Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Gregory J Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Augusto Villanueva
- Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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11
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Rohr-Udilova N, Tsuchiya K, Timelthaler G, Salzmann M, Meischl T, Wöran K, Stift J, Herac M, Schulte-Hermann R, Peck-Radosavljevic M, Sieghart W, Eferl R, Jensen-Jarolim E, Trauner M, Pinter M. Morphometric Analysis of Mast Cells in Tumor Predicts Recurrence of Hepatocellular Carcinoma After Liver Transplantation. Hepatol Commun 2021; 5:1939-1952. [PMID: 34558826 PMCID: PMC8557312 DOI: 10.1002/hep4.1770] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 05/10/2021] [Accepted: 05/23/2021] [Indexed: 12/19/2022] Open
Abstract
Tumor-infiltrating immune cells are relevant prognostic and immunotherapeutic targets in hepatocellular carcinoma (HCC). Mast cells play a key role in allergic response but may also be involved in anticancer immunity. Digital morphometric analysis of patient tissue sections has become increasingly available for clinical routine and provides unbiased quantitative data. Here, we apply morphometric analysis of mast cells to retrospectively evaluate their relevance for HCC recurrence in patients after orthotopic liver transplantation (OLT). A total of 173 patients underwent OLT for HCC at the Medical University of Vienna (21 women, 152 men; 55.2 ± 7.9 years; 74 beyond Milan criteria, 49 beyond up-to-7 criteria for liver transplantation). Tissue arrays from tumors and corresponding surrounding tissues were immunohistochemically stained for mast cell tryptase. Mast cells were quantified by digital tissue morphometric analysis and correlated with HCC recurrence. Mast cells were detected in 93% of HCC tumors and in all available surrounding liver tissues. Tumor tissues revealed lower mast cell density than corresponding surrounding tissues (P < 0.0001). Patients lacking intratumoral mast cells (iMCs) displayed larger tumors and higher tumor recurrence rates both in the whole cohort (hazard ratio [HR], 2.74; 95% confidence interval [CI], 1.09-6.93; P = 0.029) and in patients beyond transplant criteria (Milan HR, 2.81; 95% CI, 1.04-7.62; P = 0.01; up-to-7 HR, 3.58; 95% CI, 1.17-10.92; P = 0.02). Notably, high iMC identified additional patients at low risk classified outside the Milan and up-to-7 criteria, whereas low iMC identified additional patients at high risk classified within the alpha-fetoprotein French and Metroticket criteria. iMCs independently predicted tumor recurrence in a multivariate Cox regression analysis (Milan HR, 2.38; 95% CI, 1.16-4.91; P = 0.019; up-to-7 HR, 2.21; 95% CI, 1.05-4.62; P = 0.035). Conclusion: Hepatic mast cells might be implicated in antitumor immunity in HCC. Morphometric analysis of iMCs refines prognosis of HCC recurrence after liver transplantation.
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Affiliation(s)
- Nataliya Rohr-Udilova
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Kaoru Tsuchiya
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria.,Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Gerald Timelthaler
- Institute of Cancer ResearchInternal Medicine IMedical University of Vienna and Comprehensive Cancer CenterViennaAustria
| | - Martina Salzmann
- Institute of Pathophysiology and Allergy ResearchCenter of Pathophysiology, Infectiology, and ImmunologyMedical University of ViennaViennaAustria
| | - Tobias Meischl
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Katharina Wöran
- Clinical Institute of PathologyMedical University of ViennaViennaAustria
| | - Judith Stift
- Clinical Institute of PathologyMedical University of ViennaViennaAustria
| | - Merima Herac
- Clinical Institute of PathologyMedical University of ViennaViennaAustria
| | - Rolf Schulte-Hermann
- Institute of Cancer ResearchInternal Medicine IMedical University of Vienna and Comprehensive Cancer CenterViennaAustria
| | - Markus Peck-Radosavljevic
- Internal Medicine and Gastroenterology, Central Admission, and First AidPublic Hospital Klagenfurt am WoertherseeKlagenfurtAustria
| | | | - Robert Eferl
- Institute of Cancer ResearchInternal Medicine IMedical University of Vienna and Comprehensive Cancer CenterViennaAustria
| | - Erika Jensen-Jarolim
- Institute of Pathophysiology and Allergy ResearchCenter of Pathophysiology, Infectiology, and ImmunologyMedical University of ViennaViennaAustria.,Comparative MedicineInteruniversity Messerli Research Institute of the University of Veterinary Medicine ViennaMedical University of Vienna and University of ViennaViennaAustria
| | - Michael Trauner
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Matthias Pinter
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
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12
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Ochi M, Kamoshida T, Araki M, Ikegami T. Prolonged survival in patients with hand-foot skin reaction secondary to cooperative sorafenib treatment. World J Gastroenterol 2021; 27:5424-5437. [PMID: 34539142 PMCID: PMC8409165 DOI: 10.3748/wjg.v27.i32.5424] [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: 04/09/2021] [Revised: 06/22/2021] [Accepted: 08/10/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Sorafenib is an oral drug that prolongs overall survival (OS) in patients with hepatocellular carcinoma. Adverse events, including hand-foot skin reaction (HFSR), lead to permanent sorafenib discontinuation.
AIM To clarify the association between interventions for adverse events and patient prognosis.
METHODS We performed a retrospective, multicenter study of patients treated with sorafenib monotherapy between May 2009 and March 2018. We developed a mutual cooperation system that was initiated at the start of sorafenib treatment to effectively manage adverse events. The mutual cooperation system entailed patients receiving consultations during which pharmacists provided accurate information about sorafenib to alleviate the fear and anxiety related to adverse events. We stratified the patients into three groups: Group A, patients without HFSR but with pharmacist intervention; Group B, patients with HFSR and pharmacist interventions unreported to oncologists (nonmutual cooperation system); and Group C, patients with HFSR and pharmacist interventions known to oncologists (mutual cooperation system). OS and time to treatment failure (TTF) were evaluated using the Kaplan-Meier method.
RESULTS We enrolled 134 patients (Group A, n = 41; Group B, n = 30; Group C, n = 63). The median OS was significantly different between Groups A and C (6.2 vs 13.9 mo, p < 0.01) but not between Groups A and B (6.2 vs 7.7 mo, P = 0.62). Group A vs Group C was an independent OS predictor (HR, 0.41; 95%CI: 0.25-0.66; P < 0.01). In Group B alone, TTF was significantly lower and the nonadherence rate was higher (P < 0.01). In addition, the Spearman’s rank correlation coefficients between OS and TTF in each group were 0.41 (Group A; P < 0.01), 0.13 (Group B; P = 0.51), and 0.58 (Group C; P < 0.01). There was a highly significant correlation between OS and TTF in Group C. However, there was no correlation between OS and TTF in Group B.
CONCLUSION The mutual cooperation system increased treatment duration and improved prognosis in patients with HFSR. Future prospective studies (e.g., randomized controlled trials) and improved adherence could help prevent OS underestimation.
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Affiliation(s)
- Masanori Ochi
- Department of Gastroenterology, Hitachi General Hospital, Ibaraki 317–0077, Japan
| | - Toshiro Kamoshida
- Department of Gastroenterology, Hitachi General Hospital, Ibaraki 317–0077, Japan
| | - Masahiro Araki
- Department of Gastroenterology and Hepatology, Ibaraki Prefectural Central Hospital, Ibaraki Cancer Center, Ibaraki 309-1793, Japan
| | - Tadashi Ikegami
- Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Ibaraki 309-1793, Japan
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13
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Wang HW, Chuang PH, Su WP, Kao JT, Hsu WF, Lin CC, Huang GT, Lin JT, Lai HC, Peng CY. On-Treatment Albumin-Bilirubin Grade: Predictor of Response and Outcome of Sorafenib-Regorafenib Sequential Therapy in Patients with Unresectable Hepatocellular Carcinoma. Cancers (Basel) 2021; 13:3758. [PMID: 34359658 PMCID: PMC8345148 DOI: 10.3390/cancers13153758] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Revised: 07/21/2021] [Accepted: 07/22/2021] [Indexed: 02/08/2023] Open
Abstract
In the RESORCE study, regorafenib after sorafenib therapy improved survival in patients with advanced hepatocellular carcinoma (HCC). In total, 88 patients with unresectable HCC who received sorafenib-regorafenib sequential therapy were enrolled. The objective response rate and disease control rate were 19.3% and 48.9%, respectively, for regorafenib therapy (median duration: 8.1 months). Median progression-free survival (PFS) after regorafenib therapy was 4.2 months (95% CI: 3.2-5.1). The median overall survival (OS; from initiation of either sorafenib or regorafenib) was not reached in this cohort. According to multivariate Cox regression analyses, albumin-bilirubin (ALBI) grade at the initiation of regorafenib therapy is an independent predictor of disease control, PFS, and OS. Moreover, the combination of ALBI grade 2 and an alpha-fetoprotein (AFP) level of ≥20 ng/mL was an independent predictor of PFS (hazard ratio (HR): 3.088, 95% CI: 1.704-5.595; p < 0.001) for regorafenib therapy, and OS for both regorafenib (HR: 3.783, 95% CI: 1.316-10.88; p = 0.014) and sorafenib-regorafenib sequential (HR: 4.603, 95% CI: 1.386-15.29; p = 0.013) therapy. A combination of ALBI grade and AFP level can be used to stratify patients with unresectable HCC by PFS and OS probability for sorafenib-regorafenib sequential therapy.
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Affiliation(s)
- Hung-Wei Wang
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan; (H.-W.W.); (P.-H.C.); (W.-P.S.); (J.-T.K.); (W.-F.H.); (C.-C.L.); (G.-T.H.); (J.-T.L.)
- School of Medicine, China Medical University, Taichung 404, Taiwan
| | - Po-Heng Chuang
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan; (H.-W.W.); (P.-H.C.); (W.-P.S.); (J.-T.K.); (W.-F.H.); (C.-C.L.); (G.-T.H.); (J.-T.L.)
| | - Wen-Pang Su
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan; (H.-W.W.); (P.-H.C.); (W.-P.S.); (J.-T.K.); (W.-F.H.); (C.-C.L.); (G.-T.H.); (J.-T.L.)
| | - Jung-Ta Kao
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan; (H.-W.W.); (P.-H.C.); (W.-P.S.); (J.-T.K.); (W.-F.H.); (C.-C.L.); (G.-T.H.); (J.-T.L.)
- School of Medicine, China Medical University, Taichung 404, Taiwan
| | - Wei-Fan Hsu
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan; (H.-W.W.); (P.-H.C.); (W.-P.S.); (J.-T.K.); (W.-F.H.); (C.-C.L.); (G.-T.H.); (J.-T.L.)
- School of Medicine, China Medical University, Taichung 404, Taiwan
| | - Chun-Che Lin
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan; (H.-W.W.); (P.-H.C.); (W.-P.S.); (J.-T.K.); (W.-F.H.); (C.-C.L.); (G.-T.H.); (J.-T.L.)
- School of Medicine, China Medical University, Taichung 404, Taiwan
| | - Guan-Tarn Huang
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan; (H.-W.W.); (P.-H.C.); (W.-P.S.); (J.-T.K.); (W.-F.H.); (C.-C.L.); (G.-T.H.); (J.-T.L.)
- School of Medicine, China Medical University, Taichung 404, Taiwan
| | - Jaw-Town Lin
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan; (H.-W.W.); (P.-H.C.); (W.-P.S.); (J.-T.K.); (W.-F.H.); (C.-C.L.); (G.-T.H.); (J.-T.L.)
- School of Medicine, China Medical University, Taichung 404, Taiwan
| | - Hsueh-Chou Lai
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan; (H.-W.W.); (P.-H.C.); (W.-P.S.); (J.-T.K.); (W.-F.H.); (C.-C.L.); (G.-T.H.); (J.-T.L.)
- School of Chinese Medicine, China Medical University, Taichung 404, Taiwan
| | - Cheng-Yuan Peng
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan; (H.-W.W.); (P.-H.C.); (W.-P.S.); (J.-T.K.); (W.-F.H.); (C.-C.L.); (G.-T.H.); (J.-T.L.)
- School of Medicine, China Medical University, Taichung 404, Taiwan
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14
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Díaz-González Á, Sapena V, Boix L, Torres F, Sanduzzi-Zamparelli M, Da Fonseca LG, LLarch N, Iserte G, Guedes C, Muñoz-Martínez S, Darnell A, Belmonte E, Rimola J, Forner A, Ayuso C, Bruix J, Reig M. Early diarrhoea under sorafenib as a marker to consider the early migration to second-line drugs. United European Gastroenterol J 2021; 9:655-661. [PMID: 34228394 PMCID: PMC8280813 DOI: 10.1002/ueg2.12111] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 03/14/2021] [Accepted: 03/31/2021] [Indexed: 12/24/2022] Open
Abstract
Background Despite atezolizumab and bevacizumab (A + B) is currently the first‐line treatment for hepatocellular carcinoma (HCC) patients, some patients will not be adequate for this combination. In the setting of sorafenib some adverse events have been proposed as prognostic factors. Objective To characterize the early diarrhoea development as prognostic factor in 344 HCC patients. Methods The development of early diarrhoea in sorafenib treatment defined as patients who developed diarrhoea and needed dose modification within the first 60 days of treatment (e‐diarrhoea) and 3‐grouping variables were analysed: Patients with e‐diarrhoea, patients who developed diarrhoea after the first 60 days of treatment (L‐diarrhoea) and patients that never developed diarrhoea (never diarrhoea). Results The median overall survival in sorafenib treated patients was significantly different across groups (6.8 months for e‐diarrhoea, 26.7 months for L‐diarrhoea and 13.3 months for never‐diarrhoea). The emergence of e‐diarrhoea was associated with poor outcomes (hazard ratio [HR] 1.84 [95%CI 1.15–2.95]), while there was no increased/decreased risk of dismal evolution in patients with L‐diarrhoea (HR 0.66 [95%CI 0.42–1.03]). Conclusion The emergence of e‐diarrhoea in HCC patients treated with sorafenib is an early predictor of dismal evolution under this therapy. Thus, prompt identification of these non‐responders may be useful for an early switch to second‐line therapies. Established knowledge on this subject
Diarrhoea is a frequent adverse event of sorafenib and its emergence has been associated to better outcomes. What are the significant and/or new findings of this study?
Early diarrhoea (e‐diarrhoea) in hepatocellular carcinoma patients treated with sorafenib is an early predictor of dismal evolution. Diarrhoea under sorafenib should not be taken as a predictive parameter of lack of benefit. E‐diarrhoea could be used as clinical biomarker for switching to second‐line therapies.
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Affiliation(s)
- Álvaro Díaz-González
- Barcelona Clinic Liver Cancer (BCLC) Group. Liver Unit, Hospital Clínic de Barcelona. IDIBAPS. CIBERehd. University of Barcelona, Barcelona, Spain
| | - Víctor Sapena
- Barcelona Clinic Liver Cancer (BCLC) Group. Liver Unit, Hospital Clínic de Barcelona. IDIBAPS. CIBERehd. University of Barcelona, Barcelona, Spain
| | - Loreto Boix
- Barcelona Clinic Liver Cancer (BCLC) Group. Liver Unit, Hospital Clínic de Barcelona. IDIBAPS. CIBERehd. University of Barcelona, Barcelona, Spain
| | - Ferrán Torres
- Medical Statistics Core Facility, IDIBAPS. Hospital Clínic de Barcelona. Biostatistics Unit, Faculty of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Marco Sanduzzi-Zamparelli
- Barcelona Clinic Liver Cancer (BCLC) Group. Liver Unit, Hospital Clínic de Barcelona. IDIBAPS. CIBERehd. University of Barcelona, Barcelona, Spain
| | - Leonardo G Da Fonseca
- Barcelona Clinic Liver Cancer (BCLC) Group. Liver Unit, Hospital Clínic de Barcelona. IDIBAPS. CIBERehd. University of Barcelona, Barcelona, Spain
| | - Neus LLarch
- Barcelona Clinic Liver Cancer (BCLC) Group. Liver Unit, Hospital Clínic de Barcelona. IDIBAPS. CIBERehd. University of Barcelona, Barcelona, Spain
| | - Gemma Iserte
- Barcelona Clinic Liver Cancer (BCLC) Group. Liver Unit, Hospital Clínic de Barcelona. IDIBAPS. CIBERehd. University of Barcelona, Barcelona, Spain
| | - Cassia Guedes
- Barcelona Clinic Liver Cancer (BCLC) Group. Liver Unit, Hospital Clínic de Barcelona. IDIBAPS. CIBERehd. University of Barcelona, Barcelona, Spain
| | - Sergio Muñoz-Martínez
- Barcelona Clinic Liver Cancer (BCLC) Group. Liver Unit, Hospital Clínic de Barcelona. IDIBAPS. CIBERehd. University of Barcelona, Barcelona, Spain
| | - Anna Darnell
- Barcelona Clinic Liver Cancer (BCLC) Group. Radiology Department, Hospital Clínic de Barcelona. IDIBAPS. CIBERehd. University of Barcelona, Barcelona, Spain
| | - Ernest Belmonte
- Barcelona Clinic Liver Cancer (BCLC) Group. Radiology Department, Hospital Clínic de Barcelona. IDIBAPS. CIBERehd. University of Barcelona, Barcelona, Spain
| | - Jordi Rimola
- Barcelona Clinic Liver Cancer (BCLC) Group. Radiology Department, Hospital Clínic de Barcelona. IDIBAPS. CIBERehd. University of Barcelona, Barcelona, Spain
| | - Alejandro Forner
- Barcelona Clinic Liver Cancer (BCLC) Group. Liver Unit, Hospital Clínic de Barcelona. IDIBAPS. CIBERehd. University of Barcelona, Barcelona, Spain
| | - Carmen Ayuso
- Barcelona Clinic Liver Cancer (BCLC) Group. Radiology Department, Hospital Clínic de Barcelona. IDIBAPS. CIBERehd. University of Barcelona, Barcelona, Spain
| | - Jordi Bruix
- Barcelona Clinic Liver Cancer (BCLC) Group. Liver Unit, Hospital Clínic de Barcelona. IDIBAPS. CIBERehd. University of Barcelona, Barcelona, Spain
| | - María Reig
- Barcelona Clinic Liver Cancer (BCLC) Group. Liver Unit, Hospital Clínic de Barcelona. IDIBAPS. CIBERehd. University of Barcelona, Barcelona, Spain
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The TGF-β Pathway: A Pharmacological Target in Hepatocellular Carcinoma? Cancers (Basel) 2021; 13:cancers13133248. [PMID: 34209646 PMCID: PMC8268320 DOI: 10.3390/cancers13133248] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 06/23/2021] [Accepted: 06/24/2021] [Indexed: 02/07/2023] Open
Abstract
Transforming Growth Factor-beta (TGF-β) superfamily members are essential for tissue homeostasis and consequently, dysregulation of their signaling pathways contributes to the development of human diseases. In the liver, TGF-β signaling participates in all the stages of disease progression from initial liver injury to hepatocellular carcinoma (HCC). During liver carcinogenesis, TGF-β plays a dual role on the malignant cell, behaving as a suppressor factor at early stages, but contributing to later tumor progression once cells escape from its cytostatic effects. Moreover, TGF-β can modulate the response of the cells forming the tumor microenvironment that may also contribute to HCC progression, and drive immune evasion of cancer cells. Thus, targeting the TGF-β pathway may constitute an effective therapeutic option for HCC treatment. However, it is crucial to identify biomarkers that allow to predict the response of the tumors and appropriately select the patients that could benefit from TGF-β inhibitory therapies. Here we review the functions of TGF-β on HCC malignant and tumor microenvironment cells, and the current strategies targeting TGF-β signaling for cancer therapy. We also summarize the clinical impact of TGF-β inhibitors in HCC patients and provide a perspective on its future use alone or in combinatorial strategies for HCC treatment.
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Reig M, Forner A, Ávila MA, Ayuso C, Mínguez B, Varela M, Bilbao I, Bilbao JI, Burrel M, Bustamante J, Ferrer J, Gómez MÁ, Llovet JM, De la Mata M, Matilla A, Pardo F, Pastrana MA, Rodríguez-Perálvarez M, Tabernero J, Urbano J, Vera R, Sangro B, Bruix J. Diagnosis and treatment of hepatocellular carcinoma. Update of the consensus document of the AEEH, AEC, SEOM, SERAM, SERVEI, and SETH. Med Clin (Barc) 2021; 156:463.e1-463.e30. [PMID: 33461840 DOI: 10.1016/j.medcli.2020.09.022] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 09/12/2020] [Accepted: 09/15/2020] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver neoplasm and one of the most common causes of death in patients with cirrhosis of the liver. In parallel, with recognition of the clinical relevance of this cancer, major new developments have recently appeared in its diagnosis, prognostic assessment and in particular, in its treatment. Therefore, the Spanish Association for the Study of the Liver (AEEH) has driven the need to update the clinical practice guidelines, once again inviting all the societies involved in the diagnosis and treatment of this disease to participate in the drafting and approval of the document: Spanish Society for Liver Transplantation (SETH), Spanish Society of Diagnostic Radiology (SERAM), Spanish Society of Vascular and Interventional Radiology (SERVEI), Spanish Association of Surgeons (AEC) and Spanish Society of Medical Oncology (SEOM). The clinical practice guidelines published in 2016 and accepted as National Health System Clinical Practice Guidelines were taken as the reference documents, incorporating the most important recent advances. The scientific evidence and the strength of the recommendation is based on the GRADE system.
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Affiliation(s)
- María Reig
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Hepatología, Hospital Clínic, IDIBAPS, Universidad de Barcelona, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Barcelona, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España
| | - Alejandro Forner
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Hepatología, Hospital Clínic, IDIBAPS, Universidad de Barcelona, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Barcelona, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España
| | - Matías A Ávila
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Programa de Hepatología, Centro de Investigación Médica Aplicada, Universidad de Navarra-IDISNA, Pamplona, España
| | - Carmen Ayuso
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Servicio de Radiodiagnóstico, Hospital Clínic Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, España
| | - Beatriz Mínguez
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Servicio de Hepatología, Hospital Universitario Vall d́Hebron, Grupo de Investigación en Enfermedades Hepáticas (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universidad Autónoma de Barcelona. Barcelona, España
| | - María Varela
- Sección de Hepatología, Servicio de Aparato Digestivo, Hospital Universitario Central de Asturias. Oviedo, España
| | - Itxarone Bilbao
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Servicio de Cirugía Hepatobiliopancreática y Trasplantes Digestivos, Hospital Universitario Vall d'Hebron, Universidad Autónoma de Barcelona. Barcelona, España
| | - José Ignacio Bilbao
- Unidad de Radiología Vascular e Intervencionista, Departamento de Radiodiagnóstico, Clínica Universidad de Navarra, Pamplona, España
| | - Marta Burrel
- Servicio de Radiodiagnóstico, Hospital Clínic Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, España
| | - Javier Bustamante
- Servicio de Gastroenterología y Hepatología, Sección de Hepatología y Trasplante, Hospital Universitario de Cruces, Baracaldo, España
| | - Joana Ferrer
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Cirugía Hepatobiliopancreática, Hospital Clínic, IDIBAPS, Universidad de Barcelona, Barcelona, España
| | - Miguel Ángel Gómez
- Unidad de Cirugía Hepatobiliopancreática y Trasplantes, Hospital Universitario Virgen del Rocío, Sevilla, España
| | - Josep María Llovet
- Grupo de Investigación Traslacional en Oncología Hepática, Servicio de Hepatología, Hospital Clínic, IDIBAPS, Universidad de Barcelona, Barcelona, España
| | - Manuel De la Mata
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Unidad Clínica de Aparato Digestivo, Hospital Universitario Reina Sofía, Córdoba, España
| | - Ana Matilla
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Sección de Hepatología, Servicio de Aparato Digestivo, Hospital General Universitario Gregorio Marañón, Madrid, España
| | - Fernando Pardo
- Servicio de Cirugía Hepatobiliopancreática y Trasplante, Clínica Universidad de Navarra, Pamplona, España
| | - Miguel A Pastrana
- Servicio de Radiodiagnóstico, Hospital Universitario Puerta de Hierro, Universidad Autónoma de Madrid, Madrid, España
| | - Manuel Rodríguez-Perálvarez
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Unidad Clínica de Aparato Digestivo, Hospital Universitario Reina Sofía, Córdoba, España
| | - Josep Tabernero
- Servicio de Oncología Médica, Hospital Universitario Vall d'Hebron, Universidad Autónoma de Barcelona, Barcelona, España
| | - José Urbano
- Unidad de Radiología Vascular e Intervencionista, Servicio de Radiodiagnóstico, Hospital Universitario Ramón y Cajal, Universidad de Alcalá, Madrid, España
| | - Ruth Vera
- Servicio de Oncología Médica, Complejo hospitalario de Navarra, Navarrabiomed-IDISNA, Pamplona, España
| | - Bruno Sangro
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Unidad de Hepatología y Área de Oncología HBP, Clínica Universidad de Navarra-IDISNA, Pamplona, España.
| | - Jordi Bruix
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Hepatología, Hospital Clínic, IDIBAPS, Universidad de Barcelona, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Barcelona, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España.
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Cerrito L, Santopaolo F, Monti F, Pompili M, Gasbarrini A, Ponziani FR. Advances in pharmacotherapeutics for hepatocellular carcinoma. Expert Opin Pharmacother 2021; 22:1343-1354. [PMID: 33637024 DOI: 10.1080/14656566.2021.1892074] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Although hepatocellular carcinoma (HCC) is the most frequent primary liver cancer, there are limited therapeutic options for the advanced stages. Sorafenib was the first tyrosine-kinase inhibitor (TKI) approved for unresectable HCC and remained the only effective choice for a decade. The horizon of systemic treatments drastically expanded in the latest years, opening new interesting possibilities. AREAS COVERED In this manuscript, the authors have analysed the recent advances in pharmacotherapy for HCC, discussing their mechanisms of action, the clinical efficacy and the safety profile of currently available first, second-and third-line treatments. The authors have also analysed the role of immune system modulators, in particular immune checkpoints inhibitors (ICIs), based on the limited data published so far. EXPERT OPINION The emergence of new targeted therapies, such as lenvatinib, have changed the landscape of HCC therapy. Tumor extension, differences in objective response rates and adverse events profiles should be considered to tailor the choice of the first-line agent. Sorafenib remains the most studied drug, with much real-world data available. The efficacy of second line therapies has only been proven in non-responder or sorafenib-intolerant patients. Unfortunately, studies directly comparing the second-line agents regorafenib, ramucirumab and cabozantinib are still lacking.
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Affiliation(s)
- Lucia Cerrito
- Internal Medicine, Gastroenterology And Hepatology, Fondazione Policlinico Universitario Agostino Gemelli Irccs, Università Cattolica Del Sacro Cuore, ROMA, ITALY
| | - Francesco Santopaolo
- Internal Medicine, Gastroenterology And Hepatology, Fondazione Policlinico Universitario Agostino Gemelli Irccs, Università Cattolica Del Sacro Cuore, ROMA, ITALY
| | | | - Maurizio Pompili
- Internal Medicine, Gastroenterology And Hepatology, Fondazione Policlinico Universitario Agostino Gemelli Irccs, Università Cattolica Del Sacro Cuore, ROMA, ITALY
| | - Antonio Gasbarrini
- Internal Medicine, Gastroenterology And Hepatology, Fondazione Policlinico Universitario Agostino Gemelli Irccs, Università Cattolica Del Sacro Cuore, ROMA, ITALY
| | - Francesca Romana Ponziani
- Internal Medicine, Gastroenterology And Hepatology, Fondazione Policlinico Universitario Agostino Gemelli Irccs, Università Cattolica Del Sacro Cuore, ROMA, ITALY
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da Fonseca LG, Fuster-Anglada C, Carrera C, Millán C, Samper E, Sapena V, Díaz-González Á, Sanduzzi-Zamparelli M, Leal C, Forner A, Bruix J, Reig M, Boix L, Díaz A. Mutational profile of skin lesions in hepatocellular carcinoma patients under tyrosine kinase inhibition: a repercussion of a wide-spectrum activity. Oncotarget 2021; 12:440-449. [PMID: 33747359 PMCID: PMC7939531 DOI: 10.18632/oncotarget.27891] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 02/01/2021] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND/AIM Dermatological adverse events (DAE) in hepatocellular carcinoma (HCC) patients treated with sorafenib predicts better outcome. Some turn into skin lesions (SL) requiring pathology examination. We describe incidence, characteristics and molecular profile of SL in HCC patients treated with sorafenib. MATERIALS AND METHODS SL were prospectively collected in 311 HCC patients who started sorafenib. SL from sorafenib cohort were compared to those from a control patient group selected to match SL type and demographics. HRAS, KRAS and BRAF mutations were analyzed by CAST-PCR, mutated p53 and MAPK pathway activation by immunohistochemistry and immune infiltration by hematoxylin-eosin staining. RESULTS Eighty-eight out of 311 patients developed DAE and 7.4% SL required histological assessment. Most frequent lesions were keratoacanthomas (n = 4), squamous-cell carcinomas (SCC)(n = 5), basal-cell carcinomas (BCC)(n = 3) and seborrheic keratosis (n = 5). HRAS and KRAS mutations were detected in 4 SL, while no mutations showed in control SL. Nuclear pERK immunostaining was identified in 33.3% of cases versus 5.3% of controls. Most SL (90%) from patients with DAE were proliferative with intense immune infiltration (73%). CONCLUSIONS The onset of SL and their molecular profile did not impact negatively on patient's prognosis, but intense proliferation of SL may reflect compensatory activation of MAPK pathway and warrants their close monitoring.
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Affiliation(s)
- Leonardo G da Fonseca
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic de Barcelona, IDIBAPS, Universitat de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain.,Authors collaborated equally as first author
| | - Carla Fuster-Anglada
- Barcelona Clinic Liver Cancer (BCLC) Group, Department of Pathology, Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona, Spain.,Authors collaborated equally as first author
| | - Cristina Carrera
- Melanoma Unit, Dermatology Department, Hospital Clínic de Barcelona, Universitat de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain
| | - Cristina Millán
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic de Barcelona, IDIBAPS, Universitat de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| | - Esther Samper
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic de Barcelona, IDIBAPS, Universitat de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| | - Victor Sapena
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic de Barcelona, IDIBAPS, Universitat de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| | - Álvaro Díaz-González
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic de Barcelona, IDIBAPS, Universitat de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| | - Marco Sanduzzi-Zamparelli
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic de Barcelona, IDIBAPS, Universitat de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| | - Cassia Leal
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic de Barcelona, IDIBAPS, Universitat de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| | - Alejandro Forner
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic de Barcelona, IDIBAPS, Universitat de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| | - Jordi Bruix
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic de Barcelona, IDIBAPS, Universitat de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| | - Maria Reig
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic de Barcelona, IDIBAPS, Universitat de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| | - Loreto Boix
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic de Barcelona, IDIBAPS, Universitat de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain.,Authors collaborated equally as senior author
| | - Alba Díaz
- Barcelona Clinic Liver Cancer (BCLC) Group, Department of Pathology, Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona, Spain.,Authors collaborated equally as senior author
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19
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Corominas J, Sapena V, Sanduzzi-Zamparelli M, Millán C, Samper E, Llarch N, Iserte G, Torres F, Da Fonseca LG, Muñoz-Martínez S, Forner A, Bruix J, Boix L, Reig M. Activated Lymphocytes and Increased Risk of Dermatologic Adverse Events during Sorafenib Therapy for Hepatocellular Carcinoma. Cancers (Basel) 2021; 13:cancers13030426. [PMID: 33498698 PMCID: PMC7865624 DOI: 10.3390/cancers13030426] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 01/17/2021] [Accepted: 01/18/2021] [Indexed: 12/17/2022] Open
Abstract
Simple Summary Hepatocellular carcinoma is the second cause of cancer-related death worldwide. Of those advanced-stage patients who are treated with sorafenib, those who develop early dermatologic adverse events have a better prognosis. These events are possibly immune-related. Therefore, we analyzed the phenotype of 52 sorafenib-treated patients’ circulating lymphocytes throughout treatment. We found that different co-stimulatory and immune exhaustion markers, such as Programmed cell death protein 1 (PD-1) and DNAX accessory molecule 1 (DNAM-1) amongst others, correlate with the probability of developing these adverse events, both before and during the treatment. We also compared the phenotype of those lymphocytes expressing DNAM-1 with those that do not, and while NK DNAM-1-expressing cells have a co-stimulatory phenotype, T DNAM-1-expressing cells are immune-suppressors. Overall, we set a rationale for the combination of sorafenib and immune-targeted therapies; and for the use of immune markers (such as DNAM-1) for patients’ prognosis evaluation. Abstract Advanced hepatocellular carcinoma patients treated with sorafenib who develop early dermatologic adverse events (eDAEs) have a better prognosis. This may be linked to immune mechanisms, and thus, it is relevant to assess the association between peripheral immunity and the probability of developing eDAEs. Peripheral blood mononuclear cells of 52 HCC patients treated with sorafenib were analyzed at baseline and throughout the first eight weeks of therapy. T, B, Natural Killer cells, and their immune checkpoints expression data were characterized by flow cytometry. Cytokine release and immune-suppression assays were carried out ex vivo. Cox baseline and time-dependent regression models were applied to evaluate the probability of increased risk of eDAEs. DNAM-1, PD-1, CD69, and LAG-3 in T cells, plus CD16 and LAG-3 in NK cells, are significantly associated with the probability of developing eDAEs. While NK DNAM-1+ cells express activation markers, T DNAM-1+ cells induce immune suppression and show immune exhaustion. This is the first study to report an association between immune checkpoints expression in circulating immune cells and the increased incidence of eDAEs. Our results support the hypothesis for an off-target role of sorafenib in immune modulation. We also describe a novel association between DNAM-1 and immune exhaustion in T cells.
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Affiliation(s)
- Josep Corominas
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clinic, IDIBAPS, University of Barcelona, 08036 Barcelona, Spain; (J.C.); (V.S.); (M.S.-Z.); (C.M.); (E.S.); (N.L.); (G.I.); (L.G.D.F.); (S.M.-M.); (A.F.); (J.B.)
- Fundació Clínic Recerca Biomèdica, 08036 Barcelona, Spain
| | - Victor Sapena
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clinic, IDIBAPS, University of Barcelona, 08036 Barcelona, Spain; (J.C.); (V.S.); (M.S.-Z.); (C.M.); (E.S.); (N.L.); (G.I.); (L.G.D.F.); (S.M.-M.); (A.F.); (J.B.)
- Fundació Clínic Recerca Biomèdica, 08036 Barcelona, Spain
| | - Marco Sanduzzi-Zamparelli
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clinic, IDIBAPS, University of Barcelona, 08036 Barcelona, Spain; (J.C.); (V.S.); (M.S.-Z.); (C.M.); (E.S.); (N.L.); (G.I.); (L.G.D.F.); (S.M.-M.); (A.F.); (J.B.)
- Fundació Clínic Recerca Biomèdica, 08036 Barcelona, Spain
| | - Cristina Millán
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clinic, IDIBAPS, University of Barcelona, 08036 Barcelona, Spain; (J.C.); (V.S.); (M.S.-Z.); (C.M.); (E.S.); (N.L.); (G.I.); (L.G.D.F.); (S.M.-M.); (A.F.); (J.B.)
- Fundació Clínic Recerca Biomèdica, 08036 Barcelona, Spain
| | - Esther Samper
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clinic, IDIBAPS, University of Barcelona, 08036 Barcelona, Spain; (J.C.); (V.S.); (M.S.-Z.); (C.M.); (E.S.); (N.L.); (G.I.); (L.G.D.F.); (S.M.-M.); (A.F.); (J.B.)
- Fundació Clínic Recerca Biomèdica, 08036 Barcelona, Spain
| | - Neus Llarch
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clinic, IDIBAPS, University of Barcelona, 08036 Barcelona, Spain; (J.C.); (V.S.); (M.S.-Z.); (C.M.); (E.S.); (N.L.); (G.I.); (L.G.D.F.); (S.M.-M.); (A.F.); (J.B.)
- Fundació Clínic Recerca Biomèdica, 08036 Barcelona, Spain
| | - Gemma Iserte
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clinic, IDIBAPS, University of Barcelona, 08036 Barcelona, Spain; (J.C.); (V.S.); (M.S.-Z.); (C.M.); (E.S.); (N.L.); (G.I.); (L.G.D.F.); (S.M.-M.); (A.F.); (J.B.)
- Fundació Clínic Recerca Biomèdica, 08036 Barcelona, Spain
| | - Ferràn Torres
- Biostatistics Unit, Faculty of Medicine, Universitat Autònoma de Barcelona, 08193 Barcelona, Span;
- Medical Statistics Core Facility, Clinical Pharmacology Department, IDIBAPS-Hospital Clínic de Barcelona, 08036 Barcelona, Spain
| | - Leonardo G. Da Fonseca
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clinic, IDIBAPS, University of Barcelona, 08036 Barcelona, Spain; (J.C.); (V.S.); (M.S.-Z.); (C.M.); (E.S.); (N.L.); (G.I.); (L.G.D.F.); (S.M.-M.); (A.F.); (J.B.)
- Fundació Clínic Recerca Biomèdica, 08036 Barcelona, Spain
| | - Sergio Muñoz-Martínez
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clinic, IDIBAPS, University of Barcelona, 08036 Barcelona, Spain; (J.C.); (V.S.); (M.S.-Z.); (C.M.); (E.S.); (N.L.); (G.I.); (L.G.D.F.); (S.M.-M.); (A.F.); (J.B.)
- Fundació Clínic Recerca Biomèdica, 08036 Barcelona, Spain
| | - Alejandro Forner
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clinic, IDIBAPS, University of Barcelona, 08036 Barcelona, Spain; (J.C.); (V.S.); (M.S.-Z.); (C.M.); (E.S.); (N.L.); (G.I.); (L.G.D.F.); (S.M.-M.); (A.F.); (J.B.)
- Fundació Clínic Recerca Biomèdica, 08036 Barcelona, Spain
| | - Jordi Bruix
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clinic, IDIBAPS, University of Barcelona, 08036 Barcelona, Spain; (J.C.); (V.S.); (M.S.-Z.); (C.M.); (E.S.); (N.L.); (G.I.); (L.G.D.F.); (S.M.-M.); (A.F.); (J.B.)
- Fundació Clínic Recerca Biomèdica, 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28028 Madrid, Spain
| | - Loreto Boix
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clinic, IDIBAPS, University of Barcelona, 08036 Barcelona, Spain; (J.C.); (V.S.); (M.S.-Z.); (C.M.); (E.S.); (N.L.); (G.I.); (L.G.D.F.); (S.M.-M.); (A.F.); (J.B.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28028 Madrid, Spain
- Correspondence: (L.B.); (M.R.)
| | - María Reig
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clinic, IDIBAPS, University of Barcelona, 08036 Barcelona, Spain; (J.C.); (V.S.); (M.S.-Z.); (C.M.); (E.S.); (N.L.); (G.I.); (L.G.D.F.); (S.M.-M.); (A.F.); (J.B.)
- Fundació Clínic Recerca Biomèdica, 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28028 Madrid, Spain
- Correspondence: (L.B.); (M.R.)
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20
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Sansone V, Tovoli F, Casadei-Gardini A, Di Costanzo GG, Magini G, Sacco R, Pressiani T, Trevisani F, Rimini M, Tortora R, Nardi E, Ielasi L, Piscaglia F, Granito A. Comparison of Prognostic Scores in Patients With Hepatocellular Carcinoma Treated With Sorafenib. Clin Transl Gastroenterol 2021; 12:e00286. [PMID: 33443944 PMCID: PMC7808555 DOI: 10.14309/ctg.0000000000000286] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 11/06/2020] [Indexed: 02/07/2023] Open
Abstract
INTRODUCTION Prognostic classifications for patients treated with sorafenib for hepatocellular carcinoma (HCC) facilitate stratification in trials and inform clinical decision making. Recently, 3 different prognostic models (hepatoma arterial-embolization prognosis [HAP] score, sorafenib advanced HCC prognosis [SAP] score, and Prediction Of Survival in Advanced Sorafenib-treated HCC [PROSASH]-II) have been proposed specifically for patients treated with sorafenib. This study aimed to compare the prognostic performance of different scores. METHODS We analyzed a large prospective database gathering data of 552 patients treated with sorafenib from 7 Italian centers. The performance of the HAP, SAP, and PROSASH-II models were compared with those of generic HCC prognostic models (including the Barcelona Clinic for Liver Cancer and Italian Liver Cancer staging systems, albumin-bilirubin grade, and Child-Pugh score) to verify whether they could provide additional information. RESULTS The PROSASH-II model improved discrimination (C-index 0.62) compared with existing prognostic scores (C-index ≤0.59). Its stratification significantly discriminated patients, with a median overall survival of 21.5, 15.3, 9.3, and 6.0 months for risk group 1, 2, 3, and 4, respectively. The HAP and SAP score were also validated but with a poorer performance compared with the PROSASH-II. DISCUSSION Although suboptimal, PROSASH-II is the most effective prognostic classification model among other available scores in a large Italian population of patients treated with sorafenib.
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Affiliation(s)
- Vito Sansone
- Division of Internal Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italia
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Francesco Tovoli
- Division of Internal Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italia
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Andrea Casadei-Gardini
- Department of Medical Oncology, Università Vita-Salute, San Raffaele Hospital IRCCS, Milan, Italy
- Dipartimento di Oncologia, IRCCS Ospedale San Raffaele, Milan, Italy
- School of Medicine, Vita-Salute San Raffaele University, Milan, Italy
- Unit of Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | | | - Giulia Magini
- Department of Gastroenterology and Transplant Hepatology, Papa Giovanni XXIII Hospital, Bergamo, Italy
| | - Rodolfo Sacco
- Gastroenterology Unit, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
- Gastroenterology and Digestive Endoscopy Unit, Foggia University Hospital, Foggia, Italy
| | - Tiziana Pressiani
- Medical Oncology and Hematology Unit, Humanitas Clinical and Research Center, Rozzano (Milan), Italy
| | - Franco Trevisani
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- Semeiotica Medica, Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italia
| | - Margherita Rimini
- Division of Oncology, Department of Oncology and Hematology, University of Modena and Reggio Emilia, Modena, Italy
| | - Raffaella Tortora
- Dipartimento di Oncologia, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Elena Nardi
- Division of Internal Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italia
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Luca Ielasi
- Division of Internal Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italia
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Fabio Piscaglia
- Division of Internal Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italia
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Alessandro Granito
- Division of Internal Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italia
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
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21
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Hajiev S, Allara E, Motedayеn Aval L, Arizumi T, Bettinger D, Pirisi M, Rimassa L, Pressiani T, Personeni N, Giordano L, Kudo M, Thimme R, Park JW, Taddei TH, Kaplan DE, Ramaswami R, Pinato DJ, Sharma R. Impact of age on sorafenib outcomes in hepatocellular carcinoma: an international cohort study. Br J Cancer 2021; 124:407-413. [PMID: 33071284 PMCID: PMC7852559 DOI: 10.1038/s41416-020-01116-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 09/15/2020] [Accepted: 09/25/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND There is no consensus on the effect of sorafenib dosing on efficacy and toxicity in elderly patients with hepatocellular carcinoma (HCC). Older patients are often empirically started on low-dose therapy with the aim to avoid toxicities while maximising clinical efficacy. We aimed to verify whether age impacts on overall survival (OS) and whether a reduced starting dose impacts on OS or toxicity experienced by the elderly. METHODS In an international, multicentre cohort study, outcomes for those aged <75 or ≥75 years were determined while accounting for common prognostic factors and demographic characteristics in univariable and multivariable models. RESULTS Five thousand five hundred and ninety-eight patients were recruited; 792 (14.1%) were aged ≥75 years. The elderly were more likely to have larger tumours (>7 cm) (39 vs 33%, p < 0.01) with preserved liver function (67 vs 57.7%) (p < 0.01). No difference in the median OS of those aged ≥75 years and <75 was noted (7.3 months vs 7.2 months; HR 1.00 (95% CI 0.93-1.08), p = 0.97). There was no relationship between starting dose of sorafenib 800 mg vs 400 mg/200 mg and OS between those <75 and ≥75 years. The elderly experienced a similar overall incidence of grade 2-4 sorafenib-related toxicity compared to <75 years (63.5 vs 56.7%, p = 0.11). However, the elderly were more likely to discontinue sorafenib due to toxicity (27.0 vs 21.6%, p < 0.01). This did not vary between different starting doses of sorafenib. CONCLUSIONS Clinical outcomes in the elderly is equivalent to patients aged <75 years, independent of dose of sorafenib prescribed.
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Affiliation(s)
- Saur Hajiev
- Division of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
| | - Elias Allara
- Division of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
- Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Leila Motedayеn Aval
- Division of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
| | - Tadaaki Arizumi
- Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka-Sayama, Japan
| | - Dominik Bettinger
- Department of Medicine II, University Medical Center, Freiburg, Germany
- Berta-Ottenstein Programme, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Mario Pirisi
- Department of Translational Medicine, Università degli Studi del Piemonte Orientale, Novara, Italy
| | - Lorenza Rimassa
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center-IRCCS, Rozzano (Milan), Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (Milan), Italy
| | - Tiziana Pressiani
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center-IRCCS, Rozzano (Milan), Italy
| | - Nicola Personeni
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center-IRCCS, Rozzano (Milan), Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (Milan), Italy
| | - Laura Giordano
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center-IRCCS, Rozzano (Milan), Italy
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka-Sayama, Japan
| | - Robert Thimme
- Department of Medicine II, University Medical Center, Freiburg, Germany
| | | | - Tamar H Taddei
- University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - David E Kaplan
- University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Ramya Ramaswami
- Division of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
| | - David J Pinato
- Division of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
| | - Rohini Sharma
- Division of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.
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22
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Kulik L, da Fonseca LG, He AR, Rimola J, Wilson Woods A, Zöllner YF, Galle PR. Potential Impact of IMbrave150 Results in the Evolving Treatment Landscape of Advanced Hepatocellular Carcinoma: A Multidisciplinary Expert Opinion. J Hepatocell Carcinoma 2020; 7:423-433. [PMID: 33376711 PMCID: PMC7762763 DOI: 10.2147/jhc.s274930] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 11/10/2020] [Indexed: 12/22/2022] Open
Abstract
A virtual expert roundtable was convened on April 16, 2020, to discuss the evolving landscape of care for treating patients with advanced hepatocellular carcinoma (HCC) and discuss questions related to patient care and treatment selection. This commentary presents highlights from this discussion and provides an expert opinion about approaches to treatment for HCC in the Americas and the European Union. We anticipate that atezolizumab plus bevacizumab will become the standard of care for advanced HCC patients. However, this approach will make decisions regarding the sequencing of treatments for second-line therapies and beyond more challenging. Therapy will require individualization based on patient characteristics and preferences, while insurance coverage decisions and requirements may also impact the options that patients can access. Additional research regarding prognostic and predictive biomarkers is needed to help better identify optimal treatment approaches for specific patient populations. Multidisciplinary tumor boards will continue to play a critical role in guiding treatment selection for individual patients. Atezolizumab plus bevacizumab offers a promising new first-line therapeutic option for patients with advanced HCC, but more research is needed to optimize and individualize patient therapy.
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Affiliation(s)
| | | | | | - Jordi Rimola
- Radiology Department, Hospital Clínic de Barcelona, Barcelona, Catalonia, Spain
| | - Andrea Wilson Woods
- Blue Faery: The Adrienne Wilson Liver Cancer Association, Birmingham, AL, USA
| | - York F Zöllner
- Hamburg University of Applied Sciences, Competence Center Health, Hamburg, Germany
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23
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Piñero F, Thompson M, Marín JI, Silva M. Lenvatinib as first-line therapy for recurrent hepatocellular carcinoma after liver transplantation: Is the current evidence applicable to these patients? World J Transplant 2020; 10:297-306. [PMID: 33312891 PMCID: PMC7708877 DOI: 10.5500/wjt.v10.i11.297] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 06/09/2020] [Accepted: 09/22/2020] [Indexed: 02/05/2023] Open
Abstract
Liver transplantation (LT) is one of the leading curative therapies for hepatocellular carcinoma (HCC). Despite recent optimization of transplant selection criteria, including alpha-feto protein, HCC recurrence after LT is still the leading cause of death in these patients. During the last decades, effective systemic treatments for HCC, including tyrosine kinase inhibitors and immunotherapy, have been approved. We describe the clinical scenario of a patient with recurrence of HCC five years after LT, who received lenvatinib as first-line systemic therapy to introduce systemic treatment options in this clinical setting. In this opinion review, we detail first and second-line systemic treatment options, focusing on those feasible for patients with recurrent HCC after LT. Several trials have evaluated new drugs to treat HCC patients in first and second-line therapy, but patients with recurrent HCC after LT have been excluded from these trials. Consequently, most of the evidence comes from observational retrospective studies. Whether tyrosine kinase inhibitors will remain the primary therapeutic approach in these patients, due to a relative contraindication for immunotherapy, may be clarified in the near future.
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Affiliation(s)
- Federico Piñero
- Hepatology and Liver Transplant Unit, Hospital Universitario Austral, Buenos Aires B1629HJ, Argentina
- Hospital Universitario Austral, Facultad de Ciencias Biomédicas, Universidad Austral, Buenos Aires B1629HJ, Argentina
- Latin American Liver Research Educational and Awareness Network (LALREAN), Buenos Aires B1629HJ, Argentina
| | - Marcos Thompson
- Hospital Universitario Austral, Facultad de Ciencias Biomédicas, Universidad Austral, Buenos Aires B1629HJ, Argentina
| | - Juan Ignacio Marín
- Hepatology and Liver Transplantation Unit, Hospital Pablo Tobón Uribe, Medellín 240, Colombia
| | - Marcelo Silva
- Hospital Universitario Austral, Facultad de Ciencias Biomédicas, Universidad Austral, Buenos Aires B1629HJ, Argentina
- Latin American Liver Research Educational and Awareness Network (LALREAN), Buenos Aires B1629HJ, Argentina
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24
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Abstract
Sorafenib was the first tyrosine kinase inhibitor (TKI) that showed success in extending survival in patients with advanced hepatocellular carcinoma (HCC). In recent years, additional TKIs have been shown to improve survival and expanded the armamentarium for treating this malignancy. The current landscape includes other classes of drugs, such as immune checkpoint inhibitors and monoclonal antibodies. The challenge is now placed on how to best select, combine, and sequence drugs with the goal of improving efficacy and minimizing toxicities to deliver better outcomes for HCC patients.
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Affiliation(s)
- Leonardo G da Fonseca
- Clinical Oncology, Instituto do Cancer do Estado de São Paulo, University of São Paulo, Av. Dr. Arnaldo, 251-Cerqueira Cesar, São Paulo, São Paulo CEP 01246-000, Brazil
| | - Maria Reig
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clinic Barcelona, IDIBAPS, Villarroel 170, Barcelona 08036, Spain; University of Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Jordi Bruix
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clinic Barcelona, IDIBAPS, Villarroel 170, Barcelona 08036, Spain; University of Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.
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25
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Díaz-González Á, Sapena V, Boix L, Brunet M, Torres F, LLarch N, Samper E, Millán O, Corominas J, Iserte G, Sanduzzi-Zamparelli M, da Fonseca LG, Darnell A, Belmonte E, Forner A, Ayuso C, Bruix J, Reig M. Pharmacokinetics and pharmacogenetics of sorafenib in patients with hepatocellular carcinoma: Implications for combination trials. Liver Int 2020; 40:2476-2488. [PMID: 33021346 DOI: 10.1111/liv.14587] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 06/07/2020] [Accepted: 06/09/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS Sorafenib and lenvatinib are the first-line treatments approved in hepatocellular carcinoma (HCC), but information is lacking about the relationships between their pharmacokinetics, patients pharmacogenetic profiles, adverse events (AE) and overall survival. We aimed to elucidate these relationships of tyrosine Kinase Inhibitors, such as sorafenib, in order to improve the design of trials testing it in combination with checkpoint inhibitors. METHODS We assessed the pharmacokinetics of sorafenib and its N-oxide metabolite at day-0, day-7, day-30, day-60, day-90, day-120, day-150 and day-180 and nine single-nucleotide polymorphisms (SNP) in five genes related to sorafenib metabolism/transport to identify the best point for starting the combination between tyrosine kinases and checkpoint inhibitors. RESULTS We prospectively included 49 patients (96% cirrhotic, 37% hepatitis-C, 82% Child-Pugh-A and 59% BCLC-C). Pharmacokinetic values peaked at day-7 and progressively declined until day-60. In the 16 patients without further dose modifications after day-60, pharmacokinetic values remained stable through day-180 (sorafenib P = .90; N-oxide P = .93). Pharmacokinetic values were higher in patients with early dermatological adverse events and lower in patients with early diarrhoea. Sorafenib and N-oxide pharmacokinetic values varied linearly with different alleles of MRP2*3972. CONCLUSIONS Sorafenib's pharmacokinetics is heterogeneous across HCC patients. This heterogeneity affects adverse events development and must be taken into account in setting the dose and timing of its combination with checkpoint inhibitors.
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Affiliation(s)
- Álvaro Díaz-González
- BCLC group. Liver Unit, Hospital Clínic de Barcelona. IDIBAPS. CIBERehd, University of Barcelona, Barcelona, Spain
| | - Víctor Sapena
- BCLC group. Liver Unit, Hospital Clínic de Barcelona. IDIBAPS. CIBERehd, University of Barcelona, Barcelona, Spain
| | - Loreto Boix
- BCLC group. Liver Unit, Hospital Clínic de Barcelona. IDIBAPS. CIBERehd, University of Barcelona, Barcelona, Spain
| | - Mercè Brunet
- Pharmacology and Toxicology Laboratory, Biochemistry and Molecular Genetics Department, Biomedical Diagnostic Center, Hospital Clínic de Barcelona. IDIBAPS. CIBERehd, University of Barcelona, Barcelona, Spain
| | - Ferrán Torres
- Medical Statistics Core Facility, IDIBAPS. Hospital Clínic de Barcelona. Biostatistics Unit, Faculty of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Neus LLarch
- BCLC group. Liver Unit, Hospital Clínic de Barcelona. IDIBAPS. CIBERehd, University of Barcelona, Barcelona, Spain
| | - Esther Samper
- BCLC group. Liver Unit, Hospital Clínic de Barcelona. IDIBAPS. CIBERehd, University of Barcelona, Barcelona, Spain
| | - Olga Millán
- Pharmacology and Toxicology Laboratory, Biochemistry and Molecular Genetics Department, Biomedical Diagnostic Center, Hospital Clínic de Barcelona. IDIBAPS. CIBERehd, University of Barcelona, Barcelona, Spain
| | - Josep Corominas
- BCLC group. Liver Unit, Hospital Clínic de Barcelona. IDIBAPS. CIBERehd, University of Barcelona, Barcelona, Spain
| | - Gemma Iserte
- BCLC group. Liver Unit, Hospital Clínic de Barcelona. IDIBAPS. CIBERehd, University of Barcelona, Barcelona, Spain
| | - Marco Sanduzzi-Zamparelli
- BCLC group. Liver Unit, Hospital Clínic de Barcelona. IDIBAPS. CIBERehd, University of Barcelona, Barcelona, Spain
| | - Leonardo G da Fonseca
- BCLC group. Liver Unit, Hospital Clínic de Barcelona. IDIBAPS. CIBERehd, University of Barcelona, Barcelona, Spain
| | - Anna Darnell
- BCLC group. Radiology department, Hospital Clínic de Barcelona. IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Ernest Belmonte
- BCLC group. Radiology department, Hospital Clínic de Barcelona. IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Alejandro Forner
- BCLC group. Liver Unit, Hospital Clínic de Barcelona. IDIBAPS. CIBERehd, University of Barcelona, Barcelona, Spain
| | - Carmen Ayuso
- BCLC group. Radiology department, Hospital Clínic de Barcelona. IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Jordi Bruix
- BCLC group. Liver Unit, Hospital Clínic de Barcelona. IDIBAPS. CIBERehd, University of Barcelona, Barcelona, Spain
| | - María Reig
- BCLC group. Liver Unit, Hospital Clínic de Barcelona. IDIBAPS. CIBERehd, University of Barcelona, Barcelona, Spain
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26
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Labeur TA, Hofsink Q, Takkenberg RB, van Delden OM, Mathôt RAA, Schinner R, Malfertheiner P, Amthauer H, Schütte K, Basu B, Kuhl C, Mayerle J, Ricke J, Klümpen HJ. The value of sorafenib trough levels in patients with advanced hepatocellular carcinoma - a substudy of the SORAMIC trial. Acta Oncol 2020; 59:1028-1035. [PMID: 32366155 DOI: 10.1080/0284186x.2020.1759826] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Background: Sorafenib for advanced hepatocellular carcinoma (HCC) is dose adjusted by toxicity. Preliminary studies have suggested an association between plasma concentrations of sorafenib and its main metabolite (M2) and clinical outcomes. This study aimed to validate these findings and establish target values for sorafenib trough concentrations.Methods: Patients with advanced HCC were prospectively recruited within a multicenter phase II study (SORAMIC). Patients with blood samples available at trough level were included for this pharmacokinetic (PK) substudy. Trough plasma concentrations of sorafenib and its main metabolite (M2) were associated with sorafenib-related toxicity and overall survival (OS).Results: Seventy-four patients were included with a median OS of 19.7 months (95% CI 16.1-23.3). Patients received sorafenib for a median of 51 weeks (IQR 27-62) and blood samples were drawn after a median of 25 weeks (IQR 10-42). Patients had a median trough concentration of 3217 ng/ml (IQR 2166-4526) and 360 ng/ml (IQR 190-593) with coefficients of variation of 65% and 146% for sorafenib and M2, respectively. Patients who experienced severe sorafenib-related toxicity received a lower average daily dose (551 vs 730 mg/day, p = .003), but showed no significant differences in sorafenib (3298 vs 2915 ng/ml, p = .442) or M2 trough levels (428 vs 283 ng/ml, p = .159). Trough levels of sorafenib or M2 showed no significant association with OS.Conclusions: In patients with advanced HCC treated with sorafenib, the administered dose, trough levels of sorafenib or M2, and clinical outcomes were poorly correlated. Toxicity-adjusted dosing remains the standard for sorafenib treatment.
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Affiliation(s)
- Tim A. Labeur
- Department of Medical Oncology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
- Cancer Center Amsterdam, Amsterdam, The Netherlands
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
- Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
| | - Quincy Hofsink
- Department of Medical Oncology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
- Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - R. Bart Takkenberg
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
| | - Otto M. van Delden
- Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
| | - Ron A. A. Mathôt
- Hospital Pharmacy, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
| | - Regina Schinner
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | | | - Holger Amthauer
- Department of Nuclear Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Kerstin Schütte
- Department of Internal Medicine and Gastroenterology, Niels-Stensen-Kliniken, Marienhospital Osnabrück, Osnabrück, Germany
| | - Bristi Basu
- Department of Oncology, University of Cambridge, Cambridge, UK
| | - Christiane Kuhl
- Department of Diagnostic and Interventional Radiology, University Hospital RWTH Aachen, Aachen, Germany
| | - Julia Mayerle
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Jens Ricke
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Heinz-Josef Klümpen
- Department of Medical Oncology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
- Cancer Center Amsterdam, Amsterdam, The Netherlands
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Lin Z, Chen B, Hung Y, Huang P, Shen Y, Shao Y, Hsu C, Cheng A, Lee R, Chao Y, Hsu C. A Multicenter Phase II Study of Second-Line Axitinib for Patients with Advanced Hepatocellular Carcinoma Failing First-Line Sorafenib Monotherapy. Oncologist 2020; 25:e1280-e1285. [PMID: 32271494 PMCID: PMC7485356 DOI: 10.1634/theoncologist.2020-0143] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Accepted: 02/18/2020] [Indexed: 12/24/2022] Open
Abstract
LESSONS LEARNED For patients with advanced hepatocellular carcinoma after failure of first-line sorafenib monotherapy, second-line axitinib provides modest efficacy with tolerable toxicity. The discrepant tumor responses and survival outcomes in trials using axitinib as salvage therapy highlight the importance of optimal patient selection with the aid of clinical biomarkers. BACKGROUND Multikinase inhibitors have been effective treatment for hepatocellular carcinoma (HCC). This multicenter phase II study explored the efficacy and safety of second-line axitinib for advanced HCC. METHODS Patients with advanced HCC and Child-Pugh A liver function, experiencing progression on first-line sorafenib monotherapy, were eligible. Axitinib 5 mg twice daily was given continuously with allowed dose escalation. Tumor assessment was performed according to RECIST version 1.1. The primary endpoint was rate of disease control. RESULTS From April 2011 to March 2016, 45 patients were enrolled. Thirty-seven patients (82%) tested positive for hepatitis B surface antigen. The disease control rate was 62.2%, and the response rate was 6.7%, according to RECIST criteria. Median progression-free survival (PFS) and overall survival (OS) were 2.2 months and 10.1 months, respectively. Treatment-related adverse events were compatible with previous reports of axitinib. CONCLUSION Second-line axitinib has moderate activity and acceptable toxicity for patients with advanced HCC after failing the first-line sorafenib monotherapy.
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Affiliation(s)
- Zhong‐Zhe Lin
- Department of Medical Oncology, National Taiwan University Cancer CenterTaipeiTaiwan
- Department of Oncology, National Taiwan University HospitalTaipeiTaiwan
- Department of Internal Medicine, National Taiwan University College of MedicineTaipeiTaiwan
| | - Bang‐Bin Chen
- Department of Radiology, National Taiwan University HospitalTaipeiTaiwan
| | - Yi‐Ping Hung
- Department of Oncology, Taipei Veterans General HospitalTaipeiTaiwan
| | - Po‐Hsiang Huang
- Department of Oncology, National Taiwan University HospitalTaipeiTaiwan
| | - Ying‐Chun Shen
- Department of Medical Oncology, National Taiwan University Cancer CenterTaipeiTaiwan
- Department of Oncology, National Taiwan University HospitalTaipeiTaiwan
- Graduate Institute of Oncology, National Taiwan University College of MedicineTaipeiTaiwan
| | - Yu‐Yun Shao
- Department of Oncology, National Taiwan University HospitalTaipeiTaiwan
- Graduate Institute of Oncology, National Taiwan University College of MedicineTaipeiTaiwan
| | - Chih‐Hung Hsu
- Department of Medical Oncology, National Taiwan University Cancer CenterTaipeiTaiwan
- Department of Oncology, National Taiwan University HospitalTaipeiTaiwan
- Graduate Institute of Oncology, National Taiwan University College of MedicineTaipeiTaiwan
| | - Ann‐Lii Cheng
- Department of Medical Oncology, National Taiwan University Cancer CenterTaipeiTaiwan
- Department of Oncology, National Taiwan University HospitalTaipeiTaiwan
- Department of Internal Medicine, National Taiwan University College of MedicineTaipeiTaiwan
- Graduate Institute of Oncology, National Taiwan University College of MedicineTaipeiTaiwan
| | - Rheun‐Chuan Lee
- Department of Radiology, Taipei Veterans General HospitalTaipeiTaiwan
| | - Yee Chao
- Department of Oncology, Taipei Veterans General HospitalTaipeiTaiwan
- School of Medicine, National Yang‐Ming UniversityTaipeiTaiwan
| | - Chiun Hsu
- Department of Medical Oncology, National Taiwan University Cancer CenterTaipeiTaiwan
- Department of Oncology, National Taiwan University HospitalTaipeiTaiwan
- Graduate Institute of Oncology, National Taiwan University College of MedicineTaipeiTaiwan
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28
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Dong Y, Liu TH, Yau T, Hsu C. Novel systemic therapy for hepatocellular carcinoma. Hepatol Int 2020; 14:638-651. [PMID: 32661949 DOI: 10.1007/s12072-020-10073-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Accepted: 07/01/2020] [Indexed: 12/11/2022]
Abstract
Systemic therapy for hepatocellular carcinoma (HCC) used to be limited to patients with advanced diseases and multi-kinase inhibitors targeting tumor angiogenesis the major approach of developing new treatment options. In the past 3 years, new data from trials of both molecular targeted therapy and immune checkpoint inhibitors (ICI) provided many new options of first- and second-line treatment for advanced HCC. Most notably, combination of ICI targeting the program cell death-1 (PD-1) pathway with other novel agents or conventional anti-cancer therapy may further improve treatment efficacy in different clinical settings. In this paper updated data of clinical trials of systemic therapy in the first- and second-line settings for advanced HCC were reviewed and the following issues were discussed: (1) lessons of trial design learned from positive and negative trials; (2) the balance between efficacy and safety in clinical practice; and (3) impact on future multi-disciplinary management of HCC.
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Affiliation(s)
- Yawen Dong
- Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China
| | - Tsung-Hao Liu
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Oncology, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, 10002, Taiwan
| | - Thomas Yau
- Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China.
| | - Chiun Hsu
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan. .,Department of Oncology, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, 10002, Taiwan.
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29
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Grothey A, Blay JY, Pavlakis N, Yoshino T, Bruix J. Evolving role of regorafenib for the treatment of advanced cancers. Cancer Treat Rev 2020; 86:101993. [DOI: 10.1016/j.ctrv.2020.101993] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 02/14/2020] [Accepted: 02/17/2020] [Indexed: 12/13/2022]
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Piñero F, Silva M, Iavarone M. Sequencing of systemic treatment for hepatocellular carcinoma: Second line competitors. World J Gastroenterol 2020; 26:1888-1900. [PMID: 32390700 PMCID: PMC7201145 DOI: 10.3748/wjg.v26.i16.1888] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2019] [Revised: 03/27/2020] [Accepted: 04/04/2020] [Indexed: 02/06/2023] Open
Abstract
During the last decades, further knowledge of hepatocellular carcinoma (HCC) molecular mechanisms has led to development of effective systemic treatments including tyrosine kinase inhibitors (TKIs) and immunotherapy. In this review, we describe first and second line systemic treatment options for advanced HCC. Several trials have evaluated new drugs for the treatment of HCC patients: In first line, lenvatinib resulted non-inferior to sorafenib and it can be used as alternative, even in the lack of evidence for sequential treatment options in second line after lenvatinib. Recently, atezolizumab plus bevacizumab have shown superiority over sorafenib in first-line. Sorafenib-regorafenib sequential administration in selected patients has opened a new paradigm of treatment in advanced HCC with a life expectancy exceeding two years. Other TKIs for second line treatment include cabozantinib and ramucirumab (specifically for patients with Alpha-fetoprotein values ≥ 400 ng/mL). The combination of TKIs with immunotherapy may represent a big step forward for these patients in the near future.
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Affiliation(s)
- Federico Piñero
- Hospital Universitario Austral, Facultad de Ciencias Biomédicas, Universidad Austral, Buenos Aires B1629HJ, Argentina
- Latin American Liver Research Educational and Awareness Network, Buenos Aires B1629HJ, Argentina
| | - Marcelo Silva
- Hospital Universitario Austral, Facultad de Ciencias Biomédicas, Universidad Austral, Buenos Aires B1629HJ, Argentina
- Latin American Liver Research Educational and Awareness Network, Buenos Aires B1629HJ, Argentina
| | - Massimo Iavarone
- Division of Gastroenterology and Hepatology, CRC “A.M. e A. Migliavacca” Center for the Study of Liver Disease, University of Milan, Fondazione IRCCS Ca’ Granda Maggiore Hospital, Milan 20121, Italy
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31
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Wang H, Liu Y, Shen K, Dong Y, Sun J, Shu Y, Wan X, Ren X, Wei X, Zhai B. A comparison between radiofrequency ablation combined with transarterial chemoembolization and surgical resection in hepatic carcinoma: A meta-analysis. J Cancer Res Ther 2020; 15:1617-1623. [PMID: 31939446 DOI: 10.4103/jcrt.jcrt_503_19] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
Objective This study determined whether the effect of combination therapy for hepatic carcinoma (HCC) is comparable to surgical resection (SR). According to the guidelines of the American Association for the Study of Liver Disease, radiofrequency ablation (RFA) and SR are recommended for early HCC. However, patients treated with RFA had worse long-term survival than those who received SR. Many studies utilizing the combination therapy with RFA and transarterial chemoembolization (TACE) have reported better prognosis as compared to RFA alone. Materials and Methods A comprehensive search in databases was conducted. Six retrospective studies and one cohort were enrolled in this meta-analysis. The overall survival (OS), disease-free survival (DFS), and major complications were compared between RFA plus TACE and SR. The pooled hazard ratio and 95% confidence interval (CI) were calculated and analyzed. Results After comparison, no significant difference in the OS and DFS at 1 and 3 years between the combination therapy and SR was observed (OS1: pooled relative risk [RR]: 0.82, 95% CI [0.56, 1.21]; OS3: pooled RR: 1.07, 95% CI [0.82, 1.39]; DFS1: pooled RR: 0.92, 95% CI [0.58, 1.45]; DFS3: pooled RR: 1.18, 95% CI [1.00, 1.40]). SR had better clinical outcomes than combination therapy with respect to long-term survival and disease progression (OS5: pooled RR: 1.12, 95% CI [1.03, 1.23]; DFS5: pooled RR: 1.15, 95% CI [1.03, 1.28]). Major complications were reduced with combination therapy (pooled RR: 0.46, 95% CI [0.25, 0.85]). Conclusion SR should remain as the first-line therapy for early HCC.
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Affiliation(s)
- Hongye Wang
- Department of Interventional Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Yihai Liu
- Department of Lightning Scientific Research Group, The First Clinical Medical School; Department of Cardiology, Nanjing Drum Tower Hospital, Nanjing Medical University, Nanjing, China
| | - Kangjie Shen
- Department of Interventional Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Yuxiang Dong
- Department of Interventional Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Jinyu Sun
- Department of Interventional Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Yimei Shu
- Department of Interventional Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Xiaojie Wan
- Department of Lightning Scientific Research Group, The Image Clinical School, Nanjing Medical University, Nanjing, China
| | - Xiaohan Ren
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiyi Wei
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Bo Zhai
- Department of Lightning Scientific Research Group, The First Clinical Medical School, Nanjing Medical University, Nanjing, China
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32
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Kumar A, Acharya SK, Singh SP, Arora A, Dhiman RK, Aggarwal R, Anand AC, Bhangui P, Chawla YK, Datta Gupta S, Dixit VK, Duseja A, Kalra N, Kar P, Kulkarni SS, Kumar R, Kumar M, Madhavan R, Mohan Prasad V, Mukund A, Nagral A, Panda D, Paul SB, Rao PN, Rela M, Sahu MK, Saraswat VA, Shah SR, Shalimar, Sharma P, Taneja S, Wadhawan M, The INASL Task-Force on Hepatocellular Carcinoma. 2019 Update of Indian National Association for Study of the Liver Consensus on Prevention, Diagnosis, and Management of Hepatocellular Carcinoma in India: The Puri II Recommendations. J Clin Exp Hepatol 2020; 10:43-80. [PMID: 32025166 PMCID: PMC6995891 DOI: 10.1016/j.jceh.2019.09.007] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Accepted: 09/15/2019] [Indexed: 01/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the major causes of morbidity, mortality, and healthcare expenditure in patients with chronic liver disease in India. The Indian National Association for Study of the Liver (INASL) had published its first guidelines on diagnosis and management of HCC (The Puri Recommendations) in 2014, and these guidelines were very well received by the healthcare community involved in diagnosis and management of HCC in India and neighboring countries. However, since 2014, many new developments have taken place in the field of HCC diagnosis and management, hence INASL endeavored to update its 2014 consensus guidelines. A new Task Force on HCC was constituted that reviewed the previous guidelines as well as the recent developments in various aspects of HCC that needed to be incorporated in the new guidelines. A 2-day round table discussion was held on 5th and 6th May 2018 at Puri, Odisha, to discuss, debate, and finalize the revised consensus statements. Each statement of the guideline was graded according to the Grading of Recommendations Assessment Development and Evaluation system with minor modifications. We present here the 2019 Update of INASL Consensus on Prevention, Diagnosis, and Management of Hepatocellular Carcinoma in India: The Puri-2 Recommendations.
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Key Words
- AFP, alpha-fetoprotein
- AIH, autoimmune hepatitis
- ALT, alanine aminotransferase
- DAA, direct-acting antiviral
- DALY, disability-adjusted life-year
- DNA, deoxyribonucleic acid
- GRADE, Grading of Recommendations Assessment Development and Evaluation
- Gd-BOPTA, gadolinium benzyloxypropionictetraacetate
- Gd-EOB-DTPA, gadolinium ethoxybenzyl diethylenetriamine penta-acetic acid
- HBV, hepatitis B virus
- HBeAg, hepatitis B envelope antigen
- HCC, hepatocellular carcinoma
- HIV, human immunodeficiency virus
- IARC, International Agency for Research on Cancer
- IFN, interferon
- INASL, Indian National Association for Study of the Liver
- MiRNA, micro-RNA
- NAFLD, non-alcoholic fatty liver disease
- NASH, non-alcoholic steatohepatitis
- PIVKA, protein induced by vitamin K absence
- RFA
- RNA, ribonucleic acid
- SVR, sustained virological response
- TACE
- TACE, trans-arterial chemoembolization
- TARE, transarterial radioembolization
- TNF, tumor necrosis factor
- WHO, World Health Organization
- liver cancer
- targeted therapy
- transplant
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Affiliation(s)
- Ashish Kumar
- Institute of Liver Gastroenterology & Pancreatico Biliary Sciences, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi, 110 060, India
| | - Subrat K. Acharya
- Department of Gastroenterology and Hepatology, KIIT University, Patia, Bhubaneswar, Odisha, 751 024, India
| | - Shivaram P. Singh
- Department of Gastroenterology, SCB Medical College, Cuttack, Dock Road, Manglabag, Cuttack, Odisha, 753 007, India
| | - Anil Arora
- Institute of Liver Gastroenterology & Pancreatico Biliary Sciences, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi, 110 060, India
| | - Radha K. Dhiman
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012, India
| | - Rakesh Aggarwal
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow, Uttar Pradesh, 226 014, India
| | - Anil C. Anand
- Department of Gastroenterology, Indraprastha Apollo Hospital, Sarita Vihar, New Delhi, 110 076, India
| | - Prashant Bhangui
- Medanta Institute of Liver Transplantation and Regenerative Medicine, Medanta the Medicity, CH Baktawar Singh Road, Sector 38, Gurugram, Haryana, 122 001, India
| | - Yogesh K. Chawla
- Department of Gastroenterology, Kalinga Institute of Medical Sciences (KIMS), Kushabhadra Campus (KIIT Campus-5), Patia, Bhubaneswar, Odisha, 751 024, India
| | - Siddhartha Datta Gupta
- Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110 029, India
| | - Vinod K. Dixit
- Department of Gastroenterology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, 221 005, India
| | - Ajay Duseja
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012, India
| | - Naveen Kalra
- Department of Radio Diagnosis and Imaging, Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012, India
| | - Premashish Kar
- Department of Gastroenterology and Hepatology, Max Super Speciality Hospital, Vaishali, Ghaziabad, Uttar Pradesh, 201 012, India
| | - Suyash S. Kulkarni
- Division of Interventional Radiology, Tata Memorial Hospital, Dr. E Borges Road, Parel, Mumbai, Maharashtra, 400 012, India
| | - Rakesh Kumar
- Department of Nuclear Medicine, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110 029, India
| | - Manoj Kumar
- Department of Hepatology, Institute of Liver & Biliary Sciences, Sector D-1, Vasant Kunj, New Delhi, 110 070, India
| | - Ram Madhavan
- Department of Radiation Oncology, Amrita Institute of Medical Sciences, Amrita University, Peeliyadu Road, Ponekkara, Edappally, Kochi, Kerala, 682 041, India
| | - V.G. Mohan Prasad
- Department of Gastroenterology, VGM Gastro Centre, 2100, Trichy Road, Rajalakshmi Mills Stop, Singanallur, Coimbatore, Tamil Nadu, 641 005, India
| | - Amar Mukund
- Department of Radiology, Institute of Liver & Biliary Sciences, Sector D-1, Vasant Kunj, New Delhi, 110 070, India
| | - Aabha Nagral
- Department of Gastroenterology, Jaslok Hospital & Research Centre, 15, Dr Deshmukh Marg, Pedder Road, Mumbai, Maharashtra, 400 026, India
| | - Dipanjan Panda
- Department of Oncology, Institutes of Cancer, Indraprastha Apollo Hospital, Sarita Vihar, New Delhi, 110 076, India
| | - Shashi B. Paul
- Department of Radiodiagnosis, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110 029, India
| | - Padaki N. Rao
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, No. 6-3-661, Punjagutta Road, Somajiguda, Hyderabad, Telangana, 500 082, India
| | - Mohamed Rela
- The Institute of Liver Disease & Transplantation, Gleneagles Global Health City, 439, Cheran Nagar, Perumbakkam, Chennai, Tamil Nadu, 600 100, India
| | - Manoj K. Sahu
- Department of Medical Gastroenterology, IMS & SUM Hospital, K8 Kalinga Nagar, Shampur, Bhubaneswar, Odisha 751 003, India
| | - Vivek A. Saraswat
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow, Uttar Pradesh, 226 014, India
| | - Samir R. Shah
- Department of Gastroenterology, Jaslok Hospital & Research Centre, 15, Dr Deshmukh Marg, Pedder Road, Mumbai, Maharashtra, 400 026, India
| | - Shalimar
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110 029, India
| | - Praveen Sharma
- Institute of Liver Gastroenterology & Pancreatico Biliary Sciences, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi, 110 060, India
| | - Sunil Taneja
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012, India
| | - Manav Wadhawan
- Liver & Digestive Diseases Institute, Institute of Liver & Digestive Diseases, BLK Super Specialty Hospital, Delhi, 110 005, India
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33
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Li JX, Liu X, Tang ST, Liang GL, Xiang BD. Letter: are sorafenib-related adverse events associated with prolonged survival? Aliment Pharmacol Ther 2020; 51:191. [PMID: 31850555 DOI: 10.1111/apt.15567] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Affiliation(s)
- Jian-Xu Li
- Hepatobiliary Surgery Department, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China.,Radiotherapy Department, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Xu Liu
- Hepatobiliary Surgery Department, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Shao-Tong Tang
- Hepatobiliary Surgery Department, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Guang-Lan Liang
- Hepatobiliary Surgery Department, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Bang-De Xiang
- Hepatobiliary Surgery Department, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
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34
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Sanduzzi-Zamparelli M, Sapena V, Bruix J, Reig M. Letter: are sorafenib-related adverse events associated with prolonged survival? Authors' reply. Aliment Pharmacol Ther 2020; 51:192. [PMID: 31850569 DOI: 10.1111/apt.15572] [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: 12/09/2022]
Affiliation(s)
- Marco Sanduzzi-Zamparelli
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Universidad de Barcelona, Barcelona, Spain
| | - Víctor Sapena
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Universidad de Barcelona, Barcelona, Spain
| | - Jordi Bruix
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Universidad de Barcelona, Barcelona, Spain
| | - María Reig
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Universidad de Barcelona, Barcelona, Spain
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35
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Tovoli F, Ielasi L, Casadei-Gardini A, Granito A, Foschi FG, Rovesti G, Negrini G, Orsi G, Renzulli M, Piscaglia F. Management of adverse events with tailored sorafenib dosing prolongs survival of hepatocellular carcinoma patients. J Hepatol 2019; 71:1175-1183. [PMID: 31449860 DOI: 10.1016/j.jhep.2019.08.015] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Revised: 07/10/2019] [Accepted: 08/02/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Sorafenib is associated with multiple adverse events (AEs), potentially causing its permanent interruption. It is unknown how physicians' experience has impacted on the management of these AEs and consequently on clinical outcomes. We aimed to assess whether AE management changed over time and if these modifications impacted on treatment duration and overall survival (OS). METHODS We analysed the prospectively collected data of 338 consecutive patients who started sorafenib between January 2008 and December 2017 in 3 tertiary care centres in Italy. Patients were divided according to the starting date: Group A (2008-2012; n = 154), and Group B (2013-2017, n = 184). Baseline and follow-up data were compared. In the OS analysis, patients who received second-line treatments were censored when starting the new therapy. RESULTS Baseline characteristics, AEs, and radiological response were consistent across groups. Patients in Group B received a lower median daily dose (425 vs. 568 mg/day, p <0.001) due to more frequent dose modifications. However, treatment duration was longer (5.8 vs. 4.1 months, p = 0.021) with a trend toward a higher cumulative dose in Group B. Notably, the OS was also higher (12.0 vs. 11.0 months, p = 0.003) with a sharp increase in the 2-year survival rate (28.1 vs. 18.4%, p = 0.003) in Group B. Multivariate time-dependent Cox regression analysis confirmed later period of treatment (2013-2017) as an independent predictor of survival (HR 0.728; 95%CI 0.581-0.937; p = 0.013). Unconsidered confounders were unlikely to affect these results at the sensitivity analysis. CONCLUSIONS Experience in the management of sorafenib-related AEs prolongs treatment duration and survival. This factor should be considered in the design of future randomised clinical trials including a sorafenib treatment arm, as an underestimate of sample size may derive. LAY SUMMARY Sorafenib has been the standard frontline systemic treatment for hepatocellular carcinoma for over a decade. Its tolerability is limited by different adverse events, which might lead to its permanent discontinuation in a sizeable proportion of patients. After a careful analysis of potential confounders, we demonstrated that the physicians' experience in managing adverse events related to sorafenib has improved over time, with longer treatment periods and less permanent discontinuation for toxicities. More importantly, these improvements also translated into longer patient survival. Our results have relevant repercussions in clinical practice and in the design of future clinical trials.
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Affiliation(s)
- Francesco Tovoli
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
| | - Luca Ielasi
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Andrea Casadei-Gardini
- Department of Medical Oncology, Istituto Scientifico Romagnolo per Lo Studio e Cura Dei Tumori, Meldola, Italy; Department of Oncology and Haematology, University Hospital of Modena, Modena, Italy
| | - Alessandro Granito
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | | | - Giulia Rovesti
- Department of Oncology and Haematology, University Hospital of Modena, Modena, Italy
| | - Giulia Negrini
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Giulia Orsi
- Department of Oncology and Haematology, University Hospital of Modena, Modena, Italy
| | - Matteo Renzulli
- Unit of Radiology, Department of Diagnostic Medicine and Prevention, Sant'Orsola Hospital, University of Bologna, Bologna, Italy
| | - Fabio Piscaglia
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
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36
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Zhou K, Fountzilas C. Outcomes and Quality of Life of Systemic Therapy in Advanced Hepatocellular Carcinoma. Cancers (Basel) 2019; 11:E861. [PMID: 31234316 PMCID: PMC6627968 DOI: 10.3390/cancers11060861] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2019] [Revised: 06/18/2019] [Accepted: 06/19/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed cancers worldwide; most patients are diagnosed with advanced disease for which there is no known cure. Tremendous progress has been made over the past decade in the development of new agents for HCC, including small-molecule kinase inhibitors such as sorafenib, lenvatinib, cabozantinib, regorafenib, and monoclonal antibodies like ramucirumab, nivolumab, and pembrolizumab. Ideal use of these agents in clinics has improved the long-term outcome of patients with advanced HCC as well as introduced unique toxicities that can affect quality of life. These toxicities usually are thought to be partially related to cirrhosis, a major risk factor for the development of HCC and a pathophysiological barrier complicating the optimal delivery of antineoplastic therapy. Additionally, side effects of medications together with advanced HCC symptoms not only decrease quality of life, but also cause treatment interruptions and dose reductions that can potentially decrease efficacy. Physicians caring for patients with advanced HCC are called to optimally manage HCC along with cirrhosis in order to prolong life while at the same time preserve the quality of life. In this review, we aimed to summarize outcomes and quality of life with the use of modern systemic treatments in advanced HCC and provide a physician reference for treatment toxicity and cirrhosis management.
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Affiliation(s)
- Kehua Zhou
- Catholic Health System Internal Medicine Training Program, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14214, USA.
| | - Christos Fountzilas
- Division of Gastrointestinal Medicine, Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
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Doycheva I, Thuluvath PJ. Systemic Therapy for Advanced Hepatocellular Carcinoma: An Update of a Rapidly Evolving Field. J Clin Exp Hepatol 2019; 9:588-596. [PMID: 31695249 PMCID: PMC6823698 DOI: 10.1016/j.jceh.2019.07.012] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2019] [Accepted: 07/21/2019] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) incidence and mortality have shown an unfavorable upward trend over the last two decades, especially in developed countries. More than one-sixth of the patients have advanced HCC at presentation. Systemic therapy remains the treatment of choice for these patients. Current options include tyrosine kinase inhibitors (TKIs) and immunotherapy. This review aims to summarize current knowledge on the rapidly evolving field of systemic therapy with several newly approved medications over the last year. Sorafenib remains one of the first-line treatment choices for patients with hepatitis C etiology, intermediate to advanced HCC stage, and Child-Pugh class A. Lenvatinib is the other first-line drug that might have better efficacy in non-hepatitis C etiologies and advanced HCC without portal vein thrombosis. Patients intolerant to first-line therapy might benefit from immunotherapy with nivolumab or pembrolizumab. In those who fail first-line therapy, the choice should be based on the side effects related to previous treatment, performance status, and underlying liver dysfunction. Ongoing studies are investigating immunotherapy alone or immunotherapy in combination with TKIs as first-line therapy. Several second-line options for combination systemic therapy and systemic plus local-regional treatment are under investigation. Future studies should focus on identifying reliable biomarkers to predict response to therapy and to better stratify patients at high risk for progression. Multidisciplinary approach is pivotal for successful outcomes in patients with advanced HCC.
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Key Words
- AFP, alpha-fetoprotein
- ATP, adenosine triphosphate
- BCLC, Barcelona Clinic Liver Cancer
- CI, confidence interval
- CTLA-4, cytotoxic T lymphocyte-associated antigen-4
- CTP, Child-Turcotte-Pugh
- ECOG, Eastern Cooperative Oncology Group
- EGFR, epidermal growth factor receptor
- FDA, Food and Drug Administration
- FGFR, fibroblast growth factor receptor
- HBV, hepatitis B virus
- HCC
- HCC, hepatocellular carcinoma
- HCV, hepatitis C virus
- HR, hazard ratio
- LRT, local-regional therapy
- LT, liver transplantation
- OS, overall survival
- PD-1, programmed cell death-1
- PDGFR, platelet-derived growth factor receptor
- PFS, progression-free survival
- RCT, randomized controlled trial
- RTK, receptor tyrosine kinase
- TACE, transarterial chemoembolization
- TEAE, treatment-emergent adverse effect
- TKI, tyrosine kinase inhibitor
- TTP, time to progression
- VEGFR, vascular endothelial growth factor receptor
- combination therapy
- immunotherapy
- irAE, immune-related adverse events
- systemic therapy
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Affiliation(s)
- Iliana Doycheva
- Institute for Digestive Heath and Liver Disease, Mercy Medical Center, Baltimore, MD, USA
| | - Paul J. Thuluvath
- Institute for Digestive Heath and Liver Disease, Mercy Medical Center, Baltimore, MD, USA,University of Maryland School of Medicine, 655 W Baltimore S, Baltimore, MD 21201, USA,Address for correspondence: Paul J. Thuluvath, MD Institute for Digestive Health and Liver Disease, Mercy Medical Center, 301 St. Paul Place, Baltimore, MD, 21202, USA.
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