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1
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Bejjani A, Finn RS. Evolution of Systemic Therapy in Advanced Hepatocellular Carcinoma. Surg Oncol Clin N Am 2024; 33:73-85. [PMID: 37945146 DOI: 10.1016/j.soc.2023.06.003] [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] [Indexed: 11/12/2023]
Abstract
The recognition that hepatocellular carcinoma (HCC) is a rising problem globally dates back decades; however, the development of effective medical treatment for the disease has only led to robust improvements in patient outcomes in the recent past. As knowledge evolves and regimens are proven to be more active, the importance of multidisciplinary management in patients with all stages of HCC will become more important to optimize patient outcomes. Key to optimizing patient outcomes is an understanding of the evolution and current role of these therapies in the HCC landscape.
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Affiliation(s)
- Anthony Bejjani
- Hematology/Oncology, VA Greater Los Angeles Health System, 11301 Wilshire Boulevard, Los Angeles, CA 90073, USA
| | - Richard S Finn
- Department of Medicine, Division of Hematology/ Oncology, Geffen School of Medicine at UCLA, 2825 Santa Monica Boulevard, Suite 200, Santa Monica, CA 90404, USA.
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2
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Lyles L, Farmer R, Abougergi M. A Potential New Use for Tocilizumab: Refractory Checkpoint Inhibitor Hepatitis. ACG Case Rep J 2023; 10:e01162. [PMID: 37753105 PMCID: PMC10519460 DOI: 10.14309/crj.0000000000001162] [Citation(s) in RCA: 1] [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: 04/18/2023] [Accepted: 08/29/2023] [Indexed: 09/28/2023] Open
Abstract
Immune checkpoint inhibitors are becoming more commonly used for many forms of malignancy. With this class of medications being more heavily used, there has been an associated rise in medication-induced autoimmune hepatitis. This case involves a 35-year-old woman being treated with nivolumab/ipilimumab for renal cell carcinoma who developed a steroid-refractory autoimmune hepatitis.
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Affiliation(s)
- Laine Lyles
- Prisma Health-University of South Carolina in Columbia, Columbia, SC
| | - Reagan Farmer
- University of South Carolina School of Medicine Columbia, Columbia, SC
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3
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Shannon AH, Manne A, Diaz Pardo DA, Pawlik TM. Combined radiotherapy and immune checkpoint inhibition for the treatment of advanced hepatocellular carcinoma. Front Oncol 2023; 13:1193762. [PMID: 37554167 PMCID: PMC10405730 DOI: 10.3389/fonc.2023.1193762] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Accepted: 07/03/2023] [Indexed: 08/10/2023] Open
Abstract
Hepatocellular Carcinoma (HCC) is one of the most common cancers and a leading cause of cancer related death worldwide. Until recently, systemic therapy for advanced HCC, defined as Barcelona Clinic Liver Cancer (BCLC) stage B or C, was limited and ineffective in terms of long-term survival. However, over the past decade, immune check point inhibitors (ICI) combinations have emerged as a potential therapeutic option for patients with nonresectable disease. ICI modulate the tumor microenvironment to prevent progression of the tumor. Radiotherapy is a crucial tool in treating unresectable HCC and may enhance the efficacy of ICI by manipulating the tumor microenvironment and decreasing tumor resistance to certain therapies. We herein review developments in the field of ICI combined with radiotherapy for the treatment of HCC, as well as look at challenges associated with these treatment modalities, and review future directions of combination therapy.
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Affiliation(s)
- Alexander H. Shannon
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Ashish Manne
- Department of Internal Medicine, Division of Medical Oncology at the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States
| | - Dayssy A. Diaz Pardo
- Department of Radiation Oncology, The Ohio State University, Comprehensive Cancer Center-James Hospital and Solove Research Institute, Columbus, OH, United States
| | - Timothy M. Pawlik
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, United States
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4
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Cheung TT, Yu SCH, Chan SL, Poon RTP, Kwok P, Lee AS, Tai A, Tam D, Cheung CC, Lai TW, Chia NH, Law A, Shum T, Lam YK, Lau V, Lee V, Chong C, Tang CN, Yau T. The Hong Kong consensus statements on unresectable hepatocellular carcinoma: narrative review and update for 2021. Hepatobiliary Surg Nutr 2023; 12:366-385. [PMID: 37351136 PMCID: PMC10282685 DOI: 10.21037/hbsn-21-405] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 02/10/2022] [Indexed: 08/30/2023]
Abstract
Background and Objective Hong Kong, like many parts of Asia, faces a high burden of hepatocellular carcinoma (HCC) caused by high endemic rates of hepatitis B virus infection. Hong Kong clinicians have developed a high level of expertise in HCC treatment across surgical, transarterial, ablative, radiotherapeutic and systemic modalities. This publication summarizes the latest evidence-based recommendations on how these modalities should be used. Methods In two meetings held in 2020, a multidisciplinary panel of surgeons, oncologists and interventional radiologists performed a narrative review of evidence on the management of HCC, with an emphasis on treatment of HCC not amenable to surgical resection. Close attention was paid to new evidence published since the previous version of these statements in 2018. Key Content and Findings The expert panel has formulated 60 consensus statements to guide the staging and treatment of unresectable HCC. Since the previous version of these statements, considerable additions have been made to the recommendations on use of targeted therapies and immunotherapies because of the large volume of new evidence. Conclusions Our consensus statements offer guidance on how to select HCC patients for surgical or non-surgical treatment and for choosing among non-surgical modalities for patients who are not candidates for resection. In particular, there is a need for more evidence to aid physicians in the selection of second-line systemic therapies, as currently most data are limited to patients with disease progression on first-line sorafenib.
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Affiliation(s)
- Tan-To Cheung
- Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Simon Chun-Ho Yu
- Department of Imaging & Interventional Radiology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Stephen L. Chan
- State Key Laboratory of Translational Oncology and Department of Clinical Oncology, Sir YK Pao Centre for Cancer, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Ronnie T. P. Poon
- Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Philip Kwok
- Department of Radiology and Imaging, Queen Elizabeth Hospital, Hong Kong, China
| | - Ann-Shing Lee
- Department of Clinical Oncology, Tuen Mun Hospital, Hong Kong, China
| | - Anna Tai
- Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong, China
| | - Derek Tam
- Department of Surgery, United Christian Hospital, Hong Kong, China
| | | | - Tak-Wing Lai
- Department of Surgery, Princess Margaret Hospital, Hong Kong, China
| | - Nam-Hung Chia
- Department of Surgery, Queen Elizabeth Hospital, Hong Kong, China
| | - Ada Law
- Department of Clinical Oncology, Pamela Youde Nethersole Eastern Hospital, Hong Kong, China
| | - Tracy Shum
- Department of Clinical Oncology, Princess Margaret Hospital, Hong Kong, China
| | - Yim-Kwan Lam
- Department of Medicine and Geriatrics, United Christian Hospital, Hong Kong, China
| | - Vince Lau
- Department of Radiology, Queen Mary Hospital, Hong Kong, China
| | - Victor Lee
- Department of Clinical Oncology, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Charing Chong
- Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Chung-Ngai Tang
- Department of Surgery, Pamela Youde Nethersole Eastern Hospital, Hong Kong, China
| | - Thomas Yau
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
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5
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Farasati Far B, Rabie D, Hemati P, Fooladpanjeh P, Faal Hamedanchi N, Broomand Lomer N, Karimi Rouzbahani A, Naimi-Jamal MR. Unresectable Hepatocellular Carcinoma: A Review of New Advances with Focus on Targeted Therapy and Immunotherapy. LIVERS 2023; 3:121-160. [DOI: 10.3390/livers3010011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Abstract
With an expected incidence of more than 1 million cases by 2025, liver cancer remains a problem for world health. With over 90% of cases, hepatocellular carcinoma (HCC) is the most prevalent kind of liver cancer. In this review, we presented the range of experimental therapeutics for patients with advanced HCC, the successes and failures of new treatments, areas for future development, the evaluation of dose-limiting toxicity in different drugs, and the safety profile in patients with liver dysfunction related to the underlying chronic liver disease. In addition to the unmet demand for biomarkers to guide treatment decisions and the burgeoning fields of immunotherapy and systemic therapy in hepatocellular carcinoma, the development of old and new drugs, including their failures and current advancements, has been reviewed. This review aims to evaluate the updated optimal clinical treatment of unresectable hepatocellular carcinomas in clinical practice, mainly through targeted therapy. Although surgical treatment can significantly enhance the survival probability of early and intermediate-stage patients, it is unsuitable for most HCC patients due to a lack of donors. Due to their severe toxicity, the few first-line anti-HCC drugs, such as sorafenib, are often reserved for advanced HCC patients for whom other therapies have failed. The second-line drugs are usually alternatives for patients with intolerance or resistance. Consequently, the ongoing growth of possible preclinical drugs and studies on miRNAs, lncRNAs, and numerous other signaling pathway targets for developing novel drugs may introduce additional treatment prospects for HCC.
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Affiliation(s)
- Bahareh Farasati Far
- Department of Chemistry, Iran University of Science and Technology, Tehran 1684613114, Iran
| | - Dorsa Rabie
- Faculty of Pharmaceutical Chemistry, Tehran Medical Sciences, Islamic Azad University, Tehran 193951495, Iran
| | - Parisa Hemati
- Faculty of Pharmaceutical Chemistry, Tehran Medical Sciences, Islamic Azad University, Tehran 193951495, Iran
| | - Parastoo Fooladpanjeh
- Faculty of Pharmaceutical Chemistry, Tehran Medical Sciences, Islamic Azad University, Tehran 193951495, Iran
| | - Neda Faal Hamedanchi
- Faculty of Medicine, Islamic Azad University, Tehran Medical Sciences Branch, Tehran 193951495, Iran
| | - Nima Broomand Lomer
- Faculty of Medicine, Guilan University of Medical Sciences, Rasht 4314637758, Iran
| | - Arian Karimi Rouzbahani
- Student Research Committee, Lorestan University of Medical Sciences, Khorramabad 6718773654, Iran
- USERN Office, Lorestan University of Medical Sciences, Khorramabad 6718773654, Iran
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6
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Jeng KS, Chang CF, Sheen IS, Jeng CJ, Wang CH. Cellular and Molecular Biology of Cancer Stem Cells of Hepatocellular Carcinoma. Int J Mol Sci 2023; 24:1417. [PMID: 36674932 PMCID: PMC9861908 DOI: 10.3390/ijms24021417] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 01/03/2023] [Accepted: 01/04/2023] [Indexed: 01/12/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death globally. The cancer stem cells (CSCs) of HCC are responsible for tumor growth, invasion, metastasis, recurrence, chemoresistance, target therapy resistance and radioresistance. The reported main surface markers used to identify liver CSCs include epithelial cell adhesion/activating molecule (EpCAM), cluster differentiation 90 (CD90), CD44 and CD133. The main molecular signaling pathways include the Wnt/β-catenin, transforming growth factors-β (TGF-β), sonic hedgehog (SHH), PI3K/Akt/mTOR and Notch. Patients with EpCAM-positive alpha-fetoprotein (AFP)-positive HCC are usually young but have advanced tumor-node-metastasis (TNM) stages. CD90-positive HCCs are usually poorly differentiated with worse prognosis. Those with CD44-positive HCC cells develop early metastases. Those with CD133 expression have a higher recurrence rate and a shorter overall survival. The Wnt/β-catenin signaling pathway triggers angiogenesis, tumor infiltration and metastasis through the enhancement of angiogenic factors. All CD133+ liver CSCs, CD133+/EpCAM+ liver CSCs and CD44+ liver CSCs contribute to sorafenib resistance. SHH signaling could protect HCC cells against ionizing radiation in an autocrine manner. Reducing the CSC population of HCC is crucial for the improvement of the therapy of advanced HCC. However, targeting CSCs of HCC is still challenging.
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Affiliation(s)
- Kuo-Shyang Jeng
- Department of Surgery, Far Eastern Memorial Hospital, New Taipei City 22060, Taiwan
| | - Chiung-Fang Chang
- Department of Surgery, Far Eastern Memorial Hospital, New Taipei City 22060, Taiwan
| | - I-Shyang Sheen
- Department of Hepato Gastroenterology, Linkou Medical Center, Chang-Gung University, Taoyuan City 33305, Taiwan
| | - Chi-Juei Jeng
- Postgraduate of Institute of Medicine, National Taiwan University, Taipei 10617, Taiwan
| | - Chih-Hsuan Wang
- Department of Surgery, Far Eastern Memorial Hospital, New Taipei City 22060, Taiwan
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7
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Li Q, Han J, Yang Y, Chen Y. PD-1/PD-L1 checkpoint inhibitors in advanced hepatocellular carcinoma immunotherapy. Front Immunol 2022; 13:1070961. [PMID: 36601120 PMCID: PMC9806143 DOI: 10.3389/fimmu.2022.1070961] [Citation(s) in RCA: 105] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Accepted: 12/06/2022] [Indexed: 12/23/2022] Open
Abstract
Hepatocellular carcinoma (HCC) has a high prevalence and mortality rate worldwide. Sorafenib monotherapy has been the standard of first-line treatment for advanced HCC for a long time, but there are still many shortcomings. In recent years, with the deepening of research on tumor immune microenvironment, researchers have begun to explore new approaches in immunotherapy, and the introduction of immune checkpoint inhibitors has brought fundamental changes to the treatment of HCC. Programmed cell death protein 1 (PD-1) is an immune checkpoint molecule that plays an important role in down-regulating immune system function and promoting tolerance. Programmed cell death ligand 1 (PDL-1) is involved in tumor immune evasion by binding to PD-1, resulting in failure of treatment. Currently, immunotherapy targeting the PD-1/PD-L1 axis has achieved unprecedented success in HCC, but it also faces great challenges, with its low remission rate still to be solved. For most patients with HCC, the PD-1/PD-L1 pathway is not the only rate limiting factor of antitumor immunity, and blocking only the PD-1/PD-L1 axis is not enough to stimulate an effective antitumor immune response; thus, combination therapy may be a better option. In this study, changes in the immune microenvironment of HCC patients were reviewed to clarify the feasibility of anti-PD-1/PD-L1 therapy, and a series of monotherapy and combination therapy clinical trials were summarized to verify the safety and efficacy of this newly developed treatment in patients with advanced HCC. Furthermore, we focused on hyperprogressive disease and drug resistance to gain a better understanding of PD-1/PD-L1 blockade as a promising treatment.
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Affiliation(s)
- Qian Li
- Department of Anesthesiology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jingjing Han
- Department of Anesthesiology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yonglin Yang
- Department of Infectious Diseases, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou, China
| | - Yu Chen
- Department of Anesthesiology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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8
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Shannon AH, Ruff SM, Pawlik TM. Expert Insights on Current Treatments for Hepatocellular Carcinoma: Clinical and Molecular Approaches and Bottlenecks to Progress. J Hepatocell Carcinoma 2022; 9:1247-1261. [PMID: 36514693 PMCID: PMC9741819 DOI: 10.2147/jhc.s383922] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 11/18/2022] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a primary liver tumor that typically occurs in the setting of chronic liver disease/cirrhosis. Treatment modalities for HCC have evolved and given the variety of treatment options, a multi-disciplinary approach requiring input from surgical, medical, and radiation oncology, hepatology, and interventional radiology is necessary. Multiple advances have been made over the last decade regarding treatment of HCC, especially advanced disease. Resection and transplantation remain as cornerstone curative-intent treatment options. For patients who are not candidates for curative-intent therapy, exciting progress has been made in molecular and cellular approaches to systemic therapy for HCC including immunotherapies and tyrosine kinase inhibitors. Although the prognosis for advanced HCC remains poor, the armamentarium of therapies has increased, and valuable years of life can be gained with these therapies. While the main therapeutic modality for early-stage disease remains resection, multimodal immunotherapy has emerged as first-line treatment for advanced disease. We herein review different clinical and molecular treatment modalities related to the treatment of HCC, as well as provide insights into future directions for HCC treatment. We highlight how research and progress are needed to move into a new era of molecular and cellular treatments.
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Affiliation(s)
- Alexander H Shannon
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Samantha M Ruff
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Timothy M Pawlik
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, USA,Correspondence: Timothy M Pawlik, Department of Surgery, The Urban Meyer III and Shelley Meyer Chair for Cancer Research, Professor of Surgery, Oncology, Health Services Management and Policy, The Ohio State University, Wexner Medical Center, 395 W. 12th Ave., Suite 670, Columbus, OH, USA, Tel +1 614 293 8701, Fax +1 614 293 4063, Email
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9
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Cammarota A, Zanuso V, Pressiani T, Personeni N, Rimassa L. Assessment and Monitoring of Response to Systemic Treatment in Advanced Hepatocellular Carcinoma: Current Insights. J Hepatocell Carcinoma 2022; 9:1011-1027. [PMID: 36128575 PMCID: PMC9482774 DOI: 10.2147/jhc.s268293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 08/22/2022] [Indexed: 11/23/2022] Open
Abstract
Advanced hepatocellular carcinoma (HCC) management has become more complex as novel therapies have been proven effective. After sorafenib, the approval of other multikinase inhibitors (MKIs) and immune checkpoints inhibitors (ICIs) has considerably increased the number of systemic therapies available. Therefore, careful assessment and monitoring of response to systemic treatment are essential to identify surrogate endpoints of overall survival (OS) in clinical trials and reliable tools to gauge treatment benefit in clinical practice. Progression-free survival (PFS) and objective response rate (ORR) are early informative parameters of efficacy that are not influenced by further lines of therapy. However, none of them has shown sufficient surrogacy to be recommended in place of OS in phase 3 trials. With such a wealth of therapeutic options, the prime intent of tumor assessments is no longer limited to identifying progressive disease to spare ineffective treatments to non-responders. Indeed, the early detection of responders could also help tailor treatment sequencing. Tumor assessment relies on the Response Evaluation Criteria for Solid Tumors (RECIST), which are easy to interpret - being based on dimensional principles - but could misread the activity of targeted agents. The HCC-specific modified RECIST (mRECIST), considering both the MKI-induced biological modifications and some of the cirrhosis-induced liver changes, better capture tumor response. Yet, mRECIST could not be considered a standard in advanced HCC. Further prognosticators including progression patterns, baseline and on-treatment liver function deterioration, and baseline alpha-fetoprotein (AFP) levels and AFP response have been extensively evaluated for MKIs. However, limited information is available for patients receiving ICIs and regarding their predictive role. Finally, there is increasing interest in incorporating novel imaging techniques which go beyond sizes and novel serum biomarkers in the advanced HCC framework. Hopefully, multiparametric models grouping dimensional and functional radiological parameters with biochemical markers will most precisely reflect treatment response.
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Affiliation(s)
- Antonella Cammarota
- Department of Biomedical Sciences, Humanitas University, Milan, Pieve Emanuele, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Milan, Rozzano, Italy
| | - Valentina Zanuso
- Department of Biomedical Sciences, Humanitas University, Milan, Pieve Emanuele, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Milan, Rozzano, Italy
| | - Tiziana Pressiani
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Milan, Rozzano, Italy
| | - Nicola Personeni
- Department of Biomedical Sciences, Humanitas University, Milan, Pieve Emanuele, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Milan, Rozzano, Italy
| | - Lorenza Rimassa
- Department of Biomedical Sciences, Humanitas University, Milan, Pieve Emanuele, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Milan, Rozzano, Italy
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10
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Advances in novel systemic therapies for advanced hepatocellular carcinoma. Future Med Chem 2022; 14:1455-1470. [PMID: 35997677 DOI: 10.4155/fmc-2022-0045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) represents the most frequent type of primary liver tumor. Most HCC patients present with advanced disease at diagnosis and the recurrence rate after surgery remains high. Treatment options for advanced HCC are limited, with sorafenib representing the only systemic agent approved for treatment of advanced HCC in more than a decade. However, in recent years new molecular targeted therapies and immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced HCC. In particular, combinations of ICIs with antiangiogenic drugs, or with other ICIs, represent one of the most promising strategies. Herein we provide a comprehensive overview of the main therapeutic advances in the systemic treatment of HCC, focusing on the most relevant ongoing clinical trials.
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11
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Prognosis and treatment pattern of advanced hepatocellular carcinoma after failure of first-line atezolizumab and bevacizumab treatment. Hepatol Int 2022; 16:1199-1207. [PMID: 35986846 DOI: 10.1007/s12072-022-10392-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 07/08/2022] [Indexed: 11/04/2022]
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12
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Khagazheeva MN, Dzhanyan IA, Breder VV, Laktionov KK. Nivolumab with Ipilimumab in the treatment of refractory hepatocellular carcinoma. MEDITSINSKIY SOVET = MEDICAL COUNCIL 2022:157-162. [DOI: 10.21518/2079-701x-2022-16-9-157-162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
HCC is considered refractory when it comes to progression during treatment with TKIs (sorafenib, lenvatinib). The combined immunotherapy of nivolumab with ipilimumab was studied in the one cohort of CheckMate-040 study, excluding immunotherapy-naive patients. The question of choosing an immunotherapy option in the presence of several options remains open. Like separate issue remains the prospect of using immunotherapeutic combinations after progression on immunotherapy. We present a long history of treatment of a patient with advanced HCC, which has been observed for 8 years at the Blokhin National Medical Research Center of Oncology. The example of this clinical observation shows the result of a multidisciplinary individual approach to the treatment of advanced HCC with the background of hepatitis C virus without liver cirrhosis (Child -Pugh A), stage BCLC-C. During this period of time, the patient received 5 lines of antitumor therapy, which were repeatedly supplemented with TACE procedures, radiation therapy and surgical treatment, with oligometastatic progression. The longest period of therapy without progression was recorded with the use of Nivolumab 240 mg in the 3rd line for 18 months, without clinically significant toxicity. The disease progressed with damage of the brain substance, one-stage microsurgical removal of metastases was performed, followed by EBRT. 4-line TKI therapy was not long-term. Due to the lack of a potential therapy option, it was recommended to resume therapy with anti-PD-1 with the addition of anti-CTLA-4, which gave its objective effect. Since November 2021 patient received 4 courses of Nivolumab 1 mg/kg + ipilimumab 3 mg/kg once every 3 weeks, and a partial effect was achieved (-42% according to RECIST 1.1). Then we performed nivolumab 240 mg IV every 2 weeks — which the patient continues to the present time.
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Affiliation(s)
| | | | - V. V. Breder
- Blokhin National Medical Research Center of Oncology
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13
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Ayoub WS, Jones PD, Yang JD, Martin P. Emerging drugs for the treatment of hepatocellular carcinoma. Expert Opin Emerg Drugs 2022; 27:141-149. [PMID: 35642526 DOI: 10.1080/14728214.2022.2083107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) remains a leading cause of liver related mortality. Cirrhosis of any etiology is the major risk factor although HCC can develop in its absence in patients with Hepatitis B and increasingly in those with non-alcoholic fatty liver disease. When detected at an early stage, curative options include surgical resection, liver transplantation and/or ablative therapies. Unfortunately, most cases of HCC are recognized at an advanced state when options are limited and non-curative. However new systemic therapies with tyrosine kinase inhibitors and immunotherapy have expanded therapeutic options in advanced HCC. Advances in systemic therapy have given patients with advanced HCC hope and prolonged their survival. Ongoing trials addressing different combination therapies with checkpoint inhibitors, tyrosine kinase inhibitors (TKI) or anti-VEGF therapies are expected to further enhance the management of advanced HCC. AREAS COVERED We discuss recent data and ongoing research efforsts to improve the treatment of hepatocellular carcinoma with discussion of current and upcoming systemic therapy combining agents of different classes. EXPERT OPINION Sustemic therapy for HCC is in evolution. The inclusion of immunotherapy to systemic therapy has revolutionalized the field of HCC treatment. Identificantion of the appropriate combination and sequence of systemic therapy coupled with discovery of reliable HCC biomarkers will lead to improved survival and inidividulized HCC therapy.
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Affiliation(s)
- Walid S Ayoub
- Cedars-Sinai Medical Center, Los Angeles, United States
| | - Patricia D Jones
- University of Miami Miller School of Medicine, Miami, Florida, United States
| | - Ju Dong Yang
- Cedars-Sinai Medical Center, Los Angeles, United States
| | - Paul Martin
- University of Miami Miller School of Medicine, Miami, Florida, United States
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14
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D'Avola D, Granito A, Torre-Aláez MDL, Piscaglia F. The importance of liver functional reserve in the non-surgical treatment of hepatocellular carcinoma. J Hepatol 2022; 76:1185-1198. [PMID: 34793869 DOI: 10.1016/j.jhep.2021.11.013] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 11/02/2021] [Accepted: 11/05/2021] [Indexed: 02/08/2023]
Abstract
The aim of any oncological treatment is not just to eliminate the tumour, but to maximise patient survival and quality of life. Since the liver has a vital function, any radical treatment that severely compromises liver function will result in a shortening of life expectancy, rather than a prolongation. Furthermore, even non-severe liver damage may prevent the delivery of further effective therapies. This is particularly important in the case of hepatocellular carcinoma (HCC), as it is associated with underlying cirrhosis in most patients - cirrhosis itself is not only a potentially lethal disease and independent prognostic factor in HCC, but it also makes liver function fragile. Accordingly, some information about liver dysfunction is included in most staging systems for HCC and can be used to guide the selection of treatments that the functional liver reserve can tolerate. Unfortunately, the prediction of functional damage to the liver in the case of antitumor treatments is very challenging and still suboptimal in any given patient. Moreover, while the assessment of functional reserve can now be used to avoid postoperative liver failure in the surgical setting, its use has been less well clarified for non-surgical therapies, which is of particular relevance today, as several lines of effective non-surgical treatments, including systemic therapies, have become available. The present article will a) critically review the implications of the assessment of liver functional reserve in patients with HCC, b) illustrate the available tools to assess liver functional reserve and c) discuss the role of functional assessment for each type of non-surgical therapy for HCC.
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Affiliation(s)
- Delia D'Avola
- Liver Unit, Internal Medicine Department, Clinica Universidad de Navarra, Pamplona and Madrid, Spain; Centro de Investigación Bio Medica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Pamplona, Spain
| | - Alessandro Granito
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy; Department of Medical and Surgical Sciences, University of Bologna, Italy
| | - Manuel de la Torre-Aláez
- Liver Unit, Internal Medicine Department, Clinica Universidad de Navarra, Pamplona and Madrid, Spain
| | - Fabio Piscaglia
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy; Department of Medical and Surgical Sciences, University of Bologna, Italy.
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15
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Akce M, El-Rayes BF, Bekaii-Saab TS. Frontline therapy for advanced hepatocellular carcinoma: an update. Therap Adv Gastroenterol 2022; 15:17562848221086126. [PMID: 35432597 PMCID: PMC9006370 DOI: 10.1177/17562848221086126] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 02/21/2022] [Indexed: 02/04/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fastest increasing cause of cancer-related mortality in the United States and is projected to be the third leading cause of cancer-related mortality in the United States by 2030. Main risk factors include alcoholic cirrhosis, chronic hepatitis B, hepatitis C, and nonalcoholic steatohepatitis (NASH). More than half of the patients have advanced-stage disease at presentation. Currently approved frontline systemic therapy options include sorafenib, lenvatinib, and atezolizumab/bevacizumab. Over the past decade, there has been a significant improvement in survival with a median overall survival of 19.2 months reported with first-line treatment with atezolizumab/bevacizumab. Based on positive results of randomized phase III HIMALAYA trial, durvalumab and tremelimumab combination could become another frontline option. Multiple frontline clinical trials with immune checkpoint inhibitor (ICI) or ICI combined with other novel agents are underway. In the frontline setting, identifying predictive biomarkers for ICI-based or tyrosine kinase (TKI)-based therapy is an unmet need. Subsequent treatment is poorly defined in patients with prior ICI-based therapy since all the available second-line and beyond therapy was studied after first-line sorafenib. Frontline systemic therapy is poorly defined in certain subgroups of HCC such as Child-Pugh B and post-transplant recurrent HCC. The landscape of frontline HCC treatment is rapidly changing, and this article reviews the most recent treatment approaches to frontline therapy for advanced HCC.
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Affiliation(s)
- Mehmet Akce
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
| | - Bassel F. El-Rayes
- Division of Hematology and Oncology, Department of Internal Medicine, O’Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, AL, USA
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16
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El-Khoueiry AB, Meyer T, Cheng AL, Rimassa L, Sen S, Milwee S, Kelley RK, Abou-Alfa GK. Safety and efficacy of cabozantinib for patients with advanced hepatocellular carcinoma who advanced to Child-Pugh B liver function at study week 8: a retrospective analysis of the CELESTIAL randomised controlled trial. BMC Cancer 2022; 22:377. [PMID: 35397508 PMCID: PMC8994237 DOI: 10.1186/s12885-022-09453-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 03/16/2022] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Patients with hepatocellular carcinoma (HCC) and Child-Pugh B liver cirrhosis have poor prognosis and are underrepresented in clinical trials. The CELESTIAL trial, in which cabozantinib improved overall survival (OS) and progression-free survival (PFS) versus placebo in patients with HCC and Child-Pugh A liver cirrhosis at baseline, was evaluated for outcomes in patients who had Child-Pugh B cirrhosis at Week 8. METHODS This was a retrospective analysis of adult patients with previously treated advanced HCC. Child-Pugh B status was assessed by the investigator. Patients were randomised 2:1 to cabozantinib (60 mg once daily) or placebo. RESULTS Fifty-one patients receiving cabozantinib and 22 receiving placebo had Child-Pugh B cirrhosis at Week 8. Safety and tolerability of cabozantinib for the Child-Pugh B subgroup were consistent with the overall population. For cabozantinib- versus placebo-treated patients, median OS from randomisation was 8.5 versus 3.8 months (HR 0.32, 95% CI 0.18-0.58), median PFS was 3.7 versus 1.9 months (HR 0.44, 95% CI 0.25-0.76), and best response was stable disease in 57% versus 23% of patients. CONCLUSIONS These encouraging results with cabozantinib support the initiation of prospective studies in patients with advanced HCC and Child-Pugh B liver function. CLINICAL TRIAL REGISTRATION NCT01908426.
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Affiliation(s)
| | - Tim Meyer
- Royal Free Hospital, University College London, London, UK
| | | | - Lorenza Rimassa
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | | | | | - Robin Kate Kelley
- UCSF Helen Diller Family Comprehensive Cancer Center, CA, San Francisco, USA
| | - Ghassan K Abou-Alfa
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Medical College at Cornell University, New York, NY, USA
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17
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Kang SM, Khalil L, El-Rayes BF, Akce M. Rapidly Evolving Landscape and Future Horizons in Hepatocellular Carcinoma in the Era of Immuno-Oncology. Front Oncol 2022; 12:821903. [PMID: 35433430 PMCID: PMC9008732 DOI: 10.3389/fonc.2022.821903] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 03/08/2022] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a serious global health problem as one of the leading causes of cancer-related death worldwide. Systemic therapy for advanced HCC has progressed with the development of molecular targeted agents, however survival benefits remain modest. More recently, immune checkpoint inhibitors (ICI) have emerged and exhibited promising therapeutic benefits in a subset of patients. Physiologically, the intrinsic microenvironment in the liver is immunosuppressive, which represents a major obstacle for effective immune therapies in primary and secondary liver malignancies. For this reason, combination therapies that can overcome immune inhibitory mechanisms and enhance the immune response are a rationale approach for drug development in HCC. A recent example is the combination of the anti-PD-L1 antibody (atezolizumab) and anti-VEGF-A antibody (bevacizumab), which has shown significant improvement in survival as compared to standard of care in the first-line treatment for HCC. Other immunotherapy approaches including cancer vaccines and adoptive cell therapy are also under investigation. This review summarizes the key trials leading to our current HCC treatment options and provides an overview of future immune-based strategies in development.
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Affiliation(s)
| | | | | | - Mehmet Akce
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, United States
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18
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The Treatment Landscape of Advanced Hepatocellular Carcinoma. Curr Oncol Rep 2022; 24:917-927. [PMID: 35347594 DOI: 10.1007/s11912-022-01247-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/10/2022] [Indexed: 02/08/2023]
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19
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Carloni R, Rizzo A, Ricci AD, Frega G, Federico AD, Palloni A, Marco MD, Gadaleta-Caldarola G, Brandi G. Dual immune checkpoint blockade in hepatocellular carcinoma: where do we stand? Future Oncol 2022; 18:1023-1034. [PMID: 35109664 DOI: 10.2217/fon-2021-0905] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC) represents the fourth most common cause of cancer-related death. Surgery, local ablative therapies and liver transplantation are the only potentially curative strategies, but the majority of patients present with advanced disease at diagnosis or develop recurrence after surgery. In recent years, immunotherapy for HCC has received growing interest, and one of the most promising strategies is the association of two immune checkpoint inhibitors (ICIs), which has already demonstrated its potential in other solid tumors such as melanoma and renal cell carcinoma. Herein, we discuss the role and the biologic rationale of dual immune checkpoint blockade in HCC patients, focusing on the two ICI combinations: nivolumab plus ipilimumab and durvalumab plus tremelimumab.
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Affiliation(s)
- Riccardo Carloni
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, Bologna, Italy
| | - Alessandro Rizzo
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, Bologna, Italy.,Medical Oncology Unit, 'Mons. R. Dimiccoli' Hospital, Barletta (BT), Azienda Sanitaria Locale Barletta, 76121, Italy
| | - Angela Dalia Ricci
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, Bologna, Italy.,Medical Oncology Unit, 'Mons. R. Dimiccoli' Hospital, Barletta (BT), Azienda Sanitaria Locale Barletta, 76121, Italy
| | - Giorgio Frega
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, Bologna, Italy
| | - Alessandro Di Federico
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, Bologna, Italy
| | - Andrea Palloni
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, Bologna, Italy
| | - Mariacristina Di Marco
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, Bologna, Italy
| | - Gennaro Gadaleta-Caldarola
- Medical Oncology Unit, 'Mons. R. Dimiccoli' Hospital, Barletta (BT), Azienda Sanitaria Locale Barletta, 76121, Italy
| | - Giovanni Brandi
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, Bologna, Italy
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20
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Huang X, Xu L, Ma T, Yin X, Huang Z, Ran Y, Ni Y, Bi X, Che X. Lenvatinib Plus Immune Checkpoint Inhibitors Improve Survival in Advanced Hepatocellular Carcinoma: A Retrospective Study. Front Oncol 2021; 11:751159. [PMID: 34868952 PMCID: PMC8637826 DOI: 10.3389/fonc.2021.751159] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 10/28/2021] [Indexed: 12/12/2022] Open
Abstract
Background Nivolumab and pembrolizumab disrupt the programmed cell death-1 immune checkpoint and display promising efficacy and safety results in advanced hepatocellular carcinoma (HCC). However, the benefits remain limited. The preliminary results of lenvatinib (LEN) combined with immune checkpoint inhibitors (ICIs) reveal that the combinations were well-tolerated and encouraging. This study aimed to analyze the safety and efficacy of LEN plus ICIs in a real-world cohort of patients with advanced HCC. Method Between June 4, 2017, and June 30, 2019, 16 patients received LEN plus nivolumab, and 13 patients were treated with LEN plus pembrolizumab, with the confirmed advanced HCC retrospectively analyzed. The clinical parameters, as well as the outcomes, were assessed. Results All the patients had Barcelona Clinical Liver Cancer Stage C. LEN with ICIs was used as systemic second-, third-, and fourth-line treatments in seven (24.1%), 14 (48.3%), and eight (27.6%) patients, respectively. At the time of data cutoff, six patients (37.5%) were still receiving LEN with nivolumab, while another six patients (46.2%) were still receiving LEN with pembrolizumab. An objective response was recorded in seven patients (25.9%), while the best overall responses were from one complete response and six partial responses. The 6- and 12-month over survival (OS) rates were 62.6% and 53.7%, respectively. Furthermore, the 6- and 12-month progression-free survival (PFS) rates were 43.5% and 31.8%, respectively. In the subgroup analyses, the 6- and 12-month OS and PFS rates for patients treated with LEN plus nivolumab were 62.5% and 52.1%, respectively, and 43.8% and 30.0%, respectively. The 6- and 12-month OS and PFS rates for patients treated with LEN plus pembrolizumab were 51.3% and 51.3%, respectively, and 49.2% and 49.2%, respectively. A total of 11 (31%) deaths were reported in this study, four of which were attributed to grade 5 adverse events presented as fatal treatment-related hepatitis. Conclusion The combination of LEN and ICIs is a promising new strategy for the treatment of HCC patients. However, high-grade hepatic toxicity was observed and further evaluation of this combination is still required.
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Affiliation(s)
- Xiaozhun Huang
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Lin Xu
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Teng Ma
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Xin Yin
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Zhangkan Huang
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Yihong Ran
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Yong Ni
- Department of Hepatological Surgery, Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Xinyu Bi
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xu Che
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China.,Department of Gastrointestinal & Pancreatic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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21
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Di Federico A, Rizzo A, Carloni R, De Giglio A, Bruno R, Ricci D, Brandi G. Atezolizumab-bevacizumab plus Y-90 TARE for the treatment of hepatocellular carcinoma: preclinical rationale and ongoing clinical trials. Expert Opin Investig Drugs 2021; 31:361-369. [PMID: 34798793 DOI: 10.1080/13543784.2022.2009455] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION The treatment algorithm of advanced hepatocellular carcinoma (HCC) has evolved since the introduction of immunotherapy. The IMbrave150 trial set atezolizumab-bevacizumab as a new standard-of-care first-line treatment for unresectable HCC patients. However, for patients with intermediate or advanced stage with portal vein thrombosis but without distant metastases, 90Yttrium transarterial radioembolization (90Y-TARE) is considered the treatment of choice. AREAS COVERED We discuss the main evidence regarding the use of 90Y-TARE in HCC, the recent progress of immunotherapy in this tumor, and the preclinical rationale of combining VEGF blockade with the other two treatment strategies. EXPERT OPINION HCC has an extremely heterogeneous tumor immune microenvironment. This may explain the inconsistent outcomes obtained with immune-checkpoint inhibitors. The identification of patients who could benefit most from immunotherapy is crucial; however, reliable markers of response are lacking. Radiation therapy and VEGF inhibition have an established synergism with immunotherapy, mainly linked to enhanced antigen presentation and reduced immunosuppressive immune infiltrate. Combining an immune-checkpoint inhibitor with VEGF blockade and 90Y-TARE might hence overcome primary resistances observed when each of these treatments is administerd alone.
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Affiliation(s)
- Alessandro Di Federico
- Division of Medical Oncology, Irccs Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy.,Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Bologna, Italy
| | - Alessandro Rizzo
- Division of Medical Oncology, Irccs Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy.,Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Bologna, Italy
| | - Riccardo Carloni
- Division of Medical Oncology, Irccs Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy.,Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Bologna, Italy
| | - Andrea De Giglio
- Division of Medical Oncology, Irccs Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy.,Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Bologna, Italy
| | - Riccardo Bruno
- Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Bologna, Italy.,Department of Radiology, Irccs Azienda Ospedaliero Universitaria Di Bologna, Bologna, Italia
| | - Dalia Ricci
- Division of Medical Oncology, Irccs Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy.,Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Bologna, Italy
| | - Giovanni Brandi
- Division of Medical Oncology, Irccs Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy.,Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Bologna, Italy
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22
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Khan AA, Liu ZK, Xu X. Recent advances in immunotherapy for hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int 2021; 20:511-520. [PMID: 34344612 DOI: 10.1016/j.hbpd.2021.06.010] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 06/22/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND Treatment of hepatocellular carcinoma (HCC) is challenging as most patients are diagnosed at advanced stage with underlying chronic liver conditions. Conventional systemic chemotherapy has failed in HCC, and the clinical efficacy of FDA-approved molecular targeted agents such as sorafenib and lenvatinib remains unsatisfactory. DATA SOURCES Literature search was conducted in PubMed for relevant articles published before January 2021. The search aimed to identify recent developments in immune-based treatment approaches for HCC. Information of clinical trials was obtained from https://clinicaltrials.gov/. RESULTS Two immune checkpoint inhibitors (ICIs), nivolumab and pembrolizumab were approved as monotherapies, which has revolutionized HCC treatment. Besides, combination ICIs have also got accelerated FDA approval recently. Immune-based therapies have challenged targeted drugs owing to their safety, tolerability, and survival benefits. In addition to the significant success in ICIs, other immunotherapeutic strategies such as cancer vaccine, chimeric antigen receptor T-cells, natural killer cells, cytokines, and combination therapy, have also shown promising outcomes in clinical trials. Various diagnostic and prognostic biomarkers have been identified which can help in clinical decision making when starting treatment with ICIs. CONCLUSIONS Immunotherapy has emerged as one of the mainstream treatment modalities for advanced HCC in recent years. However, challenges such as low response rate and acquired resistance in previously respondent patients still exist. Further research is needed to understand the unique resistance mechanism to immunotherapy and to discover more predictive biomarkers to guide clinical decision making.
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Affiliation(s)
- Abid Ali Khan
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Key Lab of Combined Multi-Organ Transplantation, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Ministry of Public Health, Hangzhou 310003, China
| | - Zhi-Kun Liu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Key Lab of Combined Multi-Organ Transplantation, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Ministry of Public Health, Hangzhou 310003, China
| | - Xiao Xu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Key Lab of Combined Multi-Organ Transplantation, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Ministry of Public Health, Hangzhou 310003, China; Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.
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23
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Chen CT, Liu TH, Shao YY, Liu KL, Liang PC, Lin ZZ. Revisiting Hepatic Artery Infusion Chemotherapy in the Treatment of Advanced Hepatocellular Carcinoma. Int J Mol Sci 2021; 22:12880. [PMID: 34884684 PMCID: PMC8657421 DOI: 10.3390/ijms222312880] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 11/25/2021] [Accepted: 11/25/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatic artery infusion chemotherapy (HAIC) is a well-established and common treatment for advanced hepatocellular carcinoma (HCC), particularly in East Asia. However, HAIC is not recognized internationally. Although several trials have demonstrated the safety and efficacy of HAIC, evidence corroborating its overall survival (OS) benefits compared with standard treatments is insufficient. Nevertheless, HAIC may provide prominent benefits in selected patients such as patients with portal vein thrombosis or high intrahepatic tumor burden. Moreover, HAIC has been combined with several therapeutic agents and modalities, including interferon-alpha, multikinase inhibitors, radiation therapy, and immunotherapy, to augment its treatment efficacy. Most of these combinations appeared to increase overall response rates compared with HAIC alone, but results regarding OS are inconclusive. Two prospective randomized controlled trials comparing HAIC plus sorafenib with sorafenib alone have reported conflicting results, necessitating further research. As immunotherapy-based combinations became the mainstream treatments for advanced HCC, HAIC plus immunotherapy-based treatments also showed encouraging preliminary results. The trials of HAIC were heterogeneous in terms of patient selection, chemotherapy regimens and doses, HAIC combination agent selections, and HAIC technical protocols. These heterogeneities may contribute to differences in treatment efficacy, thus increasing the difficulty of interpreting trial results. We propose that future trials of HAIC standardize these key factors to reveal the clinical value of HAIC-based treatments for HCC.
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Affiliation(s)
- Ching-Tso Chen
- Department of Oncology, National Taiwan University Hospital Hsinchu Branch, Hsinchu 300195, Taiwan;
- Department of Oncology, National Taiwan University Hospital, Taipei 100225, Taiwan; (T.-H.L.); (Y.-Y.S.)
| | - Tsung-Hao Liu
- Department of Oncology, National Taiwan University Hospital, Taipei 100225, Taiwan; (T.-H.L.); (Y.-Y.S.)
- Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei 100233, Taiwan
| | - Yu-Yun Shao
- Department of Oncology, National Taiwan University Hospital, Taipei 100225, Taiwan; (T.-H.L.); (Y.-Y.S.)
- Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei 100233, Taiwan
| | - Kao-Lang Liu
- Department of Medical Imaging, National Taiwan University Hospital, Taipei 100225, Taiwan;
- Department of Medical Imaging, National Taiwan University Cancer Center, Taipei 106328, Taiwan
| | - Po-Chin Liang
- Department of Medical Imaging, National Taiwan University Hospital, Taipei 100225, Taiwan;
- Department of Medical Imaging, National Taiwan University Hospital Hsinchu Branch, Hsinchu 300195, Taiwan
| | - Zhong-Zhe Lin
- Department of Oncology, National Taiwan University Hospital, Taipei 100225, Taiwan; (T.-H.L.); (Y.-Y.S.)
- Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei 100233, Taiwan
- Department of Medical Oncology, National Taiwan University Cancer Center, Taipei 106328, Taiwan
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24
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Bruix J, Chan SL, Galle PR, Rimassa L, Sangro B. Systemic treatment of hepatocellular carcinoma: An EASL position paper. J Hepatol 2021; 75:960-974. [PMID: 34256065 DOI: 10.1016/j.jhep.2021.07.004] [Citation(s) in RCA: 244] [Impact Index Per Article: 61.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 06/22/2021] [Accepted: 07/05/2021] [Indexed: 12/12/2022]
Abstract
The last 5 years have witnessed relevant advances in the systemic treatment of hepatocellular carcinoma. New data have emerged since the development of the EASL Clinical Practice Guidelines on the management of hepatocellular carcinoma in 2018. Drugs licensed in some countries now include 4 oral multi-tyrosine kinase inhibitors (sorafenib, lenvatinib, regorafenib and cabozantinib), 1 anti-angiogenic antibody (ramucirumab) and 4 immune checkpoint inhibitors, alone or in combination (atezolizumab in combination with bevacizumab, ipilimumab in combination with nivolumab, nivolumab and pembrolizumab in monotherapy). Prolonged survival in excess of 2 years can be expected in most patients with sensitive tumours and well-preserved liver function that renders them fit for sequential therapies. With different choices available in any given setting, the robustness of the evidence of efficacy and a correct matching of the safety profile of a given agent with patient characteristics and preferences are key in making sound therapeutic decisions. The recommendations in this document amend the previous EASL Clinical Practice Guidelines and aim to help clinicians provide the best possible care for patients today. In view of several ongoing and promising trials, further advances in systemic therapy of hepatocellular carcinoma are foreseen in the near future and these recommendations will have to be updated regularly.
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Affiliation(s)
- Jordi Bruix
- BCLC Group, Liver Unit, Hospital Clínic, University of Barcelona, IDIBAPS, CIBEREHD, Barcelona, Spain
| | - Stephen L Chan
- Department of Clinical Oncology, State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China
| | | | - Lorenza Rimassa
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Bruno Sangro
- Liver Unit and HPB Oncology Area, Clinica Universidad de Navarra-IDISNA and CIBEREHD, Pamplona, Spain.
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25
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Fessas P, Kaseb A, Wang Y, Saeed A, Szafron D, Jun T, Dharmapuri S, Rafeh Naqash A, Muzaffar M, Navaid M, Khan U, Lee C, Bulumulle A, Yu B, Paul S, Nimkar N, Bettinger D, Benevento F, Hildebrand H, Pressiani T, Abugabal YI, Personeni N, Huang YH, Rimassa L, Ang C, Marron T, Pinato DJ. Post-registration experience of nivolumab in advanced hepatocellular carcinoma: an international study. J Immunother Cancer 2021; 8:jitc-2020-001033. [PMID: 32868393 PMCID: PMC7462152 DOI: 10.1136/jitc-2020-001033] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/06/2020] [Indexed: 12/11/2022] Open
Abstract
Background Nivolumab is Food and Drug Administration approved in sorafenib-experienced, advanced hepatocellular carcinoma (HCC). Post-registration data of treatment in a real-world setting is lacking. Patients and methods We performed an international, multicenter observational study to confirm safety and efficacy of nivolumab in 233 patients treated outside clinical trials from eight centers in North America, Europe and Asia. Results Patients received nivolumab for Barcelona Clinic Liver Cancer stage C (n=191, 92.0%) and Child-Pugh (CP) A (n=158, 67.8%) or B (n=75, 32.2%) HCC as first (n=85, 36.5%) or second to fourth systemic therapy line (n=148, 63.5%). Objective response rate (ORR) was 22.4% and disease control rate was 52.1%. Median overall survival (OS) was 12.2 months (95% CI 8.4 to 16.0) and median progression-free survival was 10.1 months (95% CI 6.1 to 14.2). Treatment-related adverse events of grade >2 occurred in 26 patients (11.2%). Efficacy and safety were similar across CP classes and therapy line. OS was shorter in CP-B than A (7.3 months vs 16.3 months, p<0.001) and in post-first line use (10.4 months vs 16.3 months, p=0.05). Achievement of an objective response predicted for improved OS (25.4 months vs 13.2 months, p<0.001). Conclusions This study confirms safety and efficacy of nivolumab in advanced HCC across various lines of therapy and degrees of liver dysfunction. Despite equal ORR and toxicity to nivolumab, patients with CP-B functional class have shorter survival than the patients with CP-A.
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Affiliation(s)
- Petros Fessas
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Ahmed Kaseb
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
| | - Yinghong Wang
- Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
| | - Anwaar Saeed
- Division of Medical Oncology, Department of Medicine, Kansas University Cancer Center, Westwood, Kansas, United States
| | - David Szafron
- Department of Internal Medicine, Baylor College of Medicine, Houston, Texas, United States
| | - Tomi Jun
- Department of Medicine, Division of Hematology/Oncology, Tisch Cancer Institute, Mount Sinai Hospital, New York City, New York, United States
| | - Sirish Dharmapuri
- Department of Medicine, Division of Hematology/Oncology, Tisch Cancer Institute, Mount Sinai Hospital, New York City, New York, United States
| | - Abdul Rafeh Naqash
- Division of Hematology/Oncology, East Carolina University, Greenville, North Carolina, United States
| | - Mahvish Muzaffar
- Division of Hematology/Oncology, East Carolina University, Greenville, North Carolina, United States
| | - Musharraf Navaid
- Division of Hematology/Oncology, East Carolina University, Greenville, North Carolina, United States
| | - Uqba Khan
- Division of Hematology and Oncology, Weill Cornell Medicine/New York Presbyterian Hospital, New York City, New York, United States
| | - ChiehJu Lee
- Division of Gastroenterology and Hepatology, Department of Medicine at Taipei Veterans General Hospital and Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Anushi Bulumulle
- Division of Hematology/Oncology, East Carolina University, Greenville, North Carolina, United States
| | - Bo Yu
- Department of Medicine, New York Presbyterian Brooklyn Methodist Hospital, Brooklyn, New York, United States
| | - Sonal Paul
- Department of Medicine, New York Presbyterian Brooklyn Methodist Hospital, Brooklyn, New York, United States
| | - Neil Nimkar
- Department of Medicine, New York Presbyterian Brooklyn Methodist Hospital, Brooklyn, New York, United States
| | - Dominik Bettinger
- Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, Freiburg, Germany
| | - Francesca Benevento
- Department of Medical and Surgical Sciences, University of Bologna, S Orsola-Malpighi Hospital, Bologna, Italy
| | - Hannah Hildebrand
- Division of Medical Oncology, Department of Medicine, Kansas University Cancer Center, Westwood, Kansas, United States
| | - Tiziana Pressiani
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, IRCCS, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Yehia I Abugabal
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
| | - Nicola Personeni
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, IRCCS, Via Manzoni 56, 20089 Rozzano, Milan, Italy.,Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele, Milan, Italy
| | - Yi-Hsiang Huang
- Division of Gastroenterology and Hepatology, Department of Medicine at Taipei Veterans General Hospital and Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Lorenza Rimassa
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, IRCCS, Via Manzoni 56, 20089 Rozzano, Milan, Italy.,Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele, Milan, Italy
| | - Celina Ang
- Department of Medicine, Division of Hematology/Oncology, Tisch Cancer Institute, Mount Sinai Hospital, New York City, New York, United States
| | - Thomas Marron
- Department of Medicine, Division of Hematology/Oncology, Tisch Cancer Institute, Mount Sinai Hospital, New York City, New York, United States
| | - David J Pinato
- Department of Surgery and Cancer, Imperial College London, London, UK
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26
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Carballo-Folgoso L, Álvarez-Velasco R, Lorca R, Castaño-García A, Cuevas J, González-Diéguez ML, Martín M, Álvarez-Navascués C, Cadahía V, Morís C, Rodríguez M, Varela M. Evaluation of cardiovascular events in patients with hepatocellular carcinoma treated with sorafenib in the clinical practice. The CARDIO-SOR study. Liver Int 2021; 41:2200-2211. [PMID: 33966333 DOI: 10.1111/liv.14941] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 03/31/2021] [Accepted: 05/04/2021] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIMS The effectiveness of systemic treatment in advanced hepatocellular carcinoma (HCC) depends on the selection of patients, management of cirrhosis complications and expertise to treat adverse events. The aims of the study are to assess the frequency and management of cardiovascular events in HCC patients treated with sorafenib (SOR) and to create a scale to predict the onset of major adverse cardiovascular events (MACE). METHOD Observational retrospective study with consecutive HCC patients treated with SOR between 2007 and 2019 in a western centre. In order to classify cardiovascular risk pre-SOR, we designed the CARDIOSOR scale with age, hypertension, diabetes, dyslipidaemia and peripheral vascular disease. Other adverse events, dosing and outcome data were collected during a homogeneous protocolled follow-up. RESULTS Two hundred ninety-nine patients were included (219 BCLC-C). The median overall survival was 11.1 months (IQR 5.6-20.5), and duration of treatment was 7.4 months (IQR 3.3-14.7). Seventeen patients (6%) stopped SOR due to cardiovascular event. Thirty-three patients suffered MACE (7 heart failure, 11 acute coronary syndrome, 12 cerebrovascular accident and 8 peripheral vascular ischemia); 99 had a minor cardiovascular event, mainly hypertension (n = 81). Age was the only independent factor associated to MACE (HR 1.07; 95% CI 1.03-1.12; P = .002). The CARDIOSOR scale allows to identify the group of patients with higher risk of MACE (sHR 3.4; 95% CI 1.4-6.7; P = .04). CONCLUSION The incidence of cardiovascular events in HCC patients treated with SOR is higher than expected. Multidisciplinary approach and clinical tools like CARDIOSOR scale could be helpful to manage these patients.
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Affiliation(s)
- Lorena Carballo-Folgoso
- Liver Unit, Division of Gastroenterology and Hepatology, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Rut Álvarez-Velasco
- Department of Cardiology, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Rebeca Lorca
- Department of Cardiology, Hospital Universitario Central de Asturias, Oviedo, Spain.,ISPA, Oviedo, Spain
| | - Andrés Castaño-García
- Liver Unit, Division of Gastroenterology and Hepatology, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Javier Cuevas
- Department of Cardiology, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - María Luisa González-Diéguez
- Liver Unit, Division of Gastroenterology and Hepatology, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - María Martín
- Department of Cardiology, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Carmen Álvarez-Navascués
- Liver Unit, Division of Gastroenterology and Hepatology, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Valle Cadahía
- Liver Unit, Division of Gastroenterology and Hepatology, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - César Morís
- Department of Cardiology, Hospital Universitario Central de Asturias, Oviedo, Spain.,ISPA, Oviedo, Spain.,Department of Medicine, Universidad de Oviedo, Oviedo, Spain
| | - Manuel Rodríguez
- Liver Unit, Division of Gastroenterology and Hepatology, Hospital Universitario Central de Asturias, Oviedo, Spain.,ISPA, Oviedo, Spain.,Department of Medicine, Universidad de Oviedo, Oviedo, Spain
| | - María Varela
- Liver Unit, Division of Gastroenterology and Hepatology, Hospital Universitario Central de Asturias, Oviedo, Spain.,ISPA, Oviedo, Spain.,Department of Medicine, Universidad de Oviedo, Oviedo, Spain.,IUOPA, Oviedo, Spain
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27
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Remash D, Prince DS, McKenzie C, Strasser SI, Kao S, Liu K. Immune checkpoint inhibitor-related hepatotoxicity: A review. World J Gastroenterol 2021; 27:5376-5391. [PMID: 34539139 PMCID: PMC8409159 DOI: 10.3748/wjg.v27.i32.5376] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 06/28/2021] [Accepted: 08/03/2021] [Indexed: 02/06/2023] Open
Abstract
The application of immune checkpoint inhibitors (ICI) in advanced cancer has been a major development in the last decade. The indications for ICIs are constantly expanding into new territory across different cancers, disease stages and lines of therapy. With this increased use, adverse events including immune checkpoint inhibitor-related hepatotoxicity (ICH) have emerged as an important clinical problem. This along with the introduction of ICI as first- and second-line treatments for advanced hepatocellular carcinoma makes ICH very relevant to gastroenterologists and hepatologists. The incidence of ICH varies between 1%-20% depending on the number, type and dose of ICI received. Investigation and management generally involve excluding differential diagnoses and following a stepwise escalation of withholding or ceasing ICI, corticosteroid treatment and adding other immunosuppressive agents depending on the severity of toxicity. The majority of patients with ICH recover and some may even safely recommence ICI therapy. Guideline recommendations are largely based on evidence derived from retrospective case series which highlights a priority for future research.
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Affiliation(s)
- Devika Remash
- AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney 2050, NSW, Australia
| | - David S Prince
- AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney 2050, NSW, Australia
| | - Catriona McKenzie
- AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney 2050, NSW, Australia
- Sydney Medical School, University of Sydney, Sydney 2006, NSW, Australia
- Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney 2050, NSW, Australia
- New South Wales Health Pathology, New South Wales Health, Sydney 2050, NSW, Australia
| | - Simone I Strasser
- AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney 2050, NSW, Australia
- Sydney Medical School, University of Sydney, Sydney 2006, NSW, Australia
| | - Steven Kao
- Sydney Medical School, University of Sydney, Sydney 2006, NSW, Australia
- Medical Oncology, Chris O’Brien Lifehouse, Sydney 2050, NSW, Australia
| | - Ken Liu
- AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney 2050, NSW, Australia
- Sydney Medical School, University of Sydney, Sydney 2006, NSW, Australia
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28
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Atwa SM, Odenthal M, El Tayebi HM. Genetic Heterogeneity, Therapeutic Hurdle Confronting Sorafenib and Immune Checkpoint Inhibitors in Hepatocellular Carcinoma. Cancers (Basel) 2021; 13:4343. [PMID: 34503153 PMCID: PMC8430643 DOI: 10.3390/cancers13174343] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 08/03/2021] [Accepted: 08/05/2021] [Indexed: 12/24/2022] Open
Abstract
Despite the latest advances in hepatocellular carcinoma (HCC) screening and treatment modalities, HCC is still representing a global burden. Most HCC patients present at later stages to an extent that conventional curative options are ineffective. Hence, systemic therapy represented by the tyrosine kinase inhibitor, sorafenib, in the first-line setting is the main treatment modality for advanced-stage HCC. However, in the two groundbreaking phase III clinical trials, the SHARP and Asia-Pacific trials, sorafenib has demonstrated a modest prolongation of overall survival in almost 30% of HCC patients. As HCC develops in an immune-rich milieu, particular attention has been placed on immune checkpoint inhibitors (ICIs) as a novel therapeutic modality for HCC. Yet, HCC therapy is hampered by the resistance to chemotherapeutic drugs and the subsequent tumor recurrence. HCC is characterized by substantial genomic heterogeneity that has an impact on cellular response to the applied therapy. And hence, this review aims at giving an insight into the therapeutic impact and the different mechanisms of resistance to sorafenib and ICIs as well as, discussing the genomic heterogeneity associated with such mechanisms.
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Affiliation(s)
- Sara M. Atwa
- Pharmaceutical Biology Department, German University in Cairo, Cairo 11865, Egypt;
- Molecular Pharmacology Research Group, Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt
| | - Margarete Odenthal
- Institute for Pathology, University Hospital Cologne, 50924 Cologne, Germany;
| | - Hend M. El Tayebi
- Molecular Pharmacology Research Group, Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt
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29
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D'Alessio A, Rimassa L, Cortellini A, Pinato DJ. PD-1 Blockade for Hepatocellular Carcinoma: Current Research and Future Prospects. J Hepatocell Carcinoma 2021; 8:887-897. [PMID: 34386437 DOI: 10.2147/jhc.s284440] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 07/26/2021] [Indexed: 12/12/2022] Open
Abstract
The treatment of hepatocellular carcinoma (HCC) has witnessed radical changes over the last few years, with the introduction of immune checkpoint inhibitors (ICI) in clinical practice, namely the combination of atezolizumab plus bevacizumab as the standard of care for first-line treatment of advanced HCC. The immunosuppressive microenvironment of the chronically inflamed liver makes HCC a fertile ground for the use of ICI. This review focuses on anti-programmed cell death-1 (PD-1) monoclonal antibodies (mAb), which have been extensively studied, as monotherapy, in combination with other ICI or with antiangiogenic agents. Currently, anti-PD-1 agents are approved by the United States Food and Drug Administration for second-line treatment in advanced HCC: nivolumab, alone or in combination with ipilimumab, and pembrolizumab. Lack of demonstration of survival benefit in first and second line led to the investigation of PD-1 agents in combination with multi-kinase inhibitors, with a number of first-line treatment regimens being actively investigated. Mounting evidence suggests a potential role of PD-1 blockade as adjuvant or neoadjuvant therapies. A key challenge remains the identification of biomarkers of response, since only a minority of patients appear to benefit from ICI.
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Affiliation(s)
- Antonio D'Alessio
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, W120HS, UK.,Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Lorenza Rimassa
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.,Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Alessio Cortellini
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, W120HS, UK.,Department of Biotechnology and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - David James Pinato
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, W120HS, UK.,Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
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30
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Hsu C, Rimassa L, Sun HC, Vogel A, Kaseb AO. Immunotherapy in hepatocellular carcinoma: evaluation and management of adverse events associated with atezolizumab plus bevacizumab. Ther Adv Med Oncol 2021; 13:17588359211031141. [PMID: 34377156 PMCID: PMC8327224 DOI: 10.1177/17588359211031141] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 06/21/2021] [Indexed: 12/14/2022] Open
Abstract
In light of positive efficacy and safety findings from the IMbrave150 trial of atezolizumab plus bevacizumab, this novel combination has become the preferred first-line standard of care for patients with unresectable hepatocellular carcinoma (HCC). Several additional trials are ongoing that combine an immune checkpoint inhibitor with another agent such as a multiple kinase inhibitor or antiangiogenic agent. Therefore, the range of first-line treatment options for unresectable HCC is likely to increase, and healthcare providers need succinct information about the use of such combinations, including their efficacy and key aspects of their safety profiles. Here, we review efficacy and safety data on combination immunotherapies and offer guidance on monitoring and managing adverse events, especially those associated with atezolizumab plus bevacizumab. Because of their underlying liver disease and high likelihood of portal hypertension, patients with unresectable HCC are at particular risk of gastrointestinal bleeding, and this risk may be exacerbated by treatments that include antiangiogenic agents. Healthcare providers also need to be alert to the risks of proteinuria and hypertension, colitis, hepatitis, and reactivation of hepatitis B or C virus infection. They should also be aware of the possibility of rarer but potentially life-threatening adverse events such as pneumonitis and cardiovascular events. Awareness of the risks associated with these therapies and knowledge of adverse event monitoring and management will become increasingly important as the therapeutic range broadens in unresectable HCC.
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Affiliation(s)
- Chiun Hsu
- Graduate Institute of Oncology, National University College of Medicine, National University Hospital, and National University Cancer Center, Taipei
| | - Lorenza Rimassa
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Hui-Chuan Sun
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Arndt Vogel
- Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Carl-Neubergstrasse 1, Hannover, 30625, Germany
| | - Ahmed O Kaseb
- Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 426, Houston, TX 77030, USA
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31
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Plaz Torres MC, Lai Q, Piscaglia F, Caturelli E, Cabibbo G, Biasini E, Pelizzaro F, Marra F, Trevisani F, Giannini EG. Treatment of Hepatocellular Carcinoma with Immune Checkpoint Inhibitors and Applicability of First-Line Atezolizumab/Bevacizumab in a Real-Life Setting. J Clin Med 2021; 10:3201. [PMID: 34361985 PMCID: PMC8347923 DOI: 10.3390/jcm10153201] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 07/16/2021] [Accepted: 07/19/2021] [Indexed: 02/06/2023] Open
Abstract
Immune checkpoint inhibitors (ICIs) are the new frontier for the treatment of advanced hepatocellular carcinoma (HCC). Since the first trial with tremelimumab, a cytotoxic T-lymphocyte-associated protein 4 inhibitor, increasing evidence has confirmed that these drugs can significantly extend the survival of patients with advanced hepatocellular carcinoma (HCC). As a matter of fact, the overall survival and objective response rates reported in patients with advanced HCC treated with ICIs are the highest ever reported in the second-line setting and, most recently, the combination of the anti-programmed death ligand protein-1 atezolizumab with bevacizumab-an anti-vascular endothelial growth factor monoclonal antibody-demonstrated superiority to sorafenib in a Phase III randomized clinical trial. Therefore, this regimen has been approved in several countries as first-line treatment for advanced HCC and is soon expected to be widely used in clinical practice. However, despite the promising results of trials exploring ICIs alone or in combination with other agents, there are still some critical issues to deal with to optimize the prognosis of advanced HCC patients. For instance, the actual proportion of patients who are deemed eligible for ICIs in the real-life ranges from 10% to 20% in the first-line setting, and is even lower in the second-line scenario. Moreover, long-term data regarding the safety of ICIs in the population of patients with cirrhosis and impaired liver function are lacking. Lastly, no biomarkers have been identified to predict response, and thus to help clinicians to individually tailor treatment. This review aimed to summarize the state of the art immunotherapy in HCC and, by analyzing a large, multicenter cohort of Italian patients with HCC, to assess the potential applicability of the combination of atezolizumab/bevacizumab in the real-life setting.
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Affiliation(s)
- Maria Corina Plaz Torres
- Gastroenterology Unit, Department of Internal Medicine, IRCCS—Ospedale Policlinico San Martino, University of Genoa, 16132 Genoa, Italy;
| | - Quirino Lai
- Hepatobiliary and Organ Transplantation Unit, Umberto I Polyclinic of Rome, Sapienza University of Rome, 00185 Rome, Italy;
| | - Fabio Piscaglia
- Internal Medicine Unit, Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero—Universitaria di Bologna, 40138 Bologna, Italy;
| | | | - Giuseppe Cabibbo
- Gastroenterology and Hepatology Unit, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90133 Palermo, Italy;
| | - Elisabetta Biasini
- Infectious Diseases and Hepatology Unit, Azienda Ospedaliero—Universitaria di Parma, 43126 Parma, Italy;
| | - Filippo Pelizzaro
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy;
| | - Fabio Marra
- Internal Medicine and Hepatology Unit, Department of Experimental and Clinical Medicine, University of Firenze, 50134 Firenze, Italy;
| | - Franco Trevisani
- Medical Semeiotics Unit, Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero—Universitaria di Bologna, 40138 Bologna, Italy;
| | - Edoardo G. Giannini
- Gastroenterology Unit, Department of Internal Medicine, IRCCS—Ospedale Policlinico San Martino, University of Genoa, 16132 Genoa, Italy;
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32
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Shek D, Read SA, Nagrial A, Carlino MS, Gao B, George J, Ahlenstiel G. Immune-Checkpoint Inhibitors for Advanced Hepatocellular Carcinoma: A Synopsis of Response Rates. Oncologist 2021; 26:e1216-e1225. [PMID: 33818870 PMCID: PMC8265367 DOI: 10.1002/onco.13776] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 03/22/2021] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death worldwide. A first-line standard of care, sorafenib results in median overall survival of 12 months in patients with Child-Pugh class A disease and 6 months in patients with Child-Pugh class B disease with objective response rates (ORRs) not exceeding 19%. These low efficacy rates have driven research on alternative therapeutic options, particularly immune-checkpoint inhibitors (ICIs). We reviewed the response rates (estimated by RECIST 1.1 criteria) across patients with advanced HCC treated with ICIs in phase I-IV clinical trials published between December 2012 to December 2020; 17 reports were identified as eligible and included in the quantitative analysis. Within the selected studies, pembrolizumab + lenvatinib reached the highest absolute ORR (36%), with first-line atezolizumab + bevacizumab showing the second highest ORR (27.3%). With regard to second-line therapy, nivolumab + ipilimumab reached an ORR of 32%, and pembrolizumab alone resulted in an ORR of 17% among sorafenib-experienced patients with advanced HCC. In summary, current studies show high response rates of ICIs in patients with advanced HCC. Nonetheless, further studies are required in the second-line setting to further evaluate ICI therapeutic superiority. Finally, it is of particular interest to examine the therapeutic potential of ICIs for patients with decompensated liver disease (Child-Pugh class C), currently not eligible for any systemic therapy. IMPLICATIONS FOR PRACTICE: Immune-checkpoint inhibitors (ICIs) can provide high objective response rates (ORR, estimated with RECIST 1.1. criteria) when used as first-line treatment in advanced hepatocellular carcinoma, particularly pembrolizumab + lenvatinib (ORR 36%) or atezolizumab + bevacizumab (ORR 27.3%). In sorafenib-experienced patients, nivolumab + ipilimumab (ORR 32%) provided the highest ORR among ICI-based regimens. These findings emphasize high therapeutic potential of ICI-based therapies in patients with advanced hepatocellular carcinoma, although further studies are required to further validate and define their role in this context.
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Affiliation(s)
- Dmitrii Shek
- Blacktown Clinical School, Western Sydney UniversitySydneyNew South WalesAustralia
- Storr Liver Centre, Westmead Institute for Medical ResearchSydneyNew South WalesAustralia
- Blacktown HospitalSydneyNew South WalesAustralia
| | - Scott A. Read
- Blacktown Clinical School, Western Sydney UniversitySydneyNew South WalesAustralia
- Storr Liver Centre, Westmead Institute for Medical ResearchSydneyNew South WalesAustralia
- Blacktown HospitalSydneyNew South WalesAustralia
| | - Adnan Nagrial
- Blacktown HospitalSydneyNew South WalesAustralia
- Westmead HospitalSydneyNew South WalesAustralia
- Westmead Clinical School, University of SydneySydneyNew South WalesAustralia
| | - Matteo S. Carlino
- Blacktown HospitalSydneyNew South WalesAustralia
- Westmead HospitalSydneyNew South WalesAustralia
- Westmead Clinical School, University of SydneySydneyNew South WalesAustralia
- Melanoma Institute AustraliaSydneyNew South WalesAustralia
| | - Bo Gao
- Blacktown HospitalSydneyNew South WalesAustralia
- Westmead HospitalSydneyNew South WalesAustralia
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical ResearchSydneyNew South WalesAustralia
- Westmead HospitalSydneyNew South WalesAustralia
- Westmead Clinical School, University of SydneySydneyNew South WalesAustralia
| | - Golo Ahlenstiel
- Blacktown Clinical School, Western Sydney UniversitySydneyNew South WalesAustralia
- Storr Liver Centre, Westmead Institute for Medical ResearchSydneyNew South WalesAustralia
- Blacktown HospitalSydneyNew South WalesAustralia
- Westmead Clinical School, University of SydneySydneyNew South WalesAustralia
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33
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D'Alessio A, Cammarota A, Prete MG, Pressiani T, Rimassa L. The evolving treatment paradigm of advanced hepatocellular carcinoma: putting all the pieces back together. Curr Opin Oncol 2021; 33:386-394. [PMID: 33867478 DOI: 10.1097/cco.0000000000000744] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW The therapeutic landscape of advanced hepatocellular carcinoma (HCC) has become notably complex in recent years. With this review, we aimed to put the most recent findings in perspective and tried to delineate the rapidly changing treatment algorithm. RECENT FINDINGS The combination of atezolizumab and bevacizumab has become the new first-line standard of care treatment for unresectable HCC after the positive results of the phase 3 IMbrave150 study. Nivolumab monotherapy failed to demonstrate advantage versus sorafenib in the CheckMate 459 trial, while two different therapeutic strategies (sintilimab and bevacizumab biosimilar and donafenib) outperformed sorafenib in two phase 2/3 studies conducted in the Chinese population. Several immunotherapy combinations are currently under study in large phase 3 trials after promising results in earlier phase studies. About further lines of treatment, the combination of ipilimumab and nivolumab was approved for sorafenib-pretreated patients after the positive results of the phase 1/2 CheckMate 040 study and apatinib was proven effective in the Chinese population in a phase 2/3 study, while pembrolizumab as monotherapy did not show statistically significant superiority when compared with placebo in the KEYNOTE-240 study. SUMMARY Because of the growing complexity of advanced HCC treatment, the implementation of predictive biomarkers of response is eagerly needed.
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Affiliation(s)
- Antonio D'Alessio
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Antonella Cammarota
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Maria Giuseppina Prete
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Tiziana Pressiani
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Lorenza Rimassa
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
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Dyhl-Polk A, Mikkelsen MK, Ladekarl M, Nielsen DL. Clinical Trials of Immune Checkpoint Inhibitors in Hepatocellular Carcinoma. J Clin Med 2021; 10:2662. [PMID: 34208788 PMCID: PMC8234948 DOI: 10.3390/jcm10122662] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 06/09/2021] [Accepted: 06/10/2021] [Indexed: 02/06/2023] Open
Abstract
Introduction: Several immune checkpoint inhibitors (CPIs) are under clinical development in hepatocellular carcinoma (HCC) and the field is advancing rapidly. In this comprehensive review, we discuss published results and report on ongoing clinical trials. Methods: A literature search was carried out using PubMed and EMBASE; data reported at international meetings and clinicaltrials.gov were included as well. The search was updated 5 March 2021. We evaluated studies with monotherapy CPI's, combinations of CPI's and combinations of CPI's with other treatment modalities separately. Only studies with at least 10 included patients were considered. Results: We identified 2649 records published in the English language literature. After review, 29 studies remained, including 12 studies with preliminary data only. The obtained overall response rate of PD-1/PDL-1 monotherapy in phase II studies in the second-line setting was 15-20% with disease control in approximately 60% of patients. The responses were of long duration in a subset of patients. Furthermore, the safety profiles were manageable. However, a phase III study comparing nivolumab with sorafenib in the first-line setting and a phase III study evaluating pembrolizumab versus best supportive care in the second-line setting did not meet their prespecified endpoints. More recently, a phase I/II study of nivolumab and ipilimumab has resulted in a response rate of approximately 30% with a median OS of 22 months in the second-line setting. Multiple trials have been initiated to evaluate CPIs in combination with molecularly targeted drugs, especially anti-angiogenic drugs or local therapy. A phase III study investigating atezolizumab plus bevacizumab versus sorafenib in the first-line setting showed significantly increased survival in the combination arm. Conclusions: The combination of atezolizumab and bevacizumab represents a new standard of care in the first-line setting for fit patients with preserved liver function. CPIs can produce durable tumor remission and induce long-standing anti-tumor immunity in a subgroup of patients with advanced HCC. Although phase III trials of CPI monotherapy have been negative, the combination of PD-1/PD-L1 inhibitors with other anti-angiogenic drugs, CTLA-4 inhibitors or other modalities may result in new treatment options for patients with HCC. Research on predictive biomarkers is crucial for further development of CPIs in HCC.
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Affiliation(s)
- Anne Dyhl-Polk
- Department of Oncology, Herlev and Gentofte Hospital, University of Copenhagen, Borgmester Ib Juuls Vej 1, 2730 Herlev, Denmark; (M.K.M.); (D.L.N.)
| | - Marta Kramer Mikkelsen
- Department of Oncology, Herlev and Gentofte Hospital, University of Copenhagen, Borgmester Ib Juuls Vej 1, 2730 Herlev, Denmark; (M.K.M.); (D.L.N.)
| | - Morten Ladekarl
- Department of Oncology, Clinical Cancer Research Center, Aalborg University Hospital, Hobrovej 19-22, 9000 Aalborg, Denmark;
| | - Dorte Lisbet Nielsen
- Department of Oncology, Herlev and Gentofte Hospital, University of Copenhagen, Borgmester Ib Juuls Vej 1, 2730 Herlev, Denmark; (M.K.M.); (D.L.N.)
- Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
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Ren Z, Xu J, Bai Y, Xu A, Cang S, Du C, Li Q, Lu Y, Chen Y, Guo Y, Chen Z, Liu B, Jia W, Wu J, Wang J, Shao G, Zhang B, Shan Y, Meng Z, Wu J, Gu S, Yang W, Liu C, Shi X, Gao Z, Yin T, Cui J, Huang M, Xing B, Mao Y, Teng G, Qin Y, Wang J, Xia F, Yin G, Yang Y, Chen M, Wang Y, Zhou H, Fan J. Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study. Lancet Oncol 2021; 22:977-990. [PMID: 34143971 DOI: 10.1016/s1470-2045(21)00252-7] [Citation(s) in RCA: 637] [Impact Index Per Article: 159.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 04/16/2021] [Accepted: 04/19/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND China has a high burden of hepatocellular carcinoma, and hepatitis B virus (HBV) infection is the main causative factor. Patients with hepatocellular carcinoma have a poor prognosis and a substantial unmet clinical need. The phase 2-3 ORIENT-32 study aimed to assess sintilimab (a PD-1 inhibitor) plus IBI305, a bevacizumab biosimilar, versus sorafenib as a first-line treatment for unresectable HBV-associated hepatocellular carcinoma. METHODS This randomised, open-label, phase 2-3 study was done at 50 clinical sites in China. Patients aged 18 years or older with histologically or cytologically diagnosed or clinically confirmed unresectable or metastatic hepatocellular carcinoma, no previous systemic treatment, and a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were eligible for inclusion. In the phase 2 part of the study, patients received intravenous sintilimab (200 mg every 3 weeks) plus intravenous IBI305 (15 mg/kg every 3 weeks). In the phase 3 part, patients were randomly assigned (2:1) to receive either sintilimab plus IBI305 (sintilimab-bevacizumab biosimilar group) or sorafenib (400 mg orally twice daily; sorafenib group), until disease progression or unacceptable toxicity. Randomisation was done using permuted block randomisation, with a block size of six, via an interactive web response system, and stratified by macrovascular invasion or extrahepatic metastasis, baseline α-fetoprotein, and ECOG performance status. The primary endpoint of the phase 2 part of the study was safety, assessed in all patients who received at least one dose of study drug. The co-primary endpoints of the phase 3 part of the study were overall survival and independent radiological review committee (IRRC)-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03794440. The study is closed to new participants and follow-up is ongoing for long-term outcomes. FINDINGS Between Feb 11, 2019 and Jan 15, 2020, we enrolled 595 patients: 24 were enrolled directly into the phase 2 safety run-in and 571 were randomly assigned to sintilimab-bevacizumab biosimilar (n=380) or sorafenib (n=191). In the phase 2 part of the trial, 24 patients received at least one dose of the study drug, with an objective response rate of 25·0% (95% CI 9·8-46·7). Based on the preliminary safety and activity data of the phase 2 part, in which grade 3 or worse treatment-related adverse events occurred in seven (29%) of 24 patients, the randomised phase 3 part was started. At data cutoff (Aug 15, 2020), the median follow-up was 10·0 months (IQR 8·5-11·7) in the sintilimab-bevacizumab biosimilar group and 10·0 months (8·4-11·7) in the sorafenib group. Patients in the sintilimab-bevacizumab biosimilar group had a significantly longer IRRC-assessed median progression-free survival (4·6 months [95% CI 4·1-5·7]) than did patients in the sorafenib group (2·8 months [2·7-3·2]; stratified hazard ratio [HR] 0·56, 95% CI 0·46-0·70; p<0·0001). In the first interim analysis of overall survival, sintilimab-bevacizumab biosimilar showed a significantly longer overall survival than did sorafenib (median not reached [95% CI not reached-not reached] vs 10·4 months [8·5-not reached]; HR 0·57, 95% CI 0·43-0·75; p<0·0001). The most common grade 3-4 treatment-emergent adverse events were hypertension (55 [14%] of 380 patients in the sintilimab-bevacizumab biosimilar group vs 11 [6%] of 185 patients in the sorafenib group) and palmar-plantar erythrodysaesthesia syndrome (none vs 22 [12%]). 123 (32%) patients in the sintilimab-bevacizumab biosimilar group and 36 (19%) patients in the sorafenib group had serious adverse events. Treatment-related adverse events that led to death occurred in six (2%) patients in the sintilimab-bevacizumab biosimilar group (one patient with abnormal liver function, one patient with both hepatic failure and gastrointestinal haemorrhage, one patient with interstitial lung disease, one patient with both hepatic faliure and hyperkalemia, one patient with upper gastrointestinal haemorrhage, and one patient with intestinal volvulus) and two (1%) patients in the sorafenib group (one patient with gastrointestinal haemorrhage and one patient with death of unknown cause). INTERPRETATION Sintilimab plus IBI305 showed a significant overall survival and progression-free survival benefit versus sorafenib in the first-line setting for Chinese patients with unresectable, HBV-associated hepatocellular carcinoma, with an acceptable safety profile. This combination regimen could provide a novel treatment option for such patients. FUNDING Innovent Biologics. TRANSLATION For the Chinese translation of the abstract see Supplementary Materials section.
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Affiliation(s)
- Zhenggang Ren
- Department of Hepatic Oncology, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Jianming Xu
- Digestive Oncology Department, The Fifth Medical Centre of PLA General Hospital, Beijing, China
| | - Yuxian Bai
- Department of Internal Medicine, Harbin Medical University Cancer Hospital, Harbin, China
| | - Aibing Xu
- Department of Oncological Internal Medicine, Nantong Tumour Hospital, Nantong, China
| | - Shundong Cang
- Department of Internal Medicine-Oncology, Henan Provincial People's Hospital, Zhengzhou, China
| | - Chengyou Du
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qiu Li
- Abdominal Tumour Department, West China Hospital, Sichuan University, Chengdu, China
| | - Yinying Lu
- Treatment and Research Centre for Liver Cancer Department 2, The Fifth Medical Centre of PLA General Hospital, Beijing, China
| | - Yajin Chen
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yabing Guo
- Department of Tumours of Liver, Nan Fang Hospital, Guangzhou, China
| | - Zhendong Chen
- Oncology Department, The Second Hospital of Anhui Medical University, Hefei, China
| | - Baorui Liu
- Department of Oncology, Nanjing Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Weidong Jia
- General Surgery Department, Anhui Provincial Hospital, Hefei, China
| | - Jian Wu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Junye Wang
- Department of Oncology, Affiliated Hospital of Jining Medical University, Jining, China
| | - Guoliang Shao
- Department of Interventional Therapy, Zhejiang Cancer Hospital, Hangzhou, China
| | - Bixiang Zhang
- Department of Hepatobiliary Surgery, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Yunfeng Shan
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zhiqiang Meng
- Department of Traditional Chinese Medicine/Integrative Oncology, Fudan University Shanghai Cancer Centre, Shanghai, China
| | - Jianbing Wu
- Oncology Department, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Shanzhi Gu
- Radioactive Interventional Department, Hunan Cancer Hospital, Changsha, China
| | - Wei Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China
| | - Chao Liu
- Department of Pancreaticobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xuetao Shi
- Department of Hepatobiliary Surgery, Shandong Cancer Hospital, Jinan, China
| | - Zhenyuan Gao
- Medical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Tao Yin
- Department of Hepatobiliary Surgery, Hubei Cancer Hospital, Wuhan, China
| | - Jiuwei Cui
- Oncology Department, Bethune First Hospital of Jilin University, Changchun, China
| | - Ming Huang
- Department of Minimally Invasive Interventional Medicine, Yunnan Cancer Hospital, Kunming, China
| | - Baocai Xing
- Hepatobiliary Pancreatic Surgery 1, Beijing Cancer Hospital, Beijing, China
| | - Yilei Mao
- Live Surgery Ward, Peking Union Medical College Hospital, Beijing, China
| | - Gaojun Teng
- Radiology Department, Zhongda Hospital Southeast University, Nanjing, China
| | - Yanru Qin
- Department of Internal Medicine Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jinhai Wang
- Department of Gastroenterology, The Second Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China
| | - Feng Xia
- Department of Hepatobiliary Surgery, The First Hospital Affiliated to AMU (Southwest Hospital), Chongqing, China
| | - Guowen Yin
- Intervention Department, Jiangsu Cancer Hospital, Nanjing, China
| | - Yong Yang
- Department of Medical Science and Strategy Oncology, Innovent Biologics, Suzhou, China
| | - Mingxia Chen
- Department of Biostatistics and Information, Innovent Biologics, Suzhou, China
| | - Yan Wang
- Department of Medical Science and Strategy Oncology, Innovent Biologics, Suzhou, China
| | - Hui Zhou
- Department of Medical Science and Strategy Oncology, Innovent Biologics, Suzhou, China
| | - Jia Fan
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China.
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Hewitt DB, Rahnemai-Azar AA, Pawlik TM. Potential experimental immune checkpoint inhibitors for the treatment of cancer of the liver. Expert Opin Investig Drugs 2021; 30:827-835. [PMID: 34102935 DOI: 10.1080/13543784.2021.1940948] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Introduction: Traditional systemic therapies offer limited benefit for advanced cancers of the liver. Immune checkpoints are inhibitory regulators of the immune system and the success of immune checkpoint inhibitors (ICIs) in the treatment of other cancers has led to clinical trials investigating the use of ICIs alone or in combination with other therapies for liver cancers.Area covered: Clinical trials involving ICIs for the treatment of liver cancer were broadly reviewed. Hepatocellular carcinoma and intrahepatic cholangiocarcinoma were examined. Phase I/II trials were prioritized, and relevant phase III trials were discussed. MEDLINE, PubMed, ASCO meeting library, and Web of Science databases were searched with the keywords 'immune checkpoint inhibitor' or 'targeted therapy' in combination with 'hepatocellular carcinoma,' or 'intrahepatic cholangiocarcinoma'. Major outcomes were safety and efficacy defined by response rate, progression-free survival, or overall survival.Expert opinion: ICIs can improve progression-free and overall survival among patients with advanced disease with an acceptable safety profile. Given the heterogeneity of liver disease, ideal strategies will likely include a combination of ICIs with additional therapies to achieve the most robust and durable response. Additional biomarkers will be needed to guide combination therapy to personalize treatment regimen for patients with primary liver cancers.
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Affiliation(s)
- D Brock Hewitt
- Division of Surgical Oncology, Department of Surgery, The Ohio State Wexner Medical Center, the James Comprehensive Cancer Center, Columbus, OH, USA
| | - Amir A Rahnemai-Azar
- Division of Surgical Oncology, Department of Surgery, Arrowhead Regional Cancer Center, California University of Science and Medicine, Colton, CA, USA
| | - Timothy M Pawlik
- Division of Surgical Oncology, Department of Surgery, The Ohio State Wexner Medical Center, the James Comprehensive Cancer Center, Columbus, OH, USA
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Tsang J, Wong JSL, Kwok GGW, Li BCW, Leung R, Chiu J, Cheung TT, Yau T. Nivolumab + Ipilimumab for patients with hepatocellular carcinoma previously treated with Sorafenib. Expert Rev Gastroenterol Hepatol 2021; 15:589-598. [PMID: 33666530 DOI: 10.1080/17474124.2021.1899808] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION The systemic treatment of advanced, unresectable hepatocellular carcinoma (HCC) has undergone an evolution in recent years. In March 2020, a combination of nivolumab and ipilimumab was approved by the FDA for treatment of patients with advanced HCC who received prior sorafenib. This was based on the results of the phase I/II CheckMate-040 cohort 4 trials, which showed a promising overall response rate and encouraging overall survival with a manageable safety profile. AREAS COVERED This article reviews the pharmacology, efficacy and safety of nivolumab-ipilimumab in advanced HCC with prior sorafenib. Other existing systemic treatment options for advanced HCC will be described and compared to nivolumab-ipilimumab. Impact of different dose regimes, ongoing research and future developments of nivolumab-ipilimumab will be discussed. We focus on the analysis from the aforementioned CheckMate-040 cohort 4 registration trial. EXPERT OPINION The approval of nivolumab-ipilimumab in the second-line treatment of advanced HCC by the FDA is an important development for treatment of advanced HCC. However, further investigations are needed to optimize dosing regimens and explore the use of nivolumab-ipilimumab in other combinations and settings.
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Affiliation(s)
- Josephine Tsang
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Jeffrey Sum Lung Wong
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Gerry Gin Wai Kwok
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Bryan Cho Wing Li
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Roland Leung
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Joanne Chiu
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Tan To Cheung
- Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Thomas Yau
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
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Liu ZL, Liu JH, Staiculescu D, Chen J. Combination of molecularly targeted therapies and immune checkpoint inhibitors in the new era of unresectable hepatocellular carcinoma treatment. Ther Adv Med Oncol 2021; 13:17588359211018026. [PMID: 34104226 PMCID: PMC8150670 DOI: 10.1177/17588359211018026] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 04/23/2021] [Indexed: 02/06/2023] Open
Abstract
Multikinase inhibitors (MKIs) have been the only first-line treatment for advanced hepatocellular carcinoma (HCC) for more than a decade, until the approval of immune checkpoint inhibitors (ICIs). Moreover, the combination regimen of atezolizumab (anti-programmed cell death protein ligand 1 antibody) plus bevacizumab (anti-vascular endothelial growth factor monoclonal antibody) has recently been demonstrated to have superior efficacy when compared with sorafenib monotherapy. The remarkable efficacy has made this combination therapy the new standard treatment for advanced HCC. In addition to MKIs, many other molecularly targeted therapies are under investigation, some of which have shown promising results. Therefore, in the era of immuno-oncology, there is a significant rationale for testing the combinations of molecularly targeted therapies and ICIs. Indeed, numerous preclinical and clinical studies have shown the synergic antitumor efficacy of such combinations. In this review, we aim to summarize the current knowledge on the combination of molecularly targeted therapies and immune checkpoint therapies for HCC from both preclinical and clinical perspectives.
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Affiliation(s)
- Ze-Long Liu
- Division of Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China
- Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Jing-Hua Liu
- Department of Hepatobiliary Surgery and Professor Cai’s Laboratory, Linyi People’s Hospital, Linyi, Shandong Province, China
| | - Daniel Staiculescu
- Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Jiang Chen
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University, No. 3, East Qingchun Road, Hangzhou, Zhejiang Province, 310016, China
- Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
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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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Zarębska I, Gzil A, Durślewicz J, Jaworski D, Antosik P, Ahmadi N, Smolińska-Świtała M, Grzanka D, Szylberg Ł. The clinical, prognostic and therapeutic significance of liver cancer stem cells and their markers. Clin Res Hepatol Gastroenterol 2021; 45:101664. [PMID: 33667731 DOI: 10.1016/j.clinre.2021.101664] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 09/24/2020] [Accepted: 02/17/2021] [Indexed: 02/04/2023]
Abstract
Hepatocellular carcinoma (HCC) is the fourth most common cause of death among cancers. The poor prognosis of HCC might be caused by a population of cancer stem cells (CSC). CSC have similar characteristics to normal stem cells and are responsible for cancer recurrence, chemoresistance, radioresistance and metastasis. Liver cancer stem cells (LCSC) are identified via specific surface markers, such as CD44, CD90, CD133, and EpCAM (CD326). Recent studies suggested a complex interaction between mentioned LCSC markers and clinical features of HCC. A high expression of CSC is correlated with a negative prognostic factor after surgical resection of HCC and is connected with more aggressive tumor behavior. Moreover, LCSC might be responsible for increasing resistance to sorafenib, a kinase inhibitor drug. A reduction in the LCSC population may be crucial to successful advanced HCC therapy.
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Affiliation(s)
- Izabela Zarębska
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Sklodowskiej-Curie Str. 9, 85-094 Bydgoszcz, Poland.
| | - Arkadiusz Gzil
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Sklodowskiej-Curie Str. 9, 85-094 Bydgoszcz, Poland
| | - Justyna Durślewicz
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Sklodowskiej-Curie Str. 9, 85-094 Bydgoszcz, Poland
| | - Damian Jaworski
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Sklodowskiej-Curie Str. 9, 85-094 Bydgoszcz, Poland
| | - Paulina Antosik
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Sklodowskiej-Curie Str. 9, 85-094 Bydgoszcz, Poland
| | - Navid Ahmadi
- Chair and Department of Oncologic Pathology and Prophylactics, Greater Poland Cancer Center, Poznan University of Medical Sciences, Poland
| | - Marta Smolińska-Świtała
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Sklodowskiej-Curie Str. 9, 85-094 Bydgoszcz, Poland
| | - Dariusz Grzanka
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Sklodowskiej-Curie Str. 9, 85-094 Bydgoszcz, Poland
| | - Łukasz Szylberg
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Sklodowskiej-Curie Str. 9, 85-094 Bydgoszcz, Poland; Department of Pathomorphology, Military Clinical Hospital, Bydgoszcz, Poland; Department of Tumor Pathology and Pathomorphology, Oncology Center, Prof. Franciszek Łukaszczyk Memorial Hospital, Bydgoszcz, Poland
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41
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Benson AB, D'Angelica MI, Abbott DE, Anaya DA, Anders R, Are C, Bachini M, Borad M, Brown D, Burgoyne A, Chahal P, Chang DT, Cloyd J, Covey AM, Glazer ES, Goyal L, Hawkins WG, Iyer R, Jacob R, Kelley RK, Kim R, Levine M, Palta M, Park JO, Raman S, Reddy S, Sahai V, Schefter T, Singh G, Stein S, Vauthey JN, Venook AP, Yopp A, McMillian NR, Hochstetler C, Darlow SD. Hepatobiliary Cancers, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2021; 19:541-565. [PMID: 34030131 DOI: 10.6004/jnccn.2021.0022] [Citation(s) in RCA: 537] [Impact Index Per Article: 134.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The NCCN Guidelines for Hepatobiliary Cancers focus on the screening, diagnosis, staging, treatment, and management of hepatocellular carcinoma (HCC), gallbladder cancer, and cancer of the bile ducts (intrahepatic and extrahepatic cholangiocarcinoma). Due to the multiple modalities that can be used to treat the disease and the complications that can arise from comorbid liver dysfunction, a multidisciplinary evaluation is essential for determining an optimal treatment strategy. A multidisciplinary team should include hepatologists, diagnostic radiologists, interventional radiologists, surgeons, medical oncologists, and pathologists with hepatobiliary cancer expertise. In addition to surgery, transplant, and intra-arterial therapies, there have been great advances in the systemic treatment of HCC. Until recently, sorafenib was the only systemic therapy option for patients with advanced HCC. In 2020, the combination of atezolizumab and bevacizumab became the first regimen to show superior survival to sorafenib, gaining it FDA approval as a new frontline standard regimen for unresectable or metastatic HCC. This article discusses the NCCN Guidelines recommendations for HCC.
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Affiliation(s)
- Al B Benson
- 1Robert H. Lurie Comprehensive Cancer Center of Northwestern University
| | | | | | | | - Robert Anders
- 5The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
| | | | | | | | | | | | - Prabhleen Chahal
- 11Case Comprehensive Cancer Center, University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute
| | | | - Jordan Cloyd
- 13The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute
| | | | - Evan S Glazer
- 14St. Jude Children's Research HospitalThe University of Tennessee Health Science Center
| | | | - William G Hawkins
- 16Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine
| | | | | | - R Kate Kelley
- 19UCSF Helen Diller Family Comprehensive Cancer Center
| | - Robin Kim
- 20Huntsman Cancer Institute at the University of Utah
| | - Matthew Levine
- 21Abramson Cancer Center at the University of Pennsylvania
| | | | - James O Park
- 23Fred Hutchinson Cancer Research CenterSeattle Cancer Care Alliance
| | | | | | | | | | | | | | | | - Alan P Venook
- 19UCSF Helen Diller Family Comprehensive Cancer Center
| | - Adam Yopp
- 31UT Southwestern Simmons Comprehensive Cancer Center; and
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42
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Systemic treatment of HCC in special populations. J Hepatol 2021; 74:931-943. [PMID: 33248171 DOI: 10.1016/j.jhep.2020.11.026] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 11/05/2020] [Accepted: 11/18/2020] [Indexed: 12/13/2022]
Abstract
Recent years have seen significant progress in the systemic treatment of hepatocellular carcinoma (HCC), including the advent of immunotherapy. While several large phase III trials have provided the evidence for a multi-line treatment paradigm, they have focused on a highly selected group of patients by excluding potentially confounding comorbidities. As a result, high quality evidence for the systemic treatment of HCC in patients with various comorbidities is missing. This review summarises current knowledge on the use of approved medicines in patients with HIV, autoimmune disease, cardiovascular disease, diabetes, fibrolamellar HCC, mixed HCC-cholangiocarcinoma, decompensated cirrhosis (Child-Pugh B and C), a significant bleeding history, vascular invasion or portal vein thrombosis, as well as the elderly, those on haemodialysis, and those after solid organ transplantation. The article highlights relevant knowledge gaps and current clinical challenges. To improve the safety and efficacy of HCC treatment in these subgroups, future trials should be designed to specifically include patients with comorbidities.
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43
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Shao YY, Wang SY, Lin SM. Management consensus guideline for hepatocellular carcinoma: 2020 update on surveillance, diagnosis, and systemic treatment by the Taiwan Liver Cancer Association and the Gastroenterological Society of Taiwan. J Formos Med Assoc 2021; 120:1051-1060. [PMID: 33199101 DOI: 10.1016/j.jfma.2020.10.031] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 09/28/2020] [Accepted: 10/30/2020] [Indexed: 02/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality in Taiwan. The Taiwan Liver Cancer Association and the Gastroenterological Society of Taiwan had established a management consensus guideline in 2016. The current recommendations focus on updating critical issues regarding the management of HCC, including surveillance, diagnosis, and systemic treatment. For surveillance, the updated guideline suggests the role of dynamic computed tomography or magnetic resonance imaging and contrast-enhanced ultrasound (CEUS) in selected patients. For diagnosis, this update incorporates CEUS and recognizes the role of gadoxetic acid-enhanced magnetic resonance imaging. For systemic therapy, the updated guideline summarizes the multiple choices of targeted therapy, immune checkpoint inhibitors, and the combination of both. Through this update of the management consensus guideline, patients with HCC can benefit from receiving optimal diagnostic and therapeutic modalities.
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Affiliation(s)
- Yu-Yun Shao
- Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan; Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
| | - Shen-Yung Wang
- Division of Gastroenterology and Hepatology, Department of Medicine, MacKay Memorial Hospital, Taipei, Taiwan
| | - Shi-Ming Lin
- Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan; Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan; Division of Gastroenterology and Hepatology, Department of Medicine, MacKay Memorial Hospital, Taipei, Taiwan.
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Parikh ND, Marshall A, Betts KA, Song J, Zhao J, Yuan M, Wu A, Huff KD, Kim R. Network meta-analysis of nivolumab plus ipilimumab in the second-line setting for advanced hepatocellular carcinoma. J Comp Eff Res 2021; 10:343-352. [PMID: 33442996 DOI: 10.2217/cer-2020-0236] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Aims: To compare the efficacy of nivolumab 1 mg/kg + ipilimumab 3 mg/kg with regorafenib 160 mg, cabozantinib 60 mg and nivolumab 3 mg/kg monotherapy for second-line treatment of advanced hepatocellular carcinoma. Materials & methods: Indirect comparison using network meta-analysis and propensity score weighting. Results: Nivolumab 1 mg/kg + ipilimumab 3 mg/kg had significantly higher objective response rate (median 31.2% [95% credible interval: 19.6-44.5%]) than cabozantinib (4.2% [2.0-6.5%]) and regorafenib (4.8% [1.1-8.3%]), and significantly longer overall survival (cabozantinib: hazard ratio: 0.46 [95% credible interval: 0.27-0.79]; regorafenib: 0.56 [0.32-0.97]). Nivolumab 1 mg/kg + ipilimumab 3 mg/kg had significantly better objective response rate (difference 21.0% [4.5-37.5%]) and overall survival (hazard ratio: 0.58 [0.35-0.96]) than nivolumab monotherapy. Conclusion: Nivolumab 1 mg/kg + ipilimumab 3 mg/kg had a superior efficacy versus cabozantinib 60 mg, regorafenib 160 mg and nivolumab 3 mg/kg monotherapy as second-line therapy for advanced hepatocellular carcinoma.
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Affiliation(s)
- Neehar D Parikh
- Division of Gastroenterology & Hepatology, University of Michigan, Ann Arbor, MI 48109, USA
| | | | | | - Jinlin Song
- Analysis Group Inc., Los Angeles, CA 90071, USA
| | - Jing Zhao
- Analysis Group Inc., Boston, MA 02199, USA
| | - Muhan Yuan
- Analysis Group Inc., Boston, MA 02199, USA
| | - Aozhou Wu
- Analysis Group Inc., Los Angeles, CA 90071, USA
| | | | - Richard Kim
- Department of Gastroenterology Oncology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
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Mohr R, Jost-Brinkmann F, Özdirik B, Lambrecht J, Hammerich L, Loosen SH, Luedde T, Demir M, Tacke F, Roderburg C. Lessons From Immune Checkpoint Inhibitor Trials in Hepatocellular Carcinoma. Front Immunol 2021; 12:652172. [PMID: 33859646 PMCID: PMC8042255 DOI: 10.3389/fimmu.2021.652172] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 03/15/2021] [Indexed: 12/12/2022] Open
Abstract
The implementation of immune checkpoint inhibitors (ICI) into the clinical management of different malignancies has largely changed our understanding of cancer treatment. After having proven efficacy in different tumor entities such as malignant melanoma and lung cancer, ICI were intensively tested in the setting of hepatocellular carcinoma (HCC). Here they could achieve higher and more durable response rates compared to tyrosine-kinase inhibitors (TKI), that were sole standard of care for the last decade. Most recently, ICI treatment was approved in a first line setting of HCC, for cases not suitable for curative strategies. However, only a subset of patients benefits from ICI therapy, while others experience rapid tumor progression, worsening of liver function and poor prognosis. Efforts are being made to find immune characteristics that predict tumor responsiveness to ICI, but no reliable biomarker could be identified so far. Nevertheless, data convincingly demonstrate that combination therapies (such as dual inhibition of PD-L1 and VEGF) are more effective than the application of single agents. In this review, we will briefly recapitulate the current algorithms for systemic treatment, discuss available results from checkpoint inhibitor trials and give an outlook on future directions of immunotherapy in HCC.
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Affiliation(s)
- Raphael Mohr
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany
| | - Fabian Jost-Brinkmann
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany
| | - Burcin Özdirik
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany
| | - Joeri Lambrecht
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany
| | - Linda Hammerich
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany
| | - Sven H. Loosen
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Düsseldorf, Germany
| | - Tom Luedde
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Düsseldorf, Germany
| | - Münevver Demir
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany
| | - Christoph Roderburg
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Düsseldorf, Germany
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D’Alessio A, Prete MG, Cammarota A, Personeni N, Rimassa L. The Role of Cabozantinib as a Therapeutic Option for Hepatocellular Carcinoma: Current Landscape and Future Challenges. J Hepatocell Carcinoma 2021; 8:177-191. [PMID: 33824862 PMCID: PMC8018438 DOI: 10.2147/jhc.s268310] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 03/15/2021] [Indexed: 12/12/2022] Open
Abstract
The systemic treatment of advanced hepatocellular carcinoma (HCC) has significantly changed over the last years, with the introduction of two new standard-of-care first-line treatments (lenvatinib and the combination of atezolizumab and bevacizumab) and the success of several new agents in second line. In particular, after the approval of regorafenib, ramucirumab and cabozantinib, the landscape of second-line treatment has become notably complex, providing a serious challenge in clinical practice. In this review, we focus on cabozantinib, a multikinase inhibitor which was proven effective in improving overall and progression-free survival of patients previously treated with sorafenib in the randomized Phase III CELESTIAL trial. CELESTIAL is the only phase III study to have included patients in the third-line setting and cabozantinib efficacy was confirmed in several post hoc analyses, irrespective of alpha-fetoprotein levels, albumin-bilirubin score, age, and duration of previous sorafenib treatment. The safety profile of cabozantinib in the CELESTIAL trial was comparable with other multikinase inhibitors used for HCC and the most frequent grade ≥3 adverse events were diarrhea, palmar-plantar erythrodysesthesia, fatigue, hypertension, and aspartate aminotransferase increase. Tolerability did not differ between younger and older patients and quality of life was significantly improved compared to placebo during the treatment. In this review, we also make a particular mention to the use of cabozantinib in populations which are normally excluded from clinical trials, such as older patients and Child-Pugh B patients. Finally, we present the new treatment strategies in which cabozantinib is being tested, most notably the combination of cabozantinib and atezolizumab in the first-line setting in the phase III COSMIC-312 trial and the use of cabozantinib after progression on immune-checkpoint inhibitors.
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Affiliation(s)
- Antonio D’Alessio
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (Milan), 20090, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano (Milan), 20089, Italy
| | - Maria Giuseppina Prete
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (Milan), 20090, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano (Milan), 20089, Italy
| | - Antonella Cammarota
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (Milan), 20090, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano (Milan), 20089, Italy
| | - Nicola Personeni
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (Milan), 20090, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano (Milan), 20089, Italy
| | - Lorenza Rimassa
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (Milan), 20090, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano (Milan), 20089, Italy
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Zhu M, Jin Z, Hubbard JM. Management of Non-Colorectal Digestive Cancers with Microsatellite Instability. Cancers (Basel) 2021; 13:651. [PMID: 33561950 PMCID: PMC7915546 DOI: 10.3390/cancers13040651] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 01/26/2021] [Accepted: 02/03/2021] [Indexed: 02/08/2023] Open
Abstract
Microsatellite instability (MSI) is a hallmark of genetic predisposition to DNA damage. It arises from either germline or somatic events leading to impaired function of the mismatch repair system. It can be detected via genetic sequencing or immunohistochemistry with relatively high concordance rates. The presence of MSI in a tumor reflects a high neoantigen load and predicts favorable treatment response to immune checkpoint inhibitors (ICIs). In gastrointestinal cancers, MSI is a predictive biomarker for ICIs with potential prognostic impact but its clinical utility varies widely depending on tumor type. This may be explained by the complexity of tumor microenvironment as highlighted by recent translational studies. In this review, we will discuss the predictive and prognostic value of MSI status in non-colorectal cancers of the digestive system, important clinical trials involving ICIs and potential strategies to overcome resistance to immunotherapy.
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Affiliation(s)
- Mojun Zhu
- Department of Medical Oncology, Mayo Clinic, Rochester, MN 55905, USA; (Z.J.); (J.M.H.)
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48
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Meriggi F, Graffeo M. Clinical Characterisation and Management of the Main Treatment-Induced Toxicities in Patients with Hepatocellular Carcinoma and Cirrhosis. Cancers (Basel) 2021; 13:584. [PMID: 33540870 PMCID: PMC7867371 DOI: 10.3390/cancers13030584] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 01/24/2021] [Accepted: 01/28/2021] [Indexed: 12/12/2022] Open
Abstract
The incidence of hepatocellular carcinoma (HCC) continues to increase worldwide, particularly in Western countries. In almost all cases, HCC develops in subjects with hepatic cirrhosis, often as the result of hepatitis B or C virus infection, alcohol abuse or metabolic forms secondary to non-alcoholic steatohepatitis. Patients with HCC and hepatic symptoms can therefore present symptoms that are attributable to both conditions. These patients require multidisciplinary management, calling for close interaction between the hepatologist and the oncologist. Indeed, the treatment of HCC requires, depending on the disease stage and the degree of hepatic impairment, locoregional therapies that can in turn be broken down into surgical and nonsurgical treatments and systemic treatments used in the event of progression after the administration of locoregional treatments. The past decade has seen the publication of countless papers of great interest that have radically changed the scenario of treatment for HCC. Novel therapies with biological agents and immunotherapy have come to be standard options in the approach to treatment of this cancer, obtaining very promising results where in the past chemotherapy was almost never able to have an impact on the course of the disease. However, in addition to being costly, these drugs are not devoid of adverse effects and their management cannot forgo the consideration of the underlying hepatic impairment. Patients with HCC and cirrhosis therefore require special attention, starting from the initial characterisation needed for an appropriate selection of those to be referred for treatment, as these patients are almost never fit. In this chapter, we will attempt to investigate and clarify the key points of the management of the main toxicities induced by locoregional and systemic treatments for HCC secondary to cirrhosis.
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Affiliation(s)
- Fausto Meriggi
- Oncology Department, Istituto Ospedaliero Fondazione Poliambulanza, Via Leonida Bissolati 57, 25124 Brescia, Italy
| | - Massimo Graffeo
- Hepatology Unit, Istituto Ospedaliero Fondazione Poliambulanza, Via Leonida Bissolati 57, 25124 Brescia, Italy;
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49
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Wong JSL, Kwok GGW, Tang V, Li BCW, Leung R, Chiu J, Ma KW, She WH, Tsang J, Lo CM, Cheung TT, Yau T. Ipilimumab and nivolumab/pembrolizumab in advanced hepatocellular carcinoma refractory to prior immune checkpoint inhibitors. J Immunother Cancer 2021; 9:e001945. [PMID: 33563773 PMCID: PMC7875295 DOI: 10.1136/jitc-2020-001945] [Citation(s) in RCA: 96] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/26/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Programmed cell death protein 1 (PD-1) pathway blockade with immune checkpoint inhibitors (ICIs) is a standard therapy in advanced hepatocellular carcinoma (HCC) nowadays. No strategies to overcome ICI resistance have been described. We aimed to evaluate the use of ipilimumab and anti-PD-1 ICIs (nivolumab or pembrolizumab) combinations in patients with advanced HCC with progression on prior ICIs. METHODS Patients with advanced HCC with documented tumor progression on prior ICIs and subsequently received ipilimumab with nivolumab/pembrolizumab were analyzed. Objective response rate (ORR), median duration of response (DOR), time-to-progression (TTP), overall survival (OS), and treatment-related adverse events (TRAEs) were assessed. RESULTS Twenty-five patients were included. The median age was 62 (range: 51-83). About 68% were of Child-Pugh (CP) Grade A and 48% had primary resistance to prior ICI. At median follow-up of 37.7 months, the ORR was 16% with a median DOR of 11.5 months (range: 2.76-30.3). Three patients achieved complete response. The median TTP was 2.96 months (95% CI: 1.61 to 4.31). Median OS was 10.9 months (95% CI: 3.99 to 17.8) and the 1 year, 2 year and 3 year survival rates were 42.4%, 32.3% and 21.6%, respectively. The ORR was 16.7% in primary resistance group and 15.4% in acquired resistance group (p=1.00). All responders were of CP A and Albumin-Bilirubin (ALBI) Grade 1 or 2. CP and ALBI Grades were significantly associated with OS (p=0.006 and p<0.001, respectively). Overall, 52% of patients experienced TRAEs and 12% experienced Grade 3 or above TRAEs. CONCLUSIONS Ipilimumab and nivolumab/pembrolizumab can achieve durable antitumor activity and encouraging survival outcomes with acceptable toxicity in patients with advanced HCC who had prior treatment with ICIs.
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MESH Headings
- Aged
- Aged, 80 and over
- Antibodies, Monoclonal, Humanized/adverse effects
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antineoplastic Combined Chemotherapy Protocols/adverse effects
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/mortality
- Carcinoma, Hepatocellular/pathology
- Disease Progression
- Drug Resistance, Neoplasm
- Female
- Humans
- Immune Checkpoint Inhibitors/adverse effects
- Immune Checkpoint Inhibitors/therapeutic use
- Ipilimumab/adverse effects
- Ipilimumab/therapeutic use
- Liver Neoplasms/drug therapy
- Liver Neoplasms/immunology
- Liver Neoplasms/mortality
- Liver Neoplasms/pathology
- Male
- Middle Aged
- Nivolumab/adverse effects
- Nivolumab/therapeutic use
- Retrospective Studies
- Salvage Therapy
- Time Factors
- Treatment Outcome
- Tumor Microenvironment
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Affiliation(s)
- Jeffrey Sum Lung Wong
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Gerry Gin Wai Kwok
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Vikki Tang
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Bryan Cho Wing Li
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Roland Leung
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Joanne Chiu
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Ka Wing Ma
- Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Wong Hoi She
- Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Josephine Tsang
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Chung Mau Lo
- Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Tan To Cheung
- Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Thomas Yau
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
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Donisi C, Puzzoni M, Ziranu P, Lai E, Mariani S, Saba G, Impera V, Dubois M, Persano M, Migliari M, Pretta A, Liscia N, Astara G, Scartozzi M. Immune Checkpoint Inhibitors in the Treatment of HCC. Front Oncol 2021; 10:601240. [PMID: 33585218 PMCID: PMC7874239 DOI: 10.3389/fonc.2020.601240] [Citation(s) in RCA: 84] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Accepted: 11/11/2020] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the typical inflammation-induced neoplasia. It often prospers where a chronic liver disease persists, thus leading a strong rationale for immune therapy. Several immune-based treatments, including immune checkpoint inhibitors (ICI), cytokines, adoptive cell transfer, and vaccines, have been tested in the treatment of HCC. In this review, we summarize the role of the ICI in HCC patients in various sets of treatment. As for advanced HCC, the anti-Programmed cell Death protein 1 (PD1) antibodies and the anti-Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) antibodies have been examined in patients with enthusiastic results in phase I-II-III studies. Overall, this led the Food and Drug Administration (FDA) to approve pembrolizumab, nivolumab, and nivolumab + ipilimumab in the second-line setting. The anti- Programmed Death-Ligand 1 (PDL-1) antibodies have also been evaluated. Thanks to the results obtained from phase III IMbrave study, atezolizumab + bevacizumab is now the standard of care in the first-line advanced setting of HCC. As for localized HCC, the putative immunological effect of locoregional therapies led to evaluate the combination strategy with ICI. This way, chemoembolization, ablation with radiofrequency, and radioembolization combined with ICI are currently under study. Likewise, the study of adjuvant immunotherapy following surgical resection is underway. In addition, the different ICI has been studied in combination with other ICI as well as with multikinase inhibitors and anti-angiogenesis monoclonal antibody. The evidence available suggests that combining systemic therapies and locoregional treatments with ICI may represent an effective strategy in this context.
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Affiliation(s)
- Clelia Donisi
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Marco Puzzoni
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Pina Ziranu
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Eleonora Lai
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Stefano Mariani
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Giorgio Saba
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Valentino Impera
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
- Medical Oncology Unit, Sapienza University of Rome, Rome, Italy
| | - Marco Dubois
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Mara Persano
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Marco Migliari
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Andrea Pretta
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
- Medical Oncology Unit, Sapienza University of Rome, Rome, Italy
| | - Nicole Liscia
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
- Medical Oncology Unit, Sapienza University of Rome, Rome, Italy
| | - Giorgio Astara
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Mario Scartozzi
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
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