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Magyar CTJ, Perera S, Rajendran L, Li Z, Almugbel FA, Feng S, Choi WJ, Aceituno L, Vogel A, Grant RC, Selzner N, Jaeckel E, Falla-Rad N, Knox JJ, Chen EX, Sapisochin G, O'Kane GM. Comparative Outcome Analysis of Lenvatinib Versus Sorafenib for Recurrence of Hepatocellular Carcinoma After Liver Transplantation. Transplantation 2025; 109:681-690. [PMID: 39531339 DOI: 10.1097/tp.0000000000005240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2024]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) recurs after liver transplantation (LT) in ~17% of patients. We aimed to retrospectively compare the outcomes of patients treated with different tyrosine kinase inhibitors (TKIs) for recurrent HCC post-LT. METHODS Patients with recurrent HCC post-LT between 2006 and 2019 were included. The impact of sorafenib and lenvatinib treatment for recurrent disease was assessed using survival analysis with an a priori multivariable Cox regression (alpha-fetoprotein [AFP] at recurrence, recurrence lesion diameter, single-site versus multisite metastases). RESULTS Seven hundred fifty-four patients underwent LT for HCC, of whom 120 (15.9%) developed recurrence. Of these patients, 56 received TKIs: sorafenib (n = 42) or lenvatinib (n = 14). The median age at LT was 60.8 y (interquartile range, 54.0-66.2); 52 (93%) were men and 26 (46%) were within Milan criteria at listing. Baseline characteristics at recurrence were comparable between the 2 groups, including largest tumor diameter ( P = 0.15), receipt of local therapies before TKI ( P = 0.33), and single-site recurrence ( P = 0.75), and time from interventional treatment to start of TKI ( P = 0.44). The AFP at recurrence was higher in the sorafenib group (95.0 versus 3.0 µg/L, P < 0.001). The median overall survival (OS) after initiation of TKI treatment was longer in the lenvatinib group (15.0 mo [95% confidence interval [CI], 11.5-31.5] versus 7.8 mo [95% CI, 4.0-15.4]; P = 0.02) with a 2.3-fold a priori adjusted effect on OS (adjusted hazard ratio 2.32 [95% CI, 1.03-5.20], P = 0.04). CONCLUSIONS Our findings suggest lenvatinib is a valuable treatment option for patients with HCC recurrence after LT.
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Affiliation(s)
- Christian T J Magyar
- University Health Network, HPB Surgical Oncology, Toronto, ON, Canada
- Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Sheron Perera
- University of Toronto, Toronto, ON, Canada
- Odette Cancer Centre, Sunnybrook Health Science Centre, Toronto, ON, Canada
| | - Luckshi Rajendran
- University Health Network, HPB Surgical Oncology, Toronto, ON, Canada
- Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada
| | - Zhihao Li
- University Health Network, HPB Surgical Oncology, Toronto, ON, Canada
- Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada
| | - Fahad A Almugbel
- King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Sophie Feng
- Redcliffe Hospital, Redcliffe, QLD, Australia
| | - Woo Jin Choi
- University Health Network, HPB Surgical Oncology, Toronto, ON, Canada
- Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada
| | - Laia Aceituno
- University Health Network, HPB Surgical Oncology, Toronto, ON, Canada
- Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada
| | - Arndt Vogel
- Division of Gastroenterology and Hepatology, Toronto General Hospital, Toronto, ON, Canada
- Hannover Medical School, Hannover, Germany
- Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada
| | - Robert C Grant
- University of Toronto, Toronto, ON, Canada
- Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada
| | - Nazia Selzner
- University Health Network, HPB Surgical Oncology, Toronto, ON, Canada
- Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada
| | - Elmar Jaeckel
- University Health Network, HPB Surgical Oncology, Toronto, ON, Canada
- Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada
| | - Nazanin Falla-Rad
- University of Toronto, Toronto, ON, Canada
- Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada
| | - Jennifer J Knox
- University of Toronto, Toronto, ON, Canada
- Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada
| | - Eric X Chen
- University of Toronto, Toronto, ON, Canada
- Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada
| | - Gonzalo Sapisochin
- University Health Network, HPB Surgical Oncology, Toronto, ON, Canada
- Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada
| | - Grainne M O'Kane
- University of Toronto, Toronto, ON, Canada
- Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada
- St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
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Cao S, Yu S, Huang L, Seery S, Xia Y, Zhao Y, Si Z, Zhang X, Zhu J, Lang R, Kou J, Zhang H, Wei L, Zhou G, Sun L, Wang L, Li T, He Q, Zhu Z. Deep learning for hepatocellular carcinoma recurrence before and after liver transplantation: a multicenter cohort study. Sci Rep 2025; 15:7730. [PMID: 40044774 PMCID: PMC11882823 DOI: 10.1038/s41598-025-91728-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Accepted: 02/24/2025] [Indexed: 03/09/2025] Open
Abstract
Hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) is a major contributor to mortality. We developed a recurrence prediction system for HCC patients before and after LT. Data from patients with HCC who underwent LT were retrospectively collected from three specialist centres in China. Pre- and post-operative variables were selected using support vector machine, random forest, and logistic regression (LR). Then, pre- and post-operative models were developed using three machine learning methods: LR, stacking, and two survival-based approaches. Models were evaluated using seven assessment indices, and patients were classified as either high- or low-risk based on recurrence risk. 466 patients were included and followed for a median of 51.0 months (95% CI 47.8-54.2). The pre-DeepSurv model (pre-DSM) had a C-index of 0.790 ± 0.003 during training, 0.775 ± 0.037 during testing, and 0.765 ± 0.001 and 0.819 ± 0.002 during external validation. After incorporating clinicopathologic variables, the post-DeepSurv model (post-DSM) had a 0.835 ± 0.008 C-index during training, 0.812 ± 0.082 during testing, and 0.839 ± 0.001 and 0.831 ± 0.002 during external validation. The post-DSM outperformed the Milan criteria by more accurately identifying patients at high risk of recurrence. Tumour recurrence predictions also improved significantly with DeepSurv. Both pre- and post-DSMs have the potential to guide personalised surveillance strategies for LT patients with HCC.
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Affiliation(s)
- Shuang Cao
- Liver Transplantation Center, Clinical Research Center for Pediatric Liver Transplantation, State Key Lab of Digestive Health, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, 95 Yong'an Road, Xicheng District, Beijing, 100050, China
| | - Sihan Yu
- Cardiology Department, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Liangbin Huang
- Department of Breast and Thyroid Surgery, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, 410028, Hunan, China
| | - Samuel Seery
- Department of Humanities and Social Sciences, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
- School of Pharmacy, Newcastle University, Newcastle, NE1 4LP, UK
| | - Yu Xia
- Graduate School, Tsinghua University, Beijing, 100084, China
| | - Yongwei Zhao
- State Key Laboratory of Processors, Institute of Computing Technology, Chinese Academy of Sciences, Beijing, 100190, China
| | - Zhongzhou Si
- Department of Liver Transplantation, The Second Xiang-ya Hospital, Central South University, Changsha, 410011, China
| | - Xinxue Zhang
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China
| | - Jiqiao Zhu
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China
| | - Ren Lang
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China
| | - Jiantao Kou
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China
| | - Haiming Zhang
- Liver Transplantation Center, Clinical Research Center for Pediatric Liver Transplantation, State Key Lab of Digestive Health, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, 95 Yong'an Road, Xicheng District, Beijing, 100050, China
| | - Lin Wei
- Liver Transplantation Center, Clinical Research Center for Pediatric Liver Transplantation, State Key Lab of Digestive Health, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, 95 Yong'an Road, Xicheng District, Beijing, 100050, China
| | - Guangpeng Zhou
- Liver Transplantation Center, Clinical Research Center for Pediatric Liver Transplantation, State Key Lab of Digestive Health, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, 95 Yong'an Road, Xicheng District, Beijing, 100050, China
| | - Liying Sun
- Liver Transplantation Center, Clinical Research Center for Pediatric Liver Transplantation, State Key Lab of Digestive Health, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, 95 Yong'an Road, Xicheng District, Beijing, 100050, China
| | - Lei Wang
- Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, 100026, China.
| | - Ting Li
- Department of Liver Transplantation, The Second Xiang-ya Hospital, Central South University, Changsha, 410011, China.
| | - Qiang He
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China.
| | - Zhijun Zhu
- Liver Transplantation Center, Clinical Research Center for Pediatric Liver Transplantation, State Key Lab of Digestive Health, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, 95 Yong'an Road, Xicheng District, Beijing, 100050, China.
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Di Marco L, Romanzi A, Pivetti A, De Maria N, Ravaioli F, Salati M, Villa E, Di Benedetto F, Magistri P, Dominici M, Colecchia A, Di Sandro S, Spallanzani A. Suppressing, stimulating and/or inhibiting: The evolving management of HCC patient after liver transplantation. Crit Rev Oncol Hematol 2025; 207:104607. [PMID: 39725094 DOI: 10.1016/j.critrevonc.2024.104607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 12/20/2024] [Accepted: 12/22/2024] [Indexed: 12/28/2024] Open
Abstract
Liver transplantation (LT) is a curative strategy for hepatocellular carcinoma (HCC), but the risk of HCC recurrence remains a challenging problem. In patients with HCC recurrence after LT (HCC-R_LT), the locoregional and surgical approaches are complex, and the guidelines do not report evidence-based strategies for the management of immunosuppression. In recent years, immunotherapy has become an effective option for patients with advanced HCC in pre-transplant settings. However, due to the risk of potentially fatal allograft rejection, the use of immunotherapy is avoided in post-transplant settings. Combining immunosuppressants with immunotherapy in transplant patients is also challenging due to the complex tumor microenvironment and immunoreactivity. The fear of acute liver rejection and the lack of predictive factors hinder the successful clinical application of immunotherapy for post-liver transplantation HCC recurrence. This review aims to comprehensively summarize the risk of HCC-R_LT, the available evidence for the efficacy of immunotherapy in patients with HCC-R_LT, and the clinical issues regarding the innovative management of this patient population.
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Affiliation(s)
- Lorenza Di Marco
- Department of Oncology and Hematology, Oncology Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41124, Italy; Department of Biomedical, Metabolic and Neural Sciences, Clinical and Experimental Medicine Program, University of Modena and Reggio Emilia, Modena 41124, Italy.
| | - Adriana Romanzi
- Chimomo Department, Gastroenterology Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41125, Italy.
| | - Alessandra Pivetti
- Chimomo Department, Gastroenterology Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41125, Italy.
| | - Nicola De Maria
- Chimomo Department, Gastroenterology Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41125, Italy.
| | - Federico Ravaioli
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum University of Bologna, Bologna 40138, Italy.
| | - Massimiliano Salati
- Department of Oncology and Hematology, Oncology Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41124, Italy.
| | - Erica Villa
- Chimomo Department, Gastroenterology Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41125, Italy; National Institute of Gastroenterology IRCCS "Saverio de Bellis", Research Hospital, Castellana Grotte 70013, Italy.
| | - Fabrizio Di Benedetto
- Hepato-Pancreato-Biliary Surgery and Liver Transplantation Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41125, Italy.
| | - Paolo Magistri
- Hepato-Pancreato-Biliary Surgery and Liver Transplantation Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41125, Italy.
| | - Massimo Dominici
- Department of Oncology and Hematology, Oncology Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41124, Italy.
| | - Antonio Colecchia
- Chimomo Department, Gastroenterology Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41125, Italy.
| | - Stefano Di Sandro
- Hepato-Pancreato-Biliary Surgery and Liver Transplantation Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41125, Italy.
| | - Andrea Spallanzani
- Department of Oncology and Hematology, Oncology Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41124, Italy.
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Badwei N. Challenges related to clinical decision-making in hepatocellular carcinoma recurrence post-liver transplantation: Is there a hope? World J Transplant 2024; 14:96637. [PMID: 39295978 PMCID: PMC11317853 DOI: 10.5500/wjt.v14.i3.96637] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Revised: 06/08/2024] [Accepted: 06/24/2024] [Indexed: 07/31/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a common liver malignancy and represents a serious cause of cancer-related mortality and morbidity. One of the favourable curative surgical therapeutic options for HCC is liver transplantation (LT) in selected patients fulfilling the known standard Milan/University of California San Francisco criteria which have shown better outcomes and longer-term survival. Despite careful adherence to the strict HCC selection criteria for LT in different transplant centres, the recurrence rate still occurs which could negatively affect HCC patients' survival. Hence HCC recurrence post-LT could predict patients' survival and prognosis, depending on the exact timing of recurrence after LT (early or late), and whether intra/extrahepatic HCC recurrence. Several factors may aid in such a complication, particularly tumour-related criteria including larger sizes, higher grades or poor tumour differentiation, microvascular invasion, and elevated serum alpha-fetoprotein. Therefore, managing such cases is challenging, different therapeutic options have been proposed, including curative surgical and ablative treatments that have shown better outcomes, compared to the palliative locoregional and systemic therapies, which may be helpful in those with unresectable tumour burden. To handle all these issues in our review.
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Affiliation(s)
- Nourhan Badwei
- Department of Tropical Medicine, Gastroenterology and Hepatology, Hepatoma Group, Ain Shams University, Cairo 11517, Egypt
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Liu J, Xia S, Zhang B, Mohammed DM, Yang X, Zhu Y, Jiang X. Small molecule tyrosine kinase inhibitors approved for systemic therapy of advanced hepatocellular carcinoma: recent advances and future perspectives. Discov Oncol 2024; 15:259. [PMID: 38960980 PMCID: PMC11222362 DOI: 10.1007/s12672-024-01110-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 06/18/2024] [Indexed: 07/05/2024] Open
Abstract
Liver cancer is the sixth most commonly diagnosed cancer and the third leading cause of cancer death in the world, and hepatocellular carcinoma (HCC) is the most common form of liver cancer. More than half of the HCC patients are diagnosed at an advanced stage and often require systemic therapy. Dysregulation of the activity of receptor tyrosine kinases (RTKs) is involved in the development and progress of HCC, RTKs are therefore the potential targets for systemic therapy of advanced HCC (aHCC). Currently, a total of six small molecule tyrosine kinase inhibitors (TKIs) have been approved for aHCC, including first-line sorafenib, lenvatinib, and donafenib, and second-line regorafenib, cabozantinib, and apatinib. These TKIs improved patients survival, which are associated with disease stage, etiology, liver function, tumor burden, baseline levels of alpha-fetoprotein, and treatment history. This review focuses on the clinical outcomes of these TKIs in key clinical trials, retrospective and real-world studies and discusses the future perspectives of TKIs for aHCC, with an aim to provide up-to-date evidence for decision-making in the treatment of aHCC.
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Affiliation(s)
- Jianzhong Liu
- Clinical Laboratory, Wuhan No.7 Hospital, Zhong Nan 2nd Road, Wuhan, 430071, China
| | - Shuai Xia
- Department of Biochemistry and Molecular Biology, Jining Medical University, Jining, 272067, Shandong, China
| | - Baoyi Zhang
- National Engineering Research Center for Nanomedicine, Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, Hubei, China
| | - Dina Mostafa Mohammed
- Nutrition and Food Sciences Department, National Research Centre, Dokki, Cairo, Egypt
| | - Xiangliang Yang
- National Engineering Research Center for Nanomedicine, Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, Hubei, China
| | - Yanhong Zhu
- National Engineering Research Center for Nanomedicine, Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, Hubei, China
| | - Xinnong Jiang
- National Engineering Research Center for Nanomedicine, Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, Hubei, China.
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Cillo U, Carraro A, Avolio AW, Cescon M, Di Benedetto F, Giannelli V, Magistri P, Nicolini D, Vivarelli M, Lanari J. Immunosuppression in liver transplant oncology: position paper of the Italian Board of Experts in Liver Transplantation (I-BELT). Updates Surg 2024; 76:725-741. [PMID: 38713396 DOI: 10.1007/s13304-024-01845-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 07/31/2023] [Indexed: 05/08/2024]
Abstract
Liver transplant oncology (TO) represents an area of increasing clinical and scientific interest including a heterogeneous group of clinical-pathological settings. Immunosuppressive management after LT is a key factor relevantly impacting result. However, disease-related guidance is still lacking, and many open questions remain in the field. Based on such a substantial lack of solid evidences, the Italian Board of Experts in Liver Transplantation (I-BELT) (a working group including representatives of all national transplant centers), unprecedently promoted a methodologically sound consensus conference on the topic, based on the GRADE approach. The group final recommendations are herein presented and commented. The 18 PICOs and Statements and their levels of evidence and grades of recommendation are reported and grouped into seven areas: (1) risk stratification by histopathological and bio-molecular parameters and role of mTORi post-LT; (2) steroids and HCC recurrence; (3) management of immunosuppression when HCC recurs after LT; (4) mTORi monotherapy; (5) machine perfusion and HCC recurrence after LT; (6) physiopathology of tumor-infiltrating lymphocytes and immunosuppression, the role of inflammation; (7) immunotherapy in liver transplanted patients. The interest in mammalian targets of rapamycin inhibitors (mTORi), for steroid avoidance and the need for a reduction to CNI exposure emerged from the consensus process. A selected list of unmet needs prompting further investigations have also been developed. The so far heterogeneous and granular approach to immunosuppression in oncologic patients deserves greater efforts for a more standardized therapeutic response to the different clinical scenarios. This consensus process makes a first unprecedented step in this direction, to be developed on a larger scale.
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Affiliation(s)
- Umberto Cillo
- Department of Surgical, Oncological and Gastroenterological Sciences, General Surgery 2 Hepato-Pancreato-Biliary Surgery and Liver Transplantation, Padua University Hospital, Via Giustiniani 2, 34128, Padua, PD, Italy.
| | - Amedeo Carraro
- Liver Transplant Unit, Department of Surgery and Oncology, University Hospital Trust of Verona, Verona, Italy
| | - Alfonso W Avolio
- Department of General Surgery and Liver Transplantation, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Matteo Cescon
- General Surgery and Transplantation Unit, Department of Medical and Surgical Sciences, Azienda Ospedaliero-Universitaria-Policlinico S.Orsola-Malpighi, Bologna, Italy
| | - Fabrizio Di Benedetto
- Hepatopancreatobiliary Surgery and Liver Transplantation Unit, University of Modena and Reggio Emilia, Modena, Italy
| | - Valerio Giannelli
- Liver Unit, Department of Liver Transplant, Azienda Ospedaliera San Camillo Forlanini, Rome, Italy
| | - Paolo Magistri
- Hepatopancreatobiliary Surgery and Liver Transplantation Unit, University of Modena and Reggio Emilia, Modena, Italy
| | - Daniele Nicolini
- Hepatobiliary and Abdominal Transplantation Surgery, Department of Experimental and Clinical Medicine, Riuniti Hospital, Polytechnic University of Marche, Ancona, Italy
| | - Marco Vivarelli
- Hepatobiliary and Abdominal Transplantation Surgery, Department of Experimental and Clinical Medicine, Riuniti Hospital, Polytechnic University of Marche, Ancona, Italy
| | - Jacopo Lanari
- Department of Surgical, Oncological and Gastroenterological Sciences, General Surgery 2 Hepato-Pancreato-Biliary Surgery and Liver Transplantation, Padua University Hospital, Via Giustiniani 2, 34128, Padua, PD, Italy
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7
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Tajiri K, Muraishi N, Murayama A, Hayashi Y, Yasuda I. Impact of post-progression survival in second-line treatment with molecular target agents for unresectable hepatocellular carcinoma. Hepatol Res 2024; 54:403-408. [PMID: 37924508 DOI: 10.1111/hepr.13986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 10/24/2023] [Accepted: 10/31/2023] [Indexed: 11/06/2023]
Abstract
AIM Sequential therapies are essential to extend overall survival (OS) in patients with unresectable hepatocellular carcinoma (HCC). Several second-line treatments with molecular target agents have shown survival benefits. However, the significance of post-progression survival (PPS) in extending OS in patients with HCC given such treatments remains uncertain. METHODS Through a systematic review of the literature in the PubMed database, this study investigated the correlation between PPS and OS and that between progression-free survival (PFS) and OS in patients with HCC given second-line treatments. RESULTS In total, 3935 patients who had received second-line treatment with regorafenib, ramucirumab, or cabozantinib, which are approved molecular target agents, were identified. In the patients treated with regorafenib, PPS showed a strong correlation with OS (R2 = 0.729, R = 0.854, p < 0.001) whereas PFS showed a weak correlation (R2 = 0.218, R = 0.467, p = 0.021). In the patients treated with ramucirumab, PPS showed a strong correlation with OS (R2 = 0.800, R = 0.894, p = 0.016) whereas PFS showed a negligible correlation (R2 = 0.020, R = 0.140, p = 0.791). In the patients treated with cabozantinib, PPS showed a strong correlation with OS (R2 = 0.856, R = 0.925, p = 0.003) as did PFS (R2 = 0.946, R = 0.973, p < 0.001). CONCLUSIONS PPS plays a more significant role than PFS in extending OS in patients given second-line treatment for unresectable HCC. Sequential therapies after disease progression in second-line treatment are essential to acquire good OS. Maintenance of hepatic reserve function and the patient's general condition is essential during systemic treatments for unresectable HCC.
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Affiliation(s)
- Kazuto Tajiri
- Third Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan
| | - Nozomu Muraishi
- Third Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan
| | - Aiko Murayama
- Third Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan
| | - Yuka Hayashi
- Third Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan
| | - Ichiro Yasuda
- Third Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan
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8
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Sankar K, Gong J, Osipov A, Miles SA, Kosari K, Nissen NN, Hendifar AE, Koltsova EK, Yang JD. Recent advances in the management of hepatocellular carcinoma. Clin Mol Hepatol 2024; 30:1-15. [PMID: 37482076 PMCID: PMC10776289 DOI: 10.3350/cmh.2023.0125] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Revised: 07/18/2023] [Accepted: 07/18/2023] [Indexed: 07/25/2023] Open
Abstract
Liver cancer remains a challenge of global health, being the 4th leading cause of cancer death worldwide. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, and is usually precipitated by chronic viral infections (hepatitis B and C), non-alcoholic steatohepatitis, heavy alcohol use, and other factors which may lead to chronic inflammation and cirrhosis of the liver. There have been significant advances in the systemic treatment options for HCC over the past decades, with several approvals of both immune checkpoint inhibitors and tyrosine kinase inhibitors in patients with preserved liver function. These advances have led to improvement in survival outcomes, with expected survival of greater than 18 months, in those with sensitive tumors, adequate liver function, and those functionally fit to receive sequential therapies. Several ongoing and promising trials are now evaluating combinational strategies with novel systemic agents and combinations of systemic therapy with locoregional therapy. In view of these trials, further advances in the treatment of HCC are foreseen in the near future.
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Affiliation(s)
- Kamya Sankar
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Jun Gong
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Arsen Osipov
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Steven A. Miles
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Kambiz Kosari
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Nicholas N. Nissen
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Andrew E. Hendifar
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Ekaterina K. Koltsova
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Ju Dong Yang
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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9
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Marrone G, Leone MS, Biolato M, Liguori A, Bianco G, Spoletini G, Gasbarrini A, Miele L, Pompili M. Therapeutic Approach to Post-Transplant Recurrence of Hepatocellular Carcinoma: Certainties and Open Issues. Cancers (Basel) 2023; 15:5593. [PMID: 38067299 PMCID: PMC10705300 DOI: 10.3390/cancers15235593] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 11/03/2023] [Accepted: 11/18/2023] [Indexed: 01/12/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is a growing indication for liver transplantation (LT). Careful candidate selection is a prerequisite to keep post-LT recurrence rates within acceptable percentages. In the pre-LT period, various types of locoregional treatments and/or systemic therapies can be used for bridging or downstaging purposes. In this context, one of the factors limiting the possibility of treatment is the degree of functional liver impairment. In the LT subject, no widely accepted indications are available to guide treatment of disease recurrence and heterogeneity exists between transplant centers. Improved liver function post LT makes multiple therapeutic strategies theoretically feasible, but patient management is complicated by the need to adjust immunosuppressive therapy and to assess potential toxicities and drug-drug interactions. Finally, there is controversy and uncertainty about the use of recently introduced immunotherapeutic drugs, mainly due to the risk of organ rejection. In this paper, we will review the most recent available literature on the management of post-transplant HCC recurrence, discussing evidence and controversies.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Maurizio Pompili
- Medical and Surgical Sciences Department, Policlinico Universitario A. Gemelli-IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
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10
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Zhou J, Sun H, Wang Z, Cong W, Zeng M, Zhou W, Bie P, Liu L, Wen T, Kuang M, Han G, Yan Z, Wang M, Liu R, Lu L, Ren Z, Zeng Z, Liang P, Liang C, Chen M, Yan F, Wang W, Hou J, Ji Y, Yun J, Bai X, Cai D, Chen W, Chen Y, Cheng W, Cheng S, Dai C, Guo W, Guo Y, Hua B, Huang X, Jia W, Li Q, Li T, Li X, Li Y, Li Y, Liang J, Ling C, Liu T, Liu X, Lu S, Lv G, Mao Y, Meng Z, Peng T, Ren W, Shi H, Shi G, Shi M, Song T, Tao K, Wang J, Wang K, Wang L, Wang W, Wang X, Wang Z, Xiang B, Xing B, Xu J, Yang J, Yang J, Yang Y, Yang Y, Ye S, Yin Z, Zeng Y, Zhang B, Zhang B, Zhang L, Zhang S, Zhang T, Zhang Y, Zhao M, Zhao Y, Zheng H, Zhou L, Zhu J, Zhu K, Liu R, Shi Y, Xiao Y, Zhang L, Yang C, Wu Z, Dai Z, Chen M, Cai J, Wang W, Cai X, Li Q, Shen F, Qin S, Teng G, Dong J, Fan J. Guidelines for the Diagnosis and Treatment of Primary Liver Cancer (2022 Edition). Liver Cancer 2023; 12:405-444. [PMID: 37901768 PMCID: PMC10601883 DOI: 10.1159/000530495] [Citation(s) in RCA: 112] [Impact Index Per Article: 56.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 01/24/2023] [Indexed: 10/31/2023] Open
Abstract
Background Primary liver cancer, of which around 75-85% is hepatocellular carcinoma in China, is the fourth most common malignancy and the second leading cause of tumor-related death, thereby posing a significant threat to the life and health of the Chinese people. Summary Since the publication of Guidelines for Diagnosis and Treatment of Primary Liver Cancer in China in June 2017, which were updated by the National Health Commission in December 2019, additional high-quality evidence has emerged from researchers worldwide regarding the diagnosis, staging, and treatment of liver cancer, that requires the guidelines to be updated again. The new edition (2022 Edition) was written by more than 100 experts in the field of liver cancer in China, which not only reflects the real-world situation in China but also may reshape the nationwide diagnosis and treatment of liver cancer. Key Messages The new guideline aims to encourage the implementation of evidence-based practice and improve the national average 5-year survival rate for patients with liver cancer, as proposed in the "Health China 2030 Blueprint."
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Affiliation(s)
- Jian Zhou
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Huichuan Sun
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zheng Wang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wenming Cong
- Department of Pathology, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Mengsu Zeng
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Weiping Zhou
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Ping Bie
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Lianxin Liu
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Tianfu Wen
- Department of Liver Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Ming Kuang
- Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Guohong Han
- Department of Liver Diseases and Digestive Interventional Radiology, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Zhiping Yan
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Maoqiang Wang
- Department of Interventional Radiology, Chinese PLA General Hospital, Beijing, China
| | - Ruibao Liu
- Department of Interventional Radiology, The Tumor Hospital of Harbin Medical University, Harbin, China
| | - Ligong Lu
- Department of Interventional Oncology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Zhenggang Ren
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhaochong Zeng
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ping Liang
- Department of Interventional Ultrasound, Chinese PLA General Hospital, Beijing, China
| | - Changhong Liang
- Department of Radiology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Min Chen
- Editorial Department of Chinese Journal of Digestive Surgery, Chongqing, China
| | - Fuhua Yan
- Department of Radiology, Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Wenping Wang
- Department of Ultrasound, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jinlin Hou
- Department of Infectious Diseases, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yuan Ji
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jingping Yun
- Department of Pathology, Tumor Prevention and Treatment Center, Sun Yat-sen University, Guangzhou, China
| | - Xueli Bai
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Dingfang Cai
- Department of Integrative Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Weixia Chen
- Department of Radiology, West China Hospital of Sichuan University, Chengdu, China
| | - Yongjun Chen
- Department of Hematology, Ruijin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wenwu Cheng
- Department of Integrated Therapy, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Shuqun Cheng
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Chaoliu Dai
- Department of Hepatobiliary and Spleenary Surgery, The Affiliated Shengjing Hospital, China Medical University, Shenyang, China
| | - Wengzhi Guo
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yabing Guo
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Baojin Hua
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Xiaowu Huang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Weidong Jia
- Department of Hepatic Surgery, Affiliated Provincial Hospital, Anhui Medical University, Hefei, China
| | - Qiu Li
- Department of Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Tao Li
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Xun Li
- The First Hospital of Lanzhou University, Lanzhou, China
| | - Yaming Li
- Department of Nuclear Medicine, The First Hospital of China Medical University, Shenyang, China
| | - Yexiong Li
- Department of Radiation Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jun Liang
- Department of Oncology, Peking University International Hospital, Beijing, China
| | - Changquan Ling
- Changhai Hospital of Traditional Chinese Medicine, Second Military Medical University, Shanghai, China
| | - Tianshu Liu
- Department of Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiufeng Liu
- Department of Medical Oncology, PLA Cancer Center, Nanjing Bayi Hospital, Nanjing, China
| | - Shichun Lu
- Institute and Hospital of Hepatobiliary Surgery of Chinese PLA, Chinese PLA Medical School, Chinese PLA General Hospital, Beijing, China
| | - Guoyue Lv
- Department of General Surgery, The First Hospital of Jilin University, Jilin, China
| | - Yilei Mao
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC and Chinese Academy of Medical Sciences, Beijing, China
| | - Zhiqiang Meng
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Weixin Ren
- Department of Interventional Radiology the First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Hongcheng Shi
- Department of Nuclear Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Guoming Shi
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ming Shi
- Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Tianqiang Song
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Kaishan Tao
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Jianhua Wang
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Kui Wang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Lu Wang
- Department of Hepatic Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China
| | - Wentao Wang
- Department of Liver Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Xiaoying Wang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhiming Wang
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, China
| | - Bangde Xiang
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Baocai Xing
- Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital and Institute, Beijing, China
| | - Jianming Xu
- Department of Gastrointestinal Oncology, Affiliated Hospital Cancer Center, Academy of Military Medical Sciences, Beijing, China
| | - Jiamei Yang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Jianyong Yang
- Department of Interventional Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yefa Yang
- Department of Hepatic Surgery and Interventional Radiology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Yunke Yang
- Department of Integrative Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Shenglong Ye
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhenyu Yin
- Department of Hepatobiliary Surgery, Zhongshan Hospital of Xiamen University, Xiamen, China
| | - Yong Zeng
- Department of Liver Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Bixiang Zhang
- Department of Surgery, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Boheng Zhang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Leida Zhang
- Department of Hepatobiliary Surgery Institute, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Shuijun Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, ZhengZhou, China
| | - Ti Zhang
- Department of Hepatic Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China
| | - Yanqiao Zhang
- Department of Gastrointestinal Medical Oncology, The Affiliated Tumor Hospital of Harbin Medical University, Harbin, China
| | - Ming Zhao
- Minimally Invasive Interventional Division, Liver Cancer Group, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Yongfu Zhao
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, ZhengZhou, China
| | - Honggang Zheng
- Department of Oncology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Ledu Zhou
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Jiye Zhu
- Department of Hepatobiliary Surgery, Peking University People’s Hospital, Beijing, China
| | - Kangshun Zhu
- Department of Minimally Invasive Interventional Radiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Rong Liu
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yinghong Shi
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yongsheng Xiao
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Lan Zhang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Chun Yang
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhifeng Wu
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhi Dai
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Minshan Chen
- Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jianqiang Cai
- Department of Abdominal Surgical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Weilin Wang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiujun Cai
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Qiang Li
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Feng Shen
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Shukui Qin
- Department of Medical Oncology, PLA Cancer Center, Nanjing Bayi Hospital, Nanjing, China
| | - Gaojun Teng
- Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China
| | - Jiahong Dong
- Department of Hepatobiliary and Pancreas Surgery, Beijing Tsinghua Changgung Hospital (BTCH), School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Jia Fan
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
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11
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Sun H, Yang H, Mao Y. Personalized treatment for hepatocellular carcinoma in the era of targeted medicine and bioengineering. Front Pharmacol 2023; 14:1150151. [PMID: 37214451 PMCID: PMC10198383 DOI: 10.3389/fphar.2023.1150151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 04/24/2023] [Indexed: 05/24/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a major global health burden, causing approximately 8.3 million deaths each year, and it is the third leading cause of cancer-related death worldwide, with a relative 5-year survival rate of around 18%. Due to the advanced stage of diagnosis in most patients, systemic treatment based on targeted therapy has become the only feasible option. Genomic studies have established a profile of molecular alterations in hepatocellular carcinoma with potentially actionable mutations, but these mutations have yet to be translated into clinical practice. The first targeted drug approved for systemic treatment of patients with advanced hepatocellular carcinoma was Sorafenib, which was a milestone. Subsequent clinical trials have identified multiple tyrosine kinase inhibitors, such as Lenvatinib, Cabozantinib, and Regorafenib, for the treatment of hepatocellular carcinoma, with survival benefits for the patient. Ongoing systemic therapy studies and trials include various immune-based combination therapies, with some early results showing promise and potential for new therapy plans. Systemic therapy for hepatocellular carcinoma is complicated by the significant heterogeneity of the disease and its propensity for developing drug resistance. Therefore, it is essential to choose a better, individualized treatment plan to benefit patients. Preclinical models capable of preserving in vivo tumor characteristics are urgently needed to circumvent heterogeneity and overcome drug resistance. In this review, we summarize current approaches to targeted therapy for HCC patients and the establishment of several patient-derived preclinical models of hepatocellular carcinoma. We also discuss the challenges and opportunities of targeted therapy for hepatocellular carcinoma and how to achieve personalized treatment with the continuous development of targeted therapies and bioengineering technologies.
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Affiliation(s)
| | - Huayu Yang
- *Correspondence: Huayu Yang, ; Yilei Mao,
| | - Yilei Mao
- *Correspondence: Huayu Yang, ; Yilei Mao,
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12
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Gao YX, Ning QQ, Yang PX, Guan YY, Liu PX, Liu ML, Qiao LX, Guo XH, Yang TW, Chen DX. Recent advances in recurrent hepatocellular carcinoma therapy. World J Hepatol 2023; 15:460-476. [PMID: 37206651 PMCID: PMC10190692 DOI: 10.4254/wjh.v15.i4.460] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 12/20/2022] [Accepted: 03/24/2023] [Indexed: 04/20/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most prevalent form of primary liver cancer, accounting for 75%-85% of cases. Although treatments are given to cure early-stage HCC, up to 50%-70% of individuals may experience a relapse of the illness in the liver after 5 years. Research on the fundamental treatment modalities for recurrent HCC is moving significantly further. The precise selection of individuals for therapy strategies with established survival advantages is crucial to ensuring better outcomes. These strategies aim to minimize substantial morbidity, support good life quality, and enhance survival for patients with recurrent HCC. For individuals with recurring HCC after curative treatment, no approved therapeutic regimen is currently available. A recent study presented novel approaches, like immunotherapy and antiviral medication, to improve the prognosis of patients with recurring HCC with the apparent lack of data to guide the clinical treatment. The data supporting several neoadjuvant and adjuvant therapies for patients with recurring HCC are outlined in this review. We also discuss the potential for future clinical and translational investigations.
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Affiliation(s)
- Yu-Xue Gao
- Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing 100069, China
- Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing 100069, China
| | - Qi-Qi Ning
- Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing 100069, China
- Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing 100069, China
| | - Peng-Xiang Yang
- Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing 100069, China
- Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing 100069, China
| | - Yuan-Yue Guan
- Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing 100069, China
- Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing 100069, China
| | - Peng-Xiang Liu
- Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing 100069, China
- Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing 100069, China
| | - Meng-Lu Liu
- Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing 100069, China
- Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing 100069, China
| | - Lu-Xin Qiao
- Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing 100069, China
- Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing 100069, China
| | - Xiang-Hua Guo
- Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing 100069, China
- Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing 100069, China
| | - Tong-Wang Yang
- Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing 100069, China
- Academician Workstation, Changsha Medical University, Changsha 410219, Hunan Province, China
- Hunan Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha 410219, Hunan Province, China
| | - De-Xi Chen
- Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing 100069, China
- Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing 100069, China
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13
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Stefanini B, Ielasi L, Chen R, Abbati C, Tonnini M, Tovoli F, Granito A. TKIs in combination with immunotherapy for hepatocellular carcinoma. Expert Rev Anticancer Ther 2023; 23:279-291. [PMID: 36794716 DOI: 10.1080/14737140.2023.2181162] [Citation(s) in RCA: 77] [Impact Index Per Article: 38.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/17/2023]
Abstract
INTRODUCTION The treatment landscape of hepatocellular carcinoma (HCC) has significantly changed over the last 5 years with multiple options in the frontline, second line, and beyond. Tyrosine kinase inhibitors (TKIs) were the first approved systemic treatments for the advanced stage of HCC; however, thanks to the increasing knowledge and characterization of the immunological features of the tumor microenvironment, the systemic treatment of HCC has been further expanded with the immune checkpoint inhibitor (ICI) approach and the following evidence of the higher efficacy obtained with combined treatment with atezolizumab plus bevacizumab over sorafenib. AREAS COVERED In this review, we look at rationale, efficacy, and safety profiles of current and emerging ICI/TKI combination treatments and discuss the available results from other clinical trials using similar combinatorial therapeutic approaches. EXPERT OPINION Angiogenesis and immune evasion are the two key pathogenic hallmarks of HCC. While the pioneering regimen of atezolizumab/bevacizumab is consolidating as the first-line treatment of advanced HCC, it will be essential, in the near future, to determine the best second-line treatment options and how to optimize the selection of the most effective therapies. These points still need to be addressed by future studies that are largely warranted to enhance the treatment's effectiveness and ultimately to tackle down HCC lethality.
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Affiliation(s)
- Bernardo Stefanini
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.,Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Luca Ielasi
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.,Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Rusi Chen
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.,Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Chiara Abbati
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.,Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Matteo Tonnini
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.,Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Francesco Tovoli
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.,Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Alessandro Granito
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.,Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
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14
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2022 KLCA-NCC Korea practice guidelines for the management of hepatocellular carcinoma. JOURNAL OF LIVER CANCER 2023; 23:1-120. [PMID: 37384024 PMCID: PMC10202234 DOI: 10.17998/jlc.2022.11.07] [Citation(s) in RCA: 68] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Accepted: 11/07/2022] [Indexed: 06/30/2023]
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the fourth most common cancer among men in South Korea, where the prevalence of chronic hepatitis B infection is high in middle and old age. The current practice guidelines will provide useful and sensible advice for the clinical management of patients with HCC. A total of 49 experts in the fields of hepatology, oncology, surgery, radiology, and radiation oncology from the Korean Liver Cancer Association-National Cancer Center Korea Practice Guideline Revision Committee revised the 2018 Korean guidelines and developed new recommendations that integrate the most up-to-date research findings and expert opinions. These guidelines provide useful information and direction for all clinicians, trainees, and researchers in the diagnosis and treatment of HCC.
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Affiliation(s)
- Korean Liver Cancer Association (KLCA) and National Cancer Center (NCC) Korea
- Corresponding author: KLCA-NCC Korea Practice Guideline Revision Committee (KPGRC) (Committee Chair: Joong-Won Park) Center for Liver and Pancreatobiliary Cancer, Division of Gastroenterology, Department of Internal Medicine, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang 10408, Korea Tel. +82-31-920-1605, Fax: +82-31-920-1520, E-mail:
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15
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Zhu Q, Rao W, Huo J, Li Z, Wang S, Qiu W, Guan G, Xin Y, Fan N, Cai J, Wu L. Real-world systemic sequential therapy with regorafenib for recurrent hepatocellular carcinoma: analysis of 93 cases from a single center. BMC Gastroenterol 2023; 23:28. [PMID: 36726082 PMCID: PMC9890826 DOI: 10.1186/s12876-023-02661-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 01/20/2023] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND Regorafenib is an oral multikinase inhibitor and became the first second-line systemic treatment for hepatocellular carcinoma (HCC) following the phase III RESORCE trial. This single-center study retrospectively analyzed the clinical data and follow-up results of patients with recurrent HCC treated with regorafenib and discussed the prognostic factors to provide guidance for clinical treatment. METHODS Ninety-three recurrent HCC patients were enrolled in the research and follow up from December 2017 to December 2020. Clinical and pathological data were collected. SPSS software v26.0 was used (Chicago, IL, USA) for statistical analysis. A two-sided P < 0.05 was considered statistically significant. RESULTS The patients included 81 males and 12 females with a median age of 57 years. Eighty-seven patients had hepatitis B virus (HBV) infection. The objective response rate (ORR) was 14.0%, and the disease control rate (DCR) was 62.4%. The median overall survival (mOS) and median time to progression (mTTP) were 15.9 and 5.0 months. Multivariate analysis showed that Child-Pugh classification, the Eastern Cooperative Oncology Group performance status (ECOG PS), the neutrophil-to-lymphocyte ratio (NLR), combined treatment, and the time from first diagnosis of HCC to second-line treatment were independent factors affecting the prognosis of recurrent HCC patients. CONCLUSIONS This real-world study demonstrated similar findings to those of the RESORCE trial. Regorafenib could effectively improve the prognosis of patients after first-line treatment failure. Combination therapy under multidisciplinary treatment (MDT) team guidance could be effective in impeding tumor progression and improving the prognosis of recurrent HCC patients.
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Affiliation(s)
- Qingwei Zhu
- grid.412521.10000 0004 1769 1119Liver Disease Center, The Affiliated Hospital of Qingdao University, No.59 Haier Road, Qingdao, 266003 Shandong People’s Republic of China
| | - Wei Rao
- grid.412521.10000 0004 1769 1119Liver Disease Center, The Affiliated Hospital of Qingdao University, No.59 Haier Road, Qingdao, 266003 Shandong People’s Republic of China
| | - Junyu Huo
- grid.412521.10000 0004 1769 1119Liver Disease Center, The Affiliated Hospital of Qingdao University, No.59 Haier Road, Qingdao, 266003 Shandong People’s Republic of China
| | - Zixiang Li
- grid.412521.10000 0004 1769 1119Department of Interventional Medicine Cancer Hospital, The Affiliated Hospital of Qingdao University, Qingdao, 266003 Shandong People’s Republic of China
| | - Song Wang
- grid.412521.10000 0004 1769 1119Department of Interventional Medicine Cancer Hospital, The Affiliated Hospital of Qingdao University, Qingdao, 266003 Shandong People’s Republic of China
| | - Wensheng Qiu
- grid.412521.10000 0004 1769 1119Tumor Hospital, The Affiliated Hospital of Qingdao University, Qingdao, 266003 Shandong People’s Republic of China
| | - Ge Guan
- grid.412521.10000 0004 1769 1119Liver Disease Center, The Affiliated Hospital of Qingdao University, No.59 Haier Road, Qingdao, 266003 Shandong People’s Republic of China
| | - Yang Xin
- grid.412521.10000 0004 1769 1119Liver Disease Center, The Affiliated Hospital of Qingdao University, No.59 Haier Road, Qingdao, 266003 Shandong People’s Republic of China
| | - Ning Fan
- grid.412521.10000 0004 1769 1119Liver Disease Center, The Affiliated Hospital of Qingdao University, No.59 Haier Road, Qingdao, 266003 Shandong People’s Republic of China
| | - Jinzhen Cai
- grid.412521.10000 0004 1769 1119Liver Disease Center, The Affiliated Hospital of Qingdao University, No.59 Haier Road, Qingdao, 266003 Shandong People’s Republic of China
| | - Liqun Wu
- grid.412521.10000 0004 1769 1119Liver Disease Center, The Affiliated Hospital of Qingdao University, No.59 Haier Road, Qingdao, 266003 Shandong People’s Republic of China
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16
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Li J, Yang F, Li J, Huang ZY, Cheng Q, Zhang EL. Postoperative adjuvant therapy for hepatocellular carcinoma with microvascular invasion. World J Gastrointest Surg 2023; 15:19-31. [PMID: 36741072 PMCID: PMC9896490 DOI: 10.4240/wjgs.v15.i1.19] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 10/29/2022] [Accepted: 12/21/2022] [Indexed: 01/17/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most lethal tumors in the world. Liver resection (LR) and liver transplantation (LT) are widely considered as radical treatments for early HCC. However, the recurrence rates after curative treatment are still high and overall survival is unsatisfactory. Microvascular invasion (MVI) is considered to be one of the important prognostic factors affecting postoperative recurrence and long-term survival. Unfortunately, whether HCC patients with MVI should receive postoperative adjuvant therapy remains unknown. In this review, we summarize the therapeutic effects of transcatheter arterial chemoembolization, hepatic arterial infusion chemotherapy, tyrosine protein kinase inhibitor-based targeted therapy, and immune checkpoint inhibitors in patients with MVI after LR or LT, aiming to provide a reference for the best adjuvant treatment strategy for HCC patients with MVI after LT or LR.
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Affiliation(s)
- Jiang Li
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, College of Medicine, Shihezi University, Shihezi 832000, Xinjiang Uygur Autonomous Regions, China
| | - Fan Yang
- Department of General Surgery, Affiliated Hospital of Hubei Minzu University, Enshi 445000, Hubei Province, China
| | - Jian Li
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Zhi-Yong Huang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Qi Cheng
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Er-Lei Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
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17
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Liang J, Bai Y, Ha FS, Luo Y, Deng HT, Gao YT. Combining local regional therapy and systemic therapy: Expected changes in the treatment landscape of recurrent hepatocellular carcinoma. World J Gastrointest Oncol 2023; 15:1-18. [PMID: 36684055 PMCID: PMC9850755 DOI: 10.4251/wjgo.v15.i1.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 12/06/2022] [Accepted: 12/28/2022] [Indexed: 01/10/2023] Open
Abstract
Improvements in early screening, new diagnostic techniques, and surgical treatment have led to continuous downward trends in hepatocellular carcinoma (HCC) morbidity and mortality rates. However, high recurrence and refractory cancer after hepatectomy remain important factors affecting the long-term prognosis of HCC. The clinical characteristics and prognosis of recurrent HCC are heterogeneous, and guidelines on treatment strategies for recurrent HCC are lacking. Therapies such as surgical resection, radiofrequency ablation, and transhepatic arterial chemoembolization are effective for tumors confined to the liver, and targeted therapy is a very important treatment for unresectable recurrent HCC with systemic metastasis. With the deepening of the understanding of the immune microenvironment of HCC, blocking immune checkpoints to enhance the antitumor immune response has become a new direction for the treatment of HCC. In addition, improvements in the tumor immune microenvironment caused by local treatment may provide an opportunity to improve the therapeutic effect of HCC treatment. Ongoing and future clinical trial data of combined therapy may develop the new treatment scheme for recurrent HCC. This paper reviews the pattern of recurrent HCC and the characteristics of the immune microenvironment, demonstrates the basis for combining local treatment and systemic treatment, and reports current evidence to better understand current progress and future approaches in the treatment of recurrent HCC.
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Affiliation(s)
- Jing Liang
- Department of Hepatology, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Nankai University Affiliated Third Center Hospital, Tianjin 300170, China
| | - Yi Bai
- Department of Hepatobiliary Surgery, Tianjin First Central Hospital, Tianjin 300192, China
| | - Fu-Shuang Ha
- Department of Hepatology, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Nankai University Affiliated Third Center Hospital, Tianjin 300170, China
| | - Ying Luo
- Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Nankai University Affiliated Third Center Hospital, Tianjin 300170, China
| | - Hui-Ting Deng
- Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Nankai University Affiliated Third Center Hospital, Tianjin 300170, China
| | - Ying-Tang Gao
- Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Nankai University Affiliated Third Center Hospital, Tianjin 300170, China
- Tianjin Institute of Hepatobiliary Disease, The Third Central Clinical College of Tianjin Medical University, Tianjin 300170, China
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18
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2022 KLCA-NCC Korea Practice Guidelines for the Management of Hepatocellular Carcinoma. Korean J Radiol 2022; 23:1126-1240. [PMID: 36447411 PMCID: PMC9747269 DOI: 10.3348/kjr.2022.0822] [Citation(s) in RCA: 74] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 10/28/2022] [Indexed: 11/18/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the fourth most common cancer among men in South Korea, where the prevalence of chronic hepatitis B infection is high in middle and old age. The current practice guidelines will provide useful and sensible advice for the clinical management of patients with HCC. A total of 49 experts in the fields of hepatology, oncology, surgery, radiology, and radiation oncology from the Korean Liver Cancer Association-National Cancer Center Korea Practice Guideline Revision Committee revised the 2018 Korean guidelines and developed new recommendations that integrate the most up-to-date research findings and expert opinions. These guidelines provide useful information and direction for all clinicians, trainees, and researchers in the diagnosis and treatment of HCC.
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19
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2022 KLCA-NCC Korea practice guidelines for the management of hepatocellular carcinoma. Clin Mol Hepatol 2022; 28:583-705. [PMID: 36263666 PMCID: PMC9597235 DOI: 10.3350/cmh.2022.0294] [Citation(s) in RCA: 161] [Impact Index Per Article: 53.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 09/23/2022] [Indexed: 01/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the fourth most common cancer among men in South Korea, where the prevalence of chronic hepatitis B infection is high in middle and old age. The current practice guidelines will provide useful and sensible advice for the clinical management of patients with HCC. A total of 49 experts in the fields of hepatology, oncology, surgery, radiology, and radiation oncology from the Korean Liver Cancer Association-National Cancer Center Korea Practice Guideline Revision Committee revised the 2018 Korean guidelines and developed new recommendations that integrate the most up-to-date research findings and expert opinions. These guidelines provide useful information and direction for all clinicians, trainees, and researchers in the diagnosis and treatment of HCC.
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20
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Sposito C, Citterio D, Virdis M, Battiston C, Droz Dit Busset M, Flores M, Mazzaferro V. Therapeutic strategies for post-transplant recurrence of hepatocellular carcinoma. World J Gastroenterol 2022; 28:4929-4942. [PMID: 36160651 PMCID: PMC9494935 DOI: 10.3748/wjg.v28.i34.4929] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 03/05/2022] [Accepted: 07/26/2022] [Indexed: 02/06/2023] Open
Abstract
Despite stringent selection criteria, hepatocellular carcinoma recurrence after liver transplantation (LT) still occurs in up to 20% of cases, mostly within the first 2–3 years. No adjuvant treatments to prevent such an occurrence have been developed so far. However, a balanced use of immunosuppression with minimal dose of calcineurin inhibitors and possible addition of mammalian target of rapamycin inhibitors is strongly advisable. Moreover, several pre- and post-transplant predictors of recurrence have been identified and may help determine the frequency and duration of post-transplant follow-up. When recurrence occurs, the outcomes are poor with a median survival of 12 mo according to most retrospective studies. The factor that most impacts survival after recurrence is timing (within 1–2 years from LT according to different authors). Several therapeutic options may be chosen in case of recurrence, according to timing and disease presentation. Surgical treatment seems to provide a survival benefit, especially in case of late recurrence, while the benefit of locoregional treatments has been suggested only in small retrospective studies. When systemic treatment is indicated, sorafenib has been proved safe and effective, while only few data are available for lenvatinib and regorafenib in second line. The use of immune checkpoint inhibitors is controversial in this setting, given the safety warnings for the risk of acute rejection.
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Affiliation(s)
- Carlo Sposito
- HPB Surgery, Hepatology and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori di Milano, Milan 20133, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan 20100, Italy
| | - Davide Citterio
- HPB Surgery, Hepatology and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori di Milano, Milan 20133, Italy
| | - Matteo Virdis
- HPB Surgery, Hepatology and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori di Milano, Milan 20133, Italy
| | - Carlo Battiston
- HPB Surgery, Hepatology and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori di Milano, Milan 20133, Italy
| | - Michele Droz Dit Busset
- HPB Surgery, Hepatology and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori di Milano, Milan 20133, Italy
| | - Maria Flores
- HPB Surgery, Hepatology and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori di Milano, Milan 20133, Italy
| | - Vincenzo Mazzaferro
- HPB Surgery, Hepatology and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori di Milano, Milan 20133, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan 20100, Italy
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21
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Azhie A, Grant RC, Herman M, Wang L, Knox JJ, Bhat M. Phase II clinical trial of cabozantinib for the treatment of recurrent hepatocellular carcinoma after liver transplantation. Future Oncol 2022; 18:2173-2191. [PMID: 35287469 DOI: 10.2217/fon-2021-1635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Recurrent hepatocellular carcinoma (HCC) develops in 15-20% of liver transplant recipients, and it tends to be more aggressive due to underlying immunosuppression. The multikinase inhibitor cabozantinib has been shown to be effective for the treatment of advanced HCC. However, there is no study evaluating this medication in patients with recurrent HCC. Adult patients with measurable biopsy-proven recurrent HCC are eligible for enrollment provided they are not amenable to curative treatments and no prior treatment with cabozantinib. In this study, 60 mg once daily cabozantinib will be administered orally. Participants will receive study treatment as long as they continue to experience clinical benefit or until there is unacceptable toxicity. Tumor measurements will be repeated every 8 weeks to evaluate response. The primary end point of this study will be the disease control rate at 4 months after treatment. The secondary end points will be overall survival, progression-free survival and safety profile of cabozantinib. Furthermore, potential biomarkers will be evaluated to identify their role in tumor progression. The total duration of this trial is expected to be 3 years. We anticipate that this trial will show the effectiveness and safety of cabozantinib in the treatment of post-liver transplant recurrent HCC. Cabozantinib is expected to be an effective treatment due to its activity against many protein kinases, including MET and AXL which are not inhibited by sorafenib.
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Affiliation(s)
- Amirhossein Azhie
- Ajmera Transplant Program, University Health Network, Toronto, Ontario, M5G 2N2, Canada
| | - Robert C Grant
- Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, M5G 2M9, Canada
| | - Michael Herman
- Oakville Trafalgar Memorial Hospital, Oakville, Ontario, L6M 0L8, Canada
| | - Lisa Wang
- Biostatistics Division, Princess Margaret Cancer Centre, University Health Network, Toronto, M5G 2M9, Canada
| | - Jennifer J Knox
- Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, M5G 2M9, Canada
| | - Mamatha Bhat
- Ajmera Transplant Program, University Health Network, Toronto, Ontario, M5G 2N2, Canada
- Division of Gastroenterology & Hepatology, Department of Medicine, University of Toronto, Ontario, M5S 1A8, Canada
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22
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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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23
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He X, Peng Y, Zhou Z, Li W. Immune Checkpoint Inhibitor-Based Systemic Therapy Shows Remarkable Curative Effect in a Hepatocellular Carcinoma Patient With Intractable Postoperative Recurrence and Metastases: A Case Report and Literature Review. Front Oncol 2022; 12:784224. [PMID: 35372050 PMCID: PMC8965061 DOI: 10.3389/fonc.2022.784224] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 02/18/2022] [Indexed: 01/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a systemic disease, and most patients make the diagnosis at an advanced stage. In the past, treatments for recurrence of liver cancer with multiple metastases after surgery was very palliative, The case we present is a primary massive HCC patient with inferior vena cava tumor thrombus. Radical hepatectomy was performed in July 2016. Postoperative follow-up showed that sorafenib (a tyrosine kinase inhibitor TKI, 0.8g qd) failed to stop the progression of the disease. Fourteen months later, the patient gradually developed residual liver recurrence, multiple lung metastases and suspected splenic metastasis. The monotherapy regimen was changed from sorafenib to regorafenib (a TKI,160mg qd), but the disease continued to progress. The systematic treatment regimen was changed to Lenvatinib (a TKI, 8mg qd) plus Pembrolizumab (a immune checkpoint inhibitor ICI, 200mg q3w) in April 2019. Following treatment, partial remission (PR) was achieved. According to the mRECIST standard, the PFS has reached 24 months until March 2021, and the overall postoperative survival is 60 months until July 2021. The case we provide show that immune checkpoint inhibitor (ICI)-based systemic therapy may be an effective rescue treatment choice for HCC patients with intractable postoperative recurrence and metastasis.
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Affiliation(s)
- Xing He
- Department of Biliary and Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yaorong Peng
- Department of Biliary and Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhenyu Zhou
- Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Wenbin Li
- Department of Biliary and Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
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24
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Agarwal PD, Lucey MR. Management of hepatocellular carcinoma recurrence after liver transplantation. Ann Hepatol 2022; 27:100654. [PMID: 34929349 DOI: 10.1016/j.aohep.2021.100654] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 11/30/2021] [Accepted: 11/30/2021] [Indexed: 02/04/2023]
Abstract
Despite careful selection for liver transplantation (LT) of patients with hepatocellular carcinoma (HCC), HCC may still recur after LT and is frequently associated with dismal outcome. Tumor factors, including serum alpha-fetoprotein (AFP), the presence of microvascular invasion, tumor grade/differentiation, and largest tumor size are amongst the most important predictors of recurrence after transplantation. The nature of recurrence can be highly variable, but often presents with extra-hepatic involvement. As such, management of patients with HCC can be challenging, and consensus guidelines are lacking. Curative options, with surgery or ablation, which may be applicable in patients with isolated intra-or extrahepatic metastases, offer the best chance for improved long-term outcome in patients with HCC recurrence after transplantation. Most patients with recurrence have unresectable disease, and may benefit from palliative treatments, including intra-arterial therapies and/or systemic therapy.
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Affiliation(s)
- Parul D Agarwal
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, 1685 Highland Avenue, Suite 4224, Madison, WI 53705, United States.
| | - Michael R Lucey
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, 1685 Highland Avenue, Suite 4224, Madison, WI 53705, United States
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25
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Development and validation of a simple and sensitive HPLC method for the determination of related substances in regorafenib tablets. ANAL SCI 2022; 38:591-599. [DOI: 10.1007/s44211-022-00068-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 12/20/2021] [Indexed: 11/25/2022]
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26
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Farooq A, Ahmed Z, Wert J, Jalil A, Yu J, Zaytsev V, Ahmad S. Updates on clinical trials for the management of hepatocellular carcinoma. THERANOSTICS AND PRECISION MEDICINE FOR THE MANAGEMENT OF HEPATOCELLULAR CARCINOMA, VOLUME 3 2022:259-273. [DOI: 10.1016/b978-0-323-99283-1.00013-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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27
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Iavarone M, Invernizzi F, Ivanics T, Mazza S, Zavaglia C, Sanduzzi-Zamparelli M, Fraile-López M, Czauderna C, Di Costanzo G, Bhoori S, Pinter M, Manini MA, Amaddeo G, Yunquera AF, Piñero F, Blanco Rodríguez MJ, Anders M, Aballay Soteras G, Villadsen GE, Yoon PD, Cesarini L, Díaz-González Á, González-Diéguez ML, Tortora R, Weinmann A, Mazzaferro V, Romero Cristóbal M, Crespo G, Regnault H, De Giorgio M, Varela M, Prince R, Scudeller L, Donato MF, Wörns MA, Bruix J, Sapisochin G, Lampertico P, Reig M. Regorafenib Efficacy After Sorafenib in Patients With Recurrent Hepatocellular Carcinoma After Liver Transplantation: A Retrospective Study. Liver Transpl 2021; 27:1767-1778. [PMID: 34388851 DOI: 10.1002/lt.26264] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 06/28/2021] [Accepted: 07/06/2021] [Indexed: 12/13/2022]
Abstract
Safety of regorafenib in hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) has been recently demonstrated. We aimed to assess the survival benefit of regorafenib compared with best supportive care (BSC) in LT patients after sorafenib discontinuation. This observational multicenter retrospective study included LT patients with HCC recurrence who discontinued first-line sorafenib. Group 1 comprised regorafenib-treated patients, whereas the control group was selected among patients treated with BSC due to unavailability of second-line options at the time of sorafenib discontinuation and who were sorafenib-tolerant progressors (group 2). Primary endpoint was overall survival (OS) of group 1 compared with group 2. Secondary endpoints were safety and OS of sequential treatment with sorafenib + regorafenib/BSC. Among 132 LT patients who discontinued sorafenib included in the study, 81 were sorafenib tolerant: 36 received regorafenib (group 1) and 45 (group 2) received BSC. Overall, 24 (67%) patients died in group 1 and 40 (89%) in group 2: the median OS was significantly longer in group 1 than in group 2 (13.1 versus 5.5 months; P < 0.01). Regorafenib treatment was an independent predictor of reduced mortality (hazard ratio, 0.37; 95% confidence interval [CI], 0.16-0.89; P = 0.02). Median treatment duration with regorafenib was 7.0 (95% CI, 5.5-8.5) months; regorafenib dose was reduced in 22 (61%) patients for adverse events and discontinued for tumor progression in 93% (n = 28). The median OS calculated from sorafenib start was 28.8 months (95% CI, 17.6-40.1) in group 1 versus 15.3 months (95% CI, 8.8-21.7) in group 2 (P < 0.01). Regorafenib is an effective second-line treatment after sorafenib in patients with HCC recurrence after LT.
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Affiliation(s)
- Massimo Iavarone
- Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Federica Invernizzi
- Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Tommy Ivanics
- Multi-Organ Transplant Program, Division of General Surgery, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Canada
| | - Stefano Mazza
- Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Claudio Zavaglia
- Hepatology and Gastroenterology Department, Niguarda Ca' Granda Hospital, Milan, Italy
| | - Marco Sanduzzi-Zamparelli
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic, IDIBAPS, CIBEREHD, University of Barcelona, Barcelona, Spain
| | - Miguel Fraile-López
- Liver Unit, Hospital Universitario Central de Asturias, Oviedo, Spain.,Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
| | - Carolin Czauderna
- Department of Internal Medicine I, University Medical Centre of the Johannes Gutenberg-University, Mainz, Germany
| | | | - Sherrie Bhoori
- G. I. Surgery and Liver Transplantation Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Matthias Pinter
- Department of Internal Medicine III, Division of Gastroenterology & Hepatology, Medical University of Vienna, Vienna, Austria
| | - Matteo Angelo Manini
- Gastroenterology, Hepatology and Transplant Unit, Department of Specialty and Transplant Medicine, Azienda Socio Sanitaria Territoriale (ASST) Papa Giovanni XXIII, Bergamo, Italy
| | - Giuliana Amaddeo
- Service d'Hepatologie, Hôpital Henri Mondor, Equipe 18, INSERM U955, Virus Immunité Cancer, Créteil, France
| | | | - Federico Piñero
- School of Medicine, Latin American Liver Research Educational and Awareness Network (LALREAN), Hospital Universitario Austral, Buenos Aires, Argentina
| | | | - Margarita Anders
- Unidad de Hepatología y Trasplante Hepático, Hospital Aleman, Buenos Aires, Argentina
| | | | | | - Peter Daechul Yoon
- Multi-Organ Transplant Program, Division of General Surgery, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Canada
| | - Lucia Cesarini
- Hepatology and Gastroenterology Department, Niguarda Ca' Granda Hospital, Milan, Italy
| | - Álvaro Díaz-González
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic, IDIBAPS, CIBEREHD, University of Barcelona, Barcelona, Spain
| | | | - Raffaella Tortora
- Department of Transplantation, Liver Unit, Cardarelli Hospital, Naples, Italy
| | - Arndt Weinmann
- Department of Internal Medicine I, University Medical Centre of the Johannes Gutenberg-University, Mainz, Germany
| | - Vincenzo Mazzaferro
- G. I. Surgery and Liver Transplantation Unit, Fondazione IRCCS Istituto Nazionale dei Tumori and University of Milan, Milan, Italy
| | | | - Gonzalo Crespo
- Liver Transplant Unit, Liver Unit, Hospital Clínic, IDIBAPS, CIBEREHD, University of Barcelona, Barcelona, Spain
| | - Helene Regnault
- Service d'Hepatologie, Hôpital Henri Mondor, Equipe 18, INSERM U955, Virus Immunité Cancer, Créteil, France
| | - Massimo De Giorgio
- Gastroenterology, Hepatology and Transplant Unit, Department of Specialty and Transplant Medicine, Azienda Socio Sanitaria Territoriale (ASST) Papa Giovanni XXIII, Bergamo, Italy
| | - Maria Varela
- Liver Unit, Hospital Universitario Central de Asturias, Oviedo, Spain.,Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
| | - Rebecca Prince
- Division of Medical Oncology and Hematology, Princess Margaret Hospital, University of Toronto, Toronto, Canada
| | - Luigia Scudeller
- Scientific Direction, Clinical Trial Center, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Maria Francesca Donato
- Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Marcus-Alexander Wörns
- Department of Internal Medicine I, University Medical Centre of the Johannes Gutenberg-University, Mainz, Germany
| | - Jordi Bruix
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic, IDIBAPS, CIBEREHD, University of Barcelona, Barcelona, Spain
| | - Gonzalo Sapisochin
- Multi-Organ Transplant Program, Division of General Surgery, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Canada
| | - Pietro Lampertico
- Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.,Department of Pathophysiology and Transplantation, CRC "A. M. and A. Migliavacca" Center for Liver Disease, University of Milan, Milan, Italy
| | - Maria Reig
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic, IDIBAPS, CIBEREHD, University of Barcelona, Barcelona, Spain
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28
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Zhuo J, Lu D, Lin Z, Yang X, Yang M, Wang J, Tao Y, Wen X, Li H, Lian Z, Cen B, Dong S, Wei X, Xie H, Zheng S, Shen Y, Xu X. The distinct responsiveness of cytokeratin 19-positive hepatocellular carcinoma to regorafenib. Cell Death Dis 2021; 12:1084. [PMID: 34785656 PMCID: PMC8595883 DOI: 10.1038/s41419-021-04320-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 10/11/2021] [Accepted: 10/13/2021] [Indexed: 02/07/2023]
Abstract
Cytokeratin 19-positive (CK19+) hepatocellular carcinoma (HCC) is an aggressive subtype characterized by early recurrence and chemotherapy tolerance. However, there is no specific therapeutic option for CK19+ HCC. The correlation between tumor recurrence and expression status of CK19 were studied in 206 patients undergoing liver transplantation for HCC. CK19-/+ HCC cells were isolated to screen effective antitumor drugs. The therapeutic effects of regorafenib were evaluated in patient-derived xenograft (PDX) models from 10 HCC patients. The mechanism of regorafenib on CK19+ HCC was investigated. CK19 positiveness indicated aggressiveness of tumor and higher recurrence risk of HCC after liver transplantation. The isolated CK19+ HCC cells had more aggressive behaviors than CK19- cells. Regorafenib preferentially increased the growth inhibition and apoptosis of CK19+ cells in vitro, whereas sorafenib, apatinib, and 5-fluorouracil did not. In PDX models from CK19-/+ HCC patients, the tumor control rate of regorafenib achieved 80% for CK19+ HCCs, whereas 0% for CK19- HCCs. RNA-sequencing revealed that CK19+ cells had elevated expression of mitochondrial ribosomal proteins, which are essential for mitochondrial function. Further experiments confirmed that regorafenib attenuated the mitochondrial respiratory capacity in CK19+ cells. However, the mitochondrial respiration in CK19- cells were faint and hardly repressed by regorafenib. The mitochondrial respiration was regulated by the phosphorylation of signal transducer and activator of transcription 3 (STAT3), which was inhibited by regorafenib in CK19+ cells. Hence, CK19 could be a potential marker of the therapeutic benefit of regorafenib, which facilitates the individualized therapy for HCC. STAT3/mitochondria axis determines the distinct response of CK19+ cells to regorafenib treatment.
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Affiliation(s)
- Jianyong Zhuo
- Department of Hepatobiliary and Pancreatic Surgery, Center for Integrated Oncology and Precision Medicine, the Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Institute of Organ Transplantation, Zhejiang University School of Medicine, Hangzhou, China
| | - Di Lu
- Department of Hepatobiliary and Pancreatic Surgery, Center for Integrated Oncology and Precision Medicine, the Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zuyuan Lin
- Department of Hepatobiliary and Pancreatic Surgery, Center for Integrated Oncology and Precision Medicine, the Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xinyu Yang
- Department of Hepatobiliary and Pancreatic Surgery, Center for Integrated Oncology and Precision Medicine, the Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Modan Yang
- Department of Hepatobiliary and Pancreatic Surgery, Center for Integrated Oncology and Precision Medicine, the Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jianguo Wang
- Department of Hepatobiliary and Pancreatic Surgery, Center for Integrated Oncology and Precision Medicine, the Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yaoye Tao
- Department of Hepatobiliary and Pancreatic Surgery, Center for Integrated Oncology and Precision Medicine, the Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xue Wen
- Department of Pathology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Huihui Li
- Department of Hepatobiliary and Pancreatic Surgery, Center for Integrated Oncology and Precision Medicine, the Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhengxing Lian
- Department of Hepatobiliary and Pancreatic Surgery, Center for Integrated Oncology and Precision Medicine, the Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Beini Cen
- Department of Hepatobiliary and Pancreatic Surgery, Center for Integrated Oncology and Precision Medicine, the Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Siyi Dong
- National Center for Healthcare Quality Management in Liver Transplant, Hangzhou, China
| | - Xuyong Wei
- Department of Hepatobiliary and Pancreatic Surgery, Center for Integrated Oncology and Precision Medicine, the Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Haiyang Xie
- Institute of Organ Transplantation, Zhejiang University School of Medicine, Hangzhou, China
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- National Health Commission Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
| | - Shusen Zheng
- Institute of Organ Transplantation, Zhejiang University School of Medicine, Hangzhou, China
- National Center for Healthcare Quality Management in Liver Transplant, Hangzhou, China
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- National Health Commission Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
- Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital, Hangzhou, China
| | - Youqing Shen
- Center for Bionanoengineering and Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China
| | - Xiao Xu
- Department of Hepatobiliary and Pancreatic Surgery, Center for Integrated Oncology and Precision Medicine, the Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
- Institute of Organ Transplantation, Zhejiang University School of Medicine, Hangzhou, China.
- National Center for Healthcare Quality Management in Liver Transplant, Hangzhou, China.
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29
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L R, T I, Mpaw C, H M, G S. THE MANAGEMENT OF POST-TRANSPLANTATION RECURRENCE OF HEPATOCELLULAR CARCINOMA. Clin Mol Hepatol 2021; 28:1-16. [PMID: 34610652 PMCID: PMC8755475 DOI: 10.3350/cmh.2021.0217] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 10/03/2021] [Indexed: 11/15/2022] Open
Abstract
The annual incidence of hepatocellular carcinoma (HCC) continues to rise. Over the last two decades, liver transplantation (LT) has become the preferable treatment of HCC, when feasible and strict selection criteria are met. With the rise in HCC-related LT, compounded by downstaging techniques and expansion of transplant selection criteria, a parallel increase in number of post-transplantation HCC recurrence is expected. Additionally, in the context of an immunosuppressed transplant host, recurrences may behave aggressively and more challenging to manage, resulting in poor prognosis. Despite this, no consensus or best practice guidelines for post-transplantation cancer surveillance and recurrence management for HCC currently exist. Studies with adequate population sizes and high-level evidence are lacking, and the role of systemic and locoregional therapies for graft and extrahepatic recurrences remains under debate. This review seeks to summarize the existing literature on post-transplant HCC surveillance and recurrence management. It highlights the value of early tumour detection, re-evaluating the immunosuppression regimen, and staging to differentiate disseminated recurrence from intrahepatic or extrahepatic oligo-recurrence. This ultimately guides decision-making and maximizes treatment effect. Treatment recommendations specific to recurrence type are provided based on currently available locoregional and systemic therapies.
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Affiliation(s)
- Rajendran L
- Division of General Surgery, University of Toronto, Toronto, Ontario, Canada
| | - Ivanics T
- Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada.,Department of Surgery, Henry Ford Hospital, Detroit, MI, USA.,Department of Surgical Sciences, Akademiska Sjukhuset, Uppsala University, Uppsala, Sweden
| | - Claasen Mpaw
- Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada.,Department of Surgery, Erasmus MC, University Medical Centre, Rotterdam, the Netherlands
| | - Muaddi H
- Division of General Surgery, University of Toronto, Toronto, Ontario, Canada
| | - Sapisochin G
- Division of General Surgery, University of Toronto, Toronto, Ontario, Canada.,Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
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30
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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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31
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Pelizzaro F, Gambato M, Gringeri E, Vitale A, Cillo U, Farinati F, Burra P, Russo FP. Management of Hepatocellular Carcinoma Recurrence after Liver Transplantation. Cancers (Basel) 2021; 13:cancers13194882. [PMID: 34638365 PMCID: PMC8508053 DOI: 10.3390/cancers13194882] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 09/19/2021] [Accepted: 09/24/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Hepatocellular carcinoma (HCC) is an increasingly important indication for liver transplantation (LT) worldwide. However, LT in the setting of liver cancer is burdened by the risk of tumor recurrence. The prognosis of patients with post-LT HCC recurrence is still very poor and several areas of uncertainty remain in the management of these patients. In this paper, we provide a comprehensive evaluation of available evidence regarding the management of HCC recurrence after LT, starting from the pre- and post-transplant stratification criteria and encompassing post-LT surveillance, preventive strategies and treatment. Much work has been done in the last several years but further effort is still needed in order to improve the outcome of these patients. Abstract Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT), occurring in 10–15% of cases, is a major concern. A lot of work has been done in order to refine the selection of LT candidates with HCC and to improve the outcome of patients with recurrence. Despite this, the prognosis of these patients remains poor, partly due to the several areas of uncertainty in their management. Even if surveillance for HCC recurrence is crucial for early detection, there is currently no evidence to support a specific and cost-effective post-LT surveillance strategy. Concerning preventive measures, consensus on the best immunosuppressive drugs has not been reached and not enough data to support adjuvant therapy are present. Several therapeutic approaches (surgical, locoregional and systemic treatments) are available in case of recurrence, but there are still few data in the post-LT setting. Moreover, the use of immune checkpoint inhibitors is controversial in transplant recipients considered the risk of rejection. In this paper, the available evidence on the management of HCC recurrence after LT is comprehensively reviewed, considering pre- and post-transplant risk stratification, post-transplant surveillance, preventive strategies and treatment options.
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Affiliation(s)
- Filippo Pelizzaro
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (F.P.); (M.G.); (F.F.); (P.B.)
| | - Martina Gambato
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (F.P.); (M.G.); (F.F.); (P.B.)
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy
| | - Enrico Gringeri
- Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (E.G.); (A.V.); (U.C.)
| | - Alessandro Vitale
- Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (E.G.); (A.V.); (U.C.)
| | - Umberto Cillo
- Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (E.G.); (A.V.); (U.C.)
| | - Fabio Farinati
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (F.P.); (M.G.); (F.F.); (P.B.)
| | - Patrizia Burra
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (F.P.); (M.G.); (F.F.); (P.B.)
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy
| | - Francesco Paolo Russo
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (F.P.); (M.G.); (F.F.); (P.B.)
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy
- Correspondence:
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32
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Mahn R, Sadeghlar F, Bartels A, Zhou T, Weismüller T, Kupczyk P, Meyer C, Gaertner FC, Toma M, Vilz T, Knipper P, Glowka T, Manekeller S, Kalff J, Strassburg CP, Gonzalez-Carmona MA. Multimodal and systemic therapy with cabozantinib for treatment of recurrent hepatocellular carcinoma after liver transplantation: A case report with long term follow-up outcomes. Medicine (Baltimore) 2021; 100:e27082. [PMID: 34559100 PMCID: PMC8462617 DOI: 10.1097/md.0000000000027082] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 08/12/2021] [Indexed: 01/05/2023] Open
Abstract
RATIONALE Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) remains a major therapeutic challenge. In recent years, new molecular-targeted therapies, such as cabozantinib, have been approved for the treatment of advanced HCC. However, clinical experience with these new drugs in the treatment of HCC in the LT setting is very limited. PATIENT CONCERNS In 2003, a 36-year-old woman was referred to the hospital with right upper abdominal pain. DIAGNOSIS An initial ultrasound of the liver demonstrated a large unclear lesion of the left lobe of the liver. The magnet resonance imaging findings confirmed a multifocal inoperable HCC in a non-cirrhotic liver. Seven years after receiving a living donor LT, pulmonary and intra-hepatic recurrence of the HCC was radiologically diagnosed and histologically confirmed. INTERVENTIONS Following an interdisciplinary therapy concept consisting of surgical, interventional-radiological (with radiofrequency ablation [RFA]) as well as systemic treatment, the patient achieved a survival of more than 10 years after tumor recurrence. As systemic first line therapy with sorafenib was accompanied by grade 3 to 4 toxicities, such as mucositis, hand-foot skin reaction, diarrhea, liver dysfunction, and hyperthyroidism, it had to be discontinued. After switching to cabozantinib from June 2018 to April 2020, partial remission of all tumor manifestations was achieved. The treatment of the remaining liver metastasis could be completed by RFA. The therapy with cabozantinib was well tolerated, only mild arterial hypertension and grade 1 to 2 mucositis were observed. Liver transplant function was stable during the therapy, no drug interaction with immunosuppressive drugs was observed. OUTCOMES More than 10 years survival after recurrence of HCC after living-donor LT due to intensive multimodal therapy concepts, including surgery, RFA, and systemic therapy with cabozantinib in the second line therapy. LESSONS In conclusion, this report highlights the tolerability and effectiveness of cabozantinib for the treatment of HCC recurrence after LT. We show that our patient with a late recurrence of HCC after LT benefitted from intensive multimodal therapy concepts, including surgery, RFA, and systemic therapy.
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Affiliation(s)
- Robert Mahn
- Department of Internal Medicine I, University Hospital Bonn, Germany
| | | | - Alexandra Bartels
- Department of Internal Medicine I, University Hospital Bonn, Germany
| | - Taotao Zhou
- Department of Internal Medicine I, University Hospital Bonn, Germany
| | - Tobias Weismüller
- Department of Internal Medicine I, University Hospital Bonn, Germany
| | | | - Carsten Meyer
- Department of Radiology, University Hospital Bonn, Germany
| | | | - Marieta Toma
- Department of Pathology, University Hospital Bonn, Germany
| | - Tim Vilz
- Department of Visceral Surgery, University Hospital Bonn, Germany
| | - Petra Knipper
- Department of Visceral Surgery, University Hospital Bonn, Germany
| | - Tim Glowka
- Department of Visceral Surgery, University Hospital Bonn, Germany
| | | | - Jörg Kalff
- Department of Visceral Surgery, University Hospital Bonn, Germany
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33
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Karabicici M, Azbazdar Y, Ozhan G, Senturk S, Firtina Karagonlar Z, Erdal E. Changes in Wnt and TGF-β Signaling Mediate the Development of Regorafenib Resistance in Hepatocellular Carcinoma Cell Line HuH7. Front Cell Dev Biol 2021; 9:639779. [PMID: 34458250 PMCID: PMC8386122 DOI: 10.3389/fcell.2021.639779] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 07/05/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is an aggressive, chemo resistant neoplasm with poor prognosis and limited treatment options. Exploring activated pathways upon drug treatment can be used to discover more effective anticancer agents to overcome therapy resistance and enhance therapeutic outcomes for patients with advanced HCC. Human tumor-derived cell lines recapitulate HCC diversity and are widely used for studying mechanisms that drive drug resistance in HCC. In this study, we show that regorafenib treatment activates Wnt/β-catenin signaling only in hepatoblast-like HCC cell lines and induces enrichment of markers associated with hepatic stem/progenitor cells. Moreover, activation of Wnt/β-catenin signaling via Wnt3a/R-Spo1 treatment protects these cells from regorafenib induced apoptosis. On the other hand, regorafenib resistant cells established by long-term regorafenib treatment demonstrate diminished Wnt/β-catenin signaling activity while TGF-β signaling activity of these cells is significantly enhanced. Regorafenib resistant cells (RRCs) also show increased expression of several mesenchymal genes along with an induction of CD24 and CD133 cancer stem cell markers. Moreover, regorafenib resistant cells also exhibit significantly augmented in vitro and in vivo migration capacity which could be reversed by TGF-β type 1 receptor (TGFb -R1) inhibition. When combined with regorafenib treatment, TGFβ-R1 inhibition also significantly decreased colony formation ability and augmented cell death in resistant spheroids. Importantly, when we knocked down TGFβ-R1 using a lentiviral plasmid, regorafenib resistant cells entered senescence indicating that this pathway is important for their survival. Treatment of RRCs with TGFβ-R1 inhibitor and regorafenib significantly abolished pSTAT3, pSMAD2 and pERK (44/42) expression suggesting the involvement of both canonical and non-canonical pathways. In conclusion, our data suggest that HCC tumors with aberrant activation in the Wnt/β-catenin pathway, might have higher intrinsic regorafenib resistance and the inhibition of this pathway along with regorafenib administration might increase regorafenib-induced cell death in combinational therapies. However, to resolve acquired regorafenib resistance developed in HCC patients, the combined use of TGF-β pathway inhibitors and Regorafenib constitute a promising approach that can increase regorafenib sensitization and prevent tumor recurrence.
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Affiliation(s)
- Mustafa Karabicici
- Izmir Biomedicine and Genome Center (IBG), Dokuz Eylul University Health Campus, Izmir, Turkey.,Izmir International Biomedicine and Genome Institute (IBG-Izmir), Dokuz Eylul University, Izmir, Turkey
| | - Yagmur Azbazdar
- Izmir Biomedicine and Genome Center (IBG), Dokuz Eylul University Health Campus, Izmir, Turkey.,Izmir International Biomedicine and Genome Institute (IBG-Izmir), Dokuz Eylul University, Izmir, Turkey
| | - Gunes Ozhan
- Izmir Biomedicine and Genome Center (IBG), Dokuz Eylul University Health Campus, Izmir, Turkey.,Izmir International Biomedicine and Genome Institute (IBG-Izmir), Dokuz Eylul University, Izmir, Turkey
| | - Serif Senturk
- Izmir Biomedicine and Genome Center (IBG), Dokuz Eylul University Health Campus, Izmir, Turkey.,Izmir International Biomedicine and Genome Institute (IBG-Izmir), Dokuz Eylul University, Izmir, Turkey
| | | | - Esra Erdal
- Izmir Biomedicine and Genome Center (IBG), Dokuz Eylul University Health Campus, Izmir, Turkey.,Department of Medical Biology and Genetics, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey
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34
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Piñero F, Tanno M, Aballay Soteras G, Tisi Baña M, Dirchwolf M, Fassio E, Ruf A, Mengarelli S, Borzi S, Fernández N, Ridruejo E, Descalzi V, Anders M, Mazzolini G, Reggiardo V, Marciano S, Perazzo F, Spina JC, McCormack L, Maraschio M, Lagues C, Gadano A, Villamil F, Silva M, Cairo F, Ameigeiras B. Argentinian clinical practice guideline for surveillance, diagnosis, staging and treatment of hepatocellular carcinoma. Ann Hepatol 2021; 19:546-569. [PMID: 32593747 DOI: 10.1016/j.aohep.2020.06.003] [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: 04/25/2020] [Revised: 06/05/2020] [Accepted: 06/10/2020] [Indexed: 02/08/2023]
Abstract
The A.A.E.E.H has developed this guideline for the best care of patients with hepatocellular carcinoma (HCC) from Argentina. It was done from May 2018 to March 2020. Specific clinical research questions were systematically searched. The quality of evidence and level of recommendations were organized according to GRADE. HCC surveillance is strongly recommended with abdominal ultrasound (US) every six months in the population at risk for HCC (cirrhosis, hepatitis B or hepatitis C); it is suggested to add alpha-feto protein (AFP) levels in case of inexeperienced sonographers. Imaging diagnosis in patients at risk for HCC has high specificity and tumor biopsy is not mandatory. The Barcelona Clinic Liver Cancer algorithm is strongly recommended for HCC staging and treatment-decision processes. Liver resection is strongly recommended for patients without portal hypertension and preserved liver function. Composite models are suggested for liver transplant selection criteria. Therapies for HCC with robust clinical evidence include transarterial chemoembolization (TACE) and first to second line systemic treatment options (sorafenib, lenvatinib, regorafenib, cabozantinib and ramucirumab). Immunotherapy with nivolumab and pembrolizumab has failed to show statistical benefit but the novel combination of atezolizumab plus bevacizumab has recently shown survival benefit over sorafenib in frontline.
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Affiliation(s)
- Federico Piñero
- Hepatology and Liver Unit, Hospital Universitario Austral, School of Medicine, Austral University, B1629HJ Buenos Aires, Argentina.
| | - Mario Tanno
- Hospital Centenario de Rosario, Santa Fe, Argentina
| | | | - Matías Tisi Baña
- Internal Medicine and Epidemiology Department, Hospital Universitario Austral, School of Medicine, Austral University, B1629HJ Buenos Aires, Argentina
| | | | | | - Andrés Ruf
- Hospital Privado de Rosario, Santa Fe, Argentina
| | | | - Silvia Borzi
- Instituto Rossi, La Plata, Buenos Aires, Argentina
| | | | - Ezequiel Ridruejo
- Hepatology and Liver Unit, Hospital Universitario Austral, School of Medicine, Austral University, B1629HJ Buenos Aires, Argentina; Centro de Educación Médica e Investigaciones Clínicas (CEMIC), Ciudad de Buenos Aires, Argentina
| | | | | | - Guillermo Mazzolini
- Hepatology and Liver Unit, Hospital Universitario Austral, School of Medicine, Austral University, B1629HJ Buenos Aires, Argentina
| | | | | | | | | | | | | | - Cecilia Lagues
- Hepatology and Liver Unit, Hospital Universitario Austral, School of Medicine, Austral University, B1629HJ Buenos Aires, Argentina
| | | | | | - Marcelo Silva
- Hepatology and Liver Unit, Hospital Universitario Austral, School of Medicine, Austral University, B1629HJ Buenos Aires, Argentina
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Muñoz-Martínez S, Iserte G, Sanduzzi-Zamparelli M, Llarch N, Reig M. Current pharmacological treatment of hepatocellular carcinoma. Curr Opin Pharmacol 2021; 60:141-148. [PMID: 34418875 DOI: 10.1016/j.coph.2021.07.009] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 06/14/2021] [Accepted: 07/07/2021] [Indexed: 02/06/2023]
Abstract
The landscape of hepatocellular carcinoma (HCC) has changed since the incorporation of sorafenib in 2007 as the first pharmacological treatment for HCC. The combination of atezolizumab plus bevacizumab is currently the first-line treatment for HCC patients, and there are several second-line options approved for patients who had received sorafenib as the first-line treatment. The advantage of having multiple options of pharmacological treatment for HCC patients is associated to the need to redefine the clinical decision-making approach and considering new endpoints for the clinical trials design. The aim of this review was to share the Barcelona Clinic Liver Cancer approach and to summarize the ongoing clinical trials, which are testing pharmacological treatments.
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Affiliation(s)
- Sergio Muñoz-Martínez
- Barcelona Clinic Liver Cancer (BCLC), Liver Unit, Hospital Clinic of Barcelona, IDIBAPS, Fundació Clínic per la Recerca Biomèdica (FCRB), Barcelona, Spain
| | - Gemma Iserte
- Barcelona Clinic Liver Cancer (BCLC), Liver Unit, Hospital Clinic of Barcelona, IDIBAPS, Fundació Clínic per la Recerca Biomèdica (FCRB), Barcelona, Spain; Barcelona Clinic Liver Cancer (BCLC), Liver Unit, Hospital Clinic of Barcelona, IDIBAPS, CIBEREHD, ERN RARE-LIVER, Barcelona, Spain
| | - Marco Sanduzzi-Zamparelli
- Barcelona Clinic Liver Cancer (BCLC), Liver Unit, Hospital Clinic of Barcelona, IDIBAPS, Fundació Clínic per la Recerca Biomèdica (FCRB), Barcelona, Spain; Barcelona Clinic Liver Cancer (BCLC), Liver Unit, Hospital Clinic of Barcelona, IDIBAPS, CIBEREHD, ERN RARE-LIVER, Barcelona, Spain
| | - Neus Llarch
- Barcelona Clinic Liver Cancer (BCLC), Liver Unit, Hospital Clinic of Barcelona, IDIBAPS, CIBEREHD, ERN RARE-LIVER, Barcelona, Spain
| | - Maria Reig
- Barcelona Clinic Liver Cancer (BCLC), Liver Unit, Hospital Clinic of Barcelona, IDIBAPS, CIBEREHD, Universidad de Barcelona, Barcelona, Spain.
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Li BCW, Chiu J, Shing K, Kwok GGW, Tang V, Leung R, Ma KW, She WH, Tsang J, Chan A, Cheung TT, Lo CM, Yau T. The Outcomes of Systemic Treatment in Recurrent Hepatocellular Carcinomas Following Liver Transplants. Adv Ther 2021; 38:3900-3910. [PMID: 34061324 DOI: 10.1007/s12325-021-01800-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Accepted: 05/19/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Treatment of hepatocellular carcinoma (HCC) recurrences following liver transplant (LT) is challenging. Most clinical trials of systemic therapies for advanced HCC excluded patients with any history of organ transplant. We aimed to assess the outcomes in using various systemic therapies in patients with post-LT recurrence. METHODS Consecutive patients with HCC and recurrences following LT at a large tertiary centre from 2005 to 2018 were reviewed. Overall survival (OS), response rates and adverse events (AEs) were analysed. RESULTS Forty-three consecutive patients with a recurrence of HCC following LT were identified from 2005 to 2018. Median OS from diagnosis of recurrence was 17 months (CI 11.3, 22.7). Early recurrence within 12 months of transplant was associated with a significantly worse median survival of 10 months (CI 8.5, 11.4) compared to 26 months (CI 18.8, 33.2) when recurrences occurred after 12 months from transplant (p < 0.001) with a hazard ratio of 0.104 (log-rank test, p < 0.001). A total of 41 patients had received systemic therapies and 79.1% of them were on sorafenib as the first-line treatment. Among these patients treated with sorafenib, median OS from recurrence was 14 months (CI 7.3, 20.7). Hand-foot syndrome (34.7%) was most common among AEs followed by diarrhoea (26.7%). Overall, AEs led to dose interruptions in 8.8% of patients. Notably, 47.1% of patients received subsequent lines of systemic therapies after sorafenib. CONCLUSIONS Early recurrence within 1 year from transplant was the most significant risk factor. Treatment efficacy and adverse events and tolerability of sorafenib were comparable with those in the setting of advanced HCC without transplant.
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Affiliation(s)
- Bryan Cho Wing Li
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, 102 Pokfulam Road, Hong Kong, China
| | - Joanne Chiu
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, 102 Pokfulam Road, Hong Kong, China
| | - Kit Shing
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, 102 Pokfulam Road, Hong Kong, China
| | - Gerry Gin Wai Kwok
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, 102 Pokfulam Road, Hong Kong, China
| | - Vikki Tang
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, 102 Pokfulam Road, Hong Kong, China
| | - Roland Leung
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, 102 Pokfulam Road, 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, 102 Pokfulam Road, Hong Kong, China
| | - Albert Chan
- 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
| | - Chung Mau Lo
- 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, 102 Pokfulam Road, Hong Kong, China.
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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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Piñero F, da Fonseca LG. Trial eligibility in advanced hepatocellular carcinoma: Does it support clinical practice in underrepresented subgroups? World J Gastroenterol 2021; 27:3429-3439. [PMID: 34239261 PMCID: PMC8240059 DOI: 10.3748/wjg.v27.i24.3429] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 05/06/2021] [Accepted: 05/20/2021] [Indexed: 02/06/2023] Open
Abstract
Although hepatocellular carcinoma is considered a highly lethal malignancy, recent therapeutic advances have been achieved during the last 10 years. This scenario resulted in an unprecedented improvement in survival for patients with advanced hepatocellular carcinoma, almost reaching 20-26 mo of overall survival after first-second line sequential treatment. The advent of the combination of atezolizumab with bevacizumab showed, for the first time, superiority over sorafenib with improvement in overall survival. However, first and second-line trials were correctly based on the premise that a strict selection of patients enhances the power to capture the positive effect of treatment by excluding competing risks for mortality such as liver failure, decompensated cirrhosis or other underlying medical conditions. As a result, the inclusion criteria used in clinical trials do not support the use of novel therapies in several real-world scenarios involving underrepresented subgroups, such as patients with unpreserved liver function, other comorbid conditions, a history of solid-organ transplantation, autoimmune disorders and those with a high risk of bleeding. The present text aims at discussing treatment strategies in these subgroups.
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Affiliation(s)
- Federico Piñero
- Hepatology and Liver Unit, Hospital Universitario Austral, School of Medicine, Austral University, Buenos Aires B1629HJ, Argentina
| | - Leonardo Gomes da Fonseca
- Clinical Oncology, Insituto do Cancer do Estado de São Paulo, University of São Paulo, São Paulo 05403-000, Brazil
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Granito A, Marinelli S, Forgione A, Renzulli M, Benevento F, Piscaglia F, Tovoli F. Regorafenib Combined with Other Systemic Therapies: Exploring Promising Therapeutic Combinations in HCC. J Hepatocell Carcinoma 2021; 8:477-492. [PMID: 34079777 PMCID: PMC8165211 DOI: 10.2147/jhc.s251729] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 03/25/2021] [Indexed: 02/05/2023] Open
Abstract
Regorafenib was the first drug to demonstrate a survival benefit as a second-line agent after sorafenib failure in patients with unresectable hepatocellular carcinoma (HCC). Recent studies have shown that its mechanism of action is not only limited to its very broad spectrum of inhibition of angiogenesis, tumor proliferation, spread, and metastasis, but also to its immunomodulatory properties that have favorable effects on the very intricate role that the tumor microenvironment plays in carcinogenesis and tumor growth. In this review, we discuss rationale and evidence supporting regorafenib efficacy in HCC and that led to its approval as a second-line treatment, after sorafenib failure. We also discuss the evidence from clinical practice studies that confirm the results previously achieved in clinical trials. Finally, we analyze the potential role of regorafenib in emerging combined treatment approach with immunotherapy strategies using immune checkpoint blockade and its potential extension to patient categories not included in the registrative study.
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Affiliation(s)
- Alessandro Granito
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Sara Marinelli
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Antonella Forgione
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Matteo Renzulli
- Radiology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Francesca Benevento
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Fabio Piscaglia
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Francesco Tovoli
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
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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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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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Maccali C, Chagas AL, Boin I, Quiñonez E, Marciano S, Vilatobá M, Varón A, Anders M, Hoyos Duque S, Lima AS, Menendez J, Padilla-Machaca M, Poniachik J, Zapata R, Maraschio M, Chong Menéndez R, Muñoz L, Arufe D, Figueroa R, Soza A, Fauda M, Perales SR, Vergara Sandoval R, Bermudez C, Beltran O, Arenas Hoyos I, McCormack L, Mattera FJ, Gadano A, Parente García JH, Tani CM, Augusto Carneiro D'Albuquerque L, Carrilho FJ, Silva M, Piñero F. Recurrence of hepatocellular carcinoma after liver transplantation: Prognostic and predictive factors of survival in a Latin American cohort. Liver Int 2021; 41:851-862. [PMID: 33217193 DOI: 10.1111/liv.14736] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 10/20/2020] [Accepted: 11/16/2020] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIM Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) has a poor prognosis, and the adjusted effect of different treatments on post-recurrence survival (PRS) has not been well defined. This study aims to evaluate prognostic and predictive variables associated with PRS. METHODS This Latin American multicenter retrospective cohort study included HCC patients who underwent LT between the years 2005-2018. We evaluated the effect of baseline characteristics at time of HCC recurrence diagnosis and PRS (Cox regression analysis). Early recurrences were those occurring within 12 months of LT. To evaluate the adjusted treatment effect for HCC recurrence, a propensity score matching analysis was performed to assess the probability of having received any specific treatment for recurrence. RESULTS From a total of 1085 transplanted HCC patients, the cumulative incidence of recurrence was 16.6% (CI 13.5-20.3), with median time to recurrence of 13.0 months (IQR 6.0-26.0). Factors independently associated with PRS were early recurrence (47.6%), treatment with sorafenib and surgery/trans-arterial chemoembolization (TACE). Patients who underwent any treatment presented "early recurrences" less frequently, and more extrahepatic metastasis. This unbalanced distribution was included in the propensity score matching, with correct calibration and discrimination (receiving operator curve of 0.81 [CI 0.72;0.88]). After matching, the adjusted effect on PRS for any treatment was HR of 0.2 (0.10;0.33); P < .0001, for sorafenib therapy HR of 0.4 (0.27;0.77); P = .003, and for surgery/TACE HR of 0.4 (0.18;0.78); P = .009. CONCLUSION Although early recurrence was associated with worse outcome, even in this population, systemic or locoregional treatments were associated with better PRS.
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Affiliation(s)
- Claudia Maccali
- São Paulo Clinics Liver Cancer Group - Hospital das Clínicas Complex, Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Aline L Chagas
- São Paulo Clinics Liver Cancer Group - Hospital das Clínicas Complex, Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Ilka Boin
- Unit of Liver Transplantation, State University of Campinas, Campinas, Brazil
| | | | | | - Mario Vilatobá
- Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", México
| | | | | | - Sergio Hoyos Duque
- Hospital Pablo Tobón Uribe and Gastrohepatology Group, Universidad de Antioquia, Medellín, Colombia
| | - Agnaldo S Lima
- Hospital das Clínicas da Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | | | | | | | - Rodrigo Zapata
- Clinica Alemana, Facultad de Medicina, Universidad del Desarrollo, Santiago, Chile
| | | | | | | | - Diego Arufe
- Sanatorio Sagrado Corazón, Buenos Aires, Argentina
| | | | - Alejandro Soza
- Department of Gastroenterology, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Martín Fauda
- Hospital Universitario Austral, Buenos Aires, Argentina
| | - Simone R Perales
- Unit of Liver Transplantation, State University of Campinas, Campinas, Brazil
| | | | - Carla Bermudez
- Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | | | - Isabel Arenas Hoyos
- Hospital Pablo Tobón Uribe and Gastrohepatology Group, Universidad de Antioquia, Medellín, Colombia
| | | | | | - Adrián Gadano
- Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | | | - Claudia Megumi Tani
- São Paulo Clinics Liver Cancer Group - Hospital das Clínicas Complex, Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Luiz Augusto Carneiro D'Albuquerque
- São Paulo Clinics Liver Cancer Group - Hospital das Clínicas Complex, Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Flair J Carrilho
- São Paulo Clinics Liver Cancer Group - Hospital das Clínicas Complex, Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Marcelo Silva
- Hospital Universitario Austral, Buenos Aires, Argentina.,Latin American Liver Research Educational and Awareness Network (LALREAN), Buenos Aires, Argentina
| | - Federico Piñero
- Hospital Universitario Austral, Buenos Aires, Argentina.,Latin American Liver Research Educational and Awareness Network (LALREAN), Buenos Aires, Argentina
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Cerrito L, Santopaolo F, Monti F, Pompili M, Gasbarrini A, Ponziani FR. Advances in pharmacotherapeutics for hepatocellular carcinoma. Expert Opin Pharmacother 2021; 22:1343-1354. [PMID: 33637024 DOI: 10.1080/14656566.2021.1892074] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Although hepatocellular carcinoma (HCC) is the most frequent primary liver cancer, there are limited therapeutic options for the advanced stages. Sorafenib was the first tyrosine-kinase inhibitor (TKI) approved for unresectable HCC and remained the only effective choice for a decade. The horizon of systemic treatments drastically expanded in the latest years, opening new interesting possibilities. AREAS COVERED In this manuscript, the authors have analysed the recent advances in pharmacotherapy for HCC, discussing their mechanisms of action, the clinical efficacy and the safety profile of currently available first, second-and third-line treatments. The authors have also analysed the role of immune system modulators, in particular immune checkpoints inhibitors (ICIs), based on the limited data published so far. EXPERT OPINION The emergence of new targeted therapies, such as lenvatinib, have changed the landscape of HCC therapy. Tumor extension, differences in objective response rates and adverse events profiles should be considered to tailor the choice of the first-line agent. Sorafenib remains the most studied drug, with much real-world data available. The efficacy of second line therapies has only been proven in non-responder or sorafenib-intolerant patients. Unfortunately, studies directly comparing the second-line agents regorafenib, ramucirumab and cabozantinib are still lacking.
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Affiliation(s)
- Lucia Cerrito
- Internal Medicine, Gastroenterology And Hepatology, Fondazione Policlinico Universitario Agostino Gemelli Irccs, Università Cattolica Del Sacro Cuore, ROMA, ITALY
| | - Francesco Santopaolo
- Internal Medicine, Gastroenterology And Hepatology, Fondazione Policlinico Universitario Agostino Gemelli Irccs, Università Cattolica Del Sacro Cuore, ROMA, ITALY
| | | | - Maurizio Pompili
- Internal Medicine, Gastroenterology And Hepatology, Fondazione Policlinico Universitario Agostino Gemelli Irccs, Università Cattolica Del Sacro Cuore, ROMA, ITALY
| | - Antonio Gasbarrini
- Internal Medicine, Gastroenterology And Hepatology, Fondazione Policlinico Universitario Agostino Gemelli Irccs, Università Cattolica Del Sacro Cuore, ROMA, ITALY
| | - Francesca Romana Ponziani
- Internal Medicine, Gastroenterology And Hepatology, Fondazione Policlinico Universitario Agostino Gemelli Irccs, Università Cattolica Del Sacro Cuore, ROMA, ITALY
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Lee SK, Jang JW, Nam H, Sung PS, Kim HY, Kwon JH, Lee SW, Song DS, Kim CW, Song MJ, Choi HJ, You YK, Bae SH, Choi JY, Yoon SK. Sorafenib for advanced hepatocellular carcinoma provides better prognosis after liver transplantation than without liver transplantation. Hepatol Int 2021; 15:137-145. [PMID: 33496932 DOI: 10.1007/s12072-020-10131-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 12/26/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND Although sorafenib has been used to treat advanced hepatocellular carcinoma (HCC), the efficacy of sorafenib in patients with recurrent HCCs after liver transplantation (LT) has not been compared with that in patients without LT (non-LT). METHODS Between 2008 and 2019, a total of 832 consecutive HCC patients treated with sorafenib (790 in the non-LT group and 42 in the LT group) were enrolled. The primary outcome was overall survival (OS). Secondary outcomes were time-to-progression (TTP), objective response rate (ORR) and disease control rate (DCR). Treatment outcomes were assessed by multiple subgroup analyses and propensity-score matching (PSM). RESULTS The median follow-up duration was 152.5 days. The LT group was younger and had smaller intrahepatic HCC than the non-LT group. The LT group showed significantly better OS (16.8 vs. 7.1 months, p < 0.001), TTP, ORR and DCR than the non-LT group. The superior efficacy of sorafenib in the LT group was corroborated in multiple subgroup analyses stratified by metastasis, effective sorafenib maintenance dose, or Child-Turcotte-Pugh class A. LT was identified as an independent factor for favorable OS. Intrahepatic HCC was the strongest tumor-related factor for both OS and TTP and was significantly associated with tumor response and hepatic function. Finally, subanalyses including only patients with small intrahepatic HCC or PSM modeling showed no difference in sorafenib efficacy between the LT and the non-LT groups. CONCLUSION Sorafenib provides better outcomes in the LT setting than the non-LT setting. This benefit may be associated with the smaller intrahepatic HCC coupled with preserved hepatic function in LT recipients.
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Affiliation(s)
- Soon Kyu Lee
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, #222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea.,The Catholic University Liver Research Center, Seoul, Republic of Korea
| | - Jeong Won Jang
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, #222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea. .,The Catholic University Liver Research Center, Seoul, Republic of Korea.
| | - Heechul Nam
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, #222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea.,The Catholic University Liver Research Center, Seoul, Republic of Korea
| | - Pil Soo Sung
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, #222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea.,The Catholic University Liver Research Center, Seoul, Republic of Korea
| | - Hee Yeon Kim
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, #222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea.,The Catholic University Liver Research Center, Seoul, Republic of Korea
| | - Jung Hyun Kwon
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, #222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea.,The Catholic University Liver Research Center, Seoul, Republic of Korea
| | - Sung Won Lee
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, #222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea.,The Catholic University Liver Research Center, Seoul, Republic of Korea
| | - Do Seon Song
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, #222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea.,The Catholic University Liver Research Center, Seoul, Republic of Korea
| | - Chang Wook Kim
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, #222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea.,The Catholic University Liver Research Center, Seoul, Republic of Korea
| | - Myeong Jun Song
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, #222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea.,The Catholic University Liver Research Center, Seoul, Republic of Korea
| | - Ho Joong Choi
- Department of Surgery, The Catholic University of Korea, Seoul, Republic of Korea
| | - Young Kyoung You
- Department of Surgery, The Catholic University of Korea, Seoul, Republic of Korea
| | - Si Hyun Bae
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, #222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea.,The Catholic University Liver Research Center, Seoul, Republic of Korea
| | - Jong Young Choi
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, #222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea.,The Catholic University Liver Research Center, Seoul, Republic of Korea
| | - Seung Kew Yoon
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, #222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea.,The Catholic University Liver Research Center, Seoul, Republic of Korea
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Combining Sorafenib and Immunosuppression in Liver Transplant Recipients with Hepatocellular Carcinoma. Pharmaceuticals (Basel) 2021; 14:ph14010046. [PMID: 33435321 PMCID: PMC7826978 DOI: 10.3390/ph14010046] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 01/05/2021] [Accepted: 01/06/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) recurrence after liver transplantation occurs in approximately 20% of patients. Most of these patients use immunosuppressant drugs. Meanwhile, patients with HCC recurrence are frequently treated with the small molecule kinase inhibitor (SMKI) sorafenib. However, sorafenib and many immunosuppressants are substrates of the same enzymatic pathways (e.g., CYP3A4), which may potentially result in altered SMKI or immunosuppressant plasma levels. Therefore, we investigated changes in drug exposure of both sorafenib and immunosuppressants over time in four patients with systemic immunosuppressant and sorafenib treatment after HCC recurrence. In this study, sorafenib exposure declined over time during combined treatment with immunosuppressants, while two patients also experienced declining tacrolimus plasma levels. Importantly, patients were unable to increase the sorafenib dose higher than 200 mg b.i.d. without experiencing significant toxicity. We recommend to treat patients using both sorafenib and immunosuppressants with a sorafenib starting dose of 200 mg b.i.d.
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Pinter M, Scheiner B, Peck-Radosavljevic M. Immunotherapy for advanced hepatocellular carcinoma: a focus on special subgroups. Gut 2021; 70:204-214. [PMID: 32747413 PMCID: PMC7788203 DOI: 10.1136/gutjnl-2020-321702] [Citation(s) in RCA: 163] [Impact Index Per Article: 40.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 05/27/2020] [Accepted: 06/13/2020] [Indexed: 02/06/2023]
Abstract
Following the success of immune checkpoint blockers (ICBs) in different cancer types, a large number of studies are currently investigating ICBs in patients with hepatocellular carcinoma (HCC), alone or in combination with other treatments. Both nivolumab and pembrolizumab, as well as the combination of nivolumab plus ipilimumab have been granted accelerated approval by the United States Food and Drug Administration for sorafenib-pretreated patients. While nivolumab and pembrolizumab both failed to meet their primary endpoints in phase III trials, the combination of atezolizumab plus bevacizumab eventually improved overall and progression-free survival compared with sorafenib in a front-line phase III trial, and thus, will become the new standard of care in this setting. Despite this breakthrough, there are patient populations with certain underlying conditions that may not be ideal candidates for this new treatment either due to safety concerns or potential lack of efficacy. In this review, we discuss the safety of ICBs in patients with pre-existing autoimmune disease, IBD or a history of solid organ transplantation. Moreover, we summarise emerging preclinical and clinical data suggesting that ICBs may be less efficacious in patients with underlying non-alcoholic steatohepatitis or HCCs with activated Wnt/β-catenin signalling.
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Affiliation(s)
- Matthias Pinter
- Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria .,Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria
| | - Bernhard Scheiner
- Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria,Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria
| | - Markus Peck-Radosavljevic
- Department of Internal Medicine and Gastroenterology (IMuG), Hepatology, Endocrinology, Rheumatology and Nephrology including Centralized Emergency Department (ZAE), Klinikum Klagenfurt am Worthersee, Klagenfurt, Kärnten, Austria
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Kawanami GH, Katsuda L, Rocha TB, da Silva Yamashiro F, Pelafsky L, Qi X, Romeiro FG. How Much Time Should Be Waited and What Are the Main Findings to Evaluate the Hepatocellular Carcinoma Response to Regorafenib? A Real-Life Experience. Can J Gastroenterol Hepatol 2021; 2021:6219896. [PMID: 33614533 PMCID: PMC7878098 DOI: 10.1155/2021/6219896] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 08/26/2020] [Accepted: 08/26/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma is a relevant cause of mortality worldwide, mainly among patients who have a prior liver disease. In spite of clear recommendations regarding surveillance and screening methods, most patients are still diagnosed only when they are no longer candidates to curative treatment modalities, while others do not achieve the goals of such treatments, thus increasing the need of anticancer drugs. Moreover, when cirrhotic patients begin to receive these drugs, many types of adverse events are seen as a reason to withdrawal, even when there are findings suggesting a good response to the treatment. Case Summary. This case report is about a cirrhotic patient who received many types of treatment, from surgery and chemoembolization during early stages to first- and second-line systemic therapy when the disease turned to be advanced. Since he had no signs of liver dysfunction and suffered tumor progression during sorafenib treatment, regorafenib was initiated. The main findings that make this case important are the adverse events after taking this second-line agent, which would certainly be considered unacceptable and would lead to the drug withdrawal. The reasons why regorafenib was maintained are explained based on clinical and imaging findings, showing how this decision led to an excellent response. CONCLUSIONS The knowledge of the main adverse events described in the pilot clinical trials can avoid unnecessary withdrawal of regorafenib. In addition, some clinical and imaging findings can be deemed as predictors of good response to tyrosine kinase inhibitors.
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Affiliation(s)
- Gustavo Hideki Kawanami
- 1Fundação para o Desenvolvimento Médico e Hospitalar (FAMESP) Hospital Estadual de Bauru, São Paulo, Brazil
| | | | - Thiara Barcelos Rocha
- 3Gastroenterology Division, Department of Internal Medicine, Faculdade de Medicina de Botucatu, Universidade Estadual Paulista (UNESP), São Paulo, Brazil
| | - Fabio da Silva Yamashiro
- 1Fundação para o Desenvolvimento Médico e Hospitalar (FAMESP) Hospital Estadual de Bauru, São Paulo, Brazil
- 3Gastroenterology Division, Department of Internal Medicine, Faculdade de Medicina de Botucatu, Universidade Estadual Paulista (UNESP), São Paulo, Brazil
| | - Leonardo Pelafsky
- 4Surgery Department, Faculdade de Medicina de Botucatu, Universidade Estadual Paulista (UNESP), São Paulo, Brazil
| | - Xingshun Qi
- 5Department of Gastroenterology, General Hospital of Northern Theater Command (Formerly General Hospital of Shenyang Military Area), Shenyang 110840, China
| | - Fernando Gomes Romeiro
- 3Gastroenterology Division, Department of Internal Medicine, Faculdade de Medicina de Botucatu, Universidade Estadual Paulista (UNESP), São Paulo, Brazil
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Granito A, Forgione A, Marinelli S, Renzulli M, Ielasi L, Sansone V, Benevento F, Piscaglia F, Tovoli F. Experience with regorafenib in the treatment of hepatocellular carcinoma. Therap Adv Gastroenterol 2021; 14:17562848211016959. [PMID: 34104211 PMCID: PMC8165525 DOI: 10.1177/17562848211016959] [Citation(s) in RCA: 97] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Accepted: 04/20/2021] [Indexed: 02/06/2023] Open
Abstract
Regorafenib is a diphenylurea oral multikinase inhibitor, structurally comparable to sorafenib, which targets a variety of kinases implicated in angiogenic and tumor growth-promoting pathways. Regorafenib was the first agent to positively show significant survival advantage as a second-line therapy in patients with unresectable hepatocellular carcinoma (HCC) who had previously failed first-line treatment with sorafenib. Recent evidence has shown that its antitumor efficacy is due to a comprehensive spectrum of tumor neo-angiogenesis and proliferation inhibition and immunomodulatory effects on the tumor microenvironment, which plays a crucial role in tumor development. This review addresses the rationale and supporting evidence for regorafenib's efficacy in HCC that led to regorafenib's approval as a second-line therapy. In addition, we review proof from clinical practice studies that validate the RESORCE trial results. We discuss regorafenib's potential role in the newly emerging therapeutic strategy based on combination with immune checkpoint blockade and its possible extensibility to patient categories not enrolled in the registrative study.
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Affiliation(s)
| | - Antonella Forgione
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italia
| | - Sara Marinelli
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Matteo Renzulli
- Radiology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Luca Ielasi
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italia
| | - Vito Sansone
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italia
| | - Francesca Benevento
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italia
| | - Fabio Piscaglia
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italia
| | - Francesco Tovoli
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italia
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Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) is an increasingly common disease with liver transplant (LT) the best long-term therapy for early stage disease. We will review the data for assessing risk and managing recurrence for patients undergoing LT for HCC. AREAS COVERED In this review, we will provide an overview of methods of patient risk stratification in the post-transplant period, the data around surveillance for HCC recurrence, and the evidence for and against post-LT adjuvant treatment strategies. Finally, we will provide data regarding treatment options for patients with HCC recurrence after LT. Using an extensive search of original papers and society guidelines, this paper provides a comprehensive review of the data for assessing risk and managing recurrence for patients undergoing LT for HCC. EXPERT OPINION The development of multiple post-transplant prognostic scoring systems have allowed for improved assessment of recurrence risk and stratification of patients. However, the ability to translate this information into surveillance and therapeutic strategies that improve patient outcomes still have to be fully demonstrated. Post-LT immunosuppression strategies have been implemented in order to attempt to reduce this risk. Evidence-based strategies for managing recurrent HCC are evolving. We expect that with further understanding of individual patient characteristics will allow for optimal therapeutic selection.
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Affiliation(s)
- Daniel Hoffman
- Department of Surgery, University of California , San Francisco, CA, USA
| | - Neil Mehta
- Division of Gastroenterology, Department of Medicine, University of California , San Francisco, CA, USA
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Piñero F, Thompson M, Marín JI, Silva M. Lenvatinib as first-line therapy for recurrent hepatocellular carcinoma after liver transplantation: Is the current evidence applicable to these patients? World J Transplant 2020; 10:297-306. [PMID: 33312891 PMCID: PMC7708877 DOI: 10.5500/wjt.v10.i11.297] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 06/09/2020] [Accepted: 09/22/2020] [Indexed: 02/05/2023] Open
Abstract
Liver transplantation (LT) is one of the leading curative therapies for hepatocellular carcinoma (HCC). Despite recent optimization of transplant selection criteria, including alpha-feto protein, HCC recurrence after LT is still the leading cause of death in these patients. During the last decades, effective systemic treatments for HCC, including tyrosine kinase inhibitors and immunotherapy, have been approved. We describe the clinical scenario of a patient with recurrence of HCC five years after LT, who received lenvatinib as first-line systemic therapy to introduce systemic treatment options in this clinical setting. In this opinion review, we detail first and second-line systemic treatment options, focusing on those feasible for patients with recurrent HCC after LT. Several trials have evaluated new drugs to treat HCC patients in first and second-line therapy, but patients with recurrent HCC after LT have been excluded from these trials. Consequently, most of the evidence comes from observational retrospective studies. Whether tyrosine kinase inhibitors will remain the primary therapeutic approach in these patients, due to a relative contraindication for immunotherapy, may be clarified in the near future.
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Affiliation(s)
- Federico Piñero
- Hepatology and Liver Transplant Unit, Hospital Universitario Austral, Buenos Aires B1629HJ, Argentina
- Hospital Universitario Austral, Facultad de Ciencias Biomédicas, Universidad Austral, Buenos Aires B1629HJ, Argentina
- Latin American Liver Research Educational and Awareness Network (LALREAN), Buenos Aires B1629HJ, Argentina
| | - Marcos Thompson
- Hospital Universitario Austral, Facultad de Ciencias Biomédicas, Universidad Austral, Buenos Aires B1629HJ, Argentina
| | - Juan Ignacio Marín
- Hepatology and Liver Transplantation Unit, Hospital Pablo Tobón Uribe, Medellín 240, Colombia
| | - Marcelo Silva
- Hospital Universitario Austral, Facultad de Ciencias Biomédicas, Universidad Austral, Buenos Aires B1629HJ, Argentina
- Latin American Liver Research Educational and Awareness Network (LALREAN), Buenos Aires B1629HJ, Argentina
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