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Li Z, Chen ICY, Centonze L, Magyar CTJ, Choi WJ, Shah S, O'Kane GM, Vogel A, De Carlis L, Lerut J, Lai Q, Mehta N, Chen CL, Sapisochin G. Analysis of treatment benefits and prognostic factors for posttransplant HCC recurrence in a large Euro-American-Asian cohort. Liver Transpl 2025; 31:450-463. [PMID: 39356515 DOI: 10.1097/lvt.0000000000000501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Accepted: 09/16/2024] [Indexed: 10/03/2024]
Abstract
Posttransplant HCC recurrence significantly impacts survival, yet its management is challenging due to limited evidence. With recent advancements in HCC treatment, updated data on managing recurrent diseases are needed. In this retrospective study across 6 centers (2000-2022), we employed Cox proportional-hazards regression and log-rank tests to assess survival differences. A prognostic score model was developed to categorize patient survival. The efficacy of tyrosine kinase inhibitors was evaluated through propensity score matching. In our study, 431 of 3349 (14%) patients with HCC who underwent transplantation developed recurrence within a median interval of 18 (IQR: 9-32) months. One hundred forty-seven (34%) underwent curative-intent treatments, 207 (48%) received palliative treatments, and 77 (18%) were given best-supportive care. Patients undergoing curative-intent treatments had better survival from the time of recurrence with a median survival of 45 (95% CI: 36-63) months and 1/3/5-year survival of 90%/56%/43% compared to those receiving noncurative treatments (median: 11 [95% CI: 10-13] mo, 1/3/5-y survival of 46%/10%/7%, log-rank p < 0.001). Patients with recurrence diagnosed in the era 2018-2022 showed improved survival over the previous era (HR 0.64 [95% CI: 0.47-0.86]). Multivariable analysis identified 5 prognostic factors: ineligibility for curative-intent treatment (HR: 3.5 [95% CI: 2.7-4.6]), recurrence within 1 year (HR: 1.7 [95% CI: 1.3-2.1]), poor tumor differentiation (HR: 1.5 [95% CI: 1.1-1.9]), RETREAT score ≥3 (HR: 1.4 [95% CI: 1.1-1.8]), and alpha-fetoprotein at recurrence ≥400 ng/mL (HR: 1.4 [95% CI: 1.1-1.9]). These factors contributed to a prognostic scoring system (0-9) that stratified patients into 3 prognosis groups. Both propensity score-matched analysis and multivariable regression indicated that lenvatinib was not statistically superior to sorafenib in terms of efficacy. Curative-intent treatments should be advocated for patients with posttransplant recurrence whenever possible. Prognostic factors linked to aggressive tumor biology significantly influence survival. Advancements in HCC management have improved survival outcomes over the past 5 years.
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Affiliation(s)
- Zhihao Li
- HBP & Multi-Organ Transplant Program, Department of Surgery, University Health Network, Toronto, Ontario, Canada
| | - Itsuko Chih-Yi Chen
- Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Leonardo Centonze
- Department of General Surgery and Transplantation, Niguarda Ca' Granda Hospital, Milan, Italy
- Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, Modena, Italy
| | - Christian T J Magyar
- HBP & Multi-Organ Transplant Program, Department of Surgery, University Health Network, Toronto, Ontario, Canada
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Woo Jin Choi
- HBP & Multi-Organ Transplant Program, Department of Surgery, University Health Network, Toronto, Ontario, Canada
| | - Sachin Shah
- Department of Medicine, Division of Gastroenterology, University of California San Francisco, San Francisco, California, USA
| | - Grainne M O'Kane
- Department of Medical Oncology, St. Vincent's University Hospital and School of Medicine University College Dublin, Dublin, Republic of Ireland
- Wallace McCain Centre for Pancreatic Cancer, Division of Medical Oncology, Princess Margaret Hospital, Toronto, Ontario, Canada
| | - Arndt Vogel
- Division of Gastroenterology and Hepatology, University Health Network, Toronto, Ontario, Canada
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Luciano De Carlis
- Department of General Surgery and Transplantation, Niguarda Ca' Granda Hospital, Milan, Italy
- School of Medicine and Surgery, Department of Surgery, University of Milan-Bicocca, Milan, Italy
| | - Jan Lerut
- Institut de Recherche Expérimentale et Clinique, Department of Surgery, Université catholique de Louvain, Brussels, Belgium
| | - Quirino Lai
- General Surgery and Organ Transplantation Unit, Department of Surgery, Sapienza University of Rome, Rome, Italy
| | - Neil Mehta
- Department of Medicine, Division of Gastroenterology, University of California San Francisco, San Francisco, California, USA
| | - Chao-Long Chen
- Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Gonzalo Sapisochin
- HBP & Multi-Organ Transplant Program, Department of Surgery, University Health Network, Toronto, Ontario, Canada
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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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Kanbayashi Y, Tomii R, Yamamoto N, Wakabayashi H, Anzai M, Shimizu T, Uchida M. Evaluation of Times-to-onset and Outcomes of Lung Adverse Events Associated With Sorafenib Using JADER. In Vivo 2025; 39:360-366. [PMID: 39740895 PMCID: PMC11705118 DOI: 10.21873/invivo.13836] [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: 08/30/2024] [Revised: 09/19/2024] [Accepted: 09/20/2024] [Indexed: 01/02/2025]
Abstract
BACKGROUND/AIM Despite the seriousness of lung adverse events (AEs) associated with sorafenib, comprehensive data are limited. This study was conducted to examine the disproportionality, times to onset, incidence rates, and outcomes of sorafenib-associated lung AEs, using the Japanese Adverse Drug Event Report database. PATIENTS AND METHODS Data for the period between April 2004 and May 2023 were analyzed. Data on lung AEs were extracted, and the relative disproportionality of AEs was estimated using reporting odds ratios (RORs). RESULTS A total of 2,230,863 reports were analyzed, and 8,374 reports of AEs associated with sorafenib, including 381 lung AEs, were identified. Signals were detected for two lung AEs: metastases to the lung and tracheal hemorrhage. Fatal outcomes were observed for both AEs. Histograms of the median times to onset of the two detected lung AE signals showed that AEs occurred from 49 to 275 days after sorafenib administration. Weibull distributions showed that the incidences of these AEs occurred constantly throughout the exposure period (random failure type). CONCLUSION This study focused on lung AEs associated with sorafenib, highlighting serious outcomes such as lung metastases and tracheal hemorrhage. Continuous monitoring for these AEs is crucial from treatment initiation through the entire therapy course.
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Affiliation(s)
- Yuko Kanbayashi
- Department of Education and Research Center for Clinical Pharmacy, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, Takatsuki, Japan;
| | - Rio Tomii
- Department of Education and Research Center for Pharmacy Practice, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts, Kyotanabe, Japan
| | - Naru Yamamoto
- Department of Education and Research Center for Pharmacy Practice, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts, Kyotanabe, Japan
| | - Haruka Wakabayashi
- Department of Education and Research Center for Pharmacy Practice, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts, Kyotanabe, Japan
| | - Miku Anzai
- Department of Education and Research Center for Pharmacy Practice, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts, Kyotanabe, Japan
| | | | - Mayako Uchida
- Department of Education and Research Center for Pharmacy Practice, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts, Kyotanabe, Japan
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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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Liu H, Sethi V, Li X, Xiao Y, Humar A. Liver Transplantation for Hepatocellular Carcinoma: A Narrative Review and A Glimpse into The Future. Semin Liver Dis 2024; 44:79-98. [PMID: 38211621 DOI: 10.1055/a-2242-7543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2024]
Abstract
Liver transplantation (LT) is a highly effective treatment for carefully selected patients with hepatocellular carcinoma (HCC). In this review, we explored the development of LT selection criteria and organ allocation policies, comparing original data to underscore their historical progression into the intricate task of quantitatively estimating pre- and post-LT survivals. We emphasized the role of biomarkers such as serum alpha-fetoprotein, Des-gamma-carboxy-prothrombin, circulating tumor cells, and circulating tumor DNA in predicting patient outcomes. Additionally, we examined the transplant-associated survival benefits and the difficulties in accurately calculating these benefits. We also reviewed recent advancements in targeted therapy and checkpoint inhibitors for advanced, inoperable HCC and projected their integration into LT for HCC. We further discussed the growing use of living donor liver transplants in the United States and compared its outcomes with those of deceased donor liver transplants. Furthermore, we examined the progress in machine perfusion techniques, which have shown potential in improving patient outcomes and enlarging the donor pool. These advancements present opportunities to enhance LT patient survivals, refine selection criteria, establish new priority metrics, develop innovative bridging and downstaging strategies, and formulate redesigned LT strategies for HCC treatments.
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Affiliation(s)
- Hao Liu
- Department of Surgery, Starzl Transplant Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Vrishketan Sethi
- Department of Surgery, Starzl Transplant Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Xingjie Li
- Division of Transplant Surgery, Department of Surgery, Mayo Clinic Arizona, Phoenix, Arizona
| | - Yao Xiao
- Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Abhinav Humar
- Department of Surgery, Starzl Transplant Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
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Todeschini L, Cristin L, Martinino A, Mattia A, Agnes S, Giovinazzo F. The Role of mTOR Inhibitors after Liver Transplantation for Hepatocellular Carcinoma. Curr Oncol 2023; 30:5574-5592. [PMID: 37366904 DOI: 10.3390/curroncol30060421] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 06/06/2023] [Accepted: 06/07/2023] [Indexed: 06/28/2023] Open
Abstract
Liver transplantation is a treatment option for nonresectable patients with early-stage HCC, with more significant advantages when Milan criteria are fulfilled. An immunosuppressive regimen is required to reduce the risk of graft rejection after transplantation, and CNIs represent the drugs of choice in this setting. However, their inhibitory effect on T-cell activity accounts for a higher risk of tumour regrowth. mTOR inhibitors (mTORi) have been introduced as an alternative immunosuppressive approach to conventional CNI-based regimens to address both immunosuppression and cancer control. The PI3K-AKT-mTOR signalling pathway regulates protein translation, cell growth, and metabolism, and the pathway is frequently deregulated in human tumours. Several studies have suggested the role of mTORi in reducing HCC progression after LT, accounting for a lower recurrence rate. Furthermore, mTOR immunosuppression controls the renal damage associated with CNI exposure. Conversion to mTOR inhibitors is associated with stabilizing and recovering renal dysfunction, suggesting an essential renoprotective effect. Limitations in this therapeutic approach are related to their negative impact on lipid and glucose metabolism as well as on proteinuria development and wound healing. This review aims to summarize the roles of mTORi in managing patients with HCC undergoing LT. Strategies to overcome common adverse effects are also proposed.
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Affiliation(s)
- Letizia Todeschini
- Faculty of Medicine and Surgery, University of Verona, 37134 Verona, Italy
| | - Luca Cristin
- Faculty of Medicine and Surgery, University of Verona, 37134 Verona, Italy
| | | | - Amelia Mattia
- General Surgery and Liver Transplantation Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Salvatore Agnes
- General Surgery and Liver Transplantation Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Francesco Giovinazzo
- General Surgery and Liver Transplantation Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
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7
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Kucukkaya AS, Zeevi T, Chai NX, Raju R, Haider SP, Elbanan M, Petukhova-Greenstein A, Lin M, Onofrey J, Nowak M, Cooper K, Thomas E, Santana J, Gebauer B, Mulligan D, Staib L, Batra R, Chapiro J. Predicting tumor recurrence on baseline MR imaging in patients with early-stage hepatocellular carcinoma using deep machine learning. Sci Rep 2023; 13:7579. [PMID: 37165035 PMCID: PMC10172370 DOI: 10.1038/s41598-023-34439-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Accepted: 04/29/2023] [Indexed: 05/12/2023] Open
Abstract
Tumor recurrence affects up to 70% of early-stage hepatocellular carcinoma (HCC) patients, depending on treatment option. Deep learning algorithms allow in-depth exploration of imaging data to discover imaging features that may be predictive of recurrence. This study explored the use of convolutional neural networks (CNN) to predict HCC recurrence in patients with early-stage HCC from pre-treatment magnetic resonance (MR) images. This retrospective study included 120 patients with early-stage HCC. Pre-treatment MR images were fed into a machine learning pipeline (VGG16 and XGBoost) to predict recurrence within six different time frames (range 1-6 years). Model performance was evaluated with the area under the receiver operating characteristic curves (AUC-ROC). After prediction, the model's clinical relevance was evaluated using Kaplan-Meier analysis with recurrence-free survival (RFS) as the endpoint. Of 120 patients, 44 had disease recurrence after therapy. Six different models performed with AUC values between 0.71 to 0.85. In Kaplan-Meier analysis, five of six models obtained statistical significance when predicting RFS (log-rank p < 0.05). Our proof-of-concept study indicates that deep learning algorithms can be utilized to predict early-stage HCC recurrence. Successful identification of high-risk recurrence candidates may help optimize follow-up imaging and improve long-term outcomes post-treatment.
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Affiliation(s)
- Ahmet Said Kucukkaya
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, 330 Cedar Street, New Haven, CT, 06520-8042, USA
- Institute of Radiology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität, and Berlin Institute of Health, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Tal Zeevi
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, 330 Cedar Street, New Haven, CT, 06520-8042, USA
| | - Nathan Xianming Chai
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, 330 Cedar Street, New Haven, CT, 06520-8042, USA
| | - Rajiv Raju
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, 330 Cedar Street, New Haven, CT, 06520-8042, USA
| | - Stefan Philipp Haider
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, 330 Cedar Street, New Haven, CT, 06520-8042, USA
| | - Mohamed Elbanan
- Department of Diagnostic Radiology, Bridgeport Hospital, Yale New Haven Health System, 267 Grant Street, Bridgeport, CT, 06610, USA
| | - Alexandra Petukhova-Greenstein
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, 330 Cedar Street, New Haven, CT, 06520-8042, USA
- Institute of Radiology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität, and Berlin Institute of Health, Augustenburger Platz 1, 13353, Berlin, Germany
| | - MingDe Lin
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, 330 Cedar Street, New Haven, CT, 06520-8042, USA
- Visage Imaging, Inc., 12625 High Bluff Drive, Suite 205, San Diego, CA, 92130, USA
| | - John Onofrey
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, 330 Cedar Street, New Haven, CT, 06520-8042, USA
| | - Michal Nowak
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, 330 Cedar Street, New Haven, CT, 06520-8042, USA
| | - Kirsten Cooper
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, 330 Cedar Street, New Haven, CT, 06520-8042, USA
| | - Elizabeth Thomas
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, 330 Cedar Street, New Haven, CT, 06520-8042, USA
| | - Jessica Santana
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, 330 Cedar Street, New Haven, CT, 06520-8042, USA
| | - Bernhard Gebauer
- Institute of Radiology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität, and Berlin Institute of Health, Augustenburger Platz 1, 13353, Berlin, Germany
| | - David Mulligan
- Transplantation and Immunology, Department of Surgery, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06520, USA
| | - Lawrence Staib
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, 330 Cedar Street, New Haven, CT, 06520-8042, USA
| | - Ramesh Batra
- Transplantation and Immunology, Department of Surgery, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06520, USA
| | - Julius Chapiro
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, 330 Cedar Street, New Haven, CT, 06520-8042, USA.
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8
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Fuochi E, Anastasio L, Lynch EN, Campani C, Dragoni G, Milani S, Galli A, Innocenti T. Main factors influencing long-term outcomes of liver transplantation in 2022. World J Hepatol 2023; 15:321-352. [PMID: 37034235 PMCID: PMC10075010 DOI: 10.4254/wjh.v15.i3.321] [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: 10/18/2022] [Revised: 11/24/2022] [Accepted: 02/22/2023] [Indexed: 04/11/2023] Open
Abstract
Liver transplant (LT) outcomes have markedly improved in the recent decades, even if long-term morbidity and mortality are still considerable. Most of late deaths are independent from graft function and different comorbidities, including complications of metabolic syndrome and de novo neoplasms, seem to play a key role in determining long-term outcomes in LT recipients. This review discusses the main factors associated with late mortality and suggests possible strategies to improve long-term management and follow-up after liver transplantation. In particular, the reduction of drug toxicity, the use of tools to identify high-risk patients, and setting up a multidisciplinary team also for long-term management of LT recipients may further improve survival after liver transplantation.
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Affiliation(s)
- Elisa Fuochi
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
| | - Lorenzo Anastasio
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
| | - Erica Nicola Lynch
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
| | - Claudia Campani
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
| | - Gabriele Dragoni
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
- Department of Medical Biotechnologies, University of Siena, Siena 53100, Italy
| | - Stefano Milani
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
| | - Andrea Galli
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
| | - Tommaso Innocenti
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
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Bang K, Casadei‐Gardini A, Yoo C, Iavarone M, Ryu M, Park SR, Kim H, Yoon Y, Jung D, Park G, Ahn C, Moon D, Hwang S, Kim K, Song G, Mazzarelli C, Alimenti E, Chan SL, De Giorgio M, Ryoo B, Lee S. Efficacy and safety of lenvatinib in patients with recurrent hepatocellular carcinoma after liver transplantation. Cancer Med 2023; 12:2572-2579. [PMID: 36812124 PMCID: PMC9939097 DOI: 10.1002/cam4.5123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 07/20/2022] [Accepted: 07/28/2022] [Indexed: 11/06/2022] Open
Abstract
INTRODUCTION Lenvatinib is approved for the treatment of patients with metastatic or recurrent hepatocellular carcinoma (HCC); however, clinical outcomes of lenvatinib therapy in patients with post-liver transplantation (LT) HCC recurrence remain unclear. We investigated the efficacy and safety of lenvatinib in patients with post-LT HCC recurrence. METHODS This multinational, multicenter, retrospective study included 45 patients with recurrent HCC after LT who received lenvatinib at six institutions in three countries (Korea, Italy, and Hong Kong) from June 2017 to October 2021. RESULTS At the time of lenvatinib initiation, 95.6% (n = 43) of patients had Child-Pugh A status, and 35 (77.8%) and 10 (22.2%) participants were classified as having albumin-bilirubin (ALBI) grades 1 and 2, respectively. The objective response rate was 20.0%. With a median follow-up duration of 12.9 months (95% confidence interval [CI]: 11.2-14.7), the median progression-free survival and overall survival (OS) were 7.6 (95% CI: 5.3-9.8) months, and 14.5 (95% CI: 0.8-28.2) months, respectively. Patients with ALBI grade 1 showed significantly better OS (52.3 months, [95% CI: not assessable]) than patients with ALBI grade 2 (11.1 months [95% CI: 0.0-30.4 months], p = 0.003). The most common adverse events were hypertension (n = 25, 55.6%), fatigue (n = 17, 37.8%), and anorexia (n = 14, 31.1%). CONCLUSION Lenvatinib showed consistent efficacy and toxicity profiles in patients with post-LT HCC recurrence that were comparable to those reported from previous studies among non-LT HCC patients. The baseline ALBI grade correlated with better OS in post-LT lenvatinib-treated patients.
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Affiliation(s)
- Kyunghye Bang
- Department of Oncology, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulRepublic of Korea
- Division of Hemato‐Oncology, Department of Internal MedicineChung‐Ang University Gwangmyeong HospitalGwangmyeongRepublic of Korea
| | - Andrea Casadei‐Gardini
- Department of Medical OncologyVita‐Salute San Raffaele University, IRCCS San Raffaele Scientific InstituteMilanItaly
| | - Changhoon Yoo
- Department of Oncology, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulRepublic of Korea
| | - Massimo Iavarone
- Division of Gastroenterology and HepatologyFoundation IRCCS Ca' Granda Ospedale Maggiore PoliclinicoMilanItaly
| | - Min‐Hee Ryu
- Department of Oncology, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulRepublic of Korea
| | - Sook Ryun Park
- Department of Oncology, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulRepublic of Korea
| | - Hyung‐Don Kim
- Department of Oncology, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulRepublic of Korea
| | - Young‐In Yoon
- Division of Hepatobiliary Surgery and Liver TransplantationDepartment of Surgery, Asan Medical Center, University of Ulsan College of MedicineSeoulRepublic of Korea
| | - Dong‐Hwan Jung
- Division of Hepatobiliary Surgery and Liver TransplantationDepartment of Surgery, Asan Medical Center, University of Ulsan College of MedicineSeoulRepublic of Korea
| | - Gil‐Chun Park
- Division of Hepatobiliary Surgery and Liver TransplantationDepartment of Surgery, Asan Medical Center, University of Ulsan College of MedicineSeoulRepublic of Korea
| | - Chul‐Soo Ahn
- Division of Hepatobiliary Surgery and Liver TransplantationDepartment of Surgery, Asan Medical Center, University of Ulsan College of MedicineSeoulRepublic of Korea
| | - Deok‐Bog Moon
- Division of Hepatobiliary Surgery and Liver TransplantationDepartment of Surgery, Asan Medical Center, University of Ulsan College of MedicineSeoulRepublic of Korea
| | - Shin Hwang
- Division of Hepatobiliary Surgery and Liver TransplantationDepartment of Surgery, Asan Medical Center, University of Ulsan College of MedicineSeoulRepublic of Korea
| | - Ki‐Hun Kim
- Division of Hepatobiliary Surgery and Liver TransplantationDepartment of Surgery, Asan Medical Center, University of Ulsan College of MedicineSeoulRepublic of Korea
| | - Gi‐Won Song
- Division of Hepatobiliary Surgery and Liver TransplantationDepartment of Surgery, Asan Medical Center, University of Ulsan College of MedicineSeoulRepublic of Korea
| | - Chiara Mazzarelli
- Hepatology and Gastro‐Enterology UnitASST Ospedale NiguardaMilanItaly
| | - Eleonora Alimenti
- Division of Gastroenterology and HepatologyFoundation IRCCS Ca' Granda Ospedale Maggiore PoliclinicoMilanItaly
| | - Stephen L. Chan
- State Key Laboratory of Translational OncologyDepartment of Clinical Oncology, Sir YK Pao Centre for Cancer, The Chinese University of Hong KongHong Kong
| | - Massimo De Giorgio
- Department of GastroenterologyHepatology and Liver Transplantation, Papa Giovanni XXIII HospitalBergamoItaly
| | - Baek‐Yeol Ryoo
- Department of Oncology, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulRepublic of Korea
| | - Sung‐Gyu Lee
- Division of Hepatobiliary Surgery and Liver TransplantationDepartment of Surgery, Asan Medical Center, University of Ulsan College of MedicineSeoulRepublic of Korea
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10
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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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11
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Kayali S, Pasta A, Plaz Torres MC, Jaffe A, Strazzabosco M, Marenco S, Giannini EG. Immune checkpoint inhibitors in malignancies after liver transplantation: A systematic review and pooled analysis. Liver Int 2023; 43:8-17. [PMID: 36102312 PMCID: PMC10087158 DOI: 10.1111/liv.15419] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 08/13/2022] [Accepted: 09/06/2022] [Indexed: 01/04/2023]
Abstract
BACKGROUND AND AIMS Treatment of de novo malignancies and recurrent hepatocellular carcinoma with immune checkpoint inhibitors (ICI) in liver transplant recipients (LT) is an attractive strategy that is infrequently pursued because of the lack of strong evidence regarding their safety and efficacy. In this systematic review with pooled analysis, we aimed to assess safety and efficacy of ICI therapy following LT. METHODS We performed a systematic search of case reports and series published until January 2022. We included 31 publications reporting a total of 52 patients treated with ICIs after LT and assessed in a pooled analysis the risk of graft rejection and the outcome of ICI therapy. RESULTS Acute graft rejection occurred in 15 patients (28.8%) and 7 patients (13.4% of the total cohort) died because of graft loss. Rejection was associated with shorter overall survival (OS) (17.2 months, confidence interval [CI] 12.1-22.2 vs. 3.5 months, CI 1.6-5.4, p < 0.001). Disease control rate was 44.2% (n = 23), and in these patients, OS was longer than in non-responders (26.4 months, CI 20.8-32.0 vs. 3.4 months, CI 2.1-4.7, p < 0.001). CONCLUSIONS Observational, off-label experience suggests that treatment with ICI for advanced malignancies in LT recipients might not be discarded a priori. This notwithstanding, ICI treatment in these patients is associated with a substantial risk of graft rejection and mortality. Prospective studies are needed to provide adequate safety and efficacy figures of ICI treatment in this fragile population.
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Affiliation(s)
- Stefano Kayali
- Gastroenterology Unit, Department of Internal Medicine, IRCCS Ospedale Policlinico San Martino, University of Genoa, Genoa, Italy
| | - Andrea Pasta
- Gastroenterology Unit, Department of Internal Medicine, IRCCS Ospedale Policlinico San Martino, University of Genoa, Genoa, Italy
| | - Maria Corina Plaz Torres
- Gastroenterology Unit, Department of Internal Medicine, IRCCS Ospedale Policlinico San Martino, University of Genoa, Genoa, Italy
| | - Ariel Jaffe
- Liver Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.,Smilow Cancer Hospital and Liver Cancer Program, New Haven, Connecticut, USA
| | - Mario Strazzabosco
- Liver Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.,Smilow Cancer Hospital and Liver Cancer Program, New Haven, Connecticut, USA
| | - Simona Marenco
- Gastroenterology Unit, Department of Internal Medicine, IRCCS Ospedale Policlinico San Martino, University of Genoa, Genoa, Italy
| | - Edoardo G Giannini
- Gastroenterology Unit, Department of Internal Medicine, IRCCS Ospedale Policlinico San Martino, University of Genoa, Genoa, Italy
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12
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Tovoli F, Pallotta DP, Sansone V, Iavarone M, De Giorgio M, Ielasi L, Di Costanzo GG, Giuffrida P, Sacco R, Pressiani T, Di Donato MF, Trevisani F, Fagiuoli S, Piscaglia F, Granito A. Outcomes of Sorafenib for Recurrent Hepatocellular Carcinoma After Liver Transplantation in the Era of Combined and Sequential Treatments. Transplantation 2023; 107:156-161. [PMID: 35996072 DOI: 10.1097/tp.0000000000004271] [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: 02/07/2023]
Abstract
BACKGROUND Sorafenib and other tyrosine kinase inhibitors are the current standard of care for hepatocellular carcinoma (HCC) recurring after liver transplantation (LT). Sorafenib is sometimes regarded as a scarcely effective treatment in this setting because of some studies showing a short overall survival (OS) indirectly compared with historical series of nontransplanted patients. Additional data from multicenter prospective studies are needed before drawing definite conclusions. METHODS Retrospective analyses of a large prospective multicenter dataset of sorafenib-treated HCC patients to report the characteristics and outcomes of LT recipients (n = 81). RESULTS At the baseline, LT patients had key prognostic features (high prevalence of metastatic disease, and low prevalence of macrovascular invasion, α-fetoprotein >400 ng/mL, ALBI grade >1, performance status >0) that differentiated them from the typical populations of non-LT patient reported in clinical trials and observational studies. Moreover, a relevant proportion of LT patients received concurrent locoregional (12.3%) and postprogression systemic treatments (34.2%), resulting in a median OS of 18.7 mo. CONCLUSIONS Multimodal and sequential treatments are relatively frequent in post-LT HCC patients and contribute to a remarkable OS, together with favorable baseline characteristics. Despite the impossibility of matching with non-LT patients, our results indirectly suggest that the metastatic nature of post-LT recurrence and concurrent antirejection regimens should not discourage systemic treatments.
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Affiliation(s)
- Francesco Tovoli
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italia
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Dante Pio Pallotta
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italia
| | - Vito Sansone
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italia
| | - Massimo Iavarone
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, Milan, Italy
| | - Massimo De Giorgio
- Gastroenterology, Hepatology and Transplantation Unit, Department of Specialty and Transplant Medicine, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
| | - Luca Ielasi
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italia
| | | | - Paolo Giuffrida
- Gastroenterology, Hepatology and Transplantation Unit, Department of Specialty and Transplant Medicine, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
- Section of Gastroenterology and Hepatology, Department of Health Promotion Sciences Maternal and Infant Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, Palermo, Italy
| | - Rodolfo Sacco
- Gastroenterology Unit, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
- Gastroenterology and Digestive Endoscopy Unit, Foggia University Hospital, Foggia, Italy
| | - Tiziana Pressiani
- Medical Oncology and Hematology Unit, Humanitas Clinical and Research Center, IRCCS Humanitas Research Hospital, Rozzano (Milan), Italy
| | - Maria Francesca Di Donato
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, Milan, Italy
| | - Franco Trevisani
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italia
- Semeiotica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italia
| | - Stefano Fagiuoli
- Gastroenterology, Hepatology and Transplantation Unit, Department of Specialty and Transplant Medicine, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
- Department of Medicine and Surgery, University of Milan, Bicocca
| | - Fabio Piscaglia
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italia
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Alessandro Granito
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italia
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
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13
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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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14
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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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15
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Au KP, Fung JYY, Dai WC, Chan ACY, Lo CM, Chok KSH. Verifying the Benefits of Radical Treatment in Posttransplant Hepatocellular Carcinoma Oligo-recurrence: A Propensity Score Analysis. Liver Transpl 2022; 28:51-64. [PMID: 34351682 DOI: 10.1002/lt.26251] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 07/22/2021] [Accepted: 08/03/2021] [Indexed: 12/13/2022]
Abstract
This study verified whether radical treatment for hepatocellular carcinoma (HCC) oligo-recurrence after liver transplantation conveys survival benefits. A retrospective study of 144 patients with posttransplant HCC recurrence was performed. Propensity score matching was performed to adjust for baseline covariates between patients who received radical and palliative treatments. The primary endpoint was postrecurrence survival. A total of 50 patients (35%) received radical treatment for recurrence, and 76 (53%) and 18 (13%) patients received palliative and supportive treatments, respectively. Compared with the radical group, patients who received palliative treatment had more early recurrences (time from transplant 17 versus 11 months; P = 0.01) and more extensive disease in terms of tumor numbers (1 versus 4; P < 0.001), size of largest tumor (1.8 versus 2.5 cm; P = 0.046), numbers of involved organs (interquartile range [IQR], 1-1 versus 1-2; P = 0.02), and alpha-fetoprotein (AFP) level (7 versus 40 ng/mL; P = 0.01). Multivariate Cox regression analysis revealed that early recurrence (time from transplant hazard ratio [HR], 1.02; 95% confidence interval [CI], 1.01-1.03; P = 0.001), larger recurrent tumor (HR, 1.12; 95% CI, 1.03-1.23; P = 0.01), liver recurrence (HR, 1.84; 95% CI, 1.17-2.90; P = 0.01), and log10 AFP level at recurrence (HR, 1.27; 95% CI, 1.07-1.52; P = 0.01) predicted poor survival. Mammalian target of rapamycin inhibitor (HR, 0.331; 95% CI, 0.213-0.548; P < 0.001) and radical treatment (HR, 0.342; 95% CI, 0.213-0.548; P < 0.001) were associated with improved survival. After 2-to-1 propensity score matching for covariates, the 50 patients who received curative treatment survived significantly longer than the 25 matched patients who received palliative treatment (median survival time, 30.9 ± 2.4 versus 19.5 ± 3.0 months; P = 0.01). Radical treatment conveys survival benefits to HCC oligo-recurrence after liver transplantation.
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Affiliation(s)
- Kin Pan Au
- Department of Surgery, Queen Mary Hospital, Hong Kong, China
| | - James Yan Yue Fung
- Department of Surgery and State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China
| | - Wing Chiu Dai
- Department of Surgery and State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China
| | - Albert Chi Yan Chan
- Department of Surgery and State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China
| | - Chung Mau Lo
- Department of Surgery and State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China
| | - Kenneth Siu Ho Chok
- Department of Surgery and State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China
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16
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Al-Ameri A, Yu X, Zheng S. Predictors of post-recurrence survival in hepatocellular carcinoma patients following liver transplantation: Systematic review and meta-analysis. Transplant Rev (Orlando) 2021; 36:100676. [PMID: 34999555 DOI: 10.1016/j.trre.2021.100676] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 12/12/2021] [Accepted: 12/14/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND Data on predictors of post-recurrence survival (PRS) of recurrent hepatocellular carcinoma (HCC) after liver transplantation (LT) have not been reviewed and analysed systematically. We aimed to systematically analyse all published data on the predictors for PRS. METHODS In accordance with PRISMA and MOOSE guidelines, online search of PubMed and EMBASE databases was done for all reports that evaluate the predictors of PRS based on multivariate analyses. Cumulative analyses of hazard ratios (HRs) and their corresponding 95% CIs were conducted to assess the potential predictors of PRS. RESULTS Twenty-three studies met the inclusion criteria. Among the 11,868 patients involved, 1921 (16%) had HCC recurrence within a median time of 16 months. The following were recurrence and tumour-related predictors: time to recurrence (<1 year; HR: 1.97; p < 0.001), AFP level at recurrence(≥100 ng/ml; HR: 1.82; p < 0.001), multiple recurrence (HR: 1.22; p < 0.001), bone recurrence (HR: 2.10; p < 0.001), poor differentiation (HR: 1.52; p < 0.001), intrahepatic recurrence (HR: 0.91; p = 0.03), extrahepatic recurrence (HR: 1.87; p < 0.001), Milan criteria at LT (HR: 1.34; p < 0.001), microvascular invasion (HR: 1.59; p < 0.001), multiorgan recurrence (HR: 1.28; p < 0.001), and recurrent HCV infection (HR: 1.21; p < 0.001). The treatment-related predictors were as follows: surgical resection (HR: 0.33; p < 0.001), mTOR inhibitors (HR: 0.63; p < 0.001), sorafenib (HR: 1.00; p = 0.01), palliative treatment (HR: 3.07; p < 0.001), RFA (HR: 0.47; p < 0.001), and radiotherapy (HR: 1.19; p < 0.001). CONCLUSIONS Systematic evaluation of these predictors could guide surgeons to design risk-adapted algorithms for the management of post-LT HCC recurrence to construct reliable predictive models and to design future prospective studies or clinical trials.
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Affiliation(s)
- Abdulahad Al-Ameri
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; NHC Key Laboratory of Combined Multi-organ Transplantation, China; Key Laboratory of the diagnosis and treatment of organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences, China; Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Zhejiang Province, Hangzhou 310003, China
| | - Xiaobo Yu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; NHC Key Laboratory of Combined Multi-organ Transplantation, China; Key Laboratory of the diagnosis and treatment of organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences, China; Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Zhejiang Province, Hangzhou 310003, China
| | - Shusen Zheng
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; NHC Key Laboratory of Combined Multi-organ Transplantation, China; Key Laboratory of the diagnosis and treatment of organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences, China; Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Zhejiang Province, Hangzhou 310003, China.
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17
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Decraecker M, Toulouse C, Blanc JF. Is There Still a Place for Tyrosine Kinase Inhibitors for the Treatment of Hepatocellular Carcinoma at the Time of Immunotherapies? A Focus on Lenvatinib. Cancers (Basel) 2021; 13:6310. [PMID: 34944930 PMCID: PMC8699782 DOI: 10.3390/cancers13246310] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 12/12/2021] [Accepted: 12/14/2021] [Indexed: 02/08/2023] Open
Abstract
The systemic treatment of hepatocellular carcinoma is changing rapidly. Three main classes of treatment are now available. Historically, multi-targeted tyrosine kinase inhibitors (TKIs) (sorafenib and lenvatinib as first-line; regorafenib and cabozantinib as second-line) were the first to show an improvement in overall survival (OS). Anti-vascular endothelial growth factor (anti-VEGF) antibodies can be used in first-line (bevacizumab) or second-line (ramucirumab) combination therapy. More recently, immuno-oncology (IO) has profoundly changed therapeutic algorithms, and the combination of atezolizumab-bevacizumab is now the first-line standard of care. Therefore, the place of TKIs needs to be redefined. The objective of this review was to define the place of TKIs in the therapeutic algorithm at the time of IO treatment in first-line therapy, with a special focus on lenvatinib that exhibits one of the higher anti-tumoral activity among TKI in HCC. We will discuss the place of lenvatinib in first line (especially if there is a contra-indication to IO) but also after failure of atezolizumab and bevacizumab. New opportunities for lenvatinib will also be presented, including the use at an earlier stage of the disease and combination with IOs.
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Affiliation(s)
- Marie Decraecker
- Department of Oncology, Hospital Haut Leveque-CHU Bordeaux, Avenue Magellan, 33604 Pessac, France; (C.T.); (J.-F.B.)
| | - Caroline Toulouse
- Department of Oncology, Hospital Haut Leveque-CHU Bordeaux, Avenue Magellan, 33604 Pessac, France; (C.T.); (J.-F.B.)
| | - Jean-Frédéric Blanc
- Department of Oncology, Hospital Haut Leveque-CHU Bordeaux, Avenue Magellan, 33604 Pessac, France; (C.T.); (J.-F.B.)
- INSERM U1053, BaRITOn, University Victor Segalen, 146 Rue Léo Saignat, 33000 Bordeaux, France
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18
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Au KP, Chok KSH. Immunotherapy after liver transplantation: Where are we now? World J Gastrointest Surg 2021; 13:1267-1278. [PMID: 34754394 PMCID: PMC8554723 DOI: 10.4240/wjgs.v13.i10.1267] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Revised: 03/25/2021] [Accepted: 08/04/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND There is limited evidence on the safety of immunotherapy use after liver transplantation and its efficacy in treating post-liver transplant hepatocellular carcinoma (HCC) recurrence.
AIM To assess the safety of immunotherapy after liver transplant and its efficacy in treating post-liver transplant HCC recurrence.
METHODS A literature review was performed to identify patients with prior liver transplantation and subsequent immunotherapy. We reviewed the rejection rate and risk factors of rejection. In patients treated for HCC, the oncological outcomes were evaluated including objective response rate, progression-free survival (PFS), and overall survival (OS).
RESULTS We identified 25 patients from 16 publications and 3 patients from our institutional database (total n = 28). The rejection rate was 32% (n = 9). Early mortality occurred in 21% (n = 6) and was mostly related to acute rejection (18%, n = 5). Patients who developed acute rejection were given immunotherapy earlier after transplantation (median 2.9 years vs 5.3 years, P = 0.02) and their graft biopsies might be more frequently programmed death ligand-1-positive (100% vs 33%, P = 0.053). Their PFS (1.0 ± 0.1 mo vs 3.5 ± 1.1 mo, P = 0.02) and OS (1.0 ± 0.1 mo vs 19.2 ± 5.5 mo, P = 0.001) compared inferiorly to patients without rejection. Among the 19 patients treated for HCC, the rejection rate was 32% (n = 6) and the overall objective response rate was 11%. The median PFS and OS were 2.5 ± 1.0 mo and 7.3 ± 2.7 mo after immunotherapy.
CONCLUSION Rejection risk is the major obstacle to immunotherapy use in liver transplant recipients. Further studies on the potential risk factors of rejection are warranted.
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Affiliation(s)
- Kin Pan Au
- Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Kenneth Siu Ho Chok
- Department of Surgery and State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China
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19
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Au KP, Chok KSH. Immunotherapy after liver transplantation: Where are we now? World J Gastrointest Surg 2021. [DOI: 10.4240/wjgs.v13.i10.1266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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20
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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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21
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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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22
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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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23
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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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24
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Ho CM, Lee CH, Lee MC, Zhang JF, Chen CH, Wang JY, Hu RH, Lee PH. Survival After Treatable Hepatocellular Carcinoma Recurrence in Liver Recipients: A Nationwide Cohort Analysis. Front Oncol 2021; 10:616094. [PMID: 33598433 PMCID: PMC7883828 DOI: 10.3389/fonc.2020.616094] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Accepted: 12/11/2020] [Indexed: 12/15/2022] Open
Abstract
Background Survival after post-transplant recurrence of HCC is dismal, and almost all treatments for recurrent HCC are off-labeled, without an extensive large-scale analysis. We aimed to delineate their post-recurrence courses and define benchmarks for comparing future treatment effectiveness. Methods Three national databases, including health insurance, catastrophic illness, and the cause of death, were linked for cohort establishment and data collection during the period from 2005 to 2016. Patients with HCC recurrence ≥6 months after transplant surgery and under treatment were recruited for survival analysis. Selection of treatment strategies for HCC recurrence after liver transplant was based on the same criteria for those without liver transplant. Results Of 2,123 liver transplant recipients, 349 developed HCC recurrence ≥6 months after liver transplant, and the median recurrence time was 17.8 months post-transplant. Within 2 years of treatment, 61% patients showed recurrence (early recurrence group), and survival in these patients was poorer than in the late recurrence group. According to a multivariable analysis, the transplant era before 2008 and radiofrequency ablation were associated with good prognosis, whereas receiving sorafenib and radiotherapy was associated with poor prognosis. The effect of transplant era became insignificant after stratification by recently receiving pretransplant transarterial chemoembolization. Conclusion Timing of recurrence and interventions used were associated with the outcomes of patients with post-transplant HCC recurrence. These data provide the benchmark and indicate the critical period and high-risk factors for further therapeutic trial consideration.
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Affiliation(s)
- Cheng-Maw Ho
- Department of Surgery, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
| | - Chih-Hsin Lee
- Division of Pulmonary Medicine and Pulmonary Research Center, Wanfang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Ming-Chia Lee
- Department of Pharmacy, New Taipei City Hospital, New Taipei City, Taiwan.,School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Jun-Fu Zhang
- Biostatistics Center, College of Management, Taipei Medical University, Taipei, Taiwan.,Big Data Center, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan, Taiwan
| | - Chin-Hua Chen
- Biostatistics Center, College of Management, Taipei Medical University, Taipei, Taiwan.,Graduate Institute of Data Science, College of Management, Taipei Medical University, Taipei, Taiwan.,Department of Medical Education and Research, Wanfang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Jann-Yuan Wang
- Department of Internal Medicine, National Taiwan University Hospital, and College of Medicine, Taipei, Taiwan
| | - Rey-Heng Hu
- Department of Surgery, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
| | - Po-Huang Lee
- Department of Surgery, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
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25
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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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26
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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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27
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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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Posttransplant Management of Recipients Undergoing Liver Transplantation for Hepatocellular Carcinoma. Working Group Report From the ILTS Transplant Oncology Consensus Conference. Transplantation 2020; 104:1143-1149. [PMID: 32217940 DOI: 10.1097/tp.0000000000003196] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Although liver transplantation (LT) is the best treatment for patients with localized hepatocellular carcinoma (HCC), recurrence occurs in 6%-18% of patients. Several factors, particularly morphological criteria combined with dynamic parameters, known before LT modify this risk and combined in prediction models may be used to stratify patients at need of variable surveillance strategies. Additional variables though likely explain differences in recurrence rates in patients with the same pre-LT HCC status. One of these variables is possibly immunosuppression (IS). Once recurrence takes place, management is highly heterogenous. Within the International Liver Transplantation Society Consensus Conference on Liver Transplant Oncology, working group 4 aim was to analyze the data regarding posttransplant management of recipients undergoing LT for HCC. Three areas of research were considered: (1) cancer prediction models and surveillance strategies; (2) tailored IS for cancer recipients; and (3) new adjuvant therapies for HCC recurrence. Following formulation of several questions, a literature search was undertaken with abstract review followed by article retrieval and full-data extraction. The grading of recommendations assessment, development and evaluation (GRADE) system was used for evidence rating incorporating strength of recommendation and quality of evidence.
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Schwartz G, Darling JO, Mindo M, Damicis L. Management of Adverse Events Associated with Cabozantinib Treatment in Patients with Advanced Hepatocellular Carcinoma. Target Oncol 2020; 15:549-565. [PMID: 32770441 PMCID: PMC7434721 DOI: 10.1007/s11523-020-00736-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Cabozantinib is an oral multikinase inhibitor whose targets include vascular endothelial growth factor receptors, MET, and the TAM family of kinases (TYRO3, AXL, MER). Cabozantinib is approved for patients with advanced hepatocellular carcinoma who have been previously treated with sorafenib, based on improved overall survival and progression-free survival relative to placebo in the phase III CELESTIAL study. During CELESTIAL, the most common adverse events (AEs) experienced by patients receiving cabozantinib included palmar-plantar erythrodysesthesia, fatigue, gastrointestinal-related events, and hypertension. These AEs can significantly impact treatment tolerability and patient quality of life. However, AEs can be effectively managed with supportive care and dose modifications. During CELESTIAL, more than half of the patients receiving cabozantinib required a dose reduction, while the rate of treatment discontinuation due to AEs was low. Here, we review the safety profile of cabozantinib and provide guidance on the prevention and management of the more common AEs, based on current evidence from the literature as well as our clinical experience. We consider the specific challenges faced by clinicians in treating this patient population and discuss factors that may affect exposure and tolerability to cabozantinib.
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Affiliation(s)
- Gabriel Schwartz
- Gastrointestinal Medical Oncology Clinic, University of California San Francisco, 1825 Fourth St, Fourth Floor, San Francisco, CA, 94158, USA.
| | | | - Malori Mindo
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Lucia Damicis
- IRCCS Istituto Clinico Humanitas, Rozzano, Milan, Italy
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30
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31
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The Authors' Reply. Transplantation 2020; 104:e244. [PMID: 32732857 DOI: 10.1097/tp.0000000000003229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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32
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Chagas AL, Mattos AAD, Carrilho FJ, Bittencourt PL, Vezozzo DCP, Horvat N, Rocha MDS, Alves VAF, Coral GP, Alvares-DA-Silva MR, Barros FMDR, Menezes MR, Monsignore LM, Coelho FF, Silva RFD, Silva RDCMA, Boin IDFSF, D Albuquerque LAC, Garcia JHP, Felga GEG, Moreira AM, Braghiroli MIFM, Hoff PMG, Mello VBD, Dottori MF, Branco TP, Schiavon LDL, Costa TDFA. BRAZILIAN SOCIETY OF HEPATOLOGY UPDATED RECOMMENDATIONS FOR DIAGNOSIS AND TREATMENT OF HEPATOCELLULAR CARCINOMA. ARQUIVOS DE GASTROENTEROLOGIA 2020; 57:1-20. [PMID: 32294682 DOI: 10.1590/s0004-2803.202000000-20] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 12/19/2019] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. The Brazilian Society of Hepatology (SBH) published in 2015 its first recommendations about the management of HCC. Since then, new data have emerged in the literature, prompting the governing board of SBH to sponsor a single-topic meeting in August 2018 in São Paulo. All the invited experts were asked to make a systematic review of the literature reviewing the management of HCC in subjects with cirrhosis. After the meeting, all panelists gathered together for the discussion of the topics and the elaboration of updated recommendations. The text was subsequently submitted for suggestions and approval of all members of the Brazilian Society of Hepatology through its homepage. The present manuscript is the final version of the reviewed manuscript containing the recommendations of SBH.
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Affiliation(s)
- Aline Lopes Chagas
- Universidade de São Paulo, Faculdade de Medicina, Hospital das Clínicas, São Paulo, SP, Brasil.,Universidade de São Paulo, Instituto do Câncer do Estado de São Paulo, São Paulo, SP, Brasil
| | - Angelo Alves de Mattos
- Universidade Federal de Ciências da Saúde de Porto Alegre e Irmandade da Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, RS, Brasil
| | - Flair José Carrilho
- Universidade de São Paulo, Faculdade de Medicina, Hospital das Clínicas, São Paulo, SP, Brasil.,Universidade de São Paulo, Instituto do Câncer do Estado de São Paulo, São Paulo, SP, Brasil
| | | | | | | | - Natally Horvat
- Universidade de São Paulo, Faculdade de Medicina, Hospital das Clínicas, São Paulo, SP, Brasil.,Hospital Sírio-Libanês, São Paulo, SP, Brasil
| | - Manoel de Souza Rocha
- Universidade de São Paulo, Faculdade de Medicina, Hospital das Clínicas, São Paulo, SP, Brasil
| | - Venâncio Avancini Ferreira Alves
- Universidade de São Paulo, Faculdade de Medicina, Hospital das Clínicas, São Paulo, SP, Brasil.,Universidade de São Paulo, Instituto do Câncer do Estado de São Paulo, São Paulo, SP, Brasil
| | - Gabriela Perdomo Coral
- Universidade Federal de Ciências da Saúde de Porto Alegre e Irmandade da Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, RS, Brasil
| | | | | | - Marcos Roberto Menezes
- Universidade de São Paulo, Faculdade de Medicina, Hospital das Clínicas, São Paulo, SP, Brasil.,Universidade de São Paulo, Instituto do Câncer do Estado de São Paulo, São Paulo, SP, Brasil.,Hospital Sírio-Libanês, São Paulo, SP, Brasil
| | - Lucas Moretti Monsignore
- Universidade de São Paulo, Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto, São Paulo, SP, Brasil
| | | | - Renato Ferreira da Silva
- Faculdade de Medicina de São José do Rio Preto (FAMERP) e Hospital de Base de São José do Rio Preto (FUNFARME), São José do Rio Preto, SP, Brasil
| | - Rita de Cássia Martins Alves Silva
- Faculdade de Medicina de São José do Rio Preto (FAMERP) e Hospital de Base de São José do Rio Preto (FUNFARME), São José do Rio Preto, SP, Brasil
| | | | | | | | | | - Airton Mota Moreira
- Universidade de São Paulo, Faculdade de Medicina, Hospital das Clínicas, São Paulo, SP, Brasil.,Universidade de São Paulo, Instituto do Câncer do Estado de São Paulo, São Paulo, SP, Brasil
| | | | - Paulo Marcelo Gehm Hoff
- Universidade de São Paulo, Instituto do Câncer do Estado de São Paulo, São Paulo, SP, Brasil
| | | | | | - Tiago Pugliese Branco
- Universidade de São Paulo, Instituto do Câncer do Estado de São Paulo, São Paulo, SP, Brasil
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López Ortega S, González Grande R, Santaella Leiva I, De la Cruz Lombardo J, Jiménez Pérez M. Efficacy and Safety of Sorafenib After Liver Transplantation: Experience in Our Center. Transplant Proc 2020; 52:540-542. [PMID: 32057495 DOI: 10.1016/j.transproceed.2019.12.016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 11/26/2019] [Accepted: 12/26/2019] [Indexed: 01/10/2023]
Abstract
Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) is increasing, with a consequent impact on survival. Here we report our experience with sorafenib to treat HCC recurrence after LT. PATIENTS AND METHODS: We undertook a retrospective cohort study of LT patients with recurrent HCC. RESULTS: The study included 12 patients with recurrent HCC after LT between January 2008 and March 2019; 9 were men and 3 women, with a median age of 58 years. Adverse effects were manageable in most patients with symptomatic treatment or with sorafenib dose adjustment. Stable disease was the best response and was achieved. Eight patients (66.7%) died during the study period, 5 (62.5%) due to tumor progression and 3 (37.5%) because of sepsis. The median survival time was 7.5 months.
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Affiliation(s)
- S López Ortega
- UGC Aparato Digestivo, Liver Unit, Regional University Hospital, Malaga, Spain.
| | - R González Grande
- UGC Aparato Digestivo, Liver Unit, Regional University Hospital, Malaga, Spain
| | - I Santaella Leiva
- UGC Aparato Digestivo, Liver Unit, Regional University Hospital, Malaga, Spain
| | | | - M Jiménez Pérez
- UGC Aparato Digestivo, Liver Unit, Regional University Hospital, Malaga, Spain
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Verna EC, Patel YA, Aggarwal A, Desai AP, Frenette C, Pillai AA, Salgia R, Seetharam A, Sharma P, Sherman C, Tsoulfas G, Yao FY. Liver transplantation for hepatocellular carcinoma: Management after the transplant. Am J Transplant 2020; 20:333-347. [PMID: 31710773 DOI: 10.1111/ajt.15697] [Citation(s) in RCA: 96] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 10/03/2019] [Accepted: 10/21/2019] [Indexed: 02/05/2023]
Abstract
Hepatocellular carcinoma (HCC) is an increasingly common indication for liver transplantation (LT) in the United States and in many parts of the world. In the last decade, significant work has been done to better understand how to risk stratify LT candidates for recurrence of HCC following transplant using a combination of biomarker and imaging findings. However, despite the high frequency of HCC in the LT population, guidance regarding posttransplant management is lacking. In particular, there is no current evidence to support specific post-LT surveillance strategies, leading to significant heterogeneity in practices. In addition, there are no current recommendations regarding recurrence prevention, including immunosuppression regimen or secondary prevention with adjuvant chemotherapy. Finally, guidance on treatment of disease recurrence is also lacking and there is significant controversy about the use of immunotherapy in transplant recipients due to the risk of rejection. Thus, outcomes for patients with recurrence are poor. This paper therefore provides a comprehensive review of the current literature on post-LT management of patients with HCC and identifies gaps in our current knowledge that are in urgent need of further investigation.
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Affiliation(s)
- Elizabeth C Verna
- Center for Liver Disease and Transplantation, Columbia University, New York, New York, USA
| | - Yuval A Patel
- Division of Gastroenterology, Department of Medicine, Duke University, Durham, North Carolina, USA
| | - Avin Aggarwal
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Arizona College of Medicine, Tuscon, Arizona, USA
| | - Archita P Desai
- Division of Gastroenterology, Department of Medicine, Indiana University, Indianapolis, Indiana, USA
| | - Catherine Frenette
- Scripps Center for Organ Transplantation, Scripps Green Hospital, La Jolla, California, USA
| | - Anjana A Pillai
- Center for Liver Diseases, University of Chicago Medicine, Chicago, Illinois, USA
| | - Reena Salgia
- Department of Gastroenterology/Hepatology, Henry Ford Hospital, Detroit, Michigan, USA
| | - Anil Seetharam
- Transplant Hepatology, University of Arizona College of Medicine, Phoenix, Arizona, USA
| | - Pratima Sharma
- Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Courtney Sherman
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, California, USA
| | - Georgios Tsoulfas
- Department of Surgery, Aristotle University School of Medicine, Thessaloniki, Greece
| | - Francis Y Yao
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, California, USA
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35
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36
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Xu X, Chen J, Wei Q, Liu ZK, Yang Z, Zhang M, Wang GY, Gao J, Yang ZX, Guo WY, Xing TH, Shao Z, Xie QF, Zheng SS. Clinical practice guidelines on liver transplantation for hepatocellular carcinoma in China (2018 edition). Hepatobiliary Pancreat Dis Int 2019; 18:307-312. [PMID: 31279679 DOI: 10.1016/j.hbpd.2019.06.010] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Accepted: 06/11/2019] [Indexed: 02/05/2023]
Affiliation(s)
- Xiao Xu
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
| | - Jun Chen
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Qiang Wei
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Zhi-Kun Liu
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Zhe Yang
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Ming Zhang
- Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Guo-Ying Wang
- Department of Hepatic Surgery, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China
| | - Jie Gao
- Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing 100044, China
| | - Zhao-Xu Yang
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi'an 710032, China
| | - Wen-Yuan Guo
- Department of Liver Surgery and Organ Transplantation, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Tong-Hai Xing
- General Surgery Center, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, China
| | - Zhou Shao
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Qin-Fen Xie
- Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital, Hangzhou 310004, China
| | - Shu-Sen Zheng
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
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37
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Sanduzzi-Zamparelli M, Díaz-Gonzalez Á, Reig M. New Systemic Treatments in Advanced Hepatocellular Carcinoma. Liver Transpl 2019; 25:311-322. [PMID: 30317696 DOI: 10.1002/lt.25354] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Accepted: 10/07/2018] [Indexed: 12/28/2022]
Abstract
The principal advancements in the treatment of hepatocellular carcinoma (HCC) are the use of new systemic treatments, such as lenvatinib in first-line treatment and regorafenib, cabozantinib, and ramucirumab in second-line treatment, because of their benefits in terms of overall survival. In addition, nivolumab as a second-line agent was approved by the US Food and Drug Administration in 2017 based on improved radiological response data. Physicians and patients alike will greatly benefit from this expanded arsenal of treatments once all these new drugs for the treatment of HCC finally become available. Unfortunately, in our review of the available data, we found a conspicuous lack of approved systemic treatments for HCC in the distinct setting of after liver transplantation (LT). Careful evaluation of the clinical trials for approved systemic treatments of HCC is crucial when considering the best options for those with HCC recurrence after LT. Although several first-line or second-line treatments have been shown to be effective for HCC, each of these trials was composed of its own specific populations, and those with HCC recurrence after LT were excluded. We have also summarized from a critical and clinical point of view the issues involved in the management of patients who are candidates for systemic treatment in this era of multiple drugs for the same indication.
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Affiliation(s)
- Marco Sanduzzi-Zamparelli
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clinic Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Álvaro Díaz-Gonzalez
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clinic Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - María Reig
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clinic Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
- Centro de Investigación Médica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
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38
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Au KP, Chok KSH. Multidisciplinary approach for post-liver transplant recurrence of hepatocellular carcinoma: A proposed management algorithm. World J Gastroenterol 2018; 24:5081-5094. [PMID: 30568386 PMCID: PMC6288653 DOI: 10.3748/wjg.v24.i45.5081] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Revised: 10/21/2018] [Accepted: 11/07/2018] [Indexed: 02/06/2023] Open
Abstract
A large number of liver transplants have been performed for hepatocellular carcinoma (HCC), and recurrence is increasingly encountered. The recurrence of HCC after liver transplantation is notoriously difficult to manage. We hereby propose multi-disciplinary management with a systematic approach. The patient is jointly managed by the transplant surgeon, physician, oncologist and radiologist. Immunosuppressants should be tapered to the lowest effective dose to protect against rejection. The combination of a mammalian target of rapamycin inhibitor with a reduced calcineurin inhibitor could be considered with close monitoring of graft function and toxicity. Comprehensive staging can be performed by dual-tracer positron emission tomography-computed tomography or the combination of contrast computed tomography and a bone scan. In patients with disseminated recurrence, sorafenib confers survival benefits but is associated with significant drug toxicity. Oligo-recurrence encompasses recurrent disease that is limited in number and location so that loco-regional treatments convey disease control and survival benefits. Intra-hepatic recurrence can be managed with graft resection, but significant operative morbidity is expected. Radiofrequency ablation and stereotactic body radiation therapy (SBRT) are effective alternative strategies. In patients with more advanced hepatic disease, regional treatment with trans-arterial chemoembolization or intra-arterial Yttrium-90 can be considered. For patients with extra-hepatic oligo-recurrence, loco-regional treatment can be considered if practical. Patients with more than one site of recurrence are not always contraindicated for curative treatments. Surgical resection is effective for patients with pulmonary oligo-recurrence, but adequate lung function is a pre-requisite. SBRT is a non-invasive and effective modality that conveys local control to pulmonary and skeletal oligo-recurrences.
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Affiliation(s)
- Kin Pan Au
- Department of Surgery, Queen Mary Hospital, Hong Kong, China
| | - Kenneth Siu Ho Chok
- Department of Surgery and State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China
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39
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40
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Ravaioli M, Cucchetti A, Pinna AD, De Pace V, Neri F, Barbera MA, Maroni L, Frega G, Palloni A, De Lorenzo S, Ripoli MC, Pantaleo MA, Cescon M, Del Gaudio M, Brandi G. The role of metronomic capecitabine for treatment of recurrent hepatocellular carcinoma after liver transplantation. Sci Rep 2017; 7:11305. [PMID: 28900245 PMCID: PMC5595852 DOI: 10.1038/s41598-017-11810-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Accepted: 08/14/2017] [Indexed: 12/17/2022] Open
Abstract
The management of recurrent hepatocellular carcinoma untreatable with surgical options is based on systemic therapy with sorafenib. Due to the high rates of adverse events connected to the therapy with sorafenib, metronomic capecitabine seems a promising strategy for these patients. We analyzed the data of 38 patients with hepatocellular carcinoma recurrent after liver transplantation performed at our center. We compared the outcome of 17 patients receiving metronomic capecitabine versus 20 patients experiencing best supportive care and versus the data of the literature about treatment with sorafenib. In the group treated with metronomic capecitabine we observed an increased survival after tumor recurrence at the univariate and multivariate analysis compared to the group of best supportive care (median 22 months vs. 7 months, p < 0.01). Data from the literature on the use of sorafenib showed outcomes like our study group, with similar patient and tumoral features. The episodes of acute rejection and the tumor stage at the recurrence showed a correlation with patient survival at the univariate analysis. The metronomic capecitabine for hepatocellular cancer recurrent after liver transplantation seems effective without important adverse events and comparable results to sorafenib.
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Affiliation(s)
- Matteo Ravaioli
- Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, Alma Mater Studiorum, University of Bologna, V. Massarenti 9, 40138, Bologna, Italy.
| | - Alessandro Cucchetti
- Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, Alma Mater Studiorum, University of Bologna, V. Massarenti 9, 40138, Bologna, Italy
| | - Antonio Daniele Pinna
- Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, Alma Mater Studiorum, University of Bologna, V. Massarenti 9, 40138, Bologna, Italy
| | - Vanessa De Pace
- Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, Alma Mater Studiorum, University of Bologna, V. Massarenti 9, 40138, Bologna, Italy
| | - Flavia Neri
- Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, Alma Mater Studiorum, University of Bologna, V. Massarenti 9, 40138, Bologna, Italy
| | - Maria Aurelia Barbera
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), S. Orsola-Malpighi Hospital, Alma Mater Studiorum, Bologna University, V. Massarenti 9, 40138, Bologna, Italy
| | - Lorenzo Maroni
- Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, Alma Mater Studiorum, University of Bologna, V. Massarenti 9, 40138, Bologna, Italy
| | - Giorgio Frega
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), S. Orsola-Malpighi Hospital, Alma Mater Studiorum, Bologna University, V. Massarenti 9, 40138, Bologna, Italy
| | - Andrea Palloni
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), S. Orsola-Malpighi Hospital, Alma Mater Studiorum, Bologna University, V. Massarenti 9, 40138, Bologna, Italy
| | - Stefania De Lorenzo
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), S. Orsola-Malpighi Hospital, Alma Mater Studiorum, Bologna University, V. Massarenti 9, 40138, Bologna, Italy
| | - Maria Cristina Ripoli
- Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, Alma Mater Studiorum, University of Bologna, V. Massarenti 9, 40138, Bologna, Italy
| | - Maria Abbondanza Pantaleo
- "G. Prodi" Interdepartmental Center for Cancer Research (C.I.R.C.), University of Bologna, V. Massarenti 9, 40138, Bologna, Italy
| | - Matteo Cescon
- Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, Alma Mater Studiorum, University of Bologna, V. Massarenti 9, 40138, Bologna, Italy
| | - Massimo Del Gaudio
- Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, Alma Mater Studiorum, University of Bologna, V. Massarenti 9, 40138, Bologna, Italy
| | - Giovanni Brandi
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), S. Orsola-Malpighi Hospital, Alma Mater Studiorum, Bologna University, V. Massarenti 9, 40138, Bologna, Italy
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41
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Mancuso A, Maringhini A. Management of hepatocellular carcinoma recurrence after liver transplant is far from perfect. Am J Surg 2017; 216:389-390. [PMID: 28454660 DOI: 10.1016/j.amjsurg.2017.04.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Accepted: 04/05/2017] [Indexed: 02/07/2023]
Affiliation(s)
- Andrea Mancuso
- Medicina Interna 1, Azienda di Rilievo Nazionale ad Alta Specializzazione Civico - Di Cristina - Benfratelli, Piazzale Leotta 4, 90100, Palermo, Italy.
| | - Alberto Maringhini
- Medicina Interna 1, Azienda di Rilievo Nazionale ad Alta Specializzazione Civico - Di Cristina - Benfratelli, Piazzale Leotta 4, 90100, Palermo, Italy
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42
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Mancuso A. Management of hepatocellular carcinoma in thalassemia and importance of the human factor. Cancer 2017; 123:1071-1072. [PMID: 28085196 DOI: 10.1002/cncr.30551] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Accepted: 12/16/2016] [Indexed: 12/26/2022]
Affiliation(s)
- Andrea Mancuso
- Internal Medicine 1, Azienda di Rilievo Nazionale e di Alta Specializzazione, Civico di Cristina Benfratelli, Palermo, Italy.,Hepatology and Gastroenterology, Niguarda Cà Granda Hospital, Milan, Italy
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43
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de'Angelis N, Landi F, Nencioni M, Palen A, Lahat E, Salloum C, Compagnon P, Lim C, Costentin C, Calderaro J, Luciani A, Feray C, Azoulay D. Role of Sorafenib in Patients With Recurrent Hepatocellular Carcinoma After Liver Transplantation. Prog Transplant 2016; 26:348-355. [PMID: 27555074 DOI: 10.1177/1526924816664083] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
CONTEXT The management of hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) is challenging, especially if it is not treatable by surgery or embolization. OBJECTIVES The present study aims to compare the survival rates of liver transplanted patients receiving sorafenib or best supportive care (BSC) for HCC recurrence not amenable to curative intent treatments. DESIGN This is a retrospective comparative study on a prospectively maintained database. PARTICIPANTS Liver transplanted patients with untreatable HCC recurrence receiving BSC (n = 18) until 2007 or sorafenib (n = 15) thereafter were compared. RESULTS No group difference was observed for demographic characteristics at the time of transplantation and at the time of HCC recurrence. On the explant pathology of the native liver, 81.2% patients were classified within the Milan criteria, and 53.1% presented with microvascular invasion. Hepatocellular carcinoma recurrence was diagnosed 17.8 months (standard deviation: 14.5) after LT, with 17 (53.1%) patients presenting with early recurrence (≤12 months). The 1-year survival from untreatable progression of HCC recurrence was 23.9% for the BSC and 60% for the sorafenib group ( P = .002). The type of treatment (sorafenib vs BSC) was the sole independent predictor of survival (hazard ratio: 2.98; 95% confidence interval: 1.09-8.1; P = .033). In the sorafenib group, 8 (53.3%) patients required dose reduction, and 2 (13.3%) patients discontinued the treatment due to intolerable side effects. CONCLUSION Sorafenib improves survival and is superior to the BSC in cases of untreatable posttransplant hepatocellular carcinoma recurrence.
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Affiliation(s)
- Nicola de'Angelis
- 1 Department of HPB Surgery and Liver Transplantation, Henri-Mondor Hospital, Université Paris Est-UPEC, Créteil, France
| | - Filippo Landi
- 1 Department of HPB Surgery and Liver Transplantation, Henri-Mondor Hospital, Université Paris Est-UPEC, Créteil, France
| | - Marco Nencioni
- 1 Department of HPB Surgery and Liver Transplantation, Henri-Mondor Hospital, Université Paris Est-UPEC, Créteil, France
| | - Anais Palen
- 1 Department of HPB Surgery and Liver Transplantation, Henri-Mondor Hospital, Université Paris Est-UPEC, Créteil, France
| | - Eylon Lahat
- 1 Department of HPB Surgery and Liver Transplantation, Henri-Mondor Hospital, Université Paris Est-UPEC, Créteil, France
| | - Chady Salloum
- 1 Department of HPB Surgery and Liver Transplantation, Henri-Mondor Hospital, Université Paris Est-UPEC, Créteil, France
| | - Philippe Compagnon
- 1 Department of HPB Surgery and Liver Transplantation, Henri-Mondor Hospital, Université Paris Est-UPEC, Créteil, France
| | - Chetana Lim
- 1 Department of HPB Surgery and Liver Transplantation, Henri-Mondor Hospital, Université Paris Est-UPEC, Créteil, France
| | - Charlotte Costentin
- 2 Department of Hepatology, Henri-Mondor Hospital, Université Paris Est-UPEC, Créteil, France
| | - Julien Calderaro
- 3 Department of Pathology, Henri-Mondor Hospital, Université Paris Est-UPEC, Créteil, France.,4 INSERM Unit UMR1162, Créteil, France
| | - Alain Luciani
- 5 Department of Radiology and Medical Imaging, Henri-Mondor Hospital, Université Paris Est-UPEC, Créteil, France.,6 INSERM Unit 955, Créteil, France
| | - Cyrille Feray
- 2 Department of Hepatology, Henri-Mondor Hospital, Université Paris Est-UPEC, Créteil, France.,6 INSERM Unit 955, Créteil, France
| | - Daniel Azoulay
- 1 Department of HPB Surgery and Liver Transplantation, Henri-Mondor Hospital, Université Paris Est-UPEC, Créteil, France.,6 INSERM Unit 955, Créteil, France
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Xie ZR, Luo YL, Xiao FM, Liu Q, Ma Y. Health-related quality of life of patients with intermediate hepatocellular carcinoma after liver resection or transcatheter arterial chemoembolization. Asian Pac J Cancer Prev 2016; 16:4451-6. [PMID: 26028113 DOI: 10.7314/apjcp.2015.16.10.4451] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND The aim of our present study was to compare quality of life (QoL) between intermediate-stage (BCLC-B) HCC patients who had undergone either liver resection or transcatheter arterial chemoembolization (TACE). MATERIALS AND METHODS A total of 102 intermediate-stage HCC patients participated in our study, including 58 who had undergone liver resection and 44 who had undergone TACE. Baseline demographic characteristics, tumor characteristics, and long-term outcomes, such as tumor recurrence, were compared and analyzed. QoL was assessed using the Short Form (SF)-36 health survey questionnaire with the mental and physical component scales (SF-36 MCS and PCS). This questionnaire was filled out at HCC diagnosis and 1, 3, 6, 12, 24 months after surgery. RESULTS For the preoperative QoL evaluation, the 8 domains related to QoL were comparable between the two groups. The PCS and MCS scores were significantly decreased in both the TACE and resection groups at1 month after surgery, and this decrease was greater in the resection group. These scores were significantly lower in the resection group compared with the TACE group (P<0.05). However, these differences disappeared at 3 and 6 months following surgery. One year after surgery, the resection group showed much higher PCS scores than the TACE patients (P=0.018), and at 2 years after surgery, the PCS and MCS scores for the resection group were significantly higher than those for the TACE group (P<0.05). Eleven patients (19.0%) in the resection group and 17 (38.6%) in the TACE group suffered HCC recurrence (P<0.05). Univariate and multivariate analyses indicated that tumor recurrence (HR=1.211, 95%CI: 1.086-1.415, P=0.012) was a significant risk factor for poorpostoperative QoL in the HCC patients. CONCLUSIONS Due to its effects on reducing HCC recurrence and improving long-term QoL, liver resection should be the first choice for the treatment of patients with intermediate-stage HCC.
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Affiliation(s)
- Z R Xie
- Liver Surgery, West China Hospital, Sichuan University, Chengdu, China E-mail :
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Zhai H, Liang P, Yu XL, Cheng Z, Han ZY, Liu F, Yu J. Microwave ablation in treating intrahepatic recurrence of hepatocellular carcinoma after liver transplantation: An analysis of 11 cases. Int J Hyperthermia 2015; 31:863-8. [DOI: 10.3109/02656736.2015.1091953] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
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Mazzola A, Costantino A, Petta S, Bartolotta TV, Raineri M, Sacco R, Brancatelli G, Cammà C, Cabibbo G. Recurrence of hepatocellular carcinoma after liver transplantation: an update. Future Oncol 2015; 11:2923-36. [PMID: 26414336 DOI: 10.2217/fon.15.239] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Liver transplantation is the only curative alternative for selected patients with hepatocellular carcinoma (HCC) who are not eligible for resection and/or with decompensated cirrhosis. According to Milan criteria the 5-year survival rate is 70-85%, with a recurrence-free survival of 75%. However, HCC recurrence rate after liver transplantation remains a significant problem in the clinical practice. The prognosis in patients with HCC recurrence is poor. The treatment of choice for HCC recurrence is surgery, but it seems that a systemic treatment based on combination of an mTOR inhibitor with sorafenib can be used. Data on safety and efficacy are limited, clinical monitoring is necessary. The aim of this review is to underline the main concerns, pitfalls and warnings for these patients.
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Affiliation(s)
- Alessandra Mazzola
- Section of Gastroenterology - Di.Bi.M.I.S., University of Palermo, Palermo, Italy.,Unité Médicale de Transplantation Hépatique AP-HP, Hôpital Pitié-Salpêtrière, UPMC Paris, Paris, France
| | - Andrea Costantino
- Section of Gastroenterology - Di.Bi.M.I.S., University of Palermo, Palermo, Italy
| | - Salvatore Petta
- Section of Gastroenterology - Di.Bi.M.I.S., University of Palermo, Palermo, Italy
| | | | - Maurizio Raineri
- Section of Anesthesiology, Analgesia, Intensive Care & Emergency, Department of Biopathology, Medical & Forensic Biotechnologies (DIBIMEF), Policlinico 'P Giaccone', University of Palermo, Palermo, Italy
| | - Rodolfo Sacco
- Gastroenterology Unit, Cisanello Hospital, Pisa, Italy
| | | | - Calogero Cammà
- Section of Gastroenterology - Di.Bi.M.I.S., University of Palermo, Palermo, Italy
| | - Giuseppe Cabibbo
- Section of Gastroenterology - Di.Bi.M.I.S., University of Palermo, Palermo, Italy
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