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Zhang X, Chen C, Wang Y, Xu J. Recurrence risk prediction models for hepatocellular carcinoma after liver transplantation. J Gastroenterol Hepatol 2024; 39:2272-2280. [PMID: 39113259 DOI: 10.1111/jgh.16693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 07/05/2024] [Accepted: 07/17/2024] [Indexed: 12/06/2024]
Abstract
Liver transplantation (LT) is an effective method for curing hepatocellular carcinoma (HCC). However postoperative tumor recurrence can lead to higher mortality rates. To select suitable candidates for LT, the Milan Criteria (MC) were first proposed based on tumor morphological characteristics. For those patients who meet the MC, the MC can effectively reduce the postoperative tumor recurrence rate and improve the prognosis of patients undergoing LT. It has always been internationally recognized as the gold standard for selecting candidates for LT, marking a milestone in the history of LT for HCC. However, its strict conditions exclude some HCC patients who could benefit from LT. Therefore, comprehension consideration criteria, including serum biomarkers, tumor histology, and other factor, have been continuously proposed in addition to tumor morphology. This article summaries the prediction model for HCC recurrence after LT from five aspects: tumor morphology, serum markers, histopathology, cellular inflammatory factors and downstaging treatment before transplantation. The aim is to assist clinicians in accurately assessing HCC status, selecting appropriate liver transplant candidates, maximize graft and patients' survival, and optimizing the utilization of social health resources.
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Affiliation(s)
- Xu Zhang
- Academy of Medical Sciences, Shanxi Medical University, Taiyuan, China
| | - Chi Chen
- Department of Statistics, School of Public Health, Shanxi Medical University, Taiyuan, China
| | - Yan Wang
- Hepatobiliary and Pancreatic Surgery and Liver Transplantation Center, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Jun Xu
- Hepatobiliary and Pancreatic Surgery and Liver Transplantation Center, First Hospital of Shanxi Medical University, Taiyuan, China
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Barreto SG, Strasser SI, McCaughan GW, Fink MA, Jones R, McCall J, Munn S, Macdonald GA, Hodgkinson P, Jeffrey GP, Jaques B, Crawford M, Brooke-Smith ME, Chen JW. Expansion of Liver Transplantation Criteria for Hepatocellular Carcinoma from Milan to UCSF in Australia and New Zealand and Justification for Metroticket 2.0. Cancers (Basel) 2022; 14:2777. [PMID: 35681757 PMCID: PMC9179466 DOI: 10.3390/cancers14112777] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 05/24/2022] [Accepted: 05/29/2022] [Indexed: 12/12/2022] Open
Abstract
Background: Expansion in liver transplantation (LT) criteria for HCC from Milan to UCSF has not adversely impacted overall survival, prompting further expansion towards Metroticket 2.0 (MT2). In this study, we compared patient survival post-transplant before and after 2007 and long-term outcomes for LT within Milan versus UCSF criteria (to determine the true benefit of the expansion of criteria) and retrospectively validated the MT2 criteria. Methods: Retrospective analysis of ANZLITR (including all patients transplanted for HCC since July 1997). The entire cohort was divided based on criteria used at the time of listing, namely, Milan era (1997−2006) and the UCSF era (2007−July 2015). Results: The overall 5- and 10-year cumulative survival rates for the entire cohort of 691 patients were 78% and 69%, respectively. Patients transplanted in UCSF era had significantly higher 5- and 10-year survival rates than in the Milan era (80% vs. 73% and 72% vs. 65%, respectively; p = 0.016). In the UCSF era, the 5-year survival rate for patients transplanted within Milan criteria was significantly better than those transplanted outside Milan but within UCSF criteria (83% vs. 73%; p < 0.024). Patients transplanted within the MT2 criteria had a significantly better 5- and 10-year survival rate as compared to those outside the criteria (81% vs. 64% and 73% vs. 50%, respectively; p = 0.001). Conclusion: Overall survival following LT for HCC has significantly improved over time despite expanding criteria from Milan to UCSF. Patients fulfilling the MT2 criteria have a survival comparable to the UCSF cohort. Thus, expansion of criteria to MT2 is justifiable.
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Affiliation(s)
- Savio G. Barreto
- South Australia Liver Transplant Unit, Flinders Medical Centre, Adelaide, SA 5042, Australia; (S.G.B.); (M.E.B.-S.)
| | - Simone I. Strasser
- Australian National Liver Transplant Unit, Royal Prince Alfred Hospital, University of Sydney, Sydney, NSW 2050, Australia; (S.I.S.); (G.W.M.); (M.C.)
| | - Geoffrey W. McCaughan
- Australian National Liver Transplant Unit, Royal Prince Alfred Hospital, University of Sydney, Sydney, NSW 2050, Australia; (S.I.S.); (G.W.M.); (M.C.)
| | - Michael A. Fink
- Austin Health, Heidelberg, VIC 3081, Australia; (M.A.F.); (R.J.)
- Department of Surgery, The University of Melbourne, Melbourne, VIC 3010, Australia
| | - Robert Jones
- Austin Health, Heidelberg, VIC 3081, Australia; (M.A.F.); (R.J.)
| | - John McCall
- Auckland City Hospital, Auckland 1023, New Zealand; (J.M.); (S.M.)
| | - Stephen Munn
- Auckland City Hospital, Auckland 1023, New Zealand; (J.M.); (S.M.)
| | - Graeme A. Macdonald
- Queensland Liver Transplant Service, Princess Alexandra Hospital, Woolloongabba, QLD 4102, Australia; (G.A.M.); (P.H.)
| | - Peter Hodgkinson
- Queensland Liver Transplant Service, Princess Alexandra Hospital, Woolloongabba, QLD 4102, Australia; (G.A.M.); (P.H.)
| | - Gary P. Jeffrey
- Sir Charles Gairdner Hospital, Nedlands, WA 6009, Australia; (G.P.J.); (B.J.)
| | - Bryon Jaques
- Sir Charles Gairdner Hospital, Nedlands, WA 6009, Australia; (G.P.J.); (B.J.)
| | - Michael Crawford
- Australian National Liver Transplant Unit, Royal Prince Alfred Hospital, University of Sydney, Sydney, NSW 2050, Australia; (S.I.S.); (G.W.M.); (M.C.)
| | - Mark E. Brooke-Smith
- South Australia Liver Transplant Unit, Flinders Medical Centre, Adelaide, SA 5042, Australia; (S.G.B.); (M.E.B.-S.)
| | - John W. Chen
- South Australia Liver Transplant Unit, Flinders Medical Centre, Adelaide, SA 5042, Australia; (S.G.B.); (M.E.B.-S.)
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Lozanovski VJ, Ramouz A, Aminizadeh E, Al-Saegh SAH, Khajeh E, Probst H, Picardi S, Rupp C, Chang DH, Probst P, Mehrabi A. Prognostic role of selection criteria for liver transplantation in patients with hepatocellular carcinoma: a network meta-analysis. BJS Open 2022; 6:zrab130. [PMID: 35211739 PMCID: PMC8874238 DOI: 10.1093/bjsopen/zrab130] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 10/27/2021] [Accepted: 11/07/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Patients with hepatocellular carcinoma (HCC) are selected for transplantation if they have a low tumour burden and low risk of recurrence. The morphometric Milan criteria have been the cornerstone for patient selection, but dynamic morphological and biological tumour characteristics surfaced as an encouraging tool to refine the selection of patients with HCC and to support the expansion of the Milan criteria. The outcomes of the most prevalent models that select patients with HCC for liver transplantation were analysed in this study, which aimed to identify the selection model that offered the best recurrence-free and overall survival after transplantation. METHODS Studies that compared Milan, University of California San Francisco (UCSF), up-to-seven (UPTS), alpha-fetoprotein (AFP), and MetroTicket 2.0 (MT2) models were included. One-year, 3-year, and 5-year recurrence-free and overall survival rates of patients selected for transplantation using different models were analysed. RESULTS A total of 60 850 adult patients with HCC selected for liver transplantation using Milan, UCSF, UPTS, AFP, or MT2 criteria were included. Patients selected for transplantation using the MT2 model had the highest 1-, 3-, and 5-year recurrence-free survival. In addition, patients selected for transplantation using MT2 criteria had the best 1- and 3-year overall survival, whereas patients selected for transplantation using the Milan criteria had the best 5-year overall survival rates. CONCLUSION The MT2 model offered the best post-transplant outcomes in patients with HCC, highlighting the importance of considering tumour morphology and biology when selecting patients with HCC for liver transplantation.
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Affiliation(s)
- Vladimir J Lozanovski
- Department of General, Visceral and Transplant Surgery, University Hospital Heidelberg, Heidelberg, Germany
- Liver Cancer Center Heidelberg (LCCH), University Hospital Heidelberg, Heidelberg, Germany
| | - Ali Ramouz
- Department of General, Visceral and Transplant Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Ehsan Aminizadeh
- Department of General, Visceral and Transplant Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Sadeq Ali-Hasan Al-Saegh
- Department of General, Visceral and Transplant Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Elias Khajeh
- Department of General, Visceral and Transplant Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Heike Probst
- Department of General, Visceral and Transplant Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Susanne Picardi
- Department of Anesthesiology, University Hospital Heidelberg, Heidelberg, Germany
| | - Christian Rupp
- Liver Cancer Center Heidelberg (LCCH), University Hospital Heidelberg, Heidelberg, Germany
- Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany
| | - De-Hua Chang
- Liver Cancer Center Heidelberg (LCCH), University Hospital Heidelberg, Heidelberg, Germany
- Department of Radiology, University Hospital Heidelberg, Heidelberg, Germany
| | - Pascal Probst
- Department of General, Visceral and Transplant Surgery, University Hospital Heidelberg, Heidelberg, Germany
- The Study Center of the German Surgical Society (SDGC), University Hospital Heidelberg, Heidelberg, Germany
| | - Arianeb Mehrabi
- Department of General, Visceral and Transplant Surgery, University Hospital Heidelberg, Heidelberg, Germany
- Liver Cancer Center Heidelberg (LCCH), University Hospital Heidelberg, Heidelberg, Germany
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Muhammad H, Tehreem A, Ting PS, Gurakar M, Li SY, Simsek C, Alqahtani SA, Kim AK, Kohli R, Gurakar A. Hepatocellular Carcinoma and the Role of Liver Transplantation: A Review. J Clin Transl Hepatol 2021; 9:738-748. [PMID: 34722189 PMCID: PMC8516838 DOI: 10.14218/jcth.2021.00125] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/01/2021] [Accepted: 05/18/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer deaths worldwide and liver transplantation (LT) is the only potentially curative treatment. Over the years, Milan criteria has been used for patient selection. There is ongoing research in this field with introduction of new biomarkers for HCC that can help guide future treatment. Furthermore, newer therapies for downstaging of the tumor are being implemented to prevent dropout from the transplant list. In addition, combination therapies for better outcome are under investigation. Interestingly, the concept of living-donor LT and possible use of hepatitis C virus-positive donors has been implemented as an attempt to expand the organ pool. However, there is a conflict of opinion between different centers regarding its efficacy and data is scarce. The aim of this review article is to outline the various selection criteria for LT, discuss the outcomes of LT in HCC patients, and explore future directions of LT for HCC. Therefore, a comprehensive PubMed/MEDLINE review was conducted. To expand our search, references of the retrieved articles were also screened for additional data. After selecting the studies, the authors independently reviewed them to identify the relevant studies. After careful evaluation 120 studies relevant to out topic are cited in the manuscript. Three tables and two figures are also included. In conclusion LT for HCC has evolved over the years. With the introduction of several expanded criteria beyond Milan, the introduction of bridging therapies, such as transcatheter arterial chemoembolization and radiofrequency ablation, and the approval of newer systemic therapies, it is evident that there will be more LT recipients in the future. It is promising to see ongoing trials and the continuous evolution of protocols. Prospective studies are needed to guide the development of a pre-LT criteria that can ensure low HCC recurrence risk and is not overly stringent, clarify the role of LDLT, and determine the optimal bridging therapies to LT.
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Affiliation(s)
- Haris Muhammad
- Department of Internal Medicine, Greater Baltimore Medical Center, MD, USA
| | - Aniqa Tehreem
- Department of Internal Medicine, Sinai Hospital, Baltimore, MD, USA
| | - Peng-Sheng Ting
- Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Merve Gurakar
- Department of Medicine, Osler Residency Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | | | - Cem Simsek
- Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Saleh A. Alqahtani
- Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Amy K. Kim
- Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ruhail Kohli
- Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ahmet Gurakar
- Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Correspondence to: Ahmet Gurakar, Section of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross Research Building, Suite 918 Baltimore, MD 21205, USA. ORCID: https://orcid.org/0000-0002-2221-9148. Tel: +1-410-614-3369, Fax: +1-443-683-8349, E-mail:
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An FDG PET/CT metabolic parameter-based nomogram for predicting the early recurrence of hepatocellular carcinoma after liver transplantation. Eur J Nucl Med Mol Imaging 2021; 48:3656-3665. [PMID: 33813592 DOI: 10.1007/s00259-021-05328-w] [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: 01/02/2021] [Accepted: 03/21/2021] [Indexed: 12/25/2022]
Abstract
PURPOSE To construct an FDG PET/CT metabolic parameter-based model to predict early recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT). METHODS A total of 62 patients with HCC after LT were enrolled with a follow-up period of 1 year. Basic clinical, pathology, and laboratory data, CT features (CPLC), and PET metabolic parameters (CPLCP) were collected for model construction. A CPLC nomogram without metabolic parameters and a CPLCP nomogram with metabolic parameters were established. The net reclassification index (NRI) and integrated discrimination improvement (IDI) of the two models were calculated. The constructed model was compared with Milan criteria and University of California San Francisco (UCSF) criteria. The time-dependent area under the receiver operating characteristic curve (time-AUC) was used to compare the efficiency of the models, and the bootstrap method was used to for verification. Harrell's concordance index (C-index) was used to evaluate the performance of these models. Decision curve analysis (DCA) was used to evaluate the clinical practicability of each model. RESULTS Thirty out of 62 patients experienced a recurrence during the 1-year follow-up. BCLC stage (P = 0.009), MVI (P = 0.032), AFP (P = 0.004), CTdmax (P = 0.033), and MTV (P = 0.039) were the independent predictors. The CPLC nomogram and the CPLCP nomogram were established. Compared with the CPLC nomogram, the NRI of the CPLCP nomogram increased by 38.98% (95% CI = -18.77-60.43%) and the IDI increased by 4.40% (95% CI = -1.00-16.62%). The AUC value of the CPLCP nomogram was higher than those of Milan criteria and UCSF criteria in the time-AUC curve. Moreover, the CPLCP nomogram had a higher C-index (0.774) than other models. Finally, the DCA curve showed that clinical practicability of the CPLCP nomogram outperformed the Milan criteria and UCSF criteria. CONCLUSIONS The CPLCP nomogram combining basic clinical data, pathology data, laboratory data, CT features, and PET metabolic parameters showed good efficacy and high clinical practicability in predicting the early recurrence of HCC after LT.
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6
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Meischl T, Rasoul-Rockenschaub S, Győri G, Scheiner B, Trauner M, Soliman T, Berlakovich G, Pinter M. Alpha-fetoprotein-adjusted-to-HCC-size criteria are associated with favourable survival after liver transplantation for hepatocellular carcinoma. United European Gastroenterol J 2021; 9:209-219. [PMID: 32741316 PMCID: PMC8259374 DOI: 10.1177/2050640620948665] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 07/15/2020] [Indexed: 12/24/2022] Open
Abstract
Background The Milan criteria are recommended to select hepatocellular carcinoma (HCC) patients for liver transplantation (LT). The utility of other selection criteria, such as the alpha‐fetoprotein‐adjusted‐to‐HCC‐size (AFP‐UTS) criteria, is still unclear. Objective We investigated, in HCC patients who underwent LT, the survival and the recurrence after LT according to AFP‐UTS and Milan criteria, the impact of early recurrence and the correlation between radiological and pathological staging. Methods Adult HCC patients undergoing deceased donor LT at the Medical University of Vienna between 1997 and 2014 were retrospectively analysed. Results Among 166 patients included, the number of patients who fulfilled Milan or AFP‐UTS criteria was the same (139 [84%] each), although not all of them were the same individuals; 127 patients (77%) fulfilled both Milan and AFP‐UTS criteria. Median overall survival of patients within AFP‐UTS was 126.9 versus 34.2 months outside AFP‐UTS (5‐year survival rate 71% vs. 43%; p = 0.104). The 5‐year recurrence rate was significantly lower in patients fulfilling the AFP‐UTS criteria (18%) than in those exceeding AFP‐UTS (64%; p < 0.001). Of the 139 patients within Milan criteria on imaging, 24 (17%) had microvascular invasion and 47 (34%) were outside Milan according to explant histology. Early recurrence correlated with AFP‐UTS and was associated with dismal survival (median overall survival 17.2 vs. 122.1 months, p = 0.002). Conclusions The overall survival of patients within AFP‐UTS criteria was favourable with a 5‐year survival rate above 70%. Early recurrence is associated with worse survival after LT. The AFP‐UTS criteria may be more suitable to exclude patients at high risk of (early) recurrence than Milan criteria.
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Affiliation(s)
- Tobias Meischl
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.,Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria
| | | | - Georg Győri
- Division of Transplantation, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - Bernhard Scheiner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.,Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Thomas Soliman
- Division of Transplantation, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - Gabriela Berlakovich
- Division of Transplantation, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - Matthias Pinter
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.,Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria
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7
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Victor DW, Monsour HP, Boktour M, Lunsford K, Balogh J, Graviss EA, Nguyen DT, McFadden R, Divatia MK, Heyne K, Ankoma-Sey V, Egwim C, Galati J, Duchini A, Saharia A, Mobley C, Gaber AO, Ghobrial RM. Outcomes of Liver Transplantation for Hepatocellular Carcinoma Beyond the University of California San Francisco Criteria: A Single-center Experience. Transplantation 2020; 104:113-121. [PMID: 31233480 DOI: 10.1097/tp.0000000000002835] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the most common primary malignant liver tumor. Currently, liver transplantation may be the optimal treatment for HCC in cirrhotic patients. Patient selection is currently based on tumor size. We developed a program to offer liver transplantation to selected patients with HCC outside of traditional criteria. METHODS Retrospective review for patients transplanted with HCC between April 2008 and June 2017. Patients were grouped by tumor size according to Milan, University of California San Francisco (UCSF), and outside UCSF criteria. Patient demographics, laboratory values, and outcomes were compared. Patients radiographically outside Milan criteria were selected based on tumor control with locoregional therapy (LRT) and 9 months of stability from LRT. α-fetoprotein values were not exclusionary. RESULTS Two hundred twenty HCC patients were transplanted, 138 inside Milan, 23 inside UCSF, and 59 beyond UCSF criteria. Patient survival was equivalent at 1, 3, or 5 years despite pathologic tumor size. Waiting time to transplantation was not significantly different at an average of 344 days. In patients outside UCSF, tumor recurrence was equivalent to Milan and UCSF criteria recipients who waited >9 months from LRT. Although tumor recurrence was more likely in outside of UCSF patients (3% versus 9% versus 15%; P = 0.02), recurrence-free survival only trended toward significance among the groups (P = 0.053). CONCLUSIONS Selective patients outside of traditional size criteria can be effectively transplanted with equivalent survival to patients with smaller tumors, even when pathologic tumor burden is considered. Tumor stability over time can be used to help select patients for transplantation.
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Affiliation(s)
- David W Victor
- Houston Methodist Hospital, Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston, TX
| | - Howard P Monsour
- Houston Methodist Hospital, Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston, TX
| | - Maha Boktour
- Houston Methodist Hospital, Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston, TX
| | - Keri Lunsford
- Houston Methodist Hospital, Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston, TX
| | - Julius Balogh
- Department of Anesthesia, University of Texas Health Science Center at Houston, Houston, TX
| | | | - Duc T Nguyen
- Department of Anesthesia, University of Texas Health Science Center at Houston, Houston, TX
| | - Robert McFadden
- Houston Methodist Hospital, Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston, TX
| | | | - Kirk Heyne
- The Methodist Hospital Research Institute, Houston, TX
| | - Victor Ankoma-Sey
- Houston Methodist Hospital, Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston, TX
| | - Chukwuma Egwim
- Houston Methodist Hospital, Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston, TX
| | - Joseph Galati
- Houston Methodist Hospital, Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston, TX
| | - Andrea Duchini
- Houston Methodist Hospital, Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston, TX
| | - Ashish Saharia
- Houston Methodist Hospital, Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston, TX
| | - Constance Mobley
- Houston Methodist Hospital, Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston, TX
| | - A Osama Gaber
- Houston Methodist Hospital, Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston, TX
| | - R Mark Ghobrial
- Houston Methodist Hospital, Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston, TX
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Lai Q, Vitale A, Manzia TM, Foschi FG, Levi Sandri GB, Gambato M, Melandro F, Russo FP, Miele L, Viganò L, Burra P, Giannini EG. Platelets and Hepatocellular Cancer: Bridging the Bench to the Clinics. Cancers (Basel) 2019; 11:1568. [PMID: 31618961 PMCID: PMC6826649 DOI: 10.3390/cancers11101568] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2019] [Revised: 10/10/2019] [Accepted: 10/14/2019] [Indexed: 02/06/2023] Open
Abstract
Growing interest is recently being focused on the role played by the platelets in favoring hepatocellular cancer (HCC) growth and dissemination. The present review reports in detail both the experimental and clinical evidence published on this topic. Several growth factors and angiogenic molecules specifically secreted by platelets are directly connected with tumor progression and neo-angiogenesis. Among them, we can list the platelet-derived growth factor, the vascular endothelial growth factor, the endothelial growth factor, and serotonin. Platelets are also involved in tumor spread, favoring endothelium permeabilization and tumor cells' extravasation and survival in the bloodstream. From the bench to the clinics, all of these aspects were also investigated in clinical series, showing an evident correlation between platelet count and size of HCC, tumor biological behavior, metastatic spread, and overall survival rates. Moreover, a better understanding of the mechanisms involved in the platelet-tumor axis represents a paramount aspect for optimizing both current tumor treatment and development of new therapeutic strategies against HCC.
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Affiliation(s)
- Quirino Lai
- Department of General Surgery and Organ Transplantation, Umberto I Hospital, Sapienza University, 00161 Rome, Italy.
| | - Alessandro Vitale
- Department of Surgery, Oncology, and Gastroenterology, University of Padua, 35122 Padua, Italy.
| | - Tommaso M Manzia
- Department of Transplant Surgery, Polyclinic Tor Vergata Foundation, Tor Vergata University, 00133 Rome, Italy.
| | - Francesco G Foschi
- Department of Internal Medicine, Ospedale per gli Infermi di Faenza, 48018 Faenza, Italy.
| | | | - Martina Gambato
- Department of Surgery, Oncology, and Gastroenterology, University of Padua, 35122 Padua, Italy.
| | - Fabio Melandro
- Hepatobiliary Surgery and Liver Transplantation Unit, University of Pisa Medical School Hospital, 56126 Pisa, Italy.
| | - Francesco P Russo
- Department of Surgery, Oncology, and Gastroenterology, University of Padua, 35122 Padua, Italy.
| | - Luca Miele
- Internal Medicine, Gastroenterology and Liver Unit, A. Gemelli Polyclinic, Sacro Cuore Catholic University, 20123 Rome, Italy.
| | - Luca Viganò
- Division of Hepatobiliary and General Surgery, Department of Surgery, Humanitas Clinical and Research Center, Rozzano, 20089 Milan, Italy.
| | - Patrizia Burra
- Department of Surgery, Oncology, and Gastroenterology, University of Padua, 35122 Padua, Italy.
| | - Edoardo G Giannini
- Gastroenterology Unit, Department of Internal Medicine, Università di Genova, IRCCS-Ospedale Policlinico San Martino, 16132 Genoa, Italy.
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9
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Meischl T, Rasoul-Rockenschaub S, Györi G, Sieghart W, Reiberger T, Trauner M, Soliman T, Berlakovich G, Pinter M. C-reactive protein is an independent predictor for hepatocellular carcinoma recurrence after liver transplantation. PLoS One 2019; 14:e0216677. [PMID: 31141535 PMCID: PMC6541257 DOI: 10.1371/journal.pone.0216677] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2019] [Accepted: 04/26/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Serum C-reactive protein (CRP) is a prognostic factor for overall survival (OS) and recurrence of hepatocellular carcinoma (HCC) in patients treated with resection or non-surgical treatment. Here, we investigated the association of elevated CRP (≥1 vs. <1 mg/dL) with (i) recurrence of HCC and (ii) OS after liver transplantation (LT). METHODS Adult HCC patients undergoing orthotopic deceased donor LT at the Medical University of Vienna between 1997 and 2014 were retrospectively analysed. RESULTS Among 216 patients included, 132 (61.1%) were transplanted within the Milan criteria and forty-two patients (19.4%) had microvascular invasion on explant histology. Seventy patients (32.4%) showed elevated CRP (≥ 1 mg/dL). On multivariate analysis, a CRP ≥ 1 mg/dL was an independent risk factor for HCC recurrence with a 5-year recurrence rate of 27.4% vs. 16.4% (HR 2.33; 95% CI 1.13-4.83; p = 0.022). OS was similar in patients with normal vs. elevated CRP levels. CONCLUSIONS Elevated serum CRP is associated with HCC recurrence after LT and may be a marker for more aggressive tumor biology. Future studies should evaluate whether patients with elevated pre-transplant CRP levels benefit from closer monitoring for HCC recurrence.
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Affiliation(s)
- Tobias Meischl
- Division of Gastroenterology und Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria
| | | | - Georg Györi
- Division of Transplantation, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - Wolfgang Sieghart
- Division of Gastroenterology und Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria
| | - Thomas Reiberger
- Division of Gastroenterology und Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology und Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Thomas Soliman
- Division of Transplantation, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - Gabriela Berlakovich
- Division of Transplantation, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - Matthias Pinter
- Division of Gastroenterology und Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria
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10
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Pavel MC, Fuster J. Expansion of the hepatocellular carcinoma Milan criteria in liver transplantation: Future directions. World J Gastroenterol 2018; 24:3626-3636. [PMID: 30166858 PMCID: PMC6113720 DOI: 10.3748/wjg.v24.i32.3626] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2018] [Revised: 06/24/2018] [Accepted: 06/30/2018] [Indexed: 02/06/2023] Open
Abstract
Milan criteria are currently the benchmark related to liver transplantation (LT) for hepatocellular carcinoma. However, several groups have proposed different expanded criteria with acceptable results. In this article, we review the current status of LT beyond the Milan criteria in three different scenarios-expanded criteria with cadaveric LT, downstaging to Milan criteria before LT, and expansion in the context of adult living donor LT. The review focuses on three main questions: what would the impact of the expansion beyond Milan criteria be on the patients on the waiting list; whether the dichotomous criteria (yes/no) currently used are appropriate for LT or continuous survival estimations, such as the one of “Metroticket” and whether it should enter into the clinical practice; and, whether the use of living donor LT in the context of expansion beyond Milan criteria is justified.
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Affiliation(s)
- Mihai-Calin Pavel
- HepatoBilioPancreatic Surgery and Transplant Unit, Department of Surgery, Digestive and Metabolic Diseases Institute, Hospital Clínic, University of Barcelona, Barcelona, Catalonia 08036, Spain
| | - Josep Fuster
- HepatoBilioPancreatic Surgery and Transplant Unit, Department of Surgery, Digestive and Metabolic Diseases Institute, Hospital Clínic, University of Barcelona, Barcelona, Catalonia 08036, Spain
- Barcelona-Clínic Liver Cancer Group (BCLC), Liver Unit, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBEREHD, Universitat de Barcelona, Barcelona, Catalonia 08036, Spain
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11
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Pavel M, Sanchez Cabus S, Crespo G, Ferrer J, Fondevila C, Fuster J, Garcia-Valdecasas J. Role of Adult Living Donor Liver Transplantation in the Treatment of Hepatocellular Carcinoma Within and Beyond Milan Criteria: A Comparative Study. Transplant Proc 2018; 50:1386-1395. [DOI: 10.1016/j.transproceed.2018.02.093] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Accepted: 02/17/2018] [Indexed: 02/07/2023]
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12
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Llovet JM, Pavel M, Rimola J, Diaz MA, Colmenero J, Saavedra-Perez D, Fondevila C, Ayuso C, Fuster J, Ginès P, Bruix J, Garcia-Valdecasas JC. Pilot study of living donor liver transplantation for patients with hepatocellular carcinoma exceeding Milan Criteria (Barcelona Clinic Liver Cancer extended criteria). Liver Transpl 2018; 24:369-379. [PMID: 29140601 DOI: 10.1002/lt.24977] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Revised: 10/25/2017] [Accepted: 10/29/2017] [Indexed: 12/15/2022]
Abstract
A subset of patients with hepatocellular carcinoma (HCC) beyond Milan criteria might obtain acceptable survival outcomes after liver transplantation. Living donor liver transplantation (LDLT) has emerged as a feasible alternative to overcome the paucity of donors. In 2001, we started a protocol for LDLT in Child A-B patients with HCC fulfilling a set of criteria-the Barcelona Clinic Liver Cancer (BCLC) expanded criteria-that expanded the conventional indications of transplantation: 1 tumor ≤ 7 cm, 5 tumors ≤ 3 cm, and 3 tumors ≤ 5 cm without macrovascular invasion or downstaging to Milan after locoregional therapies. We present a prospective cohort of 22 patients with BCLC extended indications based on size/number (n = 17) or downstaging (n = 5) treated with LDLT between 2001 and 2014. Characteristics of the patients were as follows: median age, 57 years old; males/female, n = 20/2; Child-Pugh A/B, n = 16/6; and alpha fetoprotein < 100 ng/mL, n = 21. Twelve patients received neoadjuvant locoregional therapies. At the time of transplantation, 12 patients had HCC staging beyond Milan criteria and 10 within. Pathological reports showed that 50% exceeded BCLC expanded criteria. Perioperative mortality was 0%. After a median follow-up of 81 months, the 1-, 3-, 5-, and 10-year survival was 95.5%, 86.4%, 80.2%, and 66.8%, respectively. Overall, 7 patients recurred (range, 9-108 months), and the 5-year and 10-year actuarial recurrence rates were 23.8% and 44.4%, respectively. In conclusion, a proper selection of candidates for extended indications of LDLT for HCC patients provide survival outcomes comparable to those obtained within the Milan criteria, but these results need confirmation. Liver Transplantation 24 369-379 2018 AASLD.
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Affiliation(s)
- Josep M Llovet
- Barcelona Clinic Liver Cancer Group, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clinic Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Catalonia, Spain.,Mount Sinai Liver Cancer Program, Icahn School of Medicine at Mount Sinai, New York, NY.,Institució Catalana de Recerca i Estudis Avançats, Barcelona, Catalonia, Spain
| | - Mihai Pavel
- Liver Transplant Unit, Barcelona, Catalonia, Spain
| | - Jordi Rimola
- Barcelona Clinic Liver Cancer Group, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clinic Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Catalonia, Spain
| | - Maria Alba Diaz
- Pathology Department, Hospital Clínic, University of Barcelona, Barcelona, Catalonia, Spain
| | - Jordi Colmenero
- Liver Transplant Unit, Barcelona, Catalonia, Spain.,Liver Unit, Digestive and Metabolic Diseases Institute, Barcelona, Catalonia, Spain
| | | | | | - Carmen Ayuso
- Barcelona Clinic Liver Cancer Group, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clinic Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Catalonia, Spain
| | - Josep Fuster
- Barcelona Clinic Liver Cancer Group, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clinic Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Catalonia, Spain.,Liver Transplant Unit, Barcelona, Catalonia, Spain
| | - Pere Ginès
- Liver Transplant Unit, Barcelona, Catalonia, Spain.,Liver Unit, Digestive and Metabolic Diseases Institute, Barcelona, Catalonia, Spain
| | - Jordi Bruix
- Barcelona Clinic Liver Cancer Group, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clinic Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Catalonia, Spain.,Liver Unit, Digestive and Metabolic Diseases Institute, Barcelona, Catalonia, Spain
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13
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Mazzaferro V, Sposito C, Zhou J, Pinna AD, De Carlis L, Fan J, Cescon M, Di Sandro S, Yi-Feng H, Lauterio A, Bongini M, Cucchetti A. Metroticket 2.0 Model for Analysis of Competing Risks of Death After Liver Transplantation for Hepatocellular Carcinoma. Gastroenterology 2018; 154:128-139. [PMID: 28989060 DOI: 10.1053/j.gastro.2017.09.025] [Citation(s) in RCA: 463] [Impact Index Per Article: 66.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2016] [Revised: 09/05/2017] [Accepted: 09/25/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Outcomes of liver transplantation for hepatocellular carcinoma (HCC) are determined by cancer-related and non-related events. Treatments for hepatitis C virus infection have reduced non-cancer events among patients receiving liver transplants, so reducing HCC-related death might be an actionable end point. We performed a competing-risk analysis to evaluate factors associated with survival of patients with HCC and developed a prognostic model based on features of HCC patients before liver transplantation. METHODS We performed multivariable competing-risk regression analysis to identify factors associated with HCC-specific death of patients who underwent liver transplantation. The training set comprised 1018 patients who underwent liver transplantation for HCC from January 2000 through December 2013 at 3 tertiary centers in Italy. The validation set comprised 341 consecutive patients who underwent liver transplantation for HCC during the same period at the Liver Cancer Institute in Shanghai, China. We collected pretransplantation data on etiology of liver disease, number and size of tumors, patient level of α-fetoprotein (AFP), model for end-stage liver disease score, tumor stage, numbers and types of treatment, response to treatments, tumor grade, microvascular invasion, dates, and causes of death. Death was defined as HCC-specific when related to HCC recurrence after transplantation, disseminated extra- and/or intrahepatic tumor relapse and worsened liver function in presence of tumor spread. The cumulative incidence of death was segregated for hepatitis C virus status. RESULTS In the competing-risk regression, the sum of tumor number and size and of log10 level of AFP were significantly associated with HCC-specific death (P < .001), returning an average c-statistic of 0.780 (95% confidence interval, 0.763-0.798). Five-year cumulative incidence of non-HCC-related death was 8.6% in HCV-negative patients and 18.1% in HCV-positive patients. For patients with HCC to have a 70% chance of HCC-specific survival 5 years after transplantation, their level of AFP should be <200 ng/mL and the sum of number and size of tumors (in centimeters) should not exceed 7; if the level of AFP was 200-400 ng/mL, the sum of the number and size of tumors should be ≤5; if their level of AFP was 400-1000 ng/mL, the sum of the number and size of tumors should be ≤4. In the validation set, the model identified patients who survived 5 years after liver transplantation with 0.721 accuracy (95% confidence interval, 0.648%-0.793%). Our model, based on patients' level of AFP and HCC number and size, outperformed the Milan; University of California, San Francisco; Shanghai-Fudan; Up-to-7 criteria (P < .001); and AFP French model (P = .044) to predict which patients will survive for 5 years after liver transplantation. CONCLUSIONS We developed a model based on level of AFP, tumor size, and tumor number, to determine risk of death from HCC-related factors after liver transplantation. This model might be used to select end points and refine selection criteria for liver transplantation for patients with HCC. To predict 5-year survival and risk of HCC-related death using an online calculator, please see www.hcc-olt-metroticket.org/. ClinicalTrials.gov ID NCT02898415.
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Affiliation(s)
- Vincenzo Mazzaferro
- General Surgery and Liver Transplantation Unit, University of Milan, Istituto Nazionale Tumori (National Cancer Institute), Istituto di Ricovero e Cura a Carattere Scientifico Foundation, Milan, Italy.
| | - Carlo Sposito
- General Surgery and Liver Transplantation Unit, University of Milan, Istituto Nazionale Tumori (National Cancer Institute), Istituto di Ricovero e Cura a Carattere Scientifico Foundation, Milan, Italy
| | - Jian Zhou
- Liver Surgery Department, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Antonio D Pinna
- General Surgery and Transplant Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy
| | - Luciano De Carlis
- General Surgery and Abdominal Transplantation Unit, University of Milano-Bicocca and Niguarda-Cà Granda Hospital, Milan, Italy
| | - Jia Fan
- Liver Surgery Department, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Matteo Cescon
- General Surgery and Transplant Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy
| | - Stefano Di Sandro
- General Surgery and Abdominal Transplantation Unit, University of Milano-Bicocca and Niguarda-Cà Granda Hospital, Milan, Italy
| | - He Yi-Feng
- Liver Surgery Department, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Andrea Lauterio
- General Surgery and Abdominal Transplantation Unit, University of Milano-Bicocca and Niguarda-Cà Granda Hospital, Milan, Italy
| | - Marco Bongini
- General Surgery and Liver Transplantation Unit, University of Milan, Istituto Nazionale Tumori (National Cancer Institute), Istituto di Ricovero e Cura a Carattere Scientifico Foundation, Milan, Italy
| | - Alessandro Cucchetti
- General Surgery and Transplant Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy
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14
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Biolato M, Marrone G, Miele L, Gasbarrini A, Grieco A. Liver transplantation for intermediate hepatocellular carcinoma: An adaptive approach. World J Gastroenterol 2017; 23:3195-3204. [PMID: 28566879 PMCID: PMC5434425 DOI: 10.3748/wjg.v23.i18.3195] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2017] [Revised: 03/12/2017] [Accepted: 04/12/2017] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma is becoming an increasing indication for liver transplantation, but selection and allocation of patients are challenging because of organ shortages. Conventional Milan criteria are the reference for the selection of patients worldwide, but many expanded criteria, like University of California San Francisco criteria and up-to-7 criteria, have demonstrated that survival and recurrence results are lower than those for restricted indications. Correct staging is crucial and should include surrogate markers of biological aggressiveness (α-fetoprotein, response to loco-regional treatments). Successful down-staging can select between patients with tumor burden initially beyond transplantation criteria those with a more favorable biology, provided a 3-mo stability in meeting the transplantation criteria. Allocation rules are constantly adjusted to minimize the imbalance between the priorities of candidates with and without hepatocellular carcinoma, and take into account local donor rate and waitlist dynamics. Recently, Mazzaferro et al proposed a benefit-oriented "adaptive approach", in which the selection and allocation of patients are based on their response to non-transplantation treatments: low priority for transplantation in case of complete response, high priority in case of partial response or recurrence, and no listing in case of progression beyond transplantation criteria.
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15
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Clinical validity of Metroticket calculator in transplant patients undergoing prior chemoembolization for hepatocellular carcinoma. Hepatol Int 2017; 11:209-219. [PMID: 28144812 DOI: 10.1007/s12072-017-9785-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Accepted: 01/10/2017] [Indexed: 01/15/2023]
Abstract
AIM To test the predictive performance of the Metroticket calculator for survival after liver transplantation (LT) of patients with hepatocellular carcinoma (HCC) undergoing prior transarterial chemoembolization (TACE). METHODS A total of 142 patients treated with TACE and subsequent LT who had arterial enhancing HCC(s) were entered into this analysis. Tumor parameters measured by the enhancement radiological method pre-LT or by pathology post-LT were incorporated into the Metroticket analysis. The calculator was validated in terms of calibration and discrimination capacity. RESULTS Mean 3- and 5-year survival rates predicted in the radiological model for all 142 patients were 76.4 and 70.1 %, respectively, lying comfortably within the 95 % confidence interval (CI) of the observed survival rate estimates (72.8-86.2 and 68.6-83.2 %, respectively). In the pathological model incorporating microvascular invasion, the mean anticipated survival rate at 5 years of 120 patients with viable nodules on explants was 69.5 %, also lying inside the 95 % CI of the actuarial rates (67.9-83.5 %). The c-indices as measures of discriminatory power were 0.61 and 0.62, respectively, for the 3- and 5-year predictions in the radiological model, and 0.72 for the 5-year prediction in the pathological model. The corresponding findings were similar for subgroups with hepatitis B virus infection and undergoing living-donor LT. CONCLUSIONS The Metroticket calculation based on explant data accurately predicts post-LT survival of HCC patients with prior TACE. Imaging estimate-based predictions before LT appear to provide poorer discrimination than calibration.
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16
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Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide, and its incidence has been increasing in the last decade largely in parallel to the incidence and duration of exposure to hepatitis B and C. The widespread implementation of hepatitis B vaccine, hepatitis B antivirals, and the introduction of direct antiviral therapies for hepatitis C virus may have a substantial impact in reducing the incidence of HCC. This report reviews the risk factors and underlying mechanisms associated with the development of HCC in hepatitis B, along with advances in the diagnosis, imaging, and management of HCC.
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Affiliation(s)
- Alan W Hemming
- Division of Transplantation and Hepatobiliary Surgery, Department of Surgery, University of California, San Diego, 9300 Campus Point Drive, # 7745 La Jolla, CA 92037-1300, USA.
| | - Jennifer Berumen
- Division of Transplantation and Hepatobiliary Surgery, Department of Surgery, University of California, San Diego, 9300 Campus Point Drive, # 7745 La Jolla, CA 92037-1300, USA
| | - Kristin Mekeel
- Division of Transplantation and Hepatobiliary Surgery, Department of Surgery, University of California, San Diego, 9300 Campus Point Drive, # 7745 La Jolla, CA 92037-1300, USA
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17
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Strassburg CP. HCC-Associated Liver Transplantation - Where Are the Limits and What Are the New Regulations? Visc Med 2016; 32:263-271. [PMID: 27722163 DOI: 10.1159/000446385] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) represents an increasing health burden worldwide and a challenging disease both in terms of diagnosis and treatment. METHODS The literature available on PubMed for the period of 1990-2016 was reviewed with reference to liver allocation, HCC, liver transplantation (LT), and prediction, and the allocation rules of the German Transplant Act were reviewed. RESULTS Due to etiological and geographical diversity, HCC is not a homogeneous disease. In the vast majority of patients, HCC develops as a complication of chronic liver disease and cirrhosis. While most patients present with advanced HCC for which palliative strategies are the only available option, LT is the best treatment approach as it not only eliminates the diseased liver and the underlying hepatocarcinogenic mechanisms but also the cancer. The decision for LT is not an easy one to make, because outcome prediction, staging, bridging therapy, and recurrence prevention are difficult and are estimated against the background of the scarce resource of donor organs which are also competitively sought after by patients suffering from non-neoplastic terminal liver diseases, raising the issue of equality of chances in a rationed therapeutic modality. Currently, the Milan criteria are the best evaluated decision tool for LT, but many issues such as down-staging, favorable biological behavior during treatment, expansion of the morphological classification, molecular predictors, and individualized approaches are not yet satisfactorily addressed. CONCLUSION In order to provide a fair and effective approach to LT in HCC, the employed allocation rules require continuous development and scientific evaluation. Recently, the allocation rules for standard exception priority according to the German Transplant Act have been revised to improve patient selection for LT in HCC.
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18
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Bruix J, Reig M, Sherman M. Evidence-Based Diagnosis, Staging, and Treatment of Patients With Hepatocellular Carcinoma. Gastroenterology 2016; 150:835-53. [PMID: 26795574 DOI: 10.1053/j.gastro.2015.12.041] [Citation(s) in RCA: 1268] [Impact Index Per Article: 140.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Revised: 12/09/2015] [Accepted: 12/16/2015] [Indexed: 02/07/2023]
Abstract
Evidence-based management of patients with hepatocellular carcinoma (HCC) is key to their optimal care. For individuals at risk for HCC, surveillance usually involves ultrasonography (there is controversy over use of biomarkers). A diagnosis of HCC is made based on findings from biopsy or imaging analyses. Molecular markers are not used in diagnosis or determination of prognosis and treatment for patients. The Barcelona Clinic Liver Cancer algorithm is the most widely used staging system. Patients with single liver tumors or as many as 3 nodules ≤3 cm are classified as having very early or early-stage cancer and benefit from resection, transplantation, or ablation. Those with a greater tumor burden, confined to the liver, and who are free of symptoms are considered to have intermediate-stage cancer and can benefit from chemoembolization if they still have preserved liver function. Those with symptoms of HCC and/or vascular invasion and/or extrahepatic cancer are considered to have advanced-stage cancer and could benefit from treatment with the kinase inhibitor sorafenib. Patients with end-stage HCC have advanced liver disease that is not suitable for transplantation and/or have intense symptoms. Studies now aim to identify molecular markers and imaging techniques that can detect patients with HCC at earlier stages and better predict their survival time and response to treatment.
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Affiliation(s)
- Jordi Bruix
- Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clinic, IDIBAPS, University of Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain.
| | - Maria Reig
- Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clinic, IDIBAPS, University of Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| | - Morris Sherman
- Division of Gastroenterology, Department of Medicine, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
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19
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Pascual S, Herrera I, Irurzun J. New advances in hepatocellular carcinoma. World J Hepatol 2016; 8:421-38. [PMID: 27028578 PMCID: PMC4807304 DOI: 10.4254/wjh.v8.i9.421] [Citation(s) in RCA: 108] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Revised: 03/06/2016] [Accepted: 03/14/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the leading cause of deaths in cirrhotic patients and the third cause of cancer related deaths. Most HCC are associated with well known underlying risk factors, in fact, HCC arise in cirrhotic patients in up to 90% of cases, mainly due to chronic viral hepatitis and alcohol abuse. The worldwide prevention strategies are conducted to avoid the infection of new subjects and to minimize the risk of liver disease progression in infected patients. HCC is a condition which lends itself to surveillance as at-risk individuals can readily be identified. The American and European guidelines recommended implementation of surveillance programs with ultrasound every six months in patient at-risk for developing HCC. The diagnosis of HCC can be based on non-invasive criteria (only in cirrhotic patient) or pathology. Accurately staging patients is essential to oncology practice. The ideal tumour staging system in HCC needs to account for both tumour characteristics and liver function. Treatment allocation is based on several factors: Liver function, size and number of tumours, macrovascular invasion or extrahepatic spread. The recommendations in terms of selection for different treatment strategies must be based on evidence-based data. Resection, liver transplant and interventional radiology treatment are mainstays of HCC therapy and achieve the best outcomes in well-selected candidates. Chemoembolization is the most widely used treatment for unresectable HCC or progression after curative treatment. Finally, in patients with advanced HCC with preserved liver function, sorafenib is the only approved systemic drug that has demonstrated a survival benefit and is the standard of care in this group of patients.
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Affiliation(s)
- Sonia Pascual
- Sonia Pascual, Iván Herrera, Javier Irurzun, Liver Unit, Gastroenterology Department, Interventional Radiological Unit, Hospital General Universitario de Alicante, 03010 Alicante, Spain
| | - Iván Herrera
- Sonia Pascual, Iván Herrera, Javier Irurzun, Liver Unit, Gastroenterology Department, Interventional Radiological Unit, Hospital General Universitario de Alicante, 03010 Alicante, Spain
| | - Javier Irurzun
- Sonia Pascual, Iván Herrera, Javier Irurzun, Liver Unit, Gastroenterology Department, Interventional Radiological Unit, Hospital General Universitario de Alicante, 03010 Alicante, Spain
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Forner A, Reig M, Varela M, Burrel M, Feliu J, Briceño J, Sastre J, Martí-Bonmati L, Llovet JM, Bilbao JI, Sangro B, Pardo F, Ayuso C, Bru C, Tabernero J, Bruix J. [Diagnosis and treatment of hepatocellular carcinoma. Update consensus document from the AEEH, SEOM, SERAM, SERVEI and SETH]. Med Clin (Barc) 2016; 146:511.e1-511.e22. [PMID: 26971984 DOI: 10.1016/j.medcli.2016.01.028] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2015] [Revised: 01/22/2016] [Accepted: 01/28/2016] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma is the most common primary malignancy of the liver and one of the most frequent causes of death in patients with liver cirrhosis. Simultaneously with the recognition of the clinical relevance of this neoplasm, in recent years there have been important developments in the diagnosis, staging and treatment of HCC. Consequently, the Asociación Española para el Estudio del Hígado has driven the need to update clinical practice guidelines, continuing to invite all the societies involved in the diagnosis and treatment of this disease to participate in the drafting and approval of the document (Sociedad Española de Trasplante Hepático, Sociedad Española de Radiología Médica, Sociedad Española de Radiología Vascular e Intervencionista y Sociedad Española de Oncología Médica). The clinical practice guidelines published in 2009 accepted as Clinical Practice Guidelines of the National Health System has been taken as reference document, incorporating the most important advances that have been made in recent years. The scientific evidence for the treatment of HCC has been evaluated according to the recommendations of the National Cancer Institute (www.cancer.gov) and the strength of recommendation is based on the GRADE system.
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Affiliation(s)
- Alejandro Forner
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Hepatología, Hospital Clínic, Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), España
| | - María Reig
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Hepatología, Hospital Clínic, Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), España
| | - María Varela
- Sección de Hepatología, Servicio de Aparato Digestivo, Hospital Universitario Central de Asturias (HUCA), Universidad de Oviedo, Oviedo, España
| | - Marta Burrel
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Radiodiagnóstico, Hospital Clínic, Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, España
| | - Jaime Feliu
- Servicio de Oncología Médica, Hospital Universitario La Paz, Universidad Autónoma de Madrid, Sociedad Española de Oncología Médica, Madrid, España
| | - Javier Briceño
- Unidad de Trasplante Hepático, Servicio de Cirugía General y del Aparato Digestivo, Hospital Universitario Reina Sofía, Córdoba, España
| | - Javier Sastre
- Servicio de Oncología Médica, Hospital Clínico San Carlos, Madrid, España
| | - Luis Martí-Bonmati
- Departamento de Radiología, Hospital Universitario y Politécnico La Fe, Valencia, España
| | - Josep María Llovet
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Hepatología, Hospital Clínic, Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), España; Mount Sinai Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, Estados Unidos
| | - José Ignacio Bilbao
- Unidad de Radiología Vascular e Intervencionista, Departamento de Radiodiagnóstico, Clínica Universidad de Navarra, Pamplona, España
| | - Bruno Sangro
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), España; Unidad de Hepatología, Departamento de Medicina Interna, Clínica Universidad de Navarra, Pamplona, España
| | - Fernando Pardo
- Servicio de Cirugía Hepatobliopancreática y Trasplante, Clínica Universidad de Navarra, Pamplona, España
| | - Carmen Ayuso
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Radiodiagnóstico, Hospital Clínic, Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, España
| | - Concepció Bru
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Radiodiagnóstico, Hospital Clínic, Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, España
| | - Josep Tabernero
- Servicio de Oncología Médica, Hospital Universitario Vall d'Hebrón, Barcelona, Universidad Autónoma de Barcelona, Barcelona, España
| | - Jordi Bruix
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Hepatología, Hospital Clínic, Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), España.
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Waller LP, Deshpande V, Pyrsopoulos N. Hepatocellular carcinoma: A comprehensive review. World J Hepatol 2015; 7:2648-2663. [PMID: 26609342 PMCID: PMC4651909 DOI: 10.4254/wjh.v7.i26.2648] [Citation(s) in RCA: 137] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Revised: 05/19/2015] [Accepted: 10/14/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is rapidly becoming one of the most prevalent cancers worldwide. With a rising rate, it is a prominent source of mortality. Patients with advanced fibrosis, predominantly cirrhosis and hepatitis B are predisposed to developing HCC. Individuals with chronic hepatitis B and C infections are most commonly afflicted. Different therapeutic options, including liver resection, transplantation, systemic and local therapy, must be tailored to each patient. Liver transplantation offers leading results to achieve a cure. The Milan criteria is acknowledged as the model to classify the individuals that meet requirements to undergo transplantation. Mean survival remains suboptimal because of long waiting times and limited donor organ resources. Recent debates involve expansion of these criteria to create options for patients with HCC to increase overall survival.
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Affiliation(s)
- Lisa P Waller
- Lisa P Waller, Vrushak Deshpande, Nikolaos Pyrsopoulos, Division of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, Newark, NJ 07103, United States
| | - Vrushak Deshpande
- Lisa P Waller, Vrushak Deshpande, Nikolaos Pyrsopoulos, Division of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, Newark, NJ 07103, United States
| | - Nikolaos Pyrsopoulos
- Lisa P Waller, Vrushak Deshpande, Nikolaos Pyrsopoulos, Division of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, Newark, NJ 07103, United States
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Piras-Straub K, Khairzada K, Gerken G, Saner F, Treckmann J, Paul A, Canbay A, Herzer K. Glutamate dehydrogenase and alkaline phosphatase as very early predictors of hepatocellular carcinoma recurrence after liver transplantation. Digestion 2015; 91:117-27. [PMID: 25662469 DOI: 10.1159/000370212] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2014] [Accepted: 11/26/2014] [Indexed: 02/04/2023]
Abstract
BACKGROUND Although long-term survival rates for patients undergoing liver transplant (LT) for hepatocellular carcinoma (HCC) are good, the relatively high rate of tumor recurrence after LT necessitates the identification of biological parameters that supplement morphological predictors of recurrence. METHOD From chart review we identified 175 patients who received liver transplantation due to HCC at our center between January 2000 and December 2013. We documented demographic and clinical data, as well as clinicopathological characteristics of the tumors, with a focus on liver values at the time of LT. RESULTS HCC recurred in 23% of LT patients. Most recurrences (59%) occurred within 12 months after LT; hardly any recurrence was detected later than 3 years after LT. Recurrence was positively correlated with tumor size, tumor stage and alpha-fetoprotein level (AFP), and it was most likely with certain causes of liver disease. Interestingly, tumor recurrence was independently predicted by serum levels of glutamate dehydrogenase (GLDH) and alkaline phosphatase (AP) at the time of LT. CONCLUSIONS Because all HCC recurrence occurs within 36 months after LT, HCC detected more than 3 years after LT may be considered de novo. Liver values, with GLDH and AP being the most preponderant, serve as easy-to-assess biomarkers which contribute to predict the risk of tumor recurrence.
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Affiliation(s)
- Katja Piras-Straub
- Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany
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Machado A, Kiss G, Ernani L, Marroni C, Zanotelli ML, Cantisani G, Cerski CT, Coral G, Brandão A. Validation of the "Metroticket" model in a cohort of patients transplanted for hepatocellular carcinoma in southern Brazil. Clin Transplant 2015; 29:806-812. [PMID: 26119109 DOI: 10.1111/ctr.12583] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/24/2015] [Indexed: 12/21/2022]
Abstract
This retrospective study evaluated the ability of the Metroticket model to predict five-yr post-transplant survival in patients with hepatocellular carcinoma (HCC) based only on explant data. Five-yr survival after transplant was estimated using the Metroticket Calculator, and observed survival was calculated using the Kaplan-Meier method. Metroticket-predicted survival was compared between deceased and surviving patients using the Mann-Whitney test. The accuracy of Metroticket estimates in discriminating between these two patient groups was assessed using the c-statistic. Median patient age (n = 109) was 55.7 yr, and 72.5% of the sample were men. Metroticket-predicted and observed post-transplant survival at five yr was 71.1% and 58.7%, respectively. Predictions were calculated using the explant data of the 64 survivors and 45 deceased patients. Median five-yr survival was 72.9% in the former and 69.7% in the latter. The c-statistic of the Metroticket model for distinguishing surviving from deceased patients was 0.55. In this cohort, the Metroticket model was unable to accurately predict five-yr post-transplant survival based only on explant data.
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Affiliation(s)
- Adriana Machado
- Postgraduate Program in Medicine: Hepatology, School of Medicine, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, Brazil
| | - Guillermo Kiss
- Liver Transplantation Group, Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, RS, Brazil
| | - Lucas Ernani
- School of Medicine, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, Brazil
| | - Claudio Marroni
- Postgraduate Program in Medicine: Hepatology, School of Medicine, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, Brazil
- Liver Transplantation Group, Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, RS, Brazil
| | - Maria Lúcia Zanotelli
- Liver Transplantation Group, Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, RS, Brazil
| | - Guido Cantisani
- Liver Transplantation Group, Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, RS, Brazil
| | - Carlos Thadeu Cerski
- Liver Transplantation Group, Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, RS, Brazil
| | - Gabriela Coral
- Postgraduate Program in Medicine: Hepatology, School of Medicine, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, Brazil
| | - Ajacio Brandão
- Postgraduate Program in Medicine: Hepatology, School of Medicine, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, Brazil
- Liver Transplantation Group, Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, RS, Brazil
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Kim HD, Shim JH, Kim GA, Shin YM, Yu E, Lee SG, Lee D, Kim KM, Lim YS, Lee HC, Chung YH, Lee YS. Optimal methods for measuring eligibility for liver transplant in hepatocellular carcinoma patients undergoing transarterial chemoembolization. J Hepatol 2015; 62:1076-84. [PMID: 25529626 DOI: 10.1016/j.jhep.2014.12.013] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2014] [Revised: 12/01/2014] [Accepted: 12/08/2014] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS We investigated the optimal radiologic method for measuring hepatocellular carcinoma (HCC) treated by transarterial chemoembolization (TACE) in order to assess suitability for liver transplantation (LT). METHODS 271 HCC patients undergoing TACE prior to LT were classified according to both Milan and up-to-seven criteria after TACE by using the enhancement or size method on computed tomography images. The cumulative incidence function curves with competing risks regression was used in post-LT time-to-recurrence analysis. The predictive accuracy for recurrence was compared using area under the time-dependent receiver operating characteristic curves (AUC) estimation. RESULTS Of the 271 patients, 246 (90.8%) and 164 (60.5%) fell within Milan and 252 (93.0%) and 210 (77.5%) fell within up-to-seven criteria, when assessed by enhancement and size methods, respectively. Competing risks regression analyses adjusting for covariates indicated that meeting the criteria by enhancement and by size methods was independently related to post-LT time-to-recurrence in the Milan or up-to-seven model. Higher AUC values were observed with the size method only in the up-to-seven model (p<0.05). Mean differences in the sum of tumor diameter and number of tumors between pathologic and radiologic findings were significantly less by the enhancement method (p<0.05). Cumulative incidence curves showed similar recurrence results between patients with and without prior TACE within the criteria based on either method, except for the within up-to-seven by the enhancement method (p=0.017). CONCLUSIONS The enhancement method is a reliable tool for assessing the control or downstaging of HCC within Milan after TACE, although the size method may be preferable when applying the up-to-seven criterion.
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Affiliation(s)
- Hyung-Don Kim
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Ju Hyun Shim
- Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
| | - Gi-Ae Kim
- Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Yong Moon Shin
- Department of Radiology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Eunsil Yu
- Department of Pathology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Sung-Gyu Lee
- Department of Surgery, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Danbi Lee
- Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Kang Mo Kim
- Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Young-Suk Lim
- Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Han Chu Lee
- Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Young-Hwa Chung
- Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Yung Sang Lee
- Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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Gomaa AI, Waked I. Recent advances in multidisciplinary management of hepatocellular carcinoma. World J Hepatol 2015; 7:673-87. [PMID: 25866604 PMCID: PMC4388995 DOI: 10.4254/wjh.v7.i4.673] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 12/17/2014] [Accepted: 01/15/2015] [Indexed: 02/06/2023] Open
Abstract
The incidence of hepatocellular carcinoma (HCC) is increasing, and it is currently the second leading cause of cancer-related death worldwide. Potentially curative treatment options for HCC include resection, transplantation, and percutaneous ablation, whereas palliative treatments include trans-arterial chemoembolization (TACE), radioembolization, and systemic treatments. Due to the diversity of available treatment options and patients' presentations, a multidisciplinary team should decide clinical management of HCC, according to tumor characteristics and stage of liver disease. Potentially curative treatments are suitable for very-early- and early-stage HCC. However, the vast majority of HCC patients are diagnosed in later stages, where the tumor characteristics or progress of liver disease prevent curative interventions. For patients with intermediate-stage HCC, TACE and radioembolization improve survival and are being evaluated in addition to potentially curative therapies or with systemic targeted therapy. There is currently no effective systemic chemotherapy, immunologic, or hormonal therapy for HCC, and sorafenib is the only approved molecular-targeted treatment for advanced HCC. Other targeted agents are under investigation; trials comparing new agents in combination with sorafenib are ongoing. Combinations of systemic targeted therapies with local treatments are being evaluated for further improvements in HCC patient outcomes. This article provides an updated and comprehensive overview of the current standards and trends in the treatment of HCC.
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Affiliation(s)
- Asmaa I Gomaa
- Asmaa I Gomaa, Imam Waked, Hepatology Department, National Liver Institute, Menoufiya University, Shebeen El-Kom 35111, Egypt
| | - Imam Waked
- Asmaa I Gomaa, Imam Waked, Hepatology Department, National Liver Institute, Menoufiya University, Shebeen El-Kom 35111, Egypt
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Mancuso A, Mazzola A, Cabibbo G, Perricone G, Enea M, Galvano A, Zavaglia C, Belli L, Cammà C. Survival of patients treated with sorafenib for hepatocellular carcinoma recurrence after liver transplantation: a systematic review and meta-analysis. Dig Liver Dis 2015; 47:324-30. [PMID: 25641331 DOI: 10.1016/j.dld.2015.01.001] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2014] [Revised: 12/24/2014] [Accepted: 01/04/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND Data on survival and safety of sorafenib for hepatocellular carcinoma recurrence after liver transplant are still equivocal. AIM We performed a meta-analysis of published studies, with the aim of estimating the 1-year rates of survival, analysing the variability in survival rates and, finally, identifying the factors associated with a longer survival. METHODS Data from 8 of the 17 selected studies were pooled, while the other 9 were excluded because survival rates were missing. All included studies were retrospective. RESULTS Overall, the 1-year survival ranged from 18% to 90%. Tumour progression was the main cause of death. The second cause was bleeding, reported only in patients undergoing m-Tor inhibitor therapy. The pooled estimate of 1-year survival was 63%. There was a significant heterogeneity among studies (P < 0.0001). Among the 34 variables assessed by univariate meta-regression, 5 were associated with an increase in the 1-year survival rate: (1) male gender (P = 0.001); (2) Time to progression (P = 0.038); and adverse drug events, divided in (3) gastrointestinal (P = 0.038), (4) cardiovascular (P = 0.029), and (5) dermatological (P = 0.014). CONCLUSIONS Additional data from multicentre prospective studies are required to clearly determine if sorafenib is a safe and acceptable treatment in hepatocellular carcinoma recurrence after liver transplant. Nevertheless, its association with m-Tor inhibitors should be discouraged.
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Affiliation(s)
- Andrea Mancuso
- Hepatology and Gastroenterology Department, Ospedale Niguarda Ca' Granda, Milano, Italy; Internal Medicine Department, Azienda di Rilievo Nazionale ad Alta Specializzazione Civico - Di Cristina - Benfratelli, Palermo, Italy
| | - Alessandra Mazzola
- Gastroenterology Unit, Internal Medicine Department, University of Palermo, Palermo, Italy
| | - Giuseppe Cabibbo
- Gastroenterology Unit, Internal Medicine Department, University of Palermo, Palermo, Italy
| | - Giovanni Perricone
- Hepatology and Gastroenterology Department, Ospedale Niguarda Ca' Granda, Milano, Italy
| | - Marco Enea
- "S Vianelli" Department, University of Palermo, Italy
| | | | - Claudio Zavaglia
- Hepatology and Gastroenterology Department, Ospedale Niguarda Ca' Granda, Milano, Italy
| | - Luca Belli
- Hepatology and Gastroenterology Department, Ospedale Niguarda Ca' Granda, Milano, Italy
| | - Calogero Cammà
- Gastroenterology Unit, Internal Medicine Department, University of Palermo, Palermo, Italy.
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27
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Mancuso A, Perricone G. Hepatocellular Carcinoma and Liver Transplantation: State of the Art. J Clin Transl Hepatol 2014; 2:176-81. [PMID: 26357625 PMCID: PMC4521243 DOI: 10.14218/jcth.2014.00013] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2014] [Revised: 06/30/2014] [Accepted: 07/01/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is an aggressive tumor that often occurs in chronic liver disease and cirrhosis. The incidence of HCC is growing worldwide. With respect to any other available treatment for liver cancer, liver transplantation (LT) has the highest potential to cure. LT allows for removal at once of both the tumor ("seed") and the damaged-hepatic tissue ("soil") where cancerogenesis and chronic liver disorders have progressed together. The Milan criteria (MC) have been applied worldwide to select patients with HCC for LT, yielding a 4-year survival rate of 75%. These criteria represent the benchmark for patient selection and are the basis for comparison with any other suggested criteria. However, MC are often considered to be too restrictive, and recent data show that between 25% and 50% of patients with HCC are currently transplanted beyond conventional indications. Consequently, any unrestricted expansion of selection criteria will increase the need for donor organs, lengthen waiting periods, increase drop-out rates, and impair outcomes on intention-to-treat analysis. Management of HCC recurrence after LT is challenging. There are a few reports available regarding the safety and efficacy of sorafenib for HCC recurrence after LT, but the data are heterogeneous. A multi-center prospective randomized controlled trial comparing placebo with sorafenib is advised. Alternatively, a meta-analysis of patient survival with sorafenib for HCC recurrence after LT could be helpful to characterize the therapeutic benefit and safety of sorafenib. Here, we review the use of LT for HCC, with particular emphasis on the selection criteria for transplantation in patients with HCC and management of HCC recurrence after LT.
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Affiliation(s)
- Andrea Mancuso
- Epatologia e Gastroenterologia, Ospedale Niguarda Ca' Granda, Milano, Italy
- Medicina Interna 1, Azienda di Rilievo Nazionale ad Alta Specializzazione Civico - Di Cristina – Benfratelli, Palermo, Italy
- Correspondence to: Andrea Mancuso, Medicina Interna 1, A.R.N.A.S. Civico, Piazzale Liotti 4, Palermo 90100, Italy. Tel: +39-329-899-7893, Fax: +39-091-609-0252. E-mail:
| | - Giovanni Perricone
- Epatologia e Gastroenterologia, Ospedale Niguarda Ca' Granda, Milano, Italy
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Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death and is currently the main event leading to death in patients with cirrhosis. Evolving information suggests that the metabolic syndrome with non-alcoholic liver disease may be an important cause of HCC in addition to viral hepatitis and alcohol-induced liver disease. The molecular pathogenesis is extremely complex and heterogeneous. To date the molecular information has not impacted on treatment decisions. Periodic surveillance imaging of patients with cirrhosis is widely practiced, especially because diagnostic, radiographic criteria for early-stage HCC have been defined (including nodules between 1 and 2 cm) and effective treatment is available for tumours detected at an early stage. Worldwide the approach to resection versus transplantation varies depending upon local resources, expertise and donor availability. The criteria for transplantation are discussed, and the controversial areas highlighted with evidence-based recommendations provided. Several approaches are available for intermediate stage disease, including radiofrequency ablation, transarterial chemoembolisation and radioembolisation; the rationale for these therapies is buttressed by appropriate outcome-based studies. For advanced disease, systemic therapy with sorafenib remains the option best supported by current data. Thus, while several trials have failed to improve the benefits of established therapies, studies assessing the sequential or combined application of those already known to be beneficial are needed. Also, new concepts are provided in regards to selecting and stratifying patients for second-line studies, which may help explain the failure of prior studies.
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Affiliation(s)
- Jordi Bruix
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clinic Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain
| | - Gregory J Gores
- Mayo Clinic, Mayo College of Medicine, Rochester, Minnesota, USA
| | - Vincenzo Mazzaferro
- Gastrointestinal Surgery and Liver Transplantation, Istituto Nazionale Tumori IRCCS (National Cancer Institute), Milan, Italy
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Lei JY, Wang WT, Yan LN. "Metroticket" predictor for assessing liver transplantation to treat hepatocellular carcinoma: a single-center analysis in mainland China. World J Gastroenterol 2013; 19:8093-8. [PMID: 24307805 PMCID: PMC3848159 DOI: 10.3748/wjg.v19.i44.8093] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2013] [Revised: 10/17/2013] [Accepted: 11/01/2013] [Indexed: 02/06/2023] Open
Abstract
AIM To validate the "Metroticket" predictor using a large cohort of liver transplantation (LT) patients with hepatocellular carcinoma (HCC) in China. METHODS In total, 230 cases of LT for HCC treatment at our center, from July 2000 to August 2008, were included in the present study. The predicted 1-, 3- and 5-year post-LT survival rates were calculated using the Metroticket model (http://89.96.76.14/metroticket/calculator/). The predicted and observed long-term survival rates were then compared and analyzed. RESULTS The predicted survival rates for all 230 cases, as calculated by the Metroticket model, were 64.7% and 56.2% at 3 and 5 years, respectively, and the observed survival rates for these patients were 71.3% and 57.8%, respectively. For the 23 cases with macrovascular invasion, the predicted 5-year survival rate was 43.5%, whereas the observed 5-year survival rate was only 8.7%. For the 42 cases with microvascular invasion but an absence of macrovascular invasion, the predicted 5-year survival rate was 44.9%, and the observed 5-year survival rate was 50%. For the remaining 165 patients without any vascular invasion, the predicted 5-year survival rate was 65.8%, and the observed 5-year survival rate was 66.7%. CONCLUSION The Metroticket model can be used to accurately predict survival in HCC-related LT cases with an absence of macrovascular invasion.
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Mancuso A. Management of hepatocellular carcinoma: Enlightening the gray zones. World J Hepatol 2013; 5:302-310. [PMID: 23805354 PMCID: PMC3692971 DOI: 10.4254/wjh.v5.i6.302] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2013] [Accepted: 05/20/2013] [Indexed: 02/06/2023] Open
Abstract
Management of hepatocellular carcinoma (HCC) has been continuously evolving during recent years. HCC is a worldwide clinical and social issue and typically a complicates cirrhosis. The incidence of HCC is increasing, not only in the general population of patients with cirrhosis, but particularly in some subgroups of patients, like those with human immunodeficiency virus infection or thalassemia. Since a 3% annual HCC incidence has been estimated in cirrhosis, a bi-annual screening is generally suggested. The diagnostic criteria of HCC has recently had a dramatic evolution during recent years. HCC diagnosis is now made only on radiological criteria in the majority of the cases. In the context of cirrhosis, the universally accepted criteria for HCC diagnosis is contrast enhancement in arterial phase and washout in venous/late phase at imaging, the so called “typical pattern”. However, recently updated guidelines slightly differ in diagnostic criteria. Apart from liver transplantation, the only cure of both HCC and underlying liver cirrhosis, all the other treatments have to match with higher rate of HCC recurrence. The latter can be classified into curative (resection and percutaneous ablation) and palliative treatments. The aim of this paper was to review the current knowledge on management of HCC and to enlighten the areas of uncertainty.
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Maggs JRL, Suddle AR, Aluvihare V, Heneghan MA. Systematic review: the role of liver transplantation in the management of hepatocellular carcinoma. Aliment Pharmacol Ther 2012; 35:1113-34. [PMID: 22432733 DOI: 10.1111/j.1365-2036.2012.05072.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2011] [Revised: 09/18/2011] [Accepted: 03/02/2012] [Indexed: 02/06/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a major cause of morbidity and mortality worldwide. Liver transplantation offers a potential cure for this otherwise devastating disease. The selection of the most appropriate candidates is paramount in an era of graft shortage. AIM To review systematically the role of liver transplantation in the management of HCC in current clinical practice. METHODS An electronic literature search using PUBMED (1980-2010) was performed. Search terms included HCC, hepatoma, liver cancer, and liver transplantation. RESULTS Liver transplantation is a highly successful treatment for HCC, in patients within Milan criteria (MC), defined as a solitary tumour ≤50 mm in diameter or ≤3 tumours ≤30 mm in diameter in the absence of extra-hepatic or vascular spread. Other eligibility criteria for liver transplantation are also used in clinical practice, such as the University of California, San Francisco criteria, with outcomes comparable to MC. Loco-regional therapies have a role in the bridging treatment of HCC by minimising wait-list drop-out secondary to tumour progression. Beyond MC, encouraging results have been demonstrated for patients with down-staged tumours. Post-liver transplantation, there is no evidence to support a specific immunosuppressive regimen. In the context of an insufficient cadaveric donor pool to meet demand, the role of adult living donation may be increasingly important. CONCLUSIONS Liver transplantation offers a curative therapy for selected patients with HCC. The optimisation of eligibility criteria is paramount to ensure that maximum benefit is accrued. Although wait-list therapies have been incorporated into clinical practice, additional high quality data are required to support this strategy.
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Affiliation(s)
- J R L Maggs
- Institute of Liver Studies, King's College Hospital, London, UK
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33
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EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012; 56:908-43. [PMID: 22424438 DOI: 10.1016/j.jhep.2011.12.001] [Citation(s) in RCA: 4506] [Impact Index Per Article: 346.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2011] [Accepted: 12/15/2011] [Indexed: 12/04/2022]
Affiliation(s)
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- EASL Office, 7 rue des Battoirs, CH-1205 Geneva, Switzerland.
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