|
1
|
Alnagar A, Zakeri N, Koilias K, Faulkes RE, Brown R, Cain O, Perera MTPR, Roberts KJ, Sanabria-Mateos R, Bartlett DC, Ma YT, Sivakumar S, Shetty S, Shah T, Dasari BVM. SIMAP500: A novel risk score to identify recipients at higher risk of hepatocellular carcinoma recurrence following liver transplantation. World J Transplant 2024; 14:95849. [PMID: 39295983 PMCID: PMC11317860 DOI: 10.5500/wjt.v14.i3.95849] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2024] [Revised: 05/28/2024] [Accepted: 07/01/2024] [Indexed: 07/31/2024] Open
Abstract
BACKGROUND Recurrence of hepatocellular carcinoma (HCC) following liver transplantation (LT) has a devastating influence on recipients' survival; however, the risk of recurrence is not routinely stratified. Risk stratification is vital with a long LT waiting time, as that could influence the recurrence despite strict listing criteria. AIM This study aims to identify predictors of recurrence and develop a novel risk prediction score to forecast HCC recurrence following LT. METHODS A retrospective review of LT for HCC recipients at University Hospitals Birmingham between July 2011 and February 2020. Univariate and multivariate analyses were performed to identify recurrence predictors, based on which the novel SIMAP500 (satellite nodules, increase in size, microvascular invasion, AFP > 500, poor differentiation) risk score was proposed. RESULTS 234 LTs for HCC were performed with a median follow-up of 5.3 years. Recurrence developed in 25 patients (10.7%). On univariate analyses, RETREAT score > 3, α-fetoprotein (AFP) at listing 100-500 and > 500, bridging, increased tumour size between imaging at the listing time and explant histology, increase in the size of viable tumour between listing and explant, presence of satellite nodules, micro- and macrovascular invasion on explant and poor differentiation of tumours were significantly associated with recurrence, based on which, the SIMAP500 risk score is proposed. The SIMAP500 demonstrated an excellent predictive ability (c-index = 0.803) and outperformed the RETREAT score (c-index = 0.73). SIMAP500 is indicative of the time to disease recurrence. CONCLUSION SIMAP500 risk score identifies the LT recipients at risk of HCC recurrence. Risk stratification allows patient-centric post-transplant surveillance programs. Further validation of the score is recommended.
Collapse
Affiliation(s)
- Amr Alnagar
- Department of HBP and Liver Transplantation Surgery, Queen Elizabeth Hospital, University Hospitals Birmingham, Birmingham B15 2GW, United Kingdom
| | - Nekisa Zakeri
- Centre for Liver Research, Institute of Biomedical Research, Birmingham B15 2TT, United Kingdom
| | - Konstantinos Koilias
- Department of HBP and Liver Transplantation Surgery, Queen Elizabeth Hospital, University Hospitals Birmingham, Birmingham B15 2GW, United Kingdom
| | - Rosemary E Faulkes
- Department of Hepatology, Queen Elizabeth Hospital, University Hospitals Birmingham, Birmingham B15 2GW, United Kingdom
| | - Rachel Brown
- Department of Pathology, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2GW, United Kingdom
| | - Owen Cain
- Department of Pathology, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2GW, United Kingdom
| | - M Thamara P R Perera
- Department of HBP and Liver Transplantation Surgery, Queen Elizabeth Hospital, University Hospitals Birmingham, Birmingham B15 2GW, United Kingdom
| | - Keith J Roberts
- Department of HBP and Liver Transplantation Surgery, Queen Elizabeth Hospital, University Hospitals Birmingham, Birmingham B15 2GW, United Kingdom
| | - Rebeca Sanabria-Mateos
- Department of HBP and Liver Transplantation Surgery, Queen Elizabeth Hospital, University Hospitals Birmingham, Birmingham B15 2GW, United Kingdom
| | - David C Bartlett
- Department of HBP and Liver Transplantation Surgery, Queen Elizabeth Hospital, University Hospitals Birmingham, Birmingham B15 2GW, United Kingdom
| | - Yuk Ting Ma
- Department of Oncology, Queen Elizabeth Hospital, University Hospitals of Birmingham, Birmingham B15 2GW, United Kingdom
| | - Shivan Sivakumar
- Department of Oncology, Queen Elizabeth Hospital, University Hospitals of Birmingham, Birmingham B15 2GW, United Kingdom
| | - Shishir Shetty
- Centre for Liver Research, Institute of Biomedical Research, Birmingham B15 2TT, United Kingdom
| | - Tahir Shah
- Department of Hepatology, Queen Elizabeth Hospital, University Hospitals Birmingham, Birmingham B15 2GW, United Kingdom
| | - Bobby V M Dasari
- Department of HBP and Liver Transplantation Surgery, Queen Elizabeth Hospital, University Hospitals Birmingham, Birmingham B15 2GW, United Kingdom
| |
Collapse
|
|
2
|
Endo Y, Moazzam Z, Alaimo L, Woldesenbet S, Lima HA, Munir MM, Katayama E, Yang J, Azap L, Shaikh CF, Ratti F, Marques HP, Cauchy F, Lam V, Poultsides GA, Kitago M, Popescu I, Alexandrescu S, Martel G, Guglielmi A, Gleisner A, Hugh T, Aldrighetti L, Shen F, Endo I, Pawlik TM. Modified integrated tumor burden, liver function, systemic inflammation, and tumor biology score to predict long-term outcomes after resection for hepatocellular carcinoma. HPB (Oxford) 2023; 25:1484-1493. [PMID: 37544855 DOI: 10.1016/j.hpb.2023.07.901] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 05/15/2023] [Accepted: 07/20/2023] [Indexed: 08/08/2023]
Abstract
BACKGROUND A preoperative predictive score for hepatocellular carcinoma (HCC) can help stratify patients who undergo resection relative to long-term outcomes and tailor treatment strategies. METHODS Patients who underwent curative-intent hepatectomy for HCC between 2000 and 2020 were identified from an international multi-institutional database. A risk score (mFIBA) was developed using an Eastern cohort and then validated using a Western cohort. RESULTS Among 957 patients, 443 and 514 patients were included from the Eastern and Western cohorts, respectively. On multivariable analysis, alpha-feto protein (HR1.97, 95%CI 1.42-2.72), neutrophil-to-lymphocyte ratio (HR1.74, 95%CI 1.28-2.38), albumin-bilirubin grade (HR1.66, 95%CI 1.21-2.28), and imaging tumor burden score (HR1.25, 95%CI 1.12-1.40) were associated with OS. The c-index in the Eastern test and Western validation cohorts were 0.69 and 0.67, respectively. Notably, mFIBA score outperformed previous HCC staging systems. 5-year OS incrementally decreased with an increase in mFIBA. On multivariable Cox regression analysis, the mFIBA score was associated with worse OS (HR1.18, 95%CI 1.13-1.23) and higher risk of recurrence (HR1.16, 95%CI 1.11-1.20). An easy-to-use calculator of the mFIBA score was made available online (https://yutaka-endo.shinyapps.io/mFIBA_score/). DISCUSSION The online mFIBA calculator may help surgeons with clinical decision-making to individualize perioperative treatment strategies for patients undergoing resection of HCC.
Collapse
Affiliation(s)
- Yutaka Endo
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Zorays Moazzam
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Laura Alaimo
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA; Department of Surgery, University of Verona, Verona, Italy
| | - Selamawit Woldesenbet
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Henrique A Lima
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Muhammad M Munir
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Erryk Katayama
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Jason Yang
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Lovette Azap
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Chanza F Shaikh
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | | | - Hugo P Marques
- Department of Surgery, Curry Cabral Hospital, Lisbon, Portugal
| | - François Cauchy
- Department of Hepatobiliopancreatic Surgery, APHP, Beaujon Hospital, Clichy, France
| | - Vincent Lam
- Department of Surgery, Westmead Hospital, Sydney, NSW, Australia
| | | | - Minoru Kitago
- Department of Surgery, Keio University, Tokyo, Japan
| | - Irinel Popescu
- Department of Surgery, Fundeni Clinical Institute, Bucharest, Romania
| | | | | | | | - Ana Gleisner
- Department of Surgery, University of Colorado, Denver, CO, USA
| | - Tom Hugh
- Department of Surgery, School of Medicine, The University of Sydney, Sydney, NSW, Australia
| | | | - Feng Shen
- Department of Hepatic Surgery IV, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Itaru Endo
- Yokohama City University School of Medicine, Yokohama, Japan
| | - Timothy M Pawlik
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA.
| |
Collapse
|
|
3
|
Norman JS, Li PJ, Kotwani P, Shui AM, Yao F, Mehta N. AFP-L3 and DCP strongly predict early hepatocellular carcinoma recurrence after liver transplantation. J Hepatol 2023; 79:1469-1477. [PMID: 37683735 PMCID: PMC10998694 DOI: 10.1016/j.jhep.2023.08.020] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 07/27/2023] [Accepted: 08/22/2023] [Indexed: 09/10/2023]
Abstract
BACKGROUND & AIMS Alpha-fetoprotein (AFP) predicts hepatocellular carcinoma (HCC) recurrence after liver transplant (LT) but remains an imperfect biomarker. The role of DCP (des-gamma-carboxyprothrombin) and AFP-L3 (AFP bound to Lens culinaris agglutinin) in predicting HCC recurrence remains incompletely characterized. AFP-L3 and DCP could identify patients at high risk of post-transplant HCC recurrence and serve as liver transplant exclusion criteria to defer transplant until patients receive additional risk-reducing pre-transplant locoregional therapy. METHODS This prospective cohort study included consecutive patients with HCC who underwent LT (within or down-staged to Milan criteria) between 2017 and 2022. Pre-transplant AFP, AFP-L3, and DCP measurements were obtained. The primary endpoint was the ability of biomarkers to predict HCC recurrence-free survival. RESULTS This cohort included 285 patients with a median age of 67 (IQR 63-71). At LT, median biomarker values were AFP 5.0 ng/ml (IQR 3.0-12.1), AFP-L3 6.7% (0.5-13.2), and DCP 1.0 ng/ml (0.3-2.8). Most (94.7%) patients received pre-LT locoregional therapy. After a median post-LT follow-up of 3.1 years, HCC recurrence was observed in 18 (6.3%) patients. AFP-L3 and DCP outperformed AFP with C-statistics of 0.81 and 0.86 respectively, compared with 0.74 for AFP. A dual-biomarker combination of AFP-L3 ≥15% and DCP ≥7.5 predicted 61.1% of HCC recurrences, whereas HCC only recurred in 7 of 265 (2.6%) patients not meeting this threshold. The Kaplan-Meier recurrence-free survival rate at 3 years post-LT was 43.7% for patients with dual-positive biomarkers compared to 97.0% for all others (p <0.001). CONCLUSIONS Dual-positivity for AFP-L3 ≥15% and DCP ≥7.5 strongly predicted post-LT HCC recurrence. This model could refine LT selection criteria and identify high-risk patients who require additional locoregional therapy prior to LT. IMPACT AND IMPLICATIONS Alpha-fetoprotein (AFP) is used to predict hepatocellular carcinoma (HCC) recurrence after liver transplant, but it remains an imperfect biomarker. In this prospective study, the biomarkers DCP (des-gamma-carboxyprothrombin) and AFP-L3 (AFP bound to Lens culinaris agglutinin) strongly predicted early HCC recurrence and outperformed AFP. A dual-biomarker combination of AFP-L3 ≥15% and DCP ≥7.5 predicted the majority of recurrences and could be used to further refine liver transplant eligibility criteria.
Collapse
Affiliation(s)
- Joshua S Norman
- University of California San Francisco School of Medicine, San Francisco, CA, USA; Department of Internal Medicine, Stanford, CA, USA
| | - P Jonathan Li
- University of California San Francisco School of Medicine, San Francisco, CA, USA
| | - Prashant Kotwani
- Division of Gastroenterology and Hepatology, Department of Medicine, University of California San Francisco, San Francisco, California, USA
| | - Amy M Shui
- Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA
| | - Francis Yao
- Division of Gastroenterology and Hepatology, Department of Medicine, University of California San Francisco, San Francisco, California, USA
| | - Neil Mehta
- Division of Gastroenterology and Hepatology, Department of Medicine, University of California San Francisco, San Francisco, California, USA.
| |
Collapse
|
|
4
|
van der Meeren PE, de Wilde RF, Sprengers D, IJzermans JNM. Benefit and harm of waiting time in liver transplantation for HCC. Hepatology 2023:01515467-990000000-00646. [PMID: 37972979 DOI: 10.1097/hep.0000000000000668] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 10/26/2023] [Indexed: 11/19/2023]
Abstract
Liver transplantation is the most successful treatment for limited-stage HCC. The waiting time for liver transplantation (LT) can be a critical factor affecting the oncological prognosis and outcome of patients with HCC. Efficient strategies to optimize waiting time are essential to maximize the benefits of LT and to reduce the harm of delay in transplantation. The ever-increasing demand for donor livers emphasizes the need to improve the organization of the waiting list for transplantation and to optimize organ availability for patients with and without HCC. Current progress in innovations to expand the donor pool includes the implementation of living donor LT and the use of grafts from extended donors. By expanding selection criteria, an increased number of patients are eligible for transplantation, which necessitates criteria to prevent futile transplantations. Thus, the selection criteria for LT have evolved to include not only tumor characteristics but biomarkers as well. Enhancing our understanding of HCC tumor biology through the analysis of subtypes and molecular genetics holds significant promise in advancing the personalized approach for patients. In this review, the effect of waiting time duration on outcome in patients with HCC enlisted for LT is discussed.
Collapse
Affiliation(s)
- Pam Elisabeth van der Meeren
- Department of Surgery, Division of HPB & Transplant Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Roeland Frederik de Wilde
- Department of Surgery, Division of HPB & Transplant Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Dave Sprengers
- Department of Gastroenterology & Hepatology, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Jan Nicolaas Maria IJzermans
- Department of Surgery, Division of HPB & Transplant Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands
| |
Collapse
|
|
5
|
Frager SZ, Cooper W, Saenger Y, Schwartz JM. Treatment of recurrent hepatocellular carcinoma following liver resection, ablation or liver transplantation. World J Meta-Anal 2023; 11:47-54. [DOI: 10.13105/wjma.v11.i2.47] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 11/30/2022] [Accepted: 01/17/2023] [Indexed: 02/02/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and causes one third of cancer related deaths world-wide. Approximately one third of patients with HCC are eligible for curative treatments that include hepatic resection, liver transplantation or imaging guided tumor ablation. Recurrence rates after primary therapy depends on tumor biology and pre-treatment tumor burden with early recurrence rates ranging from 30%-80% following surgical resection and ablation. HCC recurs in over ten percent following liver transplantation for HCC. Treatment modalities for tumor recurrence following resection and ablation include repeat liver resection, salvage liver transplantation, locoregional therapies, and systemic chemotherapy/immunotherapy. Locoregional and immune mediated therapies are limited for patients with tumor recurrence following liver transplantation given potential immune related allograft rejection. Given the high HCC recurrence rates after primary tumor treatment, it is imperative for the clinician to review the appropriate treatment strategy for this disease entity. This article will review the current literature regarding HCC recurrence after primary curative therapies and will discuss the relevant future trends in the HCC field.
Collapse
Affiliation(s)
- Shalom Z Frager
- Department of Medicine, Division of Hepatology, Montefiore Medical Center, Bronx, NY 10467, United States
| | - Weston Cooper
- Cancer Center, Montefiore Medical Center, Bronx, NY 10467, United States
| | - Yvonne Saenger
- Cancer Center, Montefiore Medical Center, Bronx, NY 10467, United States
| | - Jonathan M Schwartz
- Department of Medicine, Division Hepatology, Montefiore Medical Center, Bronx, NY 10467, United States
| |
Collapse
|
|
6
|
Posttransplant Hepatocellular Carcinoma Surveillance: A Cost-effectiveness and Cost-utility Analysis. Ann Surg 2023; 277:e359-e365. [PMID: 34928553 DOI: 10.1097/sla.0000000000005295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE Assess cost-effectiveness and -utility associated with posttransplant HCC surveillance compared to standard follow-up. SUMMARY OF BACKGROUND DATA Despite lack of prospective clinical data, expert consensus recommends posttransplant surveillance to detect HCC recurrence in a latent phase, while it might be amenable to curative-intent therapy. METHODS A Markov-based transition model was created to estimate life expectancy and quality-of-life among liver transplant patients undergoing HCC surveillance. Models were built for 2 cohorts: 1 undergoing HCC surveillance with contrast-enhanced computed tomography of chest and abdomen and serum alpha-fetoprotein analysis and the other receiving standard posttransplant follow-up. Primary model outputs included LY and QALY gains, incremental cost-effectiveness ratio, and incremental cost-utility ratio. Willingness-to-pay for a QALY gain (cost-effectiveness threshold) was used to estimate efficiency. RESULTS Surveillance was marginally more effective versus no surveillance, resulting in means of 0.069 LYs and 0.026 QALYs gained. Costs for surveillance were increased by an average of 988.32€, resulting in incremental cost-effectiveness ratio 14,410.15€/LY and incremental cost-utility ratio 37,547.97€/QALY. Surveillance did not seem cost-effective in our setting, considering willingness-to-pay threshold of 25,000€/QALY. Probabilistic sensitivity analysis indicated surveillance might be cost-effective in 42% of cases, but degree of uncertainty in the analysis was high. CONCLUSIONS Performing posttransplant HCC surveillance offers marginal clinical benefits and increases costs. Although expert consensus supports surveillance, results of this decision analysis raise doubt regarding the utility of such recommendations and support ongoing need for prospective clinical trials.
Collapse
|
|
7
|
Milana F, Polidoro MA, Famularo S, Lleo A, Boldorini R, Donadon M, Torzilli G. Surgical Strategies for Recurrent Hepatocellular Carcinoma after Resection: A Review of Current Evidence. Cancers (Basel) 2023; 15:cancers15020508. [PMID: 36672457 PMCID: PMC9856445 DOI: 10.3390/cancers15020508] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 01/07/2023] [Accepted: 01/10/2023] [Indexed: 01/17/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer, and both liver resection and liver transplantation are considered potentially curative options. However, high recurrence rates affect the prognosis depending both on the primary HCC pathology characteristics or on the type and time of the relapse. While great attention has been usually posted on treatment algorithms for the first HCC, treatment algorithms for recurrent HCC (rHCC) are lacking. In these cases, surgery still represents a curative option with both redo hepatectomy and/or salvage liver transplantation, which are considered valid treatments in selected patients. In the current era of personalised medicine with promises of new systemic-targeted immuno-chemotherapies, we wished to perform a narrative review of the literature on the role of surgical strategies for rHCC.
Collapse
Affiliation(s)
- Flavio Milana
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, MI, Italy
- Department of Hepatobiliary and General Surgery, IRCCS Humanitas Research Hospital, 20089 Rozzano, MI, Italy
| | - Michela Anna Polidoro
- Hepatobiliary Immunopathology Laboratory, IRCCS Humanitas Research Hospital, 20089 Rozzano, MI, Italy
| | - Simone Famularo
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, MI, Italy
- Department of Hepatobiliary and General Surgery, IRCCS Humanitas Research Hospital, 20089 Rozzano, MI, Italy
| | - Ana Lleo
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, MI, Italy
- Department of Internal Medicine, IRCCS Humanitas Research Hospital, 20089 Rozzano, MI, Italy
| | - Renzo Boldorini
- Department of Health Sciences, Università del Piemonte Orientale, 28100 Novara, NO, Italy
- Department of Pathology, University Maggiore Hospital, 28100 Novara, NO, Italy
| | - Matteo Donadon
- Hepatobiliary Immunopathology Laboratory, IRCCS Humanitas Research Hospital, 20089 Rozzano, MI, Italy
- Department of Health Sciences, Università del Piemonte Orientale, 28100 Novara, NO, Italy
- Department of General Surgery, University Maggiore Hospital, 28100 Novara, NO, Italy
- Correspondence:
| | - Guido Torzilli
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, MI, Italy
- Department of Hepatobiliary and General Surgery, IRCCS Humanitas Research Hospital, 20089 Rozzano, MI, Italy
| |
Collapse
|
|
8
|
Sposito C, Citterio D, Virdis M, Battiston C, Droz Dit Busset M, Flores M, Mazzaferro V. Therapeutic strategies for post-transplant recurrence of hepatocellular carcinoma. World J Gastroenterol 2022; 28:4929-4942. [PMID: 36160651 PMCID: PMC9494935 DOI: 10.3748/wjg.v28.i34.4929] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 03/05/2022] [Accepted: 07/26/2022] [Indexed: 02/06/2023] Open
Abstract
Despite stringent selection criteria, hepatocellular carcinoma recurrence after liver transplantation (LT) still occurs in up to 20% of cases, mostly within the first 2–3 years. No adjuvant treatments to prevent such an occurrence have been developed so far. However, a balanced use of immunosuppression with minimal dose of calcineurin inhibitors and possible addition of mammalian target of rapamycin inhibitors is strongly advisable. Moreover, several pre- and post-transplant predictors of recurrence have been identified and may help determine the frequency and duration of post-transplant follow-up. When recurrence occurs, the outcomes are poor with a median survival of 12 mo according to most retrospective studies. The factor that most impacts survival after recurrence is timing (within 1–2 years from LT according to different authors). Several therapeutic options may be chosen in case of recurrence, according to timing and disease presentation. Surgical treatment seems to provide a survival benefit, especially in case of late recurrence, while the benefit of locoregional treatments has been suggested only in small retrospective studies. When systemic treatment is indicated, sorafenib has been proved safe and effective, while only few data are available for lenvatinib and regorafenib in second line. The use of immune checkpoint inhibitors is controversial in this setting, given the safety warnings for the risk of acute rejection.
Collapse
Affiliation(s)
- Carlo Sposito
- HPB Surgery, Hepatology and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori di Milano, Milan 20133, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan 20100, Italy
| | - Davide Citterio
- HPB Surgery, Hepatology and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori di Milano, Milan 20133, Italy
| | - Matteo Virdis
- HPB Surgery, Hepatology and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori di Milano, Milan 20133, Italy
| | - Carlo Battiston
- HPB Surgery, Hepatology and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori di Milano, Milan 20133, Italy
| | - Michele Droz Dit Busset
- HPB Surgery, Hepatology and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori di Milano, Milan 20133, Italy
| | - Maria Flores
- HPB Surgery, Hepatology and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori di Milano, Milan 20133, Italy
| | - Vincenzo Mazzaferro
- HPB Surgery, Hepatology and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori di Milano, Milan 20133, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan 20100, Italy
| |
Collapse
|
|
9
|
Agarwal PD, Lucey MR. Management of hepatocellular carcinoma recurrence after liver transplantation. Ann Hepatol 2022; 27:100654. [PMID: 34929349 DOI: 10.1016/j.aohep.2021.100654] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 11/30/2021] [Accepted: 11/30/2021] [Indexed: 02/04/2023]
Abstract
Despite careful selection for liver transplantation (LT) of patients with hepatocellular carcinoma (HCC), HCC may still recur after LT and is frequently associated with dismal outcome. Tumor factors, including serum alpha-fetoprotein (AFP), the presence of microvascular invasion, tumor grade/differentiation, and largest tumor size are amongst the most important predictors of recurrence after transplantation. The nature of recurrence can be highly variable, but often presents with extra-hepatic involvement. As such, management of patients with HCC can be challenging, and consensus guidelines are lacking. Curative options, with surgery or ablation, which may be applicable in patients with isolated intra-or extrahepatic metastases, offer the best chance for improved long-term outcome in patients with HCC recurrence after transplantation. Most patients with recurrence have unresectable disease, and may benefit from palliative treatments, including intra-arterial therapies and/or systemic therapy.
Collapse
Affiliation(s)
- Parul D Agarwal
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, 1685 Highland Avenue, Suite 4224, Madison, WI 53705, United States.
| | - Michael R Lucey
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, 1685 Highland Avenue, Suite 4224, Madison, WI 53705, United States
| |
Collapse
|
|
10
|
Au KP, Fung JYY, Dai WC, Chan ACY, Lo CM, Chok KSH. Verifying the Benefits of Radical Treatment in Posttransplant Hepatocellular Carcinoma Oligo-recurrence: A Propensity Score Analysis. Liver Transpl 2022; 28:51-64. [PMID: 34351682 DOI: 10.1002/lt.26251] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 07/22/2021] [Accepted: 08/03/2021] [Indexed: 12/13/2022]
Abstract
This study verified whether radical treatment for hepatocellular carcinoma (HCC) oligo-recurrence after liver transplantation conveys survival benefits. A retrospective study of 144 patients with posttransplant HCC recurrence was performed. Propensity score matching was performed to adjust for baseline covariates between patients who received radical and palliative treatments. The primary endpoint was postrecurrence survival. A total of 50 patients (35%) received radical treatment for recurrence, and 76 (53%) and 18 (13%) patients received palliative and supportive treatments, respectively. Compared with the radical group, patients who received palliative treatment had more early recurrences (time from transplant 17 versus 11 months; P = 0.01) and more extensive disease in terms of tumor numbers (1 versus 4; P < 0.001), size of largest tumor (1.8 versus 2.5 cm; P = 0.046), numbers of involved organs (interquartile range [IQR], 1-1 versus 1-2; P = 0.02), and alpha-fetoprotein (AFP) level (7 versus 40 ng/mL; P = 0.01). Multivariate Cox regression analysis revealed that early recurrence (time from transplant hazard ratio [HR], 1.02; 95% confidence interval [CI], 1.01-1.03; P = 0.001), larger recurrent tumor (HR, 1.12; 95% CI, 1.03-1.23; P = 0.01), liver recurrence (HR, 1.84; 95% CI, 1.17-2.90; P = 0.01), and log10 AFP level at recurrence (HR, 1.27; 95% CI, 1.07-1.52; P = 0.01) predicted poor survival. Mammalian target of rapamycin inhibitor (HR, 0.331; 95% CI, 0.213-0.548; P < 0.001) and radical treatment (HR, 0.342; 95% CI, 0.213-0.548; P < 0.001) were associated with improved survival. After 2-to-1 propensity score matching for covariates, the 50 patients who received curative treatment survived significantly longer than the 25 matched patients who received palliative treatment (median survival time, 30.9 ± 2.4 versus 19.5 ± 3.0 months; P = 0.01). Radical treatment conveys survival benefits to HCC oligo-recurrence after liver transplantation.
Collapse
Affiliation(s)
- Kin Pan Au
- Department of Surgery, Queen Mary Hospital, Hong Kong, China
| | - James Yan Yue Fung
- Department of Surgery and State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China
| | - Wing Chiu Dai
- Department of Surgery and State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China
| | - Albert Chi Yan Chan
- Department of Surgery and State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China
| | - Chung Mau Lo
- Department of Surgery and State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China
| | - Kenneth Siu Ho Chok
- Department of Surgery and State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China
| |
Collapse
|
|
11
|
Al-Ameri A, Yu X, Zheng S. Predictors of post-recurrence survival in hepatocellular carcinoma patients following liver transplantation: Systematic review and meta-analysis. Transplant Rev (Orlando) 2021; 36:100676. [PMID: 34999555 DOI: 10.1016/j.trre.2021.100676] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 12/12/2021] [Accepted: 12/14/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND Data on predictors of post-recurrence survival (PRS) of recurrent hepatocellular carcinoma (HCC) after liver transplantation (LT) have not been reviewed and analysed systematically. We aimed to systematically analyse all published data on the predictors for PRS. METHODS In accordance with PRISMA and MOOSE guidelines, online search of PubMed and EMBASE databases was done for all reports that evaluate the predictors of PRS based on multivariate analyses. Cumulative analyses of hazard ratios (HRs) and their corresponding 95% CIs were conducted to assess the potential predictors of PRS. RESULTS Twenty-three studies met the inclusion criteria. Among the 11,868 patients involved, 1921 (16%) had HCC recurrence within a median time of 16 months. The following were recurrence and tumour-related predictors: time to recurrence (<1 year; HR: 1.97; p < 0.001), AFP level at recurrence(≥100 ng/ml; HR: 1.82; p < 0.001), multiple recurrence (HR: 1.22; p < 0.001), bone recurrence (HR: 2.10; p < 0.001), poor differentiation (HR: 1.52; p < 0.001), intrahepatic recurrence (HR: 0.91; p = 0.03), extrahepatic recurrence (HR: 1.87; p < 0.001), Milan criteria at LT (HR: 1.34; p < 0.001), microvascular invasion (HR: 1.59; p < 0.001), multiorgan recurrence (HR: 1.28; p < 0.001), and recurrent HCV infection (HR: 1.21; p < 0.001). The treatment-related predictors were as follows: surgical resection (HR: 0.33; p < 0.001), mTOR inhibitors (HR: 0.63; p < 0.001), sorafenib (HR: 1.00; p = 0.01), palliative treatment (HR: 3.07; p < 0.001), RFA (HR: 0.47; p < 0.001), and radiotherapy (HR: 1.19; p < 0.001). CONCLUSIONS Systematic evaluation of these predictors could guide surgeons to design risk-adapted algorithms for the management of post-LT HCC recurrence to construct reliable predictive models and to design future prospective studies or clinical trials.
Collapse
Affiliation(s)
- Abdulahad Al-Ameri
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; NHC Key Laboratory of Combined Multi-organ Transplantation, China; Key Laboratory of the diagnosis and treatment of organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences, China; Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Zhejiang Province, Hangzhou 310003, China
| | - Xiaobo Yu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; NHC Key Laboratory of Combined Multi-organ Transplantation, China; Key Laboratory of the diagnosis and treatment of organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences, China; Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Zhejiang Province, Hangzhou 310003, China
| | - Shusen Zheng
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; NHC Key Laboratory of Combined Multi-organ Transplantation, China; Key Laboratory of the diagnosis and treatment of organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences, China; Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Zhejiang Province, Hangzhou 310003, China.
| |
Collapse
|
|
12
|
Efficacy and Safety of Lenvatinib in Hepatocellular Carcinoma Patients with Liver Transplantation: A Case-Control Study. Cancers (Basel) 2021; 13:cancers13184584. [PMID: 34572811 PMCID: PMC8469287 DOI: 10.3390/cancers13184584] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 09/06/2021] [Accepted: 09/11/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Growing evidence has reported the role of sorafenib in hepatocellular carcinoma (HCC) patients with liver transplantation (LT). However, the clinical impact of lenvatinib in this population is limited. Our study enrolled 10 HCC patients who received lenvatinib after LT in our institute. Partial response was 20% and disease control rate was 70%. The median progression-free survival and overall survival were 3.7 and 16.4 months, respectively. Adverse events (AEs) were predominantly grade 1–2 in severity, and the majority of patients tolerated. Additionally, 25 HCC patients without LT who underwent lenvatinib treatment were identified as the control group; there was no significant difference in survival or AEs between these two groups. The significance of our study is that it is the first to investigate the efficacy and safety of lenvatinib among HCC patients with LT. It provides more information to physicians about the role of lenvatinib in this special population in clinical practice. Abstract Tumor recurrence is the most common cause of death in hepatocellular carcinoma (HCC) patients who received liver transplantation (LT). Recently, lenvatinib was approved for the systemic treatment of unresectable HCC patients; however, the role of lenvatinib in HCC patients after LT remains unclear. There were 56 patients with recurrent HCC after LT from 2008 to 2018 in our institute, and 10 patients who received lenvatinib were identified. Additionally, to understand the difference in the clinical impact of lenvatinib in the LT and non-LT settings, 25 HCC patients without LT who underwent lenvatinib treatment were identified from our HCC database and regarded as the control group. In the LT group, partial response was 20% and stable disease was 50%, resulting in a disease control rate of 70%; the median progression-free survival (PFS), time to treatment failure (TTF) and overall survival (OS) were 3.7, 3.6 and 16.4 months, respectively. Adverse events (AEs) were predominantly grade 1–2 in severity, and the majority of patients tolerated the side effects. There was no significant difference in PFS/OS, and we observed a similar pattern of AEs between these two groups. Our study confirms the comparable efficacy and safety of lenvatinib in HCC patients with LT and non-LT in clinical practice.
Collapse
|
|
13
|
Piñero F, Tanno M, Aballay Soteras G, Tisi Baña M, Dirchwolf M, Fassio E, Ruf A, Mengarelli S, Borzi S, Fernández N, Ridruejo E, Descalzi V, Anders M, Mazzolini G, Reggiardo V, Marciano S, Perazzo F, Spina JC, McCormack L, Maraschio M, Lagues C, Gadano A, Villamil F, Silva M, Cairo F, Ameigeiras B. Argentinian clinical practice guideline for surveillance, diagnosis, staging and treatment of hepatocellular carcinoma. Ann Hepatol 2021; 19:546-569. [PMID: 32593747 DOI: 10.1016/j.aohep.2020.06.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 06/05/2020] [Accepted: 06/10/2020] [Indexed: 02/08/2023]
Abstract
The A.A.E.E.H has developed this guideline for the best care of patients with hepatocellular carcinoma (HCC) from Argentina. It was done from May 2018 to March 2020. Specific clinical research questions were systematically searched. The quality of evidence and level of recommendations were organized according to GRADE. HCC surveillance is strongly recommended with abdominal ultrasound (US) every six months in the population at risk for HCC (cirrhosis, hepatitis B or hepatitis C); it is suggested to add alpha-feto protein (AFP) levels in case of inexeperienced sonographers. Imaging diagnosis in patients at risk for HCC has high specificity and tumor biopsy is not mandatory. The Barcelona Clinic Liver Cancer algorithm is strongly recommended for HCC staging and treatment-decision processes. Liver resection is strongly recommended for patients without portal hypertension and preserved liver function. Composite models are suggested for liver transplant selection criteria. Therapies for HCC with robust clinical evidence include transarterial chemoembolization (TACE) and first to second line systemic treatment options (sorafenib, lenvatinib, regorafenib, cabozantinib and ramucirumab). Immunotherapy with nivolumab and pembrolizumab has failed to show statistical benefit but the novel combination of atezolizumab plus bevacizumab has recently shown survival benefit over sorafenib in frontline.
Collapse
Affiliation(s)
- Federico Piñero
- Hepatology and Liver Unit, Hospital Universitario Austral, School of Medicine, Austral University, B1629HJ Buenos Aires, Argentina.
| | - Mario Tanno
- Hospital Centenario de Rosario, Santa Fe, Argentina
| | | | - Matías Tisi Baña
- Internal Medicine and Epidemiology Department, Hospital Universitario Austral, School of Medicine, Austral University, B1629HJ Buenos Aires, Argentina
| | | | | | - Andrés Ruf
- Hospital Privado de Rosario, Santa Fe, Argentina
| | | | - Silvia Borzi
- Instituto Rossi, La Plata, Buenos Aires, Argentina
| | | | - Ezequiel Ridruejo
- Hepatology and Liver Unit, Hospital Universitario Austral, School of Medicine, Austral University, B1629HJ Buenos Aires, Argentina; Centro de Educación Médica e Investigaciones Clínicas (CEMIC), Ciudad de Buenos Aires, Argentina
| | | | | | - Guillermo Mazzolini
- Hepatology and Liver Unit, Hospital Universitario Austral, School of Medicine, Austral University, B1629HJ Buenos Aires, Argentina
| | | | | | | | | | | | | | - Cecilia Lagues
- Hepatology and Liver Unit, Hospital Universitario Austral, School of Medicine, Austral University, B1629HJ Buenos Aires, Argentina
| | | | | | - Marcelo Silva
- Hepatology and Liver Unit, Hospital Universitario Austral, School of Medicine, Austral University, B1629HJ Buenos Aires, Argentina
| | | | | | | |
Collapse
|
|
14
|
Early Versus Late Hepatocellular Carcinoma Recurrence After Transplantation: Predictive Factors, Patterns, and Long-term Outcome. Transplantation 2021; 105:1778-1790. [PMID: 32890134 DOI: 10.1097/tp.0000000000003434] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is currently the first indication of liver transplantation (LT) in Europe and Asia-Pacific region and the third in the United States. HCC recurrence is the main complication affecting short- and medium-term outcomes after LT. METHODS A total of 433 consecutive adult recipients transplanted for HCC between 2000 and 2017 (mean age: 57.8 ± 8.5 y; 83.8% were males) with a mean follow-up of 74.6 ± 58.6 months were included. Patients had to meet Milan criteria and, since 2014, alpha-fetoprotein score to be listed. Patients with HCC recurrence were classified into early (≤2 y) and late recurrence (>2 y) and were retrospectively reviewed. RESULTS Patients who developed recurrence (75 patients, 17%) had more tumors outside Milan and University of California San Francisco criteria, high alpha-fetoprotein score, and microvascular invasion at pathology. Early recurrence developed in 46 patients (61.3%); the overall 5- and 10-year survival rates of these patients from time of LT were 6.7% and 0%, which were significantly lower than those with late recurrence 64.0% and 27.1%, respectively (P < 0.001). The median survival times from the diagnosis of HCC recurrence were 15 and 17 months, respectively, in the 2 groups (P < 0.001). Multivariable Cox regression analysis identified alcoholic cirrhosis as etiology of the underlying liver disease (hazard ratio [HR] = 3.074; P = 0.007), bilobar tumor at time of LT (HR = 2.001; P = 0.037), and a tumor size (>50 mm) in the explant (HR = 1.277; P = 0.045) as independent predictors of early recurrence. CONCLUSIONS Improving the prediction of early HCC recurrence could optimize patient selection for LT, potential adjuvant therapy with new targeted drugs and hence, improve long-term survival.
Collapse
|
|
15
|
Li BCW, Chiu J, Shing K, Kwok GGW, Tang V, Leung R, Ma KW, She WH, Tsang J, Chan A, Cheung TT, Lo CM, Yau T. The Outcomes of Systemic Treatment in Recurrent Hepatocellular Carcinomas Following Liver Transplants. Adv Ther 2021; 38:3900-3910. [PMID: 34061324 DOI: 10.1007/s12325-021-01800-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Accepted: 05/19/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Treatment of hepatocellular carcinoma (HCC) recurrences following liver transplant (LT) is challenging. Most clinical trials of systemic therapies for advanced HCC excluded patients with any history of organ transplant. We aimed to assess the outcomes in using various systemic therapies in patients with post-LT recurrence. METHODS Consecutive patients with HCC and recurrences following LT at a large tertiary centre from 2005 to 2018 were reviewed. Overall survival (OS), response rates and adverse events (AEs) were analysed. RESULTS Forty-three consecutive patients with a recurrence of HCC following LT were identified from 2005 to 2018. Median OS from diagnosis of recurrence was 17 months (CI 11.3, 22.7). Early recurrence within 12 months of transplant was associated with a significantly worse median survival of 10 months (CI 8.5, 11.4) compared to 26 months (CI 18.8, 33.2) when recurrences occurred after 12 months from transplant (p < 0.001) with a hazard ratio of 0.104 (log-rank test, p < 0.001). A total of 41 patients had received systemic therapies and 79.1% of them were on sorafenib as the first-line treatment. Among these patients treated with sorafenib, median OS from recurrence was 14 months (CI 7.3, 20.7). Hand-foot syndrome (34.7%) was most common among AEs followed by diarrhoea (26.7%). Overall, AEs led to dose interruptions in 8.8% of patients. Notably, 47.1% of patients received subsequent lines of systemic therapies after sorafenib. CONCLUSIONS Early recurrence within 1 year from transplant was the most significant risk factor. Treatment efficacy and adverse events and tolerability of sorafenib were comparable with those in the setting of advanced HCC without transplant.
Collapse
Affiliation(s)
- Bryan Cho Wing Li
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, 102 Pokfulam Road, Hong Kong, China
| | - Joanne Chiu
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, 102 Pokfulam Road, Hong Kong, China
| | - Kit Shing
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, 102 Pokfulam Road, Hong Kong, China
| | - Gerry Gin Wai Kwok
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, 102 Pokfulam Road, Hong Kong, China
| | - Vikki Tang
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, 102 Pokfulam Road, Hong Kong, China
| | - Roland Leung
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, 102 Pokfulam Road, Hong Kong, China
| | - Ka Wing Ma
- Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Wong Hoi She
- Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Josephine Tsang
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, 102 Pokfulam Road, Hong Kong, China
| | - Albert Chan
- Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Tan To Cheung
- Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Chung Mau Lo
- Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Thomas Yau
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, 102 Pokfulam Road, Hong Kong, China.
| |
Collapse
|
|
16
|
Abstract
BACKGROUND Liver transplantation is the best treatment option for hepatocellular carcinoma (HCC). Although centers use strict selection criteria, there is a risk of recurrence, reaching up to 20% which are mostly observed within two years following the procedure. The survival after the recurrence is poor and it has been reported to be between 7-16 months. This poor prognosis is due to the systemic course of the recurrence even its presentation is local initially. RESULTS The clinical management and treatment algorithm of recurrence is challenging and there is no guideline regarding the situation. Staging of the disease and multi-disciplinary approach are important. The decision for choice of treatment is given depending on the localization and spread of the recurrence. Adjusting and switching the immunosuppressive therapy should be the first attempt. When the recurrence is limited or confined to resectable regions, surgery should be the choice of treatment. Multiple recurrence sites such as adrenal glands, lung, lymph nodes are not contraindication for curative surgery. Resection of the graft for intrahepatic recurrence is the most beneficial procedure for survival. If resection is not possible due to advanced hepatic disease, loco-regional therapies such as TACE, RF, microwave ablation should be considered. SBRT may be an alternative both for hepatic and extra-hepatic recurrence. In case of systemic disease, sorafenib should be the drug choice.
Collapse
Affiliation(s)
- Baris Sarici
- Departmant of Surgery, Liver Transplantation Institute, Inonu University, 44315, Malatya, Turkey.
| | - Burak Isik
- Departmant of Surgery, Liver Transplantation Institute, Inonu University, 44315, Malatya, Turkey
| | - Sezai Yilmaz
- Departmant of Surgery, Liver Transplantation Institute, Inonu University, 44315, Malatya, Turkey
| |
Collapse
|
|
17
|
Maccali C, Chagas AL, Boin I, Quiñonez E, Marciano S, Vilatobá M, Varón A, Anders M, Hoyos Duque S, Lima AS, Menendez J, Padilla-Machaca M, Poniachik J, Zapata R, Maraschio M, Chong Menéndez R, Muñoz L, Arufe D, Figueroa R, Soza A, Fauda M, Perales SR, Vergara Sandoval R, Bermudez C, Beltran O, Arenas Hoyos I, McCormack L, Mattera FJ, Gadano A, Parente García JH, Tani CM, Augusto Carneiro D'Albuquerque L, Carrilho FJ, Silva M, Piñero F. Recurrence of hepatocellular carcinoma after liver transplantation: Prognostic and predictive factors of survival in a Latin American cohort. Liver Int 2021; 41:851-862. [PMID: 33217193 DOI: 10.1111/liv.14736] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 10/20/2020] [Accepted: 11/16/2020] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIM Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) has a poor prognosis, and the adjusted effect of different treatments on post-recurrence survival (PRS) has not been well defined. This study aims to evaluate prognostic and predictive variables associated with PRS. METHODS This Latin American multicenter retrospective cohort study included HCC patients who underwent LT between the years 2005-2018. We evaluated the effect of baseline characteristics at time of HCC recurrence diagnosis and PRS (Cox regression analysis). Early recurrences were those occurring within 12 months of LT. To evaluate the adjusted treatment effect for HCC recurrence, a propensity score matching analysis was performed to assess the probability of having received any specific treatment for recurrence. RESULTS From a total of 1085 transplanted HCC patients, the cumulative incidence of recurrence was 16.6% (CI 13.5-20.3), with median time to recurrence of 13.0 months (IQR 6.0-26.0). Factors independently associated with PRS were early recurrence (47.6%), treatment with sorafenib and surgery/trans-arterial chemoembolization (TACE). Patients who underwent any treatment presented "early recurrences" less frequently, and more extrahepatic metastasis. This unbalanced distribution was included in the propensity score matching, with correct calibration and discrimination (receiving operator curve of 0.81 [CI 0.72;0.88]). After matching, the adjusted effect on PRS for any treatment was HR of 0.2 (0.10;0.33); P < .0001, for sorafenib therapy HR of 0.4 (0.27;0.77); P = .003, and for surgery/TACE HR of 0.4 (0.18;0.78); P = .009. CONCLUSION Although early recurrence was associated with worse outcome, even in this population, systemic or locoregional treatments were associated with better PRS.
Collapse
Affiliation(s)
- Claudia Maccali
- São Paulo Clinics Liver Cancer Group - Hospital das Clínicas Complex, Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Aline L Chagas
- São Paulo Clinics Liver Cancer Group - Hospital das Clínicas Complex, Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Ilka Boin
- Unit of Liver Transplantation, State University of Campinas, Campinas, Brazil
| | | | | | - Mario Vilatobá
- Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", México
| | | | | | - Sergio Hoyos Duque
- Hospital Pablo Tobón Uribe and Gastrohepatology Group, Universidad de Antioquia, Medellín, Colombia
| | - Agnaldo S Lima
- Hospital das Clínicas da Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | | | | | | | - Rodrigo Zapata
- Clinica Alemana, Facultad de Medicina, Universidad del Desarrollo, Santiago, Chile
| | | | | | | | - Diego Arufe
- Sanatorio Sagrado Corazón, Buenos Aires, Argentina
| | | | - Alejandro Soza
- Department of Gastroenterology, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Martín Fauda
- Hospital Universitario Austral, Buenos Aires, Argentina
| | - Simone R Perales
- Unit of Liver Transplantation, State University of Campinas, Campinas, Brazil
| | | | - Carla Bermudez
- Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | | | - Isabel Arenas Hoyos
- Hospital Pablo Tobón Uribe and Gastrohepatology Group, Universidad de Antioquia, Medellín, Colombia
| | | | | | - Adrián Gadano
- Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | | | - Claudia Megumi Tani
- São Paulo Clinics Liver Cancer Group - Hospital das Clínicas Complex, Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Luiz Augusto Carneiro D'Albuquerque
- São Paulo Clinics Liver Cancer Group - Hospital das Clínicas Complex, Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Flair J Carrilho
- São Paulo Clinics Liver Cancer Group - Hospital das Clínicas Complex, Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Marcelo Silva
- Hospital Universitario Austral, Buenos Aires, Argentina.,Latin American Liver Research Educational and Awareness Network (LALREAN), Buenos Aires, Argentina
| | - Federico Piñero
- Hospital Universitario Austral, Buenos Aires, Argentina.,Latin American Liver Research Educational and Awareness Network (LALREAN), Buenos Aires, Argentina
| |
Collapse
|
|
18
|
Gül-Klein S, Kästner A, Haber PK, Krenzien F, Wabitsch S, Krannich A, Andreou A, Eurich D, Tacke F, Horst D, Pratschke J, Schmelzle M. Recurrence of Hepatocellular Carcinoma After Liver Transplantation is Associated with Episodes of Acute Rejections. J Hepatocell Carcinoma 2021; 8:133-143. [PMID: 33777855 PMCID: PMC7987264 DOI: 10.2147/jhc.s292010] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 01/21/2021] [Indexed: 12/24/2022] Open
Abstract
Purpose The impact of acute rejection (AR) after liver transplantation (LT) for hepatocellular carcinoma (HCC) on patient outcome is uncertain. This aim of this study is to investigate whether AR is associated with HCC relapse and overall survival. Patients and Methods Patients undergoing LT for HCC between 2001 and 2015 were retrospectively analyzed with regard to histopathological proven AR within the median time until recurrence. Cox’s regression analysis was conducted revealing risk factors for HCC recurrence. Results HCC recurred in 47 of 252 analyzed patients with a median time to recurrence of 20 months. Patients with AR (28.6%) had a significantly higher frequency of recurrence compared to patients without AR (13.0%, p=0.002). Multiple Cox regression analyses identified AR within 20 months to be an independent risk factor for HCC recurrence both as dichotomized (HR=2.91, 95%CI: 1.30–6.53; p=0.009) and as a continuous variable (HR=1.81, 95%CI: 1.28–2.54; p=0.001). HCC recurrence and AR were associated with higher grades of liver fibrosis one year after LT, when compared to patients without AR (p=0.019). Conclusion Our results demonstrate an association of AR with HCC recurrence after LT with implications for intervals of monitoring in tumor surveillance. Graft fibrosis and immune mechanisms are potentially related and causal interactions are worth further investigation.
Collapse
Affiliation(s)
- Safak Gül-Klein
- Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Anika Kästner
- Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Philipp Konstantin Haber
- Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Felix Krenzien
- Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Simon Wabitsch
- Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Alexander Krannich
- Clinical Study Center, Clinical Trial Office, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Andreas Andreou
- Division of Acute Care Surgery, Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, Bern, Switzerland
| | - Dennis Eurich
- Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Frank Tacke
- Department of Hepatology/Gastroenterology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - David Horst
- Institute of Pathology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Johann Pratschke
- Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Moritz Schmelzle
- Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
| |
Collapse
|
|
19
|
Surveillance for HCC After Liver Transplantation: Increased Monitoring May Yield Aggressive Treatment Options and Improved Postrecurrence Survival. Transplantation 2021; 104:2105-2112. [PMID: 31972705 DOI: 10.1097/tp.0000000000003117] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Currently, no surveillance guidelines for hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) exist. In this retrospective, multicenter study, we have investigated the role of surveillance imaging on postrecurrence outcomes. METHODS Patients with recurrent HCC after LT from 2002 to 2016 were reviewed from 3 transplant centers (University of California San Francisco, Mayo Clinic Florida, and University of Toronto). For this study, we proposed the term cumulative exposure to surveillance (CETS) as a way to define the cumulative sum of all the protected intervals that each surveillance test provides. In our analysis, CETS has been treated as a continuous variable in months. RESULTS Two hundred twenty-three patients from 3 centers had recurrent HCC post-LT. The median follow-up was 31.3 months, and median time to recurrence was 13.3 months. Increasing CETS was associated with improved postrecurrence survival (hazard ratio, 0.94; P < 0.01) as was treatment of recurrence with resection or ablation (hazard ratio, 0.31; P < 0.001). An receiver operating characteristic curve (area under the curve, 0.64) for CETS covariate showed that 252 days of coverage (or 3 surveillance scans) within the first 24 months provided the highest probability for aggressive postrecurrence treatment. CONCLUSIONS In this review of 223 patients with post-LT HCC recurrence, we found that increasing CETS does lead to improved postrecurrence survival as well as a higher probability for aggressive recurrence treatment. We found that 252 days of monitoring (ie, 3 surveillance scans) in the first 24 months was associated with the ability to offer potentially curative treatment.
Collapse
|
|
20
|
Piñero F, Thompson M, Marín JI, Silva M. Lenvatinib as first-line therapy for recurrent hepatocellular carcinoma after liver transplantation: Is the current evidence applicable to these patients? World J Transplant 2020; 10:297-306. [PMID: 33312891 PMCID: PMC7708877 DOI: 10.5500/wjt.v10.i11.297] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 06/09/2020] [Accepted: 09/22/2020] [Indexed: 02/05/2023] Open
Abstract
Liver transplantation (LT) is one of the leading curative therapies for hepatocellular carcinoma (HCC). Despite recent optimization of transplant selection criteria, including alpha-feto protein, HCC recurrence after LT is still the leading cause of death in these patients. During the last decades, effective systemic treatments for HCC, including tyrosine kinase inhibitors and immunotherapy, have been approved. We describe the clinical scenario of a patient with recurrence of HCC five years after LT, who received lenvatinib as first-line systemic therapy to introduce systemic treatment options in this clinical setting. In this opinion review, we detail first and second-line systemic treatment options, focusing on those feasible for patients with recurrent HCC after LT. Several trials have evaluated new drugs to treat HCC patients in first and second-line therapy, but patients with recurrent HCC after LT have been excluded from these trials. Consequently, most of the evidence comes from observational retrospective studies. Whether tyrosine kinase inhibitors will remain the primary therapeutic approach in these patients, due to a relative contraindication for immunotherapy, may be clarified in the near future.
Collapse
Affiliation(s)
- Federico Piñero
- Hepatology and Liver Transplant Unit, Hospital Universitario Austral, Buenos Aires B1629HJ, Argentina
- Hospital Universitario Austral, Facultad de Ciencias Biomédicas, Universidad Austral, Buenos Aires B1629HJ, Argentina
- Latin American Liver Research Educational and Awareness Network (LALREAN), Buenos Aires B1629HJ, Argentina
| | - Marcos Thompson
- Hospital Universitario Austral, Facultad de Ciencias Biomédicas, Universidad Austral, Buenos Aires B1629HJ, Argentina
| | - Juan Ignacio Marín
- Hepatology and Liver Transplantation Unit, Hospital Pablo Tobón Uribe, Medellín 240, Colombia
| | - Marcelo Silva
- Hospital Universitario Austral, Facultad de Ciencias Biomédicas, Universidad Austral, Buenos Aires B1629HJ, Argentina
- Latin American Liver Research Educational and Awareness Network (LALREAN), Buenos Aires B1629HJ, Argentina
| |
Collapse
|
|
21
|
Moeckli B, Ivanics T, Claasen M, Toso C, Sapisochin G. Recent developments and ongoing trials in transplant oncology. Liver Int 2020; 40:2326-2344. [PMID: 33021344 DOI: 10.1111/liv.14621] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 07/17/2020] [Accepted: 07/21/2020] [Indexed: 12/17/2022]
Abstract
Over the past two decades since the introduction of the Milan criteria, the field of transplant oncology has undergone a rapid development with a rising proportion of liver transplantations being performed for oncological indications. For many patients with liver tumours, transplantation represents the only chance for cure. However, many challenges remain, such as the adequate patient selection, management of post-transplant recurrence and refinement of neoadjuvant treatment protocols. This review provides an overview of the current state of the art of liver transplantation for oncological indications such as hepatocellular carcinoma, cholangiocarcinoma, colorectal liver metastasis and metastatic neuroendocrine tumours. We also summarize the ongoing research and explore future trends. Clinical trials are currently studying new diagnostic modalities, innovative pharmacological treatments, novel surgical techniques, downstaging regimens and new indications for liver transplantation. These emerging results will continue to shape the field of transplant oncology and provide us with the necessary tools to better select, treat and follow patients with liver tumours qualifying for liver transplantation.
Collapse
Affiliation(s)
- Beat Moeckli
- Department of Visceral and Transplantation Surgery, University of Geneva Hospitals, Geneva, Switzerland
| | - Tommy Ivanics
- Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada
| | - Marco Claasen
- Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada.,Department of Surgery, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Christian Toso
- Department of Visceral and Transplantation Surgery, University of Geneva Hospitals, Geneva, Switzerland
| | - Gonzalo Sapisochin
- Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada.,Division of General Surgery, University Health Network, Toronto, ON, Canada
| |
Collapse
|
|
22
|
Goldaracena N, Mehta N, Scalera I, Sposito C, Atenafu EG, Yao FY, Muiesan P, Mazzaferro V, Sapisochin G. Multicenter validation of a score to predict prognosis after the development of HCC recurrence following liver transplantation. HPB (Oxford) 2019; 21:731-738. [PMID: 30391218 DOI: 10.1016/j.hpb.2018.10.005] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Revised: 09/12/2018] [Accepted: 10/07/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND HCC recurrence after LT impacts negatively on survival. A recent study detected late recurrence (≥12 months), alpha-fetoprotein (AFP) <100 ng/mL at recurrence and being amenable for curative-intent treatments as good prognostic factors. With these variables a prognostic score was proposed. The objective of this study was to validate the prognostic score for hepatocellular carcinoma (HCC) recurrence following liver transplantation (LT). METHODS Data from the University of California, San Francisco, the University Hospital of Birmingham and Instituto Nazionale dei Tumori, Milan including patients with HCC recurrence after LT were analyzed. The previous reported score was applied to this cohort. RESULTS From June 2002-December 2014, 1328 patients had a confirmed HCC in their explanted liver. The study group comprised 130 patients (9.8%) diagnosed with HCC recurrence after LT. Overall median survival after HCC recurrence was 12.4 (95% CI 10.2-16.3) months. Application of the previously reported score showed a significantly superior survival for the good prognosis group compared to moderate and poor prognosis groups (p < 0.0001). CONCLUSION The score continues to identify a group of patients who would benefit from aggressive treatment and experience significant improved survival following recurrent HCC after LT.
Collapse
Affiliation(s)
- Nicolás Goldaracena
- Multi-Organ Transplant, Division of General Surgery, Department of Surgery, University Health Network, University of Toronto, Canada
| | - Neil Mehta
- Department of Gastroenterology, Division of Medicine, University of California San Francisco, USA
| | - Irene Scalera
- Liver - University Hospital Birmingham NHS Foundation Trust, Birmingham, UK
| | - Carlo Sposito
- Department of Surgery, GI Surgery and Liver Transplantation, Instituto Nazionale dei Tumori, Milan, Italy
| | - Eshetu G Atenafu
- Biostatistics Department, University Health Network, University of Toronto, Canada
| | - Francis Y Yao
- Department of Gastroenterology, Division of Medicine, University of California San Francisco, USA
| | - Paolo Muiesan
- Liver - University Hospital Birmingham NHS Foundation Trust, Birmingham, UK
| | - Vincenzo Mazzaferro
- Department of Surgery, GI Surgery and Liver Transplantation, Instituto Nazionale dei Tumori, Milan, Italy
| | - Gonzalo Sapisochin
- Multi-Organ Transplant, Division of General Surgery, Department of Surgery, University Health Network, University of Toronto, Canada.
| |
Collapse
|
|
23
|
Abstract
Liver transplantation is the definitive treatment for patients with end-stage liver disease. Liver transplantation is also the optimal treatment for patients with hepatocellular carcinoma (HCC), especially in the setting of chronic liver disease. Unfortunately, due to the worldwide shortage of organs, this treatment is not available for all patients with HCC. Strict selection criteria have been developed in order to obtain optimal results. A surgical perspective of the preoperative selection, perioperative management, and postoperative care of patients is reviewed in depth and provides an overview for obtaining optimal long-term results from liver transplantation for HCC. With rigorous selection and patient management, excellent long-term outcomes can be obtained with liver transplantation for patients with HCC.
Collapse
|
|
24
|
Filgueira NA. Hepatocellular carcinoma recurrence after liver transplantation: Risk factors, screening and clinical presentation. World J Hepatol 2019; 11:261-272. [PMID: 30967904 PMCID: PMC6447422 DOI: 10.4254/wjh.v11.i3.261] [Citation(s) in RCA: 87] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 03/06/2019] [Accepted: 03/16/2019] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation is the best treatment option for cirrhotic patients with early-stage hepatocellular carcinoma, but it faces the problem of scarcity of donors and the risk of tumor recurrence, which affects between 15% and 20% of the cases, despite the use of restrictive criteria. The risk of recurrence depends on a number of factors, related to the tumor, the patient, and the treatment, which are discussed in this review. Some of these factors are already well established, such as the histopathological characteristics of the tumor, Alpha-fetoprotein (AFP) levels, and waiting time. Other factors related to the biological behavior of the tumor and treatment should be recognized because they can be used in the refinement of the selection criteria of transplant candidates and in an attempt to reduce recurrence. This review also discusses the clinical presentation of recurrence and its prognosis, contributing to the identification of a subgroup of patients who may have better survival, if they are timely identified and treated. Development of recurrence after the first year, with AFP levels ≤ 100 ng/mL, and single site capable of locoregional therapy are associated with better survival after recurrence.
Collapse
Affiliation(s)
- Norma Arteiro Filgueira
- Department of Internal Medicine, Universidade Federal de Pernambuco, Recife, Pernambuco 50670-901, Brazil
| |
Collapse
|
|
25
|
Sanduzzi-Zamparelli M, Díaz-Gonzalez Á, Reig M. New Systemic Treatments in Advanced Hepatocellular Carcinoma. Liver Transpl 2019; 25:311-322. [PMID: 30317696 DOI: 10.1002/lt.25354] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Accepted: 10/07/2018] [Indexed: 12/28/2022]
Abstract
The principal advancements in the treatment of hepatocellular carcinoma (HCC) are the use of new systemic treatments, such as lenvatinib in first-line treatment and regorafenib, cabozantinib, and ramucirumab in second-line treatment, because of their benefits in terms of overall survival. In addition, nivolumab as a second-line agent was approved by the US Food and Drug Administration in 2017 based on improved radiological response data. Physicians and patients alike will greatly benefit from this expanded arsenal of treatments once all these new drugs for the treatment of HCC finally become available. Unfortunately, in our review of the available data, we found a conspicuous lack of approved systemic treatments for HCC in the distinct setting of after liver transplantation (LT). Careful evaluation of the clinical trials for approved systemic treatments of HCC is crucial when considering the best options for those with HCC recurrence after LT. Although several first-line or second-line treatments have been shown to be effective for HCC, each of these trials was composed of its own specific populations, and those with HCC recurrence after LT were excluded. We have also summarized from a critical and clinical point of view the issues involved in the management of patients who are candidates for systemic treatment in this era of multiple drugs for the same indication.
Collapse
Affiliation(s)
- Marco Sanduzzi-Zamparelli
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clinic Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Álvaro Díaz-Gonzalez
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clinic Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - María Reig
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clinic Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
- Centro de Investigación Médica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| |
Collapse
|
|
26
|
Kang SH, Cho H, Cho EJ, Lee JH, Yu SJ, Kim YJ, Yi NJ, Lee KW, Suh KS, Yoon JH. Efficacy of Sorafenib for the Treatment of Post-Transplant Hepatocellular Carcinoma Recurrence. J Korean Med Sci 2018; 33:e283. [PMID: 30402048 PMCID: PMC6209769 DOI: 10.3346/jkms.2018.33.e283] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Accepted: 07/18/2018] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The role of sorafenib in patients with hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) has been rarely studied. The aim of this study was to evaluate the efficacy of sorafenib in post-LT era. METHODS Consecutive patients with post-transplant HCC recurrence not eligible to resection or locoregional therapy were included. Patients receiving best supportive care (BSC) until 2007 were compared with those treated by sorafenib thereafter. RESULTS Of a total of 65 patients, 20 patients received BSC and 45 received sorafenib. Clinical characteristics were similar between two groups except that sorafenib group received tacrolimus and mammalian target-of-rapamycin inhibitors more frequently than BSC group. Treatment with sorafenib conferred a survival advantage as compared with BSC for survival after recurrence (median, 14.2 vs. 6.8 months; P = 0.01). In multivariate analyses, high serum α-fetoprotein level, synchronous intrahepatic recurrence and distant metastasis at the time of recurrence, and BSC were independently associated with poorer survival after recurrence. Sorafenib treatment was associated with better survival after recurrence as compared with BSC (hazard ratio, 0.25; 95% confidence interval, 0.10-0.62; P = 0.002). In addition, sorafenib group showed tolerable toxicity in the post-transplant setting. CONCLUSION Sorafenib may be beneficial in patients with post-transplant HCC recurrence.
Collapse
Affiliation(s)
- Seong Hee Kang
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Hyeki Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Eun Ju Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Jeong-Hoon Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Su Jong Yu
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Yoon Jun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Nam-Joon Yi
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Kwang-Woong Lee
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Kyung-Suk Suh
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Jung-Hwan Yoon
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| |
Collapse
|
|
27
|
Kim BH, Park JW. Sorafenib for Recurrent Hepatocellular Carcinoma after Liver Transplantation. J Korean Med Sci 2018; 33:e286. [PMID: 30402051 PMCID: PMC6209768 DOI: 10.3346/jkms.2018.33.e286] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Accepted: 10/15/2018] [Indexed: 12/12/2022] Open
Affiliation(s)
- Bo Hyun Kim
- Center for Liver Cancer, National Cancer Center, Goyang, Korea
| | - Joong-Won Park
- Center for Liver Cancer, National Cancer Center, Goyang, Korea
| |
Collapse
|
|
28
|
Predicting Mortality in Patients Developing Recurrent Hepatocellular Carcinoma After Liver Transplantation: Impact of Treatment Modality and Recurrence Characteristics. Ann Surg 2017; 266:118-125. [PMID: 27433914 DOI: 10.1097/sla.0000000000001894] [Citation(s) in RCA: 122] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE To evaluate predictors of mortality and impact of treatment in patients developing recurrent hepatocellular carcinoma (HCC) following liver transplantation (LT). SUMMARY OF BACKGROUND DATA Despite well-described clinicopathologic predictors of posttransplant HCC recurrence, data on prognosis following recurrence are scarce. METHODS Multivariate predictors of mortality following HCC recurrence were identified to develop a risk score model to stratify prognostic subgroups among 106 patients developing posttransplant recurrence from 1984 to 2014, including analysis of recurrence treatment modality on survival. RESULTS Of 857 patients undergoing LT, 106 (12.4%) developed posttransplant HCC recurrence (median 15.8 months following LT) with a median post-recurrence survival of 10.6 months. Patients receiving surgical therapy (n = 25) had a median survival of 27.8 months, significantly superior to patients receiving nonsurgical therapy (10.6 months) and best supportive care (3.7 months, P < 0.001). Multivariate predictors of mortality following recurrence included model for end-stage liver disease at LT >23, time to recurrence, >3 recurrent nodules, maximum recurrence size, bone recurrence, alphafetoprotein at recurrence, donor serum sodium, and pretransplant recipient neutrophil-lymphocyte ratio. A risk score model based on multivariate predictors accurately stratified recurrent HCC patients into prognostic subgroups, with low-risk patients (<10 points) demonstrating excellent median survival of 70.6 months, significantly superior to the medium-risk (12.2 months, 10-16 points) and high-risk (3.4 months, >16 points) groups (C-statistic 0.75, P < 0.001). CONCLUSIONS In the largest single-center report of recurrent HCC following LT, surgical treatment in well-selected patients is associated with significantly improved survival and should be pursued. A risk score model accurately stratifies prognostic subgroups, and may help guide treatment strategies.
Collapse
|
|
29
|
Giakoustidis AE, Giakoustidis DE. Immunosuppression strategies in liver transplantation patient; patients with hepatocellular carcinoma. Immunotherapy 2017; 9:197-206. [PMID: 28128716 DOI: 10.2217/imt-2016-0110] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) consists the main primary malignant tumor of the liver. There is an underlining liver cirrhosis mainly attributed to chronic hepatitis B virus or hepatitis C virus, alcoholic liver disease, nonalcoholic steatohepatitis and other pathologic conditions. Liver transplantation consists a radical management, treating both cancer and cirrhosis. By introducing the Milan Criteria for liver transplantation in HCC patients there was a 5-year survival escalation. Even though there is a careful selection of patients with HCC for transplantation, recurrent disease is still high. The role of immusuppression therapy is of paramount importance, in order to avoid acute and chronic graft rejection while protecting the patient from tumor recurrence. In recent years newer immunosuppressive agents such as the mTOR inhibitors are proposed, having dual properties, as both immunosuppressive and antitumors agents.
Collapse
Affiliation(s)
- Alexander E Giakoustidis
- Hepato-Pancreato-Biliary Surgery Department, The Royal London Hospital, Barts Health, Whitechapel Road, London E1 1BB, UK
| | - Dimitrios E Giakoustidis
- Division of Transplant Surgery, Department of Surgery, School of Health Sciences, Aristotle University of Thessaloniki & Hippokration General Hospital, Thessaloniki, Greece
| |
Collapse
|
|
30
|
Zhang JA, Kwee SA, Wong LL. Late recurrence of hepatocellular carcinoma after liver transplantation. ACTA ACUST UNITED AC 2017; 3:58-66. [PMID: 28966983 DOI: 10.20517/2394-5079.2017.05] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
AIMS Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide and liver transplant (LT) prolongs survival. However, 15-20% will experience recurrent HCC, most occurring within 2 years of LT. HCC patients with late recurrences (>5 years after LT) may have distinctive clinical/biological characteristics. METHODS A retrospective review was conducted of 88 patients who underwent LT for HCC between 1993-2015, analyzing demographics, clinical factors, explant pathology, and outcome. RESULTS Median follow-up was 6.4 years. HCC recurred in 15 (17.0%) patients with mean time to recurrence of 3.96 +/- 3.99 years. Five patients recurred >5 years post-LT. All late recurrences involved males in their 50s, recurring at 8.5 years on average. Recurrences occurred in chest wall (2), liver (2), lung (2), bone (1) and pelvis (1), with multifocal involvement in 2 patients. Four patients died within 18 months of late recurrence. The fifth patient is alive after ablation of liver recurrence and treatment with sorafenib and everolimus. CONCLUSIONS One-third of post-LT patients with recurrent HCC experienced late recurrence. Although the sample size makes it difficult to identify significant risk factors, this study highlights the importance of long-term follow up and need for biomarkers to identify patients at risk for late recurrences.
Collapse
Affiliation(s)
- Julia A Zhang
- Department of Surgery, University of Hawaii School of Medicine, Honolulu, HI 96813, United States
| | - Sandi A Kwee
- The Queens Medical Center, Honolulu, HI 96813, United States
| | - Linda L Wong
- Department of Surgery, University of Hawaii School of Medicine, Honolulu, HI 96813, United States
| |
Collapse
|
|
31
|
Fernandez-Sevilla E, Allard MA, Selten J, Golse N, Vibert E, Sa Cunha A, Cherqui D, Castaing D, Adam R. Recurrence of hepatocellular carcinoma after liver transplantation: Is there a place for resection? Liver Transpl 2017; 23:440-447. [PMID: 28187493 DOI: 10.1002/lt.24742] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Revised: 01/12/2017] [Accepted: 01/26/2017] [Indexed: 02/06/2023]
Abstract
Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) is widely considered as a terminal condition. Therefore, the role of surgery is uncertain in this case. The purpose of this study was to identify the prognostic factors of survival after post-LT HCC recurrence and to evaluate the impact of surgery in this setting. All patients transplanted for HCC between 1991 and 2013 in a single institution and who further developed a post-LT recurrence were included in this study. Univariate and multivariate analyses were performed to identify factors affecting postrecurrence survival. Of the 493 patients transplanted for HCC, a total of 70 (14.2%) consecutive patients developed a recurrence after a median disease-free interval of 17 months. Median survival (MS) from the time of recurrence was 19 months, with a 3-year postrecurrence survival of 26%. Most recurrences were extrahepatic (lung, lymph node, and bone; n = 51; 72.9%), whereas only intrahepatic recurrences were observed in 2 (2.8%) patients. Both intrahepatic and extrahepatic locations were found in 17 (24.3%) patients. A total of 22 (31.4%) patients underwent macroscopically complete resection of the recurrence (intrahepatic [n = 2] and extrahepatic [n = 20]). The MS for resected patients after transplantation was 35 months compared with 15 months for nonresected patients (P < 0.001). In multivariate analysis, the independent unfavorable factors of postrecurrence survival were alpha-fetoprotein level > 100 ng/mL at relapse (hazard ratio [HR], 2.1; 95% confidence interval [CI], 1.1-4.1; P = 0.03), intrahepatic location (HR, 1.8; 95% CI, 1.0-3.2; P = 0.05), and multifocal recurrence (HR, 1.8; 95% CI, 1.1-3.1; P = 0.04). The management including surgery (HR, 0.4; 95% CI, 0.2-0.7; P = 0.004) was identified as an independent favorable factor. In conclusion, recurrence of HCC after LT is associated with a poor prognosis. However, resection is associated with improved survival and should therefore be considered when feasible. Liver Transplantation 23 440-447 2017 AASLD.
Collapse
Affiliation(s)
| | - Marc-Antoine Allard
- Centre Hépatobiliaire, Hôpital Paul Brousse, Villejuif, France.,Université Paris-Sud, Villejuif, France.,Unité 935, Institut National de la Santé et de la Recherche, Villejuif, France
| | - Jasmijn Selten
- Centre Hépatobiliaire, Hôpital Paul Brousse, Villejuif, France
| | - Nicolas Golse
- Centre Hépatobiliaire, Hôpital Paul Brousse, Villejuif, France.,Université Paris-Sud, Villejuif, France.,Unité 785, Institut National de la Santé et de la Recherche, Villejuif, France
| | - Eric Vibert
- Centre Hépatobiliaire, Hôpital Paul Brousse, Villejuif, France.,Université Paris-Sud, Villejuif, France.,Unité 785, Institut National de la Santé et de la Recherche, Villejuif, France
| | - Antonio Sa Cunha
- Centre Hépatobiliaire, Hôpital Paul Brousse, Villejuif, France.,Université Paris-Sud, Villejuif, France
| | - Daniel Cherqui
- Centre Hépatobiliaire, Hôpital Paul Brousse, Villejuif, France.,Université Paris-Sud, Villejuif, France.,Unité 785, Institut National de la Santé et de la Recherche, Villejuif, France
| | - Denis Castaing
- Centre Hépatobiliaire, Hôpital Paul Brousse, Villejuif, France.,Université Paris-Sud, Villejuif, France.,Unité 785, Institut National de la Santé et de la Recherche, Villejuif, France
| | - René Adam
- Centre Hépatobiliaire, Hôpital Paul Brousse, Villejuif, France.,Université Paris-Sud, Villejuif, France.,Unité 935, Institut National de la Santé et de la Recherche, Villejuif, France
| |
Collapse
|
|
32
|
Affiliation(s)
- Adam S Bodzin
- Department of Surgery, Section of Abdominal Organ Transplantation, University of Chicago, California, USA
| |
Collapse
|
|
33
|
de'Angelis N, Landi F, Nencioni M, Palen A, Lahat E, Salloum C, Compagnon P, Lim C, Costentin C, Calderaro J, Luciani A, Feray C, Azoulay D. Role of Sorafenib in Patients With Recurrent Hepatocellular Carcinoma After Liver Transplantation. Prog Transplant 2016; 26:348-355. [PMID: 27555074 DOI: 10.1177/1526924816664083] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
CONTEXT The management of hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) is challenging, especially if it is not treatable by surgery or embolization. OBJECTIVES The present study aims to compare the survival rates of liver transplanted patients receiving sorafenib or best supportive care (BSC) for HCC recurrence not amenable to curative intent treatments. DESIGN This is a retrospective comparative study on a prospectively maintained database. PARTICIPANTS Liver transplanted patients with untreatable HCC recurrence receiving BSC (n = 18) until 2007 or sorafenib (n = 15) thereafter were compared. RESULTS No group difference was observed for demographic characteristics at the time of transplantation and at the time of HCC recurrence. On the explant pathology of the native liver, 81.2% patients were classified within the Milan criteria, and 53.1% presented with microvascular invasion. Hepatocellular carcinoma recurrence was diagnosed 17.8 months (standard deviation: 14.5) after LT, with 17 (53.1%) patients presenting with early recurrence (≤12 months). The 1-year survival from untreatable progression of HCC recurrence was 23.9% for the BSC and 60% for the sorafenib group ( P = .002). The type of treatment (sorafenib vs BSC) was the sole independent predictor of survival (hazard ratio: 2.98; 95% confidence interval: 1.09-8.1; P = .033). In the sorafenib group, 8 (53.3%) patients required dose reduction, and 2 (13.3%) patients discontinued the treatment due to intolerable side effects. CONCLUSION Sorafenib improves survival and is superior to the BSC in cases of untreatable posttransplant hepatocellular carcinoma recurrence.
Collapse
Affiliation(s)
- Nicola de'Angelis
- 1 Department of HPB Surgery and Liver Transplantation, Henri-Mondor Hospital, Université Paris Est-UPEC, Créteil, France
| | - Filippo Landi
- 1 Department of HPB Surgery and Liver Transplantation, Henri-Mondor Hospital, Université Paris Est-UPEC, Créteil, France
| | - Marco Nencioni
- 1 Department of HPB Surgery and Liver Transplantation, Henri-Mondor Hospital, Université Paris Est-UPEC, Créteil, France
| | - Anais Palen
- 1 Department of HPB Surgery and Liver Transplantation, Henri-Mondor Hospital, Université Paris Est-UPEC, Créteil, France
| | - Eylon Lahat
- 1 Department of HPB Surgery and Liver Transplantation, Henri-Mondor Hospital, Université Paris Est-UPEC, Créteil, France
| | - Chady Salloum
- 1 Department of HPB Surgery and Liver Transplantation, Henri-Mondor Hospital, Université Paris Est-UPEC, Créteil, France
| | - Philippe Compagnon
- 1 Department of HPB Surgery and Liver Transplantation, Henri-Mondor Hospital, Université Paris Est-UPEC, Créteil, France
| | - Chetana Lim
- 1 Department of HPB Surgery and Liver Transplantation, Henri-Mondor Hospital, Université Paris Est-UPEC, Créteil, France
| | - Charlotte Costentin
- 2 Department of Hepatology, Henri-Mondor Hospital, Université Paris Est-UPEC, Créteil, France
| | - Julien Calderaro
- 3 Department of Pathology, Henri-Mondor Hospital, Université Paris Est-UPEC, Créteil, France.,4 INSERM Unit UMR1162, Créteil, France
| | - Alain Luciani
- 5 Department of Radiology and Medical Imaging, Henri-Mondor Hospital, Université Paris Est-UPEC, Créteil, France.,6 INSERM Unit 955, Créteil, France
| | - Cyrille Feray
- 2 Department of Hepatology, Henri-Mondor Hospital, Université Paris Est-UPEC, Créteil, France.,6 INSERM Unit 955, Créteil, France
| | - Daniel Azoulay
- 1 Department of HPB Surgery and Liver Transplantation, Henri-Mondor Hospital, Université Paris Est-UPEC, Créteil, France.,6 INSERM Unit 955, Créteil, France
| |
Collapse
|
|
34
|
Na GH, Hong TH, You YK, Kim DG. Clinical analysis of patients with hepatocellular carcinoma recurrence after living-donor liver transplantation. World J Gastroenterol 2016; 22:5790-5799. [PMID: 27433092 PMCID: PMC4932214 DOI: 10.3748/wjg.v22.i25.5790] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2016] [Revised: 04/26/2016] [Accepted: 05/23/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluated patterns and outcomes of hepatocellular carcinoma (HCC) recurrence after living donor liver transplantation (LDLT).
METHODS: From 2001 to 2014, 293 patients underwent LDLT for HCC at our transplant center. We retrospectively reviewed 54 (18.4%) patients with HCC recurrence after LDLT. We evaluated patterns and outcomes of HCC recurrence after LDLT, with particular attention to the Milan criteria at transplantation, treatments for HCC-recurrent patients, and factors related to survival after HCC recurrence. Furthermore, we evaluated the efficacy of combination treatment of sorafenib and an mTOR inhibitor.
RESULTS: The 1-, 2-, and 3-year overall survival rates after HCC recurrence were 41.1%, 20.5%, and 15.4%, respectively. The median time interval between LDLT and HCC recurrence was 6.5 mo. Although recurrence rates according to the Milan criteria at LDLT were significantly different, HCC recurrence patterns and survival rates after HCC recurrence were not significantly different between the two groups. Time to recurrence < 12 mo (P = 0.048), multiple recurrences at HCC recurrence (P = 0.038), and palliative treatment for recurrent tumors (P = 0.003) were significant independent prognostic factors for poor survival after HCC recurrence in a multivariate analysis. The combination treatment of sorafenib and sirolimus showed survival benefits in the palliative treatment group (P = 0.005).
CONCLUSION: Curative treatment for recurrent HCC after LDLT is the most important factor in survival rates after HCC recurrence and combination treatments of sorafenib and an mTOR inhibitor could have survival benefits in patients with HCC recurrence after LT in the palliative treatment group.
Collapse
|
|
35
|
de’Angelis N, Landi F, Carra MC, Azoulay D. Managements of recurrent hepatocellular carcinoma after liver transplantation: A systematic review. World J Gastroenterol 2015; 21:11185-11198. [PMID: 26494973 PMCID: PMC4607916 DOI: 10.3748/wjg.v21.i39.11185] [Citation(s) in RCA: 133] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2015] [Revised: 04/06/2015] [Accepted: 08/25/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the efficacy (survival) and safety of treatments for recurrent hepatocellular carcinoma (HCC) in liver transplantation (LT) patients.
METHODS: Literature search was performed on available online databases without a time limit until January 2015. Clinical studies describing survival after HCC recurrence in LT patients were retrieved for a full-text evaluation. A total of 61 studies were selected: 13 case reports, 41 retrospective case series, and 7 retrospective comparative studies.
RESULTS: Based on all included studies, the mean HCC recurrence rate was 16% of all LTs for HCC. A total of 1021 LT patients experienced HCC recurrence. The median time from LT to HCC recurrence was 13 mo (range 2-132 mo). The majority of patients (67%) presented with HCC extra-hepatic recurrences, involving lung, bone, adrenal gland, peritoneal lymph nodes, and rarely the brain. Overall survival after HCC recurrence was 12.97 mo. Surgical resection of localized HCC recurrence and Sorafenib for controlling systemic spread of HCC recurrence were associated with the higher survival rates (42 and 18 mo, respectively). However, Sorafenib, especially when combined with mTOR, was frequently associated with severe side effects that required dose reduction or discontinuation
CONCLUSION: Management of recurrent HCC in LT patients is challenging and associated with poor prognosis independently of the type of treatment.
Collapse
|
|
36
|
Follow-up Imaging After Liver Transplantation Should Take Into Consideration Primary Hepatocellular Carcinoma Characteristics. Transplantation 2015; 99:1613-8. [DOI: 10.1097/tp.0000000000000659] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
|
|
37
|
Borzio M, Dionigi E, Parisi G, Raguzzi I, Sacco R. Management of hepatocellular carcinoma in the elderly. World J Hepatol 2015; 7:1521-1529. [PMID: 26085911 PMCID: PMC4462690 DOI: 10.4254/wjh.v7.i11.1521] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Revised: 03/09/2015] [Accepted: 04/14/2015] [Indexed: 02/06/2023] Open
Abstract
Mean age of hepatocellular carcinoma (HCC) patients has been progressively increasing over the last decades and ageing of these patients is becoming a real challenge in every day clinical practice. Unfortunately, international guidelines on HCC management do not address this problem exhaustively and do not provide any specific recommendation. We carried out a literature search in MEDLINE database for studies reporting on epidemiology, clinical characteristics and treatment outcome of HCC in elderly patients. Available data seem to indicate that in elderly patients the outcome of HCC is mostly influenced by liver function and tumor stage rather than by age and the latter should not influence treatment allocation. Age is not a risk for resection and older patients with resectable HCC and good liver function could gain benefit from surgery. Mild comorbidities do not seem a contraindication for surgery in aged patients. Conversely, major resection in elderly, even when performed in experienced high-volume centres, should be avoided. Both percutaneous ablation and transarterial chemoembolization are not contraindicated in aged patients and safety profile of these procedures is acceptable. Sorafenib is a viable option for advanced HCC in elderly provided that a careful evaluation of concomitant comorbidities, particularly cardiovascular ones, is taken into account. Available data seem to suggest that in either elderly and younger, treatment is a main predictor of outcome. Consequently, a nihilistic attitude of physicians towards under- or no-treatment of aged patients should not be longer justified.
Collapse
|
|
38
|
Hypothermic Oxygenated Perfusion (HOPE) downregulates the immune response in a rat model of liver transplantation. Ann Surg 2015; 260:931-7; discussion 937-8. [PMID: 25243553 DOI: 10.1097/sla.0000000000000941] [Citation(s) in RCA: 96] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
OBJECTIVE To evaluate the impact of a novel oxygenated perfusion approach on rejection after orthotopic liver transplantation (OLT). BACKGROUND Hypothermic oxygenated perfusion (HOPE) was designed to prevent graft failure after OLT. One of the mechanisms is downregulation of Kupffer cells (in situ macrophages). We, therefore, designed experiments to test the effects of HOPE on the immune response in an allogeneic rodent model of nonarterialized OLT. METHODS Livers from Lewis rats were transplanted into Brown Norway rats to induce liver rejection in untreated recipients within 4 weeks. Next, Brown Norway recipients were treated with tacrolimus (1 mg/kg), whereas in a third group, liver grafts from Lewis rats underwent HOPE or deoxygenated machine perfusion for 1 hour before implantation, but recipients received no immunosuppression. In a last step, low-dose tacrolimus treatment (0.3 mg/kg) was assessed with and without HOPE. RESULTS Allogeneic OLT without immunosuppression led to death within 3 weeks after nonarterialized OLT due to severe acute rejection. Full-dose tacrolimus prevented rejection, whereas low-dose tacrolimus led to graft fibrosis within 4 weeks. HOPE treatment without immunosuppression also protected from lethal rejection. The combination of low-dose tacrolimus and 1-hour HOPE resulted in 100% survival within 4 weeks without any signs of rejection. CONCLUSIONS We demonstrate that allograft treatment by HOPE not only protects against preservation injury but also impressively downregulates the immune system, blunting the alloimmune response. Therefore, HOPE may offer many beneficial effects, not only to rescue marginal grafts but also by preventing rejection and the need for immunosuppression.
Collapse
|
|
39
|
EXP CLIN TRANSPLANTExp Clin Transplant 2015; 13. [DOI: 10.6002/ect.mesot2014.o92] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
|
|
40
|
Sposito C, Mazzaferro V. Reply to: "Time is a crucial factor for the use of oncological treatment for post-transplantation recurrence of hepatocellular carcinoma". J Hepatol 2014; 60:230-1. [PMID: 24018319 DOI: 10.1016/j.jhep.2013.09.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2013] [Accepted: 09/01/2013] [Indexed: 12/04/2022]
Affiliation(s)
- Carlo Sposito
- The Hepato-Oncology Group, Gastro-Intestinal Surgery, Liver Transplantation and Hepatology - Fondazione IRCCS Istituto Nazionale Tumori, via Venezian 1, 20133 Milan, Italy
| | - Vincenzo Mazzaferro
- The Hepato-Oncology Group, Gastro-Intestinal Surgery, Liver Transplantation and Hepatology - Fondazione IRCCS Istituto Nazionale Tumori, via Venezian 1, 20133 Milan, Italy.
| |
Collapse
|
|
41
|
Kaido T, Ogawa K, Mori A, Fujimoto Y, Ito T, Tomiyama K, Takada Y, Uemoto S. Usefulness of the Kyoto criteria as expanded selection criteria for liver transplantation for hepatocellular carcinoma. Surgery 2013; 154:1053-60. [PMID: 24074704 DOI: 10.1016/j.surg.2013.04.056] [Citation(s) in RCA: 125] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2013] [Accepted: 04/25/2013] [Indexed: 12/13/2022]
Abstract
BACKGROUND Previously, we proposed expanded selection criteria for liver transplantation (LT) for hepatocellular carcinoma (HCC), the Kyoto criteria, involving a combination of tumor number ≤10, maximal diameter of each tumor ≤5 cm, and serum des-gamma-carboxy prothrombin levels ≤400 mAU/mL, and we have used these criteria since January 2007. In the present study, the usefulness of the criteria was validated prospectively as well as retrospectively. METHODS One hundred ninety-eight patients with HCC who underwent living donor LT (LDLT) from February 1999 through December 2011 were enrolled in this study. Overall survival and recurrence rates were investigated in patients classified according to the Kyoto criteria, the Milan criteria, or previous treatments for HCC. Tumor biological aggressiveness, including microvascular invasion and histologic differentiation, according to selection criteria was also examined. RESULTS The 5-year overall survival for patients within the Kyoto criteria (n = 147; 82%) was greater than that for the 49 patients exceeding them (n = 49; 42%; P < .001). The 5-year recurrence rate for patients within the Kyoto criteria (4.4%) was less than that for patients exceeding them (51%; P < .001). Intention-to-treat analysis of the 62 patients who underwent LDLT after implementation of the Kyoto criteria showed that the 5-year overall survival rate and the recurrence rate were 82% and 7%, respectively. Tumor biology was significantly less aggressive in patients within the Kyoto criteria. CONCLUSION The Kyoto criteria are useful expanded criteria for LDLT for HCC and could help to achieve favorable outcomes.
Collapse
Affiliation(s)
- Toshimi Kaido
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
| | | | | | | | | | | | | | | |
Collapse
|
|
42
|
Nishikawa H, Kimura T, Kita R, Osaki Y. Treatment for hepatocellular carcinoma in elderly patients: a literature review. J Cancer 2013; 4:635-43. [PMID: 24155775 PMCID: PMC3805991 DOI: 10.7150/jca.7279] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2013] [Accepted: 09/07/2013] [Indexed: 02/06/2023] Open
Abstract
An aging society means that the number of elderly patients with cancer is predicted to rise in the future. Hepatocellular carcinoma (HCC) usually develops in patients with hepatitis B virus infection, hepatitis C virus infection, or alcoholic liver disease. The risk of developing HCC is also known to be age-dependent and elderly patients sometimes present with HCC. The increased longevity of the population thus means that more elderly HCC patients are to be expected in the coming years. In general, many elderly patients are not receiving optimal therapy for malignancies, because it is often withheld from them because of perceived minimal survival advantage and the fear of potential toxicity. Comprehensive data with regard to treatment of elderly patients with HCC are currently limited. Furthermore, current guidelines for the management of HCC do not satisfy strategies according to age. Thus, there is urgent need for investigation of safety and clinical outcomes in elderly patients who receive therapy for HCC. In this review, we primarily refer to current knowledge of clinical characteristics and outcome in elderly patients with HCC who underwent different treatment approaches (i.e., surgical resection, liver transplantation, locoregional therapies, and molecular-targeting therapy).
Collapse
Affiliation(s)
- Hiroki Nishikawa
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
| | | | | | | |
Collapse
|
|
43
|
Sposito C, Mariani L, Germini A, Flores Reyes M, Bongini M, Grossi G, Bhoori S, Mazzaferro V. Comparative efficacy of sorafenib versus best supportive care in recurrent hepatocellular carcinoma after liver transplantation: a case-control study. J Hepatol 2013; 59:59-66. [PMID: 23500153 DOI: 10.1016/j.jhep.2013.02.026] [Citation(s) in RCA: 113] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2012] [Revised: 02/19/2013] [Accepted: 02/22/2013] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS The efficacy of sorafenib in the post-liver transplantation (LT) setting has been scarcely studied. The aim of this study was to evaluate the efficacy of sorafenib, compared to best supportive care (BSC), in two cohorts of patients which presented with hepatocellular carcinoma (HCC) recurrence after LT. METHODS Data from patients who developed presentation or progression of HCC recurrence after LT not amenable to surgical/locoregional treatments (untreatable presentation/progression, UP) were retrieved. The cohort of patients receiving sorafenib starting from 2007 was compared to that of patients receiving BSC in the previous era. Disease outcome was investigated in terms of survival from recurrence or from UP by means of univariate and multivariate Cox regression models with event times left-truncated at the date of UP. RESULTS Of a total of 39 patients, 24 received BSC and 15 sorafenib. The two groups were well matched at baseline, with time-related imbalances regarding mTOR-based immunosuppression and median time from LT to recurrence, significantly higher in the sorafenib group. Patients' outcome in the sorafenib group was significantly improved (median survival from recurrence 21.3 vs.11.8 months, HR=5.2, p=0.0009; median survival from UP 10.6 vs. 2.2 months, HR=21.1, p<0.0001). The only factor associated with survival after HCC recurrence in multivariate analysis was treatment with sorafenib (HR=4.0; p=0.0325). No severe adverse event was registered in this post-LT setting. CONCLUSIONS Although the use of historical controls weakens final interpretation, sorafenib seems to be associated with an acceptable safety profile and benefit in survival in HCC patients suffering recurrence after LT.
Collapse
Affiliation(s)
- Carlo Sposito
- The Hepato-Oncology Group, Gastro-Intestinal Surgery, Liver Transplantation and Hepatology, Fondazione IRCCS Istituto Nazionale Tumori (National Cancer Institute), Milan, Italy
| | | | | | | | | | | | | | | |
Collapse
|
|
44
|
Integrating sorafenib into an algorithm for the management of post-transplant hepatocellular carcinoma recurrence. J Hepatol 2013; 59:3-5. [PMID: 23567081 DOI: 10.1016/j.jhep.2013.03.029] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2013] [Revised: 03/22/2013] [Accepted: 03/27/2013] [Indexed: 12/12/2022]
|