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Pascale MM, Marandola C, Frongillo F, Nure E, Agnes S. Locoregional and Surgical Treatment of Single-Nodule Hepatocellular Carcinoma Recurrence After Liver Transplantation: A Systematic Review and a Meta-Analysis. Cancers (Basel) 2025; 17:1501. [PMID: 40361428 PMCID: PMC12071104 DOI: 10.3390/cancers17091501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2025] [Revised: 04/22/2025] [Accepted: 04/27/2025] [Indexed: 05/15/2025] Open
Abstract
Background: Liver transplantation (LT) is regarded as a curative approach for patients with hepatocellular carcinoma (HCC), especially those with underlying advanced liver disease. However, the recurrence of HCC post-LT poses significant challenges, with reported rates of 15-20% within the first two years following surgery. Effective management of single-nodule recurrence is critical to improving patient outcomes. Methods: This meta-analysis evaluates the efficacy of surgical resection versus locoregional therapies (LRT) in patients with localized HCC recurrence after LT. We adhered to the PRISMA Statement in conducting a thorough search of relevant studies published from 2009 to 2024, ultimately including ten studies that met our eligibility criteria. Results: The results indicate that patients undergoing surgical treatment displayed superior one-year overall survival (OS) rates compared to those receiving LRT (71% vs. 62%, p = 0.038), as well as higher one-year disease-free survival (DFS) rates (60% vs. 54%, p = 0.042). Notably, patients in the LRT group presented with more advanced HCC characteristics prior to transplantation, including higher rates of microvascular invasion and elevated alpha-fetoprotein levels. Conclusions: Our findings suggest that while surgical resection is associated with better survival outcomes, the choice between surgical and locoregional approaches must be individualized based on tumor characteristics and liver function. The ongoing development of standardized guidelines with the inclusion of immunotherapy or targeted agents will be essential in refining treatment pathways and improving outcomes for patients experiencing HCC recurrence following LT.
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Affiliation(s)
- Marco Maria Pascale
- General Surgery and Organ Transplant Unit, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy
| | - Camilla Marandola
- General Surgery and Organ Transplant Unit, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy
| | - Francesco Frongillo
- General Surgery and Organ Transplant Unit, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy
| | - Erida Nure
- General Surgery and Organ Transplant Unit, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy
| | - Salvatore Agnes
- General Surgery and Organ Transplant Unit, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy
- Faculty of Medicine, Università Cattolica del Sacro Cuore, 20123 Milan, Italy
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2
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Matevish L, Patel MS, Vagefi PA. Downstaging Techniques for Hepatocellular Carcinoma in Candidates Awaiting Liver Transplantation. Surg Clin North Am 2024; 104:145-162. [PMID: 37953033 DOI: 10.1016/j.suc.2023.07.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2023]
Abstract
During the last decade, downstaging for hepatocellular carcinoma has expanded the pool of patients eligible for liver transplantation. The literature is rife with attempts to elucidate best treatment strategies with novel locoregional and systemic therapies continuing to emerge. Several trials have confirmed the large-scale success of downstaging protocols, with equitable long-term survival and recurrence rates after liver transplant. We review the currently available techniques used for downstaging, including their indications, complications, and efficacies. New frontiers have focused on the potential role of immunotherapy in the neoadjuvant setting, although more research is needed to delineate its role in current treatment paradigms.
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Affiliation(s)
- Lauren Matevish
- Division of Surgical Transplantation, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Madhukar S Patel
- Division of Surgical Transplantation, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Parsia A Vagefi
- Division of Surgical Transplantation, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
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3
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Biolato M, Galasso T, Marrone G, Miele L, Grieco A. Upper Limits of Downstaging for Hepatocellular Carcinoma in Liver Transplantation. Cancers (Basel) 2021; 13:6337. [PMID: 34944957 PMCID: PMC8699392 DOI: 10.3390/cancers13246337] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 12/07/2021] [Accepted: 12/13/2021] [Indexed: 11/30/2022] Open
Abstract
In Europe and the United States, approximately 1100 and 1800 liver transplantations, respectively, are performed every year for hepatocellular carcinoma (HCC), compared with an annual incidence of 65,000 and 39,000 new cases, respectively. Because of organ shortages, proper patient selection is crucial, especially for those exceeding the Milan criteria. Downstaging is the reduction of the HCC burden to meet the eligibility criteria for liver transplantation. Many techniques can be used in downstaging, including ablation, chemoembolisation, radioembolisation and systemic treatments, with a reported success rate of 60-70%. In recent years, an increasing number of patient responders to downstaging procedures has been included in the waitlist, generally with a comparable five-year post-transplant survival but with a higher probability of dropout than HCC patients within the Milan criteria. While the Milan criteria are generally accepted as the endpoint of downstaging, the upper limits of tumour burden for downstaging HCC for liver transplantation are controversial. Very challenging situations involve HCC patients with large nodules, macrovascular invasion or even extrahepatic metastasis at baseline who respond to increasingly more effective downstaging procedures and who aspire to be placed on the waitlist for transplantation. This narrative review analyses the most important evidence available on cohorts subjected to "extended" downstaging, including HCC patients over the up-to-seven criteria and over the University of California San Francisco downstaging criteria. We also address surrogate markers of biological aggressiveness, such as alpha-fetoprotein and the response stability to locoregional treatments, which are very useful in selecting responders to downstaging procedures for waitlisting inclusion.
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Affiliation(s)
- Marco Biolato
- Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Roma, Italy; (M.B.); (G.M.); (L.M.)
- Institute of Internal Medicine, Catholic University of Sacred Hearth, 00168 Rome, Italy;
| | - Tiziano Galasso
- Institute of Internal Medicine, Catholic University of Sacred Hearth, 00168 Rome, Italy;
| | - Giuseppe Marrone
- Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Roma, Italy; (M.B.); (G.M.); (L.M.)
- Institute of Internal Medicine, Catholic University of Sacred Hearth, 00168 Rome, Italy;
| | - Luca Miele
- Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Roma, Italy; (M.B.); (G.M.); (L.M.)
- Institute of Internal Medicine, Catholic University of Sacred Hearth, 00168 Rome, Italy;
| | - Antonio Grieco
- Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Roma, Italy; (M.B.); (G.M.); (L.M.)
- Institute of Internal Medicine, Catholic University of Sacred Hearth, 00168 Rome, Italy;
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4
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Qin JM. Conversion therapy for primary liver cancer: Indications and selective strategies. Shijie Huaren Xiaohua Zazhi 2021; 29:501-510. [DOI: 10.11569/wcjd.v29.i10.501] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Primary liver cancer has an insidious onset and no specific symptoms at early stage. Most patients are in the middle or advanced stage when diagnosed, and only 20%-40% of patients meet the criteria for radical resection. At present, surgical resection is still the main radical treatment for primary liver cancer, but factors such as liver function decompensation, too large tumor volume, too small future liver remnant, intrahepatic multiple metastasis, tumor thrombus invading the large vessels or bile duct, and distant metastasis limit the application of surgical resection or liver transplantation. In recent years, with the advances of basic research of primary liver cancer, the development of surgical techniques and equipment, as well as the development of new molecular targeted drugs and immunotherapy drugs, a part of unresectable patients with primary liver cancer can receive conversion therapy to improve liver function, minimize tumor volume, minimize or inactivate tumor thrombus, and increase the residual liver volume. Following conversion therapy, patients with primary liver cancer can undergo surgical resection or liver transplantation, which greatly improve the therapeutic efficacy and patient survival.
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Affiliation(s)
- Jian-Min Qin
- Department of General Surgery, the Third Hospital Affiliated to Naval Military Medical University, Shanghai 201805, China
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5
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Eilard MS, Andersson M, Naredi P, Geronymakis C, Lindnér P, Cahlin C, Bennet W, Rizell M. A prospective clinical trial on sorafenib treatment of hepatocellular carcinoma before liver transplantation. BMC Cancer 2019; 19:568. [PMID: 31185950 PMCID: PMC6560824 DOI: 10.1186/s12885-019-5760-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Accepted: 05/27/2019] [Indexed: 12/17/2022] Open
Abstract
Background Patients with hepatocellular carcinoma waiting for liver transplantation are commonly treated with locoregional treatments, such as TACE and ablation, to prevent tumor progression and dropout and to improve long-term outcome after transplantation. We wanted to prospectively assess feasibility of systemic antitumor treatment with sorafenib as neoadjuvant treatment for hepatocellular carcinoma while waiting for liver transplantation, evaluating tolerability, toxicity and posttransplant morbidity. We also wanted to evaluate perfusion CT parameters to assess tumor properties and response early after start of sorafenib treatment in patients with early hepatocellular carcinoma. Methods Twelve patients assigned for liver transplantation due to hepatocellular carcinoma, within the UCSF and who fulfilled other criteria, were included January 2012–August 2014. After baseline evaluation, sorafenib treatment was started. Treatment was evaluated by perfusion CT at 1, 4 and 12 weeks and thereafter every 8 weeks. Toxicity and quality of life was assessed at 1 and 4 weeks and every 4 weeks thereafter during treatment. Treatment was stopped when patients were prioritized on the transplantation waiting list or when intolerable side effects or tumor progress warranted other treatments. Posttransplant morbidity after 90 days was registered according to Clavien-Dindo. Results Baseline perfusion CT parameters in the tumors predicted the outcome according to RECIST/mRECIST at three months, but no change in CTp parameters was detected as a result of sorafenib. Sorafenib as neoadjuvant treatment was associated with intolerability and dose reductions. Therefore the prerequisites for evaluation of the sorafenib effect on both CT parameters and tumor response were impaired. Conclusions This study failed to show changes in CTp parameters during sorafenib treatment. Despite the curative treatment intention, tolerability of neoadjuvant sorafenib treatment before liver transplantation was inadequate in this study. Trial registration EudraCT number: 2010–024306-36 (date 2011-04-07). Electronic supplementary material The online version of this article (10.1186/s12885-019-5760-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Malin Sternby Eilard
- Transplantation Center, Sahlgrenska University Hospital, Gothenburg, 413 45, Gothenburg, Sweden. .,Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
| | - Mats Andersson
- Department of Radiology, Sahlgrenska University Hospital and Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Peter Naredi
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Charalampos Geronymakis
- Department of Radiology, Sahlgrenska University Hospital and Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Per Lindnér
- Transplantation Center, Sahlgrenska University Hospital, Gothenburg, 413 45, Gothenburg, Sweden.,Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Christian Cahlin
- Transplantation Center, Sahlgrenska University Hospital, Gothenburg, 413 45, Gothenburg, Sweden
| | - William Bennet
- Transplantation Center, Sahlgrenska University Hospital, Gothenburg, 413 45, Gothenburg, Sweden.,Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Magnus Rizell
- Transplantation Center, Sahlgrenska University Hospital, Gothenburg, 413 45, Gothenburg, Sweden.,Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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6
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Ziogas IA, Tsoulfas G. Evolving role of Sorafenib in the management of hepatocellular carcinoma. World J Clin Oncol 2017; 8:203-213. [PMID: 28638790 PMCID: PMC5465010 DOI: 10.5306/wjco.v8.i3.203] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2017] [Revised: 04/03/2017] [Accepted: 04/23/2017] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant diseases worldwide and comes third in cancer-related mortality. Although there is a broad spectrum of treatment options to choose from, only a few patients are eligible candidates to receive a curative therapy according to their stage of disease, and thus palliative treatment is implemented in the majority of the patients suffering from liver cancer. Sorafenib, a multikinase inhibitor, is the only currently approved agent for systemic therapy in patients with advanced stage HCC and early stage liver disease. It has been shown to improve the overall survival, but with various side effects, while its cost is not negligible. Sorafenib has been in the market for a decade and has set the stage for personalized targeted therapy. Its role during this time has ranged from monotherapy to neoadjuvant and adjuvant treatment with surgical resection, liver transplantation and chemoembolization or even in combination with other chemotherapeutic agents. In this review our aim is to highlight in depth the current position of Sorafenib in the armamentarium against HCC and how that has evolved over time in its use either as a single agent or in combination with other therapies.
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7
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Takada H, Tsuchiya K, Nakakuki N, Tamaki N, Yasui Y, Suzuki S, Nakanishi H, Itakura J, Takahashi Y, Kurosaki M, Asahina Y, Ban D, Kudo A, Tanabe M, Tanaka S, Arii S, Enomoto N, Izumi N. Four cases with advanced hepatocellular carcinoma who achieved long survival, after surgical resection following to down-staging therapies. KANZO 2016; 57:649-655. [DOI: 10.2957/kanzo.57.649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/17/2025]
Affiliation(s)
- Hitomi Takada
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital
| | - Kaoru Tsuchiya
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital
| | - Natsuko Nakakuki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital
| | - Nobuharu Tamaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital
| | - Yutaka Yasui
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital
| | - Shoko Suzuki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital
| | - Hiroyuki Nakanishi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital
| | - Jun Itakura
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital
| | - Yuka Takahashi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital
| | - Yasuhiro Asahina
- Department of Gastroenterology and Hepatology and Liver Disease Control, Tokyo Medical and Dental University
| | - Daisuke Ban
- Department of Hepato-Biliary-Pancreatic and General Surgery, Tokyo Medical and Dental University
| | - Atsushi Kudo
- Department of Hepato-Biliary-Pancreatic and General Surgery, Tokyo Medical and Dental University
| | - Minoru Tanabe
- Department of Hepato-Biliary-Pancreatic and General Surgery, Tokyo Medical and Dental University
| | - Shinji Tanaka
- Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University
| | | | - Nobuyuki Enomoto
- Department of Gastroenterology and Hepatology, University of Yamanashi
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital
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8
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Hoffmann K, Ganten T, Gotthardtp D, Radeleff B, Settmacher U, Kollmar O, Nadalin S, Karapanagiotou-Schenkel I, von Kalle C, Jäger D, Büchler MW, Schemmer P. Impact of neo-adjuvant Sorafenib treatment on liver transplantation in HCC patients - a prospective, randomized, double-blind, phase III trial. BMC Cancer 2015; 15:392. [PMID: 25957784 PMCID: PMC4449604 DOI: 10.1186/s12885-015-1373-z] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2014] [Accepted: 04/27/2015] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Liver Transplantation (LT) is treatment of choice for patients with hepatocellular carcinoma (HCC) within MILAN Criteria. Tumour progression and subsequent dropout from waiting list have significant impact on the survival. Transarterial chemoembolization (TACE) controls tumour growth in the treated HCC nodule, however, the risk of tumour development in the untreated liver is increased by simultaneous release of neo-angiogenic factors. Due to its anti-angiogenic effects, Sorafenib delays the progression of HCC. Aim of this study was to determine whether combination of TACE and Sorafenib improves tumour control in HCC patients on waiting list for LT. METHODS Fifty patients were randomly assigned on a 1:1 ratio in double-blinded fashion at four centers in Germany and treated with TACE plus either Sorafenib (n = 24) or placebo (n = 26). The end of treatment was development of progressive disease according to mRECIST criteria or LT. The primary endpoint of the trial was the Time-to-Progression (TTP). Other efficacy endpoints were Tumour Response, Progression-free Survival (PFS), and Time-to-LT (TTLT). RESULTS The median time of treatment was 125 days with Sorafenib and 171 days with the placebo. Fourteen patients (seven from each group) developed tumour progression during the course of the study period. The Hazard Ratio of TTP was 1.106 (95% CI: 0.387, 3.162). The results of the Objective Response Rate, Disease Control Rate, PFS, and TTLT were comparable in both groups. The incidence of AEs was comparable in the placebo group (n = 23, 92%) and in the Sorafenib group (n = 23, 96%). Twelve patients (50%) on Sorafenib and four patients (16%) on placebo experienced severe treatment-related AEs. CONCLUSION The TTP is similar after neo-adjuvant treatment with TACE and Sorafenib before LT compared to TACE and placebo. The Tumour Response, PFS, and TTLT were comparable. The safety profile of the Sorafenib group was similar to that of the placebo group. TRIAL REGISTRATION ISRCTN24081794.
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Affiliation(s)
- Katrin Hoffmann
- Department of General-, Visceral- and Transplantation-Surgery, Ruprecht-Karls-University, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
| | - Tom Ganten
- Department of Internal Medicine, Ruprecht-Karls-University, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
| | - Daniel Gotthardtp
- Department of Internal Medicine, Ruprecht-Karls-University, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
| | - Boris Radeleff
- Department of Radiology, Ruprecht-Karls-University, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
| | - Utz Settmacher
- Department of General-, Visceral- and Vascular-Surgery, University Hospital, Erlanger Allee 101, 07747, Jena, Germany.
| | - Otto Kollmar
- Department of General and Visceral Surgery, Georg-August-University, Robert-Koch-Str. 40, 37075, Göttingen, Germany.
| | - Silvio Nadalin
- Department of Surgery, University Hospital, Hoppe-Seyler-Straße 3, 72076, Tübingen, Germany.
| | | | - Christof von Kalle
- National Centre of Tumour Diseases, Ruprecht-Karls-University, Im Neuenheimer Feld 460, 69120, Heidelberg, Germany.
| | - Dirk Jäger
- National Centre of Tumour Diseases, Ruprecht-Karls-University, Im Neuenheimer Feld 460, 69120, Heidelberg, Germany.
| | - Markus W Büchler
- Department of General-, Visceral- and Transplantation-Surgery, Ruprecht-Karls-University, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
| | - Peter Schemmer
- Department of General-, Visceral- and Transplantation-Surgery, Ruprecht-Karls-University, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
- Department of General- Visceral- and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, D-69120, Heidelberg, Germany.
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9
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Castelli G, Burra P, Giacomin A, Vitale A, Senzolo M, Cillo U, Farinati F. Sorafenib use in the transplant setting. Liver Transpl 2014; 20:1021-8. [PMID: 24809799 DOI: 10.1002/lt.23911] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2013] [Accepted: 05/06/2014] [Indexed: 12/14/2022]
Abstract
Liver transplantation (LT) is an established treatment for hepatocellular carcinoma (HCC), and sorafenib (SFN) is a validated treatment for patients harboring advanced tumors. It is still not clear whether the combination of the 2 treatments, with SFN used in the neoadjuvant, adjuvant, or recurrence setting, is useful and cost-effective. This article summarizes the present evidence in favor of and against the use of SFN in the setting of LT for HCC, and it also includes the problem of toxicity, particularly when mammalian target of rapamycin inhibitors, which play a central role in regulating cellular growth and proliferation, are used as immunosuppressants. Overall, the data do not support the use of SFN in the pre- or post-LT setting as adjuvant therapy, and additional studies are needed to reach sound conclusions on the topic.
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Affiliation(s)
- Giulia Castelli
- Department of Surgery, Oncology, and Gastroenterology, Padua University School of Medicine, Padua, Italy
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10
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Dodson RM, He J, Pawlik TM. Resection and transplantation for hepatocellular carcinoma: factors influencing surgical options. Future Oncol 2014; 10:587-607. [DOI: 10.2217/fon.13.225] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
ABSTRACT: The management of hepatocellular carcinoma within the Milan criteria and with well-compensated cirrhosis is a topic of debate. Recent surveillance programs in patients with hepatitis C and cirrhosis have allowed some patients to be diagnosed with early, potentially curable, disease via liver resection (LR), liver transplantation (LT) or liver ablation. LT has excellent outcomes with 5–year survival rates >70% for patients within the Milan criteria. However, its utilization is limited by increasing organ shortages. LR is also effective with 5–year survival outcomes between 50–70% and safe in light of advances in surgical technique, preresection optimization and patient selection. Patients with solitary tumors and well-preserved liver function are good candidates for LR, whereas LT is best reserved for patients with compromised liver function and multifocal disease. LT and LR should not be viewed as competing tools but as complementary tools in the current armamentarium to treat early hepatocellular carcinoma.
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Affiliation(s)
- Rebecca M Dodson
- Johns Hopkins University School of Medicine, Department of Surgery, 600 North Wolfe Street, Blalock 688, Baltimore, MD 21287, USA
| | - Jin He
- Johns Hopkins University School of Medicine, Department of Surgery, 600 North Wolfe Street, Blalock 688, Baltimore, MD 21287, USA
| | - Timothy M Pawlik
- Johns Hopkins University School of Medicine, Department of Surgery, 600 North Wolfe Street, Blalock 688, Baltimore, MD 21287, USA
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11
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Brochard C, Hamy A, Michalak S, Aubé C, Picquet J, Nebout N, Caroli-Bosc FX, Oberti F, Calès P, Boursier J. Metastatic hepatocellular carcinoma: when surgery and successive palliative treatments lead to remission. Clin Res Hepatol Gastroenterol 2014; 38:e19-22. [PMID: 23608740 DOI: 10.1016/j.clinre.2013.02.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2012] [Revised: 02/04/2013] [Accepted: 02/19/2013] [Indexed: 02/04/2023]
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of death by cancer worldwide. The prognosis of patients with metastatic HCC remains limited, with an expected median survival lower than 50% at 1 year. Here, we report the case of a 63-year-old man who suffered from a small HCC in the liver and a large unique metastasis in the right adrenal gland. A surgical resection of both lesions was performed. Seven months later, HCC recurred with an isolated right renal metastatic lymphadenopathy and a high alpha-fetoprotein level. HCC was brought under control by sorafenib; the alpha-fetoprotein level was greatly reduced but remained moderately elevated and stable over 2 years after the onset of chemotherapy. Additional external radiotherapy on the metastatic lymphadenopathy led to a normalization of the alpha-fetoprotein level and discontinuation of sorafenib treatment. One year after the end of radiotherapy, a second isolated metastasis occurred in the right lung. This tumor was surgically removed. Twenty-one months after this second surgical procedure, i.e., more than 5.5 years after the initial diagnosis of metastatic HCC, the patient was asymptomatic and tumor free.
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Affiliation(s)
- Charlène Brochard
- Department of Hepato-Gastroenterology, University Hospital, Angers, France
| | - Antoine Hamy
- Department of Visceral Surgery, University Hospital, Angers, France
| | - Sophie Michalak
- Department of Pathology, University Hospital, Angers, France
| | - Christophe Aubé
- Department of Radiology, University Hospital, Angers, France
| | - Jean Picquet
- Department of Vascular and Thoracic Surgery, University Hospital, Angers, France
| | - Nathalie Nebout
- Department of Radiotherapy, Centre Paul-Papin, Angers, France
| | | | - Frédéric Oberti
- Department of Hepato-Gastroenterology, University Hospital, Angers, France
| | - Paul Calès
- Department of Hepato-Gastroenterology, University Hospital, Angers, France
| | - Jérôme Boursier
- Department of Hepato-Gastroenterology, University Hospital, Angers, France.
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12
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Barbier L, Fuks D, Pessaux P, Muscari F, Le Treut YP, Faivre S, Belghiti J. Safety of liver resection for hepatocellular carcinoma after sorafenib therapy: a multicenter case-matched study. Ann Surg Oncol 2013; 20:3603-9. [PMID: 23715965 DOI: 10.1245/s10434-013-3029-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2013] [Indexed: 02/06/2023]
Abstract
BACKGROUND Liver resection can be considered in some hepatocellular carcinoma (HCC) patients who received sorafenib. The lack of clinical data about safety of resection after sorafenib treatment led us to assess its potential impact on perioperative course in a multicentric study. METHODS From 2008 to 2011, a total of 23 HCC patients who underwent liver resection after treatment with sorafenib (sorafenib group) were compared with 46 HCC patients (control group) matched for age, gender, underlying liver disease, tumor characteristics and type of resection. Patients received sorafenib for a median duration of 1 (range 0.2-11) months and drug was interrupted at least 7 days before surgery. End points were intraoperative (operative time, vascular clamping, blood loss and transfusion), and postoperative outcomes focusing on recovery of liver function. RESULTS In the sorafenib group, HCC was developed on F4 cirrhosis in 48 % and the rate of major resection was 44 %. Surgical procedure duration (280 vs. 240 min), transfusion rate (26 vs. 15 %), blood loss (400 vs. 300 mL) and vascular clamping (70 vs. 74 %) were similar in the two groups. Mortality was zero in the sorafenib group and one (2.1 %) in the control group (p = 1.000). The incidence of postoperative complications was 44 % in the sorafenib group and 59 % in the control group (p = 0.307). Recovery of liver function was similar in the two groups in terms of prothrombin time (90 vs. 81 %, p = 0.429) and bilirubin level (16 vs. 24 μmol/L, p = 102) at postoperative day 5. CONCLUSIONS No adverse effect of preoperative administration of sorafenib was observed during and immediately after liver resection for HCC.
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Affiliation(s)
- Louise Barbier
- Department of HPB Surgery, Beaujon Hospital, Clichy, France
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Frenette CT, Boktour M, Burroughs SG, Kaseb A, Aloia TA, Galati J, Gaber AO, Monsour H, Ghobrial RM. Pre-transplant utilization of sorafenib is not associated with increased complications after liver transplantation. Transpl Int 2013; 26:734-9. [PMID: 23701126 DOI: 10.1111/tri.12117] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2012] [Revised: 12/23/2012] [Accepted: 04/20/2013] [Indexed: 12/16/2022]
Abstract
Hepatocellular carcinoma (HCC) is increasing in incidence, resulting in approximately 35% of orthotopic liver transplantation (OLT) performed each year. Sorafenib (SOR) is a multi-kinase inhibitor that is approved for the treatment of unresectable HCC. Concerns have been raised regarding the safety of SOR in patients undergoing major surgery. We retrospectively reviewed 79 consecutive patients with HCC receiving OLT. Patient data were compared for those who received SOR pre-OLT with those who did not. SOR was continued until time of transplant. During this time period, 15 patients received SOR pre-OLT and 64 did not. The two groups were similar with regards to demographic and clinical data. SOR patients were more likely to have larger tumors, more tumor nodules, and be outside of Milan criteria. The rate of recurrence of HCC was not different between the groups (13% in SOR group, 11% in no-SOR group). Surgical complications were not increased in patients receiving SOR prior to OLT. Survival rate was also similar between the two groups (median follow-up 19.7 months). In this small cohort of patients, use of SOR prior to liver transplantation does not confer an increased risk of surgical complications, even when continued until the day of surgery.
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Kudo M, Tateishi R, Yamashita T, Ikeda M, Furuse J, Ikeda K, Kokudo N, Izumi N, Matsui O. Current status of hepatocellular carcinoma treatment in Japan: case study and discussion-voting system. Clin Drug Investig 2013. [PMID: 22873626 DOI: 10.2165/1163024-s0-000000000-00000] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The Toward Integrated Treatment of Advanced Hepatocellular Carcinoma with Nexavar (TiTAN) Symposium was held in August 2010 in Tokyo, Japan, during which the position of sorafenib (Nexavar®) in the treatment of HCC in Japan (for which it received approval in 2009) was discussed by a panel of eight expert hepatologists in a session chaired by Dr Kudo. The following article focuses on the discussion that went on during this session, including question and answer sessions regarding the experiences of the 350 conference attendees in treating patients with HCC, as well as some of the more challenging disease management issues. Since 2008, when the phase III Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) trial demonstrated an increase in the median overall survival (OS) for patients with unresectable HCC treated with sorafenib compared with placebo, international and Japanese guidelines recommend sorafenib as a first-line option for patients with advanced HCC Child-Pugh liver function class A who have extrahepatic metastasis. Sorafenib is also recommended for patients unresponsive to transarterial chemoembolization (TACE) or hepatic arterial infusion chemotherapy (HAIC). Importantly, if HCC is judged to be unresponsive to TACE, treatment should be switched to sorafenib in a timely manner. Almost half of the conference attendees said that they used both the Japan Society of Hepatology clinical practice guidelines and the clinical practice guidelines for HCC when determining treatment strategies for individual HCC patients. Sorafenib should currently not be used as adjuvant therapy or in combination with TACE or HAIC until evidence from ongoing clinical trials shows that it is beneficial in these settings.
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Affiliation(s)
- Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kinki University School of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, Japan.
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Kudo M, Tateishi R, Yamashita T, Ikeda M, Furuse J, Ikeda K, Kokudo N, Izumi N, Matsui O. Current status of hepatocellular carcinoma treatment in Japan: case study and discussion-voting system. Clin Drug Investig 2013; 32 Suppl 2:37-51. [PMID: 22873626 DOI: 10.1007/bf03265495] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
The Toward Integrated Treatment of Advanced Hepatocellular Carcinoma with Nexavar (TiTAN) Symposium was held in August 2010 in Tokyo, Japan, during which the position of sorafenib (Nexavar®) in the treatment of HCC in Japan (for which it received approval in 2009) was discussed by a panel of eight expert hepatologists in a session chaired by Dr Kudo. The following article focuses on the discussion that went on during this session, including question and answer sessions regarding the experiences of the 350 conference attendees in treating patients with HCC, as well as some of the more challenging disease management issues. Since 2008, when the phase III Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) trial demonstrated an increase in the median overall survival (OS) for patients with unresectable HCC treated with sorafenib compared with placebo, international and Japanese guidelines recommend sorafenib as a first-line option for patients with advanced HCC Child-Pugh liver function class A who have extrahepatic metastasis. Sorafenib is also recommended for patients unresponsive to transarterial chemoembolization (TACE) or hepatic arterial infusion chemotherapy (HAIC). Importantly, if HCC is judged to be unresponsive to TACE, treatment should be switched to sorafenib in a timely manner. Almost half of the conference attendees said that they used both the Japan Society of Hepatology clinical practice guidelines and the clinical practice guidelines for HCC when determining treatment strategies for individual HCC patients. Sorafenib should currently not be used as adjuvant therapy or in combination with TACE or HAIC until evidence from ongoing clinical trials shows that it is beneficial in these settings.
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Affiliation(s)
- Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kinki University School of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, Japan.
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Vagefi PA, Hirose R. Sorafenib Combined with Locoregional Therapy Prior to Liver Transplantation for Hepatocellular Carcinoma: An Update on a Previous Case Report. J Gastrointest Cancer 2012; 44:246-7. [DOI: 10.1007/s12029-012-9417-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Truesdale AE, Caldwell SH, Shah NL, Argo CK, Al-Osaimi AMS, Schmitt TM, Northup PG. Sorafenib therapy for hepatocellular carcinoma prior to liver transplant is associated with increased complications after transplant. Transpl Int 2011; 24:991-8. [PMID: 21777298 DOI: 10.1111/j.1432-2277.2011.01299.x] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
This study compared post-transplant outcomes of patients with hepatocellular carcinoma (HCC) who took sorafenib prior to orthotopic liver transplantation (OLT) with those patients who were not treated with sorafenib. Thirty-three patients with HCC who were listed for liver transplantation were studied: 10 patients were treated with sorafenib prior to transplantation in an attempt to prevent progression of HCC while awaiting transplant. The remaining 23 patients were considered controls. The mean duration of sorafenib use was 19.2 (SD 25.2) weeks. Overall death rates were similar between the sorafenib group and control group (20% vs. 8.7%, respectively, P = 0.56). However, the patients in the sorafenib group had a higher incidence of acute cellular rejection following transplantation (67% vs. 22%, OR = 7.2, 95% CI 1.3-39.6, P = 0.04). The sorafenib group also had a higher rate of early biliary complications (67% vs. 17%, OR = 9.5, 1.6-55.0, P = 0.01). The use of sorafenib was found to be an independent predictor of post-transplant biliary complications (OR 12.6, 1.4-116.2, P = 0.03). Sorafenib administration prior to OLT appears to be associated with an increase in biliary complications and possibly in acute rejection following liver transplantation. Caution should be taken in this setting until larger studies are completed.
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Affiliation(s)
- Aimee E Truesdale
- Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, VA 22908-0708, USA
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Barbier L, Muscari F, Le Guellec S, Pariente A, Otal P, Suc B. Liver resection after downstaging hepatocellular carcinoma with sorafenib. Int J Hepatol 2011; 2011:791013. [PMID: 22135750 PMCID: PMC3226249 DOI: 10.4061/2011/791013] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2010] [Accepted: 01/24/2011] [Indexed: 12/14/2022] Open
Abstract
Background. Sorafenib is a molecular-targeted therapy used in palliative treatment of advanced hepatocellular carcinoma in Child A patients. Aims. To address the question of sorafenib as neoadjuvant treatment. Methods. We describe the cases of 2 patients who had surgery after sorafenib. Results. The patients had a large hepatocellular carcinoma in the right liver with venous neoplastic thrombi (1 in the right portal branch, 1 in the right hepatic vein). After 9 months of sorafenib, reassessment showed that tumours had decreased in size with a necrotic component. A right hepatectomy with thrombectomy was performed, and histopathology showed 35% to 60% necrosis. One patient had a recurrence after 6 months and had another liver resection; they are both recurrence-free since then. Conclusion. Sorafenib can downstage hepatocellular carcinoma and thus could represent a bridge to surgery. It may be possible to select patients in good general condition with partial regression of the tumour with sorafenib for a treatment in a curative intent.
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Affiliation(s)
- L. Barbier
- Department of Digestive Surgery and Liver Transplantation, Rangueil Hospital, 1 avenue du Professor Jean Poulhès, 31059 Toulouse Cedex 9, France,*L. Barbier:
| | - F. Muscari
- Department of Digestive Surgery and Liver Transplantation, Rangueil Hospital, 1 avenue du Professor Jean Poulhès, 31059 Toulouse Cedex 9, France
| | - S. Le Guellec
- Department of Pathology, Rangueil Hospital, 31059 Toulouse, France
| | - A. Pariente
- Department of Hepato-Gastro-Enterology, Pau Hospital, 4 Boulevard Hauterive, 64046 Pau, France
| | - P. Otal
- Department of Radiology, Rangueil Hospital, 31059 Toulouse, France
| | - B. Suc
- Department of Digestive Surgery and Liver Transplantation, Rangueil Hospital, 1 avenue du Professor Jean Poulhès, 31059 Toulouse Cedex 9, France
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