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Goto R, Shimamura T, Nakajima T, Ogawa K, Tanaka K, Shimizu T, Minami R, Matsui T, Akutsu N, Sasaki S, Kakisaka T, Kawamura N, Watanabe M, Taketomi A. Potential indications for liver transplant in Child-Pugh A and Model for End-stage Liver Disease exception for hepatocellular carcinoma in Japan. Hepatol Res 2025. [PMID: 40317837 DOI: 10.1111/hepr.14178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 02/10/2025] [Accepted: 02/15/2025] [Indexed: 05/07/2025]
Abstract
AIM In 2019, expanded criteria for hepatocellular carcinoma (HCC), known as 5-5-500 (size ≤5 cm, number ≤5, alpha-fetoprotein ≤500 ng/mL), as well as Model for End-stage Liver Disease (MELD) exception, were implemented in Japan. In the present study, we evaluated liver transplantation indications and the Japanese allocation policy for HCC. METHODS Adults with HCC were evaluated between January 2013 and December 2017 in a multicenter study in Japan. The patients were aged ≤65 years, in line with the limits of Japanese transplant center limits. RESULTS HCC patients (n = 289) were classified as Child-Pugh A (74%), B (18%), or C (8%). Of these, 178 (62%) and 185 (64%) met the Milan and 5-5-500 criteria, respectively. The respective 1- and 5-year overall survival rates of patients who met the criteria were 100% and 88.1% in Child-Pugh A, 91.7% and 30.6% in B, and 72.9% and 0% in C without access to liver transplantation. For Child-Pugh A patients, we developed a risk score using the Child-Pugh score, des-gamma-carboxy prothrombin, tumor-node-metastasis stage grade, as well as albumin-bilirubin and albumin-bilirubin tumor-node-metastasis stage , which predicted worse prognosis. Additionally, we showed the characteristics of patients who achieved MELD exception points high enough to receive an organ: survival at least 2 years after waitlist registration, relatively good liver functional reserve, and sufficient tumor control with multiple treatments. CONCLUSIONS High-risk patients, identified by our scoring system and albumin-bilirubin tumor-node-metastasis stage ≥2 in Child-Pugh A, should be considered for liver transplantation eligibility. The allocation policy for HCC should be revised based on precise evaluations on a regular basis.
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Affiliation(s)
- Ryoichi Goto
- Department of Gastroenterological Surgery 1, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Tsuyoshi Shimamura
- Division of Organ Transplantation, Hokkaido University Hospital, Sapporo, Japan
| | - Tomoaki Nakajima
- Department of Hepatology, Sapporo Kosei General Hospital, Sapporo, Japan
| | - Koji Ogawa
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Kazunari Tanaka
- Center for Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan
| | - Takao Shimizu
- Center for Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan
| | - Ryosuke Minami
- Center for Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan
| | - Takeshi Matsui
- Center for Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan
| | - Noriyuki Akutsu
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Shigeru Sasaki
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Tatsuhiko Kakisaka
- Department of Gastroenterological Surgery 1, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Norio Kawamura
- Department of Gastroenterological Surgery 1, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Masaaki Watanabe
- Department of Transplant Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Akinobu Taketomi
- Department of Gastroenterological Surgery 1, Hokkaido University Graduate School of Medicine, Sapporo, Japan
- Department of Transplant Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan
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Lai Q, Ito T, Iesari S, Ikegami T, Nicolini D, Larghi Laureiro Z, Rossi M, Vivarelli M, Yoshizumi T, Hatano E, Lerut J. Role of protein induced by vitamin-K absence-II in transplanted patients with HCC not producing alpha-fetoprotein. Liver Transpl 2024; 30:472-483. [PMID: 37729520 DOI: 10.1097/lvt.0000000000000259] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 08/30/2023] [Indexed: 09/22/2023]
Abstract
Elevated Protein Induced by Vitamin-K Absence-II (PIVKA-II) has been shown to be an adverse prognostic factor in HCC patients undergoing liver transplantation (LT). No definitive data are available about the impact of PIVKA-II concerning post-LT recurrence in patients not secreting (≤ 20 ng/mL) alpha-fetoprotein (AFP). An observational retrospective study of the East-West HCC-LT consortium is reported. Between 2000 and 2019, 639 HCC patients were enrolled in 5 collaborative European and Japanese centers. To minimize the initial selection bias, an inverse probability therapy weighting method was adopted to analyze the data. In the post-inverse probability therapy weighting population, PIVKA-II (HR = 2.00; 95% CI: 1.52-2.64; p < 0.001) and AFP (HR=1.82; 95% CI: 1.48-2.24; p < 0.001) were the most relevant independent risk factors for post-LT recurrence. A sub-analysis focusing only on patients who are AFP non-secreting confirmed the negative role of PIVKA-II (HR=2.06, 95% CI: 1.26-3.35; p =0.004). When categorizing the entire population into 4 groups according to the AFP levels (≤ or > 20 ng/mL) and PIVKA (≤ or > 300 mUA/mL) at the time of LT, the lowest recurrence rates were observed in the low AFP-PIVKA-II group (5-year recurrence rate = 8.0%). Conversely, the high AFP-PIVKA-II group had the worst outcome (5-year recurrence rate = 35.1%). PIVKA-II secretion is a relevant risk factor for post-LT HCC recurrence. The role of this marker is independent of the AFP status. Combining both tumor markers, especially in the setting of LT, should be of great relevance for adding information about predicting the post-LT risk of tumor recurrence and selecting these patients for transplantation.
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Affiliation(s)
- Quirino Lai
- Department of General and Specialistic Surgery, General Surgery and Organ Transplantation Unit, Sapienza University of Rome, Rome, Italy
| | - Takashi Ito
- Department of Surgery, Kyoto University, Kyoto, Japan
| | - Samuele Iesari
- Department of Surgery, Universitè catholique de Louvain, Brussels, Belgium
| | - Toru Ikegami
- Department of Surgery and Science, Kyushu University, Fukuoka, Japan
| | - Daniele Nicolini
- Department of Experimental and Clinical Medicine, Polytechnic University of Marche, Ancona, Italy
| | - Zoe Larghi Laureiro
- Department of General and Specialistic Surgery, General Surgery and Organ Transplantation Unit, Sapienza University of Rome, Rome, Italy
| | - Massimo Rossi
- Department of General and Specialistic Surgery, General Surgery and Organ Transplantation Unit, Sapienza University of Rome, Rome, Italy
| | - Marco Vivarelli
- Department of Experimental and Clinical Medicine, Polytechnic University of Marche, Ancona, Italy
| | | | | | - Jan Lerut
- Institute for Experimental and Clinical Research IREC-Université catholique de Louvain, Brussels, Belgium
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Lerut J. Liver transplantation and liver resection as alternative treatments for primary hepatobiliary and secondary liver tumors: Competitors or allies? Hepatobiliary Pancreat Dis Int 2024; 23:111-116. [PMID: 38195351 DOI: 10.1016/j.hbpd.2023.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 12/28/2023] [Indexed: 01/11/2024]
Affiliation(s)
- Jan Lerut
- Institute for Experimental and Clinical Research (IREC), Université catholique Louvain (UCL), Avenue Hippocrate 56, 1200 Woluwe Saint Pierre, Brussels, Belgium.
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Schwenk L, Rauchfuß F, Ali-Deeb A, Dondorf F, Rohland O, Ardelt M, Settmacher U. [Individualized curative treatment for malignant diseases through liver transplantation]. CHIRURGIE (HEIDELBERG, GERMANY) 2024; 95:122-128. [PMID: 37847311 DOI: 10.1007/s00104-023-01973-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 09/22/2023] [Indexed: 10/18/2023]
Abstract
BACKGROUND For patients with primary and secondary liver tumors that are functionally or technically nonresectable, liver transplantation remains the sole curative treatment option. Over the years the benefits of transplantation have also been validated for conditions other than hepatocellular carcinoma. Currently, amidst a period of organ shortage the broadening of transplantation indications is a topic of ongoing debate. Although recent studies have confirmed the long-term success of transplantation within multimodal treatment regimens, this approach has yet to become the standard treatment for many conditions. OBJECTIVE This article explores the potential of liver transplantation in individualized multimodal oncological treatment strategies. RESULTS AND CONCLUSION Liver transplantation has become an integral component of the treatment regimen for hepatocellular carcinoma. In Germany there is a prioritized organ allocation facilitated by the granting of a standard exception for cases with a smaller tumor burden. Over the years numerous studies have demonstrated comparable long-term results using different listing criteria. Both intrahepatic cholangiocarcinoma and perihilar cholangiocarcinoma can be curatively treated with transplantation in Germany, although this is typically within the context of clinical studies. The neoadjuvant therapy and patient selection, based on tumor burden and the response to preliminary treatment, play a crucial role in influencing long-term survival and recurrence rates. The success of transplantation for liver metastases from neuroendocrine malignancies or colorectal carcinomas, which cannot be removed by partial resection, also significantly hinges on the patient selection. The role of living donor liver transplantation is becoming increasingly more pivotal in this context.
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Affiliation(s)
- Laura Schwenk
- Klinik für Allgemein‑, Viszeral- und Gefäßchirurgie, Universitätsklinikum Jena, Am Klinikum 1, 07747, Jena, Deutschland.
| | - Falk Rauchfuß
- Klinik für Allgemein‑, Viszeral- und Gefäßchirurgie, Universitätsklinikum Jena, Am Klinikum 1, 07747, Jena, Deutschland
| | - Aladdin Ali-Deeb
- Klinik für Allgemein‑, Viszeral- und Gefäßchirurgie, Universitätsklinikum Jena, Am Klinikum 1, 07747, Jena, Deutschland
| | - Felix Dondorf
- Klinik für Allgemein‑, Viszeral- und Gefäßchirurgie, Universitätsklinikum Jena, Am Klinikum 1, 07747, Jena, Deutschland
| | - Oliver Rohland
- Klinik für Allgemein‑, Viszeral- und Gefäßchirurgie, Universitätsklinikum Jena, Am Klinikum 1, 07747, Jena, Deutschland
| | - Michael Ardelt
- Klinik für Allgemein‑, Viszeral- und Gefäßchirurgie, Universitätsklinikum Jena, Am Klinikum 1, 07747, Jena, Deutschland
| | - Utz Settmacher
- Klinik für Allgemein‑, Viszeral- und Gefäßchirurgie, Universitätsklinikum Jena, Am Klinikum 1, 07747, Jena, Deutschland
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Devillers MJC, Pluimers JKF, van Hooff MC, Doukas M, Polak WG, de Man RA, Sonneveld MJ, Boonstra A, den Hoed CM. The Role of PIVKA-II as a Predictor of Early Hepatocellular Carcinoma Recurrence-Free Survival after Liver Transplantation in a Low Alpha-Fetoprotein Population. Cancers (Basel) 2023; 16:4. [PMID: 38201435 PMCID: PMC10778448 DOI: 10.3390/cancers16010004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 12/13/2023] [Accepted: 12/13/2023] [Indexed: 01/12/2024] Open
Abstract
INTRODUCTION AFP and the RETREAT score are currently used to predict HCC recurrence after LT. However, superior discriminating models are needed for low AFP populations. The aim of this study is to investigate the predictive value of PIVKA-II on recurrence-free survival after LT in a low AFP population and microvascular invasion on explant. METHODS A retrospective cohort study including all consecutive patients transplanted for HCC between 1989 and 2019 in the Erasmus MC University Medical Center in Rotterdam, the Netherlands, was used. AFP and PIVKA-II levels were determined in serum samples collected at the time of transplantation. Data on tumor load and microvascular invasion were retrieved from patients' records. RESULTS The study cohort consisted of 121 patients, with HCC recurrence in 15 patients (12.4%). The median AFP was 7.7 ng/mL (4.4-20.2), and the median PIVKA-II was 72.0 mAU/mL (41.0-213.5). Patients with low AFP (≤8 ng/mL) and PIVKA-II (≤90 mAU/mL) had a 5-year recurrence-free survival of 100% compared to 85.7% in patients with low AFP and high PIVKA-II (p = 0.026). Regardless of the AFP level, patients within the Milan criteria (based on explant pathology) with a low PIVKA-II level had a 5-year recurrence-free survival of 100% compared to patients with a high PIVKA-II level of 81.1% (p = 0.002). In patients with microvascular invasion, the AUC for PIVKA-II was slightly better than the AUC for AFP (0.775 vs. 0.687). CONCLUSIONS The dual model of PIVKA-II ≤ 90 mAU/mL with either AFP ≤ 8 ng/mL or with patients within the Milan criteria identifies patient groups which can be exempted from HCC surveillance after LT in a low AFP population. PIVKA-II may be a better predictor for explant microvascular invasion than AFP and could play a role in future models identifying LT candidates with the highest risk for HCC recurrence.
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Affiliation(s)
- Monique J. C. Devillers
- Department of Gastroenterology and Hepatology, Erasmus MC Transplant Institute, Erasmus MC University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands; (M.J.C.D.); (J.K.F.P.); (M.C.v.H.); (R.A.d.M.); (M.J.S.); (A.B.)
| | - Johanna K. F. Pluimers
- Department of Gastroenterology and Hepatology, Erasmus MC Transplant Institute, Erasmus MC University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands; (M.J.C.D.); (J.K.F.P.); (M.C.v.H.); (R.A.d.M.); (M.J.S.); (A.B.)
| | - Maria C. van Hooff
- Department of Gastroenterology and Hepatology, Erasmus MC Transplant Institute, Erasmus MC University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands; (M.J.C.D.); (J.K.F.P.); (M.C.v.H.); (R.A.d.M.); (M.J.S.); (A.B.)
| | - Michail Doukas
- Department of Pathology, Erasmus MC University Medical Center, 3000 CA Rotterdam, The Netherlands;
| | - Wojciech G. Polak
- Department of Surgery, Division of Hepatopancreatobiliary and Transplant Surgery, Erasmus MC Transplant Institute, Erasmus MC University Medical Center, 3000 CA Rotterdam, The Netherlands;
| | - Robert A. de Man
- Department of Gastroenterology and Hepatology, Erasmus MC Transplant Institute, Erasmus MC University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands; (M.J.C.D.); (J.K.F.P.); (M.C.v.H.); (R.A.d.M.); (M.J.S.); (A.B.)
| | - Milan J. Sonneveld
- Department of Gastroenterology and Hepatology, Erasmus MC Transplant Institute, Erasmus MC University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands; (M.J.C.D.); (J.K.F.P.); (M.C.v.H.); (R.A.d.M.); (M.J.S.); (A.B.)
| | - Andre Boonstra
- Department of Gastroenterology and Hepatology, Erasmus MC Transplant Institute, Erasmus MC University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands; (M.J.C.D.); (J.K.F.P.); (M.C.v.H.); (R.A.d.M.); (M.J.S.); (A.B.)
| | - Caroline M. den Hoed
- Department of Gastroenterology and Hepatology, Erasmus MC Transplant Institute, Erasmus MC University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands; (M.J.C.D.); (J.K.F.P.); (M.C.v.H.); (R.A.d.M.); (M.J.S.); (A.B.)
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Yoon JH, Choi SK. Management of early-stage hepatocellular carcinoma: challenges and strategies for optimal outcomes. JOURNAL OF LIVER CANCER 2023; 23:300-315. [PMID: 37734717 PMCID: PMC10565545 DOI: 10.17998/jlc.2023.08.27] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 08/24/2023] [Accepted: 08/27/2023] [Indexed: 09/23/2023]
Abstract
Although hepatocellular carcinoma (HCC) is associated with a poor prognosis, management of early-stage HCC is often successful with highly efficacious treatment modalities such as liver transplantation, surgical resection, and radiofrequency ablation. However, unfavorable clinical outcomes have been observed under certain circumstances, even after efficient treatment. Factors that predict unsuitable results after treatment include tumor markers, inflammatory markers, imaging findings reflecting tumor biology, specific outcome indicators for each treatment modality, liver functional reserve, and the technical feasibility of the treatment modalities. Various strategies may overcome these challenges, including the application of reinforced treatment indication criteria with predictive markers reflecting tumor biology, compensation for technical issues with up-to-date technologies, modification of treatment modalities, downstaging with locoregional therapies (such as transarterial chemotherapy or radiotherapy), and recently introduced combination immunotherapies. In this review, we discuss the challenges to achieving optimal outcomes in the management of early-stage HCC and suggest strategies to overcome these obstacles.
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Affiliation(s)
- Jae Hyun Yoon
- Department of Gastroenterology and hepatology, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, Korea
| | - Sung Kyu Choi
- Department of Gastroenterology and hepatology, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, Korea
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Kim DY, Toan BN, Tan CK, Hasan I, Setiawan L, Yu ML, Izumi N, Huyen NN, Chow PKH, Mohamed R, Chan SL, Tanwandee T, Lee TY, Hai TTN, Yang T, Lee WC, Chan HLY. Utility of combining PIVKA-II and AFP in the surveillance and monitoring of hepatocellular carcinoma in the Asia-Pacific region. Clin Mol Hepatol 2023; 29:277-292. [PMID: 36710606 PMCID: PMC10121296 DOI: 10.3350/cmh.2022.0212] [Citation(s) in RCA: 63] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 11/18/2022] [Accepted: 01/25/2023] [Indexed: 01/31/2023] Open
Abstract
Even though the combined use of ultrasound (US) and alpha-fetoprotein (AFP) is recommended for the surveillance of hepatocellular carcinoma (HCC), the utilization of AFP has its challenges, including accuracy dependent on its cut-off levels, degree of liver necroinflammation, and etiology of liver disease. Though various studies have demonstrated the utility of protein induced by vitamin K absence II (PIVKA-II) in surveillance, treatment monitoring, and predicting recurrence, it is still not recommended as a routine biomarker test. A panel of 17 experts from Asia-Pacific, gathered to discuss and reach a consensus on the clinical usefulness and value of PIVKA-II for the surveillance and treatment monitoring of HCC, based on six predetermined statements. The experts agreed that PIVKA-II was valuable in the detection of HCC in AFP-negative patients, and could potentially benefit detection of early HCC in combination with AFP. PIVKA-II is clinically useful for monitoring curative and intra-arterial locoregional treatments, outcomes, and recurrence, and could potentially predict microvascular invasion risk and facilitate patient selection for liver transplant. However, combining PIVKA-II with US and AFP for HCC surveillance, including small HCC, still requires more evidence, whilst its role in detecting AFP-negative HCC will potentially increase as more patients are treated for hepatitis-related HCC. PIVKA-II in combination with AFP and US has a clinical role in the Asia-Pacific region for surveillance. However, implementation of PIVKA-II in the region will have some challenges, such as requiring standardization of cut-off values, its cost-effectiveness and improving awareness among healthcare providers.
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Affiliation(s)
- Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Bao Nguyen Toan
- Clinical Pathology Department, Medic Center, Ho Chi Minh, Vietnam
| | - Chee-Kiat Tan
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore
| | - Irsan Hasan
- Faculty of Medicine, University Indonesia/Ciptomangunkusumo Hospital, Jakarta, Indonesia
| | - Lyana Setiawan
- Clinical Pathology Department, Integrated Laboratory, Dharmais National Cancer Hospital, Jakarta, Indonesia
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital; College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- School of Medicine, College of Medicine and Center of Excellence for Metabolic Associated Fatty Liver Disease, National Sun Yat-sen University, Koahsiung, Taiwan
| | - Namiki Izumi
- Japanese Red Cross Musashino Hospital, Musashino, Japan
| | | | - Pierce Kah-Hoe Chow
- Department of Hepato-pancreato-biliary and Transplant Surgery, National Cancer Center Singapore and Singapore General Hospital, Singapore
- Surgery Academic Clinical Program, Duke-NUS Medical School, Singapore
| | | | - Stephen Lam Chan
- State Key Laboratory of Oncology in South China, Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong
| | - Tawesak Tanwandee
- Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Teng-Yu Lee
- Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
- Department of Medicine, School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Thi Thanh Nguyen Hai
- National Hospital for Tropical Diseases, Hanoi, Vietnam
- Biochemistry Department, Hanoi Medical University, Hanoi, Vietnam
| | - Tian Yang
- Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai, China
| | - Woo-Chang Lee
- Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Henry Lik Yuen Chan
- Department of Internal Medicine, The Chinese University of Hong Kong and Union Hospital, Hong Kong
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2022 KLCA-NCC Korea practice guidelines for the management of hepatocellular carcinoma. JOURNAL OF LIVER CANCER 2023; 23:1-120. [PMID: 37384024 PMCID: PMC10202234 DOI: 10.17998/jlc.2022.11.07] [Citation(s) in RCA: 68] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Accepted: 11/07/2022] [Indexed: 06/30/2023]
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the fourth most common cancer among men in South Korea, where the prevalence of chronic hepatitis B infection is high in middle and old age. The current practice guidelines will provide useful and sensible advice for the clinical management of patients with HCC. A total of 49 experts in the fields of hepatology, oncology, surgery, radiology, and radiation oncology from the Korean Liver Cancer Association-National Cancer Center Korea Practice Guideline Revision Committee revised the 2018 Korean guidelines and developed new recommendations that integrate the most up-to-date research findings and expert opinions. These guidelines provide useful information and direction for all clinicians, trainees, and researchers in the diagnosis and treatment of HCC.
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Affiliation(s)
- Korean Liver Cancer Association (KLCA) and National Cancer Center (NCC) Korea
- Corresponding author: KLCA-NCC Korea Practice Guideline Revision Committee (KPGRC) (Committee Chair: Joong-Won Park) Center for Liver and Pancreatobiliary Cancer, Division of Gastroenterology, Department of Internal Medicine, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang 10408, Korea Tel. +82-31-920-1605, Fax: +82-31-920-1520, E-mail:
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Nishio T, Ito T, Hata K, Taura K, Hatano E. Current status of liver transplantation for non-B non-C liver cirrhosis and hepatocellular carcinoma. Ann Gastroenterol Surg 2023; 7:42-52. [PMID: 36643372 PMCID: PMC9831911 DOI: 10.1002/ags3.12612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Accepted: 08/05/2022] [Indexed: 01/18/2023] Open
Abstract
Recently, non-B non-C chronic liver diseases, including alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH), have markedly increased worldwide. Liver transplantation (LT) is an effective curative therapy for hepatocellular carcinoma (HCC) as well as decompensated liver cirrhosis. In Japan, where the source of liver grafts is strongly dependent on living donors, efforts have been made to unify the indications for eligibility of HCC patients for LT, leading to the development of 5-5-500 criteria. Along with the expansion of eligibility for LT, the current changing trends in underlying liver diseases of LT recipients, which are related to the rising tide of non-B non-C cirrhosis and HCC, are highlighting the importance of peri-transplant management of patients with various comorbidities. The post-LT prognosis of patients with ALD is significantly affected by de novo malignancies and metabolic syndrome-related complications as well as posttransplant alcohol relapse. NAFLD/NASH patients often suffer from obesity, type 2 diabetes mellitus, and other metabolic syndrome-related disorders, and nonneoplastic factors such as cardiovascular events and recurrence of NAFLD/NASH have a significant impact on post-LT outcomes. Patient management in the peri-transplant period as well as risk assessment for LT are key to improving post-LT outcomes in the era of a growing number of cases of LT for non-B non-C liver diseases.
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Affiliation(s)
- Takahiro Nishio
- Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Takashi Ito
- Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Koichiro Hata
- Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Kojiro Taura
- Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Etsuro Hatano
- Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
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2022 KLCA-NCC Korea Practice Guidelines for the Management of Hepatocellular Carcinoma. Korean J Radiol 2022; 23:1126-1240. [PMID: 36447411 PMCID: PMC9747269 DOI: 10.3348/kjr.2022.0822] [Citation(s) in RCA: 80] [Impact Index Per Article: 26.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 10/28/2022] [Indexed: 11/18/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the fourth most common cancer among men in South Korea, where the prevalence of chronic hepatitis B infection is high in middle and old age. The current practice guidelines will provide useful and sensible advice for the clinical management of patients with HCC. A total of 49 experts in the fields of hepatology, oncology, surgery, radiology, and radiation oncology from the Korean Liver Cancer Association-National Cancer Center Korea Practice Guideline Revision Committee revised the 2018 Korean guidelines and developed new recommendations that integrate the most up-to-date research findings and expert opinions. These guidelines provide useful information and direction for all clinicians, trainees, and researchers in the diagnosis and treatment of HCC.
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11
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2022 KLCA-NCC Korea practice guidelines for the management of hepatocellular carcinoma. Clin Mol Hepatol 2022; 28:583-705. [PMID: 36263666 PMCID: PMC9597235 DOI: 10.3350/cmh.2022.0294] [Citation(s) in RCA: 174] [Impact Index Per Article: 58.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 09/23/2022] [Indexed: 01/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the fourth most common cancer among men in South Korea, where the prevalence of chronic hepatitis B infection is high in middle and old age. The current practice guidelines will provide useful and sensible advice for the clinical management of patients with HCC. A total of 49 experts in the fields of hepatology, oncology, surgery, radiology, and radiation oncology from the Korean Liver Cancer Association-National Cancer Center Korea Practice Guideline Revision Committee revised the 2018 Korean guidelines and developed new recommendations that integrate the most up-to-date research findings and expert opinions. These guidelines provide useful information and direction for all clinicians, trainees, and researchers in the diagnosis and treatment of HCC.
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12
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Lai Q, Lesari S, Lerut JP. The impact of biological features for a better prediction of posttransplant hepatocellular cancer recurrence. Curr Opin Organ Transplant 2022; 27:305-311. [PMID: 36354256 DOI: 10.1097/mot.0000000000000955] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
PURPOSE OF REVIEW Morphological criteria (i.e., Milan Criteria) have been considered for a long time to be the best tool for selecting patients with hepatocellular cancer (HCC) waiting for liver transplantation (LT). In the last ten years, a refinement of the selection criteria has been observed, with the introduction of biological tumor characteristics enabling to enlarge the number of potential transplant candidates and to select LT candidates with a lower risk of posttransplant recurrence. RECENT FINDINGS Several biological tumor aspects have been explored and validated in international cohorts to expand the ability to predict patients at high risk for recurrence. Alpha-fetoprotein, radiological response to locoregional treatments, and other more recently proposed markers have been principally explored. Moreover, more complex statistical approaches (i.e., deep learning) have been advocated to explore the nonlinear intercorrelations between the investigated features. SUMMARY The addition of biological aspects to morphology has improved the ability to discriminate among high- and low-risk patients for recurrence. New prognostic algorithms based on the more sophisticated artificial intelligence approach are further improving the capability to select LT candidates with HCC.
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Affiliation(s)
- Quirino Lai
- General Surgery and Organ Transplantation Unit, Department of General and Specialistic Surgery 'Paride Stefanini', Sapienza University of Rome, AOU Policlinico Umberto I of Rome, Rome
| | - Samuele Lesari
- Kidney Transplantation Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Jan P Lerut
- Institute for Experimental and Clinical Research (IREC), Universite catholique Louvain (UCL), Brussels, Belgium
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13
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Silverstein J, Yao FY, Grab JD, Braun HJ, Roberts J, Dodge JL, Mehta N. National experience with living donor liver transplantation for hepatocellular carcinoma. Liver Transpl 2022; 28:1144-1157. [PMID: 35226793 PMCID: PMC10266543 DOI: 10.1002/lt.26439] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 01/10/2022] [Accepted: 01/20/2022] [Indexed: 01/13/2023]
Abstract
Living donor liver transplantation (LDLT) is an attractive option to decrease waitlist dropout, particularly for patients with hepatocellular carcinoma (HCC) who face lengthening waiting times. Using the United Network for Organ Sharing (UNOS) national database, trends in LDLT utilization for patients with HCC were evaluated, and post-LT outcomes for LDLT versus deceased donor liver transplantation (DDLT) were compared. From 1998 to 2018, LT was performed in 20,161 patients with HCC including 726 (3.6%) who received LDLT. The highest LDLT utilization was prior to the 2002 HCC Model for End-Stage Liver Disease (MELD) exception policy (17.5%) and dropped thereafter (3.1%) with a slight increase following the 6-month wait policy in 2015 (3.8%). LDLT was more common in patients from long-wait UNOS regions with blood type O, in those with larger total tumor diameter (2.3 vs. 2.1 cm, p = 0.02), and higher alpha-fetoprotein at LT (11.5 vs. 9.0 ng/ml, p = 0.04). The 5-year post-LT survival (LDLT 77% vs. DDLT 75%), graft survival (72% vs. 72%), and HCC recurrence (11% vs. 13%) were similar between groups (all p > 0.20). In conclusion, LDLT utilization for HCC has remained low since 2002 with only a slight increase after the 6-month wait policy introduction in 2015. Given the excellent post-LT survival, LDLT appears to be an underutilized but valuable option for patients with HCC, especially those at high risk for waitlist dropout.
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Affiliation(s)
- Jordyn Silverstein
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, California, USA
| | - Francis Y. Yao
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, California, USA
- Division of Transplant Surgery, Department of Surgery, University of California, San Francisco, San Francisco, California, USA
| | - Joshua D. Grab
- Division of Transplant Surgery, Department of Surgery, University of California, San Francisco, San Francisco, California, USA
| | - Hillary J. Braun
- Division of Transplant Surgery, Department of Surgery, University of California, San Francisco, San Francisco, California, USA
| | - John Roberts
- Division of Transplant Surgery, Department of Surgery, University of California, San Francisco, San Francisco, California, USA
| | - Jennifer L. Dodge
- Division of Transplant Surgery, Department of Surgery, University of California, San Francisco, San Francisco, California, USA
- Department of Gastroenterology and Liver Diseases, University of Southern California Keck School of Medicine, Los Angeles, California, USA
| | - Neil Mehta
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, California, USA
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14
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Shimamura T, Goto R, Watanabe M, Kawamura N, Takada Y. Liver Transplantation for Hepatocellular Carcinoma: How Should We Improve the Thresholds? Cancers (Basel) 2022; 14:cancers14020419. [PMID: 35053580 PMCID: PMC8773688 DOI: 10.3390/cancers14020419] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/06/2022] [Accepted: 01/10/2022] [Indexed: 02/01/2023] Open
Abstract
Simple Summary The ideal treatment for hepatocellular carcinoma (HCC) is liver transplantation (LT), which both eliminates the HCC and cures the diseased liver. Once considered an experimental treatment with dismal survival rates, LT for HCC entered a new era with the establishment of the Milan criteria over 20 years ago. However, over the last two decades, the Milan criteria, which are based on tumor morphology, have come under intense scrutiny and are now largely regarded as too restrictive, and limit the access of transplantation for many patients who would otherwise achieve good clinical outcomes. The liver transplant community has been making every effort to reach a goal of establishing more reliable selection criteria. This article addresses how the criteria have been extended, as well as the concept of pre-transplant down-staging to maximize the eligibility. Abstract Hepatocellular carcinoma (HCC) is the third highest cause of cancer-related mortality, and liver transplantation is the ideal treatment for this disease. The Milan criteria provided the opportunity for HCC patients to undergo LT with favorable outcomes and have been the international gold standard and benchmark. With the accumulation of data, however, the Milan criteria are not regarded as too restrictive. After the implementation of the Milan criteria, many extended criteria have been proposed, which increases the limitations regarding the morphological tumor burden, and incorporates the tumor’s biological behavior using surrogate markers. The paradigm for the patient selection for LT appears to be shifting from morphologic criteria to a combination of biologic, histologic, and morphologic criteria, and to the establishment of a model for predicting post-transplant recurrence and outcomes. This review article aims to characterize the various patient selection criteria for LT, with reference to several surrogate markers for the biological behavior of HCC (e.g., AFP, PIVKA-II, NLR, 18F-FDG PET/CT, liquid biopsy), and the response to locoregional therapy. Furthermore, the allocation rules in each country and the present evidence on the role of down-staging large tumors are addressed.
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Affiliation(s)
- Tsuyoshi Shimamura
- Division of Organ Transplantation, Hokkaido University Hospital, N-14, W-5, Kita-ku, Sapporo 060-8648, Hokkaido, Japan
- Correspondence:
| | - Ryoichi Goto
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, N-15, W-7, Kita-ku, Sapporo 060-8638, Hokkaido, Japan;
| | - Masaaki Watanabe
- Department of Transplant Surgery, Hokkaido University Graduate School of Medicine, N-15, W-7, Kita-ku, Sapporo 060-8638, Hokkaido, Japan; (M.W.); (N.K.)
| | - Norio Kawamura
- Department of Transplant Surgery, Hokkaido University Graduate School of Medicine, N-15, W-7, Kita-ku, Sapporo 060-8638, Hokkaido, Japan; (M.W.); (N.K.)
| | - Yasutsugu Takada
- Department of HBP and Breast Surgery, Ehime University Graduate School of Medicine, Shitsukawa, Toon 791-0295, Ehime, Japan;
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15
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Liang HR, Hsieh CE, Lin KH, Ko CJ, Hung YJ, Hsu YL, Chen YL. Living donor liver transplantation for hepatocellular carcinoma beyond the Milan criteria: outcome of expanded criteria in tumor size. BMC Surg 2021; 21:401. [PMID: 34798847 PMCID: PMC8603535 DOI: 10.1186/s12893-021-01403-z] [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: 07/07/2021] [Accepted: 11/09/2021] [Indexed: 11/23/2022] Open
Abstract
Background The Milan criteria are the universal standard of liver transplantation for hepatocellular carcinoma (HCC). Numerous expanded criteria have shown outcomes as good as the Milan criteria. In Taiwan, living donor liver transplant (LDLT) accounts for the majority of transplantations due to organ shortages. Methods We retrospectively enrolled 155 patients who underwent LDLT for HCC from July 2005 to June 2017 and were followed up for at least 2 years. Patients beyond the Milan criteria (n = 78) were grouped as recurrent or nonrecurrent, and we established new expanded criteria based on these data. Results Patients beyond the Milan criteria with recurrence (n = 31) had a significantly larger maximal tumor diameter (4.13 ± 1.96 cm versus 6.10 ± 3.41 cm, p = 0.006) and total tumor diameter (7.19 ± 4.13 cm versus 10.21 ± 5.01 cm, p = 0.005). Therefore, we established expanded criteria involving maximal tumor diameter ≤ 6 cm and total tumor diameter < 10 cm. The 5-year survival rate of patients who met these criteria (n = 134) was 77.3%, and the 5-year recurrence rate was 20.5%; both showed no significant differences from those of the Milan criteria. Under the expanded criteria, the pool of eligible recipients was 35% larger than that of the Milan criteria. Conclusion Currently, patients with HCC who undergo LDLT can achieve good outcomes even when they are beyond the Milan criteria. Under the new expanded criteria, patients can achieve outcomes as good as those with the Milan criteria and more patients can benefit.
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Affiliation(s)
- Hsin-Rou Liang
- Department of General Surgery, Changhua Christian Hospital, No. 135 Nanxiao St., Changhua, 500, Taiwan (R.O.C.)
| | - Chia-En Hsieh
- Department of Nursing, Changhua Christian Hospital, No. 135 Nanxiao St., Changhua, 500, Taiwan (R.O.C.)
| | - Kuo-Hua Lin
- Department of General Surgery, Changhua Christian Hospital, No. 135 Nanxiao St., Changhua, 500, Taiwan (R.O.C.)
| | - Chih-Jan Ko
- Department of General Surgery, Changhua Christian Hospital, No. 135 Nanxiao St., Changhua, 500, Taiwan (R.O.C.)
| | - Yu-Ju Hung
- Department of General Surgery, Changhua Christian Hospital, No. 135 Nanxiao St., Changhua, 500, Taiwan (R.O.C.)
| | - Ya-Lan Hsu
- Department of Nursing, Changhua Christian Hospital, No. 135 Nanxiao St., Changhua, 500, Taiwan (R.O.C.)
| | - Yao-Li Chen
- Department of General Surgery, Changhua Christian Hospital, No. 135 Nanxiao St., Changhua, 500, Taiwan (R.O.C.).
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16
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Lerut J, Foguenne M, Lai Q. Hepatocellular cancer selection systems and liver transplantation: from the tower of babel to an ideal comprehensive score. Updates Surg 2021; 73:1599-1614. [PMID: 34003479 PMCID: PMC8500859 DOI: 10.1007/s13304-021-01078-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Accepted: 05/03/2021] [Indexed: 12/13/2022]
Abstract
The Milan criteria (MC) remain the cornerstone for the selection of patients with hepatocellular cancer (HCC) to be listed for liver transplantation (LT). Recently, several expanded criteria have been proposed to increase the transplantability of HCC patients without compromising their (oncologic) outcome. This paper aims to systematically review the different reported HCC-LT selection systems looking thereby at their ability to increase the number of transplantable patients and the overall survival and oncological outcome. A systematic review of the literature covering the period 1993 (date of the first reported HCC-LT selection system)-2021 identified 59 different inclusion criteria of HCC for LT. Among the 59 studies reporting HCC-LT selection systems, 15 (28.3%) were exclusively based on morphological aspects of the tumor; 29 (54.7%) included biologic, seven (13.2%) radiological, and two (3.8%) only included pathological tumor features. Overall, 31% more patients could be transplanted when adhering to the new HCC-LT selection systems. Despite the increased number of LT, 5-year patient and disease-free survival rates were similar between MC-IN and MC-OUT/new HCC-LT-IN criteria. A careful extension of the inclusion criteria should allow many more patients to access a potentially curative LT without compromising their outcome. The development of a widely accepted "comprehensive" HCC-LT Score able to offer a fair chance of justified transplantation to more patients should become a priority within the liver transplant community. Further studies are needed to develop internationally accepted, expanded selection criteria for liver transplantation of HCC patients.
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Affiliation(s)
- Jan Lerut
- Institute for Experimental and Clinical Research (IREC), Université Catholique de Louvain (UCL), Avenue Hippocrates 55, 1200 Brussels, Belgium
| | - Maxime Foguenne
- University Hospitals Saint-Luc Université Catholique de Louvain (UCL), Brussels, Belgium
| | - Quirino Lai
- General Surgery and Organ Transplantation Unit, Sapienza University of Rome, Rome, Italy
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17
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Kwong A, Mehta N. Expanding the Limits of Liver Transplantation for Hepatocellular Carcinoma: Is There a Limit? Clin Liver Dis 2021; 25:19-33. [PMID: 33978578 DOI: 10.1016/j.cld.2020.08.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Liver transplantation is a treatment option for hepatocellular carcinoma within Milan criteria. With careful selection practices, patients with larger tumors can do well with successful downstaging followed by liver transplantation and should not be excluded based on tumor size or number alone. When considering expanded criteria for hepatocellular carcinoma, however, survival outcomes after liver transplantation should be comparable with patients without hepatocellular carcinoma. Surrogate measures of tumor biology, such as α-fetoprotein, other biomarkers, and dynamic tumor behavior including response to locoregional therapy can aid in risk stratification of patients before liver transplantation.
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Affiliation(s)
- Allison Kwong
- Division of Gastroenterology and Hepatology, Stanford University, 420 Broadway Street, 3rd Floor, Redwood City, CA 94063, USA
| | - Neil Mehta
- Division of Gastroenterology, University of California, San Francisco, 513 Parnassus Avenue, S-357, San Francisco, CA 94143, USA.
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18
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Halazun KJ, Sapisochin G, von Ahrens D, Agopian VG, Tabrizian P. Predictors of outcome after liver transplantation for hepatocellular carcinoma (HCC) beyond Milan criteria. Int J Surg 2020; 82S:61-69. [PMID: 32707331 DOI: 10.1016/j.ijsu.2020.07.029] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 07/07/2020] [Accepted: 07/08/2020] [Indexed: 12/16/2022]
Abstract
The Milan criteria have been the cornerstone of selection policies for patients with hepatocellular carcinoma (HCC) awaiting liver transplantation (LT) globally for over two decades. Many groups have proposed the transplantation of patients with larger and more numerous tumors achieving comparable results. Many of these use radiologic morphometric criteria as surrogates for explant pathology to predict outcomes. Several other indices have been developed both within and beyond Milan incorporating biological indices as well as dynamic markers of response to pre-transplant locoregional treatments and waiting time. These have allowed for successful expansion of transplant selection criteria without compromising outcomes with limited organ supplies. In this review we will discuss the predictors of outcome in patients beyond Milan criteria.
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Affiliation(s)
- K J Halazun
- Division of Liver Transplantation and Hepatobiliary Surgery, Department of Surgery, Weill Cornell Medicine, 525 East 68th, F-763, New York, NY, 10065, USA; Center for Liver Disease and Transplantation, Columbia University Medical Center, NY Presbyterian Hospital, 622 West 168th St, PH14-101, New York, NY, 10032, USA.
| | - G Sapisochin
- Center for Liver Disease and Transplantation, Columbia University Medical Center, NY Presbyterian Hospital, 622 West 168th St, PH14-101, New York, NY, 10032, USA; Multi-Organ Transplant, Division of General Surgery, Toronto General Hospital, University of Toronto, 585 University Avenue Toronto, ON, M5G 2N2, Canada.
| | - D von Ahrens
- Division of Liver Transplantation and Hepatobiliary Surgery, Department of Surgery, Weill Cornell Medicine, 525 East 68th, F-763, New York, NY, 10065, USA.
| | - V G Agopian
- Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, 200 UCLA Medical Plaza, Los Angeles, CA, 90095, USA.
| | - P Tabrizian
- Department of Transplantation, Recanati/Miller Transplantation Institute, 5 East 98th St. Mount Sinai Medical Center, New York, 10029, USA.
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19
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Comparison of Models for Tumor Recurrence after Liver Transplantation for the Patients with Hepatocellular Carcinoma: A Multicenter Long-Term Follow-Up Study. Cancers (Basel) 2019; 11:cancers11091295. [PMID: 31484287 PMCID: PMC6769632 DOI: 10.3390/cancers11091295] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 08/22/2019] [Accepted: 08/30/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND AND AIMS Several models have been developed to predict tumor the recurrence of hepatocellular carcinoma (HCC) after liver transplantation besides the conventional Milan criteria (MC), including the MoRAL score. This study aimed to compare the prognostication power of the MoRAL score to most models designed so far in the Eastern and Western countries. METHODS This study included 564 patients who underwent living donor liver transplantation (LDLT) in three large-volume hospitals in Korea. The primary and secondary endpoints were time-to-recurrence, and overall survival (OS), respectively. The performance of the MoRAL score was compared with those of other various Liver transplantation (LT) criteria, including the Milan criteria, University of California San Francisco (UCSF) criteria, up-to-seven criteria, Kyoto criteria, AFP model, total tumor volume/AFP criteria, Metroticket 2.0 model, and Weill Cornell Medical College group model. RESULTS The median follow-up duration was 78.1 months. Among all models assessed, the MoRAL score showed the best discrimination function for predicting the risk of tumor recurrence after LT, with c-index of 0.78, compared to other models (all p < 0.001). The MoRAL score also represented the best calibration function by Hosmer-Lemeshow test (p = 0.15). Especially in the beyond-MC sub-cohort, the MoRAL score predicted tumor recurrence (c-index, 0.80) and overall survival (OS) (c-index, 0.70) significantly better than any other models (all p < 0.001). When the MoRAL score was low (<314.8), the five-year cumulative risks of tumor recurrence and death were excellent in beyond-MC (27.8%, and 20.5%, respectively) and within-MC (16.3%, and 21.1%, respectively) sub-cohorts. CONCLUSIONS The MoRAL score provides the most refined prognostication for predicting HCC recurrence after LDLT.
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20
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2018 Korean Liver Cancer Association-National Cancer Center Korea Practice Guidelines for the Management of Hepatocellular Carcinoma. Korean J Radiol 2019; 20:1042-1113. [PMID: 31270974 PMCID: PMC6609431 DOI: 10.3348/kjr.2019.0140] [Citation(s) in RCA: 191] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Accepted: 02/24/2019] [Indexed: 01/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer globally and the fourth most common cancer in men in Korea, where the prevalence of chronic hepatitis B infection is high in middle-aged and elderly patients. These practice guidelines will provide useful and constructive advice for the clinical management of patients with HCC. A total of 44 experts in hepatology, oncology, surgery, radiology, and radiation oncology in the Korean Liver Cancer Association-National Cancer Center Korea Practice Guideline Revision Committee revised the 2014 Korean guidelines and developed new recommendations that integrate the most up-to-date research findings and expert opinions.
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21
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2018 Korean Liver Cancer Association-National Cancer Center Korea Practice Guidelines for the Management of Hepatocellular Carcinoma. Gut Liver 2019; 13:227-299. [PMID: 31060120 PMCID: PMC6529163 DOI: 10.5009/gnl19024] [Citation(s) in RCA: 241] [Impact Index Per Article: 40.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2019] [Accepted: 01/24/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer globally and the fourth most common cancer in men in Korea, where the prevalence of chronic hepatitis B infection is high in middle-aged and elderly patients. These practice guidelines will provide useful and constructive advice for the clinical management of patients with HCC. A total of 44 experts in hepatology, oncology, surgery, radiology and radiation oncology in the Korean Liver Cancer Association-National Cancer Center Korea Practice Guideline Revision Committee revised the 2014 Korean guidelines and developed new recommendations that integrate the most up-to-date research findings and expert opinions.
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22
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Shimamura T, Akamatsu N, Fujiyoshi M, Kawaguchi A, Morita S, Kawasaki S, Uemoto S, Kokudo N, Hasegawa K, Ohdan H, Egawa H, Furukawa H, Todo S. Expanded living-donor liver transplantation criteria for patients with hepatocellular carcinoma based on the Japanese nationwide survey: the 5-5-500 rule - a retrospective study. Transpl Int 2019; 32:356-368. [PMID: 30556935 DOI: 10.1111/tri.13391] [Citation(s) in RCA: 100] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 11/26/2018] [Accepted: 12/11/2018] [Indexed: 12/14/2022]
Abstract
Expansion of the liver transplantation indication criteria for patients with hepatocellular carcinoma (HCC) has long been debated. Here we propose new, expanded living-donor liver transplantation (LDLT) criteria for HCC patients based on a retrospective data analysis of the Japanese nationwide survey. A total of 965 HCC patients undergoing LDLT were included, 301 (31%) of whom were beyond the Milan criteria. Here, we applied the Greenwood formula to investigate new criteria enabling the maximal enrollment of candidates while securing a 5-year recurrence rate (95% upper confidence limit) below 10% by examining various combinations of tumor numbers and serum alpha-fetoprotein values, and maintaining the maximal nodule diameter at 5 cm. Finally, new expanded criteria for LDLT candidates with HCC, the 5-5-500 rule (nodule size ≤5 cm in diameter, nodule number ≤5, and alfa-fetoprotein value ≤500 ng/ml), were established as a new regulation with a 95% confidence interval of a 5-year recurrence rate of 7.3% (5.2-9.3) and a 19% increase in the number of eligible patients. In addition, the 5-5-500 rule could identify patients at high risk of recurrence, among those within and beyond the Milan criteria. In conclusion, the new criteria - the 5-5-500 rule - might provide rational expansion for LDLT candidates with HCC.
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Affiliation(s)
- Tsuyoshi Shimamura
- Division of Organ Transplantation, Hokkaido University Hospital, Sapporo, Japan
| | - Nobuhisa Akamatsu
- Artificial Organ and Transplantation Surgery Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Masato Fujiyoshi
- Department of Gastroenterological Surgery 1, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Atushi Kawaguchi
- Center for Comprehensive Community Medicine, Faculty of Medicine, Saga University, Saga, Japan
| | - Satoshi Morita
- Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan
| | - Seiji Kawasaki
- Department of Hepatobiliary-Pancreatic Surgery, Juntendo University School of Medicine, Tokyo, Japan
| | - Shinji Uemoto
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Norihiro Kokudo
- Artificial Organ and Transplantation Surgery Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Kiyoshi Hasegawa
- Artificial Organ and Transplantation Surgery Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Hideki Ohdan
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hiroto Egawa
- Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
| | - Hiroyuki Furukawa
- Division of Gastroenterological Surgery, Department of Surgery, Asahikawa Medical University, Asahikawa, Japan
| | - Satoru Todo
- Research Institute of St. Mary's Hospital, Kurume, Japan
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23
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Citores MJ, Lucena JL, de la Fuente S, Cuervas-Mons V. Serum biomarkers and risk of hepatocellular carcinoma recurrence after liver transplantation. World J Hepatol 2019; 11:50-64. [PMID: 30705718 PMCID: PMC6354126 DOI: 10.4254/wjh.v11.i1.50] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 11/13/2018] [Accepted: 12/05/2018] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation (LT) is the only potentially curative treatment for selected patients with cirrhosis and hepatocellular carcinoma (HCC) who are not candidates for resection. When the Milan criteria are strictly applied, 75% to 85%of 3- to 4-year actuarial survival rates are achieved, but up to 20% of the patients experience HCC recurrence after transplantation. The Milan criteria are based on the preoperative tumor macromorphology, tumor size and number on computed tomography or magnetic resonance imaging that neither correlate well with posttransplant histological study of the liver explant nor accurately predict HCC recurrence after LT, since they do not include objective measures of tumor biology. Preoperative biological markers, including alpha-fetoprotein, des-gamma-carboxiprothrombin or neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio, can predict the risk for HCC recurrence after transplantation. These biomarkers have been proposed as surrogate markers of tumor differentiation and vascular invasion, with varied risk magnitudes depending on the defined cutoffs. Different studies have shown that the combination of one or several biomarkers integrated into prognostic models predict the risk of HCC recurrence after LT more accurately than Milan criteria alone. In this review, we focus on the potential utility of these serum biological markers to improve the performance of Milan criteria to identify patients at high risk of tumoral recurrence after LT.
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Affiliation(s)
- Maria J Citores
- Department of Internal Medicine, Instituto de Investigación Sanitaria Puerta de Hierro-Segovia de Arana, Majadahonda 28222, Spain.
| | - Jose L Lucena
- Liver Transplantation Unit, Hospital Universitario Puerta de Hierro-Majadahonda, Majadahonda 28222, Spain
| | - Sara de la Fuente
- Department of Internal Medicine, Hospital Universitario Puerta de Hierro-Majadahonda, Majadahonda 28222, Spain
| | - Valentin Cuervas-Mons
- Department of Internal Medicine, Hospital Universitario Puerta de Hierro-Majadahonda, Majadahonda 28222, Spain
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Amado V, Rodríguez-Perálvarez M, Ferrín G, De la Mata M. Selecting patients with hepatocellular carcinoma for liver transplantation: incorporating tumor biology criteria. J Hepatocell Carcinoma 2018; 6:1-10. [PMID: 30613572 PMCID: PMC6306074 DOI: 10.2147/jhc.s174549] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Liver transplantation (LT) is the optimal therapeutic option for patients with liver cirrhosis and hepatocellular carcinoma (HCC). Due to universal donor shortage, only the patients with limited tumor burden (under the so-called Milan criteria) are considered as potential candidates for LT in most institutions. It is expected that in the near future, more liver grafts will be available for patients with HCC due to the implementation of new direct antivirals against hepatitis C, leaving a prone scenario to consider expanding Milan criteria. A moderate expansion of Milan criteria could be implemented without increasing the risk of tumor recurrence if patients with favorable biological behavior are carefully selected. Incorporating information regarding tumor biology in the decision-making algorithm would result in a more rational use of LT in patients with HCC. In the present review, surrogate markers of tumor biology are critically evaluated as potential tools to be combined with existing radiological criteria. In addition, the current state of liquid biopsy is discussed, as this cutting-edge technology may reshape the management of HCC in the upcoming years.
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Affiliation(s)
- Víctor Amado
- Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, IMIBIC, CIBERehd, Córdoba, Spain,
| | - Manuel Rodríguez-Perálvarez
- Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, IMIBIC, CIBERehd, Córdoba, Spain,
| | - Gustavo Ferrín
- Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, IMIBIC, CIBERehd, Córdoba, Spain,
| | - Manuel De la Mata
- Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, IMIBIC, CIBERehd, Córdoba, Spain,
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Yoon YI, Song GW, Lee SG, Hwang S, Kim KH, Kim SH, Kang WH, Cho HD, Jwa EK, Kwon JH, Tak EY, Kirchner VA. Outcome of ABO-incompatible adult living-donor liver transplantation for patients with hepatocellular carcinoma. J Hepatol 2018; 68:1153-1162. [PMID: 29452208 DOI: 10.1016/j.jhep.2018.02.002] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Revised: 02/01/2018] [Accepted: 02/04/2018] [Indexed: 01/10/2023]
Abstract
BACKGROUND & AIMS Living-donor liver transplantation (LDLT) can simultaneously cure hepatocellular carcinoma (HCC) and underlying liver cirrhosis, improving long-term results in patients with HCC. ABO-incompatible LDLT could expand the living-donor pool, reduce waiting times for deceased-donor liver transplantation, and improve long-term survival for some patients with HCC. METHODS We retrospectively reviewed the medical records of patients undergoing LDLT for HCC from November 2008 to December 2015 at a single institution in Korea. In total, 165 patients underwent ABO-incompatible and 753 patients underwent ABO-compatible LDLT for HCC. ABO-incompatible recipients underwent desensitization to overcome the ABO blood group barrier, including pretransplant plasma exchange and rituximab administration (300-375 mg/m2 /body surface area). RESULTS We performed 1:1 propensity score matching and included 165 patients in each group. 82.4% of ABO-incompatible and 83.0% of -compatible LDLT groups had HCC within conventional Milan criteria, respectively, and 92.1% and 92.7% of patients in each group had a Child-Pugh score of A or B. ABO-incompatible and -compatible LDLT groups were followed up for 48.0 and 48.7 months, respectively, with both groups showing comparable recurrence-free survival rates (hazard ratio [HR] 1.14; 95% CI 0.68-1.90; p = 0.630) and overall patient-survival outcomes (HR 1.10; 95% CI 0.60-2.00; p = 0.763). CONCLUSIONS These findings suggested that ABO-incompatible liver transplantation is a feasible option for patients with HCC, especially for those with compensated cirrhosis with HCC within conventional Milan criteria. LAY SUMMARY Despite hypothetical immunological concerns that the desensitization protocol for breaking through the ABO blood group barrier might have a negative impact on the recurrence of hepatocellular carcinoma, our experience demonstrated no significant differences in the long-term overall survival and recurrence-free survival rates between patients receiving ABO-compatible or ABO-incompatible liver transplantation. In conclusion, results from our institution indicated that ABO-incompatible living-donor liver transplantation constitutes a potentially feasible option for patients with hepatocellular carcinoma, especially those with compensated cirrhosis with hepatocellular carcinoma within conventional Milan criteria.
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Affiliation(s)
- Young-In Yoon
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Gi-Won Song
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
| | - Sung-Gyu Lee
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Shin Hwang
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Ki-Hun Kim
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Seok-Hwan Kim
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Woo-Hyoung Kang
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Hwui-Dong Cho
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Eun-Kyoung Jwa
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jae-Hyun Kwon
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Eun-Young Tak
- Asan Institute for Life Sciences and Asan-Minnesota Institute for Innovating Transplantation, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Varvara A Kirchner
- Division of Transplantation, Department of Surgery and Asan-Minnesota Institute for Innovating Transplantation, University of Minnesota, Minneapolis, MN, USA
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26
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Lai Q, Iesari S, Levi Sandri GB, Lerut J. Des-gamma-carboxy prothrombin in hepatocellular cancer patients waiting for liver transplant: a systematic review and meta-analysis. Int J Biol Markers 2017; 32:e370-e374. [PMID: 28561879 DOI: 10.5301/ijbm.5000276] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/27/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND The use of des-gamma-carboxy prothrombin (DCP) as a predictor of the risk of recurrence of hepatocellular cancer (HCC) after liver transplant (LT) has recently gained interest, especially in view of the recent extension of the eligibility criteria of these patients for LT. The aim of the present study is to look into this important matter based on a systematic review and meta-analysis. METHODS A systematic literature review about the role of DCP in the specific setting of LT for HCC has been conducted. RESULTS Three selected studies, which showed a high rate of homogeneity (I2 = 0.0%), confirmed that the tumor marker DCP is a useful predictive factor, indicating a 5-fold increased risk for HCC recurrence after LT (p<0.001). CONCLUSIONS The meta-analysis enabled us to underline the importance of DCP in the refinement of the eligibility criteria of HCC patients for LT. This information, based on Japanese studies performed in the setting of living-donor LT only, needs further validation in the Western world both in the setting of post-mortem and living-donor LT.
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Affiliation(s)
- Quirino Lai
- Starzl Abdominal Transplant Unit, University Hospitals Saint Luc, Université Catholique Louvain, Brussels - Belgium
- Transplant Unit, Department of Surgery, La Sapienza University, Rome - Italy
| | - Samuele Iesari
- Starzl Abdominal Transplant Unit, University Hospitals Saint Luc, Université Catholique Louvain, Brussels - Belgium
| | | | - Jan Lerut
- Starzl Abdominal Transplant Unit, University Hospitals Saint Luc, Université Catholique Louvain, Brussels - Belgium
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Park MS, Lee KW, Kim H, Choi Y, Hong G, Yi NJ, Suh KS. Usefulness of PIVKA-II After Living-donor Liver Transplantation for Hepatocellular Carcinoma. Transplant Proc 2017; 49:1109-1113. [DOI: 10.1016/j.transproceed.2017.03.017] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Donat M, Alonso S, Pereira F, Ferrero E, Carrión L, Acin-Gándara D, Moreno E. Impact of Histological Factors of Hepatocellular Carcinoma on the Outcome of Liver Transplantation. Transplant Proc 2017; 48:1968-77. [PMID: 27569930 DOI: 10.1016/j.transproceed.2016.04.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Revised: 04/10/2016] [Accepted: 04/27/2016] [Indexed: 12/13/2022]
Abstract
BACKGROUND The aim of this study was to identify predictors of overall survival (OS), disease-free survival (DFS), and recurrence in a cohort of 151 patients with hepatocellular carcinoma (HCC) and cirrhosis who were treated by liver transplantation (LT). PATIENTS AND METHODS A retrospective database of patients undergoing LT for radiologically diagnosed HCC at "12 de Octubre" Hospital, Madrid during 1986-2006 was analyzed. RESULTS The median follow-up was 67.44 months (SD = 55.7 months). Overall 1-, 3-, 5-, and 10-year survival was 87.5%, 73.7%, 64.1% and 43.4%, respectively. The 5-year OS of patients beyond the Milan criteria was 47.14%, whereas that of patients within the Milan criteria was 70.13% (P = .011). The 5-year OS of patients beyond the Milan criteria and with microvascular invasion (MVI) was 27.27%, whereas that of patients beyond the Milan criteria and without MVI criteria was 57.89% (P = .003). Multivariate analysis of prognostic factors revealed MVI and G3 to be independent and statistically significant factors affecting OS (P < .0001 and P = .045, respectively), DFS (P < .0001 and P = .004, respectively), and recurrence (P = .0002 and P = .028, respectively). Multivariate analysis of prognostic factors also revealed preoperative fine-needle aspiration (FNA) to be an independent negative statistically significant factor affecting recurrence (P = .0022). Multivariate analysis of predictive MVI factors revealed preoperative α-fetoprotein (AFP) levels >200 ng/mL to be an independent positive and statistically significant predictor of MVI (P = .0004). CONCLUSION MVI and G3 are independent negative factors affecting OS, DFS, and recurrence. The presence of MVI or AFP levels >200 ng/mL represent a contraindication for LT, as long as the patient is beyond the Milan criteria.
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Affiliation(s)
- M Donat
- Department of General and Visceral Surgery, Infanta Leonor Hospital, Madrid, Spain
| | - S Alonso
- Department of General and Visceral Surgery, Fuenlabrada University Hospital, Madrid, Spain.
| | - F Pereira
- Department of General and Visceral Surgery, Fuenlabrada University Hospital, Madrid, Spain
| | - E Ferrero
- Department of General and Visceral Surgery, "12 de Octubre" University Hospital, Madrid, Spain
| | - L Carrión
- Department of General and Visceral Surgery, Fuenlabrada University Hospital, Madrid, Spain
| | - D Acin-Gándara
- Department of General and Visceral Surgery, Fuenlabrada University Hospital, Madrid, Spain
| | - E Moreno
- Department of General and Visceral Surgery, "12 de Octubre" University Hospital, Madrid, Spain
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Lee KW, Suh SW, Choi Y, Jeong J, Yi NJ, Kim H, Yoon KC, Hong SK, Kim HS, Lee KB, Suh KS. Macrovascular invasion is not an absolute contraindication for living donor liver transplantation. Liver Transpl 2017; 23:19-27. [PMID: 27540701 DOI: 10.1002/lt.24610] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2016] [Accepted: 08/06/2016] [Indexed: 01/10/2023]
Abstract
The indication of liver transplantation (LT) for the treatment of advanced hepatocellular carcinoma (HCC) is expanding. However, portal vein tumor thrombus (PVTT) has been still accepted as an absolute contraindication. We experienced an unexpectedly good prognosis in selected patients. Therefore, we tried to identify the prognostic factors after LT for HCC with major PVTT. Among 282 patients who underwent living donor liver transplantation (LDLT) for HCC from January 2009 to December 2013, 11 (3.9%) patients with major PVTT that was preoperatively diagnosed were investigated. The 1-, 3-, and 5-year recurrence-free survival rates were 63.6%, 45.5%, and 45.5%, respectively, and all recurrent cases showed intrahepatic and extrahepatic recurrence. The 1-, 3-, and 5-year overall survival rates were 72.7%, 63.6%, and 63.6%, respectively, and 2 patients with delayed recurrence survived approximately 5 years after LT. Main portal vein (PV) invasion (P < 0.01), high alpha-fetoprotein × protein induced by vitamin K absence/antagonist-II (AP) score (≥20,000; P < 0.01), high standardized uptake value (SUV) ratio (tumor/background liver) in positron emission tomography (≥2.1; P < 0.01), and a large original tumor (≥7 cm; P = 0.03) were significant risk factors for recurrence. In conclusion, if the PVTT has not expanded to the main PV and the AP score is not high, we can consider LDLT as a curative treatment option. Liver Transplantation 23:19-27 2017 AASLD.
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Affiliation(s)
- Kwang-Woong Lee
- Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea
| | - Suk-Won Suh
- Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea
| | - YoungRok Choi
- Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea
| | - Jaehong Jeong
- Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea
| | - Nam-Joon Yi
- Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea
| | - Hyeyoung Kim
- Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea
| | - Kyung Chul Yoon
- Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea
| | - Suk Kyun Hong
- Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea
| | - Hyo-Sin Kim
- Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea
| | - Kyung-Bun Lee
- Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea
| | - Kyung-Suk Suh
- Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea
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30
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Sugawara Y. Living donor liver transplantation for patients with hepatocellular carcinoma-20 years after introduction of the Milan criteria. Hepatobiliary Surg Nutr 2016; 5:492-494. [PMID: 28124005 PMCID: PMC5218907 DOI: 10.21037/hbsn.2016.12.06] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Accepted: 11/11/2016] [Indexed: 12/11/2022]
Affiliation(s)
- Yasuhiko Sugawara
- Department of Transplantation/Pediatric Surgery, Postgraduate School of Life Science, Kumamoto University, Chuo-ku, Kumamoto 8603-8556, Japan
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31
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Development and Applicability of the A-P 200 Criteria for Liver Transplantation for Hepatocellular Carcinoma. Transplant Proc 2016; 48:3317-3322. [PMID: 27931576 DOI: 10.1016/j.transproceed.2016.08.050] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Revised: 07/28/2016] [Accepted: 08/22/2016] [Indexed: 02/07/2023]
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32
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Togashi J, Akamastu N, Kokudo N. Living donor liver transplantation for hepatocellular carcinoma at the University of Tokyo Hospital. Hepatobiliary Surg Nutr 2016; 5:399-407. [PMID: 27826554 PMCID: PMC5075828 DOI: 10.21037/hbsn.2016.08.05] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2016] [Accepted: 07/18/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND Living donor liver transplantation (LDLT) is an established treatment not only for those with end-stage liver disease but for those with hepatocellular carcinoma (HCC) developing in cirrhotic liver. The aim of this study was to present a single-center experience of LDLT for HCC at the University of Tokyo Hospital, Japan. METHODS Among 573 liver transplant recipients from January 1996 until the end of 2015, 139 patients have been indicated LDLT for the treatment of HCC, and were the subjects of the present study. We use the expanded criteria for HCC as follows; the number of tumor should be five or less, and the maximum diameter of the tumor should be 5 cm or less, without the distant metastasis nor the vascular invasion (Tokyo criteria, 5-5 rule). We also focused on the identification of the incidental intrahepatic cholangiocarcinoma (ICC) and combined hepatocellular carcinoma/cholangiocarcinoma (cHCC-CC) in liver explants. RESULTS The overall 1-, 5-, and 10-year recurrence-free and patient survival rates were 95%, 91%, and 91%, 91%, and 80%, 78%, respectively. The 1-, 3-, and 5-year cumulative recurrence rate was 5%, 6%, and 6% for within Milan, 0%, 8%, and 8% for beyond Milan/within Tokyo, and 33%, 50%, and 50% for beyond Tokyo, respectively, demonstrating the significantly impaired outcome of those beyond Tokyo criteria (P<0.001). The high alpha-fetoprotein (AFP) value (≥400 ng/mL), the high des-gamma-carboxy prothrombin (DCP) value (≥200 mAU/mL) and beyond the Tokyo criteria were proved to be significant predictors for the HCC recurrence, but the size or the type of the partial graft was not associated. Incidental ICC and cHCC-CC were found in one and two patients, respectively, with the size of less than 2 cm in all cases. ICC was not detected in preoperative evaluation but cHCC-CCs were misdiagnosed as HCC preoperatively. All three patients were alive without recurrence with a follow-up period of 2 to 14 years. CONCLUSIONS The present results of our institution seem acceptable in terms of the recurrence-free and patient survival. The issues of the expansion of indication, living donor vs. deceased donor for HCC, and liver transplantation (LT) for cholangiocarcinoma are still left to be investigated in future studies.
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Affiliation(s)
- Junichi Togashi
- Artificial Organ and Transplantation Surgery Division, Department of Surgery, University of Tokyo, Tokyo, Japan
| | - Nobuhisa Akamastu
- Artificial Organ and Transplantation Surgery Division, Department of Surgery, University of Tokyo, Tokyo, Japan
| | - Norihiro Kokudo
- Artificial Organ and Transplantation Surgery Division, Department of Surgery, University of Tokyo, Tokyo, Japan
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Elshamy M, Aucejo F, Menon KVN, Eghtesad B. Hepatocellular carcinoma beyond Milan criteria: Management and transplant selection criteria. World J Hepatol 2016; 8:874-880. [PMID: 27478537 PMCID: PMC4958697 DOI: 10.4254/wjh.v8.i21.874] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Revised: 06/17/2016] [Accepted: 07/13/2016] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation (LT) for hepatocellular carcinoma (HCC) has been established as a standard treatment in selected patients for the last two and a half decades. After initially dismal outcomes, the Milan criteria (MC) (single HCC ≤ 5 cm or up to 3 HCCs ≤ 3 cm) have been adopted worldwide to select HCC patients for LT, however cumulative experience has shown that MC can be too strict. This has led to the development of numerous expanded criteria worldwide. Morphometric expansions on MC as well as various criteria which incorporate biomarkers as surrogates of tumor biology have been described. HCC that presents beyond MC initially can be downstaged with locoregional therapy (LRT). Post-LRT monitoring aims to identify candidates with favorable tumor behavior. Similarly, tumor marker levels as response to LRT has been utilized as surrogate of tumor biology. Molecular signatures of HCC have also been correlated to outcomes; these have yet to be incorporated into HCC-LT selection criteria formally. The ongoing discrepancy between organ demand and supply makes patient selection the most challenging element of organ allocation. Further validation of extended HCC-LT criteria models and pre-LT treatment strategies are required.
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Charrière B, Maulat C, Suc B, Muscari F. Contribution of alpha-fetoprotein in liver transplantation for hepatocellular carcinoma. World J Hepatol 2016; 8:881-890. [PMID: 27478538 PMCID: PMC4958698 DOI: 10.4254/wjh.v8.i21.881] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2016] [Revised: 05/30/2016] [Accepted: 06/29/2016] [Indexed: 02/06/2023] Open
Abstract
Alpha-fetoprotein (AFP) is the main tumor biomarker available for the management of hepatocellular carcinoma (HCC). Although it is neither a good screening test nor an accurate diagnostic tool for HCC, it seems to be a possible prognostic marker. However, its contribution in liver transplantation for HCC has not been fully determined, although its use to predict recurrence after liver transplantation has been underlined by international societies. In an era of organ shortages, it could also have a key role in the selection of patients eligible for liver transplantation. Yet unanswered questions remain. First, the cut-off value of serum AFP above which liver transplantation should not be performed is still a subject of debate. We show that a concentration of 1000 ng/mL could be an exclusion criterion, whereas values of < 15 ng/mL indicate patients with an excellent prognosis whatever the size and number of tumors. Monitoring the dynamics of AFP could also prove useful. However, evidence is lacking regarding the values that should be used. Today, the real input of AFP seems to be its integration into new criteria to select patients eligible for a liver transplantation. These recent tools have associated AFP values with morphological criteria, thus refining pre-existing criteria, such as Milan, University of California, San Francisco, or “up-to-seven”. We provide a review of the different criteria submitted within the past years. Finally, AFP can be used to monitor recurrence after transplantation, although there is little evidence to support this claim. Future challenges will be to draft new international guidelines to implement the use of AFP as a selection tool, and to determine a clear cut-off value above which liver transplantation should not be performed.
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Ogawa K, Takada Y. Living vs. deceased-donor liver transplantation for patients with hepatocellular carcinoma. Transl Gastroenterol Hepatol 2016; 1:35. [PMID: 28138602 DOI: 10.21037/tgh.2016.04.03] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Accepted: 04/07/2016] [Indexed: 12/12/2022] Open
Abstract
With the scarcity of deceased donor liver grafts, living donor liver transplantation (LDLT) is gaining popularity as an alternative to deceased donor liver transplantation (DDLT) for patients with hepatocellular carcinoma (HCC). However, as the evidence of cases of LDLT accumulates, several authors have reported higher HCC recurrence rates after LDLT. The suggested reasons for the higher recurrence rates following LDLT are related to the small-for-size graft in LDLT, surgical procedures that are specific to LDLT, and the fast-track to LDLT. Fast-tracking to LDLT may not allow sufficient time for evaluation of the biological aggressiveness of tumors, which may result in high recurrence rates due to inclusion of patients with more inherently aggressive tumors. Actually, some studies that reported higher recurrence rates with LDLT included a larger number of cases of HCC with microvascular invasion or poorly differentiated HCC. In order to exclude biologically aggressive HCC preoperatively, selection criteria incorporating tumor markers, such as alpha-fetoprotein (AFP) and des-gamma-carboxyprothrombin (DCP), as well as morphological tumor number and size have been proposed. With more reliable selection criteria incorporating biological markers to eliminate biologically aggressive HCC, LDLT can be a viable treatment option for patients with HCC, providing similar recurrence rates as those achieved with DDLT.
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Affiliation(s)
- Kohei Ogawa
- Department of HBP and Breast Surgery, Ehime University, Ehime, Japan
| | - Yasutsugu Takada
- Department of HBP and Breast Surgery, Ehime University, Ehime, Japan
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36
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Liver transplantation for hepatobiliary malignancies: a new era of "Transplant Oncology" has begun. Surg Today 2016; 47:403-415. [PMID: 27130463 DOI: 10.1007/s00595-016-1337-1] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Accepted: 04/06/2016] [Indexed: 01/10/2023]
Abstract
The indications of liver transplantation for hepatobiliary malignancies have been carefully expanded in a stepwise fashion, despite the fundamental limitations in oncological, immunological, and technical aspects. A new era of "Transplant Oncology," the fusion of transplant surgery and surgical oncology, has begun, and we stand at the dawn of a paradigm shift in multidisciplinary cancer treatment. For hepatocellular carcinoma, new strategies have been undertaken to select recipients based on biological and dynamic markers instead of conventional morphological and static parameters, opening the doors for a more deliberate expansion of the Milan criteria and locoregional therapies before liver transplantation. Neoadjuvant chemoradiation therapy followed by liver transplantation for unresectable perihilar cholangiocarcinoma developed by the Mayo Clinic provided excellent outcomes in a US multicenter study; however, the surgical indications are not necessarily universal and await international validation. Similarly, an aggressive multidisciplinary approach has been applied for other tumors, including intrahepatic cholangiocarcinoma, hepatoblastoma, liver metastases from colorectal and neuroendocrine primary and gastrointestinal stromal tumors as well as rare tumors, such as hepatic undifferentiated embryonal sarcoma and infantile choriocarcinoma. In conclusion, liver transplantation is an important option for hepatobiliary malignancies; however, prospective studies are urgently needed to ensure the appropriate patient selection, organ allocation and living donation policies, and administration of antineoplastic immunosuppression.
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37
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Xu DW, Wan P, Xia Q. Liver transplantation for hepatocellular carcinoma beyond the Milan criteria: A review. World J Gastroenterol 2016; 22:3325-34. [PMID: 27022214 PMCID: PMC4806190 DOI: 10.3748/wjg.v22.i12.3325] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Revised: 12/14/2015] [Accepted: 01/30/2016] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation (LT) has been accepted as an effective therapy for hepatocellular carcinoma (HCC). The Milan criteria (MC) are widely used across the world to select LT candidates in HCC patients. However, the MC may be too strict because a substantial subset of patients who have HCC exceed the MC and who would benefit from LT may be unnecessarily excluded from the waiting list. In recent years, many extended criteria beyond the MC were raised, which were proved to be able to yield similar outcomes compared with those patients meeting the MC. Because the simple use of tumor size and number was insufficient to indicate HCC biological features and to predict the risk of tumor recurrence, some biological markers such as Alpha-fetoprotein, Des-Gamma-carboxy prothrombin and the neutrophil-to-lymphocyte ratio were useful in selecting LT candidates in HCC patients beyond the MC. For patients with advanced HCC, downstaging therapy is an effective way to reduce the tumor stage to fulfill the MC by using liver-directed therapy such as transarterial chemoembolization, radiofrequency ablation and percutaneous ethanol injection. This article reviews the recent advances in LT for HCC beyond the MC.
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38
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Cillo U, Giuliani T, Polacco M, Herrero Manley LM, Crivellari G, Vitale A. Prediction of hepatocellular carcinoma biological behavior in patient selection for liver transplantation. World J Gastroenterol 2016; 22:232-252. [PMID: 26755873 PMCID: PMC4698488 DOI: 10.3748/wjg.v22.i1.232] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2015] [Revised: 08/14/2015] [Accepted: 11/09/2015] [Indexed: 02/06/2023] Open
Abstract
Morphological criteria have always been considered the benchmark for selecting hepatocellular carcinoma (HCC) patients for liver transplantation (LT). These criteria, which are often inappropriate to express the tumor’s biological behavior and aggressiveness, offer only a static view of the disease burden and are frequently unable to correctly stratify the tumor recurrence risk after LT. Alpha-fetoprotein (AFP) and its progression as well as AFP-mRNA, AFP-L3%, des-γ-carboxyprothrombin, inflammatory markers and other serological tests appear to be correlated with post-transplant outcomes. Several other markers for patient selection including functional imaging studies such as 18F-FDG-PET imaging, histological evaluation of tumor grade, tissue-specific biomarkers, and molecular signatures have been outlined in the literature. HCC growth rate and response to pre-transplant therapies can further contribute to the transplant evaluation process of HCC patients. While AFP, its progression, and HCC response to pre-transplant therapy have already been used as a part of an integrated prognostic model for selecting patients, the utility of other markers in the transplant setting is still under investigation. This article intends to review the data in the literature concerning predictors that could be included in an integrated LT selection model and to evaluate the importance of biological aggressiveness in the evaluation process of these patients.
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Lerut J, Lai Q. Morphology does not tell us the entire story: biological behavior improves our ability to select patients with hepatocellular carcinoma waiting for liver transplantation. Hepatobiliary Pancreat Dis Int 2015; 14:570-571. [PMID: 26663003 DOI: 10.1016/s1499-3872(15)60028-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Jan Lerut
- Starzl Unit of Abdominal Transplantation, Universite catholique Louvain (UCL), Brussels, Belgium.
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Andreou A, Bahra M, Guel S, Struecker B, Sauer IM, Klein F, Pascher A, Pratschke J, Seehofer D. Tumor DNA Index and α-Fetoprotein Level Define Outcome following Liver Transplantation for Advanced Hepatocellular Carcinoma. Eur Surg Res 2015; 55:302-318. [PMID: 26440793 DOI: 10.1159/000439565] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2015] [Accepted: 08/20/2015] [Indexed: 11/19/2022]
Abstract
BACKGROUND Patients with hepatocellular carcinoma (HCC) beyond the Milan criteria are expected to have inferior outcome after liver transplantation (LT) and are therefore currently not considered for LT in many countries. The purpose of this study was to identify predictive factors for overall survival following LT for HCC that may support the Milan criteria in the selection of appropriate transplant candidates. METHODS Clinicopathological data on 364 patients with HCC who underwent LT between 1989 and 2010 were retrospectively evaluated. Predictors of overall survival in the entire cohort as well as in subsets of patients within (n = 214) and beyond (n = 150) the Milan criteria were analyzed. RESULTS Multivariate analysis in the entire cohort identified DNA index >1.5 (p < 0.0001), α-fetoprotein level (AFP) >200 ng/ml (p = 0.005), and HCC beyond the Milan criteria (p = 0.002) to be associated with worse overall survival. In patients within the Milan criteria (median survival: 170 months), DNA index >1.5 (p < 0.0001) was the only predictor of worse overall survival in multivariate analysis. In patients beyond the Milan criteria (median survival: 44 months), DNA index >1.5, AFP >200 ng/ml, microvascular invasion, patient age >60 years, and DNA index >1.5 concomitant with AFP >200 ng/ml were associated with worse overall survival in univariate analysis. Multivariate analysis identified DNA index >1.5 concomitant with AFP >200 ng/ml (p < 0.0001) as the only independent predictor of worse overall survival. Consequently, patients beyond the Milan criteria with a combined favorable DNA index ≤1.5 and AFP ≤200 ng/ml had a median survival (147 months) comparable to that of patients within the Milan criteria. CONCLUSIONS DNA index and AFP level predict overall survival following LT in patients with advanced HCC beyond the Milan criteria. A combined assessment of these markers during the evaluation of transplant candidates can contribute to the selection of patients with HCC who may benefit from LT independently of their tumor burden.
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Affiliation(s)
- Andreas Andreou
- Department of General, Visceral and Transplant Surgery, Charitx00E9; - Universitx00E4;tsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany
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Mazzola A, Costantino A, Petta S, Bartolotta TV, Raineri M, Sacco R, Brancatelli G, Cammà C, Cabibbo G. Recurrence of hepatocellular carcinoma after liver transplantation: an update. Future Oncol 2015; 11:2923-36. [PMID: 26414336 DOI: 10.2217/fon.15.239] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Liver transplantation is the only curative alternative for selected patients with hepatocellular carcinoma (HCC) who are not eligible for resection and/or with decompensated cirrhosis. According to Milan criteria the 5-year survival rate is 70-85%, with a recurrence-free survival of 75%. However, HCC recurrence rate after liver transplantation remains a significant problem in the clinical practice. The prognosis in patients with HCC recurrence is poor. The treatment of choice for HCC recurrence is surgery, but it seems that a systemic treatment based on combination of an mTOR inhibitor with sorafenib can be used. Data on safety and efficacy are limited, clinical monitoring is necessary. The aim of this review is to underline the main concerns, pitfalls and warnings for these patients.
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Affiliation(s)
- Alessandra Mazzola
- Section of Gastroenterology - Di.Bi.M.I.S., University of Palermo, Palermo, Italy.,Unité Médicale de Transplantation Hépatique AP-HP, Hôpital Pitié-Salpêtrière, UPMC Paris, Paris, France
| | - Andrea Costantino
- Section of Gastroenterology - Di.Bi.M.I.S., University of Palermo, Palermo, Italy
| | - Salvatore Petta
- Section of Gastroenterology - Di.Bi.M.I.S., University of Palermo, Palermo, Italy
| | | | - Maurizio Raineri
- Section of Anesthesiology, Analgesia, Intensive Care & Emergency, Department of Biopathology, Medical & Forensic Biotechnologies (DIBIMEF), Policlinico 'P Giaccone', University of Palermo, Palermo, Italy
| | - Rodolfo Sacco
- Gastroenterology Unit, Cisanello Hospital, Pisa, Italy
| | | | - Calogero Cammà
- Section of Gastroenterology - Di.Bi.M.I.S., University of Palermo, Palermo, Italy
| | - Giuseppe Cabibbo
- Section of Gastroenterology - Di.Bi.M.I.S., University of Palermo, Palermo, Italy
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Schlachterman A, Jr WWC, Hilgenfeldt E, Mitra A, Cabrera R. Current and future treatments for hepatocellular carcinoma. World J Gastroenterol 2015; 21:8478-8491. [PMID: 26229392 PMCID: PMC4515831 DOI: 10.3748/wjg.v21.i28.8478] [Citation(s) in RCA: 132] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2014] [Revised: 04/27/2015] [Accepted: 06/26/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) represents a unique challenge for physicians and patients. There is no definitively curative treatment. Rather, many treatment and management modalities exist with differing advantages and disadvantages. Both current guidelines and individual patient concerns must be taken into account in order to properly manage HCC. In addition, quality of life issues are particularly complex in patients with HCC and these concerns must also be factored into treatment strategies. Thus, considering all the options and their various pros and cons can quickly become complex for both clinicians and patients. In this review, we systematically discuss the current treatment modalities available for HCC, detailing relevant clinical data, risks and rewards and overall outcomes for each approach. Surgical options discussed include resection, transplantation and ablation. We also discuss the radiation modalities: conformal radiotherapy, yttrium 90 microspheres and proton and heavy ion radiotherapy. The biologic agent Sorafenib is discussed as a promising new approach, and recent clinical trials are reviewed. We then detail currently described molecular pathways implicated in the initiation and progression of HCC, and we explore the potential of each pathway as an avenue for drug exploitation. We hope this comprehensive and forward-looking review enables both clinicians and patients to understand various options and thereby make more informed decisions regarding this disease.
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2014 KLCSG-NCC Korea Practice Guideline for the Management of Hepatocellular Carcinoma. Gut Liver 2015; 9:267-317. [PMID: 25918260 PMCID: PMC4413964 DOI: 10.5009/gnl14460] [Citation(s) in RCA: 101] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Accepted: 03/09/2015] [Indexed: 12/23/2022] Open
Abstract
The guideline for the management of hepatocellular carcinoma (HCC) was first developed in 2003 and revised in 2009 by the Korean Liver Cancer Study Group and the National Cancer Center, Korea. Since then, many studies on HCC have been carried out in Korea and other countries. In particular, a substantial body of knowledge has been accumulated on diagnosis, staging, and treatment specific to Asian characteristics, especially Koreans, prompting the proposal of new strategies. Accordingly, the new guideline presented herein was developed on the basis of recent evidence and expert opinions. The primary targets of this guideline are patients with suspicious or newly diagnosed HCC. This guideline provides recommendations for the initial treatment of patients with newly diagnosed HCC.
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2014 Korean Liver Cancer Study Group-National Cancer Center Korea practice guideline for the management of hepatocellular carcinoma. Korean J Radiol 2015; 16:465-522. [PMID: 25995680 PMCID: PMC4435981 DOI: 10.3348/kjr.2015.16.3.465] [Citation(s) in RCA: 143] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2015] [Accepted: 04/02/2015] [Indexed: 02/07/2023] Open
Abstract
The guideline for the management of hepatocellular carcinoma (HCC) was first developed in 2003 and revised in 2009 by the Korean Liver Cancer Study Group and the National Cancer Center, Korea. Since then, many studies on HCC have been carried out in Korea and other countries. In particular, a substantial body of knowledge has been accumulated on diagnosis, staging, and treatment specific to Asian characteristics, especially Koreans, prompting the proposal of new strategies. Accordingly, the new guideline presented herein was developed on the basis of recent evidence and expert opinions. The primary targets of this guideline are patients with suspicious or newly diagnosed HCC. This guideline provides recommendations for the initial treatment of patients with newly diagnosed HCC.
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45
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Macdonald B, Sewell JL, Harper AM, Roberts JP, Yao FY. Liver transplantation for hepatocellular carcinoma: analysis of factors predicting outcome in 1074 patients in OPTN Region 5. Clin Transplant 2015; 29:506-12. [PMID: 25777321 DOI: 10.1111/ctr.12542] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/12/2015] [Indexed: 12/25/2022]
Abstract
Previous studies on loco-regional therapy (LRT) and alpha-fetoprotein (AFP) in predicting outcome after liver transplant (LT) for hepatocellular carcinoma (HCC) have shown inconsistent results. We analyzed the OPTN database in Region 5 from January 2004 to January 2009 and performed univariate and multivariate analysis of 11 pre-transplant recipient and donor variables in 1074 patients with HCC meeting Milan criteria to detect association with post-LT tumor recurrence or mortality. Mean waitlist time was 438 d. The 1- and 5-yr post-LT survival was 91.1% and 71.1%, respectively. In multivariate analysis, AFP before LT was the only predictor of HCC recurrence. The association between AFP and HCC recurrence was observed only in the subgroup receiving LRT but not in the subgroup without LRT. Predictors of mortality in multivariate analysis were HCC recurrence, Donor Risk Index, last AFP before LT, and MELD score. AFP before LT was the strongest predictor of post-transplant HCC recurrence or death in multivariate analysis. In conclusion, in Region 5 with prolonged waitlist time, high AFP was the only pre-transplant variable predicting post-transplant tumor recurrence and mortality for HCC meeting Milan criteria. Our results also supported the importance of the effects of LRT on AFP in predicting prognosis.
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Affiliation(s)
- Brock Macdonald
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, CA, USA
| | - Justin L Sewell
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, CA, USA
| | - Ann M Harper
- Department of Research and Policy, United Network of Organ Sharing, Richmond, VA, USA
| | - John P Roberts
- Division of Transplant Surgery, Department of Surgery, University of California, San Francisco, CA, USA
| | - Francis Y Yao
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, CA, USA.,Division of Transplant Surgery, Department of Surgery, University of California, San Francisco, CA, USA
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Abstract
Liver transplantation (LT) has become an acceptable and effective treatment for selected patients with hepatocellular carcinoma with excellent outcomes. More recently, LT has been tried in different primary and secondary malignancies of the liver. The outcomes of LT for very selected group of patients with hilar cholangiocarcinoma (CCA) have been promising. Excellent results have been reported in LT for patients with unresectable hepatic epithelioid hemangioendothelioma (HEHE). In contrast to excellent results after LT for HEHE, results of LT for angiosarcoma have been disappointing with no long-term survivors. Hepatoblastoma (HB) is the most common primary liver cancer in pediatric age group. Long-term outcomes after LT in patients with unresectable tumor and good response to chemotherapy have been promising. Indication for LT for hepatic metastasis from neuroendocrine tumors (NETs) is mainly for patients with unresectable tumors and for palliation of medically uncontrollable symptoms. Posttransplant survival in those patients with low tumor activity index is excellent, despite recurrence of the tumor. More recent limited outcomes data on LT for unresectable hepatic metastases from colorectal cancer have claimed some survival benefit compared to the previous reports. However, due to the high rate of tumor recurrence in a very short time after LT, especially in the era of organ shortage, this indication has not been favored by the transplant community.
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Comparative Study of Living and Deceased Donor Liver Transplantation as a Treatment for Hepatocellular Carcinoma. J Am Coll Surg 2015; 220:297-304.e3. [DOI: 10.1016/j.jamcollsurg.2014.12.009] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2014] [Accepted: 12/09/2014] [Indexed: 02/07/2023]
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Kudo A, Matsumura S, Ban D, Irie T, Ochiai T, Tanaka S, Arii S, Tanabe M. Does the preoperative alpha-fetoprotein predict the recurrence and mortality after hepatectomy for hepatocellular carcinoma without macrovascular invasion in patients with normal liver function? Hepatol Res 2014; 44:E437-E446. [PMID: 24690156 DOI: 10.1111/hepr.12335] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2014] [Revised: 03/25/2014] [Accepted: 03/26/2014] [Indexed: 12/24/2022]
Abstract
AIM It has been highly controversial whether elevated serum α-fetoprotein (AFP) level before hepatectomy predicts recurrence and mortality of patients with hepatocellular carcinoma (HCC) or not. This study is to identify whether the index predicts recurrence and mortality after hepatectomy in HCC. METHODS Of 568 consecutive patients, 342 with normal liver function (Child-Pugh score, 5) and no macrovascular invasion were enrolled between April 2000 and March 2013. Multivariate analysis was performed to identify risk factors for disease-free survival (DFS) and overall survival (OS). RESULTS In multivariate analysis, the elevated serum AFP level was an independent risk factor for DFS (hazard ratio [HR], 1.9; P < 0.0001) and OS (HR, 2.0; P < 0.0001). Histological hepatic venous tumor thrombus was also an independent risk factor for DFS (HR, 2.6; P < 0.0001) and OS (HR, 2.5; P = 0.001). Anatomical resection decreases the risk factor for recurrence after hepatectomy (HR, 0.6; P = 0.003), though it did not decrease the risk for OS (P = 0.3). At 5 years, DFS rates were 42% and 21% (P < 0.0001) and OS rates were 75% and 46% among patients with low and high AFP levels, respectively (P < 0.0001). The area under the receiver-operator curves (AUROC) of serum AFP and des-γ-carboxy prothrombin were 0.65 and 0.58 for DFS and 0.65 and 0.57 for OS, respectively. Tumor size was the best predictor of microvascular invasion (AUROC, 0.70, P < 0.0001). CONCLUSION Serum AFP was a highly reliable index for DFS and OS.
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Affiliation(s)
- Atsushi Kudo
- Department of Hepatobiliary Pancreatic Surgery, Tokyo Medical and Dental University, Tokyo, Japan
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Takada Y, Tohyama T, Watanabe J. Biological markers of hepatocellular carcinoma for use as selection criteria in liver transplantation. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2014; 22:279-86. [PMID: 25408520 DOI: 10.1002/jhbp.195] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The Milan criteria (MC) have been widely accepted as an effective way of selecting patients with early-stage hepatocellular carcinoma (HCC) for curative liver transplantation (LT). However, since a substantial subset of HCC patients exists that is beyond the MC but with the potential for good outcomes after LT, several institutions have recently proposed new extended criteria. To explore optimal criteria that can reasonably predict the risk of recurrence, it is considered that new markers of biological behavior are needed in addition to morphological tumor size and number. Several promising candidates for such biological markers have been reported, including serum tumor markers such as alpha-fetoprotein and des-gamma-carboxy prothrombin, inflammatory markers such as C-reactive protein and neutrophil-to-lymphocyte ratio, response to pre-transplant treatments for bridging therapy or down-staging, and fluorine-18-fluorodeoxyglucose positron emission tomography. However, the role of these biological markers in patient selection criteria for LT has yet to be clarified. This review article aims to summarize the results of recent reported studies and to display perspectives for the establishment of optimal criteria that incorporate such biological markers.
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Affiliation(s)
- Yasutsugu Takada
- Department of HPB and Breast Surgery, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan.
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Hameed B, Mehta N, Sapisochin G, Roberts JP, Yao FY. Alpha-fetoprotein level > 1000 ng/mL as an exclusion criterion for liver transplantation in patients with hepatocellular carcinoma meeting the Milan criteria. Liver Transpl 2014; 20:945-51. [PMID: 24797281 PMCID: PMC4807739 DOI: 10.1002/lt.23904] [Citation(s) in RCA: 216] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2014] [Revised: 04/15/2014] [Accepted: 04/21/2014] [Indexed: 12/13/2022]
Abstract
Serum alpha-fetoprotein (AFP) has been increasingly recognized as a marker for a poor prognosis after liver transplantation (LT) for hepatocellular carcinoma (HCC). Many published reports, however, have included a large proportion of patients with HCC beyond the Milan criteria, and the effects of incorporating AFP as an exclusion criterion for LT remain unclear. We studied 211 consecutive patients undergoing LT for HCC within the Milan criteria according to imaging under the Model for End-Stage Liver Disease organ allocation system between June 2002 and January 2009. The majority (93.4%) had locoregional therapy before LT. The median follow-up was 4.5 years (minimum = 2 years). The Kaplan-Meier 1- and 5-year patient survival rates were 94.3% and 83.4%, respectively. In a univariate analysis, significant predictors of HCC recurrence included vascular invasion [hazard ratio (HR) = 10, 95% confidence interval (CI) = 3.9-26, P < 0.001], a pathological tumor stage beyond the University of California San Francisco criteria (HR = 4.1, 95% CI = 1.36-12.6, P = 0.01), an AFP level > 1000 ng/mL (HR = 4.5, 95% CI = 1.3-15.3, P = 0.02), and an AFP level > 500 ng/mL (HR = 3.1, 95% CI = 1.04-9.4, P = 0.04). In a multivariate analysis, vascular invasion was the only significant predictor of tumor recurrence (HR = 5.6, 95% CI = 1.9-19, P = 0.02). An AFP level > 1000 ng/mL was the strongest pretransplant variable predicting vascular invasion (odds ratio = 6.8, 95% CI = 1.6-19.1, P = 0.006). The 1- and 5-year rates of survival without recurrence were 90% and 52.7%, respectively, for patients with an AFP level > 1000 ng/mL and 95% and 80.3%, respectively, for patients with an AFP level ≤ 1000 ng/mL (P = 0.026). Applying an AFP level > 1000 ng/mL as a cutoff would have resulted in the exclusion of 4.7% of the patients fr m LT and a 20% reduction in HCC recurrence. In conclusion, an AFP level > 1000 ng/mL may be a surrogate for vascular invasion and may be used to predict posttransplant HCC recurrence. Incorporating an AFP level > 1000 ng/mL as an exclusion criterion for LT within the Milan criteria may further improve posttransplant outcomes.
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