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Ciria R, Ivanics T, Aliseda D, Claasen M, Alconchel F, Gaviria F, Briceño J, Berardi G, Rotellar F, Sapisochin G. Liver transplantation for primary and secondary liver tumors: Patient-level meta-analyses compared to UNOS conventional indications. Hepatology 2025; 81:1700-1713. [PMID: 39465987 DOI: 10.1097/hep.0000000000001129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Accepted: 08/26/2024] [Indexed: 10/29/2024]
Abstract
BACKGROUND AND AIMS Liver transplant (LT) for transplant oncology (TO) indications is being slowly adopted worldwide and has been recommended to be incorporated cautiously due to concerns about mid-long-term survival and its impact on the waiting list. APPROACH AND RESULTS We conducted 4 systematic reviews of all series on TO indications (intrahepatic cholangiocarcinoma and perihilar cholangiocarcinoma [phCC]) and liver metastases from neuroendocrine tumors (NETs) and colorectal cancer (CRLM) and compared them using patient-level meta-analyses to data obtained from the United Network for Organ Sharing (UNOS) database considering conventional daily-practice indications. Secondary analyses were done for specific selection criteria (Mayo-like protocols for phCC, SECA-2 for CRLM, and Milan criteria for NET). A total of 112,014 LT were analyzed from 2005 to 2020 from the UNOS databases and compared with 345, 721, 494, and 103 patients obtained from meta-analyses on intrahepatic cholangiocarcinoma and phCC, and liver metastases from NET and CRLM, respectively. Five-year overall survival was 53.3%, 56.4%, 68.6%, and 53.8%, respectively. In Mantel-Cox one-to-one comparisons, survival of TO indications was superior to combined LT, second, and third LT and not statistically significantly different from LT in recipients >70 years and high BMI. CONCLUSIONS Liver transplantation for TO indications has adequate 5-year survival rates, mostly when performed under the selection criteria available in the literature (Mayo-like protocols for phCC, SECA-2 for CRLM, and Milan for NET). Despite concerns about its impact on the waiting list, some other LT indications are being performed with lower survival rates. These oncological patients should be given the opportunity to have a definitive curative therapy within validated criteria.
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Affiliation(s)
- Ruben Ciria
- Unit of Hepatobiliary Surgery and Liver Transplantation, University Hospital Reina Sofia, University of Cordoba, IMIBIC, Cordoba, Spain
- Unit of Hepatobiliary Surgery, Hospital Quiron Salud, Cordoba, Spain
| | - Tommy Ivanics
- Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
- Department of Surgery, Henry Ford Hospital, Detroit, Michigan, USA
- Department of Surgical Sciences, Uppsala University, Akademiska Sjukhuset, Uppsala, Sweden
| | - Daniel Aliseda
- Hepatobiliary Surgery and Liver Transplant Unit, Clinica Universidad de Navarra, Pamplona, Spain
- Institute of Health Research of Navarra (IdisNA), Pamplona, Spain
| | - Marco Claasen
- Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
- Department of Surgery, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Felipe Alconchel
- Unit of Hepatobiliary Surgery and Liver Transplantation, Hospital Clínico Universitario Virgen Arrixaca, University of Medicine, IMIB-Pascual Parrilla, Murcia, Spain
| | - Felipe Gaviria
- Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
- Division of General Surgery, University of Toronto, Toronto, Ontario, Canada
| | - Javier Briceño
- Unit of Hepatobiliary Surgery and Liver Transplantation, University Hospital Reina Sofia, University of Cordoba, IMIBIC, Cordoba, Spain
| | - Giammauro Berardi
- General Surgery and Organ Transplantation Unit, San Camillo-Forlanini Hospital, Rome, Italy
| | - Fernando Rotellar
- Hepatobiliary Surgery and Liver Transplant Unit, Clinica Universidad de Navarra, Pamplona, Spain
- Institute of Health Research of Navarra (IdisNA), Pamplona, Spain
| | - Gonzalo Sapisochin
- Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
- Division of General Surgery, University of Toronto, Toronto, Ontario, Canada
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Soliman N, Maqsood A, Connor AA. Role of genomics in liver transplantation for cholangiocarcinoma. Curr Opin Organ Transplant 2025; 30:158-170. [PMID: 39917813 DOI: 10.1097/mot.0000000000001209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/06/2025]
Abstract
PURPOSE OF REVIEW The purpose of this review is to summarize the current knowledge of cholangiocarcinoma molecular biology and to suggest a framework for implementation of next-generation sequencing in all stages of liver transplantation. This is timely as recent guidelines recommend increased use of these technologies with promising results. RECENT FINDINGS The main themes covered here address germline and somatic genetic alterations recently discovered in cholangiocarcinoma, particularly those associated with prognosis and treatment responses, and nascent efforts to translate these into contemporary practice in the peri-liver transplantation period. SUMMARY Early efforts to translate molecular profiling to cholangiocarcinoma care demonstrate a growing number of potentially actionable alterations. Still lacking is a consensus on what biomarkers and technologies to adopt, at what scale and cost, and how to integrate them most effectively into care with the ambition of increasing the number of patients eligible for liver transplantation and improving their long-term outcomes.
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Affiliation(s)
- Nadine Soliman
- Department of Surgery
- J. C. Walter Jr. Transplant Center, Houston Methodist Hospital
- Houston Methodist Academic Institute
| | - Anaum Maqsood
- Department of Medicine
- Neill Cancer Center, Houston Methodist Hospital, Houston, Texas
| | - Ashton A Connor
- Department of Surgery
- J. C. Walter Jr. Transplant Center, Houston Methodist Hospital
- Houston Methodist Academic Institute
- Neill Cancer Center, Houston Methodist Hospital, Houston, Texas
- Department of Surgery, Weill Cornell Medicine, Cornell University, New York, New York, USA
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Ito T, Taura K, Fukumitsu K, Okumura S, Ogiso S, Anazawa T, Nagai K, Uchida Y, Ishii T, Hatano E. Safety and efficacy of living donor liver transplantation for unresectable perihilar cholangiocarcinoma: A single center prospective study. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2025; 32:276-286. [PMID: 39996522 PMCID: PMC12038382 DOI: 10.1002/jhbp.12121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/26/2025]
Abstract
BACKGROUND The prognosis for unresectable perihilar cholangiocarcinoma (phCCA) is extremely poor. Liver transplantation in combination with neoadjuvant chemoradiation therapy has become the treatment of choice for unresectable phCCA in the USA. In 2018, we launched a prospective study to evaluate the safety and efficacy of living donor liver transplantation (LDLT) for unresectable phCCA. METHODS A total of 10 patients were enrolled in this study between 2018 and 2024. Finally, five patients with unresectable phCCA underwent LDLT after neoadjuvant chemotherapy, radiation, and staging laparotomy, while the other five patients dropped out of the protocol. RESULTS The median follow-up period was 23.7 months. The overall survival rate for the five patients who underwent LDLT was 100% after one year. Hepatic artery thrombosis and delayed gastric emptying occurred in two and three cases, respectively. The histological efficacy of preoperative treatment was grade IIb and III, according to the Evans classification, in all five patients. All surgical margins and dissected lymph nodes were negative. Four patients were alive with no evidence of disease recurrence while one patient had recurrence 10 months after LDLT. CONCLUSIONS LDLT is feasible and may be a last-resort treatment option for unresectable phCCA, although the long-term outcomes need to be carefully monitored. CLINICAL TRIAL REGISTER AND CLINICAL REGISTRATION NUMBER The UMIN registration number for this study is 000033348.
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Affiliation(s)
- Takashi Ito
- Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Kojiro Taura
- Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
- Department of Gastroenterological Surgery and OncologyMedical Research Institute, Kitano HospitalOsakaJapan
| | - Ken Fukumitsu
- Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
- Department of SurgeryGastrointestinal Center, Kyoto Katsura HospitalKyotoJapan
| | - Shinya Okumura
- Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Satoshi Ogiso
- Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Takayuki Anazawa
- Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Kazuyuki Nagai
- Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Yoichiro Uchida
- Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Takamichi Ishii
- Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Etsuro Hatano
- Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
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Malik AK, Davidson BR, Manas DM. Surgical management, including the role of transplantation, for intrahepatic and peri-hilar cholangiocarcinoma. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2025; 51:108248. [PMID: 38467524 DOI: 10.1016/j.ejso.2024.108248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 02/28/2024] [Accepted: 03/03/2024] [Indexed: 03/13/2024]
Abstract
Intrahepatic and peri-hilar cholangiocarcinoma are life threatening disease with poor outcomes despite optimal treatment currently available (5-year overall survival following resection 20-35%, and <10% cured at 10-years post resection). The insidious onset makes diagnosis difficult, the majority do not have a resection option and the high recurrence rate post-resection suggests that occult metastatic disease is frequently present. Advances in perioperative management, such as ipsilateral portal vein (and hepatic vein) embolisation methods to increase the future liver remnant volume, genomic profiling, and (neo)adjuvant therapies demonstrate great potential in improving outcomes. However multiple areas of controversy exist. Surgical resection rate and outcomes vary between centres with no global consensus on how 'resectable' disease is defined - molecular profiling and genomic analysis could potentially identify patients unlikely to benefit from resection or likely to benefit from targeted therapies. FDG-PET scanning has also improved the ability to detect metastatic disease preoperatively and avoid futile resection. However tumours frequently invade major vasculo-biliary structures, with resection and reconstruction associated with significant morbidity and mortality even in specialist centres. Liver transplantation has been investigated for very selected patients for the last decade and yet the selection algorithm, surgical approach and both value of both neoadjuvant and adjuvant therapies remain to be clarified. In this review, we discuss the contemporary management of intrahepatic and peri-hilar cholangiocarcinoma.
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Affiliation(s)
- Abdullah K Malik
- Department of HPB and Transplant Surgery, Freeman Hospital, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK; NIHR Blood and Transplant Research Unit, Newcastle University and Cambridge University, Newcastle Upon Tyne, UK.
| | - Brian R Davidson
- Department of HPB and Liver Transplant Surgery, Royal Free Hospital, Royal Free London NHS Foundation Trust, London, UK; Division of Surgery and Interventional Sciences, University College London, London, UK
| | - Derek M Manas
- Department of HPB and Transplant Surgery, Freeman Hospital, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK; NIHR Blood and Transplant Research Unit, Newcastle University and Cambridge University, Newcastle Upon Tyne, UK; NHS Blood and Transplant, Bristol, UK
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Gringeri E, Furlanetto A, Billato I, Cescon M, De Carlis L, Mazzaferro V, Romagnoli R, De Simone P, Vivarelli M, Di Benedetto F, Ravaioli M, Lauterio A, Sposito C, Patrono D, Ghinolfi D, Moccheggiani F, Di Sandro S, D'Amico FE, Lanari J, Gambato M, Trapani S, Bergamo F, Cardillo M, Burra P, Cillo U. The Italian experience on liver transplantation for unresectable peri-hilar cholangiocarcinoma: a national survey and future perspectives. Updates Surg 2024; 76:2505-2513. [PMID: 39210194 DOI: 10.1007/s13304-024-01889-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Accepted: 05/18/2024] [Indexed: 09/04/2024]
Abstract
Liver transplantation (LT) was considered an ineffective treatment for perihilar cholangiocarcinoma (pCCA) until the successful experience of the Mayo Clinic, proposing a protocol with strict inclusion criteria and neoadjuvant radio-chemotherapy. Since 2015, pCCA is considered an indication for LT in Italy only in the context of controlled prospective studies. We performed a survey among the 22 Italian Liver Transplant Centers to assess the results of LT for pCCA. Eight centers reported 53 cases from 1986 to 2021 (Bologna 12, Padova 10, Niguarda 10, Milano Tumori 8, Torino 5, Pisa 4, Ancona 2, Modena 2). Patients were divided according to whether they recieved neoadjuvant radio-chemotherapy (Group 1, 25 cases) or not (Group 2, 28 cases). Eleven patients were transplanted without neoadjuvant treatment after 2015. Overall survival at 1, 3 and 5 years was 83.8%, 56.6% and 50.6% in Group 1 and 72.4%, 41.4% and 35.5% in Gropu 2 (p = 0.13). Recurrence-free survival at 1, 3, and 5 years was 91.2%, 61.1% and 47.2% in Group 1 and 58.2%, 42.2%, and 36.1% in Group 2 (p = 0.16). A competing risk regression analysis showed a 5-year risk of cancer-related death of 19% for patients in Group 1 against 62.3% in Group 2, with a hazard ratio of 0.31 (95%CI [0.10-0.98], p 0.047). This survey promoted a discussion about the limitations of the Mayo protocol and set the basis for the adoption of a new nationwide protocol (LITHALICA-NCT06125769), having the same inclusion criteria but proposing standard of care chemotherapy as neoadjuvant regimen.
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Affiliation(s)
- Enrico Gringeri
- General Surgery 2, Hepato-biliary-Pancreatic Surgery and Liver Transplantation Unit, Padua University Hospital, Padua, Italy.
- Department of Surgery Oncology and Gastroenterology, University of Padova, Via Giustiniani 2, 35128, Padua, Italy.
| | - Alessandro Furlanetto
- General Surgery 2, Hepato-biliary-Pancreatic Surgery and Liver Transplantation Unit, Padua University Hospital, Padua, Italy
- Department of Surgery Oncology and Gastroenterology, University of Padova, Via Giustiniani 2, 35128, Padua, Italy
| | - Ilaria Billato
- General Surgery 2, Hepato-biliary-Pancreatic Surgery and Liver Transplantation Unit, Padua University Hospital, Padua, Italy
| | - Matteo Cescon
- Department of General Surgery and Transplantation, IRCCS, Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Luciano De Carlis
- Department of General Surgery and Transplantation, Niguarda Ca' Granda Hospital, 20162, Milan, Italy
| | - Vincenzo Mazzaferro
- Hepato-Pancreato-Biliary Surgery and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori Di Milano, Milan, Italy
| | - Renato Romagnoli
- Liver Transplant Center, General Surgery 2, University of Turin, AOU Città della Salute e della Scienza di Torino, Turin, Italy
| | - Paolo De Simone
- Liver Transplant Program, University of Pisa Medical School Hospital, Pisa, Italy
| | - Marco Vivarelli
- Hepato-Pancreato-Biliary and Transplant Surgery, Department of Experimental and Clinical Medicine, Polytechnic University of Marche, 60126, Ancona, Italy
| | - Fabrizio Di Benedetto
- Hepato-Pancreato-Biliary Surgery and Liver Transplantation Unit, University Hospital of Modena "Policlinico", University of Modena and Reggio Emilia, Modena, Italy
| | - Matteo Ravaioli
- Department of General Surgery and Transplantation, IRCCS, Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Andrea Lauterio
- Department of General Surgery and Transplantation, Niguarda Ca' Granda Hospital, 20162, Milan, Italy
| | - Carlo Sposito
- Hepato-Pancreato-Biliary Surgery and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori Di Milano, Milan, Italy
| | - Damiano Patrono
- Liver Transplant Center, General Surgery 2, University of Turin, AOU Città della Salute e della Scienza di Torino, Turin, Italy
| | - Davide Ghinolfi
- Liver Transplant Program, University of Pisa Medical School Hospital, Pisa, Italy
| | - Federico Moccheggiani
- Hepato-Pancreato-Biliary and Transplant Surgery, Department of Experimental and Clinical Medicine, Polytechnic University of Marche, 60126, Ancona, Italy
| | - Stefano Di Sandro
- Hepato-Pancreato-Biliary Surgery and Liver Transplantation Unit, University Hospital of Modena "Policlinico", University of Modena and Reggio Emilia, Modena, Italy
| | - Francesco Enrico D'Amico
- General Surgery 2, Hepato-biliary-Pancreatic Surgery and Liver Transplantation Unit, Padua University Hospital, Padua, Italy
- Department of Surgery Oncology and Gastroenterology, University of Padova, Via Giustiniani 2, 35128, Padua, Italy
| | - Jacopo Lanari
- General Surgery 2, Hepato-biliary-Pancreatic Surgery and Liver Transplantation Unit, Padua University Hospital, Padua, Italy
- Department of Surgery Oncology and Gastroenterology, University of Padova, Via Giustiniani 2, 35128, Padua, Italy
| | - Martina Gambato
- Multivisceral Transplant Unit, Padova University, Padua, Italy
| | - Silvia Trapani
- Italian National Transplant Center-Istituto Superiore Di Sanità, Rome, Italy
| | - Francesca Bergamo
- Medical Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Massimo Cardillo
- Italian National Transplant Center-Istituto Superiore Di Sanità, Rome, Italy
| | - Patrizia Burra
- Multivisceral Transplant Unit, Padova University, Padua, Italy
- Department of Surgery Oncology and Gastroenterology, University of Padova, Via Giustiniani 2, 35128, Padua, Italy
| | - Umberto Cillo
- General Surgery 2, Hepato-biliary-Pancreatic Surgery and Liver Transplantation Unit, Padua University Hospital, Padua, Italy
- Department of Surgery Oncology and Gastroenterology, University of Padova, Via Giustiniani 2, 35128, Padua, Italy
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Patrono D, De Stefano N, Romagnoli R. Liver transplantation for tumor entities. Curr Opin Organ Transplant 2024; 29:255-265. [PMID: 38716718 DOI: 10.1097/mot.0000000000001149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/03/2024]
Abstract
PURPOSE OF REVIEW Tumor entities represent an increasing indication for liver transplantation (LT). This review addresses the most contentious indications of LT in transplant oncology. RECENT FINDINGS Patient selection based on tumor biology in LT for colorectal cancer liver metastases (CRLM) demonstrated promising long-term outcomes and preserved quality of life despite high recurrence rates. In selected cases, LT for intrahepatic cholangiocarcinoma (iCCA) is feasible, with acceptable survival even in high-burden cases responsive to chemotherapy. LT following a strict neoadjuvant protocol for perihilar cholangiocarcinoma (pCCA) resulted in long-term outcomes consistently surpassing benchmark values, and potentially outperforming liver resection. SUMMARY While preliminary results are promising, prospective trials are crucial to define applications in routine clinical practice. Molecular profiling and targeted therapies pave the way for personalized approaches, requiring evolving allocation systems for equitable LT access.
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Affiliation(s)
- Damiano Patrono
- General Surgery 2U - Liver Transplant Unit, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino - University of Turin, Turin, Italy
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7
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Pang NQ, Chan ACY, Kow AWC. Trends of liver transplantation in Asia. Updates Surg 2024:10.1007/s13304-024-01924-1. [PMID: 39046632 DOI: 10.1007/s13304-024-01924-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 06/18/2024] [Indexed: 07/25/2024]
Abstract
Liver transplantation (LT) in Asia started comparatively early in 1964, just 1 year after Starzl's trail-blazing first attempt. Despite the quick start, LT was slow to develop in this region. Limited access to universal healthcare, lack of public understanding and support as well as the absence of strong legislation, on a backdrop of a wide range of diverse social, religious, economic and cultural background are all contributory factors. Through strong administrative efforts, the number of DDLTs in selected Asian countries has been slowly rising in recent years. However, Asians are generally still less likely to donate organs than Caucasians after death. The strong demand for LT with limited access to deceased organs has, therefore, led to constant need for innovation in LT this region, with the pioneering of various LDLT techniques and safe expansion of donor pool being driven primarily by Asian centers. Familiarity and the development of technical expertise in donor surgery have also resulted in Asian centers repeatedly pushing the boundaries on minimally invasive donor and recipient surgery. In this article, we focus on the past and present states of LT in Asia and explore the future trends of LT in this region.
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Affiliation(s)
- Ning Qi Pang
- Division of Hepatobiliary & Pancreatic Surgery, Department of Surgery, National University Hospital, National University Health System, NUHS Tower Block, 1E, Kent Ridge Road, Level 8, Singapore, 119228, Singapore
- National University Centre for Organ Transplantation (NUCOT), National University Hospital, National University Health System, Singapore, Singapore
| | - Albert C Y Chan
- Division of Liver Transplantation, Department of Surgery, The University of Hong Kong, Hong Kong SAR, China
| | - Alfred Wei Chieh Kow
- Division of Hepatobiliary & Pancreatic Surgery, Department of Surgery, National University Hospital, National University Health System, NUHS Tower Block, 1E, Kent Ridge Road, Level 8, Singapore, 119228, Singapore.
- National University Centre for Organ Transplantation (NUCOT), National University Hospital, National University Health System, Singapore, Singapore.
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
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Esmail A, Badheeb M, Alnahar B, Almiqlash B, Sakr Y, Khasawneh B, Al-Najjar E, Al-Rawi H, Abudayyeh A, Rayyan Y, Abdelrahim M. Cholangiocarcinoma: The Current Status of Surgical Options including Liver Transplantation. Cancers (Basel) 2024; 16:1946. [PMID: 38893067 PMCID: PMC11171350 DOI: 10.3390/cancers16111946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 05/15/2024] [Accepted: 05/16/2024] [Indexed: 06/21/2024] Open
Abstract
Cholangiocarcinoma (CCA) poses a substantial threat as it ranks as the second most prevalent primary liver tumor. The documented annual rise in intrahepatic CCA (iCCA) incidence in the United States is concerning, indicating its growing impact. Moreover, the five-year survival rate after tumor resection is only 25%, given that tumor recurrence is the leading cause of death in 53-79% of patients. Pre-operative assessments for iCCA focus on pinpointing tumor location, biliary tract involvement, vascular encasements, and metastasis detection. Numerous studies have revealed that portal vein embolization (PVE) is linked to enhanced survival rates, improved liver synthetic functions, and decreased overall mortality. The challenge in achieving clear resection margins contributes to the notable recurrence rate of iCCA, affecting approximately two-thirds of cases within one year, and results in a median survival of less than 12 months for recurrent cases. Nearly 50% of patients initially considered eligible for surgical resection in iCCA cases are ultimately deemed ineligible during surgical exploration. Therefore, staging laparoscopy has been proposed to reduce unnecessary laparotomy. Eligibility for orthotopic liver transplantation (OLT) requires certain criteria to be granted. OLT offers survival advantages for early-detected unresectable iCCA; it can be combined with other treatments, such as radiofrequency ablation and transarterial chemoembolization, in specific cases. We aim to comprehensively describe the surgical strategies available for treating CCA, including the preoperative measures and interventions, alongside the current options regarding liver resection and OLT.
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Affiliation(s)
- Abdullah Esmail
- Section of GI Oncology, Department of Medicine, Houston Methodist Cancer Center, Houston, TX 77030, USA
| | - Mohamed Badheeb
- Department of Internal Medicine, Yale New Haven Health, Bridgeport Hospital, Bridgeport, CT 06605, USA
| | - Batool Alnahar
- College of Medicine, Almaarefa University, Riyadh 13713, Saudi Arabia
| | - Bushray Almiqlash
- Zuckerman College of Public Health, Arizona State University, Tempe, AZ 85287, USA
| | - Yara Sakr
- Department of GI Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Bayan Khasawneh
- Section of GI Oncology, Department of Medicine, Houston Methodist Cancer Center, Houston, TX 77030, USA
| | - Ebtesam Al-Najjar
- Section of GI Oncology, Department of Medicine, Houston Methodist Cancer Center, Houston, TX 77030, USA
| | - Hadeel Al-Rawi
- Faculty of Medicine, The University of Jordan, Amman 11942, Jordan
| | - Ala Abudayyeh
- Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Yaser Rayyan
- Department of Gastroenterology & Hepatology, Faculty of Medicine, The University of Jordan, Amman 11942, Jordan
| | - Maen Abdelrahim
- Section of GI Oncology, Department of Medicine, Houston Methodist Cancer Center, Houston, TX 77030, USA
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9
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Kodali S, Connor AA, Thabet S, Brombosz EW, Ghobrial RM. Liver transplantation as an alternative for the treatment of intrahepatic cholangiocarcinoma: Past, present, and future directions. Hepatobiliary Pancreat Dis Int 2024; 23:129-138. [PMID: 37517983 DOI: 10.1016/j.hbpd.2023.07.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 07/21/2023] [Indexed: 08/01/2023]
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is a rare biliary tract cancer with high mortality rate. Complete resection of the iCCA lesion is the first choice of treatment, with good prognosis after margin-negative resection. Unfortunately, only 12%-40% of patients are eligible for resection at presentation due to cirrhosis, portal hypertension, or large tumor size. Liver transplantation (LT) offers margin-negative iCCA extirpation for patients with unresectable tumors. Initially, iCCA was a contraindication for LT until size-based selection criteria were introduced to identify patients with satisfied post-LT outcomes. Recent studies have shown that tumor biology-based selection can yield high post-LT survival in patients with locally advanced iCCA. Another selection criterion is the tumor response to neoadjuvant therapy. Patients with response to neoadjuvant therapy have better outcomes after LT compared with those without tumor response to neoadjuvant therapy. Another index that helps predict the treatment outcome is the biomarker. Improved survival outcomes have also opened the door for living donor LT for iCCA. Patients undergoing LT for iCCA now have statistically similar survival rates as patients undergoing resection. The combination of surgery and locoregional and systemic therapies improves the prognosis of iCCA patients.
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Affiliation(s)
- Sudha Kodali
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston Methodist Hospital, Houston, TX 77030, USA; JC Walter Jr Transplant Center, Houston Methodist Hospital, Houston, TX 77030, USA; Department of Medicine, Weill Cornell Medical College, New York, NY, USA
| | - Ashton A Connor
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston Methodist Hospital, Houston, TX 77030, USA; JC Walter Jr Transplant Center, Houston Methodist Hospital, Houston, TX 77030, USA; Department of Surgery, Houston Methodist Hospital, Houston, TX 77030, USA; Department of Surgery, Weill Cornell Medical College, New York, NY, USA
| | | | | | - R Mark Ghobrial
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston Methodist Hospital, Houston, TX 77030, USA; JC Walter Jr Transplant Center, Houston Methodist Hospital, Houston, TX 77030, USA; Department of Surgery, Houston Methodist Hospital, Houston, TX 77030, USA; Department of Surgery, Weill Cornell Medical College, New York, NY, USA.
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10
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Bragazzi MC, Venere R, Ribichini E, Covotta F, Cardinale V, Alvaro D. Intrahepatic cholangiocarcinoma: Evolving strategies in management and treatment. Dig Liver Dis 2024; 56:383-393. [PMID: 37722960 DOI: 10.1016/j.dld.2023.08.052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 08/07/2023] [Accepted: 08/21/2023] [Indexed: 09/20/2023]
Abstract
Intrahepatic cholangiocarcinoma is the second most frequent primary liver cancer after hepatocellular carcinoma. According to International Classification of Diseases-11 (ICD-11), intrahepatic cholangiocarcinoma is identified by a specific diagnostic code, different with respect to perihilar-CCA or distal-CCA. Intrahepatic cholangiocarcinoma originates from intrahepatic small or large bile ducts including the second-order bile ducts and has a silent presentation that combined with the highly aggressive nature and refractoriness to chemotherapy contributes to the alarming increasing incidence and mortality. Indeed, at the moment of the diagnosis, less than 40% of intrahepatic cholangiocarcinoma are suitable of curative surgical therapy, that is so far the only effective treatment. The main goals of clinicians and researchers are to make an early diagnosis, and to carry out molecular characterization to provide the patient with personalized treatment. Unfortunately, these goals are not easily achievable because of the heterogeneity of this tumor from anatomical, molecular, biological, and clinical perspectives. However, recent progress has been made in molecular characterization, surgical treatment, and management of intrahepatic cholangiocarcinoma and, this article deals with these advances.
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Affiliation(s)
- Maria Consiglia Bragazzi
- Department of Medical-Surgical Sciences and Biotechnology, Sapienza University of Rome Polo Pontino, Italy.
| | - Rosanna Venere
- Department of Medical-Surgical Sciences and Biotechnology, Sapienza University of Rome Polo Pontino, Italy
| | - Emanuela Ribichini
- Department Translational and Precision, Sapienza University of Rome, Italy
| | - Francesco Covotta
- Department Translational and Precision, Sapienza University of Rome, Italy
| | - Vincenzo Cardinale
- Department Translational and Precision, Sapienza University of Rome, Italy
| | - Domenico Alvaro
- Department Translational and Precision, Sapienza University of Rome, Italy
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11
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Yin Y, Tao J, Xian Y, Hu J, Li Y, Li Q, Xiong Y, He Y, He K, Li J. Survival analysis of laparoscopic surgery and open surgery for hilar cholangiocarcinoma: a retrospective cohort study. World J Surg Oncol 2024; 22:58. [PMID: 38369496 PMCID: PMC10875844 DOI: 10.1186/s12957-024-03327-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Accepted: 01/30/2024] [Indexed: 02/20/2024] Open
Abstract
BACKGROUND/PURPOSE This study compared the clinical efficacy and safety of laparoscopic versus open resection for hilar cholangiocarcinoma (HCCA) and analyzed potential prognostic factors. METHODS The study included patients who underwent HCCA resection at our center from March 2012 to February 2022. Perioperative complications and postoperative prognosis were compared between the laparoscopic surgery (LS) and open surgery (OS) groups. RESULTS After screening 313 HCCA patients, 68 patients were eligible for the study in the LS group (n = 40) and OS group (n = 28). Kaplan-Meier survival curve analysis revealed that overall survival > 2 years and 3-year disease-free survival (DFS) were more common in the LS than OS group, but the rate of 2-year DFS was lower in the LS group than OS group. Cox multivariate regression analysis revealed age (< 65 years), radical resection, and postoperative adjuvant therapy were associated with reduced risk of death (hazard ratio [HR] = 0.380, 95% confidence interval [CI] = 0.150-0.940, P = 0.036; HR = 0.080, 95% CI = 0.010-0.710, P = 0.024 and HR = 0.380, 95% CI = 0.150-0.960, P = 0.040), whereas preoperative biliary drainage was an independent factor associated with increased risk of death (HR = 2.810, 95% CI = 1.130-6.950, P = 0.026). Perineuronal invasion was identified as an independent risk factor affecting DFS (HR = 5.180, 95% CI = 1.170-22.960, P = 0.030). CONCLUSIONS Compared with OS, laparoscopic HCCA resection does not significantly differ in terms of clinical efficacy. Age (<65 years), radical resection, and postoperative adjuvant therapy reduce the risk of death, and preoperative biliary drainage increases the risk of death.
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Affiliation(s)
- Yaolin Yin
- Department of Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, China
- Department of Hepatobiliary Pancreatic Gastric Surgery, Gaoping District People's Hospital of Nanchong, Nanchong, 637000, China
| | - Jilin Tao
- Department of Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, China
- Institute of Hepato-Biliary-Pancreatic-Intestinal Disease, North Sichuan Medical College, Nanchong, 637000, China
| | - Yin Xian
- Nanchong Psychosomatic Hospital, Nanchong, 637000, China
| | - Junhao Hu
- Clinical Medical College, North Sichuan Medical College, Nanchong, 637000, China
| | - Yonghe Li
- Department of Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, China
- Institute of Hepato-Biliary-Pancreatic-Intestinal Disease, North Sichuan Medical College, Nanchong, 637000, China
| | - Qiang Li
- Department of Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, China
- Institute of Hepato-Biliary-Pancreatic-Intestinal Disease, North Sichuan Medical College, Nanchong, 637000, China
| | - Yongfu Xiong
- Department of Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, China
- Institute of Hepato-Biliary-Pancreatic-Intestinal Disease, North Sichuan Medical College, Nanchong, 637000, China
| | - Yi He
- Department of Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, China
- Institute of Hepato-Biliary-Pancreatic-Intestinal Disease, North Sichuan Medical College, Nanchong, 637000, China
| | - Kun He
- Department of Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, China
- Institute of Hepato-Biliary-Pancreatic-Intestinal Disease, North Sichuan Medical College, Nanchong, 637000, China
| | - Jingdong Li
- Department of Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, China.
- Institute of Hepato-Biliary-Pancreatic-Intestinal Disease, North Sichuan Medical College, Nanchong, 637000, China.
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12
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Gorji L, Brown ZJ, Limkemann A, Schenk AD, Pawlik TM. Liver Transplant as a Treatment of Primary and Secondary Liver Neoplasms. JAMA Surg 2024; 159:211-218. [PMID: 38055245 DOI: 10.1001/jamasurg.2023.6083] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/07/2023]
Abstract
Importance Liver malignancies are an increasing global health concern with a high mortality. We review outcomes following liver transplant for primary and secondary hepatic malignancies. Observations Transplant may be a suitable treatment option for primary and secondary hepatic malignancies in well-selected patient populations. Conclusions and Relevance Many patients with primary or secondary liver tumors are not eligible for liver resection because of advanced underlying liver disease or high tumor burden, precluding complete tumor clearance. Although liver transplant has been a long-standing treatment modality for patients with hepatocellular carcinoma, recently transplant has been considered for patients with other malignant diagnoses. In particular, while well-established for hepatocellular carcinoma and select patients with perihilar cholangiocarcinoma, transplant has been increasingly used to treat patients with intrahepatic cholangiocarcinoma, as well as metastatic disease from colorectal liver and neuroendocrine primary tumors. Because of the limited availability of grafts and the number of patients on the waiting list, optimal selection criteria must be further defined. The ethics of organ allocation to individuals who may benefit from prolonged survival after transplant yet have a high incidence of recurrence, as well as the role of living donation, need to be further discerned in the setting of transplant oncology.
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Affiliation(s)
- Leva Gorji
- Department of Surgery, Kettering Health Dayton, Dayton, Ohio
| | - Zachary J Brown
- Division of Surgical Oncology, Department of Surgery, New York University-Long Island, Mineola
| | - Ashley Limkemann
- Division of Transplant, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus
| | - Austin D Schenk
- Division of Transplant, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus
| | - Timothy M Pawlik
- Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center, James Cancer Hospital, Columbus
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13
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Loosen SH, Leyh C, Neumann UP, Bock H, Weigel C, Luedde T, Roderburg C. Liver transplantation meets gastrointestinal cancer. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2024; 62:62-72. [PMID: 38195110 DOI: 10.1055/a-2226-0123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2024]
Abstract
Liver transplantation (LT) has emerged as a standard of care for patients with end-stage liver disease, providing a life-saving intervention for patients with severely compromised liver function in both the acute and chronic setting. While LT has also become a routine procedure for early-stage hepatocellular carcinoma (HCC), offering a potential cure by treating both the tumor and the underlying liver disease, its relevance in the context of other malignancies such as cholangiocellular carcinoma (CCA), combined hepatocellular-cholangiocarcinoma (cHCC-CCA) or liver metastases is still the subject of intense debate and no definite recommendations have yet been established. This review summarizes the current therapeutic standards in the context of LT for gastrointestinal malignancies and provides a reflection and outlook on current scientific and clinical developments.
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Affiliation(s)
- Sven H Loosen
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany
| | - Catherine Leyh
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany
| | - Ulf Peter Neumann
- Department of General, Visceral and Transplantation Surgery, University Hospital RWTH Aachen, Aachen, Germany
- Department of Surgery and Transplantation, University Hospital Essen, Essen, Germany
| | - Hans Bock
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany
| | - Christian Weigel
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Tom Luedde
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany
| | - Christoph Roderburg
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany
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14
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Rushbrook SM, Kendall TJ, Zen Y, Albazaz R, Manoharan P, Pereira SP, Sturgess R, Davidson BR, Malik HZ, Manas D, Heaton N, Prasad KR, Bridgewater J, Valle JW, Goody R, Hawkins M, Prentice W, Morement H, Walmsley M, Khan SA. British Society of Gastroenterology guidelines for the diagnosis and management of cholangiocarcinoma. Gut 2023; 73:16-46. [PMID: 37770126 PMCID: PMC10715509 DOI: 10.1136/gutjnl-2023-330029] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 09/05/2023] [Indexed: 10/03/2023]
Abstract
These guidelines for the diagnosis and management of cholangiocarcinoma (CCA) were commissioned by the British Society of Gastroenterology liver section. The guideline writing committee included a multidisciplinary team of experts from various specialties involved in the management of CCA, as well as patient/public representatives from AMMF (the Cholangiocarcinoma Charity) and PSC Support. Quality of evidence is presented using the Appraisal of Guidelines for Research and Evaluation (AGREE II) format. The recommendations arising are to be used as guidance rather than as a strict protocol-based reference, as the management of patients with CCA is often complex and always requires individual patient-centred considerations.
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Affiliation(s)
- Simon M Rushbrook
- Department of Hepatology, Norfolk and Norwich University Hospitals NHS Trust, Norwich, UK
| | - Timothy James Kendall
- Division of Pathology, University of Edinburgh, Edinburgh, UK
- University of Edinburgh MRC Centre for Inflammation Research, Edinburgh, UK
| | - Yoh Zen
- Department of Pathology, King's College London, London, UK
| | - Raneem Albazaz
- Department of Radiology, Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | | | | | - Richard Sturgess
- Digestive Diseases Unit, Aintree University Hospitals NHS Foundation Trust, Liverpool, UK
| | - Brian R Davidson
- Department of Surgery, Royal Free Campus, UCL Medical School, London, UK
| | - Hassan Z Malik
- Department of Surgery, University Hospital Aintree, Liverpool, UK
| | - Derek Manas
- Department of Surgery, Newcastle University, Newcastle upon Tyne, Tyne and Wear, UK
| | - Nigel Heaton
- Department of Hepatobiliary and Pancreatic Surgery, King's College London, London, UK
| | - K Raj Prasad
- John Goligher Colorectal Unit, St. James University Hospital, Leeds, UK
| | - John Bridgewater
- Department of Oncology, UCL Cancer Institute, University College London, London, UK
| | - Juan W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust/University of Manchester, Manchester, UK
| | - Rebecca Goody
- Department of Oncology, St James's University Hospital, Leeds, UK
| | - Maria Hawkins
- Department of Medical Physics and Biomedical Engineering, University College London, London, UK
| | - Wendy Prentice
- King's College Hospital NHS Foundation Trust, London, UK
| | | | | | - Shahid A Khan
- Hepatology and Gastroenterology Section, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
- Imperial College Healthcare NHS Trust, London, UK
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15
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Abdelrahim M, Esmail A, Abudayyeh A, Murakami N, Victor D, Kodali S, Cheah YL, Simon CJ, Noureddin M, Connor A, Saharia A, Moore LW, Heyne K, Kaseb AO, Gaber AO, Ghobrial RM. Transplant Oncology: An Emerging Discipline of Cancer Treatment. Cancers (Basel) 2023; 15:5337. [PMID: 38001597 PMCID: PMC10670243 DOI: 10.3390/cancers15225337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Accepted: 10/30/2023] [Indexed: 11/26/2023] Open
Abstract
Transplant oncology is an emerging concept of cancer treatment with a promising prospective outcome. The applications of oncology, transplant medicine, and surgery are the core of transplant oncology to improve patients' survival and quality of life. The main concept of transplant oncology is to radically cure cancer by removing the diseased organ and replacing it with a healthy one, aiming to improve the survival outcomes and quality of life of cancer patients. Subsequently, it seeks to expand the treatment options and research for hepatobiliary malignancies, which have seen significantly improved survival outcomes after the implementation of liver transplantation (LT). In the case of colorectal cancer (CRC) in the transplant setting, where the liver is the most common site of metastasis of patients who are considered to have unresectable disease, initial studies have shown improved survival for LT treatment compared to palliative therapy interventions. The indications of LT for hepatobiliary malignancies have been slowly expanded over the years beyond Milan criteria in a stepwise manner. However, the outcome improvements and overall patient survival are limited to the specifics of the setting and systematic intervention options. This review aims to illustrate the representative concepts and history of transplant oncology as an emerging discipline for the management of hepatobiliary malignancies, in addition to other emerging concepts, such as the uses of immunotherapy in a peri-transplant setting as well as the use of circulating tumor DNA (ctDNA) for surveillance post-transplantation.
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Affiliation(s)
- Maen Abdelrahim
- Section of GI Oncology, Department of Medical Oncology, Houston Methodist Cancer Center, Houston, TX 77030, USA; (A.E.)
- Cockrell Center of Advanced Therapeutics Phase I Program, Houston Methodist Research Institute, Houston, TX 77030, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
| | - Abdullah Esmail
- Section of GI Oncology, Department of Medical Oncology, Houston Methodist Cancer Center, Houston, TX 77030, USA; (A.E.)
| | - Ala Abudayyeh
- Section of Nephrology, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Naoka Murakami
- Division of Renal Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA;
| | - David Victor
- Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, JC Walter Jr. Center for Transplantation, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Sudha Kodali
- Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, JC Walter Jr. Center for Transplantation, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Yee Lee Cheah
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, JC Walter Jr. Center for Transplantation, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Caroline J. Simon
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, JC Walter Jr. Center for Transplantation, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Mazen Noureddin
- Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, JC Walter Jr. Center for Transplantation, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Ashton Connor
- Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, JC Walter Jr. Center for Transplantation, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Ashish Saharia
- Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, JC Walter Jr. Center for Transplantation, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Linda W. Moore
- Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, JC Walter Jr. Center for Transplantation, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Kirk Heyne
- Section of GI Oncology, Department of Medical Oncology, Houston Methodist Cancer Center, Houston, TX 77030, USA; (A.E.)
- Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
| | - Ahmed O. Kaseb
- Department of Gastrointestinal (GI) Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - A. Osama Gaber
- Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, JC Walter Jr. Center for Transplantation, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Rafik Mark Ghobrial
- Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, JC Walter Jr. Center for Transplantation, Houston Methodist Hospital, Houston, TX 77030, USA
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16
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Shannon AH, Ruff SM, Schenk AD, Washburn K, Pawlik TM. Updates and Expert Opinions on Liver Transplantation for Gastrointestinal Malignancies. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1290. [PMID: 37512101 PMCID: PMC10383519 DOI: 10.3390/medicina59071290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 07/12/2023] [Accepted: 07/12/2023] [Indexed: 07/30/2023]
Abstract
Transplant oncology is a relatively new field in which transplantation is used to treat patients who would otherwise be unresectable. New anticancer treatment paradigms using tumor and transplant immunology and cancer immunogenomics are emerging. In turn, liver transplantation (LT) has become a potential therapy for certain patients with colorectal cancer (CRC) with liver metastasis, hepatocellular (HCC), cholangiocarcinoma (CCA), and metastatic neuroendocrine tumor (NET) of the liver. Although there are established criteria for LT in HCC, evidence regarding LT as a treatment modality for certain gastrointestinal malignancies is still debated. The aim of this review is to highlight updates in the role of LT for certain malignancies, including HCC, metastatic CRC, hilar CCA, and neuroendocrine tumor (NET), as well as contextualize LT use and discuss controversies in transplant oncology.
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17
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Alvaro D, Gores GJ, Walicki J, Hassan C, Sapisochin G, Komuta M, Forner A, Valle JW, Laghi A, Ilyas SI, Park JW, Kelley RK, Reig M, Sangro B. EASL-ILCA Clinical Practice Guidelines on the management of intrahepatic cholangiocarcinoma. J Hepatol 2023; 79:181-208. [PMID: 37084797 DOI: 10.1016/j.jhep.2023.03.010] [Citation(s) in RCA: 114] [Impact Index Per Article: 57.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 03/10/2023] [Indexed: 04/23/2023]
Abstract
Intrahepatic cholangiocarcinoma (iCCA) develops inside the liver, between bile ductules and the second-order bile ducts. It is the second most frequent primary liver cancer after hepatocellular carcinoma, and its global incidence is increasing. It is associated with an alarming mortality rate owing to its silent presentation (often leading to late diagnosis), highly aggressive nature and resistance to treatment. Early diagnosis, molecular characterisation, accurate staging and personalised multidisciplinary treatments represent current challenges for researchers and physicians. Unfortunately, these challenges are beset by the high heterogeneity of iCCA at the clinical, genomic, epigenetic and molecular levels, very often precluding successful management. Nonetheless, in the last few years, progress has been made in molecular characterisation, surgical management, and targeted therapy. Recent advances together with the awareness that iCCA represents a distinct entity amongst the CCA family, led the ILCA and EASL governing boards to commission international experts to draft dedicated evidence-based guidelines for physicians involved in the diagnostic, prognostic, and therapeutic management of iCCA.
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18
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Chin RI, Schiff JP, Bommireddy A, Kang KH, Andruska N, Price AT, Green OL, Huang Y, Korenblat K, Parikh PJ, Olsen J, Samson PP, Henke LE, Kim H, Badiyan SN. Clinical outcomes of patients with unresectable primary liver cancer treated with MR-guided stereotactic body radiation Therapy: A Six-Year experience. Clin Transl Radiat Oncol 2023; 41:100627. [PMID: 37441543 PMCID: PMC10334127 DOI: 10.1016/j.ctro.2023.100627] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 03/13/2023] [Accepted: 04/11/2023] [Indexed: 07/15/2023] Open
Abstract
Purpose Magnetic resonance-guided stereotactic body radiation therapy (MRgSBRT) with optional online adaptation has shown promise in delivering ablative doses to unresectable primary liver cancer. However, there remain limited data on the indications for online adaptation as well as dosimetric and longer-term clinical outcomes following MRgSBRT. Methods and Materials Patients with unresectable hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and combined biphenotypic hepatocellular-cholangiocarcinoma (cHCC-CCA) who completed MRgSBRT to 50 Gy in 5 fractions between June of 2015 and December of 2021 were analyzed. The necessity of adaptive techniques was evaluated. The cumulative incidence of local progression was evaluated and survival and competing risk analyses were performed. Results Ninety-nine analyzable patients completed MRgSBRT during the study period and 54 % had planning target volumes (PTVs) within 1 cm of the duodenum, small bowel, or stomach at the time of simulation. Online adaptive RT was used in 53 % of patients to correct organ-at-risk constraint violation and/or to improve target coverage. In patients who underwent adaptive RT planning, online replanning resulted in superior target coverage when compared to projected, non-adaptive plans (median coverage ≥ 95 % at 47.5 Gy: 91 % [IQR: 82-96] before adaptation vs 95 % [IQR: 87-99] after adaptation, p < 0.01). The median follow-up for surviving patients was 34.2 months for patients with HCC and 10.1 months for patients with CCA/cHCC-CCA. For all patients, the 2-year cumulative incidence of local progression was 9.8 % (95 % CI: 1.5-18 %) for patients with HCC and 9.0 % (95 % CI: 0.1-18) for patients with CCA/cHCC-CCA. Grade 3 through 5 acute and late clinical gastrointestinal toxicities were observed in < 10 % of the patients. Conclusions MRgSBRT, with the option for online adaptive planning when merited, allows delivery of ablative doses to primary liver tumors with excellent local control with acceptable toxicities. Additional studies evaluating the efficacy and safety of MRgSBRT in the treatment of primary liver cancer are warranted.
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Affiliation(s)
- Re-I Chin
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis MO, USA
| | - Joshua P. Schiff
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis MO, USA
| | | | - Kylie H. Kang
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis MO, USA
| | - Neal Andruska
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis MO, USA
| | - Alexander T. Price
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis MO, USA
| | - Olga L. Green
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis MO, USA
| | - Yi Huang
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis MO, USA
| | - Kevin Korenblat
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis MO, USA
| | - Parag J Parikh
- Department of Radiation Oncology, Henry Ford Cancer Institute, Detroit, MI, USA
| | - Jefferey Olsen
- Department of Radiation Oncology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Pamela P. Samson
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis MO, USA
| | - Lauren E. Henke
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis MO, USA
| | - Hyun Kim
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis MO, USA
| | - Shahed N. Badiyan
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis MO, USA
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19
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Borakati A, Froghi F, Bhogal RH, Mavroeidis VK. Liver transplantation in the management of cholangiocarcinoma: Evolution and contemporary advances. World J Gastroenterol 2023; 29:1969-1981. [PMID: 37155529 PMCID: PMC10122785 DOI: 10.3748/wjg.v29.i13.1969] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 02/10/2023] [Accepted: 03/21/2023] [Indexed: 04/06/2023] Open
Abstract
Cholangiocarcinoma (CCA) is an aggressive malignancy arising from the biliary epithelium. It may occur at any location along the biliary tree with the perihilar area being the most common. Prognosis is poor with 5-year overall survival at less than 10%, typically due to unresectable disease at presentation. Radical surgical resection with clear margins offers a chance of cure in patients with resectable tumours, but is frequently not possible due to locally advanced disease. On the other hand, orthotopic liver transplantation (LT) allows for a radical and potentially curative resection for these patients, but has been historically controversial due to the limited supply of donor grafts and previously poor outcomes. In patients with perihilar CCA, within specific criteria and following the implementation of a protocol combining neoadjuvant chemoradiation and LT, excellent results have been achieved in the last decades, resulting in its increasing acceptance as an indication for LT and the standard of care in several centres with significant experience. However, in intrahepatic CCA, the role of LT remains controversial and owing to dismal previous results it is not an accepted indication. Nevertheless, more recent studies have demonstrated favourable results with LT in early intrahepatic CCA, indicating that, under defined criteria, its role may increase in the future. This review highlights the history and contemporary advances of LT in CCA, with particular focus on the improving outcomes of LT in intrahepatic and perihilar CCA and future perspectives.
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Affiliation(s)
- Aditya Borakati
- Department of HPB and Liver Transplantation Surgery, Royal Free Hospital NHS Foundation Trust, London NW3 2QG, United Kingdom
| | - Farid Froghi
- Department of HPB and Liver Transplantation Surgery, Royal Free Hospital NHS Foundation Trust, London NW3 2QG, United Kingdom
| | - Ricky H Bhogal
- Department of Academic Surgery, The Royal Marsden NHS Foundation Trust, London SW3 6JJ, United Kingdom
| | - Vasileios K Mavroeidis
- Department of Academic Surgery, The Royal Marsden NHS Foundation Trust, London SW3 6JJ, United Kingdom
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Re OL, López-López V, Balaguer-Román A, Martínez-Sánchez MA, Eshmuminov D, Llamoza-Torres CJ, Miura K, Baroja-Mazo A, Ramírez P, Robles-Campos R, Ramos-Molina B. New challenges in cholangiocarcinoma candidates for elective surgery: harnessing the microbiome dysbiosis. Langenbecks Arch Surg 2023; 408:134. [PMID: 37000331 DOI: 10.1007/s00423-023-02867-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 03/21/2023] [Indexed: 04/01/2023]
Abstract
BACKGROUND The gut microbiota, composed by several species of microorganisms, works to preserve the liver-gut homeostasis and plays an important role during digestion and absorption of nutrients, and in the immune response of the host. In this review, we analyzed the influence of microbiota in patients with cholangiocarcinoma (CCA) who were candidates for elective surgery. METHODS A literature review was conducted to identify papers that provided empiric evidence to support that the altered microbiota composition (dysbiosis) is related also to CCA development. RESULTS Bacteria such as Helicobacter pylori, Helicobacter hepaticus, and Opisthorchis viverrini increase the risk of CCA. The most abundant genera were Enterococcus, Streptococcus, Bacteroides, Klebsiella, and Pyramidobacter in CCA's biliary microbiota. Additionally, levels of Bacteroides, Geobacillus, Meiothermus, and Anoxybacillus genera were significantly higher. An enrichment of Bifidobacteriaceae, Enterobacteriaceae, and Enterococcaceae families has also been observed in CCA tumor tissue. Microbiota is related to postoperative outcomes in abdominal surgery. The combination of caloric restriction diets in liver cancer or CCA increases the effect of the chemotherapy treatment. CONCLUSION The correct use of nutrition for microbiota modulation according to each patient's needs could be a therapeutic tool in combination with elective surgery and chemotherapy to diminish side effects and improve prognosis. Further investigations are needed to fully understand the mechanisms by which they are related.
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Affiliation(s)
- Oriana Lo Re
- International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic
- Department of Translational Stem Cell Biology, Research Institute of the Medical University of Varna, Varna, Bulgaria
| | - Victor López-López
- Department of General, Visceral and Transplantation Surgery, Clinic and University Hospital Virgen de La Arrixaca, IMIB-ARRIXACA, 30120, Murcia, Spain.
- Digestive and Endocrine Surgery and Transplantation of Abdominal Organs Research Group, Biomedical Research Institute of Murcia (IMIB), Murcia, Spain.
| | - Andrés Balaguer-Román
- Department of General, Visceral and Transplantation Surgery, Clinic and University Hospital Virgen de La Arrixaca, IMIB-ARRIXACA, 30120, Murcia, Spain
- Obesity and Metabolism Laboratory, Biomedical Research Institute of Murcia (IMIB), Murcia, Spain
| | | | - Dilmurodjon Eshmuminov
- Department of Surgery and Transplantation, Swiss Hepato-Pancreato-Biliary (HPB) Center, University Hospital Zurich, Zurich, Switzerland
| | | | - Kohei Miura
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Alberto Baroja-Mazo
- Digestive and Endocrine Surgery and Transplantation of Abdominal Organs Research Group, Biomedical Research Institute of Murcia (IMIB), Murcia, Spain
| | - Pablo Ramírez
- Department of General, Visceral and Transplantation Surgery, Clinic and University Hospital Virgen de La Arrixaca, IMIB-ARRIXACA, 30120, Murcia, Spain
- Digestive and Endocrine Surgery and Transplantation of Abdominal Organs Research Group, Biomedical Research Institute of Murcia (IMIB), Murcia, Spain
| | - Ricardo Robles-Campos
- Department of General, Visceral and Transplantation Surgery, Clinic and University Hospital Virgen de La Arrixaca, IMIB-ARRIXACA, 30120, Murcia, Spain
- Digestive and Endocrine Surgery and Transplantation of Abdominal Organs Research Group, Biomedical Research Institute of Murcia (IMIB), Murcia, Spain
| | - Bruno Ramos-Molina
- Obesity and Metabolism Laboratory, Biomedical Research Institute of Murcia (IMIB), Murcia, Spain
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Patrono D, Colli F, Colangelo M, De Stefano N, Apostu AL, Mazza E, Catalano S, Rizza G, Mirabella S, Romagnoli R. How Can Machine Perfusion Change the Paradigm of Liver Transplantation for Patients with Perihilar Cholangiocarcinoma? J Clin Med 2023; 12:jcm12052026. [PMID: 36902813 PMCID: PMC10004136 DOI: 10.3390/jcm12052026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 02/24/2023] [Accepted: 03/01/2023] [Indexed: 03/08/2023] Open
Abstract
Perihilar cholangiocarcinomas (pCCA) are rare yet aggressive tumors originating from the bile ducts. While surgery remains the mainstay of treatment, only a minority of patients are amenable to curative resection, and the prognosis of unresectable patients is dismal. The introduction of liver transplantation (LT) after neoadjuvant chemoradiation for unresectable pCCA in 1993 represented a major breakthrough, and it has been associated with 5-year survival rates consistently >50%. Despite these encouraging results, pCCA has remained a niche indication for LT, which is most likely due to the need for stringent candidate selection and the challenges in preoperative and surgical management. Machine perfusion (MP) has recently been reintroduced as an alternative to static cold storage to improve liver preservation from extended criteria donors. Aside from being associated with superior graft preservation, MP technology allows for the safe extension of preservation time and the testing of liver viability prior to implantation, which are characteristics that may be especially useful in the setting of LT for pCCA. This review summarizes current surgical strategies for pCCA treatment, with a focus on unmet needs that have contributed to the limited spread of LT for pCCA and how MP could be used in this setting, with a particular emphasis on the possibility of expanding the donor pool and improving transplant logistics.
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Wegermann K, Henson JB, King LY. CON: Intrahepatic cholangiocarcinoma should be a contraindication to liver transplantation. Clin Liver Dis (Hoboken) 2023; 21:52-55. [PMID: 36950307 PMCID: PMC10022851 DOI: 10.1097/cld.0000000000000010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 11/13/2022] [Indexed: 03/24/2023] Open
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Yilmaz S, Carr BI, Akbulut S. Can the Limits of Liver Transplantation Be Expanded in Perihilar Cholangiocarcinoma? J Gastrointest Cancer 2022; 53:1104-1112. [PMID: 34738188 DOI: 10.1007/s12029-021-00735-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/12/2021] [Indexed: 02/07/2023]
Abstract
The most common location of cholangiocarcinomas is the perihilar region with a frequency of 50-70%. Current standard treatment for perihilar cholangiocarcinomas (pCCA) is surgical resection. In cases where resection treatment is possible, the 5-year survival rate is 8-40%. However, using a very strict patient selection, neoadjuvant radiochemotherapy (NRCT), staging laparotomy, and liver transplantation (LT), called "the Mayo protocol," 5-year survivals of up to 70% in pCCA were reported. This treatment protocol clearly requires an intensive workforce and a harmonious multidisciplinary approach. Reoperation and retransplantation rates are high, which is a reflection of the NRCT. Multicenter studies, systemic reviews, and meta-analysis results, comparing both resection and LT in pCCA treatment and evaluating only LT results, pointed to LT with strict patient selection and full compliance with the treatment. The results of centers experienced in LT are better in treating pCCA. According to Mayo clinical data, histopathological diagnosis could not be obtained in half of the patients with pCCA before NRCT was given. This situation can be explained by the necrosis of the tumor due to the effect of NRCT and the fact that the tumor cannot be detected in the explant liver. This situation raises the following questions: did all patients actually have pCCA? Were these good results due to some patients not having pCCA? The 5-year survival rate was worse in patients with a pathological diagnosis than those without a pathological diagnosis. However, interestingly, recurrence rates were statistically similar in both groups. There was no difference in survival between LT and resection in the R0N0 subgroup in de novo pCCA. There are still many issues that need to be addressed and corrected in pCCA, which is one of the most problematic indications for LT. Significant success has been achieved with NRCT, staging laparotomy, and LT in selected patients with pCCA developing on the basis of PSC or early-stage unresectable de novo pCCA. It can be expected that new NRCT modalities will provide better survival by expanding the indications for LT in pCCA.
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Affiliation(s)
- Sezai Yilmaz
- Liver Transplant Institute, Faculty of Medicine, Inonu University, Malatya, 44280, Turkey
| | - Brian I Carr
- Liver Transplant Institute, Faculty of Medicine, Inonu University, Malatya, 44280, Turkey
| | - Sami Akbulut
- Liver Transplant Institute, Faculty of Medicine, Inonu University, Malatya, 44280, Turkey.
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Connor AA, Kodali S, Abdelrahim M, Javle MM, Brombosz EW, Ghobrial RM. Intrahepatic cholangiocarcinoma: The role of liver transplantation, adjunctive treatments, and prognostic biomarkers. Front Oncol 2022; 12:996710. [PMID: 36479082 PMCID: PMC9719919 DOI: 10.3389/fonc.2022.996710] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 10/31/2022] [Indexed: 08/01/2023] Open
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is a primary epithelial cell malignancy of the liver with rising incidence rate globally. Its insidious presentation, heterogeneous and aggressive biology, and recalcitrance to current therapies results in unacceptably high morbidity and mortality. This has spurred research efforts in the last decade to better characterize it molecularly with translation to improved diagnostic tools and treatments. Much of this has been driven by patient advocacy. This has renewed interest in orthotopic liver transplantation (LT) with adjunctive therapies for iCCA, which was historically disparaged due to poor recipient outcomes and donor organ scarcity. However, the optimal use of LT as a treatment for iCCA care remains unclear. Here, we review the epidemiology of iCCA, the history of LT as a treatment modality, alternative approaches to iCCA local control, the evidence for peri-operative systemic therapies, and the potential roles of biomarkers and targeted agents. In doing so, we hope to prioritize areas for continued research and identify areas where multidisciplinary care can improve outcomes.
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Affiliation(s)
- Ashton A. Connor
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, JC Walter Jr Transplant Center, Houston Methodist Hospital, Houston, TX, United States
- Department of Surgery, Houston Methodist Hospital, Houston, TX, United States
| | - Sudha Kodali
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, JC Walter Jr Transplant Center, Houston Methodist Hospital, Houston, TX, United States
- Department of Medicine, Weill Cornell Medical College, New York, NY, United States
| | - Maen Abdelrahim
- Department of Medicine, Weill Cornell Medical College, New York, NY, United States
- Section of Gastrointestinal Oncology, Department of Medical Oncology, Houston Methodist Cancer Center, Houston, TX, United States
- Cockrell Center Phase 1 Unit, Cockrell Center for Advanced Therapeutics, Houston Methodist Hospital, Houston, TX, United States
| | - Milind M. Javle
- Department of Gastrointestinal Medical Oncology, MD Anderson Cancer Center, Houston, TX, United States
| | | | - R. Mark Ghobrial
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, JC Walter Jr Transplant Center, Houston Methodist Hospital, Houston, TX, United States
- Department of Surgery, Houston Methodist Hospital, Houston, TX, United States
- Department of Medicine, Weill Cornell Medical College, New York, NY, United States
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Liver Transplantation as a New Standard of Care in Patients With Perihilar Cholangiocarcinoma? Results From an International Benchmark Study. Ann Surg 2022; 276:846-853. [PMID: 35894433 PMCID: PMC9983747 DOI: 10.1097/sla.0000000000005641] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE To define benchmark values for liver transplantation (LT) in patients with perihilar cholangiocarcinoma (PHC) enabling unbiased comparisons. BACKGROUND Transplantation for PHC is used with reluctance in many centers and even contraindicated in several countries. Although benchmark values for LT are available, there is a lack of specific data on LT performed for PHC. METHODS PHC patients considered for LT after Mayo-like protocol were analyzed in 17 reference centers in 2 continents over the recent 5-year period (2014-2018). The minimum follow-up was 1 year. Benchmark patients were defined as operated at high-volume centers (≥50 overall LT/year) after neoadjuvant chemoradiotherapy, with a tumor diameter <3 cm, negative lymph nodes, and with the absence of relevant comorbidities. Benchmark cutoff values were derived from the 75th to 25th percentiles of the median values of all benchmark centers. RESULTS One hundred thirty-four consecutive patients underwent LT after completion of the neoadjuvant treatment. Of those, 89.6% qualified as benchmark cases. Benchmark cutoffs were 90-day mortality ≤5.2%; comprehensive complication index at 1 year of ≤33.7; grade ≥3 complication rates ≤66.7%. These values were better than benchmark values for other indications of LT. Five-year disease-free survival was largely superior compared with a matched group of nodal negative patients undergoing curative liver resection (n=106) (62% vs 32%, P <0.001). CONCLUSION This multicenter benchmark study demonstrates that LT offers excellent outcomes with superior oncological results in early stage PHC patients, even in candidates for surgery. This provocative observation should lead to a change in available therapeutic algorithms for PHC.
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Eguchi S, Hidaka M, Hara T, Matsushima H, Soyama A. Liver transplantation for intrahepatic and hilar cholangiocellular carcinoma: Most recent updates in the literature. Ann Gastroenterol Surg 2022; 6:616-622. [PMID: 36091305 PMCID: PMC9444854 DOI: 10.1002/ags3.12567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 02/24/2022] [Accepted: 03/01/2022] [Indexed: 11/24/2022] Open
Abstract
Liver transplantation (LT) for non-hepatocellular carcinoma is still a debatable indication. Recently, hilar cholangiocellular carcinoma (hCCC) has attracted interest as a new indication for LT, but LT in this case should be carefully considered. Based on the recent meta-analysis for intrahepatic CCC (IHCCC) and our results from incidental IHCCC transplanted for other diseases such as primary sclerosing cholangitis, the indication for LT for IHCCC should be limited to a single tumor less than 2 cm. For hCCC, with pre-transplant chemoradiotherapy and careful selection criteria, long-term survival after LT could be attained. In order to improve the results of LT for intrahepatic and hCCC, further studies are required on the ingenuity of immunosuppressive therapy combined with chemotherapy, and optimal treatment methods to prevent recurrence, as well as initial case selection.
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Affiliation(s)
- Susumu Eguchi
- Department of SurgeryNagasaki University Graduate School of Biomedical SciencesNagasakiJapan
| | - Masaaki Hidaka
- Department of SurgeryNagasaki University Graduate School of Biomedical SciencesNagasakiJapan
| | - Takanobu Hara
- Department of SurgeryNagasaki University Graduate School of Biomedical SciencesNagasakiJapan
| | - Hajime Matsushima
- Department of SurgeryNagasaki University Graduate School of Biomedical SciencesNagasakiJapan
| | - Akihiko Soyama
- Department of SurgeryNagasaki University Graduate School of Biomedical SciencesNagasakiJapan
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Elvevi A, Laffusa A, Scaravaglio M, Rossi RE, Longarini R, Stagno AM, Cristoferi L, Ciaccio A, Cortinovis DL, Invernizzi P, Massironi S. Clinical treatment of cholangiocarcinoma: an updated comprehensive review. Ann Hepatol 2022; 27:100737. [PMID: 35809836 DOI: 10.1016/j.aohep.2022.100737] [Citation(s) in RCA: 77] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 06/25/2022] [Indexed: 02/04/2023]
Abstract
Cholangiocarcinoma (CCA) is a heterogeneous group of neoplasms of the bile ducts and represents the second most common hepatic cancer after hepatocellular carcinoma; it is sub-classified as intrahepatic cholangiocarcinoma (iCCA) and extrahepatic cholangiocarcinoma (eCCA), the latter comprising both perihilar cholangiocarcinoma (pCCA or Klatskin tumor), and distal cholangiocarcinoma (dCCA). The global incidence of CCA has increased worldwide in recent decades. Chronic inflammation of biliary epithelium and bile stasis represent the main risk factors shared by all CCA sub-types. When feasible, liver resection is the treatment of choice for CCA, followed by systemic chemotherapy with capecitabine. Liver transplants represent a treatment option in patients with very early iCCA, in referral centers only. CCA diagnosis is often performed at an advanced stage when CCA is unresectable. In this setting, systemic chemotherapy with gemcitabine and cisplatin represents the first treatment option, but the prognosis remains poor. In order to ameliorate patients' survival, new drugs have been studied in the last few years. Target therapies are directed against different molecules, which are altered in CCA cells. These therapies have been studied as second-line therapy, alone or in combination with chemotherapy. In the same setting, the immune checkpoints inhibitors targeting programmed death 1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte antigen-4 (CTLA-4), have been proposed, as well as cancer vaccines and adoptive cell therapy (ACT). These experimental treatments showed promising results and have been proposed as second- or third-line treatment, alone or in combination with chemotherapy or target therapies.
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Affiliation(s)
- Alessandra Elvevi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital and Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Alice Laffusa
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital and Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Miki Scaravaglio
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital and Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Roberta Elisa Rossi
- Gastroenterology and Endoscopy Unit, Humanitas Clinical and Research Center, IRCCS, Rozzano, Milan, Italy
| | - Raffaella Longarini
- Division of Oncology, San Gerardo Hospital and Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Anna Maria Stagno
- Division of Oncology, San Gerardo Hospital and Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Laura Cristoferi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital and Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Antonio Ciaccio
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital and Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Diego Luigi Cortinovis
- Division of Oncology, San Gerardo Hospital and Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital and Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Sara Massironi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital and Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
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Liver transplantation and intrahepatic cholangiocarcinoma: time to go forward again? Curr Opin Organ Transplant 2022; 27:320-328. [PMID: 36354258 DOI: 10.1097/mot.0000000000000983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
PURPOSE OF REVIEW Liver transplantation for intrahepatic cholangiocarcinoma (iCCA) has been mired in controversy. High rates of recurrence posttransplant combined with donor organ scarcity resulted in most transplant centers treating iCCA as a contraindication for liver transplantation. RECENT FINDINGS Recent studies have shown that carefully selected patients with unresectable iCCA can have good outcomes after liver transplantation. Better outcomes have been seen in patients with smaller tumors and favorable tumor biology. SUMMARY Because many patients are diagnosed with iCCA at later stages, tumor biology and genetics are useful tools to identify patients who will have excellent overall and recurrence-free survival after liver transplantation. Further larger multicenter prospective studies are needed to identify patients who would benefit from liver transplantation with good outcomes. Additional advances will come through early diagnosis and utilizing a combination of chemotherapy and locoregional modalities as a bridge to transplant. There is also a need to recognize and develop additional neo- and adjuvant therapies for patients whose tumor biology currently precludes their inclusion on the liver transplantation waitlist.
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Abdelrahim M, Al-Rawi H, Esmail A, Xu J, Umoru G, Ibnshamsah F, Abudayyeh A, Victor D, Saharia A, McMillan R, Al Najjar E, Bugazia D, Al-Rawi M, Ghobrial RM. Gemcitabine and Cisplatin as Neo-Adjuvant for Cholangiocarcinoma Patients Prior to Liver Transplantation: Case-Series. Curr Oncol 2022; 29:3585-3594. [PMID: 35621680 PMCID: PMC9139862 DOI: 10.3390/curroncol29050290] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 05/01/2022] [Accepted: 05/06/2022] [Indexed: 01/04/2023] Open
Abstract
Background: The management of cholangiocarcinoma is continually reviewed on a current evidence basis to develop practice guidelines and consensus statements. However, the standardized treatment guidelines are still unclear for cholangiocarcinoma patients who are listed for liver transplantation. We aimed to validate and evaluate the potential efficacy of chemotherapy combination of Gemcitabine and Cisplatin as a neo-adjuvant treatment for cholangiocarcinoma patients before liver transplantation. Methods: In this prospective case series, patients with locally advanced, unresectable, hilar, or intrahepatic cholangiocarcinoma with no evidence of extrahepatic disease or vascular involvement were treated with a combination of neoadjuvant gemcitabine and cisplatin with no radiation. All patients included received chemotherapy prior to being listed for liver transplantation at a single cancer center according to an open-labeled, and center-approved clinical management protocol. The primary endpoints were the overall survival and recurrence-free survival after liver transplantation. Results: Between 1 March 2016, and 15 March 2022, 10 patients (8 males and 2 females) with a median age of 62.71(interquartile range: 60.02–71.87) had a confirmed diagnosis of intrahepatic or hilar cholangiocarcinoma and underwent liver transplantation. Median days of neoadjuvant therapy for a given combination of gemcitabine and cisplatin were 181 (IRQ: 120–250). Nine patients (90%) were reported with no recurrence or metastasis, and only 1 patient had confirmed metastasis (10%); days for metastasis after transplantation were 612 for this patient. All patients received a combination of gemcitabine and cisplatin as neo-adjuvant while awaiting liver transplantation. The median days of follow-up were 851 (813–967). Overall survival was 100% (95% CI 100–100%) at both years one and two; 75% (95% CI 13–96%) at years three to five. One patient died at eight hundred and eighty-five days. No adverse events were reported after liver transplantation including the patient who was confirmed with recurrence. Conclusions: Our finding demonstrated that neo-adjuvant gemcitabine and cisplatin with no radiation prior to liver transplantation resulted in excellent outcomes for patients with cholangiocarcinoma.
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Affiliation(s)
- Maen Abdelrahim
- Section of GI Oncology, Department of Medical Oncology, Houston Methodist Cancer Center, Houston, TX 77030, USA; (H.A.-R.); (A.E.)
- Cockrell Center of Advanced Therapeutics Phase I Program, Houston Methodist Research Institute, Houston, TX 77030, USA
- Weill Cornell Medical College, New York, NY 14853, USA; (A.S.); (R.M.); (R.M.G.)
- Correspondence:
| | - Hadeel Al-Rawi
- Section of GI Oncology, Department of Medical Oncology, Houston Methodist Cancer Center, Houston, TX 77030, USA; (H.A.-R.); (A.E.)
- Faculty of Medicine, University of Jordan, Amman 11942, Jordan;
| | - Abdullah Esmail
- Section of GI Oncology, Department of Medical Oncology, Houston Methodist Cancer Center, Houston, TX 77030, USA; (H.A.-R.); (A.E.)
- Cancer Clinical Trials, Houston Methodist Research Institute, Houston, TX 77030, USA
- JC Walter Jr Center for Transplantation and Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston, TX 77030, USA;
| | - Jiaqiong Xu
- Center for Outcomes Research, Houston Methodist Research Institute, Houston, TX 77030, USA;
| | - Godsfavour Umoru
- Department of Pharmacy, Houston Methodist Cancer Center, Houston, TX 77030, USA;
| | - Fahad Ibnshamsah
- Medical Oncology, King Fahd Specialist Hospital, Buraydah 52366, Saudi Arabia;
- Faculty of Medicine, Imam Abdulrahman Bin Faisal University, Dammam 34212, Saudi Arabia
| | - Ala Abudayyeh
- Section of Nephrology, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - David Victor
- JC Walter Jr Center for Transplantation and Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston, TX 77030, USA;
| | - Ashish Saharia
- Weill Cornell Medical College, New York, NY 14853, USA; (A.S.); (R.M.); (R.M.G.)
- JC Walter Jr Center for Transplantation and Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston, TX 77030, USA;
| | - Robert McMillan
- Weill Cornell Medical College, New York, NY 14853, USA; (A.S.); (R.M.); (R.M.G.)
- JC Walter Jr Center for Transplantation and Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston, TX 77030, USA;
| | - Ebtesam Al Najjar
- Faculty of Medicine and Health Sciences, University of Science and Technology, Sanaa 15201, Yemen;
| | - Doaa Bugazia
- Faculty of Medicine, University of Tripoli, Tripoli 22131, Libya;
| | - Maryam Al-Rawi
- Faculty of Medicine, University of Jordan, Amman 11942, Jordan;
| | - Rafik M. Ghobrial
- Weill Cornell Medical College, New York, NY 14853, USA; (A.S.); (R.M.); (R.M.G.)
- JC Walter Jr Center for Transplantation and Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston, TX 77030, USA;
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Liver Transplant for Non-Hepatocellular Malignancies: A Review for Radiologists. AJR Am J Roentgenol 2022; 219:590-603. [PMID: 35544376 DOI: 10.2214/ajr.22.27783] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Although traditionally only performed for hepatocellular carcinoma (HCC), the last decade has seen a resurgence in the use of liver transplant (LT) for non-HCC malignancies, likely due to improvements in neoadjuvant treatment regimens as well as the establishment of well-defined eligibility criteria. Given promising survival results, patients with perihilar cholangiocarcinoma, neuroendocrine liver metastases, and hepatic hemangioendothelioma are eligible to receive Model for End Stage Liver Disease (MELD) exception for tumors that meet well-defined criteria. Additional tumors such as colorectal cancer liver metastases, intrahepatic cholangiocarcinoma, and hepatocholangiocarcinoma may undergo transplant at specialized centers with well-defined protocols, although are not yet eligible for MELD exception. Transplant eligibility criteria commonly incorporate imaging findings, yet due to the relatively novel and evolving nature of LT for non-HCC malignancies, radiologists may be unaware of relevant criteria or of the implications of their imaging interpretations. Knowledge of the allocation process, background, and liver transplant selection criteria facilitates the radiologist' active participation in multidisciplinary discussion, leading to better and more equitable care for transplant candidates with non-HCC malignancy. This review provides an overview of transplant allocation and selection criteria in patients with non-HCC malignancy, with an emphasis on imaging features and the role of the radiologist.
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Wang SY, Jiang N, Zeng JP, Yu SQ, Xiao Y, Jin S. Characteristic of Perineural Invasion in Hilar Cholangiocarcinoma Based on Whole-Mount Histologic Large Sections of Liver. Front Oncol 2022; 12:855615. [PMID: 35350570 PMCID: PMC8957852 DOI: 10.3389/fonc.2022.855615] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Accepted: 02/14/2022] [Indexed: 12/30/2022] Open
Abstract
Background & Objective Perineural invasion is an important biological feature of hilar cholangiocarcinoma (HCCA). We developed a whole-mount histologic large sections (WHLS) of the liver to evaluate peripheral nerve invasion (PNI) of HCCA. Methods Using sampling, fixation, dehydration, embedding, sectioning, hematoxylin and eosin (H&E) and immunohistochemical (IHC) staining, and scanning, the characteristics of intrahepatic and extrahepatic PNI in 20 patients with Bismuth type III and type IV HCCA were analyzed with WHLS. Correlation between the characteristics of nerve invasion and tumor size, vascular invasion (artery, portal vein), degree of differentiation, microvascular invasion (MVI), carbohydrate antigen19-9 (CA19-9), and differentiation degree of HCCA was statistically evaluated. Results The WHLS of the liver was successfully established, which enabled us to observe intrahepatic and extrahepatic distribution of HCCA and whether surrounding tissues including nervous, blood, and lymph vessels were infiltrated. Extrahepatic and intrahepatic PNI were identified in 20 (100%) patients and 1 (5.0%) patient, respectively. Vessel density decreased in most invaded nerves presented by CD-34, which correlated with 100% of poorly differentiated and 83% of moderately differentiated tumors (P<0.008). Conclusion This study established a WHLS of the liver that can be used for clinical diagnosis and research, and confirmed that extrahepatic PNI is prevalent, but intrahepatic nerve invasion is rare and does not accompany the invasion scope of bile ducts in types III and IV HCCA. In addition, moderately and poorly differentiated malignant tumors are more prone to PNI, independent of blood supply.
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Affiliation(s)
- Si-Yuan Wang
- Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Institute for Precision Medicine, Tsinghua University, Beijing, China.,State Key Laboratory of Precision Measurement Technology and Instruments, Department of Precision Instrument, Tsinghua University, Beijing, China
| | - Nan Jiang
- Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Institute for Precision Medicine, Tsinghua University, Beijing, China.,State Key Laboratory of Precision Measurement Technology and Instruments, Department of Precision Instrument, Tsinghua University, Beijing, China
| | - Jian-Ping Zeng
- Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Institute for Precision Medicine, Tsinghua University, Beijing, China.,State Key Laboratory of Precision Measurement Technology and Instruments, Department of Precision Instrument, Tsinghua University, Beijing, China
| | - Shao-Qing Yu
- Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Institute for Precision Medicine, Tsinghua University, Beijing, China.,State Key Laboratory of Precision Measurement Technology and Instruments, Department of Precision Instrument, Tsinghua University, Beijing, China
| | - Ying Xiao
- Department of Pathology, Beijing Tsinghua Changgung Hospital, Beijing, China
| | - Shuo Jin
- Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Institute for Precision Medicine, Tsinghua University, Beijing, China.,State Key Laboratory of Precision Measurement Technology and Instruments, Department of Precision Instrument, Tsinghua University, Beijing, China
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McMillan RR, Javle M, Kodali S, Saharia A, Mobley C, Heyne K, Hobeika MJ, Lunsford KE, Victor DW, Shetty A, McFadden RS, Abdelrahim M, Kaseb A, Divatia M, Yu N, Nolte Fong J, Moore LW, Nguyen DT, Graviss EA, Gaber AO, Vauthey JN, Ghobrial RM. Survival following liver transplantation for locally advanced, unresectable intrahepatic cholangiocarcinoma. Am J Transplant 2022; 22:823-832. [PMID: 34856069 DOI: 10.1111/ajt.16906] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Revised: 11/05/2021] [Accepted: 11/17/2021] [Indexed: 01/25/2023]
Abstract
Intrahepatic cholangiocarcinoma (iCCA) has previously been considered a contraindication to liver transplantation (LT). However, recent series showed favorable outcomes for LT after neoadjuvant therapy. Our center developed a protocol for neoadjuvant therapy and LT for patients with locally advanced, unresectable iCCA in 2010. Patients undergoing LT were required to demonstrate disease stability for 6 months on neoadjuvant therapy with no extrahepatic disease. During the study period, 32 patients were listed for LT and 18 patients underwent LT. For transplanted patients, the median number of iCCA tumors was 2, and the median cumulative tumor diameter was 10.4 cm. Patients receiving LT had an overall survival at 1-, 3-, and 5-years of 100%, 71%, and 57%. Recurrences occurred in seven patients and were treated with systemic therapy and resection. The study population had a higher than expected proportion of patients with genetic alterations in fibroblast growth factor receptor (FGFR) and DNA damage repair pathways. These data support LT as a treatment for highly selected patients with locally advanced, unresectable iCCA. Further studies to identify criteria for LT in iCCA and factors predicting survival are warranted.
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Affiliation(s)
- Robert R McMillan
- Department of Surgery, Houston Methodist Hospital, Houston, Texas, USA
| | - Milind Javle
- Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
| | - Sudha Kodali
- Department of Medicine, Hepatology, Houston Methodist Hospital, Houston, Texas, USA
| | - Ashish Saharia
- Department of Surgery, Houston Methodist Hospital, Houston, Texas, USA
| | - Constance Mobley
- Department of Surgery, Houston Methodist Hospital, Houston, Texas, USA
| | - Kirk Heyne
- Department of Medicine, Cancer Center, Houston Methodist Hospital, Houston, Texas, USA
| | - Mark J Hobeika
- Department of Surgery, Houston Methodist Hospital, Houston, Texas, USA
| | - Keri E Lunsford
- Department of Surgery, Rutgers New Jersey Medical School, Newark, New Jersey, USA
| | - David W Victor
- Department of Medicine, Hepatology, Houston Methodist Hospital, Houston, Texas, USA
| | - Akshay Shetty
- Department of Medicine, Hepatology, Houston Methodist Hospital, Houston, Texas, USA
| | - Robert S McFadden
- Department of Medicine, Hepatology, Houston Methodist Hospital, Houston, Texas, USA
| | - Maen Abdelrahim
- Department of Medicine, Cancer Center, Houston Methodist Hospital, Houston, Texas, USA
| | - Ahmed Kaseb
- Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
| | - Mukul Divatia
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas, USA
| | - Nam Yu
- Houston Radiology Associates, Houston, Texas, USA
| | - Joy Nolte Fong
- Department of Surgery, Houston Methodist Hospital, Houston, Texas, USA
| | - Linda W Moore
- Department of Surgery, Houston Methodist Hospital, Houston, Texas, USA
| | - Duc T Nguyen
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas, USA
| | - Edward A Graviss
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas, USA
| | - A Osama Gaber
- Department of Surgery, Houston Methodist Hospital, Houston, Texas, USA
| | - Jean-Nicolas Vauthey
- Department of Surgical Oncology, Division of Surgery, University of Texas M.D. Anderson Cancer Center, Houston, Texas
| | - R Mark Ghobrial
- Department of Surgery, Houston Methodist Hospital, Houston, Texas, USA
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34
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Laughlin BS, Petersen MM, Yu NY, Anderson JD, Rule WG, Borad MJ, Aqel BA, Sonbol MB, Mathur AK, Moss AA, Bekaii-Saab TS, Ahn DH, DeWees TA, Sio TT, Ashman JB. Clinical outcomes for hilar and extrahepatic cholangiocarcinoma with adjuvant, definitive, or liver transplant-based neoadjuvant chemoradiotherapy strategies: a single-center experience. J Gastrointest Oncol 2022; 13:288-297. [PMID: 35284111 PMCID: PMC8899753 DOI: 10.21037/jgo-21-615] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 01/11/2022] [Indexed: 01/17/2024] Open
Abstract
BACKGROUND We report our experience with 3 strategies for treating hilar and extrahepatic cholangiocarcinoma (CCA) including chemoradiotherapy: neoadjuvant chemoradiotherapy (nCRT) and orthotopic liver transplant, surgical resection and adjuvant chemoradiotherapy (aCRT), and definitive chemoradiotherapy (dCRT). METHODS We included patients treated from 1998 through 2019. Kaplan-Meier estimates, log-rank testing, and univariate/multivariate Cox models were used to assess outcomes (local progression-free survival, disease-free survival, and overall survival). RESULTS Sixty-five patients (nCRT, n=20; aCRT, n=16; dCRT, n=29) met inclusion criteria [median (range) age 65 years (27-84 years)]. Median posttreatment follow-up was 19.1 months (0.8-164.8 months) for all patients and 38.6, 24.3, and 9.0 months for the nCRT, aCRT, and dCRT groups, respectively. At 3 and 5 years, overall survival was 78% and 59% for the nCRT group; 47% and 35%, aCRT group; and 11% and 0%, dCRT group. Compared with the dCRT group, the nCRT group (hazard ratio =0.13, 95% CI: 0.05-0.33) and the aCRT group (hazard ratio =0.29, 95% CI: 0.14-0.64) had significantly improved overall survival (P<0.001). The 5-year local progression-free survival (50% nCRT vs. 30% aCRT vs. 0% dCRT, P<0.001) and 5-year disease-free survival (61% nCRT vs. 30% aCRT vs. 0% dCRT, P=0.01) were significantly better for strategies combined with surgery. CONCLUSIONS Outcomes for patients with extrahepatic CCA were superior for those who underwent nCRT/orthotopic liver transplant or postsurgical aCRT than for patients treated with dCRT. The excellent outcomes after nCRT/orthotopic liver transplant provide additional independent data supporting the validity of this strategy. The poor survival of patients treated with dCRT highlights a need for better therapies when surgery is not possible.
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Affiliation(s)
- Brady S. Laughlin
- Mayo Clinic School of Graduate Medical Education, Mayo Clinic College of Medicine and Science, Phoenix, Arizona, USA
| | - Molly M. Petersen
- Clinical Trials and Biostatistics, Mayo Clinic, Scottsdale, Arizona, USA
| | - Nathan Y. Yu
- Mayo Clinic School of Graduate Medical Education, Mayo Clinic College of Medicine and Science, Phoenix, Arizona, USA
| | - Justin D. Anderson
- Mayo Clinic School of Graduate Medical Education, Mayo Clinic College of Medicine and Science, Phoenix, Arizona, USA
| | - William G. Rule
- Department of Radiation Oncology, Mayo Clinic Hospital, Phoenix, Arizona, USA
| | - Mitesh J. Borad
- Division of Hematology and Medical Oncology, Mayo Clinic Hospital, Phoenix, Arizona, USA
| | - Bashar A. Aqel
- Division of Gastroenterology and Hepatology, Mayo Clinic Hospital, Phoenix, Arizona, USA
- Transplant Center, Mayo Clinic Hospital, Phoenix, Arizona, USA
| | - Mohamad B. Sonbol
- Division of Hematology and Medical Oncology, Mayo Clinic Hospital, Phoenix, Arizona, USA
| | - Amit K. Mathur
- Transplant Center, Mayo Clinic Hospital, Phoenix, Arizona, USA
- Division of Transplant and Hepatobiliary Surgery, Mayo Clinic Hospital, Phoenix, Arizona, USA
| | - Adyr A. Moss
- Transplant Center, Mayo Clinic Hospital, Phoenix, Arizona, USA
- Division of Transplant and Hepatobiliary Surgery, Mayo Clinic Hospital, Phoenix, Arizona, USA
| | - Tanios S. Bekaii-Saab
- Division of Hematology and Medical Oncology, Mayo Clinic Hospital, Phoenix, Arizona, USA
| | - Daniel H. Ahn
- Division of Hematology and Medical Oncology, Mayo Clinic Hospital, Phoenix, Arizona, USA
- Mayo Clinic Cancer Center, Mayo Clinic Hospital, Phoenix, Arizona, USA
| | - Todd A. DeWees
- Clinical Trials and Biostatistics, Mayo Clinic, Scottsdale, Arizona, USA
- Department of Radiation Oncology, Mayo Clinic Hospital, Phoenix, Arizona, USA
| | - Terence T. Sio
- Department of Radiation Oncology, Mayo Clinic Hospital, Phoenix, Arizona, USA
| | - Jonathan B. Ashman
- Department of Radiation Oncology, Mayo Clinic Hospital, Phoenix, Arizona, USA
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Sapisochin G, Ivanics T, Heimbach J. Liver Transplantation for Intrahepatic Cholangiocarcinoma: Ready for Prime Time? Hepatology 2022; 75:455-472. [PMID: 34859465 DOI: 10.1002/hep.32258] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 11/16/2021] [Accepted: 11/22/2021] [Indexed: 12/16/2022]
Abstract
Cholangiocarcinoma (CCA) represents the second-most common primary liver malignancy after HCC and has risen in incidence globally in the past decades. Intrahepatic cholangiocarcinoma (iCCA) comprises 20% of all CCAs, with the rest being extrahepatic (including perihilar [pCCA] and distal CCA). Though long representing an absolute contraindication for liver transplantation (LT), recent analyses of outcomes of LT for iCCA have suggested that iCCA may be a potentially feasible option for highly selected patients. This has been motivated both by successes noted in outcomes of LT for other malignancies, such as HCC and pCCA, and by several retrospective reviews demonstrating favorable results with LT for a selected group of iCCA patients with small lesions. LT for iCCA is primarily relevant within two clinical scenarios. The first includes patients with very early disease (single tumor, ≤2 cm) with cirrhosis and are not candidates for liver resection (LR). The second scenario is patients with locally advanced iCCA, but where the extent of LR would be too extensive to be feasible. Preliminary single-center reports have described LT in a selected group of patients with locally advanced tumors who have responded to neoadjuvant therapy and have a period of disease stability. Currently, there are three prospective trials underway that will help clarify the role of LT in iCCA. This review seeks to explore the available studies involving LT for iCCA, the challenges of ongoing trials, and opportunities for the future.
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Affiliation(s)
- Gonzalo Sapisochin
- Multi-Organ Transplant ProgramUniversity Health Network TorontoTorontoOntarioCanada
| | - Tommy Ivanics
- Multi-Organ Transplant ProgramUniversity Health Network TorontoTorontoOntarioCanada
- Department of SurgeryHenry Ford HospitalDetroitMichiganUSA
- Department of Surgical SciencesAkademiska SjukhusetUppsala UniversityUppsalaSweden
| | - Julie Heimbach
- Divison of Transplant SurgeryDepartment of SurgeryMayo ClinicRochesterMinnesotaUSA
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36
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Twohig P, Peeraphatdit TB, Mukherjee S. Current status of liver transplantation for cholangiocarcinoma. World J Gastrointest Surg 2022; 14:1-11. [PMID: 35126858 PMCID: PMC8790328 DOI: 10.4240/wjgs.v14.i1.1] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 07/12/2022] [Accepted: 12/28/2021] [Indexed: 02/06/2023] Open
Abstract
Cholangiocarcinoma (CCA) is the second most common liver cancer with a median survival of 12-24 mo without treatment. It is further classified based on its location into intrahepatic CCA (iCCA), perihilar CCA (pCCA), and distal CCA. Surgical resection is the mainstay of treatment, but up to 70% of these tumors are inoperable at the time of diagnosis. CCA was previously an absolute contraindication for liver transplantation (LT) due to poor outcomes primary due to early recurrent disease. However, improvement in patient selection criteria and neoadjuvant treatment protocols have improved outcomes for inoperable pCCA patients with recent studies reporting LT may improve survival in iCCA. Future advances in the treatment of CCA should include refining patient selection criteria and organ allocation for all subtypes of CCA, determining effective immunotherapies and the evolving role of personalized medicine in patients ineligible for surgical resection or LT. Our article reviews the current status of LT in CCA, along with future directions in managing patients with CCA.
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Affiliation(s)
- Patrick Twohig
- Department of Internal Medicine, Division of Gastroenterology and Transplant Hepatology, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Thoetchai Bee Peeraphatdit
- Department of Internal Medicine, Division of Gastroenterology and Transplant Hepatology, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Sandeep Mukherjee
- Department of Internal Medicine, Division of Gastroenterology, Creighton University, Omaha, NE 68124, United States
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Ernani L, Martino RBD, Andraus W, Fernandes EDSM, Mello FPTD, Andrade R, Pimentel LS, Haddad LBDP, Coelho FF, Herman P, D'Albuquerque LAC. PROTOCOL FOR LIVER TRANSPLANTATION IN HILAR CHOLANGIOCARCINOMA. ABCD-ARQUIVOS BRASILEIROS DE CIRURGIA DIGESTIVA 2022; 34:e1618. [PMID: 35019130 PMCID: PMC8735267 DOI: 10.1590/0102-672020210002e1618] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Accepted: 04/25/2021] [Indexed: 11/22/2022]
Abstract
Background: Hilar cholangiocarcinoma represents more than half of all cholangiocarcinoma cases, having poor prognosis and presenting a median overall survival after diagnosis of 12-24 months. In patients who have unresectable tumors with a better prognosis, the proposal to perform liver transplantation emerged for expanding the possibility of free margins by performing total hepatectomy.
Aim: To provide a Brazilian protocol for liver transplantation in patients with hilar cholangiocarcinoma.
Method: The protocol was carried out by two Brazilian institutions which perform a large volume of resections and liver transplantations, based on the study carried out at the Mayo Clinic. The elaboration of the protocol was conducted in four stages.
Result: A protocol proposal for this disease is presented, which needs to be validated for clinical use.
Conclusion: The development of a liver transplantation protocol for cholangiocarcinoma aims not only to standardize the treatment, but also enable a better assessment of the surgical results in the future.
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Affiliation(s)
- Lucas Ernani
- Department of Gastroenterology, Hospital de Clínicas, Medical School, University of São Paulo, São Paulo, SP, Brazil
| | - Rodrigo Bronze de Martino
- Department of Gastroenterology, Hospital de Clínicas, Medical School, University of São Paulo, São Paulo, SP, Brazil
| | - Wellington Andraus
- Department of Gastroenterology, Hospital de Clínicas, Medical School, University of São Paulo, São Paulo, SP, Brazil
| | - Eduardo de Souza Martins Fernandes
- Department of General Surgery and Transplantation, Hospital Adventista Silvestre, Rio de Janeiro, RJ, Brazil.,Abdominal Transplant Surgery, Hospital São Lucas - Copacabana, Rio de Janeiro, RJ, Brazil
| | - Felipe Pedreira Tavares de Mello
- Department of General Surgery and Transplantation, Hospital Adventista Silvestre, Rio de Janeiro, RJ, Brazil.,Abdominal Transplant Surgery, Hospital São Lucas - Copacabana, Rio de Janeiro, RJ, Brazil
| | - Ronaldo Andrade
- Department of General Surgery and Transplantation, Hospital Adventista Silvestre, Rio de Janeiro, RJ, Brazil.,Abdominal Transplant Surgery, Hospital São Lucas - Copacabana, Rio de Janeiro, RJ, Brazil
| | - Leandro Savattone Pimentel
- Department of General Surgery and Transplantation, Hospital Adventista Silvestre, Rio de Janeiro, RJ, Brazil.,Abdominal Transplant Surgery, Hospital São Lucas - Copacabana, Rio de Janeiro, RJ, Brazil
| | | | - Fabricio Ferreira Coelho
- Department of Gastroenterology, Hospital de Clínicas, Medical School, University of São Paulo, São Paulo, SP, Brazil
| | - Paulo Herman
- Department of Gastroenterology, Hospital de Clínicas, Medical School, University of São Paulo, São Paulo, SP, Brazil
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Saffioti F, Mavroeidis VK. Review of incidence and outcomes of treatment of cholangiocarcinoma in patients with primary sclerosing cholangitis. World J Gastrointest Oncol 2021; 13:1336-1366. [PMID: 34721770 PMCID: PMC8529934 DOI: 10.4251/wjgo.v13.i10.1336] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 07/05/2021] [Accepted: 08/23/2021] [Indexed: 02/06/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is a premalignant condition and a well-documented risk factor for cholangiocarcinoma (CCA) which is the most common malignancy in this setting and the leading cause of deaths in the recent years, with an increasing incidence. PSC-associated CCA has a geographical distribution that follows the incidence of PSC, with an observed ascending gradient from the Eastern to the Western and from the Southern to the Northern countries. It may arise at any location along the biliary tree but is most common in the perihilar area. Patients with PSC and intrahepatic or perihilar CCA are typically not suitable for liver resection, which is otherwise the treatment of choice with curative intent in patients with resectable tumours, providing a radical resection with clear margins can be achieved. This largely relates to the commonly advanced stage of liver disease at presentation, which allows consideration for liver resection only for a very limited number of suitable patients with PSC. On the other hand, remarkable progress has been reached in the last decades with the implementation of a protocol combining neoadjuvant chemoradiation and orthotopic liver transplantation (OLT) for the treatment of perihilar CCA, within specific criteria. Excellent results have been achieved particularly for PSC patients with this cancer, who seem to benefit the most from this treatment, having converted this into an accepted indication for transplantation and the standard of care in several experienced centres. Intrahepatic CCA as an indication for OLT remains controversial and has not been accepted given disappointing previous results. However, as recent studies have shown favourable outcomes in early intrahepatic CCA, it may be that under defined criteria, OLT may play a more prominent role in the future. Distal CCA in the context of PSC requires aggressive surgical treatment with curative intent, when feasible. This review provides insight about particular features of CCA in the setting of PSC, with a main focus on its incidence, considerations relating to its anatomical location and implications to treatment and outcomes, through the viewpoint of historical evolution of management, and future perspectives.
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Affiliation(s)
- Francesca Saffioti
- Department of Gastroenterology and Hepatology, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, Oxfordshire, United Kingdom
- UCL Institute for Liver and Digestive Health and Sheila Sherlock Liver Unit, Royal Free Hospital, University College London, London NW3 2QG, United Kingdom
| | - Vasileios K Mavroeidis
- Department of Surgery, The Royal Marsden NHS Foundation Trust, London SW3 6JJ, United Kingdom
- Department of Transplant Surgery, North Bristol NHS Trust, Southmead Hospital, Bristol BS10 5NB, United Kingdom
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39
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Ziogas IA, Giannis D, Economopoulos KP, Hayat MH, Montenovo MI, Matsuoka LK, Alexopoulos SP. Liver Transplantation for Intrahepatic Cholangiocarcinoma: A Meta-analysis and Meta-regression of Survival Rates. Transplantation 2021; 105:2263-2271. [PMID: 33196623 DOI: 10.1097/tp.0000000000003539] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Intrahepatic cholangiocarcinoma (iCCA) is a contraindication to liver transplantation in most centers worldwide. Therefore, only a few such cases have been performed in each individual center, and the need for a systematic review and meta-analysis to cumulatively pool these results is apparent. METHODS A systematic literature review was conducted using the MEDLINE and Cochrane Library databases according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement (end-of-search date: May 29, 2020). Meta-analyses of proportions were conducted to pool the overall survival (OS), recurrence-free survival (RFS), and overall recurrence rates using the random-effects model. Meta-regression was used to examine cirrhosis and incidental diagnosis as confounders on OS and RFS. RESULTS Eighteen studies comprising 355 patients and a registry study of 385 patients were included. The pooled 1-, 3-, and 5-y OS rates were 75% (95% CI, 64%-84%), 56% (95% CI, 46%-67%), and 42% (95% CI, 29%-55%), respectively. The pooled 1-, 3-, and 5-y RFS rates were 70% (95% CI, 63%-75%), 49% (95% CI, 41%-57%), and 38% (95% CI, 27%-50%), respectively. Cirrhosis was positively associated with RFS, while incidental diagnosis was not. Neither cirrhosis nor incidental diagnosis was associated with OS. The pooled overall recurrence rate was 43% (95% CI, 33%-53%) over a mean follow-up of 40.6 ± 37.7 mo. Patients with very early (single ≤2 cm) iCCA exhibited superior pooled 5-y RFS (67%; 95% CI, 47%-86%) versus advanced iCCA (34%; 95% CI, 23%-46%). CONCLUSIONS Cirrhotics with very early iCCA or carefully selected patients with advanced iCCA after neoadjuvant therapy may benefit from liver transplantation under research protocols.
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Affiliation(s)
- Ioannis A Ziogas
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation, Vanderbilt University Medical Center, Nashville, TN
- Surgery Working Group, Society of Junior Doctors, Athens, Greece
| | - Dimitrios Giannis
- Surgery Working Group, Society of Junior Doctors, Athens, Greece
- Institute of Health Innovations and Outcomes Research, The Feinstein Institute for Medical Research, Manhasset, NY
| | - Konstantinos P Economopoulos
- Surgery Working Group, Society of Junior Doctors, Athens, Greece
- Department of Surgery, Duke University Medical Center, Durham, NC
| | - Muhammad H Hayat
- Division of Gastroenterology, Department of Medicine, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN
| | - Martin I Montenovo
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation, Vanderbilt University Medical Center, Nashville, TN
| | - Lea K Matsuoka
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation, Vanderbilt University Medical Center, Nashville, TN
| | - Sophoclis P Alexopoulos
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation, Vanderbilt University Medical Center, Nashville, TN
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40
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Transplant Oncology: An Evolving Field in Cancer Care. Cancers (Basel) 2021; 13:cancers13194911. [PMID: 34638395 PMCID: PMC8508383 DOI: 10.3390/cancers13194911] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 09/24/2021] [Accepted: 09/25/2021] [Indexed: 12/12/2022] Open
Abstract
Transplant oncology is an emerging concept of cancer treatment with a promising prospective outcome. The application of oncology, transplant medicine, and surgery to improve patients' survival and quality of life is the core of transplant oncology. Hepatobiliary malignancies have been treated by liver transplantation (LT) with significant improved outcome. In addition, as the liver is the most common site of metastasis for colorectal cancer (CRC), patients with CRC who have stable unresectable liver metastases are good candidates for LT, and initial studies have shown improved survival compared to palliative systemic therapy. The indications of LT for hepatobiliary malignancies have been slowly expanded over the years in a stepwise manner; however, they have only been shown to improve patient survival in the setting of limited systemic therapy options. This review illustrates the concept and history of transplant oncology as an evolving field for the management of hepatocellular carcinoma, intrahepatic biliary cancer, and liver-only metastasis of non-hepatobiliary carcinoma. The utility of immunotherapy in the transplant setting is discussed as well as the feasibility of using circulating tumor DNA for surveillance post-transplantation.
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Safarpour AR, Askari H, Ejtehadi F, Azarnezhad A, Raeis-Abdollahi E, Tajbakhsh A, Abazari MF, Tarkesh F, Shamsaeefar A, Niknam R, Sivandzadeh GR, Lankarani KB, Ejtehadi F. Cholangiocarcinoma and liver transplantation: What we know so far? World J Gastrointest Pathophysiol 2021; 12:84-105. [PMID: 34676129 PMCID: PMC8481789 DOI: 10.4291/wjgp.v12.i5.84] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 04/28/2021] [Accepted: 08/11/2021] [Indexed: 02/06/2023] Open
Abstract
Cholangiocarcinoma (CCA) is a type of cancer with increasing prevalence around the world that originates from cholangiocytes, the epithelial cells of the bile duct. The tumor begins insidiously and is distinguished by high grade neoplasm, poor outcome, and high risk for recurrence. Liver transplantation has become broadly accepted as a treatment option for CCA. Liver transplantation is expected to play a crucial role as palliative and curative therapy for unresectable hilar CCA and intrahepatic CCA. The purpose of this study was to determine which cases with CCA should be subjected to liver transplantation instead of resection, although reported post-transplant recurrence rate averages approximately 20%. This review also aims to highlight the molecular current frontiers of CCA and directions of liver transplantation for CCA.
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Affiliation(s)
- Ali Reza Safarpour
- Department of Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz 7134814336, Iran
| | - Hassan Askari
- Department of Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz 7134814336, Iran
| | - Farshid Ejtehadi
- The Princess Alexandra Hospital HNS Trust, Harlow, Essex CM20 1QX, United Kingdom
| | - Asaad Azarnezhad
- Liver and Digestive Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj 6617913446, Iran
| | - Ehsan Raeis-Abdollahi
- Department of Basic Medical Sciences, Qom Medical Branch, Islamic Azad University, Qom, Iran
| | - Amir Tajbakhsh
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz 7134814336, Iran
| | - Mohammad Foad Abazari
- Research Center for Clinical Virology, Tehran University of Medical Sciences, Tehran 1417653761, Iran
| | - Firoozeh Tarkesh
- Department of Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz 7134814336, Iran
| | - Alireza Shamsaeefar
- Shiraz Organ Transplant Center, Shiraz University of Medical Sciences, Shiraz 7193711351, Iran
| | - Ramin Niknam
- Department of Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz 7134814336, Iran
| | - Gholam Reza Sivandzadeh
- Department of Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz 7134814336, Iran
| | | | - Fardad Ejtehadi
- Department of Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz 7134814336, Iran
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42
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Zanetto A, Shalaby S, Gambato M, Germani G, Senzolo M, Bizzaro D, Russo FP, Burra P. New Indications for Liver Transplantation. J Clin Med 2021; 10:3867. [PMID: 34501314 PMCID: PMC8432035 DOI: 10.3390/jcm10173867] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 08/20/2021] [Accepted: 08/27/2021] [Indexed: 12/12/2022] Open
Abstract
Liver transplantation (LT) is an important therapeutic option for the treatment of several liver diseases. Modern LT is characterized by remarkable improvements in post-transplant patient survival, graft survival, and quality of life. Thanks to these great improvements, indications for LT are expanding. Nowadays, clinical conditions historically considered exclusion criteria for LT, have been considered new indications for LT, showing survival advantages for patients. In this review, we provide an updated overview of the principal newer indications for LT, with particular attention to alcoholic hepatitis, acute-on-chronic liver failure (ACLF), cholangiocarcinoma and colorectal cancer metastases.
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Affiliation(s)
| | | | | | | | | | | | | | - Patrizia Burra
- Multivisceral Transplant Unit, Department of Surgery Oncology and Gastroenterology, University of Padova, Via Giustiniani 2, 35128 Padova, Italy; (A.Z.); (S.S.); (M.G.); (G.G.); (M.S.); (D.B.); (F.P.R.)
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43
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Istanbouli A, Patel S, Almerey T, Li Z, Stauffer JA. Surgical Treatment for Intrahepatic, Peri-Hilar, and Distal Cholangiocarcinoma: 20-Single Institutional Year Experience. Am Surg 2021:31348211034751. [PMID: 34314644 DOI: 10.1177/00031348211034751] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND Surgical resection is the curative treatment for all subtypes of cholangiocarcinoma (CCA), including intrahepatic, hilar/peri-hilar, and distal. This study evaluates patients with CCA who underwent surgery and determines factors that impact their survival. METHODS A retrospective cohort study was performed for patients who underwent surgical resection for CCA at our institution from 1995 to 2016. Demographics, operative variables between CCA tumors, and postoperative complications were analyzed. Predictors of overall and recurrence-free survival were determined via statistical analysis. RESULTS A total of 170 patients with a mean age of 61 years old underwent surgical resection of intrahepatic (n = 64, 37.6%), hilar/peri-hilar (n = 75, 44.1%), and distal (n = 31, 18.2%) CCA. Operations performed included liver resections (n = 83, 48.8%), liver transplants (n = 56, 32.9%), and pancreaticoduodenectomies (n = 31, 18.2%). The overall survival rate at 1, 5, and 10 years was 81.1%, 32.4%, and 17.2%, respectively. Low pathological stage and negative resection margins were associated with lower recurrence and higher survival rates. Tumor location and the type of operation performed were not predictive of recurrence or OS in this cohort. DISCUSSION This study shows that definitive surgical resection with negative margins can result in long-term survival even at 10 years. Small tumor size and low pathological stage are predictive of higher survival rates post-surgery, emphasizing the importance of early diagnosis and appropriate surgical treatment in achieving positive outcomes.
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Affiliation(s)
- Ayah Istanbouli
- Department of General Surgery, 156400Mayo Clinic, Jacksonville, FL, USA
| | - Shreya Patel
- Department of General Surgery, 156400Mayo Clinic, Jacksonville, FL, USA
| | - Tariq Almerey
- Department of General Surgery, 156400Mayo Clinic, Jacksonville, FL, USA
| | - Zhuo Li
- Department of Biomedical Statistics and Informatics, 156400Mayo Clinic, Jacksonville, FL, USA
| | - John A Stauffer
- Department of General Surgery, 156400Mayo Clinic, Jacksonville, FL, USA
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44
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Oguz S, Kucukaslan H, Topaloglu S, Ones T, Baltacioglu F, Cobanoglu U, Calik A. Is it Possible to Increase Survival of Patients with Intrahepatic Cholangiocarcinoma? A Case Report. J Gastrointest Cancer 2021; 52:342-346. [PMID: 32617830 DOI: 10.1007/s12029-020-00446-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Affiliation(s)
- Sukru Oguz
- Faculty of Medicine, Department of Radiology, Karadeniz Technical University, Trabzon, Turkey
| | - Hakan Kucukaslan
- Faculty of Medicine, Department of Surgery, Karadeniz Technical University, Trabzon, Turkey
| | - Serdar Topaloglu
- Faculty of Medicine, Department of Surgery, Karadeniz Technical University, Trabzon, Turkey.
| | - Tunc Ones
- Faculty of Medicine, Department of Nuclear Medicine, Marmara University, İstanbul, Turkey
| | - Feyyaz Baltacioglu
- Faculty of Medicine, Department of Radiology, Marmara University, İstanbul, Turkey
| | - Umit Cobanoglu
- Faculty of Medicine, Department of Pathology, Karadeniz Technical University, Trabzon, Turkey
| | - Adnan Calik
- Faculty of Medicine, Department of Surgery, Karadeniz Technical University, Trabzon, Turkey
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45
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Acher AW, Weber SM, Pawlik TM. Liver transplantation for perihilar cholangiocarcinoma: patient selection and outcomes. Expert Rev Gastroenterol Hepatol 2021; 15:555-566. [PMID: 33577361 DOI: 10.1080/17474124.2021.1890584] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Introduction: Peri-hilar cholangiocarcinoma is an aggressive bile duct cancer. Long-term survival is possible with margin-negative surgery. Historically, unresectable disease was approached with non-curative treatment options. In recent decades, an innovative approach of neoadjuvant chemoradiation and liver transplantation has demonstrated long-term survival for highly selected patients.Areas covered: This is a critical analysis of studies published to date on neoadjuvant chemoradiation and liver transplantation for selected patients with peri-hilar cholangiocarcinoma. A PubMed literature search was conducted for years 1970-2020 with the following search criteria: ['hilar' OR 'peri-hilar' AND 'cholangiocarcinoma'] AND ['treatment' OR 'transplantation' OR 'survival' OR 'outcome']; 'neoadjuvant chemoradiation' AND 'unresectable cholangiocarcinoma'. All peer-reviewed original research studies were selected for review.Expert opinion: Neoadjuvant chemoradiation and liver transplantation for patients with early stage unresectable peri-hilar cholangiocarcinoma can achieve long-term survival in highly selected patients who survive to transplantation without disease progression. There are observed differences in survival for patients with PSC-associated versus de novo cholangiocarcinoma and transplanted versus resected patients; however, these differences are not contextualized by established tumor and patient factors that influence recurrence and survival. Therefore, these results must be interpreted within the limitations of the study designs upon which they are based.
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Affiliation(s)
- Alexandra W Acher
- Department of Surgery, Division of Surgical Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Sharon M Weber
- Department of Surgery, Division of Surgical Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Timothy M Pawlik
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA
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46
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Soares KC, Jarnagin WR. The Landmark Series: Hilar Cholangiocarcinoma. Ann Surg Oncol 2021; 28:4158-4170. [PMID: 33829358 DOI: 10.1245/s10434-021-09871-6] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 03/01/2021] [Indexed: 12/15/2022]
Abstract
Hilar cholangiocarcinoma (HC) is a rare and highly aggressive biliary tract neoplasm. As such, the data driving the management of this disease generally are not based on prospective clinical trial data but rather consist of retrospective experiences and limited level 1 data. Surgical resection offers the best chance of a long-term survival, but local and distant recurrences are common. This report presents landmark articles that form the basis of preoperative, operative, and adjuvant strategies for HC.
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Affiliation(s)
- Kevin C Soares
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.,Department of Surgery, Weill Cornell Medical College, New York, NY, USA
| | - William R Jarnagin
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. .,Department of Surgery, Weill Cornell Medical College, New York, NY, USA.
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47
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Finotti M, Auricchio P, Vitale A, Gringeri E, Cillo U. Liver transplantation for rare liver diseases and rare indications for liver transplant. Transl Gastroenterol Hepatol 2021; 6:27. [PMID: 33824931 DOI: 10.21037/tgh-19-282] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Accepted: 06/12/2020] [Indexed: 12/13/2022] Open
Abstract
Liver transplantation (LT) is currently considered the gold standard treatment for end-stage liver failure. Compared to the first decades of its use, LT is associated with lower comorbidity and mortality, with a 5-year survival over 70%. Worldwide, liver cirrhosis and hepatocellular carcinoma represent the major indications to LT. However, almost 1% of LT is performed for rare diseases or rare indications, which include non-hepatocellular malignancy, vascular disorders, metabolic and congenital liver disorders. These diseases can lead to hepatocellular necrosis, biliary tree abnormality and/or hepatomegaly. Most of these diseases are not associated with liver failure but in highly selected patients, LT represent an effective therapy improving the overall survival and quality of life. Rare indications for LT often overlap with rare diseases. However, rare LT indications for non-rare diseases are rising in the last decades, especially for benign primary liver tumor, colon rectal liver metastasis, neuroendocrine liver metastasis, and cholangiocarcinoma (CCA). Non-rare diseases with rare indication for LT and rare adult disease with an indication for LT are categorized and discussed in detail, focusing on some disorders for which the literature provides a more definitive evidence base. Early referral to a transplant center is encouraged to provide an effective therapeutic option in these non-standard indications for LT.
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Affiliation(s)
- Michele Finotti
- Department of Surgery, Oncology and Gastroenterology, Hepatobiliary Surgery and Liver Transplantation Unit, Padova University Hospital, Padova, Italy
| | - Pasquale Auricchio
- Department of Surgery, Oncology and Gastroenterology, Hepatobiliary Surgery and Liver Transplantation Unit, Padova University Hospital, Padova, Italy
| | - Alessandro Vitale
- Department of Surgery, Oncology and Gastroenterology, Hepatobiliary Surgery and Liver Transplantation Unit, Padova University Hospital, Padova, Italy
| | - Enrico Gringeri
- Department of Surgery, Oncology and Gastroenterology, Hepatobiliary Surgery and Liver Transplantation Unit, Padova University Hospital, Padova, Italy
| | - Umberto Cillo
- Department of Surgery, Oncology and Gastroenterology, Hepatobiliary Surgery and Liver Transplantation Unit, Padova University Hospital, Padova, Italy
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48
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Dageforde LA, Vachharajani N, Tabrizian P, Agopian V, Halazun K, Maynard E, Croome K, Nagorney D, Hong JC, Lee D, Ferrone C, Baker E, Jarnagin W, Hemming A, Schnickel G, Kimura S, Busuttil R, Lindemann J, Florman S, Holzner ML, Srouji R, Najjar M, Yohanathan L, Cheng J, Amin H, Rickert CA, Yang JD, Kim J, Pasko J, Chapman WC, Majella Doyle MB. Multi-Center Analysis of Liver Transplantation for Combined Hepatocellular Carcinoma-Cholangiocarcinoma Liver Tumors. J Am Coll Surg 2021; 232:361-371. [DOI: 10.1016/j.jamcollsurg.2020.11.017] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Accepted: 11/30/2020] [Indexed: 02/08/2023]
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49
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Neoadjuvant Chemoradiotherapy and Liver Transplantation for Unresectable Hilar Cholangiocarcinoma: The Irish Experience of the Mayo Protocol. Transplantation 2021; 104:2097-2104. [PMID: 31972704 DOI: 10.1097/tp.0000000000003114] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Pioneered by the Mayo Clinic, multimodal therapy with neoadjuvant chemoradiotherapy and orthotopic liver transplant has emerged as a promising option for unresectable hilar cholangiocarcinoma (hCCA). This study reports the experience of the Irish National Liver Transplant Programme with the Mayo Protocol. METHODS All patients diagnosed with unresectable hCCA between 2004 and 2016, who were eligible for the treatment protocol, were prospectively studied. RESULTS Thirty-seven patients commenced chemoradiotherapy. Of those, 11 were excluded due to disease progression and 26 proceeded to liver transplantation. There were 24 males, the median age was 49, and 88% had underlying primary sclerosing cholangitis. R0 and pathologic complete response rates were 96% and 62%, respectively. Overall median survival was 53 months and 1-, 3-, and 5-year survival was 81%, 69%, and 55%, respectively. The median survival of patients achieving a pathologic complete response was 83.8 months compared with 20.9 months in the group with residual disease (P = 0.036). Six patients (23%) developed disease recurrence. Among the patients who developed metastatic disease during neoadjuvant treatment, median survival was 10.5 months compared with 53 months in patients who proceeded to transplant (P < 0.001). CONCLUSIONS Neoadjuvant chemoradiotherapy followed by liver transplantation substantially increases the survival of patients with unresectable hCCA. Achieving a pathologic complete response confers a significant survival benefit.
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50
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McMillan RR, Saharia A, Abdelrahim M, Ghobrial RM. New Breakthroughs for Liver Transplantation of Cholangiocarcinoma. CURRENT TRANSPLANTATION REPORTS 2021. [DOI: 10.1007/s40472-021-00313-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Abstract
Purpose
Liver transplantation (LT) has gained ground as a treatment for cholangiocarcinoma. LT has achieved an established role as curative treatment for unresectable hilar cholangiocarcinoma (hCCA), and there are emerging data supporting its use in select patients with intrahepatic cholangiocarcinoma (iCCA). This review explores the current frontiers and future directions of LT for CCA.
Recent Findings
Results of retrospective studies support randomized trials of LT for resectable hCCA. Select patients with iCCA who have small tumors or favorable disease biology, as demonstrated by response to neoadjuvant therapy, have long-term survival after LT. Discoveries in the biology of iCCA show patients with FGFR and other genetic abnormalities have improved outcomes and may benefit from targeted therapies.
Summary
The outcomes of LT for CCA support its increased utilization. Policies should be considered to increase accessibility of donor organs for patients with iCCA.
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