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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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Soliman N, Connor AA, Saharia A, Kodali S, Elaileh A, Patel K, Semaan S, Basra T, Victor DW, Simon CJ, Cheah YL, Hobeika MJ, Mobley CM, Divatia M, Dhingra S, Schwartz M, Maqsood A, Heyne K, Abdelrahim M, Javle M, Vauthey JN, Gaber AO, Ghobrial RM. Neoadjuvant Multiagent Systemic Therapy Approach to Liver Transplantation for Perihilar Cholangiocarcinoma. Transplant Direct 2025; 11:e1760. [PMID: 39936132 PMCID: PMC11809964 DOI: 10.1097/txd.0000000000001760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Accepted: 11/12/2024] [Indexed: 02/13/2025] Open
Abstract
Background Perihilar cholangiocarcinoma (phCCA) has excellent outcomes following liver transplantation (LT). Neoadjuvant radiation-based locoregional therapy is standard-of-care. Gemcitabine and cisplatin (gem/cis) combination systemic therapies have improved outcomes in advanced settings, but their efficacy pre-LT has not been studied. Methods We review our experience following neoadjuvant gem/cis alone versus radiation-based approaches. Patients with phCCA undergoing LT at a single center between January 2008 and February 2023 were identified retrospectively. Neoadjuvant therapy was categorized as gem/cis systemic therapy (ST) alone, or any ST and radiotherapy (RT). Outcomes were posttransplant overall survival (OS), recurrence-free survival (RFS), waitlist time, and pathologic tumor response. Results During study period, 27 phCCA patients underwent LT. One patient decompensated with neoadjuvant therapy and was excluded. Median age was 61 y (interquartile range, 53-68 y) and 14 (54%) were male. Of 26 patients, 12 (46%) received ST and 14 (54%) RT. Six RT patients received gem/cis ST. Median waitlist time was 199 d (interquartile range, 98-405 d) and did not differ by neoadjuvant regimen. Explanted tumors were predominantly T1 stage, without lymphovascular invasion or nodal involvement. Neither pathologic features nor percent tumor necrosis differed by regimen. OS probabilities at 1 and 3 y were 84% and 55% for the cohort. There was no significant difference in OS and RFS when stratified by regimen. Conclusions Post-LT OS, RFS, waitlist time, and tumor response were similar in the 2 groups. Patients with phCCA who do not undergo RT may still be considered for LT under appropriate institution-based protocols that adhere to other established criteria.
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Affiliation(s)
- Nadine Soliman
- Faculty of Biology, Medicine, and Health, University of Manchester, Manchester, United Kingdom
| | - Ashton A. Connor
- Department of Surgery, Houston Methodist Hospital, Houston, TX
- Department of Surgery, Weill Cornell Medical College, New York, NY
| | - Ashish Saharia
- Department of Surgery, Houston Methodist Hospital, Houston, TX
- Department of Surgery, Weill Cornell Medical College, New York, NY
| | - Sudha Kodali
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, Department of Medicine, Houston Methodist Hospital, Houston, TX
- Department of Medicine, Weill Cornell Medical College, New York, NY
| | - Ahmed Elaileh
- Department of Surgery, Houston Methodist Hospital, Houston, TX
| | - Khush Patel
- Department of Surgery, Houston Methodist Hospital, Houston, TX
| | - Samar Semaan
- Department of Surgery, Houston Methodist Hospital, Houston, TX
| | - Tamneet Basra
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, Department of Medicine, Houston Methodist Hospital, Houston, TX
| | - David W. Victor
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, Department of Medicine, Houston Methodist Hospital, Houston, TX
- Department of Medicine, Weill Cornell Medical College, New York, NY
| | | | - Yee Lee Cheah
- Department of Surgery, Houston Methodist Hospital, Houston, TX
| | - Mark J. Hobeika
- Department of Surgery, Houston Methodist Hospital, Houston, TX
- Department of Surgery, Weill Cornell Medical College, New York, NY
| | - Constance M. Mobley
- Department of Surgery, Houston Methodist Hospital, Houston, TX
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, Department of Medicine, Houston Methodist Hospital, Houston, TX
| | - Mukul Divatia
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX
| | - Sadhna Dhingra
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX
| | - Mary Schwartz
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX
| | - Anaum Maqsood
- Division of Medical Oncology, Department of Medicine, Houston Methodist Hospital, Houston, TX
| | - Kirk Heyne
- Department of Medicine, Weill Cornell Medical College, New York, NY
- Division of Medical Oncology, Department of Medicine, Houston Methodist Hospital, Houston, TX
| | - Maen Abdelrahim
- Department of Medicine, Weill Cornell Medical College, New York, NY
- Division of Medical Oncology, Department of Medicine, Houston Methodist Hospital, Houston, TX
| | - Milind Javle
- Department of Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Jean-Nicolas Vauthey
- Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX
| | - A. Osama Gaber
- Department of Surgery, Houston Methodist Hospital, Houston, TX
- Department of Surgery, Weill Cornell Medical College, New York, NY
| | - R. Mark Ghobrial
- Department of Surgery, Houston Methodist Hospital, Houston, TX
- Department of Surgery, Weill Cornell Medical College, New York, NY
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Pierrard J, Foguenne M, Baldin P, Bonaccorsi-Riani E, Coubeau L, Ciccarelli O, Dahlqvist G, Delire B, Van Ooteghem G. Does prior radiotherapy impact the acute cellular liver graft rejection? Cancer Radiother 2025; 29:104590. [PMID: 40043526 DOI: 10.1016/j.canrad.2025.104590] [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: 04/11/2024] [Revised: 08/19/2024] [Accepted: 08/26/2024] [Indexed: 04/01/2025]
Abstract
PURPOSE Radiotherapy can be used as a bridge therapy prior to liver transplantation. Radiotherapy generates immune reactions involving T cells, which are the main effectors of acute cellular rejection after transplantation. Here, we investigated the impact of radiotherapy on acute cellular rejection. MATERIALS AND METHODS We retrospectively reviewed the data of oncological patients who benefited from liver transplantation. Patients who received radiotherapy prior to liver transplantation ("RT cohort", n=17) were compared to a matched cohort ("NoRTmatched cohort", n=17) obtained through propensity score-matching analysis of the total non-irradiated cohort ("NoRTall" cohort, n=136). The acute cellular rejection was evaluated using the Banff score for rejection (mild:<5, moderate: 5-6, and severe: 7-9) obtained on an early post-transplantation biopsy. Overall and disease-free survival were reported for patients with hepatocellular carcinoma. RESULTS Median Banff scores was significantly lower for the RT cohort compared to the NoRTall cohort (2.5 versus 5, respectively, P=0.043) but this statistical difference was eliminated after comparison with the NoRTmatched cohort (median: 4, P=0.62). The 5-year overall and disease-free survival rates were 62 % and 69 %, respectively, for hepatocellular carcinoma patients of the RT cohort (n=14) and did not differ from the 5-year overall (83 %, P=0.15) and disease-free survival rates (90 %, P=0.05) of those of the NoRTmatched cohort (n=16). CONCLUSION Radiotherapy given prior to liver transplantation did not impact the rate or severity of acute cellular rejection. Furthermore, overall and disease-free survival rates were not impacted by radiotherapy.
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Affiliation(s)
- Julien Pierrard
- UCLouvain, Institut de recherche expérimentale et clinique (Irec), Center of Molecular Imaging, Radiotherapy and Oncology (MIRO), Brussels, Belgium; Department of Radiation Oncology, cliniques universitaires Saint-Luc, Brussels, Belgium.
| | - Maxime Foguenne
- Department of Abdominal Transplantation, cliniques universitaires Saint-Luc, Brussels, Belgium
| | - Pamela Baldin
- UCLouvain, Institut de recherche expérimentale et clinique (Irec), Morphology Lab (MORF), Brussels, Belgium; Department of Pathology, cliniques universitaires Saint-Luc, Brussels, Belgium
| | - Eliano Bonaccorsi-Riani
- Department of Abdominal Transplantation, cliniques universitaires Saint-Luc, Brussels, Belgium
| | - Laurent Coubeau
- Department of Abdominal Transplantation, cliniques universitaires Saint-Luc, Brussels, Belgium
| | - Olga Ciccarelli
- Department of Abdominal Transplantation, cliniques universitaires Saint-Luc, Brussels, Belgium
| | - Géraldine Dahlqvist
- Department of Abdominal Transplantation, cliniques universitaires Saint-Luc, Brussels, Belgium; Department of Hepato-gastroenterology, cliniques universitaires Saint-Luc, Brussels, Belgium
| | - Bénédicte Delire
- Department of Abdominal Transplantation, cliniques universitaires Saint-Luc, Brussels, Belgium; Department of Hepato-gastroenterology, cliniques universitaires Saint-Luc, Brussels, Belgium
| | - Geneviève Van Ooteghem
- UCLouvain, Institut de recherche expérimentale et clinique (Irec), Center of Molecular Imaging, Radiotherapy and Oncology (MIRO), Brussels, Belgium; Department of Radiation Oncology, cliniques universitaires Saint-Luc, Brussels, Belgium
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Cillo U, Carraro A, Avolio AW, Cescon M, Di Benedetto F, Giannelli V, Magistri P, Nicolini D, Vivarelli M, Lanari J. Immunosuppression in liver transplant oncology: position paper of the Italian Board of Experts in Liver Transplantation (I-BELT). Updates Surg 2024; 76:725-741. [PMID: 38713396 DOI: 10.1007/s13304-024-01845-z] [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: 07/13/2023] [Accepted: 07/31/2023] [Indexed: 05/08/2024]
Abstract
Liver transplant oncology (TO) represents an area of increasing clinical and scientific interest including a heterogeneous group of clinical-pathological settings. Immunosuppressive management after LT is a key factor relevantly impacting result. However, disease-related guidance is still lacking, and many open questions remain in the field. Based on such a substantial lack of solid evidences, the Italian Board of Experts in Liver Transplantation (I-BELT) (a working group including representatives of all national transplant centers), unprecedently promoted a methodologically sound consensus conference on the topic, based on the GRADE approach. The group final recommendations are herein presented and commented. The 18 PICOs and Statements and their levels of evidence and grades of recommendation are reported and grouped into seven areas: (1) risk stratification by histopathological and bio-molecular parameters and role of mTORi post-LT; (2) steroids and HCC recurrence; (3) management of immunosuppression when HCC recurs after LT; (4) mTORi monotherapy; (5) machine perfusion and HCC recurrence after LT; (6) physiopathology of tumor-infiltrating lymphocytes and immunosuppression, the role of inflammation; (7) immunotherapy in liver transplanted patients. The interest in mammalian targets of rapamycin inhibitors (mTORi), for steroid avoidance and the need for a reduction to CNI exposure emerged from the consensus process. A selected list of unmet needs prompting further investigations have also been developed. The so far heterogeneous and granular approach to immunosuppression in oncologic patients deserves greater efforts for a more standardized therapeutic response to the different clinical scenarios. This consensus process makes a first unprecedented step in this direction, to be developed on a larger scale.
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Affiliation(s)
- Umberto Cillo
- Department of Surgical, Oncological and Gastroenterological Sciences, General Surgery 2 Hepato-Pancreato-Biliary Surgery and Liver Transplantation, Padua University Hospital, Via Giustiniani 2, 34128, Padua, PD, Italy.
| | - Amedeo Carraro
- Liver Transplant Unit, Department of Surgery and Oncology, University Hospital Trust of Verona, Verona, Italy
| | - Alfonso W Avolio
- Department of General Surgery and Liver Transplantation, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Matteo Cescon
- General Surgery and Transplantation Unit, Department of Medical and Surgical Sciences, Azienda Ospedaliero-Universitaria-Policlinico S.Orsola-Malpighi, Bologna, Italy
| | - Fabrizio Di Benedetto
- Hepatopancreatobiliary Surgery and Liver Transplantation Unit, University of Modena and Reggio Emilia, Modena, Italy
| | - Valerio Giannelli
- Liver Unit, Department of Liver Transplant, Azienda Ospedaliera San Camillo Forlanini, Rome, Italy
| | - Paolo Magistri
- Hepatopancreatobiliary Surgery and Liver Transplantation Unit, University of Modena and Reggio Emilia, Modena, Italy
| | - Daniele Nicolini
- Hepatobiliary and Abdominal Transplantation Surgery, Department of Experimental and Clinical Medicine, Riuniti Hospital, Polytechnic University of Marche, Ancona, Italy
| | - Marco Vivarelli
- Hepatobiliary and Abdominal Transplantation Surgery, Department of Experimental and Clinical Medicine, Riuniti Hospital, Polytechnic University of Marche, Ancona, Italy
| | - Jacopo Lanari
- Department of Surgical, Oncological and Gastroenterological Sciences, General Surgery 2 Hepato-Pancreato-Biliary Surgery and Liver Transplantation, Padua University Hospital, Via Giustiniani 2, 34128, Padua, PD, Italy
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Howell TC, Rhodin KE, Shaw B, Bao J, Kanu E, Masoud S, Bartholomew AJ, Gao Q, Anwar IJ, Ladowski JM, Nussbaum DP, Blazer DG, Zani S, Allen PJ, Barbas AS, Lidsky ME. Contemporary trends and outcomes after liver transplantation and resection for intrahepatic cholangiocarcinoma. J Gastrointest Surg 2024; 28:738-745. [PMID: 38704208 DOI: 10.1016/j.gassur.2024.02.029] [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: 06/27/2023] [Revised: 11/10/2023] [Accepted: 02/17/2024] [Indexed: 05/06/2024]
Abstract
BACKGROUND Liver transplantation (LT) has been shown to be superior to resection in highly selected patients with perihilar cholangiocarcinoma (CCA), yet has traditionally been contraindicated for intrahepatic CCA (iCCA). Herein, we aimed to examine contemporary trends and outcomes for surgical resection and LT for iCCA. METHODS The National Cancer Database was queried for patients presenting with stage I-III iCCA between 2010 and 2018 who underwent resection or LT. Overall survival (OS) was compared with Kaplan-Meier and multivariable Cox proportional hazards methods stratified by management. Secondary analysis of patients undergoing transplant for CCA was performed with the United Network for Organ Sharing database. RESULTS Of 2565 patients, 2412 (94.0%) underwent resection and 153 (5.96%) LT of whom 84 (54.9%) received neoadjuvant therapy. Utilization of LT remained between 3.9% and 7.8% annually. Unadjusted 5-year OS was higher for LT than resection (59.8% vs 39.9%, P = .0067), yet adjusted analysis revealed no significant difference in mortality (hazard ratio, 0.91; 95% CI, 0.66-1.27; P = .58). On secondary analysis including 437 patients with all subtypes of CCA, unadjusted 5-year OS was higher for non-CCA indications (79% vs 52%-54%, P < .001). CONCLUSION Utilization of LT for iCCA remains low and many cases are likely incidental. Although partial hepatectomy remains the standard of care for patients with resectable disease, our findings suggest that highly selected patients with unresectable iCCA may achieve favorable outcomes after LT. Granular, prospective data are needed to identify patients most likely to benefit from transplant and allocate scarce liver grafts.
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Affiliation(s)
- Thomas Clark Howell
- Department of Surgery, Duke University Medical Center, Durham, North Carolina, United States
| | - Kristen E Rhodin
- Department of Surgery, Duke University Medical Center, Durham, North Carolina, United States
| | - Brian Shaw
- Department of Surgery, Duke University Medical Center, Durham, North Carolina, United States
| | - Jiayin Bao
- Department of Surgery, Duke University Medical Center, Durham, North Carolina, United States
| | - Elishama Kanu
- Department of Surgery, Duke University Medical Center, Durham, North Carolina, United States
| | - Sabran Masoud
- Department of Surgery, Duke University Medical Center, Durham, North Carolina, United States
| | - Alex J Bartholomew
- Department of Surgery, Duke University Medical Center, Durham, North Carolina, United States
| | - Qimeng Gao
- Department of Surgery, Duke University Medical Center, Durham, North Carolina, United States
| | - Imran J Anwar
- Department of Surgery, Duke University Medical Center, Durham, North Carolina, United States
| | - Joseph M Ladowski
- Department of Surgery, Duke University Medical Center, Durham, North Carolina, United States
| | - Daniel P Nussbaum
- Department of Surgery, Duke University Medical Center, Durham, North Carolina, United States
| | - Dan G Blazer
- Department of Surgery, Duke University Medical Center, Durham, North Carolina, United States
| | - Sabino Zani
- Department of Surgery, Duke University Medical Center, Durham, North Carolina, United States
| | - Peter J Allen
- Department of Surgery, Duke University Medical Center, Durham, North Carolina, United States
| | - Andrew S Barbas
- Department of Surgery, Duke University Medical Center, Durham, North Carolina, United States
| | - Michael E Lidsky
- Department of Surgery, Duke University Medical Center, Durham, North Carolina, United States.
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Guba M, Werner J. [Liver transplantation for treatment of nonresectable primary and secondary liver malignancies : Hepatocellular and cholangiocellular carcinomas and colorectal liver metastases]. CHIRURGIE (HEIDELBERG, GERMANY) 2024; 95:268-273. [PMID: 38329517 DOI: 10.1007/s00104-024-02036-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 01/10/2024] [Indexed: 02/09/2024]
Abstract
BACKGROUND With the increasing efficacy of systemic therapy, liver transplantation plays an important role not only for hepatocellular carcinoma (HCC) but also for nonresectable intrahepatic cholangiocellular carcinoma (iCC), perihilar cholangiocellular carcinoma (phCC) and colorectal liver metastases (CRLM). AIM To review the current state of knowledge regarding the indications, patient selection and expected outcomes of liver transplantation for HCC, iCC, phCC and CRLM. RESULTS When combined with neoadjuvant locoregional therapy (LRT) and/or systemic therapy, patients with nonresectable HCC, iCC, pCC and CRLM confined to the liver can be successfully transplanted with 5‑year survival rates exceeding 65%. The key to success is strict patient selection, which includes oncogenetic (e.g., BRAFV600E mutation status) and clinical criteria indicative of individual tumor biology (tumor markers: alpha-fetoprotein, AFP/carbohydrate antigen 19‑9, CA19-9/carcinoembryonic antigen, CEA, stable response to neoadjuvant therapy) in addition to morphometric criteria. CONCLUSION Liver transplantation offers the possibility of curative treatment even for nonresectable hepatic malignancies. A major limitation of this treatment is the lack of donor organs. Crucial for success is patient selection based on individual tumor biology.
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Affiliation(s)
- Markus Guba
- Klinik für Allgemein‑, Viszeral-, und Transplantationschirurgie, LMU München, Marchioninistraße 15, 81377, München, Deutschland.
| | - Jens Werner
- Klinik für Allgemein‑, Viszeral-, und Transplantationschirurgie, LMU München, Marchioninistraße 15, 81377, München, Deutschland
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7
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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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8
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Chen W, Hu Z, Li G, Zhang L, Li T. The State of Systematic Therapies in Clinic for Hepatobiliary Cancers. J Hepatocell Carcinoma 2024; 11:629-649. [PMID: 38559555 PMCID: PMC10981875 DOI: 10.2147/jhc.s454666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Accepted: 03/16/2024] [Indexed: 04/04/2024] Open
Abstract
Hepatobiliary cancer (HBC) includes hepatocellular carcinoma and biliary tract carcinoma (cholangiocarcinoma and gallbladder carcinoma), and its morbidity and mortality are significantly correlated with disease stage. Surgery is the cornerstone of curative therapy for early stage of HBC. However, a large proportion of patients with HBC are diagnosed with advanced stage and can only receive systemic treatment. According to the results of clinical trials, the first-line and second-line treatment programs are constantly updated with the improvement of therapeutic effectiveness. In order to improve the therapeutic effect, reduce the occurrence of drug resistance, and reduce the adverse reactions of patients, the treatment of HBC has gradually developed from single-agent therapy to combination. The traditional therapeutic philosophy proposed that patients with advanced HBC are only amenable to systematic therapies. With some encouraging clinical trial results, the treatment concept has been revolutionized, and patients with advanced HBC who receive novel systemic combination therapies with multi-modality treatment (including surgery, transplant, TACE, HAIC, RT) have significantly improved survival time. This review summarizes the treatment options and the latest clinical advances of HBC in each stage and discusses future direction, in order to inform the development of more effective treatments for HBC.
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Affiliation(s)
- Weixun Chen
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People’s Republic of China
| | - Zhengnan Hu
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People’s Republic of China
| | - Ganxun Li
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People’s Republic of China
| | - Lei Zhang
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People’s Republic of China
| | - Tao Li
- Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, People’s Republic of China
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Wu TC, Smith CP, Li JS, Burton J, Jackson NJ, Tao R, Ludmir EB, Raldow AC. A systematic review and meta-analysis of pathologic complete response rates for patients with cholangiocarcinoma treated on liver transplant protocols. J Surg Oncol 2024; 129:574-583. [PMID: 37986552 DOI: 10.1002/jso.27511] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 09/26/2023] [Accepted: 11/04/2023] [Indexed: 11/22/2023]
Abstract
BACKGROUND AND OBJECTIVES: Many heterogenous orthotopic liver transplant (OLT) protocols exist for patients with unresectable cholangiocarcinoma. Little is known about the incidence, predictors for, and the significance of achieving a pathologic complete response (pCR). METHODS We performed a systematic review through September 2022 of the PubMed, Embase, and Web of Science databases. A random-effect meta-analysis was conducted to pool data across studies with reported pCR rates. Heterogeneity between treatment protocols was assessed via subgroup analysis. The pCR and 1-, 3-, and 5-year recurrence-free survival (RFS) and overall survival (OS) rates were extracted as outcomes of interest. RESULTS A total of 15 studies reported pCR rates and were grouped by use of the Mayo protocol (4/15), stereotactic body radiation therapy (2/15), and an Other category (9/15). The pooled pCR rate among all studies was 32%. Both radiation technique and duration of CHT showed no significant association with pCR (p = 0.05 and 0.13, respectively). Pooled 1-year RFS and OS after any neoadjuvant therapy and OLT was 80% (95% confidence interval [CI], 0.61-0.91), and 91% (95% CI, 0.87-0.94), respectively. There was no 1-year OS difference detected among the three groups. pCR was not associated with OS in the meta-regression. Pooled 3- and 5-year OS among all studies was 72% and 61%, respectively. CONCLUSIONS The pooled incidence of pCR was 32%. Differences in radiation technique did not appear to influence pCR rates and upon meta-regression, pCR was not a surrogate marker for survival.
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Affiliation(s)
- Trudy C Wu
- Department of Radiation Oncology, University of California Los Angeles, Los Angeles, California, USA
| | - Clayton P Smith
- Department of Radiation Oncology, University of California Los Angeles, Los Angeles, California, USA
| | - Joshua S Li
- Department of Medicine Statistics Core, University of California Los Angeles, Los Angeles, California, USA
| | - Jason Burton
- Louise M. Darling Biomedical Library, University of California Los Angeles, Los Angeles, California, USA
| | - Nicholas J Jackson
- Department of Medicine Statistics Core, University of California Los Angeles, Los Angeles, California, USA
| | - Randa Tao
- Department of Radiation Oncology, University of Utah, Salt Lake City, Utah, USA
| | - Ethan B Ludmir
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Ann C Raldow
- Department of Radiation Oncology, University of California Los Angeles, Los Angeles, California, USA
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10
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Krendl FJ, Bellotti R, Sapisochin G, Schaefer B, Tilg H, Scheidl S, Margreiter C, Schneeberger S, Oberhuber R, Maglione M. Transplant oncology - Current indications and strategies to advance the field. JHEP Rep 2024; 6:100965. [PMID: 38304238 PMCID: PMC10832300 DOI: 10.1016/j.jhepr.2023.100965] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 10/31/2023] [Accepted: 11/04/2023] [Indexed: 02/03/2024] Open
Abstract
Liver transplantation (LT) was originally described by Starzl as a promising strategy to treat primary malignancies of the liver. Confronted with high recurrence rates, indications drifted towards non-oncologic liver diseases with LT finally evolving from a high-risk surgery to an almost routine surgical procedure. Continuously improving outcomes following LT and evolving oncological treatment strategies have driven renewed interest in transplant oncology. This is not only reflected by constant refinements to the criteria for LT in patients with HCC, but especially by efforts to expand indications to other primary and secondary liver malignancies. With new patient-centred oncological treatments on the rise and new technologies to expand the donor pool, the field has the chance to come full circle. In this review, we focus on the concept of transplant oncology, current indications, as well as technical and ethical aspects in the context of donor organs as precious resources.
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Affiliation(s)
- Felix J. Krendl
- Department of Visceral, Transplant and Thoracic Surgery, Center for Operative Medicine, Medical University of Innsbruck, Austria
| | - Ruben Bellotti
- Department of Visceral, Transplant and Thoracic Surgery, Center for Operative Medicine, Medical University of Innsbruck, Austria
| | - Gonzalo Sapisochin
- Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Benedikt Schaefer
- Department of Medicine I, Gastroenterology, Hepatology and Endocrinology, Medical University of Innsbruck, Austria
| | - Herbert Tilg
- Department of Medicine I, Gastroenterology, Hepatology and Endocrinology, Medical University of Innsbruck, Austria
| | - Stefan Scheidl
- Department of Visceral, Transplant and Thoracic Surgery, Center for Operative Medicine, Medical University of Innsbruck, Austria
| | - Christian Margreiter
- Department of Visceral, Transplant and Thoracic Surgery, Center for Operative Medicine, Medical University of Innsbruck, Austria
| | - Stefan Schneeberger
- Department of Visceral, Transplant and Thoracic Surgery, Center for Operative Medicine, Medical University of Innsbruck, Austria
| | - Rupert Oberhuber
- Department of Visceral, Transplant and Thoracic Surgery, Center for Operative Medicine, Medical University of Innsbruck, Austria
| | - Manuel Maglione
- Department of Visceral, Transplant and Thoracic Surgery, Center for Operative Medicine, Medical University of Innsbruck, Austria
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11
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Wilbur HC, Soares HP, Azad NS. Neoadjuvant and adjuvant therapy for biliary tract cancer: Advances and limitations. Hepatology 2024:01515467-990000000-00725. [PMID: 38266282 DOI: 10.1097/hep.0000000000000760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Accepted: 12/31/2023] [Indexed: 01/26/2024]
Abstract
Biliary tract cancers (BTC) are a rare and aggressive consortium of malignancies, consisting of intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder carcinoma. While most patients present with metastatic disease, a minority of patients with BTC are eligible for curative surgical resection at the time of presentation. However, these patients have poor 5-year overall survival rates and high rates of recurrence, necessitating the improvement of the neoadjuvant and adjuvant treatment of BTC. In this review, we assess the neoadjuvant and adjuvant clinical trials for the treatment of BTC and discuss the challenges and limitations of clinical trials, as well as future directions for the treatment of BTC.
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Affiliation(s)
- H Catherine Wilbur
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA
| | - Heloisa P Soares
- Division of Oncology, Department of Internal Medicine Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA
| | - Nilofer S Azad
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA
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12
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Wheless M, Agarwal R, Goff L, Lockney N, Padmanabhan C, Heumann T. Current Standards, Multidisciplinary Approaches, and Future Directions in the Management of Extrahepatic Cholangiocarcinoma. Curr Treat Options Oncol 2024; 25:127-160. [PMID: 38177560 PMCID: PMC10824875 DOI: 10.1007/s11864-023-01153-5] [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] [Accepted: 11/19/2023] [Indexed: 01/06/2024]
Abstract
OPINION STATEMENT Biliary tract cancers are molecularly and anatomically diverse cancers which include intrahepatic cholangiocarcinoma, extrahepatic (perihilar and distal) cholangiocarcinoma, and gallbladder cancer. While recognized as distinct entities, the rarer incidence of these cancers combined with diagnostic challenges in classifying anatomic origin has resulted in clinical trials and guideline recommended strategies being generalized patients with all types of biliary tract cancer. In this review, we delve into the unique aspects, subtype-specific clinical trial outcomes, and multidisciplinary management of patients with extrahepatic cholangiocarcinoma. When resectable, definitive surgery followed by adjuvant chemotherapy (sometimes with selective radiation/chemoradiation) is current standard of care. Due to high recurrence rates, there is growing interest in the use of upfront/neoadjuvant therapy to improve surgical outcomes and to downstage patients who may not initially be resectable. Select patients with perihilar cholangiocarcinoma are being successfully treated with novel approaches such as liver transplant. In the advanced disease setting, combination gemcitabine and cisplatin remains the standard base for systemic therapy and was recently improved upon with the addition of immune checkpoint blockade to the chemotherapy doublet in the recently reported TOPAZ-1 and KEYNOTE-966 trials. Second-line all-comer treatments for these patients remain limited in both options and efficacy, so clinical trial participation should be strongly considered. With increased use of molecular testing, detection of actionable mutations and opportunities to receive indicated targeted therapies are on the rise and are the most significant driver of improved survival for patients with advanced stage disease. Though these targeted therapies are currently reserved for the second or later line, future trials are looking at moving these to earlier treatment settings and use in combination with chemotherapy and immunotherapy. In addition to cross-disciplinary management with surgical, medical, and radiation oncology, patient-centered care should also include collaboration with advanced endoscopists, palliative care specialists, and nutritionists to improve global patient outcomes.
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Affiliation(s)
- Margaret Wheless
- Department of Medicine, Division of Hematology Oncology, Vanderbilt University Medical Center, 2220 Pierce Avenue, Preston Research Building Suite 798, Nashville, TN, 37232, USA
| | - Rajiv Agarwal
- Department of Medicine, Division of Hematology Oncology, Vanderbilt University Medical Center, 2220 Pierce Avenue, Preston Research Building Suite 798, Nashville, TN, 37232, USA
- Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
| | - Laura Goff
- Department of Medicine, Division of Hematology Oncology, Vanderbilt University Medical Center, 2220 Pierce Avenue, Preston Research Building Suite 798, Nashville, TN, 37232, USA
- Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
| | - Natalie Lockney
- Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
- Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Chandrasekhar Padmanabhan
- Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
- Department of Surgery, Division of Surgical Oncology & Endocrine Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Thatcher Heumann
- Department of Medicine, Division of Hematology Oncology, Vanderbilt University Medical Center, 2220 Pierce Avenue, Preston Research Building Suite 798, Nashville, TN, 37232, USA.
- Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.
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13
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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: 21] [Impact Index Per Article: 10.5] [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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14
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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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15
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Bellefkih FZ, Benchakroun N, Lalya I, Amaoui B, El Kacemi H, Acharki A, El Hfid M, El Mazghi A, Chekrine T, Bouchbika Z, Jouhadi H, Sahraoui S, Tawfiq N, Michalet M. Radiotherapy in the management of rare gastrointestinal cancers: A systematic review. Cancer Radiother 2023; 27:622-637. [PMID: 37500390 DOI: 10.1016/j.canrad.2023.06.010] [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: 06/06/2023] [Revised: 06/10/2023] [Accepted: 06/13/2023] [Indexed: 07/29/2023]
Abstract
The aim of this analysis is to assess radiotherapy's role and technical aspects in an array of rare gastrointestinal (GI) cancers for adult patients. Collection data pertaining to radiotherapy and digestive rare cancers were sourced from Medline, EMBASE, and Cochrane Library. Preoperative chemoradiotherapy improved outcomes for patients with esophageal undifferentiated carcinoma compared with esophageal salivary gland types of carcinomas. For rare gastric epithelial carcinoma, perioperative chemotherapy is the common treatment. Adjuvant chemoradiotherapy showed no benefice compared with adjuvant chemotherapy for duodenal adenocarcinoma. Small bowel sarcomas respond well to radiotherapy. By analogy to anal squamous cell carcinoma, exclusive chemoradiotherapy provided better outcomes for patients with rectal squamous cell carcinoma. For anal adenocarcinoma, neoadjuvant chemoradiotherapy, followed by radical surgery, was the most effective regimen. For pancreatic neuroendocrine tumors, chemoradiotherapy can be a suitable option as postoperative or exclusive for unresectable/borderline disease. The stereotactic body radiotherapy (SBRT) is a promising approach for hepatobiliary malignancy. Radiotherapy is a valuable option in gastrointestinal stromal tumors (GIST) for palliative intent, tyrosine kinase inhibitors (TKIs) resistant disease, and unresectable or residual disease. Involved field (IF) radiotherapy for digestive lymphoma provides good results, especially for gastric extranodal marginal zone lymphoma (MALT). In conclusion, radiotherapy is not an uncommon indication in this context. A multidisciplinary approach is needed for better management of digestive rare cancers.
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Affiliation(s)
- F Z Bellefkih
- Department of Radiotherapy-Oncology, Ibn Rochd University Hospital, Hassan II University, Casablanca, Morocco.
| | - N Benchakroun
- Department of Radiotherapy-Oncology, Ibn Rochd University Hospital, Hassan II University, Casablanca, Morocco; Association marocaine d'oncologie-radiothérapie (Aoram), Casablanca, Morocco
| | - I Lalya
- Association marocaine d'oncologie-radiothérapie (Aoram), Casablanca, Morocco
| | - B Amaoui
- Association marocaine d'oncologie-radiothérapie (Aoram), Casablanca, Morocco
| | - H El Kacemi
- Association marocaine d'oncologie-radiothérapie (Aoram), Casablanca, Morocco
| | - A Acharki
- Association marocaine d'oncologie-radiothérapie (Aoram), Casablanca, Morocco
| | - M El Hfid
- Association marocaine d'oncologie-radiothérapie (Aoram), Casablanca, Morocco
| | - A El Mazghi
- Association marocaine d'oncologie-radiothérapie (Aoram), Casablanca, Morocco
| | - T Chekrine
- Department of Radiotherapy-Oncology, Ibn Rochd University Hospital, Hassan II University, Casablanca, Morocco
| | - Z Bouchbika
- Department of Radiotherapy-Oncology, Ibn Rochd University Hospital, Hassan II University, Casablanca, Morocco
| | - H Jouhadi
- Department of Radiotherapy-Oncology, Ibn Rochd University Hospital, Hassan II University, Casablanca, Morocco
| | - S Sahraoui
- Department of Radiotherapy-Oncology, Ibn Rochd University Hospital, Hassan II University, Casablanca, Morocco; Association marocaine d'oncologie-radiothérapie (Aoram), Casablanca, Morocco
| | - N Tawfiq
- Department of Radiotherapy-Oncology, Ibn Rochd University Hospital, Hassan II University, Casablanca, Morocco
| | - M Michalet
- Service d'oncologie-radiothérapie, institut du cancer de Montpellier, Fédération d'oncologie-radiothérapie d'Occitanie Méditerranée (Forom), Montpellier, France
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16
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Jena SS, Mehta NN, Nundy S. Surgical management of hilar cholangiocarcinoma: Controversies and recommendations. Ann Hepatobiliary Pancreat Surg 2023; 27:227-240. [PMID: 37408334 PMCID: PMC10472117 DOI: 10.14701/ahbps.23-028] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 04/12/2023] [Accepted: 04/17/2023] [Indexed: 07/07/2023] Open
Abstract
Hilar cholangiocarcinomas are highly aggressive malignancies. They are usually at an advanced stage at initial presentation. Surgical resection with negative margins is the standard of management. It provides the only chance of cure. Liver transplantation has increased the number of 'curative' procedures for cases previously considered to be unresectable. Meticulous and thorough preoperative planning is required to prevent fatal post-operative complications. Extended resection procedures, including hepatic trisectionectomy for Bismuth type IV tumors, hepatopancreaticoduodenectomy for tumors with extensive longitudinal spread, and combined vascular resection with reconstruction for tumors involving hepatic vascular structures, are challenging procedures with surgical indications expanded. Liver transplantation after the standardization of a neoadjuvant protocol described by the Mayo Clinic has increased the number of patients who can undergo operation.
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Affiliation(s)
- Suvendu Sekhar Jena
- Department of Surgical Gastroenterology and Liver Transplantation, Sir Ganga Ram Hospital, New Delhi, India
| | - Naimish N Mehta
- Department of Surgical Gastroenterology and Liver Transplantation, Sir Ganga Ram Hospital, New Delhi, India
| | - Samiran Nundy
- Department of Surgical Gastroenterology and Liver Transplantation, Sir Ganga Ram Hospital, New Delhi, India
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17
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Ramjeesingh R, Chaudhury P, Tam VC, Roberge D, Lim HJ, Knox JJ, Asselah J, Doucette S, Chhiber N, Goodwin R. A Practical Guide for the Systemic Treatment of Biliary Tract Cancer in Canada. Curr Oncol 2023; 30:7132-7150. [PMID: 37622998 PMCID: PMC10453186 DOI: 10.3390/curroncol30080517] [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: 06/17/2023] [Revised: 07/17/2023] [Accepted: 07/20/2023] [Indexed: 08/26/2023] Open
Abstract
Biliary tract cancers (BTC) are rare and aggressive tumors with poor prognosis. Radical surgery offers the best chance for cure; however, most patients present with unresectable disease, and among those receiving curative-intent surgery, recurrence rates remain high. While other locoregional therapies for unresectable disease may be considered, only select patients may be eligible. Consequently, systemic therapy plays a significant role in the treatment of BTC. In the adjuvant setting, capecitabine is recommended following curative-intent resection. In the neoadjuvant setting, systemic therapy has mostly been explored for downstaging in borderline resectable tumours, although evidence for its routine use is lacking. For advanced unresectable or metastatic disease, gemcitabine-cisplatin plus durvalumab has become the standard of care, while the addition of pembrolizumab to gemcitabine-cisplatin has also recently demonstrated improved survival compared to chemotherapy alone. Following progression on gemcitabine-cisplatin, several chemotherapy combinations and biomarker-driven targeted agents have been explored. However, the optimum regimen remains unclear, and access to targeted agents remains challenging in Canada. Overall, this article serves as a practical guide for the systemic treatment of BTC in Canada, providing valuable insights into the current and future treatment landscape for this challenging disease.
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Affiliation(s)
- Ravi Ramjeesingh
- Division of Medical Oncology, Department of Medicine, Nova Scotia Health, Dalhousie University, Halifax, NS B3H 2Y9, Canada
| | - Prosanto Chaudhury
- Department of Surgery and Oncology, McGill University Health Centre, Royal Victoria Hospital, Montreal, QC H4A 3J1, Canada
| | - Vincent C. Tam
- Division of Medical Oncology, Department of Oncology, University of Calgary, Calgary, AB T2N 4N2, Canada
| | - David Roberge
- Department of Radiology, Radiation Oncology and Nuclear Medicine, University of Montreal, Montreal, QC H3T 1A4, Canada
| | - Howard J. Lim
- Division of Medical Oncology, BC Cancer, Vancouver, BC V5Z 4E6, Canada
| | - Jennifer J. Knox
- Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON M5G 2M9, Canada
| | - Jamil Asselah
- Department of Medicine, Division of Medical Oncology, McGill University Health Centre, Montreal, QC H4A 3J1, Canada
| | - Sarah Doucette
- IMPACT Medicom Inc., Toronto, ON M6S 3K2, Canada; (S.D.)
| | - Nirlep Chhiber
- IMPACT Medicom Inc., Toronto, ON M6S 3K2, Canada; (S.D.)
| | - Rachel Goodwin
- Division of Medical Oncology, The Ottawa Hospital Cancer Centre, University of Ottawa, Ottawa, ON K1H 8L6, Canada
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18
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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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19
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Angelico R, Siragusa L, Serenari M, Scalera I, Kauffman E, Lai Q, Vitale A. Rescue liver transplantation after post-hepatectomy acute liver failure: A systematic review and pooled analysis. Transplant Rev (Orlando) 2023; 37:100773. [PMID: 37356212 DOI: 10.1016/j.trre.2023.100773] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Revised: 06/14/2023] [Accepted: 06/15/2023] [Indexed: 06/27/2023]
Abstract
BACKGROUND Post-hepatectomy liver failure is a severe complication after major liver resection and is associated with a high mortality rate. Nevertheless, there is no effective treatment for severe liver failure. In such a setting, rescue liver transplantation (LT) is used only in extraordinary cases with unclear results. This systematic review aims to define indication of LT in post-hepatectomy liver failure and post-LT outcomes, in terms of patient and disease-free survivals, to assess the procedure's feasibility and effectiveness. METHODS A systematic review of all English language full-text articles published until September 2022 was conducted. Inclusion criteria were articles describing patients undergoing LT for post-hepatectomy liver failure after liver resection, which specified at least one outcome of interest regarding patient/graft survival, postoperative complications, tumour recurrence and cause of death. A pseudo-individual participant data meta-analysis was performed to analyse data. Study quality was assessed with MINORS system. PROSPERO CRD42022349358. RESULTS Postoperative complication rate was 53.6%. All patients transplanted for benign indications survived. For malignant tumours, 1-, 3- and 5-year overall survival was 94.7%, 82.1% and 74.6%, respectively. The causes of death were tumour recurrence in 83.3% of cases and infection-related in 16.7% of LT recipients. At Cox regression, being transplanted for unconventional malignant indications (colorectal liver metastasis, cholangiocarcinoma) was a risk factor for death HR = 8.93 (95%CI = 1.04-76.63; P-value = 0.046). Disease-free survival differs according to different malignant tumours (P-value = 0.045). CONCLUSIONS Post-hepatectomy liver failure is an emergent indication for rescue LT, but it is not universally accepted. In selected patients, LT can be a life-saving procedure with low short-term risks. However, special attention must be given to long-term oncological prognosis before proceeding with rescue LT in an urgent setting, considering the severity of liver malignancy, organ scarcity, the country's organ allocation policies and the resource of living-related donation.
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Affiliation(s)
- Roberta Angelico
- Department of Surgical Sciences, Transplant and HPB Unit, University of Rome Tor Vergata, 00133 Rome, Italy.
| | - Leandro Siragusa
- Department of Surgical Sciences, Transplant and HPB Unit, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Matteo Serenari
- General Surgery and Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Sant'Orsola-Malpighi Hospital, Bologna, Italy; Department of Medical and Surgical Sciences-DIMEC, Alma Mater Studiorum, University of Bologna, Bologna, Italy
| | - Irene Scalera
- Unità di Chirurgia Epatobiliare e Trapianti di Fegato, Azienda Ospedaliero Universitaria -Consorziale Policlinico di Bari, Bari, Italy
| | - Emanuele Kauffman
- Division of General and Transplant Surgery, Pisa University, Pisa, Italy
| | - Quirino Lai
- General Surgery and Organ Transplantation Unit, Sapienza University of Rome, AUO Policlinico I of Rome, Rome, Italy
| | - Alessandro Vitale
- Department of Surgical Oncological and Gastroenterological Sciences, Padua University, Padua, Italy
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20
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Berardi G, Lucarini A, Colasanti M, Mariano G, Ferretti S, Meniconi RL, Guglielmo N, Angrisani M, Usai S, Borcea MC, Canali G, Moschetta G, Ettorre GM. Minimally Invasive Surgery for Perihilar Cholangiocarcinoma: A Systematic Review of the Short- and Long-Term Results. Cancers (Basel) 2023; 15:cancers15113048. [PMID: 37297010 DOI: 10.3390/cancers15113048] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Revised: 05/25/2023] [Accepted: 06/01/2023] [Indexed: 06/12/2023] Open
Abstract
Surgery and postoperative systemic chemotherapy represent the standard treatment for patients with perihilar cholangiocarcinoma (PHC). Minimally Invasive Surgery (MIS) for hepatobiliary procedures has spread worldwide in the last two decades. Since resections for PHC are technically demanding, the role of MIS in this field is yet to be established. This study aimed to systematically review the existing literature on MIS for PHC, to evaluate its safety and its surgical and oncological outcomes. A systematic literature review on PubMed and SCOPUS was performed according to the PRISMA guidelines. Overall, a total of 18 studies reporting 372 MIS procedures for PHC were included in our analysis. A progressive increase in the available literature was observed over the years. A total of 310 laparoscopic and 62 robotic resections were performed. A pooled analysis showed an operative time ranging from 205.3 ± 23.9 and 840 (770-890) minutes, and intraoperative bleeding between 101.1 ± 13.6 and 1360 ± 809 mL. Minor and major morbidity rates were 43.9% and 12.7%, respectively, with a 5.6% mortality rate. R0 resections were achieved in 80.6% of patients and the number of retrieved lymph nodes ranged between 4 (3-12) and 12 (8-16). This systematic review shows that MIS for PHC is feasible, with safe postoperative and oncological outcomes. Recent data has shown encouraging results and more reports are being published. Future studies should address differences between robotic and laparoscopic approaches. Given the management and technical challenges, MIS for PHC should be performed by experienced surgeons, in high-volume centers, on selected patients.
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Affiliation(s)
- Giammauro Berardi
- Department of General and Hepatobiliary and Pancreatic Surgery, Liver Transplantation Service, San Camillo-Forlanini Hospital, 00152 Rome, Italy
| | - Alessio Lucarini
- Department of General and Hepatobiliary and Pancreatic Surgery, Liver Transplantation Service, San Camillo-Forlanini Hospital, 00152 Rome, Italy
| | - Marco Colasanti
- Department of General and Hepatobiliary and Pancreatic Surgery, Liver Transplantation Service, San Camillo-Forlanini Hospital, 00152 Rome, Italy
| | - Germano Mariano
- Department of General and Hepatobiliary and Pancreatic Surgery, Liver Transplantation Service, San Camillo-Forlanini Hospital, 00152 Rome, Italy
| | - Stefano Ferretti
- Department of General and Hepatobiliary and Pancreatic Surgery, Liver Transplantation Service, San Camillo-Forlanini Hospital, 00152 Rome, Italy
| | - Roberto Luca Meniconi
- Department of General and Hepatobiliary and Pancreatic Surgery, Liver Transplantation Service, San Camillo-Forlanini Hospital, 00152 Rome, Italy
| | - Nicola Guglielmo
- Department of General and Hepatobiliary and Pancreatic Surgery, Liver Transplantation Service, San Camillo-Forlanini Hospital, 00152 Rome, Italy
| | - Marco Angrisani
- Department of General and Hepatobiliary and Pancreatic Surgery, Liver Transplantation Service, San Camillo-Forlanini Hospital, 00152 Rome, Italy
| | - Sofia Usai
- Department of General and Hepatobiliary and Pancreatic Surgery, Liver Transplantation Service, San Camillo-Forlanini Hospital, 00152 Rome, Italy
| | - Maria Carola Borcea
- Department of General and Hepatobiliary and Pancreatic Surgery, Liver Transplantation Service, San Camillo-Forlanini Hospital, 00152 Rome, Italy
| | - Giulia Canali
- Department of General and Hepatobiliary and Pancreatic Surgery, Liver Transplantation Service, San Camillo-Forlanini Hospital, 00152 Rome, Italy
| | - Giovanni Moschetta
- Department of General and Hepatobiliary and Pancreatic Surgery, Liver Transplantation Service, San Camillo-Forlanini Hospital, 00152 Rome, Italy
| | - Giuseppe Maria Ettorre
- Department of General and Hepatobiliary and Pancreatic Surgery, Liver Transplantation Service, San Camillo-Forlanini Hospital, 00152 Rome, Italy
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21
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Keltner SJ, Hallemeier C, Wang K, Tao R, Shah S, Heimbach J, Kharofa JR. Neoadjuvant Therapy Regimens for Hilar Cholangiocarcinoma Before Liver Transplant. Am J Clin Oncol 2023; 46:276-278. [PMID: 37036238 DOI: 10.1097/coc.0000000000001002] [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: 04/11/2023]
Abstract
OBJECTIVES Patients with unresectable hilar cholangiocarcinoma (hCCA) may be eligible for curative treatment through liver transplantation (LT). Neoadjuvant protocols often include radiotherapy (RT), however, there is no standard RT approach. The purpose of this study is to characterize practice patterns of RT use before transplantation for hCCA. METHODS A survey was administered to radiation oncologists practicing at LT centers identified through the U.S. Organ Procurement and Transplant Network and the International Cholangiocarcinoma Research Network. The survey consisted of 13 questions regarding RT details as well as approaches to systemic therapy. For cross-regimen comparison, the cumulative RT tumor dose was standardized using the EQD2 method. RESULTS Twenty-three centers utilizing neoadjuvant therapy for hCCA were identified. Most respondents (96%) use both chemotherapy and RT as part of their protocol. Elective nodal volumes commonly included the portal vein lymph nodes (91%) and celiac artery lymph nodes (70%). After an initial 45 Gy plan, a wide range of sequential boost regimens was used. The median cumulative dose including boosts to the gross disease was 58 Gy (EQD2) with a wide range of 40 to 110 Gy. Five (22%) include brachytherapy as part of their treatment plan. The majority (96%) used concurrent chemotherapy with fluoropyrimidines. CONCLUSIONS These results suggest significant variability of neoadjuvant RT use for hCCA before LT. A wide range of doses and fractionation schemes are utilized with cumulative doses ranging from 40 to 110 Gy (EQD2). A further study evaluating the efficacy and toxicity of these various approaches is warranted to better inform best practices.
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Affiliation(s)
| | | | - Kyle Wang
- University of Cincinnati Cancer Center
| | - Randa Tao
- University of Utah Huntsman Cancer Institute, Salt Lake City, UT
| | - Shimul Shah
- University of Cincinnati Medical Center/College of Medicine, Cincinnati, OH
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22
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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: 12] [Impact Index Per Article: 6.0] [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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23
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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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24
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Tchelebi LT, Jethwa KR, Levy AT, Anker CJ, Kennedy T, Grodstein E, Hallemeier CL, Jabbour SK, Kim E, Kumar R, Lee P, Small W, Williams VM, Sharma N, Russo S. American Radium Society (ARS) Appropriate Use Criteria (AUC) for Extrahepatic Cholangiocarcinoma. Am J Clin Oncol 2023; 46:73-84. [PMID: 36534388 PMCID: PMC9855763 DOI: 10.1097/coc.0000000000000969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Although uncommon, extrahepatic cholangiocarcinoma (EHCC) is a deadly malignancy, and the treatment approaches remain controversial. While surgery remains the only cure, few patients are candidates for resection up front, and there are high rates of both local and distant failure following resection. Herein, we systematically review the available evidence regarding treatment approaches for patients with EHCC, including surgery, radiation, and chemotherapy. The evidence regarding treatment outcomes was assessed using the Population, Intervention, Comparator, Outcome, and Study design (PICOS) framework. A summary of recommendations based on the available literature is outlined for specific clinical scenarios encountered by providers in the clinic to guide the management of these patients.
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Affiliation(s)
| | - Krishan R. Jethwa
- Department of Radiation Oncology, Mayo Clinic College of Medicine, Rochester, MN
| | | | - Christopher J. Anker
- Division of Radiation Oncology, University of Vermont Larner College of Medicine, Burlington, VT
| | - Timothy Kennedy
- Department of Surgery, Rutgers Cancer Institute, New Brunswick, NJ
| | - Elliot Grodstein
- Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead
| | | | - Salma K. Jabbour
- Department of Radiation Oncology, Rutgers Cancer Institute, New Brunswick, NJ
| | - Ed Kim
- Department of Radiation Oncology, University of Washington, Seattle, WA
| | - Rachit Kumar
- Department of Radiation Oncology, Banner MD Anderson Cancer Center, Phoenix, AZ
| | - Percy Lee
- Department of Radiation Oncology, City of Hope National Medical Center, Los Angeles, CA
| | - William Small
- Department of Radiation Oncology, Loyola University Stritch School of Medicine, Maywood, IL
| | | | - Navesh Sharma
- Department of Radiation Oncology, WellSpan Cancer Center, York, PA
| | - Suzanne Russo
- Department of Radiation Oncology, University Hospitals Cleveland, Case Western Reserve University School of Medicine, Cleveland, OH
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25
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Bowlus CL, Arrivé L, Bergquist A, Deneau M, Forman L, Ilyas SI, Lunsford KE, Martinez M, Sapisochin G, Shroff R, Tabibian JH, Assis DN. AASLD practice guidance on primary sclerosing cholangitis and cholangiocarcinoma. Hepatology 2023; 77:659-702. [PMID: 36083140 DOI: 10.1002/hep.32771] [Citation(s) in RCA: 124] [Impact Index Per Article: 62.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 07/26/2022] [Indexed: 01/28/2023]
Affiliation(s)
- Christopher L Bowlus
- Division of Gastroenterology , University of California Davis Health , Sacramento , California , USA
| | | | - Annika Bergquist
- Karolinska Institutet , Karolinska University Hospital , Stockholm , Sweden
| | - Mark Deneau
- University of Utah , Salt Lake City , Utah , USA
| | - Lisa Forman
- University of Colorado , Aurora , Colorado , USA
| | - Sumera I Ilyas
- Mayo Clinic College of Medicine and Science , Rochester , Minnesota , USA
| | - Keri E Lunsford
- Rutgers University-New Jersey Medical School , Newark , New Jersey , USA
| | - Mercedes Martinez
- Vagelos College of Physicians and Surgeons , Columbia University , New York , New York , USA
| | | | | | - James H Tabibian
- David Geffen School of Medicine at UCLA , Los Angeles , California , USA
| | - David N Assis
- Yale School of Medicine , New Haven , Connecticut , USA
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26
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Shah T, Manas DM, Ford SJ, Dasari BVM, Gibbs P, Venkataraman H, Moore J, Hughes S, Elshafie M, Karkhanis S, Smith S, Hoti E, O'Toole D, Caplin ME, Isaac J, Mazzafero V, Thorburn D. Where Are We Now with Liver Transplantation in Neuroendocrine Neoplasms? The Place of Liver Transplantation for Grades 1 and 2 Well-Differentiated Unresectable Liver Metastatic Neuroendocrine Tumours. Curr Oncol Rep 2023; 25:135-144. [PMID: 36648705 DOI: 10.1007/s11912-022-01343-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/15/2022] [Indexed: 01/18/2023]
Abstract
PURPOSE OF REVIEW This review outlines the role of liver transplantation in selected patients with unresectable neuroendocrine tumour liver metastases. It discusses the international consensus on eligibility criteria and outlines the efforts taking place in the UK and Ireland to develop effective national liver transplant programmes for neuroendocrine tumour patients. RECENT FINDINGS In the early history of liver transplantation, indications included cancer metastases to the liver as well as primaries of liver origin. Often, liver transplantation was a salvage procedure. The early results were disappointing, including in patients with neuroendocrine tumours. These data discouraged the widespread adoption of liver transplantation for neuroendocrine tumour liver metastases (NET LM). A few centres persisted in performing liver transplantation for patients with NET LM and in determining parameters predictive of good outcomes. Their work has provided evidence for benefit of liver transplantation in a selected group of patients with NET LM. Liver transplantation for NET LM is now accepted as a valid indication by many professional bodies, including the European Neuroendocrine Tumour Society (ENETS) and the United Network for Organ Sharing (UNOS). It is nevertheless rarely utilised. The UK and the Republic of Ireland are commencing a pilot programme of liver transplantation in selected patients. This programme will help develop the expertise and infrastructure to make liver transplantation for NET LM a routine procedure.
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Affiliation(s)
- Tahir Shah
- Queen Elizabeth Hospital Birmingham, Birmingham, UK.
| | | | | | | | | | | | | | - Simon Hughes
- Queen Elizabeth Hospital Birmingham, Birmingham, UK
| | | | | | - Stacey Smith
- Queen Elizabeth Hospital Birmingham, Birmingham, UK
| | - Emir Hoti
- St Vincent's University Hospital, Dublin, UK
| | | | | | - John Isaac
- Queen Elizabeth Hospital Birmingham, Birmingham, UK
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27
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Cremen S, Kelly ME, Gallagher TK. The role of neo-adjuvant therapy in cholangiocarcinoma: A systematic review. Front Oncol 2022; 12:975136. [PMID: 36568243 PMCID: PMC9779982 DOI: 10.3389/fonc.2022.975136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 11/17/2022] [Indexed: 12/13/2022] Open
Abstract
Introduction Cholangiocarcinoma (CCA) is the most common malignancy affecting the biliary tree. The only curative treatment is surgical resection, aiming for negative margins (R0). For those who have locally advanced disease, which is borderline resectable, neoadjuvant chemoradiation presents an opportunity to reduce tumour size and allow for surgical resection. The aim of this review is to establish the role of neoadjuvant therapy in each subtype of CCA and establish its impact on survival. Methods Search terms such as 'neoadjuvant therapy' and 'cholangiocarcinoma' were searched on multiple databases, including Pubmed, Ovid and Embase. They were then reviewed separately by two reviewers for inclusion criteria. 978 studies were initially identified from the search strategy, with 21 being included in this review. Results 5,009 patients were included across 21 studies. 1,173 underwent neoadjuvant therapy, 3,818 had surgical resection alone. 359 patients received Gemcitabine based regimes, making it the most commonly utilised regimen for patients CCA and Biliary Tract Cancer (BTC). Data on tolerability of regimes was limited. All included papers were found to have low risk of bias when assessed using The Newcastle Ottawa Scale. Patients who underwent neoadjuvant therapy had a similar median overall survival compared to those who underwent upfront surgery (38.4 versus 35.1 months respectively). Pre-operative CA19-9, microvascular invasion, perineurial invasion and positive lymph nodes were of prognostic significance across BTC and CCA subtypes. Conclusion Neoadjuvant therapy and surgical resection is associated with improved patient outcomes and longer median overall survival compared to therapy and upfront surgery, however heterogeneity between research papers limited the ability to further analyse the significance of these results. Although initial studies are promising, further research is required in order to define suitable treatment protocols and tolerability of neoadjuvant regimes. Systematic review registration https://www.crd.york.ac.uk/prospero/, identifier CRD42020164781.
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Affiliation(s)
- Sinead Cremen
- Department of Hepatobiliary Surgery, St. Vincent’s University Hospital, Dublin, Ireland
| | - Michael E. Kelly
- Department of Surgery, Tallaght University Hospital, Tallaght, Dublin, Ireland
| | - Tom K. Gallagher
- Department of Hepatobiliary Surgery, St. Vincent’s University Hospital, Dublin, Ireland,*Correspondence: Tom K. Gallagher,
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28
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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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29
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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: 9] [Impact Index Per Article: 3.0] [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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30
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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: 37] [Impact Index Per Article: 12.3] [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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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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Miyagi S, Fujio A, Nakagawa K, Tokodai K, Kashiwadate T, Miyazawa K, Sasaki K, Matsumura M, Nishimaki H, Hibi T, Kamei T, Unno M. A New Strategy of Liver Transplantation for Locally Advanced Unresectable Perihilar Cholangiocarcinoma Using Living Grafts With Simultaneous Resection of Recipients' Hepatic Artery and Portal Vein Without Neoadjuvant Radiation: A Case Report. Transplant Proc 2022; 54:1643-1647. [PMID: 35810018 DOI: 10.1016/j.transproceed.2022.03.054] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 03/13/2022] [Accepted: 03/14/2022] [Indexed: 11/26/2022]
Abstract
BACKGROUND Perihilar cholangiocarcinoma (pCCA) is often unresectable, because it includes crucial blood vessels in portal area. The prognosis of locally advanced unresectable cholangiocarcinomas is extremely poor. Recently, there have been several reports of the prognosis improving drastically with transplantation and combined chemoradiation therapy. However, liver transplantation for pCCA has 2 big problems. The first is that pCCA is located at a lethal position and its progress is sometimes rapid; therefore, the optimal timing of transplantation is sometimes lost. The second is vascular complications associated with neoadjuvant radiation, especially in living donor liver transplantation (LDLT). To overcome these problems, we performed conversion surgery using LDLT with simultaneous resection of the hepatic artery and portal vein, instead of neoadjuvant radiation. Herein, we report our experience of interposition reconstruction. METHODS A 31-year-old man with primary sclerosing cholangitis (PSC) was diagnosed with locally advanced unresectable pCCA. The patient underwent radical chemotherapy (gemcitabine/cisplatin/S-1) and avoided radiation because of PSC. After 6 months, positron emission tomography-computed tomography revealed no lymph node metastasis. There was no time to wait. We immediately performed LDLT with simultaneous resection of hepatic artery and portal vein, and microsurgical reconstruction using auto-vessel grafts. RESULTS The recipient recovered and was discharged 31 days posttransplant. His liver function improved, and he has had no recurrence after LDLT. CONCLUSION LDLT with neoadjuvant radiation is associated with high risk of vascular complications. In some cases, conversion surgery after radical chemotherapy using good timing LDLT without radiation may increase chances of transplantation for locally advanced pCCA.
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Affiliation(s)
- Shigehito Miyagi
- Department of Surgery, Tohoku University Graduate School of Medicine, Seiryo, Sendai, Japan.
| | - Atsushi Fujio
- Department of Surgery, Tohoku University Graduate School of Medicine, Seiryo, Sendai, Japan
| | - Kei Nakagawa
- Department of Surgery, Tohoku University Graduate School of Medicine, Seiryo, Sendai, Japan
| | - Kazuaki Tokodai
- Department of Surgery, Tohoku University Graduate School of Medicine, Seiryo, Sendai, Japan
| | - Toshiaki Kashiwadate
- Department of Surgery, Tohoku University Graduate School of Medicine, Seiryo, Sendai, Japan
| | - Koji Miyazawa
- Department of Surgery, Tohoku University Graduate School of Medicine, Seiryo, Sendai, Japan
| | - Kengo Sasaki
- Department of Surgery, Tohoku University Graduate School of Medicine, Seiryo, Sendai, Japan
| | - Muneyuki Matsumura
- Department of Surgery, Tohoku University Graduate School of Medicine, Seiryo, Sendai, Japan
| | - Hiroyasu Nishimaki
- Department of Surgery, Tohoku University Graduate School of Medicine, Seiryo, Sendai, Japan
| | - Taizo Hibi
- Department of Pediatric Surgery and Transplantation, Kumamoto University School of Medicine, Honjo, Kumamoto, Japan
| | - Takashi Kamei
- Department of Surgery, Tohoku University Graduate School of Medicine, Seiryo, Sendai, Japan
| | - Michiaki Unno
- Department of Surgery, Tohoku University Graduate School of Medicine, Seiryo, Sendai, Japan
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Current Perspectives on the Surgical Management of Perihilar Cholangiocarcinoma. Cancers (Basel) 2022; 14:cancers14092208. [PMID: 35565335 PMCID: PMC9104954 DOI: 10.3390/cancers14092208] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Revised: 04/21/2022] [Accepted: 04/21/2022] [Indexed: 02/08/2023] Open
Abstract
Cholangiocarcinoma (CCA) represents nearly 15% of all primary liver cancers and 2% of all cancer-related deaths worldwide. Perihilar cholangiocarcinoma (pCCA) accounts for 50-60% of all CCA. First described in 1965, pCCAs arise between the second-order bile ducts and the insertion of the cystic duct into the common bile duct. CCA typically has an insidious onset and commonly presents with advanced, unresectable disease. Complete surgical resection is technically challenging, as tumor proximity to the structures of the central liver often necessitates an extended hepatectomy to achieve negative margins. Intraoperative frozen section can aid in assuring negative margins and complete resection. Portal lymphadenectomy provides important prognostic and staging information. In specialized centers, vascular resection and reconstruction can be performed to achieve negative margins in appropriately selected patients. In addition, minimally invasive surgical techniques (e.g., robotic surgery) are safe, feasible, and provide equivalent short-term oncologic outcomes. Neoadjuvant chemoradiation therapy followed by liver transplantation provides a potentially curative option for patients with unresectable disease. New trials are needed to investigate novel chemotherapies, immunotherapies, and targeted therapies to better control systemic disease in the adjuvant setting and, potentially, downstage disease in the neoadjuvant setting.
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34
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Ellis RJ, Soares KC, Jarnagin WR. Preoperative Management of Perihilar Cholangiocarcinoma. Cancers (Basel) 2022; 14:cancers14092119. [PMID: 35565250 PMCID: PMC9104035 DOI: 10.3390/cancers14092119] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 04/19/2022] [Accepted: 04/21/2022] [Indexed: 02/01/2023] Open
Abstract
Perihilar cholangiocarcinoma is a rare hepatobiliary malignancy that requires thoughtful, multidisciplinary evaluation in the preoperative setting to ensure optimal patient outcomes. Comprehensive preoperative imaging, including multiphase CT angiography and some form of cholangiographic assessment, is key to assessing resectability. While many staging systems exist, the Blumgart staging system provides the most useful combination of resectability assessment and prognostic information for use in the preoperative setting. Once resectability is confirmed, volumetric analysis should be performed. Upfront resection without biliary drainage or portal venous embolization may be considered in patients without cholangitis and an estimated functional liver remnant (FLR) > 40%. In patients with FLR < 40%, judicious use of biliary drainage is advised, with the goal of selective biliary drainage of the functional liver remnant. Percutaneous biliary drainage may avoid inadvertent contamination of the contralateral biliary tree and associated infectious complications, though the relative effectiveness of percutaneous and endoscopic techniques is an ongoing area of study and debate. Patients with low FLR also require intervention to induce hypertrophy, most commonly portal venous embolization, in an effort to reduce the rate of postoperative liver failure. Even with extensive preoperative workup, many patients will be found to have metastatic disease at exploration and diagnostic laparoscopy may reduce the rate of non-therapeutic laparotomy. Management of perihilar cholangiocarcinoma continues to evolve, with ongoing efforts to improve preoperative liver hypertrophy and to further define the role of transplantation in disease management.
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Affiliation(s)
- Ryan J. Ellis
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; (R.J.E.); (K.C.S.)
| | - Kevin C. Soares
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; (R.J.E.); (K.C.S.)
- Department of Surgery, Weill Cornell Medical College, New York, NY 10021, USA
| | - William R. Jarnagin
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; (R.J.E.); (K.C.S.)
- Department of Surgery, Weill Cornell Medical College, New York, NY 10021, USA
- Correspondence:
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35
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Wang N, Huang A, Kuang B, Xiao Y, Xiao Y, Ma H. Progress in Radiotherapy for Cholangiocarcinoma. Front Oncol 2022; 12:868034. [PMID: 35515132 PMCID: PMC9063097 DOI: 10.3389/fonc.2022.868034] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 03/23/2022] [Indexed: 12/30/2022] Open
Abstract
Cholangiocarcinoma (CCA) originates from the epithelium of the bile duct and is highly malignant with a poor prognosis. Radical resection is the only treatment option to completely cure primary CCA. Due to the insidious onset of CCA, most patients are already in an advanced stage at the time of the initial diagnosis and may lose the chance of radical surgery. Radiotherapy is an important method of local treatment, which plays a crucial role in preoperative neoadjuvant therapy, postoperative adjuvant therapy, and palliative treatment of locally advanced lesions. However, there is still no unified and clear recommendation on the timing, delineating the range of target area, and the radiotherapy dose for CCA. This article reviews recent clinical studies on CCA, including the timing of radiotherapy, delineation of the target area, and dose of radiotherapy. Further, we summarize large fraction radiotherapy (stereotactic body radiotherapy [SBRT]; proton therapy) in CCA and the development of immunotherapy and the use of targeted drugs combined with radiotherapy.
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Affiliation(s)
- Ningyu Wang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ai Huang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bohua Kuang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yu Xiao
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yong Xiao
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Hong Ma, ; Yong Xiao,
| | - Hong Ma
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Hong Ma, ; Yong Xiao,
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Ahmed O, Vachharajani N, Chang SH, Park Y, Khan AS, Chapman WC, Doyle MBM. Single-center experience of liver transplantation for perihilar cholangiocarcinoma. HPB (Oxford) 2022; 24:461-469. [PMID: 34465528 DOI: 10.1016/j.hpb.2021.08.940] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 06/15/2021] [Accepted: 08/09/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Traditionally, curative resection was considered the cornerstone of treatment for perihilar cholangiocarcinoma. More recently, liver transplantation (LT) offered an alternative for patients with unresectable disease. The purpose of this study was to assess our experience with perihilar cholangiocarcinoma and LT. METHODS A perihilar cholangiocarcinoma protocol was commenced in 2006 whereby diagnosed patients were enrolled onto an institutional registry for LT consideration. Data on patient progression and oncologic outcomes were assessed. RESULTS Fifty-eight patients were initially enrolled onto the protocol and 38 proceeded to LT following neoadjuvant chemoradiation (mean age 55.6 ± 11.4 years). Mean time to LT was 3.7 ± 2 months and, among those transplanted, 14 (37%) had underlying primary sclerosing cholangitis (PSC). Thirteen (34%) patients developed malignant recurrence and there were no differences in disease recurrence between PSC (n = 3) and non-PSC (n = 10) patients (p = 0.32). Overall patient survival was 91%, 58% and 52% at 1-, 3- and 5-years corresponding with 81%, 52% and 46% graft survival, respectively. CONCLUSION Rigorous patient selection and chemoradiation treatment algorithms can be highly effective in treating perihilar cholangiocarcinoma. For appropriately selected candidates, LT can provide a 52% 5-year survival for patients who would otherwise have no surgical treatment option.
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Affiliation(s)
- Ola Ahmed
- Department of Abdominal Organ Transplantation Surgery, Washington University School of Medicine, St Louis, MO, USA
| | - Neeta Vachharajani
- Department of Abdominal Organ Transplantation Surgery, Washington University School of Medicine, St Louis, MO, USA
| | - Su-Hsin Chang
- Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA
| | - Yikyung Park
- Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA
| | - Adeel S Khan
- Department of Abdominal Organ Transplantation Surgery, Washington University School of Medicine, St Louis, MO, USA
| | - William C Chapman
- Department of Abdominal Organ Transplantation Surgery, Washington University School of Medicine, St Louis, MO, USA
| | - M B M Doyle
- Department of Abdominal Organ Transplantation Surgery, Washington University School of Medicine, St Louis, MO, USA.
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37
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Ito T, Butler JR, Noguchi D, Ha M, Aziz A, Agopian VG, DiNorcia J, Yersiz H, Farmer DG, Busuttil RW, Hong JC, Kaldas FM. A 3-Decade, Single-Center Experience of Liver Transplantation for Cholangiocarcinoma: Impact of Era, Tumor Size, Location, and Neoadjuvant Therapy. Liver Transpl 2022; 28:386-396. [PMID: 34482610 DOI: 10.1002/lt.26285] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 08/14/2021] [Accepted: 08/18/2021] [Indexed: 12/13/2022]
Abstract
Liver transplantation (LT) for cholangiocarcinoma (CCA) remains limited to a small number of centers. Although the role of neoadjuvant therapy (NAT) has been explored over time, an in-depth analysis of NAT strategies remains limited. Furthermore, controversy exists regarding acceptable tumor size during patient selection for LT. This study explores the impact of era, tumor size, and NAT strategy on LT outcomes for CCA. We conducted a retrospective review of 53 patients with CCA treated with LT from 1985 to 2019; 19 hilar CCA (hCCA) and 30 intrahepatic CCA (iCCA) were included. The relative contributions of varying NAT (neoadjuvant chemotherapy [NAC], neoadjuvant local therapy [NALT], and combined NAC and NALT [NACLT]) as well as the implication of tumor size and era were analyzed. The primary endpoint was overall survival (OS). Compared with the old era (1985-2007), 5-year OS in patients who underwent LT in the recent era (2008-2019) showed a superior trend. The 5-year OS from initial treatment in patients receiving NACLT for hCCA and iCCA were 88% and 100% versus 9% and 41% in patients without it, respectively (P = 0.01 for hCCA; P = 0.02 for iCCA), whereas NAC or NALT alone did not show significant differences in OS versus no NAT (P > 0.05). Although 33 patients had large-size tumors (hCCA ≥ 30 mm, n = 12, or iCCA ≥ 50 mm, n = 21), tumor size had no impact on survival outcomes. Outcomes of LT for CCA seem to have improved over time. Multimodal NAT is associated with improved survival in LT for both iCCA and hCCA regardless of tumor size.
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Affiliation(s)
- Takahiro Ito
- The UCLA Division of Liver and Pancreas Transplantation, Department of Surgery, University of California Los Angeles, Los Angeles, CA
| | - James R Butler
- The UCLA Division of Liver and Pancreas Transplantation, Department of Surgery, University of California Los Angeles, Los Angeles, CA
| | - Daisuke Noguchi
- The UCLA Division of Liver and Pancreas Transplantation, Department of Surgery, University of California Los Angeles, Los Angeles, CA
| | - Minah Ha
- The UCLA Division of Liver and Pancreas Transplantation, Department of Surgery, University of California Los Angeles, Los Angeles, CA
| | - Antony Aziz
- The UCLA Division of Liver and Pancreas Transplantation, Department of Surgery, University of California Los Angeles, Los Angeles, CA
| | - Vatche G Agopian
- The UCLA Division of Liver and Pancreas Transplantation, Department of Surgery, University of California Los Angeles, Los Angeles, CA
| | - Joseph DiNorcia
- The UCLA Division of Liver and Pancreas Transplantation, Department of Surgery, University of California Los Angeles, Los Angeles, CA
| | - Hasan Yersiz
- The UCLA Division of Liver and Pancreas Transplantation, Department of Surgery, University of California Los Angeles, Los Angeles, CA
| | - Douglas G Farmer
- The UCLA Division of Liver and Pancreas Transplantation, Department of Surgery, University of California Los Angeles, Los Angeles, CA
| | - Ronald W Busuttil
- The UCLA Division of Liver and Pancreas Transplantation, Department of Surgery, University of California Los Angeles, Los Angeles, CA
| | - Johnny C Hong
- Division of Transplant Surgery, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI
| | - Fady M Kaldas
- The UCLA Division of Liver and Pancreas Transplantation, Department of Surgery, University of California Los Angeles, Los Angeles, CA
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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: 2] [Impact Index Per Article: 0.7] [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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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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40
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Manzia TM, Parente A, Lenci I, Sensi B, Milana M, Gazia C, Signorello A, Angelico R, Grassi G, Tisone G, Baiocchi L. Moving forward in the treatment of cholangiocarcinoma. World J Gastrointest Oncol 2021; 13:1939-1955. [PMID: 35070034 PMCID: PMC8713313 DOI: 10.4251/wjgo.v13.i12.1939] [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: 03/16/2021] [Revised: 05/14/2021] [Accepted: 10/14/2021] [Indexed: 02/06/2023] Open
Abstract
Despite being the second most frequent primary liver tumor in humans, early diagnosis and treatment of cholangiocarcinoma (CCA) are still unsatisfactory. In fact, survival after 5 years is expected in less than one fourth of patients diagnosed with this disease. Rare incidence, late appearance of symptoms and heterogeneous biology are all factors contributing to our limited knowledge of this cancer and determining its poor prognosis in the clinical setting. Several efforts have been made in the last decades in order to achieve an improved classification/understanding with regard to the diverse CCA forms. Location within the biliary tree has helped to distinguish between intrahepatic, perihilar and distal CCA types. Sequence analysis contributed to identifying several characteristic genetic aberrations in CCA that may also serve as possible targets for therapy. Novel findings are expected to significantly improve the management of this malignancy in the near future. In this changing scenario our review focuses on the current and future strategies for CCA treatment. Both systemic and surgical treatments are discussed in detail. The results of the main studies in this field are reported, together with the ongoing trials. The current findings suggest that an integrated multidisciplinary approach to this malignancy would be helpful to improve its outcome.
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Affiliation(s)
- Tommaso M Manzia
- Hepato-Pancreato-Biliary and Transplant, Department of Surgery, University of Rome Tor Vergata, Rome 00133, Italy
| | - Alessandro Parente
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham B15 2TH, United Kingdom
| | - Ilaria Lenci
- Hepatology Unit, University of Tor Vergata, Rome 00133, Italy
| | - Bruno Sensi
- Hepato-Pancreato-Biliary and Transplant, Department of Surgery, University of Rome Tor Vergata, Rome 00133, Italy
| | - Martina Milana
- Hepatology Unit, University of Tor Vergata, Rome 00133, Italy
| | - Carlo Gazia
- Hepato-Pancreato-Biliary and Transplant, Department of Surgery, University of Rome Tor Vergata, Rome 00133, Italy
| | | | - Roberta Angelico
- Hepato-Pancreato-Biliary and Transplant, Department of Surgery, University of Rome Tor Vergata, Rome 00133, Italy
| | - Giuseppe Grassi
- Hepatology Unit, University of Tor Vergata, Rome 00133, Italy
| | - Giuseppe Tisone
- Hepato-Pancreato-Biliary and Transplant, Department of Surgery, University of Rome Tor Vergata, Rome 00133, Italy
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41
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Nakamura T, Shirouzu T. Antibody-Mediated Rejection and Recurrent Primary Disease: Two Main Obstacles in Abdominal Kidney, Liver, and Pancreas Transplants. J Clin Med 2021; 10:5417. [PMID: 34830699 PMCID: PMC8619797 DOI: 10.3390/jcm10225417] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Revised: 11/17/2021] [Accepted: 11/18/2021] [Indexed: 02/08/2023] Open
Abstract
The advances in acute phase care have firmly established the practice of organ transplantation in the last several decades. Then, the next issues that loom large in the field of transplantation include antibody-mediated rejection (ABMR) and recurrent primary disease. Acute ABMR is a daunting hurdle in the performance of organ transplantation. The recent progress in desensitization and preoperative monitoring of donor-specific antibodies enables us to increase positive outcomes. However, chronic active ABMR is one of the most significant problems we currently face. On the other hand, recurrent primary disease is problematic for many recipients. Notably, some recipients, unfortunately, lost their vital organs due to this recurrence. Although some progress has been achieved in these two areas, many other factors remain largely obscure. In this review, these two topics will be discussed in light of recent discoveries.
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Affiliation(s)
- Tsukasa Nakamura
- Department of Organ Transplantation and General Surgery, Kyoto Prefectural University of Medicine, Kajii-cho 465, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Takayuki Shirouzu
- Molecular Diagnositcs Division, Wakunaga Pharmaceutical Co., Ltd., 13-4 Arakicho, shinjyuku-ku, Tokyo 160-0007, Japan;
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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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43
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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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Liver Transplantation for Cholangiocarcinoma: Charting a Path With Lessons Learned From Center Experience. Transplant Direct 2021; 7:e686. [PMID: 34549084 PMCID: PMC8440016 DOI: 10.1097/txd.0000000000001133] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 01/15/2021] [Indexed: 01/06/2023] Open
Abstract
Supplemental Digital Content is available in the text. Background. While liver transplantation (LT) with neoadjuvant chemoradiation is increasingly utilized for the management of unresectable cholangiocarcinoma (CCA), data on post-LT survival are limited. Methods. We identified 844 patients who underwent LT (2002–2019) for nonincidental (CCA listing) or incidental (CCA on explant, not at listing) CCA in the Scientific Registry of Transplant Recipients. Kaplan–Meier and multivariable proportional hazards regression methods evaluated the effects of patient characteristics, donor type, transplant era (before/after 2010), and center volume (center-level CCALTs/active year) on the risk of graft failure and patient mortality. Results. One center performed >12 CCALTs/y, and the rest performed ≤4. Five-year graft survival was 50.6%. Multivariable models demonstrated laboratory model of end-stage liver disease ≥40 versus <15 and center volumes of 1, >1 to ≤2, and >2 to ≤4 CCALTs/y compared to >12 were associated with increased risk of graft failure and mortality (all P ≤ 0.002). Extra vessel use was associated with center volume. Among all recipients, extra vessel use occurred in 55.4% of CCALTs performed at the highest volume center and in 14.0% of cases at centers having ≤4 CCAs/y (P < 0.05). Conclusions. Center volume-related differences in outcomes and extra vessel use highlight the importance of establishing a unified, effective treatment protocol and the potential utility of regionalization of LT for CCA.
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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: 18] [Impact Index Per Article: 4.5] [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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46
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Lang SA, Bednarsch J, Czigany Z, Joechle K, Kroh A, Amygdalos I, Strnad P, Bruns T, Heise D, Ulmer F, Neumann UP. Liver transplantation in malignant disease. World J Clin Oncol 2021; 12:623-645. [PMID: 34513597 PMCID: PMC8394155 DOI: 10.5306/wjco.v12.i8.623] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 06/15/2021] [Accepted: 07/23/2021] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation for malignant disease has gained increasing attention as part of transplant oncology. Following the implementation of the Milan criteria, hepatocellular carcinoma (HCC) was the first generally accepted indication for transplantation in patients with cancer. Subsequently, more liberal criteria for HCC have been developed, and research on this topic is still ongoing. The evident success of liver transplantation for HCC has led to the attempt to extend its indication to other malignancies. Regarding perihilar cholangiocarcinoma, more and more evidence supports the use of liver transplantation, especially after neoadjuvant therapy. In addition, some data also show a benefit for selected patients with very early stage intrahepatic cholangiocarcinoma. Hepatic epithelioid hemangioendothelioma is a very rare but nonetheless established indication for liver transplantation in primary liver cancer. In contrast, patients with hepatic angiosarcoma are currently not considered to be optimal candidates. In secondary liver tumors, neuroendocrine cancer liver metastases are an accepted but comparability rare indication for liver transplantation. Recently, some evidence has been published supporting the use of liver transplantation even for colorectal liver metastases. This review summarizes the current evidence for liver transplantation for primary and secondary liver cancer.
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Affiliation(s)
- Sven Arke Lang
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Jan Bednarsch
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Zoltan Czigany
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Katharina Joechle
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Andreas Kroh
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Iakovos Amygdalos
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Pavel Strnad
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Tony Bruns
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Daniel Heise
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Florian Ulmer
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Ulf Peter Neumann
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
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Current Surgical Management of Peri-Hilar and Intra-Hepatic Cholangiocarcinoma. Cancers (Basel) 2021; 13:cancers13153657. [PMID: 34359560 PMCID: PMC8345178 DOI: 10.3390/cancers13153657] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 07/06/2021] [Accepted: 07/19/2021] [Indexed: 01/17/2023] Open
Abstract
Cholangiocarcinoma accounts for approximately 10% of all hepatobiliary tumors and represents 3% of all new-diagnosed malignancies worldwide. Intrahepatic cholangiocarcinoma (i-CCA) accounts for 10% of all cases, perihilar (h-CCA) cholangiocarcinoma represents two-thirds of the cases, while distal cholangiocarcinoma accounts for the remaining quarter. Originally described by Klatskin in 1965, h-CCA represents one of the most challenging tumors for hepatobiliary surgeons, mainly because of the anatomical vascular relationships of the biliary confluence at the hepatic hilum. Surgery is the only curative option, with the goal of a radical, margin-negative (R0) tumor resection. Continuous efforts have been made by hepatobiliary surgeons in order to achieve R0 resections, leading to the progressive development of aggressive approaches that include extended hepatectomies, associating liver partition, and portal vein ligation for staged hepatectomy, pre-operative portal vein embolization, and vascular resections. i-CCA is an aggressive biliary cancer that arises from the biliary epithelium proximal to the second-degree bile ducts. The incidence of i-CCA is dramatically increasing worldwide, and surgical resection is the only potentially curative therapy. An aggressive surgical approach, including extended liver resection and vascular reconstruction, and a greater application of systemic therapy and locoregional treatments could lead to an increase in the resection rate and the overall survival in selected i-CCA patients. Improvements achieved over the last two decades and the encouraging results recently reported have led to liver transplantation now being considered an appropriate indication for CCA patients.
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48
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Comment on "Meta-analysis and Meta-regression of Survival after Liver Transplantation for Unresectable Perihilar Cholangiocarcinoma". Ann Surg 2021; 274:e920-e921. [PMID: 34171876 DOI: 10.1097/sla.0000000000005016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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49
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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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50
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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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