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Ciria R, Ivanics T, Aliseda D, Claasen M, Alconchel F, Gaviria F, Briceño J, Berardi G, Rotellar F, Sapisochin G. Liver transplantation for primary and secondary liver tumors: Patient-level meta-analyses compared to UNOS conventional indications. Hepatology 2025; 81:1700-1713. [PMID: 39465987 DOI: 10.1097/hep.0000000000001129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Accepted: 08/26/2024] [Indexed: 10/29/2024]
Abstract
BACKGROUND AND AIMS Liver transplant (LT) for transplant oncology (TO) indications is being slowly adopted worldwide and has been recommended to be incorporated cautiously due to concerns about mid-long-term survival and its impact on the waiting list. APPROACH AND RESULTS We conducted 4 systematic reviews of all series on TO indications (intrahepatic cholangiocarcinoma and perihilar cholangiocarcinoma [phCC]) and liver metastases from neuroendocrine tumors (NETs) and colorectal cancer (CRLM) and compared them using patient-level meta-analyses to data obtained from the United Network for Organ Sharing (UNOS) database considering conventional daily-practice indications. Secondary analyses were done for specific selection criteria (Mayo-like protocols for phCC, SECA-2 for CRLM, and Milan criteria for NET). A total of 112,014 LT were analyzed from 2005 to 2020 from the UNOS databases and compared with 345, 721, 494, and 103 patients obtained from meta-analyses on intrahepatic cholangiocarcinoma and phCC, and liver metastases from NET and CRLM, respectively. Five-year overall survival was 53.3%, 56.4%, 68.6%, and 53.8%, respectively. In Mantel-Cox one-to-one comparisons, survival of TO indications was superior to combined LT, second, and third LT and not statistically significantly different from LT in recipients >70 years and high BMI. CONCLUSIONS Liver transplantation for TO indications has adequate 5-year survival rates, mostly when performed under the selection criteria available in the literature (Mayo-like protocols for phCC, SECA-2 for CRLM, and Milan for NET). Despite concerns about its impact on the waiting list, some other LT indications are being performed with lower survival rates. These oncological patients should be given the opportunity to have a definitive curative therapy within validated criteria.
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Affiliation(s)
- Ruben Ciria
- Unit of Hepatobiliary Surgery and Liver Transplantation, University Hospital Reina Sofia, University of Cordoba, IMIBIC, Cordoba, Spain
- Unit of Hepatobiliary Surgery, Hospital Quiron Salud, Cordoba, Spain
| | - Tommy Ivanics
- Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
- Department of Surgery, Henry Ford Hospital, Detroit, Michigan, USA
- Department of Surgical Sciences, Uppsala University, Akademiska Sjukhuset, Uppsala, Sweden
| | - Daniel Aliseda
- Hepatobiliary Surgery and Liver Transplant Unit, Clinica Universidad de Navarra, Pamplona, Spain
- Institute of Health Research of Navarra (IdisNA), Pamplona, Spain
| | - Marco Claasen
- Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
- Department of Surgery, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Felipe Alconchel
- Unit of Hepatobiliary Surgery and Liver Transplantation, Hospital Clínico Universitario Virgen Arrixaca, University of Medicine, IMIB-Pascual Parrilla, Murcia, Spain
| | - Felipe Gaviria
- Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
- Division of General Surgery, University of Toronto, Toronto, Ontario, Canada
| | - Javier Briceño
- Unit of Hepatobiliary Surgery and Liver Transplantation, University Hospital Reina Sofia, University of Cordoba, IMIBIC, Cordoba, Spain
| | - Giammauro Berardi
- General Surgery and Organ Transplantation Unit, San Camillo-Forlanini Hospital, Rome, Italy
| | - Fernando Rotellar
- Hepatobiliary Surgery and Liver Transplant Unit, Clinica Universidad de Navarra, Pamplona, Spain
- Institute of Health Research of Navarra (IdisNA), Pamplona, Spain
| | - Gonzalo Sapisochin
- Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
- Division of General Surgery, University of Toronto, Toronto, Ontario, Canada
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Dasari BVM, Line PD, Sapisochin G, Hibi T, Bhangui P, Halazun KJ, Shetty S, Shah T, Magyar CTJ, Donnelly C, Chatterjee D. Liver transplantation as a treatment for cancer: comprehensive review. BJS Open 2025; 9:zraf034. [PMID: 40380811 PMCID: PMC12084677 DOI: 10.1093/bjsopen/zraf034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 01/30/2025] [Accepted: 02/07/2025] [Indexed: 05/19/2025] Open
Abstract
BACKGROUND Liver transplantation for cancer indications has gained momentum in recent years. This review is intended to optimize the care setting of liver transplant candidates by highlighting current indications, technical aspects and barriers with available solutions to facilitate the guidance of available strategies for healthcare professionals in specialized centres. METHODS A review of the most recent relevant literature was conducted for all the cancer indications of liver transplantation including colorectal cancer liver metastases, hilar cholangiocarcinoma, intrahepatic cholangiocarcinoma, neuroendocrine tumours, hepatocellular carcinoma and hepatic epitheloid haemangioendothelioma. RESULTS Transplant benefit from the best available evidence, including SECA I, SECA II, TRANSMET studies for colorectal liver metastases, various preoperative protocols for cholangiocarcinoma patients, standard, extended selection criteria for hepatocellular carcinoma and neuroendocrine tumours, are discussed. Innovative approaches to deal with organ shortages, including machine-perfused deceased grafts, living donor liver transplantation and RAPID procedures, are also explored. CONCLUSION Cancer indications for liver transplantation are here to stay, and the selection criteria among all cancer groups are likely to evolve further with improved prognostication of tumour biology using adjuncts such as radiomics, cancer genomics, and circulating DNA and RNA status. International prospective registry-based studies could overcome the limitations of smaller patient cohorts and lack of level 1 evidence.
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Affiliation(s)
- Bobby V M Dasari
- Department of Liver Transplantation and HBP Surgery, Queen Elizabeth Hospital, Birmingham, UK
- Department of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Pal-Dag Line
- Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
| | - Gonzalo Sapisochin
- Department of Surgery, Multi-Organ Transplant Program, University Health Network, Toronto, Canada
| | - Taizo Hibi
- Department of Pediatric Surgery and Transplantation, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
| | - Prashant Bhangui
- Liver Transplantation and Hepatobiliary Surgery, Medanta Institute of Liver Transplantation and Regenerative Medicine, Medanta-The Medicity, Gurgaon (Delhi NCR), India
| | - Karim J Halazun
- Department of Liver Transplantation and Hepatobiliary Surgery, NYU Grossman School of Medicine, NYU Langone Health, New York, USA
| | - Shishir Shetty
- Department of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
- Department of Hepatology, Queen Elizabeth Hospital, Birmingham, UK
| | - Tahir Shah
- Department of Hepatology, Queen Elizabeth Hospital, Birmingham, UK
| | - Christian T J Magyar
- Department of Abdominal Transplant & HBP Surgical Oncology, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Canada
| | - Conor Donnelly
- Department of Liver Transplantation and Hepatobiliary Surgery, NYU Grossman School of Medicine, NYU Langone Health, New York, USA
| | - Dev Chatterjee
- BRC Clinical Fellow Liver Medicine, University Hospitals of Birmingham, Birmingham, UK
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Ito T, Taura K, Fukumitsu K, Okumura S, Ogiso S, Anazawa T, Nagai K, Uchida Y, Ishii T, Hatano E. Safety and efficacy of living donor liver transplantation for unresectable perihilar cholangiocarcinoma: A single center prospective study. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2025; 32:276-286. [PMID: 39996522 PMCID: PMC12038382 DOI: 10.1002/jhbp.12121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/26/2025]
Abstract
BACKGROUND The prognosis for unresectable perihilar cholangiocarcinoma (phCCA) is extremely poor. Liver transplantation in combination with neoadjuvant chemoradiation therapy has become the treatment of choice for unresectable phCCA in the USA. In 2018, we launched a prospective study to evaluate the safety and efficacy of living donor liver transplantation (LDLT) for unresectable phCCA. METHODS A total of 10 patients were enrolled in this study between 2018 and 2024. Finally, five patients with unresectable phCCA underwent LDLT after neoadjuvant chemotherapy, radiation, and staging laparotomy, while the other five patients dropped out of the protocol. RESULTS The median follow-up period was 23.7 months. The overall survival rate for the five patients who underwent LDLT was 100% after one year. Hepatic artery thrombosis and delayed gastric emptying occurred in two and three cases, respectively. The histological efficacy of preoperative treatment was grade IIb and III, according to the Evans classification, in all five patients. All surgical margins and dissected lymph nodes were negative. Four patients were alive with no evidence of disease recurrence while one patient had recurrence 10 months after LDLT. CONCLUSIONS LDLT is feasible and may be a last-resort treatment option for unresectable phCCA, although the long-term outcomes need to be carefully monitored. CLINICAL TRIAL REGISTER AND CLINICAL REGISTRATION NUMBER The UMIN registration number for this study is 000033348.
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Affiliation(s)
- Takashi Ito
- Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Kojiro Taura
- Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
- Department of Gastroenterological Surgery and OncologyMedical Research Institute, Kitano HospitalOsakaJapan
| | - Ken Fukumitsu
- Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
- Department of SurgeryGastrointestinal Center, Kyoto Katsura HospitalKyotoJapan
| | - Shinya Okumura
- Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Satoshi Ogiso
- Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Takayuki Anazawa
- Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Kazuyuki Nagai
- Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Yoichiro Uchida
- Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Takamichi Ishii
- Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Etsuro Hatano
- Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
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4
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Patrono D, De Stefano N, Romagnoli R. Liver transplantation for tumor entities. Curr Opin Organ Transplant 2024; 29:255-265. [PMID: 38716718 DOI: 10.1097/mot.0000000000001149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/03/2024]
Abstract
PURPOSE OF REVIEW Tumor entities represent an increasing indication for liver transplantation (LT). This review addresses the most contentious indications of LT in transplant oncology. RECENT FINDINGS Patient selection based on tumor biology in LT for colorectal cancer liver metastases (CRLM) demonstrated promising long-term outcomes and preserved quality of life despite high recurrence rates. In selected cases, LT for intrahepatic cholangiocarcinoma (iCCA) is feasible, with acceptable survival even in high-burden cases responsive to chemotherapy. LT following a strict neoadjuvant protocol for perihilar cholangiocarcinoma (pCCA) resulted in long-term outcomes consistently surpassing benchmark values, and potentially outperforming liver resection. SUMMARY While preliminary results are promising, prospective trials are crucial to define applications in routine clinical practice. Molecular profiling and targeted therapies pave the way for personalized approaches, requiring evolving allocation systems for equitable LT access.
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Affiliation(s)
- Damiano Patrono
- General Surgery 2U - Liver Transplant Unit, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino - University of Turin, Turin, Italy
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5
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Verma S, Grindrod N, Breadner D, Lock M. The Current Role of Radiation in the Management of Cholangiocarcinoma-A Narrative Review. Cancers (Basel) 2024; 16:1776. [PMID: 38730728 PMCID: PMC11083065 DOI: 10.3390/cancers16091776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 04/30/2024] [Accepted: 05/01/2024] [Indexed: 05/13/2024] Open
Abstract
Cholangiocarcinoma (CCA) is a rare cancer of bile ducts. It is associated with a poor prognosis. The incidence of CCA is rising worldwide. Anatomical subgroups have been used to classify patients for treatment and prognosis. There is a growing understanding of clinically important distinctions based on underlying genetic differences that lead to different treatment options and outcomes. Its management is further complicated by a heterogeneous population and relative rarity, which limits the conduct of large trials to guide management. Surgery has been the primary method of therapy for localized disease; however, recurrence and death remain high with or without surgery. Therefore, there have been concerted efforts to investigate new treatment options, such as the use of neoadjuvant treatments to optimize surgical outcomes, targeted therapy, leveraging a new understanding of immunobiology and stereotactic radiation. In this narrative review, we address the evidence to improve suboptimal outcomes in unresectable CCA with radiation, as well as the role of radiation in neoadjuvant and postoperative treatment. We also briefly discuss the recent developments in systemic treatment with targeted therapies and immune checkpoint inhibitors.
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Affiliation(s)
- Saurav Verma
- Division of Medical Oncology, Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London, ON N6A 3K7, Canada; (S.V.); (N.G.); (D.B.)
- London Regional Cancer Program, London Health Sciences Centre, London, ON N6A 5W9, Canada
| | - Natalie Grindrod
- Division of Medical Oncology, Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London, ON N6A 3K7, Canada; (S.V.); (N.G.); (D.B.)
- London Regional Cancer Program, London Health Sciences Centre, London, ON N6A 5W9, Canada
| | - Daniel Breadner
- Division of Medical Oncology, Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London, ON N6A 3K7, Canada; (S.V.); (N.G.); (D.B.)
- London Regional Cancer Program, London Health Sciences Centre, London, ON N6A 5W9, Canada
| | - Michael Lock
- Division of Medical Oncology, Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London, ON N6A 3K7, Canada; (S.V.); (N.G.); (D.B.)
- London Regional Cancer Program, London Health Sciences Centre, London, ON N6A 5W9, Canada
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Kim DS, Yoon YI, Kim BK, Choudhury A, Kulkarni A, Park JY, Kim J, Sinn DH, Joo DJ, Choi Y, Lee JH, Choi HJ, Yoon KT, Yim SY, Park CS, Kim DG, Lee HW, Choi WM, Chon YE, Kang WH, Rhu J, Lee JG, Cho Y, Sung PS, Lee HA, Kim JH, Bae SH, Yang JM, Suh KS, Al Mahtab M, Tan SS, Abbas Z, Shresta A, Alam S, Arora A, Kumar A, Rathi P, Bhavani R, Panackel C, Lee KC, Li J, Yu ML, George J, Tanwandee T, Hsieh SY, Yong CC, Rela M, Lin HC, Omata M, Sarin SK. Asian Pacific Association for the Study of the Liver clinical practice guidelines on liver transplantation. Hepatol Int 2024; 18:299-383. [PMID: 38416312 DOI: 10.1007/s12072-023-10629-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 12/18/2023] [Indexed: 02/29/2024]
Abstract
Liver transplantation is a highly complex and challenging field of clinical practice. Although it was originally developed in western countries, it has been further advanced in Asian countries through the use of living donor liver transplantation. This method of transplantation is the only available option in many countries in the Asia-Pacific region due to the lack of deceased organ donation. As a result of this clinical situation, there is a growing need for guidelines that are specific to the Asia-Pacific region. These guidelines provide comprehensive recommendations for evidence-based management throughout the entire process of liver transplantation, covering both deceased and living donor liver transplantation. In addition, the development of these guidelines has been a collaborative effort between medical professionals from various countries in the region. This has allowed for the inclusion of diverse perspectives and experiences, leading to a more comprehensive and effective set of guidelines.
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Affiliation(s)
- Dong-Sik Kim
- Department of Surgery, Korea University College of Medicine, Seoul, Republic of Korea
| | - Young-In Yoon
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | | | | | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jongman Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Dong Hyun Sinn
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Dong Jin Joo
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - YoungRok Choi
- Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jeong-Hoon Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Ho Joong Choi
- Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Ki Tae Yoon
- Department of Internal Medicine, Pusan National University College of Medicine, Yangsan, Republic of Korea
| | - Sun Young Yim
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Cheon-Soo Park
- Department of Surgery, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Deok-Gie Kim
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hae Won Lee
- Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea
| | - Won-Mook Choi
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Young Eun Chon
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
| | - Woo-Hyoung Kang
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jinsoo Rhu
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jae Geun Lee
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yuri Cho
- Center for Liver and Pancreatobiliary Cancer, National Cancer Center, Ilsan, Republic of Korea
| | - Pil Soo Sung
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Han Ah Lee
- Department of Internal Medicine, Ewha Womans University, Seoul, Republic of Korea
| | - Ji Hoon Kim
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Si Hyun Bae
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jin Mo Yang
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
| | - Kyung-Suk Suh
- Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
| | - Mamun Al Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Soek Siam Tan
- Department of Medicine, Hospital Selayang, Batu Caves, Selangor, Malaysia
| | - Zaigham Abbas
- Sindh Institute of Urology and Transplantation, Karachi, Pakistan
| | - Ananta Shresta
- Department of Hepatology, Alka Hospital, Lalitpur, Nepal
| | - Shahinul Alam
- Crescent Gastroliver and General Hospital, Dhaka, Bangladesh
| | - Anil Arora
- Department of Gastroenterology and Hepatology, Sir Ganga Ram Hospital New Delhi, New Delhi, India
| | - Ashish Kumar
- Department of Gastroenterology and Hepatology, Sir Ganga Ram Hospital New Delhi, New Delhi, India
| | - Pravin Rathi
- TN Medical College and BYL Nair Hospital, Mumbai, India
| | - Ruveena Bhavani
- University of Malaya Medical Centre, Petaling Jaya, Selangor, Malaysia
| | | | - Kuei Chuan Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Jun Li
- College of Medicine, Zhejiang University, Hangzhou, China
| | - Ming-Lung Yu
- Department of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | | | | | | | | | | | - H C Lin
- Endoscopy Center for Diagnosis and Treatment, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Masao Omata
- Department of Gastroenterology, Yamanashi Central Hospital, Yamanashi, Japan
- University of Tokyo, Bunkyo City, Japan
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7
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de Jong DM, den Hoed CM, Willemssen FEJA, Thomeer MGJ, Bruno MJ, Koerkamp BG, de Jonge J, Alwayn IPJ, van Hooft JE, Hoogwater F, van der Heide F, Inderson A, van Vilsteren FGI, van Driel LMJW. Impact of EUS in liver transplantation workup for patients with unresectable perihilar cholangiocarcinoma. Gastrointest Endosc 2024; 99:548-556. [PMID: 37890597 DOI: 10.1016/j.gie.2023.10.047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Revised: 09/02/2023] [Accepted: 10/20/2023] [Indexed: 10/29/2023]
Abstract
BACKGROUND AND AIMS For a highly selected group of patients with unresectable perihilar cholangiocarcinoma (pCCA), liver transplantation (LT) is a treatment option. The Dutch screening protocol comprises nonregional lymph node (LN) assessment by EUS, and whenever LN metastases are identified, further LT screening is precluded. The aim of this study is to investigate the yield of EUS in patients with pCCA who are potentially eligible for LT. METHODS In this retrospective, nationwide cohort study, all consecutive patients with suspected unresectable pCCA who underwent EUS in the screening protocol for LT were included from 2011 to 2021. During EUS, sampling of a "suspicious" nonregional LN was performed based on the endoscopist's discretion. The primary outcome was the added value of EUS, defined as the number of patients who were precluded from further screening because of malignant LNs. RESULTS A total of 75 patients were included in whom 84 EUS procedures were performed, with EUS-guided tissue acquisition confirming malignancy in LNs in 3 of 75 (4%) patients. In the 43 who underwent surgical staging according to the protocol, nonregional LNs with malignancy were identified in 6 (14%) patients. Positive regional LNs were found in 7 patients in post-LT-resected specimens. CONCLUSIONS Our current EUS screening for the detection of malignant LNs in patients with pCCA eligible for LT shows a limited but clinically important yield. EUS with systematic screening of all LN stations, both regional and nonregional, and the sampling of suspicious lymph nodes according to defined and set criteria could potentially increase this yield.
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Affiliation(s)
- David M de Jong
- Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute University Medical Center, Rotterdam, The Netherlands
| | - Caroline M den Hoed
- Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute University Medical Center, Rotterdam, The Netherlands; Erasmus MC Transplant Institute, Rotterdam, The Netherlands
| | - Francois E J A Willemssen
- Department of Radiology and Nuclear Medicine, Erasmus MC Cancer Institute University Medical Center, Rotterdam, The Netherlands
| | - Maarten G J Thomeer
- Department of Radiology and Nuclear Medicine, Erasmus MC Cancer Institute University Medical Center, Rotterdam, The Netherlands
| | - Marco J Bruno
- Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute University Medical Center, Rotterdam, The Netherlands
| | - Bas Groot Koerkamp
- Department of Surgery, Erasmus MC Cancer Institute University Medical Center, Rotterdam, The Netherlands
| | - Jeroen de Jonge
- Erasmus MC Transplant Institute, Rotterdam, The Netherlands; Department of Surgery, Erasmus MC Cancer Institute University Medical Center, Rotterdam, The Netherlands
| | - Ian P J Alwayn
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
| | - Jeanin E van Hooft
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Frederik Hoogwater
- Department of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University Medical Center Groningen, Groningen, The Netherlands
| | - Frans van der Heide
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands
| | - Akin Inderson
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Frederike G I van Vilsteren
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands
| | - Lydi M J W van Driel
- Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute University Medical Center, Rotterdam, The Netherlands.
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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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9
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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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Sonnenday CJ. Liver Transplantation for Hilar Cholangiocarcinoma. Surg Clin North Am 2024; 104:183-196. [PMID: 37953035 DOI: 10.1016/j.suc.2023.09.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2023]
Abstract
Hilar cholangiocarcinoma (hCCA) is an infiltrative disease that often presents with locally advanced and/or metastatic disease, with a minority of patients eligible for surgical resection. Select patients with unresectable hCCA, or patients with hCCA in the setting of primary sclerosing cholangitis, with tumors less than 3 cm and no evidence of extrahepatic disease, can be effectively treated with neoadjuvant chemoradiation followed by liver transplantation. Staging laparotomy documenting lack of occult metastatic disease, including a portal lymphadenectomy documenting no nodal metastases, is essential to achieve optimal outcomes. Overall 5 year survival among treated patients is approximately 60%.
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Affiliation(s)
- Christopher J Sonnenday
- Department of Surgery, University of Michigan Health, F6686 UH-South, 1500 East Medical Center Drive, Ann Arbor, MI 48109-5296, USA.
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11
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Prime S, Schiff JP, Hosni A, Stanescu T, Dawson LA, Henke LE. The Use of MR-Guided Radiation Therapy for Liver Cancer. Semin Radiat Oncol 2024; 34:36-44. [PMID: 38105091 DOI: 10.1016/j.semradonc.2023.10.006] [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: 12/19/2023]
Abstract
The role of radiotherapy in the management of primary and metastatic liver malignancies has expanded in recent years due to advances such as IGRT and SBRT. MRI-guided radiotherapy (MRgRT) has arisen as an excellent option for the management of hepatocellular carcinoma, cholangiocarcinoma, and liver metastases due to the ability to combine improved hepatic imaging with conformal treatment planning paradigms like adaptive radiotherapy and advanced motion management techniques. Herein we review the data for MRgRT for liver malignancies, as well as describe workflow and technical considerations for the 2 commercially available MRgRT delivery platforms.
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Affiliation(s)
- Sabrina Prime
- Washington University School of Medicine in St. Louis, Department of Radiation Oncology, St. Louis, MO
| | - Joshua P Schiff
- Washington University School of Medicine in St. Louis, Department of Radiation Oncology, St. Louis, MO
| | - Ali Hosni
- Radiation Medicine Program, Princess Margaret Cancer Centre, Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada
| | - Teodor Stanescu
- Radiation Medicine Program, Princess Margaret Cancer Centre, Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada
| | - Laura A Dawson
- Radiation Medicine Program, Princess Margaret Cancer Centre, Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada
| | - Lauren E Henke
- University Hospitals/Case Western Reserve University, Department of Radiation Oncology, Cleveland, OH.
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12
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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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13
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Giovinazzo F, Pascale MM, Cardella F, Picarelli M, Molica S, Zotta F, Martullo A, Clarke G, Frongillo F, Grieco A, Agnes S. Current Perspectives in Liver Transplantation for Perihilar Cholangiocarcinoma. Curr Oncol 2023; 30:2942-2953. [PMID: 36975438 PMCID: PMC10047046 DOI: 10.3390/curroncol30030225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 01/17/2023] [Accepted: 01/30/2023] [Indexed: 03/05/2023] Open
Abstract
Cholangiocarcinoma (CCA) encompasses all malignant neoplasms arising from the epithelial cells of the biliary tree. About 40% of CCAs are perihilar, involving the bile ducts distal to the second-order biliary branches and proximal to the cystic duct implant. About two-thirds of pCCAs are considered unresectable at the time of diagnosis or exploration. When resective surgery is deemed unfeasible, liver transplantation (LT) could be an effective alternative. The overall survival rates after LT at 1 and 3 years are 91% and 81%, respectively. The overall five-year survival rate after transplantation is 73% (79% for patients with underlying PSC and 63% for de novo pCCA). Multicenter case series reported a 5-year disease-free survival rate of ~65%. However, different protocols, including neoadjuvant therapy, have been proposed. The scarcity of organ availability represents a crucial limiting factor in recommending LT preferentially in treating pCCA. Living donor transplantations and marginal cadaveric allografts have proven to be exciting options to overcome organ shortage. Management of jaundice and cholangitis is still challenging for these patients and could impact LT listing. Whether to adopt surgical resection or LT as standard-of-care in pCCA is still a matter of debate, and more prospective studies are needed.
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Affiliation(s)
- Francesco Giovinazzo
- General Surgery and Liver Transplant Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Marco Maria Pascale
- General Surgery and Liver Transplant Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Francesca Cardella
- Surgical Oncology of Gastrointestinal Tract Unit, Vanvitelli University, 80138 Naples, Italy
| | - Matteo Picarelli
- General Surgery and Liver Transplant Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Serena Molica
- General Surgery and Liver Transplant Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Francesca Zotta
- General Surgery and Liver Transplant Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Annamaria Martullo
- General Surgery and Liver Transplant Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - George Clarke
- Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham B15 2TH, UK
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TH, UK
| | - Francesco Frongillo
- General Surgery and Liver Transplant Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Antonio Grieco
- General Surgery and Liver Transplant Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Department of Medicine and Translational Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Salvatore Agnes
- General Surgery and Liver Transplant Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Department of Medicine and Translational Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
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14
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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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15
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Jiang J, Diaz DA, Nuguru SP, Mittra A, Manne A. Stereotactic Body Radiation Therapy (SBRT) Plus Immune Checkpoint Inhibitors (ICI) in Hepatocellular Carcinoma and Cholangiocarcinoma. Cancers (Basel) 2022; 15:50. [PMID: 36612046 PMCID: PMC9817712 DOI: 10.3390/cancers15010050] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 12/18/2022] [Accepted: 12/20/2022] [Indexed: 12/24/2022] Open
Abstract
The combination of stereotactic body radiation therapy (SBRT) plus immune checkpoint inhibitors (ICI) must be explored to treat advanced primary liver tumors such as hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). Limited retrospective reviews and case reports/series suggest this combination can be effective and safe in both cancer types. With ICIs moving into the first line (IMbrave 150, HIMALAYA, and TOPAZ-1) to manage these cancers, identifying a suitable population for this approach is challenging. Patients with macrovascular invasion (MVI)-positive HCC (especially if larger veins are involved) or recurrent HCCs post-locoregional therapies (such as transarterial radioembolization (TARE), transarterial chemoembolization (TACE), or ablation), as well as those ineligible for bevacizumab or tyrosine kinase inhibitors (TKIs), should be the focus of exploring this combination in HCC. Unresectable or oligometastatic CCA patients who cannot tolerate gemcitabine/cisplatin (GC) or those who progressed on GC without durvalumab and do not have targetable mutations could also be considered for this approach. In both HCC and CCA disease groups, SBRT plus ICI can be examined post-ICI as these two modalities act synergistically to enhance anti-tumor activity (based on pre-clinical studies). Large-scale randomized trials are needed to identify the subsets of primary liver cancers suitable for this approach and to clearly define its clinical benefit.
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Affiliation(s)
- Joanna Jiang
- Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH 43210, USA
| | - Dayssy Alexandra Diaz
- Department of Radiation Oncology, Ohio State University James Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Surya Pratik Nuguru
- School of Medicine, Kamineni Academy of Medical Sciences and Research Center, Hyderabad 500012, India
| | - Arjun Mittra
- Department of Internal Medicine, Division of Medical Oncology at the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Ashish Manne
- Department of Internal Medicine, Division of Medical Oncology at the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
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16
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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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17
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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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18
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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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19
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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: 29] [Impact Index Per Article: 9.7] [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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20
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Zanetto A, Shalaby S, Gambato M, Germani G, Senzolo M, Bizzaro D, Russo FP, Burra P. New Indications for Liver Transplantation. J Clin Med 2021; 10:3867. [PMID: 34501314 PMCID: PMC8432035 DOI: 10.3390/jcm10173867] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 08/20/2021] [Accepted: 08/27/2021] [Indexed: 12/12/2022] Open
Abstract
Liver transplantation (LT) is an important therapeutic option for the treatment of several liver diseases. Modern LT is characterized by remarkable improvements in post-transplant patient survival, graft survival, and quality of life. Thanks to these great improvements, indications for LT are expanding. Nowadays, clinical conditions historically considered exclusion criteria for LT, have been considered new indications for LT, showing survival advantages for patients. In this review, we provide an updated overview of the principal newer indications for LT, with particular attention to alcoholic hepatitis, acute-on-chronic liver failure (ACLF), cholangiocarcinoma and colorectal cancer metastases.
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Affiliation(s)
| | | | | | | | | | | | | | - Patrizia Burra
- Multivisceral Transplant Unit, Department of Surgery Oncology and Gastroenterology, University of Padova, Via Giustiniani 2, 35128 Padova, Italy; (A.Z.); (S.S.); (M.G.); (G.G.); (M.S.); (D.B.); (F.P.R.)
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21
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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: 5] [Impact Index Per Article: 1.3] [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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22
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Baak R, Willemssen FEJA, van Norden Y, Eskens FALM, Milder MTW, Heijmen BJM, Koerkamp BG, Sprengers D, van Driel LMJW, Klümpen HJ, den Toom W, Koedijk MS, IJzermans JNM, Méndez Romero A. Stereotactic Body Radiation Therapy after Chemotherapy for Unresectable Perihilar Cholangiocarcinoma: The STRONG Trial, a Phase I Safety and Feasibility Study. Cancers (Basel) 2021; 13:cancers13163991. [PMID: 34439146 PMCID: PMC8394718 DOI: 10.3390/cancers13163991] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 08/02/2021] [Accepted: 08/02/2021] [Indexed: 12/25/2022] Open
Abstract
Simple Summary The role of radiotherapy in the treatment of perihilar cholangiocarcinoma has not yet been properly defined. In this prospective study, we therefore explored the addition to first-line chemotherapy of stereotactic body radiation therapy (SBRT) delivered in 15 fractions. Patients eligible for the study had been diagnosed with unresectable perihilar cholangiocarcinoma, and then had no progressive disease after completing treatment with 6–8 cycles of cisplatin-gemcitabine. Primary endpoints were feasibility and safety. Secondary endpoints were local control, progression-free survival, overall survival, and quality of life. As each patient completed the SBRT successfully and no dose-limiting toxicity was found, we consider this treatment to be both feasible and safe. The local control rate and overall survival were promising. However, due to the small sample size of this study, we urge the analysis of this treatment in a larger series of patients. Abstract Background: In unresectable pCCA, the standard of care is palliative chemotherapy. We investigated the feasibility and safety of adding stereotactic body radiation therapy (SBRT) after chemotherapy. Methods: Patients with unresectable pCCA, stage T1-T4N0-N1M0, ECOG 0-1, having finished 6–8 cycles of cisplatin and gemcitabine without disease progression were eligible. SBRT was planned in 15 fractions of 3.0–4.5 Gy. The primary endpoints were feasibility (defined as completing SBRT as planned) and toxicity, evaluated within 3 months after SBRT (CTCAE v4.03). A conventional “3 + 3” design was used, corresponding to a sample size of 6 patients. Dose-limiting toxicity (DLT) was defined as grade ≥ 4 hepatobiliary or grade ≥ 3 gastrointestinal toxicity. The secondary endpoints, measured from the start of radiotherapy, were local control, progression-free survival, overall survival, and quality of life (QoL). ClinicalTrials.gov identifier: NCT03307538. Results: Six patients were enrolled between November 2017 and March 2020. SBRT was delivered as planned. All patients were treated with 60Gy (15 × 4.0Gy). No SBRT-related DLT was observed. The most common grade ≥ 3 toxicity was cholangitis (n = 5). The median follow-up was 14 months. The 12-month local control rate was 80%. We observed no substantial changes in QoL. Conclusion: In patients with unresectable pCCA with stable disease after palliative chemotherapy, adding SBRT is feasible and safe. The observed local control merits an additional evaluation of effectiveness.
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Affiliation(s)
- Rogier Baak
- Department of Radiotherapy, Erasmus MC Cancer Institute, 3015 CN Rotterdam, The Netherlands; (Y.v.N.); (M.T.W.M.); (B.J.M.H.); (W.d.T.); (A.M.R.)
- Correspondence:
| | - François E. J. A. Willemssen
- Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center, 3015 CN Rotterdam, The Netherlands;
| | - Yvette van Norden
- Department of Radiotherapy, Erasmus MC Cancer Institute, 3015 CN Rotterdam, The Netherlands; (Y.v.N.); (M.T.W.M.); (B.J.M.H.); (W.d.T.); (A.M.R.)
| | - Ferry A. L. M. Eskens
- Department of Medical Oncology, Erasmus MC Cancer Institute, 3015 CN Rotterdam, The Netherlands;
| | - Maaike T. W. Milder
- Department of Radiotherapy, Erasmus MC Cancer Institute, 3015 CN Rotterdam, The Netherlands; (Y.v.N.); (M.T.W.M.); (B.J.M.H.); (W.d.T.); (A.M.R.)
| | - Ben J. M. Heijmen
- Department of Radiotherapy, Erasmus MC Cancer Institute, 3015 CN Rotterdam, The Netherlands; (Y.v.N.); (M.T.W.M.); (B.J.M.H.); (W.d.T.); (A.M.R.)
| | - Bas Groot Koerkamp
- Department of Surgery, Erasmus MC University Medical Center, 3015 CN Rotterdam, The Netherlands; (B.G.K.); (J.N.M.I.)
| | - Dave Sprengers
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, 3015 CN Rotterdam, The Netherlands; (D.S.); (L.M.J.W.v.D.)
| | - Lydi M. J. W. van Driel
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, 3015 CN Rotterdam, The Netherlands; (D.S.); (L.M.J.W.v.D.)
| | - Heinz-Josef Klümpen
- Department of Medical Oncology, Amsterdam University Medical Centers, University of Amsterdam, 1081 HV Amsterdam, The Netherlands;
| | - Wilhelm den Toom
- Department of Radiotherapy, Erasmus MC Cancer Institute, 3015 CN Rotterdam, The Netherlands; (Y.v.N.); (M.T.W.M.); (B.J.M.H.); (W.d.T.); (A.M.R.)
| | - Merel S. Koedijk
- Radiotherapeutisch Instituut Friesland, 8934 AD Leeuwarden, The Netherlands;
| | - Jan N. M. IJzermans
- Department of Surgery, Erasmus MC University Medical Center, 3015 CN Rotterdam, The Netherlands; (B.G.K.); (J.N.M.I.)
| | - Alejandra Méndez Romero
- Department of Radiotherapy, Erasmus MC Cancer Institute, 3015 CN Rotterdam, The Netherlands; (Y.v.N.); (M.T.W.M.); (B.J.M.H.); (W.d.T.); (A.M.R.)
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Renzulli M, Ramai D, Singh J, Sinha S, Brandi N, Ierardi AM, Albertini E, Sacco R, Facciorusso A, Golfieri R. Locoregional Treatments in Cholangiocarcinoma and Combined Hepatocellular Cholangiocarcinoma. Cancers (Basel) 2021; 13:3336. [PMID: 34283065 PMCID: PMC8268054 DOI: 10.3390/cancers13133336] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 06/30/2021] [Accepted: 06/30/2021] [Indexed: 12/11/2022] Open
Abstract
Cholangiocarcinoma (CCA) is a primary and aggressive cancer of the biliary tree. Combined hepatocellular cholangiocarcinoma (CHC) is a distinctive primary liver malignancy which has properties of both hepatocytic and cholangiocytic differentiation. CHC appears to have a worse prognosis compared to hepatocellular carcinoma, and similar to that of intrahepatic CCA. While significant advances have been made in understanding the pathophysiology and treatment of these two tumor types, their prognosis remains poor. Currently, liver resection is the primary treatment modality; however, only a minority of patients are eligible for surgery. However, the use of locoregional therapies proves an alternative approach to treating locally advanced disease with the aim of converting to resectability or even transplantation. Locoregional therapies such as transarterial chemoembolization (TACE), selective internal radiation therapy (SIRT), radiofrequency ablation (RFA), and photodynamic therapy (PDT) can provide patients with tumor control and increase the chances of survival. In this review, we appraise the evidence surrounding the use of locoregional therapies in treating patients with CCA and CHC.
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Affiliation(s)
- Matteo Renzulli
- Department of Radiology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, 40138 Bologna, Italy; (N.B.); (R.G.)
| | - Daryl Ramai
- Department of Internal Medicine, The Brooklyn Hospital Center, Brooklyn, New York, NY 11201, USA; (D.R.); (S.S.)
| | - Jameel Singh
- Department of Internal Medicine, Mather Hospital, Northwell Health, Port Jefferson, New York, NY 11777, USA;
| | - Samridhi Sinha
- Department of Internal Medicine, The Brooklyn Hospital Center, Brooklyn, New York, NY 11201, USA; (D.R.); (S.S.)
| | - Nicolò Brandi
- Department of Radiology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, 40138 Bologna, Italy; (N.B.); (R.G.)
| | - Anna Maria Ierardi
- Diagnostic and Interventional Radiology, ASST Santi Paolo e Carlo, San Paolo Hospital, 20142 Milan, Italy;
| | - Elisa Albertini
- Pathology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, 40138 Bologna, Italy;
| | - Rodolfo Sacco
- Section of Gastroenterology, Department of Medical Sciences, University of Foggia, 71122 Foggia, Italy; (R.S.); (A.F.)
| | - Antonio Facciorusso
- Section of Gastroenterology, Department of Medical Sciences, University of Foggia, 71122 Foggia, Italy; (R.S.); (A.F.)
| | - Rita Golfieri
- Department of Radiology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, 40138 Bologna, Italy; (N.B.); (R.G.)
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24
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Cambridge WA, Fairfield C, Powell JJ, Harrison EM, Søreide K, Wigmore SJ, Guest RV. Meta-analysis and Meta-regression of Survival After Liver Transplantation for Unresectable Perihilar Cholangiocarcinoma. Ann Surg 2021; 273:240-250. [PMID: 32097164 DOI: 10.1097/sla.0000000000003801] [Citation(s) in RCA: 77] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVE To systematically review studies reporting survival data following neoadjuvant chemoradiation and orthotopic liver transplantation (NCR-OLT) for unresectable perihilar cholangiocarcinoma (pCC). BACKGROUND Despite survival improvements for other cancers, the prognosis of pCC remains dismal. Since publication of the Mayo protocol in 2000, increasing numbers of series globally are reporting outcomes after NCR-OLT. METHODS MEDLINE, EMBASE, Scopus, and Web of Science databases were searched from January 2000 to February 2019. A meta-analysis of proportions was conducted, pooling 1, 3-, and 5-year overall survival and recurrence rates following NCR-OLT across centers. Per protocol and intention to treat data were interrogated. Meta-regression was used to evaluate PSC as a confounder affecting survival. RESULTS Twenty studies comprising 428 patients were eligible for analysis. No RCTs were retrieved; the majority of studies were noncomparative cohort studies. The pooled 1, 3-, and 5-year overall survival rates following OLT without neoadjuvant therapy were 71.2% (95% CI 62.2%-79.4%), 48.0% (95% CI 35.0%-60.9%), and 31.6% (95% CI 23.1%-40.7%). These improved to 82.8% (95% CI 73.0%-90.8%), 65.5% (95% CI 48.7%-80.5%), and 65.1% (95% CI 55.1%-74.5%) if neoadjuvant chemoradiation was completed. Pooled recurrence after 3 years was 24.1% (95% CI 17.9%-30.9%) with neoadjuvant chemoradiation, 51.7% (95% CI 33.8%-69.4%) without. CONCLUSIONS In unresectable pCC, NCR-OLT confers long-term survival in highly selected patients able to complete neoadjuvant chemoradiation followed by transplantation. PSC patients appear to have the most favorable outcomes. A high recurrence rate is of concern when considering extending national graft selection policy to pCC.
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Affiliation(s)
- William A Cambridge
- Department of Clinical Surgery, University of Edinburgh, Little France Crescent, Edinburgh, UK
| | - Cameron Fairfield
- Department of Clinical Surgery, University of Edinburgh, Little France Crescent, Edinburgh, UK
| | - James J Powell
- Department of Clinical Surgery, University of Edinburgh, Little France Crescent, Edinburgh, UK
| | - Ewen M Harrison
- Department of Clinical Surgery, University of Edinburgh, Little France Crescent, Edinburgh, UK
| | - Kjetil Søreide
- Department of Gastrointestinal Surgery, Stavanger University Hospital, Stavanger, Norway
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Stephen J Wigmore
- Department of Clinical Surgery, University of Edinburgh, Little France Crescent, Edinburgh, UK
| | - Rachel V Guest
- Department of Clinical Surgery, University of Edinburgh, Little France Crescent, Edinburgh, UK
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25
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Gkika E, Hawkins MA, Grosu AL, Brunner TB. The Evolving Role of Radiation Therapy in the Treatment of Biliary Tract Cancer. Front Oncol 2021; 10:604387. [PMID: 33381458 PMCID: PMC7768034 DOI: 10.3389/fonc.2020.604387] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 11/04/2020] [Indexed: 12/13/2022] Open
Abstract
Biliary tract cancers (BTC) are a disease entity comprising diverse epithelial tumors, which are categorized according to their anatomical location as intrahepatic (iCCA), perihilar (pCCA), distal (dCCA) cholangiocarcinomas, and gallbladder carcinomas (GBC), with distinct epidemiology, biology, and prognosis. Complete surgical resection is the mainstay in operable BTC as it is the only potentially curative treatment option. Nevertheless, even after curative (R0) resection, the 5-year survival rate ranges between 20 and 40% and the disease free survival rates (DFS) is approximately 48–65% after one year and 23–35% after three years without adjuvant treatment. Improvements in adjuvant chemotherapy have improved the DFS, but the role of adjuvant radiotherapy is unclear. On the other hand, more than 50% of the patients present with unresectable disease at the time of diagnosis, which limits the prognosis to a few months without treatment. Herein, we review the role of radiotherapy in the treatment of cholangiocarcinoma in the curative and palliative setting.
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Affiliation(s)
- Eleni Gkika
- Department of Radiation Oncology, University Medical Centre Freiburg, Freiburg, Germany
| | - Maria A Hawkins
- Medical Physics and Biomedical Engineering, University College London, London, United Kingdom
| | - Anca-Ligia Grosu
- Department of Radiation Oncology, University Medical Centre Freiburg, Freiburg, Germany
| | - Thomas B Brunner
- Department of Radiation Oncology, University of Magdeburg, Magdeburg, Germany
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26
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Italian Clinical Practice Guidelines on Cholangiocarcinoma - Part II: Treatment. Dig Liver Dis 2020; 52:1430-1442. [PMID: 32952071 DOI: 10.1016/j.dld.2020.08.030] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 08/17/2020] [Accepted: 08/17/2020] [Indexed: 01/27/2023]
Abstract
Currently, the only curative treatment for cholangiocarcinoma (CCA) is surgical resection, though this treatment is possible in less than 40% of patients. However, recent improvements in preoperative management have led to a higher number of patients who are candidates for this procedure. For unresectable patients, progress is ongoing in terms of locoregional and chemoradiation treatments and target therapies, especially in the definition of patient selection criteria. This is the second part of the Italian CCA guidelines, dealing with CCA treatment, that have been formulated in accordance with Italian National Institute of Health indications and developed according to the GRADE method and related advancements.
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27
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Tan EK, Taner T, Heimbach JK, Gores GJ, Rosen CB. Liver Transplantation for Peri-hilar Cholangiocarcinoma. J Gastrointest Surg 2020; 24:2679-2685. [PMID: 32671802 DOI: 10.1007/s11605-020-04721-4] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 06/28/2020] [Indexed: 01/31/2023]
Abstract
BACKGROUND Liver transplantation for peri-hilar cholangiocarcinoma (pCCA) following neoadjuvant chemoradiation achieves excellent long-term survival in carefully selected patients with early-stage unresectable pCCA and patients with primary sclerosing cholangitis (PSC)-associated pCCA. Strict adherence to selection criteria, aggressive neoadjuvant therapy, operative staging prior to transplantation, and several technical accommodations during the transplant operation are necessary for success. In this review, we provide a contemporaneous overview of liver transplantation for pCCA, including selection criteria, neoadjuvant therapy, operative staging, and technical aspects of liver transplantation unique to patients with pCCA and an irradiated operative field. We also discuss several evolving trends intended to improve patient outcomes. RESULTS AND CONCLUSION Intention-to-treat and patient outcomes after liver transplantation for PSC-associated pCCA are superior to de novo pCCA. Outcomes between living donor liver transplantation (LDLT) and deceased donor liver transplantation are similar for patients with PSC-associated pCCA. However, LDLT for de novo pCCA shows a trend toward more disease recurrence and worse patient survival. A period of waiting time before transplant may be beneficial in selecting for patients with superior outcomes after transplant. Compared with liver transplantation for other indications, there is an increased risk of late arterial and portal vein complications, presumably due to the radiation. However, with close follow-up and prompt intervention for vascular complications, graft loss can be avoided. Neoadjuvant therapy and liver transplantation can achieve results comparable with resection for patients with early-stage unresectable pCCA and is the treatment of choice for patients with pCCA arising in the setting of PSC.
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Affiliation(s)
- Ek Khoon Tan
- Department of Surgery, Division of Transplantation Surgery, Mayo Clinic, Rochester, MN, USA
| | - Timucin Taner
- Department of Surgery, Division of Transplantation Surgery, Mayo Clinic, Rochester, MN, USA.,Department of Immunology, Mayo Clinic, Rochester, MN, USA
| | - Julie K Heimbach
- Department of Surgery, Division of Transplantation Surgery, Mayo Clinic, Rochester, MN, USA
| | - Gregory J Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Charles B Rosen
- Department of Surgery, Division of Transplantation Surgery, Mayo Clinic, Rochester, MN, USA.
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28
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Hand F, Hoti E. Surgical Volume Alone Does Not Determine Outcome Following Liver Transplant for Perihilar Cholangiocarcinoma. Ann Surg Oncol 2020; 27:930-931. [PMID: 32901313 DOI: 10.1245/s10434-020-09115-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 07/15/2020] [Indexed: 01/06/2023]
Affiliation(s)
- Fiona Hand
- Department of Hepatobiliary and Liver Transplant Surgery, St. Vincent's University Hospital, Elm Park, Dublin 4, Ireland.
| | - Emir Hoti
- Department of Hepatobiliary and Liver Transplant Surgery, St. Vincent's University Hospital, Elm Park, Dublin 4, Ireland
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29
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Baltatzis M, Jegatheeswaran S, Siriwardena AK. Neoadjuvant chemoradiotherapy before resection of perihilar cholangiocarcinoma: A systematic review. Hepatobiliary Pancreat Dis Int 2020; 19:103-108. [PMID: 32147487 DOI: 10.1016/j.hbpd.2020.02.007] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 02/17/2020] [Indexed: 02/05/2023]
Abstract
BACKGROUND Treatment with neoadjuvant chemoradiotherapy followed by liver transplantation yields promising results in perihilar cholangiocarcinoma (PH-CCA). This study reviews the literature to assess whether there is evidence to justify modern phase II studies of neoadjuvant chemoradiotherapy prior to resection of PH-CCA. DATA SOURCES A systematic review of the literature for reports of patients undergoing resection of PH-CCA after neoadjuvant chemoradiotherapy was performed using MEDLINE and EMBASE databases for the period between 1990 and 2019. The keywords and MeSH headings "hilar cholangiocarcinoma", "Klatskin", "chemoradiotherapy" and "chemotherapy" were used. Data were extracted on demographic profile, disease staging, chemoradiotherapy protocols, complications and outcome. Risks of bias were assessed using Cochrane methodology. RESULTS There were seven reports on this topic, with median recruitment period of 14 (range 4-31) years. The total number of patients in these studies was 87. Interval from completion of neoadjuvant treatment to surgery varied from 3 days to 6 months. Resection was by hepatectomy with three studies reporting an R0 rate of 100%, 24% and 63%, respectively. Three studies reported histopathological evidence of prior treatment response. There were two treatment related deaths at 90 days. Median survival was 19 (95% CI: 9.9-28) months and 5-year survival 20%. CONCLUSIONS There are potential benefits of treatment on both R0 rate and complete response in resected specimens. Scientific equipoise exists in relation to neoadjuvant chemoradiotherapy for PH-CCA.
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Affiliation(s)
- Minas Baltatzis
- Regional Hepato-Pancreato-Biliary Surgery Unit, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK
| | - Santhalingam Jegatheeswaran
- Regional Hepato-Pancreato-Biliary Surgery Unit, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK
| | - Ajith K Siriwardena
- Regional Hepato-Pancreato-Biliary Surgery Unit, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK; Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9WL, UK.
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30
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Machairas N, Kostakis ID, Tsilimigras DI, Prodromidou A, Moris D. Liver transplantation for hilar cholangiocarcinoma: A systematic review. Transplant Rev (Orlando) 2020; 34:100516. [PMID: 31711828 DOI: 10.1016/j.trre.2019.100516] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2019] [Revised: 10/27/2019] [Accepted: 11/03/2019] [Indexed: 02/07/2023]
Abstract
Patients with hilar cholangiocarcinoma (hCCA) have advanced disease at presentation and therefore curative treatment options are limited. Liver transplantation (LT), in the case of unresectable disease, is theoretically an attractive option, as it offers the maximum resection margin and at the same time removes the underlying parenchymal liver disease. In the past years a number of studies have aimed to evaluate to potential beneficial role of neo adjuvant therapy followed by LT for treating patients with unresectable hCCA. The objective of our systematic review was to collect and evaluate long-term outcomes of patients with hCCA undergoing LT. A systematic search of 4 electronic databases (Medline, Scopus, Google Scholar and ClinicalTrails.gov databases) was performed for articles published between January 2000 and May 2019. A total of 13 studies with 698 patients were finally included in the present systematic review. A proportion of 74.4% of patients received combination of chemotherapy and radiation as a part of neoadjuvant therapy. One-, 3- and 5-year overall survival rates ranged greatly among the included studies from 58% to 92%, 31% to 80% and 20% to 74%, respectively. Recurrence rates ranged from 16% to 61%, whilst perioperative mortality ranged from 0% to 25.5%. LT could provide acceptable long-term outcomes in the setting of neoadjuvant chemoradiation and strict patient selection criteria. Taking into account organ shortage, combined with the lack of level I evidence, more prospective randomized trials are needed in order to establish certain indications, rigorous criteria and standardized protocols for LT in hCCA and provide the maximal potential benefits for these patients.
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Affiliation(s)
- Nikolaos Machairas
- Department of HPB Surgery and Liver Transplantation, Royal Free London, London, United Kingdom
| | - Ioannis D Kostakis
- Department of HPB Surgery and Liver Transplantation, Royal Free London, London, United Kingdom
| | | | | | - Dimitrios Moris
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
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31
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Lee TC, Morris MC, Patel SH, Shah SA. Expanding the Surgical Pool for Hepatic Resection to Treat Biliary and Primary Liver Tumors. Surg Oncol Clin N Am 2019; 28:763-782. [PMID: 31472918 DOI: 10.1016/j.soc.2019.06.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Surgical management of primary liver and biliary tract tumors has evolved over the past several decades, resulting in improved outcomes in these malignancies with historically poor prognoses. Expansion of patient selection criteria, progress in neoadjuvant and adjuvant therapies, development of techniques to increase future liver remnant, and the select utilization of liver transplantation have all contributed to increasing the patient pool for surgical intervention. Ongoing and future studies need to focus on improving multimodality treatment regimens and further refining the selection criteria for transplantation in order to optimize utilization of limited organ resources.
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Affiliation(s)
- Tiffany C Lee
- Cincinnati Research on Outcomes and Safety in Surgery (CROSS), Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way, ML 0558, Cincinnati, OH 45267-0558, USA
| | - Mackenzie C Morris
- Cincinnati Research on Outcomes and Safety in Surgery (CROSS), Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way, ML 0558, Cincinnati, OH 45267-0558, USA
| | - Sameer H Patel
- Cincinnati Research on Outcomes and Safety in Surgery (CROSS), Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way, ML 0558, Cincinnati, OH 45267-0558, USA
| | - Shimul A Shah
- Cincinnati Research on Outcomes and Safety in Surgery (CROSS), Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way, ML 0558, Cincinnati, OH 45267-0558, USA.
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Liver transplantation for unresectable malignancies: Beyond hepatocellular carcinoma. Eur J Surg Oncol 2019; 45:2268-2278. [PMID: 31387755 DOI: 10.1016/j.ejso.2019.07.024] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2019] [Revised: 07/02/2019] [Accepted: 07/18/2019] [Indexed: 12/12/2022] Open
Abstract
Indications for liver transplantation have expanded over the past few decades owing to improved outcomes and better understanding of underlying pathologies. In particular, there has been a growing interest in the field of transplant oncology in recent years that has led to considerable developments which have pushed the boundaries of malignant indications for liver transplantation beyond hepatocellular carcinoma (HCC). In this article, we review and summarise the published evidence for liver transplantation in non-HCC primary and metastatic liver malignancies and highlight ongoing clinical trials that address unresolved questions therein. We also examine the current technical, immunological and oncological challenges that face liver transplantation in this growing field and explore potential approaches to overcome these barriers.
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Wong M, Kim J, George B, Eriksen C, Pearson T, Robbins J, Zimmerman MA, Hong JC. Downstaging Locally Advanced Cholangiocarcinoma Pre-Liver Transplantation: A Prospective Pilot Study. J Surg Res 2019; 242:23-30. [PMID: 31059945 DOI: 10.1016/j.jss.2019.04.023] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Revised: 03/13/2019] [Accepted: 04/04/2019] [Indexed: 12/21/2022]
Abstract
BACKGROUND Orthotopic liver transplantation (OLT) after neoadjuvant therapy (NT) in well-selected patients with unresectable hilar cholangiocarcinoma (CCA) achieves excellent recurrence-free survival. Current criteria for NT-OLT exclude patients with locally advanced hilar and intrahepatic CCA from potential cure. We sought to evaluate the efficacy of NT in downstaging locally advanced CCA, and examine outcomes after OLT. METHODS Among 24 patients referred for unresectable hilar and intrahepatic CCA from January 2013 through August 2017, 18 met center-specific inclusion criteria for the NT-OLT treatment protocol: hilar tumor size ≤3.5 cm or intrahepatic ≤8 cm, and regional lymphadenopathy but without distant metastasis. Median follow-up was 22.1 mo from diagnosis. RESULTS Of 18 patients who initiated NT, 11 were removed from the protocol due to tumor progression (n = 6) or uncontrolled infection and failure-to-thrive (n = 5). Median NT duration tended to be shorter for patients progressing to dropout than for those surviving to OLT (5.5 versus 13.5 mo, P = 0.109). Among five patients who received OLT, 1-y post-OLT patient survival was 80%: three survive recurrence-free (14.5-29.2 mo post-OLT); one developed an isolated tumor recurrence in a single portacaval lymph node at 12 mo post-OLT; and one experienced non-tumor-related death. All dropout patients died at a median of 14.4 mo after diagnosis. CONCLUSIONS This is the first prospective study to show successful NT downstaging of unresectable locally advanced hilar and intrahepatic CCA before OLT. NT-OLT for select patients with locally advanced hilar and intrahepatic CCA achieved acceptable short-term recurrence-free survival.
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Affiliation(s)
- Melissa Wong
- Division of Transplant Surgery, Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin; The Transplant Center, Froedtert and The Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Joohyun Kim
- Division of Transplant Surgery, Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin; The Transplant Center, Froedtert and The Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Ben George
- Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Calvin Eriksen
- Division of Transplant Surgery, Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin; The Transplant Center, Froedtert and The Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Terra Pearson
- Division of Transplant Surgery, Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin; The Transplant Center, Froedtert and The Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Jared Robbins
- Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Michael A Zimmerman
- Division of Transplant Surgery, Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin; The Transplant Center, Froedtert and The Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Johnny C Hong
- Division of Transplant Surgery, Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin; The Transplant Center, Froedtert and The Medical College of Wisconsin, Milwaukee, Wisconsin.
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Yadav S, Xie H, Bin-Riaz I, Sharma P, Durani U, Goyal G, Borah B, Borad MJ, Smoot RL, Roberts LR, Go RS, McWilliams RR, Mahipal A. Neoadjuvant vs. adjuvant chemotherapy for cholangiocarcinoma: A propensity score matched analysis. Eur J Surg Oncol 2019; 45:1432-1438. [PMID: 30914290 DOI: 10.1016/j.ejso.2019.03.023] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Revised: 03/01/2019] [Accepted: 03/16/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Chemotherapy is frequently used in cholangiocarcinoma as an adjunct to surgical resection, but the appropriate sequence of chemotherapy with surgery is unclear. PATIENTS AND METHODS Using the National Cancer Database, we identified patients who underwent surgery and chemotherapy for stage I-III cholangiocarcinoma between 2006 and 2014. The propensity score reflecting the probability of receiving neoadjuvant chemotherapy was estimated by multivariate logistic regression method. Patients in the neoadjuvant and adjuvant chemotherapy study arms were then propensity-matched in 1:3 ratios using the nearest neighbor method. Overall Survival (OS) in the matched data set was estimated using the Kaplan-Meier method. Hazard ratios (HRs) were calculated using Cox proportional hazard regression model. RESULTS Of the 1450 patients who met our inclusion criteria, 299 (20.6%) received neoadjuvant chemotherapy while 1151 (79.3%) received adjuvant chemotherapy. The median age at diagnosis was 63 years. 278 patients in the neoadjuvant group were matched to 700 patients in the adjuvant group. In the matched cohort, patients who received neoadjuvant chemotherapy had a superior OS compared to those who received adjuvant chemotherapy (Median OS: 40.3 vs. 32.8 months; HR: 0.78; 95% CI: 0.64-0.94, p = 0.01). The 1- and 5-year OS rates for the neoadjuvant chemotherapy group were 85.8% and 42.5% respectively compared to 84.6% and 31.7% for the adjuvant chemotherapy group. CONCLUSION In this large national database study, neoadjuvant chemotherapy was associated with a longer OS in a select group of patients with cholangiocarcinoma compared to those who underwent upfront surgical resection followed by adjuvant chemotherapy.
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Affiliation(s)
| | - Hao Xie
- Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA
| | - Irbaz Bin-Riaz
- Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA
| | - Prabin Sharma
- Department of Gastroenterology, Yale New Haven Health - Bridgeport Hospital, Bridgeport, CT, 06610, USA
| | - Urshila Durani
- Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA
| | - Gaurav Goyal
- Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA
| | - Bijan Borah
- Robert D. and Patricia E. Kern Mayo Clinic Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN, 55905, USA
| | - Mitesh J Borad
- Division of Hematology/Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ, 85259, USA
| | - Rory L Smoot
- Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, Mayo Clinic, Rochester, MN, 55905, USA
| | - Lewis R Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, 55905, USA
| | - Ronald S Go
- Division of Hematology, Mayo Clinic, Rochester, MN, 55905, USA
| | | | - Amit Mahipal
- Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA.
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Zhu YZ, Zhou K, Ruan LL, Sun F, Wang G, Li WF. Metadherin overexpression in perihilar cholangiocarcinoma is associated with lymph node metastasis and poor prognosis. Oncol Lett 2019; 17:4514-4520. [PMID: 30988817 PMCID: PMC6447862 DOI: 10.3892/ol.2019.10141] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2018] [Accepted: 01/22/2019] [Indexed: 12/17/2022] Open
Abstract
Metadherin (MTDH) is a protein that is also named astrocyte elevated gene-1, and is highly expressed in a number of different tumor tissues. Although the expression of MTDH is associated with tumor invasion and recurrence, the expression of this protein in perihilar cholangiocarcinoma (PCCA) and its clinical use have not yet been investigated. In the present study, the expression of MTDH in patients with PCCA was investigated in order to determine its clinicopathological use. An immunohistochemical method was used to detect MTDH expression and the epithelial-mesenchymal transition markers E-cadherin and vimentin in 66 cases of PCCA. In addition to the expression of MTDH, the clinical and pathological data and the postoperative outcomes were analyzed. The MTDH positive expression rate was 48.5% (32/66) in PCCA. A significantly higher MTDH expression level was identified in the poor tumor differentiation group compared with the well differentiation group (P=0.007). In the positive lymph node metastasis group, a significantly higher MTDH expression level was revealed compared with the negative lymph node metastasis group (P=0.023). No association was noted with regard to the expression of MTDH and the variables age, sex, tumor diameter, tumor grade and tumor classification stage. Positive MTDH expression was significantly associated with high vimentin expression (P=0.037) compared with negative vimentin expression and inversely associated with positive E-cadherin expression compared with negative E-cadherin expression (P=0.030). Survival analysis suggested that the high MTDH expression group was associated with a worse overall survival (OS) rate and recurrence free survival (RFS) rate compared with the low MTDH expression group (P<0.001 and P=0.01, respectively). Cox regression analysis indicated that the Tumor-Node-Metastasis, surgery margin and high MTDH expression were independent OS and RFS factors for PCCA. MTDH expression may serve an important function in PCCA tumor growth and metastasis. Targeting MTDH may have important therapeutic applications for patients with PCCA.
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Affiliation(s)
- Yan-Zhi Zhu
- Department of General Surgery, Taihe Hospital Affiliated with Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Ke Zhou
- Department of General Surgery, Taihe Hospital Affiliated with Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Lin-Lin Ruan
- Department of Pathology, Taihe Hospital Affiliated with Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Fu Sun
- Department of Pathology, First Affiliated Hospital of Xi'an Medical University, Xi'an, Shanxi 710000, P.R. China
| | - Gen Wang
- Department of General Surgery, Taihe Hospital Affiliated with Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Wen-Fang Li
- Department of General Surgery, Taihe Hospital Affiliated with Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
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Frakulli R, Buwenge M, Macchia G, Cammelli S, Deodato F, Cilla S, Cellini F, Mattiucci GC, Bisello S, Brandi G, Parisi S, Morganti AG. Stereotactic body radiation therapy in cholangiocarcinoma: a systematic review. Br J Radiol 2019; 92:20180688. [PMID: 30673295 DOI: 10.1259/bjr.20180688] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVE Stereotactic body radiation therapy (SBRT) has been used in the treatment of cholangiocarcinoma (CC) but toxicity and clinical results of SBRT in CC are still limited and sparse. Therefore, the aim of this systematic review was to analyze the results of SBRT in the setting of advanced CC. METHODS A systematic literature search was conducted on PubMed, Scopus, and Cochrane library using the PRISMA methodology. Studies including at least 10 patients with diagnosis of advanced CC regardless of tumor site and other treatments were included. The primary outcome was overall survival (OS) and secondary endpoints were local control (LC) and toxicity rates. The ROBINS-I risk of bias tool was used. RESULTS 10 studies (231 patients) fulfilled the selection criteria and were included in this review. All but one study showed moderate to serious risk of bias. Median follow up was 15 months (range: 7.8-64.0 months). Pooled 1 year OS was 58.3% (95% CI: 50.2-66.1%) and pooled 2 year OS was 35.5% (95% CI: 22.1-50.1%). Pooled 1 year LC was 83.4%, (95% CI: 76.5-89.4%). The reported toxicities were acceptable and manageable with only one treatment-related death. CONCLUSION The role of SBRT in CC is not yet supported by robust evidence in literature. However, within this limit, preliminary results seem almost comparable to the ones of standard chemotherapy or chemoradiation. ADVANCES IN KNOWLEDGE SBRT seems effective in terms of LC with acceptable treatment-related toxicities. Therefore, SBRT can be considered a therapeutic option at least in selected patients with CC, possibly combined with adjuvant chemotherapy (CHT).
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Affiliation(s)
- Rezarta Frakulli
- 1 Department of Experimental, Diagnostic and Specialty Medicine - DIMES, University of Bologna, S. Orsola-Malpighi Hospital , Bologna , Italy
| | - Milly Buwenge
- 1 Department of Experimental, Diagnostic and Specialty Medicine - DIMES, University of Bologna, S. Orsola-Malpighi Hospital , Bologna , Italy
| | - Gabriella Macchia
- 2 Radiotherapy Unit, Fondazione "Giovanni Paolo II", Catholic University of Sacred Heart , Campobasso , Italy
| | - Silvia Cammelli
- 1 Department of Experimental, Diagnostic and Specialty Medicine - DIMES, University of Bologna, S. Orsola-Malpighi Hospital , Bologna , Italy
| | - Francesco Deodato
- 2 Radiotherapy Unit, Fondazione "Giovanni Paolo II", Catholic University of Sacred Heart , Campobasso , Italy
| | - Savino Cilla
- 3 Medical Physic Unit, Fondazione "Giovanni Paolo II", Catholic University of Sacred Heart , Campobasso , Italy
| | - Francesco Cellini
- 4 Department of Radiotherapy, Policlinico Universitario "A. Gemelli", Università Cattolica del Sacro Cuore , Rome , Italy
| | - Gian C Mattiucci
- 4 Department of Radiotherapy, Policlinico Universitario "A. Gemelli", Università Cattolica del Sacro Cuore , Rome , Italy
| | - Silvia Bisello
- 1 Department of Experimental, Diagnostic and Specialty Medicine - DIMES, University of Bologna, S. Orsola-Malpighi Hospital , Bologna , Italy
| | - Giovanni Brandi
- 5 Department of Experimental, Diagnostic, and Specialty Medicine, S. Orsola-Malpighi University Hospital, Cancer Research, University of Bologna , Bologna , Italy
| | - Salvatore Parisi
- 6 Unit of Radiotherapy, IRCCS"Casa Sollievo della Sofferenza" San Giovanni Rotondo , Italy
| | - Alessio G Morganti
- 1 Department of Experimental, Diagnostic and Specialty Medicine - DIMES, University of Bologna, S. Orsola-Malpighi Hospital , Bologna , Italy
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Koedijk MS, Heijmen BJM, Groot Koerkamp B, Eskens FALM, Sprengers D, Poley JW, van Gent DC, van der Laan LJW, van der Holt B, Willemssen FEJA, Méndez Romero A. Protocol for the STRONG trial: stereotactic body radiation therapy following chemotherapy for unresectable perihilar cholangiocarcinoma, a phase I feasibility study. BMJ Open 2018; 8:e020731. [PMID: 30327398 PMCID: PMC6196820 DOI: 10.1136/bmjopen-2017-020731] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
INTRODUCTION For patients with perihilar cholangiocarcinoma (CCA), surgery is the only treatment modality that can result in cure. Unfortunately, in the majority of these patients, the tumours are found to be unresectable at presentation due to either local invasive tumour growth or the presence of distant metastases. For patients with unresectable CCA, palliative chemotherapy is the standard treatment yielding an estimated median overall survival (OS) of 12-15.2 months. There is no evidence from randomised trials to support the use of stereotactic body radiation therapy (SBRT) for CCA. However, small and most often retrospective studies combining chemotherapy with SBRT have shown promising results with OS reaching up to 33-35 months. METHODS AND ANALYSIS This study has been designed as a single-centre phase I feasibility trial and will investigate the addition of SBRT after standard chemotherapy in patients with unresectable perihilar CCA (T1-4 N0-1 M0). A total of six patients will be included. SBRT will be delivered in 15 fractions of 3-4.5 Gy (risk adapted). The primary objective of this study is to determine feasibility and toxicity. Secondary outcomes include local tumour control, progression-free survival (PFS), OS and quality of life. Length of follow-up will be 2 years. As an ancillary study, the personalised effects of radiotherapy will be measured in vitro, in patient-derived tumour and bile duct organoid cultures. ETHICS AND DISSEMINATION Ethics approval for the STRONG trial has been granted by the Medical Ethics Committee of Erasmus MC Rotterdam, the Netherlands. It is estimated that all patients will be included between October 2017 and October 2018. The results of this study will be published in a peer-reviewed journal, and presented at national and international conferences. TRIAL REGISTRATION NUMBER NCT03307538; Pre-results.
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Affiliation(s)
- Merel S Koedijk
- Department of Radiation Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Ben J M Heijmen
- Department of Radiation Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Bas Groot Koerkamp
- Department of Surgery, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Ferry A L M Eskens
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Dave Sprengers
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Jan-Werner Poley
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Dik C van Gent
- Department of Molecular Genetics, Erasmus MC University Medical Centre, Rotterdam, The Netherlands
| | - Luc J W van der Laan
- Department of Surgery, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Bronno van der Holt
- Department of Haematology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - François E J A Willemssen
- Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands
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Loveday BPT, Knox JJ, Dawson LA, Metser U, Brade A, Horgan AM, Gallinger S, Greig PD, Moulton CA. Neoadjuvant hyperfractionated chemoradiation and liver transplantation for unresectable perihilar cholangiocarcinoma in Canada. J Surg Oncol 2018; 117:213-219. [PMID: 29480952 DOI: 10.1002/jso.24833] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Accepted: 08/17/2017] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND OBJECTIVES Neoadjuvant chemoradiation and liver transplantation may be offered for unresectable perihilar cholangiocarcinoma (pCCA). This study aimed to determine the dropout rate and survival of patients who entered a national tri-modality protocol. METHOD Patients enrolled Jan 2009-Aug 2015 were included. Enrolment criteria: ≤65 years, brush biopsy-proven unresectable pCCA <3.5 cm diameter. Conformal radiotherapy was given concurrently with Capecitabine. Following surgical staging, patients received maintenance Cisplatin and Gemcitabine until transplant or progression. Time to event analyses were performed from start of neoadjuvant therapy. RESULTS Of 43 patients screened, 18 started treatment; median age 53.9 (26.7-62.8) years, tumour diameter 2.7 (2.0-3.4) cm. 11/18 dropped out due to metastatic disease identified during chemoradiation (n = 2), surgical staging (n = 6), or maintenance chemotherapy (n = 3). Six patients underwent transplantation. Median follow up was 17.6 (4.9-57.7) months and overall survival 16.4 months. One and two year survival was 70.6% and 35.3%, respectively. One and 2 year post transplant survival was 83.3% and 55.6%. Median progression free survival was 11.5 months. CONCLUSION Neoadjuvant chemoradiation and liver transplantation for unresectable early stage pCCA is feasible, although with high rates of dropout and disease progression. Further research is required to determine factors to help select patients for treatment.
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Affiliation(s)
| | - Jennifer J Knox
- Department of Medical Oncology, Princess Margaret Cancer Centre (PMCC), Ontario, Canada.,The University of Toronto, Toronto, Canada
| | - Laura A Dawson
- The University of Toronto, Toronto, Canada.,Department of Radiation Oncology, Princess Margaret Cancer Centr (PMCC), Ontario, Canada
| | - Ur Metser
- The University of Toronto, Toronto, Canada.,Joint Department of Medical Imaging, Toronto General Hospital, Ontario, Canada
| | - Anthony Brade
- The University of Toronto, Toronto, Canada.,Department of Radiation Oncology, Princess Margaret Cancer Centr (PMCC), Ontario, Canada
| | - Anne M Horgan
- Department of Medical Oncology, Princess Margaret Cancer Centre (PMCC), Ontario, Canada.,The University of Toronto, Toronto, Canada
| | - Steven Gallinger
- Department of Surgery, Toronto General Hospital, Ontario, Canada.,The University of Toronto, Toronto, Canada
| | - Paul D Greig
- Department of Surgery, Toronto General Hospital, Ontario, Canada.,The University of Toronto, Toronto, Canada
| | - Carol-Anne Moulton
- Department of Surgery, Toronto General Hospital, Ontario, Canada.,The University of Toronto, Toronto, Canada
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Goldaracena N, Gorgen A, Sapisochin G. Current status of liver transplantation for cholangiocarcinoma. Liver Transpl 2018; 24:294-303. [PMID: 29024405 DOI: 10.1002/lt.24955] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Revised: 09/06/2017] [Accepted: 10/01/2017] [Indexed: 12/12/2022]
Abstract
Cholangiocarcinoma (CCA) is the second most common liver cancer, and it is associated with a poor prognosis. CCA can be divided into intrahepatic, hilar, and distal. Despite the subtype, the median survival is 12-24 months without treatment. Liver transplantation (LT) is recognized worldwide as a curative option for hepatocellular carcinoma. On the other hand, the initial results for LT for CCA were very poor mainly due to a lack of adequate patient selection. In the last 2 decades, improvements have been made in the management of unresectable hilar CCA, and the results of LT after neoadjuvant chemoradiation have been shown to be promising. This has prompted a consideration of hilar CCA as an indication for LT in some centers. Furthermore, some recent research has shown promising results after LT for patients with early stages of intrahepatic CCA. A better understanding of the best tools to prognosticate the outcomes of LT for CCA is still needed. Here, we aimed to review the role of LT for the treatment of patients with perihilar and intrahepatic CCA. Also, we will discuss the most recent advances in the field and the future direction of the management of this disease in an era of transplantation oncology. Liver Transplantation 24 294-303 2018 AASLD.
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Affiliation(s)
- Nicolás Goldaracena
- Multi-Organ Transplant, Division of General Surgery, Department of Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Andre Gorgen
- Multi-Organ Transplant, Division of General Surgery, Department of Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Gonzalo Sapisochin
- Multi-Organ Transplant, Division of General Surgery, Department of Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada
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40
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Sahai P, Kumar S. External radiotherapy and brachytherapy in the management of extrahepatic and intrahepatic cholangiocarcinoma: available evidence. Br J Radiol 2017; 90:20170061. [PMID: 28466653 DOI: 10.1259/bjr.20170061] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
This review aims to summarize the currently available evidence for the role of external radiotherapy and brachytherapy in the management of cholangiocarcinoma. High locoregional disease recurrence rates after surgical resection alone for both the extrahepatic cholangiocarcinoma (EHCC) and intrahepatic cholangiocarcinoma (IHCC) provide a rationale for using adjuvant radiotherapy with chemotherapy. We performed a literature search related to radiotherapy in cholangiocarcinoma published between 2000 and 2016. The role of radiation is discussed in the adjuvant, neoadjuvant, definitive and the palliative setting. Evidence from Phase II trials have demonstrated efficacy of adjuvant chemoradiation in combination with chemotherapy in EHCC. Locally advanced cholangiocarcinoma may be treated with neoadjuvant chemoradiotherapy. In the case of downsizing, assessment for resection may be considered. Brachytherapy offers dose escalation after external radiotherapy. Selected unresectable cases of cholangiocarcinoma may be considered for stereotactic body radiation therapy with neoadjuvant and/or concurrent chemotherapy. Liver transplantation is a treatment option in selected patients with EHCC and IHCC after neoadjuvant chemoradiation. Stenting in combination with palliative external radiotherapy and/or brachytherapy provides improved stent patency and survival. Newer advanced radiation techniques provide a scope for achieving better disease control with reduced morbidity. Effective multimodality treatment incorporating radiotherapy is the way forward for improving survival in patients with cholangiocarcinoma.
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Affiliation(s)
- Puja Sahai
- 1 Department of Radiation Oncology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Senthil Kumar
- 2 Department of HPB Surgery and Liver Transplantation, Institute of Liver and Biliary Sciences, New Delhi, India
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Vannas MJ, Boyd S, Färkkilä MA, Arola J, Isoniemi H. Value of brush cytology for optimal timing of liver transplantation in primary sclerosing cholangitis. Liver Int 2017; 37:735-742. [PMID: 28453918 DOI: 10.1111/liv.13276] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Accepted: 10/08/2016] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIMS Primary sclerosing cholangitis is associated with a high risk of cholangiocarcinoma. Here, we investigated the value of surveillance for dysplasia using brush cytology, to determine the optimal timing of liver transplantation in primary sclerosing cholangitis. We compared our preoperative findings, with the final explanted liver histopathology. METHODS 126 consecutive patients were transplanted for primary sclerosing cholangitis from 1984 to 2012. Patients were divided into two groups: symptomatic (n=91), and asymptomatic (n=35). RESULTS Brush cytology was available for 101 patients; 66 symptomatic and 35 asymptomatic. Suspicious cytological findings were found in nine patients (14%) in the symptomatic group and 17 (49%) in the asymptomatic group. DNA flow cytometry was available for 49 patients (25 symptomatic, 24 asymptomatic), with aneuploidy detected in six patients (24%) in the symptomatic group and 15 (63%) in the asymptomatic group. Explanted liver histology showed biliary dysplasia or cholangiocarcinoma in 11 symptomatic patients (12%) and 15 asymptomatic patients (43%). A combination of cytological and DNA flow cytometry findings resulted in a test sensitivity of 68%, with a specificity of 86%. Ten-year survival in the asymptomatic group was 91%. CONCLUSIONS Dysplasia surveillance using brush specimens may help to select those patients likely to benefit from early liver transplantation. It remains unclear as to whether surveillance with brush cytology improves long-term survival, but there is presently no better method with which to predict transplantation timing.
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Affiliation(s)
- Marko J Vannas
- Transplantation and Liver Surgery Clinic, Helsinki University Hospital, Helsinki, Finland
| | - Sonja Boyd
- Department of Pathology, University of Helsinki and HUSLAB, Helsinki University Hospital, Helsinki, Finland
| | - Martti A Färkkilä
- Clinic of Gastroenterology, University of Helsinki, Helsinki University Hospital, Helsinki, Finland
| | - Johanna Arola
- Department of Pathology, University of Helsinki and HUSLAB, Helsinki University Hospital, Helsinki, Finland
| | - Helena Isoniemi
- Transplantation and Liver Surgery Clinic, Helsinki University Hospital, Helsinki, Finland
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Abstract
Hepatobiliary malignancies represent a heterogeneous group of diseases, which often arise in a background of underlying hepatic dysfunction complicating their local management. Surgical resection continues to be the standard of care for hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC); unfortunately the majority of patients are inoperable at presentation. The aggressiveness of these lesions makes locoregional control of particular importance. Historical experience with less sophisticated radiotherapy resulted in underwhelming efficacy and oftentimes prohibitive liver toxicity. However, with the advent of extremely conformal and precise radiotherapy delivery, dose escalation to the tumor with sparing of surrounding normal tissue has yielded notable improvements in efficacy for this modality of treatment. Dose escalation has come in a variety of forms most notably as stereotactic body radiation therapy (SBRT) and hypofractionated proton therapy. As radiation techniques continue to improve, their proper incorporation into the local management of hepatobiliary malignancies will be paramount in improving the prognosis of what is a grave diagnosis.
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Affiliation(s)
- Jonathan W Lischalk
- Department of Radiation Medicine, Georgetown University Hospital, Washington, DC, USA
| | - Michael C Repka
- Department of Radiation Medicine, Georgetown University Hospital, Washington, DC, USA
| | - Keith Unger
- Department of Radiation Medicine, Georgetown University Hospital, Washington, DC, USA
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Rabinel P, Dousse D, Muscari F, Suc B. Management of liver cancer. The Surgeon's point of view. Rep Pract Oncol Radiother 2017; 22:176-180. [PMID: 28490990 DOI: 10.1016/j.rpor.2017.02.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Revised: 12/27/2016] [Accepted: 02/06/2017] [Indexed: 02/07/2023] Open
Abstract
During the last twenty years, a huge progress has been achieved in the treatment of liver cancer and recent strategies include interventional radiology, chemotherapy regimens and surgery. Meanwhile, Stereotactic Body Radiation Therapy (SRBT) has developed in the treatment of all organs with millimetre accuracy, very few side effects and a high control rate. So, SRBT has become a therapeutic weapon in his own right in liver tumour treatment. Many publications have reported encouraging results in colorectal liver metastasis, hepatocellular carcinoma on cirrhosis and peripheric cholangiocarcinoma. It is important that radiation therapists involve systematic multidisciplinary "liver tumour" meetings to discuss therapeutic indications and initiate treatments quickly.
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Affiliation(s)
- Pierre Rabinel
- Department of Digestive Surgery and Liver Transplantation, Rangueil Hospital, 1, Avenue du Pr Jean Poulhès TSA 50032, 31059 Toulouse Cedex, France
| | - Damien Dousse
- Department of Digestive Surgery and Liver Transplantation, Rangueil Hospital, 1, Avenue du Pr Jean Poulhès TSA 50032, 31059 Toulouse Cedex, France
| | - Fabrice Muscari
- Department of Digestive Surgery and Liver Transplantation, Rangueil Hospital, 1, Avenue du Pr Jean Poulhès TSA 50032, 31059 Toulouse Cedex, France
| | - Bertrand Suc
- Department of Digestive Surgery and Liver Transplantation, Rangueil Hospital, 1, Avenue du Pr Jean Poulhès TSA 50032, 31059 Toulouse Cedex, France
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Squadroni M, Tondulli L, Gatta G, Mosconi S, Beretta G, Labianca R. Cholangiocarcinoma. Crit Rev Oncol Hematol 2016; 116:11-31. [PMID: 28693792 DOI: 10.1016/j.critrevonc.2016.11.012] [Citation(s) in RCA: 94] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Revised: 11/07/2016] [Accepted: 11/22/2016] [Indexed: 12/15/2022] Open
Abstract
Biliary tract cancer accounts for <1% of all cancers and affects chiefly an elderly population, with predominance in men. We distinguish cholangiocarcinoma (intrahepatic, hilar and distal) and gallbladder cancer, with different pathogenesis and prognosis. The treatment is based on surgery (whenever possible), radiotherapy in selected cases, and chemotherapy. The standard cytotoxic treatment for advanced/metastatic disease is represented by the combination of gemcitabine and cisplatin, whereas fluoropyrimidines are generally administered in second line setting. At the present time, no biologic drug demonstrated a clear efficacy in this cancer, although the molecular characterisation could provide a promising basis for experimental treatments. A good supportive care and an early palliative care are warranted in most patients and should be delivered as a part of a global approach.
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Affiliation(s)
| | - Luca Tondulli
- Medical Oncology Unit, Borgo Roma Hospital, Verona, Italy
| | - Gemma Gatta
- Italian National Cancer Institute, Milan, Italy
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Stereotactic body radiotherapy (SBRT) for locally advanced extrahepatic and intrahepatic cholangiocarcinoma. Adv Radiat Oncol 2016; 1:237-243. [PMID: 28740893 PMCID: PMC5514222 DOI: 10.1016/j.adro.2016.10.008] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Revised: 09/30/2016] [Accepted: 10/24/2016] [Indexed: 12/14/2022] Open
Abstract
Objectives We report single-institution clinical efficacy and safety outcomes for patients with unresectable locally advanced cholangiocarcinoma who were treated with stereotactic body radiation therapy (SBRT) and a subset of patients who received neoadjuvant SBRT and chemotherapy as part of an orthotopic liver transplantation (OLT) protocol. Methods and materials From October 2008 to June 2015, 31 consecutive patients with unresectable extrahepatic (n = 25) or intrahepatic (n = 6) cholangiocarcinoma were treated with SBRT and retrospectively analyzed. Four patients underwent liver transplantation, and 1 underwent resection. SBRT was delivered in 5 fractions with a median dose of 40 Gy. Toxicity was scored using the Common Terminology Criteria for Adverse Events Version 4.0. Overall survival (OS), time to progression, and local control were estimated using the Kaplan-Meier method. Results The median follow-up time was 11.5 months. The 1- and 2-year OS rates were 59% and 33%, respectively, with a median survival of 15.7 months. The 1- and 2-year freedom from progression was 67% and 34%, respectively. Median time to progression was 16.8 months. Nine patients had local failure. The actuarial 1- and 2-year local control rates were 78% and 47%, respectively. Among patients who also had OLT, the median OS was 31.3 months. Twenty-four patients (77%) experienced some form of acute grade 1-2 toxicity, most commonly fatigue or pain. Five patients (16%) experienced grade ≥3 toxicity. Conclusions SBRT is a promising option for patients with unresectable or recurrent cholangiocarcinoma either as a component of neoadjuvant therapy prior to OLT or as part of definitive therapy for patients who are unresectable and not eligible for transplantation.
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Méndez Romero A, de Man RA. Stereotactic body radiation therapy for primary and metastatic liver tumors: From technological evolution to improved patient care. Best Pract Res Clin Gastroenterol 2016; 30:603-16. [PMID: 27644908 DOI: 10.1016/j.bpg.2016.06.003] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2016] [Revised: 05/08/2016] [Accepted: 06/18/2016] [Indexed: 01/31/2023]
Abstract
Technical developments allowed stereotactic body radiation therapy (SBRT) to deliver effective doses of irradiation with high precision in a small number of fractions. This paper reviews the role of SBRT for liver metastases, hepatocellular carcinoma and cholangiocarcinoma, paying special attention to patient eligibility and treatment outcomes regarding local control, toxicity and quality of life. As well as discussing specific issues of these different tumors, such as the presence of underlying liver cirrhosis and the impact on toxicity, it outlines the limitations of SBRT and future areas of development and research.
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Affiliation(s)
- Alejandra Méndez Romero
- Department of Radiation Oncology, Erasmus MC University Medical Center (Cancer Institute), Rotterdam, The Netherlands.
| | - Robert A de Man
- Department of Gastroenterology & Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
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47
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Imperatori M, D'Onofrio L, Marrucci E, Pantano F, Zoccoli A, Tonini G. Neoadjuvant treatment of biliary tract cancer: state-of-the-art and new perspectives. Hepat Oncol 2015; 3:93-99. [PMID: 30191029 PMCID: PMC6095316 DOI: 10.2217/hep.15.43] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2015] [Accepted: 10/22/2015] [Indexed: 12/11/2022] Open
Abstract
Gall bladder cancer (GBC), and intrahepatic and extrahepatic (perihilar or distal bile duct's) cholangiocarcinomas (CCA) are usually diagnosed in locally advanced or node-positive stage, with a short survival rate. Thus, it appears essential to explore novel strategies for improving disease downstage and radical surgery. Chemoradiotherapy followed by liver transplantation seems to be one of the most promising approaches for intrahepatic or perihilar disease while chemotherapy with novel radiotherapy techniques (such stereotactic body radiation) emerged as an attractive preoperative treatment in distal diseases. In this paper, we will review currently available knowledge about neoadjuvant treatment of biliary tract cancers (BTC) paying attention to challenges that make this type of management in clinical practice difficult.
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48
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Gulamhusein AF, Sanchez W. Liver transplantation in the management of perihilar cholangiocarcinoma. Hepat Oncol 2015; 2:409-421. [PMID: 30191020 DOI: 10.2217/hep.15.30] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Cholangiocarcinoma (CCA) is the second most common primary hepatic neoplasm and accounts for 10-20% of hepatobiliary cancer-related deaths. The prognosis of patients with CCA is poor with 5-year survival rates of 10%, partially due to the limited effective treatment options that exist for this disease. In this review, we discuss the evolving role of liver transplantation in the management of patients with perihilar CCA (pCCA). We specifically discuss the Mayo Clinic protocol of neoadjuvant chemoradiation followed by liver transplantation in selected patients with pCCA and describe pretransplant, peritransplant, and post-transplant considerations and challenges with this approach. Finally, we review local, national and international outcomes and discuss future directions in optimizing this treatment strategy for patients who otherwise have few therapeutic options and limited survival.
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Affiliation(s)
- Aliya F Gulamhusein
- Division of Gastroenterology & Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - William Sanchez
- Division of Gastroenterology & Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA
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49
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Mahadevan A, Dagoglu N, Mancias J, Raven K, Khwaja K, Tseng JF, Ng K, Enzinger P, Miksad R, Bullock A, Evenson A. Stereotactic Body Radiotherapy (SBRT) for Intrahepatic and Hilar Cholangiocarcinoma. J Cancer 2015; 6:1099-104. [PMID: 26516357 PMCID: PMC4615345 DOI: 10.7150/jca.13032] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Accepted: 02/09/2015] [Indexed: 12/15/2022] Open
Abstract
Background: Unresectable intrahepatic and hilar cholangiocarcinomas carry a dismal prognosis. Systemic chemotherapy and conventional external beam radiation and brachytherapy have been used with limited success. We explored the use of stereotactic body radiotherapy (SBRT) for these patients. Methods: Patients with unresectable intrahepatic or hilar cholangiocarcinoma or those with positive margins were included in this study. Systemic therapy was used at the discretion of the medical oncologist. The CyberknifeTM stereotactic body radiotherapy system used to treat these patients. Patients were treated with three daily fractions. Clinical and radiological follow-up were performed every three months. Results: 34 patients (16 male and 18 female) with 42 lesions were included in this study. There were 32 unresectable tumors and two patients with resected tumors with positive margins. The median SBRT dose was 30Gy in three fractions. The median follow-up was 38 months (range 8-71 months). The actuarial local control rate was 79%. The median overall survival was 17 months and the median progression free survival was ten months. There were four Grade III toxicities (12%), including duodenal ulceration, cholangitis and liver abscess. Conclusions: SBRT is an effective and reasonably safe local therapy option for unresectable intrahepatic or hilar cholangiocarcinoma.
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Affiliation(s)
- Anand Mahadevan
- 1. Department of Radiation Oncology, Harvard Medical School, Boston, Massachusetts, USA
| | - Nergiz Dagoglu
- 1. Department of Radiation Oncology, Harvard Medical School, Boston, Massachusetts, USA
| | - Joseph Mancias
- 1. Department of Radiation Oncology, Harvard Medical School, Boston, Massachusetts, USA
| | - Kristin Raven
- 2. Department of Surgery, Harvard Medical School, Boston, Massachusetts, USA
| | - Khalid Khwaja
- 2. Department of Surgery, Harvard Medical School, Boston, Massachusetts, USA
| | - Jennifer F Tseng
- 2. Department of Surgery, Harvard Medical School, Boston, Massachusetts, USA
| | - Kimmie Ng
- 3. Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Peter Enzinger
- 3. Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Rebecca Miksad
- 4. Department of Medical Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Andrea Bullock
- 4. Department of Medical Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Amy Evenson
- 2. Department of Surgery, Harvard Medical School, Boston, Massachusetts, USA
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50
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EXP CLIN TRANSPLANTExp Clin Transplant 2015; 13. [DOI: 10.6002/ect.2015.0048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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