1
|
Malik AK, Davidson BR, Manas DM. Surgical management, including the role of transplantation, for intrahepatic and peri-hilar cholangiocarcinoma. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2025; 51:108248. [PMID: 38467524 DOI: 10.1016/j.ejso.2024.108248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 02/28/2024] [Accepted: 03/03/2024] [Indexed: 03/13/2024]
Abstract
Intrahepatic and peri-hilar cholangiocarcinoma are life threatening disease with poor outcomes despite optimal treatment currently available (5-year overall survival following resection 20-35%, and <10% cured at 10-years post resection). The insidious onset makes diagnosis difficult, the majority do not have a resection option and the high recurrence rate post-resection suggests that occult metastatic disease is frequently present. Advances in perioperative management, such as ipsilateral portal vein (and hepatic vein) embolisation methods to increase the future liver remnant volume, genomic profiling, and (neo)adjuvant therapies demonstrate great potential in improving outcomes. However multiple areas of controversy exist. Surgical resection rate and outcomes vary between centres with no global consensus on how 'resectable' disease is defined - molecular profiling and genomic analysis could potentially identify patients unlikely to benefit from resection or likely to benefit from targeted therapies. FDG-PET scanning has also improved the ability to detect metastatic disease preoperatively and avoid futile resection. However tumours frequently invade major vasculo-biliary structures, with resection and reconstruction associated with significant morbidity and mortality even in specialist centres. Liver transplantation has been investigated for very selected patients for the last decade and yet the selection algorithm, surgical approach and both value of both neoadjuvant and adjuvant therapies remain to be clarified. In this review, we discuss the contemporary management of intrahepatic and peri-hilar cholangiocarcinoma.
Collapse
Affiliation(s)
- Abdullah K Malik
- Department of HPB and Transplant Surgery, Freeman Hospital, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK; NIHR Blood and Transplant Research Unit, Newcastle University and Cambridge University, Newcastle Upon Tyne, UK.
| | - Brian R Davidson
- Department of HPB and Liver Transplant Surgery, Royal Free Hospital, Royal Free London NHS Foundation Trust, London, UK; Division of Surgery and Interventional Sciences, University College London, London, UK
| | - Derek M Manas
- Department of HPB and Transplant Surgery, Freeman Hospital, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK; NIHR Blood and Transplant Research Unit, Newcastle University and Cambridge University, Newcastle Upon Tyne, UK; NHS Blood and Transplant, Bristol, UK
| |
Collapse
|
2
|
Gringeri E, Furlanetto A, Billato I, Cescon M, De Carlis L, Mazzaferro V, Romagnoli R, De Simone P, Vivarelli M, Di Benedetto F, Ravaioli M, Lauterio A, Sposito C, Patrono D, Ghinolfi D, Moccheggiani F, Di Sandro S, D'Amico FE, Lanari J, Gambato M, Trapani S, Bergamo F, Cardillo M, Burra P, Cillo U. The Italian experience on liver transplantation for unresectable peri-hilar cholangiocarcinoma: a national survey and future perspectives. Updates Surg 2024; 76:2505-2513. [PMID: 39210194 DOI: 10.1007/s13304-024-01889-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Accepted: 05/18/2024] [Indexed: 09/04/2024]
Abstract
Liver transplantation (LT) was considered an ineffective treatment for perihilar cholangiocarcinoma (pCCA) until the successful experience of the Mayo Clinic, proposing a protocol with strict inclusion criteria and neoadjuvant radio-chemotherapy. Since 2015, pCCA is considered an indication for LT in Italy only in the context of controlled prospective studies. We performed a survey among the 22 Italian Liver Transplant Centers to assess the results of LT for pCCA. Eight centers reported 53 cases from 1986 to 2021 (Bologna 12, Padova 10, Niguarda 10, Milano Tumori 8, Torino 5, Pisa 4, Ancona 2, Modena 2). Patients were divided according to whether they recieved neoadjuvant radio-chemotherapy (Group 1, 25 cases) or not (Group 2, 28 cases). Eleven patients were transplanted without neoadjuvant treatment after 2015. Overall survival at 1, 3 and 5 years was 83.8%, 56.6% and 50.6% in Group 1 and 72.4%, 41.4% and 35.5% in Gropu 2 (p = 0.13). Recurrence-free survival at 1, 3, and 5 years was 91.2%, 61.1% and 47.2% in Group 1 and 58.2%, 42.2%, and 36.1% in Group 2 (p = 0.16). A competing risk regression analysis showed a 5-year risk of cancer-related death of 19% for patients in Group 1 against 62.3% in Group 2, with a hazard ratio of 0.31 (95%CI [0.10-0.98], p 0.047). This survey promoted a discussion about the limitations of the Mayo protocol and set the basis for the adoption of a new nationwide protocol (LITHALICA-NCT06125769), having the same inclusion criteria but proposing standard of care chemotherapy as neoadjuvant regimen.
Collapse
Affiliation(s)
- Enrico Gringeri
- General Surgery 2, Hepato-biliary-Pancreatic Surgery and Liver Transplantation Unit, Padua University Hospital, Padua, Italy.
- Department of Surgery Oncology and Gastroenterology, University of Padova, Via Giustiniani 2, 35128, Padua, Italy.
| | - Alessandro Furlanetto
- General Surgery 2, Hepato-biliary-Pancreatic Surgery and Liver Transplantation Unit, Padua University Hospital, Padua, Italy
- Department of Surgery Oncology and Gastroenterology, University of Padova, Via Giustiniani 2, 35128, Padua, Italy
| | - Ilaria Billato
- General Surgery 2, Hepato-biliary-Pancreatic Surgery and Liver Transplantation Unit, Padua University Hospital, Padua, Italy
| | - Matteo Cescon
- Department of General Surgery and Transplantation, IRCCS, Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Luciano De Carlis
- Department of General Surgery and Transplantation, Niguarda Ca' Granda Hospital, 20162, Milan, Italy
| | - Vincenzo Mazzaferro
- Hepato-Pancreato-Biliary Surgery and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori Di Milano, Milan, Italy
| | - Renato Romagnoli
- Liver Transplant Center, General Surgery 2, University of Turin, AOU Città della Salute e della Scienza di Torino, Turin, Italy
| | - Paolo De Simone
- Liver Transplant Program, University of Pisa Medical School Hospital, Pisa, Italy
| | - Marco Vivarelli
- Hepato-Pancreato-Biliary and Transplant Surgery, Department of Experimental and Clinical Medicine, Polytechnic University of Marche, 60126, Ancona, Italy
| | - Fabrizio Di Benedetto
- Hepato-Pancreato-Biliary Surgery and Liver Transplantation Unit, University Hospital of Modena "Policlinico", University of Modena and Reggio Emilia, Modena, Italy
| | - Matteo Ravaioli
- Department of General Surgery and Transplantation, IRCCS, Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Andrea Lauterio
- Department of General Surgery and Transplantation, Niguarda Ca' Granda Hospital, 20162, Milan, Italy
| | - Carlo Sposito
- Hepato-Pancreato-Biliary Surgery and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori Di Milano, Milan, Italy
| | - Damiano Patrono
- Liver Transplant Center, General Surgery 2, University of Turin, AOU Città della Salute e della Scienza di Torino, Turin, Italy
| | - Davide Ghinolfi
- Liver Transplant Program, University of Pisa Medical School Hospital, Pisa, Italy
| | - Federico Moccheggiani
- Hepato-Pancreato-Biliary and Transplant Surgery, Department of Experimental and Clinical Medicine, Polytechnic University of Marche, 60126, Ancona, Italy
| | - Stefano Di Sandro
- Hepato-Pancreato-Biliary Surgery and Liver Transplantation Unit, University Hospital of Modena "Policlinico", University of Modena and Reggio Emilia, Modena, Italy
| | - Francesco Enrico D'Amico
- General Surgery 2, Hepato-biliary-Pancreatic Surgery and Liver Transplantation Unit, Padua University Hospital, Padua, Italy
- Department of Surgery Oncology and Gastroenterology, University of Padova, Via Giustiniani 2, 35128, Padua, Italy
| | - Jacopo Lanari
- General Surgery 2, Hepato-biliary-Pancreatic Surgery and Liver Transplantation Unit, Padua University Hospital, Padua, Italy
- Department of Surgery Oncology and Gastroenterology, University of Padova, Via Giustiniani 2, 35128, Padua, Italy
| | - Martina Gambato
- Multivisceral Transplant Unit, Padova University, Padua, Italy
| | - Silvia Trapani
- Italian National Transplant Center-Istituto Superiore Di Sanità, Rome, Italy
| | - Francesca Bergamo
- Medical Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Massimo Cardillo
- Italian National Transplant Center-Istituto Superiore Di Sanità, Rome, Italy
| | - Patrizia Burra
- Multivisceral Transplant Unit, Padova University, Padua, Italy
- Department of Surgery Oncology and Gastroenterology, University of Padova, Via Giustiniani 2, 35128, Padua, Italy
| | - Umberto Cillo
- General Surgery 2, Hepato-biliary-Pancreatic Surgery and Liver Transplantation Unit, Padua University Hospital, Padua, Italy
- Department of Surgery Oncology and Gastroenterology, University of Padova, Via Giustiniani 2, 35128, Padua, Italy
| |
Collapse
|
3
|
Wang L, Singhal M, Valderrama A, Nepal B, Kamble S, Eluri M, Malhotra U, Siegel A, Grabner M, Swami S, Javle M. Real-world treatment patterns, resource utilization and costs in biliary tract cancers in the USA. Future Oncol 2024; 20:2625-2636. [PMID: 39155836 PMCID: PMC11534106 DOI: 10.1080/14796694.2024.2379237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Accepted: 07/09/2024] [Indexed: 08/20/2024] Open
Abstract
Aim: To evaluate real-world treatment patterns, survival and healthcare-resource utilization in US patients with advanced biliary tract cancers (BTC) receiving systemic therapy.Patients & methods: This study used claims data from the Healthcare Integrated Research Database (HIRD®) linked to clinical data from the Cancer Care Quality Program (January 1, 2015-September 30, 2020).Results: Of 413 patients, 84.5% received gemcitabine-based first-line (1L) treatment, 46% received second-line treatment, and 16.5% received third-line (3L) treatment. All-cause mortality was 53% and approximately 70% of patients had ≥1 inpatient visit. The total mean per-patient-per-month all-cause costs were $19,589 for 1L and $33,534 for 3L treatment.Conclusion: Results showed poor survival, significant resource use and high costs as treatment line progresses for patients with advanced BTC.
Collapse
Affiliation(s)
| | | | | | - Bal Nepal
- Carelon Research, Wilmington, DE, US
| | | | | | | | | | | | | | | |
Collapse
|
4
|
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.
Collapse
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
| | | | | |
Collapse
|
5
|
Esmail A, Badheeb M, Alnahar B, Almiqlash B, Sakr Y, Khasawneh B, Al-Najjar E, Al-Rawi H, Abudayyeh A, Rayyan Y, Abdelrahim M. Cholangiocarcinoma: The Current Status of Surgical Options including Liver Transplantation. Cancers (Basel) 2024; 16:1946. [PMID: 38893067 PMCID: PMC11171350 DOI: 10.3390/cancers16111946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 05/15/2024] [Accepted: 05/16/2024] [Indexed: 06/21/2024] Open
Abstract
Cholangiocarcinoma (CCA) poses a substantial threat as it ranks as the second most prevalent primary liver tumor. The documented annual rise in intrahepatic CCA (iCCA) incidence in the United States is concerning, indicating its growing impact. Moreover, the five-year survival rate after tumor resection is only 25%, given that tumor recurrence is the leading cause of death in 53-79% of patients. Pre-operative assessments for iCCA focus on pinpointing tumor location, biliary tract involvement, vascular encasements, and metastasis detection. Numerous studies have revealed that portal vein embolization (PVE) is linked to enhanced survival rates, improved liver synthetic functions, and decreased overall mortality. The challenge in achieving clear resection margins contributes to the notable recurrence rate of iCCA, affecting approximately two-thirds of cases within one year, and results in a median survival of less than 12 months for recurrent cases. Nearly 50% of patients initially considered eligible for surgical resection in iCCA cases are ultimately deemed ineligible during surgical exploration. Therefore, staging laparoscopy has been proposed to reduce unnecessary laparotomy. Eligibility for orthotopic liver transplantation (OLT) requires certain criteria to be granted. OLT offers survival advantages for early-detected unresectable iCCA; it can be combined with other treatments, such as radiofrequency ablation and transarterial chemoembolization, in specific cases. We aim to comprehensively describe the surgical strategies available for treating CCA, including the preoperative measures and interventions, alongside the current options regarding liver resection and OLT.
Collapse
Affiliation(s)
- Abdullah Esmail
- Section of GI Oncology, Department of Medicine, Houston Methodist Cancer Center, Houston, TX 77030, USA
| | - Mohamed Badheeb
- Department of Internal Medicine, Yale New Haven Health, Bridgeport Hospital, Bridgeport, CT 06605, USA
| | - Batool Alnahar
- College of Medicine, Almaarefa University, Riyadh 13713, Saudi Arabia
| | - Bushray Almiqlash
- Zuckerman College of Public Health, Arizona State University, Tempe, AZ 85287, USA
| | - Yara Sakr
- Department of GI Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Bayan Khasawneh
- Section of GI Oncology, Department of Medicine, Houston Methodist Cancer Center, Houston, TX 77030, USA
| | - Ebtesam Al-Najjar
- Section of GI Oncology, Department of Medicine, Houston Methodist Cancer Center, Houston, TX 77030, USA
| | - Hadeel Al-Rawi
- Faculty of Medicine, The University of Jordan, Amman 11942, Jordan
| | - Ala Abudayyeh
- Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Yaser Rayyan
- Department of Gastroenterology & Hepatology, Faculty of Medicine, The University of Jordan, Amman 11942, Jordan
| | - Maen Abdelrahim
- Section of GI Oncology, Department of Medicine, Houston Methodist Cancer Center, Houston, TX 77030, USA
| |
Collapse
|
6
|
Kodali S, Connor AA, Thabet S, Brombosz EW, Ghobrial RM. Liver transplantation as an alternative for the treatment of intrahepatic cholangiocarcinoma: Past, present, and future directions. Hepatobiliary Pancreat Dis Int 2024; 23:129-138. [PMID: 37517983 DOI: 10.1016/j.hbpd.2023.07.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 07/21/2023] [Indexed: 08/01/2023]
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is a rare biliary tract cancer with high mortality rate. Complete resection of the iCCA lesion is the first choice of treatment, with good prognosis after margin-negative resection. Unfortunately, only 12%-40% of patients are eligible for resection at presentation due to cirrhosis, portal hypertension, or large tumor size. Liver transplantation (LT) offers margin-negative iCCA extirpation for patients with unresectable tumors. Initially, iCCA was a contraindication for LT until size-based selection criteria were introduced to identify patients with satisfied post-LT outcomes. Recent studies have shown that tumor biology-based selection can yield high post-LT survival in patients with locally advanced iCCA. Another selection criterion is the tumor response to neoadjuvant therapy. Patients with response to neoadjuvant therapy have better outcomes after LT compared with those without tumor response to neoadjuvant therapy. Another index that helps predict the treatment outcome is the biomarker. Improved survival outcomes have also opened the door for living donor LT for iCCA. Patients undergoing LT for iCCA now have statistically similar survival rates as patients undergoing resection. The combination of surgery and locoregional and systemic therapies improves the prognosis of iCCA patients.
Collapse
Affiliation(s)
- Sudha Kodali
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston Methodist Hospital, Houston, TX 77030, USA; JC Walter Jr Transplant Center, Houston Methodist Hospital, Houston, TX 77030, USA; Department of Medicine, Weill Cornell Medical College, New York, NY, USA
| | - Ashton A Connor
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston Methodist Hospital, Houston, TX 77030, USA; JC Walter Jr Transplant Center, Houston Methodist Hospital, Houston, TX 77030, USA; Department of Surgery, Houston Methodist Hospital, Houston, TX 77030, USA; Department of Surgery, Weill Cornell Medical College, New York, NY, USA
| | | | | | - R Mark Ghobrial
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston Methodist Hospital, Houston, TX 77030, USA; JC Walter Jr Transplant Center, Houston Methodist Hospital, Houston, TX 77030, USA; Department of Surgery, Houston Methodist Hospital, Houston, TX 77030, USA; Department of Surgery, Weill Cornell Medical College, New York, NY, USA.
| |
Collapse
|
7
|
Rodríguez-Espinosa D, Morantes L, García J, Broseta JJ, Cuadrado-Payán E, Colmenero J, Torregrosa JV, Diekmann F, Esforzado N. Long-Term Outcomes of Incidental Liver Malignancies in Simultaneous Liver-Kidney Transplant Recipients. Transplant Proc 2024; 56:330-334. [PMID: 38350821 DOI: 10.1016/j.transproceed.2024.01.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2023] [Accepted: 01/16/2024] [Indexed: 02/15/2024]
Abstract
BACKGROUND The pretransplant diagnosis of liver malignancies in nodular cirrhotic livers remains a diagnostic challenge despite current advances. Although the prognostic impact of incidental hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (iCC) in liver transplant recipients is well documented, there are no data on the impact in simultaneous liver kidney transplant (LKT) recipients. METHODS This is a single-center observational, retrospective study of all LKT performed from May 1993 to April 2022. Among these patients, demographic data, immunosuppressive therapy, rejection episodes, and prevalence of incidental HCC or iCC were evaluated. RESULTS One hundred eight LKTs were performed and 6 were excluded. There were 13 patients with incidental carcinomas in the explanted liver: one of them with both an HCC and iCC, one with an iCC, and the remaining with an HCC. One case of iCC died. No other recurrences occurred. There were no cases of incidental HCC nor iCC in patients with a hereditary or metabolic LKT indication. We found no differences in the 5-year patient survival, and death-censored kidney and liver graft survival rates for those LKT with an incidental HCC and those without it (76.9% vs 84.2%, P = .5; 100% vs 91.6%, P = .28; and 100% vs 94.7%, P = 0.39, respectively). Finally, there were no significant associations between explant carcinoma and rejections of the liver (7.7% vs 17.9%, P = .34) or kidney graft (0% vs 16.8%, P = 0.11). CONCLUSION Despite a high prevalence of incidental HCC or iCC, patient, kidney, and liver graft 5-year survival were unaffected by incidental HCC.
Collapse
Affiliation(s)
- Diana Rodríguez-Espinosa
- Department of Nephrology and Renal Transplantation, Hospital Clínic of Barcelona, Barcelona, Spain.
| | - Laura Morantes
- Department of Nephrology and Renal Transplantation, Hospital Clínic of Barcelona, Barcelona, Spain
| | - Jenmy García
- Department of Nephrology and Renal Transplantation, Hospital Clínic of Barcelona, Barcelona, Spain
| | - José Jesús Broseta
- Department of Nephrology and Renal Transplantation, Hospital Clínic of Barcelona, Barcelona, Spain
| | - Elena Cuadrado-Payán
- Department of Nephrology and Renal Transplantation, Hospital Clínic of Barcelona, Barcelona, Spain
| | | | - Josep Vicens Torregrosa
- Department of Nephrology and Renal Transplantation, Hospital Clínic of Barcelona, Barcelona, Spain
| | - Fritz Diekmann
- Department of Nephrology and Renal Transplantation, Hospital Clínic of Barcelona, Barcelona, Spain
| | - Nuria Esforzado
- Department of Nephrology and Renal Transplantation, Hospital Clínic of Barcelona, Barcelona, Spain
| |
Collapse
|
8
|
Bragazzi MC, Venere R, Ribichini E, Covotta F, Cardinale V, Alvaro D. Intrahepatic cholangiocarcinoma: Evolving strategies in management and treatment. Dig Liver Dis 2024; 56:383-393. [PMID: 37722960 DOI: 10.1016/j.dld.2023.08.052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 08/07/2023] [Accepted: 08/21/2023] [Indexed: 09/20/2023]
Abstract
Intrahepatic cholangiocarcinoma is the second most frequent primary liver cancer after hepatocellular carcinoma. According to International Classification of Diseases-11 (ICD-11), intrahepatic cholangiocarcinoma is identified by a specific diagnostic code, different with respect to perihilar-CCA or distal-CCA. Intrahepatic cholangiocarcinoma originates from intrahepatic small or large bile ducts including the second-order bile ducts and has a silent presentation that combined with the highly aggressive nature and refractoriness to chemotherapy contributes to the alarming increasing incidence and mortality. Indeed, at the moment of the diagnosis, less than 40% of intrahepatic cholangiocarcinoma are suitable of curative surgical therapy, that is so far the only effective treatment. The main goals of clinicians and researchers are to make an early diagnosis, and to carry out molecular characterization to provide the patient with personalized treatment. Unfortunately, these goals are not easily achievable because of the heterogeneity of this tumor from anatomical, molecular, biological, and clinical perspectives. However, recent progress has been made in molecular characterization, surgical treatment, and management of intrahepatic cholangiocarcinoma and, this article deals with these advances.
Collapse
Affiliation(s)
- Maria Consiglia Bragazzi
- Department of Medical-Surgical Sciences and Biotechnology, Sapienza University of Rome Polo Pontino, Italy.
| | - Rosanna Venere
- Department of Medical-Surgical Sciences and Biotechnology, Sapienza University of Rome Polo Pontino, Italy
| | - Emanuela Ribichini
- Department Translational and Precision, Sapienza University of Rome, Italy
| | - Francesco Covotta
- Department Translational and Precision, Sapienza University of Rome, Italy
| | - Vincenzo Cardinale
- Department Translational and Precision, Sapienza University of Rome, Italy
| | - Domenico Alvaro
- Department Translational and Precision, Sapienza University of Rome, Italy
| |
Collapse
|
9
|
Gorji L, Brown ZJ, Limkemann A, Schenk AD, Pawlik TM. Liver Transplant as a Treatment of Primary and Secondary Liver Neoplasms. JAMA Surg 2024; 159:211-218. [PMID: 38055245 DOI: 10.1001/jamasurg.2023.6083] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/07/2023]
Abstract
Importance Liver malignancies are an increasing global health concern with a high mortality. We review outcomes following liver transplant for primary and secondary hepatic malignancies. Observations Transplant may be a suitable treatment option for primary and secondary hepatic malignancies in well-selected patient populations. Conclusions and Relevance Many patients with primary or secondary liver tumors are not eligible for liver resection because of advanced underlying liver disease or high tumor burden, precluding complete tumor clearance. Although liver transplant has been a long-standing treatment modality for patients with hepatocellular carcinoma, recently transplant has been considered for patients with other malignant diagnoses. In particular, while well-established for hepatocellular carcinoma and select patients with perihilar cholangiocarcinoma, transplant has been increasingly used to treat patients with intrahepatic cholangiocarcinoma, as well as metastatic disease from colorectal liver and neuroendocrine primary tumors. Because of the limited availability of grafts and the number of patients on the waiting list, optimal selection criteria must be further defined. The ethics of organ allocation to individuals who may benefit from prolonged survival after transplant yet have a high incidence of recurrence, as well as the role of living donation, need to be further discerned in the setting of transplant oncology.
Collapse
Affiliation(s)
- Leva Gorji
- Department of Surgery, Kettering Health Dayton, Dayton, Ohio
| | - Zachary J Brown
- Division of Surgical Oncology, Department of Surgery, New York University-Long Island, Mineola
| | - Ashley Limkemann
- Division of Transplant, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus
| | - Austin D Schenk
- Division of Transplant, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus
| | - Timothy M Pawlik
- Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center, James Cancer Hospital, Columbus
| |
Collapse
|
10
|
Schwenk L, Rauchfuß F, Ali-Deeb A, Dondorf F, Rohland O, Ardelt M, Settmacher U. [Individualized curative treatment for malignant diseases through liver transplantation]. CHIRURGIE (HEIDELBERG, GERMANY) 2024; 95:122-128. [PMID: 37847311 DOI: 10.1007/s00104-023-01973-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 09/22/2023] [Indexed: 10/18/2023]
Abstract
BACKGROUND For patients with primary and secondary liver tumors that are functionally or technically nonresectable, liver transplantation remains the sole curative treatment option. Over the years the benefits of transplantation have also been validated for conditions other than hepatocellular carcinoma. Currently, amidst a period of organ shortage the broadening of transplantation indications is a topic of ongoing debate. Although recent studies have confirmed the long-term success of transplantation within multimodal treatment regimens, this approach has yet to become the standard treatment for many conditions. OBJECTIVE This article explores the potential of liver transplantation in individualized multimodal oncological treatment strategies. RESULTS AND CONCLUSION Liver transplantation has become an integral component of the treatment regimen for hepatocellular carcinoma. In Germany there is a prioritized organ allocation facilitated by the granting of a standard exception for cases with a smaller tumor burden. Over the years numerous studies have demonstrated comparable long-term results using different listing criteria. Both intrahepatic cholangiocarcinoma and perihilar cholangiocarcinoma can be curatively treated with transplantation in Germany, although this is typically within the context of clinical studies. The neoadjuvant therapy and patient selection, based on tumor burden and the response to preliminary treatment, play a crucial role in influencing long-term survival and recurrence rates. The success of transplantation for liver metastases from neuroendocrine malignancies or colorectal carcinomas, which cannot be removed by partial resection, also significantly hinges on the patient selection. The role of living donor liver transplantation is becoming increasingly more pivotal in this context.
Collapse
Affiliation(s)
- Laura Schwenk
- Klinik für Allgemein‑, Viszeral- und Gefäßchirurgie, Universitätsklinikum Jena, Am Klinikum 1, 07747, Jena, Deutschland.
| | - Falk Rauchfuß
- Klinik für Allgemein‑, Viszeral- und Gefäßchirurgie, Universitätsklinikum Jena, Am Klinikum 1, 07747, Jena, Deutschland
| | - Aladdin Ali-Deeb
- Klinik für Allgemein‑, Viszeral- und Gefäßchirurgie, Universitätsklinikum Jena, Am Klinikum 1, 07747, Jena, Deutschland
| | - Felix Dondorf
- Klinik für Allgemein‑, Viszeral- und Gefäßchirurgie, Universitätsklinikum Jena, Am Klinikum 1, 07747, Jena, Deutschland
| | - Oliver Rohland
- Klinik für Allgemein‑, Viszeral- und Gefäßchirurgie, Universitätsklinikum Jena, Am Klinikum 1, 07747, Jena, Deutschland
| | - Michael Ardelt
- Klinik für Allgemein‑, Viszeral- und Gefäßchirurgie, Universitätsklinikum Jena, Am Klinikum 1, 07747, Jena, Deutschland
| | - Utz Settmacher
- Klinik für Allgemein‑, Viszeral- und Gefäßchirurgie, Universitätsklinikum Jena, Am Klinikum 1, 07747, Jena, Deutschland
| |
Collapse
|
11
|
Wilbur HC, Soares HP, Azad NS. Neoadjuvant and adjuvant therapy for biliary tract cancer: Advances and limitations. Hepatology 2024:01515467-990000000-00725. [PMID: 38266282 DOI: 10.1097/hep.0000000000000760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Accepted: 12/31/2023] [Indexed: 01/26/2024]
Abstract
Biliary tract cancers (BTC) are a rare and aggressive consortium of malignancies, consisting of intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder carcinoma. While most patients present with metastatic disease, a minority of patients with BTC are eligible for curative surgical resection at the time of presentation. However, these patients have poor 5-year overall survival rates and high rates of recurrence, necessitating the improvement of the neoadjuvant and adjuvant treatment of BTC. In this review, we assess the neoadjuvant and adjuvant clinical trials for the treatment of BTC and discuss the challenges and limitations of clinical trials, as well as future directions for the treatment of BTC.
Collapse
Affiliation(s)
- H Catherine Wilbur
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA
| | - Heloisa P Soares
- Division of Oncology, Department of Internal Medicine Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA
| | - Nilofer S Azad
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA
| |
Collapse
|
12
|
Loosen SH, Leyh C, Neumann UP, Bock H, Weigel C, Luedde T, Roderburg C. Liver transplantation meets gastrointestinal cancer. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2024; 62:62-72. [PMID: 38195110 DOI: 10.1055/a-2226-0123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2024]
Abstract
Liver transplantation (LT) has emerged as a standard of care for patients with end-stage liver disease, providing a life-saving intervention for patients with severely compromised liver function in both the acute and chronic setting. While LT has also become a routine procedure for early-stage hepatocellular carcinoma (HCC), offering a potential cure by treating both the tumor and the underlying liver disease, its relevance in the context of other malignancies such as cholangiocellular carcinoma (CCA), combined hepatocellular-cholangiocarcinoma (cHCC-CCA) or liver metastases is still the subject of intense debate and no definite recommendations have yet been established. This review summarizes the current therapeutic standards in the context of LT for gastrointestinal malignancies and provides a reflection and outlook on current scientific and clinical developments.
Collapse
Affiliation(s)
- Sven H Loosen
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany
| | - Catherine Leyh
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany
| | - Ulf Peter Neumann
- Department of General, Visceral and Transplantation Surgery, University Hospital RWTH Aachen, Aachen, Germany
- Department of Surgery and Transplantation, University Hospital Essen, Essen, Germany
| | - Hans Bock
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany
| | - Christian Weigel
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Tom Luedde
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany
| | - Christoph Roderburg
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany
| |
Collapse
|
13
|
Rushbrook SM, Kendall TJ, Zen Y, Albazaz R, Manoharan P, Pereira SP, Sturgess R, Davidson BR, Malik HZ, Manas D, Heaton N, Prasad KR, Bridgewater J, Valle JW, Goody R, Hawkins M, Prentice W, Morement H, Walmsley M, Khan SA. British Society of Gastroenterology guidelines for the diagnosis and management of cholangiocarcinoma. Gut 2023; 73:16-46. [PMID: 37770126 PMCID: PMC10715509 DOI: 10.1136/gutjnl-2023-330029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 09/05/2023] [Indexed: 10/03/2023]
Abstract
These guidelines for the diagnosis and management of cholangiocarcinoma (CCA) were commissioned by the British Society of Gastroenterology liver section. The guideline writing committee included a multidisciplinary team of experts from various specialties involved in the management of CCA, as well as patient/public representatives from AMMF (the Cholangiocarcinoma Charity) and PSC Support. Quality of evidence is presented using the Appraisal of Guidelines for Research and Evaluation (AGREE II) format. The recommendations arising are to be used as guidance rather than as a strict protocol-based reference, as the management of patients with CCA is often complex and always requires individual patient-centred considerations.
Collapse
Affiliation(s)
- Simon M Rushbrook
- Department of Hepatology, Norfolk and Norwich University Hospitals NHS Trust, Norwich, UK
| | - Timothy James Kendall
- Division of Pathology, University of Edinburgh, Edinburgh, UK
- University of Edinburgh MRC Centre for Inflammation Research, Edinburgh, UK
| | - Yoh Zen
- Department of Pathology, King's College London, London, UK
| | - Raneem Albazaz
- Department of Radiology, Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | | | | | - Richard Sturgess
- Digestive Diseases Unit, Aintree University Hospitals NHS Foundation Trust, Liverpool, UK
| | - Brian R Davidson
- Department of Surgery, Royal Free Campus, UCL Medical School, London, UK
| | - Hassan Z Malik
- Department of Surgery, University Hospital Aintree, Liverpool, UK
| | - Derek Manas
- Department of Surgery, Newcastle University, Newcastle upon Tyne, Tyne and Wear, UK
| | - Nigel Heaton
- Department of Hepatobiliary and Pancreatic Surgery, King's College London, London, UK
| | - K Raj Prasad
- John Goligher Colorectal Unit, St. James University Hospital, Leeds, UK
| | - John Bridgewater
- Department of Oncology, UCL Cancer Institute, University College London, London, UK
| | - Juan W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust/University of Manchester, Manchester, UK
| | - Rebecca Goody
- Department of Oncology, St James's University Hospital, Leeds, UK
| | - Maria Hawkins
- Department of Medical Physics and Biomedical Engineering, University College London, London, UK
| | - Wendy Prentice
- King's College Hospital NHS Foundation Trust, London, UK
| | | | | | - Shahid A Khan
- Hepatology and Gastroenterology Section, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
- Imperial College Healthcare NHS Trust, London, UK
| |
Collapse
|
14
|
Abdelrahim M, Esmail A, Abudayyeh A, Murakami N, Victor D, Kodali S, Cheah YL, Simon CJ, Noureddin M, Connor A, Saharia A, Moore LW, Heyne K, Kaseb AO, Gaber AO, Ghobrial RM. Transplant Oncology: An Emerging Discipline of Cancer Treatment. Cancers (Basel) 2023; 15:5337. [PMID: 38001597 PMCID: PMC10670243 DOI: 10.3390/cancers15225337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Accepted: 10/30/2023] [Indexed: 11/26/2023] Open
Abstract
Transplant oncology is an emerging concept of cancer treatment with a promising prospective outcome. The applications of oncology, transplant medicine, and surgery are the core of transplant oncology to improve patients' survival and quality of life. The main concept of transplant oncology is to radically cure cancer by removing the diseased organ and replacing it with a healthy one, aiming to improve the survival outcomes and quality of life of cancer patients. Subsequently, it seeks to expand the treatment options and research for hepatobiliary malignancies, which have seen significantly improved survival outcomes after the implementation of liver transplantation (LT). In the case of colorectal cancer (CRC) in the transplant setting, where the liver is the most common site of metastasis of patients who are considered to have unresectable disease, initial studies have shown improved survival for LT treatment compared to palliative therapy interventions. The indications of LT for hepatobiliary malignancies have been slowly expanded over the years beyond Milan criteria in a stepwise manner. However, the outcome improvements and overall patient survival are limited to the specifics of the setting and systematic intervention options. This review aims to illustrate the representative concepts and history of transplant oncology as an emerging discipline for the management of hepatobiliary malignancies, in addition to other emerging concepts, such as the uses of immunotherapy in a peri-transplant setting as well as the use of circulating tumor DNA (ctDNA) for surveillance post-transplantation.
Collapse
Affiliation(s)
- Maen Abdelrahim
- Section of GI Oncology, Department of Medical Oncology, Houston Methodist Cancer Center, Houston, TX 77030, USA; (A.E.)
- Cockrell Center of Advanced Therapeutics Phase I Program, Houston Methodist Research Institute, Houston, TX 77030, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
| | - Abdullah Esmail
- Section of GI Oncology, Department of Medical Oncology, Houston Methodist Cancer Center, Houston, TX 77030, USA; (A.E.)
| | - Ala Abudayyeh
- Section of Nephrology, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Naoka Murakami
- Division of Renal Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA;
| | - David Victor
- Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, JC Walter Jr. Center for Transplantation, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Sudha Kodali
- Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, JC Walter Jr. Center for Transplantation, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Yee Lee Cheah
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, JC Walter Jr. Center for Transplantation, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Caroline J. Simon
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, JC Walter Jr. Center for Transplantation, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Mazen Noureddin
- Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, JC Walter Jr. Center for Transplantation, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Ashton Connor
- Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, JC Walter Jr. Center for Transplantation, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Ashish Saharia
- Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, JC Walter Jr. Center for Transplantation, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Linda W. Moore
- Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, JC Walter Jr. Center for Transplantation, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Kirk Heyne
- Section of GI Oncology, Department of Medical Oncology, Houston Methodist Cancer Center, Houston, TX 77030, USA; (A.E.)
- Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
| | - Ahmed O. Kaseb
- Department of Gastrointestinal (GI) Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - A. Osama Gaber
- Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, JC Walter Jr. Center for Transplantation, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Rafik Mark Ghobrial
- Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, JC Walter Jr. Center for Transplantation, Houston Methodist Hospital, Houston, TX 77030, USA
| |
Collapse
|
15
|
Dhote A, Tzedakis S, Shapira OI, Nassar A, Boudjema K, Fuks D. Current status and perspectives in the surgical and oncological management of intrahepatic cholangiocarcinoma. J Visc Surg 2023; 160:346-355. [PMID: 37563006 DOI: 10.1016/j.jviscsurg.2023.07.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/12/2023]
Abstract
Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver tumor after hepatocellular carcinoma (HCC). Management depends on their resectability at the time of diagnosis. Two types can be distinguished by imaging: resectable ICCs amenable to surgery and locally advanced and/or metastatic ICCs, that are treated by chemotherapy, radiotherapy or loco-regional treatment (radioembolization, chemoembolization, intra-arterial chemotherapy and thermoablation). Over the last decade, the management strategy for these tumors has been modified by the appearance of loco-regional treatments as well as the introduction of immunotherapy that have shown their efficacy in the control of ICC. The aim of this review is to describe the current status of treatments for ICCs, as well as the different therapeutic strategies being assessed.
Collapse
Affiliation(s)
- Alix Dhote
- AP-HP, Cochin Port Royal Hospital Group, DMU Cancerology and medical-surgical specialties, Digestive, Hepatobiliary and Endocrine Surgery Department, Paris, France; Paris-Sorbonne University, Paris, France
| | - Stylianos Tzedakis
- AP-HP, Cochin Port Royal Hospital Group, DMU Cancerology and medical-surgical specialties, Digestive, Hepatobiliary and Endocrine Surgery Department, Paris, France; Paris Cité University, Paris, France
| | - Ortal Itzaki Shapira
- AP-HP, Cochin Port Royal Hospital Group, DMU Cancerology and medical-surgical specialties, Digestive, Hepatobiliary and Endocrine Surgery Department, Paris, France
| | - Alexandra Nassar
- AP-HP, Cochin Port Royal Hospital Group, DMU Cancerology and medical-surgical specialties, Digestive, Hepatobiliary and Endocrine Surgery Department, Paris, France; Paris Cité University, Paris, France
| | - Karim Boudjema
- Hepatobiliary and Digestive Surgery Department, Pontchaillou Hospital, Rennes 1 University, Rennes, France
| | - David Fuks
- AP-HP, Cochin Port Royal Hospital Group, DMU Cancerology and medical-surgical specialties, Digestive, Hepatobiliary and Endocrine Surgery Department, Paris, France; Paris Cité University, Paris, France.
| |
Collapse
|
16
|
Shannon AH, Ruff SM, Schenk AD, Washburn K, Pawlik TM. Updates and Expert Opinions on Liver Transplantation for Gastrointestinal Malignancies. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1290. [PMID: 37512101 PMCID: PMC10383519 DOI: 10.3390/medicina59071290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 07/12/2023] [Accepted: 07/12/2023] [Indexed: 07/30/2023]
Abstract
Transplant oncology is a relatively new field in which transplantation is used to treat patients who would otherwise be unresectable. New anticancer treatment paradigms using tumor and transplant immunology and cancer immunogenomics are emerging. In turn, liver transplantation (LT) has become a potential therapy for certain patients with colorectal cancer (CRC) with liver metastasis, hepatocellular (HCC), cholangiocarcinoma (CCA), and metastatic neuroendocrine tumor (NET) of the liver. Although there are established criteria for LT in HCC, evidence regarding LT as a treatment modality for certain gastrointestinal malignancies is still debated. The aim of this review is to highlight updates in the role of LT for certain malignancies, including HCC, metastatic CRC, hilar CCA, and neuroendocrine tumor (NET), as well as contextualize LT use and discuss controversies in transplant oncology.
Collapse
|
17
|
Lin K, Cao J, Chen H, Topatana W, Cai J, Zhang B, Hu J, Jin R. Research trends in cholangiocarcinoma treatments during the last 3 decades. Heliyon 2023; 9:e17100. [PMID: 37455974 PMCID: PMC10338968 DOI: 10.1016/j.heliyon.2023.e17100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 06/05/2023] [Accepted: 06/07/2023] [Indexed: 07/18/2023] Open
Abstract
Background Over the past 30 years, numerous studies have focused on the treatment of cholangiocarcinoma (CCA), and these treatments have greatly evolved. Objectives To better understand the research trends, we evaluated the most influential publications and attempted to identify their characteristics using bibliometric methods. Methods The most influential publications were identified from the Clarivate Analytics Web of Science Core Collection database. The general characteristics of included papers were identified, and the research trends were explored via the bibliometric method. Results The average total number of citations for of the listed publications were 312 (range from 165 to 1922). The highest number of papers were published during period II (2001-2010, n = 50), followed by period III (2011-2020, n = 28), and period I (1991-2000, n = 22). The United States and Germany have made remarkable achievements in this field. Institutionally, Mayo Clinic and Memorial Sloan-Kettering Cancer Center were the leading institutions, with Blumgart and Zhu from the United States being the most influential authors. Close collaboration was established between the leading countries, institutions, and authors. The Annals of Surgery contributed the most to the papers with the highest total number of citations. Surgery predominated during period I (n = 14, 63.6%), with a gradual decline occurring during periods II (n = 19, 41.3%, P = 0.085) and period III (n = 3, 9.4%, P = 0.002). Contrastingly, the number of publications related to systemic therapy has increased significantly since period II and peaked in period III. Conclusions Surgery remains the most important treatment for CCA. However systemic therapy has become a research and clinical application hotspot. These findings will contribute to the translation of treatments for CCA and provide researchers with relevant research directions.
Collapse
Affiliation(s)
- Kainan Lin
- Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310058, Zhejiang Province, China
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, Zhejiang Province, China
| | - Jiasheng Cao
- Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310058, Zhejiang Province, China
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, Zhejiang Province, China
| | - Haibo Chen
- Department of Gastrointestinal Surgery, The First People's Hospital of Wenling, Taizhou, 317500, Zhejiang Province, China
| | - Win Topatana
- Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310058, Zhejiang Province, China
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, Zhejiang Province, China
| | - Jingwei Cai
- Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310058, Zhejiang Province, China
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, Zhejiang Province, China
| | - Bin Zhang
- Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310058, Zhejiang Province, China
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, Zhejiang Province, China
| | - Jiahao Hu
- Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310058, Zhejiang Province, China
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, Zhejiang Province, China
| | - Renan Jin
- Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310058, Zhejiang Province, China
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, Zhejiang Province, China
| |
Collapse
|
18
|
Alvaro D, Gores GJ, Walicki J, Hassan C, Sapisochin G, Komuta M, Forner A, Valle JW, Laghi A, Ilyas SI, Park JW, Kelley RK, Reig M, Sangro B. EASL-ILCA Clinical Practice Guidelines on the management of intrahepatic cholangiocarcinoma. J Hepatol 2023; 79:181-208. [PMID: 37084797 DOI: 10.1016/j.jhep.2023.03.010] [Citation(s) in RCA: 81] [Impact Index Per Article: 40.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 03/10/2023] [Indexed: 04/23/2023]
Abstract
Intrahepatic cholangiocarcinoma (iCCA) develops inside the liver, between bile ductules and the second-order bile ducts. It is the second most frequent primary liver cancer after hepatocellular carcinoma, and its global incidence is increasing. It is associated with an alarming mortality rate owing to its silent presentation (often leading to late diagnosis), highly aggressive nature and resistance to treatment. Early diagnosis, molecular characterisation, accurate staging and personalised multidisciplinary treatments represent current challenges for researchers and physicians. Unfortunately, these challenges are beset by the high heterogeneity of iCCA at the clinical, genomic, epigenetic and molecular levels, very often precluding successful management. Nonetheless, in the last few years, progress has been made in molecular characterisation, surgical management, and targeted therapy. Recent advances together with the awareness that iCCA represents a distinct entity amongst the CCA family, led the ILCA and EASL governing boards to commission international experts to draft dedicated evidence-based guidelines for physicians involved in the diagnostic, prognostic, and therapeutic management of iCCA.
Collapse
|
19
|
Keltner SJ, Hallemeier C, Wang K, Tao R, Shah S, Heimbach J, Kharofa JR. Neoadjuvant Therapy Regimens for Hilar Cholangiocarcinoma Before Liver Transplant. Am J Clin Oncol 2023; 46:276-278. [PMID: 37036238 DOI: 10.1097/coc.0000000000001002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/11/2023]
Abstract
OBJECTIVES Patients with unresectable hilar cholangiocarcinoma (hCCA) may be eligible for curative treatment through liver transplantation (LT). Neoadjuvant protocols often include radiotherapy (RT), however, there is no standard RT approach. The purpose of this study is to characterize practice patterns of RT use before transplantation for hCCA. METHODS A survey was administered to radiation oncologists practicing at LT centers identified through the U.S. Organ Procurement and Transplant Network and the International Cholangiocarcinoma Research Network. The survey consisted of 13 questions regarding RT details as well as approaches to systemic therapy. For cross-regimen comparison, the cumulative RT tumor dose was standardized using the EQD2 method. RESULTS Twenty-three centers utilizing neoadjuvant therapy for hCCA were identified. Most respondents (96%) use both chemotherapy and RT as part of their protocol. Elective nodal volumes commonly included the portal vein lymph nodes (91%) and celiac artery lymph nodes (70%). After an initial 45 Gy plan, a wide range of sequential boost regimens was used. The median cumulative dose including boosts to the gross disease was 58 Gy (EQD2) with a wide range of 40 to 110 Gy. Five (22%) include brachytherapy as part of their treatment plan. The majority (96%) used concurrent chemotherapy with fluoropyrimidines. CONCLUSIONS These results suggest significant variability of neoadjuvant RT use for hCCA before LT. A wide range of doses and fractionation schemes are utilized with cumulative doses ranging from 40 to 110 Gy (EQD2). A further study evaluating the efficacy and toxicity of these various approaches is warranted to better inform best practices.
Collapse
Affiliation(s)
| | | | - Kyle Wang
- University of Cincinnati Cancer Center
| | - Randa Tao
- University of Utah Huntsman Cancer Institute, Salt Lake City, UT
| | - Shimul Shah
- University of Cincinnati Medical Center/College of Medicine, Cincinnati, OH
| | | | | |
Collapse
|
20
|
Borakati A, Froghi F, Bhogal RH, Mavroeidis VK. Liver transplantation in the management of cholangiocarcinoma: Evolution and contemporary advances. World J Gastroenterol 2023; 29:1969-1981. [PMID: 37155529 PMCID: PMC10122785 DOI: 10.3748/wjg.v29.i13.1969] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 02/10/2023] [Accepted: 03/21/2023] [Indexed: 04/06/2023] Open
Abstract
Cholangiocarcinoma (CCA) is an aggressive malignancy arising from the biliary epithelium. It may occur at any location along the biliary tree with the perihilar area being the most common. Prognosis is poor with 5-year overall survival at less than 10%, typically due to unresectable disease at presentation. Radical surgical resection with clear margins offers a chance of cure in patients with resectable tumours, but is frequently not possible due to locally advanced disease. On the other hand, orthotopic liver transplantation (LT) allows for a radical and potentially curative resection for these patients, but has been historically controversial due to the limited supply of donor grafts and previously poor outcomes. In patients with perihilar CCA, within specific criteria and following the implementation of a protocol combining neoadjuvant chemoradiation and LT, excellent results have been achieved in the last decades, resulting in its increasing acceptance as an indication for LT and the standard of care in several centres with significant experience. However, in intrahepatic CCA, the role of LT remains controversial and owing to dismal previous results it is not an accepted indication. Nevertheless, more recent studies have demonstrated favourable results with LT in early intrahepatic CCA, indicating that, under defined criteria, its role may increase in the future. This review highlights the history and contemporary advances of LT in CCA, with particular focus on the improving outcomes of LT in intrahepatic and perihilar CCA and future perspectives.
Collapse
Affiliation(s)
- Aditya Borakati
- Department of HPB and Liver Transplantation Surgery, Royal Free Hospital NHS Foundation Trust, London NW3 2QG, United Kingdom
| | - Farid Froghi
- Department of HPB and Liver Transplantation Surgery, Royal Free Hospital NHS Foundation Trust, London NW3 2QG, United Kingdom
| | - Ricky H Bhogal
- Department of Academic Surgery, The Royal Marsden NHS Foundation Trust, London SW3 6JJ, United Kingdom
| | - Vasileios K Mavroeidis
- Department of Academic Surgery, The Royal Marsden NHS Foundation Trust, London SW3 6JJ, United Kingdom
| |
Collapse
|
21
|
Duggan WP, Brosnan C, Christodoulides N, Nolan N, Kambakamba P, Gallagher TK. Outruling cholangiocarcinoma in patients with primary sclerosing cholangitis wait-listed for liver transplantation: A report on the Irish national experience. Surgeon 2023; 21:e83-e88. [PMID: 35680491 DOI: 10.1016/j.surge.2022.05.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Revised: 05/05/2022] [Accepted: 05/18/2022] [Indexed: 11/18/2022]
Abstract
BACKGROUND The presence of diffuse biliary stricturing in Primary Sclerosing Cholangitis (PSC) makes the diagnosis of early Cholangiocarcinoma (CCA) in this context difficult. A finding of incidental CCA on liver explant is associated with poor oncological outcomes, despite this; there remains no international consensus on how best to outrule CCA in this group ahead of transplantation. The objectives of this study were to report the Irish incidence of incidental CCA in individuals with PSC undergoing liver transplantation, and to critically evaluate the accuracy of diagnostic modalities in outruling CCA in our wait-listed PSC cohort. METHODS We conducted a retrospective analysis of our prospectively maintained database, which included all PSC patients wait-listed for liver transplant in Ireland. RESULTS 4.41% of patients (n = 3) were found to have an incidental finding of CCA on liver explant. Despite only being performed in 35.06% of wait-listed PSC patients (n = 27), Endoscopic Retrograde Cholangiopancreatogram (ERCP) with brush cytology was found to be the most effective tool in correctly outruling CCA in this context; associated with a specificity of 96.15%. CONCLUSION Our findings support a future role for routine surveillance of PSC patients awaiting liver transplantation; however further research is required in order to identify which investigative modalities are of optimal diagnostic utility in this specific context.
Collapse
Affiliation(s)
- William P Duggan
- Department of Hepatobiliary and Transplant Surgery, St. Vincent's University Hospital, Elm Park, Dublin 4, Ireland; Department of Surgery, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
| | - Conor Brosnan
- Department of Hepatobiliary and Transplant Surgery, St. Vincent's University Hospital, Elm Park, Dublin 4, Ireland; Department of Surgery, Royal College of Surgeons in Ireland, Dublin 2, Ireland
| | | | - Niamh Nolan
- Department of Pathology, St. Vincent's University Hospital, Elm Park, Dublin, Ireland
| | - Patryk Kambakamba
- Department of Hepatobiliary and Transplant Surgery, St. Vincent's University Hospital, Elm Park, Dublin 4, Ireland
| | - Tom K Gallagher
- Department of Hepatobiliary and Transplant Surgery, St. Vincent's University Hospital, Elm Park, Dublin 4, Ireland
| |
Collapse
|
22
|
Quaresima S, Melandro F, Giovanardi F, Shah K, De Peppo V, Mennini G, Ghinolfi D, Limkemann A, Pawlik TM, Lai Q. New Insights in the Setting of Transplant Oncology. Medicina (B Aires) 2023; 59:medicina59030568. [PMID: 36984569 PMCID: PMC10058845 DOI: 10.3390/medicina59030568] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 03/10/2023] [Accepted: 03/13/2023] [Indexed: 03/17/2023] Open
Abstract
Background and Objectives: Liver transplantation (LT) is the best strategy for curing several primary and secondary hepatic malignancies. In recent years, growing interest has been observed in the enlargement of the transplant oncology indications. This paper aims to review the most recent developments in the setting of LT oncology, with particular attention to LT for unresectable colorectal liver metastases (CRLM) and cholangiocellular carcinoma (CCA). Materials and Methods: A review of the recently published literature was conducted. Results: Growing evidence exists on the efficacy of LT in curing CRLM and peri-hilar and intrahepatic CCA in well-selected patients when integrating this strategy with (neo)-adjuvant chemotherapy, radiotherapy, or locoregional treatments. Conclusion: For unresectable CCA and CRLM management, several prospective protocols are forthcoming to elucidate LT’s impact relative to alternative therapies. Advances in diagnosis, treatment protocols, and donor-to-recipient matching are needed to better define the oncological indications for transplantation. Prospective, multicenter trials studying these advances and their impact on outcomes are still required.
Collapse
Affiliation(s)
- Silvia Quaresima
- General Surgery and Organ Transplantation Unit, AOU Policlinico Umberto I, Sapienza University of Rome, 00161 Rome, Italy
| | - Fabio Melandro
- General Surgery and Organ Transplantation Unit, AOU Policlinico Umberto I, Sapienza University of Rome, 00161 Rome, Italy
| | - Francesco Giovanardi
- General Surgery and Organ Transplantation Unit, AOU Policlinico Umberto I, Sapienza University of Rome, 00161 Rome, Italy
| | - Kejal Shah
- Department of Surgery, Division of Surgical Oncology, James Cancer Center, The Ohio State University, Columbus, OH 43210, USA
| | - Valerio De Peppo
- General Surgery and Organ Transplantation Unit, AOU Policlinico Umberto I, Sapienza University of Rome, 00161 Rome, Italy
| | - Gianluca Mennini
- General Surgery and Organ Transplantation Unit, AOU Policlinico Umberto I, Sapienza University of Rome, 00161 Rome, Italy
| | - Davide Ghinolfi
- Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, 56124 Pisa, Italy
| | - Ashley Limkemann
- Department of Surgery, Division of Surgical Oncology, James Cancer Center, The Ohio State University, Columbus, OH 43210, USA
| | - Timothy M. Pawlik
- Department of Surgery, Division of Surgical Oncology, James Cancer Center, The Ohio State University, Columbus, OH 43210, USA
| | - Quirino Lai
- General Surgery and Organ Transplantation Unit, AOU Policlinico Umberto I, Sapienza University of Rome, 00161 Rome, Italy
- Correspondence: ; Tel.: +39-3493020126; Fax: +39-06499701
| |
Collapse
|
23
|
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] [MESH Headings] [Track Full Text] [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.
Collapse
Affiliation(s)
- Francesco Giovinazzo
- General Surgery and Liver Transplant Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Correspondence:
| | - 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
| |
Collapse
|
24
|
Mauro E, Ferrer-Fàbrega J, Sauri T, Soler A, Cobo A, Burrel M, Iserte G, Forner A. New Challenges in the Management of Cholangiocarcinoma: The Role of Liver Transplantation, Locoregional Therapies, and Systemic Therapy. Cancers (Basel) 2023; 15:1244. [PMID: 36831586 PMCID: PMC9953927 DOI: 10.3390/cancers15041244] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Revised: 02/03/2023] [Accepted: 02/11/2023] [Indexed: 02/18/2023] Open
Abstract
Cholangiocarcinoma (CCA) is a neoplasm with high mortality that represents 15% of all primary liver tumors. Its worldwide incidence is on the rise, and despite important advances in the knowledge of molecular mechanisms, diagnosis, and treatment, overall survival has not substantially improved in the last decade. Surgical resection remains the cornerstone therapy for CCA. Unfortunately, complete resection is only possible in less than 15-35% of cases, with a risk of recurrence greater than 60%. Liver transplantation (LT) has been postulated as an effective therapeutic strategy in those intrahepatic CCA (iCCA) smaller than 3 cm. However, the low rate of early diagnosis in non-resectable patients justifies the low applicability in clinical practice. The evidence regarding LT in locally advanced iCCA is scarce and based on small, retrospective, and, in most cases, single-center case series. In this setting, the response to neoadjuvant chemotherapy could be useful in identifying a subgroup of patients with biologically less aggressive tumors in whom LT may be successful. The results of LT in pCCA are promising, however, we need a very careful selection of patients and adequate experience in the transplant center. Locoregional therapies may be relevant in unresectable, liver-only CCA. In iCCA smaller than 2 cm, particularly those arising in patients with advanced chronic liver disease in whom resection or LT may not be feasible, thermal ablation may become a reliable alternative. The greatest advances in the management of CCA occur in systemic treatment. Immunotherapy associated with chemotherapy has emerged as the gold standard in the first-line treatment. Likewise, the most encouraging results have been obtained with targeted therapies, where the use of personalized treatments has shown high rates of objective and durable tumor response, with clear signs of survival benefit. In conclusion, the future of CCA treatment seems to be marked by the development of new treatment strategies but high-quality, prospective studies that shed light on their use and applicability are mandatory.
Collapse
Affiliation(s)
- Ezequiel Mauro
- Barcelona Clinic Liver Cancer (BCLC) Group, IDIBAPS, 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Av. Monforte de Lemos, 3-5. Pabellón 11, Planta 0, 28029 Madrid, Spain
| | - Joana Ferrer-Fàbrega
- Barcelona Clinic Liver Cancer (BCLC) Group, IDIBAPS, 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Av. Monforte de Lemos, 3-5. Pabellón 11, Planta 0, 28029 Madrid, Spain
- Hepatobiliopancreatic Surgery and Liver and Pancreatic Transplantation Unit, Department of Surgery, ICMDM, Hospital Clinic Barcelona, 08036 Barcelona, Spain
- Faculty of Medicine, University of Barcelona, C/ de Casanova, 143, 08036 Barcelona, Spain
| | - Tamara Sauri
- Barcelona Clinic Liver Cancer (BCLC) Group, IDIBAPS, 08036 Barcelona, Spain
- Faculty of Medicine, University of Barcelona, C/ de Casanova, 143, 08036 Barcelona, Spain
- Medical Oncology Department, ICMHO, Hospital Clinic Barcelona, 08036 Barcelona, Spain
| | - Alexandre Soler
- Barcelona Clinic Liver Cancer (BCLC) Group, IDIBAPS, 08036 Barcelona, Spain
- Radiology Department, CDI, Hospital Clinic Barcelona, 08036 Barcelona, Spain
| | - Amparo Cobo
- Barcelona Clinic Liver Cancer (BCLC) Group, IDIBAPS, 08036 Barcelona, Spain
- Nuclear Medicine Department, CDI, Hospital Clinic Barcelona, 08036 Barcelona, Spain
| | - Marta Burrel
- Barcelona Clinic Liver Cancer (BCLC) Group, IDIBAPS, 08036 Barcelona, Spain
- Department of Interventional Radiology, CDI, Hospital Clinic Barcelona, 08036 Barcelona, Spain
| | - Gemma Iserte
- Barcelona Clinic Liver Cancer (BCLC) Group, IDIBAPS, 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Av. Monforte de Lemos, 3-5. Pabellón 11, Planta 0, 28029 Madrid, Spain
- Liver Unit, Liver Oncology Unit, ICMDM, Hospital Clinic Barcelona, 08036 Barcelona, Spain
| | - Alejandro Forner
- Barcelona Clinic Liver Cancer (BCLC) Group, IDIBAPS, 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Av. Monforte de Lemos, 3-5. Pabellón 11, Planta 0, 28029 Madrid, Spain
- Faculty of Medicine, University of Barcelona, C/ de Casanova, 143, 08036 Barcelona, Spain
- Liver Unit, Liver Oncology Unit, ICMDM, Hospital Clinic Barcelona, 08036 Barcelona, Spain
| |
Collapse
|
25
|
Clinical Features and Prognostic Models in Patients with Intrahepatic Cholangiocarcinoma: a Population-Based Analysis. J Gastrointest Surg 2023; 27:945-955. [PMID: 36729234 DOI: 10.1007/s11605-023-05602-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2022] [Accepted: 01/07/2023] [Indexed: 02/03/2023]
Abstract
BACKGROUND This study aims to construct a risk classification system and a nomogram in intrahepatic cholangiocarcinomafor patients (ICC). METHODS Three thousand seven hundred thirty-seven patients diagnosed with ICC between 2010 and 2015 were selected from the Surveillance, Epidemiology and End Results. The consistency index, time-dependent receiver operating characteristic curve, and the calibration plots were adopted to evaluate the effective performance of nomogram. Decision curve analysis (DCA), net reclassification index (NRI), and comprehensive discrimination improvement (IDI) were used to compare the advantages and disadvantages of two models. Kaplan-Meier curve showed the difference in prognosis among different groups. RESULTS Ten variables were selected to establish the nomogram for ICCA. The C-index (training cohort: 0.765, P < 0.05; validation cohort: 0.776, P < 0.05) and the time-dependent AUCs (the training cohort: the values of 1, 3, 5 years were 0.836, 0.873, and 0.888; the validation cohort: the values of 1, 3, 5 years were 0.833, 0.838, and 0.881) showed satisfactory discrimination. The calibration curves also revealed that the nomogram was consistent with the actual observations. The NRI (training cohort: 1-, 3-, 5-year CSS: 0.879, 0.94, 0.771; validation cohort: 1-, 3-, 5-year CSS: 0.905, 0.945, 0.717) and IDI (training cohort: 1-, 3-, 5-year CSS: 0.24, 0.23, 0.22; validation cohort: 1-, 3-, 5-year CSS: 0.24, 0.46, 0.27) (P < 0.05) (compared with AJCC staging). DCA showed that the new model was more practical and had better recognition than AJCC staging. CONCLUSIONS A new risk stratification system for ICC patients has been developed, which can be a practical tool for patient management.
Collapse
|
26
|
Wegermann K, Henson JB, King LY. CON: Intrahepatic cholangiocarcinoma should be a contraindication to liver transplantation. Clin Liver Dis (Hoboken) 2023; 21:52-55. [PMID: 36950307 PMCID: PMC10022851 DOI: 10.1097/cld.0000000000000010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 11/13/2022] [Indexed: 03/24/2023] Open
|
27
|
Yang Y, Zhang X. An overview of extrahepatic cholangiocarcinoma: from here to where? Front Oncol 2023; 13:1171098. [PMID: 37197436 PMCID: PMC10183586 DOI: 10.3389/fonc.2023.1171098] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 04/11/2023] [Indexed: 05/19/2023] Open
Abstract
Extrahepatic cholangiocarcinoma (eCCA) contains perihilar cholangiocarcinoma and distal cholangiocarcinoma both of which can arise at any point of the biliary tree and originate from disparate anatomical sites. Generally, the incidence of eCCA is increasing globally. Though surgical resection is the principal treatment of choice for the early stages of eCCA, optimal survival remains restricted by the high risk of recurrence when most patients are present with unresectable disease or distant metastasis. Furthermore, both intra- and intertumoral heterogeneity make it laborious to determine molecularly targeted therapies. In this review, we mainly focused on current findings in the field of eCCA, mostly including epidemiology, genomic abnormalities, molecular pathogenesis, tumor microenvironment, and other details while a summary of the biological mechanisms driving eCCA may shed light on intricate tumorigenesis and feasible treatment strategies.
Collapse
|
28
|
Smith EN, Coleman A, J. Galgano S, Burgan CM, Porter KK. Cholangiocarcinoma. ONCOLOGIC IMAGING : A MULTIDISCIPLINARY APPROACH 2023:133-159. [DOI: 10.1016/b978-0-323-69538-1.00011-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
29
|
FGFR Inhibitors in Cholangiocarcinoma-A Novel Yet Primary Approach: Where Do We Stand Now and Where to Head Next in Targeting This Axis? Cells 2022; 11:cells11233929. [PMID: 36497187 PMCID: PMC9737583 DOI: 10.3390/cells11233929] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 11/20/2022] [Accepted: 12/01/2022] [Indexed: 12/12/2022] Open
Abstract
Cholangiocarcinomas (CCAs) are rare but aggressive tumours with poor diagnosis and limited treatment options. Molecular targeted therapies became a promising proposal for patients after progression under first-line chemical treatment. In light of an escalating prevalence of CCA, it is crucial to fully comprehend its pathophysiology, aetiology, and possible targets in therapy. Such knowledge would play a pivotal role in searching for new therapeutic approaches concerning diseases' symptoms and their underlying causes. Growing evidence showed that fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) pathway dysregulation is involved in a variety of processes during embryonic development and homeostasis as well as tumorigenesis. CCA is known for its close correlation with the FGF/FGFR pathway and targeting this axis has been proposed in treatment guidelines. Bearing in mind the significance of molecular targeted therapies in different neoplasms, it seems most reasonable to move towards intensive research and testing on these in the case of CCA. However, there is still a need for more data covering this topic. Although positive results of many pre-clinical and clinical studies are discussed in this review, many difficulties lie ahead. Furthermore, this review presents up-to-date literature regarding the outcomes of the latest clinical data and discussion over future directions of FGFR-directed therapies in patients with CCA.
Collapse
|
30
|
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.
Collapse
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.
| |
Collapse
|
31
|
Connor AA, Kodali S, Abdelrahim M, Javle MM, Brombosz EW, Ghobrial RM. Intrahepatic cholangiocarcinoma: The role of liver transplantation, adjunctive treatments, and prognostic biomarkers. Front Oncol 2022; 12:996710. [PMID: 36479082 PMCID: PMC9719919 DOI: 10.3389/fonc.2022.996710] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 10/31/2022] [Indexed: 08/01/2023] Open
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is a primary epithelial cell malignancy of the liver with rising incidence rate globally. Its insidious presentation, heterogeneous and aggressive biology, and recalcitrance to current therapies results in unacceptably high morbidity and mortality. This has spurred research efforts in the last decade to better characterize it molecularly with translation to improved diagnostic tools and treatments. Much of this has been driven by patient advocacy. This has renewed interest in orthotopic liver transplantation (LT) with adjunctive therapies for iCCA, which was historically disparaged due to poor recipient outcomes and donor organ scarcity. However, the optimal use of LT as a treatment for iCCA care remains unclear. Here, we review the epidemiology of iCCA, the history of LT as a treatment modality, alternative approaches to iCCA local control, the evidence for peri-operative systemic therapies, and the potential roles of biomarkers and targeted agents. In doing so, we hope to prioritize areas for continued research and identify areas where multidisciplinary care can improve outcomes.
Collapse
Affiliation(s)
- Ashton A. Connor
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, JC Walter Jr Transplant Center, Houston Methodist Hospital, Houston, TX, United States
- Department of Surgery, Houston Methodist Hospital, Houston, TX, United States
| | - Sudha Kodali
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, JC Walter Jr Transplant Center, Houston Methodist Hospital, Houston, TX, United States
- Department of Medicine, Weill Cornell Medical College, New York, NY, United States
| | - Maen Abdelrahim
- Department of Medicine, Weill Cornell Medical College, New York, NY, United States
- Section of Gastrointestinal Oncology, Department of Medical Oncology, Houston Methodist Cancer Center, Houston, TX, United States
- Cockrell Center Phase 1 Unit, Cockrell Center for Advanced Therapeutics, Houston Methodist Hospital, Houston, TX, United States
| | - Milind M. Javle
- Department of Gastrointestinal Medical Oncology, MD Anderson Cancer Center, Houston, TX, United States
| | | | - R. Mark Ghobrial
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, JC Walter Jr Transplant Center, Houston Methodist Hospital, Houston, TX, United States
- Department of Surgery, Houston Methodist Hospital, Houston, TX, United States
- Department of Medicine, Weill Cornell Medical College, New York, NY, United States
| |
Collapse
|
32
|
Safdar NZ, Hakeem AR, Faulkes R, James F, Mason L, Masson S, Powell J, Rowe I, Shetty S, Jones R, Spiers HVM, Halliday N, Baker J, Thorburn D, Prasad R, Parker R. Outcomes After Liver Transplantation With Incidental Cholangiocarcinoma. Transpl Int 2022; 35:10802. [PMID: 36406780 PMCID: PMC9667791 DOI: 10.3389/ti.2022.10802] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 10/18/2022] [Indexed: 12/03/2022]
Abstract
Cholangiocarcinoma (CCA) is currently a contraindication to liver transplantation (LT) in the United Kingdom (UK). Incidental CCA occurs rarely in some patients undergoing LT. We report on retrospective outcomes of patients with incidental CCA from six UK LT centres. Cases were identified from pathology records. Data regarding tumour characteristics and post-transplant survival were collected. CCA was classified by TNM staging and anatomical location. 95 patients who underwent LT between 1988-2020 were identified. Median follow-up after LT was 2.1 years (14 days-18.6 years). Most patients were male (68.4%), median age at LT was 53 (IQR 46-62), and the majority had underlying PSC (61%). Overall median survival after LT was 4.4 years. Survival differed by tumour site: 1-, 3-, and 5-year estimated survival was 82.1%, 68.7%, and 57.1%, respectively, in intrahepatic CCA (n = 40) and 58.5%, 42.6%, and 30.2% in perihilar CCA (n = 42; p = 0.06). 1-, 3-, and 5-year estimated survival was 95.8%, 86.5%, and 80.6%, respectively, in pT1 tumours (28.2% of cohort), and 65.8%, 44.7%, and 31.1%, respectively, in pT2-4 (p = 0.018). Survival after LT for recipients with incidental CCA is inferior compared to usual outcomes for LT in the United Kingdom. LT for earlier stage CCA has similar survival to LT for hepatocellular cancer, and intrahepatic CCAs have better survival compared to perihilar CCAs. These observations may support LT for CCA in selected cases.
Collapse
Affiliation(s)
- Nawaz Z. Safdar
- School of Medicine, University of Leeds, Leeds, United Kingdom
- Leeds Liver Unit, St James’ University Hospital, Leeds, United Kingdom
| | - Abdul R. Hakeem
- Leeds Liver Unit, St James’ University Hospital, Leeds, United Kingdom
| | | | - Fiona James
- Leeds Liver Unit, St James’ University Hospital, Leeds, United Kingdom
| | - Lisa Mason
- Royal Infirmary of Edinburgh, Edinburgh, United Kingdom
| | - Steven Masson
- Newcastle Upon Tyne Hospitals, Newcastle, United Kingdom
| | - James Powell
- Royal Infirmary of Edinburgh, Edinburgh, United Kingdom
| | - Ian Rowe
- Leeds Liver Unit, St James’ University Hospital, Leeds, United Kingdom
| | - Shishir Shetty
- University Hospitals Birmingham, Birmingham, United Kingdom
| | - Rebecca Jones
- Leeds Liver Unit, St James’ University Hospital, Leeds, United Kingdom
| | - Harry V. M. Spiers
- Roy Calne Transplant Unit, Addenbrooke’s Hospital, Cambridge, United Kingdom
| | | | | | | | - Raj Prasad
- Leeds Liver Unit, St James’ University Hospital, Leeds, United Kingdom
| | - Richard Parker
- Leeds Liver Unit, St James’ University Hospital, Leeds, United Kingdom
| |
Collapse
|
33
|
Knavel Koepsel EM, Smolock AR, Pinchot JW, Kim CY, Ahmed O, Chamarthy MRK, Hecht EM, Hwang GL, Kaplan DE, Luh JY, Marrero JA, Monroe EJ, Poultsides GA, Scheidt MJ, Hohenwalter EJ. ACR Appropriateness Criteria® Management of Liver Cancer: 2022 Update. J Am Coll Radiol 2022; 19:S390-S408. [PMID: 36436965 DOI: 10.1016/j.jacr.2022.09.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 09/01/2022] [Indexed: 11/27/2022]
Abstract
The treatment and management of hepatic malignancies can be complex because it encompasses a variety of primary and metastatic malignancies and an assortment of local and systemic treatment options. When to use each of these treatments is critical to ensure the most appropriate care for patients. Interventional radiologists have a key role to play in the delivery of a variety of liver directed treatments including percutaneous ablation, transarterial embolization with bland embolic particles alone, transarterial chemoembolization (TACE) with injection of a chemotherapeutic emulsion, and transarterial radioembolization (TARE). Based on 9 clinical variants, the appropriateness of each treatment is described in this document. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances in which peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.
Collapse
Affiliation(s)
| | - Amanda R Smolock
- Froedtert & The Medical College of Wisconsin, Milwaukee, Wisconsin
| | | | - Charles Y Kim
- Panel Vice-Chair, Duke University Medical Center, Durham, North Carolina
| | - Osmanuddin Ahmed
- Vice-Chair of Wellness, Director of Venous Interventions, University of Chicago, Chicago, Illinois
| | - Murthy R K Chamarthy
- Vascular Institute of North Texas, Dallas, Texas; Commission on Nuclear Medicine and Molecular Imaging
| | - Elizabeth M Hecht
- Vice-Chair of Academic Affairs, Professor of Radiology, Weill Cornell Medicine, New York, New York; RADS Committee; Member of Appropriateness Subcommittees on Hepatobiliary Topics; Member of LI-RADS
| | - Gloria L Hwang
- Associate Chair of Clinical Performance Improvement, Stanford Radiology, Stanford Medical Center, Stanford, California
| | - David E Kaplan
- Section Chief of Hepatology at the University of Pennsylvania Division of Gastroenterology and Hepatology, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania; American Association for the Study of Liver Diseases
| | - Join Y Luh
- Providence Health Radiation Oncology Focus Group Chair, Providence St. Joseph Health, Eureka, California; Commission on Radiation Oncology; ACR CARROS President; ACR Council Steering Committee; California Radiological Society Councilor to ACR
| | - Jorge A Marrero
- University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; American Gastroenterological Association
| | | | - George A Poultsides
- Chief of Surgical Oncology and Professor of Surgery, Stanford University School of Medicine, Stanford, California; Society of Surgical Oncology
| | - Matthew J Scheidt
- Program Director of Independent IR Residency, Froedtert & The Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Eric J Hohenwalter
- Specialty Chair; Chief, MCW VIR, Froedtert & The Medical College of Wisconsin, Milwaukee, Wisconsin
| |
Collapse
|
34
|
Liver Transplantation as a New Standard of Care in Patients With Perihilar Cholangiocarcinoma? Results From an International Benchmark Study. Ann Surg 2022; 276:846-853. [PMID: 35894433 PMCID: PMC9983747 DOI: 10.1097/sla.0000000000005641] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE To define benchmark values for liver transplantation (LT) in patients with perihilar cholangiocarcinoma (PHC) enabling unbiased comparisons. BACKGROUND Transplantation for PHC is used with reluctance in many centers and even contraindicated in several countries. Although benchmark values for LT are available, there is a lack of specific data on LT performed for PHC. METHODS PHC patients considered for LT after Mayo-like protocol were analyzed in 17 reference centers in 2 continents over the recent 5-year period (2014-2018). The minimum follow-up was 1 year. Benchmark patients were defined as operated at high-volume centers (≥50 overall LT/year) after neoadjuvant chemoradiotherapy, with a tumor diameter <3 cm, negative lymph nodes, and with the absence of relevant comorbidities. Benchmark cutoff values were derived from the 75th to 25th percentiles of the median values of all benchmark centers. RESULTS One hundred thirty-four consecutive patients underwent LT after completion of the neoadjuvant treatment. Of those, 89.6% qualified as benchmark cases. Benchmark cutoffs were 90-day mortality ≤5.2%; comprehensive complication index at 1 year of ≤33.7; grade ≥3 complication rates ≤66.7%. These values were better than benchmark values for other indications of LT. Five-year disease-free survival was largely superior compared with a matched group of nodal negative patients undergoing curative liver resection (n=106) (62% vs 32%, P <0.001). CONCLUSION This multicenter benchmark study demonstrates that LT offers excellent outcomes with superior oncological results in early stage PHC patients, even in candidates for surgery. This provocative observation should lead to a change in available therapeutic algorithms for PHC.
Collapse
|
35
|
Jiang D, Ji T, Liu W, Bednarsch J, Selzner M, Pratschke J, Lurje G, Cao T, Brüggenwirth IMA, Martins PN, Arke Lang S, Peter Neumann U, Czigany Z. Four Decades of Clinical Liver Transplantation Research: Results of a Comprehensive Bibliometric Analysis. Transplantation 2022; 106:1897-1908. [PMID: 35831925 DOI: 10.1097/tp.0000000000004224] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Nearly 40 y have passed since the 1983 National Institutes of Health Consensus-Development-Conference, which has turned liver transplantation (LT) from a clinical experiment into a routine therapeutic modality. Since' clinical LT has changed substantially. We aimed to comprehensively analyze the publication trends in the most-cited top-notch literature in LT science over a 4-decade period. METHODS A total of 106 523 items were identified between January 1981 and May 2021 from the Web of Science Core Collection. The top 100 articles published were selected using 2 distinct citation-based strategies to minimize bias. Various bibliometric tools were used for data synthesis and visualization. RESULTS The citation count for the final dataset of the top 100 articles ranged from 251 to 4721. Most articles were published by US authors (n = 61). The most prolific institution was the University of Pittsburgh (n = 15). The highest number of articles was published in Annals of Surgery, Hepatology, and Transplantation ; however, Hepatology publications resulted in the highest cumulative citation of 9668. Only 10% of the articles were classified as evidence level 1. Over 90% of first/last authors were male. Our data depict the evolution of research focus over 40 y. In part, a disproportional flow of citations was observed toward already well-cited articles. This might also project a slowed canonical progress, which was described in other fields of science. CONCLUSIONS This study highlights key trends based on a large dataset of the most-cited articles over a 4-decade period. The present analysis not only provides an important cross-sectional and forward-looking guidance to clinicians, funding bodies, and researchers but also draws attention to important socio-academic or demographic aspects in LT.
Collapse
Affiliation(s)
- Decan Jiang
- Department of Surgery and Transplantation, Faculty of Medicine, University Hospital RWTH Aachen, Aachen, Germany
| | - Tengfei Ji
- Department of Hepatobiliary Surgery, Affiliated Huadu Hospital of Southern Medical University (People's Hospital of Huadu District), Guangzhou, P.R. China
| | - Wenjia Liu
- Department of Surgery and Transplantation, Faculty of Medicine, University Hospital RWTH Aachen, Aachen, Germany
| | - Jan Bednarsch
- Department of Surgery and Transplantation, Faculty of Medicine, University Hospital RWTH Aachen, Aachen, Germany
| | - Markus Selzner
- Multi Organ Transplant Program, University Health Network, Toronto, ON, Canada
| | - Johann Pratschke
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Georg Lurje
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Tiansheng Cao
- Department of Hepatobiliary Surgery, Affiliated Huadu Hospital of Southern Medical University (People's Hospital of Huadu District), Guangzhou, P.R. China
| | - Isabel M A Brüggenwirth
- Department of Surgery, Section of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University Medical Center Groningen, Groningen, The Netherlands
| | - Paulo N Martins
- Transplant Division, Department of Surgery, UMass Memorial Hospital, University of Massachusetts, Worcester, MA
| | - Sven Arke Lang
- Department of Surgery and Transplantation, Faculty of Medicine, University Hospital RWTH Aachen, Aachen, Germany
| | - Ulf Peter Neumann
- Department of Surgery and Transplantation, Faculty of Medicine, University Hospital RWTH Aachen, Aachen, Germany
- Department of Surgery, Maastricht University Medical Centre (MUMC), Maastricht, The Netherlands
| | - Zoltan Czigany
- Department of Surgery and Transplantation, Faculty of Medicine, University Hospital RWTH Aachen, Aachen, Germany
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
| |
Collapse
|
36
|
Elvevi A, Laffusa A, Scaravaglio M, Rossi RE, Longarini R, Stagno AM, Cristoferi L, Ciaccio A, Cortinovis DL, Invernizzi P, Massironi S. Clinical treatment of cholangiocarcinoma: an updated comprehensive review. Ann Hepatol 2022; 27:100737. [PMID: 35809836 DOI: 10.1016/j.aohep.2022.100737] [Citation(s) in RCA: 69] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 06/25/2022] [Indexed: 02/04/2023]
Abstract
Cholangiocarcinoma (CCA) is a heterogeneous group of neoplasms of the bile ducts and represents the second most common hepatic cancer after hepatocellular carcinoma; it is sub-classified as intrahepatic cholangiocarcinoma (iCCA) and extrahepatic cholangiocarcinoma (eCCA), the latter comprising both perihilar cholangiocarcinoma (pCCA or Klatskin tumor), and distal cholangiocarcinoma (dCCA). The global incidence of CCA has increased worldwide in recent decades. Chronic inflammation of biliary epithelium and bile stasis represent the main risk factors shared by all CCA sub-types. When feasible, liver resection is the treatment of choice for CCA, followed by systemic chemotherapy with capecitabine. Liver transplants represent a treatment option in patients with very early iCCA, in referral centers only. CCA diagnosis is often performed at an advanced stage when CCA is unresectable. In this setting, systemic chemotherapy with gemcitabine and cisplatin represents the first treatment option, but the prognosis remains poor. In order to ameliorate patients' survival, new drugs have been studied in the last few years. Target therapies are directed against different molecules, which are altered in CCA cells. These therapies have been studied as second-line therapy, alone or in combination with chemotherapy. In the same setting, the immune checkpoints inhibitors targeting programmed death 1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte antigen-4 (CTLA-4), have been proposed, as well as cancer vaccines and adoptive cell therapy (ACT). These experimental treatments showed promising results and have been proposed as second- or third-line treatment, alone or in combination with chemotherapy or target therapies.
Collapse
Affiliation(s)
- Alessandra Elvevi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital and Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Alice Laffusa
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital and Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Miki Scaravaglio
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital and Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Roberta Elisa Rossi
- Gastroenterology and Endoscopy Unit, Humanitas Clinical and Research Center, IRCCS, Rozzano, Milan, Italy
| | - Raffaella Longarini
- Division of Oncology, San Gerardo Hospital and Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Anna Maria Stagno
- Division of Oncology, San Gerardo Hospital and Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Laura Cristoferi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital and Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Antonio Ciaccio
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital and Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Diego Luigi Cortinovis
- Division of Oncology, San Gerardo Hospital and Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital and Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Sara Massironi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital and Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
| |
Collapse
|
37
|
Brandão ABDM, Rodriguez S, Fleck Jr ADM, Marroni CA, Wagner MB, Hörbe A, Fernandes MV, Cerski CTS, Coral GP. Propensity-matched analysis of patients with intrahepatic cholangiocarcinoma or mixed hepatocellular-cholangiocarcinoma and hepatocellular carcinoma undergoing a liver transplant. World J Clin Oncol 2022; 13:688-701. [PMID: 36160465 PMCID: PMC9476608 DOI: 10.5306/wjco.v13.i8.688] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 06/14/2022] [Accepted: 07/11/2022] [Indexed: 11/08/2022] Open
Abstract
BACKGROUND Cholangiocarcinoma (CC) is a rare tumor that arises from the epithelium of the bile ducts. It is classified according to anatomic location as intrahepatic, perihilar, and distal. Intrahepatic CC (ICC) is rare in patients with cirrhosis due to causes other than primary sclerosing cholangitis. Mixed hepatocellular carcinoma-CC (HCC-CC) is a rare neoplasm that shows histologic findings of both HCC and ICC within the same tumor mass. Due to the difficulties in arriving at the correct diagnosis, patients eventually undergo liver transplantation (LT) with a presumptive diagnosis of HCC on imaging when, in fact, they have ICC or HCC-CC.
AIM To evaluate the outcomes of patients with intrahepatic cholangiocarcinoma or mixed hepatocellular-cholangiocarcinoma on pathological examination after liver transplant.
METHODS Propensity score matching was used to analyze tumor recurrence (TR), overall mortality (OM), and recurrence-free survival (RFS) in LT recipients with pathologically confirmed ICC or HCC-CC matched 1:8 to those with HCC. Progression-free survival and overall mortality rates were computed with the Kaplan-Meier method using Cox regression for comparison.
RESULTS Of 475 HCC LT recipients, 1.7% had the diagnosis of ICC and 1.5% of HCC-CC on pathological examination of the explant. LT recipients with ICC had higher TR (46% vs 11%; P = 0.006), higher OM (63% vs 23%; P = 0.002), and lower RFS (38% vs 89%; P = 0.002) than those with HCC when matched for pretransplant tumor characteristics, as well as higher TR (46% vs 23%; P = 0.083), higher OM (63% vs 35%; P = 0.026), and lower RFS (38% vs 59%; P = 0.037) when matched for posttransplant tumor characteristics. Two pairings were performed to compare the outcomes of LT recipients with HCC-CC vs HCC. There was no significant difference between the outcomes in either pairing.
CONCLUSION Patients with ICC had worse outcomes than patients undergoing LT for HCC. The outcomes of patients with HCC-CC did not differ significantly from those of patients with HCC.
Collapse
Affiliation(s)
- Ajacio Bandeira de Mello Brandão
- Graduate Program in Medicine: Hepatology, School of Medicine, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre 90050170, RS, Brazil
- Liver Transplantation Group, Santa Casa de Misericórdia de Porto Alegre, Porto Alegre 90020090, RS, Brazil
| | - Santiago Rodriguez
- Graduate Program in Medicine: Hepatology, School of Medicine, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre 90050170, RS, Brazil
- Department of Hepatology, Hospital Vozandes Quito-HVQ, Quito 170521, Ecuador
| | - Alfeu de Medeiros Fleck Jr
- Liver Transplantation Group, Santa Casa de Misericórdia de Porto Alegre, Porto Alegre 90020090, RS, Brazil
| | - Claudio Augusto Marroni
- Graduate Program in Medicine: Hepatology, School of Medicine, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre 90050170, RS, Brazil
- Liver Transplantation Group, Santa Casa de Misericórdia de Porto Alegre, Porto Alegre 90020090, RS, Brazil
| | - Mário B Wagner
- School of Medicine, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre 90035002, RS, Brazil
| | - Alex Hörbe
- Interventional Radiology Unit, Santa Casa de Misericórdia de, Porto Alegre 90020090, RS, Brazil
| | - Matheus V Fernandes
- Graduate Program in Medicine: Hepatology, School of Medicine, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre 90050170, RS, Brazil
| | - Carlos TS Cerski
- Department of Pathology, School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035002, RS, Brazil
| | - Gabriela Perdomo Coral
- Graduate Program in Medicine: Hepatology, School of Medicine, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre 90050170, RS, Brazil
| |
Collapse
|
38
|
Liver transplantation and intrahepatic cholangiocarcinoma: time to go forward again? Curr Opin Organ Transplant 2022; 27:320-328. [PMID: 36354258 DOI: 10.1097/mot.0000000000000983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
PURPOSE OF REVIEW Liver transplantation for intrahepatic cholangiocarcinoma (iCCA) has been mired in controversy. High rates of recurrence posttransplant combined with donor organ scarcity resulted in most transplant centers treating iCCA as a contraindication for liver transplantation. RECENT FINDINGS Recent studies have shown that carefully selected patients with unresectable iCCA can have good outcomes after liver transplantation. Better outcomes have been seen in patients with smaller tumors and favorable tumor biology. SUMMARY Because many patients are diagnosed with iCCA at later stages, tumor biology and genetics are useful tools to identify patients who will have excellent overall and recurrence-free survival after liver transplantation. Further larger multicenter prospective studies are needed to identify patients who would benefit from liver transplantation with good outcomes. Additional advances will come through early diagnosis and utilizing a combination of chemotherapy and locoregional modalities as a bridge to transplant. There is also a need to recognize and develop additional neo- and adjuvant therapies for patients whose tumor biology currently precludes their inclusion on the liver transplantation waitlist.
Collapse
|
39
|
|
40
|
The Role of Immunosuppression for Recurrent Cholangiocellular Carcinoma after Liver Transplantation. Cancers (Basel) 2022; 14:cancers14122890. [PMID: 35740555 PMCID: PMC9221145 DOI: 10.3390/cancers14122890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 06/02/2022] [Accepted: 06/06/2022] [Indexed: 02/04/2023] Open
Abstract
Liver transplantation (LT) for cholangiocarcinoma (CCA), or biliary tract cancer (BTC), remains controversial regarding high recurrence rates and poor prognosis. Oncological follow-up may benefit from tumor-inhibiting properties of mTOR inhibitors (mTORI), shown with improved survival for recurrent hepatocellular carcinoma (HCC) patients after LT. The aim of this study was to investigate the recurrence and survival in relation to tumor type and type of immunosuppression (IS). LT patients with CCA or mixed HCC/CCA (mHCC/CCA) (n = 67) were retrospectively analyzed. Endpoints were the time from LT to recurrence (n = 44) and survival after recurrence. Statistically significant impairment in survival for recurrent CCA (rCCA) was shown in patients not eligible for surgical resection (HR 2.46 (CI: 1.2−5.1; p = 0.02). Histological proven grading >1 and N1 status at initial transplantation were associated with impaired survival (HR 0.13 (CI: 0.03−0.58); p < 0.01 and HR 3.4 (CI: 1.0−11.65); p = 0.05). Reduced IS after tumor recurrence improved survival (HR 4.2/CI: 1.3−13.6; p = 0.02). MTORI initiation before recurrence or after had no significant impact on survival. Our data thereby indicate, similar to findings in recurrent HCC after LT, that patients with rCCA after LT benefit from a reduction in IS upon recurrence.
Collapse
|
41
|
Noji T, Hirano S, Tanaka K, Matsui A, Nakanishi Y, Asano T, Nakamura T, Tsuchikawa T. Concomitant Hepatic Artery Resection for Advanced Perihilar Cholangiocarcinoma: A Narrative Review. Cancers (Basel) 2022; 14:cancers14112672. [PMID: 35681652 PMCID: PMC9179358 DOI: 10.3390/cancers14112672] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 05/16/2022] [Accepted: 05/24/2022] [Indexed: 12/10/2022] Open
Abstract
Simple Summary In the eighth edition of their cancer classification system, the Union for International Cancer Control (UICC) defines contralateral hepatic artery invasion as T4, which is considered unresectable as it is a “locally advanced” tumour. However, in the last decade, several reports on hepatic artery resection (HAR) for perihilar cholangiocarcinoma (PHCC) have been published. The reported five-year survival rate after HAR is 16–38.5%. Alternative procedures for the treatment of HAR have also been reported. In this paper, we review HAR for PHCC, focusing on its history, diagnosis, procedures, and alternative procedures. Abstract Perihilar cholangiocarcinoma (PHCC) is one of the most intractable gastrointestinal malignancies. These tumours lie in the core section of the biliary tract. Patients who undergo curative surgery have a 40–50-month median survival time, and a five-year overall survival rate of 35–45%. Therefore, curative intent surgery can lead to long-term survival. PHCC sometimes invades the surrounding tissues, such as the portal vein, hepatic artery, perineural tissues around the hepatic artery, and hepatic parenchyma. Contralateral hepatic artery invasion is classed as T4, which is considered unresectable due to its “locally advanced” nature. Recently, several reports have been published on concomitant hepatic artery resection (HAR) for PHCC. The morbidity and mortality rates in these reports were similar to those non-HAR cases. The five-year survival rate after HAR was 16–38.5%. Alternative procedures for arterial portal shunting and non-vascular reconstruction (HAR) have also been reported. In this paper, we review HAR for PHCC, focusing on its history, diagnosis, procedures, and alternatives. HAR, undertaken by established biliary surgeons in selected patients with PHCC, can be feasible.
Collapse
|
42
|
Abdelrahim M, Al-Rawi H, Esmail A, Xu J, Umoru G, Ibnshamsah F, Abudayyeh A, Victor D, Saharia A, McMillan R, Al Najjar E, Bugazia D, Al-Rawi M, Ghobrial RM. Gemcitabine and Cisplatin as Neo-Adjuvant for Cholangiocarcinoma Patients Prior to Liver Transplantation: Case-Series. Curr Oncol 2022; 29:3585-3594. [PMID: 35621680 PMCID: PMC9139862 DOI: 10.3390/curroncol29050290] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 05/01/2022] [Accepted: 05/06/2022] [Indexed: 01/04/2023] Open
Abstract
Background: The management of cholangiocarcinoma is continually reviewed on a current evidence basis to develop practice guidelines and consensus statements. However, the standardized treatment guidelines are still unclear for cholangiocarcinoma patients who are listed for liver transplantation. We aimed to validate and evaluate the potential efficacy of chemotherapy combination of Gemcitabine and Cisplatin as a neo-adjuvant treatment for cholangiocarcinoma patients before liver transplantation. Methods: In this prospective case series, patients with locally advanced, unresectable, hilar, or intrahepatic cholangiocarcinoma with no evidence of extrahepatic disease or vascular involvement were treated with a combination of neoadjuvant gemcitabine and cisplatin with no radiation. All patients included received chemotherapy prior to being listed for liver transplantation at a single cancer center according to an open-labeled, and center-approved clinical management protocol. The primary endpoints were the overall survival and recurrence-free survival after liver transplantation. Results: Between 1 March 2016, and 15 March 2022, 10 patients (8 males and 2 females) with a median age of 62.71(interquartile range: 60.02–71.87) had a confirmed diagnosis of intrahepatic or hilar cholangiocarcinoma and underwent liver transplantation. Median days of neoadjuvant therapy for a given combination of gemcitabine and cisplatin were 181 (IRQ: 120–250). Nine patients (90%) were reported with no recurrence or metastasis, and only 1 patient had confirmed metastasis (10%); days for metastasis after transplantation were 612 for this patient. All patients received a combination of gemcitabine and cisplatin as neo-adjuvant while awaiting liver transplantation. The median days of follow-up were 851 (813–967). Overall survival was 100% (95% CI 100–100%) at both years one and two; 75% (95% CI 13–96%) at years three to five. One patient died at eight hundred and eighty-five days. No adverse events were reported after liver transplantation including the patient who was confirmed with recurrence. Conclusions: Our finding demonstrated that neo-adjuvant gemcitabine and cisplatin with no radiation prior to liver transplantation resulted in excellent outcomes for patients with cholangiocarcinoma.
Collapse
Affiliation(s)
- Maen Abdelrahim
- Section of GI Oncology, Department of Medical Oncology, Houston Methodist Cancer Center, Houston, TX 77030, USA; (H.A.-R.); (A.E.)
- Cockrell Center of Advanced Therapeutics Phase I Program, Houston Methodist Research Institute, Houston, TX 77030, USA
- Weill Cornell Medical College, New York, NY 14853, USA; (A.S.); (R.M.); (R.M.G.)
- Correspondence:
| | - Hadeel Al-Rawi
- Section of GI Oncology, Department of Medical Oncology, Houston Methodist Cancer Center, Houston, TX 77030, USA; (H.A.-R.); (A.E.)
- Faculty of Medicine, University of Jordan, Amman 11942, Jordan;
| | - Abdullah Esmail
- Section of GI Oncology, Department of Medical Oncology, Houston Methodist Cancer Center, Houston, TX 77030, USA; (H.A.-R.); (A.E.)
- Cancer Clinical Trials, Houston Methodist Research Institute, Houston, TX 77030, USA
- JC Walter Jr Center for Transplantation and Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston, TX 77030, USA;
| | - Jiaqiong Xu
- Center for Outcomes Research, Houston Methodist Research Institute, Houston, TX 77030, USA;
| | - Godsfavour Umoru
- Department of Pharmacy, Houston Methodist Cancer Center, Houston, TX 77030, USA;
| | - Fahad Ibnshamsah
- Medical Oncology, King Fahd Specialist Hospital, Buraydah 52366, Saudi Arabia;
- Faculty of Medicine, Imam Abdulrahman Bin Faisal University, Dammam 34212, Saudi Arabia
| | - Ala Abudayyeh
- Section of Nephrology, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - David Victor
- JC Walter Jr Center for Transplantation and Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston, TX 77030, USA;
| | - Ashish Saharia
- Weill Cornell Medical College, New York, NY 14853, USA; (A.S.); (R.M.); (R.M.G.)
- JC Walter Jr Center for Transplantation and Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston, TX 77030, USA;
| | - Robert McMillan
- Weill Cornell Medical College, New York, NY 14853, USA; (A.S.); (R.M.); (R.M.G.)
- JC Walter Jr Center for Transplantation and Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston, TX 77030, USA;
| | - Ebtesam Al Najjar
- Faculty of Medicine and Health Sciences, University of Science and Technology, Sanaa 15201, Yemen;
| | - Doaa Bugazia
- Faculty of Medicine, University of Tripoli, Tripoli 22131, Libya;
| | - Maryam Al-Rawi
- Faculty of Medicine, University of Jordan, Amman 11942, Jordan;
| | - Rafik M. Ghobrial
- Weill Cornell Medical College, New York, NY 14853, USA; (A.S.); (R.M.); (R.M.G.)
- JC Walter Jr Center for Transplantation and Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston, TX 77030, USA;
| |
Collapse
|
43
|
Liver Transplant for Non-Hepatocellular Malignancies: A Review for Radiologists. AJR Am J Roentgenol 2022; 219:590-603. [PMID: 35544376 DOI: 10.2214/ajr.22.27783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Although traditionally only performed for hepatocellular carcinoma (HCC), the last decade has seen a resurgence in the use of liver transplant (LT) for non-HCC malignancies, likely due to improvements in neoadjuvant treatment regimens as well as the establishment of well-defined eligibility criteria. Given promising survival results, patients with perihilar cholangiocarcinoma, neuroendocrine liver metastases, and hepatic hemangioendothelioma are eligible to receive Model for End Stage Liver Disease (MELD) exception for tumors that meet well-defined criteria. Additional tumors such as colorectal cancer liver metastases, intrahepatic cholangiocarcinoma, and hepatocholangiocarcinoma may undergo transplant at specialized centers with well-defined protocols, although are not yet eligible for MELD exception. Transplant eligibility criteria commonly incorporate imaging findings, yet due to the relatively novel and evolving nature of LT for non-HCC malignancies, radiologists may be unaware of relevant criteria or of the implications of their imaging interpretations. Knowledge of the allocation process, background, and liver transplant selection criteria facilitates the radiologist' active participation in multidisciplinary discussion, leading to better and more equitable care for transplant candidates with non-HCC malignancy. This review provides an overview of transplant allocation and selection criteria in patients with non-HCC malignancy, with an emphasis on imaging features and the role of the radiologist.
Collapse
|
44
|
Current Perspectives on the Surgical Management of Perihilar Cholangiocarcinoma. Cancers (Basel) 2022; 14:cancers14092208. [PMID: 35565335 PMCID: PMC9104954 DOI: 10.3390/cancers14092208] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Revised: 04/21/2022] [Accepted: 04/21/2022] [Indexed: 02/08/2023] Open
Abstract
Cholangiocarcinoma (CCA) represents nearly 15% of all primary liver cancers and 2% of all cancer-related deaths worldwide. Perihilar cholangiocarcinoma (pCCA) accounts for 50-60% of all CCA. First described in 1965, pCCAs arise between the second-order bile ducts and the insertion of the cystic duct into the common bile duct. CCA typically has an insidious onset and commonly presents with advanced, unresectable disease. Complete surgical resection is technically challenging, as tumor proximity to the structures of the central liver often necessitates an extended hepatectomy to achieve negative margins. Intraoperative frozen section can aid in assuring negative margins and complete resection. Portal lymphadenectomy provides important prognostic and staging information. In specialized centers, vascular resection and reconstruction can be performed to achieve negative margins in appropriately selected patients. In addition, minimally invasive surgical techniques (e.g., robotic surgery) are safe, feasible, and provide equivalent short-term oncologic outcomes. Neoadjuvant chemoradiation therapy followed by liver transplantation provides a potentially curative option for patients with unresectable disease. New trials are needed to investigate novel chemotherapies, immunotherapies, and targeted therapies to better control systemic disease in the adjuvant setting and, potentially, downstage disease in the neoadjuvant setting.
Collapse
|
45
|
Ellis RJ, Soares KC, Jarnagin WR. Preoperative Management of Perihilar Cholangiocarcinoma. Cancers (Basel) 2022; 14:cancers14092119. [PMID: 35565250 PMCID: PMC9104035 DOI: 10.3390/cancers14092119] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 04/19/2022] [Accepted: 04/21/2022] [Indexed: 02/01/2023] Open
Abstract
Perihilar cholangiocarcinoma is a rare hepatobiliary malignancy that requires thoughtful, multidisciplinary evaluation in the preoperative setting to ensure optimal patient outcomes. Comprehensive preoperative imaging, including multiphase CT angiography and some form of cholangiographic assessment, is key to assessing resectability. While many staging systems exist, the Blumgart staging system provides the most useful combination of resectability assessment and prognostic information for use in the preoperative setting. Once resectability is confirmed, volumetric analysis should be performed. Upfront resection without biliary drainage or portal venous embolization may be considered in patients without cholangitis and an estimated functional liver remnant (FLR) > 40%. In patients with FLR < 40%, judicious use of biliary drainage is advised, with the goal of selective biliary drainage of the functional liver remnant. Percutaneous biliary drainage may avoid inadvertent contamination of the contralateral biliary tree and associated infectious complications, though the relative effectiveness of percutaneous and endoscopic techniques is an ongoing area of study and debate. Patients with low FLR also require intervention to induce hypertrophy, most commonly portal venous embolization, in an effort to reduce the rate of postoperative liver failure. Even with extensive preoperative workup, many patients will be found to have metastatic disease at exploration and diagnostic laparoscopy may reduce the rate of non-therapeutic laparotomy. Management of perihilar cholangiocarcinoma continues to evolve, with ongoing efforts to improve preoperative liver hypertrophy and to further define the role of transplantation in disease management.
Collapse
Affiliation(s)
- Ryan J. Ellis
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; (R.J.E.); (K.C.S.)
| | - Kevin C. Soares
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; (R.J.E.); (K.C.S.)
- Department of Surgery, Weill Cornell Medical College, New York, NY 10021, USA
| | - William R. Jarnagin
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; (R.J.E.); (K.C.S.)
- Department of Surgery, Weill Cornell Medical College, New York, NY 10021, USA
- Correspondence:
| |
Collapse
|
46
|
Laughlin BS, Petersen MM, Yu NY, Anderson JD, Rule WG, Borad MJ, Aqel BA, Sonbol MB, Mathur AK, Moss AA, Bekaii-Saab TS, Ahn DH, DeWees TA, Sio TT, Ashman JB. Clinical outcomes for hilar and extrahepatic cholangiocarcinoma with adjuvant, definitive, or liver transplant-based neoadjuvant chemoradiotherapy strategies: a single-center experience. J Gastrointest Oncol 2022; 13:288-297. [PMID: 35284111 PMCID: PMC8899753 DOI: 10.21037/jgo-21-615] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 01/11/2022] [Indexed: 01/17/2024] Open
Abstract
BACKGROUND We report our experience with 3 strategies for treating hilar and extrahepatic cholangiocarcinoma (CCA) including chemoradiotherapy: neoadjuvant chemoradiotherapy (nCRT) and orthotopic liver transplant, surgical resection and adjuvant chemoradiotherapy (aCRT), and definitive chemoradiotherapy (dCRT). METHODS We included patients treated from 1998 through 2019. Kaplan-Meier estimates, log-rank testing, and univariate/multivariate Cox models were used to assess outcomes (local progression-free survival, disease-free survival, and overall survival). RESULTS Sixty-five patients (nCRT, n=20; aCRT, n=16; dCRT, n=29) met inclusion criteria [median (range) age 65 years (27-84 years)]. Median posttreatment follow-up was 19.1 months (0.8-164.8 months) for all patients and 38.6, 24.3, and 9.0 months for the nCRT, aCRT, and dCRT groups, respectively. At 3 and 5 years, overall survival was 78% and 59% for the nCRT group; 47% and 35%, aCRT group; and 11% and 0%, dCRT group. Compared with the dCRT group, the nCRT group (hazard ratio =0.13, 95% CI: 0.05-0.33) and the aCRT group (hazard ratio =0.29, 95% CI: 0.14-0.64) had significantly improved overall survival (P<0.001). The 5-year local progression-free survival (50% nCRT vs. 30% aCRT vs. 0% dCRT, P<0.001) and 5-year disease-free survival (61% nCRT vs. 30% aCRT vs. 0% dCRT, P=0.01) were significantly better for strategies combined with surgery. CONCLUSIONS Outcomes for patients with extrahepatic CCA were superior for those who underwent nCRT/orthotopic liver transplant or postsurgical aCRT than for patients treated with dCRT. The excellent outcomes after nCRT/orthotopic liver transplant provide additional independent data supporting the validity of this strategy. The poor survival of patients treated with dCRT highlights a need for better therapies when surgery is not possible.
Collapse
Affiliation(s)
- Brady S. Laughlin
- Mayo Clinic School of Graduate Medical Education, Mayo Clinic College of Medicine and Science, Phoenix, Arizona, USA
| | - Molly M. Petersen
- Clinical Trials and Biostatistics, Mayo Clinic, Scottsdale, Arizona, USA
| | - Nathan Y. Yu
- Mayo Clinic School of Graduate Medical Education, Mayo Clinic College of Medicine and Science, Phoenix, Arizona, USA
| | - Justin D. Anderson
- Mayo Clinic School of Graduate Medical Education, Mayo Clinic College of Medicine and Science, Phoenix, Arizona, USA
| | - William G. Rule
- Department of Radiation Oncology, Mayo Clinic Hospital, Phoenix, Arizona, USA
| | - Mitesh J. Borad
- Division of Hematology and Medical Oncology, Mayo Clinic Hospital, Phoenix, Arizona, USA
| | - Bashar A. Aqel
- Division of Gastroenterology and Hepatology, Mayo Clinic Hospital, Phoenix, Arizona, USA
- Transplant Center, Mayo Clinic Hospital, Phoenix, Arizona, USA
| | - Mohamad B. Sonbol
- Division of Hematology and Medical Oncology, Mayo Clinic Hospital, Phoenix, Arizona, USA
| | - Amit K. Mathur
- Transplant Center, Mayo Clinic Hospital, Phoenix, Arizona, USA
- Division of Transplant and Hepatobiliary Surgery, Mayo Clinic Hospital, Phoenix, Arizona, USA
| | - Adyr A. Moss
- Transplant Center, Mayo Clinic Hospital, Phoenix, Arizona, USA
- Division of Transplant and Hepatobiliary Surgery, Mayo Clinic Hospital, Phoenix, Arizona, USA
| | - Tanios S. Bekaii-Saab
- Division of Hematology and Medical Oncology, Mayo Clinic Hospital, Phoenix, Arizona, USA
| | - Daniel H. Ahn
- Division of Hematology and Medical Oncology, Mayo Clinic Hospital, Phoenix, Arizona, USA
- Mayo Clinic Cancer Center, Mayo Clinic Hospital, Phoenix, Arizona, USA
| | - Todd A. DeWees
- Clinical Trials and Biostatistics, Mayo Clinic, Scottsdale, Arizona, USA
- Department of Radiation Oncology, Mayo Clinic Hospital, Phoenix, Arizona, USA
| | - Terence T. Sio
- Department of Radiation Oncology, Mayo Clinic Hospital, Phoenix, Arizona, USA
| | - Jonathan B. Ashman
- Department of Radiation Oncology, Mayo Clinic Hospital, Phoenix, Arizona, USA
| |
Collapse
|
47
|
Sapisochin G, Ivanics T, Heimbach J. Liver Transplantation for Intrahepatic Cholangiocarcinoma: Ready for Prime Time? Hepatology 2022; 75:455-472. [PMID: 34859465 DOI: 10.1002/hep.32258] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 11/16/2021] [Accepted: 11/22/2021] [Indexed: 12/16/2022]
Abstract
Cholangiocarcinoma (CCA) represents the second-most common primary liver malignancy after HCC and has risen in incidence globally in the past decades. Intrahepatic cholangiocarcinoma (iCCA) comprises 20% of all CCAs, with the rest being extrahepatic (including perihilar [pCCA] and distal CCA). Though long representing an absolute contraindication for liver transplantation (LT), recent analyses of outcomes of LT for iCCA have suggested that iCCA may be a potentially feasible option for highly selected patients. This has been motivated both by successes noted in outcomes of LT for other malignancies, such as HCC and pCCA, and by several retrospective reviews demonstrating favorable results with LT for a selected group of iCCA patients with small lesions. LT for iCCA is primarily relevant within two clinical scenarios. The first includes patients with very early disease (single tumor, ≤2 cm) with cirrhosis and are not candidates for liver resection (LR). The second scenario is patients with locally advanced iCCA, but where the extent of LR would be too extensive to be feasible. Preliminary single-center reports have described LT in a selected group of patients with locally advanced tumors who have responded to neoadjuvant therapy and have a period of disease stability. Currently, there are three prospective trials underway that will help clarify the role of LT in iCCA. This review seeks to explore the available studies involving LT for iCCA, the challenges of ongoing trials, and opportunities for the future.
Collapse
Affiliation(s)
- Gonzalo Sapisochin
- Multi-Organ Transplant ProgramUniversity Health Network TorontoTorontoOntarioCanada
| | - Tommy Ivanics
- Multi-Organ Transplant ProgramUniversity Health Network TorontoTorontoOntarioCanada
- Department of SurgeryHenry Ford HospitalDetroitMichiganUSA
- Department of Surgical SciencesAkademiska SjukhusetUppsala UniversityUppsalaSweden
| | - Julie Heimbach
- Divison of Transplant SurgeryDepartment of SurgeryMayo ClinicRochesterMinnesotaUSA
| |
Collapse
|
48
|
Twohig P, Peeraphatdit TB, Mukherjee S. Current status of liver transplantation for cholangiocarcinoma. World J Gastrointest Surg 2022; 14:1-11. [PMID: 35126858 PMCID: PMC8790328 DOI: 10.4240/wjgs.v14.i1.1] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 07/12/2022] [Accepted: 12/28/2021] [Indexed: 02/06/2023] Open
Abstract
Cholangiocarcinoma (CCA) is the second most common liver cancer with a median survival of 12-24 mo without treatment. It is further classified based on its location into intrahepatic CCA (iCCA), perihilar CCA (pCCA), and distal CCA. Surgical resection is the mainstay of treatment, but up to 70% of these tumors are inoperable at the time of diagnosis. CCA was previously an absolute contraindication for liver transplantation (LT) due to poor outcomes primary due to early recurrent disease. However, improvement in patient selection criteria and neoadjuvant treatment protocols have improved outcomes for inoperable pCCA patients with recent studies reporting LT may improve survival in iCCA. Future advances in the treatment of CCA should include refining patient selection criteria and organ allocation for all subtypes of CCA, determining effective immunotherapies and the evolving role of personalized medicine in patients ineligible for surgical resection or LT. Our article reviews the current status of LT in CCA, along with future directions in managing patients with CCA.
Collapse
Affiliation(s)
- Patrick Twohig
- Department of Internal Medicine, Division of Gastroenterology and Transplant Hepatology, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Thoetchai Bee Peeraphatdit
- Department of Internal Medicine, Division of Gastroenterology and Transplant Hepatology, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Sandeep Mukherjee
- Department of Internal Medicine, Division of Gastroenterology, Creighton University, Omaha, NE 68124, United States
| |
Collapse
|
49
|
Ernani L, Martino RBD, Andraus W, Fernandes EDSM, Mello FPTD, Andrade R, Pimentel LS, Haddad LBDP, Coelho FF, Herman P, D'Albuquerque LAC. PROTOCOL FOR LIVER TRANSPLANTATION IN HILAR CHOLANGIOCARCINOMA. ABCD-ARQUIVOS BRASILEIROS DE CIRURGIA DIGESTIVA 2022; 34:e1618. [PMID: 35019130 PMCID: PMC8735267 DOI: 10.1590/0102-672020210002e1618] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Accepted: 04/25/2021] [Indexed: 11/22/2022]
Abstract
Background: Hilar cholangiocarcinoma represents more than half of all cholangiocarcinoma cases, having poor prognosis and presenting a median overall survival after diagnosis of 12-24 months. In patients who have unresectable tumors with a better prognosis, the proposal to perform liver transplantation emerged for expanding the possibility of free margins by performing total hepatectomy.
Aim: To provide a Brazilian protocol for liver transplantation in patients with hilar cholangiocarcinoma.
Method: The protocol was carried out by two Brazilian institutions which perform a large volume of resections and liver transplantations, based on the study carried out at the Mayo Clinic. The elaboration of the protocol was conducted in four stages.
Result: A protocol proposal for this disease is presented, which needs to be validated for clinical use.
Conclusion: The development of a liver transplantation protocol for cholangiocarcinoma aims not only to standardize the treatment, but also enable a better assessment of the surgical results in the future.
Collapse
Affiliation(s)
- Lucas Ernani
- Department of Gastroenterology, Hospital de Clínicas, Medical School, University of São Paulo, São Paulo, SP, Brazil
| | - Rodrigo Bronze de Martino
- Department of Gastroenterology, Hospital de Clínicas, Medical School, University of São Paulo, São Paulo, SP, Brazil
| | - Wellington Andraus
- Department of Gastroenterology, Hospital de Clínicas, Medical School, University of São Paulo, São Paulo, SP, Brazil
| | - Eduardo de Souza Martins Fernandes
- Department of General Surgery and Transplantation, Hospital Adventista Silvestre, Rio de Janeiro, RJ, Brazil.,Abdominal Transplant Surgery, Hospital São Lucas - Copacabana, Rio de Janeiro, RJ, Brazil
| | - Felipe Pedreira Tavares de Mello
- Department of General Surgery and Transplantation, Hospital Adventista Silvestre, Rio de Janeiro, RJ, Brazil.,Abdominal Transplant Surgery, Hospital São Lucas - Copacabana, Rio de Janeiro, RJ, Brazil
| | - Ronaldo Andrade
- Department of General Surgery and Transplantation, Hospital Adventista Silvestre, Rio de Janeiro, RJ, Brazil.,Abdominal Transplant Surgery, Hospital São Lucas - Copacabana, Rio de Janeiro, RJ, Brazil
| | - Leandro Savattone Pimentel
- Department of General Surgery and Transplantation, Hospital Adventista Silvestre, Rio de Janeiro, RJ, Brazil.,Abdominal Transplant Surgery, Hospital São Lucas - Copacabana, Rio de Janeiro, RJ, Brazil
| | | | - Fabricio Ferreira Coelho
- Department of Gastroenterology, Hospital de Clínicas, Medical School, University of São Paulo, São Paulo, SP, Brazil
| | - Paulo Herman
- Department of Gastroenterology, Hospital de Clínicas, Medical School, University of São Paulo, São Paulo, SP, Brazil
| | | |
Collapse
|
50
|
Acher AW, Rahnemai-Azar AA, Weber SM, Pawlik TM. Surgical Approach to Pancreas, Liver, Biliary Physiologic Impairment. THE IASGO TEXTBOOK OF MULTI-DISCIPLINARY MANAGEMENT OF HEPATO-PANCREATO-BILIARY DISEASES 2022:31-49. [DOI: 10.1007/978-981-19-0063-1_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|