Joana Ferrer-Fàbrega1, Jaime Sampson-Dávila2, Alejandro Forner3, Victor Sapena4, Alba Díaz5, Ramón Vilana6, Miquel Navasa7, Constantino Fondevila8, Rosa Miquel9, Carmen Ayuso6, Juan Carlos García-Valdecasas8, Jordi Bruix3, María Reig3, Josep Fuster10. 1. Hepatobiliopancreatic Surgery and Liver and Pancreatic Transplantation Unit, Department of Surgery, Institute Clínic of Digestive and Metabolic Diseases (ICMDiM), Hospital Clínic, University of Barcelona, Barcelona, Spain; Barcelona Clínic Liver Cancer Group (BCLC), University of Barcelona, Barcelona, Spain; August Pi i Sunyer Biomedical Research Institute (IDIBAPS), University of Barcelona, Barcelona, Spain. Electronic address: 2008jff@gmail.com. 2. Hepatobiliopancreatic Surgery and Liver and Pancreatic Transplantation Unit, Department of Surgery, Institute Clínic of Digestive and Metabolic Diseases (ICMDiM), Hospital Clínic, University of Barcelona, Barcelona, Spain. 3. Barcelona Clínic Liver Cancer Group (BCLC), University of Barcelona, Barcelona, Spain; August Pi i Sunyer Biomedical Research Institute (IDIBAPS), University of Barcelona, Barcelona, Spain; Liver Unit, Hospital Clínic, University of Barcelona, Barcelona, Spain; Network for Biomedical Research in Hepatic and Digestive Diseases (CIBERehd), Barcelona, Spain. 4. Barcelona Clínic Liver Cancer Group (BCLC), University of Barcelona, Barcelona, Spain; Network for Biomedical Research in Hepatic and Digestive Diseases (CIBERehd), Barcelona, Spain; Medical Statistics Core Facility, Hospital Clínic, University of Barcelona, Barcelona, Spain. 5. Barcelona Clínic Liver Cancer Group (BCLC), University of Barcelona, Barcelona, Spain; August Pi i Sunyer Biomedical Research Institute (IDIBAPS), University of Barcelona, Barcelona, Spain; Department of Pathology, Hospital Clínic. University of Barcelona, Barcelona, Spain. 6. Barcelona Clínic Liver Cancer Group (BCLC), University of Barcelona, Barcelona, Spain; August Pi i Sunyer Biomedical Research Institute (IDIBAPS), University of Barcelona, Barcelona, Spain; Network for Biomedical Research in Hepatic and Digestive Diseases (CIBERehd), Barcelona, Spain; Department of Radiology, Hospital Clínic, University of Barcelona, Barcelona, Spain. 7. August Pi i Sunyer Biomedical Research Institute (IDIBAPS), University of Barcelona, Barcelona, Spain; Liver Unit, Hospital Clínic, University of Barcelona, Barcelona, Spain; Network for Biomedical Research in Hepatic and Digestive Diseases (CIBERehd), Barcelona, Spain. 8. Hepatobiliopancreatic Surgery and Liver and Pancreatic Transplantation Unit, Department of Surgery, Institute Clínic of Digestive and Metabolic Diseases (ICMDiM), Hospital Clínic, University of Barcelona, Barcelona, Spain; August Pi i Sunyer Biomedical Research Institute (IDIBAPS), University of Barcelona, Barcelona, Spain; Network for Biomedical Research in Hepatic and Digestive Diseases (CIBERehd), Barcelona, Spain. 9. Barcelona Clínic Liver Cancer Group (BCLC), University of Barcelona, Barcelona, Spain; Department of Pathology, Hospital Clínic. University of Barcelona, Barcelona, Spain; Liver Histopathology Laboratory, Institute of Liver Studies, King's College Hospital, London, UK. 10. Hepatobiliopancreatic Surgery and Liver and Pancreatic Transplantation Unit, Department of Surgery, Institute Clínic of Digestive and Metabolic Diseases (ICMDiM), Hospital Clínic, University of Barcelona, Barcelona, Spain; Barcelona Clínic Liver Cancer Group (BCLC), University of Barcelona, Barcelona, Spain; August Pi i Sunyer Biomedical Research Institute (IDIBAPS), University of Barcelona, Barcelona, Spain; Network for Biomedical Research in Hepatic and Digestive Diseases (CIBERehd), Barcelona, Spain. Electronic address: jfuster@clinic.cat.
Abstract
BACKGROUND & AIMS: Defining optimum management of patients progressing beyond Milan criteria on the waiting list is a controversial topic. Our aim was to determine whether the policy of allowing a limited progression beyond enlistment criteria permits acceptable post-transplant outcomes in terms of survival and recurrence. METHODS: Patients with hepatocellular carcinoma included on the waiting list for orthotopic liver transplantation (OLT) between January 1989 and December 2016 were analysed. Tumour features were assessed at inclusion on the waiting list, before OLT and at explant pathology. Patients were retained on the waiting list despite exceeding enlistment criteria if not presenting with macrovascular invasion, extrahepatic spread or cancer-related symptoms. RESULTS: A total of 495 patients constituted the target population. Comparison between the Milan-in (n = 434) and Milan-out (n = 61) groups showed statistically significant differences in: largest tumour size; BCLC stage; patients treated before OLT; alpha-fetoprotein, and time on the waiting list. Milan-out patients showed a significantly higher number of poorly differentiated nodules, satellitosis and microscopic vascular invasion. The 1-, 3-, 5- and 10-year survival rate was 89.6%, 82.5%, 75%, and 55.5%, vs. 83.6%, 70.5%, 65.5%, and 53.9% for Milan-in/Milan-out patients, respectively. Recurrence rates at 1, 3, 5 and 10 years were 1.2%, 3.3%, 5.5%, and 10.8% vs. 7.1% 14.5%, 23%, and 23% for Milan-in and Milan-out patients, respectively (p <0.01). CONCLUSION: This study shows that although limited tumour progression without reaching major adverse predictors (vascular invasion, extrahepatic spread, cancer symptoms) has an expected impact on recurrence rate, overall survival remains above the minimum proposed benchmark of 65% at 5 years. The clinically relevant increase in tumour recurrence must be considered when analysing the benefit of this approach in the face of limited organ supply. LAY SUMMARY: When considering orthotopic liver transplantation for patients with hepatocellular carcinoma, optimum results are achieved when transplanting patients within the Milan criteria. However, the most appropriate strategy for patients who progress beyond these criteria while on the waiting list is still unclear. Herein, we show that transplantation is associated with acceptable overall survival in select patients who progress beyond the Milan criteria, although recurrence rates were notably higher. Therefore, the assessment of transplantation viability in these patients must consider the availability of organs and the impact on other patient categories.
BACKGROUND & AIMS: Defining optimum management of patients progressing beyond Milan criteria on the waiting list is a controversial topic. Our aim was to determine whether the policy of allowing a limited progression beyond enlistment criteria permits acceptable post-transplant outcomes in terms of survival and recurrence. METHODS: Patients with hepatocellular carcinoma included on the waiting list for orthotopic liver transplantation (OLT) between January 1989 and December 2016 were analysed. Tumour features were assessed at inclusion on the waiting list, before OLT and at explant pathology. Patients were retained on the waiting list despite exceeding enlistment criteria if not presenting with macrovascular invasion, extrahepatic spread or cancer-related symptoms. RESULTS: A total of 495 patients constituted the target population. Comparison between the Milan-in (n = 434) and Milan-out (n = 61) groups showed statistically significant differences in: largest tumour size; BCLC stage; patients treated before OLT; alpha-fetoprotein, and time on the waiting list. Milan-out patients showed a significantly higher number of poorly differentiated nodules, satellitosis and microscopic vascular invasion. The 1-, 3-, 5- and 10-year survival rate was 89.6%, 82.5%, 75%, and 55.5%, vs. 83.6%, 70.5%, 65.5%, and 53.9% for Milan-in/Milan-out patients, respectively. Recurrence rates at 1, 3, 5 and 10 years were 1.2%, 3.3%, 5.5%, and 10.8% vs. 7.1% 14.5%, 23%, and 23% for Milan-in and Milan-out patients, respectively (p <0.01). CONCLUSION: This study shows that although limited tumour progression without reaching major adverse predictors (vascular invasion, extrahepatic spread, cancer symptoms) has an expected impact on recurrence rate, overall survival remains above the minimum proposed benchmark of 65% at 5 years. The clinically relevant increase in tumour recurrence must be considered when analysing the benefit of this approach in the face of limited organ supply. LAY SUMMARY: When considering orthotopic liver transplantation for patients with hepatocellular carcinoma, optimum results are achieved when transplanting patients within the Milan criteria. However, the most appropriate strategy for patients who progress beyond these criteria while on the waiting list is still unclear. Herein, we show that transplantation is associated with acceptable overall survival in select patients who progress beyond the Milan criteria, although recurrence rates were notably higher. Therefore, the assessment of transplantation viability in these patients must consider the availability of organs and the impact on other patient categories.
Authors: Maria Reig; Alejandro Forner; Jordi Rimola; Joana Ferrer-Fàbrega; Marta Burrel; Ángeles Garcia-Criado; Robin K Kelley; Peter R Galle; Vincenzo Mazzaferro; Riad Salem; Bruno Sangro; Amit G Singal; Arndt Vogel; Josep Fuster; Carmen Ayuso; Jordi Bruix Journal: J Hepatol Date: 2021-11-19 Impact factor: 30.083