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Abstract Details
Limited tumor progression beyond Milan criteria while on the waiting list does not result in unacceptable impairment of survival
J Hepatol. 2021 Jun 22;S0168-8278(21)00435-9. doi: 10.1016/j.jhep.2021.06.015.Online ahead of print.
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
Author information
1Hepatobiliopancreatic 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); August Pi i Sunyer Biomedical Research Institute (IDIBAPS). Electronic address: 2008jff@gmail.com.
2Hepatobiliopancreatic 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.
3Barcelona Clínic Liver Cancer Group (BCLC); August Pi i Sunyer Biomedical Research Institute (IDIBAPS); Liver Unit, Hospital Clínic, University of Barcelona, Barcelona, Spain; Network for Biomedical Research in Hepatic and Digestive Diseases (CIBERehd), Barcelona, Spain.
4Barcelona Clínic Liver Cancer Group (BCLC); Network for Biomedical Research in Hepatic and Digestive Diseases (CIBERehd), Barcelona, Spain; Medical Statistics Core Facility. Hospital Clínic. University of Barcelona. Barcelona. Spain.
5Barcelona Clínic Liver Cancer Group (BCLC); August Pi i Sunyer Biomedical Research Institute (IDIBAPS); Department of Pathology. Hospital Clínic. University of Barcelona. Barcelona. Spain.
6Barcelona Clínic Liver Cancer Group (BCLC); August Pi i Sunyer Biomedical Research Institute (IDIBAPS); Network for Biomedical Research in Hepatic and Digestive Diseases (CIBERehd), Barcelona, Spain; Department of Radiology. Hospital Clínic. University of Barcelona. Barcelona. Spain.
7August Pi i Sunyer Biomedical Research Institute (IDIBAPS); Liver Unit, Hospital Clínic, University of Barcelona, Barcelona, Spain; Network for Biomedical Research in Hepatic and Digestive Diseases (CIBERehd), Barcelona, Spain.
8Hepatobiliopancreatic 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); Network for Biomedical Research in Hepatic and Digestive Diseases (CIBERehd), Barcelona, Spain.
9Barcelona Clínic Liver Cancer Group (BCLC); Department of Pathology. Hospital Clínic. University of Barcelona. Barcelona. Spain; Liver Histopathology Laboratory. Institute of Liver Studies. King's College Hospital. UK.
10Hepatobiliopancreatic 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); August Pi i Sunyer Biomedical Research Institute (IDIBAPS); 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 outcomes in terms of survival and recurrence.
Methods: Patients with hepatocellular carcinoma included on the waiting list for liver transplantation (OLT) between January 1989 and December 2016 were analyzed. 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 macrovascular invasion, extrahepatic spread or cancer-related symptoms.
Results: A total of 495 patients constituted the target population. Comparison between Milan-in (n=434) and Milan-out group (n=61) whilst transplanted showed statistically significant differences in: largest tumour size; BCLC stage; patients treated before OLT; α-fetoprotein, and time on 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 rate at 1,3,5 and 10 years was 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 five years. The clinically relevant increase in tumour recurrence must be taken into account when analysing the benefit of this approach in the case of a limited organ supply.
Lay summary: Optimum results are indeed obtained for hepatocellular carcinoma (HCC) patients following orthotopic liver transplantation (OLT) when the Milan criteria (MC) are used. However, the most appropriate strategy in cases of progression beyond MC while on the waiting list is still unclear. Herein, we present 27 years' experience in OLT for HCC, using a conservative approach for those who progress beyond MC while still continuing enlistment for OLT. Although the survival in Milan-out patients is in accordance with previous published studies, the recurrence rate was notably higher. Therefore, the assessment of transplantation viability in those patients has to take into account the availability of organs and the impact on other patient categories.