Development and validation of a REcurrent Liver cAncer Prediction ScorE (RELAPSE) following liver transplantation in patients with hepatocellular carcinoma: Analysis of the US Multicenter HCC Transplant Consortium

Author:

Tran Benjamin V.1ORCID,Moris Dimitrios2ORCID,Markovic Daniela3,Zaribafzadeh Hamed24ORCID,Henao Ricardo4ORCID,Lai Quirino5ORCID,Florman Sander S.6ORCID,Tabrizian Parissa6ORCID,Haydel Brandy6ORCID,Ruiz Richard M.7,Klintmalm Goran B.7ORCID,Lee David D.8ORCID,Taner C. Burcin8ORCID,Hoteit Maarouf9ORCID,Levine Matthew H.9ORCID,Cillo Umberto1011ORCID,Vitale Alessandro1011,Verna Elizabeth C.12ORCID,Halazun Karim J.12ORCID,Tevar Amit D.13ORCID,Humar Abhinav13ORCID,Chapman William C.14ORCID,Vachharajani Neeta14ORCID,Aucejo Federico15ORCID,Lerut Jan16ORCID,Ciccarelli Olga16ORCID,Nguyen Mindie H.17ORCID,Melcher Marc L.18ORCID,Viveiros Andre19ORCID,Schaefer Benedikt19ORCID,Hoppe-Lotichius Maria20ORCID,Mittler Jens20ORCID,Nydam Trevor L.21,Markmann James F.22ORCID,Rossi Massimo5ORCID,Mobley Constance23ORCID,Ghobrial Mark23ORCID,Langnas Alan N.24,Carney Carol A.24,Berumen Jennifer25ORCID,Schnickel Gabriel T.25ORCID,Sudan Debra L.2ORCID,Hong Johnny C.26ORCID,Rana Abbas27ORCID,Jones Christopher M.28ORCID,Fishbein Thomas M.29,Busuttil Ronald W.1ORCID,Barbas Andrew S.2ORCID,Agopian Vatche G.1ORCID

Affiliation:

1. Department of Surgery, David Geffen School of Medicine at UCLA, Dumont-UCLA (University of California, Los Angeles) Transplant and Liver Cancer Centers, Los Angeles, California, USA

2. Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA

3. Department of Medicine, Statistics Core, University of California, Los Angeles, USA

4. Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, North Carolina, USA

5. General Surgery and Organ Transplantation Unit, Sapienza University, AOU Policlinico Umberto I, Rome, Italy

6. Recanati/Miller Transplantation Institute, Mount Sinai Medical Center, New York, New York, USA

7. Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, Texas, USA

8. Department of Transplantation, Mayo Clinic, Jacksonville, Florida, USA

9. Penn Transplant Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA

10. Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy

11. New York-Presbyterian Hospital, Weill Cornell, New York, New York, USA

12. New York-Presbyterian Hospital, Columbia University, New York, New York, USA

13. Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA

14. Section of Transplantation, Department of Surgery, Washington University in St. Louis, St. Louis, Missouri, USA

15. Cleveland Clinic Foundation, Cleveland, Ohio, USA

16. Department of Abdominal and Transplantation Surgery, Institute for Experimental and Clinical Research, Universite Catholique Louvain, Brussels, Belgium

17. Division of Gastroenterology and Hepatology, Stanford University, Palo Alto, California, USA

18. Department of Surgery, Stanford University, Palo Alto, California, USA

19. Department of Medicine I, Medical University of Innsbruck, Innsbruck, Austria

20. Clinic for General, Visceral and Transplantation Surgery, Universitatsmedizin Mainz, Mainz, Germany

21. Department of Surgery, Division of Transplant Surgery, University of Colorado School of Medicine, Denver, Colorado, USA

22. Division of Transplant Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA

23. Sherrie & Alan Conover Center for Liver Disease & Transplantation, Houston Methodist Hospital, Houston, Texas, USA

24. Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska, USA

25. Department of Surgery, Division of Transplantation and Hepatobiliary Surgery, University of California, San Diego, San Diego, California, USA

26. Department of Hepatobiliary Surgery & Transplantation, Division of Transplantation, Penn State College of Medicine, Hershey, Pennsylvania, USA

27. Department of Surgery, Baylor College of Medicine, Houston, Texas, USA

28. Section of Hepatobiliary and Transplant Surgery, University of Louisville School of Medicine, Louisville, Kentucky, USA

29. Medstar Georgetown Transplant Institute, Georgetown University, Washington, District of Columbia, USA

Abstract

HCC recurrence following liver transplantation (LT) is highly morbid and occurs despite strict patient selection criteria. Individualized prediction of post-LT HCC recurrence risk remains an important need. Clinico-radiologic and pathologic data of 4981 patients with HCC undergoing LT from the US Multicenter HCC Transplant Consortium (UMHTC) were analyzed to develop a REcurrent Liver cAncer Prediction ScorE (RELAPSE). Multivariable Fine and Gray competing risk analysis and machine learning algorithms (Random Survival Forest and Classification and Regression Tree models) identified variables to model HCC recurrence. RELAPSE was externally validated in 1160 HCC LT recipients from the European Hepatocellular Cancer Liver Transplant study group. Of 4981 UMHTC patients with HCC undergoing LT, 71.9% were within Milan criteria, 16.1% were initially beyond Milan criteria with 9.4% downstaged before LT, and 12.0% had incidental HCC on explant pathology. Overall and recurrence-free survival at 1, 3, and 5 years was 89.7%, 78.6%, and 69.8% and 86.8%, 74.9%, and 66.7%, respectively, with a 5-year incidence of HCC recurrence of 12.5% (median 16 months) and non-HCC mortality of 20.8%. A multivariable model identified maximum alpha-fetoprotein (HR = 1.35 per-log SD, 95% CI,1.22–1.50, p < 0.001), neutrophil-lymphocyte ratio (HR = 1.16 per-log SD, 95% CI,1.04–1.28, p < 0.006), pathologic maximum tumor diameter (HR = 1.53 per-log SD, 95% CI, 1.35–1.73, p < 0.001), microvascular (HR = 2.37, 95%–CI, 1.87–2.99, p < 0.001) and macrovascular (HR = 3.38, 95% CI, 2.41–4.75, p < 0.001) invasion, and tumor differentiation (moderate HR = 1.75, 95% CI, 1.29–2.37, p < 0.001; poor HR = 2.62, 95% CI, 1.54–3.32, p < 0.001) as independent variables predicting post-LT HCC recurrence (C-statistic = 0.78). Machine learning algorithms incorporating additional covariates improved prediction of recurrence (Random Survival Forest C-statistic = 0.81). Despite significant differences in European Hepatocellular Cancer Liver Transplant recipient radiologic, treatment, and pathologic characteristics, external validation of RELAPSE demonstrated consistent 2- and 5-year recurrence risk discrimination (AUCs 0.77 and 0.75, respectively). We developed and externally validated a RELAPSE score that accurately discriminates post-LT HCC recurrence risk and may allow for individualized post-LT surveillance, immunosuppression modification, and selection of high-risk patients for adjuvant therapies.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Transplantation,Hepatology,Surgery

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