Ani Kardashian1, Sander S Florman2, Brandy Haydel2, Richard M Ruiz3, Goran B Klintmalm3, David D Lee4, C Burcin Taner4, Federico Aucejo5, Amit D Tevar6, Abhinav Humar6, Elizabeth C Verna7, Karim J Halazun8, William C Chapman9, Neeta Vachharajani9, Maarouf Hoteit10, Matthew H Levine10, Mindie H Nguyen11, Marc L Melcher12, Alan N Langnas13, Carol A Carney13, Constance Mobley14, Mark Ghobrial14, Beth Amundsen15, James F Markmann15, Debra L Sudan16, Christopher M Jones17, Jennifer Berumen18, Alan W Hemming18, Johnny C Hong19, Joohyun Kim19, Michael A Zimmerman19, Trevor L Nydam20, Abbas Rana21, Michael L Kueht21, Thomas M Fishbein22, Daniela Markovic23, Ronald W Busuttil24, Vatche G Agopian24. 1. Vatche and Tamar Manoukian Division of Digestive Diseases, University of California, Los Angeles, Los Angeles, CA. 2. Recanati/Miller Transplantation Institute, Mount Sinai Medical Center, New York, NY. 3. Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX. 4. Department of Transplantation, Mayo Clinic, Jacksonville, FL. 5. Cleveland Clinic Foundation, Cleveland, OH. 6. Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA. 7. New York-Presbyterian Hospital, Columbia University, New York, NY. 8. New York-Presbyterian Hospital, Weill Cornell, New York, NY. 9. Section of Transplantation, Department of Surgery, Washington University in St. Louis, St. Louis, MO. 10. Penn Transplant Institute, University of Pennsylvania, Philadelphia, PA. 11. Division of Gastroenterology and Hepatology, Stanford University, Palo Alto, CA. 12. Department of Surgery, Stanford University, Palo Alto, CA. 13. Department of Surgery, University of Nebraska Medical Center, Omaha, NE. 14. Sherrie & Alan Conover Center for Liver Disease & Transplantation, Houston Methodist Hospital, Houston, TX. 15. Division of Transplant Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA. 16. Department of Surgery, Duke University Medical Center, Durham, NC. 17. Section of Hepatobiliary and Transplant Surgery, University of Louisville School of Medicine, Louisville, KY. 18. Division of Transplantation and Hepatobiliary Surgery, Department of Surgery, University of California, San Diego, San Diego, CA. 19. Division of Transplant Surgery, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI. 20. Division of Transplant Surgery, Department of Surgery, University of Colorado School of Medicine, Denver, CO. 21. Department of Surgery, Baylor College of Medicine, Houston, TX. 22. Medstar Georgetown Transplant Institute, Georgetown University, Washington, DC. 23. Department of Biomathematics, David Geffen School of Medicine at UCLA, Los Angeles, CA. 24. Dumont-UCLA (University of California, Los Angeles) Transplant and Liver Cancer Centers, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA.
Abstract
BACKGROUND AND AIMS: The Organ Procurement and Transplantation Network recently approved liver transplant (LT) prioritization for patients with hepatocellular carcinoma (HCC) beyond Milan Criteria (MC) who are down-staged (DS) with locoregional therapy (LRT). We evaluated post-LT outcomes, predictors of down-staging, and the impact of LRT in patients with beyond-MC HCC from the U.S. Multicenter HCC Transplant Consortium (20 centers, 2002-2013). APPROACH AND RESULTS: Clinicopathologic characteristics, overall survival (OS), recurrence-free survival (RFS), and HCC recurrence (HCC-R) were compared between patients within MC (n = 3,570) and beyond MC (n = 789) who were down-staged (DS, n = 465), treated with LRT and not down-staged (LRT-NoDS, n = 242), or untreated (NoLRT-NoDS, n = 82). Five-year post-LT OS and RFS was higher in MC (71.3% and 68.2%) compared with DS (64.3% and 59.5%) and was lowest in NoDS (n = 324; 60.2% and 53.8%; overall P < 0.001). DS patients had superior RFS (60% vs. 54%, P = 0.043) and lower 5-year HCC-R (18% vs. 32%, P < 0.001) compared with NoDS, with further stratification by maximum radiologic tumor diameter (5-year HCC-R of 15.5% in DS/<5 cm and 39.1% in NoDS/>5 cm, P < 0.001). Multivariate predictors of down-staging included alpha-fetoprotein response to LRT, pathologic tumor number and size, and wait time >12 months. LRT-NoDS had greater HCC-R compared with NoLRT-NoDS (34.1% vs. 26.1%, P < 0.001), even after controlling for clinicopathologic variables (hazard ratio [HR] = 2.33, P < 0.001) and inverse probability of treatment-weighted propensity matching (HR = 1.82, P < 0.001). CONCLUSIONS: In LT recipients with HCC presenting beyond MC, successful down-staging is predicted by wait time, alpha-fetoprotein response to LRT, and tumor burden and results in excellent post-LT outcomes, justifying expansion of LT criteria. In LRT-NoDS patients, higher HCC-R compared with NoLRT-NoDS cannot be explained by clinicopathologic differences, suggesting a potentially aggravating role of LRT in patients with poor tumor biology that warrants further investigation.
BACKGROUND AND AIMS: The Organ Procurement and Transplantation Network recently approved liver transplant (LT) prioritization for patients with hepatocellular carcinoma (HCC) beyond Milan Criteria (MC) who are down-staged (DS) with locoregional therapy (LRT). We evaluated post-LT outcomes, predictors of down-staging, and the impact of LRT in patients with beyond-MCHCC from the U.S. Multicenter HCC Transplant Consortium (20 centers, 2002-2013). APPROACH AND RESULTS: Clinicopathologic characteristics, overall survival (OS), recurrence-free survival (RFS), and HCC recurrence (HCC-R) were compared between patients within MC (n = 3,570) and beyond MC (n = 789) who were down-staged (DS, n = 465), treated with LRT and not down-staged (LRT-NoDS, n = 242), or untreated (NoLRT-NoDS, n = 82). Five-year post-LT OS and RFS was higher in MC (71.3% and 68.2%) compared with DS (64.3% and 59.5%) and was lowest in NoDS (n = 324; 60.2% and 53.8%; overall P < 0.001). DSpatients had superior RFS (60% vs. 54%, P = 0.043) and lower 5-year HCC-R (18% vs. 32%, P < 0.001) compared with NoDS, with further stratification by maximum radiologic tumor diameter (5-year HCC-R of 15.5% in DS/<5 cm and 39.1% in NoDS/>5 cm, P < 0.001). Multivariate predictors of down-staging included alpha-fetoprotein response to LRT, pathologic tumor number and size, and wait time >12 months. LRT-NoDS had greater HCC-R compared with NoLRT-NoDS (34.1% vs. 26.1%, P < 0.001), even after controlling for clinicopathologic variables (hazard ratio [HR] = 2.33, P < 0.001) and inverse probability of treatment-weighted propensity matching (HR = 1.82, P < 0.001). CONCLUSIONS: In LT recipients with HCC presenting beyond MC, successful down-staging is predicted by wait time, alpha-fetoprotein response to LRT, and tumor burden and results in excellent post-LT outcomes, justifying expansion of LT criteria. In LRT-NoDS patients, higher HCC-R compared with NoLRT-NoDS cannot be explained by clinicopathologic differences, suggesting a potentially aggravating role of LRT in patients with poor tumor biology that warrants further investigation.
Authors: Quirino Lai; Andre Viveiros; Samuele Iesari; Alessandro Vitale; Gianluca Mennini; Simona Onali; Maria Hoppe-Lotichius; Marco Colasanti; Tommaso M Manzia; Federico Mocchegiani; Gabriele Spoletini; Salvatore Agnes; Marco Vivarelli; Giuseppe Tisone; Giuseppe M Ettorre; Jens Mittler; Emmanuel Tsochatzis; Massimo Rossi; Umberto Cillo; Benedikt Schaefer; Jan P Lerut Journal: Front Oncol Date: 2022-04-27 Impact factor: 5.738