American Surgical Association

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Is It Time To Abandon The Milan Criteria? Results of a Tri-Institutional US Collaboration to Redefine Hepatocellular Carcinoma Liver Transplantation Selection Policies
Karim J. Halazun*1, Parissa Tabrizian*2, Marc Najjar*3, Sander Florman*2, Myron Schwartz2, Fabrizzio Michelassi1, Benjamin Samstein*1, Roberts S. Brown, Jr.*1, Jean C. Emond3, Ronald W. Busuttil4, Vatche G. Agopian*4
1Weill Cornell Medicine, New York, NY;2Mount Sinai School of Medicine, New York, NY;3Columbia University Medical Center, New York, NY;4UCLA Medical Center, Los Angles, CA

Objectives European liver transplant (LT) centers have moved away from Milan Criteria (MC) for hepatocellular carcinoma (HCC) patient selection, turning to models including tumor biological indices, namely alpha-fetoprotein (AFP). We present the first US model to incorporate an AFP response (AFP-R), with comparisons to MC and French-AFP models (F-AFP).
Methods AFP-R was measured as differences between maximum and final pre-LT AFP in HCC patients undergoing LT at three US centers (2001-2013). Cox and Competing-risk-regression analyses identified predictors of recurrence free survival (RFS).
Results Of 1,440 patients, 232 (16.2%) were outside MC. Tumor size, number and AFP-R were independent predictors of RFS, and were assigned weighted points based on Cox-regression analysis (Table-1). An AFP-R consistently <200ng/ml predicted best outcome (figure-1a). A 3-tiered competing-risk RFS model was developed, accurately discriminating between groups (p<0.001,figure-1b), and correlating with overall survival (p<0.001,figure-1c). 192 of 232 patients outside MC (82%) would be re-categorized into low/acceptable-risk groups. The c-statistic for our Tri-institutional score is 0.70 compared to 0.61 for MC and 0.63 for F-AFP (p<0.001).
Conclusion Incorporation of AFP-R into HCC selection criteria allows for MC expansion. As UNOS considers adding AFP to selection algorithms, this score provides an objective, user-friendly tool for centers to appropriately risk-stratify patients.

Table1- Summary of Cox-Regression, Points Assignments and AFP-R. Group Scores with RFS/OS also shown
SCORE ELEMENTSHR (95% CI)ASSIGNED POINTS
Maximum Tumor Size At diagnosis:
0-3 cm-0
>3cm-6cm1.98 (1.44-2.72)2
>6cm3.66 (2.11-6.32)4
Maximum Tumor Number at Diagnosis
1-0
2-31.55 (1.13-2.14)2
>44.14 (2.41-7.10.)4
AFP Response (Maximum to Final AFP):
•Always <200-0
Responders:
•Max >200-1000 to Final <2001.66 (1.01-2.80)2
•Max >1000 to Final <1000 (Must be >50% Drop)1.78 (1.0-3.53)2
Non-Responders:
•Max >200-400 to Final >2002.83 (1.42- 5.70)3
•Max >400-1000 to Final > 2003.94 (2.38-6.53)4
•Max >1000 to Final >10005.91 (3.70-9.45)6
GROUPING CATEGORIESPOINTS1,3,5 Year RFS1,3,5 Year OS
•Group 1 - Low Risk0-298%,93%,87%92%,83%,75%
•Group 2 - Acceptable Risk3-687%,76%,70%91%,72%,62%
•Group 3 - High Risk>761%,42%,42%84%,45%,39%
Abbreviations: AFP: Alpha-fetoprotein, HR: Hazard Ratio, CI: Confidence Interval, RFS: Recurrence Free Survival, OS: Overall Survival


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