*Purpose: United Network of Organ Sharing (UNOS) Region 5 has reported excellent liver transplantation (LT) outcomes after successful down-staging (DS) in HCC patients exceeding Milan criteria. This protocol was adopted nationally though the experience with DS in other UNOS regions and the optimal type of therapy to achieve successful DS is largely unknown. In this prospective multi-regional study, we aimed to examine DS success rates as well as LT related outcomes.

*Methods: Consecutive patients from 7 LT centers in 4 UNOS regions with HCC meeting UNOS-DS eligibility criteria (1 lesion 5.1-8 cm, 2-3 lesions at least one 3.1-5 cm and total tumor diameter (TTD) ≤8 cm, or 4-5 tumors ≤3 cm with TTD ≤8 cm) were enrolled from 2015-2019 and prospectively followed.

*Results: Among 319 patients with tumor burden meeting UNOS-DS criteria, 115 (36%) were excluded (83% due to medical or psychosocial contraindications to LT). The remaining 204 patients comprised the study cohort (85% male, 59% Caucasian, 60% HCV). Pre-treatment characteristics included median MELD 9 (IQR 7-11), TTD 6.3 cm (5.6-7.3), AFP 13 ng/ml (5-86), and AFP-L3 10.3% (4.6-16.9). 21% underwent a single DS treatment and 33% received >3 treatments. TACE (63%) and Y90 radio-embolization (30%) were the most common initial DS treatments received. Probability of successful DS to within Milan criteria at 1 and 2 years from first treatment was 83% and 88%. Probability of dropout by competing risks (CR) at 1 and 3 years from first DS procedure was 22% and 39%. In bivariate CR analysis, AFP-L3 >10% (HR 3.7, p=0.02) was associated with increased dropout even with separate adjustment for age or AFP. When comparing TACE and Y90 as initial DS treatment, there were no observed differences in mRECIST response, probability of or time to successful DS, or probability of waitlist dropout (all p>0.40). Cumulative probability of LT (n=62) at 3 years from first DS procedure was 46% and median time from first DS treatment to LT was 1.4 yrs (IQR 0.9-2.0). In the explant, 18% had microvascular invasion, 12% had poorly differentiated grade, and 41% exceeded Milan criteria. Median post-LT follow-up was 1.1 years (IQR 0.7-2.1) with 2-year post-LT survival of 95% and HCC recurrence of 8% (5/62).

*Conclusions: In this first prospective multi-regional study based on UNOS-DS criteria, we observed a nearly 90% probability of successful DS to within Milan criteria, and similar efficacy of TACE and Y-90 as initial DS treatment. Patients with AFP-L3 >10% had a greater probability of dropout. We observed excellent post-LT survival of 95% at 2 years, but longer post-LT follow-up is needed.

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