*Purpose: Recent studies from United Network of Organ Sharing (UNOS) Region 5 reported excellent outcomes after liver transplantation (LT) after successful down-staging in HCC patients exceeding Milan criteria. This protocol was adopted nationally for priority listing for LT though the experience with down-staging in other UNOS regions is largely unknown. In this multi-region prospective study, we aimed to examine down-staging success rates as well as intention to treat outcomes related to down-staging.

*Methods: Consecutive patients from 6 LT centers in 3 UNOS regions (2, 5, 9) with HCC meeting down-staging (UNOS-DS) eligibility criteria (1 lesion >5 cm and ≤ 8 cm, 2-3 lesions at least one >3 cm but ≤ 5 cm and total tumor diameter (TTD) ≤ 8 cm, or 4-5 tumors ≤ 3 cm with TTD ≤ 8 cm) were enrolled from 2015-2018 and prospectively followed.

*Results: Among 210 patients with tumor burden meeting UNOS-DS criteria, 79 (38%) were not considered for LT. The common reasons for exclusion were medical (40%) or psychosocial (33%) contraindications to LT, AFP >1000 ng/ml with decompensated liver disease (15%), and bilirubin >4 mg/dL (6%). The remaining 131 patients comprised the study cohort (median age 63, 85% male, 61% Caucasian, 61% HCV). Pre-treatment median MELD score was 9 (IQR 7-11), Child-Pugh score was 6 (5-6), TTD was 6.4 cm (5.6-7.2), and AFP was 16 ng/ml (5-88). 25% underwent a single down-staging treatment and 33% received >3 treatments. Trans-arterial chemoembolization (TACE) was used in 83%, Y-90 radio-embolization in 32%, and ablation in 18%. Cumulative probability of successful down-staging to within Milan criteria at 1 and 2 years from first down-staging procedure were 82% and 90%, respectively. Dropout occurred in 40 patients (30%), mostly from tumor progression (67%). Cumulative probability of dropout by competing risks (CR) at 1 and 2 years from first down-staging procedure were 25% and 36%, respectively. Factors predicting dropout in multivariate CR analysis were AFP >100 ng/ml (HR 2.4, p=0.01) and increasing MELD score (HR 1.13 per point, p=0.04) whereas TACE was associated with a lower risk of dropout (HR 0.30 vs no TACE, p=0.02). At the end of study follow-up, 32 patients (24%) had received LT and 59 (45%) were still undergoing down-staging or awaiting LT. Median time from 1^st down-staging treatment to LT was 1.5 years (IQR 1.0-2.0). In the explant, 20% had vascular invasion, 10% had poorly differentiated tumor, and 37% had tumor burden beyond Milan criteria. There were no observed post-LT recurrences after a median post-LT follow-up of 1.0 year (IQR 0.5-1.9). Intention-to-treat survival at 1 and 3 years after first down-staging procedure was 92% and 78%, respectively.

*Conclusions: In this first prospective multi-region study, 62% of HCC patients presenting within UNOS-DS criteria were potential LT candidates and underwent attempted down-staging. These patients had a 90% probability of successful down-staging to within Milan, acceptable explant features, and excellent intention-to-treat survival. Patients with pre-treatment AFP >100 and higher MELD score had a greater probability of dropout. Our results support broad application of the UNOS down-staging protocol in LT.

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