R3-AFP score is a new composite tool to refine prediction of hepatocellular carcinoma recurrence after liver transplantation

Abstract

Background & aims: Patients with hepatocellular carcinoma (HCC) are selected for liver transplantation (LT) based on pre-LT imaging ± alpha-foetoprotein (AFP) level, but discrepancies between pre-LT tumour assessment and explant are frequent. Our aim was to design an explant-based recurrence risk reassessment score to refine prediction of recurrence after LT and provide a framework to guide post-LT management.

Methods: Adult patients who underwent transplantation between 2000 and 2018 for HCC in 47 centres were included. A prediction model for recurrence was developed using competing-risk regression analysis in a European training cohort (TC; n = 1,359) and tested in a Latin American validation cohort (VC; n=1,085).

Results: In the TC, 76.4% of patients with HCC met the Milan criteria, and 89.9% had an AFP score of ≤2 points. The recurrence risk reassessment (R3)-AFP model was designed based on variables independently associated with recurrence in the TC (with associated weights): ≥4 nodules (sub-distribution of hazard ratio [SHR] = 1.88, 1 point), size of largest nodule (3-6 cm: SHR = 1.83, 1 point; >6 cm: SHR = 5.82, 5 points), presence of microvascular invasion (MVI; SHR = 2.69, 2 points), nuclear grade >II (SHR = 1.20, 1 point), and last pre-LT AFP value (101-1,000 ng/ml: SHR = 1.57, 1 point; >1,000 ng/ml: SHR = 2.83, 2 points). Wolber's c-index was 0.76 (95% CI 0.72-0.80), significantly superior to an R3 model without AFP (0.75; 95% CI 0.72-0.79; p = 0.01). Four 5-year recurrence risk categories were identified: very low (score = 0; 5.5%), low (1-2 points; 15.1%), high (3-6 points; 39.1%), and very high (>6 points; 73.9%). The R3-AFP score performed well in the VC (Wolber's c-index of 0.78; 95% CI 0.73-0.83).

Conclusions: The R3 score including the last pre-LT AFP value (R3-AFP score) provides a user-friendly, standardised framework to design post-LT surveillance strategies, protocols, or adjuvant therapy trials for HCC not limited to the Milan criteria.

Clinical trials registration: NCT03775863.

Lay summary: Considering discrepancies between pre-LT tumour assessment and explant are frequent, reassessing the risk of recurrence after LT is critical to further refine the management of patients with HCC. In a large and international cohort of patients who underwent transplantation for HCC, we designed and validated the R3-AFP model based on variables independently associated with recurrence post-LT (number of nodules, size of largest nodule, presence of MVI, nuclear grade, and last pre-LT AFP value). The R3-AFP model including last available pre-LT AFP value outperformed the original R3 model only based on explant features. The final R3-AFP scoring system provides a robust framework to design post-LT surveillance strategies, protocols, or adjuvant therapy trials, irrespective of criteria used to select patients with HCC for LT.

Keywords: AFP, alpha-foetoprotein; Explants pathology; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; LT, liver transplantation; Liver cancer; Liver transplantation; MVI, microvascular invasion; Prediction; R3, recurrence risk reassessment; RETREAT, Risk Estimation of Tumour Recurrence After Transplant; Recurrence; SHR, sub-distribution of hazard ratio; TC, test cohort; TTR, time to recurrence; VC, validation cohort.

Graphical abstract

Fig. 1

Cumulative recurrence curves in the test cohort according to R3-AFP score categories. R3-AFP, recurrence risk reassessment–alpha-foetoprotein.

Fig. 2

Cumulative survival curves in the test cohort according to R3-AFP score categories. R3-AFP, recurrence risk reassessment–alpha-foetoprotein.

Fig. 3

Cumulative recurrence curves in the validation cohort according to R3-AFP score categories. R3-AFP, recurrence risk reassessment–alpha-foetoprotein.

Fig. 4

Cumulative survival curves in the validation cohort according to R3-AFP score categories. R3-AFP, recurrence risk reassessment–alpha-foetoprotein.