AFP score and metroticket 2.0 perform similarly and could be used in a "within-ALL" clinical decision tool

Abstract

Background & aims: Two recently developed composite models, the alpha-fetoprotein (AFP) score and Metroticket 2.0, could be used to select patients with hepatocellular carcinoma (HCC) who are candidates for liver transplantation (LT). The aim of this study was to compare the predictive performance of both models and to evaluate the net risk reclassification of post-LT recurrence between them using each model's original thresholds.

Methods: This multicenter cohort study included 2,444 adult patients who underwent LT for HCC in 47 centers from Europe and Latin America. A competing risk regression analysis estimating sub-distribution hazard ratios (SHRs) and 95% CIs for recurrence was used (Fine and Gray method). Harrell's adapted c-statistics were estimated. The net reclassification index for recurrence was compared based on each model's original thresholds.

Results: During a median follow-up of 3.8 years, there were 310 recurrences and 496 competing events (20.3%). Both models predicted recurrence, HCC survival and survival better than Milan criteria (p <0.0001). At last tumor reassessment before LT, c-statistics did not significantly differ between the two composite models, either as original or threshold versions, for recurrence (0.72 vs. 0.68; p = 0.06), HCC survival, and overall survival after LT. We observed predictive gaps and overlaps between the model's thresholds, and no significant gain on reclassification. Patients meeting both models ("within-ALL") at last tumor reassessment presented the lowest 5-year cumulative incidence of HCC recurrence (7.7%; 95% CI 5.1-11.5) and higher 5-year post-LT survival (70.0%; 95% CI 64.9-74.6).

Conclusions: In this multicenter cohort, Metroticket 2.0 and the AFP score demonstrated a similar ability to predict HCC recurrence post-LT. The combination of these composite models might be a promising clinical approach.

Impact and implications: Composite models were recently proposed for the selection of liver transplant (LT) candidates among individuals with hepatocellular carcinoma (HCC). We found that both the AFP score and Metroticket 2.0 predicted post-LT HCC recurrence and survival better than Milan criteria; the Metroticket 2.0 did not result in better reclassification for transplant selection compared to the AFP score, with predictive gaps and overlaps between the two models; patients who met low-risk thresholds for both models had the lowest 5-year recurrence rate. We propose prospectively testing the combination of both models, to further optimize the LT selection process for candidates with HCC.

Keywords: AFP, alpha-fetoprotein; HCC, hepatocellular carcinoma; HR, hazard ratio; LT, liver transplantation; NRI, net reclassification index; Prediction; SHR, sub-hazard ratio; reclassification; recurrence; transplantation.

Graphical abstract

Fig. 1

Stratified analysis according to the AFP model and Metroticket 2.0. The first threshold for Metroticket 2.0 is shown here (sum up-to 7 plus AFP <200 ng/ml). (A) Nelson-Aelen cumulative hazard estimates. Corresponding cumulative post-LT recurrence at 5 years for patients meeting both model’s thresholds, patients with AFP scores ≤2 and exceeding Metroticket 2.0 (SHR 2.2; 95% CI 1.51-3.13; p <0.0001), patients with AFP scores >2 and meeting Metroticket 2.0 (SHR 2.2; 95% CI 1.12-4.53; p = 0.02), and for patients with AFP scores >2 and exceeding Metroticket 2.0 (SHR 4.4; 95% CI 3.38-5.74; p <0.0001). (B) Corresponding 5-year cumulative survival for each stratum. Level of significance, p <0.05. AFP, alpha-fetoprotein; SHR, subdistribution hazard ratio; LT, liver transplantation.

Fig. 2

Cumulative recurrence according to the AFP model and the other two thresholds of Metroticket 2.0. The other two thresholds for the Metroticket 2.0 are shown here. (A) Sum up-to 5 plus AFP <400 ng/ml: Nelson-Aelen cumulative hazard estimates. Corresponding cumulative post-LT recurrence at 5 years for patients meeting both model’s thresholds, for patients with AFP scores ≤2 and exceeding Metroticket 2.0 (SHR 1.5; 95% CI 1.36-1.98; p = 0.004), for patients with AFP scores >2 and meeting Metroticket 2.0 (SHR 2.4; 95% CI 1.06-5.48; p = 0.04), and for patients with AFP scores >2 and exceeding Metroticket 2.0 (SHR 4.3; 95% CI 3.38-5.82; p <0.0001). (B) Sum up-to 4 plus AFP <1,000 ng/ml: Corresponding cumulative post-LT recurrence at 5 years for patients meeting both model’s thresholds, for patients with AFP scores ≤2 and exceeding Metroticket 2.0 (SHR 1.5; 95% CI 1.17-2.01; p = 0.002), there were no patients with AFP scores >2 and meeting Metroticket 2.0, and for patients with AFP scores >2 and exceeding Metroticket 2.0 (SHR 4.7; 95% CI 3.48-6.30; p <0.0001). Level of significance, p <0.05. AFP, alpha-fetoprotein; SHR, subdistribution hazard ratio; LT, liver transplantation.

Fig. 3

Clinical use of the “within-ALL” decision algorithm. (A,B) Using both models, patients meeting or exceeding Milan criteria and within the AFP score and each of the Metroticket thresholds at time of listing showed lower recurrence rates (A) and better survival (B). Log-rank test, level of significance, p <0.05. AFP, alpha-fetoprotein.

Fig. 4

Cumulative recurrence rates according to the “within-ALL” decision algorithm at last tumor reassessment. Nelson-Aelen cumulative hazard estimates at last tumor reassessment. Level of significance, p <0.05.