Downstaging strategies for HCC within the AFP score allocation system: a tale of two trajectories

Intro: Downstaging (DS), usually within Milan criteria, is now accepted by scientific societies as a standard strategy for hepatocellular carcinoma (HCC), with acceptable survival despite a slightly increased recurrence risk. In France, since 2012, liver transplantation (LT) eligibility for HCC has been based on the AFP score, which better predicts tumour recurrence than Milan criteria. We aimed to describe patient trajectories within a DS strategy and compare 5-year post-LT overall survival and HCC recurrence between downstaged patients and those always listed within AFP score criteria, to assess the efficacy and fairness of this allocation strategy in an organ shortage setting.
Methods: Using the French national LT database Cristal, we identified 1,518 patients listed for HCC between 2015 and 2018 and classified them into 3 groups:

• primary downstaging (PD), defined by AFP score >2 at diagnosis, entering DS before or at listing;
• secondary downstaging (SD), defined by AFP score <2 at diagnosis and then >2 at listing, or progression from AFP score <2 at diagnosis and listing to >2 while on the waitlist;
• control group (CG), with AFP score <2 throughout.

Final decisions to transplant patients after DS failure were left to each centre. The 18-month cumulative incidence of dropout and 5-year post-LT cumulative incidence of recurrence and the overall survival were compared across groups.
Results: AFP score and tumour features differed significantly at listing and at LT among groups.(data not shown) Overall, 253 patients (16.7%) entered a DS strategy. According to treatment response, 126/171 (74%) PD patients achieved successful PD (SPD) and 45/171 (26%) failed PD (FPD), whereas 28/82 (34%) SD patients achieved successful SD (SSD) and 54/82 (66%) failed SD (FSD) (p<0.0001). Among failures, 17/45 FPD patients (37.8%) and 12/54 FSD patients (22.2%) still underwent LT, (mostly out-of-criteria grafts). Pre-LT dropout, 5-year survival and HCC recurrence differed significantly between groups (p<0.001, p=0.0246 and p<0.001, respectively). However, selected FPD patients who underwent LT had post-LT outcomes comparable to the CG, whereas this was not observed in selected FSD patients.
Conclusion: This study shows for the 1st time that DS encompasses 2 distinct clinical trajectories with different impacts on pre-/post-LT outcomes. Within the AFP score system, primary DS was effective across scenarios : 74% success rate and post-LT outcomes comparable to patients always within criteria; even selected patients transplanted after PD failure had acceptable results. By contrast, secondary DS followed a fundamentally different course: 34% were successfully downstaged, and success did not translate into equivalent post-transplant survival, while failure was associated with markedly higher recurrence and mortality. These findings suggest that waitlist progression identifies a more aggressive tumour phenotype that DS cannot fully offset, regardless of its success.