Importance: Multiple criteria are used worldwide to select hepatocellular carcinoma (HCC) patients with a low risk of recurrence for liver transplantation (LT). However, it remains unclear which criteria are best for the LT-involved stakeholders, particularly in accurately identifying patients at high risk of recurrence. Objective: To identify the most accurate criteria for selecting HCC patients for LT. Data Sources: In June 2023, a systematic literature search was conducted in PubMed and CENTRAL to identify studies including LT selection criteria of HCC patients. Study Selection: The selected studies had LT selection criteria based solely on pre-LT variables. They included a minority of down-staged patients, over 80% of deceased donors, presented recurrence-free survival curves (or equivalent) with the number of patients at risk at different times, and had a follow-up period of over 3 years. Data Extraction and Synthesis: Data was extracted from recurrence-free survival curves using a validated algorithm and subsequently used to calculate accuracy measures. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines were applied. Main Outcome(s) and Measures(s): Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy at 3- and 5-years post-LT. Results: Of 815 records screened, only 17 met our study inclusion parameters, embodying 14 LT selection criteria. All LT criteria achieved an adjusted PPV (aPPV) over 80%, indicating the correct selection of at least 80% of low-risk HCC patients. However, the adjusted NPV (aNPV) was below 50% in most cases, indicating that these criteria cannot correctly identify patients with a true high risk of recurrence. This raises major ethical concerns regarding the models' ability to exclude patients from LT. Since a perfect model is nonexistent, we created a ranking to account for the distinct concerns of all stakeholders in LT eligibility in the context of HCC. Conclusions and Relevance: These results highlight the urgent need for new tools/models with improved NPV to select more patients amenable to LT who are currently excluded. Whether through refined existing criteria or newly developed criteria, emphasis should be placed on specificity and NPV as key performance indicators in the emerging era of transplant oncology.

JPL and JC, declare an ownership interest in the company Ophiomics. LPF is an employee at Ophiomics and CD is an advisor at Ophiomics.

This study did not receive any funding.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study used only openly available human data that had been previously published in other studies.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

The data analyzed during the current study are available from the corresponding author upon reasonable request.