Liver transplantation for hepatocellular carcinoma beyond the Milan criteria

Abstract

Objective: Liver transplantation is an optimal radical therapy for selected patients with hepatocellular carcinoma. The stringent organ allocation system driven by the Milan criteria has been challenged by alternative sets of expanded criteria. Careful analysis is needed to prove that the Milan criteria can be expanded safely and effectively.

Design: This study collectively reviewed 6012 patients of hepatocellular carcinoma from the China Liver Transplant Registry. Expanded criteria were evaluated to characterise an optimised expansion with acceptable outcomes beyond the Milan criteria.

Results: Compared with the Milan criteria, Valencia, University of California, San Francisco, University Clinic of Navarra and Hangzhou criteria provided an expansion of 12.4%, 16.3%, 19.6%, and 51.5%, respectively. The post-transplant survivals of patients fulfilling the expanded criteria were comparable to that of the Milan criteria. The analysis of net reclassification improvement and area under the receiver operating characteristic curves showed an excellent efficiency in recurrence prediction for the expanded criteria compared with the Milan criteria. In patients exceeding Milan but fulfilling the Hangzhou criteria (N=1352), α-fetoprotein (AFP) >100 ng/mL and tumour burden>8 cm were the only two independent prognostic factors (p<0.001). Accordingly, the Hangzhou criteria were stratified as type A (tumour burden ≤8 cm, or tumour burden >8 cm but AFP≤100 ng/mL) and type B (tumour burden >8 cm but AFP between 100 and 400 ng/mL). Type A showed significantly higher 5-year tumour-free survival rates compared with type B (p<0.001).

Conclusions: The Milan criteria can be expanded safely and effectively. The prognostic stratification system based on the Hangzhou criteria serves as a hierarchy of transplant candidates for hepatocellular carcinoma.

Keywords: HEPATOCELLULAR CARCINOMA; LIVER TRANSPLANTATION.

Figure 1

Flow chart of patient selection procedures. HCC, hepatocellular carcinoma; LT, liver transplant.

Figure 2

Survival curves for different criteria (N=6012). The overall and tumour-free survival curves for (A) the Valencia criteria, (B) University of California, San Francisco (UCSF) criteria, (C) University Clinic of Navarra (CUN) criteria and (D) Hangzhou criteria.

Figure 3

The comparison of different criteria. (A) Increase in the number of eligible hepatocellular carcinoma transplant candidates compared with the Milan criteria (N=6012); (B) The time-dependent net reclassification improvement (NRI) curves for different criteria in reference to post-transplant recurrence. Patients censored before the endpoints for analysis were excluded. (C) The time-dependent area under the receiver operating characteristic curve (AUROC) value for different criteria according to death or tumour recurrence. Patients censored before the endpoints for analysis were excluded. CUN, University Clinic of Navarra criteria; UCSF, University of California, San Francisco criteria.

Figure 4

Tumour-free survival curves for patients exceeding the Milan criteria. In patients exceeding the Milan criteria, those fulfilling the Hangzhou criteria had significantly improved tumour-free survival compared with those exceeding it (p<0.001).

Figure 5

Survival analysis of the subgroup study based on the Hangzhou criteria. (A) Tumour-free survival curves of different subsets of patients exceeding the Milan but fulfilling Hangzhou criteria. Subset I: tumour burden ≤8 cm or α-fetoprotein (AFP) ≤100 ng/mL; subset II: tumour burden >8 cm but AFP between 100 and 400 ng/mL. Subset I had significantly better prognosis than Subset II (p<0.001). (B) The tumour-free survival curves for the stratified Hangzhou criteria. The Hangzhou criteria were stratified into (1) type A: tumour burden ≤8 cm or AFP ≤100 ng/mL; (2) type B: tumour burden >8 cm but AFP between 100 and 400 ng/mL. Type A had significantly better prognosis than type B (p<0.001). Both types A and B had significantly improved prognosis compared with those patients exceeding the Hangzhou criteria (p<0.001).