Liver transplantation for hepatocellular carcinoma: alpha-fetoprotein should be included in selection criteria

From the beginning it was clear that the prognosis was related to tumor characteristics in patients liver transplanted for hepatocellular carcinoma (HCC). Thus, selection criteria were needed to identify patients with survival comparable to that of non-malignant indications (1). In 1996, the Milan criteria (MC) were suggested based on size and number of HCC tumors (2). Unfortunately, MC exclude some patients with a good prognosis. These patients may present with a large tumor, however, without features of aggressive biological behavior represented by e.g., vascular invasion or high alpha-fetoprotein (AFP) levels (3-5). Despite this, MC are still recommended in recent European guidelines and as a result, most western centers still use MC (6-8).

Large efforts have been put into developing improved selection criteria and recent focus has been on including a surrogate marker for tumor biological behavior. A single measure of AFP was implemented in selection criteria in France in 2012 (9) after showing superiority to MC when used in conjunction with size and number of HCC tumors (French AFP model) (5). Lately, the founder of the MC developed a competing risk model using pretransplant AFP and imaging-based size and number of HCC tumors (10). The study showed that c-statistic for selecting patients was superior to previously proposed criteria including MC. In addition, the results were validated in a separate cohort from Shanghai.

Interestingly, locoregional treatment and response to such treatment while on waiting list have shown to be correlated with improved survival after transplantation (11,12). In addition, patients downstaged from being outside criteria have survival comparable to that of patients inside criteria (13,14). This led to the suggestion that response to locoregional treatment may be an important tool to select patients (15).

In the recent study by Halazun et al. in Annals of Surgery (16), size and number of HCC tumors were combined with AFP response while on the waiting list. As the first US-based study evaluating AFP, the authors included 1,450 patients from three US centers between 2001 and 2013, of whom 82–88% received pretransplant locoregional treatment. AFP response was calculated as difference between maximum AFP at any time and the final immediate pretransplant AFP. In addition to the established prognostic feature of a single measure of AFP, the AFP response while on the waiting list may represent progression of disease as well as response to locoregional treatment. The authors established a score which performed well in a competing risk analysis and was superior to MC and the French AFP model regarding c-statistic. Overall, a reduction in AFP was more important than the absolute AFP level in predicting prognosis. Interestingly, patients with initial AFP >1,000, however, with a >50% response had a good prognosis. These patients may be excluded by other criteria including only a single measure of AFP (17,18). However, the results of the study were not validated in a separate cohort.

Despite high-quality evidence on AFP’s utility, it was not possible to reach consensus to revise existing criteria in the European HCC guideline for 2018 (6). What it will take to reach agreement is unclear. Therefore, other countries may have to follow France’s example and implement new criteria including AFP in some form despite lack of recommendation in guidelines.

Acknowledgements

None.

Footnote

Conflicts of Interest: The author has no conflicts of interest to declare.

References

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