Reply
Authors: Quirino Lai, Alessandro Vitale
Journal: Hepatology (2018)

Potential conflict of interest: Nothing to report. Author names in bold designate shared co‐first authorship. REPLY: We read with great interest the comment letter by Winter et al. on our recently published study on the new concept of intention‐to‐treat (ITT) survival benefit of liver transplantation (LT) in patients with hepatocellular cancer (HCC).1 Winter et al. reported some comments mainly focused on the methodological approach used for constructing the mathematical model. We draw attention to the supplementary section of our article in which we explain our approach. We did not mean to imply that the construction of our benefit model was innovative. Nor did we ignore the seminal works of Merion and Schaubel, which we referred to in our article. Rather, the innovation of our work is connected with its ITT design. Regarding the decision not to use artificial censoring methods, we explained in the supplementary material that, although competing risk analysis or inverse probability censoring weight can be used to overcome informative or dependent censoring, they are still insufficient to resolve all the biases related to the complexity of waiting‐list dynamics, often requiring further, quite arbitrary, corrections.2 In particular, median waiting‐time of HCC patients is relatively short with very few failure events: therefore, prediction of long‐term survival in these patients may be inaccurate. Regarding the use of the MESIAH (Model to Estimate the Survival In Ambulatory patients with HCC) score, we observed that Merion's and Schaubel's studies used the same waiting‐list population to calculate both non‐LT and post‐LT survival models. We retained this a‐statistical forcing. In this regard, it is statistically more correct to use the real population survival figures for one of the two models and to use a simulation model as the counterpart.3 The MESIAH score is a very solid score, having good performances also when "externally vali‐dated" in different Eastern and Western series.4 Regarding the calculation of the ITT survival benefit, we used "predicted" and not "observed" median survivals, so each patient reached the median survival value by definition. Because we calculated "predicted" median survivals, patients with the same vector of covariates had the same survival predictions with and without LT. We decided to truncate median survivals at 120 months because too‐long time horizons are intrinsically unbalanced toward the utility principle.5 For the same reasons, we did not calculate the "true" value of life expectancy (area under the curve). As for the variables used in the multivariable models, we did not decide to use a priori the same ones, but the same independent variables resulted from multivariable models. This fact obviously facilitated the construction of the multivariable transplant benefit model. The candidates of all the models used in this article were always the same (n = 2,103). At the end, we used five covariates for the risk class stratification. Indeed, radiological progression and complete response were used in a combined fashion. As reported in the text, we decided not to consider the period of LT as a parameter to adopt in the model. The other significant covariates showing a small effect were not further considered in the stratification of the risk classes.