Our results are of further relevance considering that most patients with HCC are diagnosed at an advanced stage and that this group included the majority of patients

who were candidates for sorafenib treatment. By contrast, BCLC B patients who failed or were not suitable for locoregional treatments are a heterogeneous group of patients, representing a small subgroup of HCC patients who are candidates for sorafenib treatment, and not fully representative of the entire BCLC B spectrum. The robustness of these results was confirmed selleck chemical in the probabilistic sensitivity analysis, showing that the probability of dose-adjusted sorafenib providing a cost-effective alternative to BSC was about 70% for advanced and 10% for intermediate HCC at a willingness-to-pay threshold of €38,000 per QALY.

The cost-effectiveness of dose-adjusted sorafenib in both advanced and intermediate HCC was sensitive to the BSC survival rate, sorafenib treatment duration, and the choice of parametric model used to predict survival gain. It is important to highlight that dose-adjusted sorafenib remains cost-effective in BCLC C HCC patients under a wide range of survival of untreated patients. This issue is very relevant, given the high heterogeneity and the unpredictability Akt inhibitor of clinical behavior of advanced HCC. 3 On the efficacy side of the cost equation, identification of robust predictive biomarkers would increase the overall efficacy of sorafenib for HCC by treating only those patients most likely to respond. This is not a trivial point, because sorafenib therapy is costly and still in search of optimization due to the lack of serum biomarkers of early response that are deemed necessary to generate Pyruvate dehydrogenase lipoamide kinase isozyme 1 response-guided therapeutic algorithms. Moreover, the identification of stopping rules based on predictors of mortality (such as early radiologic progression)

could assist the clinician in the cost-effective management of patients with HCC. Unfortunately, stopping sorafenib in patients with early radiologic progression only marginally improves the cost-effectiveness ratio. Therefore, the identification of the optimal sorafenib dose, effective but not toxic, remains to date the only strategy to substantially improve the ICER. Modeling the indication for treatment of advanced/intermediate HCC with dose-adjusted sorafenib clearly improves its cost effectiveness. In this line, the role of dose-adjusted sorafenib should be taken into account also for the future perspectives in the adjuvant setting after resection/ablation or after transarterial chemoembolization and for the design of future comparative trials versus novel targeted therapies. Although the proposed algorithms are useful tools for decision making, the treatment strategy should be carefully agreed upon with the patient, taking into account all the different factors, particularly the safety profile, that can interfere with treatment response.