• AFP
• PIVKA-II
• HCC
• modeling
• TKI
• TACE

Transarterial chemoembolization (TACE) and tyrosine-kinase inhibitors (TKI) represent first-line treatments in intermediate and advanced hepatocellular carcinoma (HCC). Deepening TKI and TACE response mechanisms may provide insights to optimize their combination in selected patients (pts). We developed a physic-mathematical model to investigate HCC cancer cells and vasculature dynamics combining digital imaging and serological biomarkers [-Fetoprotein (AFP); protein induced by vitamin K absence II (PIVKA-II)] in 10 TKI [4 Complete Responders (CR) and 6 NON-CR] and in 8 TACE (2 CR, 6 NON-CR) treated pts. Fitting their AFP and PIVKA-II kinetics provided a quantitative assessment of anti-angiogenetic and anti-proliferative effectiveness of the treatments, which were 13.7-fold and 7.0-fold higher with TKIs. TACE, however, reached its maximal therapeutic effect in <1 day, TKI between 4.6-99.9 days. Accordingly, AFP reduction after TKI was delayed, whereas it was observed immediately in all TACE treated pts with a half-life of the AFP comparable to that of its natural decay (0.10-0.16 day-1). An early spike of PIVKA-II levels was observed in most pts receiving TKI, but not after TACE, suggesting that PIVKA-II production rate increases only when ischemia onset is slow. In conclusion, TKI and TACE show potential synergic effects that should be investigated in future studies. Our model could contribute to a better characterization of the response and help to define treatments timing.