Small molecule protein kinase inhibitors (PKIs) have become an effective strategy for cancer patients. However, hepatotoxicity is a major safety concern of these drugs, since the majority are reported to increase transaminases, and few of them (Idelalisib, Lapatinib, Pazopanib, Pexidartinib, Ponatinib, Regorafenib, Sunitinib) have a boxed label warning. The exact rate of PKI-induced hepatoxicity is not well defined due to the fact that the majority of data arise from pre-registration or registration trials on fairly selected patients, and the post-marketing data are often based only on the most severe described cases, whereas most real practice studies do not include drug-related hepatotoxicity as an end point. Although these side effects are usually reversible by dose adjustment or therapy suspension, or by switching to an alternative PKI, and fatality is uncommon, all patients undergoing PKIs should be carefully pre-evaluated and monitored. The management of this complication requires an individually tailored reappraisal of the risk/benefit ratio, especially in patients who are responding to therapy. This review reports the currently available data on the risk and management of hepatotoxicity of all the approved PKIs.

Background and Aim: Hepatocellular carcinoma (HCC) recurrence rates after liver transplantation (LT) range between 8 and 20%. Alpha-fetoprotein (AFP) levels at transplant can predict HCC recurrence, however a defined cut-off value is needed to better stratify patients. The aim of this study was to evaluate the rate of HCC recurrence at our centre and to identify predictors, focusing on AFP. Methods: We retrospectively analysed 236 consecutive patients that were waitlisted for HCC who all met the Milan criteria from January 2001 to December 2017 at our liver transplant centre. A total of twenty-nine patients dropped out while they were waitlisted, and 207 patients were included in the final analysis. All survival analyses included the competing-risk model. Results: The mean age was 56.8 ± 6.8 years. A total of 14% were female (n = 29/207). The median MELD (model for end-stage liver disease) at LT was 12 (9–16). The median time on the waitlist was 92 (41–170) days. The HCC recurrence rate was 16.4% (n = 34/208). The mean time to recurrence was 3.3 ± 2.8 years. The median AFP levels at transplant were higher in patients with HCC recurrence (p < 0.001). At multivariate analysis, the AFP value at transplant that was greater than 25.5 ng/mL (AUC 0.69) was a strong predictor of HCC recurrence after LT [sHR 3.3 (1.6–6.81); p = 0.001]. The HCC cumulative incidence function (CIF) of recurrence at 10 years from LT was significantly higher in patients with AFP > 25.5 ng/mL [34.3% vs. 11.5% (p = 0.001)]. Moreover, an increase in AFP > 20.8%, was significantly associated with HCC recurrence (p = 0.034). Conclusions: In conclusion, in our retrospective study, the AFP level at transplant > 25.5 ng/mL and its increase greater than 20.8% on the waitlist were strong predictors of HCC recurrence after LT in a cohort of patients that were waitlisted within the Milan criteria. However further studies are needed to validate these data.

Background: Liver transplantation (LT) for Hepatocellular carcinoma (HCC) is still burdened by a significant risk of tumor recurrence. The aim of this study was to apply the Risk Estimation of Tumor Recurrence After Transplant (RETREAT) score for prediction of HCC recurrence and survival. Methods: This retrospective study included all adult patients who consecutively underwent LT for HCC from January 2000 to July 2022 at a single institution. Results: During a median follow-up of 64 months, 56 (19%) out of 298 patients [54%, 36% and 10% with a RETREAT score equal to 0/1 (low), 2/3 (medium) and 4–6 (high), respectively] experienced HCC recurrence after a median of 31 months. The HCC recurrence rates at 1, 5 and 10 years were respectively 4%, 16% and 23%. The 5-year RFS for low-, medium- and high-risk groups were 93%, 78% and 58% (p < 0.001), respectively. In the competitive risk analysis, the medium- and high-risk RETREAT groups had respectively a 2.3 HR (p = 0.017) and 6.4 HR (p < 0.001) of HCC recurrence compared with the low-risk group. Overall, 119 patients died [32 (27%) due to HCC recurrence], and the 5-year survival was 74% (95%, 86% and 61% for low-, medium- and high-risk groups, respectively). In the multivariate analysis, the RETREAT score was associated with the overall survival only for the highest risk class, which yielded a 2.5 HR of death compared with the lowest risk categories (p < 0.001). Conclusions: This study validates the RETREAT score and confirms its ability to predict the risk of HCC recurrence.