Systematic review with meta-analysis: the critical role of dermatological events in patients with hepatocellular carcinoma treated with sorafenib

BACKGROUND: The positive results of the REFLECT trial in terms of survival (sorafenib vs lenvatinib) offer a new first-line option for hepatocellular carcinoma. Additionally, the expected results of immunotherapy could change the first-line treatment in hepatocellular carcinoma or the clinical trial design in first and second-line. AIMS: To evaluate the impact of dermatologic adverse events under sorafenib in hepatocellular carcinoma patients as a clinical marker to predict prognosis and critically evaluate outcomes within trials. METHODS: A systematic search of original articles published until October 2018 was performed using PubMed/MEDLINE and a meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. RESULTS: A total of 393 studies were identified and 13 articles with 2035 patients (79.5% Child-Pugh-A, 73.2% BCLC-C) were selected for qualitative and quantitative analysis. The main type of dermatologic adverse events was hand-foot skin reaction (47.7%) but other dermatologic adverse events were reported in 31.7% of the cases. Presence of dermatologic adverse events was associated with a lower mortality when compared with those patients without them (pooled Hazard Ratio for the univariate analysis 0.45 (95% CI: 0.38-0.53) and there was no heterogeneity for the analysis (P = 0.511; I2  = 0.0%). Refuting this association would require the future report of 1370 negative studies. CONCLUSIONS: This meta-analysis shows a clinically meaningful association between dermatologic adverse events and a higher probability of longer survival. These data support the use of dermatologic adverse events in the clinical decision-making when informing the prognosis and when systemic treatment is decided.