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

Aliment Pharmacol Ther. 2019 Mar;49(5):482-491. doi: 10.1111/apt.15088. Epub 2019 Jan 29.


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.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Systematic Review

MeSH terms

  • Antineoplastic Agents / adverse effects*
  • Antineoplastic Agents / therapeutic use
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / mortality
  • Humans
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / mortality
  • Retrospective Studies
  • Skin Diseases / chemically induced*
  • Skin Diseases / mortality
  • Sorafenib / adverse effects*
  • Sorafenib / therapeutic use
  • Survival Rate / trends


  • Antineoplastic Agents
  • Sorafenib