Effect of urea cream on sorafenib-associated hand–foot skin reaction in patients with hepatocellular carcinoma: A multicenter, randomised, double-blind controlled study

Background: Hand-foot skin reaction (HFSR) is the most common adverse event during sorafenib treatment, which is the main reason for dose de-escalation or discontinuation of sorafenib in hepatocellular carcinoma (HCC) patients. Here, we aimed to investigate the role of urea cream in the prevention or amelioration of HFSR severity. Methods: HCC patients at 13 hospitals in Korea were recruited from May 2016 to May 2018. Patients were treated with placebo cream and urea cream for 12 weeks concomitantly with sorafenib treatment. Development of HFSR, score for Hand-Foot Skin Reaction and Quality of Life (HF-QoL) questionnaire, and adverse event were assessed at 2, 4, 8, and 12 weeks. Findings: Of the 288 patients, 247 patients, with 117 patients in the placebo control group and 130 patients in the urea cream group, were analyzed. The urea cream group showed lower cumulative incidence of any grade of HFSR (Log-rank, p=0.247) and severe HFSR of grade 2 or higher (Log-rank, p = 0.394) without statistical significance. In the incidence by time point, the development of severe HFSR of grade 2 or higher was significantly lower in the urea cream group than in the placebo control group at two weeks (13.8% vs. 23.9%, p=0.042). The urea cream group showed a significantly improved questionnaire score compared to the placebo control group (11.8 vs. 19.7, p=0.014) at 12 weeks. Interpretation: Treatment with urea cream showed a lower incidence of severe sorafenib-induced HFSR at 2 weeks and reduced the tendency of HFSR development in HCC patients. Therefore, treatment with urea cream could be considered for prophylaxis or improvement of HFSR grade in HCC patients treated with sorafenib. Trial Registration: This study was registered at ClinicalTrial.gov (NCT03212625). Funding Statement: The Korea Liver Cancer Association and Hanmi Pharmacy (IIT-CAV-004). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: All participants provided written informed consent. This study was approved by the institutional review board of each participating institute (2016GR0350).