Zinc supplementation is associated with improvement in hand-foot skin reaction in patients on vascular endothelial growth factor receptor-tyrosine kinase inhibitors: A cohort study
Authors: Chun-Wei Lu, Chun-Nan Yeh, Hung-Chih Hsu, Chun-Bing Chen, Tsai-Sheng Yang, Yi-Ru Pan, Wen-Hung Chung, Shuen-Iu Hung
Journal: Journal of the American Academy of Dermatology (2023)

To the Editor: Hand-foot skin reaction (HFSR) is a common side effect of multikinase inhibitors, particularly vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) like sorafenib, regorafenib, and sunitinib.1Ding F. Liu B. Wang Y. Risk of hand-foot skin reaction associated with vascular endothelial growth factor-tyrosine kinase inhibitors: a meta-analysis of 57 randomized controlled trials involving 24,956 patients.J Am Acad Dermatol. 2020; 83: 788-796Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar Despite its prevalence, effective interventions for HFSR are still lacking. Considering the essential role of zinc in epidermal homeostasis and our prior research linking zinc deficiency to cutaneous toxicities from EGFR-TKI therapy,2Lu C.W. Pang J.H.S. Ko Y.S. et al.Zinc deficiency associated with cutaneous toxicities induced by epidermal growth factor receptor tyrosine kinase inhibitor therapy in patients with lung adenocarcinoma.J Eur Acad Dermatol Venereol. 2023; 37: 328-339Crossref PubMed Scopus (5) Google Scholar in this study, we investigate the relationship between serum zinc levels and HFSR severity and evaluate the effects of zinc supplementation on HFSR. We enrolled 80 patients using VEGFR-TKIs and assessed HFSR grades according to NCI-CTCAE v5.0 guidelines. Sixty-three patients had HFSR (grade 1: 12, grade 2: 28, and grade 3: 23), mainly caused by sorafenib (68.3%) (Supplementary Table I, available via Mendeley at https://data.mendeley.com/datasets/9g9v8w3s4c/1). Serum zinc levels were measured using atomic absorption spectrometry with a normal range of 70∼120 μg/dL. In comparison to individuals without HFSR (grade 0), HFSR cases exhibited lower mean zinc levels (grade 0: 67.3 μg/dL; grade 1: 61.4 μg/dL; grade 2: 60.2 μg/dL, and grade 3: 53.8 μg/dL) (Fig 1). Linear regression analysis showed a significant association between zinc levels and HFSR severity (coefficient = −4.23, P = .0006) (Fig 1). Among the 63 patients, 47 predominantly suffering from severe (grade 2/3) HFSR, received zinc supplementation with elemental zinc at 10 mg/day for 8 weeks. After supplementation, the mean zinc level was restored to the normal range (72.36 μg/dL), and cases with high-grade HFSR decreased from 45 (95.7%) to 11 (23.4%) (Fig 2, Supplementary Fig 1, available via Mendeley at https://data.mendeley.com/datasets/9g9v8w3s4c/1). Zinc supplementation led to an improvement of at least one HFSR grade in 80.85% (38/47) patients and a mean reduction of 1.3 grades. Upon zinc supplementation, most patients recovered from high-grade HFSR within 1 to 3 weeks, enabling an earlier dose escalation of VEGFR-TKIs for cancer management. Zinc supplementation continued throughout the subsequent TKI therapy, and none of the patients had to discontinue VEGFR-TKIs due to HFSR. The underlying mechanism of serum zinc decrease in VEGFR-TKI-induced HFSR remains unclear. The severity of HFSR and extensive keratinocyte necrosis correlate with drug dosage and direct toxicity.1Ding F. Liu B. Wang Y. Risk of hand-foot skin reaction associated with vascular endothelial growth factor-tyrosine kinase inhibitors: a meta-analysis of 57 randomized controlled trials involving 24,956 patients.J Am Acad Dermatol. 2020; 83: 788-796Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar Notably, some TKIs contain a zinc-binding moiety and form complexes with zinc.3Chavda J. Rajwar A. Bhatia D. Gupta I. Synthesis of novel zinc porphyrins with bioisosteric replacement of sorafenib: efficient theranostic agents for anti-cancer application.J Inorg Biochem. 2023; 249112384Crossref Scopus (1) Google Scholar The high daily dosage of VEGFR-TKIs, such as 800 mg/day sorafenib, may influence food/zinc intakes through gastrointestinal side effects and may also directly chelate zinc ions, leading to serum zinc decrease, rendering keratinocytes more susceptible to drug toxicity, and facilitating HFSR development. Zinc supplementation during VEGFR-TKI therapy may restore zinc levels in the epidermis and support keratinocyte viability. Additionally, combining VEGFR-TKIs and zinc suggests increased anticancer effects.4Chen X. Che X. Wang J. et al.Zinc sensitizes prostate cancer cells to sorafenib and regulates the expression of Livin.Acta Biochim Biophys Sin (Shanghai). 2013; 45: 353-358Crossref Scopus (8) Google Scholar Despite limitations, this cohort study provides a large group of patients who have improved with zinc supplementation. This was further corroborated by a phase II randomized trial.5Huang W.K. Hsu H.C. Yang T.S. et al.Zinc supplementation decreased incidence of grade ≥2 hand-foot skin reaction induced by regorafenib: a phase II randomized clinical trial.J Am Acad Dermatol. 2023; S0190-9622: 02383-02386Google Scholar Based on these data, clinicians may consider zinc supplementation for patients with HFSR or those undergoing VEGFR-TKI therapy. Such an approach may facilitate quicker recovery from HFSR, decrease HFSR incidence, and allow cancer patients to continue VEGFR-TKI usage at optimal doses. None disclosed. We thank the members of Drug Hypersensitivity Research Center, and Cancer Vaccine and Immune Cell Therapy core lab at Chang Gung Memorial Hospital, Linkou branch for the great support.