Zinc supplementation decreased incidence of grade ≥2 hand-foot skin reaction induced by regorafenib: A phase II randomized clinical trial.

To the editor: Hand-foot skin reaction (HFSR), characterized by skin abnormalities on palmoplantar surfaces, has an overall incidence of about 35% upon vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) treatment.1 Zinc, which plays a role in maintaining skin health, may be implicated in the pathogenesis of HFSR.2 Zinc deficiency has been shown to associate with dermatological toxicities of epidermal growth factor receptor (EGFR)-TKI.3, 4 Regorafenib, an oral multi-kinase inhibitor targeting VEGFR 1-3, PDGFR, cKIT, BRAF, and RET1, is approved for the treatment of metastatic colorectal cancer (mCRC) but commonly causes HFSR.5 This phase II randomized trial aimed to investigate whether zinc supplementation can reduce the severity of HFSR induced by regorafenib within the first 8 weeks of treatment (NCT03898102).

A Potential Association of Zinc Deficiency and Tyrosine Kinase Inhibitor-Induced Hand-Foot Skin Reaction.

Hand-foot skin reaction (HFSR) is a common skin-related adverse event induced by multikinase inhibitors targeting both platelet-derived growth factor receptor and vascular endothelial growth factor receptor, possibly due to inadequate repair following frictional trauma. Zinc is a trace element and essential nutrient in humans that plays critical roles in the development and differentiation of skin cells. Zinc transporters (Zrt- and Irt-like proteins and Zn transporters) and metallothioneins are involved in zinc efflux, uptake, and homeostasis and have been reported to be involved in skin differentiation. The underlying mechanism of HFSR remains unclear, and the association between HFSR and zinc has not been previously studied. However, some case reports and case series provide potential evidence to suggest that zinc deficiency may be involved in HFSR development and zinc supplementation may relieve HFSR symptoms. However, no large-scale clinical studies have been conducted to examine this role. Therefore, this review summarizes the evidence supporting a possible link between HFSR development and zinc and proposes potential mechanisms underlying this association based on current evidence.

Zinc deficiency associated with cutaneous toxicities induced by epidermal growth factor receptor tyrosine kinase inhibitor therapy in patients with lung adenocarcinoma.

PURPOSE: Cutaneous toxicities are common adverse effects following epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy. Zinc deficiency causes diverse diseases, including skin toxicities. Therefore, this study aimed to investigate the role of zinc deficiency in patients with EGFR-TKI-induced skin toxicities. EXPERIMENTAL DESIGN: This retrospective study enrolled 269 patients with diverse skin disorders who visited our hospital between January 2016 and December 2017. The skin toxicity severities and plasma zinc levels of 101 EGFR-TKI-treated cancer patients were analysed and compared with those of 43 non-EGFR-TKI-treated cancer patients and 125 patients without cancer but presenting cutaneous manifestations. Additionally, the role of zinc in erlotinib-induced skin eruptions was established in a 14-day-murine model. Clinical features were further evaluated following systemic zinc supplementation in EGFR-TKI-treated cancer patients. RESULTS: EGFR-TKI-treated patients demonstrated severe cutaneous manifestations and a significant decrease in plasma zinc levels than those of the control groups. The serum zinc level and Common Terminology Criteria for Adverse Events (CTCAE) 5.0 grading of EGFR-TKI-induced skin toxicities showed a significant negative correlation (r = -0.29; p < 0.0001). Moreover, erlotinib treatment decreased the plasma zinc levels and induced periorificial dermatitis in rats confirming zinc deficiency following EGFR-TKI treatment. Zinc supplementation to the EGFR-TKI-treated cancer patients showed a significant decrease in the CTCEA grading (p < 0.0005 for mucositis and p < 0.0.0001 for all other cases) after 8 weeks. CONCLUSIONS: Skin impairment following EGFR-TKI therapy could be ameliorated through zinc supplementation. Thus, zinc supplementation should be considered for cancer patients undergoing EGFR-TKI therapy.

Identification of patients with node-negative, triple-negative breast cancer who benefit from adjuvant cyclophosphamide, methotrexate, and 5-fluorouracil chemotherapy.

AIM: Triple-negative breast cancer (TNBC) has a relatively poor prognosis compared to other molecular subtypes of breast cancer. This study aimed to evaluate the role of adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) in node-negative TNBC and to identify patients who could benefit from this therapy. PATIENTS AND METHODS: We retrospectively reviewed the clinicopathological features and outcomes of patients with node-negative TNBC after surgery followed by either adjuvant chemotherapy with CMF or observation only. RESULTS: Between January 2000 and December 2006, 276 patients with node-negative TNBC were eligible for inclusion in this study. The median follow-up time was 85.0 months by the end of 2010. The CMF (N=211) and observation (N=65) groups did not significantly differ with regard to T-stage, lymphovascular invasion (LVI), and tumour grade, but patients in the former group were on average younger (p<0.01). Adjuvant CMF was associated with favourable disease-free survival (DFS) (p=0.04). The CMF group also had a significantly lower locoregional recurrence rate than the observation group (0.4% vs. 9.2%, p=0.02). Subgroup analysis revealed that patients in the CMF group had significantly better DFS than those in the observation group among those with tumours larger than 2 cm (hazard ratio=0.38, p=0.02) and those who underwent partial mastectomy (hazard ratio=0.28, p=0.01). CONCLUSION: Adjuvant CMF chemotherapy was effective in reducing locoregional recurrence rate and prolong DFS in patients with node-negative TNBC, particularly in those with tumours of more than 2 cm or who had undergone partial mastectomy.