A new phase II randomized clinical trial has found that zinc supplementation may help reduce the severity of hand-foot skin reaction (HFSR), a common side effect experienced by cancer patients taking certain targeted therapies. The study, published in both the Journal of the American Academy of Dermatology and the European Journal of Cancer, investigated whether zinc supplements could mitigate HFSR in patients with metastatic colorectal cancer being treated with regorafenib.
The trial was conducted at Chang Gung Memorial Hospital in Taiwan from March 2016 to March 2019. It was funded by the Chang Gung Memorial Foundation. A total of 65 patients with metastatic colorectal cancer were enrolled and randomly assigned to either receive zinc supplementation (32 patients) or serve as controls without supplementation (33 patients).
HFSR is characterized by skin abnormalities on the palms and soles of the feet. It occurs in about 35% of patients taking vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) like regorafenib. The painful condition can significantly impact quality of life and often leads to dose reductions or treatment discontinuation. Previous research has suggested zinc deficiency may play a role in the development of dermatologic toxicities from targeted cancer therapies.
The primary aim of this study was to determine if zinc supplementation could reduce the incidence of grade 2 or higher HFSR within the first 8 weeks of regorafenib treatment. Patients in the zinc group received 78 mg of oral zinc gluconate twice daily throughout the study period. The control group did not receive any zinc supplements.
To be eligible for inclusion, patients had to have metastatic colorectal cancer and be scheduled to start regorafenib treatment. Exclusion criteria were not explicitly stated in the research letter. Baseline characteristics appear to have been similar between the two groups, with median serum zinc concentrations of 67.75 μg/dL in the supplementation group and 65.7 μg/dL in the control group at the start of the study.
The results showed that after 4 weeks of treatment, both groups had similar rates of grade 2/3 HFSR - 30.3% in the control group versus 21.8% in the zinc group. However, by week 8, there was a significant difference. The proportion of patients with grade 2/3 HFSR decreased to just 12.5% in the zinc supplementation group, compared to 33.3% in the control group. Notably, 6 patients in the zinc group who had grade 2/3 HFSR at week 4 improved to grade 0/1 by week 8.
The researchers also tracked serum zinc concentrations throughout the study. At the 4-week mark, there was no significant difference between the two groups. But after 8 weeks, zinc levels were significantly higher in the supplementation group compared to controls. This correlated with the timing of the observed clinical benefit in reducing HFSR severity.
Interestingly, the study found that lower zinc concentrations were associated with higher grade HFSR at week 4 in the control group. However, this relationship was not seen in the zinc supplementation group. The authors suggest this provides evidence for zinc deficiency potentially playing a role in the pathogenesis of HFSR.
In terms of tolerability and impact on cancer treatment, both groups had similar rates of regorafenib dose reductions during the 8-week study period - 64% in the control group and 69% in the zinc group. There were no significant differences in median progression-free survival or overall survival between the two groups.
The study had several limitations that the authors acknowledged. The sample size was relatively small at just 65 patients. It was an open-label design, meaning both patients and researchers knew who was receiving zinc supplements. Quality of life data was not collected, which could have provided valuable insight into the patient experience. The researchers also noted that differences in skin care routines during the study period may have influenced HFSR severity, though they tried to minimize this by having all patients see the same dermatologist regardless of study group.
Despite these limitations, the authors concluded that zinc supplementation shows promise for reducing the incidence of moderate to severe HFSR in patients taking regorafenib. They suggest the findings provide justification for further research into zinc supplementation as a strategy to alleviate HFSR severity in cancer patients treated with VEGFR-TKIs more broadly.
However, this study was not without it's limitations. The study was conducted at a single center in Taiwan, which may limit generalizability to other populations. The relatively short 8-week follow-up period means longer-term effects and safety of zinc supplementation in this context remain unknown. It's also unclear if the findings would apply to other VEGFR-TKIs besides regorafenib or to non-colorectal cancer patients.
If validated in larger studies, these findings could have significant clinical implications. HFSR is a common and often dose-limiting toxicity for many patients on VEGFR-TKIs and other targeted therapies. An inexpensive, well-tolerated intervention like zinc supplementation could potentially allow more patients to stay on effective treatments at optimal doses. This in turn could translate to improved outcomes.
For oncologists and dermatologists, the results suggest it may be worthwhile to check zinc levels in patients developing HFSR on targeted therapies. Prophylactic zinc supplementation could also be considered, particularly in patients with borderline low zinc levels at baseline. However, clinicians should keep in mind this was a small study and larger trials are needed before making wholesale changes to practice.
For researchers, this work opens up several avenues for further investigation. Larger randomized trials with longer follow-up are clearly needed to confirm the findings. Studies looking at zinc supplementation with other VEGFR-TKIs and in non-colorectal cancer populations would help determine how broadly applicable the strategy may be. Mechanistic studies to elucidate exactly how zinc deficiency may contribute to HFSR development could potentially reveal other therapeutic targets.
Quality of life assessments will be important to include in future work, as reducing the severity of HFSR symptoms could have major impacts on patient well-being and ability to tolerate treatment. Cost-effectiveness analyses would also be valuable, as zinc supplements are relatively inexpensive but could potentially allow for fewer dose reductions and better outcomes.
It's worth noting that while this study focused on HFSR, zinc plays important roles in many biological processes including wound healing, immune function, and protein synthesis. As such, ensuring adequate zinc levels in cancer patients may have benefits beyond just reducing HFSR. Future studies may want to look at other potential impacts of zinc supplementation in this population.
In conclusion, this phase II randomized trial provides intriguing early evidence that zinc supplementation may help reduce the severity of HFSR in patients taking regorafenib for metastatic colorectal cancer. While larger studies are needed to confirm the findings, the low cost and good safety profile of zinc make it an attractive option to investigate further. Oncologists and dermatologists should stay tuned for additional research in this area, as it could eventually impact how we manage this common and troublesome side effect of many important cancer therapies.
References
Huang WK, Hsu HC, Yang TS, 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. 2024;90(2):368-369. doi:10.1016/j.jaad.2023.06.055
