Abstract
Palmar-plantar erythrodysaesthesia (PPE) is a common side effect of chemotherapy treatment in patients with cancer. The exact pathophysiologic mechanisms of the development of PPE remain unclear. Here, we report two important physiological functions of carotenoids without hydroxyl groups (α-carotene, β-carotene, γ-carotene, ξ-carotene, lycopene, phytoene, phytofluene and their isomers) in the stratum corneum (SC) of glabrous skin: The powerful antioxidant protection of the integrity of the SC components against the destructive action of free radicals and maintaining the skin barrier function by the creation of an orthorhombic organization of intercellular lipids within lamellae using carotenoids as a skeleton. The dual protective role of carotenoids without hydroxyl groups is important for both healthy skin and, in the authors’ opinion, for the skin of chemotherapy-treated patients against the development of PPE, as the chemotherapy-induced reduction of the carotenoid concentration in the stratum corneum considerably weakens the skin resistance to cytotoxic and other adverse reactions.
Palmar-plantar erythrodysaesthesia (PPE), also known as acral erythema or hand-foot syndrome, is a toxic side effect of various chemotherapeutic agents, most commonly pegylated liposomal doxorubicin, docetaxel, and 5-fluorouracil (1). It is mainly localized on the glabrous skin of the palms of the hands and soles of the feet – skin areas with a thick stratum corneum (SC) and a high concentration of sweat glands. PPE manifests as inflammatory skin eruptions of varying severity including dryness, hyperkeratosis, erythema, swelling, desquamation or even rhagades, blistering and ulceration, which can cause pain and considerable discomfort to patients (2). In most cases, the development of PPE forces an adjustment of the chemotherapy regimen by reducing the drug concentration in the infusion, the number of infusions, and even discontinuation of the chemotherapy treatment (3-5). Not all patients are equally susceptible to PPE: The first signs of PPE, depending on the therapeutic agent, can appear after the first cycle of chemotherapy, while most cases occur after at least three to four cycles of chemotherapy, while in some patients no PPE develops at all. The development and severity of PPE does not only depend on the applied drug, but also on individual physiological features, lifestyle habits and circumstances (6). Hackbarth et al. (7) reported that PPE is developed in 84% of patients treated with pegylated liposomal doxorubicine (40 mg/m2 every four weeks). While a cumulative cytotoxic effect may be part of the pathogenesis, the exact pathophysiologic mechanisms of the PPE development generally remain unclear and may differ depending on the specific drug.
Results and Discussion
In a study including patients with cancer, it was shown that the carotenoid concentration in the SC of palmar skin, measured non-invasively before chemotherapy, was significantly lower than in the palmar skin of healthy individuals (p<0.001) (8), which can be related to the increased disease-induced oxidative stress (9-11). The chemotherapy treatment, including infusion of paclitaxel (175 mg/m2 every 3 weeks), docetaxel (30-35 mg/m2 every 3 weeks) or 5-fluorouracil (2,400 mg/m2 every 2 weeks), leads to an additional significant reduction in carotenoid concentration in the palms of the patients shortly after each infusion – on average by 5, 12 and 7% respectively (p<0.05). This effect was reproducible and served as an indirect indicator of an increase in oxidative processes (12).
One explanation of the PPE development, previously proposed (12-15), is based on the substantial impairment of the antioxidant status of the SC, which is for the most part determined by the carotenoids and, accordingly, the strongly reduced ability to neutralize the free radicals generated in the SC after the release of the chemotherapeutic drug and/or its metabolites as part of the sweat secretion on the skin surface and their further penetration into the SC (6). Accumulating in the thick SC reservoir (16), chemotherapeutic components and the drug-induced free radicals, destroy SC constituents (17-19), which enhance inflammation and serve as one of the initial reasons for the rapid development of PPE.
The results of a recent study show that carotenoids without hydroxyl groups (α-carotene, β-carotene, γ-carotene, ξ-carotene, lycopene, phytoene, phytofluene and their isomers) are within the lamellae of the SC and always oriented parallel to the surface of the lipid bilayer serving as a skeleton for the formation of the orthorhombic lateral organization of intercellular lipids (20), which is crucial for the skin barrier function (21). A lipid bilayer without carotenoids has a fully disordered lateral state, while the presence of carotenoids with hydroxyl groups (zeaxanthin, lutein, astaxanthin and their isomers) enhances only the hexagonal organization and has no effect on the formation of the orthorhombic organization (20). Taking into consideration that most prevalent cutaneous carotenoids are α-carotene, β-carotene and lycopene (6), we conclude that the reduction of their concentration in the SC disturbs the formation of an orthorhombic lateral organization, i.e., reduces the skin barrier function provided by the SC. Thus, the significantly lower carotenoid concentration in the SC of patients with cancer gives rise to the physical impairment of the barrier function, and drugs released with the sweat onto the skin surface after infusion will permeate freely into the deeper SC parts further altering SC components and reducing the antioxidant status and barrier function, thus amplifying the probability of PPE development.
Footnotes
Authors’ Contributions
M.E.D.: direction, conceptualization, interpretation, and writing – original draft preparation. J.L.: conceptualization, interpretation, and writing – review and editing. S.J.: interpretation, supervision, and writing – review and editing. All Authors have read and approved the final version of the manuscript to be published.
Conflicts of Interest
The Authors declare no conflicts of interest in relation to this report. Maxim E. Darvin is no longer affiliated with Charité-Universitätsmedizin Berlin. However, with the permission of the Center of Experimental and Applied Cutaneous Physiology, where the entire work was carried out, the author uses the Charité affiliation.
- Received November 27, 2023.
- Revision received January 23, 2024.
- Accepted January 24, 2024.
- Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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