Chemotherapy-induced alopecia management: clinical experience and practical advice

Abstract

Chemotherapy-induced alopecia (CIA) is probably one of the most shocking aspects for oncological patients and underestimated by physicians. Among hair loss risk factors there are treatment-related aspects such as drug dose, administration regimen and exposure to X-rays, but also patient-related characteristics.

At the best of our knowledge no guidelines are available about CIA management. With this paper, based on literature background and our clinical experience, we would like to propose a list of actions in order to estimate the risk of hair loss before starting chemotherapy and to manage this condition before, during and after drug administration and to create a sort of practical guide for dermatologists and oncologist.

There is an urgent need for prospective studies in order to clarify the mechanistic basis of alopecia associated to these drugs and consequently to design evidence-based management strategies.

Background

Chemotherapy-induced alopecia (CIA) is probably one of the most shocking aspects for oncological patients and underestimated by physicians. It negatively influences body image, sexuality, and self-esteem, so that up to 8% of patients decide to refuse chemotherapy if there is the risk of hair loss. [1]

Its incidence is estimated to be 65%, even if the prevalence and severity of hair loss are related to the drug category and to the number of the administered drugs. With anti-microtubule agents it is reported more than 80% incidence of alopecia, 60%-100% with topoisomerase inhibitors, >60% with alkylators, and 10%-50% with antimetabolites (Tab.1). Poly-chemotherapy is associated with higher incidences compared to monotherapy. [2]

Tab. 1.

This table shows the incidence of alopecia associated to the main chemotherapic drug categories

DRUG CATEGORY	INCIDENCE OF ALOPECIA
Anti-microtubule agents	80%
Topoisomerase inhibitors	60%-100%
Alkylators	>60%
Antimetabolites	10%-50%

Among hair loss risk factors there are treatment-related aspects such as drug dose, administration regimen and exposure to X-rays, but also patient-related features like age, comorbidities, the presence of any type of alopecia (more frequently androgenetic alopecia) and nutritional and hormonal status. [3]

About hair-shaft shedding, it can be reached out from days to weeks after starting chemotherapy, and different shedding patterns can be observed (dystrophic anagen effluvium and telogen effluvium). Frontal or occipital hairlines are more frequent involved, suggesting that the affected areas seem to be selective.

Among factors that may influence the shedding pattern the mitotic activity of the hair follicle in the moment of the insult is probably the more important. [2] The main targets of anti-cancer drugs are the matrix keratinocytes, which are highly proliferative during anagen phase, and their pigmentary system. These structures are very sensitive to toxins and drugs, which can easily lead them to rapid apoptosis. [2,3] Catagen and telogen are not affected because they are mitotically inactive phases, but when hair is in late anagen phase, characterized by a lower mitotic rate, chemotherapy accelerates the normal transition to telogen. [2, 3]

If we consider that up to 90% of scalp hairs are normally anagen phase, it is easy to explain why the scalp is the mos t frequent affected area. Whereas hairs of the beard, eyebrows, and eyelashes, as well as axillary and pubic regions are affected depending on the percentage of hairs in anagen.

This kind of alopecia is generally reversible and hair usually regrowth after 3-6 months. Even if temporarily the new hair may show changes in color and/or texture. Although rare, cases of permanent alopecia, with severely retarded or without hair regrowth, are reported associated with high-dose chemotherapy or with busulfan and cyclophosphamide administration, and it is probably the consequence of a damage of hair-follicle stem cells. [2-4]

We consider worthwhile to mention alopecia associated to aromatase inhibitors. These agents, such as letrozole and anastrozole, are associated to a recession of the frontal and parietal hairlines, diffuse hair loss and miniaturization of follicles in the fronto-temporal area, mimicking a typically female androgenetic alopecia (FAGA) with male pattern. The pathogenic mechanism of this type of hair loss seems to be associated to the decrease in estrogens synthesis. Estrogens are potent hair growth modulators and hair protective factors and derive from the conversion of androstenedione to estrone and testosterone to estradiol by aromatase (P450arom), the levels of which in frontal and occipital follicles of women are higher than in the same areas of men. The block of this enzyme induces a relative enhancement in the activity of 5α-reductase which leads to a relative increase in amount of testosterone available for conversion to DHT. [5]

At the best of our knowledge no guidelines are available about CIA management. The aim of this paper is to propose a list of actions in order to estimate the risk of hair loss before starting chemotherapy and to menage this condition before, during and after drug administration and to create a sort of guidelines for dermatologists and oncologist.

Pre-chemotherapy management

Nowadays no guidelines are available about pre-chemotherapy management. In order to estimate the risk of hair loss in the single patient before starting the treatment, it could be interesting to create a guide for dermatologists to analyze scalp condition. To our opinion, the following aspects should be evaluated.

First of all patient selection is fundamental. Considering the better known therapeutic protocols and so the major knowledge about their side effects, in this paper we will just consider patients with solid tumor and not patients with hematological neoplasia.

Anamnestic data should be collected: previous scalp diseases (psoriasis, seborrheic dermatitis and atopic dermatitis among the most frequent) and autoimmune diseases or family story of alopecia could reveal a tendency to some types of alopecia or a subclinical disease that could become evident after chemotherapy. Obviously the drug protocol that will be administered is crucial in order to estimate the risk of hair loss.

In addition, some blood exam could be requested. As is known blood levels of hemoglobin and iron, thyroid hormone s and vitamin D could be associated to hair loss [6-9], so that it may be desired to have sufficient blood levels of these substances before starting any type of anti-cancer drugs. [10]

Scalp dermoscopy (Trichoscopy) is another rapid and non-invasive method that may help to unveil several scalp diseases or some types of alopecia that could be present even before chemotherapy. [11] Trichoscopy can reveal an early stage of androgenetic alopecia, an alopecia areata ingognita or some kind of cicatricial alopecia such as a lichen planopilaris or a discoid lupus erythematosus that can lead to a permanent alopecia even without chemotherapy, but that could be accelerate and could get worse by anti-cancer drugs. [12]

Pull test and trichogramm together to trichoscopy could also be a useful tool in order to evaluate hair condition at T0 and to know if pathological mechanisms are already acting. Moreover trichogramm could show hair cycle phase and therefore hair's susceptibility to chemotherapic agents damage.

All these evaluations can be considered in order to estimate the risk of hair loss after chemotherapy and to better manage the treatment during and after drug administration.

The following steps should be the prescription of drugs that could prevent hair loss. Even if no drugs are actually approved for this goal, some molecules have been studied.

Soref et al. studied the role of topical epinephrine or norepinephrine in preventing radiotherapy and chemotherapy-induced alopecia in 10-day-old rats with good results and no side effects. [13]. This action of vasoconstrictors could probably be explained by a work of Rathman-Josserand et al. that hypothesized that the induction of hypoxia signaling could help hair follicle stem cell to maintain their function and that hence prevent alopecia or at least favor neo-genesis [14]; moreover vasoconstriction may reduce the drug dose that reaches the hair follicle, just as scalp cooling acts. If compared to scalp cooling vasoconstrictors have the advantage of an easier administration, so that they can be applied more than once a day even before starting chemotherapy, ensuring both a preventing and a long lasting effect, meanwhile scalp cooling just acts during drug infusion.

On the basis of this experience, we are trying to use a galenic hydrogel, composed by ephedrine 0.5% and naphazoline 0.125% in our patients before the beginning of chemotherapy. We think that the use of this kind of vasoconstrictors could be a useful tool in order to prevent chemo-induced alopecia, even if more studies are necessary.

During-chemotherapy management

Implementation of gentle hair care strategies should be adopted throughout and after chemotherapy. A soft brush should be used, in order to avoid additional traumas, and hair should be washed only as often as necessary using a gentle shampoo. Cutting hair short or shaving hair is not necessary, but it could be more comfortable.

To help patients to deal with this condition and to protect the scalp from sun and cold exposure can be used a wig. To improve patients psychological condition and allow them use their own hair, an analogous wig could be used, obtained by cutting patients hair and implanting them on a prosthetic support.[2]

Another instrument proposed as a preventive therapy for alopecia is scalp cooling. Actually its mechanism is not well known, but it probably works through vasoconstriction, decreasing local concentration of chemotherapy and cellular uptake at the hair follicle and reduceing metabolic uptake. A recent meta-analysis reported that this method significantly reduces CIA [15] and patients’ compliance is good, even if some cases of headache and uncomfortable feelings could be associated [1-3;16-18] as reported by Betticher et al. Best results have been described for alopecia induced by doxorubicine, epirubicine and docetaxel [17], while it should be avoided in hematological malignancies because of the risk for scalp skin metastasis. [2, 3]

A lot of drugs have been used in order to avoid chemo-induced alopecia, but no one have been approved.

In our opinion the combination of topical steroids and topical vasoconstrictors could be a useful tool in order to prevent a massive damage of hair follicle, and in particular of hair-follicle stem cells, with the goal to prevent a permanent alopecia.

Post-chemotherapy management

In order to accelerate the regrowth after chemotherapy 2% topical minoxidil is the best treatment. Its mechanism of action is not already known, but several hypothesis have been proposed, such as: opening of potassium channels by its sulphated metabolite, stimulation of keratinocyte proliferation, inhibition of collagen synthesis and production, stimulation of vascular endothelial growth factor (VEGF) and prostaglandin synthesis. It was demonstrated that minoxidil prolongs the duration of anagen and enlarges miniaturized follicles. [19]

It must be applied twice a day on the involved areas for at least 6 month. It has been demonstrated to reduce the severity and duration of alopecia. [1-3]

Also antioxidant agents could have a role in the post-chemotherapy period. N-acetylcysteine, an analog and precursor of glutathione, have been demonstrated capable to protect neonatal rats from cyclophosphamide CIA and adult mice from doxorubicin CIA both when administered topically and parentally [20-21]. Speaking of which it is necessary to pay attention because recently it has been reported that some kind of tumor may benefit from the reduction of oxidative stress caused by antioxidant, and this effect is obviously more important when they are parentally administered.

Another agent that have been used in order to facilitate hair regrowth after chemotherapy is Calcitriol (1,25-dihydroxyvitamin D3), that was considered the most promising agent for treating CIA [22-23]. It has multiple effects on keratinocytes: inhibition of DNA synthesis, that causes cell cycle arrest at the G0/G1 interphase, inducing differentiation; inhibition of Ki67 expression, a marker of cycling cells; inhibition of the growth of multiple other cell types [22-32]. Hidalgo et al. also referred contact dermatitis associated to 1,25-dihydroxyvitamin D3, so that it must be used with caution in particular if applied topically. [33]

Target therapy-induced alopecia

What exposed before is related to “classic” anti-cancer drugs, that are better known. But several molecularly targeted anticancer therapies have been developed, with an impressive clinical benefit in terms of efficacy and survival rates, but also with new or different side-effects. These new drugs may also cause alopecia, even if its characteristics are different from which we described for conventional chemotherapies. Belum reported an overall incidence of 14.7% of alopecia associated to these drugs (lowest for bortezomib and highest for vismodegib). [34]

In contrast to conventional chemotherapy, where the mechanism is predominantly nonselective cytotoxicity, the mechanisms at the basis of hair loss induced by these drugs id poorly understood [3]. The primary target inhibited, type of the drug, variations in the target spectrum of inhibition, molecular cross-talk between pathways, and the inherent role of these molecules in hair follicle biology may all be involved in the pathogenesis of hair loss.

These drugs selectively target various oncogenic molecules/pathways such as SMO, VEGFR, MAPK, but the incidence of alopecia varies even among drugs acting on the same primary molecular target. Various pathogenic mechanisms may be involved considering two aspects: first of all each one of these drugs often target multiple other pathways, and second the spectrum of inhibition and receptor affinity might vary from a drug to another. [34]

Concerning Shh pathway in hair follicle biology and epidermal homeostasis, murine studies have shown that its inhibition in the skin can lead to reversible alopecia and arrest of hair growth in the telogen phase [35]. This explains vismodegib-induced alopecia.

Inhibition of the EGFR, is associated to follicular disintegration accompanied by inflammation because of its crucial role in anagen–catagen transition [36-38].

The onset and pattern of alopecia are not well described. The alopecia may be a frontal (androgenetic -like), diffuse, or patchy, and it is generally non-scarring [39-40], pruritus may also be present. In some cases, scarring alopecia/folliculitis decalvans with pain and infection may develop [41-42].

The onset after the beginning of treatment may range from two weeks to months, and resolves in 1–6 months after drug discontinuation; the quality of hair and rate of regrowth may also be affected [43].

With the expanding use of targeted agents, there is an urgent need for prospective studies in order to clarify the mechanistic basis of alopecia associated to these drugs and consequently to design evidence -based management strategies.

Moreover these conditions should be treat among several specialists, in order to reduce evaluation times and simplify their management. The dermatologist has a crucial role in each one of the treatment phase, and should work together to the oncologist in taking care of these patients.