Prevention and Treatment of Chemotherapy-Induced Alopecia

Background Chemotherapy-induced alopecia (CIA) is one of the most dramatic side effects of chemotherapy. Currently no guidelines are available for its prevention and treatment. Several devices and drugs are used, but results are often disappointing. Aims Our aim is to analyze drugs and devices proposed in the literature for prevention and treatment of CIA induced by cytotoxic drugs and to discuss the evidenced-based opinion. Methods and Results Scalp cooling is the only agent that has been approved by the US Food and Drug Administration for CIA prevention. Minoxidil and bimatoprost should not be used during chemotherapy administration, but they can be used after chemotherapy discontinuation to obtain greater regrowth. Conclusions Therapy should always be modulated for the patient and no fixed protocol should be used. Trichoscopy and trichogram could be useful tools in supporting this treatment.

of hematological tumors [12]. Finally, this device is contraindicated in cold agglutinin disease, cryoglobulinemia, and posttraumatic cold injury because of the risk of triggering local or generalized attack [13,14]. Soref and Fahl evaluated the efficacy of topical vasoconstrictors epinephrine and norepinephrine in preventing chemotherapy-and radiotherapy-induced alopecia in rats [15]. Induction of hypoxia signal by local vasoconstriction preserves hair follicle cells and reduces the amount of drug reaching hair follicle [16]. The use of vasoconstrictors 3 times a day leads to effective and long-lasting vasoconstriction.
In humans, when applied applied on nasal mucosae for a long time, topical vasoconstrictors could induce rhinitis medicamentosa that may present with inflamed, dry mucosa prone to bleeding, edema, and associated insomnia [17,18].
It is reasonable to hypothesize that no risk of thinning and bleeding exists in cases of scalp application, since scalp is thicker than mucosa and has a different vascularization.
The limitation of scalp cooling is that its action is confined to the application time, which usually coincides with the drug infusion. We know that the half-life of chemotherapeutic drugs is longer than their infusion time; for this reason toxic effects are prolonged too. Scalp refrigerating and consequent vasoconstriction limited to infusion time could not prevent toxic effects occurring during the weeks from one infusion to another. Meanwhile, daily topical application of vasoconstrictors could overcome this problem to ensure better results in preventing CIA. Moreover, these drugs could be used also in patients who develop severe peripheral neuropathies after receiving platinum derivatives and who do not tolerate scalp cooling.

Topical Minoxidil
Topical minoxidil 2% and 5% is widely used, but clinical studies have reported disappointing results. In particular, Rodriguez et al reported severe alopecia in 88% and 92% of the patients treated with, respectively, topical minoxidil 2% and 5% [19]. It was effective in shortening the period of baldness, as reported by Duvic et al [20], and safety and tolerability were good. Duvic et al reported scalp pruritus in 60% and scalp folliculitis in 25% of the patients, and new hair growth on the face in 8 women [20].
We would not recommend minoxidil for CIA prevention, not only because of its clinical inefficacy, but in particular because of the lack of a scientific rationale for its use.
Even if minoxidil's mechanism of action is still not completely clear, it is well known that it induces vasodilation by opening potassium channel localized on smooth muscular cells of peripheral arteries, with consequent slowing of circulation. This leads to a greater permanence of the anticancer induced by targeted therapy, and CIA induced by hormonal therapy. Each of these types is different in clinical aspect and pathogenetic mechanism, so treatment should be different too.
In this review we focus only on CIA induced by cytotoxic drugs. These agents are still largely used, and they are associated with the most extreme type of alopecia, which occurs in a high percentage of the cases. Moreover, all these drugs, although with different mechanisms, work by inducing apoptosis of rapidly proliferating cells [2,4]. This allows us to use therapeutic strategies that can be common to all of them.
This approach is not possible with CIA induced by targeted therapies or hormonal treatments. Separate works should address those treatments.
As already stated, cytotoxic drugs all have as their main targets rapidly proliferating cells. Keratinocytes of the hair follicle matrix are highly proliferative during the anagen phase, and together with the pigmentary system they are very sensitive to toxins and drugs [2,4]. Instead, catagen and telogen phases are mitotically less active, so they are protected from chemotherapy toxicity [2,4]. Normally up to 90% of scalp hairs are in the anagen phase; for this reason hair loss is usually massive. Even if this kind of alopecia is generally reversible in 3 to 6 months, and permanent alopecia is rare, this side effect has a considerable psychological effect [2,4,5].
Our aim is to analyze drugs and devices proposed in the literature for the prevention and treatment of CIA induced by cytotoxic drugs and to discuss the evidenced-based opinion.
It is important to distinguish between drugs and devices aimed to prevent alopecia (such as scalp cooling) and drugs and devices that sustain hair regrowth.

Scalp Cooling and Topical Vasoconstrictors
Scalp-cooling devices refrigerate the scalp with consequent local vasoconstriction and reduction of drug inflow to the hair follicles. It is largely used, and alopecia prevention rates are reported to be between 50% and 80% [6][7][8]. Recently, this device was approved by the US Food and Drug Administration as the only efficient agent preventing CIA [9]. Patient compliance is high, even though headache, discomfort, nausea, and xerosis may occur [10]. This device is recommended in patients affected by solid tumors undergoing chemotherapeutic protocols associated with a high risk of developing CIA. Meanwhile, patients receiving platinum derivatives have severe peripheral neuropathies which limit their tolerance to cold [11]; for this reason scalp cooling should be avoided in these patients. Moreover, the risk of scalp metastasis prohibits the use of scalp cooling in cases blood levels, weight, and height, ensuring blood concentration between 40 and 60 ng/mL, which is considered the optimal range [28][29][30].

Miscellaneous
Several other molecules have been proposed and studied for CIA prevention and treatment. Some of them did not give the expected results and thus were abandoned. Some others were studied only in vitro or in animal models, so further investigations are needed. These studies are summarized in Table 1 [31][32][33][34][35][36][37][38][39][40].

Discussion
With the exception of scalp cooling, we actually have no effective drugs for CIA prevention. We emphasize that therapy should always be modulated for the patient and no fixed protocol should be used.
Trichoscopy and trichogram could help in understanding the type and grade of hair damage and what kind of treatment is the best option in a given moment [22]. Moreover, the treatment should consider the oncological therapy and course (which and how many cycles of chemotherapy the patient will face), because the intervention acts longer than instantly. We outline these concepts in Table 2.
Ideally, there should be sufficient time (from 2 to 4 weeks) before starting chemotherapy for administering a drug capable of inducing the telogen phase, in order to bring the hair follicle to a protected state during chemotherapy. If this is possible, after chemotherapy discontinuation molecules such as minoxidil and prostaglandin analogues could be used to accelerate the regrowth in anagen. In this way we would avoid the dramatic hair shedding that occurs 14 days after the first chemotherapy dose, and hair would be maintained for about 3 months when a telogen effluvium would occur, followed by a normal anagen without dystrophy. Obviously, this is a hypothesis, and more studies should be conducted.

Conclusions
With this work we seek to clarify the mechanisms of action of drugs usually used in CIA prevention and treatment, indicating the positive and negative aspects of each (Table 3). A better understanding of the pathogenetic mechanism of CIA should lead to more successful treatment, and we hope that in the near future more efficacious, personalized, and targeted treatment options will be developed. drug around the hair follicle. Minoxidil, in addition, is able to induce angiogenesis by upregulating vascular endothelial growth factor expression, and to activate prostaglandin endoperoxide synthase 1, which is able to stimulate hair growth [21]. This effect is exactly opposite to the scalp-cooling effect. Moreover, the final effects of minoxidil are the shortening of the telogen phase and extension of the anagen phase. Since the anagen phase is the most susceptible to drug insult, it is clear that this molecule cannot be used during chemotherapy administration.
We suggest using minoxidil after chemotherapy discontinuation in order to obtain a greater regrowth. The best moment for introducing minoxidil should be evaluated considering chemotherapeutic drug half-life and monitoring scalp with trichoscopy and trichogram [22]. Topical hydrocortisone could be associated with minoxidil topical application, acting as an anti-inflammatory agent but also helping follicular growth.

Prostaglandin Analogue
Another proposed molecule is the topical bimatoprost 0.03%, which is a prostaglandin analogue. Its efficacy was demon-

1,25-Dihydroxyvitamin D3
Calcitriol (1,25-dihydroxyvitamin D3) has also been proposed as a CIA preventive agent. This molecule has several actions on keratinocytes, including DNA synthesis inhibition by blocking cellular cycle in G0/G1 phase, promoting cellular differentiation, and inhibiting Ki67 expression and cell growth [24,25]. Initially calcitriol appeared effective in preventing CIA induced by cytosine [26], but further studies conducted on patients in treatment with anthracyclines and cyclophosphamide showed no efficacy [27]. Moreover, contact dermatitis was reported after prolonged topical application of calcitriol.  The exact identification of timing could enable us to intensify the use of scalp cooling or topical vasoconstrictors when the insult is more aggressive.

Numerous yellow dots
Follicles are protected by acute damage (kenogen phase) Use scalp cooling or topical vasoconstrictors with caution (for example, reducing the time or the number of applications).
It has been hypothesized that a delayed hypoxic insult could induce neogenesis of hair follicle stem cells [15]. Indiscriminate use of scalp cooling and vasoconstrictors could be harmful if other chemotherapy cycles are expected.  [40] In this table we summarize molecules that have been proposed and studied for chemotherapy-induced alopecia (CIA) prevention and treatment, but which are not currently used in humans and for which further investigations are needed.