**3. Chemotherapy-induced alopecia**

CIA or hair loss caused by chemotherapy is the most common cutaneous side effect of chemotherapy. CIA ranks among patients as a severe side effect that affects their quality of life.

#### **3.1 Impact on cancer therapy**

CIA has an enormous psychological and social impact on patients, which can be summarized as: (i) symbol of cancer for self (constant reminder of their treatment) and others (outwardly visible); (ii) personal confrontation of being ill or mortality; (iii) vulnerability; (iv) powerlessness; (v) shame; (vi) loss of privacy; (vii) punishment, and (viii) change in self and other perception (Freedman, 1994; Pozo-Kaderman et al., 1999). Female and children have more difficulties coping with the CIA. Indeed, up to 8% of women are reported to reject chemotherapy for fear of CIA (Mundstedt et al., 1997; McGarvey et al., 2001). CIA also results in reduced social activities since hair partly plays a role in social and sexual communications (Batchelor, 2001). Additionally, these negative impacts of CIA may contribute to poor therapeutic outcome, as stress and depression lowers the body's immune function and is highly associated with cancer progression (Spiegel and Giese-Davis, 2003; O'Leary, 1990).

Chemotherapy-Induced Alopecia 57

about the CIA comes mostly from animal models. The commonly used animal models are neonatal rats and adult mice. However, there are some differences in human and rat/mouse hair growth pattern. In humans, the hair growth cycle occurs in a mosaic or asynchronous pattern, where the growth cycle of individual hair follicles is independent of neighbouring hair follicles. In contrast, rodent hair growth occurs in a wave pattern, beginning from the head and moving towards the tail. A group of hair follicles at a specific area are usually in the same stage of hair cycle. In general, only 10% of hair follicles in adult mice or rats are in the anagen phase as compared to 90% in adult humans. Some animals including guinea pigs and Angora rabbits exhibit a mosaic hair growth pattern but are not commonly used due to

The early model for CIA was established in newborn rats (Hussein et al., 1990; Hussein, 1993). Seven to eight-day old Sprague Dawley rats exhibit spontaneous anagen hair growth for about a week. In this model, administration of chemotherapeutic agents such as cytosine arabinoside, doxorubicin, cyclophosphamide, and etoposide induces alopecia one week after the treatment with the severity of CIA depending on the agents (Hussein et al., 1990;

The major advantage of neonatal rat model is the rapid and easily noticeable CIA due to progressive hair loss from the head and throughout the body in about 2 days. Several drawbacks and limitations of this animal model have been reported. For examples, the level of growth factors and cytokines and the hair follicle structure in neonatal rats differ substantially from those in mature animals, thus altering the response of hair follicles to treatment agents. Also, the lack of hair pigmentation in Sprague Dawley rats, which have a white fur, limits the study of drug effects on melanocytes. Indeed, some observations in newborn rats appear irrelevant to humans. For instance, the protective effect of topical application of 1,25-dihydroxyvitamin D3 on alopecia induced by cyclophosphamide was observed in neonatal rats but not in humans (Jimenez and Yunis, 1992; Hidalgo et al.,

The adult black C57BL/6 mouse model for CIA was first developed in 1994 (Paus et al., 1994). In this mouse strain, the skin melanocytes are confined to hair follicles and the stage of hair growth is indicated by the skin color, i.e., pink during the telogen phase and black during the anagen phase. To mimic human hair scalp, depilation is performed to induce the mouse hair follicles at telogen phase to enter anagen phase, which is normally achieved in about 9 days. At around 16 days after the depilation, morphological signs of catagen are detectable. At day 20 after the depilation, all hair follicles are in the telogen phase. The CIA model was used to study the effect of cyclophosphamide (120-150 mg/kg, ip) on day 9 after the depilation (anagen phase). Cyclophosphamide was found to induce premature catagen development, dystrophic follicles, and complete alopecia in 6 days. In the past decade, progress in the understanding of hair follicle damage and pathogenesis of CIA has been obtained largely by using this model. On a cellular level, cyclophosphamide induces massive apoptosis of keratinocytes and melanocytes, although the precise mechanism of

their insensitivity to CIA.

**4.1.1 Neonatal rat model** 

1999).

**4.1.2 Adult mouse model** 

induction is largely unknown (Hendrix et al., 2005).

Hessein, 1991; Jimenez and Yunis, 1992).

#### **3.2 Pathophysiology**

The basic principle of chemotherapy is to impair the mitotic and metabolic process of cancer cells. Unfortunately, certain normal cells and tissues with rapid metabolic and mitotic rates such as the hair follicles are also affected by the chemotherapy. Up to 90% of hair follicles undergo anagen, an active growth phase, at a given time. The rapid hair growth as well as the high blood flow rate around the hair bulb leading to the accumulation of drugs is a key predisposing factor for rapid and extensive alopecia (Batchelor, 2001). In humans, CIA usually begins approximately 2 to 4 weeks and is complete at 1 to 2 months after the initiation of chemotherapy (Batchelor, 2001). Hair might be easily depilated as early as 1 to 2 weeks after the treatment due to the weakening and breakage of hair shaft. The hair would fall out upon combing and in the bedding area. The degree of CIA depends on the type of chemotherapy, dosage regimen and route of administration. Almost all chemotherapies cause alopecia but with varying degrees of severity and frequency (Apisanthanarax and Duvic, 2003) as summarized in Table 1.


Table 1. Chemotherapeutic agents associated with alopecia.

A high-dose intravenous chemotherapy is commonly associated with more rapid and extensive alopecia. By contrast, oral therapy at lower doses on a weekly schedule tends to cause less alopecia even though the total dose may be large (Wilkes, 1996). Combination therapy consisting of two or more chemotherapeutic agents normally causes a higher incidence and more severe CIA compared to single agent therapy. Long-term chemotherapy may also result in the loss of pubic, axillary and facial hair.

CIA is usually reversible with the hair regrowth generally occurring 3 to 6 months after the end of treatment. However, in most cases the new hair is grey or differs in color, representing the distortion of pigmentation process. Moreover, the new hair typically exhibits some changes in hair structure and texture, e.g. coarser, slow growth, and reduced density (Wang et al., 2006; Trueb, 2009). Permanent alopecia has been reported but rarely occurs (Betcheler, 2001).
