**1. Introduction**

52 Topics in Cancer Survivorship

[16] Wilke LG, McCall LM, Posther KE, et al. Surgical complications associated with sentinel

[17] Ververs JM, Roumen RM, Vingerhoets AJ, et al. Risk, severity and predictors of physical

[18] Kleinhans E, Baumeister RG, Hanh D et al. Evaluation of transport Kinetics in

[19] Cambria RA, Gloviczki P, Naessens JM et al. Noninvasive evaluation of the lymphatic

trial. Ann Surg Oncol 2006; 13(4):491–500.

vessels. Eur J Nucl Med. 1985; 10:349-52.

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Eur J Cancer 2001; 37(8):991–9.

lymph node biopsy: results from a prospective international cooperative group

and psychological morbidity after axillary lymph node dissection for breast cancer.

lymphoscintigraphy: follow-up study in patients with transplanted lymphatic

system with lymphoscintigraphy: a prospective, semiquantitative analysis in 386

Chemotherapy-induced alopecia (CIA) is a frequent toxicity and arguably the most feared side effect of cancer chemotherapy (Carelle et al., 2002). The incidence of CIA is approximately 65% of all patients (Wang et al., 2006). CIA could be easily noticeable by self and others in a relative short time, thus it is linked with having cancer and chemotherapy. CIA compromises patient quality of life, especially for female and children, leading to poor therapeutic outcome. Despite significant progresses and substantial efforts in CIA research and development, no reliable and effective preventive treatment has become available. This limitation has been attributed to the lack of basic understanding of CIA pathogenesis and appropriate experimental models. This chapter will provide an overview of the basic and clinical aspects of CIA including hair follicle biology, characteristics of CIA along with the state-of-the-art experimental models and treatment strategies. Experimental approaches for pharmacologic inhibition of CIA including drug-specific antibodies, hair growth cycle modifiers, cytokines, growth factors, antioxidants, cell cycle modifiers, and apoptosis inhibitors will be discussed. Current understanding in the molecular mechanisms of CIA and the role of specific genes, e.g. p53 and Fas, in the process will also be discussed. The chapter will conclude with the perspective on the prevention and management of CIA.

### **2. Hair follicle biology**

Chemotherapy causes structural damage of human scalp hairs. The effects may vary from altered hair appearance, decreased rate of hair growth, partial or complete hair loss (alopecia). To discuss the advances in the pathogenesis of CIA, an overview of hair follicle biology is first covered.

#### **2.1 Hair follicle structure**

Hair follicle structure changes during the various stages of hair growth cycle (see *Section 2.2* for review). In the anagen phase, hair structure is composed of two distinct components, hair follicle and hair shaft (Fig. 1a). The hair follicle is embedded in the connective tissue and subcutaneous fat. Contained within the hair follicle bulb is the pluripotent keratinocytes of hair matrix. Matrix cells in the lower part of hair bulb constantly divide at a high mitotic rate, whereas the matrix cells in the upper part of hair bulb have a low mitotic rate and could differentiate to form the inner root sheath (IRS) and hair shaft (HS), which are the

Chemotherapy-Induced Alopecia 55

HS exhibits no significant proliferation, apoptosis or differentiation. The transition from telogen to anagen occurs when the bulge stem cells are activated (Cotsaleris and Millar,

Anagen (VI) Catagen Telogen

B B B

] Club Activation

Fig. 2. Hair growth cycle. A new hair shaft is produced during anagen, and the old hair is released from the follicle as the new shaft develops. Anagen VI (mature anagen) is the stage where new HS reaches the skin surface and continues to grow through the rest of anagen. During catagen, the lower two thirds of the epithelial follicle are regressed. The hair develops a club structure, which retains the hair in the follicle. Then, the follicle enters a telogen phase until a new growth cycle is activated. Abbreviations: B, bulge; DP, dermal

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

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).

papilla; HS, hair shaft.

DP

HS

life.

**3. Chemotherapy-induced alopecia** 

**3.1 Impact on cancer therapy** 

2001; Krause and Foitzik, 2006; Alonso and Fuchs, 2006; Ohnemus et al., 2006).

middle and innermost layer of hair follicle, respectively. Outer root sheath (ORS), is the outermost layer of hair follicle that separates the whole organ from dermis and is believed to contain epithelial stem cells at its bulge region (Hardy, 1992; Krause and Foitzik, 2006; Alonso and Fuchs, 2006). Pigmentation of hair shaft depends on melanocytes, which reside in the hair matrix of hair follicle. Melanocytes transfer the melanin granule to keratinocytes of the growing hair shaft (Ohnemus et al., 2006). Besides the epithelial cells, hair follicle also contains the mass of mesenchymal dermal papilla (DP) cells at its base (Fig. 1b). The DP cells are connected to capillaries to derive nutrients from the blood and also function as a regulator of hair cycle (Sakita et al., 1995). Moreover, substantial evidence supports the correlation between DP cell number and the size of hair follicle and shaft (Elliot et al., 1993; Ishino et al., 1997).

Fig. 1. Diagrammatic representation of hair follicle structure in its mature anagen phase. (a) A full-length longitudinal view of hair follicle. (b) Hair follicle bulb. Abbreviations: APM, arector pili muscle; B, bulge; CTS, connective tissue sheath; CTX, cortex of hair shaft; CU, cuticle of hair shaft; DP, dermal papilla; E, epidermis; HM, hair matrix; HS, hair shaft; IRS, inner root sheath; M, melanocytes; ORS, outer root sheath; S, sebaceous gland.

#### **2.2 Hair growth cycle**

Each hair follicle undergoes rhythmic changes through the three phases of hair cycle, which are anagen, catagen and telogen (Fig. 2). Anagen is an active growth phase of hair follicle. During anagen, daughter cells of pluripotent keratinocytes move upwards and adapt into one of the six epithelial lineages, namely Henley, Huxley and cuticle of the IRS and cuticle, cortex and medulla of the HS. As the HS cells become fully differentiated, they extrude their organelles and are tightly packed to form cysteine-rich hair keratins. The IRS and HS interlock via their cuticle structures, however, the IRS degenerates in the upper follicle, thereby releasing the HS that continues to move towards the skin surface. Subsequently, the hair follicle enters the catagen or regression phase. During catagen, there are extensive apoptosis of epithelial cells in the hair follicle bulb and ORS, leading to the formation of epithelial strands. The HS hence stops differentiation and forms the club hair, which moves up until it reaches the bulge region. Dermal papilla cells are condensed and move upwards to the bulge region. After that, the hair enters the telogen or resting phase. In this phase, the

middle and innermost layer of hair follicle, respectively. Outer root sheath (ORS), is the outermost layer of hair follicle that separates the whole organ from dermis and is believed to contain epithelial stem cells at its bulge region (Hardy, 1992; Krause and Foitzik, 2006; Alonso and Fuchs, 2006). Pigmentation of hair shaft depends on melanocytes, which reside in the hair matrix of hair follicle. Melanocytes transfer the melanin granule to keratinocytes of the growing hair shaft (Ohnemus et al., 2006). Besides the epithelial cells, hair follicle also contains the mass of mesenchymal dermal papilla (DP) cells at its base (Fig. 1b). The DP cells are connected to capillaries to derive nutrients from the blood and also function as a regulator of hair cycle (Sakita et al., 1995). Moreover, substantial evidence supports the correlation between DP cell number and the size of hair follicle and shaft (Elliot et al., 1993;

Fig. 1. Diagrammatic representation of hair follicle structure in its mature anagen phase. (a) A full-length longitudinal view of hair follicle. (b) Hair follicle bulb. Abbreviations: APM, arector pili muscle; B, bulge; CTS, connective tissue sheath; CTX, cortex of hair shaft; CU, cuticle of hair shaft; DP, dermal papilla; E, epidermis; HM, hair matrix; HS, hair shaft; IRS,

IRS

ORS

DP

M

HM

CTS

CTX

CU

Each hair follicle undergoes rhythmic changes through the three phases of hair cycle, which are anagen, catagen and telogen (Fig. 2). Anagen is an active growth phase of hair follicle. During anagen, daughter cells of pluripotent keratinocytes move upwards and adapt into one of the six epithelial lineages, namely Henley, Huxley and cuticle of the IRS and cuticle, cortex and medulla of the HS. As the HS cells become fully differentiated, they extrude their organelles and are tightly packed to form cysteine-rich hair keratins. The IRS and HS interlock via their cuticle structures, however, the IRS degenerates in the upper follicle, thereby releasing the HS that continues to move towards the skin surface. Subsequently, the hair follicle enters the catagen or regression phase. During catagen, there are extensive apoptosis of epithelial cells in the hair follicle bulb and ORS, leading to the formation of epithelial strands. The HS hence stops differentiation and forms the club hair, which moves up until it reaches the bulge region. Dermal papilla cells are condensed and move upwards to the bulge region. After that, the hair enters the telogen or resting phase. In this phase, the

inner root sheath; M, melanocytes; ORS, outer root sheath; S, sebaceous gland.

Ishino et al., 1997).

E

B

HS

] Bulb

S

APM

**(a) (b)**

**2.2 Hair growth cycle** 

HS exhibits no significant proliferation, apoptosis or differentiation. The transition from telogen to anagen occurs when the bulge stem cells are activated (Cotsaleris and Millar, 2001; Krause and Foitzik, 2006; Alonso and Fuchs, 2006; Ohnemus et al., 2006).

Fig. 2. Hair growth cycle. A new hair shaft is produced during anagen, and the old hair is released from the follicle as the new shaft develops. Anagen VI (mature anagen) is the stage where new HS reaches the skin surface and continues to grow through the rest of anagen. During catagen, the lower two thirds of the epithelial follicle are regressed. The hair develops a club structure, which retains the hair in the follicle. Then, the follicle enters a telogen phase until a new growth cycle is activated. Abbreviations: B, bulge; DP, dermal papilla; HS, hair shaft.
