Content uploaded by Christopher Dunnill
Author content
All content in this area was uploaded by Christopher Dunnill on Oct 09, 2017
Content may be subject to copyright.
A Clinical and Biological Guide for Understanding Chemotherapy-
Induced Alopecia and Its Prevention
CHRISTOPHER JOHN DUNNILL,
a,b
WAFAA AL-TAMEEMI,
a
ANDREW COLLETT,
a,b
IAIN STUART HASLAM,
a,b
NIKOLAOS THEODOROS GEORGOPOULOS
a,b
a
Department of Biological Sciences, School of Applied Sciences, and
b
Institute of Skin Integrity and Infection Prevention, University of
Huddersfield, Huddersfield, United Kingdom
Disclosures of potential conflicts of interest may be found at the end of this article.
Key Words. Chemotherapy-induced alopecia •Hair loss •Chemotherapy •Scalp cooling •Side effects •Toxicity •
Hair follicle •Cell models •Prevention •Safety
ABSTRACT
Chemotherapy-induced alopecia (CIA) is the most visibly dis-
tressing side effect of commonly administered chemotherapeu-
tic agents. Because psychological health has huge relevance to
lifestyle, diet, and self-esteem, it is important for clinicians to
fully appreciate the psychological burden that CIA can place on
patients. Here, for the first time to our knowledge, we provide
a comprehensive review encompassing the molecular charac-
teristics of the human hair follicle (HF), how different anticancer
agents damage the HF to cause CIA, and subsequent HF patho-
physiology, and we assess known and emerging prevention
modalities that have aimed to reduce or prevent CIA. We argue
that, at present, scalp cooling is the only safe and U.S. Food and
Drug Administration-cleared modality available, and we high-
light the extensive available clinical and experimental (biologi-
cal) evidence for its efficacy. The likelihood of a patient that
uses scalp cooling during chemotherapy maintaining enough
hair to not require a wig is approximately 50%. This is despite
different types of chemotherapy regimens, patient-specific dif-
ferences, and possible lack of staff experience in effectively
delivering scalp cooling. The increased use of scalp cooling and
an understanding of how to deliver it most effectively to
patients has enormous potential to ease the psychological bur-
den of CIA, until other, more efficacious, equally safe treat-
ments become available. The Oncologist 2017;22:1–13
Implications for Practice: Chemotherapy-induced alopecia (CIA) represents perhaps the most distressing side effect of
chemotherapeutic agents and is of huge concern to the majority of patients. Scalp cooling is currently the only safe option to
combat CIA. Clinical and biological evidence suggests improvements can be made, including efficacy in delivering adequately-low
temperature to the scalp and patient-specific cap design. The increased use of scalp cooling, an understanding of how to deliver it
most effectively and biological evidence-based approaches to improve its efficacy have enormous potential to ease the
psychological burden of CIA, as this could lead to improvements in treatment and patient quality-of-life.
INTRODUCTION
Chemotherapy-induced alopecia (CIA) is an acquired form of
hair loss that affects patient quality of life, negatively impacts
body image, sexuality, and self-esteem, and provides a strong
indication of the individual’s health status, with most people
associating it with cancer [1, 2]. Increasing use of polytherapies,
high-dose taxane administration, and an associated increase in
cases of permanent CIA are being reported. Although a non-
life-threatening condition, CIA is of huge concern to most
patients, yet is often viewed as being of minor clinical impor-
tance, when the focus is understandably on the treatment of a
potentially fatal malignancy. Equally, whereas considerable
efforts have been expended in the attempt to ameliorate other
side effects of chemotherapy, the pathobiology of CIA has been
heavily overlooked [3].
Chemotherapy-induced alopecia is often a particular bur-
den for those with young children who report this as the most
traumatizing aspect of treatment, because the child becomes
emotionally confused and concerned [4]. Consequently, CIA
can be one of the most emotionally difficult side effects, with
feedback from female patients showing that losing hair is/
would be more difficult to live with than the loss of a breast
[5]. Social media and the increased pressure on appearance
meanspatientsarelikelytofeelthatlosingtheirhairisdetri-
mental to their self-esteem, while dealing with a possibly life-
Correspondence: Nik T. Georgopoulos, Ph.D., Department of Biological Sciences, School of Applied Sciences, University of Huddersfield,
Queensgate, Huddersfield, HD1 3DH, United Kingdom. Telephone: 44 (0)1484 47 2721; e-mail: n.georgopoulos@hud.ac.uk Received June 5,
2017; accepted for publication August 17, 2017. http://dx.doi.org/10.1634/theoncologist.2017-0263
The Oncologist 2017;22:1–13 www.TheOncologist.com
O
cAlphaMed Press 2017
Symptom Management and Supportive Care
Published Ahead of Print on September 26, 2017 as 10.1634/theoncologist.2017-0263.
by Nik Georgopoulos on September 27, 2017http://theoncologist.alphamedpress.org/Downloaded from
threatening disease. These factors could negatively impact ther-
apeutic outcome, because severe stress and depression [2] are
linked to a weakened immune system, an instrumental factor
in cancer prognosis [6]. Although most of the research on the
emotional effects of CIA has been conducted on females, the
available research indicates that, at least for younger males, the
impact of CIA is the same as that experienced by females [7].
Chemotherapy-induced alopecia on females portrays that they
have cancer, because most women maintain their hair through-
out life. Men commonly undergo androgenic alopecia; how-
ever, most young males do not, thus males may also be
stigmatized as cancer sufferers when CIA occurs.
It is important for clinicians and even patients to fully appreci-
ate the possible psychological burden of this side effect and to
have a clear understanding of ways available to prevent it [8]. To
this end, here we provide an overview of basic human hair follicle
(HF) biology, with a focus on those events most relevant to CIA
and the processes that occur during hair loss. This includes a
description of the known mechanisms by which anticancer agents
cause CIA. We discuss the various preventative strategies that have
been investigated both in the lab and the clinic, ultimately focusing
on the most effective therapy currently available: scalp cooling.
THE HAIR FOLLICLE
Structure and Function
Hair is a skin appendage with diverse functions, being impor-
tant for thermoregulation, protection from solar radiation, and
Figure 1. Structure of the hair follicle (HF). The schematic illustrates the organization and structure of the human HF, including key areas
of the organ, such as the bulge region, the ORS and IRS, and the hair bulb that includes the hair matrix keratinocyte compartment and the
dermal papilla region.
Abbreviations: DP, dermal papilla; HFPU, hair follicle pigmentary unit; HS, hair shaft; IRS, inner route sheath; ORS, outer route sheath.
Reprinted with permission from [121].
2Chemotherapy-Induced Alopecia and Its Prevention
O
cAlphaMed Press 2017
Published Ahead of Print on September 26, 2017 as 10.1634/theoncologist.2017-0263.
by Nik Georgopoulos on September 27, 2017http://theoncologist.alphamedpress.org/Downloaded from
sexual dimorphism [9]. In humans, scalp and facial hair is asso-
ciated with general well-being, strong social status, and sexual
attraction, and is often used to make a fashion statement or
even demonstrate political affiliations [10, 11].
The HF is a mini-organ and skin appendage; its primary
function is to produce the visible hair shaft [12, 13]. The HF is
divided into distinct sections, as detailed in Figure 1. The upper
sections of the HF are permanent, with the infundibulum run-
ning from the opening of the sebaceous gland (SG) duct to the
point where the HF meets the epidermis, providing a funnel-
shaped cavity through the epidermis and offering an opening
for the hair shaft. The isthmus is located at the lower boundary
of the SG at the insertion point for the arrector pili muscle. This
region is also commonly described as the bulge, and contains a
population of epithelial HF stem cells, the identity of which has
recently been reviewed [14]. The progeny of these stem cells
produce the hair bulb matrix keratinocytes, as well as contrib-
uting to the formation of the epidermis, particularly during
wound healing, and it is damage to these cells that severely
impairs long-term hair shaft production [15]. The suprabulbar
region contains multiple layers of the outer root sheath (ORS)
and inner root sheath (IRS), which form concentric cylinders
wrapping the hair shaft itself (Fig. 1). Each of these layers has a
unique expression of structural and adhesion proteins [16].The
hair bulb contains the matrix keratinocytes, a population of
rapidly-dividing progenitor cells that differentiate (specialize) to
form the IRS and hair shaft. Matrix cells in the lower part of the
hair bulb have a higher mitotic (proliferation) rate than those
of the upper part and migrate upwards while differentiating
[15]. The bulb also contains the HF pigmentary unit, within
which are found the melanocytes responsible for hair color.
The HF is primarily epithelial in origin, with the exception of
the dermal papilla (DP) and connective tissue sheath (CTS),
which are mesenchymal. Inductive signals for HF growth and
cycling originate from the DP, an oval mass of specialized fibro-
blasts embedded in an extracellular matrix with extensive vas-
cularization [12, 17, 18]. There is a close relationship between
the size of the DP and HF, with a larger DP creating a larger HF
capable of generating a thicker hair shaft [19]. The CTS sur-
rounds the HF, separating it from the rest of the dermis, and
contains nerve endings, vasculature, and immune cells (such as
mast cells).
The Hair Cycle
Hair follicle morphogenesis (original/new HF development)
occurs antenatally, with the HF beginning a postnatal, life-long
cycle through three distinct phases. Following morphogenesis,
this hair cycle begins with a regression phase (catagen), fol-
lowed by a period of relative quiescence (telogen) and finally a
long growth phase (anagen). The hair cycle is summarized in
Figure 2 and described in more detail below.
Catagen
During the regressive catagen phase, extensive cell death (apo-
ptosis) occurs in the hair matrix keratinocytes, IRS and ORS,
greatly reducing the HF volume, with the remnants of the ORS
Figure 2. The hair “cycle.” Schematic diagram of the three main phases of hair cycle: the growth phase (anagen), the dystrophic phase
(catagen), an extremely shortened resting phase (telogen), and the ‘shedding’ of the hair (exogen). In anagen, the hair bulb is located
deep inside the skin and hair grows towards the skin surface. The dermal papilla survives catagen and moves upward to the lowermost
portion of the bulge, which then forms the secondary germ at its base during telogen. In telogen, the hair falls out and the hair bulb relo-
cates down again as the new hair grows. At their cycle end, telogen HFs can be activated through mechanical depilation, pharmacologi-
cally, and by specific signaling factors (e.g., Wnt signaling), which stimulates a return to anagen and the generation of the new lower
follicle and hair shaft. As the new hair grows in, the old hair is shed during exogen. The duration of each phase depends on the type, site
and specific genetic programming of the follicle.
Dunnill, Al-Tameemi, Collett et al. 3
www.TheOncologist.com
O
cAlphaMed Press 2017
Published Ahead of Print on September 26, 2017 as 10.1634/theoncologist.2017-0263.
by Nik Georgopoulos on September 27, 2017http://theoncologist.alphamedpress.org/Downloaded from
forming the epithelial strand [9]. Structurally, an apoptotic cell
undergoes DNA condensation and fragmentation, cytoplasmic
condensation, membrane blebbing, and formation of apoptotic
bodies, and is removed in a controlled manner by immunocytes
[20]. Apoptosis is crucial in long-term regulation of tissue main-
tenance, which particularly applies to the HF and its cycling/
regeneration, yet exogenous agents can inadvertently induce
excessive apoptosis. Many factors can stimulate apoptosis in
the HF, including UV radiation, x-rays, extreme temperature,
pathogenic toxins, lytic viruses, toxic chemicals, and chemo-
therapeutic drugs [21]. This stimulation of apoptosis can ulti-
mately drive the HF into the regressive catagen phase, which
stops hair production.
Growth factor-mediated signaling between epithelial and
mesenchymal cells orchestrates the creation of the connective
tissue that comprises a developing HF and involves diverse sig-
naling pathways, including Wnt, transforming growth factor
beta (TGF-b)/bone morphogenetic protein (BMP), Hedgehog,
epidermal growth factor (EGF), fibroblast growth factor (FGF),
and Notch [22, 23], as well as tumour necrosis factor (TNF)-
related signaling events [24, 25]. Catagen-associated apoptosis
primarily occurs in the hair matrix keratinocytes, the proximal
and central ORS but generally not in the dermal papilla, which
expresses high levels of antiapoptotic Bcl-2 [21]. The compart-
mentalized expression of pro- and antiapoptotic factors in the
HF is shown in Figure 3. A diverse array of additional molecules
have been found to play a role in catagen induction, including
FGF-5 [26, 27], interferon (IFN)-g[28], substance P [29], and
estrogens [30]. The apoptotic processes within the HF are also
controlled by caspases 21, 23, 24, and 27 [21, 31, 32], and
can also be triggered by the withdrawal of DP-derived growth
factors or by apoptotic signals produced by mast cells located
within the CTS [29, 33, 34].
In addition to apoptosis, other events occur during catagen.
In particular, the termination of melanogenesis is one of the
earliest events and results in the hair shaft becoming less pig-
mented. The DP becomes condensed and ball-shaped, detach-
ing from the surrounding matrix keratinocytes [35].The old hair
shaft forms the club hair, which comes to reside entirely in the
dermis. Overall, catagen lasts for 7–14 days, with 2% of scalp
HFs estimated to be in catagen at any one time [15].
Telogen
Although traditionally described as a quiescent or resting
phase of the hair cycle [16], recent evidence has shown that
the HF is highly metabolically and transcriptionally active dur-
ing telogen [36]. Telogen is referred to as either “refractory” or
“competent” [37]. In the first state, high levels of DP-derived
BMPs, FGF18, and Wnt antagonists prevent any response to
anagen-inducing signals. As the levels of these molecules fall,
the telogen HF becomes primed to enter anagen, which is
described as competent telogen. During telogen, the DP is in
close contact with the HF bulge (stem cell region), separated
by a shortened epithelial strand known as the secondary hair
germ [9]. An estimated 10%–15% of HFs are in the telogen
phase, which lasts approximately 3–4 months [15, 38].
Anagen
With stimulation of a new anagen phase, the more distal
cycling portions of the HF are gradually renewed, the hair bulb
ultimately reaches the dermal adipose layer, and melanogene-
sis is at its highest level [35]. Hair follicles remain in anagen for
approximately 2–6 years [16], with 80%–85% of scalp HFs in
this phase at any given time [15].
CHEMOTHERAPY DRUGS AND CIA
Anticancer Chemotherapy Agents and Their Action
Since the U.S. Food and Drug Administration (FDA) approved
mechlorethamine in 1949 for the treatment of non-small cell
lung cancer, >100 chemotherapy agents have been approved
for cancer treatment in the U.S. alone [39]. In contrast to sur-
gery and radiotherapy, which target the primary tumor, chemo-
therapy is a systemic treatment and therefore targets both
primary and metastasized tumor cells [40].The principle behind
infusing chemotherapeutic drugs is that because a greater
number of malignant cells are in the cell cycle (are dividing) at
any given time compared with healthy cells, the drug should
have a greater impact on malignant cells (by stimulating higher
levels of apoptosis). Table 1 provides a list of the main catego-
ries of commonly used anticancer compounds as well as their
point of action in the mammalian cell cycle. Chemotherapy
agents are routinely administered intravenously but some may
be oral or even topical, with their distribution depending on a
number of factors, such as blood flow, drug diffusion, protein
binding, tissue penetration, and lipid solubility. Generally, drugs
with extensive tissue penetration or high lipid solubility will
tend to exhibit prolonged elimination phases due to slower tis-
sue release [41].
Figure 3. Molecular regulators of apoptosis in the hair follicle (HF).
The diagram illustrates the expression pattern of proapoptotic
(e.g., Fas, p53, Bax) and antiapoptotic (Bcl-2, survivin) molecules
in the different HF compartments.
4Chemotherapy-Induced Alopecia and Its Prevention
O
cAlphaMed Press 2017
Published Ahead of Print on September 26, 2017 as 10.1634/theoncologist.2017-0263.
by Nik Georgopoulos on September 27, 2017http://theoncologist.alphamedpress.org/Downloaded from
Most agents are administered close to the maximum toler-
ated dose (MTD) which is quantified relatively to the individu-
al’s body surface area; this normalizes the dosage, accounting
for physiological factors such as cardiac output, body fat, and
size, and is expressed as units of mg/m
2
[41]. The frequency
and intervals between treatments depend on the cancer type
and the treatment regimen and thus are quite variable. Clinical
evidence demonstrates that most cancers are unlikely to be
managed with a single chemotherapy agent and that combina-
tions are more efficient in disease eradication [42]. The advan-
tages of combinations are believed to be that (a) they provide
maximal malignant cell death within the range of tolerated tox-
icity, (b) malignant cells in different phases of the cell cycle are
targeted (discussed below), and (c) there is a reduced risk of
malignant cell drug resistance development [43]. Chemother-
apy is administered in cycles that include rest periods, so that
the body has a chance to recover from side effects (outlined
below).
Cellular and Molecular Effects of Chemotherapy Drugs
Cells such as HF matrix keratinocytes, intestinal epithelial cells,
and bone marrow cells also divide rapidly, and thus chemother-
apy drugs cause side effects in healthy tissues. Bone marrow
toxicity causes neutropenia, thrombocytopenia, and anaemia,
and damage to the digestive tract results in mucositis, nausea,
vomiting, and diarrhea. Induction of apoptosis in keratinocytes
cancausenailbeddamage,changesinskinintegrity,and
CIA [40].
Although constant division/cell cycling is one reason why
chemotherapy affects cancer cells more than normal cells, can-
cer cells are also more susceptible to lethal oxidation/reactive
oxygen species (ROS). Due to their excessive metabolic rates
and abnormally high energy demands, cancer cells operate
under conditions of high ROS levels, a state also referred to as
oxidative stress; this may in fact represent their “Achilles heel,”
because agents that enhance ROS production can selectively
trigger more cancer cell death [44]. Many anticancer drugs can
increase ROS levels in cancer cells (examples provided below),
thus causing them to cross a “lethal proapoptotic threshold.” A
range of chemotherapeutic drugs have been shown to induce
ROS via various mechanisms, such as phosphorylation of
NADPH oxidase family members and by directly impacting on
the mitochondria, the main site of production of ROS in
cells [45].
Agents shown to augment ROS production to apoptotic lev-
els include anthracyclines (e.g., doxorubicin, epirubicin), alkyl-
ating agents (e.g., cyclophosphamide), and platinum-based
drugs (e.g., cisplatin, carboplatin, and oxaliplatin) [46]. Interest-
ingly, it is such agents that induce HF apoptosis at a greater fre-
quency/severity than most other drugs, suggesting a possible
relationship between ROS production and stimulation of HF
catagen [47]. Indeed, the high mitotic and melanogenic activity
in the hair bulb ensures a high basal level of ROS within this
compartment. Although the HF is well-equipped to deal with
high levels of reactive moieties, it has recently been shown
that exogenous sources of ROS will result in hair matrix apopto-
sis, lipid peroxidation, and induction of catagen [48]. Moreover,
it has been suggested that oxidative damage of mitochondrial
DNA [49] and inhibition of endothelial proliferation in the vas-
cular network surrounding the HF can contribute to CIA [50].
Chemotherapy-Induced HF Pathophysiology
The HF is particularly sensitive to chemotherapy-induced apo-
ptosis because >80% of scalp HFs are anagen-phased at any
one time [51]. Strikingly, the division rate displayed by HF
matrix keratinocytes during anagen can be greater than that of
malignant cells [11], thus resulting in susceptibility to chemo-
therapy agents. High levels of perfusion around the hair bulb
by the DP may also make this region of the HF more susceptible
to drug damage.
The severity of CIA depends on the chemotherapy drug, its
dose, administration route, and treatment schedule. A list of
drugs likely to cause CIA and relative severity is provided in
Table 1. High intravenous doses usually cause more rapid and
extensive hair loss, whereas oral therapy (despite administra-
tion at a higher total dosage) is likely to cause less alopecia
[52]. CIA extent can be classified using a World Health Organiza-
tion (WHO) classification system as “grade 0” implying no CIA,
Table 1. List of the main categories of commonly used anticancer compounds
Usually causes CIA Occasionally causes CIA Unlikely to cause CIA
DNA replication
(S phase)
Topoisomerase inhibitors
Doxorubicin, epirubicin, daunorubicin,
irinotecan, topotecan,
etoposide, teniposide
Amsacrine —
Alkylating agents
Cyclophosphamide, ifosfamide Busulfan, melphalan,
lomustine
Carmustine, procarbazine,
streptozocin
Antimetabolites
—Cytatarbine,
gemcitabine, 5-FU
6-MP, methotrexate,
hydroxyurea, mitoxantrone,
fludarabine, raltitrexed,
capecitabine, idarubicin
Platinum-based heavy metal alkylators
—— Cisplatin, carboplatin
Anticancer antibiotics
—— Mitomycin C
Mitosis
(M phase)
Antimicrotubule agents
Docetaxel, paclitaxel, vindesine, vinorelbine Vincristine, vinblastine —
The table lists the main categories of commonly used anticancer compounds, their point of action in the cell cycle, and the likelihood of causing
CIA [122, 123]. Note: the likelihood to cause CIA relates to the clinical administration of each drug as a monotherapy. Abbreviations: —, no data; 5-
FU, 5-fluorouracil; 6-MP, 6-mercaptopurine; CIA, chemotherapy-induced alopecia.
Dunnill, Al-Tameemi, Collett et al. 5
www.TheOncologist.com
O
cAlphaMed Press 2017
Published Ahead of Print on September 26, 2017 as 10.1634/theoncologist.2017-0263.
by Nik Georgopoulos on September 27, 2017http://theoncologist.alphamedpress.org/Downloaded from
“grade 1” minor, “grade 2” moderate with wig proposal, “grade
3” severe but reversible with wig proposal, and “grade 4” com-
plete irreversible CIA with wig proposal [53], although other
scores/scales are available, such as Dean’s scale [54]. The esti-
mated incidence of CIA is >60% for alkylating agents, >80%
for antimicrotubular agents, 60%–100% for topoisomerase
inhibitors, and 10%–50% for antimetabolites [55]. Although
even just a single drug treatment can significantly reduce hair
density [56], polytherapies (consisting of two or more drugs)
produce higher incidence and more severe CIA compared with
single administrations [53].
In most cases, HF stem cells appear to be largely unaffected
by chemotherapy agents because hair regenerates 3–6 months
after treatment [51, 57]. Although permanent CIA or incom-
plete regrowth is rare, an increasing number of cases are being
reported, and this is more common in children, thus suggesting
that acute damage to HF stem cells may occur [58–60]. In the
case of children, permanent diffuse alopecia has been associ-
ated with hematopoietic stem cell transplantation [61]. In per-
manent CIA, there is a large decrease in the total number of
HFs, but this is not associated with inflammation or fibrosis/
scarring [62]. In a study of permanent alopecia, biopsies of the
frontal scalp were assessed and showed a reduction in anagen-
phase terminal HFs [63]. Instead, permanent alopecia may be
associated with an increase in miniaturized vellus hair [63].
Although permanent CIA or incomplete regrowth is
rare, an increasing number of cases are being
reported, and this is more common in children, thus
suggesting that acute damage to HF stem cells may
occur.
Experimental Models for the Study of CIA
Because CIA remains an important unmet clinical challenge,
and because scalp biopsies from patients are difficult to access,
there is a clear need to develop robust experimental models to
both understand its pathophysiology and to generate avenues
for the development of new treatment strategies [11]. Cur-
rently available models for studying and understanding CIA
together with their advantages and disadvantages are outlined
in Table 2. These include animal models (mainly involving the
use of newborn rodents), as well as in vitro models.
Table 2. Currently available models for studying chemotherapy-induced alopecia
Model information Advantages Disadvantages References
Newborn/young rodents
Hair is depilated from the
rodents, causing all HFs to
enter anagen
7–8 days-old rats have
spontaneous hair growth
for around a week
Can experiment on hair growth
arising from the anagen-phased
follicle
Has a level of consistency
ßHFs are not matured
ßNewborn rats lack pigmentation thus
melanogenesis cannot be studied
ßOnly shows how chemotherapy
drugs affect anagen
ßIn humans, each follicle in a unique
phase, whereas in the rodent they
are all in anagen
[124, 125]
Adult C57BL6 mouse
Adult mice with fully
grown hair/mature skin
containing telogen-phased
HFs is depilated
Mature HF can be recognized by
pigmentation
Has a level of consistency
Can experiment hair growth
arising from the anagen-phased
follicle
ßIn humans, each HF in a unique
phase, whereas in the rodent
following depilation, they are all in
anagen
ßAnagen in humans lasts years as
opposed to weeks in the mice
[126]
Nude mouse human skin
graft
Human scalp skin is
grafted onto nude mice;
hair sheds within a month
and then regrows
Unique physiology of the human
HF is better maintained
Can experiment on hair growth
arising from the anagen-phased
follicle
ßThe xenograft HF cycle after
chemotherapy is not yet well
characterized
ßWound healing-, reinnervation-, and
reperfusion-related phenomena are
absent factors during normal in vivo
scalp HF cycling
[35, 127–129]
Ex vivo cultured human HFs
Anagen-phased HFs are
taken from the scalp and
grown in the laboratory (in
vitro)
HFs are human
HFs are in anagen
Experiments can be well
controlled
ßHuman HFs are difficult to obtain
(need specialist clinicians and
volunteers)
ßHFs can spontaneously enter catagen
due to stress and/or structural
damage
[130, 131]
In vitro keratinocytes
Normal or immortalized
skin cells and normal HF
keratinocyte cultures are
grown in the laboratory (in
vitro)
Like human matrix keratinocytes
are highly proliferative (relevant)
Experiments can be extremely
well controlled and repeated
systematically
Molecular mechanisms can be
studied in detail
ßCell monolayers studied compared
with the highly-structured,
differentiated HF tissue
ßImmortalized (not primary) cell lines
have genetic mutations
[102]
Abbreviation: HF, hair follicle
6Chemotherapy-Induced Alopecia and Its Prevention
O
cAlphaMed Press 2017
Published Ahead of Print on September 26, 2017 as 10.1634/theoncologist.2017-0263.
by Nik Georgopoulos on September 27, 2017http://theoncologist.alphamedpress.org/Downloaded from
PREVENTION MODALITIES AGAINST CIA
Pharmacological and Biological Interventions
Since the 1970s, there have been numerous attempts to pre-
vent CIA by means of mechanical, physical, and pharmacologi-
cal interventions [64–69]. Moreover, several classes of
biological and mainly pharmacological agents with different
mechanisms of action have been evaluated in animal models of
CIA as discussed below.
Drug-Specific Antibodies
To reduce the severity of doxorubicin-induced alopecia in the
newborn rat model, the use of a monoclonal antibody
(MAD11) incorporated in liposomes has been explored to neu-
tralize doxorubicin activity. Topical administration of these anti-
anthracyclines prevented doxorubicin-induced CIA [70]. Further
work explored the antibody’s ability to prevent the bone mar-
row [71], gastrointestinal [72], and mucosal [73] toxicity of dox-
orubicin with positive outcomes in rats; however, no clinical
trials to assess this approach for CIA prevention have been
reported.
Vasoconstrictors
Because changes in DP blood flow inevitably correlate with the
diffusion gradient of drug delivered to the HF, superficial appli-
cation of topical vasoconstrictors epinephrine or norepineph-
rine for prevention of CIA was studied in female Sprague-
Dawley (albino) adult rats treated with Cytoxan or 1-methyl-1-
nitroso-urea (MNU). Vasoconstriction proved highly effective
with MNU, which has a shorter half-life than Cytoxan, demon-
strating the effectiveness of preventing drug entry to the HF.
The effect of lack of blood flow to the human scalp, patient
response variability, and other possible contraindications are
yet to be clinically resolved and there is no evidence, as yet,
that this would be advantageous over other approaches (e.g.,
scalp cooling); however, if effective, it could be better tolerated
[65].
ROS Inhibitors/Antioxidants
The antioxidant N-acetyl cysteine, when applied topically in lip-
osomes, protected newborn rats against cyclophosphamide-
induced CIA, suggesting that cyclophosphamide stimulates ROS
to drive HF apoptosis in matrix keratinocytes [74]. Furthermore,
topical application of antioxidants resveratrol or aminothiol
PrC-210 reduced CIA in newborn mice treated with Cytoxan
[65]. Clinical trials utilizing antioxidants for prevention of CIA
have not yet been performed.
Hair Growth Cycle Modifiers
Immunosuppressive immunophilin ligands, such as cyclospo-
rine A (CSA), are used in the treatment of autoimmune disease
and after organ transplantation; however, these drugs also pro-
long anagen and inhibit the catagen entry of the hair cycle,
resulting in enhanced hair growth in several normal and patho-
genic alopecia conditions [75, 76]. Neonatal rats and mice have
been used to investigate the effects of CSA on CIA. Topical CSA
application locally protected from alopecia induced by cyclo-
phosphamide, cytosine arabinoside, and etoposide [77].
Another immunomodulator, AS101, has been shown to reduce
the severity of alopecia in patients treated with a combination
of carboplatin and etoposide [68]. Given the strong immuno-
suppressive nature of CSA, it cannot be developed as an effec-
tive CIA treatment, yet enhanced understanding of its
mechanism of action may yield information that could lead to
development of novel therapies.
Topical minoxidil is used for the treatment of male pattern
baldness (androgenetic alopecia); minoxidil modifies hair cycle
dynamics by shortening the telogen phase, thus facilitating ana-
gen and encouraging hair growth [78]. In the newborn rat
model, local application of minoxidil protected against CIA
induced by arabinosyl-cytosine, but showed no protection to
doxorubicin and cyclophosphamide-induced CIA [79]. In a clini-
cal study in breast cancer patients, minoxidil was shown to
accelerate recovery from CIA, but did not prevent the initial
hair loss [78]. Minoxidil appears to be most beneficial for men
suffering with androgenetic alopecia, for which it accelerates
hair regrowth [80]. Overall, it helps regrowth following CIA, but
currently there is no evidence supporting its use in CIA preven-
tion [64].
Cytokines and Growth Factors
Interleukin 1 (IL-1), which plays a role in the regulation of
inflammatory and immune responses to infections, and imu-
vert, a biological response modifier with immune stimulatory
properties derived from the bacterium S. marcescens,have
both been reported to protect newborn rats from CIA induced
by cell cycle-specific agents, namely cytosine arabinoside and
doxorubicin, but not from cell cycle-nonspecific agents such as
cyclophosphamide [81]. Both imuvert and IL-1 induce the
release of multiple cytokines or growth factors and it was sug-
gested that the action of imuvert is via IL-1 [82]. There is also
evidence that acidic FGF and EGF protect from CIA, but again
only if CIA is caused by cell cycle-specific agents [81]. Despite
the promise of these agents in newborn rat experimentation
models, they have not yet been tested in the clinic for CIA
prevention.
Cell Cycle or Proliferation Modifiers
As discussed above, rapid cell proliferation in HF matrix kerati-
nocytes during anagen and lack of selectivity in anticancer
agents is a primary factor in the pathogenesis of CIA. Hence,
one approach to protect against the CIA is to inhibit HF cellular
proliferation in order to decrease sensitivity to chemotherapy
[83]. An example of this “protective preconditioning” approach
is the administration of calcitriol (1,25-dihydroxyvitamin D3)
which has multiple effects on keratinocytes, including stimula-
tion of cell differentiation, inhibition of DNA synthesis and G0/
G1 cell cycle arrest [84, 85]. Therefore, it is possible that calci-
triol, by stimulating terminal keratinocyte differentiation, may
alter cell susceptibility to apoptosis. Calcitriol can protect new-
born rats from CIA induced by cyclophosphamide, etoposide,
and combination of cyclophosphamide and doxorubicin [86]. In
addition, in the adult mouse model, calcitriol could enhance
normal pigmented hair shaft regrowth and reduce apoptosis in
the hair bulb; however, it failed to prevent or retard hair loss
after administration of cyclophosphamide [87, 88]. A phase I
study showed that calcitriol was well tolerated and 21 subjects
showed improved hair retention when treated with taxane
therapy [64], but its beneficial effects are most likely limited to
Dunnill, Al-Tameemi, Collett et al. 7
www.TheOncologist.com
O
cAlphaMed Press 2017
Published Ahead of Print on September 26, 2017 as 10.1634/theoncologist.2017-0263.
by Nik Georgopoulos on September 27, 2017http://theoncologist.alphamedpress.org/Downloaded from
taxanes due to the previously mentioned mechanisms of action
for calcitriol.
Finally, inhibitors of cyclin-dependent kinase 2 (CDK2),
which plays a key role in the transition from G1 to late G2 of
the cell cycle, can block progression from late G1 phase into S
phase, reduce the sensitivity of HFs to chemotherapy agents,
and inhibit apoptosis induced by etoposide, 5-fluorouracil,
taxol, cisplatin, and doxorubicin. In newborn rats, topical appli-
cation of a CDK2 inhibitor reduced etoposide-mediated hair
loss by 50% at the site of application and by 33% in CIA induced
by combination of doxorubicin and cyclophosphamide [83].
Despite the promise of these findings, such modifiers have not
been clinically tested yet.
Inhibitors of Apoptosis
Caspase-3 is a key mediator of apoptosis, and pathways leading
to its activation can be stimulated by a number of chemother-
apy agents [89]. Tsuda et al. showed that a topical administra-
tion of M50054, an inhibitor of caspase-3, reduced CIA induced
by etoposide in the newborn rat model [90]. Further experi-
ments have not elucidated whether this would protect against
other drugs, and no clinical trials have been reported.
Parathyroid Hormones
Parathyroid hormone receptor (PPR) ligands have been shown
to have a potential role in the hair cycle by inducing hair
regrowth following CIA [91]. The best results have been
obtained using cyclophosphamide in mice in which it was found
that CIA could be reduced, hair regrowth improved, and repig-
mentation promoted. This suggests that PPR ligands can be
potentially useful as a topical application for preventing/treat-
ing CIA; however, this may rely on follicles that have not under-
gone permanent alopecia [92]. Despite initial promise, clinical
trial results were disappointing and the first trial was termi-
nated [92]. Understanding the potential issues with pharmaco-
kinetics has led to improved PPR ligands; however, there is no
information available on the clinical success of these agents to
date.
Physical Interventions/Non-Drug Therapies
Scalp Tourniquets
Scalp tourniquets are special bands that tightly fit the scalp
region to occlude the superficial blood flow and thus reduce
the amount of drug delivered to the HFs [93]. Scalp tourniquets
are applied when the plasma drug levels are at their peak, that
is, from the last 10 minutes of infusion to 10 minutes after the
cessation of drug administration [94]. Tourniquets have
achieved a small to moderate degree of rescue from CIA
induced by vincristine, cyclophosphamide, and doxorubicin.
However, it is no longer recommended due to the high pres-
sure applied causing patient discomfort [85, 94].
Scalp Cooling
Scalp cooling was introduced in the 1970s [67], with application
of cooling throughout the administration of chemotherapy in
most cases reducing CIA in patients [95].
A number of hypotheses have been proposed to explain
how scalp cooling reduces CIA. Firstly, cooling causes rapid
vasoconstriction, which has been shown to significantly reduce
blood flow in the scalp. In fact, perfusion can be reduced to
20%–40% of normal levels [96], and this should result in
reduced chemotherapeutic drug perfusion through the vascula-
ture of the DP [97]. A second hypothesis is that the rate of drug
diffusion across a plasma membrane is reduced at low temper-
atures due to lower kinetic energy, and membrane lipid fluidity
is also lower, which will impact on passive diffusion; together,
these would result in a low proportion of drugs entering HF
cells [98]. Thirdly, because cell division is an energy-dependent
metabolic process, it is likely that cooling abrogates enzyme-
dependent reactions. It has been reported that temperature
can particularly affect the G1 and S phases of the cell cycle [99],
and this could be especially important for drugs that target spe-
cific phases of the cell cycle, such as mitosis-targeting microtu-
bule-destructive drugs. Fourthly, some drugs (e.g., doxorubicin)
may enter cells via active transport mechanisms, and this
would be reduced by cooling. In support of this hypothesis, it
has been shown in cell models that doxorubicin-induced dam-
age to DNA is reduced at lower temperatures [100]. Fifthly, a
general decrease in the metabolic activity of the cells in the HF
could cause a reduction in the cytotoxicity of chemotherapy
drugs as a range of cellular processes (such as oxidation) decel-
erate [97]. In practice, it is likely that a combination of these
mechanisms play a role in reducing CIA upon cooling, and this
may explain the reported efficacy of scalp cooling.
It has been reported that the scalp temperature achieved
by cooling is a critical factor in preventing CIA, and dampening
thescalpwithwaterimprovesheattransferfromtheheadto
the cooling source [101]. It has previously been reported that a
subcutaneous temperature of 228C was a “threshold” tempera-
ture necessary for effective cooling, and a close relationship
exists between epicutaneous and subcutaneous temperatures
during cooling, with 228C subcutaneous corresponding to an
epicutaneous temperature of 198C[97].Morerecently,Komen
et al. (2016) found that breast cancer patients whose scalp tem-
perature was reduced to 188C were the least likely to require a
wig following anthracycline treatment; the study also raised
the important issue of device fitting, to ensure that all areas of
the scalp are cooled effectively, so that adequately low temper-
atures are achieved [56].
Interestingly, recent laboratory studies have provided sup-
port for these clinical observations. It was shown, using a range
of in vitro models, that cooling can efficiently protect human
keratinocytes from chemotherapy drug-induced toxicity [102].
Equally importantly, it was shown that the cooling conditions
(temperature) used were also a critical factor in preventing
cytotoxicity. These experiments provided for the first time bio-
logical evidence that progressive reduction of temperature
(268C, 228C, 188C, and 148C) positively correlated with better
protection (rescue) of keratinocytes from drug-induced cell
death [102]. It is possible that cooling may have direct cytopro-
tective effects and at the same time may reduce drug diffusion
that renders cells less susceptible to drug toxicity. This is sup-
ported by the finding that reducing the scalp temperature
below 228C does not further decrease blood flow [96], thus any
increasedprotectionbycoolerscalptemperaturesmaynotbe
a result of reduced scalp perfusion. Interestingly, this “cutoff”
point in the protective effect of cooling has been shown to
occur for doxorubicin both at the level of the cell membrane
permeability [98] and subsequent DNA damage [100].
8Chemotherapy-Induced Alopecia and Its Prevention
O
cAlphaMed Press 2017
Published Ahead of Print on September 26, 2017 as 10.1634/theoncologist.2017-0263.
by Nik Georgopoulos on September 27, 2017http://theoncologist.alphamedpress.org/Downloaded from
Practically, a marked reduction in scalp temperature may
lead to an increase in patient discomfort and therefore intoler-
ance, so although “more cold” is beneficial, it may not always
be feasible. Furthermore, the amount of temperature reduc-
tion possible for each person is likely to vary quite considerably
due to individual physiological differences/variability [56]; how-
ever, in most cases, “the colder the better.”
Scalp Cooling Using Cool Caps. Initially, scalp cooling was
achieved using crushed ice in plastic bags fixed into position
with elasticated bandages [103]. Because heat from the head
rapidly warmed the ice packs, these needed to be replaced reg-
ularly; this was time-consuming and also meant that tempera-
ture increased between replacements [104, 105]. The number
of countries and hospitals using scalp cooling increased dramat-
ically following introduction of improved commercially avail-
able products. This involved a refrigerated cryogel cap, which is
placed in a freezer at 2258C before being fitted to the head
(e.g., Penguin cold cap [Penguin Cold Caps, London, U.K.,
https://penguincoldcaps.com]) [104]. However, because of the
very low initial temperature, these gel caps are reported to be
uncomfortable, and although better than ice packs, they still
thaw rapidly and must be changed regularly to maintain
reduced scalp temperature. Thus, several changes are required
during chemotherapy perfusion protocols [104], and between
replacements, scalp temperature unavoidably increases [105].
Modern Scalp-Cooling Devices. Refrigeration unit-fitted
devices designed to circulate liquid refrigerant through a cooling
cap are the modern-day choice for scalp cooling. These caps,
such as the Paxman (Paxman, West Yorkshire, U.K., https://pax-
manscalpcooling.com) and Dignicap (Dignitana, Lund, Sweden,
http://www.dignitana.se/eng) systems, are available in a range
of sizes to ensure a suitable fit, because head sizes and shapes
vary [106]. The advantage of these systems is that the coolant
achieves a constant, reduced scalp temperature throughout
drug infusion without the need for cap replacement. This
reduces medical staff time investment, and because the caps
are not cooled to such initially low temperatures (and are not
as heavy), they are reported to be more comfortable. Recent
studies by Komen et al. (2016) have shown that 188Ccanbe
reached at the scalp of patients throughout the course of chem-
otherapy infusion, and most patients tolerate this intervention
very well, with the majority indicating either low or moderate
levels of discomfort. Only 1 of 62 patients actually reported a
mild headache, even when the scalp cooling device could
reduce temperatures down to 108C within 30 minutes [56].
Other studies have shown that the dropout rate due to intoler-
ance is around 3.3% [107]; however, tolerability varies.
Clinical Evidence for the Efficacy of Scalp Cooling in
Cancer Patients. Scalp cooling is the only FDA-cleared tech-
nique supported by statistically significant and clinical
evidence-based efficacy for CIA reduction. Numerous studies
have demonstrated that its clinical efficiency can reach 90%
depending on the chemotherapy agent and/or cooling tech-
nique used [64, 67].
Auvinen et al. showed that scalp cooling resulted in a signif-
icant reduction in CIA, with 100% of patients maintaining their
hair after doxorubicin treatment, 83.3% after docetaxel, 76.5%
after 5-fluorouracil, epirubicin, and cyclophosphamide (FEC),
and 78% after docetaxel or FEC [108].
A larger and prospective multicenter study conducted by
van den Hurk et al. (2012) explored the effect of scalp cooling
on hair preservation in 1,411 chemotherapy patients between
2006 and 2009 [53]. The data were collected by the Dutch
scalp-cooling registry; the mean age of the subjects was 53,
with 86% having treatment for breast cancer and 96% of these
being female. Treatments varied depending on the stage of the
cancer and consisted of the following: five combinatorial regi-
mens of FEC or docetaxel, doxorubicin, and cyclophosphamide
(TAC), plus several monotherapies (single dose of anthracy-
clines and taxanes). Patients in the study used the Paxman PSC-
1, PSC-2, or ORBIS scalp-cooling devices, and the median num-
ber of chemotherapy and cooling sessions was four [53]. The
results were evaluated by questionnaires, with patients scoring
their own hair loss according to the WHO scale. The best results
were obtained following monotherapy treatments, for
instance, taxanes such as docetaxel (75 mg/cm
2
)orpaclitaxel
(70–90 mg/cm
2
), with 94% and 81% of patients, respectively,
not requiring a wig. The results were less impressive in the case
of the TAC combo therapy, even when used at low doses; only
8% of patients did not require a wig. Overall, 50% of all 1,411
patients surveyed did not use head covering at the time of their
last treatment. van den Hurk et al. (2010) reported that besides
the specific chemotherapy protocol, other factors can have an
influence on the use of head cover, such as patient age (gener-
ally it is higher in those over 50), gender, ethnicity, and wetting
before scalp cooling [53].
Schaffrin-Nabe et al. found that of 226 patients with vari-
able chemotherapy regimens, 146 (88%) had positive results
from scalp cooling and did not require a head cover. The worst
results were obtained with the highest anthracyline doses or
polytherapies or when TAC was administered. Documentation
of other variables, however, identified some of the factors
other than high drug dose that affect the success of cooling,
and these included comorbidity, current medications, age,
menopause, hair thickness, and nicotine intake [107]. More-
over, Komen et al. (2016) showed that of 62 breast cancer
patients (median age 60) treated with up to six cycles (median
three cycles) of anthracycline (epirubicin or adriamycin) chemo-
therapy, 13 (12%) did not require a wig [56]. Cigler et al (2015)
evaluated the effects of scalp cooling on 20 patients receiving
docetaxel and cyclophosphamide with a total of four cycles
over 3-week intervals. Scalps were cooled 50 minutes before
administration and for 4 hours afterwards. Upon follow-up,
only 2 of 20 patients felt the need to wear a wig, whereas nor-
mally the vast majority undergo complete alopecia [54]. Ibra-
him et al. found that scalp cooling prevented up to 96% of
patients from requiring a wig after repeated cycles of taxanes
or anthracycline, and for those who did, it was due to higher
doses of anthracycline treatment [109].
More recently, Nangia and colleagues reported the results
of the Scalp Cooling Alopecia Prevention clinical trial [110]. This
is the first randomized, multicenter trial (RCT) on scalp cooling
(and the first RCT using scalp-cooling devices) and was per-
formed from 2013 to 2016. It tested the efficacy of cooling on
192 patients, with 119 patients receiving anthracycline or tax-
ane treatment versus 63 receiving no intervention (controls).
All patients in the control group needed a wig, whereas 50% of
Dunnill, Al-Tameemi, Collett et al. 9
www.TheOncologist.com
O
cAlphaMed Press 2017
Published Ahead of Print on September 26, 2017 as 10.1634/theoncologist.2017-0263.
by Nik Georgopoulos on September 27, 2017http://theoncologist.alphamedpress.org/Downloaded from
patients receiving scalp cooling did not. This study was termi-
nated on ethical grounds because the chance of preventing CIA
using scalp cooling was so significant [110].
In most studies, the precooling period has been between 5
and 30 minutes to ensure that the scalp is cooled when the
drugs reach the HFs [111–113]; however, recent evidence sug-
gests that it should be around 30 minutes [56, 105]. Another
equally important consideration during scalp cooling is the
period of time necessary to maintain cooling following comple-
tion of drug administration (infusion). Routinely, the cap
remains in place during the administration of the chemother-
apy drugs and for a period after this, referred to as the postin-
fusion cooling time (PICT), which allows the drug concentration
to drop below toxic levels before the HFs warm up. Although
until recently a 90-minute PICT was recommended, van den
Hurk et al. (2012) specifically examined the effect of PICT in
reducing CIA after docetaxel treatment and found that better
results were obtained by reducing PICT from 90 minutes to 45
minutes [114]. This is presumably because once the plasma
concentration of docetaxel drops below toxic levels, the warm-
ing of the scalp allows any drug that has accumulated during
the course of chemotherapy to be more rapidly “flushed out”
of the scalp. This study indicated that some optimization of
cooling protocols might be required to improve the efficacy for
different chemotherapy regimens [114, 115]. In line with this,
Komen et al. (2016) reported that even a 20-minute PICT is as
effective as the 45-minute period [116]. Therefore, both of
these studies represent potentially significant improvements in
scalp-cooling protocols. Shortening the PICT has the additional
advantage of reducing the time that patients would be required
to spend in the treatment environment.
Although some concerns have been raised as to whether
scalp cooling could be associated with a higher incidence of
scalp metastasis, there appears to be no evidence for a link
between metastasis and scalp cooling [117]. Studies that have
been conducted to specifically address this issue in patients
with breast cancer confirmed that scalp metastasis occurs very
rarely, with an incidence between 0.03% and 3% in individuals
who did not receive cooling, and this incidence is no different
than that for individuals who received scalp cooling, for whom
the incidence was 0.04%–4% [118]. In most cases reported so
far, scalp metastases after scalp cooling was not the first meta-
static site and thus any that occurred were part of a widespread
metastatic disease and not related to scalp cooling. These
observations are in accordance with recent studies demonstrat-
ing that use of scalp cooling has no effect on the breast cancer
patient survival [119]. The lack of any association of scalp cool-
ing with breast cancer metastasis is further supported by a
recent, comprehensive systematic review and meta-analysis
reporting that scalp cooling does not increase the incidence of
these rare scalp metastases [120]. Moreover, throughout appli-
cation of scalp cooling, only the outer part of the scalp to a
depth of 2 cm is affected, with no alteration of core tempera-
ture, excluding any risk of hypothermia [101]. However,
patients who are at risk of cold-induced urticaria, cold aggluti-
nin disease, cryoglobulinemia, and post-traumatic cold dystro-
phy should be excluded from scalp cooling [109].
In most cases reported so far, scalp metastases after
scalp cooling was not the first metastatic site and thus
any that occurred were part of a widespread meta-
static disease and not related to scalp cooling. These
observations are in accordance with recent studies
demonstrating that use of scalp cooling has no effect
on the breast cancer patient survival.
CONCLUSION
Despite the success of adjunct chemotherapy in improving the
outcome of cancers such as breast cancer, hair loss still repre-
sents a very significant psychological burden for cancer
patients. Any intervention that could reduce the side effects of
chemotherapy would be expected to lead to improvements in
both the initiation and completion of therapy, in patient quality
of life, and possibly survival outcomes. Having provided a
review of several biological and clinical aspects of CIA, here we
ultimately focused on research demonstrating that scalp cool-
ing is currently the only available safe and effective option for
CIA reduction/prevention. Despite the well-established 50%
success rate of scalp cooling, clinical and biological evidence
suggests that further improvement can be made. Improve-
ments relating to changes in PICT have clearly demonstrated
this. Another important aspect is the efficacy in delivering
adequately low temperature to the scalp, and improving clinical
staff expertise in fitting the cap, as well as the possibility of
patient-specific cap design, could prove important in increasing
the currently reported efficacy of scalp cooling. Finally, an
improved understanding of the biological mechanisms of cool-
ing may not only inform the cap design or temperature of
choice, but also provide novel avenues for enhancing the
capacity of scalp cooling to protect from CIA.
ACKNOWLEDGEMENTS
The authors would like to thank Paxman Coolers Ltd. for useful dis-
cussions. I.S.H. and N.T.G were joint senior authors on this work.
AUTHOR CONTRIBUTIONS
Conception/design: Christopher John Dunnill, Iain Stuart Haslam, Nikolaos
Theodoros Georgopoulos
Manuscript writing: Christopher John Dunnill, Wafaa Al-Tameemi, Andrew Col-
lett, Iain Stuart Haslam, Nikolaos Theodoros Georgopoulos
Final approval of manuscript: NT Georgopoulos
DISCLOSURES
The authors indicated no financial relationships.
REFERENCES
1. Hesketh PJ, Batchelor D, Golant M et al. Chemo-
therapy-induced alopecia: Psychosocial impact and
therapeutic approaches. Support Care Cancer 2004;
12:543–549.
2. Choi EK, Kim IR, Chang O et al. Impact of
chemotherapy-induced alopecia distress on body image,
psychosocial well-being, and depression in breast cancer
patients. Psychooncology 2014;23:1103–1110.
3. Paus R. Therapeutic strategies for treating hair
loss. Drug Discov Today Ther Strateg 2006;3:101–110.
4. Forrest G, Plumb C, Ziebland S et al. Breast can-
cer in the family–Children’s perceptions of their
10 Chemotherapy-Induced Alopecia and Its Prevention
O
cAlphaMed Press 2017
Published Ahead of Print on September 26, 2017 as 10.1634/theoncologist.2017-0263.
by Nik Georgopoulos on September 27, 2017http://theoncologist.alphamedpress.org/Downloaded from
mother’s cancer and its initial treatment: Qualitative
study. BMJ 2006;332:998–1003.
5. Pickard-Holley S. The symptom experience of
alopecia. Semin Oncol Nurs 1995;11:235–238.
6. Spiegel D, Giese-Davis J. Depression and cancer:
Mechanisms and disease progression. Biol Psychia-
try 2003;54:269–282.
7. Hilton S, Hunt K, Emslie C et al. Have men
been overlooked? A comparison of young men
and women’s experiences of chemotherapy-
induced alopecia. Psychooncology 2008;17:577–
583.
8. Peerbooms M, van den Hurk CJ, Breed WP.
Familiarity, opinions, experiences and knowledge
about scalp cooling: A dutch survey among breast
cancer patients and oncological professionals. Asia
Pac J Oncol Nurs 2015;2:35–41.
9. Schneider MR, Schmidt-Ullrich R, Paus R. The
hair follicle as a dynamic miniorgan. Curr Biol 2009;
19:R132–R142.
10. Hadshiew IM, Foitzik K, Arck PC et al. Burden of
hair loss: Stress and the underestimated psychoso-
cial impact of telogen effluvium and androgenetic
alopecia. J Invest Dermatol 2004;123:455–457.
11. Paus R, Haslam IS, Sharov AA et al. Pathobiol-
ogy of chemotherapy-induced hair loss. Lancet
Oncol 2013;14:e50–e59.
12. Whiting DA. The structure of the human hair
follicle. Fairfield, NJ: Canfield Publishing, 2004.
13. Paus R, Muller-Rover S, Van Der Veen C
et al. A comprehensive guide for the recognition
and classification of distinct stages of hair follicle
morphogenesis. J Invest Dermatol 1999;113:523–
532.
14. Purba TS, Haslam IS, Poblet E et al. Human epi-
thelial hair follicle stem cells and their progeny: Cur-
rent state of knowledge, the widening gap in
translational research and future challenges. Bioes-
says 2014;36:513–525.
15. Randall VA, Botchkareva NV.The biology of hair
growth. In: Ahluwalia FS, ed. Cosmetic applications
of laser and light based systems. Amsterdam, Neth-
erlands: Elsevier Inc, 2008:3–35.
16. PausR,FoitzikK.Insearchofthe“haircycle
clock”: A guided tour. Differentiation 2004;72:489–511.
17. Stenn K, Parimoo S, Prouty S. Growth of the
hair follicle: A cycling and regenerating biological sys-
tem. Molecular basis of epithelial appendage mor-
phogenesis. Austin, TX: R.G. Landes, 1998:111–130.
18. Tobin DJ, Magerl M, Gunin A et al. Plasticity
and cytokinetic dynamics of the hair follicle mesen-
chyme: Implications for hair growth control. J Invest
Dermatol 2003;120:895–904.
19. Legue E, Nicolas JF. Hair follicle renewal: Orga-
nization of stem cells in the matrix and the role of
stereotyped lineages and behaviors. Development
2005;132:4143–4154.
20. Lockshin RA, Zakeri Z. Apoptosis, autophagy, and
more. Int J Biochem Cell Biol 2004;36:2405–2419.
21. Lindner G, Botchkarev VA, Botchkareva NV
et al. Analysis of apoptosis during hair follicle regres-
sion (catagen). Am J Pathol 1997;151:1601–1617.
22. Millar SE. Molecular mechanisms regulating
hair follicle development. J Invest Dermatol 2002;
118:216–225.
23. XieG,WangH,YanZetal.Testingchemothera-
peutic agents in the feather follicle identifies a selec-
tive blockade of cell proliferation and a key role for
sonic hedgehog signaling in chemotherapy-induced
tissue damage. J Invest Dermatol 2015;135:690–
700.
24. Epstein EH Jr, Lutzner MA. Folliculitis induced by
actinomycin D. N Engl J Med 1969;281:1094–1096.
25. Tong X, Coulombe PA. Keratin 17 modulates
hair follicle cycling in a tnfalpha-dependent fashion.
Genes Dev 2006;20:1353–1364.
26. H
ebert JM, Rosenquist T, G€
otzJetal.FGF5asa
regulator of the hair growth cycle: Evidence from tar-
geted and spontaneous mutations. Cell 1994;78:
1017–1025.
27. Higgins CA, Christiano AM. Regenerative medi-
cine and hair loss: How hair follicle culture has
advanced our understanding of treatment options for
androgenetic alopecia. Regen Med 2014;9:101–111.
28. Ito T, Ito N, Saathoff M et al. Interferon-gamma
is a potent inducer of catagen-like changes in cul-
tured human anagen hair follicles. Br J Dermatol
2005;152:623–631.
29. Peters EM, Liotiri S, Bodo E et al. Probing the
effects of stress mediators on the human hair fol-
licle: Substance P holds central position. Am J Pathol
2007;171:1872–1886.
30. Ohnemus U, Uenalan M, Conrad F et al. Hair
cycle control by estrogens: Catagen induction via
estrogen receptor (ER)-alpha is checked by ER beta
signaling. Endocrinology 2005;146:1214–1225.
31. Soma T, Ogo M, Suzuki J et al. Analysis of apo-
ptotic cell death in human hair follicles in vivo and in
vitro. J Invest Dermatol 1998;111:948–954.
32. Botchkareva NV, Ahluwalia G, Shander D. Apo-
ptosis in the hair follicle. J Invest Dermatol 2006;
126:258–264.
33. Brajac I, Tkalc
ˇic
´M, Dragojevic
´DM et al. Roles
of stress, stress perception and trait-anxiety in the
onset and course of alopecia areata. J Dermatol
2003;30:871–878.
34. O’Shaughnessy RF, Christiano AM. Inherited
disorders of the skin in human and mouse: From
development to differentiation. Int J Dev Biol 2004;
48:171–179.
35. Oh JW, Kloepper J, Langan EA et al. A guide to
studying human hair follicle cycling in vivo. J Invest
Dermatol 2016;136:34–44.
36. Geyfman M, Plikus MV, Treffeisen E et al. Rest-
ing no more: Re-defining telogen, the maintenance
stage of the hair growth cycle. Biol Rev Camb Philos
Soc 2015;90:1179–1196.
37. Plikus MV, Chuong CM. Macroenvironmental
regulation of hair cycling and collective regenerative
behavior. Cold Spring Harb Perspect Med 2014;4:
015198a.
38. Botchkareva NV, Khlgatian M, Longley BJ et al.
SCF/c-kit signaling is required for cyclic regeneration of
the hair pigmentation unit. FASEB J 2001;15:645–658.
39. Payne AS, James WD, Weiss RB. Dermatologic
toxicity of chemotherapeutic agents. Semin Oncol
2006;33:86–97.
40. Symonds RP, Foweraker K. Principles of chemo-
therapy and radiotherapy. Curr Obstet Gynecol
2006;16:100–106.
41. Tannock IF, Hill RP, Bristow RG, Harrington L. The
Basic Science Of Oncology. Fifth edition. NY, USA:
McGraw-Hill education, 2013. ISBN: 9780071745208
42. Trigg ME, Flanigan-Minnick A. Mechanisms of
action of commonly used drugs to treat cancer.Com-
munity Oncol 2011;8:357–369.
43. Lilenbaum RC, Herndon JE 2nd, List MA et al.
Single-agent versus combination chemotherapy in
advanced non-small-cell lung cancer: The cancer and
leukemia group B (study 9730). J Clin Oncol 2005;23:
190–196.
44. Panieri E, Santoro MM. ROS homeostasis and
metabolism: A dangerous liason in cancer cells. Cell
Death Dis 2016;7:e2253.
45. GuptaSC,HeviaD,PatchvaSetal.Upsidesand
downsides of reactive oxygen species for cancer:
The roles of reactive oxygen species in tumorigene-
sis, prevention, and therapy. Antioxid Redox Signal
2012;16:1295–1322.
46. Nicolson GL, Conklin KA. Reversing mitochon-
drial dysfunction, fatigue and the adverse effects of
chemotherapy of metastatic disease by molecular
replacement therapy. Clin Exp Metastasis 2008;25:
161–169.
47. Simon HU, Haj-Yehia A, Levi-Schaffer F. Role of
reactive oxygen species (ROS) in apoptosis induc-
tion. Apoptosis 2000;5:415–418.
48. Haslam IS, Jadkauskaite L, Szabo IL et al. Oxida-
tive damage control in a human (mini-) organ: Nrf2
activation protects against oxidative stress-induced
hair growth inhibition. J Invest Dermatol 2017;137:
295–304.
49. Bodo E, van Beek N, Naumann V et al. Modula-
tion of chemotherapy-induced human hair follicle
damage by 17-beta estradiol and prednisolone:
Potential stimulators of normal hair regrowth by
“dystrophic catagen” promotion? J Invest Dermatol
2009;129:506–509.
50. Amoh Y, Li L, Katsuoka K et al. Chemotherapy
targets the hair-follicle vascular network but not the
stem cells. J Invest Dermatol 2007;127:11–15.
51. Batchelor D. Hair and cancer chemotherapy:
Consequences and nursing care–A literature study.
Eur J Cancer Care (Engl) 2001;10:147–163.
52. Wilkes G. Potential toxicities and nursing man-
agement. In: Cancer chemotherapy: A nursing pro-
cess approach. Boston, MA: Jones & Barlett, 1996.
53. van den Hurk CJ, Peerbooms M, van de Poll-
Franse LV et al. Scalp cooling for hair preservation
and associated characteristics in 1411 chemotherapy
patients - Results of the Dutch Scalp Cooling Regis-
try. Acta Oncol 2012;51:497–504.
54. Cigler T, Isseroff D, Fiederlein B et al. Efficacy of
scalp cooling in preventing chemotherapy-induced
alopecia in breast cancer patients receiving adjuvant
docetaxel and cyclophosphamide chemotherapy.
Clin Breast Cancer 2015;15:332–334.
55. Trueb RM. Chemotherapy-induced hair loss.
Skin Therapy Lett 2010;15:5–7.
56. Komen MM, Smorenburg CH, Nortier JW et al.
Results of scalp cooling during anthracycline contain-
ing chemotherapy depend on scalp skin tempera-
ture. Breast 2016;30:105–110.
57. Oshima H, Rochat A, Kedzia C et al. Morpho-
genesis and renewal of hair follicles from adult multi-
potent stem cells. Cell 2001;104:233–245.
58. Tosti A, Piraccini BM, Vincenzi C et al. Perma-
nent alopecia after busulfan chemotherapy. Br J Der-
matol 2005;152:1056–1058.
59. Cotsarelis G. Epithelial stem cells: A folliculo-
centric view. J Invest Dermatol 2006;126:1459–
1468.
60. Tran D, Sinclair RD, Schwarer AP et al. Perma-
nent alopecia following chemotherapy and bone
Dunnill, Al-Tameemi, Collett et al. 11
www.TheOncologist.com
O
cAlphaMed Press 2017
Published Ahead of Print on September 26, 2017 as 10.1634/theoncologist.2017-0263.
by Nik Georgopoulos on September 27, 2017http://theoncologist.alphamedpress.org/Downloaded from
marrow transplantation. Australas J Dermatol 2000;
41:106–108.
61. Bresters D, Wanders DCM, Louwerens M et al.
Permanent diffuse alopecia after haematopoietic
stem cell transplantation in childhood. Bone Marrow
Transplant 2017;52:984–988.
62. Tallon B, Blanchard E, Goldberg LJ. Permanent
chemotherapy-induced alopecia: Case report and
review of the literature. J Am Acad Dermatol 2010;
63:333–336.
63. Prevezas C, Matard B, Pinquier L et al. Irreversi-
ble and severe alopecia following docetaxel or pacli-
taxel cytotoxic therapy for breast cancer. Br J
Dermatol 2009;160:883–885.
64. Shin H, Jo SJ, Kim DH et al. Efficacy of interven-
tions for prevention of chemotherapy-induced alo-
pecia: A systematic review and meta-analysis. Int J
Cancer 2015;136:E442–E454.
65. Soref CM, Fahl WE. A new strategy to prevent
chemotherapy and radiotherapy-induced alopecia
using topically applied vasoconstrictor. Int J Cancer
2015;136:195–203.
66. Bohm M, Bodo E, Funk W et al. Alpha-melano-
cyte-stimulating hormone: A protective peptide
against chemotherapy-induced hair follicle damage?
Br J Dermatol 2014;170:956–960.
67. Grevelman EG, Breed WP. Prevention of
chemotherapy-induced hair loss by scalp cooling.
Ann Oncol 2005;16:352–358.
68. Sredni B, Xu RH, Albeck M et al. The protective
role of the immunomodulator AS101 against
chemotherapy-induced alopecia studies on human
and animal models. Int J Cancer 1996;65:97–103.
69. Young A, Arif A. The use of scalp cooling for
chemotherapy-induced hair loss. Br J Nurs 2016;25:
S22, S24–S27.
70. Balsari AL, Morelli D, Menard S et al. Protection
against doxorubicin-induced alopecia in rats by
liposome-entrapped monoclonal antibodies. FASEB J
1994;8:226–230.
71. Morelli D, Menard S, Cazzaniga S et al. Intrati-
bial injection of an anti-doxorubicinmonoclonal anti-
body prevents drug-induced myelotoxicity in mice.
Br J Cancer 1997;75:656–659.
72. Morelli D, Menard S, Colnaghi MI et al. Oral
administration of anti-doxorubicin monoclonal anti-
body prevents chemotherapy-induced gastrointesti-
nal toxicity in mice. Cancer Res 1996;56:2082–
2085.
73. Balsari A, Rumio C, Morelli D et al. Topical
administration of a doxorubicin-specific monoclonal
antibody prevents drug-induced mouth apoptosis in
mice. Br J Cancer 2001;85:1964–1967.
74. Jimenez JJ, Huang HS, Yunis AA. Treatment with
ImuVert/N-acetylcysteine protects rats from cyclo-
phosphamide/cytarabine-induced alopecia. Cancer
Invest 1992;10:271–276.
75. Taylor M, Ashcroft AT, Messenger AG. Cyclospo-
rinaprolongshumanhairgrowthinvitro.JInvest
Dermatol 1993;100:237–239.
76. Hawkshaw NJ, Haslam IS, Ansell DM et al. Re-
evaluating cyclosporine a as a hair growth-
promoting agent in human scalp hair follicles.
J Invest Dermatol 2015;135:2129–2132.
77. Hussein A, Stuart A, Peters W. Protection
against chemotherapy-induced alopecia by cyclospo-
rin a in the newborn rat animal model. Dermatology
2009;190:192–196.
78. Duvic M, Lemak NA, Valero V et al. A random-
ized trial of minoxidil in chemotherapy-induced alo-
pecia. J Am Acad Dermatol 1996;35:74–78.
79. Hussein AM. Protection against cytosine
arabinoside-induced alopecia by minoxidil in a rat
animal model. Int J Dermatol 1995;34:470–473.
80. Olsen EA, Whiting D, Bergfeld W et al. A multi-
center, randomized, placebo-controlled, double-
blind clinical trial of a novel formulation of 5%
minoxidil topical foam versus placebo in the treat-
ment of androgenetic alopecia in men. J Am Acad
Dermatol 2007;57:767–774.
81. Jimenez JJ, Yunis AA. Protection from 1-beta-d-
arabinofuranosylcytosine-induced alopecia by epi-
dermal growth factor and fibroblast growth factor in
the rat model. Cancer Res 1992;52:413–415.
82. Hussein AM. Chemotherapy-induced alopecia:
New developments. South Med J 1993;86:489–496.
83. Knockaert M, Greengard P, Meijer L. Pharmaco-
logical inhibitors of cyclin-dependent kinases. Trends
in pharmacological sciences 2002;23:417–425.
84. Kobayashi T, Okumura H, Hashimoto K et al.
Synchronization of normal human keratinocyte in
culture: Its application to the analysis of 1,25-dihy-
droxyvitamin D3 effects on cell cycle. J Dermatol Sci
1998;17:108–114.
85. Wang J, Lu Z, Au JL. Protection against
chemotherapy-induced alopecia. Pharm Res 2006;
23:2505–2514.
86. Jimenez JJ, Yunis AA. Protection from
chemotherapy-induced alopecia by 1,25-dihydroxy-
vitamin D3. Cancer Res 1992;52:5123–5125.
87. Paus R, Schilli MB, Handjiski B et al.Topical cal-
citriol enhances normal hair regrowth but does not
prevent chemotherapy-induced alopecia in mice.
Cancer Res 1996;56:4438–4443.
88. Schilli MB, Paus R, Menrad A. Reduction of
intrafollicular apoptosis in chemotherapy-induced
alopecia by topical calcitriol-analogs. J Invest Derma-
tol 1998;111:598–604.
89. Porter AG, Janicke RU. Emerging roles of
caspase-3 in apoptosis. Cell Death Differ 1999;6:99–
104.
90. Tsuda T, Ohmori Y, Muramatsu H et al. Inhibi-
tory effect of M50054, a novel inhibitor of apoptosis,
on anti-Fas-antibody-induced hepatitis and
chemotherapy-induced alopecia. Eur J Pharmacol
2001;433:37–45.
91. Gensure RC. Parathyroid hormone-related pep-
tide and the hair cycle - Is it the agonists or the
antagonists that cause hair growth? Exp Dermatol
2014;23:865–867.
92. Skrok A, Bednarczuk T, Skwarek A et al. The
effect of parathyroid hormones on hair follicle physi-
ology: Implications for treatment of chemotherapy-
induced alopecia. Skin Pharmacol Physiol 2015;28:
213–225.
93. O’Brien R, Zelson JH, Schwartz AD et al. Scalp
tourniquet to lessen alopecia after vincristine. N
Engl J Med 1970;283:1469.
94. Maxwell MB. Scalp tourniquets for
chemotherapy-induced alopecia. Am J Nurs 1980;
80:900–903.
95. Protiere C, Evans K, Camerlo J et al. Efficacy and
tolerance of a scalp-cooling system for prevention of
hair loss and the experience of breast cancer
patients treated by adjuvant chemotherapy. Support
Care Cancer 2002;10:529–537.
96. Janssen FP, Rajan V, Steenbergen W et al. The
relationship between local scalp skin temperature
and cutaneous perfusion during scalp cooling. Phys-
iol Meas 2007;28:829–839.
97. B€
ulow J, Friberg L, Gaardsting O et al. Frontal
subcutaneous blood flow, and epi-and subcutaneous
temperatures during scalp cooling in normal man.
Scand J Clin Lab Invest 1985;45:505–508.
98. Lane P, Vichi P, Bain DL et al. Temperature
dependence studies of adriamycin uptake and cyto-
toxicity. Cancer Res 1987;47:4038–4042.
99. Watanabe I, Okada S. Effects of temperature on
growth rate of cultured mammalian cells (L5178Y).
J Cell Biol 1967;32:309–323.
100. Vichi P, Robison S, Tritton TR. Temperature
dependence of adriamycin-induced DNA damage in
L1210 cells. Cancer Res 1989;49:5575–5580.
101. JanssenFE,VanLeeuwenGM,Van
Steenhoven AA. Modelling of temperature and per-
fusion during scalp cooling. Phys Med Biol 2005;50:
4065–4073.
102. Al-Tameemi W, Dunnill C, Hussain O et al. Use
of in vitro human keratinocyte models to study the
effect of cooling on chemotherapy drug-induced
cytotoxicity.Toxicol In Vitro 2014;28:1366–1376.
103. Guy R, Shah S, Parker H et al. Scalp cooling by
thermocirculator. Lancet 1982;1:937–938.
104. Katsimbri P, Bamias A, Pavlidis N. Prevention
of chemotherapy-induced alopecia usingan effective
scalp cooling system. Eur J Cancer 2000;36:766–771.
105. Pliskow B, Mitra K, Kaya M. Simulation of
scalp cooling by external devices for prevention of
chemotherapy-induced alopecia. J Therm Biol 2016;
56:31–38.
106. Massey CS. A multicentre study to determine
the efficacy and patient acceptability of the paxman
scalp cooler to prevent hair loss in patients receiving
chemotherapy. Eur J Oncol Nurs 2004;8:121–130.
107. Schaffrin-Nabe D, Schmitz I, Josten-Nabe A
et al. The influence of various parameterson the suc-
cess of sensor-controlled scalp cooling in preventing
chemotherapy-induced alopecia. Oncol Res Treat
2015;38:489–495.
108. Auvinen PK, Mahonen UA, Soininen KM et al.
The effectiveness of a scalp cooling cap in preventing
chemotherapy-induced alopecia. Tumori 2010;96:
271–275.
109. IbrahimT,KattanJ,AssiTetal.Efficacyofasili-
con based continuous scalp cooling system with
thermostat on chemotherapy induced alopecia.
J Palliat Care Med 2015;05:209.
110. Nangia J, Wang T, Osborne C et al. Effect of a
scalp cooling device on alopecia in women under-
going chemotherapy for breast cancer: The scalp
randomized clinical trial. JAMA 2017;317:596–605.
111. Lemenager M, Lecomte S, Bonneterre ME
et al. Effectiveness of cold cap in the prevention of
docetaxel-induced alopecia. Eur J Cancer 1997;33:
297–300.
112. Anderson JE, Hunt JM, Smith IE. Prevention of
doxorubicin-induced alopecia by scalp cooling in
patients with advanced breast cancer. Br Med J (Clin
Res Ed) 1981;282:423–424.
113. Vendelbo Johansen L. Scalp hypothermia in
the prevention of chemotherapy-induced alopecia.
Acta Radiol Oncol 1985;24:113–116.
114. van den Hurk CJ, Breed WP, Nortier JW. Short
post-infusion scalp cooling time in the prevention of
12 Chemotherapy-Induced Alopecia and Its Prevention
O
cAlphaMed Press 2017
Published Ahead of Print on September 26, 2017 as 10.1634/theoncologist.2017-0263.
by Nik Georgopoulos on September 27, 2017http://theoncologist.alphamedpress.org/Downloaded from
docetaxel-induced alopecia. Support Care Cancer
2012;20:3255–3260.
115. Komen MM, Smorenburg CH, van den Hurk
CJ et al. Factors influencing the effectiveness of
scalp cooling in the prevention of chemotherapy-
induced alopecia. The Oncologist 2013;18:885–
891.
116. Komen MM, Breed WP, Smorenburg CH
et al. Results of 20- versus 45-min post-infusion
scalp cooling time in the prevention of docetaxel-
induced alopecia. Support Care Cancer 2016;24:
2735–2741.
117. Lemieux J, Desbiens C, Hogue JC. Breast cancer
scalp metastasis as first metastatic site after scalp
cooling: Two cases of occurrence after 7- and 9-year
follow-up. Breast Cancer Res Treat 2011;128:563–566.
118. Lemieux J, Amireault C, Provencher L et al. Inci-
dence of scalp metastases in breast cancer: A retrospec-
tive cohort study in women who were offered scalp
cooling. Breast Cancer Res Treat 2009;118:547–552.
119. Lemieux J, Provencher L, Perron L et al. No
effect of scalp cooling on survival among women
with breast cancer. Breast Cancer Res Treat 2015;
149:263–268.
120. Rugo HS, Melin SA, Voigt J. Scalp cooling with
adjuvant/neoadjuvant chemotherapy for breast can-
cer and the risk of scalp metastases: Systematic
review and meta-analysis. Breast Cancer Res Treat
2017;163:199–205.
121. Haslam IS, El-Chami C, Faruqi H et al. Differen-
tial expression and functionality of atp-binding cas-
sette transporters in the human hair follicle. Br J
Dermatol 2015;172:1562–1572.
122. Payne S, Miles D. Mechanisms of anticancer
drugs. In: Gleeson M, ed. Scott-Brown’s Otorhinolar-
yngology: Head and Neck Surgery. 8th ed. Boca
Raton, FL: CRC Press, 2008:34–46.
123. Tr€
ueb RM. The difficult hair loss patient. Guide
to successful management of alopecia and related
conditions. Cham, Switzerland: Springer Interna-
tional Publishing, 2015.
124. Wikramanayake TC, Amini S, Simon J et al. A
novel rat model for chemotherapy-induced alopecia.
Clin Exp Dermatol 2012;37:284–289.
125. Hussein AM, Jimenez JJ, McCall CA
et al. Protection from chemotherapy-induced
alopecia in a rat model. Science 1990;249:
1564–1566.
126. Paus R, Handjiski B, Eichm€
uller S et al. Chemo-
therapy-induced alopecia in mice. Induction by
cyclophosphamide, inhibition by cyclosporine A, and
modulation by dexamethasone. Am J Pathol 1994;
144:719.
127. Manning DD, Reed ND, Shaffer CF. Mainte-
nance of skin xenografts of widely divergent phylo-
genetic origin of congenitally athymic (nude) mice.
J Exp Med 1973;138:488–494.
128. Domashenko A, Gupta S, Cotsarelis G. Effi-
cient delivery of transgenes to human hair follicle
progenitor cells using topical lipoplex. Nat Biotech-
nol 2000;18:420–423.
129. Kyoizumi S, Suzuki T,Teraoka S et al. Radiation
sensitivity of human hair follicles in SCID-hu mice.
Radiat Res 1998;149:11–18.
130. Philpott MP, Green MR, Kealey T. Human hair
growth in vitro. J Cell Sci 1990;97(Pt 3):463–471.
131. Bodo E, Tobin DJ, Kamenisch Y et al. Dissect-
ing the impact of chemotherapy on the human
hair follicle: A pragmatic in vitro assay for studying
the pathogenesis and potential management of
hair follicle dystrophy. Am J Pathol 2007;171:1153–
1167.
Dunnill, Al-Tameemi, Collett et al. 13
www.TheOncologist.com
O
cAlphaMed Press 2017
Published Ahead of Print on September 26, 2017 as 10.1634/theoncologist.2017-0263.
by Nik Georgopoulos on September 27, 2017http://theoncologist.alphamedpress.org/Downloaded from
