www.thelancet.com/oncology Vol 14 February 2013 e50
Few adverse eff ects of chemotherapy generate as much
trepidation as the often substantial and sudden hair loss
that can be induced by selected chemotherapeutic agents.
Although some treatment options, such as scalp cooling,
show a degree of effi cacy in specifi c chemotherapy
regimens (eg, taxane monotherapy), many are un-
satisfactory. As such, chemotherapy-induced alopecia
represents one of the major unmet challenges in clinical
oncology. Extreme anxiety related to this cosmetic
disfi gurement reportedly drives 8% of patients to reject
chemotherapy.1 The development of more satisfactory
management strategies for chemotherapy-induced
alopecia, therefore, remains a major research challenge
in clinical oncology.
Chemotherapy-induced alopecia has been studied in
human beings and animals since chemotherapy was fi rst
introduced into clinical medicine.2–5 Reviews on the clinical
presentation and management of chemotherapy-induced
alopecia are available,6–9 but the underlying pathobiology
remains insuffi ciently understood, which results in a lack
of well defi ned targets for intervention. Research should be
undertaken collaboratively by oncologists, hair biologists,
derma tologists, and pharmacologists, but such an inter-
disciplinary approach regrettably remains under developed.
In this Review we explore the therapeutic conundrum
of chemotherapy-induced alopecia, which aff ects patients
and physicians,10 and emphasise the psychosocial burden
of this complication. We summarise the clinical features
and current management strategies, along with the core
principles of the complex pathobiology, deduced from
analysis of experimental models. We close by discussing
concrete strategies to overcome chemotherapy-induced
alopecia and presenting some of the principal open
questions that will need to be addressed.
Chemotherapy-induced alopecia generally presents
suddenly and initially manifests as patterned hair loss
that is most prominent on the scalp.6,9,11,12 The areas of
greatest hair damage seem to be selective, and in
particular aff ect scalp regions that show low total hair
densities, such as the frontal or occipital hairlines.12 Girls
and women have widespread chemotherapy-induced
alopecia more frequently than any other pattern.12 Hair-
shaft shedding, which manifests as anagen effl uvium or
telogen effl uvium,12,13 begins days to weeks after the
initiation of many, although not all, chemotherapeutic
agents.6,8 The visible hair loss results from defi ned
disturbances of normal hair-shaft production and of hair-
follicle cycling (fi gure 1). Reversibility of alopecia depends
on the degree of hair-follicle stem-cell damage.14
The risk of chemotherapy-induced alopecia and the
degree of hair loss diff er substantially between
chemotherapeutic agents. Alkylating agents (cyclo-
phosphamide, ifosfamide), cytotoxics (doxorubicin,
daunorubicin), antimicrotubule agents (docetaxel,
paclitaxel), and topoisomerase inhibitors (etoposide) are
among the agents with the most frequent and severe
eff ects. Conversely, fl uorouracil, hydroxycarbamide,
methotrexate, and thiotepa induce alopecia much less
frequently, and the eff ects are generally mild.6,15,16
Robust data on phenotype and degree of chemotherapy-
induced alopecia in homogeneous cohorts of chemo-
therapy patients are unavailable. Nevertheless, the degree
of hair loss induced by high-risk chemotherapeutic agents,
such as cyclophosphamide, daunorubicin, etoposide, and
paclitaxel, varies by dose, administration regimen, the
patient’s age, comorbidities, and nutritional and hormonal
statuses, and multiple other factors within individual
patients. Some concomitant factors that can aff ect the risk
and the phenotype of chemotherapy-induced alopecia are
the chemotherapy protocol (curative vs a palliative
fractionated regimen) the presence of graft-versus-host
disease in patients who have undergone bone-marrow
trans plantation, exposure to X-rays, age, and the presence
and progression of androgenetic alopecia.17 Thus, the
provision of a hair-loss prognosis to chemotherapy
patients remains educated guesswork. Helpful practical
suggestions for manage ment and guidance material for
patients have, however, been published.6
Although rare, cases of permanent chemotherapy-
induced alopecia, in which hair regrowth is severely
retarded or does not occur at all, are increasingly
reported.18,19 This outcome is frequently associated with
high-dose chemotherapy, typically before bone-marrow
Pathobiology of chemotherapy-induced hair loss
Ralf Paus, Iain S Haslam, Andrey A Sharov, Vladimir A Botchkarev
Hair loss can be a psychologically devastating adverse eff ect of chemotherapy, but satisfactory management strategies for
chemotherapy-induced alopecia remain elusive. In this Review we focus on the complex pathobiology of this side-eff ect.
We discuss the clinical features and current management approaches, then draw upon evidence from mouse models and
human hair-follicle organ-culture studies to explore the main pathobiology principles and explain why chemotherapy-
induced alopecia is so challenging to manage. P53-dependent apoptosis of hair-matrix keratinocytes and chemotherapy-
induced hair-cycle abnormalities, driven by the dystrophic anagen or dystrophic catagen pathway, play important parts in
the degree of hair-follicle damage, alopecia phenotype, and hair-regrowth pattern. Additionally, the degree of hair-follicle
stem-cell damage determines whether chemotherapy-induced alopecia is reversible. We highlight the need for carefully
designed preclinical research models to generate novel, clinically relevant pointers to how this condition may be overcome.
Lancet Oncol 2013; 14: e50–59
Department of Dermatology,
University of Lübeck, Lübeck,
Germany (Prof R Paus MD);
Institute of Infl ammation and
Repair, University of
Manchester, Manchester, UK
(Prof R Paus, I S Haslam PhD);
Centre for Skin Sciences,
University of Bradford,
(Prof V A Botchkarev PhD); and
Department of Dermatology,
Boston University School of
Medicine, Boston, MA, USA
(A A Sharov MD,
Prof V A Botchkarev)
Prof Ralf Paus, Department of
Dermatology, University of
Lübeck, Ratzeburger Allee 160,
Lübeck D-23538, Germany
www.thelancet.com/oncology Vol 14 February 2013
trans plantation.19 Although the cause of permanent
chemo therapy-induced alopecia remains to be clarifi ed,
epithelial hair-follicle stem cells seem to have a crucial role.
When hair shafts have regrown after chemotherapy-
induced alopecia, the colour and structure have frequently
changed markedly, although not always in an undesired
manner, and previously straight hair has reappeared as
curls (textural, pigmentary, or both changes in phenotype
of regrowing hair occur in up to 60% of patients).12 Such
changes pose intriguing mechanistic questions.
Management of chemotherapy-induced alopecia primarily
consists of counselling and the provision of written in-
formation,6 professional psychological support, and the
recommendation to use a wig (appendix).6,9,11,20
The hypothermic eff ect of scalp cooling is thought to
reduce scalp perfusion and, therefore, access of the blood-
borne chemotherapy to the hair follicles, which aff ects
metabolism, drug uptake, and drug cytotoxic eff ects.21,22
Scalp-cooling devices produce only mild discomfort in
most patients assessed and seem to have been associated
with reduced hair loss in a substantial proportion.21 The
eff ectiveness of scalp-cooling caps cannot be judged until
data from satisfactorily designed, multicentre trials
involving well defi ned cohorts of patients have become
available, yet some trials and meta-analyses suggest
success rates well above 50%.11,21 However, this approach
has been related to some notable safety concerns.
Specifi cally, if clinically un apparent scalp metastases are
present, tumour cells could be protected from the eff ects
of chemotherapy by reduced drug uptake.23,24 These
concerns, therefore, also need to be carefully investigated.
In terms of medications to prevent chemotherapy-
induced alopecia, little information is available. The
topical application of 2% minoxidil did not prevent the
occurrence of chemotherapy-induced alopecia in fi ve of
six patients in one study.20 In another study, however, hair
regrowth was accelerated in women treated with 2%
minoxidil compared with that in those who received
placebo.25 Although the effi cacy of minoxidil in preventing
chemotherapy-induced hair loss needs to be confi rmed in
larger trials, it is viewed as a useful and safe promoter of
hair regrowth after chemotherapy-induced alopecia.11 The
encouraging pro tective eff ects against hair loss reported
for intra venous ammonium tricholoro(dioxyethylene-
O-O’)tellurate (AS101),26 an immunomodulatory tellurium
compound that doubles as a candidate anticancer agent,27
have not been followed up in further studies. Topical
vitamin D3 (calcitriol and calcipotriol), which is
commonly used as a dermatological therapy, has not
suppressed chemotherapy-induced alopecia in small
trials.13,28 This fi nding is not surprising because topical
calcitriol did not prevent cyclo phosphamide-induced
alopecia in a mouse model, even though intrafollicular
apoptosis was reduced. Regrowth of normally pigmented
hair was accelerated in the mice,29,30 but hair regrowth
eff ects have not been assessed in clinical trials. Thus,
reliable preventive pharmacological
chemotherapy-induced alopecia is still sought.
Psychosocial burden and eff ects of stress
The state of a person’s scalp and facial hair provides
psychosocial signals that range from general wellbeing to
social status, and groups' associations to features such as
sexual attraction, fashion, religion, philosophy, and
political views.31 Chemotherapy-induced alopecia isolates
patients by sending a strong indication of illness and of
deviation from the accepted visual norms. These eff ects
aggravate the psychosocial burden of cancer, promote
withdrawal from society, and lead to impaired quality of
life (appendix). It adds substantially to the burden of other
chemotherapy-related toxic eff ects (eg, nausea, bone pain,
fatigue, and peripheral neuropathy).1,32
A purported, although still theoretical, negative
repercussion of chronic psychoemotional stress related to
chemotherapy-induced alopecia is that antitumour
immune defences might be compromised, as has
been suggested in animal models.33,34 Additionally,
chemotherapy-induced hair loss, and the recovery from it,
might be negatively aff ected by psychoemotional stress.35–37
Stress mediators induce severe neurogenic infl ammation
in rodent and human skin models, which has been
associated with inhibited hair growth.37–41 Classic stress
mediators, such as corticotropin-releasing hormone,
Figure 1: Eff ects of chemotherapy on the human hair follicle
Chemotherapy-induced alopecia most prominently aff ects the highly proliferative matrix keratinocytes of anagen hair
follicles, located in the hair bulb. In certain instances, hair-follicle stem cells are also damaged, which can lead to
permanent hair loss. HFPU=hair-follicle pigmentary unit. Modifi ed from reference 14 by permission of American
Society for Clinical Investigation.
See Online for appendix
_Ar r e c t o r
c1-- - i;
E: : : : : " ' o g , " ,
www.thelancet.com/oncology Vol 14 February 2013 e52
substance P, and nerve growth factor, inhibit the growth of
human-scalp hair follicles in vitro, and promote catagen
development, which leads to telogen effl uvium.38,40 Thus,
hair loss could be aggravated by psychoemotional stress,
beyond the level of effl uvium and alopecia caused by direct
chemotherapy-related damage to hair follicles.
Although distinct hair-loss patterns are seen,12 the overall
fi nal clinical presentation of chemotherapy-induced
alopecia is similar across patients. Many chemo therapeutic
agents share proapoptotic pathways that have crucial roles
in chemotherapy-induced alopecia, especially P53-
mediated signalling (fi gure 2).42,43 The chemotherapeutic
agents most frequently associated with alopecia, however,
have distinct mechanisms of action and diff er sub stantially
according to an individual’s genetically deter mined suscep-
tibility to chemotherapy-induced cytotoxic eff ects. To treat
chemotherapy-induced alopecia as one entity is, therefore,
misleading. Nevertheless, since the principal hair-follicle
damage-response pathways are shared (fi gures 1, 2), even
between chemically distinct chemo therapeutic agents, for
practical purposes we do so in this Review.
Models of chemotherapy-induced alopecia
The preclinical development of eff ective preventive
treatment strategies for chemotherapy-induced alopecia
requires good research models in which pathobiology
can be explored and novel management strategies can be
tested. The best-characterised in-vivo models are in
neonatal rats7,44 and adult C57BL/6 mice.42,45,46 In these
models topical, oral, intravenous, and intraperitoneal
treatments have been tested before and after systemic
administration of the chemotherapeutic agent (eg,
cyclophosphamide or doxorubicin).
As chemotherapy-induced alopecia in human beings
primarily aff ects pigmented, mature anagen stage VI hair
follicles that have already undergone full cycling (fi gure 3),
the clinical relevance of the neonatal rat model is limited
because in this model chemotherapy aff ects hair follicles
that are still in the fi nal stages of postnatal morphogenesis.
Another major limitation of rodent models is that the hair
cycling is more or less synchronised across all follicles,
whereas in human beings each hair follicle follows its own
cycling rhythm.10 By contrast with organ-cultured human-
scalp hair follicles, however, rodent models permit
investigation of how chemotherapy aff ects the hair-follicle
cycling, which is a crucial factor in the pathobiology of
chemotherapy-induced alopecia (fi gures 3, 4).45–47 Addition-
ally, as in human chemotherapy-induced alopecia, hair
loss in rodent models generally follows specifi c patterns.
Animal models of chemotherapy-induced alopecia
should be complemented by organ culture of human-scalp
hair follicles where possible.48 Organ culture of scalp hair
follicles enables direct testing of the damaging eff ects of
defi ned cytostatic agents (appendix) and provides the most
clinically relevant in-vitro surrogate model for human
chemotherapy-induced alopecia of all currently available
preclinical models.48,49 Surgical grafting of human scalp
skin on to immunocompromised, chemotherapy-treated
mice might, however, become the research model of
choice for chemotherapy-induced alopecia, as it will com-
bine the benefi ts of human and rodent models (appendix).
Despite their limitations, these preclinical models have
provided invaluable insights into the pathobiology of
chemotherapy-induced alopecia that could not have been
identifi ed even by in-depth analysis of clinical hair-loss
Underlying principles of pathobiology
Rapidly proliferating, and therefore maximally vulnerable,
anagen hair follicles and their pigmentary system, which
is very sensitive to toxins, are the main targets of
chemotherapy-induced hair-follicle damage.2–4,45 In fact,
the proliferation rate of hair-matrix keratinocytes in
healthy anagen hair follicles is extremely high and easily
beats that of most malignant tumours.47,50 Moreover, the
specialised melanocytes of the hair-follicle pigmentary
unit (fi gure 1) generate huge amounts of melanin
(packaged into melanosomes) during anagen, but also
need to perfectly transfer them into the correct, terminally
diff erentiating hair-follicle keratinocyte populations that
form the hair shaft.47 These tissue systems, therefore,
rank among those most sensitive to toxins and drugs in
the mammalian body, and can easily undergo rapid
apoptosis during chemotherapy.45,46,51,52 Telogen hair
follicles are less sensitive than anagen hair follicles to
chemotherapy,46 presumably because of low-level
proliferation and arrested pigmentary activity.50 Similarly,
the slow-cycling epithelial and melanocyte stem cells of
Effectors and their targets
HIPK2 PRKDCATM ATR
XRCC6/5 HUS1, RAD1, RAD9
RAD50, MRE11A, NBN
Figure 2: Molecular damage-response pathways activated by chemotherapy
CDKN1A and CDKN2A are also known as P21 and P16INK4A. XRCC6 and XRCC5 are also known as KU70 and KU80.
www.thelancet.com/oncology Vol 14 February 2013
hair follicles, which are located primarily in the bulge,
have low sensitivity (fi gure 1),53,54 although neither is by
any means invulnerable. Additionally, chemotherapeutic
agents damage the hair-follicle vasculature55 and the
sebaceous gland,56 which negatively aff ects hair-follicle
health and function. The slow-cycling inductive
fi broblasts of the dermal papilla (fi gure 1),47,57 however,
seem to be little damaged by chemotherapy.51 Yet, even
the hair-follicle mesenchyme seems to be aff ected, at least
in some models of chemotherapy-induced alopecia.48
Since the largest, most prominent, and most densely
seeded population of terminal anagen hair follicles is
found on the scalp, the response to chemotherapy in this
region dominates the clinical phenotype of chemotherapy-
induced alopecia. For example, cyclophosphamide drives
human-scalp anagen hair follicles into apoptosis-driven
regression (catagen; fi gure 1).2,48 This change leads to
telogen effl uvium,10,13 which is characterised by shedding
of club hairs (loosely anchored hair shafts whose
proximal tip is depigmented; during catagen, the hair
shaft formed in the preceding anagen is transformed
into a club hair and shed during telogen or exogen). Even
a slight increase in the percentage of catagen hair follicles
results in a substantial increase in the number of club
hairs and visible shedding.10
The most characteristic hair-follicle response to
chemotherapy-induced damage is anagen effl uvium—the
shedding of fully pigmented hair shafts while hair follicles
are still in the growth phase (fi gure 1). Normal
intrafollicular melanogenesis, melanin transfer, and
melanocyte survival become severely disrupted in the
anagen hair bulb (fi gures 3, 4, appendix).45,46,52 Nevertheless,
telogen effl uvium is more frequent during chemotherapy-
induced alopecia than is generally assumed.6,13 This pattern
attests to the astounding capacity of human hair follicles to
cope with chemotherapy via several inter acting molecular
mechanisms of damage control.58 Sub threshold hair-
follicle damage induced, for example, by cyclophosphamide
in human hair-matrix keratinocytes can increase
proliferative activity, albeit briefl y, presumably as a repair
strategy.48 This damage defence and repair effi ciency of
anagen hair follicles58 explains why most patients with
chemotherapy-induced alopecia do not experience total
baldness, but more frequently have patchy, unevenly
distributed anagen effl uvium or diff use telogen effl uvium6
and rapid hair regrowth after the discontinuation of
chemotherapy. Therefore, the visible degree of hair loss in
chemotherapy-induced alopecia refl ects the net result of
how most aff ected anagen hair follicles have responded to
Another important pathobiological principle is that the
degree of visible hair loss in chemotherapy-induced
alopecia does not always refl ect the failure of hair-follicle
repair systems. Paradoxically, a large degree of alopecia can
• Damage to epithelial stem cells
determines reversibility of alopecia
• Damage to melanocyte stem cells?
• Main damage
• Additional damage to
• Hair-shaft shedding (effluvium/alopecia)
• Continued but retarded growth of depigmented
and/or structurally abnormal hair shaft
• Anagen abnormally prolonged
• Accelerated hair regrowth of normal hair shafts by
shortened and accelerated re-entry into anagen
Figure 3: Eff ects of chemotherapy on the hair cycle
Whether and how chemotherapy increases active hair-shaft shedding (exogen) are unknown.9,38 Additionally, the eff ects of chemotherapy on the intrafollicular
oscillator system, which drives the hair cycle,47 remains to be determined.
www.thelancet.com/oncology Vol 14 February 2013 e54
indicate that an eff ective damage-response strategy has
developed in damaged hair follicles (fi gure 4).45,46 The
sharing of this concept with distressed patients undergoing
chemotherapy might be a useful approach for oncologists.
Dystrophic anagen versus dystrophic catagen damage-
The C57BL/6 mouse model of cyclophosphamide-induced
alopecia shows that chemotherapy-damaged hair follicles
engage two major damage-response pathways that lead to
very diff erent clinical outcomes. If the chemotherapy-
induced damage is mild to moderate, the dystrophic
anagen response pathway is initiated, whereas more severe
damage activates the dystrophic catagen response pathway
(fi gures 3, 4).10,45 These distinct damage-response patterns
also apply to human-scalp hair follicles48,49 and have major
clinical consequences because they dictate the dynamics
and degree of chemotherapy-induced hair loss and the
speed and quality of hair regrowth (fi gure 4). Paradoxically,
less damaged dystrophic anagen hair follicles actually
recover much more slowly than dystrophic catagen hair
follicles. This principle of severe damage being associated
with increased speed of recovery is crucial to understanding
the pathobiology of chemotherapy-induced alopecia.
In the C57BL/6 mouse model, changes in hair phenotype
are frequently seen during regrowth. These changes are
associated with the predominant damage-response
pathway involved in hair loss (fi gure 4). If the dystrophic
anagen pathway is involved, hair-shaft production
resumes during the same anagen phase that was
disrupted by chemotherapy
Paradoxically, dystrophic anagen is frequently longer than
the duration of normal anagen, and the texture and
structure of the shafts are frequently of decreased quality
and show pigmentary defects. By contrast, if the
dystrophic catagen pathway is involved, hair-shaft
Dystrophic catagen pathway
• Massive alopecia, accelerated hair regrowth
IL-15, PTH/PTHrp 7–34
Dystrophic anagen pathway
• Less alopecia, retarded hair regrowth
Figure 4: Damage-response pathways in the human hair follicle after chemotherapy
Chemotherapy-damaged anagen hair follicles engage two major damage-response pathways, dystrophic anagen or dystrophic catagen. Several hormones and drugs
can manipulate which damage-response pathway is chosen by a chemotherapy-treated hair follicle.29,45,46,51,59–61 IL-15=interleukin 15. PTHrp=PTH-related-peptide.
www.thelancet.com/oncology Vol 14 February 2013
production is resumed only in the subsequent anagen
phase, following a greatly shortened telogen phase
(secondary recovery). Therefore, the hair matrix is newly
generated and fully functional (unless the hair-follicle
epithelial and melanocyte stem cells have suff ered major
damage). Consequently, regrowing hair shafts retain a
normal structure and are fully pigmented (fi gures 3, 4).45,46
The shape of the hair shafts (curly or straight) seems to
be controlled by asymmetric proliferation in the hair
bulb along with asymmetric diff erentiation in the
precortical hair matrix.62 Therefore, chemotherapy-
induced modulation of these hair-bulb asymmetries, and
perhaps of hair keratin gene expression,62 during the
anagen phase that follows the hair loss seems feasible.48
These eff ects might lead to alteration to the structure of
the hair shaft (eg, curly to straight).63
Pharmacological manipulation of hair-follicle response and
In mice, hair-follicle response to and recovery from
chemotherapy can be pharmacologically manipulated
by steroid hormones and immunophilin ligands
(fi gure 4).29,30,45,46,59 These fi ndings in mice might also
apply to human-scalp hair follicles. Glucocorticosteroids
and oestradiol promote the dystrophic catagen pathway
in vitro in organ-cultured, chemotherapy-damaged
human hair follicles,49 just as they do in mice in vivo,46,59
which provides important pharmacological pointers to
alopecia and hair regrowth.
of chemo therapy-induced
Eff ects of chemotherapy on the hair-follicle pigmentary unit
Chemotherapy causes oxidative damage to the hair follicle
pigmentary unit (fi gure 1), which is very sensitive to
reactive oxygen species64 and diff erentially aff ects distinct
sub popu lations of hair-follicle melanocytes: hair-bulb
melanocytes expressing FAS undergo apoptosis, whereas
those expressing the KIT receptor proliferate and migrate
upwards along the outer root sheath towards the epidermis;
the latter eff ect can be abolished by administration of a
KIT-neutralising antibody.65 Chemotherapy, therefore,
induces a complex melano cyte response. Nevertheless, if
damage to the melanocyte stem cells located in the bulge
(fi gure 1)54 is reversible, pigmentation abnormalities
should also be reversible, at least in principle. Moreover,
hair colour is determined by the proportion of eumelanin
(black) in relation to that of pheomelanin (red), which are
enzymatically determined.66 Thus, chemotherapy-induced
changes in the colour of regrowing hair shafts must refl ect
changes in the intrafollicular synthesis of eumelanin and
Molecular factors in pathobiology
Central role of P53
Anticancer drugs impair mitotic and metabolic processes
in actively growing hair follicles and induce DNA-damage
responses in rapidly proliferating hair-matrix cells.42,48
DNA-damage responses are regulated by several factors,
including response sensors, transducers, and eff ectors
(fi gure 2). Sites of DNA damage are recognised by the
primary damage sensor, the MRN complex (MRE11A,
RAD50, and NBN), which detects the lesion. ATM is
recruited and activated to phosphorylate the histone
H2AFX around the lesion to form γ-H2AX.67 MDC1
protein binds to γ-H2AX, additional copies of MRN and
ATM, and 53BP1 and BRAC1, whereas single-stranded
DNA is recognised by replication protein A and ATR
kinase is recruited to the damaged sites.67 ATM and ATR
kinases operate as transducers in DNA-damage response
to trigger eff ector-induced cell-cycle arrest (CHK1 and
CHK2 kinases), apoptosis (P53, FAS, etc), and senescence
(CDKN1A and CDKN2A [also known as P21 and
P16INK4A]; fi gure 2).67
Although the importance of many molecular factors in
the DNA-damage response remains to be elucidated in
chemotherapy-induced alopecia, P53 and its target genes
have recognised crucial roles in cyclophosphamide-
induced apoptosis, hair loss, and damage to the hair
follicles in vivo in mice42 and in vitro in human hair
follicles.48 In the C57BL/6 mouse model, administration
of cyclo phosphamide was associated with rapid increase
of P53 concentrations in hair-matrix keratinocytes,
followed by apoptosis.42,51 By contrast, genetic P53 ablation
renders hair follicles
cyclophosphamide.42 FAS as a P53 target is also involved
in mediation of apoptosis in murine hair-matrix kera-
tinocytes and melanocytes during the exposure of hair
follicles to cyclophosphamide.51,65,68 This relation is
supported by the observation that interleukin 15, a potent
inhibitor of FAS-mediated cell death, also inhibits
cyclophosphamide-induced hair-follicle apoptosis in
vivo.51 Other P53 targets, such as BAX or IGFBP3, are
upregulated in cyclophosphamide-treated hair-matrix
kera tino cytes.42,51,68,69 P53 also transactivates EDA2R during
murine chemotherapy-induced alopecia, which might,
therefore, be involved in the execution of P53 functions.70
Although the exact functions of these diff erent elements
in the mediation of chemotherapy-induced keratinocyte
apoptosis in human hair follicles remain to be elucidated,
they are rational molecular targets to explore for
completely resistant to
Other molecular factors
Members of the fi broblast-growth-factor family, including
FGF7, which are prominently produced by hair follicles
and regulate their growth, are protective against
chemotherapy-induced alopecia in rodent models.7,71 FGF7
has also shown a slight inhibitory eff ect against free-
radical-induced dystrophy and apoptosis in in-vitro studies
of human hair follicles.72 Inhibition of the generation of
reactive oxygen species by antioxidants reduces the
proapoptotic eff ect of cisplatin, which suggests an
essential role for hydroxyl radicals in cisplatin-induced cell
death of hair-follicle cells, perhaps through regulation of
www.thelancet.com/oncology Vol 14 February 2013 e56
BCL2.73 The role of BCL2 in chemotherapy-induced
alopecia, however, remains unclear, as overexpression
driven by the keratin-14 promoter in murine hair-follicle
epithelium unexpectedly augmented cyclophosphamide-
induced apoptosis and hair loss in transgenic mice.69
Erythropoietin, which is frequently administered to treat
tumour-induced anaemia, also inhibited keratinocyte
apoptosis in the human hair matrix induced by a
cyclophosphamide metabolite in vitro.74
How hair-follicle responses to chemotherapy-induced
damage in the dystrophic anagen and dystrophic catagen
pathways diff er and relate to the DNA-damage response
and repair machinery needs to be better understood
(fi gures 2, 4). For example, expression of molecules that
induce cell-cycle arrest (eg, CHK1 and CHK2 kinases)
versus proapoptotic molecules (eg, P53, FAS) might be
distinct in the two pathways. In this context, global gene-
expression profi ling of the response of the human hair
follicle to chemotherapy48 is likely to identify useful new
molecular targets for therapeutic intervention in
Hair-matrix versus hair-follicle stem-cell damage
Hair-follicle epithelial stem cells are a vital progenitor
population for all epithelial lineages within the follicle.52,75–77
By virtue of quiescence, these stem cells have evolved
mechanisms that promote survival and resistance to
apoptosis, and they are designed to replenish the whole
hair follicle numerous times throughout life.53,63,75,76 By
contrast, hair-matrix keratinocytes are shortlived, highly
proliferative progenitor cells that terminally diff erentiate
into the layered structure of the hair fi bre.47,50,77 Hair loss is
frequently reversible within 6 weeks of cessation of
chemotherapy,6,9 which indicates that hair-follicle epithelial
stem cells in the bulge (fi gure 1) must have retained their
capacity to generate new epithelial progeny, as this function
is a prerequisite for hair regrowth.47,78 When permanent
chemotherapy-induced alopecia is seen, for instance after
additional ionising radiation,6,19,79 irreversible damage has
been caused to the epithelial stem cells.
The mechanisms underlying permanent chemo-
therapy-induced alopecia are unknown, but at present
evidence suggests that resistance of epithelial hair-follicle
stem cells to apoptosis depends on various factors. Most
hair-follicle stem cells are in the G0/G1 phase of the cell
cycle and, therefore, are resistant to cell-cycle-specifi c
chemotherapy agents.53,75 Enhanced DNA repair via the
non-homologous end-joining pathway, which is mediated
by PRKDC, and asynchronous DNA synthesis protect the
cells from DNA errors induced by replication and repair.80
During asynchronous DNA synthesis, the parental,
immortal, DNA strand always segregates with the stem
cell and not the diff erentiating progeny.80 This mechanism
reduces the risk of being aff ected by DNA-damaging
agents and accumulation of replication-associated
mutations. Rapid inhibition of P53 activity in hair-follicle
stem cells via increased MDM2 expression promotes
survival of hair-follicle stem cells after DNA damage.80 A
P53 null mutation in mice was associated with prevention
of cyclophosphamide-induced apoptosis.42 Stem cells
more highly express members of the BCL2 family and
other inhibitors of apoptosis than do their diff erentiated
progeny, which also protects the stem-cell compartment.80
Multidrug-resistant proteins employ ATP hydrolysis to
actively effl ux drugs from cells, which protects them from
cytotoxic eff ects.81 In mice, epithelial progenitor cells in
skin express high levels of transporter proteins, such as
Abcg2 (also known as Bcrp), and P-glycoprotein.81
Whether homologous effl ux transport proteins have
similar eff ects in the human hair-follicle bulge remains to
be investigated. Finally, epithelial stem cells in human
hair follicles actively obstruct gap junctional transport
(eg, downregulation of GJA1 [also known as connexin-43]
expression),14,82 which hampers the entry of xenobiotics
and small-molecule toxins.
These mechanisms might refl ect chemo resistance of
hair-follicle epithelial stem cells. By contrast, the
molecular mechanisms noted above could explain the
heightened sensitivity of hair-follicle stem cells to selected
cytotoxins, such as taxanes,79 and might contribute to the
degree of damage in an individual patient’s bulge stem
cells in response to a given chemotherapeutic agent.79
Optimisation of models
The importance of developing the best possible preclinical
research models of chemotherapy-induced alopecia
cannot be overemphasised. Much more thought, funding,
and interdisciplinary eff ort are required to achieve this
goal. Neither the established C57BL/6 mouse model nor
the human hair-follicle organ-culture model is fully
satisfactory. Notable limitations of the latter model are that
it does not involve a full hair cycle and that the hair follicles
begin to degenerate after 1–2 weeks in culture. In the
mouse model, cyclophosphamide is given as one very
high dose rather than in multiple, fractionated doses,
which does not imitate the application schedule of
standard chemotherapy regimens. This diff erence is
important, since in clinical oncology, human-scalp hair
follicles damaged by cyclophosphamide will still be in the
recovery phase (fi gure 3) when they are exposed to the
next cycle of chemotherapy. Subsequent response to
chemotherapy is likely to be aff ected by this timing, and
the repair capacity of hair follicles might decline over time
(fi gure 3). Moreover, it is unknown to what extent data
from murine models of chemotherapy-induced alopecia
can be translated to the human condition.
One possible approach that will improve alopecia
research models is the transplantation of healthy, adult
human-scalp skin onto mice with severe combined
immunodefi ciency to enable testing of long-term cycling
and repeated exposure to chemotherapy in schedules
that imitate standard clinical regimens. Preliminary
evidence suggests that this model is feasible (appendix).
In conjunction with the assay for chemotherapy-induced
www.thelancet.com/oncology Vol 14 February 2013
dystrophy in organ-cultured human-scalp hair follicles,48
such humanised mouse models should enable
systematic dissection and pharmacological manipulation
of molecular triggers of pathobiological events in
Future management strategies
The search for future therapies to overcome chemo-
therapy-induced alopecia may follow several research
strategies. Many leads to potentially promising novel
agents that might prevent chemotherapy-induced
alopecia have been reported in animal studies6–8 and need
to be followed up with mechanistic studies and in organ-
cultured human hair follicles. Possible useful agents
include AS101,26 orally administered N-acetyl cysteine7
and zinc ions,83 FGF7,7,71,72 and PTH/PTH-related-peptide
receptor ligands.60 The biological-response modifi er
ImuVert might also be useful but is not yet licensed for
Some agents can greatly reduce initial hair loss. For
example, murine hair follicles enter only mildly
dystrophic anagen and show minimal hair loss if potent
calcineurin inhibitors (ciclosporin or tacrolimus) are
administered topically or systemically before and after
cyclophosphamide administration.45,46,61 Such anagen-
protective agents might reduce visible hair loss in human
beings to a tolerable degree. Nevertheless, although
ciclosporin stimulates hair growth,10,45,61 oncologists would
be ill advised to risk further compromise of a patient’s
tumour immuno surveillance by use of such a potent
immunosuppressant. Therefore, topically applicable non-
immunosuppressive calcineurin inhibitors that retain
anagen-promoting eff ects, prevent hair-follicle dystrophy,
or protect against chemotherapy-induced hair loss and
suppress activity of the transcription factor NFAT1c84 need
to be explored as alternative prevention strategies for
The cell cycle of anagen hair-matrix keratinocytes may
be arrested before and during chemotherapy to lessen
vulnerability to apoptosis. Such cell-cycle arrest would,
however, have to be strictly limited to the hair-follicle
epithelium, for example by hair-follicle-targeting
nanoparticles,85 to avoid favouring intracutaneous micro-
metastases. Unfortunately, though, agents that cause
cell-cycle arrest in the hair matrix also frequently
terminate anagen, which leads to telogen effl uvium and
would, therefore, not prevent hair loss. The development
of topically applicable agents that induce temporary cell-
cycle arrest in hair-follicle keratinocytes without
induction of apoptosis and premature catagen would,
therefore, be desirable.
Pharmacological agents are needed that protect
epithelial and melanocyte hair-follicle stem cells from
chemotherapy-induced damage, especially from taxanes
and high-dose polychemotherapy.79
upregulation of ABC transporter expression in the bulge
by topical agents is one possibility. Another is to bolster
the chemoresistance of hair-follicle stem cells by
upregulation of the intrafollicular expression and activity
of endogenous hair-follicle damage-repair agents and
systems, such as melatonin,86,87 melanin,58 erythropoietin,74
and enzymes that scavenge for reactive oxygen species or
repair DNA damage.58,64,87 Again, the eff ects of such agents
would have to be limited to the hair-follicle epithelium.
Even though chemotherapy-induced alopecia is a
daunting therapeutic challenge, feasible strategies to
meet it are available for exploration. Success will only be
achieved, however, if
interdisciplinary research eff orts are invested into
development of the best possible preclinical models of
applicable agents that target the hair follicle.
Despite substantial progress in research, many
important questions remain in relation chemotherapy-
induced alopecia. A particularly diffi cult one is whether
attempts to counteract chemotherapy-induced alopecia is
well advised at all. The dystrophic catagen pathway is
associated with the fastest and most complete recovery of
damaged hair follicles (fi gure 4). Development of
eff ective antagonists of this inbuilt, highly eff ective
organ-repair programme could reduce chemotherapy-
induced alopecia. This approach, however, also increases
the risk that the lifespan of dangerously damaged hair-
follicle cells that would otherwise undergo P53-mediated
apoptosis would be prolonged. Such an eff ect might have
harmful long-term eff ects, such as formation of hair-
follicle-derived tumours. Long-term observations in
appropriate animal models (appendix) must be made to
shed light on this vexing question.
In view of the increasing incidence of permanent
chemotherapy-induced alopecia, mostly after therapy
with taxanes and in combination with bone-marrow
transplantation,79 another important question is how to
develop agents that will protect hair-follicle stem cells but
not increase survival of cancer stem cells that have
seeded the heavily vascularised scalp. What the best
vehicles will be for the topical application of such agents
adequate funding and
and of topically
Search strategy and selection criteria
We searched PubMed for articles published from January, 1950, to May, 2012, with the
terms “chemotherapy-induced alopecia” and “chemotherapy” combined with
“hair loss/mechanisms/anagen effl uvium/mouse model/human hair follicle/stem cell/
treatment”, alone or in combination. Pathobiologically relevant murine in-vivo and
human in-vitro assays with direct relevance to chemotherapy-induced alopecia and
studies on cyclophosphamide-induced alopecia were preferentially selected for
discussion, complemented by selected historical and background papers on hair research.
Alopecia induced by non-classic chemotherapy, such as that with tyrosine-kinase
inhibitors, was not included. Older references cited in retrieved publications were traced
individually through our institutional library search services. Meeting abstracts were not
considered. Only articles published in English or German were selected.
www.thelancet.com/oncology Vol 14 February 2013 e58
to reliably target hair-follicle progenitor cells but not
tumour stem cells will also need to be investigated.85
Additional important questions to consider are the
most basic enquiries made by patients about whether
they will experience hair loss and its degree, duration,
and regrowth, to which there are often no easy answers.
To be able to provide at least reasonably reliable answers
in the future, we need to clarify which individual factors
are most important when assessing the risk of
chemotherapy-induced alopecia. In turn, this approach
requires the development of a uniform, internationally
standardised method for the classifi cation of chemo-
therapy-induced alopecia, and of a much improved,
objective, individualised prognosis system that factors in
individual parameters and characteristics of the patient.
With these tasks laid out clearly before us, and with a
deeper understanding of its pathobiology, more
satisfactory management of chemo therapy-induced
alopecia in the future should be possible.
RP wrote the overall drafts of the Review. ISH, AAS, and VAB provided
additional text and helped to extensively revise the paper.
Confl icts of interest
We declare that we have no confl icts of interest.
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