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Hair loss can be a psychologically devastating adverse eect of chemotherapy, but satisfactory management strategies for
chemotherapy-induced alopecia remain elusive. In this Review we focus on the complex pathobiology of this side-eect.
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 chemotherapyinduced alopecia is so challenging to manage. P53-dependent apoptosis of hair-matrix keratinocytes and chemotherapyinduced 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.
Introduction
Few adverse eects 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 ecacy in specic chemotherapy
regimens (eg, taxane monotherapy), many are unsatisfactory. As such, chemotherapy-induced alopecia
represents one of the major unmet challenges in clinical
oncology. Extreme anxiety related to this cosmetic
disgurement 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 rst
introduced into clinical medicine.25 Reviews on the clinical
presentation and management of chemotherapy-induced
alopecia are available,69 but the underlying pathobiology
remains insuciently understood, which results in a lack
of well dened targets for intervention. Research should be
undertaken collaboratively by oncologists, hair biologists,
dermatologists, and pharmacologists, but such an interdisciplinary approach regrettably remains underdeveloped.
In this Review we explore the therapeutic conundrum
of chemotherapy-induced alopecia, which aects 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.
Clinical characteristics
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 aect scalp regions that show low total hair
densities, such as the frontal or occipital hairlines.12 Girls
www.thelancet.com/oncology Vol 14 February 2013
e50
Review
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Management
e51
Review
Chemotherapy
DNA damage
Sensors
Pathobiology
Although distinct hair-loss patterns are seen, the overall
nal clinical presentation of chemotherapy-induced
alopecia is similar across patients. Many chemotherapeutic
agents share proapoptotic pathways that have crucial roles
in chemotherapy-induced alopecia, especially P53mediated signalling (gure 2).42,43 The chemotherapeutic
agents most frequently associated with alopecia, however,
have distinct mechanisms of action and dier substantially
according to an individuals genetically determined susceptibility to chemotherapy-induced cytotoxic eects. To treat
chemotherapy-induced alopecia as one entity is, therefore,
misleading. Nevertheless, since the principal hair-follicle
damage-response pathways are shared (gures 1, 2), even
between chemically distinct chemotherapeutic agents, for
practical purposes we do so in this Review.
RAD17
H2AFX
XRCC6/5
12
ATR
Transducers
ATM
P53/MDM2
CDKN1A
GADD45
PRKDC
CHK1, CHK2
Apoptosis
Senescence
14-3-3
HIPK2
CDKN2A
PRB
CASP3/6/7
BAX
Cell-cycle arrest
PIDD
FAS
WEE-1.3
CDK1
CDK4/6
CDC25A/B/C
Review
Late anagen
Damage to epithelial stem cells
determines reversibility of alopecia
Damage to melanocyte stem cells?
Telogen
euvium
Chemotherapy
Main damage
target: anagen
hair matrix
Additional damage to
hair-follicle vasculature
and mesenchyme?
Dystrophic anagen
Hair-shaft shedding (euvium/alopecia)
Continued but retarded growth of depigmented
and/or structurally abnormal hair shaft
Anagen abnormally prolonged
Dystrophic catagen
Accelerated hair regrowth of normal hair shafts by
shortened and accelerated re-entry into anagen
Exogen
Telogen
Late catagen
Review
Hair-shaft
shedding
Primary
recovery
Poor-quality
hair shaft
Secondary
Normal, fully recovery
pigmented
hair shaft
Lower
toxic eects
Long
recovery
Shortened
dystrophic
telogen
Hair-shaft
shedding
Severe
toxic aects
Chemotherapy
Cyclophosphamide
Short
recovery
Calcitriol,
glucocorticoids,
oestradiol,
PTH 134
Hair regrowth
e54
Review
Review
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 eort 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 12 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 dierence is
important, since in clinical oncology, human-scalp hair
follicles damaged by cyclophosphamide will still be in the
recovery phase (gure 3) when they are exposed to the
next cycle of chemotherapy. Subsequent response to
chemotherapy is likely to be aected by this timing, and
the repair capacity of hair follicles might decline over time
(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
immunodeciency 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
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nanoparticles,85 to avoid favouring intracutaneous micrometastases. Unfortunately, though, agents that cause
cell-cycle arrest in the hair matrix also frequently
terminate anagen, which leads to telogen euvium and
would, therefore, not prevent hair loss. The development
of topically applicable agents that induce temporary cellcycle 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 The selective
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 eects of such agents
would have to be limited to the hair-follicle epithelium.
Conclusions
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 adequate funding and
interdisciplinary research eorts are invested into
development of the best possible preclinical models of
chemotherapy-induced alopecia and of topically
applicable agents that target the hair follicle.
Despite substantial progress in research, many
important questions remain in relation chemotherapyinduced alopecia. A particularly dicult 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 (gure 4). Development of
eective antagonists of this inbuilt, highly eective
organ-repair programme could reduce chemotherapyinduced alopecia. This approach, however, also increases
the risk that the lifespan of dangerously damaged hairfollicle cells that would otherwise undergo P53-mediated
apoptosis would be prolonged. Such an eect might have
harmful long-term eects, such as formation of hairfollicle-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
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