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CASE REPORT
Radiation- and Chemotherapy-Induced Permanent
Alopecia: Case Series
Mansoor Haider, Issam Hamadah, and Abdulmonem Almutawa
Background: Radiation- and chemotherapy-induced alopecia is mostly temporary. However, permanent scalp alopecia is
reported, albeit infrequently.
Objective: The objective of this observational case series was to determine the kind and doses of chemotherapeutic agents and
radiation in inducing permanent alopecia of the scalp.
Methods and Results: Eleven patients referred to our department over a period of 3 years for permanent alopecia after
chemotherapy/radiotherapy or combination therapy were included. A detailed medical and therapeutic history was obtained from
each patient and from medical records. Photography was done, and the scalp biopsies were taken. Patients were divided into three
groups according to the type of therapy. The first group received conditioning chemotherapy prior to bone marrow transplantation.
The second group had radiation for brain tumors, and the third group received both.
Conclusion: A comprehensive multicenter and multidisciplinary study is required to determine the definite causative agents,
doses, and other cofactors that induce permanent alopecia following chemotherapy/radiotherapy, as well as the means to avoid this
distressing outcome in surviving patients.
Contexte: L'alopécie causée par la chimiothérapie et la radiothérapie est, la plupart du temps, temporaire, mais il arrive, dans de
rares cas, que le traitement donne lieu à une calvitie permanente.
Objectif: La présente série de cas d'observation visait à déterminer le type et la posologie des agents chimiothérapeutiques ainsi
que le type et les doses de rayonnement, incriminés dans la calvitie permanente.
Méthode et résultats: Ont participé à l'étude 11 patients dirigés vers notre service, sur une période de 3 ans, pour une calvitie
permanente, consécutive à la chimiothérapie ou à la radiothérapie, administrées seules ou en association. Une anamnèse détaillée
sur les antécédents médicaux et les interventions thérapeutiques a été fournie par chacun des patients et tirée des dossiers
médicaux. Des photographies ont été prises, et nous avons effectué des biopsies du cuir chevelu. Les sujets ont été divisés en trois
groupes selon le type de traitement reçu: (1) la chimiothérapie préparatoire à la greffe de moelle osseuse; (21 la radiothérapie pour
des tumeurs cérébrales; et (3) la chimiothérapie et la radiothérapie en association.
Conclusions: II est nécessaire de mener une étude approfondie, multicentrique, et pluridisciplinaire afin, d'une part, de déterminer
précisément les agents, les doses, et d'autres cofacteurs incriminés dans la calvitie permanente, consécutive à la chimiothérapie ou à la
radiothérapie, et, d'autre part, de trouver des moyens d'éviter cet effet indésirable pénible chez les patients ayant survécu à la maladie.
T
EMPORARY ALOPECIA resulting from chemotherapy/radiotherapy is a well-known side effect. However,
permanent loss of scalp hair may also result from
radiotherapy for brain tumors or metastasis as well as
certain chemotherapeutic agents, in particular those used
for conditioning prior to bone marrow transplantation
From the Departments of Dermatology and Pathology and Laboratory
Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh,
Saudi Arabia.
Address reprint requests to: Mansoor Haider, MBBS, FCPS(Dermatology),
Department of Dermatology, King Faisal Specialist Hospital and Research
Centre, MBC 46-1, PO Box 3354, Riyadh 11211, Saudi Arabia; e-mail:
[email protected].
DOI 10.2310/7750.2012.12033
C: 2013 Canadian Dermatology Association
(BMT). In the medical literature, such reports are no longer
rare, but why some patients develop permanent loss of hair
and others do not and what the common mechanism is
between chemotherapy and radiotherapy that results in this
condition need to be investigated thoroughly. The following
case series consisted of 11 patients who reported to the
Department of Dermatology at the King Faisal Specialist
Hospital and Research Centre in Riyadh, Saudi Arabia, for
permanent loss of scalp hair following either radiotherapy
or chemotherapy alone or in combination.
Methods and Results
This observational study includes 11 patients referred to us
over a period of 3 years for permanent loss of scalp hair after
radiotherapy, chemotherapy, or both. The female to male
DECKEI^
journal of Cutaneous Medicine and Surgery, Vol 17, No I (January/February), 2013: pp 55-61
55
56
Haider et al
Table 1. Chemotherapy-Induced Alopecia
Patient
No.
Sex
Age When
Received
Therapy
Diagnosis
1
F
2yr
Congenital
amegakaryocytic
thrombocytopenia
2
F
14 yr
Acute myeloid
leukemia
3
M
17 yr
Chronic myeloid
leukemia
4
F
2yr
Chronic
granulomatous
disease
Conditioning Regimen
Busulfan 4 mg/kg
daily X 4 d
Cyclophosphamide
IV 590 mg
daily X 4 d
Busulfan 4 mg/kg
daily X 4 d
Cyclophosphamide
IV 2,400 mg
daily X 2 d
Busulfan 4 mg/kg
daily X 4 d
Cyclophosphamide
IV 60 mg/kg
daily X 4 d
Busulfan 4 mg/kg
daily X 4 d
Cyclophosphamide
IV 60 mg/kg
daily X 4 d
Other Medications
in Addition to
Conditioning Regimen
Pattern and
Site of Alopecia
After BMT: MTX,
cyclosporine, acyclovir.
fluconazole, piperacillintazobactam, gentamicin
Frontal and parietal
Induction chemotherapy
before BMT: idarubicin.
cytarabine, etoposide
Diffuse
Treatment before
conditioning: hydroxyurea
1-2.0 g daily X 8 mo;
allopurinol
After BMT: MTX,
cyclosporine, trimethoprimsulfamethoxazole.
fluconazole, acyclovir
After BMT: MTX,
cyclosporine, trimethoprimsulfamethoxazole
Moth eaten
Diffuse
BMT = bone marrow transplantation; MTX = methotrexate.
ratio was 10:1. The patients' ages at the time of presentation
to the dermatology clinic ranged from 6 to 30 years, but the
age at which they received treatment ranged from 2 to 20
years. Four patients received chemotherapy alone (group 1),
three patients received radiotherapy (group 2), and four
patients received both (group 3). All patients were
photographed at the time of presentation, and scalp biopsies
were taken in nine patients (two declined).
Table 2. Radiotherapy-Induced Alopecia
Sex
Age When
Received
Therapy
5
F
15 yr
6
F
20 yr
7
F
12 yr
Patient
No.
Diagnosis
Ganglioglioma (post
erior cranial fossa)
Pineal ependymoma
(secondary tumors
in brain from
spinal tumor)
MeduUoblastoma
(post erior cranial
fossa)
Radiation Type
Beam Energy
Total Dose
No. of
Fractions
Site of
Alopecia
X-rays
6MV
5,040 cGy
28
X-rays
6 MV right lateral
6 MV left lateral
whole brain
6 MV dorsal spine
6 MV for
craniospinal axis
18 MV for
post erior cranial
fossa boost
3,000 cGy
10
Occipitoparietal
region
Frontoparietal
and bitemporal
region
30
20
Vertex and
occipital region
X-rays
3,000 cGy
5,400 cGy
i 3,600
(craniospinal)
+ 1,800
(post erior
cranial fossa)
-1-
10
57
Radiation- and Chemotherapy-Induced Permanent Alopecia
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58
Haider et al
Croup 1 received busulfan and cyclophosphamide as a
conditioning regimen before BMT. The age at the time of
receiving therapy ranged from 2 to 17 years. In addition to
conditioning therapy, other medications were given either
before or affer transplantation. Three different patterns of
alopecia were observed (Table 1).
Croup 2, aged 12 to 20 years at the time of therapy,
received radiation for brain tumors. Total doses given ranged
from 3,000 to 5,400 cCy in 10 to 30 ffactions (Table 2). One
patient (7) received radiation affer resection of the tumor. In
the other two patients, resection could not be performed
due to location. In the foUowing 2 to 6 months, progressive
hair loss was noticed at the sites of radiation in all patients.
Croup 3 comprised four patients suffering ffom meduUoblastoma, astrocytoma, and neuroblastoma. The first three
received radiation foUowed by chemotherapy over a period of
10 to 12 months (Table 3). In patients 8 and 9, partial
resection of the tumor was performed due to involvement of
the floor of the fourth ventricle. In patient 10, the tumor was
unresectable due to location. Patient 11 first underwent
induction chemotherapy for neuroblastoma grade IV (four
cycles in 3 months) foUowed by surgical removal and total
body irradiation and then conditioning with carboplatin,
etoposide, and melphalan prior to autologous BMT (see Table
3). AU patients developed alopecia during radiotherapy, with
only partial recovery in subsequent months.
Scalp biopsies were transversely sectioned in seven cases
and vertically in two cases. SimUar changes were observed in
all nine biopsies. There was a reduction in foUicular
densities and some degree of variation in foUicular size, as
well as significant miniaturization (Figure 1). None of the
biopsies revealed scarring, peribulbar infiammation, interface dermatitis, or graff-versus-host disease (CVHD).
Our patients were foUowed up for 2 years. Topical
minoxidil 2 to 5% was prescribed. Some patients used it
for 3 months to 1 year but then discontinued due to a lack
of response.
Discussion
Hair loss, temporary or permanent, is one of the most stressful
side effects for patients undergoing oncologic treatment. The
true prevalence of permanent alopecia by chemotherapy or
radiation may be underestimated as many patients do not
complain and accept it as the price of treatment.
Postchemotherapy Alopecia
In general, alopecia affer chemotherapy is temporary, with
regrowth expected within 4 to 6 weeks. However, irreversible
alopecia has been reported in the last two decades with
various therapeutic agents, in particular, busulfan-cyclophosphamide combination therapy (BUCY), as a conditioning
regimen prior to BMT.'"^
Permanent alopecia is defined as complete loss of
growth or partial regrowth at least 6 months affer
chemotherapy.* Increased risk factors for permanent
alopecia in transplant patients are treatment with busulfan,
chronic CVHD, and previous cranial irradiation.''
Civen that scalp hairs are one of the most rapidly
growing hairs in the body, they are the most commonly
affected. However, other body sites may also be involved,
including eyebrows, eyelashes, and axillary and pubic hair.
The exact mechanism of chemotherapy-induced permanent alopecia (CIPAL) is stiU unknown. Possible explanations are stem ceU destruction or acute damage of matrix
keratinocytes that die in the hypodermis instead of entering
the catagen phase' or permanent toxic damage to the hair
foUicle stem ceUs in their bulge (at the insertion of arrector
pili muscle).^ The p53 protein is found to be essential for
this chemotherapy-induced alopecia as it mediates apoptosis and growth arrest in TP53-negeiúve cancers.^
However, not aU patients receiving chemotherapy develop
CIPAL. In a retrospective study by Machado and coUeagues,
only 6 of 760 patients developed irreversible hair loss affer
high-dose chemotherapy.* Baker and coUeagues described 6
Figure 1. A, Transverse section at the
level of the upper dermis (isthmus)
showing reduced foUicular density and
some variation in foUicular size
(hematoxylin-eosin stain; X40 original magnification). B, Miniaturized
follicles (hematoxylin-eosin stain;
X200 original magnification).
Radiation- and Chemotherapy-Induced Permanent Alopecia
patients with incomplete regrowth of varying severity among
22 who had undergone allogenic or autologous BMT and had
BUGY conditioning.' Similarly, Ljungman and colleagues
studied 65 patients who received busulfan prior to BMT and
found some degree of permanent alopecia in 31 cases.^
Why some patients develop permanent rather than
temporary alopecia following chemotherapy is still unanswered. Serum busulfan concentration can be a factor.
Pharmacokinetic variability as a result of the bioavailability
of oral busulfan may be contributing to this.*^ In their study,
Ljungman and colleagues found extensive permanent
alopecia in patients with high busulfan concentration."
Although there is no current effective therapy for
GIPAL, one possible solution is to reduce the dose.
However, a mean plasma concentration below the median
level during conditioning can significantly increase the risk
of relapse.'* Other suggested options include scalp
hypothermia"" and topical anti-p53 treatment."
Drugs other than busulfan reported to cause permanent hair loss are docetaxel,'*'^^ carboplatin, thiotepa,''
and tamoxifen.'''
All four patients in group 1 received BUGY conditioning therapy in standard doses before BMT. None of them
suffered from acute or chronic GVHD. All developed
permanent hair loss but with variable patterns (Figure 2),
the explanation of which may be that cytotoxic drugs
damage actively proliferating foUicular cells in an apoptosisrelated manner, rendering the hair follicle cells vulnerable
depending on their state of proliferation.'^
Postradiotherapy Alopecia
Permanent alopecia is a well-known side effect of
radiation. Although the principal change following an
acute dose of radiation is apoptosis,'' radiation damage
59
can occur due to a combination of changes such as a
reduction in matrix cell reproduction, the effect on protein
synthesis/plasma membrane permeability of matrix cells,
and alteration in perifollicular blood flow.'^
Temporary alopecia following radiotherapy occurs in 2
to 3 weeks and resolves within 2 to 3 months afier
completion of radiotherapy. Doses as low as 2 Gy in a
single fraction can cause temporary anagen alopecia.'^
Telogen alopecia takes more time to occur compared to
anagen alopecia and needs higher doses than anagen (two
to three times) but stores radiation damage for long
periods.'^ The doses reported to cause permanent hair loss
vary widely. A study conducted by Shakespeare and
colleagues documented that at a dose of 36 Gy the
estimated median risk of permanent alopecia was 5% and
that a dose of 45 Gy resulted in a risk of 15%.''^
FoUicular dose (the dose of radiation at the level of hair
follicle in a particular radiation field) is the only significant
factor in determining the degree of permanent alopecia.'^''*
Most anagen follicles are at a depth of 4 to 4.5 mm
from the skin surface. If the radiation superficial to this
depth is kept under a lethal dose, the incidence of
radiation-induced alopecia can be markedly reduced.'"
The D50, the follicular dose at which 50% of patients
develop permanent alopecia, is estimated to be 43 Gy.'^
Follicular dose in turn depends on beam energy, field
position and size, and method of radiation. For patients
treated with opposed lateralfields,the follicular dose is usually
the highest at the anterior-superior and/or posterior region of
the skuU where two lateral fields overlap. Use of stereotactic
arcs minimizes the foUicular dose as arcs typicaUy do not
overlap. Similarly, higher beam energies have skin-sparing
properties.'** Other methods or materials used in animal
models/humans for radiation protection include nitroxide^'
and prostaglandin E2.^^ In our three patients who received
Figure 2. Patterns of chemotherapyinduced permanent alopecia.
60
Haider et al
Figure 3. Patterns of radiationinduced permanent alopecia.
radiotherapy alone for the brain tumors, the total dose ranged
from 30 to 54 Gy in 10 to 30fractions(see Table 2). The sites of
alopecia varied according to the field of radiation (Figure 3).
Post-Chemotherapy/Radiotherapy Alopecia
The third group comprised patients who received
combined radiotherapy and chemotherapy. Three patients
(8, 9, 10) were treated with lateral opposed fields, whereas
patient 11 had total body irradiation. The total dose
ranged from 12 to 54 Gy. Among chemotherapeutic
agents, vincristine, cyclophosphamide, carmustine, and
carboplatin were given over a period of 9 to 12 months in
the first three patients. In patients 8 and 9, weekly
intravenous vincristine was administered during radiation
and adjuvant chemotherapy for children with the medulloblastoma protocol was started 1 month after stopping
radiotherapy. Inpatient 10, chemotherapy was also started
1 month after stopping radiotherapy. Patient 11 received
induction chemotherapy prior to surgical resection of
tumor, followed by radiotherapy and conditioning with
carboplatin, etoposide, and melphalan (see Table 3).
Loss of hair was noticed soon after radiotherapy in all
patients, and hair was only partially replaced in the
following months (Figure 4).
VLncristine has no documented association with alopecia.
Cyclophosphamide causes only temporary alopecia.
Carboplatin and cyclophosphamide, the only drugs that
enhance radiosensitization,"*'"^ were administered after
completion of radiation in the first three cases and thus were
Figure 4. Patterns of combined radiotherapy/chemotiierapy-induced permanent alopecia.
Radiation- and Chemotherapy-Induced Permanent Alopecia
unlikely to be a contributing factor in inducing permanent
alopecia. Even in the study done by Lawenda and colleagues,
no statistically significant difference was found in D50 among
patients who received radiosensitization chemotherapy agents
and those who received agents without this property.'^
In a review article by Malkinson and Keane, the authors
explained that the adjuvant effects of chemotherapy/drugs
are related to the interval between the drug administered
and radiation given.'* This enhancing effect was observed
when radiation was given hours after chemotherapy, which
in turn depends on the phase of cell cycle in which activity
was arrested. Moreover, no changes were observed when the
sequence of radiation and drug was reversed and metabolic
activity failed to influence radiation changes at higher doses.
In patient 11, cyclophosphamide was administered before
radiotherapy, but the intei"val between them was over weeks
rather than hours. So in this group, radiotherapy was
considered to be the cause of permanent loss of hair, and
chemotherapy was most likely not involved.
Conclusion
Ghemotherapy/radiotherapy-induced permanent alopecia
is a distressing condition that must be addressed at
multicenter levels to determine the exact prevalence
among populations undergoing these types of therapies
and possible ways and means to minimize its occurrence.
Acknowledgments
We thank Marieta P. Ricardo for typing and uploading the
manuscript.
Financial disclosure of authors and reviewers: None
reported.
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