CASE REPORTS

Acneiform eruptions associated with epidermal

growth factor receptoretargeted chemotherapy
Christine A. DeWitt, MD, Alan E. Siroy, MPH, and Stephen P. Stone, MD
Springfield, Illinois

A relatively newer class of chemotherapy agents, known as the epidermal growth factor receptor inhibitors
(EGF-RIs), is being used to treat advanced stages of solid tumors. Acneiform eruptions are a frequent
adverse effect and one which has been associated with increased survival in some studies. We describe
3 patients who presented shortly after initiation of EGF-RI therapy. Characteristics included an absence of
comedones, facial and truncal involvement, and a perifollicular lymphoneutrophilic infiltrate detected on
biopsy. Lesion counts were reduced with topical adapalene and oral tetracyclines in two patients. Patient 3
had dramatic clearance with low-dose isotretinoin (20 mg daily) until completion of EGF-RI therapy.
Acneiform eruptions are a common adverse reaction to EGF-RI therapy and can be treated with traditional
acne therapy. This should not be considered a drug hypersensitivity eruption or allergy, and patients
should continue therapy. For patients with severe eruptions, oral isotretinoin is a consideration. ( J Am
Acad Dermatol 2007;56:500-5.)

E pidermal growth factor receptor inhibitors

(EGF-RIs) are a group of newly-approved
medications for advanced stages of cancer.
EGF receptors (EGF-Rs) are overexpressed in many
tumor types and play a role in the development
and progression of cancer.1 The expression of EGF-R
is abundant in malignant cells of solid tumors, such
as those of the head and neck, lung, breast, ovary,
prostate, and colon.1 EGF-R is also expressed in
normal, nonmalignant cells, including epidermal
keratinocytes, sebocytes, and the outer root sheath
of hair follicles.2
There are two classes of drugs that inhibit these
receptors. Small molecule EGF-RIs, such as gefitinib
(Iressa) and erlotinib (Tarceva), selectively inhibit the
tyrosine kinase activity of the intracellular domain,
preventing autophosphorylation and subsequent
activation of the signaling cascades.3,4 Monoclonal
antibodies, such as cetuximab (Erbitux) and trasta-
zumab (Herceptin), bind to the extracellular domain
of EGF-R, blocking activation and signal transduction
of the receptor.5
From the Division of Dermatology, Southern Illinois University.
Funding sources: None.
Conflicts of interest: None identified.
Reprint requests: Stephen P. Stone, MD, Division of Dermatology,
Southern Illinois University, PO Box 19644, Springfield, IL
62794-9644. E-mail: sstone@siumed.edu.
Published online December 14, 2006.
0190-9622/$32.00
ª 2007 by the American Academy of Dermatology, Inc.
doi:10.1016/j.jaad.2006.06.046
Abbreviations used:
EGF: epidermal growth factor
EGF-R: epidermal growth factor-receptor
EGF-RI: epidermal growth factor-receptor
inhibitor
Patients on a regimen of EGF-RIs may present
with acneiform eruptions shortly after initiation
of treatment. Numerous studies have revealed an
increased incidence of cutaneous adverse effects
experienced by patients taking EGF-RIs.3,6-13 We
present 3 patients who developed acneiform erup-
tions after initiation of therapy with EGR-RIs.
CASE REPORTS
Case 1
A 52-year-old white man with stage IV non-small
cell lung cancer presented with a 3-week history of
a pruritic eruption located on the face, chest, and
back. After initial diagnosis of the tumor, the patient
underwent partial lung resection, local radiation, and
chemotherapy with paclitaxel and carboplatin.
Nearly 11 months subsequent to the initial diagnosis
of the tumor, he was found to have a tumor recur-
rence and gefitinib was started 3 weeks before
presentation. The eruption developed 1 week after
the initiation of gefitinib therapy.
Physical examination revealed extensive ery-
thematous papules and small pustules on the trunk.
There was lesser involvement of the middle aspect
of the nose, cheeks, and forehead. There were no

500
J AM ACAD DERMATOL
VOLUME 56, NUMBER 3
comedones and the skin appeared normal between
the individual papules and pustules. Interestingly,
there was a focal area of sparing on the right side of
his back where he had received radiation therapy
(Fig 1).
The patient was started on a regimen of adapalene
0.1% gel applied nightly and benzoyl peroxide 4%
gel to be applied in the morning. After 3 weeks, he
had significant improvement in lesion count, with
flattening of many of those remaining. The patient
was continued on this regimen, and during the next
several months, experienced ongoing improvement.
Nearly 3½ years after initial diagnosis, however, the
patient has recently had progression of disease and
has elected to discontinue all therapy.
Case 2
A 52-year-old white man with stage IV colon
cancer presented with a papulopustular eruption on
the face, neck, chest, back, and scalp. The tumor was
diagnosed 3 months before the visit and the patient
underwent a right colectomy and ostomy placement.
His chemotherapy regimen consisted of 5-fluorou-
racil, leucovorin, and irinotecan. As an adjuvant to
his chemotherapy, he was started on a regimen of
cetuximab 1 month before presentation. He noticed
eruptions on the chest 4 to 5 days after his first
infusion of cetuximab. Eruptions on the face, neck,
and scalp progressively worsened with each sub-
sequent infusion.
Physical examination revealed numerous ery-
thematous papules on the lateral aspects of the
face, confluent to erythematous plaques with thick
honey-colored crust located on the nose and
bearded area, erythema with scant greasy scale in
the eyebrow region, and numerous erythematous
papules and pustules located on the trunk (Fig 2).
There were no comedones; however, there was
evidence of secondary impetiginization.
Therapy was initiated with minocycline, 100 mg
twice daily, and a topical regimen of adapalene 0.1%
gel applied to the chest and back twice daily, dilute
acetic acid soaks to the crusts on the face and scalp
followed by mupirocin cream 3 to 4 times daily, and
a salicylic acid shampoo for the profound crusting on
the scalp. Ten-day follow-up of the patient showed
significant improvement of the erythema and crust-
ing on the face, scalp, and trunk. Physical examina-
tion revealed a reduction in the lesion count, and
the diameter of the individual acneiform lesions
decreased from averages of 3-4 to 1-2 mm.
Subsequent visits showed further lesion improve-
ment. Two years after his initial diagnosis, he is
currently living with metastases.
Case reports 501
Fig 1. Patient 1. Monomorphous acneiform eruption
developed because of gefitinib therapy. Note zone of
clearance where previous local radiation therapy had been
administered.
Case 3
A 30-year-old white man with a diagnosis of stage
III colon cancer presented with a pustular eruption
on the face, scalp, and trunk. The patient was
diagnosed 2 months before the visit and underwent
a right hemicolectomy. His chemotherapeutic regi-
men included 5-flurouracil, leucovorin, and irinote-
can. The patient was started on a regimen of weekly
cetuximab as adjuvant therapy 4 weeks before pre-
sentation. The patient’s eruptions began a few days
after the second infusion of cetuximab. The rash had
steadily increased in severity, with greater spikes
noted within the 2 to 3 days after receiving each
infusion.
Physical examination revealed diffuse, monomor-
phic, erythematous papules and pustules located on
the scalp, face, and trunk. Biopsy results revealed a
large follicle with focal erosion of the infundibular
epithelium containing numerous neutrophils. The
follicle was surrounded by a lymphoneutrophilic
infiltrate including foreign body giant cells (Fig 3).
A cluster of coccoid bacteria was evident within the
follicle.
Therapy was initiated with adapalene 0.1% cream
applied once daily. Though he had improvement,
the acne was still of significant concern to him. After
coordinating therapeutic options with his oncologist,
the patient was started on a regimen of low-dose
isotretinoin at a dose of 20 mg daily. At 1-month
follow-up, the patient had dramatic clearing of his
pustules with only slight erythematous macules
remaining. He experienced xerosis involving the
lips, but no other adverse effects were seen. The
dosage of isotretinoin was decreased to 20 mg every
other day and he continued to maintain excellent
clearance; even in the first few days after infusions,
which had been the most problematic. He remained
on this dose until the completion of his cetuximab
502 Case reports
Fig 2. Patient 2. Facial papules and secondary impetigi-
nization (A) and characteristic monomorphous truncal
acneiform eruption (B) shortly after starting cetuximab
therapy.
therapy. It has been approximately 6 months since
completion of therapy, and he remains in remission.
DISCUSSION
EGF-R is overexpressed in malignant cells and
plays an important role in proliferation, differentia-
tion, and the eventual development and progression
of cancer.1,14,15 EGF-RIs are currently being used in
cancer therapy to prevent the activation of these
receptors in tumor cells. In nonmalignant cells, such
as epidermal keratinocytes, sebocytes, and cells
of the hair follicle, EGF-R is involved in normal
cell growth and differentiation. Numerous studies
involving cancer patients placed on a regimen of
EGF-RI therapy have reported cutaneous reactions
as being the most common side effect of therapy,
occurring shortly after the subjects were placed on
an EGF-RI regimen.3,6-13 Acneiform eruptions have
J AM ACAD DERMATOL
MARCH 2007
Fig 3. Case 3. Photomicrograph of biopsy specimen de-
monstrates a dense perifollicular lymphoneutrophilic in-
filtrate and follicular plugging. (Hematoxylin-eosin stain;
original magnification: 310.)
been seen with the use of gefitinib (66%), erlotinib
(75%, 5% grade III) and cetuximab (86%, 18% grade
III).3,11,13 As with all adverse effects, the National
Cancer Institute has developed a scale for defining
the degree of rash (Table I).16
In a phase I trial involving 88 patients receiving
escalating doses of gefitinib, Baselga et al7 noted
that the most frequent adverse reaction to the drug
was an acne-like rash, occurring in 64% of patients.
The persistence of this rash was reversible upon
cessation of gefitinib treatment. In a phase II trial of
cetuximab involving 57 patients, Saltz et al11 found
that an acne-like rash occurred in 86% of patients,
with 18% involving a grade III reaction. Areas of
involvement were mostly localized to the face and
upper torso. Albanell et al3 reported adverse skin
reactions occurring in 43 of 64 patients participating
in a pharmacodynamic study of gefitinib. These
reactions generally appeared after 7 to 14 days
of treatment, with acneiform eruptions occurring
mostly on the face and trunk. In a study by Busam
et al10 investigating the cutaneous side effects in
cancer patients treated with cetuximab, 10 of 10
patients experienced a follicular rash, which devel-
oped approximately 1 week after initiation of ther-
apy. The rash presented in an acneiform distribution,
affecting the face, scalp, chest, and upper back. The
cutaneous reactions that presented in patients of the
EGF-RI studies were described as acneiform or acne-
like in terms of clinical presentation (erythematous,
papulopustular lesions) and distribution (face, scalp,
chest, and upper back), similar to what we report in
our 3 cases.
Data from some studies show a positive correla-
tion between the presence and grade of cutaneous
eruption and survival time. Perez-Soler et al8 found
that there was a statistically significant increase in the
survival of patients treated with erlotinib who
presented with a rash of grade I, II or III versus
J AM ACAD DERMATOL
VOLUME 56, NUMBER 3
Table I. National Cancer Institute adverse event scale for acneiform eruptions*
Grade I Grade II
Degree of Intervention not Intervention
acneiform rash indicated indicated
*Using the Common Toxicity Criteria for Adverse Events v3.0.
those with no rash at all. Soulieres et al6 noted that
patients treated with erlotinib who developed a
grade II rash or higher had a significant increase in
survival time when compared with those without a
rash. In a phase II study involving 52 patients with
head and neck cancer treated with gefitinib, Cohen
et al9 found that the development of a rash predicted
statistically significant survival outcomes. Patients
who developed a rash had a greater than two-fold
median survival when compared with patients who
did not develop a rash. Saltz et al11 observed that
patients on a regimen of cetuximab with a rash of any
grade had an increase in survival compared with
patients with no occurrence of rash. Furthermore,
increase in severity of the rash seemed to corre-
late with an increase in survival time, with grade
III patients having the longest survival, grade I
and II patients having intermediate survival, and
grade 0 patients have the shortest survival. Over-
all, data from these studies suggest that EGF-RIe
induced acneiform eruptions may serve as an
important clinical tool for determining tumor re-
sponse and survival outcomes in cancer patients
treated with EGF-RIs.
An interesting discussion among oncologists is the
role of pretreatment testing for the presence and/or
intensity of EGF-R. In the initial clinical trials spec-
imens were scored on the basis of the percentage of
cells expressing EGF-R and intensity. Response rate
did not correlate with either the percentage of
positive cells or the intensity of EGF-R expression.
Current data do not support the use of the EGF-R
testing for making any clinical decisions regarding
patient management.17 Accordingly, use of the drug
should not be determined solely on the absence,
presence, or degree of EGF-R expression. As such,
our patients did not have EGF-R testing as it is not
the current standard of care to routinely conduct
screening tests.
Histopathologic findings of the skin in numerous
studies were also similar to our findings. Busam
et al10 noted infiltrates of T lymphocytes surrounding
the follicular infundibulum occurring in 4 patients
and sparse neutrophilic infiltrate in the terminal
portion of the sweat duct occurring in 2 patients.
Albanell et al3 examined the biopsy results of normal
skin from the patients in their study and observed
focal mononuclear infiltrates in hair follicles and the
Case reports 503
Grade III Grade IV Grade V
Associated with pain, disfigurement, — Death
ulceration, or desquamation
interfollicular epidermis. Thinning of the stratum
corneum was also noted. Comparatively, biopsy
specimens of lesional skin revealed prominent ker-
atin plugs and microorganisms in dilated infundib-
ula. Other specimens showed acute neutrophilic
folliculitis. In a pharmacodynamic study of the
epidermis of cancer patients treated with erlotinib,
biopsy results of normal skin demonstrated thinning
of the stratum corneum and lymphocytic infiltrates in
hair follicles.4 One specimen revealed a prominent
follicular plug and microorganisms in a dilated
infundibulum. The histopathologic findings in these
studies suggest alterations in keratinocyte prolifera-
tion and maturation with subsequent inflammation
as a result of EGF-R inhibition.
We propose this is a unique eruption that is not
acne per se, but ‘‘acneiform.’’ Others have suggested
it to be a ‘‘folliculitis.’’ We believe, however, that the
clinical and histopathologic features of follicular
dysfunction are present and are more reminiscent
of acne and acne-like eruptions to preclude use of
this particular term.
An underlying mechanism linking EGF-RIs to the
presence of acneiform eruption has not been estab-
lished. The cell cycle inhibitor p27 may play an
important role in the pathogenic mechanism of EGF-
RIeinduced eruptions. It has been shown that the
administration of EGF-RIs result in the up-regulation
of p27.3,4,10 p27 is a cell cycle regulator that inhibits
the actions of cyclin-dependent kinase-2 (Cdk2),
preventing progression from G1 to S phase in the cell
cycle.18 Alterations in cell growth and differentiation
as a result of increased expression of p27 may lead
to changes in the stratum corneum of the follicular
infundibulum, thereby resulting in hyperkeratosis,
abnormal desquamation, follicular plugging with
bacterial overgrowth, and the eventual development
of acne-like lesions. To date, no studies have specif-
ically investigated the role of p27 in follicular occlu-
sion diseases. Although Propionibacterium acnes
has not been found in the follicles of patients treated
with EGF-RIs, other microorganisms have been
found in the plugged infundibulum, which may
induce an inflammatory response similar to that of
P acnes. It is also possible that monoclonal antibody
inhibitors themselves may induce an inflammatory
reaction by the activation of neutrophils and
complement through the binding of its Fc domain.10
504 Case reports
Although an exact mechanism has not been found
for the pathogenesis of the acne-like eruptions
induced by EGF-RIs, possible explanations include
the up-regulation of p27 with subsequent hyperker-
atinization, abnormal desquamation, and follicular
plugging; the presence of microorganisms in the
follicular infundibulum; and the possibility of
monoclonal antibody inhibitors directly inducing a
cutaneous inflammatory response.
Treatment options in the current medical litera-
ture concerning acneiform eruptions due to EGF-RI
therapy vary and are limited. In one report, a patient
with rectal adenocarcinoma developed severe and
extensive acne-like lesions after 1 week of cetuximab
treatment. Therapy was started with topical clin-
damycin phosphate solution and triamcinolone
acetonide cream. Since the eruption was so severe,
cetuximab treatment was temporarily withheld. His
eruption improved within 2 weeks and cetuximab
therapy was resumed, resulting in relapse. The
patient’s lesions were controlled to some extent
with the use of topical steroids and anti-inflamma-
tory medication.19 Although triamcinolone cream
was used in this severe case, formal studies should
be conducted before recommending this class of
medications given concerns for the potential additive
adverse effects of steroid acne/rosacea. At this time,
the company and published studies do not support
the routine empirical use of these medications.10
In another report, a patient with adenocarcinoma
of the colon developed an acneiform eruption on
his face after a few days of cetuximab therapy.
Cetuximab treatment was not stopped and 4% col-
loidal sulfur galenic cream was used to control the
lesion outbreak.20
In patients 1 and 2, adapalene 0.1% gel/cream
with the addition of oral and/or topical antibiotics
resulted in significant improvement in lesion counts
and size of individual papules and pustules. The
therapy used in these patients is consistent with the
standard treatment of acne. The goal is to reduce
abnormal desquamation of stratum corneum kerat-
inocytes of the follicular infundibulum and hyper-
keratinization with retinoids and to reduce the
number of microorganisms found in the follicle
with antimicrobial agents.
It is noteworthy that in many cases, as mentioned
previously in this article, this rash has led to the
discontinuation of treatment. This is unfortunate
because those most affected appear to be most
primed for survival. There are therefore two major
concerns for the dermatologist: (1) ensure the patient
remains on the EGF-RI therapy and (2) ensure that
the therapy to treat the eruption does not negatively
affect the EGF-RI therapy. Although topical agents
J AM ACAD DERMATOL
MARCH 2007
and oral antibiotics appear to be the best approach to
start with, it is important to have options beyond
these.
In patient 3, isotretinoin was used successfully to
rapidly control the eruption; thereby assuring that
the patient would remain on EGF-RI therapy. The
ability of isotretinoin to both decrease lipogenesis
and reduce DNA synthesis and thus parakeratosis
likely represents the main mechanism for improve-
ment.21,22 It therefore seems plausible to treat this
EGF-RIeinduced rash with isotretinoin. One major
concern, however, is the impact of retinoic acids on
the EGF signaling pathway, particularly in human
neoplastic cell lines. Although few data exist, there is
a favorable study on the use of retinoic acid on
human endometrial adenocarcinoma cell lines. In
this study, retinoic acid resulted in a decrease in
tyrosine phosphorylation of the EGF-R, thus mim-
icking the EGF-RI mechanism of action. After treat-
ment with retinoic acid, the tumor cells not only
differentiated but also resulted in decreased cell
detachment, both favorable outcomes. The authors
were able to conclude that retinoic acid induced
differentiation in this tumor cell line via interference
with the EGF-R signaling pathway.23 Additionally,
human skin fibroblasts show no change in the EGF-
R number or affinity with use of retinoic acid.24
Based on this reasoning, we attempted the use of
low-dose isotretinoin in our patient with excellent
clinical results. There has been no apparent negative
effect on his tumor progression as he has been in
remission for 6 months. Further studies need to be
conducted, but isotretinoin appears to be a useful
treatment of this acneiform eruption; and given the
theorized mechanisms, it is even possible that these
two drugs may have synergistic potential.
In summary, we report 3 cases of acneiform
eruptions occurring in cancer patients shortly after
initiation of therapy with EGF-RIs. The occurrence of
an acne-like rash in cancer patients who are placed
on these medications is a known adverse effect.
Although the exact pathogenic mechanism of the
cutaneous reaction is unknown, analyses of lesional
and normal skin seem to point to a process similar to
acne. Traditional acne mediations, including isotret-
inoin, appear to be successful in treating these acne-
like lesions; though caution is warranted with the use
of systemic retinoids until further research on EGF-R
signaling pathways in tumors is delineated. An im-
portant concept for the dermatologist to realize is
that this is an expected outcome, and not a drug
reaction necessitating discontinuation. In fact, con-
tinuation of EGF-RI therapy in these patients may
be especially favorable as studies have shown an
increased survival with increasing severity of rash.
J AM ACAD DERMATOL
VOLUME 56, NUMBER 3
This epiphenomenon provides fertile ground for
areas of future investigation, such as the role of
EGF in dermatologic conditions such as rosacea
in which the pathogenic mechanism is not fully
explained.
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