Dermatological Side Effects of EGFRIs: Skin, Hair and Nails
Mario Lacouture
Monday, June 14, 2010
Epidermal growth factor receptor inhibitors (EGFRIs) are highly
specific agents that target molecular pathways involved in the
pathogenesis of multiple cancers. They are associated with lower
rates of systemic and hematopoietic toxicity when compared with
conventional cytotoxic chemotherapy but lead to a constellation of
dermatological toxicities in up to 90% of patients.1,2 (Table 1). Therefore, it
is critical that dermatologists become familiar with these agents
and their respective toxicities, in order to adequately evaluate,
manage, and counsel their patients.
Table 1. Dermatological Side
Effects of Epidermal Growth Factor Inhibitors
Drug
|
Rash
|
Mucosal
involvement
|
Hair
abnormalities
|
Paronychia
|
Reference
|
|
All grades
|
Grade 3/4
|
All grades
|
Grade 3/4
|
Trichomegaly
|
Alopecia
|
All grades
|
Grade 3/4
|
|
Cetuximab
(Erbitux®)
|
90%
|
10%
|
11%
|
<1%
|
12%
|
5%
|
14%
|
0.3%
|
(1-2)
|
Panitumumab
(Vectibix®)
|
57%
|
7%
|
6%
|
<1%
|
6%
|
N/A
|
25%
|
2%
|
(3)
|
Erlotinib
(Tarceva®)
|
76%
|
9%
|
19%
|
<1%
|
11%
|
6%
|
14%
|
N/A
|
(2, 4-5)
|
Lapatinib
(Tykerb®)
|
47%
|
3%
|
44.3%
|
0%
|
<1% (hair disorder)
|
1%
|
<1%
|
(6-7)
|
The epidermal growth factor receptor (EGFR/ErbB1/HER1) is a
tyrosine kinase receptor that regulates cell proliferation,
differentiation, migration, survival, and DNA repair.3 The EGFR is primarily
expressed in basal and suprabasal keratinocytes, outer layers of
the hair follicle, and pilosebaceous and eccrine glands.4,5 EGFR inhibitors used
clinically include monoclonal antibodies (mAbs), such as cetuximab
(Erbitux®) and panitumumab
(Vectibix®), and
low-molecular-weight agents, such as gefitinib (Iressa®) and erlotinib (Tarceva®). Lapatinib (Tykerb®) is another small molecule that
has dual activity against tyrosine kinases of ErbB2 (Her2/neu) and
EGFR.
Folliculitis
The majority (~90%) of treated patients will develop pruritic
erythematous follicular papules and pustules on the seborrheic
areas within the first 2 weeks of treatment; however, the eruption
usually improves within 8 weeks of therapy. Most of the eruptions
are mild (Grade 1), but moderate to severe eruptions affect
approximately 60% of patients.6 With lapatinib, the eruption
is less frequent and severe when compared with cetuximab,
erlotinib, and panitumumab.6
As measured by Skindex-16 (a patient-reported quality-of-life
[QoL] questionnaire that investigates the effect of a skin
condition on emotional, functional, and symptomatic aspects),
higher grades of rash result in an overall decreased QoL.7 In addition, a mean cost of
$2715 per patient results from managing these reactions.8 A survey showed that 32% of
oncology providers discontinued therapy, and 76% temporarily
interrupted treatment, because of the rash. Only 8% referred
patients to a dermatologist,9 with some reporting a lack
of confidence that dermatologists would offer an effective
therapeutic intervention. Risk factors for rash development include
being a non-smoker, being elderly (≥70 years),10 and having lower
Fitzpatrick skin phototype.11 The appearance of the rash
in sun-exposed areas, such as the face (82%) and the V-shaped
regions of the chest and back (64%), may also support this
relationship.12 Mainly,
this folliculitis predominates in sebaceous gland-rich areas,
rather than being sun induced.
Histology of the affected skin shows a superficial mixed dermal
infiltrate surrounding hyperkeratotic or ectatic follicular
infundibula or a florid neutrophilic suppurative folliculitis and
ruptured follicles. Apoptotic keratinocytes are present in affected
areas, as well as a thin stratum corneum with loss of its normal
basket-weave configuration, with foci of parakeratosis.13 Comedones are not seen, in
contrast to acne vulgaris.
Grading Systems Used to Assess Rash Severity
The most common grading system used to assess the severity of
dermatologic reactions to cancer drugs is the Common Terminology
Criteria for Adverse Events (CTCAE), the latest version of which
(4.0) was published 2009 (Table 2).14 Accurate grading of
dermatologic toxicities is critical for communication with the
oncologist. Treatment for the rash can be either
pre-emptive/prophylactic or reactive (once it has developed).
Table 2. Common Terminology
Criteria for Adverse Events (CTCAE) Version 4.0. The NCI
CTCAE is a descriptive terminology that can be utilized for Adverse
Event (AE) reporting. A grading (severity) scale is provided for
each adverse event term. Instrumental ADL refer to preparing meals,
shopping for groceries or clothes, using the telephone, managing
money, etc. Self-care ADL refer to bathing, dressing and
undressing, feeding self, using the toilet, taking medications, and
not bedridden. See also:
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.02_2009-09-15_QuickReference_5x7.pdf.
ADL, activities of daily living; IV, intravenous; NSAID,
non-steroidal anti-inflammatory drug; BSA, body surface area.
Skin and subcutaneous tissue
disorders |
|
Grade |
Adverse
events |
1 |
2 |
3 |
4 |
5 |
Dry skin |
Covering <10% BSA and no associated erythema or
pruritus |
Covering 10-30% BSA and associated with erythema or pruritus;
limiting instrumental ADL |
Covering >30% BSA and associated with pruritus; limiting
self-care ADL |
- |
- |
Definition: A disorder
characterized by flaky and dull skin; the pores are generally fine;
the texture is a papery thin texture. |
|
|
Nail discoloration |
Asymptomatic; clinical or diagnostic observations only;
intervention not indicated |
- |
- |
- |
- |
Definition: A disorder
characterized by a change in the color of the nail plate. |
|
Nail loss |
Asymptomatic separation of the nail bed from the nail plate or
nail loss |
Symptomatic separation of the nail bed from the
nail plate or nail loss; limiting instrumental ADL |
- |
- |
- |
Definition: A disorder characterized by loss of all
or a portion of the nail. |
|
Nail ridging |
Asymptomatic; clinical or diagnostic observations only;
intervention not indicated |
- |
- |
- |
- |
Definition: A disorder
characterized by vertical or horizontal ridges on the nails. |
|
Palmar-plantar
erythrodysesthesia syndrome |
Minimal skin changes or dermatitis (e.g. erythema, edema, or
hyperkeratosis) without pain |
Skin changes (e.g. peeling, blisters, bleeding, edema, or
hyperkeratosis) with pain; limiting instrumental ADL |
Severe skin changes (eg, peeling, blisters, bleeding, edema, or
hyperkeratosis) with pain; limiting self-care ADL |
- |
- |
Definition: A disorder characterized by redness,
marked discomfort, swelling, and tingling in the palms of the hands
or the soles of the feet. |
Photosensitivity |
Painless erythema and erythema covering <10% BSA |
Tender erythema covering 10-30% BSA |
Erythema covering >30% BSA and erythema with blistering;
photosensitivity; oral corticosteroid therapy indicated; pain
control indicated (eg, narcotics or NSAIDs) |
Life-threatening consequences; urgent intervention
indicated |
Death |
Definition: A disorder
characterized by an increase in sensitivity of the skin to
light. |
Pruritus |
Mild or localized; topical intervention indicated |
Intense or widespread; intermittent; skin changes from
scratching (eg, edema, papulation, excoriations, lichenification,
oozing/crusts); oral intervention indicated; limiting instrumental
ADL |
Intense or widespread; constant; limiting self-care ADL or
sleep; oral corticosteroid or immunosuppressive therapy
indicated |
- |
- |
Definition: A disorder
characterized by an intense itching sensation. |
Rash acneiform |
Papules and/or pustules covering <10% BSA, which may or may
not be associated with symptoms of pruritus or tenderness |
Papules and/or pustules covering 10-30% BSA, which may or may
not be associated with symptoms of pruritus or tenderness;
associated with psychosocial impact; limiting instrumental ADL |
Papules and/or pustules covering >30% BSA, which may or may
not be associated with symptoms of pruritus or tenderness; limiting
self-care ADL; associated with local superinfection with oral
antibiotics indicated |
Papules and/or pustules covering any % BSA,
which may or may not be associated with symptoms of pruritus or
tenderness and are associated with extensive superinfection with IV
antibiotics indicated; life-threatening
consequences |
Death |
Definition: A disorder
characterized by an eruption of papules and pustules, typically
appearing on the face, scalp, upper chest and back. |
Skin
hyperpigmentation |
Hyperpigmentation covering <10% BSA; no psychosocial
impact |
Hyperpigmentation covering >10% BSA; associated psychosocial
impact |
- |
- |
- |
Definition: A disorder
characterized by darkening of the skin due to excessive melanin
deposition. |
Skin
hypopigmentation |
Hypopigmentation or depigmentation covering <10% BSA; no
psychosocial impact |
Hypopigmentation or depigmentation covering >10% BSA;
associated psychosocial impact |
- |
- |
- |
Definition: A disorder
characterized by loss of skin pigment. |
Alopecia |
Hair loss of up to 50% of normal for that individual that is
not obvious from a distance but only on close inspection; a
different hair style may be required to cover the hair loss but it
does not require a wig or hair piece to camouflage |
Hair loss of >50% normal for that individual that is readily
apparent to others; a wig or hair piece is necessary if the patient
desires to completely camouflage the hair loss; associated with
psychosocial impact |
- |
- |
- |
Definition: A disorder
characterized by a decrease in density of hair compared with normal
for a given individual at a given age and body location. |
Folliculitis Therapy
Topical and oral antibiotics and corticosteroids remain the
mainstay of therapy for eruptions from EGFRIs. Topical retinoids
are not effective and may cause irritation.9,15,16 Recommended treatment
options include a combination of topical corticosteroids and/or
topical antibiotics applied alone or together with oral
antibiotics, depending on the severity of the rash.16 The use of systemic
semi-synthetic antibiotics (doxycycline) for moderate and severe
eruptions, in the absence of a superinfection, is recommended based
partially on their anti-inflammatory properties.16,17 Clinicians should remain
alert for signs of superinfections, which develop in 38% of
patients (most commonly with Staphylococcus aureus).18 The use of intranasal
mupirocin has been recommended to diminish the risk of secondary
infection.16 Dose
modifications to the causal EGFRI are recommended to minimize
severity; however, this limits exposure to life-prolonging
anticancer therapy, which is particularly important because
patients who develop rash appear to derive more antitumor benefit.
Thus, treatment of the rash with concomitant maintenance of EGFRI
therapy is ideal whenever possible.
Xerosis
Xerosis occurs in up to 35% of patients.6 Xerotic dermatitis with
superinfection may develop. Painful fissuring of the distal
fingertips or heels can appear in up to 33% of patients. In
particular, ammonium lactate or salicylic acid for body areas, and
zinc oxide (20-40%) for fissures on the fingertips and heels, are
effective. Cyanoacrylate glue has also been reported to aid in
healing fissures better.19 Areas of xerotic dermatitis
necessitate a 1-2-week course of topical mid-potency
corticosteroids.16 Areas
of secondary infection should be cultured to determine the
appropriate therapy. In cases of significant pruritus where oral
anti-histamines and topical corticosteroids do not provide
sufficient relief, oral gabapentin or pregabalin has been reported
to be effective.17
Hair Changes
Alopecia on the frontal scalp and body hair and enhanced hair
growth on the face are often observed. Non-scarring and scarring
inflammatory alopecia, with an interstitial infiltrate of
lymphocytes, plasma cells, and multinucleate giant cells, has been
reported.20 Trichiasis
can result in corneal ulceration, and such patients should be
referred to an ophthalmologist.2 Hair abnormalities, such as
trichomegaly and hypertrichosis, are seen in 62.5% and 56.0% of
patients, respectively, on long-term EGFRI therapy.6
Periungual and Nail Changes
After 4-8 weeks of EGFRI therapy, paronychia with erythema,
edema and tenderness of the nailfolds has been reported in up to
24% of patients, and painful granuloma-like lesions may form.21 Superinfections can also
occur in the periungual tissue. Histology shows a dermal infiltrate
comprising plasma cells, lymphocytes, and neutrophils. Treatment
consists of topical antibiotics or topical silver nitrate.12 EGFRI therapy may also lead
to onychoschizia and brittle hair.
Conclusions
EGFRIs are a group of anticancer drugs used widely against the
most frequently fatal cancers, such as lung, colorectal, pancreatic
and breast cancers. The majority of patients will experience
dermatological side effects, which may affect QoL and threaten
consistent anticancer drug administration. Effective management of
these untoward events is critical for the maintenance of QoL and to
achieve the best possible clinical outcome. Dermatologists are
uniquely positioned to manage these conditions and improve the
lives of patients. Early evaluation and intervention of such
patients is important in order to ensure that they receive
life-prolonging therapy.
References
1. Mendelsohn J, Baselga J. Status of epidermal growth
factor receptor antagonists in the biology and treatment of
cancer. J Clin
Oncol 2003;21:2787-2799.
2. Lacouture ME, Basti S, Patel J, Benson A. The SERIES
clinic: an interdisciplinary approach to the management of
toxicities of EGFR inhibitors. J Support
Oncol 2006;4:236-238.
3. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling
network. Nat Rev Mol Cell
Biol2001;2:127-137.
4. Nanney LB, Magid M, Stoscheck CM, King LE Jr. Comparison
of epidermal growth factor binding and receptor distribution in
normal human epidermis and epidermal appendages. J Invest
Dermatol 1984;83:385-393.
5. Jost M, Kari C, Rodeck U. The EGF receptor - an essential
regulator of multiple epidermal functions. Eur J
Dermatol 2000;10:505-510.
6. Roe E, Garcia Muret MP, Marcuello E, et al. Description and management
of cutaneous side effects during cetuximab or erlotinib treatments:
a prospective study of 30 patients. J Am Acad
Dermatol 2006;55:429-437.
7. Wagner L, Lai SE, Aneja M, et al. Development of a functional
assessment of side-effects to therapy (FAST) questionnaire to
assess dermatology-related quality of life in patients treated with
EGFR inhibitors (EGFRI): The FAST-EGFRI. J Clin
Oncology 2007;(Suppl):Abstract 19532.
8. Abraham T, Rademaker A, Ortiz S, et al. Economic impact associated
with the management of dermatologic adverse drug reactions (dADRs)
induced by EGFR inhibitors (EGFRIs) in lung cancer. J Clin
Oncol 2008;26 (Suppl):Abstract 19094.
9. Boone SL, Rademaker A, Liu D, et al. Impact and management of
skin toxicity associated with anti-epidermal growth factor receptor
therapy: survey results. Oncology 2007;72:152-159.
10. Jatoi A, Green EM, Rowland KM Jr, Sargent DJ, Alberts
SR. Clinical predictors of severe cetuximab-induced rash:
observations from 933 patients enrolled in north central cancer
treatment group study N0147. Oncology 2009;77:120-123.
11. Lai SE, Minnelly L, O'Keeffe P, et al. Influence of skin color in
the development of erlotinib-induced rash: a report from the SERIES
clinic. J Clin
Oncology 2007 (ASCO Annual Meeting Proceedings Part I
Vol 25, No 18S) (Suppl):9127.
12. Luu M, Lai SE, Patel J, Guitart J, Lacouture ME.
Photosensitive rash due to the epidermal growth factor receptor
inhibitor erlotinib. Photodermatol Photoimmunol
Photomed 2007;23:42-45.
13. Busam KJ, Capodieci P, Motzer R, et al. Cutaneous side-effects in
cancer patients treated with the antiepidermal growth factor
receptor antibody C225. Br J
Dermatol 2001;144:1169-1176.
14. Common Terminology Criteria for Adverse Events (CTCAE)
Version 4.0. Available from:
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.02_2009-09-15_QuickReference_5x7.pdf
[Accessed 8 April 2010].
15. Scope A, Agero AL, Dusza SW, et al. Randomized double-blind
trial of prophylactic oral minocycline and topical tazarotene for
cetuximab-associated acne-like eruption. J Clin
Oncol2007;25:5390-5396.
16. Lynch TJ Jr, Kim ES, Eaby B, et al. Epidermal growth factor
receptor inhibitor-associated cutaneous toxicities: an evolving
paradigm in clinical management. Oncologist 2007;12:610-621.
17. Lacouture ME. Mechanisms of cutaneous toxicities to EGFR
inhibitors. Nat Rev
Cancer2006;6:803-812.
18. Eilers RE Jr, Gandhi M, Patel JD, et al. Dermatologic infections in
cancer patients treated with epidermal growth factor receptor
inhibitor therapy. J Natl
Cancer Inst 2010;102:47-53.
19. Lacouture ME, Maitland ML, Segaert S, et al. A proposed EGFR inhibitor
dermatologic adverse event-specific grading scale from the MASCC
skin toxicity study group. Support Care Cancer
2010;18:509-522.
20. Graves JE, Jones BF, Lind AC, Heffernan MP. Nonscarring
inflammatory alopecia associated with the epidermal growth factor
receptor inhibitor gefitinib. J
Am Acad Dermatol 2006;55:349-353.
21. Fox LP. Nail toxicity associated with epidermal growth
factor receptor inhibitor therapy. J Am Acad
Dermatol 2007;56:460-465.
Back