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Clinical Updates

Mario E Lacouture, MD

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.

 

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