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Cutaneous Side Effects Associated With Targeted Therapy

 

Background

Skin rash associated with HER1/EGFR therapy is generally considered mild to moderate in nature 1,2 affecting more than 50% of patients receiving treatment. The incidence of severe rash (grade 3) is reported up to 16% to18% of patients.2,3 The cutaneous eruptions appear primarily on the face, neck, and upper torso, as seen in Figure 1

  • The rash is characterized by interfollicular and follicular-based erythematous papules and pustules and is seen during the first 2 weeks of therapy.1,2
  • The follicular skin lesions are without microcomedones and comedones characteristic of acne, thus indicating that this rash in not acne vulgaris.1,2,4
  • The rash tends to wax and wane during therapy, with “flare ups” occasionally noted following infusions.3,5
  • Rash symptoms typically resolve without scarring within 1 to 2 months of stopping treatment.3
  • Several studies have demonstrated a positive correlation between rash and tumor response and/or survival with cetuximab and erlotinib; findings are less consistent with gefitinib.1-3
  • Grading of skin toxicity is based on the National Cancer Institute Common Toxicity Criteria (NCI-CTC), version 3.0 (Table 1)
Figure1

Management of the Rash

There are no established evidence-based guidelines or published controlled clinical trials on the treatment of rash symptoms associated with HER1/EGFR inhibitors, with many of the interventions based on anecdotal reports.1,2,5 Dermatologic consultation is advisable in uncontrolled or severe cases.

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Patient Care Management Protocols for Managing Skin Rash

  • Dermatologist-approved cover up such as Dermablend or any cover-up may be useful; make up removal with a hypoallergenic gentle liquid cleanser (Neutrogena, Dove, or Ivory Skin Cleansing Liquid Gel 1
  • Suggested emollients (Neutrogena Norwegian Formula Hand Cream or Vaseline Intensive Care Advanced Healing Lotion to prevent skin dryness 1
  • Medications that are used to treat acne vulgaris, such as benzoyl peroxide and topical retinoids; should not be used to avoid excessive dryness and aggravation of rash 1,3
  • The benefits of topical corticosteroids is unclear; however, they may have some efficacy when used to treat mild rashes.1-3 Recent evidence shows that the efficacy of topical corticosteroid use on the face is overstated (Figure 2)
  • Sun exposure should be limited; patients are advised to wear a hat; sun barriers are recommended to reduce risk of hyperpigmentation 1,3,4 (Figure 3)
  • Pruritus associated with rash may be treated with an oral antihistamine such as diphenhydramine (Benadryl) or hydroxyzine hydrochloride (Atarax) 1,2
  • Infected skin rash can be treated with a short course of oral antibiotics such as tetracyclines because of their effectiveness against Staphylococcus 1,2,6 (Figure 4)
Figure 2
Figure 2

Other Cutaneous Toxicities

There are other cutaneous toxicities associated with HER1/EGFR targeted therapy. These include nail bed toxicity (paronychia), hair alterations, xerosis, telangiectasia, nasal mucositis and ocular irritation.1,2,4

Paronychia2,4,7

  • Described as painful inflammation of tissue around fingernails and toenails; more commonly seen in the big toe and thumbs observed in 12% to16% of patients (Figure 5)
  • Often delayed, developing after 4 to 8 weeks of treatment
  • May be prevented by wearing shoes that are not too tight; avoid friction; hot soaks and cushioning provide comfort; Epsom salt soaks help promote drainage; use of topical antiseptic or antibiotic ointments may help

Hair alterations2,4

  • Hair changes may occur 2 to 3 months after initiation of therapy, with hair thinning and developing dry, brittle, or curly texture
  • Trichomegaly can occur, although rare (increased hair growth of the eyelashes and eyebrows (Figure 6)
  • Waxing or electrolysis may be recommended

Xerosis and related changes, skin fissures2,4

  • Xerosis, (abnormally dry skin) is a common side effect of HER1/EGFR targeted therapy
  • Painful fissures may develop on the fingers and toes, in the nail folds, and over the interphalangeal joints (Figure 7)
  • Hydration of the skin with the use of bath oil or shower oil may help alleviate symptoms. Gels and soap should be avoided, because they may exacerbate dryness; dryness can be alleviated by using emollient creams
  • Liquid Band Aid may be helpful in protecting fissures

Telangiectasia4

  • Defined as chronic dilation of groups of capillaries leading to elevated dark red blotches on the skin (Figure 8)
  • May be seen in early onset of rash symptoms, appearing on the face, nose, chest, back and limbs around a follicular pustule
  • Tend to fade in time, leaving some hyperpigmentation

Nasal Mucositis

  • Sores and irritation may develop inside the nostrils, which may become uncomfortable
  • Bactroban Nasal can be applied to help prevent secondary infection1

Ocular Irritation7

  • Manifests as dry eyes, progressing to erythematous lids and crusting in the eyelash follicles; looks like blepharitis or conjunctivitis
  • Rare, but if it occurs, it is usually within the first the first 4 weeks of therapy
  • Treatment may consist of ophthalmic antibiotic ointment, warm soaks, natural tears
figure3

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Table 1 Assessment Tools

The different scales and description of the rash make it difficult to compare the severity of the rash.8 The following table is commonly used to grade adverse events associated with skin and toxicity.

The National Cancer Institute Common Toxicity Criteria, version 3.0

figure4

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References

  1. Perez-Soler R, Delord J, Halpern A, et al. HER1/EGFR inhibitor-associated rash: future directions for management and investigation outcomes from the management forum. Oncologist. 2005;10:345-356
  2. Dick S, Crawford G. Managing cutaneous side effects of epidermal growth factor receptor (HER1/EGFR) inhibitors. Community Oncol. 2005;2:492-496.
  3. Sipples R, Common side effects of anti-EGFR therapy: acneiform rash. Semin Oncol Nurs. 2006;22:28-34.
  4. Segaert S, Van Cutsem E. Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor inhibitors. Ann Oncol. 2005;16: 415-1433.
  5. Fish-Steagall A, Searcy P, Sipples R. Clinical experience with anti-EGFR therapy. Semin Oncol Nurs. 2006;22(1 suppl 1):10-19.
  6. Lacouture M, 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.
  7. Morse L, Calarese P. EGFR-targeted therapy and related skin toxicity. Semin Oncol Nurs. 2006;22:152-162.
  8. National Cancer Institute common terminology criteria for adverse events v3.0. Available at: http://ctep.cancer.gov/forms/CTCAEv3.pdf page 14. Accessed February 22, 2007.

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Key Definitions

benzoyl peroxide — bleaching agent commonly used to treat acne

blepharitis — inflammation of the eyelid

comedones — bumpy skin, commonly known as blackheads

HER1/EGFR therapy — human epidermal growth factor receptor or HER family include HER1/EGFR. Agents that target HER1/EGFR are two types: tyrosine-kinase inhibitors (TKI) and monoclonal antibodies (mAb). When activated EGFR leads to cell proliferation, inhibits cells death, enhances angiogenesis and triggers metastasis. Rash is the common side effect of HER1/EGFR inhibitors.

interfollicular — between follicles

microcomedones — follicular casts

topical retinoids — vitamin A derivatives

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This page was last modified on 10/17/2007, at 9:30:53 am ET.