Dermatology Online Journal

Papulopustular drug eruption due to an epidermal growth factor receptor inhibitors, erlotinib and cetuximab
Jennifer Bragg MD, Miriam Keltz Pomeranz MD
Dermatology Online Journal 13 (1): 1

New York University Department of Dermatology

---

Abstract

Two patients receiving epidermal growth factor receptor inhibitors for cancer treatment developed papulopustular eruptions a few days after starting treatment. One patient is a 56-year-old man with metastatic lung cancer treated with erlotinib. Bacterial cultures of the nares and a pustule showed no growth. The eruption improved with a lowered dose of erlotinib and the application of topical clindamycin solution and triamcinolone cream. The other patient is a 53-year-old man with metastatic rectal cancer treated with cetuximab. Bacterial culture of a pustule grew Staphylococcus aureus, and a skin biopsy specimen showed a suppurative folliculitis. The eruption improved with a two-week course of oral antibiotics and the application of topical clindamycin solution and triamcinolone cream. A papulopustular eruption occurs in up to 90% of patients treated with epidermal growth factor receptor blocking agents and may correlate with a positive response to chemotherapy. Treatment options are based on anecdotal evidence and may include topical antibiotics, topical glucocorticoids, and oral antibiotics for secondary infection.

---

Clinical synopses

Patient 1

A 56-year-old man was referred to the dermatology clinic at Bellevue Hospital Center for evaluation and treatment of an acneiform eruption. In July 2004 a diagnosis of adenocarcinoma of the lung with liver metastases was made. He was treated with seven courses of gemcitabine and carboplatin, but because of disease progression, a newer chemotherapeutic agent, erlotinib (Tarceva) was administered. About 1 week after starting erlotinib, he developed a papulopustular eruption on his face, neck, chest, shoulders, and upper back. He denied associated pain or pruritus. The erlotinib was stopped, and clindamycin 1 percent solution was applied twice daily to all lesions and mupirocin ointment twice daily to eroded areas. The eruption improved, so after 2 weeks, erlotinib was started at a lower dose. Several days later, the eruption worsened, and clobetasol 0.05 percent cream applied twice daily was added to his treatment regimen with improvement. He is now maintained on clindamycin 1 percent solution applied twice daily to the face, chest, and back and triamcinolone 0.05 percent cream applied twice daily as needed to chest and back lesions. He continues to take erlotinib on a daily basis.

Numerous, erythematous papules and pustules that coalesced into plaques, some with superficial scale and hemorrhagic crusts, were distributed over the face, neck, chest, shoulders, and upper back. The scalp, arms, and lower body were uninvolved. No comedones were present.

A complete blood count and basic metabolic panel were normal. An alkaline phosphatase was 107 U/L (normal range 25-100), carcinoembryonic antigen level 34.85 ng/ml in June, 2005, and increased to 70.89 ng/ml in September 2005 (normal range = 5). Bacterial cultures from the nares and one pustule on the back showed no growth.

Patient 2

A 53-year-old man was referred to the dermatology clinic at Bellevue Hospital Center for evaluation and treatment of an acneiform eruption. A diagnosis of rectal cancer had been made and treated with local resection in 1997. In 2002 the cancer recurred and subsequently metastasized to the liver and lungs. The disease progressed despite treatment with radiation therapy and numerous chemotherapeutic regimens that included 5-fluorouracil (5-fluorouracil/leucovorin/oxiplatin, and irinotecan). In January 2005 therapy with bevacizumab (Avastin) and cetuximab (Erbitux) was initiated as part of a study. A few days later, he noticed a few scattered, erythematous papules on his face. Several months later he developed a more extensive papulopustular eruption on his face, chest, back, and extremities. He denied associated pain or pruritus. His chemotherapy regimen was continued, and he was treated with application of clindamycin 1 percent solution twice daily to all lesions and of triamcinolone 0.05 percent cream twice daily to the extremities. A two-week course of cephalexin 500 mg orally four times daily was prescribed by his oncologist. The eruption improved with clearing of the lesions on the arms and legs. The patient continues to receive once weekly chemotherapy and applies clindamycin 1 percent solution twice daily to the face, chest, and back, and triamcinolone 0.05 percent cream twice daily as needed to chest and back.

Multiple, erythematous-to-violaceous papules and pustules were scattered over the face, neck, chest, upper back, and proximal portions of the arms and legs. No comedones were present.

A complete blood count, basic metabolic panel, liver function tests, magnesium, phosphate, and lactate dehydrogenase levels were normal except a glucose level of 139 mg/dL (normal range 70-118). Carcinoembryonic antigen and cancer antigen 19-9 were normal. A bacterial culture from one pustule on the back grew Staphylococcus aureus, which was sensitive to all tested antibiotics except penicillin. Histopathology reveals an intracorneal pustule located above a hair follicle. A Gram stain shows a few Gram positive cocci in clusters within the pustules.

Figure 1	Figure 2

Comment

Epidermal growth factor receptor (EGFR) is a member of the tyrosine kinase family, which has been implicated in carcinogenic cellular processes that include angiogenesis, cell proliferation and motility, inhibition of apoptosis, and metastasis [1]. Overexpression of EGFR has been identified in several different tumor types, which include colorectal carcinoma (CRC) and non-small-cell lung cancer (NSCLC).

Several new chemotherapeutic agents that target EGFR have been approved by the Food and Drug Administration for use in CRC and NSCLC. These agents include cetuximab (Erbitux), a chimeric monoclonal antibody, and erlotinib (Tarceva) and gefitinib (Iressa), small-molecule tyrosine kinase inhibitors.

The most common side effect of EGFR inhibitors is a papulopustular eruption, which occurs in up to 90 percent of patients receiving cetuximab [2] and up to 75 percent of those receiving erlotinib [3]. The eruption consists of follicular, erythematous papules and pustules on the face, chest, and upper back. It commonly occurs within the first 2 weeks of treatment and usually persists until treatment is stopped although it may resolve spontaneously. Bacterial cultures are usually negative, but secondary infection should be suspected if the number of pustules increases or if the lesions become painful. Histopathologic findings include a lymphocytic perifolliculitis and suppurative superficial folliculitis [4].

Because the presence and severity of the eruption have been shown to correlate with the clinical response, the eruption may be used as a clinical marker of response to treatment [5]. For example, in one study of 57 patients receiving erlotinib, the eruption was experienced by 100 percent of the seven patients with an objective response, 95 percent of those with stable disease, and only 54 percent of those with progressive disease [3]. In clinical trials the eruption was usually rated as mild-to-moderate, and cessation of therapy was rarely required. It is graded according to the National Cancer Institute's Common Toxicity Criteria [6], which rate rash/desquamation as Grade 1: macular or papular eruption or erythema without associated symptoms; Grade 2: macular or papular eruption or erythema with pruritus or other associated symptoms covering <50 percent of body surface or localized desquamation or other lesions covering <50 percent of body surface area; Grade 3: symptomatic generalized erythroderma or macular, papular, or vesicular eruption or desquamation covering ≥50 percent of body surface area; and Grade 4: generalized exfoliative dermatitis or ulcerative dermatitis. A newer category for acne/acneiform rash has recently been added, with Grade 1 defined as intervention not indicated; Grade 2 as intervention indicated, and Grade 3 as associated with pain, disfigurement, ulcers, or desquamation [7].

The etiology of the skin eruption is unclear. The current theory is that EGFR inhibition results in abnormal epidermal differentiation that leads to follicular obstruction and subsequent inflammation [5]. Although the eruption may appear acneiform clinically, comedones are not present, and the histopathologic features do not resemble acne vulgaris. It has been recommended that the term acneiform be avoided in favor of more descriptive terminology until the etiology has been elucidated [8].

No clinical trials assessing the treatment of the papulopustular eruption have been performed. Possible spontaneous resolution makes interpretation of anecdotal treatment successes difficult to interpret. Treatments include topical and systemic glucocorticoids, topical and systemic antibiotics, retinoids, antihistamines, benzoyl peroxide, and alpha-hydroxy acid.

The members of the HER1/EGFR Inhibitor Rash Management Forum have recommended using high-potency topical glucocorticoids even on the face, analgesia and antihistamines as needed, intranasal mupirocin, topical antibiotics, and possibly a short course of oral antibiotics. They recommend avoiding oral glucocorticoids and potentially irritating acne products, such as retinoids and benzoyl peroxide [7]. Pustules should be cultured if antibiotic resistance is suspected. A reduction of the chemotherapy dose may be useful in severe cases. Further studies of the etiology and treatment of this potentially disfiguring papulopustular eruption are needed.

References

1. Vallbohmer D, et al. Epidermal growth factor receptor as a target for chemotherapy. Clin Colorectal Cancer 2005;5 (Suppl 1):S19

2. Cetuximab prescribing information. New York, NY: ImClone Systems Inc., 2004. http://www.erbitux.com

3. Perez-Soler R, et al. Determinants of tumor response and survival with erlotinib in patients with non-small-cell lung cancer. J Clin Oncol 2004;22:3238

4. Busam KJ, et al. Cutaneous side-effects in cancer patients treated with the antiepidermal growth factor receptor antibody C225. Br J Dermatol 2001;144:1169

5. Perez-Soler R. Can rash associated with HER1/EGFR inhibition be used as a marker of treatment outcome? Oncology 2003;17 (Suppl 12):23

6. National Cancer Institute Common Toxicity Criteria, Version 2.0; March 1998:9; available at http://ctep.cancer.gov/reporting/ctc.html

7. National Cancer Institute Common Toxicity Criteria, Version 3.0; December 2003:15; available at http://ctep.cancer.gov/reporting/ctc.html

8. Perez-Soler R, et al. HER1/EGFR inhibitor-associated rash: future directions for management and investigation outcomes from the HER1/EGFR inhibitor rash management forum. Oncologist 2005;10:345

© 2007 Dermatology Online Journal