Cutaneous and Ocular Toxicology, 2009; 28(1): 41–44

C a s e s t u dy

Severe cutaneous reaction to cetuximab with possible association with the use of over-the-counter skin care products in a patient with oropharyngeal cancer

Waris Waris1, Seeta Naik1, Imran Idrees1, Hesham Taha1, Linda Camosino1, Anshu Mehrishi1, and Muhammad Wasif Saif2

1Nassau County University Hospital, East Meadow, New York, USA, and 2Yale University School of Medicine, New Haven, Connecticut, USA

Address for Correspondence: M. Wasif Saif, M.D., Associate Professor, Yale University School of Medicine, Section of Medical Oncology, 333 Cedar Street, FMP 116, New Haven, CT 06520. Tel.: 203-737-1875; Fax: 203-785-3788; E-mail: wasif.saif@yale.edu

(Received 25 November 2008)

Introduction

Cisplatin-based chemotherapy is most commonly used with radiation therapy in head and neck cancers. Cisplatin is associated with myelosuppression, neuro-toxicity, ototoxicity, nephrotoxicity, and severe nausea and vomiting. Agents that target the epidermal growth factor receptor (EGFR) are least associated with these systemic side effects. Therefore, epidermal growth fac-tor receptor inhibitors (EGFRIs) have emerged as the

most robust therapy in various malignancies as an ini-tial or metastatic regimen (1,7). Currently, cetuximab is commonly used concurrently with radiation in head and neck cancer (1). However, inhibition of receptor activity in the skin and other tissues that depends on EGFR signaling for normal function causes undesir-able consequences (2,3). The most common side effects of cetuximab are dermatologic, including an acne-like rash, xerosis (dry skin), and fissures of the skin. Although some degree of acneiform rash

ISSN 1556-9527 print/ISSN 1556-9535 online © 2009 Informa UK LtdDOI: 10.1080/15569520802646552

abstractBackground: The management of locally advanced head and neck cancer remains a challenge to most oncologists and their patients. Treatment with epithelial growth factor receptor inhibitors (EGFRIs) is associated with a good response. Cetuximab, a chimeric monoclonal antibody directed against epithe-lial growth factor receptor (EGFR), in combination with radiation therapy is indicated for the treatment of locally advanced squamous cell carcinoma of the head and neck. Although a mild acneiform skin rash (Grade 1, 2) is very common in these patients, severe rash (Grade 3) is uncommon.Case report: A 61-year-old African American man with locally advanced oropharyngeal cancer was treated with cetuximab and radiation. He developed a sudden flare-up of a skin rash after the 5th cycle of cetuximab following use of over-the-counter (OTC) skin care remedies. The rash manifested with severe maculopapular eruption and erythematous rash, along with desquamation and exfoliation of the skin, mainly on the face and neck area. The patient denied any extraordinary sun exposure. Cetuximab and radiation therapy were held for 1 week and the rash was treated with doxycycline, diphenhydramine, and continued use of natural emollient (Vaseline petroleum jelly). After 1 week, a dramatic improvement of the facial rash was noticed. Discussion: Our report describes a sudden flare-up of a skin rash (Grade 3) after the 5th cycle of cetuximab following use of OTC skin care remedies, which was unusual for this patient, suggesting a possible relation to the therapy. Skin crucially depends on EGFR for its normal function and becomes extremely sensitive during cetuximab therapy. Topical OTC acne and dry skin remedies can suddenly change the mild acnei-form rash into severe skin toxicity associated with marked desquamation and exfoliation. Avoidance of fur-ther skin damage caused by topical applications and the use of doxycycline and diphenhydramine show a significant success in the management of skin toxicity.

Keywords: epidermal growth factor receptor (EGFR); colorectal cancer (CRC); cetuximab (Erbitux); panitumumab (Vectibix); gefitinib (Iressa); erlotinib (Tarceva); rash

http://www.informapharmascience.com/cot

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occurs in most patients, severe eruptions resulting in significant pain or infectious sequelae are less com-mon. Interestingly, the presence and severity of the cetuximab-induced rash, but not the degree of EGFR expression on the surface of tumor cells, appear to cor-relate with the likelihood of response. During the treat-ment period skin is extremely sensitive, and use of any over-the-counter lotion or face wash can cause severe exacerbation, leading to debilitating skin toxicity. Not only do physicians need an improved understanding of EGFRI-related toxicities, but also our patients need better education not to use over-the-counter remedies without consultation with their physicians.

Case report

A 61-year-old African American man with a history of recently diagnosed, locally advanced oropharyngeal cancer was referred to our medical oncology clinic for further management. The patient’s relevant history went back to 4 months earlier, when he started having swelling of the left ear and left side of the neck. After approximately 2½ months he saw an ear, nose, and throat (ENT) surgeon, who sent him to get a computed tomography (CT) scan of the soft tissue of the neck. The CT scan showed a large heterogeneous posterior oropharyngeal mass, with maximum dimensions of approximately 6.4 × 5.7 × 2.5 cm. Bilateral shotty lym-phadenopathy was also seen. The biopsy showed a well-differentiated squamous cell carcinoma.

In the meantime the patient was evaluated by the radiation oncologist, and a G-tube was placed by a surgeon. The patient had very poor oral hygiene, and his teeth were removed by an oral surgeon before radiation therapy. In a multidisciplinary discus-sion, we decided to treat the patient with cetuximab and radiation. First, he was given his first dose of cetuximab 400 mg/m2 intravenously over 120 minutes, 1 week prior to radiation therapy. He was premedicated with 50 mg of diphenhydramine, and no infusion reac-tion was observed. Next, he received 4 more cycles of cetuximab 250 mg/m2 weekly with radiation. The plan was to continue the weekly cetuximab administration for the duration of radiation therapy.

After the second cycle, the patient developed a mild acneiform rash on the face (Grade 1), involving the nose and cheeks. After careful consideration, we decided to continue the weekly cetuximab without any dose modification. We did not notice any change in the rash until we finished the 5th cycle. When the patient came for the 6th cycle, we observed a severe maculopapular eruption and erythematous rash, along with desquamation and exfoliation of the skin (Grade 3) (Figures 1 and 2), mainly on the face and

neck area. He also had an acneiform rash in the front and back of the chest and abdomen. He complained of burning pain with pruritus. This kind of sudden eruption was unusual. He denied any extraordinary sun exposure. On further questioning, he told us that he had tried to treat the acne and mild itching with OTC Eucerin lotion and Aveeno oatmeal face wash. In addition, he used OTC 1% hydrocortisone cream for only 1 day. He then discontinued the use

Figure 1. Rash on the patient’s face after treatment with cetuxi-mab for head and neck cancer.

Figure 2. Marked desquamation and exfoliation in the area where local skin care remedies were used.

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Exacerbation of cetuximab rash with OTC products 43

of local steroids because the burning worsened, and he started using natural emollient (Vaseline petro-leum jelly), which gave him some comfort. He also washed his face excessively with OTC bar soaps. The rash got worse within 2 to 3 days. Interestingly, areas of the skin where local skin care remedies were used showed significant desquamation (Figure 2).

We decided to hold the cetuximab and radiation therapy for 1 week. We also gave the patient doxycy-cline 100 mg orally daily, along with diphenhydramine (Benadryl) 25 mg every 8 hours. We did not discontinue local application of Vaseline. We advised the patient not to wash his face excessively, especially with soaps. When he came for a follow-up examination after 1 week, we observed a tremendous improvement of the facial rash (Figure 3). He also had significant improve-ment in the itching and was feeling comfortable.

Discussion

EGFRIs in general, and cetuximab in particular, are gaining popularity because of less systemic toxicities, improved survival, and better quality of life in can-cer patients. Cetuximab is used in the management of colorectal, head and neck, pancreatic, and lung cancers. Therefore, the importance of a better under-standing of the mechanism of EGFRI-related skin toxicities and their management is crucial (2,3,8). Cetuximab is a recombinant human/mouse chimeric monoclonal antibody that binds specifically to the EGFR and competitively inhibits the binding of the epidermal growth factor and other ligands. Binding

to the EGFR blocks phosphorylation and activation of receptor-associated kinases, resulting in cell growth arrest and apoptosis. This binding also results in decreased production of vascular endothelial growth factor and matrix metalloproteinase (3,6,10,19).

Currently, there are no established guidelines to prevent and manage the skin toxicities caused by EGFR inhibitors. Controlled trials are lacking, and there is no uniform agreement on the most appropriate manage-ment. On the other hand, use of EGFR inhibitors is increasing not only in head and neck cancer, but also in colon and lung cancers (1,3–5,13). Topical agents must be used with extreme caution in patients being treated with EGFRIs. The skin of these patients is abnormally sensitive to irritants and allergens. Inhibition of EGFR can result in abnormal proliferation, migration, and differentiation of target cells and leads to the disrup-tion of the integrity of the skin with the recruitment of inflammatory cells (12,19,20). Significant clinical and experimental data indicate (3,11,15) that inflammation has a vital role in the skin reactions caused by EGFRIs. Epithelial cells that were exposed to EGFRIs showed an increase in the synthesis of MCP1 and other cytokines.

Studies have shown that the severity of skin toxicity is significantly associated with a response to cetuxi-mab and survival, with a higher overall response rate and a longer overall survival time for patients with grade 2 to 3 skin toxicity versus those with grade 0 to 1 skin toxicity (14,16,17,18). However, at the same time, the timing of the appearance of this skin rash dur-ing treatment with EGFR inhibitors is crucial. The patient should always be monitored closely during a treatment period, and a skin examination should be a compulsory part of every visit. Most importantly, physicians should be aware of the use of any OTC skin care product during the treatment period. Patients must be advised not to use any OTC skin care products, including but not limited to topical steroids, face wash lotions, and other skin care remedies to treat acne. On the other hand, left untreated, these dermatologic side effects could represent a threat to patient compliance and can cause a significant physical and psychosocial discomfort to already-suffering patients. Therefore, effective management is mandatory. It is still unclear how to treat mild cases of acneiform eruption. In some case reports, it is suggested that topical anti-inflam-matory therapy may be beneficial. Early interventions should include the avoidance of ultraviolet-radiation-induced injury. It is also suggested (3, 5, 9), and was definitely observed in our patient, that pruritus can be treated with oral diphenhydramine, and skin can be protected further with bland emollients.

In the literature, most reports suggest (3,5,9,11,15) that oral corticosteroids and tetracycline and its sem-isynthetic analogues doxycycline and minocycline

Figure 3. Significant improvement of the skin rash after treat-ment with doxycycline and diphenhydramine.

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can be used effectively. Our patient had a history of type 2 diabetes mellitus; therefore, we decided not to use oral corticosteroids.

As mentioned above, we treated our patient with doxycycline 100 mg orally daily, along with diphenhy-dramine 25 mg every 8 hours for 7 days. The beneficial effects of tetracyclines can be attributed to their anti-inflammatory activity.

Skin diseases in blacks can differ because of pig-ment lability, fibroblastic activity, and follicular pre-dominance (21,22). Such differences must be borne in mind, and whether such severe reactions occur more commonly in people of color versus whites also needs to be investigated to define the risk and to determine if it is necessary to take action earlier to prevent severe toxicity as well as to continue effective therapy.

On the basis of our experience, we recommend upfront discussion with the patient being treated with EGFRIs, advising him or her not to use any skin care product without consulting the medical oncologist. A skin biopsy and a culture should be performed to rule out phototoxic drug eruption and any bacte-rial infection, respectively. We also suggest that a patient who has Grade 3 toxicity can be managed comfortably as an outpatient with oral doxycycline and diphenhydramine with or without oral steroids and topical antibiotics. The skin should be protected from sunlight and can be covered with natural/bland emollients for soothing effect and protection.

Acknowledgements

Declaration of interest: The authors report no con-flict of interest.

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