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On-line version ISSN 1806-4841
An. Bras. Dermatol. vol.84 no.6 Rio de Janeiro Nov./Dec. 2009
Cutaneous reactions due to the use of epidermal growth factor receptor inhibitors: two case reports*
Camila Martins RodarteI; Omar Ali AbdallahII; Nadyesda Fagundes BarbosaIII; Ludmila de Oliveira KochIV; Uirá Maira ResendeV
IResident Physician, General Practice,
Hospital Geral de Goiânia Goiânia (GO), Brazil
IIHead Physician, Service of Oncology, Hospital Geral de Goiânia Goiânia (GO), Brazil
IIIResident Physician, General Practice, Hospital Geral de Goiânia Goiânia (GO), Brazil
IVResident Physician, Department of Oncology, Hospital Federal de São Paulo Escola Paulista de Medicina (EPM) São Paulo (SP), Brazil
VOncologist, Centro de Oncologia do Instituto de Hemoterapia de Goiânia (IHG) Goiânia (GO), Brazil
An increase in the expression of epidermal growth factor receptors (EGFR) is
involved in the stimulation of tumor development. EGFR inhibitors have shown
efficacy in the treatment of neoplasms of the head, neck, colon and lung. EGFR
when inhibited can cause cutaneous reactions in more than 50% of the patients.
They are usually reversible, but when severe, limit the use of the drug. Papulopustulars
lesions in the face and upper torso are the most common, as well as xerosis,
hair and nail changes. There is a direct relationship between the degree of
cutaneous toxicity and the antitumoral response. An adequate dermatologic approach
is necessary for an effective therapy against cancer.
An increase in the expression of epidermal growth factor receptors (EGFR) is involved in the stimulation of tumor development. EGFR inhibitors have shown efficacy in the treatment of neoplasms of the head, neck, colon and lung. EGFR when inhibited can cause cutaneous reactions in more than 50% of the patients. They are usually reversible, but when severe, limit the use of the drug. Papulopustulars lesions in the face and upper torso are the most common, as well as xerosis, hair and nail changes. There is a direct relationship between the degree of cutaneous toxicity and the antitumoral response. An adequate dermatologic approach is necessary for an effective therapy against cancer.
Keywords: antibodies, monoclonal; acneiform eruptions; receptor, epidermal growth factor
Many neoplasms present overexpression of epidermal growth factor receptor (EGFR), which is involved in the stimulation of tumor growth and resistance to chemotherapy and radiotherapy treatment. Inhibitors of these receptors, or anti-EGFR, have proven to be effective in clinical trials of head, neck, colon and lung cancer and have gained more and more attention in oncology 1,2. However, skin reactions especially acneiform, occur in more than 50% of these patients who take anti-EGFR 3, and in many situations they are severe and need dose reduction or even interruption of use. Appropriate dermatological approach is essential to satisfactorily carry on with cancer management.
CASE 1: Female 47 year-old patient with diagnosis of metastatic colon neoplasm, presented progression of the disease after first line chemotherapy treatment. She started using cetuximab, anti-EGFR monoclonal antibody, and presented severe skin reactions on the face, acneiform pattern, treated with topical antibiotic (clindamycin 1% gel) and moisturizing agent (Figure 1), without reduction of medication dose. She progressed with partial improvement of the presentation and was treated with five doses of the medication, presenting fluctuation of the skin manifestations.
CASE 2: Female 85-year-old patient with diagnosis of locally advanced lung neoplasm (adenocarcinoma). She started her treatment with erlotinib, oral medication with EGFR tyrosine-kinase inhibition. After the third month, she showed pustulous and ulcerated lesions on her lower limbs (Figure 2) and ungual lesions, compatible with paronychia (Figure 3). She was treated with oral antibiotics (doxycycline 100 mg twice a day for seven days) and topical antibiotics (clindamycin 1% gel), showing lesion improvement. Erlotinib was discontinued for other reasons and there were no recurring lesions.
EGFR is a transmembrane glucoprotein normally expressed in different human tissues and it is involved in the control of cell growth and proliferation 2. Many neoplasms have their expression deregulated and enhanced by EGFR, leading to proliferation, migration and adhesion of tumor cells, in addition to the stimulus to angiogenesis and inhibition of apoptosis. Such abnormalities are observed primarily in head and neck, colon and lung neoplasms and are related with disease progression, higher likelihood of metastases, reduction of survival and poor response to chemotherapy and radiotherapy 1,2. Inhibition of these receptors with specific agents such as cetuximab (monoclonal antibody against extracellular domain of the receptor) and erlotinib (molecule that inhibits EGFR tyrosine-kinase) has shown efficacy in the treatment of these neoplasms 1,2,4,5.
EGFR is normally present in keratinocytes, sebaceous glands and hair follicles, and if inhibited, it modifies the proliferation, differentiation and migration of keratinocytes, resulting in frequent skin reactions 6. Papulopustular eruptions (acneiform reaction or rash) on the face and trunk, without the presence of comedones, are the most frequently observed ones and seem to be a different pathology from that of acne. They frequently are developed in the following stages: erythema and edema (week 0-1), papulopustular eruption (week 1-3), crust formation (week 3-5), progressing with erythema and telangiectasias (week 5-8)7.
Xerosis followed by pruritus is frequent, especially on the upper and lower limbs and in areas affected by acneiform rash, which may progress to secondary lesions. There might also be ungual abnormalities, such as paronychia and pyogenic granuloma, hair affections, such as alopecia, eyebrow trichomegaly, facial hypertrichosis, in addition to telangectasias. In general, such abnormalities start on week one to three of treatment 8,9. Lesions tend to be reversible and regress without sequels, but if severe, they may become intolerable and require dose reduction or drug suspension, which interfere in cancer treatment 10.
There is concrete evidence that the higher the intensity of the cutaneous toxicity, the better the antitumor response and the longer the survival 10,1. Patients who have absence of gene K-ras mutation 11 seem to present better response to anti-EGFR.
The treatment of reactions has not been fully determined yet, and different centers vary in their approach, depending on the severity of the lesions 2. It is recommended to apply sun protection and skin hydration with moisturizers in all patients and the prescription of anti-histaminic drugs, in case of pruritus. In mild cases, topical medications such as hydrocortisone 1% or clindamycin 1% are used twice a day. In moderate cases, hydrocortisone 1%, clindamycin 1% or tracolimus / pimecrolimus associated with oral antibiotic therapy (doxycycline 100 mg twice a day). In severe cases, in addition to previous medications, it is indicated to have a dose of methylprednisolone and reduction of dose or therapy suspension with anti-EGFR 1.
Anti-EGFR comprise new drugs and their use has gained more attention in oncology. However, frequent skin manifestations, even though related with better antitumor response, may limit their appropriate use. More studies are required to ensure a more directed approach to skin toxicity, considering to what extend it may interfere in patients' quality of life and in his or her decision to continue antitumor therapy.
1. Lynch TJ Jr, Kim ES, Eaby B, Garey J, West DP, Lacouture ME. Epidermal growth factor receptor inhibitor - associated cutaneous toxicities: an evolving paradigm in clinical management. Oncologist. 2007;12:610-21. [ Links ]
2. Lacouture ME, Melosky BL. Cutaneous reactions to anticancer agents targeting the epidermal growth factor receptor: a dermatology-Oncology perspective. Skin Therapy Lett. 2007;12. [Available from: http://www.skintherapyletter.com/2007/12.6/1.html] [ Links ]
3. Agero AL, Dusza SW, Benvenuto-Andrade C, Busam KJ, Myskowski P, Halpern AC. Dermatologic side effects associated with the epidermal growth factor receptor inhibitors. J Am Acad Dermatol. 2006;55:657-70. [ Links ]
4. Jonker DJ, O'Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007;357:2040-8. [ Links ]
5. Krause DS, Van Etten RA. Tyrosines kinases as targets for cancer therapy. N Engl J Med. 2005;353:172-87. [ Links ]
6. Fox LP. Pathology and management of dermatologic toxicities associated with anti-EGFR therapy. Oncology (Williston Park).. 2006;20(Suppl 2):26-34. [ Links ]
7. Lacouture ME, Lai SE. The PRIDE (Papulopustules and/or paronychia, Regulatory abnormalities of hair growth, Itching, and Dryness due to epidermal growth factor receptor inhibitors) syndrome. Br J Dermatol. 2006;155:852-4. [ Links ]
8. Busam KJ, Capodieci P, Motzer R, Kiehn T, Phelan D, Halpern AC. Cutaneous side-effects in cancer patients treated with antiepidermal growth factor receptor antibody C225. Br J Dermatol. 2001;144:1169-76. [ Links ]
9. Payne AS, James WD, Weiss RB. Dermatologic toxicity of chemotherapeutic agents. Semin Oncol. 2006;33:86-97. [ Links ]
10. Segaert S, Tabernero J, Chosidow O, Dirschka T, Elsner J, Mancini L et al. The management of skin reactions in cancer patients receiving epidermal growth factor receptor targeted therapies. J Dtsch Dermatol Ges. 2005;3:599-606. [ Links ]
11. Eng C. K-ras and sensitivity to EGFR inhibitors in metastatic colorectal cancer. Clin Adv Hematol Oncol. 2008;6:174-5. [ Links ]
Mailing Address: Study awarded as Best Case Report Poster at the
Brazilian Congress of Dermatology in 2008. * Study carried
out at the Department of Oncology, Hospital Geral de Goiânia - Goiânia
Camila Martins Rodarte
Rua T-60, nº 186 Setor Bueno
74223 160 Goiânia GO
Conflict of interest: None
Study awarded as Best Case Report Poster at the
Brazilian Congress of Dermatology in 2008.
* Study carried out at the Department of Oncology, Hospital Geral de Goiânia - Goiânia (GO), Brazil.