View metadata, citation and similar papers at core.ac.uk brought to you by CORE Acta Dermatovenerol Croat 2007;15(4):246-248 CASE REPORT Acneiform Eruption Induced by Cetuximab Claudia Cotena, Paolo Gisondi, Chiara Colato1, Giampiero Girolomoni Department of Biomedical and Surgical Science, Section of Dermatology and Venereology, University of Verona; 1Department of Pathology, Azienda Ospedaliera of Verona, Verona, Italy Corresponding author: SUMMARY Cetuximab is a recombinant human/mouse chimeric Paolo Gisondi, MD monoclonal antibody that targets the extracellular domain of the epidermal growth factor receptor (EGFR). Cetuximab is approved Department of Biomedical and Surgical Science by the US Food and Drug Administration for the treatment of Section of Dermatology and Venereology EGFR-expressing metastatic colorectal cancer as monotherapy University of Verona in patients who are intolerant to irinotecan-based chemotherapy, or in combination with irinotecan in patients who are refractory to Verona irinotecan-based chemotherapy. Due to the important role of the Italy EGFR in skin homeostasis, cutaneous reactions are a common [email protected] adverse effect of cetuximab, mainly as acneiform follicular eruption seen in almost 85% of patients. We report on a 46-year-old female Caucasian patient with metastatic colorectal cancer, referred to Received: July 5, 2007 our department for acneiform eruption induced by cetuximab Accepted: October 9, 2007 in combination with irinotecan. Four days after the first infusion the patient developed intense acneiform eruption consisting of erythematous follicular papules and pustules spread to the face, neck and upper part of the trunk, accompanied by intense pruritus and fever (38.0 °C). There were no comedones. Biopsy specimen revealed superficial and florid neutrophilic suppurative folliculitis. She was treated with erythromycin tablet 600 mg, three times a day for 1 month, and topical clindamycin solution 3%. After 1 month of treatment, the lesions consistently faded, and the patient continued receiving immunochemotherapy. KEY WORDS: cetuximab, acneiforn eruption, treatment INTRODUCTION Novel biologically targeted therapies that in- migration, adhesion, differentiation and survival. terfere with specific molecular pathways affecting The EGFR is constitutively expressed in many cancer evolution have been developed as poten- normal epithelial tissues, including skin and hair tial treatment options for patients refractory or follicle. Aberrant signaling through the EGFR is intolerant to conventional chemotherapy (1). The associated with neoplastic cell proliferation, mi- epidermal growth factor receptor (EGFR), also gration, stromal invasion, resistance to apoptosis called HER-1, is a transmembrane glycoprotein and angiogenesis. EGFR is expressed by 30% to that binds specific ligands, epidermal growth fac- 100% of solid tumors (2). Some tumor cells that tor (EGF) and transforming growth factor-alpha overexpress this receptor also produce a high (TGF-α), initiating a cascade of intracellular sig- level of EGFR ligands, creating an autocrine acti- naling that ultimately regulates cell proliferation, vation loop that is thought to promote independent 246 Cotena et al. Acta Dermatovenerol Croat Skin eruption by cetuximab 2007;15(4):246-248 tumor growth. Indeed, increased EGFR activity department for acneiform eruption induced by ce- has been correlated with worse prognosis in pa- tuximab in combination with irinotecan. Previuo- tients with various types of cancer, including head, sly, she was unsuccessfully treated with eleven neck, colorectal, lung, renal and pancreatic can- cycles of polychemotherapy consisting of fluoro- cers (3). The chimeric antibody cetuximab alone uracil/leucovorin plus irinotecan (FOLFIRI), fol- and in combination with irinotecan has shown a lowed by eight cycles of another combination of consistent therapeutic activity in EGFR-expressing chemotherapy (fluorouracil/leucovorin plus oxali- refractory colorectal cancer (CRC) (4-6). Indeed, platin, FOLFOX); however, the lung and liver me- cetuximab is approved by the US Food and Drug tastases continued progressing. Capecitabina, a Administration for the treatment of EGFR-express- third-line chemotherapy, was then administered in ing metastatic colorectal cancer as monotherapy 4 cycles, with no improvement. The last cycle of in patients who are intolerant to irinotecan-based FOLFOX was then administered to the patient as chemotherapy, or in combination with irinotecan the last chance, with no success. Biopsy speci- in patients who are refractory to irinotecan-based men immunophenotyping revealed 10% of neo- chemotherapy. EGFR inhibitors are generally well plastic cells to be EGFR positive. Therefore, the tolerated and do not have severe systemic side patient underwent a first cycle of intravenous im- effects of cytotoxic drugs. However, due to the im- munochemotherapy with cetuximab 600 mg (400 portant role of EGFR in skin homeostasis, cuta- mg/m2) and irinotecan 290 mg (180 mg/m2). Four neous reactions are a common adverse effect of days after this first infusion, the patient developed cetuximab, mainly as acneiform follicular eruption intense acneiform eruption consisting of erythem- seen in almost 85% of patients (7-9). Other less atous follicular papules and pustules spread to the frequent dermatological adverse events are xero- face, neck and upper part of the trunk, accompa- sis, small oral aphthous ulcers, seborrheic derma- nied by severe pruritus and fever (38.0 °C) (Fig. titis-like eruptions, paronychia, desquamation and 1A). There were no comedones. Biopsy specimen pruritus (10). revealed superficial and florid neutrophilic suppu- rative folliculitis. A dense monomorphic infiltrate of CASE REPORT neutrophils and eosinophils was constantly dis- We report on a 46-year-old female Cauca- tributed around the infundibula (Fig. 1B). She was sian patient with metastatic CRC, referred to our treated with erythromycin tablet 600 mg, three Figure 1. (A) Erythematous follicular papules and pustules; (B) Superficial and florid neutrophilic suppura- tive folliculitis with a dense monomorphic infiltrate of neutrophils and eosinophils around the infundibula. ACTA DERMATOVENEROLOGICA CROATICA 247 Cotena et al. Acta Dermatovenerol Croat Skin eruption by cetuximab 2007;15(4):246-248 times a day for 1 month, and topical clindamycin 2. Chung KY, Saltz L. Antibody-based therapies solution 3%. After 1 month of treatment, the le- for colorectal cancer. Oncology 2005;10:701- sions consistently faded and the patient continued 9. receiving immunochemotherapy. Eight months af- 3. Nicholson RI, Gee JM, Harper ME. EGFR and ter cetuximab/irinotecan therapy, the progression cancer prognosis. Eur J Cancer 2002;37:9- of metastasis was arrested. 15. 4. Saltz L, Meropol NJ, Loehrer PJ, Needle MN, DISCUSSION Kopit J, Mayer RJ. Phase II trial of cetuximab A classic case of acneiform eruption in a fe- in patients with refractory colorectal cancer male patient receiving cetuximab for metastatic that expresses the epidermal growth factor re- CRC resistant to conventional chemotherapy is ceptor. J Clin Oncol 2004;22:1201-8. reported. Acneiform eruption is a common side ef- 5. Saltz LB, Rubin M, Hochster H. Cetuximab fect of EGFR inhibitors as biological drugs, which (IMC-C225) plus irinotecan (CPT-11) is ac- is observed in 75%-100% of patients. The erup- tive in CPT-11-refractory colorectal cancer tion is generally confined to the seborrheic areas, (CRC) that expresses epidermal growth fac- shoulders and upper trunk, whereas sometimes it tor receptor (EGFR). Proc Am Soc Clin Oncol may involve the abdomen, buttocks and even the 2001;20:3. arms and legs. The skin lesions consist of itchy erythematous follicular papules that may evolve 6. Cunningham D, Humblet Y, Siena S, Khayat into pustules. The pustules may merge into lakes D, Bleiberg H, Santoro A et al. Cetuximab mo- of pus that dry out with the formation of yellow notherapy and cetuximab plus irinotecan-re- crusts. The follicular skin lesions are not preceded fractory metastatic colorectal cancer. N Engl J by visible comedones and can therefore not be Med 2004;351:337-45. considered as true acne. The acneiform eruption 7. Segaert S, Van Custem E. Clinical sign, pat- arises after a few days up to 1 week of treatment hophysiology and management of skin toxicity and reaches maximum intensity after 2 to 3 weeks during therapy with epidermal growth factor following the beginning of therapy. Rarely, the receptor inhibitors. Ann Oncol 2005;16:1425- rash occurs in a delayed way after the first three 33. weeks of treatment. Data from a large number of 8. Saltz L, Rubin MS, Hochster H. Acne-like rash clinical trials suggest that there is a relationship predicts response in patients treated with ce- between the rash incidence and response/survival tuximab (IMC-C225) plus irinotecan (CPT-11) rate, indicating rash as a possible marker of effec- in CPT-11 refractory colorectal cancer (CRC) tive target inhibition and activity of EGFR-targeted that expresses epidermal growth factor recep- agents (8,11). Rash does not affect all patients tor (EGFR). Clin Cancer Res 2001;7:3766. and there is a high inter-individual variability. Cur- 9. Agero AL, Dusza SW, Benvenuto-Andrade C, rent data indicate that both the onset and sever- Busam KJ, Myskowski P, Halpern AC. Derma- ity of rash are related to drug exposure, although tologic side effects associated with epidermal its etiology remains unclear. It has been reported