American Journal of Therapeutics 0, 1–4 (2015)

Trichomegaly Induced by Cetuximab: Case Series and Review the Literature Ulkuhan I. Koksal, MD,* Kezban N. Pilanci, MD, Cetin Ordu, MD, Kerem Okutur, MD, Sezer Saglam, MD, and Gokhan Demir, MD

Trichomegaly is a rare side effect of epidermal growth factor receptor inhibitors. We present here 4 patients who treated with cetuximab (an epidermal growth factor receptor inhibitor) for metastatic colorectal cancer. All of the cases were treated with cetuximab 500 mg/m2 biweekly in combination protocol. The mean period from the start of the treatment until the development the trichomegaly was 4.75 (3–6) months. In all of the patients after the end of the cetuximab therapy, trichomegaly was regressed. Only 1 case resolved with topical treatment that conjunctivitis with trichomegaly. Trichomegaly is an important ocular toxicity of cetuximab that can cause visual discomfort and corneal damages. However, these side effects usually do not require discontinuation of treatment. Keywords: cetuximab, trichomegaly, colorectal carcinoma

INTRODUCTION Epidermal growth factor receptor (EGFR), a transmembrane glycoprotein, is a member of the ErbB family of receptors. It has an extracellular ligand-binding domain, a transmembrane region, and an intracellular tyrosine kinase domain. It is activated by epidermal growth factor and transforming growth factor-a, and it turns from an inactivate monomeric form to an active homodimer. EGFR dimerization stimulates its intrinsic intracellular protein kinase activity and initiates several signal transduction cascades.1 The EGFR signaling pathway regulates cell differentiation, migration, proliferation, apoptosis, and angiogenesis that are deregulated in cancer cells.2,3 The effects of EGF on turnover of the hair follicle has been known for a long time. Epithelial growth factor (EGF) was shown to retard hair growth. Because EGFR

Department of Medical Oncology, Faculty of Medicine, Bilim University, Istanbul, Turkey. The authors have no conflicts of interest to declare. *Address for correspondence: Department of Medical Oncology, Faculty of Medicine, Bilim University, Bedrettin Mah. Bedii Gor_ bon Sk. No: 1 S¸is¸hane, Beyoglu/Istanbul, Istanbul 34440, Turkey. E-mail: [email protected]

promotes the discontinuation of the anagen stage, its downregulation is associated with hair follicle formation.4 Cetuximab is a chimeric IgG1 monoclonal antibody that blocks the EGFR. Dermatologic side effects of cetuximab are acneiform rash, paronychia, xerosis, dermatitis-like eruption, pruritus, skin fissures, and hair changes.5,6 Skin toxicity is the most common side effect and a predictive indicator of treatment response.6 The most common ocular side effects are dysfunctional tear syndrome, blepharitis, eyelid skin rash/hyperemia, and eyelash changes (trichomegaly and trichiasis).7 Trichomegaly is the lengthening of the eyelashes. Familial diseases (Oliver-McFarlane syndrome, Cornelia de Lange syndrome, Aghaei-Dastgheib syndrome, Goldstein-Hutt syndrome, cone-rod dystrophy, type I oculocutaneous albinism, familial trichomegaly), paraneoplastic syndromes, malignancies (kidney adenocarcinoma), AIDS, dermatomyositis, systemic lupus erythematosus, and drugs (interferon alfa-2b, cyclosporine, bimatoprost, latanoprost, phenytoin, zidovudine, penicillamine, tacrolimus, topiramate, erlotinib, gefitinib, panitumumab) can cause trichomegaly.3,8,9 The EGFR is expressed in the epidermis, the sweat gland apparatus, and hair follicle epithelium by basal keratinocytes and outer root sheath cells.3 Disregulated keratin expression due to inhibition of EGFR

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causes premature maturation of the hair follicle epithelium cells with terminal differentiation. It usually occurs after 2–5 months of treatment with cetuximab and other EGFR inhibitors.9 The incidence of eyelash trichomegaly is not well established because the cases have been sporadically reported. In addition, it is seen nearly as often in both men and women. The problems associated with trichomegaly are uncomfortable blinking, corneal problems (damage, erosions, infection, irritation, ulcers, and scarring), inflammation of the conjunctiva and eye, ingrown hairs and trichiasis, ocular surface alteration, visual discomfort, and disturbance. We report 4 patients of our department who developed trichomegaly with cetuximab therapy.

CASE DESCRIPTIONS Case 1 A 70-year-old man underwent resection for carcinoma of transverse colon in April 2010 and did not receive any adjuvant chemotherapy. At the positron emission tomography-computed tomography (PET-CT) pericolonic metastases were detected. The patient was treated by the combination of 5-fluorouracil (400 mg/m2 intravenous bolus, 2400 mg/m2 48-hour infusion), leucovorin (200 mg/m2), irinotecan (180 mg/m2), and cetuximab (500 mg/m2) biweekly. After 4 months, the patient developed the typical acneiform erythematous rash on the face, upper chest, and back and began treatment with tetracycline. In March 2012, 6 months after the start of therapy, trichomegaly was noted (Figure 1). The patient had no complaints

FIGURE 1. Case 1. American Journal of Therapeutics (2015) 0(0)

Koksal et al

about trichomegaly, and no treatment was needed. In positron emission tomography–computed tomography, complete metabolic response was achieved in May 2012, and then oral capecitabine was started as maintenance therapy. Two months later, progressive disease was observed. In the next line of therapy, the combination of 5-fluorouracil, leucovorin, oxaliplatin (85 mg/m2), and cetuximab was administered. Because of progression, therapy by the combination of 5-fluorouracil, leucovorin, irinotecan, and cetuximab was started in August 2013. In February 2014, ascites was developed, and then the chemotherapy regimen has changed to 5-fluorouracil, leucovorin, oxaliplatin (85 mg/m2), and cetuximab combination. The patient is under control with this treatment. Case 2 A 60-year-old man was diagnosed in November 2011 with rectal carcinoma with liver metastases. Right hemicolectomy and partial liver hepatectomy were performed initially. The patient was subsequently treated by the combination of 5-fluorouracil, leucovorin, and oxaliplatin. In June 2013, progressive disease was observed, and 5-fluorouracil, leucovorin, irinotecan, and cetuximab (500 mg/m2, biweekly) combination therapy was started. Trichomegaly was developed in the fifth month of treatment and did not induce visual discomfort (Figure 2). This treatment was achieved stable response, and the patient is treated by cetuximab as a maintenance therapy. Case 3 A 69-year-old woman was diagnosed with sigmoid colon carcinoma with multiple liver metastases in January 2013. In the first-line treatment, the patient received combined of 5-fluorouracil, leucovorin, oxaliplatin, and cetuximab (500 mg/m2, biweekly). After 3 months, in April 2013, skin toxicity on face, scalp, and upper chest and trichomegaly were noted (Figure 3). In July 2013, the patient presented with conjunctivitis and was referred to an ophthalmologist. After local treatment, symptoms of conjunctivitis resolved. In January 2014, oxaliplatin was stopped because of

FIGURE 2. Case 2.

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Trichomegaly Induced by Cetuximab


FIGURE 3. Case 3.

neurotoxicity, and irinotecan was added to combination therapy. The patient still receives this treatment. Case 4 A 56-year-old man began neoadjuvant chemoradiation therapy with 5-fluorouracil for rectal carcinoma in March 2010. In June 2010, the patient underwent abdominoperineal resection and subsequently treated by the combination of 5-fluorouracil, leucovorin, and oxaliplatin. Because of progressive disease, in April 2011, the next-line combination therapy by 5-fluorouracil, leucovorin, irinotecan, and bevacizumab was administered. In April 2012, complete response was achieved. In January 2013, sacral metastases were developed and radiosurgery was performed. In March 2013, lung metastases were detected and combination treatment by 5-fluorouracil, leucovorin, oxaliplatin, and cetuximab was started. Grade 1–2 skin toxicity was occurred in the first month of treatment. In fifth month of the therapy by cetuximab and chemotherapy combination, trichomegaly was observed (Figure 4). Regression has detected after 1 year treatment. In April 2014, the patient referred to radiation oncologist for lung metastases.

FIGURE 4. Case 4.

Trichomegaly is a rare cosmetic side effect of EGFR inhibitors.10 Usually does not require any treatment but must be careful not to cause corneal damage or any vision disturbance. Simple trimming and epilation are adequate treatments. Patients who have eye irritation symptoms should be evaluated by ophthalmologists.11 The first cetuximab-induced trichomegaly case in literature was a 26-year-old female who was treated by irinotecan and cetuximab for metastatic colorectal cancer in 2003.1 In 2005, Bouche et al reported a 74year-old female who was diagnosed with metastatic rectal cancer. She received irinotecan plus cetuximab for trichomegaly, and in the fifth month of the therapy, trichomegaly was developed. Because of visual discomfort, she had to cut her eyelashes. One month after the stopping of cetuximab, her eyelashes were normal.3 In 2008, a 63-year-old man with metastatic colorectal carcinoma who was treated by irinotecan and cetuximab were described in a case report.9 Trichomegaly was occurred 10 weeks after the start of treatment. In our cases, trichomegaly was occurred in 2–5 months, which is consistent with literature. In other reports, cetuximab was administered initial dose of 400 mg/m2 and subsequent doses of 250 mg/m2 weekly. In our practice, cetuximab was received 500 mg/m2 biweekly. However, these differences did not effect the time of occurrence or grade of trichomegaly. A 62-year-old woman presented in another case report who was treated for squamous cell carcinoma of oropharynx with cetuximab.12 All of our patients had colorectal carcinomas. Melichar et al reported that among 25 patients with metastatic colorectal carcinoma, trichomegaly observed in only 1 case (4%).7 In this case report, other eye toxicity due to cetuximab was described like conjunctivitis, blepharitis, and eyelid dermatitis. In our report, only 1 patient had bilateral conjunctivitis with trichomegaly and recover with local treatment. It is not known that trichomegaly is associated with clinical response as acneiform rash.11 In our report, clinical responses of patients who developed trichomegaly were not different from other patients treated with cetuximab. In conclusion, trichomegaly is a rare ocular complication with anti-EGFR treatment. When diagnosed due to cosmetic, symptoms can be treated by simple cutting. We described trichomegaly side effects due to anti-EGFR (cetuximab) in 4 patients with metastatic colorectal cancer who were treated by dosage schedule of 14-day 500 mg/m2. It was remarkable that in the American Journal of Therapeutics (2015) 0(0)

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cases described in the literature, it was occurred by weekly dosage schedule, whereas in our patients, it was seen in 14-day treatment. We supposed that development of trichomegaly does not induce difference in different dosage schedules. More studies are required which include large number cases whether trichomegaly is a side effect that predicts survival. Because it can affect visual comfort and social activity, dermatologic toxicity of EGFR inhibitors in the periocular area is more important than the toxicity in other parts of the body. The management of cetuximab eye toxicities may require the cooperation of oncologist and ophthalmalogist. Patient that treated by cetuximab should be followed for eye toxicities.

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Koksal et al 4. Paul LJ, Cohen PR, Kurzrock R. Eyelash trichomegaly: review of congenital, acquired, and drug-associated etiologies for elongation of the eyelashes. Int J Dermatol. 2012;51:631–646. 5. Borkar DS, Lacouture ME, Basti S. Spectrum of ocular toxicities from epidermal growth factor receptor inhibitors and their intermediate-term follow-up: a five-year review. Support Care Cancer. 2013;21:1167–1174. 6. Bambury R, McCaffrey JA. Trichomegaly of the eyelashes after colorectal cancer treatment with the epidermal growth factor receptor inhibitor cetuximab. Clin Colorectal Cancer. 2009;8:235. 7. Melichar B, Nemcová I. Eye complications of cetuximab therapy. Eur J Cancer Care. 2007;16:439–443. 8. Bouche O, Brixi-Benmansour H, Bertin A, et al. Trichomegaly of the eyelashes following treatment with cetuximab. Ann Oncol. 2005;16:1711–1712. 9. Vaccaro M, Pollicino A, Barbuzza O, et al. Trichomegaly of the eyelashes following treatment with cetuximab. Clin Exp Dermatol. 2009;34:402–403. 10. Vano-Galvan S, Moreno-Martin P, Jaen P. Progressive trichomegaly. Neth J Med. 2009;67:35–36. 11. Cohen PR, Escudier SM, Kurzrock R. Cetuximab-associated elongation of the eyelashes: case report and review of eyelash trichomegaly secondary to epidermal growth factor receptor inhibitors. Am J Clin Dermatol. 2011;12:63–67. 12. Foerster CG, Cursiefen C, Kruse FE. Persisting corneal erosion under cetuximab (Erbitux) treatment (epidermal growth factor receptor antibody). Cornea. 2008;27:612–614.

Copyright Ó 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.

Trichomegaly Induced by Cetuximab: Case Series and Review the Literature.

Trichomegaly is a rare side effect of epidermal growth factor receptor inhibitors. We present here 4 patients who treated with cetuximab (an epidermal...
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