Braiteh et al

Wareef Kabbani 5. Chu TF, Rupnick MA, Kerkela R, et al: Cardiotoxicity associated with Department of , University of Texas Southwestern Medical Center, tyrosine kinase inhibitor sunitinib. Lancet 370:2011-2019, 2007 Dallas, TX 6. Wullschleger S, Loewith R, Hall MN: TOR signaling in growth and metabolism. Cell 124:471-484, 2006 ACKNOWLEDGMENT 7. Brugarolas J, Vazquez F, Reddy A, et al: TSC2 regulates VEGF through Supported by -Scientist KO8 Award (1K08NS051843) (J.B.); mTOR-dependent and -independent pathways. Cancer Cell 4:147-158, 2003 Clinical Scientist Development Award, Doris Duke Charitable 8. Serruys PW, Kutryk MJ, Ong AT: Coronary-artery stents. N Engl J Med Foundation (J.B.); and V Scholar Award, V Foundation for Cancer 354:483-495, 2006 Research (J.B.). We thank Beni Stewart and Dorothy Smith for 9. Dutcher JP, Szczylik C, Tannir N, et al: Correlation of survival with tumor figure editing. histology, age, and prognostic risk group for previously untreated patients with advanced renal cell carcinoma (adv RCC) receiving temsirolimus (TEMSR) or AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST interferon-alpha (IFN). J Clin Oncol 26:18s, 2007 (abstr 5033) The author(s) indicated no potential conflicts of interest. 10. Atkins MB, Hidalgo M, Stadler WM, et al: Randomized phase II study of REFERENCES multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol 1. Lam JS, Shvarts O, Leppert JT, et al: Postoperative surveillance protocol 22:909-918, 2004 for patients with localized and locally advanced renal cell carcinoma based on a 11. Raymond E, Alexandre J, Faivre S, et al: Safety and pharmacokinetics of validated prognostic nomogram and risk group stratification system. J Urol 174:466-472, 2005 escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR 2. Brugarolas J: Renal-cell carcinoma: Molecular pathways and . inhibitor, in patients with cancer. J Clin Oncol 22:2336-2347, 2004 N Engl J Med 356:185-187, 2007 12. Boni JP, Leister C, Bender G, et al: Population pharmacokinetics of 3. Motzer RJ, Hutson TE, Tomczak P, et al: Sunitinib versus interferon alfa in CCI-779: Correlations to safety and pharmacogenomic responses in patients with metastatic renal-cell carcinoma. N Engl J Med 356:115-124, 2007 advanced renal cancer. Clin Pharmacol Ther 77:76-89, 2005 4. Hudes G, Carducci M, Tomczak P, et al: Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356:2271-2281, 2007 DOI: 10.1200/JCO.2008.16.4590

■■■ thick, coarse hairs on the dorsal aspect of her fingers as well. Three Trichomegaly of the Eyelashes After Lung weeks after starting erlotinib, the patient noticed an accelerated Cancer Treatment with the Epidermal growth of her eyelashes, which interfered with her wearing glasses Growth Factor Receptor Inhibitor Erlotinib because the lashes pushed against the lenses. She had to trim her eyelashes with scissors on a weekly basis. Close examination revealed A 57-year-old white woman who had never smoked pre- marked bilateral coarse, thick, elongated irregular growth of the eye- sented with a history of isolated coughing for several months. Com- lashes, with marked darkening and curling of the terminal ends (Fig puted tomography scans of the chest demonstrated a 2.5 ϫ 4.5-cm 2). These changes resolved after erlotinib was discontinued when right-middle-lobe tumor, widespread bilateral pulmonary nodules disease progressed. consistent with metastases, and enlarged lymph nodes in the subcari- of the eyelashes, or eyelash trichomegaly, was nal, paratracheal, and prevascular regions (Fig 1, yellow arrows). Fine- originally described in the setting of rare congenital conditions such as needle aspiration biopsy of the lesion revealed bronchogenic Oliver-McFarlane syndrome,4 oculocutaneous albinism type I,5 or adenocarcinoma. Magnetic resonance imaging of the brain revealed familial hypertrichosis.6 Although it may be encountered in the con- four subcentimeter metastatic lesions with minimal edema. Polymer- text of generalized acquired hypertrichosis,7 hypertrichosis of the eye- ase chain reaction-based sequencing of DNA of the epidermal growth lashes is more often an isolated finding. It is defined as an increase in factor receptor (EGFR) gene revealed an 18-base pair deletion in exon the length, thickness, stiffness, curling, and pigmentation of existing 19 of the EGFR gene, which has been previously reported in patients eyelashes.8 Acquired trichomegaly of the eyelashes has been repeatedly with lung tumors that responded to erlotinib.1-3 The patient received described in case series of patients infected with HIV type 19 or in whole-brain radiation with a total of 30 Gy in ten fractions. association with uveitis.10 Trichomegaly has been reported in some She then received systemic front-line therapy with single agent erlo- patients secondary to therapy with a drug such as the antiretroviral tinib (standard oral dose, 150 mg). Her disease demonstrated a major agent zidovudine (a reverse transcriptase inhibitor),11and is usually response to erlotinib; the diffuse pulmonary nodules disappeared 6 associated with poor tolerance to the drug. Topical ocular hypotensive weeks after she started therapy, while the primary right-middle–lobe (antiglaucoma) agents such as latanoprost12 and bimatoprost13 have tumor shrank down to 1.0 ϫ 4.0 cm2 2 months later and remained on rare occasions caused trichomegaly of the eyelashes. Other ocular stable for over 1 year (Fig 1). Thirteen months after the initiation of topical treatments such as cyclosporine14 and systemic therapy with systemic therapy, clear progression of disease was noted, with devel- the anticonvulsant topiramate8 also have been reported to cause opment of new pulmonary nodules and an increase in the size of the trichomegaly. The condition was noted in some recipients of solid right-middle–lobe tumor. Since the addition of bevacizumab did not organ transplants who were given cyclosporine15 or tacrolimus.16 provide better tumor control, further treatment was switched to the Acquired trichomegaly was reported in isolated cases of patients with chemotherapy doublet of carboplatin and paclitaxel, which reinduced dermatomyositis17 and systemic erythematosus18 (Table 1). In a durable partial response. During her therapy with erlotinib, the cancer patients, trichomegaly must be distinguished from a rare para- patient experienced a mild rash on her face, chest, and back, which was neoplastic syndrome, the acquired hypertrichosis lanuginosa, charac- treated with emolients and topical clindamycin. She had mild paro- terized in adults by the abnormal growth of lanugo-type hair, confined nychia, which improved after topical therapy. The patient experienced to the face and neck and concomitant with the spread of an internal alopecia after brain radiotherapy, and it persisted with very slow hair malignancy.19,20 Trichomegaly can occur in patients with cancer in the regrowth while she was receiving erlotinib. She had growth of dark, setting of a paraneoplastic syndrome,21 or secondary to anticancer

3460 © 2008 by American Society of Clinical JOURNAL OF CLINICAL ONCOLOGY Information downloaded from jco.ascopubs.org and provided by at US Oncology on December 28, 2012 from 67.66.44.224 Copyright © 2008 American Society of Clinical Oncology. All rights reserved. Diagnosis in Oncology

Baseline After six weeks of erlotinib Primary Tumor Right-Middle-Lobe Metastatic Nodule Metastatic Nodule

Fig 1. therapy with interferon-␣.22 With the introduction of EGFR inhibi- reversible after cessation of the medication. Because of the risk of tors in clinical practice, clinicians have observed numerous cutaneous trichiasis and secondary corneal ulceration,27 it has been recom- adverse effects, such as acneiform rash, pruritus, and, less frequently, mended that patients with trichomegaly who complain of symptoms xerosis, , skin fissures, and telangiectasia.23 After treatment of eye irritation be seen by an ophthalmologist, because other ocular with the recombinant anti-EGFR antibody cetuximab, generalized conditions such as conjunctivitis and keratoconjunctivitis sicca can diffuse trichomegaly can occur.24 Eyelash trichomegaly has been en- complicate anti-EGFR therapy. Trimming and epilation have been countered after treatment with cetuximab as well25 and after the EGFR found to be satisfactory, safe therapeutic options. As illustrated in our tyrosine kinase inhibitors erlotinib26,27 and gefitinib.28,29 In these case report, sensitivity to EGFR tyrosine kinase inhibitors in non– cases, trichomegaly occurred after about 2 months of therapy and was small-cell lung adenocarcinomas has been associated with somatic mutations in the EGFR gene1-3 with subsequent constitutive ligand- independent activation of the receptor kinase and prolonged kinase activity after ligand stimulation.2,30. EGFR tyrosine kinase domain mutations are mainly either in-frame deletions in exon 19, a single- point missense mutation in exon 21, or in-frame duplications, inser- tions, or both in exon 20.31 Retrospective data showed average response rates to EGFR tyrosine kinase inhibitors of approximately 75% for tumors with EGFR mutations, and, in contrast, less than 10% for tumors with the wild-type EGFR gene.32 The patient presented here had a deletion mutation in exon 19, and exhibited an excellent long-lasting response to erlotinib. The exact incidence of eyelash trichomegaly is unknown, and the condition remains sporadically reported. Although it appears to be a class effect associated with EGFR inhibitors, the occurrence of eyelash trichomegaly in relation to EGFR Fig 2. mutations is unknown. Whether eyelash trichomegaly correlates with www.jco.org © 2008 by American Society of Clinical Oncology 3461 Information downloaded from jco.ascopubs.org and provided by at US Oncology on December 28, 2012 from 67.66.44.224 Copyright © 2008 American Society of Clinical Oncology. All rights reserved. Braiteh et al

4. Oliver GL, McFarlane DC: Congenital trichomegaly with associated pig- Table 1. Reported Causes of Eyelash Trichomegaly mentary degeneration of the retina, dwarfism, and mental retardation. Arch Ophthalmol 74:169-171, 1965 Congenital eyelash trichomegaly 5. Ziakas NG, Jogiya A, Michaelides M: A case of familial trichomegaly in Oliver-McFarlane syndrome4 association with oculocutaneous albinism type 1. Eye 18:863-864, 2004 5 Oculocutaneous albinism type I 6. Harrison DA, Mullaney PB: Familial trichomegaly. Arch Ophthalmol 115: Acquired eyelash trichomegaly 1602-1603, 1997 Systemic disease 7. Aghaei S, Dastgheib L: Acquired eyelash trichomegaly and generalized Dermatomyositis17 hypertrichosis associated with breast anomaly. Dermatol Online J 12:19, 2006 Systemic lupus erythematosus18 8. Santmyire-Rosenberger BR, Albert M: Acquired trichomegaly with topira- Systemic infection mate. J Am Acad Dermatol 53:362-363, 2005 Human immunodeficiency virus infection or acquired immunodeficiency 9. Kaplan MH, Sadick NS, Talmor M: Acquired trichomegaly of the eyelashes: syndrome9 A cutaneous marker of acquired immunodeficiency syndrome. J Am Acad Uveitis10 Dermatol 25:801-804, 1991 10. Bayer A, Bagkesen H, Sobaci G: Acquired trichomegaly in uveitis. Can J Paraneoplastic syndrome Ophthalmol 42:101-106, 2007 Renal cell cancer21 11. Klutman NE, Hinthorn DR: Excessive growth of eyelashes in a patient with Side effect of topical ophthalmic drug therapy AIDS being treated with zidovudine. N Engl J Med 324:1896, 1991 Ocular hypotensive agents (antiglaucoma) 12. Elgin U, Batman A, Berker N, et al: The comparison of eyelash Latanoprost,12 bimatoprost13 lengthening effect of latanoprost therapy in adults and children. Eur J Immunosuppressors Ophthalmol 16:247-250, 2006 Cyclosporine14 13. Centofanti M, Oddone F, Chimenti S, et al: Prevention of dermatologic Adverse effect of systemic drug therapy side effects of bimatoprost 0.03% topical therapy. Am J Ophthalmol 142: Interferon 1059-1060, 2006 14. Pucci N, Massai C, Bernardini R, et al: Eyelash length in children with vernal Interferon-alpha22 keratoconjunctivitis: Effect of treatment with cyclosporine eye drops. Int J Im- Anticonvulsants munopathol Pharmacol 20:595-599, 2007 8 Topimarate 15. Weaver DT, Bartley GB: Cyclosporine-induced trichomegaly. Am J Oph- Immunosuppressors thalmol 109:239, 1990 Cyclosporine,15 tacrolimus16 16. Ward KM, Barnett C, Fox LP, et al: Eyelash trichomegaly associated with Anti-EGFR recombinant antibody systemic tacrolimus. Arch Dermatol 142:248, 2006 Cetuximab24,25 17. Sharma RC, Mahajan VK, Sharma NL, et al: Trichomegaly of the eyelashes EGFR tyrosine kinase inhibitors in . 205:305, 2002 Erlotininib,26,27 gefitinib28,29 18. Santiago M, Travassos AC, Rocha MC, et al: Hypertrichosis in systemic lupus erythematosus (SLE). Clin Rheumatol 19:245-246, 2000 Abbreviation: EFGR, epidermal growth factor receptor. 19. Slee PH, van der Waal RI, Schagen van Leeuwen JH, et al: Paraneoplastic hypertrichosis lanuginosa acquisita: Uncommon or overlooked? Br J Dermatol 157:1087-1092, 2007 20. Vulink AJ, ten Bokkel HD: Acquired hypertrichosis lanuginosa: A rare cutaneous paraneoplastic syndrome. J Clin Oncol 25:1625-1626, 2007 21. Ve´lez A, Kindelan JM, Garcia-Herola A, et al: Acquired trichomegaly and clinical response of lung cancer to EGFR inhibitors or whether it hypertrichosis in metastatic adenocarcinoma. Clin Exp Dermatol 20:237-239, 1995 occurs as an unrelated adverse event remains to be evaluated on a 22. Herna´ndez-Nu´n˜ ez A, Fernandez-Herrera J, Buceta LR, et al: Trichomegaly larger scale. We are planning to investigate further the effect of erlo- following treatment with interferon alpha-2b. Lancet 359:1107, 2002 23. Santoro F, Cozzani E, Parodi A: Cutaneous adverse effects during therapy tinib on the eyelashes of patients with lung cancer who receive erlo- with an epidermal growth factor receptor (EGFR) inhibitor. J Dermatolog Treat tinib for adjuvant therapy or for secondary prevention. 17:160-161, 2006 24. Kerob D, Dupuy A, Reygagne P, et al: Facial hypertrichosis induced by Fadi Braiteh and Razelle Kurzrock cetuximab, an anti-EGFR monoclonal antibody. Arch Dermatol 142:1656- 1657, 2006 Department of Investigational Cancer Therapeutics, Phase I Program, The University of Texas M.D. Anderson Cancer Center; and The University of 25. Bouche O, Brixi-Benmansour H, Bertin A, et al: Trichomegaly of the Texas Graduate School of Biomedical Sciences Houston, Houston, TX eyelashes following treatment with cetuximab. Ann Oncol 16:1711-1712, 2005 26. Carser JE, Summers YJ: Trichomegaly of the eyelashes after treatment Faye M. Johnson with erlotinib in non–small-cell lung cancer. J Thorac Oncol 1:1040-1041, 2006 27. Lane K, Goldstein SM: Erlotinib-associated trichomegaly. Ophthal Plast Department of Thoracic/Head and Neck Medical Oncology, The University of Reconstr Surg 23:65-66, 2007 Texas M.D. Anderson Cancer Center; and The University of Texas Graduate School of Biomedical Sciences Houston, Houston, TX 28. Pascual JC, Banuls J, Belinchon I, et al: Trichomegaly following treatment with gefitinib (ZD1839). Br J Dermatol 151:1111-1112, 2004 29. Shah NT, Kris MG, Pao W, et al: Practical management of patients with AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST non–small-cell lung cancer treated with gefitinib. J Clin Oncol 23:165-174, 2005 The author(s) indicated no potential conflicts of interest. 30. Hirsch FR, Varella-Garcia M, McCoy J, et al: Increased epidermal growth factor receptor gene copy number detected by fluorescence in situ hybridization REFERENCES associates with increased sensitivity to gefitinib in patients with bronchioloalveo- 1. Cohen EE, Rosen F, Stadler WM, et al: Phase II trial of ZD1839 in recurrent lar carcinoma subtypes: A Southwest Oncology Group Study. J Clin Oncol or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol 23:6838-6845, 2005 21:1980-1987, 2003 31. Shigematsu H, Lin L, Takahashi T, et al: Clinical and biological features 2. Lynch TJ, Bell DW, Sordella R, et al: Activating mutations in the epidermal associated with epidermal growth factor receptor gene mutations in lung growth factor receptor underlying responsiveness of non–small-cell lung cancer cancers. J Natl Cancer Inst 97:339-346, 2005 to gefitinib. N Engl J Med 350:2129-2139, 2004 32. Riely GJ, Politi KA, Miller VA, et al: Update on epidermal growth factor receptor 3. Van Doorn R, Kirtschig G, Scheffer E, et al: Follicular and epidermal mutations in non-small cell lung cancer. Clin Cancer Res 12:7232-7241, 2006 alterations in patients treated with ZD1839 (Iressa), an inhibitor of the epidermal growth factor receptor. Br J Dermatol 147:598-601, 2002 DOI: 10.1200/JCO.2008.16.9391

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3462 © 2008 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY Information downloaded from jco.ascopubs.org and provided by at US Oncology on December 28, 2012 from 67.66.44.224 Copyright © 2008 American Society of Clinical Oncology. All rights reserved.