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Erlotinib-Associated Alopecia in a Lung Cancer Patient

2007; Elsevier BV; Volume: 2; Issue: 12 Linguagem: Inglês

10.1097/jto.0b013e31815ba7f9

1556-1380

Daniel B. Costa, Susumu Kobayashi, Susan Schumer,

HER2/EGFR in Cancer Research

The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib are effective in a subset of non-small cell lung cancers (NSCLCs). Skin-related toxicities are the main side effects of EGFR TKI use in clinical practice.1Agero AL Dusza SW Benvenuto-Andrade Busam KJ Myskowski P Halpern AC Dermatologic side effects associated with the epidermal growth factor receptor inhibitors.J Am Acad Dermatol. 2006; 55: 657-670Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar, 2Robert C Soria JC Spatz A et al.Cutaneous side-effects of kinase inhibitors and blocking antibodies.Lancet Oncol. 2005; 6: 491-500Abstract Full Text Full Text PDF PubMed Scopus (453) Google Scholar The most common skin manifestation is a rash described as a follicular or papular pustular eruption.1Agero AL Dusza SW Benvenuto-Andrade Busam KJ Myskowski P Halpern AC Dermatologic side effects associated with the epidermal growth factor receptor inhibitors.J Am Acad Dermatol. 2006; 55: 657-670Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar, 2Robert C Soria JC Spatz A et al.Cutaneous side-effects of kinase inhibitors and blocking antibodies.Lancet Oncol. 2005; 6: 491-500Abstract Full Text Full Text PDF PubMed Scopus (453) Google Scholar Patients treated with gefitinib and erlotinib can also exhibit hair abnormalities.1Agero AL Dusza SW Benvenuto-Andrade Busam KJ Myskowski P Halpern AC Dermatologic side effects associated with the epidermal growth factor receptor inhibitors.J Am Acad Dermatol. 2006; 55: 657-670Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar The most commonly described alterations include curlier, finer, and more brittle hair on the scalp and extremities.2Robert C Soria JC Spatz A et al.Cutaneous side-effects of kinase inhibitors and blocking antibodies.Lancet Oncol. 2005; 6: 491-500Abstract Full Text Full Text PDF PubMed Scopus (453) Google Scholar Trichomegaly, or curling of eyelashes and eyebrows, and hypertrichosis of the face can also be seen.1Agero AL Dusza SW Benvenuto-Andrade Busam KJ Myskowski P Halpern AC Dermatologic side effects associated with the epidermal growth factor receptor inhibitors.J Am Acad Dermatol. 2006; 55: 657-670Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar Significant or severe alopecia has seldom been reported in patients receiving TKI monotherapy.1Agero AL Dusza SW Benvenuto-Andrade Busam KJ Myskowski P Halpern AC Dermatologic side effects associated with the epidermal growth factor receptor inhibitors.J Am Acad Dermatol. 2006; 55: 657-670Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar, 2Robert C Soria JC Spatz A et al.Cutaneous side-effects of kinase inhibitors and blocking antibodies.Lancet Oncol. 2005; 6: 491-500Abstract Full Text Full Text PDF PubMed Scopus (453) Google Scholar The best described hair loss pattern among patients with NCLC treated with TKI is frontal “androgen-like” scalp alopecia, which can be seen many months after initiation of therapy.2Robert C Soria JC Spatz A et al.Cutaneous side-effects of kinase inhibitors and blocking antibodies.Lancet Oncol. 2005; 6: 491-500Abstract Full Text Full Text PDF PubMed Scopus (453) Google Scholar We describe a patient with metastatic NSCLC who developed severe alopecia while receiving erlotinib monotherapy at the recommended dose of 150 mg/day. The patient was initially diagnosed with an EGFR-mutant (L858R-EGFR) metastatic NSCLC at age 74 years.3Costa DB Schumer ST Three-year survival in metastatic non-small cell lung cancer treated with gefitinib.Lung Cancer. 2006; 53: 123-124Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar She received gefitinib monotherapy at a dose of 250 mg/day for longer than 40 months, and the highest skin toxicity profile was that of a grade 1 follicular rash, based on the National Cancer Institute-Common Toxicity Criteria (NCI-CTC). No scalp hair abnormalities were observed during the patient's use of gefitinib. Upon tumor progression, the patient was briefly exposed to an experimental EGFR TKI without any skin-related toxicity. She then received erlotinib 150 mg/day. Within 1 week of use, the patient developed a grade 2 follicular rash involving the face and, to a lesser extent, the scalp, accompanied by severe pruritus (grade 3, NCI-CTC) of the lesions and other skin areas. Management with a topical steroid and antibiotic applied to the facial area, as well as an oral antibiotic (tetracycline 500 mg twice/day) and oral anti-histamine (hydroxyzine 50 mg/day) were instituted, and the rash and pruritus improved within 2 weeks. During this time, the patient did not change any of her other medications and continued to use her usual shampoo, hair conditioner, and peroxide-based hair dye. Six weeks after initiation of erlotinib, the patient noted thinning and loss of hair from her scalp. By the 16th week of therapy, most of her scalp hair had fallen off (Figure 1), sparing some areas in a halo-pattern around the periphery of her former scalp hair. The remaining scalp hair appeared wavier than her previously straight hair. New hair had started to grow from the affected area (Figure 1). At the patient's most current contact, 20 weeks after starting erlotinib for her metastatic NSCLC, the patient continues to note slow growth of hair around her scalp. The findings of hair changes after EGFR inhibition are consistent with experimental evidence that EGFR plays a crucial role in the regulation of the hair growth cycle.1Agero AL Dusza SW Benvenuto-Andrade Busam KJ Myskowski P Halpern AC Dermatologic side effects associated with the epidermal growth factor receptor inhibitors.J Am Acad Dermatol. 2006; 55: 657-670Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar, 2Robert C Soria JC Spatz A et al.Cutaneous side-effects of kinase inhibitors and blocking antibodies.Lancet Oncol. 2005; 6: 491-500Abstract Full Text Full Text PDF PubMed Scopus (453) Google Scholar The hair cycle consists of three phases: anagen (a phase of growth), catagen (controlled involution), and telogen (resting period).1Agero AL Dusza SW Benvenuto-Andrade Busam KJ Myskowski P Halpern AC Dermatologic side effects associated with the epidermal growth factor receptor inhibitors.J Am Acad Dermatol. 2006; 55: 657-670Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar, 4Murillas R Larcher F Conti CJ Santos M Ullrich A Jorcano JL Expression of a dominant negative mutant of epidermal growth factor receptor in the epidermis of transgenic mice elicits striking alterations in hair follicle development and skin structure.EMBO J. 1995; 14: 5216-5223Crossref PubMed Scopus (236) Google Scholar, 5Hansen LA Alexander N Hogan ME et al.Genetically null mice reveal a central role for epidermal growth factor receptor in the differentiation of the hair follicle and normal hair development.Am J Pathol. 1997; 150: 1959-1975PubMed Google Scholar All phases are regulated by cytokines, hormones, and growth factors, including EGFR ligands.1Agero AL Dusza SW Benvenuto-Andrade Busam KJ Myskowski P Halpern AC Dermatologic side effects associated with the epidermal growth factor receptor inhibitors.J Am Acad Dermatol. 2006; 55: 657-670Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar EGFR may function as a signal for hair follicles at the beginning and end of the anagen phase of the hair cycle.1Agero AL Dusza SW Benvenuto-Andrade Busam KJ Myskowski P Halpern AC Dermatologic side effects associated with the epidermal growth factor receptor inhibitors.J Am Acad Dermatol. 2006; 55: 657-670Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar, 2Robert C Soria JC Spatz A et al.Cutaneous side-effects of kinase inhibitors and blocking antibodies.Lancet Oncol. 2005; 6: 491-500Abstract Full Text Full Text PDF PubMed Scopus (453) Google Scholar Transgenic mice expressing inactive mutants of EGFR in skin and hair follicles exhibited short wavy hair and curling of whiskers.4Murillas R Larcher F Conti CJ Santos M Ullrich A Jorcano JL Expression of a dominant negative mutant of epidermal growth factor receptor in the epidermis of transgenic mice elicits striking alterations in hair follicle development and skin structure.EMBO J. 1995; 14: 5216-5223Crossref PubMed Scopus (236) Google Scholar, 5Hansen LA Alexander N Hogan ME et al.Genetically null mice reveal a central role for epidermal growth factor receptor in the differentiation of the hair follicle and normal hair development.Am J Pathol. 1997; 150: 1959-1975PubMed Google Scholar Hair remained in the anagen stage, eventually followed by hair follicle degeneration and severe alopecia.4Murillas R Larcher F Conti CJ Santos M Ullrich A Jorcano JL Expression of a dominant negative mutant of epidermal growth factor receptor in the epidermis of transgenic mice elicits striking alterations in hair follicle development and skin structure.EMBO J. 1995; 14: 5216-5223Crossref PubMed Scopus (236) Google Scholar, 5Hansen LA Alexander N Hogan ME et al.Genetically null mice reveal a central role for epidermal growth factor receptor in the differentiation of the hair follicle and normal hair development.Am J Pathol. 1997; 150: 1959-1975PubMed Google Scholar EGFR may modify normal and wound-induced epidermal proliferation.5Hansen LA Alexander N Hogan ME et al.Genetically null mice reveal a central role for epidermal growth factor receptor in the differentiation of the hair follicle and normal hair development.Am J Pathol. 1997; 150: 1959-1975PubMed Google Scholar To the best of our knowledge, our patient developed a more pronounced pattern of scalp hair loss than reported previously with EGFR-targeted therapies.1Agero AL Dusza SW Benvenuto-Andrade Busam KJ Myskowski P Halpern AC Dermatologic side effects associated with the epidermal growth factor receptor inhibitors.J Am Acad Dermatol. 2006; 55: 657-670Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar, 2Robert C Soria JC Spatz A et al.Cutaneous side-effects of kinase inhibitors and blocking antibodies.Lancet Oncol. 2005; 6: 491-500Abstract Full Text Full Text PDF PubMed Scopus (453) Google Scholar It is possible that her increased skin toxicities when switching from gefitinib 250 mg/day to erlotinib 150 mg/day may indicate a higher biologic dose of the later drug, which is given at its maximal tolerated dose. Skin-related toxicities become more common as the dose of TKI is increased.1Agero AL Dusza SW Benvenuto-Andrade Busam KJ Myskowski P Halpern AC Dermatologic side effects associated with the epidermal growth factor receptor inhibitors.J Am Acad Dermatol. 2006; 55: 657-670Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar It is not inconsistent to assume that EGFR function was blocked in the patient's scalp and may have either primarily led to the severe alopecia or altered the response to any topical injury caused by her hair products.2Robert C Soria JC Spatz A et al.Cutaneous side-effects of kinase inhibitors and blocking antibodies.Lancet Oncol. 2005; 6: 491-500Abstract Full Text Full Text PDF PubMed Scopus (453) Google Scholar, 4Murillas R Larcher F Conti CJ Santos M Ullrich A Jorcano JL Expression of a dominant negative mutant of epidermal growth factor receptor in the epidermis of transgenic mice elicits striking alterations in hair follicle development and skin structure.EMBO J. 1995; 14: 5216-5223Crossref PubMed Scopus (236) Google Scholar, 5Hansen LA Alexander N Hogan ME et al.Genetically null mice reveal a central role for epidermal growth factor receptor in the differentiation of the hair follicle and normal hair development.Am J Pathol. 1997; 150: 1959-1975PubMed Google Scholar However, it seems that the erlotinib-induced alopecia was not persistent because after the initial hair loss, new scalp hair started to grow despite continued use of the TKI inhibitor.