Abstract
Purpose
Epidermal growth factor receptor (EGFR) inhibitors are approved for use as targeted chemotherapeutic agents against multiple solid-organ malignancies. The most common side effect associated with EGFR inhibitor therapy is a papulopustular eruption, which can easily be confused with bacterial folliculitis. In this study, we examine the relative timing and location of the EGFR-induced papulopustular eruption compared to the associated bacterial superinfections.
Methods
In this retrospective chart review, patients enrolled in our institution’s IRB-approved prospective registry of cutaneous reactions to chemotherapy were screened for inclusion. All patients who received an EGFR inhibitor and developed either a papulopustular eruption or bacterial superinfection at some point during treatment were included.
Results
Of the 157 patients who met inclusion criteria, 36 (23 %) developed bacterial superinfections at some point during EGFR therapy. Papulopustular eruptions developed in a highly predictable time course, with a mean time to onset of 1.5 weeks and mean duration of 9.4 weeks. Bacterial superinfections occurred at widely variable time points during therapy with a mean time to onset of 27.7 weeks. Papulopustular eruptions much more frequently affected the face (97 %), chest (75 %), and back (61 %), while bacterial superinfections occurred more commonly on the upper extremity (64 %), lower extremity (47 %), and abdomen (39 %).
Conclusions
The EGFR inhibitor-induced papulopustular eruption has a stereotypical time course and occurs in a characteristic distribution affecting the central face, upper chest, and back. Bacterial superinfections more frequently affect the extremities, abdomen, and groin and may occur at any point during EGFR therapy.
Similar content being viewed by others
References
Yarden Y (2001) The EGFR family and its ligands in human cancer: signalling mechanisms and therapeutic opportunities. Eur J Cancer 37:S3–S8
Sibilia M, Kroismayr R, Lichtenberger BM, Natarajan A, Hecking M, Holcmann M (2007) The epidermal growth factor receptor: from development to tumorigenesis. Differentiation 75:770–787
Dancey J, Sausville EA (2003) Issues and progress with protein kinase inhibitors for cancer treatment. Nat Rev Drug Discov 2:296–313
Lacouture ME, Anadkat MJ, Bensadoun RJ, MASCC Skin Toxicity Study Group et al (2011) Clinical practice guidelines for the prevention and treatment of EGFR inhibitor-associated dermatologic toxicities. Support Care Cancer 19:1079–1095
Racca P, Fanchini L, Caliendo V et al (2008) Efficacy and skin toxicity management with cetuximab in metastatic colorectal cancer: outcomes from an oncologic/dermatologic cooperation. Clin Colorectal Cancer 7:48–54
Roé E, García Muret MP, Marcuello E, Capdevila J, Pallares C, Alomar A (2006) Description and management of cutaneous side effects during cetuximab or erlotinib treatments: a prospective study of 30 patients. J Am Acad Dermatol 55:429–437
Eilers RE Jr, Gandhi M, Patel JD et al (2010) Dermatologic infections in cancer patients treated with epidermal growth factor receptor inhibitor therapy. J Natl Cancer Inst 102:47–53
Grenader T, Gipps M, Goldberg A (2008) Staphylococcus aureus bacteremia secondary to severe erlotinib skin toxicity. Clin Lung Cancer 9:59–60
Li J, Peccerillo J, Kaley K, Saif MW (2009) Staphylococcus aureus bacteremia related with erlotinib skin toxicity in a patient with pancreatic cancer. JOP 10:338–340
National Cancer Institute: Common Terminology Criteria for Adverse Events v4.0 (2009) NCI, NIH, DHHS. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. Accessed 13 April 2015
Lacouture ME (2006) Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer 6:803–812
Jost M, Kari C, Rodeck U (2000) The EGF receptor—an essential regulator of multiple epidermal functions. Eur J Dermatol 10:505–510
Nanney LB, Stoscheck CM, King LE Jr, Underwood RA, Holbrook KA (1990) Immunolocalization of epidermal growth factor receptors in normal developing human skin. J Invest Dermatol 94:742–748
Threadgill DW, Dlugosz AA, Hansen LA et al (1995) Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype. Science 269:230–234
Mascia F, Mariani V, Girolomoni G, Pastore S (2003) Blockade of the EGF receptor induces a deranged chemokine expression in keratinocytes leading to enhanced skin inflammation. Am J Pathol 163:303–312
Guttman-Yassky E, Mita A, De Jonge M et al (2010) Characterisation of the cutaneous pathology in non-small cell lung cancer (NSCLC) patients treated with the EGFR tyrosine kinase inhibitor erlotinib. Eur J Cancer 46:2010–2019
Brodell LA, Hepper D, Lind A, Gru AA, Anadkat MJ (2013) Histopathology of acneiform eruptions in patients treated with epidermal growth factor receptor inhibitors. J Cutan Pathol 40:865–870
Rosen AC, Case EC, Dusza SW et al (2013) Impact of dermatologic adverse events on quality of life in 283 cancer patients: a questionnaire study in a dermatology referral clinic. Am J Clin Dermatol 14:327–333
Joshi SS, Ortiz S, Witherspoon JN et al (2010) Effects of epidermal growth factor receptor inhibitor-induced dermatologic toxicities on quality of life. Cancer 116:3916–3923
Boone SL, Rademaker A, Liu D, Pfeiffer C, Mauro DJ, Lacouture ME (2007) Impact and management of skin toxicity associated with anti-epidermal growth factor receptor therapy: survey results. Oncology 72:152–159
Hassel JC, Kripp M, Al-Batran S, Hofheinz RD (2010) Treatment of epidermal growth factor receptor antagonist-induced skin rash: results of a survey among German oncologists. Onkologie 33:94–98
Iressa [package insert] (2010). Mississauga, Ontario: AstraZeneca Pharmaceuticals
Tarceva [package insert] (2012). Northbrook, IL: OSI Pharmaceuticals
Erbitux [package insert] (2013). Princeton, NJ: ImClone LLC
Vectibix [package insert] (2014). Thousand Oaks, CA: Amgen Inc
Gilotrif [package insert] (2014). Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc
Wu PA, Balagula Y, Lacouture ME, Anadkat MJ (2011) Prophylaxis and treatment of dermatologic adverse events from epidermal growth factor receptor inhibitors. Curr Opin Oncol 23:343–351
Liu HB, Wu Y, Lv TF et al (2013) Skin rash could predict the response to EGFR tyrosine kinase inhibitor and the prognosis for patients with non-small cell lung cancer: a systematic review and meta-analysis. PLoS One 8:e55128
Stintzing S, Kapaun C, Laubender RP et al (2013) Prognostic value of cetuximab-related skin toxicity in metastatic colorectal cancer patients and its correlation with parameters of the epidermal growth factor receptor signal transduction pathway: results from a randomized trial of the GERMAN AIO CRC Study Group. Int J Cancer 132:236–245
Bonner JA, Harari PM, Giralt J et al (2010) Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol 11:21–28
Aranda E, Manzano JL, Rivera F et al (2012) Phase II open-label study of erlotinib in combination with gemcitabine in unresectable and/or metastatic adenocarcinoma of the pancreas: relationship between skin rash and survival (Pantar study). Ann Oncol 23:1919–1925
Chiang HC, Anadkat MJ (2013) Isotretinoin for high-grade or refractory epidermal growth factor receptor inhibitor-related acneiform papulopustular eruptions. J Am Acad Dermatol 69:657–658
Ruiz JN, Belum VR, Boers-Doets CB et al (2015) Nasal vestibulitis due to targeted therapies in cancer patients. Support Care Cancer 23(8):2391–2398
Lichtenberger BM, Gerber PA, Holcmann M et al (2013) Epidermal EGFR controls cutaneous host defense and prevents inflammation. Sci Transl Med 5(199):199ra111
Luo Q, Gu Y, Zheng W et al (2011) Erlotinib inhibits T-cell-mediated immune response via down-regulation of the c-Raf/ERK cascade and Akt signaling pathway. Toxicol Appl Pharmacol 251(2):130–136
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors. Informed consent was obtained from all individual participants included in the study, and additional informed consent was obtained from all individual participants for whom identifying information is included in this article.
Rights and permissions
About this article
Cite this article
Braden, R.L., Anadkat, M.J. EGFR inhibitor-induced skin reactions: differentiating acneiform rash from superimposed bacterial infections. Support Care Cancer 24, 3943–3950 (2016). https://doi.org/10.1007/s00520-016-3231-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00520-016-3231-1