Targeted Oncology

, Volume 4, Issue 2, pp 107–119 | Cite as

Skin toxicities associated with epidermal growth factor receptor inhibitors

  • Tianhong LiEmail author
  • Roman Perez-Soler


The use of epidermal growth factor receptor (EGFR) inhibitors in several epithelial tumors has increased considerably in recent years. Currently, they are approved in non-small cell lung cancer (NSCLC), pancreatic cancer, colorectal cancer and head and neck cancer. Skin toxicity is a class-specific side effect that is typically manifested as a papulopustular rash in the majority (45–100%) of patients receiving EGFR inhibitors. The skin toxicity is related to the inhibition of EGFR in the skin, which is crucial for the normal development and physiology of the epidermis. Although rarely life-threatening, skin toxicity may cause significant physical and psycho-social discomfort. Nevertheless, the presence and severity of skin rash is associated with improved clinical efficacy in patients receiving EGFR inhibitors. The goal of managing EGFR inhibitor-associated skin toxicity is to minimize the detrimental effects of the rash on patients' quality of life and treatment course without antagonizing the clinical efficacy of EGFR inhibitors. There is currently no evidence-based treatment guideline to prevent or treat the EGFR inhibitor-associated skin toxicities. Expert panels recommend a proactive, multidisciplinary approach that includes patient education and the use of a grade-based treatment algorithm. Elucidation of the mechanisms of EGFR inhibitor-associated skin toxicity and development of mechanism-based novel therapies are urgently needed. Preclinical data suggest topical application of a potent phosphatase inhibitor menadione (Vitamin K3) can rescue the inhibition of EGFR and downstream signaling molecules in the skin of mice receiving systemic EGFR inhibitor erlotinib or cetuximab. A randomized, double-blinded, placebo-controlled study has been initiated to evaluate the clinical efficacy of menadione topical cream, in the treatment or prevention of EGFR inhibitor-induced skin toxicity.


Epidermal growth factor receptor EGFR inhibitor Skin toxicity Rash Phosphatase inhibitor Menadione 


Conflict of interest statement

No funds were received in support of this study.


  1. 1.
    Mendelsohn J, Baselga J (2003) Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol 21:2787–2799CrossRefPubMedGoogle Scholar
  2. 2.
    Hynes NE, Lane HA (2005) ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 5:341–354CrossRefPubMedGoogle Scholar
  3. 3.
    Cunningham D, Humblet Y, Siena S et al (2004) Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337–345CrossRefPubMedGoogle Scholar
  4. 4.
    Shepherd FA, Rodrigues Pereira J, Ciuleanu T et al (2005) Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353:123–132CrossRefPubMedGoogle Scholar
  5. 5.
    Moore MJ, Goldstein D, Hamm J et al (2007) Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada clinical trials group. J Clin Oncol 25:1960–1966CrossRefPubMedGoogle Scholar
  6. 6.
    Burtness B, Goldwasser MA, Flood W et al (2005) Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern cooperative oncology group study. J Clin Oncol 23:8646–8654CrossRefPubMedGoogle Scholar
  7. 7.
    Vermorken JB, Mesia R, Rivera F et al (2008) Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 359:1116–1127CrossRefPubMedGoogle Scholar
  8. 8.
    Van Cutsem E, Peeters M, Siena S et al (2007) Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 25:1658–1664CrossRefPubMedGoogle Scholar
  9. 9.
    Thatcher N, Chang A, Parikh P et al (2005) Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 366:1527–1537CrossRefPubMedGoogle Scholar
  10. 10.
    Sequist LV, Bell DW, Lynch TJ et al (2007) Molecular predictors of response to epidermal growth factor receptor antagonists in non-small-cell lung cancer. J Clin Oncol 25:587–595CrossRefPubMedGoogle Scholar
  11. 11.
    Rivera F, Vega-Villegas ME, Lopez-Brea MF et al (2008) Current situation of panitumumab, matuzumab, nimotuzumab and zalutumumab. Acta Oncol 47:9–19CrossRefPubMedGoogle Scholar
  12. 12.
    Socinski MA (2007) Antibodies to the epidermal growth factor receptor in non small cell lung cancer: current status of matuzumab and panitumumab. Clin Cancer Res 13:s4597–4601CrossRefPubMedGoogle Scholar
  13. 13.
    Dancey J, Sausville EA (2003) Issues and progress with protein kinase inhibitors for cancer treatment. Nat Rev Drug Discov 2:296–313CrossRefPubMedGoogle Scholar
  14. 14.
    Robert C, Soria JC, Spatz A et al (2005) Cutaneous side-effects of kinase inhibitors and blocking antibodies. Lancet Oncol 6:491–500CrossRefPubMedGoogle Scholar
  15. 15.
    Perez-Soler R, Saltz L (2005) Cutaneous adverse effects with HER1/EGFR-targeted agents: is there a silver lining? J Clin Oncol 23:5235–5246CrossRefPubMedGoogle Scholar
  16. 16.
    Perez-Soler R, Delord JP, Halpern A et al (2005) HER1/EGFR inhibitor-associated rash: future directions for management and investigation outcomes from the HER1/EGFR inhibitor rash management forum. Oncologist 10:345–356CrossRefPubMedGoogle Scholar
  17. 17.
    Solomon BM, Jatoi A (2008) Rash from EGFR inhibitors: opportunities and challenges for palliation. Curr Oncol Rep 10:304–308CrossRefPubMedGoogle Scholar
  18. 18.
    Jatoi A, Nguyen PL (2008) Do patients die from rashes from epidermal growth factor receptor inhibitors? A systematic review to help counsel patients about holding therapy. Oncologist 13:1201–1204CrossRefPubMedGoogle Scholar
  19. 19.
    Gridelli C, Maione P, Amoroso D et al (2008) Clinical significance and treatment of skin rash from erlotinib in non-small cell lung cancer patients: results of an Experts Panel Meeting. Crit Rev Oncol Hematol 66:155–162CrossRefPubMedGoogle Scholar
  20. 20.
    Wagner LI, Lacouture ME (2007) Dermatologic toxicities associated with EGFR inhibitors: the clinical psychologist's perspective. Impact on health-related quality of life and implications for clinical management of psychological sequelae. Oncology (Williston Park) 21:34–36Google Scholar
  21. 21.
    Perez-Soler R (2004) Phase II clinical trial data with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib (OSI-774) in non-small-cell lung cancer. Clin Lung Cancer 6(Suppl 1):S20–23CrossRefPubMedGoogle Scholar
  22. 22.
    Perez-Soler R (2006) Rash as a surrogate marker for efficacy of epidermal growth factor receptor inhibitors in lung cancer. Clin Lung Cancer 8(Suppl 1):S7–14PubMedGoogle Scholar
  23. 23.
    Wacker B, Nagrani T, Weinberg J et al (2007) Correlation between development of rash and efficacy in patients treated with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in two large phase III studies. Clin Cancer Res 13:3913–3921CrossRefPubMedGoogle Scholar
  24. 24.
    Lacouture ME (2006) Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer 6:803–812CrossRefPubMedGoogle Scholar
  25. 25.
    Busam KJ, Capodieci P, Motzer R et al (2001) Cutaneous side-effects in cancer patients treated with the anti-epidermal growth factor receptor antibody C225. Br J Dermatol 144:1169–1176CrossRefPubMedGoogle Scholar
  26. 26.
    Segaert S, Van Cutsem E (2005) Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors. Ann Oncol 16:1425–1433CrossRefPubMedGoogle Scholar
  27. 27.
    Agero AL, Dusza SW, Benvenuto-Andrade C et al (2006) Dermatologic side effects associated with the epidermal growth factor receptor inhibitors. J Am Acad Dermatol 55:657–670CrossRefPubMedGoogle Scholar
  28. 28.
    Hu JC, Sadeghi P, Pinter-Brown LC et al (2007) Cutaneous side effects of epidermal growth factor receptor inhibitors: clinical presentation, pathogenesis, and management. J Am Acad Dermatol 56:317–326CrossRefPubMedGoogle Scholar
  29. 29.
    Braiteh F, Kurzrock R, Johnson FM (2008) Trichomegaly of the eyelashes after lung cancer treatment with the epidermal growth factor receptor inhibitor erlotinib. J Clin Oncol 26:3460–3462CrossRefPubMedGoogle Scholar
  30. 30.
    Perez-Soler R, Chachoua A, Hammond LA et al (2004) Determinants of tumor response and survival with erlotinib in patients with non-small-cell lung cancer. J Clin Oncol 22:3238–3247CrossRefPubMedGoogle Scholar
  31. 31.
    Tan AR, Yang X, Hewitt SM et al (2004) Evaluation of biologic end points and pharmacokinetics in patients with metastatic breast cancer after treatment with erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor. J Clin Oncol 22:3080–3090CrossRefPubMedGoogle Scholar
  32. 32.
    Baselga J, Albanell J, Ruiz A et al (2005) Phase II and tumor pharmacodynamic study of gefitinib in patients with advanced breast cancer. J Clin Oncol 23:5323–5333CrossRefPubMedGoogle Scholar
  33. 33.
    Calvo E, Malik SN, Siu LL et al (2007) Assessment of erlotinib pharmacodynamics in tumors and skin of patients with head and neck cancer. Ann Oncol 18:761–767CrossRefPubMedGoogle Scholar
  34. 34.
    Investigator’s Brochure: OSI 774 (Erlotinib TOP), dated February 15, 2007Google Scholar
  35. 35.
    Wheatley-Price P, Ding K, Seymour L et al (2008) Erlotinib for advanced non-small-cell lung cancer in the elderly: an analysis of the National Cancer Institute of Canada clinical trials group study BR.21. J Clin Oncol 26:2350–2357CrossRefPubMedGoogle Scholar
  36. 36.
    Besse B, Smit EF, Felip E et al (2008) A phase II study of first-line erlotinib in patients (pts) with stage IIIB/IV non-small-cell lung cancer (NSCLC) including dose escalation to toxicity in current and former smokers (C/FS). J Clin Oncol (Meeting Abstracts) 26:8111-Google Scholar
  37. 37.
    Rowinsky EK, Schwartz GH, Gollob JA et al (2004) Safety, pharmacokinetics, and activity of ABX-EGF, a fully human anti-epidermal growth factor receptor monoclonal antibody in patients with metastatic renal cell cancer. J Clin Oncol 22:3003–3015CrossRefPubMedGoogle Scholar
  38. 38.
    Liu W, Innocenti F, Wu MH et al (2005) A functional common polymorphism in a Sp1 recognition site of the epidermal growth factor receptor gene promoter. Cancer Res 65:46–53PubMedGoogle Scholar
  39. 39.
    Buerger H, Gebhardt F, Schmidt H et al (2000) Length and loss of heterozygosity of an intron 1 polymorphic sequence of egfr is related to cytogenetic alterations and epithelial growth factor receptor expression. Cancer Res 60:854–857PubMedGoogle Scholar
  40. 40.
    Gebhardt F, Zanker KS, Brandt B (1999) Modulation of epidermal growth factor receptor gene transcription by a polymorphic dinucleotide repeat in intron 1. J Biol Chem 274:13176–13180CrossRefPubMedGoogle Scholar
  41. 41.
    Amador ML, Oppenheimer D, Perea S et al (2004) An epidermal growth factor receptor intron 1 polymorphism mediates response to epidermal growth factor receptor inhibitors. Cancer Res 64:9139–9143CrossRefPubMedGoogle Scholar
  42. 42.
    Cusatis G, Sparreboom A (2008) Pharmacogenomic importance of ABCG2. Pharmacogenomics 9:1005–1009CrossRefPubMedGoogle Scholar
  43. 43.
    Li J, Cusatis G, Brahmer J et al (2007) Association of variant ABCG2 and the pharmacokinetics of epidermal growth factor receptor tyrosine kinase inhibitors in cancer patients. Cancer Biol Ther 6:432–438PubMedGoogle Scholar
  44. 44.
    Rudin CM, Liu W, Desai A et al (2008) Pharmacogenomic and pharmacokinetic determinants of erlotinib toxicity. J Clin Oncol 26:1119–1127CrossRefPubMedGoogle Scholar
  45. 45.
    Cusatis G, Gregorc V, Li J et al (2006) Pharmacogenetics of ABCG2 and adverse reactions to gefitinib. J Natl Cancer Inst 98:1739–1742PubMedCrossRefGoogle Scholar
  46. 46.
    Kanazawa S, Muramatsu M, Kinoshita Y et al (2005) Gefitinib has the potential of activating cell immunity against malignant cells. J Clin Oncol 23:3865–3866 author reply 3866–3867CrossRefPubMedGoogle Scholar
  47. 47.
    Kanazawa S, Yamaguchi K, Kinoshita Y et al (2006) Elevation of soluble interleukin-2 receptor in patients with non-small cell lung cancer treated with gefitinib. J Cancer Res Clin Oncol 132:719–725CrossRefPubMedGoogle Scholar
  48. 48.
    Nyati MK, Morgan MA, Feng FY et al (2006) Integration of EGFR inhibitors with radiochemotherapy. Nat Rev Cancer 6:876–885CrossRefPubMedGoogle Scholar
  49. 49.
    Budach W, Bolke E, Homey B (2007) Severe cutaneous reaction during radiation therapy with concurrent cetuximab. N Engl J Med 357:514–515CrossRefPubMedGoogle Scholar
  50. 50.
    Bonner JA, Ang K (2007) More on severe cutaneous reaction with radiotherapy and cetuximab. N Engl J Med 357:1872–1873 author reply 1873CrossRefPubMedGoogle Scholar
  51. 51.
    Mitra SS, Simcock R (2006) Erlotinib induced skin rash spares skin in previous radiotherapy field. J Clin Oncol 24:e28–29CrossRefPubMedGoogle Scholar
  52. 52.
    Lacouture ME, Hwang C, Marymont MH et al (2007) Temporal dependence of the effect of radiation on erlotinib-induced skin rash. J Clin Oncol 25:2140 author reply 2141CrossRefPubMedGoogle Scholar
  53. 53.
    Gerber PA, Enderlein E, Homey B et al (2007) Radiation-induced prevention of erlotinib-induced skin rash is transient: a new aspect toward the understanding of epidermal growth factor receptor inhibitor associated cutaneous adverse effects. J Clin Oncol 25:4697–4698 author reply 4698–4699CrossRefPubMedGoogle Scholar
  54. 54.
    Jost M, Kari C, Rodeck U (2000) The EGF receptor—an essential regulator of multiple epidermal functions. Eur J Dermatol 10:505–510PubMedGoogle Scholar
  55. 55.
    Murillas R, Larcher F, Conti CJ et al (1995) 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 14:5216–5223PubMedGoogle Scholar
  56. 56.
    Peus D, Hamacher L, Pittelkow MR (1997) EGF-receptor tyrosine kinase inhibition induces keratinocyte growth arrest and terminal differentiation. J Invest Dermatol 109:751–756CrossRefPubMedGoogle Scholar
  57. 57.
    Woodworth CD, Michael E, Marker D et al (2005) Inhibition of the epidermal growth factor receptor increases expression of genes that stimulate inflammation, apoptosis, and cell attachment. Mol Cancer Ther 4:650–658CrossRefPubMedGoogle Scholar
  58. 58.
    Agulnik M, da Cunha Santos G, Hedley D et al (2007) Predictive and pharmacodynamic biomarker studies in tumor and skin tissue samples of patients with recurrent or metastatic squamous cell carcinoma of the head and neck treated with erlotinib. J Clin Oncol 25:2184–2190CrossRefPubMedGoogle Scholar
  59. 59.
    Albanell J, Rojo F, Averbuch S et al (2002) Pharmacodynamic studies of the epidermal growth factor receptor inhibitor ZD1839 in skin from cancer patients: histopathologic and molecular consequences of receptor inhibition. J Clin Oncol 20:110–124CrossRefPubMedGoogle Scholar
  60. 60.
    Higgins B, Kolinsky K, Smith M et al (2004) Antitumor activity of erlotinib (OSI-774, Tarceva) alone or in combination in human non-small cell lung cancer tumor xenograft models. Anticancer Drugs 15:503–512CrossRefPubMedGoogle Scholar
  61. 61.
    Pastore S, Mascia F, Mariotti F et al (2005) ERK1/2 regulates epidermal chemokine expression and skin inflammation. J Immunol 174:5047–5056PubMedGoogle Scholar
  62. 62.
    Jost M, Huggett TM, Kari C et al (2001) Epidermal growth factor receptor-dependent control of keratinocyte survival and Bcl-xL expression through a MEK-dependent pathway. J Biol Chem 276:6320–6326CrossRefPubMedGoogle Scholar
  63. 63.
    Vallbohmer D, Zhang W, Gordon M et al (2005) Molecular determinants of cetuximab efficacy. J Clin Oncol 23:3536–3544CrossRefPubMedGoogle Scholar
  64. 64.
    Kimura H, Kasahara K, Sekijima M et al (2005) Plasma MIP-1beta levels and skin toxicity in Japanese non-small cell lung cancer patients treated with the EGFR-targeted tyrosine kinase inhibitor, gefitinib. Lung Cancer 50:393–399CrossRefPubMedGoogle Scholar
  65. 65.
    El-Abaseri TB, Putta S, Hansen LA (2006) Ultraviolet irradiation induces keratinocyte proliferation and epidermal hyperplasia through the activation of the epidermal growth factor receptor. Carcinogenesis 27:225–231CrossRefPubMedGoogle Scholar
  66. 66.
    Mascia F, Mariani V, Girolomoni G et al (2003) Blockade of the EGF receptor induces a deranged chemokine expression in keratinocytes leading to enhanced skin inflammation. Am J Pathol 163:303–312PubMedGoogle Scholar
  67. 67.
    Segaert S, Tabernero J, Chosidow O et al (2005) The management of skin reactions in cancer patients receiving epidermal growth factor receptor targeted therapies. J Dtsch Dermatol Ges 3:599–606CrossRefPubMedGoogle Scholar
  68. 68.
    Lynch TJ Jr, Kim ES, Eaby B et al (2007) Epidermal growth factor receptor inhibitor-associated cutaneous toxicities: an evolving paradigm in clinical management. Oncologist 12:610–621CrossRefPubMedGoogle Scholar
  69. 69.
    Wagner L, Lai SE, Aneja M (2007) Development of a functional assessment of side-effects to therapy (FAST) questionnaire to assess dermatology-related quality of life in patients treated with EGFR inhibitors (EGFRI): The FAST-EGFRI. ASCO Meeting Abstracts 25:19532-Google Scholar
  70. 70.
    Grenader T, Gipps M, Goldberg A (2008) Staphylococcus aureus bacteremia secondary to severe erlotinib skin toxicity Clin Lung Cancer 9:59–60Google Scholar
  71. 71.
    Kardaun SH, van Duinen KF (2008) Erlotinib-induced florid acneiform rash complicated by extensive impetiginization. Clin Exp Dermatol 33:46–49PubMedGoogle Scholar
  72. 72.
    Jatoi A, Rowland K, Sloan JA et al (2008) Tetracycline to prevent epidermal growth factor receptor inhibitor-induced skin rashes: results of a placebo-controlled trial from the North Central Cancer Treatment Group (N03CB). Cancer 113:847–853CrossRefPubMedGoogle Scholar
  73. 73.
    Scope A, Agero AL, Dusza SW et al (2007) Randomized double-blind trial of prophylactic oral minocycline and topical tazarotene for cetuximab-associated acne-like eruption. J Clin Oncol 25:5390–5396CrossRefPubMedGoogle Scholar
  74. 74.
    Perez-Soler R, Zou Y, Li T et al (2006) Topical vitamin K3 (Vit K3, Menadione) prevents erlotinib and cetuximab-induced EGFR inhibition in the skin. J Clin Oncol 24(Supplement):3036aGoogle Scholar
  75. 75.
    Laux I, Jain A, Singh S et al (2006) Epidermal growth factor receptor dimerization status determines skin toxicity to HER-kinase targeted therapies. Br J Cancer 94:85–92CrossRefPubMedGoogle Scholar
  76. 76.
    Perez-Soler R, Zou Y, Li T et al (2007) Steroids and immunosuppressive agents potentiate the cytotoxicity of the EGFR inhibitor erlotinib (E) in human skin keratinocytes whereas Vit K3 exerts a protective effect: Implications for the management of the skin rash. ASCO Meeting Abstracts 25:9124–Google Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  1. 1.Department of Oncology, Montefiore Medical CenterAlbert Einstein College of MedicineBronxUSA

Personalised recommendations