Management of EGFR-inhibitor associated rash: a retrospective study in 49 patients

Peter Arne Gerber, Stephan Meller, Tatiana Eames, Bettina Alexandra Buhren, Holger Schrumpf, Sonja Hetzer, Laura Maximiliane Ehmann, Wilfried Budach, Edwin Bölke, Christiane Matuschek, Andreas Wollenberg, Bernhard Homey, Peter Arne Gerber, Stephan Meller, Tatiana Eames, Bettina Alexandra Buhren, Holger Schrumpf, Sonja Hetzer, Laura Maximiliane Ehmann, Wilfried Budach, Edwin Bölke, Christiane Matuschek, Andreas Wollenberg, Bernhard Homey

Abstract

Background: In recent years inhibitors directed against the epidermal growth factor receptor (EGFR) have evolved as effective targeting cancer drugs. Characteristic papulopustular exanthemas, often described as acneiform rashes, are the most frequent adverse effect associated with this class of novel cancer drugs and develop in > 90% of patients. Notably, the rash may significantly compromise the patients' quality of life, thereby potentially leading to incompliance as well as dose reduction or even termination of the anti-EGFR therapy. Yet, an effective dermatologic management of cutaneous adverse effects can be achieved. Whereas various case reports, case series or expert opinions on the management of EGFR-inhibitor (EGFRI) induced rashes have been published, data on systematic management studies are sparse.

Methods: Here, we present a retrospective, uncontrolled, comparative study in 49 patients on three established regimens for the management of EGFRI-associated rashes.

Results: Strikingly, patients' rash severity improved significantly over three weeks of treatment with topical mometason furoate cream, topical prednicarbate cream plus nadifloxacin cream, as well as topical prednicarbate cream plus nadifloxacin cream plus systemic isotretinoin.

Conclusions: In summary our results demonstrate that EGFRI-associated rashes can be effectively managed by specific dermatologic interventions. Whereas mild to moderate rashes should be treated with basic measures in combination with topical glucocorticosteroids or combined regiments using glucocorticosteroids and antiseptics/antibiotics, more severe or therapy-resistant rashes are likely to respond with the addition of systemic retinoids.

Figures

Figure 1
Figure 1
Severity of EGFRI-induced papulopustular rashes. Rash severity was assessed using the EGFRI-induced rash severity score (ERSS). ERSSs may range from 0 (no skin affection), over (A) 1 to 20 (mild), (B) 20 to 40 (moderate), up to (C) scores exceeding 40 points, indicating severe cases.
Figure 2
Figure 2
Significant improvement of rash severity under specific dermatologic measures. (A) Topical mometason furoate cream significantly (P = 0.0009) improved the severity of the skin rash (ERSS) in patients treated with EGFRI after three weeks. (B) A combined topical regimen with prednicarbate cream and nadifloxacin cream significantly (P = 0.03) improved the ERSS in patients treated with EGFRI after three weeks. (C) A triple therapy with topical prednicarbate cream, topical nadifloxacin cream and systemic isotretinoin significantly (P = 0.015) improved the ERSS in patients treated with EGFRI after three weeks. Statistical analyses were performed applying the Student's t-test.

References

    1. Ciardiello F, Tortora G. EGFR antagonists in cancer treatment. N Engl J Med. 2008;358:1160–1174. doi: 10.1056/NEJMra0707704.
    1. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, Hogg D, Lorigan P, Lebbe C, Jouary T, Schadendorf D, Ribas A, O'Day SJ, Sosman JA, Kirkwood JM, Eggermont AM, Dreno B, Nolop K, Li J, Nelson B, Hou J, Lee RJ, Flaherty KT, McArthur GA. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507–2516. doi: 10.1056/NEJMoa1103782.
    1. Gerber PA, Buhren BA, Kurle S, Homey B. [Therapy with epidermal growth factor receptor inhibitors. Clinical spectrum of cutaneous adverse effects] Hautarzt. 2010;61:654–661. doi: 10.1007/s00105-010-1943-6.
    1. Gerber PA, Buhren BA, Steinhoff M, Homey B. Rosacea: the cytokine and chemokine network. J Investig Dermatol Symp Proc. 2011;15:40–47. doi: 10.1038/jidsymp.2011.9.
    1. Gutzmer R, Becker JC, Enk A, Garbe C, Hauschild A, Leverkus M, Reimer G, Treudler R, Tsianakas A, Ulrich C, Wollenberg A, Homey B. Management of cutaneous side effects of EGFR inhibitors: recommendations from a German expert panel for the primary treating physician. J Dtsch Dermatol Ges. 2011;9:195–203.
    1. Potthoff K, Hofheinz R, Hassel JC, Volkenandt M, Lordick F, Hartmann JT, Karthaus M, Riess H, Lipp HP, Hauschild A, Trarbach T, Wollenberg A. Interdisciplinary management of EGFR-inhibitor-induced skin reactions: a German expert opinion. Ann Oncol. 2011;22:524–535. doi: 10.1093/annonc/mdq387.
    1. Eames T, Kroth J, Flaig MJ, Ruzicka T, Wollenberg A. Perifollicular xanthomas associated with epidermal growth factor receptor inhibitor therapy. Acta Derm Venereol. 2010;90:202–203. doi: 10.2340/00015555-0792.
    1. Perez-Soler R, Chachoua A, Hammond LA, Rowinsky EK, Huberman M, Karp D, Rigas J, Clark GM, Santabarbara P, Bonomi P. Determinants of tumor response and survival with erlotinib in patients with non-small-cell lung cancer. J Clin Oncol. 2004;22:3238–3247. doi: 10.1200/JCO.2004.11.057.
    1. Wacker B, Nagrani T, Weinberg J, Witt K, Clark G, Cagnoni PJ. 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. 2007;13:3913–3921. doi: 10.1158/1078-0432.CCR-06-2610.
    1. Eilers RE Jr, Gandhi M, Patel JD, Mulcahy MF, Agulnik M, Hensing T, Lacouture ME. Dermatologic infections in cancer patients treated with epidermal growth factor receptor inhibitor therapy. J Natl Cancer Inst. 2010;102:47–53. doi: 10.1093/jnci/djp439.
    1. Forton F, Seys B. Density of Demodex folliculorum in rosacea: a case-control study using standardized skin-surface biopsy. Br J Dermatol. 1993;128:650–659. doi: 10.1111/j.1365-2133.1993.tb00261.x.
    1. Gerber PA, Buhren BA, Cevikbas F, Bolke E, Steinhoff M, Homey B. Preliminary evidence for a role of mast cells in epidermal growth factor receptor inhibitor-induced pruritus. J Am Acad Dermatol. 2010;63:163–165. doi: 10.1016/j.jaad.2009.09.023.
    1. Gerber PA, Buhren BA, Homey B. More on aprepitant for erlotinib-induced pruritus. N Engl J Med. 2011;364:486–487.
    1. Gerber PA, Homey B. Images in clinical medicine. Erlotinib-induced hair alterations. N Engl J Med. 2008;358:1175. doi: 10.1056/NEJMicm073144.
    1. Shah NT, Kris MG, Pao W, Tyson LB, Pizzo BM, Heinemann MH, Ben-Porat L, Sachs DL, Heelan RT, Miller VA. Practical management of patients with non-small-cell lung cancer treated with gefitinib. J Clin Oncol. 2005;23:165–174.
    1. Wollenberg A, Kroth J, Hauschild A, Dirschka T. Cutaneous side effects of EGFR inhibitors-appearance and management. Dtsch Med Wochenschr. 2010;135:149–154. doi: 10.1055/s-0029-1244831.
    1. Bernier J, Russi EG, Homey B, Merlano MC, Mesia R, Peyrade F, Budach W. Management of radiation dermatitis in patients receiving cetuximab and radiotherapy for locally advanced squamous cell carcinoma of the head and neck: proposals for a revised grading system and consensus management guidelines. Ann Oncol. 2011;22:2191–2200. doi: 10.1093/annonc/mdr139.
    1. Bolke E, Gerber PA, Lammering G, Peiper M, Muller-Homey A, Pape H, Giro C, Matuschek C, Bruch-Gerharz D, Hoffmann TK, Gripp S, Homey B, Budach W. Development and management of severe cutaneous side effects in head-and-neck cancer patients during concurrent radiotherapy and cetuximab. Strahlenther Onkol. 2008;184:105–110. doi: 10.1007/s00066-008-1829-z.
    1. Budach W, Bolke E, Homey B. Severe cutaneous reaction during radiation therapy with concurrent cetuximab. N Engl J Med. 2007;357:514–515. doi: 10.1056/NEJMc071075.
    1. Sartor CI. Mechanisms of disease: Radiosensitization by epidermal growth factor receptor inhibitors. Nat Clin Pract Oncol. 2004;1:80–87.
    1. Gerber PA, Enderlein E, Homey B, Muller A, Boelke E, Budach W. 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. 2007;25:4697–4698. doi: 10.1200/JCO.2007.12.8330. author reply 4698-4699.
    1. Bernier J, Bonner J, Vermorken JB, Bensadoun RJ, Dummer R, Giralt J, Kornek G, Hartley A, Mesia R, Robert C, Segaert S, Ang KK. Consensus guidelines for the management of radiation dermatitis and coexisting acne-like rash in patients receiving radiotherapy plus EGFR inhibitors for the treatment of squamous cell carcinoma of the head and neck. Ann Oncol. 2008;19:142–149.
    1. Gutzmer R, Werfel T, Mao R, Kapp A, Elsner J. Successful treatment with oral isotretinoin of acneiform skin lesions associated with cetuximab therapy. Br J Dermatol. 2005;153:849–851. doi: 10.1111/j.1365-2133.2005.06835.x.
    1. Katzer K, Tietze J, Klein E, Heinemann V, Ruzicka T, Wollenberg A. Topical therapy with nadifloxacin cream and prednicarbate cream improves acneiform eruptions caused by the EGFR-inhibitor cetuximab - A report of 29 patients. Eur J Dermatol. 2010;20:82–84.
    1. Wollenberg A, Moosmann N, Kroth J, Heinemann V, Klein E. Therapy of severe cetuximab-induced acneiform eruptions with oral retinoid, topical antibiotic and topical corticosteroid. Hautarzt. 2007;58:615–618. doi: 10.1007/s00105-006-1256-y.
    1. Wollenberg A, Moosmann N, Klein E, Katzer K. A tool for scoring of acneiform skin eruptions induced by EGF receptor inhibition. Exp Dermatol. 2008;17:790–792. doi: 10.1111/j.1600-0625.2008.00715.x.
    1. Tokumaru S, Sayama K, Shirakata Y, Komatsuzawa H, Ouhara K, Hanakawa Y, Yahata Y, Dai X, Tohyama M, Nagai H, Yang L, Higashiyama S, Yoshimura A, Sugai M, Hashimoto K. Induction of keratinocyte migration via transactivation of the epidermal growth factor receptor by the antimicrobial peptide LL-37. J Immunol. 2005;175:4662–4668.
    1. Prakash A, Benfield P. Topical mometasone. A review of its pharmacological properties and therapeutic use in the treatment of dermatological disorders. Drugs. 1998;55:145–163. doi: 10.2165/00003495-199855010-00009.
    1. Powell FC. Clinical practice. Rosacea. N Engl J Med. 2005;352:793–803. doi: 10.1056/NEJMcp042829.
    1. Schoepe S, Schacke H, May E, Asadullah K. Glucocorticoid therapy-induced skin atrophy. Exp Dermatol. 2006;15:406–420. doi: 10.1111/j.0906-6705.2006.00435.x.
    1. Marquardt C, Matuschek E, Bolke E, Gerber PA, Peiper M, J VS-K, Buhren BA, van Griensven M, Budach W, Hassan M, Kukova G, Mota R, Hofer D, Orth K, Fleischmann W. Evaluation of the tissue toxicity of antiseptics by the hen's egg test on the chorioallantoic membrane (HETCAM) Eur J Med Res. 2010;15:204–209. doi: 10.1186/2047-783X-15-5-204.
    1. Kujath P, Kujath C. Complicated skin, skin structure and soft tissue infections - are we threatened by multi-resistant pathogens? Eur J Med Res. 2010;15:544–553.
    1. Gerber PA, Enderlein E, Homey B. The Koebner-phenomenon in epidermal growth factor receptor inhibitor-induced cutaneous adverse effects. J Clin Oncol. 2008;26:2790–2792. doi: 10.1200/JCO.2007.16.0077.
    1. Scope A, Agero AL, Dusza SW, Myskowski PL, Lieb JA, Saltz L, Kemeny NE, Halpern AC. Randomized double-blind trial of prophylactic oral minocycline and topical tazarotene for cetuximab-associated acne-like eruption. J Clin Oncol. 2007;25:5390–5396. doi: 10.1200/JCO.2007.12.6987.
    1. Wilke MH. Multiresistant bacteria and current therapy - the economical side of the story. Eur J Med Res. 2010;15:571–576. doi: 10.1186/2047-783X-15-12-571.
    1. Abdelmohsen K, Gerber PA, von Montfort C, Sies H, Klotz LO. Epidermal growth factor receptor is a common mediator of quinone-induced signaling leading to phosphorylation of connexin-43: role of glutathione and tyrosine phosphatases. J Biol Chem. 2003;278:38360–38367. doi: 10.1074/jbc.M306785200.
    1. Abdelmohsen K, von Montfort C, Stuhlmann D, Gerber PA, Decking UK, Sies H, Klotz LO. Doxorubicin induces EGF receptor-dependent downregulation of gap junctional intercellular communication in rat liver epithelial cells. Biol Chem. 2005;386:217–223. doi: 10.1515/BC.2005.027.
    1. Klotz LO, Patak P, Ale-Agha N, Buchczyk DP, Abdelmohsen K, Gerber PA, von Montfort C, Sies H. 2-Methyl-1,4-naphthoquinone, vitamin K(3), decreases gap-junctional intercellular communication via activation of the epidermal growth factor receptor/extracellular signal-regulated kinase cascade. Cancer Res. 2002;62:4922–4928.
    1. Li T, Perez-Soler R. Skin toxicities associated with epidermal growth factor receptor inhibitors. Target Oncol. 2009;4:107–119. doi: 10.1007/s11523-009-0114-0.

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir