Topical therapy with nadifloxacin cream and prednicarbate cream improves acneiform eruptions caused by the EGFR-inhibitor cetuximab – A report of 29 patients

ARTICLE

Auteur(s) : Kerstin Katzer¹, Julia Tietze¹, Elisabeth Klein¹, Volker Heinemann², Thomas Ruzicka¹, Andreas Wollenberg¹

¹Dept. of Dermatology and Allergy, Ludwig Maximilian University, Frauenlobstr. 9-11, 80337 Munich, Germany
²Dept. of Medicine III, Ludwig Maximilian University, Munich, Germany

accepté le 17 Août 2009

Epidermal growth factor receptor inhibitors are a highly effective, new class of chemotherapy agents licenced for the treatment of metastasized epithelial cancer [1]. One of these, the humanized chimeric IgG1 monoclonal antibody cetuximab, specifically inhibits epidermal growth factor receptor (EGFR) activation and signal transduction by competing with the endogenous ligands EGF and transforming growth factor alpha [2]. Working synergistically with chemotherapy and radiotherapy [3], cetuximab has been approved for the treatment of patients with EGFR-positive metastatic colorectal carcinoma and recurrent or metastatic squamous cell carcinoma of the head and neck.

The most common side effects of cetuximab therapy are acneiform eruptions [4], the occurrence of which is positively correlated to tumor regression and long term patient survival [5]. Mild acneiform skin eruptions are at least bothersome, whereas severe eruptions may be quite disfiguring and stigmatize the patient in daily life as much as suffering from metastasized cancer, thus negatively affecting compliance with anti-EGFR-therapy (figure 1). Therefore, effective management of skin lesions is essential for oncological management.

Clinical characteristics and therapeutic algorithms for the skin eruptions have been reviewed by us and others [6, 7]. Mild forms may be treated with azelaic acid or other topical acne therapeutics, whereas oral tetracyclines are frequently given for moderate skin eruptions. Severe disease should be treated by a dermatologist, e.g. with a so-called triple therapy consisting of topical nadifloxacin, topical prednicarbate and oral retinoid [6, 8].

We report a new, highly effective topical treatment regimen for mild, moderate and even severe acneiform eruptions associated with EGF receptor inhibition, which is based on a combination of nadifloxacin 1% cream and prednicarbate 0.25% cream, and report the first results of a treatment series of 29 patients.

Patients and methods

Clinical severity of the acneiform skin lesions was recorded over time using our severity score for acneiform skin eruptions (Skin-Score) before and after 1, 2 and 6 weeks of topical treatment with nadifloxacin and prednicarbate [9]. This score (figure 2), which is described in detail elsewhere, is a combined score of the severity of 5 different aspects of acneiform eruptions (colour of erythema, distribution of erythema, papulation, pustulation and scaling/crusts with a balanced score of 0-3 each), the affected facial area and the total body area involved. Two investigators (KK, JT) were specially trained to evaluate acneiform lesions in order to minimize inter-observer variability. The statistical software package SPSS was used for descriptive statistics, as well as for calculating the non-parametric statistics (Wilcoxon test) for the data set.

Results

The topical treatment was well tolerated, as only 2 patients reported mild side effects (initial burning and erythema following application of nadifloxacin cream). All patients were very satisfied with the topical therapy chosen and the clinical outcome.

Discussion

Nadifloxacin, an anti-bacterial quinolone derivate frequently used as topical treatment for acne, was selected because of its antimicrobial as well as its recently shown immunomodulatory effects on the antigen-presenting function of Langerhans cells and keratinocytes [10]. Prednicarbate was selected because it is a well established anti-inflammatory topical corticosteroid with an improved risk-benefit ratio [11]. Both components are actually part of our “triple therapy” regimen for severe acneiform eruptions [8]. This regimen consists of nadifloxacin cream, prednicarbate cream and oral isotretinoin, where both components have been chosen for exactly the same reasons.

The treatment of skin reactions caused by EGFR inhibitors is not standardised. Patients have been empirically treated with numerous substances following the principles of therapy for acne and rosacea, with varying effects [6, 12]. Mild forms of acneiform lesions are usually treated with topical antibiotics or benzoyl peroxide [13]. Tetracycline or oral antihistamine drugs are frequently added in moderate cases [14] or even to prevent skin lesions [15], whereas severe skin manifestations may require oral retinoids [8, 16]. Some authors fear an isotretinoin-induced enhanced xerosis and paronychia, or an interaction with the antineoplastic activities of EGFR inhibitors [16, 17]. The omission of any systemic drugs, such as isotretinoin or tetracycline, in our nadifloxacin-prednicarbate regimen does not only circumvent these theoretical concerns, but allows its application in every patient independent of his liver function.

The effect of topical corticosteroids is discussed controversially [18, 8]. The long term application of topical corticosteroids in our patients might be a risk factor for bacterial infection of the skin [19, 20]. Staphylococcus aureus was cultured from the face of only two patients before therapy, but none of our patients’ skin lesions showed Staphylococcus aureus or any other pathogenic bacteria during therapy. This might be due to the immunological pathogenesis of the pustules or due to the excellent antibacterial effects of topical nadifloxacin. However, bacterial infection was not a clinically relevant issue during our therapy of the acneiform eruption.

The potential concern of interference between oral medications used for the treatment of acneiform skin reactions has not been formally studied. Though there are controlled studies published dealing with the efficacy of oral tetracyclines on the skin rash, these studies have not included source data on a possibly reduced tumor response to EGFR-inhibitors due to the oral tetracycline medication [15, 21].

Conclusion

Acknowledgements

References

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