Today, there is a broad variety of independent case reports and guidelines on different options for the management of EGFRI-associated rashes [5, 22–25]. Yet, studies that compare different therapeutic regimens and analyses in larger collectives of patients are sparse. Accordingly, we conducted a comparative analysis of the clinical efficacy of different EGFRI rash management strategies that target the inflammatory and/or the infectious characteristics of the rash. Notably, our results demonstrate that all approaches were effective and significantly reduced the severity of the rash over a period of three weeks.
The statistically most significant effects were achieved with topical mometason furoate cream (P = 0.00009), followed by topical prednicarbate cream plus nadifloxacin cream plus systemic isotretinoin (P = 0.015) and finally topical prednicarbate cream plus nadifloxacin cream (P = 0.03). However, statistical comparison of different therapy regimen is limited due to variations in patient numbers and rash severity in each of the three test groups before therapy. Topical mometason furoate achieved the highest mean ERSS-reduction with 18.9 points, followed by topical prednicarbate cream plus nadifloxacin cream plus systemic isotretinoin with 15.4 points and topical prednicarbate cream plus nadifloxacin cream with 6.1 points. Moreover, topical mometason furoate was the only therapy that resulted in a complete resolution of all rash symptoms in one patient. Yet, it must be noted that statistical significance is highly dependent on the number of patients included in each group, and because the ERSS system was designed with a non-linear affected-area scale emphasizing minor variations in mild patients with face involvement only .
Mometason furoate alone appeared to be more effective than prednicarbate plus topical nadifloxacin. However, mometason furoate is the more potent glucocorticosteroid (class III) as compared to prednicarbate (class II) and therefore represents a higher risk of inducing steroid-associated adverse effects, such as skin atrophy . Nevertheless, it is questionable, whether these adverse effects may play a role in the short-term treatment of EGFRI rashes, as inflammatory skin lesions have been shown to slowly regress even without therapy in the course of sustained EGFRI-therapy. Topical nadifloxacin was administered to target the infectious component of the rash . Future studies may analyse the efficacy of a combination of topical momentason furoate plus nadifloxacin.
With regard to the variation in significance and over-all efficacy of the different approaches, it must be noted that we compared three somewhat heterogenous patient groups. Whereas patients with varying ERSS were randomly subjected to therapies with topical mometason furoate or topical prednicarbate cream plus nadifloxacin cream, the addition of systemic isotretinoin was limited to patients that were severely affected and presented either with a very high ERSS (> 50) or patients that were referred to our clinics due to rashes that were therapy-resistant to other approaches (such as topical antibiotics or topical glucocorticosteroids). Accordingly, effects observed for systemic isotretinoin may not have been as dramatic when compared to sole topical prednicarbate plus topical nadifloxacin or topical mometason furoate.
With regard to study design, it may be criticized that we did not compare the tested conditions to negative controls, such as a subgroup of EGFRI patients whose rash was left untreated for the study period. Yet, an untreated or insufficiently managed rash can significantly compromise the patients' QoL and patients included in our analysis had initially been referred to us specifically for the treatment of their cutaneous adverse effects by their treating oncologists.
Notably, all approaches that were analysed in this study are in line with recent expert recommendations that suggest an escalating strategy for the management of the EGFRI rash [5, 6, 16] with a succession of treatments, as indicated, summarized as follows: intensive skin care in combination with mild cleansers, followed by the use of mild (class II) to moderate (class III) potent topical glucocorticosteroids with low atrophogenic potential such as hydrocortisone butyrate, prednicarbate (both class II), methylprednisolone aceponate or momethason furoate (both class III). In fact, our results demonstrate a significant efficacy of topical glucocorticosteroid monotherapy. Taking into account the high incidence of bacterial superinfections of the EGFRI rash, alternative recommendations include the combination of mild topical glucocorticosteroids and topical antibiotics or antiseptics with low cytotoxic potential . Recent studies report infections at the sites of dermatologic adverse effects in 38% of EGFRI rash patients. A detailed microbiologic analysis of these cutaneous infections identified Staphylococcus aureus in 59.5% of the cases [10, 32]. Nadifloxacin is a potent topical fluoroquinolone antibiotic hence representing a probable candidate to target superinfections in EGFRI rash patients. In fact, we could show that the combination of nadifloxacin 1% cream and prednicarbate 0.25% cream significantly improved rash severity. In this context the management of cutaneous infections is also likely to exert protective effects regarding the aggravation of skin inflammation as infectious agents may trigger inflammatory rash progression by means of "Koebnerization" . Systemic isotretinoin, finally, is recommended for the management of severe EGFRI rashes of rashes that do not respond to other therapies . Hence, in our study, patients with an ERSS > 50 were subjected to a combined management approach with nadifloxacin 1% cream and prednicarbate 0.25% cream as well as systemic isotretinoin . Our results demonstrate that even severe rashes can be improved significantly by this approach. Yet, is must be noted that the use of systemic isotretinoin in EGFRI patients is controversial, since potential antagonism of the anti-tumor effect of the EGFRI is possible, although this has not been investigated systematically yet. Nevertheless, similar arguments may be proposed for any systemic approach, such as the administration of oral tetracyclines as rash prophylaxis [34, 35].