Prospective practice survey of management of cetuximab-related skin reactions

Cetuximab is a chimeric monoclonal antibody that binds and inactivates the epidermal growth factor receptor (EGFR). As a consequence of this blockade, extracellular activators like the epidermal growth factor (EGF) cannot bind to the receptor anymore and tumour-promoting downstream signalling cascades cannot be activated. This mechanism of blocking EGFR is an important strategy in the treatment of metastatic colorectal cancer (mCRC) and squamous cell cancer of the head and neck (SCCHN) [1‐4].

However, EGFR is expressed not solely on tumour cells but also on cells of the epidermis. There, EGF/EGFR-mediated signalling cascades regulate physiologic homeostasis of the tissue. Inhibition of EGFR causes abnormal growth and migration behaviour of keratinocytes. It also changes keratinocyte differentiation and maturation. These changes are accompanied by an inflammatory state of the dermis [5, 6]. In light of the physiologic relevance of the EGFR signalling cascade, one side effect of this type of drug can be explained: various cutaneous toxicities.

Most patients receiving cetuximab develop skin reactions. In the majority of cases, skin reactions like xerosis, maculo-papular rash, papulo-pustular rash, pruritus or fissures occur within the first weeks of therapy and the occurrence is time-dependent. The most frequently reported events are papulo-pustular rash (80%) which affects predominantly the face, upper trunk and the scalp. Skin reactions caused by cetuximab can severely affect patient health-related quality of life (HRQoL) and can lead eventually to dose delays, dose reductions and even permanent discontinuation of treatment [7, 8]. Normally, skin reactions resolve once the therapy is stopped or following dose reductions. Cetuximab-induced skin reactions have been positively associated with better treatment response and longer survival in mCRC and R/M SCCHN [9‐11]. Therefore, finding the optimal strategies to prevent, recognize early and treat skin reactions seems necessary. During cetuximab therapy multiple care and management options to reduce the severity of the skin reactions are used. Secondary to general measures like the avoidance of intense sun exposure and the use of disinfectant synthetic detergents and proper skin care is recommended. However, most recommendations on how to prevent or treat skin reactions are based on expert opinions, since evidence-based guidelines are scarce [12]. Optimal strategies for the management of cetuximab-induced skin reactions remain unclear. Besides the prophylactic use of emollients, use of oral or topical tetracyclines and topical application of 1% hydrocortisone cream together with a moisturizer can be considered to reduce the severity of skin reactions [13, 14], or other topical agents such as vitamin K₁ cream and antihistamines in case of pruritus [15, 16]. As cetuximab is increasingly being used in cancer therapy, optimal strategy to detect and treat anti-EGFR-induced skin reactions can help clinicians to improve patient care.

The primary objective of this current practice survey is to gain information about the perceived effectiveness of the measures taken against the skin reactions in mCRC and SCCHN patients treated with cetuximab in Dutch daily practice.

This prospective observational study provides a detailed insight into the use, acceptance and the perceived efficacy of measures taken against skin reactions related to cetuximab in the Netherlands. A wide range of skincare products and medications was used in patients with metastatic colorectal cancer (mCRC) and recurrent and/or metastatic or locally advanced squamous cell cancer of head and neck (SCCHN) in 7 sites across the country. The most frequent skin products in the study were moisturizing products, systemic antibiotics and topical antibiotics wherein the use of all products gradually increased during the first 10 weeks of the observation period. Hospital protocols were the primary reason for the choice of skin care and medical products being used as prophylactic or reactive treatment of skin reactions.

These findings are comparable with the results of a similar study conducted in Switzerland, in which patients also received a broad variety of preventive and therapeutic skin care measures for cetuximab-related skin reactions [19]. In the absence of evidence-based guidelines for an optimal approach to prevent and manage cutaneous reactions of EGFR-targeted antibodies, our practice survey and the Swiss study demonstrate the differences in choice of skin care products in the various hospitals and areas. Only a small proportion of patients developed severe cutaneous reactions and for patients, the occurrence of skin reactions did not influence their willingness to continue cetuximab therapy. However, the two studies differ in some ways. In contrast to the Swiss study, the minority of patients in our study was diagnosed with mCRC (30.2% versus 72.8%) and patients were allowed to undergo radiation therapy at the same time. In addition, there was a difference in the choice of skin care products. General skin care products frequently used in Switzerland like urea-containing products, lipid-regenerating products and vitamin K₁ cream were rarely prescribed in the Dutch population. On the other hand, antibiotics (topical and systemic) were more popular in the Netherlands. This can partly be explained by the fact that vitamin K₁ cream was not available by prescription in the Netherlands when the study was conducted. In addition, hospital protocols have often been drawn up in consultation with dermatologists, whereas differences in dermatological care between countries are common. Despite these differences in patients and chosen skincare products, the outcome in the studies was in accordance. Remarkably, topical steroids were rarely described in both countries, despite the fact that these agents are often recommended in expert guidelines.

This study was conducted to gain more information about skin reactions related to cetuximab therapy and current measures taken to prevent and manage them in daily practice. It should be mentioned that only 26 out of 102 patients (25.5%) received monotherapy with cetuximab. 48 patients (47.1%) had concurrent radiation therapy, 27 patients (26.5%) received a combination of chemotherapy and cetuximab and 1 patient (1.0%) was treated with chemotherapy, palliative radiotherapy and cetuximab at the same time. Therefore, not all skin reactions are all necessarily cetuximab-related. There might have been patients with radiation dermatitis or a chemotherapy-induced rash as well. Up to 85 to 95% of patients treated with radiotherapy developed moderate to severe skin reactions depending on the cumulative radiation dose to the skin [20‐22]. Optimal strategies for the prevention and treatment of radiation-induced dermatitis remain a challenge as well with conflicting results in various studies. Washing with water and mild soap, topical corticosteroids and silver nylon dressings have proven to be effective in radiation dermatitis; all strategies were not applied in this survey.

Cutaneous reactions caused by cetuximab can have a serious impact on patients’ HRQoL and their willingness to continue treatment [23]. In the present study, no grade 4 skin reactions were observed and less than 5% of patients had a grade 3 reaction at some point during the observation period. This has ensured that only 1 patient has stopped treatment with cetuximab due to skin reactions. We did see a decrease in the mean HRQoL overall score, as for all domains, from baseline to week 10. Possibly, mild or moderate skin reactions can negatively affect patients’ HRQoL and daily life. However, because the majority of patients received radiation or chemotherapy, the declined HRQoL scores cannot only be attributed to cetuximab-related skin reactions. The fact that a large proportion of patients have only been treated for 8 weeks may also have helped the treatment tolerance, as patients can experience a greater negative impact if side effects last longer.

Patients, physicians and nurses perceived the effectiveness of the used products generally comparable for all categories. “No effect” or at most “weak to moderate” effectiveness was reported by the majority of participating patients and physicians. A proportion of patients used multiple products at the same time, like moisturizing products and systemic antibiotics, which made it difficult to distinguish which products were less effective. Patients seemed to be most enthusiastic about moisturizing products, vitamin K₁ cream and antibiotics (systemic and topical), whereas healthcare providers reported the highest scores for vitamin K₁ cream, lipid-regenerating products and systemic antibiotics. The differences between perceived effectiveness assessments were small with no superiority for one of the used agents. In concordance with our Swiss colleagues, we have to conclude that the optimal treatment option needs to be explored individually [19]. Results from previous studies, recommendations and discussions at consensus meetings remain conflicting and so far, no evidence-based guideline for cetuximab-related skin reactions could be established.

There are a number of limitations to this study. Firstly, as a consequence of missing data only 86 patients could be analysed resulting in a relatively small sample size. It was the intention to analyse all endpoints from mCRC and SCCHN patients separately; however, the low number of patients in each subgroup and the high number of skin care medications given precluding meaningful interpretation of data in the subgroups. In addition, it would have been useful to compare the incidence, time of occurrence and grade of skin reactions in patients given prophylactic treatment and those not receiving such treatment. Due to a lack of sufficient data regarding the type of treatment given, this analysis could not be performed in a meaningful way. Secondly, the follow-up period of 16 weeks is relatively short, and many patients discontinued the study early as they were treated for a shorter planned period with cetuximab. Although the development of skin reactions in patients treated with cetuximab usually starts within the first weeks of treatment. Therefore, this time window was chosen for the observation period in this study. Thirdly, the present results were potentially biased in some aspects. Inclusion of patients in a non-blinded observational study with no control arm, at which the treating HCP assigns patients to a certain therapy of their own preference, might have influenced the reported perceived effectiveness. Furthermore, the inclusion of only Dutch patients with access to all available highly qualified care and a good health insurance system might limit the generalizability of these findings to patients in lower- or middle-income countries.

Our study shows that Dutch oncologists and nurses used a variety of products for the prevention or treatment of cetuximab-induced skin reaction, mostly based on the local hospital protocols. In general, both patients and treating healthcare providers perceived at most moderate efficacy of the various measures. Fortunately, the skin reactions that occurred during treatment were mostly mild or moderate, had no large impact on daily life and did not lead to discontinuation of treatment.