EGFR inhibitors: clinical aspects, risk factors and biomarkers for acneiform eruptions and other mucosal and cutaneous adverse effects.

The frequency of the use of drugs that act on the epidermal growth factor receptor (EGFR) is increasing, with the consequent onset of cutaneous toxicity, specifically acneiform eruption. The authors extensively review the topic, focusing on describing how these drugs can affect the skin and its appendages, that is, the pathophysiology that encompasses the cutaneous toxicity related to the use of EGFR inhibitors. In addition, it was possible to list the risk factors that may be associated with adverse effects of these drugs. Based on this recent knowledge, the authors expect to aid in the management of patients who are more vulnerable to toxicity, reduce morbidities, and improve the quality of life of patients undergoing treatment with EGFR inhibitors. Other issues related to the toxicity of EGFR inhibitors, such as the clinical aspects of the acneiform eruption grades, and other different types of cutaneous and mucosal reactions, are also included in the article.

Successful treatment of a child with MEK inhibitor-induced acneiform eruption with low-dose isotretinoin.

Selumetinib is a mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor (MEKi) approved to treat inoperable plexiform neurofibromas and used off-label for low-grade gliomas. Acneiform eruptions are a known complication of MEKi use, and in some cases, may lead to paused, dose-reduced, or discontinued therapy. Isotretinoin has been reported as an effective treatment for acneiform eruptions secondary to targeted therapies, primarily in the adult population. Here we describe a pediatric patient with a severe acneiform eruption secondary to selumetinib who was successfully treated with low-dose isotretinoin when unresponsive to conventional therapies.

Prevention and management of acneiform rash associated with EGFR inhibitor therapy: A systematic review and meta-analysis.

INTRODUCTION: Epidermal growth factor receptor (EGFR) inhibitors are established therapies for advanced lung, colorectal, and head and neck cancers. They commonly cause acneiform eruptions that affect patient quality of life and may lead to discontinuation of therapy. METHODS: A systematic review and meta-analysis was undertaken to assess strategies for the prevention and reactive management of acneiform rash associated with EGFR inhibitor therapy for advanced lung, colorectal, and head and neck cancers. A systematic Medline, Embase, and EBM Reviews database search was conducted on the 2nd of January 2021. The Preferred Reporting Items for Systematic Reviews and Meta-analyses statement was followed and the studies were critically appraised. Studies were selected if they focused on preventing or treating acneiform eruptions in adults being treated for advanced lung cancer, colorectal cancer, and head and neck cancers with EGFR inhibitors. RESULTS: Oral antibiotics had the greatest efficacy in preventing grade 2 or higher acneiform eruptions with a relative risk reduction of 40% (RR = .6, 95% CI .46-.79, p < .01). Other treatment modalities did not have statistically significant results. Topical antibiotics had a total relative risk reduction of 19% (RR = .81, 95% CI .45-1.48, p = .5). Vitamin K1 cream did not reduce the relative risk (RR = 1.08, 95% CI .45-1.48, p = .50). Sunscreen had a total relative risk reduction of 25% (RR = .75, 95% CI .49-1.14, p = .18). CONCLUSIONS: The results of this meta-analysis reinforce the fact that oral tetracycline antibiotics are the most efficacious prophylactic option for acneiform eruptions in EGFR inhibitors. They should be offered to suitable patients commencing treatment and used with a general skin-care routine involving emollients and avoidance of irritants.

A systematic review of oral retinoids for treatment of acneiform eruptions induced by epidermal growth factor receptor inhibitors.

Epidermal growth factor receptor inhibitors (EGFRi) are now standard of care in patients with EGFR mutations in non-small cell lung cancer (NSCLC) and are increasingly being used in other EGFR mutated cancers, including gastrointestinal, and head and neck. However, EGFRi are well known to cause acneiform eruptions, which are shown to positively correlate with tumor response to treatment, but may be severe enough to cause interruption of their treatment. Although most guidelines call for the use of tetracyclines to treat these acneiform eruptions, there is mounting evidence for the use of systemic retinoids instead. The objective of this review is to summarize available data on the use of systemic retinoids for management of acneiform eruptions on EGFRi. This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. MEDLINE and EMBASE were searched from database inception until December 10th, 2021. All articles were screened and relevant data extracted independently in duplicate by two reviewers. In total, 16 case reports, case series and retrospective reviews were included. Forty-three patients were treated with retinoids for their acneiform eruption due to EGFRi. The majority (77%) noted moderate to significant improvement after treatment initiation with minimal adverse events (16%). The findings of this systematic review suggest that systemic retinoids are a safe and effective therapy for the management of acneiform eruptions induced by EGFRi.

Topical corticosteroid therapy for facial acneiform eruption due to EGFR inhibitors in metastatic colorectal cancer patients: a randomized controlled trial comparing starting with a very strong or a weak topical corticosteroid (FAEISS study, NCCH1512, colorectal part).

BACKGROUND: Although pre-emptive therapy with oral tetracycline, moisturizer, sunscreen, and topical corticosteroid is useful for preventing acneiform eruption (AfE) due to epidermal growth factor receptor (EGFR) inhibitors, no studies have examined the efficacy of topical corticosteroids themselves, or investigated the optimal potency of corticosteroid for treating facial AfE (FAfE). PATIENTS AND METHODS: Screened patients with RAS wild-type colorectal cancer started pre-emptive therapy with oral minocycline and moisturizer on initiation of cetuximab or panitumumab therapy. Patients who developed grade 1 or 2 FAfE were randomly allocated to two groups: a ranking-down (RD) group that started with a very strong corticosteroid and serially ranked down every 2 weeks unless FAfE exacerbated; and a ranking-up (RU) group that started with a weak corticosteroid and serially ranked up at exacerbation. FAfE grade, patient quality of life, and adverse events (AEs) with topical corticosteroid were evaluated every 2 weeks. The primary endpoint was the total number of times grade 2 or higher FAfE was identified in the central review of the 8-week treatment period. RESULTS: No significant differences in total numbers of grade 2 or higher FAfE or in AEs caused by topical corticosteroids were observed between groups during the 8 weeks. Incidence of grade 2 or higher FAfE tended to be lower in the RD group during the first 2 weeks. CONCLUSION: Considering the long-term care of FAfE, the RU regimen appears suitable and should be considered the standard treatment for FAfE due to EGFR inhibitor therapy. TRIAL REGISTRATION: UMIN Clinical Trials Registry (UMIN000024113).

A Commentary on the "Duration of Oral Antibiotics Administration for Cetuximab-Induced Acneiform Eruption".

Acneiform eruption is a devastating cutaneous side effect of cetuximab, a monoclonal antibody used to treat a variety of cancers. Despite its effectiveness, many patients avoid or discontinue it after experiencing its dermatological side effects as it negatively impacts their quality of life (QoL). This displays the immense need for multidisciplinary collaboration to prevent and treat cetuximab-induced acneiform eruption (CIAE). Prevention methods include, but are not limited to, education, skin care routines, and prophylactic drugs. The following measures reduce the likelihood of developing CIAE and decrease its severity, making it easier to treat if it were to occur. Ongoing research on the treatment of CIAE continues. Of these treatments, oral tetracyclines and systemic corticosteroids have been shown to be the most effective by far. This commentary aims to evaluate the study by Park et al. [Dermatology. 2021;237(3):457-63], further elaborate on prevention and treatment measures of CIAE, and highlight the implications of CIAE on a patient's QoL.

Severe EGFR inhibitor-induced acneiform eruption responding to dapsone.

Epidermal growth factor receptor (EFGR) inhibitors are targeted chemotherapeutic agents that are effective in treating various epithelial cancers. Cutaneous adverse effects, most commonly acneiform/papulopustular eruption, can occur with these medications and limit their tolerability. In severe cases, patients may refuse treatment with EGFR inhibitors because of the significant impact on the quality of life and aesthetic discomfort. We present a 72-year-old-man with a history of EGFR+ non-small-cell lung carcinoma who developed a severe acneiform eruption secondary to afatinib that failed to improve with various traditional treatment modalities. The patient was treated with dapsone and his acneiform eruption resolved within two months of initiating therapy. Patient tolerated dapsone with no reported adverse effects and continues on low dose dapsone, as he will remain on afatinib indefinitely. Dapsone can be an effective therapy for refractory or severe cases of EGFR-induced acneiform eruptions. As in this case, dapsone may improve patient adherence to EGFR inhibitors, thereby allowing for effective therapy of underlying malignancy.

Efficacy and safety of topical benzoyl peroxide for prolonged acneiform eruptions induced by cetuximab and panitumumab: A multicenter, phase II trial.

The most common adverse event of epidermal growth factor receptor inhibitors, used to treat colorectal, non-small cell lung, and head and neck cancers, is acneiform eruption, with a profound effect on treatment continuation. Prolonged acneiform eruptions treated with topical corticosteroids, a standard management, may be associated with secondary bacterial infections, thus there is a need for new treatments. We conducted a multicenter, phase II trial to evaluate the efficacy and safety of topical benzoyl peroxide for epidermal growth factor receptor inhibitor-induced prolonged acneiform eruptions. Patients with colorectal, non-small lung cell, and head and neck cancers who received epidermal growth factor receptor inhibitors for >10 weeks and had persistent acneiform eruptions were eligible. Topical benzoyl peroxide was applied to the affected area of the face once daily for 8 weeks; a clinical evaluation was performed every 2 weeks. The primary endpoint was a change in acneiform eruption severity evaluated between disease onset and end of the treatment period. The quality of life of patients was assessed using the Dermatology Life Quality Index. Of the 14 enrolled patients, 11 completed the trial. The protocol-specified grade of acneiform eruptions from baseline to week 8 improved from 2.0 to 1.0 (P < 0.01). The dermatology life quality index score from baseline to week 8 improved from 3.0 to 1.0 point (P < 0.01). No patient experienced severe adverse events. Overall, topical benzoyl peroxide may be effective for treating and managing prolonged acneiform eruptions induced by epidermal growth factor receptor inhibitors.

Efficacy of treatment for acneiform eruptions related to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) for non-small cell lung cancer (NSCLC): A protocol of systematic review and network meta-analysis.

BACKGROUND: Acneiform eruptions from epidermal growth factor receptor tyrosine kinase inhibitors is a frequent adverse event in non-small cell lung cancer patients but the efficacy of its treatment including antibiotics, corticosteroid, sunscreen is still poorly understood. METHODS: Eight electronic databases (PubMed, EMBASE, ClinicalTrials.gov, etc) will be searched from inception to April 2020. Risk of bias of randomized controlled trials will be assessed in terms of the Risk of Bias 2 (RoB 2) tool. Eligible randomized controlled trials will be enrolled for a Bayesian network meta-analysis using R software. RESULTS: This study is still ongoing and the results will be submitted and published in a peer-reviewed scientific journal. CONCLUSION: We hope the results of this study will provide reliable evidence for the management of acneiform due to epidermal growth factor receptor tyrosine kinase inhibitors for non-small cell lung cancer. ETHICS AND DISSEMINATION: Ethical approval is not applicable for this study is based on published trials. PROTOCOL REGISTRATION NUMBER: CRD42020206724.

Duration of Oral Antibiotics Administration for Cetuximab-Induced Acneiform Eruption.

BACKGROUND: Acneiform eruption is the most common cutaneous adverse event associated with cetuximab. As it can affect quality of life and adversely affect chemotherapy schedule, additional medical care is required. OBJECTIVES: To investigate the adherence to and the duration of antibiotic administration to treat cetuximab-induced acneiform eruption. METHODS: Medical data of patients who were referred to the Department of Dermatology were reviewed from January 2013 to June 2018. Dermatologists assessed the severity of acneiform eruption and prescribed tetracycline-class antibiotics according to the severity every 2 or 4 weeks. We investigated the duration and amount of oral antibiotic administration and analyzed the factors that may affect the control of acneiform eruption statistically. RESULTS: A total of 207 of 267 patients referred to the Department of Dermatology showed acneiform eruption; 124 patients were treated with minocycline, 34 patients with doxycycline, 27 patients with both, and 22 patients with topical agents. The mean duration of oral antibiotic medication was 82.7 days. A statistical analysis of the factors that prolonged the use of antibiotics for more than 90 days showed that male and younger age were risk factors. Shorter time interval from starting cetuximab to starting antibiotics was associated with longer duration of antibiotic use, statistically. CONCLUSIONS: Cetuximab-induced acneiform eruption can be well controlled with tetracycline-class antibiotics in about 3 months. It can last longer in male and younger patients. The sooner and the more severe it appears, the longer it can last.

Topical aloe vera for the treatment of cetuximab-related acneiform rash in colorectal cancer: A case report.

INTRODUCTION: Colorectal cancer is one of the most common cancers in the world. Cetuximab is an epidermal growth factor receptor (EGFR) inhibitor which provides survival benefit when combined with chemotherapy in RAS wild type metastatic colorectal cancer. Cutaneous toxicities associated with cetuximab have a significant impact on patient quality of life, treatment continuation and healthcare resource utilization. CASE REPORT: A 60-year-old male patient presented with fatigue, weight loss and abdominal pain. Two closely located malignant polypoid lesions were detected in the sigmoid colon, and pathological examination revealed colonic adenocarcinoma.Management and outcome: Thorax, abdominal and pelvic computed tomography showed metastases. FOLFOX chemotherapy and cetuximab were started. The patient developed acneiform rash firstly in his face, although prophylactic vitamin K1 0.1% containing cream was given. He was given mild potency topical corticosteroid and doxycycline. The lesions progressed to his front and back body. He did not want to use topical vitamin K1 cream, topical steroid and doxycycline tablets. Instead, he wanted to use aloe vera extract which he produced from the leaves of the plant. Patient's lesions were regressed significantly. DISCUSSION: The most common and earliest skin toxicity is acneiform rash which affects 60 to 80% of the patients. In this case, cetuximab-related severe acneiform rash was effectively treated by topical aloe vera. Topical aloe vera may be used in the management of cetuximab-related cutaneous toxicities without any side effect.

When bugs and drugs conspire: driving acneiform skin toxicity.

Therapy with antineoplastic agents that inhibit EGFR and MEK is frequently limited by cutaneous adverse reactions, most commonly acne-like eruptions. In this issue of the JCI, Satoh et al. define a mechanism for acneiform skin toxicity wherein EGFR/MEK inhibitors cooperate with the skin commensal Cutibacterium acnes to induce IL-36γ in keratinocytes via the combined actions of Krüppel-like factor 4 and NF-κB transcription factors at the IL-36γ promoter, resulting in neutrophil recruitment. In addition to elucidating why EGFR/MEK inhibitor-induced rashes are often pustular and folliculocentric, this mechanism provides justification for the long-standing practice of management with antibiotic therapy.

Guidelines for the treatment of skin and mucosal lesions in Behçet's disease: A secondary publication.

In the current study, we present guidelines for the diagnosis and treatment of the mucocutaneous lesions of Behçet's disease, which is a chronic inflammatory disease characterized by the involvement of various organs, including mucocutaneous, ocular, vascular, intestinal and central nervous system lesions. It is often identified in the Middle East Mediterranean to East Asia region. Skin manifestations include erythema nodosum, papulopustular lesions and thrombophlebitis, and mucosal manifestations include oral and genital ulcers. These mucocutaneous lesions are characteristically the first signs of Behçet's disease and are important to be recognized for the early diagnosis of the disease. Moreover, these manifestations also recur and persist over the long-term course of the disease. The management of mucocutaneous lesions is important to prevent recurrence. We developed consensus guidelines that provide recommendations for general practitioners and dermatologists and physicians on the management of the mucocutaneous lesions of Behçet's disease.