Management of human epidermal growth factor receptor inhibitors-related acneiform rash: A position paper based on the first Europe/USA Delphi consensus process.

BACKGROUND: There is a need for unified guidance in the management of acneiform rash induced by epidermal growth factor receptor inhibitors (EGFRi) among dermatologists. OBJECTIVE: To establish unified international guidelines for the management of acneiform rash caused by EGFR inhibitors, based on an experts' Delphi consensus. METHODS: The initiative was led by five members of the European Academy of Dermatology and Venereology Task Force 'Dermatology for Cancer Patients' who developed a questionnaire that was circulated to a group of 32 supportive oncodermatology experts in Europe, Canada, Argentina, the US States and Asia. The questionnaire consisted of 84 statements in total, regarding diagnosis and treatment of EGFRi-induced acneiform rash. Experts responded to an anonymous 5-point Likert scale survey. The coordinators collected the first-round responses that were checked for consensus (≥75% agreement in positive [agree or strongly agree] or in negative [disagree or strongly disagree] vote). The statements that did not reach strong consensus in the first round were revised, according to experts' feedback, for a second-round survey. RESULTS: Strong consensus was reached in 75/84 (89.3%) of the statements, whilst moderate consensus was achieved in 6/84 elements. Key points include consideration of low-dose isotretinoin for refractory grade II/III acneiform rash, use of topical steroid-sparing agents like topical pimecrolimus in the maintenance phase and use of doxycycline in either 100 or 200 mg per day as prophylactic treatment. Interestingly, experts did not recommend topical antibiotics, neither for prevention, nor for treatment. Consensus failure in 3/84 objects is mostly related to the lack of robust data on these topics. CONCLUSION: This consensus offers crucial insights often overlooked by radiotherapists, general practitioners, dermatologists and oncologists, and it is expected to improve the management of oncologic patients treated with EGFRi in different settings and continents.

Operational classification of cutaneous squamous cell carcinomas based on unsupervised clustering of real cases by experts.

BACKGROUND: There is currently no staging system for cutaneous squamous cell carcinoma (cSCC) that is adapted to decision-making and universally used. Experts have unconscious ability to simplify the heterogeneity of clinical situations into a few relevant groups to drive their therapeutic decisions. Therefore, we have used unsupervised clustering of real cases by experts to generate an operational classification of cSCCs, an approach that was successful for basal cell carcinomas. OBJECTIVE: To generate a consensual and operational classification of cSCCs. METHOD: Unsupervised independent clustering of 248 cases of cSCCs considered difficult-to-treat. Eighteen international experts from different specialties classified these cases into what they considered homogeneous clusters useful for management, each with freedom regarding clustering criteria. Convergences and divergences between clustering were analysed using a similarity matrix, the K-mean approach and the average silhouette method. Mathematical modelling was used to look for the best consensual clustering. The operability of the derived classification was validated on 23 new practitioners. RESULTS: Despite the high heterogeneity of the clinical cases, a mathematical consensus was observed. It was best represented by a partition into five clusters, which appeared a posteriori to describe different clinical scenarios. Applicability of this classification was shown by a good concordance (94%) in the allocation of cases between the new practitioners and the 18 experts. An additional group of easy-to-treat cSCC was included, resulting in a six-group final classification: easy-to-treat/complex to treat due to tumour and/or patient characteristics/multiple/locally advanced/regional disease/visceral metastases. CONCLUSION: Given the methodology based on the convergence of unguided intuitive clustering of cases by experts, this new classification is relevant for clinical practice. It does not compete with staging systems, but they may complement each other, whether the objective is to select the best therapeutic approach in tumour boards or to design homogeneous groups for trials.

Cutaneous manifestations induced by check point inhibitors in 120 melanoma patients-The European MelSkinTox study.

BACKGROUND: Checkpoint inhibitors provide an effective approach for the melanoma treatment. They prolong lymphocyte effects, which explains the cytotoxicity underlying immune-related adverse events (IrAEs). Cutaneous IrAEs affect nearly 40% of PD-1i and 50% of CTLA4i-treated patients. Severe cutaneous irAE do not often occur but could be life-threatening and may persist despite treatment discontinuation. METHODS: We aimed to investigate cutaneous IrAEs in a cohort of patients treated with ICI across Europe in an effort to characterize the reactions in a real-world, phase IV, post-marketing study using a follow-up questionnaire. Data since November 2016 until March 2021 were obtained from the Melskintox database, a European multicentric biobank dedicated to the follow-up of melanoma and cutaneous adverse events, supported by EADO. The dermatoses reported were pooled into four categories: inflammatory dermatosis, bullous diseases, drug-related eruptions and pigmentary diseases. RESULTS: Inflammatory benign dermatoses (n = 63) represented the most common group of reactions (52.5%), followed by drug-related eruptions (n = 24, 20%), pigmentary diseases (n = 23, 19.2%) and bullous diseases (n = 10, 8.3%). Grade II (n = 41, 34.2%) are represented by bullous pemphigoid, eczema, hypodermitis, lichenoid eruption, maculopapular rash, pruritus, psoriasis-like rash, urticarial eruption and vitiligo. Grade III (n = 18, 15.0%) are represented by bullous pemphigoid, lichenoid eruption and rashes. Grade IV (n = 2, 1.7%) is only represented by bullous disease. Most cutaneous IrAEs led to immunotherapy continuation (n = 95, 88.0%). CR is associated with more severe the cutaneous irAEs. We report an average time-to-onset of 208 days and some late-onset events. CONCLUSION: Our study has characterized the clinical spectrum of cutaneous irAEs, their timing and severity and their relationship with tumour response. Grade I-II cutaneous IrAE are easily managed allowing ongoing anticancer treatment. Severe late-onset cutaneous irAE are not uncommon. A dermatological follow-up helps mitigate the risk of life-threatening adverse events. These findings highlight the importance of oncodermatological involvement in management of patients with melanoma receiving immunotherapy.

Dermatologic toxicities to inhibitors of cyclin-dependent kinases CDK 4 and 6: An updated review for clinical practice.

Cyclin-dependent kinase (CDK) 4/6 inhibitors (palbociclib, ribociclib and abemaciclib) have revolutionized the treatment of metastatic breast carcinoma. They currently form the first-line treatment, in combination with endocrine agents, for the management of locally advanced or metastatic hormone receptor-positive (HR + ), human epidermal growth factor receptor 2-negative (HER2-) breast cancer, the largest subtype of breast carcinoma. CDK 4/6 inhibitors have shown comparable efficacy outcomes with predictable and manageable adverse events. In this setting, dermatologic toxicity appears to be relatively frequent, accounting for up to 15% of all reported adverse events. It is usually mild to moderate in intensity and does not normally constitute a dose-limiting toxicity. The range of dermatologic adverse events includes both non-specific entities (maculopapular rash, pruritus, alopecia) and more characteristic toxicities related to CDK4/6 inhibitors, such as vitiligo-like lesions or cutaneous lupus erythematosus. Finally, more severe or life-threatening skin reactions can occasionally occur. The main dermatologic manifestations associated with CDK4/6 inhibitors, as well as management thereof, are described in this comprehensive review.

European recommendations for management of immune checkpoint inhibitors-derived dermatologic adverse events. The EADV task force 'Dermatology for cancer patients' position statement.

The introduction of immune checkpoint inhibitors (ICIs) opened a new era in oncologic therapy. The favourable profile of ICIs in terms of efficacy and safety can be overshadowed by the development of immune-related adverse events (irAEs). Dermatologic irAEs (dirAEs) appear in about 40% of patients undergoing immunotherapy and mainly include maculopapular, psoriasiform, lichenoid and eczematous rashes, auto-immune bullous disorders, pigmentary disorders, pruritus, oral mucosal lesions, hair and nail changes, as well as a few rare and potentially life-threatening toxicities. The EADV task force Dermatology for Cancer Patients merged the clinical experience of the so-far published data, incorporated the quantitative and qualitative characteristics of each specific dirAEs, and released dermatology-derived, phenotype-specific treatment recommendations for cutaneous toxicities (including levels of evidence and grades of recommendation). The basic principle of management is that the interventions should be tailored to serve the equilibrium between patients' relief from the symptoms and signs of skin toxicity and the preservation of an unimpeded oncologic treatment.

Molecular genetics of cutaneous squamous cell carcinoma: perspective for treatment strategies.

Cutaneous squamous cell carcinoma (cSCC) represents 20% of all skin cancers. Although primary cSCCs can be successfully treated with surgery, a subset of highly aggressive lesions may progress to advanced disease, representing a public healthcare problem with significant cancer-related morbidity and mortality. A complex network of genes (TP53, CDKN2A, NOTCH1 and NOTCH2, EGFR and TERT) and molecular pathways (RAS/RAF/MEK/ERK and PI3K/AKT/mTOR) have been shown to play an important role in the pathogenesis of cSCC. The epigenetic regulation of TP53 and CDKN2A is an attractive therapeutic target for the treatment of cSCC, as well as NOTCH-activating agents capable to restore its tumour-suppressor function. EGFR inhibitors including both monoclonal antibodies (cetuximab and panitumumab) and tyrosine kinase inhibitors (erlotinib, gefitinib and dasatinib) have been used in clinical trials for the treatment of advanced cSCC, achieving only partial clinical benefit. Recently, an immune-modulatory drug (cemiplimab) has been introduced for the treatment of advanced cSCC with good clinical results and a favourable safety profile, while other PD1/PD-L1 inhibitors, either as monotherapy or in combination with targeted therapies, are currently under investigation. This review focuses on molecular findings involved in the pathogenesis of cSCC and their implications for the future development of new treatment strategies. In addition, current and ongoing treatments on targeted therapies and/or immunotherapy are illustrated.

Psoriasis and erythema nodosum: two comorbidities of inflammatory bowel diseases.

Extra-intestinal manifestations are a relatively common complications of Inflammatory Bowel Diseases (IBD) and skin is one of the organs most commonly affected. Cutaneous findings in IBD patients may be related to different pathogenetic mechanisms and in some cases the etiologic link has not been fully elucidated. In particular, this is the case of psoriasis and erythema nodosum, two of the most frequent skin diseases observed in IBD patients. Aim of this paper was to review the epidemiology and the possible pathogenetic mechanisms implicated in the occurrence of these two dermatosis. In particular, an association between IBD and psoriasis has been observed in several epidemiological studies: psoriasis occurs in about 1-2% of the general population, compared with 3-11% of patients with IBD. Several studies have also evaluated the prevalence of IBD in psoriatic patients, with contrasting results. A common pathogenic pathways between these two conditions seems to be sustained by the responsiveness to therapy with biological treatments, such as anti-Tumor Necrosis Factor (TNF)-alpha agents and ustekinumab (a monoclonal antibody against p40 subunit common to IL-12 and IL-23). On the other hand, although usually idiopathic in half of the patients, erythema nodosum has been associated with a variety of disorders and conditions and IBD accounts for 1-4% of cases.

Topical and systemic medical treatments of basal cell carcinoma.

Basal cell carcinoma (BCC) is the most common non melanoma skin cancer (NMSC) in white individuals over the age of 40 years. BCCs usually grow slowly and rarely metastasize, but can be locally invasive if neglected or of an aggressive subtype. The local tissue destruction caused by an untreated BCC can be extensive, therefore optimal treatment should lead to tumour clearance. Surgery and topical medical treatments are successful therapeutic options for most superficial and nodular BCC. Systemic medical treatments may be considered when surgical procedures are not recommended on the basis of the anatomical site and tumor extension, and patients' associated comorbidities. Expected cure rates and cosmetic outcome should be also carefully considered. A better understanding of the molecular mechanisms of BCC pathogenesis can lead to new developing target medical therapies, and data on their efficacy seem encouraging.