Cutaneous Adverse Events of New Anti-melanoma Therapies: Classification and Management.

Over the past decade, targeted therapies such as BRAF inhibitors, MEK inhibitors and immunotherapies such as anti-CTLA4 and anti-PD1 antibodies have emerged as novel treatments of advanced melanoma. Along with increased use of these therapies, a range of cutaneous adverse events have also emerged, varying from more serious and frequent cutaneous squamous cell carcinoma to mere cosmetic changes such as curly hair or rare severe toxic epidermal necrolysis. Early detection and management of these cutaneous adverse events will aid patients to receive accurate treatment, avoid unnecessary discontinuation of anti-tumour treatment and improve the patient's overall quality of life. This review will describe various cutaneous adverse events of anti-melanoma therapies and its management.

Cutaneous adverse events in patients treated with BRAF inhibitor-based therapies for metastatic melanoma for longer than 52 weeks.

BACKGROUND: BRAF inhibitor-based therapies have been shown to induce cutaneous toxicities, with onset generally in the first 8-26 weeks of therapy. OBJECTIVES: To determine whether cutaneous toxicities persist in patients who have remained on BRAF inhibitor-based therapies for longer than 52 weeks, and therefore whether ongoing dermatology assessment is required. METHODS: All patients treated with the BRAF inhibitors vemurafenib or dabrafenib or combination BRAF inhibitor and mitogen-activated protein kinase kinase (MEK) inhibitor therapy at Westmead Hospital, Sydney, Australia underwent regular dermatological assessments for the duration of therapy. All patients enrolled in a clinical trial, and 18% of patients in the compassionate access scheme underwent a baseline assessment prior to commencement of therapy and every 4-8 weeks thereafter. Patients' adverse events were recorded in a specific database. RESULTS: Patients continued to develop cutaneous adverse events after 52 weeks of continuous therapy. Patients on single-agent BRAF inhibitor therapy suffered from Grover disease (45%), plantar hyperkeratosis (45%), verrucal keratosis (18%) and even cutaneous squamous cell carcinoma (16%). The most frequent adverse event seen in patients in the combination BRAF and MEK inhibitor group was an acneiform eruption (40%). CONCLUSIONS: Patients on BRAF inhibitor-based therapies need to continue to have regular dermatological follow-up independent of the duration of their therapy.

Systemic retinoids for the chemoprevention of cutaneous squamous cell carcinoma and verrucal keratosis in a cohort of patients on BRAF inhibitors.

BACKGROUND: The treatment of metastatic melanoma has changed greatly with the development of inhibitors targeted at the mutated BRAF kinase present in up to 50% of metastatic melanoma cases. These agents, vemurafenib and dabrafenib, have been shown to increase median survival. Unfortunately, they have also been associated with the development of verrucal keratosis (VK) and cutaneous squamous cell carcinoma (cuSCC). These lesions require surgical excision, and when a large number of these lesions need to be treated, it can significantly affect the patient's quality of life. OBJECTIVES: To determine if acitretin is suitable as a chemopreventative agent against the development of verrucal keratosis and cuSCC, in patients on BRAF inhibitors. METHODS: Patients treated with a BRAF inhibitor, vemurafenib or dabrafenib, for stage IV metastatic melanoma, who had undergone more than five surgical excisions to remove lesions suggestive of cuSCC, were offered the opportunity to commence acitretin as a chemopreventative agent. Patients were evaluated every 4 weeks. Clinical and histological data were collected. RESULTS: Eight patients, who had a total of 24 cuSCC removed, were included in the study. After commencement of acitretin, only five cuSCC were excised from two patients. The most significant reduction was in a patient who had developed 13 cuSCC over 10 months and only two cuSCC 3 months after commencing acitretin. No modifications in the dose of the BRAF inhibitor were made as a result of cuSCC in any of these patients. CONCLUSIONS: Acitretin should be considered as a chemopreventative agent for VK and cuSCC in patients taking BRAF inhibitors, before considering dosage reductions.

Cutaneous manifestations of dabrafenib (GSK2118436): a selective inhibitor of mutant BRAF in patients with metastatic melanoma.

BACKGROUND: Inhibitors of mutant BRAF are emerging as standard of care in patients with metastatic melanoma carrying relevant oncogenic mutations. Cutaneous reactions are frequent and significant. We conducted a systematic prospective dermatological review of all patients enrolled at a single institution in the phase I/II clinical trial of the mutant BRAF inhibitor dabrafenib (GSK2118436). OBJECTIVES: To identify the cutaneous manifestations of the BRAF inhibitor dabrafenib; to form diagnostic criteria to standardize the diagnosis of verrucal keratotic squamoproliferative lesions; and to bring awareness to the medical community of the importance of dermatological assessment of patients taking dabrafenib. METHODS: Patients enrolled in the phase I/II trial (n = 43) were monitored for the development of new skin lesions. Each new lesion was photographed, a clinical diagnosis recorded and, where appropriate, a biopsy taken. Human papillomavirus (HPV) and p16 immunohistochemistry analyses were performed. RESULTS: The most frequently observed lesions were verrucal keratotic squamoproliferative lesions (49%), Grover's disease (27%) and reactive hyperkeratotic lesions on the soles, at points of friction (22%). Eighteen squamous cell carcinomas (SCCs) occurred in 20% of patients. Most SCCs appeared between weeks 6 and 24 following commencement of therapy on both sun-damaged and nonsun-damaged skin. All SCCs were well differentiated, five were of the keratoacanthoma type, and two were SCC in situ. Other lesions observed included seborrhoeic keratoses, epidermal cysts, acneiform eruptions, hair loss and changes in hair structure. HPV was negative in 15 of the 16 tissues studied and p16 expression was higher in SCCs compared with verrucal keratoses. CONCLUSIONS: Administration of the mutant BRAF inhibitor dabrafenib is associated with induction of keratinocytic proliferation, which in some cases develops features of low-grade malignancy. Highly oncogenic HPV infection is unlikely to be a contributor to the formation of SCCs or verrucal keratoses.

Variation in the length and structure of reports written by reporting radiographers: A retrospective study.

INTRODUCTION: The literature suggests that there is variation in various features of the written radiology report for a range of body areas and imaging modalities. The retrospective study presented here aims to determine if similar variation is demonstrated in a group of 5 reporting radiographers in a UK NHS Trust. METHODS: Full reports for 1530 knee radiographic examinations performed from accident and emergency referrals were extracted for a 12-month period from a Radiology Information System (RIS) into Excel. Copied into Word, the word count function was used for each report and the number of words and characters (without spaces) was returned into Excel. Average word count and word length per report, by radiographer, were calculated for the following sections of the report: report title, main body and signature. SPSS was used to perform inferential statistical analysis. RESULTS: A wide range in the maximum and minimum average report lengths (60.88 v 17.83 words) was demonstrated. Statistically significant differences (p < 0.05) were seen between all but one pair-wise comparison (Rad 2 v Rad 4; p = 0.98) for the overall report length; for the length of the findings section, four pair-wise comparisons did not reach significance. Average word length demonstrated less variation. 4 out of 5 radiographers always included a report title; 3 out of 5 never included a report signature. There was a strong negative correlation between experience and report length. CONCLUSION: Variation in report structure and length, as well as word length, was seen, comparable to studies of radiologist reports. Further research is required to investigate the drivers of this variation, and determine if there is any clinical significance.

Cutaneous Adverse Events of New Anti-melanoma Therapies: Classification and Management / Efectos cutáneos adversos de los nuevos tratamientos para melanoma: Clasificación y Tratamiento

Over the past decade, targeted therapies such as BRAF inhibitors, MEK inhibitors and immunotherapies such as anti-CTLA4 and anti-PD1 antibodies have emerged as novel treatments of advanced melanoma. Along with increased use of these therapies, a range of cutaneous adverse events have also emerged, varying from more serious and frequent cutaneous squamous cell carcinoma to mere cosmetic changes such as curly hair or rare severe toxic epidermal necrolysis. Early detection and management of these cutaneous adverse events will aid patients to receive accurate treatment, avoid unnecessary discontinuation of anti-tumour treatment and improve the patient’s overall quality of life. This review will describe various cutaneous adverse events of anti-melanoma therapies and its management

En la última década han aparecido nuevos tratamientos para el melanoma avanzado, como las terapias contra dianas como los inhibidores de BRAF o MEK, y las inmunoterapias como los anticuerpos contra CTLA-4 y PD1. Debido al uso cada vez más frecuente de estos tratamientos también han aparecido diversos efectos secundarios cutáneos, que van desde efectos graves y frecuentes como el desarrollo de carcinomas espinocelulares, a cambios cosméticos como el pelo rizado, o casos infrecuentes y graves de necrosis epidérmica tóxica. La detección y el tratamiento temprano de estos efectos adversos ayudará a los pacientes a recibir mejor tratamiento, a evitar el cese de la terapia antitumoral y a mejorar su calidad de vida. En esta revisión describiremos los efectos cutáneos adversos de los nuevos tratamientos contra el melanoma y su tratamiento