e19644 Background: AZD6244 is a second generation MEK inhibitor that targets the RAF-MEK-ERK pathway and is currently in clinical trials for advanced melanoma. MEK kinase inhibitors are known to be associated with a skin rash. While cutaneous reactions to other targeted chemotherapy agents, such as epidermal growth factor receptor inhibitors (EGFRIs) have been intensely studied in recent years, the dermatological toxicities associated with MEK inhibitors have not been well characterized. Similarly, management of these adverse reactions with this class of agents may present a challenge in clinical trials. We reviewed the clinical presentation, evolution and management of dermatological toxicities associated with AZD6244. Methods: Retrospective review of medical records of 10 patients that manifested cutaneous toxicities secondary to AZD6244 was performed. Data from two phase II trials in which AZD6244 was used to treat advanced metastatic cutaneous, mucosal, or uveal melanomas was reviewed. Eight patients were treated with 100 mg of oral AZD6244 twice a day and 2 patients received 75mg orally twice a day. Parameters studied included the time to onset, clinical presentation, evolution, histology and complications of various dermatological toxicities. In addition, the clinical database was accessed to retrieve clinical photographs of these dermatological toxicities when available. Results: The following adverse effects were observed: papulopustular rash, xerosis cutis, fissures, erythema, telangiectasias, and acute paronychia. 10 patients developed papulopustular rash. Paronychia and telangiectasias were seen in 1 patient. Fissures also developed in 1 patient and xerosis was observed in two patients. In addition, secondary bacterial superinfection with Staphylococcus aureus was documented in 3 patients. Conclusions: Dermatological toxicities associated with AZD6244 in our retrospective review were similar in their clinical presentation, evolution, and potential complications such a superinfection to those seen with epidermal growth factor receptor inhibitors (EGFRIs). Treatment approaches used for EGFRIs induced cutaneous reactions may be potentially utilized to manage toxicities triggered by AZD6244. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca
Imatinib mesylate (STI 571; Gleevec; Novartis Pharmaceuticals, Basel, Switzerland) is an orally available tyrosine kinase inhibitor that targets a constitutively activated BCR-ABL tyrosine kinase with additional inhibitory effects on platelet derived growth factor (PDGF) receptors alpha and beta, and KIT. It has revolutionized the treatment of adult and pediatric patients with Philadelphia chromosome positive chronic myelogenous leukemia (CML) and is also FDA-approved for KIT-positive advanced gastrointestinal tumor (GIST) and dermatofibrosarcoma protuberans. A wide spectrum of dermatologic toxicities has been associated with this agent, among which a maculopapular rash is the most common event. In addition, a variety of pigmentary abnormalities of the skin and mucosal surfaces have been reported. Hypopigmentation is a well-recognized adverse effect. In contrast, paradoxical hyperpigmentation has only rarely been documented. In this case report we describe imatinib-induced cutaneous hyperpigmentation and graying of hair occurring in the same patient with dermatofibrosarcoma protuberans treated with imatinib.
As the number and uses for targeted therapies such as epidermal growth factor receptor inhibitors (EGFRIs) increase, so does the need to recognize and treat the dermatologic side-effects of these agents. Although agents such as gefitinib, erlotinib, cetuximab, lapatinib, and panitumumab have less systemic side-effects than traditional cytotoxic chemotherapy, dermatologic adverse events from EGFRIs are significantly more common. These dermatologic toxicities have previously led to reduction or cessation of therapy and recently have been shown to decrease patients' quality of life.This review provides a symptom-based treatment approach to the common dermatologic adverse effects seen with the epidermal growth factor receptor antagonists: papulopustular rash, xerosis, pruritus as well as hair, nail, and mucosal changes. Each dermatologic toxicity is described; prophylaxis and treatment options, from topical to systemic, are presented based on a review of the current literature with emphasis on new clinical trials results. We also provide specific recommendations based on our practice in a specialty clinic.Although the field continues to evolve, this review presents the most up-to-date information on managing dermatologic adverse effects of EGFRIs. Practitioners should find this article to be a practical resource in approaching patients on EGFRIs with dermatologic toxicities. As we learn how to optimally manage the adverse effects of these agents, we practitioners have the opportunity to increase patients' quality of life and decrease reductions or cessations of life-prolonging therapy.
Abstract Background. Bevacizumab, a monoclonal antibody targeting a vascular endothelial growth factor (VEGF) protein, has been reported to induce mucosal toxicities. However, the clinical characteristics of these particular toxicities have not been well characterized. We aimed at providing a detailed clinical description of signs and symptoms limited to the tongue mucosa in patients treated with bevacizumab. Methods. A retrospective review of medical records and clinical photographs was performed with specific attention to clinical presentation, evolution, associated symptoms, concomitant medications, and treatment methods. Results. In total, four patients presented to the dermatology service with clinical findings characterized by multifocal, erythematous circinate and serpiginous erosions on the dorsal tongue surrounded by white hyperkeratotic rims that were temporally related to bevacizumab therapy. Associated increased sensitivity to spicy foods was frequently observed. Conclusion. These characteristic clinical findings are consistent with geographic tongue. However, large prospective evaluations are necessary to confirm this potential relationship. If bevacizumab is indeed associated with geographic tongue, increased awareness may result in improved reporting and characterization of this particular adverse event.
The incidences of life-threatening toxicities such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are inconsistently reported. The potential association of anticancer agents with SJS or TEN has not been systematically investigated. We searched the literature (Ovid: 1950 to June 2013 and PubMed: 1948 to June 2013) using terms for SJS/TEN and anticancer therapies. Primary case reports, case series, and clinical trials were included. In addition, MedWatch, the Food and Drug Administration Adverse Event Reporting System (FAERS), was searched (1968 to August 2012) for SJS/TEN reports associated with anticancer therapies. Proportional reporting ratios (PRR>2, N>3), empirical Bayes geometric mean (EBGM>2, N>3), and lower 95% confidence interval (EBGM0.05>2) were used as thresholds to constitute a signal of association between SJS/TEN and anticancer drugs. There were 46 SJS and 37 TEN cases associated with 18 and 22 anticancer drugs in the literature, respectively. Among cases in the FAERS, significant signals were associated with SJS for bendamustine and with TEN for bendamustine, busulfan, chlorambucil, fludarabine, lomustine, and procarbazine. Several drugs reported in the published literature to be associated with SJS/TEN were not found to have significant signals in FAERS. Proactive pharmacovigilance to detect and define safety signals serves to aid oncology practitioners in the recognition of possible, yet uncommon, serious, and/or life-threatening skin reactions.
Basal cell carcinomas (BCCs) can be diagnosed using different dermoscopic modalities.To evaluate dermoscopic features of BCCs using nonpolarized and polarized dermoscopy to highlight similarities and differences between dermoscopic modalities.Retrospective study of 149 BCCs under nonpolarized dermoscopy (NPD), polarized contact dermoscopy (PCD), and polarized noncontact dermoscopy (PNCD). Images were evaluated for a range of dermoscopic colors, structures, and vessels. Features were compared according to histopathologic subtype.The most common dermoscopic structures in BCCs across all modalities included globules (50.3-51.0%), dots (49.7-50.3%), white structureless areas (63.1-74.5%), structureless gray-brown areas (24.2-24.8%), and ulcerations (28.2%). The most frequently observed vasculature included arborizing vessels (18.8-38.3%), short fine telangiectasias (SFTs) (73.8-82.6%), and vascular blush (41.6-83.2%). Structures with higher levels of agreement across modalities included pigmented structures and ulcerations. Lower levels of agreement existed between contact and noncontact modalities for certain vascular features. White shiny structures, which include shiny white lines (chrysalis and crystalline structures) (0-69.1%), shiny white areas (0-25.5%), and rosettes (0-11.4%), exhibited no agreement between NPD and polarized modalities.This study highlights differences in dermoscopic features of BCCs under three dermoscopic modalities. Shiny white lines (chrysalis and crystalline structures) and shiny white areas may be used as additional criteria to diagnose BCCs.
e19519 Background: The association of chemotherapy with potentially fatal adverse events such as SJS/TEN has not been systematically examined. Case reports in association with agents such as imatinib and docetaxel have been published in the literature. We applied data mining algorithms to assess the risk of SJS/TEN to chemotherapy. Methods: FDA Safety Information and Adverse Event Reporting Program MedWatch database was searched for cases of SJS and TEN reported in association with FDA-approved chemotherapy agents through December 2009. Proportional reporting ratios (PRR>2) and empirical Bayes geometric mean (EBGM>2) with a case count threshold ≥3 were considered signals of disproportionate reporting. Cases obtained by searching this database included those in which chemotherapeutic agents were used to treat cancer and non-cancer-related diseases. Results: Using our criteria for selection of cases, we have identified 252 TEN cases associated with 11 FDA-approved drugs. Similarly, 71 SJS cases in association with 4 FDA-approved chemotherapy agents were identified (Table). Conclusions: By identifying disproportionally reported agents we demonstrated that multiple chemotherapy agents may be associated with SJS/TEN. Although data mining may not be sufficient to establish causality, this method may serve as a supplemental tool to identify chemotherapy drugs that may warrant further investigation. Drugs Cases Signal n PRR 95% CI EBGM 95% CI SJS Bendamustine 8 6.67 3.34-13.28 5.54 2.33-10.85 Chlorambucil 10 2.66 1.43-4.93 2.21 1.16-3.92 Ibritumomab tiuxetan 17 4.64 2.48-7.65 3.52 1.88-6.03 Temozolomide 36 2.16 1.56-2.99 2.07 1.47-2.82 Total 71 TEN Bendamustine 5 9.53 3.97-23.32 7.21 2.39-16.38 Busulfan 17 3.85 2.39-6.18 3.29 2.00-5.245 Cytarabine 55 2.67 2.05-3.48 2.56 1.94-3.30 Chlorambucil 12 6.19 3.52-10.88 5.67 3.04-9.69 Dactinomycin 8 3.81 1.90-7.60 2.82 1.36-5.57 Fludarabine 40 3.62 2.65-4.93 3.37 2.44-4.56 Ibritumomab tiuxetan 4 2.96 1.11-7.86 1.93 0.69-4.52 Lomustine 14 17.17 10.23-28.79 14.81 7.49-24.27 Procarbazine 24 5.51 3.69-8.2 5.18 3.3-7.62 Thiotepa 8 4.84 2.42-9.66 3.38 1.59-6.81 Vincristine 65 2.12 1.65-2.7 2.06 1.6-2.6 Total 252
