In the past decade, the expanded use of targeted anticancer drugs has significantly prolonged survival in patients treated for a variety of cancers. Despite their increased specificity, agents such as epidermal growth factor receptor inhibitors (EGFRIs), BRAF inhibitors, and targeted immunotherapies have commonly been associated with a number of dermatologic adverse events, often necessitating treatment modifications and negatively impacting patients' quality of life. Although toxicities such as rash and xerosis are frequently discussed, symptomatic pruritus, or itch, has emerged as an important, and frequently neglected, event. The present study reviews the incidence and clinical presentation of pruritus with the EFGRIs, and with two novel anti-melanoma drugs, vemurafenib and ipilimumab, with a focus on the putative underlying pathophysiology, and current management strategies.

The development of targeted therapies has ushered in a new era in the management of melanoma. Inhibitors of the RAS-RAF-MEK-ERK pathway have taken the center stage with development at a rapid pace. Vemurafenib was recently approved by regulatory agencies, and other agents (e.g. dabrafenib) are in various stages of clinical testing. These agents are producing remarkable results for patients, but are also presenting new challenges. Clinical toxicities and drug resistance are topmost issues. Some of the most common and vivid representations of adverse events to these agents are the dermatologic manifestations. Published trials and initial observations reflect a toxicity profile (e.g. squamous cell carcinomas/keratoacanthomas, maculopapular rashes, hyperkeratosis) that is distinct from cutaneous toxicities from EGFR and mTOR inhibitors (acneiform rash, paronychia, xerosis). Their management extends beyond conservative treatment and includes specific physical and surgical treatment modalities, skill sets unique to dermatologists. All these pose significant challenges to clinicians, and sound knowledge of such toxicities and their management will likely result in improved patient outcomes and quality of life. In this manuscript, we provide an overview of the emerging scientific literature on dermatological adverse events arising out of BRAF inhibition.

Axitinib is a potent, selective vascular endothelial growth factor receptor (VEGFR) inhibitor. We have performed a systematic analysis to investigate the risk of hand-foot skin reaction (HFSR) to axitinib and compare the differences in incidences between sorafenib, sunitinib, pazopanib and axitinib. Relevant studies were identified from PubMed (1998-2012). Eligible studies were limited to prospective Phase II-III clinical trials in which cancer patients were treated with axitinib monotherapy at a starting dose of 5 mg orally twice daily. Incidence, relative risk (RR), and 95 % confidence intervals were calculated using random-effects or fixed-effects models based on heterogeneity of included studies. A total of 984 patients from 6 prospective clinical trials were included in the analysis. The overall incidence of all-grade and high-grade HFSR was 29.2 % (95 % CI: 14.0-51.1 %) and 9.6 % (95 % CI: 4.2-20.7 %), respectively. The relative risks of all-grade and high-grade HFSR to axitinib compared to sorafenib were decreased for all-grade (RR=0.54, 95 % CI: 0.44-0.65, p<0.001) and high-grade HFSR (RR=0.31, 95 % CI: 0.19-0.52, p<0.001). The risk of all-grade and high-grade HFSR to axitinib, sunitinib and sorafenib was significantly higher as compared to pazopanib (RR=6.49, 95 % CI: 4.65-9.05, p<0.001; RR=6.40, 95 % CI: 3.60-11.37, p<0.001, and RR=4.20, 95 % CI: 3.07-5.75, p<0.001; RR=3.67, 95 % CI: 2.15-6.24, p<0.001, and RR=7.51, 95 % CI: 5.5-10.3, p<0.001; RR=5.93, 95 % CI: 3.5-10.0, p<0.001, respectively). Similar to sorafenib and sunitinib, axitinib is associated with a significant risk of HFSR, despite having an increased specificity for VEGF receptors. These findings underscore the importance of supportive dermatologic care in patients treated with axitinib, in order to maintain quality of life, adherence, and persistence to therapy.

T-cell-depleted (TCD) allogeneic hematopoietic stem cell transplantation demonstrates similar efficacy and reduced incidence and severity of graft-versus-host disease (GVHD) in appropriately selected patients versus T-cell-replete transplantation. The histopathology of cutaneous acute GVHD (aGVHD) following TCD peripheral blood stem cell transplants (PBSCT) is not described. We identified 13 cases of patients post TCD-PBSCT, with definitive aGVHD, and 20 cases of non-aGVHD skin rash in patients after TCD-PBSCT, during multidisciplinary review by a dermatopathologist, dermatologist and transplant physician, incorporating clinical presentation, therapeutic response, and histopathology data. Histopathologic features of aGVHD and non-aGVHD skin rash in TCD-PBSCT patients were compared to each other, and also to features recently reported for non-TCD transplant recipients. AGVHD and non-aGVHD skin rash in TCD-PBSCT patients' biopsies had similar rates of epidermal acanthosis, dermal melanophages, neutrophils, plasma cells, eosinophils and extravasated erythrocytes. While satellitosis, exocytosis and adnexal involvement slightly favored aGVHD, more notable differential findings favoring aGVHD, were diffuse (versus focal/absent) basal vacuolization (77% aGVHD vs 25% non-aGVHD rash), involvement of the entire epidermis (versus partial thickness) by necrotic keratinocytes (42% aGVHD vs 0% non aGVHD rash), and non-dense (rather than exuberant) inflammatory infiltrates (77% vs. 20%). After filtering features seen in all TCD samples (epidermal acanthosis, dermal melanophages, neutrophils, plasma cells, eosinophils and extravasated erythrocytes), the most distinct features belonging to aGVHD-positive TCD samples were diffuse basal vacuolization, slight rather than dense inflammatory infiltrates, and necrotic keratinocytes involving the entire epidermis. Awareness of these features may help when evaluating a skin rash occurring after a TCD transplant.

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