Mechanisms of skin aging induced by EGFR inhibitors.

BACKGROUND: The mechanisms of skin aging have not been completely elucidated. Anecdotal data suggests that EGFR inhibition accelerates aging-like skin changes. OBJECTIVE: The objective of the study was to evaluate the clinical characteristics and investigate the cellular and molecular mechanisms underlying skin changes associated with the use of EFGRIs. PATIENTS AND METHODS: Patients during prolonged treatment with EGFRIs (>3 months) were analyzed for aging-like skin changes. Baseline EGFR expression was compared in young (<25 years old) vs. old (> 65 years old) skin. In addition, the regulation of extracellular matrix, senescence-associated genes, and cell cycle status was measured in primary human keratinocytes treated with erlotinib in vitro. RESULTS: There were progressive signs of skin aging, including xerosis cutis, atrophy, rhytide formation, and/or actinic purpura in 12 patients. Keratinocytes treated with erlotinib in vitro showed a significant down-modulation of hyaluronan synthases (HAS2 and HAS3), whereas senescence-associated genes (p21, p53, IL-6, maspin) were upregulated, along with a G1 cell cycle arrest and stronger SA ß-Gal activity. There was significantly decreased baseline expression in EGFR density in aged skin, when compared to young controls. CONCLUSIONS: EGFR inhibition results in molecular alterations in keratinocytes that may contribute to the observed skin aging of patients treated with respective targeted agents.

Cold thermal injury from cold caps used for the prevention of chemotherapy-induced alopecia.

INTRODUCTION: The use of scalp cooling for the prevention of chemotherapy-induced alopecia (CIA) is increasing. Cold caps are placed onto the hair-bearing areas of the scalp for varying time periods before, during, and after cytotoxic chemotherapy. Although not yet reported, improper application procedures could result in adverse events (AEs). At present, there are no evidence-based scalp cooling protocols, and there is no regulatory oversight of their use. OBJECTIVE: To report the occurrence of cold thermal injury (frostbite) on the scalp, following the use of cold caps for the prevention of CIA. MATERIALS AND METHODS: We identified four patients who developed cold thermal injuries on the scalp following the application of cold caps. Medical records were analyzed to retrieve the demographic and clinical characteristics. RESULTS: The cold thermal injuries in our patients were grade 1/2 in severity and improved with topical interventions and interruption of cold cap use, although grade 1 persistent alopecia ensued in 3 patients. The true incidence of such injuries in this setting, however, remains unknown. CONCLUSIONS: Cold thermal injuries are likely infrequent and preventable AEs that may result from improper device application procedures during cold cap use. Although these untoward events are usually mild to moderate in severity, the potential occurrence of long-term sequelae (e.g., permanent alopecia and scarring) or the need to discontinue cold cap use, are not known. Prospective studies are needed to further elucidate the risk and standardize healthcare delivery methods, and to improve patient/supportive/healthcare provider education.

Nasal vestibulitis due to targeted therapies in cancer patients.

BACKGROUND AND PURPOSE: Cancer patients treated with targeted therapies (e.g., epidermal growth factor receptor inhibitors) are susceptible to dermatologic adverse events (AEs) including secondary skin infections. Whereas infections such as paronychia and cellulitis have been reported, nasal vestibulitis (NV) has not been described with the use of these agents. The aim of our study was to characterize NV in cancer patients treated with targeted therapies. METHODS: We utilized a retrospective chart review of cancer patients who had been referred to dermatology and were diagnosed with NV. We recorded data including demographics, referral reason, underlying malignancy, targeted anticancer regimen, NV treatment, and nasal bacterial culture results. RESULTS: One Hundred Fifteen patients were included in the analysis, of which 13 % experienced multiple NV episodes. Skin rash was the most common reason (90 %) for a dermatology referral. The most common underlying malignancies were lung (43 %), breast (19 %), and colorectal (10 %) cancer. Sixty-eight percent of patients had been treated with an EGFRI-based regimen. Nasal cultures were obtained in 60 % of episodes, of which 94 % were positive for one or more organisms. Staphylococcus aureus was the most commonly isolated organism [methicillin-sensitive S. aureus 43 %; methicillin-resistant S. aureus 3 %]. CONCLUSIONS: We report the incidence and characteristics of an unreported, yet frequent dermatologic condition in cancer patients treated with targeted therapies. These findings provide the basis for additional studies to describe the incidence, treatment, and consequences of this event. A better understanding of NV would mitigate its impact on patients' quality of life and risk for additional dermatologic AEs.

Incidence and risk of xerosis with targeted anticancer therapies.

BACKGROUND: Many targeted therapies used in the treatment of cancer can lead to the development of xerosis, but the incidence and relative risk of xerosis have not been ascertained. OBJECTIVE: We conducted a systematic review and metaanalysis of clinical trials, to ascertain the incidence and risk of developing xerosis after taking anticancer drugs. METHODS: The PubMed (1966-October 2013), Web of Science (January 1998-October 2013), and American Society of Clinical Oncology abstracts (2004-2013) databases were searched for clinical trials of 58 targeted agents. Results were calculated using random or fixed effects models. RESULTS: The incidences of all- and high-grade xerosis were 17.9% (95% confidence interval [CI]: 15.6-20.4%) and 1.0% (95% CI: 0.9-1.5%), respectively. The risk of developing all-grade xerosis was 2.99 (95% CI: 2.0-4.3), and it varied across different drugs (P < .001). LIMITATIONS: The reporting of xerosis may vary among clinicians and institutions, and the incidence may be affected by age, concomitant medications, comorbidities, and underlying malignancies or skin conditions. CONCLUSION: Patients receiving targeted therapies have a significant risk of developing xerosis. Patients should be counseled and treated early for this symptom to prevent suboptimal dosing and quality of life impairment.

Dermatologic adverse events in pediatric patients receiving targeted anticancer therapies: a pooled analysis.

BACKGROUND: The dermatologic adverse events (AEs) of various molecularly targeted therapies are well-described in adult cancer patients. Little has been reported on the incidence and clinical presentation of such AEs in pediatric patients with cancer. To address this gap, we analyzed the dermatologic AEs reported across clinical trials of targeted anticancer therapies in pediatric patients. PROCEDURES: We conducted an electronic literature search (PubMed, American Society of Clinical Oncology annual meetings' abstracts, ClinicalTrials.gov, NCI's Pediatric Oncology Branch webpage) to identify clinical trials involving targeted anticancer therapies that reported dermatologic AEs in their safety data. Studies were limited to the pediatric population, monotherapy trials (oncology), and English language publications. RESULTS: Pooled data from 19 clinical studies investigating 11 targeted anticancer agents (alemtuzumab, rituximab, imatinib, dasatinib, erlotinib, vandetanib, sorafenib, cabozantinib, pazopanib, everolimus, and temsirolimus) were analyzed. The most frequently encountered dermatologic AEs were rash (127/660; 19%), xerosis (18/100; 18%), mucositis (68/402; 17%), and pruritus (12/169; 7%). Other AEs included pigmentary abnormalities of the skin/hair (13%), hair disorders (trichomegaly, hypertrichosis, alopecia, and madarosis; 14%), urticaria (7%), palmoplantar erythrodysesthesia (7%), erythema, acne, purpura, skin fissures, other 'unknown skin changes', exanthem, infection, flushing, telangiectasia, and photosensitivity. CONCLUSION: This study describes the dermatologic manifestations of targeted anticancer therapy-related AEs in the pediatric population. Since these AEs are often associated with significant morbidity, it is imperative that pediatric oncologists be familiar with their recognition and management, to avoid unnecessary dose modifications and/or termination, and to prevent impairments in patients' quality of life.

Clinico-morphological features of BRAF inhibition-induced proliferative skin lesions in cancer patients.

BACKGROUND: The use of BRAF inhibitors may lead to the development of cutaneous toxicities such as rashes, photosensitivity, alopecia, palmoplantar erythrodysesthesia, and proliferative skin lesions, including keratoacanthomas (KAs) and cutaneous squamous cell carcinomas (cuSCCs). The latter are noteworthy for their potential to exhibit malignant features, and they may necessitate invasive treatment. Their prompt identification is of primary importance for directing supportive care efforts and maintaining dose intensity while minimizing the morbidity associated with supportive care interventions. Because such lesions are less familiar to oncologists, this study was designed to characterize their clinico-morphological features, which have not been hitherto described. METHODS: The clinical and dermoscopic characteristics and risk factors of new-onset proliferative skin lesions (benign verrucous lesions and KAs/cuSCCs) developing after the initiation of treatment with vemurafenib, dabrafenib, and XL281 were analyzed; the histopathological diagnoses were ascertained. RESULTS: The majority of the lesions were benign verrucous lesions (78%, n = 87), whereas KAs/cuSCCs represented 22% (n = 25). The median times to biopsy for the initial verrucous lesions and KAs/cuSCCs were 4.8 and 10.5 weeks, respectively. The clinico-morphological features significant for KAs/cuSCCs included a larger size (P < .001), a nodular appearance (P < .001), a central keratin plug (P < .001), a central ulceration or crust (P = .04), an adherent scale (P = .02), an erythematous halo (P = .03), and a scaly ring (collarette; P < .001) at the periphery. CONCLUSIONS: Our findings represent the first detailed description of the clinico-morphological characteristics that permit distinction between the benign and malignant skin lesions induced by BRAF inhibitors. They are valuable for the recognition of lesions that require intervention and/or a dermatology referral versus those that permit provisional monitoring.

Current practices in the management of adverse events associated with targeted therapies for advanced renal cell carcinoma: a national survey of oncologists.

BACKGROUND: Oncologists treating patients with targeted therapies encounter adverse events (AEs) that pose management challenges, lead to dosing inconsistencies, and impact patient quality of life. Oncologists' practices and attitudes in the management of targeted therapy-related AEs in patients with renal cell carcinoma (RCC) are poorly understood. We sought to identify unmet needs associated with AE management and understand oncologists' treatment optimization strategies. METHODS: A 24-item online survey was administered in August 2012 to 119 US oncologists treating patients with advanced RCC. The survey solicited responses regarding demographics, practice settings, AE management practice patterns and beliefs, treatment barriers, and patient education. RESULTS: Respondents indicated that between 25% and 50% of patients require dose modification/discontinuation because of AEs. The greatest barrier to optimizing treatment for RCC is the unpredictability of patient responses to treatment (43%). Most respondents (78%) discuss AE management with patients, but only a minority of them proactively reach out to patients (46%). Most practitioners (70%) refer patients to nononcology specialists when faced with unfamiliar AEs, although finding interested physicians (43%) and time constraints (40%) were the most commonly cited barriers to consulting with other specialties. CONCLUSION: Results suggest that many patients require dose modification/discontinuation because of AEs and that nononcologists are a frequently utilized resource to manage these events. There is a need for predictive drug toxicity markers to establish counseling and prevention, along with opportunities for increased education on supportive care techniques to maintain health-related quality of life and consistent dosing.

Dermatologic adverse events to targeted therapies in lower GI cancers: clinical presentation and management.

OPINION STATEMENT: Rapid advances in drug discovery and the regulatory approval of a number of novel anticancer agents during the past decade pose unique challenges to the oncology community. While the benefits of such therapies receive most attention, adverse events (AEs), especially those pertaining to subspecialties (e.g., dermatology), often are underemphasized. To ensure best clinical outcomes, it would be important to bridge the gap between approval of a new drug and devising effective management strategies for the AEs. With the incorporation of targeted therapies to the treatment paradigm of gastrointestinal malignancies, there has been a significant rise in dermatologic AEs among those treated. In addition to significantly affecting patients' quality of life, these AEs represent a growing problem and are relatively unfamiliar to many oncologists. The issue is further complicated by the lack of evidence-based management guidelines for such AEs in the oncology setting, the "generalizing" of terminology (e.g., rash) for some AEs, as well as an insufficient number of oncodermatologists for assistance with their management. It is important for the oncologist to gain familiarity with the most common, manageable and predictable AEs. Their identification is usually based on medical history, clinical features, and full-body skin examination (FBSE) and at times by obtaining a skin biopsy to aid in diagnosis. Although efforts are underway, presently, there is a paucity of biomarkers (e.g., serologic, genetic) to predict dermatologic AEs. Management often requires a multifaceted approach and includes topical, systemic, surgical, and physical (e.g., cryotherapy) modalities of treatment. Unfortunately, very few clinical trials have focused on this aspect of supportive care; therefore, most data on management derives from anecdotal data. Patients should be encouraged to actively report skin problems, while oncologists should play a vital role in addressing these AEs in their patients. Lastly, further research at the molecular and cellular level may assist in the elucidation of the mechanisms underlying these AEs and their clinical correlates, paving way for the design of effective therapies in this subset of patients.

Skin toxicity of targeted cancer agents: mechanisms and intervention.

In recent years, targeted agents have rapidly evolved as effective tools in the clinical management of a broad range of malignant diseases. These agents disrupt molecular mechanisms and signaling modules that drive the malignant phenotype in defined subsets of malignancies. Beyond the intended cellular targets crucial to tumor growth and progression, these agents also affect signal transduction in normal cells and tissues. The resulting adverse events and their clinical management continue to change, as newer agents with an ever-increasing target spectrum are developed. We provide a succinct overview of dermatologic toxicities arising from the targeting of receptor tyrosine kinases and downstream effectors. Emergent insights into the pathomechanisms involved and the use of this knowledge base to alleviate cutaneous adverse events are discussed.

Risk of hand-foot skin reaction with the novel multikinase inhibitor regorafenib: a meta-analysis.

BACKGROUND: Regorafenib is a novel receptor tyrosine kinase inhibitor approved for use in metastatic colorectal cancer (mCRC) and locally advanced gastrointestinal stromal tumors (GISTs). The drug targets multiple receptors, including VEGF-R1/-R2/-R3, TIE-2, FGFR-1, PDGFR-α/ß, KIT, RET, RAF, p38 MAPK. Adverse events include asthenia, hypertension, diarrhea, and hand-foot skin reaction (HFSR), with the latter representing one of the most clinically significant untoward events. The incidence and risk of HFSR with regorafenib have not been systematically investigated. METHODS: We conducted a meta-analysis to ascertain the incidence and risk of developing HFSR in cancer patients treated with regorafenib. Electronic databases (PubMed, Scopus, Web of Science) and the ASCO website were searched for publications from January 1998-January 2013. Eligible studies were limited to Phase II/III clinical trials employing regorafenib (160 mg/day). The incidence, relative risk (RR), and 95 % CIs were calculated using random- or fixed-effects models based on the heterogeneity of included studies. RESULTS: A total of 1,078 patients treated with regorafenib for mCRC, GIST, renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC) were included. The overall incidence of all-grade and high-grade HFSR were 60.5 % (95 % CI: 48.3-71.6 %) and 20.4 % (95 % CI: 15.4-26.6 %), respectively. The RRs of all-grade and high-grade HFSR with regorafenib in comparison to controls were increased for all-grade (RR = 5.4, 95 % CI: 3.76-7.76, p < 0.001) and high-grade (RR = 41.99, 95 % CI: 5.88-299.93, p < 0.001) HFSR. The incidence of HFSR varied significantly with tumor type (p = 0.007), and was 71.4 % (95 % CI: 57.4-82.3 %) for RCC, 60.2 % (95 % CI: 52.3-67.6 %) for GIST, 50.0 % (95 % CI: 34.2-65.8 %) for HCC, and 46.6 % (95 % CI: 42.3-51.0 %) for mCRC. CONCLUSION: The incidence and risk of development of HFSR with regorafenib is high, and may vary significantly with tumor type. Knowledge of this is important for patient counseling and clinical trial development, to ensure adherence and maximize clinical outcomes.

The Jarisch-Herxheimer reaction: revisited.

The Jarisch-Herxheimer reaction (JHR) is a transient immunological phenomenon seen commonly in patients during treatment for syphilis, and it manifests clinically with short-term constitutional symptoms such as fever, chills, headache and myalgias, besides exacerbation of existing cutaneous lesions. The complex interplay of its underlying patho-physiological mechanisms continues to elude modern medicine, ever since it was described over a century ago. An increase in the incidence of JHR may be expected among patients co-infected with HIV and other infectious diseases including syphilis. Since this subject has not received much attention in recent literature except for brief mentions in standard textbooks, we felt it important to provide an overview of its various attributes including the current concepts in pathophysiology and management.

Dermatological adverse events from BRAF inhibitors: a growing problem.

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.

Lupus miliaris disseminatus faciei. Part I: Significance of histopathologic undertones in diagnosis.

BACKGROUND: Since its clinical discovery, lupus miliaris disseminatus faciei has sporadically been reported to have different modes of clinicopathologic expression. OBJECTIVE: The purpose of this study was to work up a list of histopathologic undertones and to project and propagate lupus miliaris disseminatus faciei as an exclusive entity. An upcoming Part II of this study will present an overview of the disease. METHODS: All patients visiting the outpatient clinic conforming to hitherto accepted clinical features were included to study patients' age and sex, duration of the disease, and above all, conduct a detailed histopathology review. Using the detailed information obtained, an endeavor was made to organize the disease into early, fully developed, and late lesions. RESULTS: The details of the various parameters were of great help in evolving this modus operandi. The clinical as well as histopathologic features of lupus miliaris disseminatus faciei are fairly distinct and facilitate visualizing the entity as a spectrum comprising early, fully developed, and late lesions. Further studies are called for.