Viswanath Reddy Belum

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.

Dermatological adverse events with taxane chemotherapy.

Taxanes (docetaxel and paclitaxel) are among the most commonly prescribed anticancer drugs approved for the treatment of metastatic or locally advanced breast, non-small cell lung, prostate, gastric, head and neck, and ovarian cancers, as well as in the adjuvant setting for operable node-positive breast cancers. Although the true incidence of dermatological adverse events (AEs) in patients receiving taxanes is not known, and has never been prospectively analysed, they clearly represent one of the major AEs associated with these agents. With an increase in the occurrence of cutaneous AEs during treatment with novel targeted and immunological therapies when used in combination with taxanes, a thorough understanding of reactions attributable to this class is imperative. Moreover, identification and management of dermatological AEs is critical for maintaining the quality of life in cancer patients and for minimizing dose modifications of their antineoplastic regimen. This analysis represents a systematic review of the dermatological conditions reported with the use of these drugs, complemented by experience at comprehensive cancer centres. The conditions reported herein include skin, hair, and nail toxicities. Lastly, we describe the dermatological data available for the new, recently FDA-and EMA- approved, solvent-free nab-paclitaxel.

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.

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

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.

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.

Dermatologic Adverse Events to Targeted Therapies in Lower GI Cancers: Clinical Presentation and Management

Opinion statementRapid 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.

The risk of nail changes with taxane chemotherapy: a systematic review of the literature and meta‐analysis

DEAR EDITOR, Taxanes are an established and powerful class of cytotoxic chemotherapeutic agents that exhibit a wide spectrum of activity against solid tumours including breast, ovarian, lung, head and neck, stomach, pancreatic and prostate cancers. This antitubulin/antimitotic class of drugs includes paclitaxel, docetaxel and the newer nanoparticle albuminbound (nab)-paclitaxel. The range of dermatological adverse events (AEs) is broad and includes nail changes such as hyperpigmentation, discolouration, splinter haemorrhages, subungual haematomas and Beau lines. Periungual erythema, oedema, exudation and granulation tissue are other nailrelated AEs that could potentially result in partial/total onycholysis and subungual abscesses, and represent the more common and often dose-limiting changes. The overall incidence of nail changes with taxanes has not been systematically investigated and tends to vary widely across the literature. To address this issue, we searched the PubMed database (January 1994–February 2014) using the drug’s generic name (e.g. paclitaxel), the operator ‘AND’ and ‘nail’ as the search terms. Subsequently, we evaluated the safety data of retrieved publications of clinical trials investigating paclitaxel, docetaxel or nab-paclitaxel, for nail-related AEs. Finally, we performed a meta-analysis to determine the overall incidence and risk of developing nail changes with these agents. We included the following trials in the final analysis: (i) prospective phase II and phase III clinical trials in cancer patients, (ii) phase I/II trials in which the phase II data alone could be extracted and (iii) trials reporting safety data pertaining to nail changes. Clinical endpoints were extracted from the safety profile reported in each trial. Nail changes were graded according to the Common Terminology Criteria for Adverse Events (CTCAE), versions 2.0 and 3.0, or the World Health Organization AE grading criteria. All statistical analyses were performed using version 2 of the Comprehensive Meta-Analysis software (Biostat Inc., Englewood, NJ, U.S.A.). For each study, the proportion of patients with nail changes was calculated and the 95% confidence interval (CI) was derived. For studies with a control arm, the relative risk (RR) of nail changes was also calculated. For the meta-analysis, the random effects model was considered. A two-tailed P-value of < 0 05 was judged to be statistically significant. Our literature search yielded 130 potentially relevant studies. Overall, 41 original studies, including 12 phase III randomized controlled trials (RCTs) and 29 single-arm phase II trials (two of which were phase I/II) were included in this analysis (Table S1; see Supporting Information). In these trials, a total of 8518 patients received docetaxel and the overall incidence of allgrade nail changes was 34 9% (95% CI 29 9–40 2); 160 patients received paclitaxel and 205 patients received nab-paclitaxel. For paclitaxel and nab-paclitaxel, the overall incidence of all-grade nail changes was 43 7% (95% CI 18 0–73 3) and 19 4% (95% CI 11 8–30 3), respectively (Fig. 1a–c). To investigate the specific contribution of individual taxanes toward the development of nail changes, and to exclude the influence of confounding factors, we determined the RR of nail changes. Compared with controls, the RR of nail changes with docetaxel was 77 74 (95% CI 41 88–144 32; P < 0 001) according to the fixed effects model. The paclitaxel and nab-paclitaxel data set was excluded due to the lack of RCTs. Our meta-analysis is the first to ascertain the increased incidence of nail changes with the use of paclitaxel, docetaxel and nab-paclitaxel, and the high RR of developing nail changes with docetaxel in patients with cancer. In general, anticancer drugs are well-known inducers of nail changes, as the continuously dividing nail matrix cells are highly susceptible to the antimitotic action of these drugs. Nail changes that result from matrix interruption of blood flow often lead to cosmetic changes (not requiring intervention), with the nail eventually growing out normally after discontinuation of treatment. Alternatively, nail changes due to disruption of the nail folds frequently require intervention including dose modifications. Paronychia, onycholysis, granulation tissue formation and subungual abscesses with potential secondary infection are often so painful that they interfere with activities of daily living and significantly impair patients’ quality of life. The development of nail changes strongly correlates with the number of chemotherapy cycles administered and increases with the cumulative taxane dose. Although pain and dysfunction typically subside within a few months of discontinuation of treatment, scarring of the nail apparatus may ensue. Currently, there is a lack of standardized and effective treatment options for nail-related AEs. Anecdotal data support the benefit of topical antibiotics and/or steroids. For moderate-tosevere cases oral antibiotics or corticosteroids may be needed, with severe cases requiring surgical intervention in the form of partial/complete nail avulsion or drainage of abscess(es). Recently, the application of povidone-iodine solution (1–2%) to the nail plate and nail folds was found to be beneficial at

Alopecia in patients treated with molecularly targeted anticancer therapies.

BACKGROUND The introduction of molecularly targeted anticancer therapies presents new challenges, among which dermatologic adverse events are noteworthy. Alopecia in particular is frequently reported, but the true incidence is not known. PATIENTS AND METHODS We sought to ascertain the incidence and risk of developing alopecia during treatment with approved inhibitors of oncogenic pathways and molecules [anaplastic lymphoma kinase, breakpoint cluster region-abelson, B-rapidly accelerated fibrosarcoma, Brutons tyrosine kinase, cytotoxic T-lymphocyte antigen-4, epidermal growth factor receptor, human epidermal growth factor receptor-2, Janus kinase, MAPK/ERK (extracellular signal-regulated kinase) Kinase, mammalian target of rapamycin, smoothened, vascular endothelial growth factor, vascular endothelial growth factor receptor, platelet derived growth factor receptor; proteasomes; CD20, CD30, CD52]. Electronic database (PubMed, Web of Science) and ASCO meeting abstract searches were conducted to identify clinical trials reporting alopecia. Meta-analysis was conducted utilizing fixed- or random-effects models. RESULTS The calculated overall incidence of all-grade alopecia was 14.7% [95% confidence interval (CI) 12.6% to 17.2%]-lowest with bortezomib, 2.2% (95% CI 0.4% to 10.9%), and highest with vismodegib, 56.9% (95% CI 50.5% to 63.1%). There was an increased risk of all-grade alopecia [relative risk (RR), 7.9 (95% CI 6.2-10.09, P ≤ 0.01)] compared with placebo, but when compared with chemotherapy, the risk was lower [RR, 0.32 (95% CI 0.2-0.55, P ≤ 0.01)]. CONCLUSIONS Targeted therapies are associated with an increased risk of alopecia.

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

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.