Milan J. Anadkat

Clinical practice guidelines for the prevention and treatment of EGFR inhibitor-associated dermatologic toxicities

BackgroundEpidermal growth factor receptor inhibitors (EGFRI) produce various dermatologic side effects in the majority of patients, and guidelines are crucial for the prevention and treatment of these untoward events. The purpose of this panel was to develop evidence-based recommendations for EGFRI-associated dermatologic toxicities.MethodsA multinational, interdisciplinary panel of experts in supportive care in cancer reviewed pertinent studies using established criteria in order to develop first-generation recommendations for EGFRI-associated dermatologic toxicities.ResultsProphylactic and reactive recommendations for papulopustular (acneiform) rash, hair changes, radiation dermatitis, pruritus, mucositis, xerosis/fissures, and paronychia are presented, as well as general dermatologic recommendations when possible.ConclusionPrevention and management of EGFRI-related dermatologic toxicities is critical to maintain patients’ health-related quality of life and dose intensity of antineoplastic regimens. More rigorous investigation of these toxicities is warranted to improve preventive and treatment strategies.

Grading dermatologic adverse events of cancer treatments: The Common Terminology Criteria for Adverse Events Version 4.0

Dermatologic adverse events to cancer therapies have become more prevalent and may to lead to dose modifications or discontinuation of life-saving or prolonging treatments. This has resulted in a new collaboration between oncologists and dermatologists, which requires accurate cataloging and grading of side effects. The Common Terminology Criteria for Adverse Events Version 4.0 is a descriptive terminology and grading system that can be used for uniform reporting of adverse events. A proper understanding of this standardized classification system is essential for dermatologists to properly communicate with all physicians caring for patients with cancer.

Cutaneous Toxic Effects Associated With Vemurafenib and Inhibition of the BRAF Pathway

BACKGROUND The development of a novel BRAF inhibitor, vemurafenib, has been associated with impressive tumor regression in patients with BRAF-positive stage IV melanoma. In the phase 3 clinical trials, dermatologic toxic effects associated with vemurafenib were described, namely, the development of eruptive squamous cell carcinomas. Herein, 3 cases are presented that highlight the development of squamous cell carcinomas and other cutaneous sequelae that have not been previously reported and are reminiscent of those observed with administration of the multikinase inhibitor sorafenib tosylate. In addition, the current understanding of the molecular mechanisms underlying these toxic effects is reviewed. OBSERVATIONS The development of keratosis pilaris-like eruptions; seborrheic dermatitis-like rashes; and hyperkeratotic, tender plantar papules reminiscent of those seen in sorafenib-associated hand-foot skin reaction, as well as squamous cell carcinomas, is presented in association with vemurafenib-based treatment of metastatic melanoma. CONCLUSIONS The development of sorafenib-like cutaneous sequelae (squamous cell carcinomas, keratosis pilaris-like eruptions, seborrheic dermatitis-like rashes, and hand-foot skin reaction) associated with vemurafenib administration suggests that BRAF inhibition alone may be sufficient to induce these changes.

Seasonal variation of Stevens-Johnson syndrome and toxic epidermal necrolysis associated with trimethoprim-sulfamethoxazole

BACKGROUND Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare and severe cutaneous adverse reactions to medications and infections. OBJECTIVE We sought to determine whether a seasonal variation to SJS and TEN exists and to define the characteristics in our tertiary referral hospital. METHODS A retrospective chart review of 50 patients from 1995 through 2007 was performed and statistically analyzed. RESULTS The most common medication implicated as a cause of SJS/TEN was trimethoprim-sulfamethoxazole (TMX) (26%). A seasonal trend, favoring springtime, was observed for the total number of cases of SJS and TEN (P = .34). There was a significant increase in cases due to TMX (53%) occurring in spring compared to other seasons (P = .002). These patients were significantly younger (37.8 +/- 13.7) than other patients with SJS and TEN (53.7 +/- 16.4) (P = .003). Their overall mortality (1 death) and average SCORTEN value (1.62 +/- 1.6) was also significantly lower (P = .04 and 0.03, respectively). Based on outpatient pharmacy records, there was no increase in TMX prescriptions filled during the spring. LIMITATIONS The study was limited by reliance on chart data, the use of inpatient records, and number of patients. CONCLUSIONS A seasonal variation in SJS and TEN caused by TMX affecting younger patients may exist.

Cutaneous Manifestations of Vasculitis

OBJECTIVES To discuss the clinical features, diagnostic evaluation, and treatment options for cutaneous vasculitis. METHODS The literature in the PubMed database was reviewed regarding the presentation, pathophysiology, clinical workup, and treatment of cutaneous vasculitis. RESULTS Available classification criteria of vasculitis are based on histopathologic criteria or clinicohistologic features. These have been designed more for research purposes than for clinical application. Skin findings such as palpable purpura, nodules, urticaria, ulcers, and infarction are clues to the presence of vasculitis. Pathologic findings of fibrinoid necrosis, infiltration by neutrophils or lymphocytes, and deposition of complement and immunoglobulin may be helpful in reaching a specific diagnosis. However, there is considerable overlap across different conditions. CONCLUSIONS The correct diagnosis of cutaneous manifestations of vasculitis requires an understanding of vasculitis classification, recognition of specific clinical patterns, and the ability to interpret histopathologic data.

Life-threatening dermatologic adverse events in oncology.

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.

Histopathology of acneiform eruptions in patients treated with epidermal growth factor receptor inhibitors.

Epidermal growth factor receptor inhibitors (EGFRIs) are anticancer agents that have been approved for use in a variety of solid tumors. EGFR‐inhibiting agents produce a variety of cutaneous adverse events: most commonly a follicular papulopustular (acneiform) eruption on the face, scalp, chest and upper back.

Tufted hair folliculitis in a woman treated with trastuzumab

Chemotherapeutic agents targeting the human epidermal receptor (HER) family are being used with increasing frequency for a variety of solid tumors. Cutaneous side effects are commonly reported with HER inhibitors, especially those agents that inhibit epidermal growth factor receptor (EGFR) or HER1. However, inhibitors of HER2 are not associated with specific skin toxicity. We present a case of tufted hair folliculitis, an inflammatory scalp condition causing scaling and pruritus, in a woman being treated with trastuzumab, a selective HER2 inhibitor. This finding has not previously been reported as a side effect of trastuzumab therapy.

The effect of smoking and age on the response to first-line therapy of hidradenitis suppurativa: An institutional retrospective cohort study

Background: Treatment for hidradenitis suppurativa is often empiric and inadequate, and determining which patients will respond is difficult. Objective: We sought to determine which patient factors are associated with a positive response to first‐line medical therapy. Methods: A single‐center retrospective cohort study of all patients with hidradenitis suppurativa seen between January 1, 1992, and October 1, 2014, was conducted. Response to first‐line medical therapy (oral/topical antibiotics, intralesional corticosteroids, and topical washes) was examined at follow‐up within 6 months of initiating therapy. A multivariate binary logistic regression model was built examining response to treatment and the interplay of patient factors and treatment initiated. Results: In all, 198 patients were included in the final model. Nonsmokers (odds ratio 2.634, 95% confidence interval 1.301‐5.332, P = .007) and older individuals (odds ratio 1.046 for each additional year, 95% confidence interval 1.020‐1.072, P < .001) were more likely to have improvement at follow‐up. In addition, current smokers differed significantly from nonsmokers in several regards. Limitations: The retrospective nature of this study is a limitation, as is relying on classification of disease severity from physical examination findings in some patients. Conclusions: The results of this study suggest that clinicians may be able to more accurately predict which patients with hidradenitis suppurativa will respond to first‐line medical therapy, and which patients may require therapy escalation.

First-in-human Phase 1 Clinical Study of the IL-15 Superagonist Complex ALT-803 to Treat Relapse after Transplantation

New therapies for patients with hematologic malignancies who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) are needed. Interleukin 15 (IL-15) is a cytokine that stimulates CD8+ T-cell and natural killer (NK) cell antitumor responses, and we hypothesized this cytokine may augment antileukemia/antilymphoma immunity in vivo. To test this, we performed a first-in-human multicenter phase 1 trial of the IL-15 superagonist complex ALT-803 in patients who relapsed >60 days after allo-HCT. ALT-803 was administered to 33 patients via the IV or subcutaneous (SQ) routes once weekly for 4 doses (dose levels of 1, 3, 6, and 10 μg/kg). ALT-803 was well tolerated, and no dose-limiting toxicities or treatment-emergent graft-versus-host disease requiring systemic therapy was observed in this clinical setting. Adverse events following IV administration included constitutional symptoms temporally related to increased serum IL-6 and interferon-γ. To mitigate these effects, the SQ route was tested. SQ delivery resulted in self-limited injection site rashes infiltrated with lymphocytes without acute constitutional symptoms. Pharmacokinetic analysis revealed prolonged (>96 hour) serum concentrations following SQ, but not IV, injection. ALT-803 stimulated the activation, proliferation, and expansion of NK cells and CD8+ T cells without increasing regulatory T cells. Responses were observed in 19% of evaluable patients, including 1 complete remission lasting 7 months. Thus, ALT-803 is a safe, well-tolerated agent that significantly increased NK and CD8+ T cell numbers and function. This immunostimulatory IL-15 superagonist warrants further investigation to augment antitumor immunity alone and combined with other immunotherapies. This trial was registered at www.clinicaltrials.gov as #NCT01885897.