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An Interdisciplinary Consensus on Managing Skin Reactions Associated with Human Epidermal Growth Factor Receptor Inhibitors

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An Interdisciplinary Consensus on Managing Skin Reactions Associated with Human Epidermal Growth Factor Receptor Inhibitors An Interdisciplinary Consensus on Managing Skin Reactions Associated With Human Epidermal Growth Factor Receptor Inhibitors Beth Eaby, MSN, CRNP, OCN®, Ann Culkin, RN, OCN®, and Mario E. Lacouture, MD The use of human epidermal growth factor receptor (HER1/EGFR) inhibitors, such as erlotinib, cetuximab, and panitumumab, often is accompanied by the development of a characteristic spectrum of skin toxicities. Although these toxicities rarely are life threatening, they can cause physical and emotional distress for patients and caregivers. As a result, practitioners often withdraw the drug, potentially depriving patients of a beneficial clinical outcome. These reactions do not necessarily require any alteration in HER1/EGFR-inhibitor treatment and often are best addressed through symptomatic treatment. Although the evidence for using such therapies is limited, an interdisciplinary HER1/EGFR-inhibitor dermatologic toxicity forum was held in October 2006 to discuss the underlying mechanisms of these toxicities and evaluate commonly used therapeutic interventions. The result was a proposal for a simple, three-tiered grading system for skin toxicities related to HER1/EGFR inhibitors to be used in therapeutic decision making and as a framework for building a stepwise approach to intervention. he use of HER1/EGFR-targeted therapies, such as erlo- tinib (Tarceva®, OSI Pharmaceuticals, Inc.), cetuximab At a Glance (Erbitux®, Bristol-Myers Squibb), and panitumumab The use of human epidermal growth factor receptor (HER1/ (VectibixTM, Amgen Inc.), often is accompanied by EGFR) inhibitors often is accompanied by the development the development of a characteristic spectrum of skin of a characteristic class-specific spectrum of skin toxicities. Ttoxicities (Rhee, Oishi, Garey, & Kim, 2005). Although these Skin toxicities related to HER1/EGFR inhibitors do not necessar- events rarely are life threatening, they can cause physical and ily require alteration in HER1/EGFR-inhibitor treatment and of- emotional distress for patients and caregivers. Often, the rash ten are addressed best through symptomatic management. may be mistaken as an uncontrollable adverse effect rather than a treatable side effect. As a result, practitioners withdraw the drug, Evidence-based treatment recommendations for skin tox- potentially depriving patients of a beneficial clinical outcome. icities related to HER1/EGFR inhibitors are not available Oncology nurses often are the first point of contact for patients because no data from controlled clinical studies have been who are receiving treatment; therefore, understanding the clinical published. basis for such skin reactions and offering effective and appropriate assessments and interventions are critical. On October 29, 2006, an interdisciplinary forum was held in ® Chicago, IL, to discuss skin toxicities associated with HER1/EGFR- Beth Eaby, MSN, CRNP, OCN , is a nurse practitioner at the University of ® targeted therapies. Oncologists, dermatologists, pharmacists, and Pennsylvania in Philadelphia; Ann Culkin, RN, OCN , is a clinical nurse at nurses shared their knowledge on the underlying mechanisms Memorial Sloan-Kettering Cancer Center in New York, NY; and Mario E. Lacouture, MD, is a dermatologist in the Department of Dermatology at of these events and evaluated existing practices in the hope of SERIES Clinic and the Robert H. Lurie Comprehensive Cancer Center at reaching a consensus strategy on how best to manage them. This Northwestern University in Chicago, IL. Eaby is a member of the Tarceva® article provides an overview of their discussions. speakers bureau and Culkin is a member of the Advisory Board and speak- ers bureau, both for Genentech. Lacouture received an honorarium from Genentech and is a speaker for Genentech, ImClone, and OSI Pharmaceu- Human Epidermal Growth Factor ticals. Mention of specific products and opinions related to those products Receptor–Targeted Therapies do not indicate or imply endosement by the Clinical Journal of Oncology Nursing or the Oncology Nursing Society. (Submitted July 2007. Accepted As a result of an increased understanding of the underly- for publication September 1, 2007.) ing molecular causes of cancer, biologic targeted agents have Digital Object Identifier:10.1188/08.CJON.283-290 Clinical Journal of Oncology Nursing • Volume 12, Number 2 • Managing Skin Reactions 283 emerged since the mid-1990s as a new strategy in the treat- tyrosine kinase (Yarden & Sliwkowski, 2001). Both prevent ment of various malignancies. These targeted agents interact the initiation of cell-signaling pathways that normally promote with specific molecules that are pivotal in tumor growth and tumor-cell proliferation, migration, adhesion and angiogenesis, development. Traditional “cytotoxic” chemotherapies not and inhibit apoptosis (Arteaga, 2001). A fourth agent, the TKI only kill tumor cells by affecting processes that commonly are gefitinib (Iressa®, AstraZeneca Pharmaceuticals), initially was overactive or enhanced in cancerous tissue but also may be approved in patients with non-small cell lung cancer (NSCLC) important in affecting normal cells. Targeted agents can exert for third-line use, based on the results of a randomized phase II their influence by, among other things, inhibiting tumor-cell trial (Kris et al., 2003). However, data from a phase III confir- proliferation, inducing programmed cell death, inhibiting matory trial failed to show a survival benefit and its use now is angiogenesis, and enhancing antitumor immune responses restricted to patients currently or previously benefiting from it (Hoang & Schiller, 2002). Common targets for these agents or to patients enrolled in a clinical study (FDA, 2005). include growth factors such as the vascular endothelial growth factor (VEGF); intracellular signaling molecules, including cyclooxygenase-2 and the BCR-ABL tyrosine kinase; and cell- Skin Reactions Associated surface receptors (e.g., members of the HER family, which With Human Epidermal Growth Factor includes HER1/EGFR). Receptor–Targeted Therapies The HER1/EGFR is an attractive target for new biologic targeted agents because it has been implicated in the develop- Largely because of their specificity of action, biologic targeted ment of a range of tumor types (Greatens et al., 1998; Ohsaki agents often are considered to have a more favorable toxic- et al., 2000; Salomon, Brandt, Ciardiello, & Normanno, 1995). ity profile than traditional chemotherapy. This also is true for Overexpression of the receptor also has been correlated with HER1/EGFR-targeted therapies, which generally are associated disease progression, poor prognosis, and a reduced sensitivity with fewer hematologic adverse events than chemotherapy. to chemotherapy (Cooke, Reeves, Lannigan, & Stanton, 2001; However, patients treated with HER1/EGFR-targeted therapies Nicholson, Gee, & Harper, 2001). Several HER1/EGFR inhibitors often do present with a unique group of skin reactions (Rhee et are in clinical development, and three (erlotinib, cetuximab, al., 2005), which occur in more than 50% of patients receiving and panitumumab) have demonstrated efficacy in a range of these treatments (Segaert & Van Cutsem, 2005). indications and received U.S. Food and Drug Administration Clinical trials with HER1/EGFR-targeted inhibitors have (FDA) approval. Erlotinib is an oral, reversible, tyrosine kinase revealed a spectrum of skin toxicities of varying severity (see inhibitor (TKI), whereas cetuximab and panitumumab are IV Table 1 and Figure 1). The most commonly reported reactions administered anti-HER1/EGFR monoclonal antibodies (MAbs). are mild-to-moderate skin rashes that occur most frequently MAbs prevent ligands, such as the EGF, from binding to the on the face and upper trunk. Other common dermatologic receptor, whereas TKIs block the activity of the receptor’s reactions include xerosis (dry skin), pruritus, nail changes Table 1. Spectrum of Dermatologic Reactions Associated With Human Epidermal Growth Factor Receptor Inhibitors ADVERSE EVENT DESCRIPTION FREQUENCY (%) TIME COURSE Rash (follicular-pustular) Monomorphous erythematous maculopapular, follicular, 60–80 Onset: one to three weeks of treatment; or pustular lesions, which may be associated with mild maximum: three to five weeks of treatment; pruritus resolution: within four weeks of treatment cessation but may wax and wane Paronychia and fissuring Painful periungual granulation-type or friable pyogenic 16–25 Onset: after two to four months of treat- granuloma-like changes associated with erythema, ment; resolution: persistent, several months swelling and fissuring of lateral nailfolds, and/or distal after withdrawal finger tufts Hair changes Curlier, finer, and more brittle hair on scalp and extremi- 15–6 Variable onset: after 7–10 weeks to many ties; also extensive growth and curling of eyelashes and months eyebrows Dry skin Diffuse fine scaling 14–35 Occurs after appearance of rash Hypersensitivity reactions Flushing, urticaria, and anaphylaxis 12–3 Occurs on the first day of initial dosing Mucositis Mild to moderate mucositis, stomatitis, aphthous ulcers 12–36 Onset during treatment, not related to dose or schedule; resolution without specific measures Note. From “Epidermal Growth Factor Receptor Inhibitor–Associated Cutaneous Toxicities: An Evolving Paradigm in Clinical Management,” by T.J. Lynch, Jr., E.S. Kim, B. Eaby, J. Garey, D.P. West, and M.E. Lacouture, 2007, Oncologist, 12(5), p. 614. Copyright 2007 by AlphaMed Press. Reprinted with permission.
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