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 erlotinib (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. toxicitiesT (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 speakers 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.

284 April 2008 • Volume 12, Number 2 • Clinical Journal of Oncology Nursing Severity The severity of rash also appears to vary between agents. In general, rash associated with the use of anti-HER1/EGFR MAbs tends to be more severe than that observed with TKIs, present- ing as a more purulent and pustular reaction, which may require more aggressive interventions (Sipples, 2006). The different modes of administration for these agents might be one reason: TKIs (e.g., erlotinib, gefitinib) are administered orally on a daily basis, whereas MAbs (e.g., cetuximab, panit- mumumab) are given intravenously once a week or every two weeks. The pharmacokinetic properties of these agents are therefore different, with potentially greater differences in peak and trough concentrations for MAbs than for TKIs. This may ex- plain the differing incidence and manifestation of rash observed To view this image, with these agents, particularly because preclinical data support a correlation between the appearance of rash and concentration please see the print version. for these agents (Bruno, Mass, Jones, Lu, & Winer, 2003). Some evidence suggests that the appearance of skin rash may be useful as a marker of efficacy for HER1/EGFR-targeted agents. Several studies with erlotinib have demonstrated a relationship between severity of skin reaction and treatment efficacy. Phase II studies in NSCLC, head and neck cancer, and ovarian cancer suggest that survival rates are significantly increased in patients with skin reactions, compared to those without (Clark, Perez-Soler, Siu, Gordon, & Santabarbara, 2003; Perez-Soler et al., 2004). This Figure 1. Dermatologic Toxicities Secondary observation was repeated in the pivotal phase III trial of erlotinib monotherapy for NSCLC, in which the patients who developed to Human Epidermal Growth Factor Receptor a rash (75%) survived significantly longer than those who did Inhibitors not: 8.5 months for patients with grade 1 rash and 19.6 months Note. From “Mechanisms of Cutaneous Toxicities to EGFR Inhibitors,” for patients with grade 2 or 3 rash versus 1.5 months for patients by M.E. Lacouture, 2006, Nature Reviews Cancer, 61(1), p. 804. Copy- who did not develop any rash (p < 0.0001) (Perez-Soler, 2006). right 2006 by Nature Publishing Group. Reprinted with permission. Overall, these observations support the consensus that patients who develop rash should be treated for the reaction while being maintained on anti-HER1/EGFR therapy; those patients may ob- (usually manifested as paronychia), and hair changes (usually tain the greatest benefit from the drugs. manifested as mild hair loss) (Lacouture, 2006; Segaert & Van Cutsem, 2005). These adverse events are observed during treatment with all HER1/EGFR-targeted agents, MAbs, and Pathobiology of Skin Reactions TKIs, and their etiology suggests that such skin toxicities are Associated With Human Epidermal a class effect of HER1/EGFR-targeted therapies. However, differences may exist in the incidence and manifestation of these Growth Factor Receptor Inhibitors events with different treatments. Although the pathobiology of HER1/EGFR-targeted inhibitor- The papulopustular rash generally develops along a char- associated skin reactions is not understood fully, drug-induced acteristic course. Within the first week, patients experience inhibition of the HER1/EGFR is believed to affect keratinocyte a sensory disturbance on the face with erythema and edema, proliferation, differentiation, migration, and attachment (Jost, followed by a papulopustular eruption (in weeks 1–3). In Kari, & Rodeck, 2000; Woodworth et al., 2005). HER1/EGFR is week 4, a crusting of the rash develops. Provided that the rash expressed in epidermal keratinocytes, sebaceous and eccrine is treated successfully, patients may continue to experience glands, and the epithelium of the hair follicle (Nanney, Sto- erythema and dry skin in the areas previously affected by the scheck, King, Underwood, & Holbrook, 1990). Such expression papulopustular eruption. is particularly high in proliferating and undifferentiated keratinocytes, which commonly are found in the basal and suprabasal Incidence layers of the epidermis, and in the outer root sheath of the hair Directly comparing the incidence of skin toxicities (and, in follicle (Fox, 2006). Inhibition of the HER1/EGFR signaling particular, rash) for different agents is challenging. Descriptive pathway is believed to play a critical role in inflammatory cell terms often differ in gradation schemes between trials, and in recruitment and subsequent cutaneous injury, which can lead some instances skin toxicities are recorded as a single event to the development of dry skin, papulopustules, and periungual (e.g., dermatitis), whereas in others, they may be broken down inflammation (Lacouture, 2006). The potential effects of HER1/ into separate categories (e.g., rash, acne, dry skin). EGFR inhibition in the skin are illustrated in Figure 2.

Clinical Journal of Oncology Nursing • Volume 12, Number 2 • Managing Skin Reactions 285 Guidelines for the Treatment of Skin Reactions Associated With Human Epidermal Growth Factor Inhibitors As yet, no data from controlled clinical studies investigating treatment options for HER1/EGFR-targeted inhibitor-associated skin reactions have been published; therefore, no peer-reviewed, evidence-based treatment recommendations are available. To date, proposed treatments are based mostly on qualitative rather than quantitative evidence (Lacouture, Basti, Patel, & Benson, 2006; Rhee et al., 2005). However, patients still require treatment and advice for skin reactions, and in the absence of suitable clinical data, best practice offers the best treatment advice. The aim of the forum in Chicago was to bring a number of experts together in an attempt to amalgamate their interdisciplinary knowledge (published or otherwise) as well as to distill the common practices employed by their institutions into a consensus approach for the treatment of dermatologic adverse events associated with HER1/EGFR-targeted inhibitor therapy. Discussion at the forum focused primarily on the clinical management of cutaneous toxicities; however, the experts also advocated a proactive approach for patients that could minimize To view this image, the occurrence and severity of toxicities. please see the print version. Practical Guidelines for Patients Two key patient education recommendations were made at the forum: Patients should regularly use a thick, alcohol-free emollient for dry skin (alcohol can dry the skin). A number of recommended emollients are listed in Table 2. Application of high-sun protection factor (≥ 15) physical sunscreen (i.e., containing zinc oxide or titanium dioxide) each morning and prior to sun exposure is recommended for all patients receiving HER1/EGFR-targeted agents. Based on the existing literature, a range of other practical guidelines also might be considered to help prevent rash and a. Normal expression of HER1/EGFR-dependent molecular markers. Be- other cutaneous toxicities, which include the following (Herb- fore treatment, the basal layer shows expression of phosphorylated st, Fox, Viele, & Messner, 2006; O’Keeffe, Parrilli, & Lacouture, HER1/EGFR, MAPK (mitogen-activated protein kinase) and the prolif- 2006; People Living With Cancer, 2006). eration marker KI67, and suprabasal expression of phopsphorylated • Patients should take care to remain hydrated. HER1/EGFR, the cyclin-dependent-kinase inhibitor p27, KRT1 (keratin • Patients should ensure that they apply an adequate amount 1) and STAT3 (signal transducer and activator of transcription 3). of sunscreen: more than half a teaspoon of sunscreen to b. During HER1/EGFR inhibitor therapy, phosphorylated HER1/EGFR each arm, the face, and neck, and a little more than one is abolished in all epidermal cells and the expression of MAPK is reduced. Inhibition of HER1/EGFR in basal keratinocytes leads to teaspoon to the chest and abdomen, back, and each leg. The growth arrest and premature differentiation, as demonstrated by use of a broad-brimmed hat also is advised if going outside. upregulated p27 KIP1, KRT1 and STAT3 in the basal layer. • Patients should avoid long, hot showers. Instead, patients c. Subsequently, the release of inflammatory cell chemoattractants should use lukewarm water and mild (preferably scent-free) (such as CXCLs and CCLs) recruits leukocytes that release enzymes, soap, ensuring that genital, rectal, and skin-fold areas are causing apoptosis and tissue damage, with consequent apoptotic cleaned thoroughly. A moisturizer should be applied within 15 keratinocytes and ectatic (dilated) vessels. minutes of showering or bathing (to prevent skin drying). d. A decrease in epidermal thickness is observed, with a thin stratum • Patients should avoid laundry detergent with strong per- corneum that lacks its characteristic basket weave configuration, fumes and use only hypoallergenic makeup. indicating abnormal differentiation. • The use of saline nasal spray followed by petroleum jelly Figure 2. The Effects of Human Epidermal Growth may reduce risk of nosebleeds. • Patients should use personal lubricant for intercourse. Factor Receptor (HER1/EGFR) Inhibition in Skin • To prevent nail problems, patients should keep finger and toe- Note. From “Mechanisms of Cutaneous Toxicities to EGFR Inhibitors,” nails clean and trimmed; avoid biting of nails, pushing back cu- by M.E. Lacouture, 2006, Nature Reviews Cancer, 61(1), p. 806. Copy- ticles, tearing the skin around the nail bed, or applying artificial right 2006 by Nature Publishing Group. Reprinted with permission. nails; and avoid tight-fitting shoes. Patients also are advised to

286 April 2008 • Volume 12, Number 2 • Clinical Journal of Oncology Nursing therapeutic decision making, forum attendees felt that a simple, Table 2. Recommended Agents for Dry Skin, more specific grading system would be the most appropriate rash Itching, and Sun Exposure associated with HER1/EGFR-targeted inhibitors. Thus, classifying

Condition Recommended agents skin reactions as mild, moderate, or severe was believed to be the most effective system for assigning therapeutic intervention. Dry skin Emollients The following is a stepwise approach to intervention, employ- • Vanicream® (Pharmaceutical Specialties, Inc.), ing the suggested three-tiered grading system developed by the ® ® Eucerin (Beiersdorf AG), Aquaphor (Beiersdorf consensus group. AG), Aveeno® (Johnson & Johnson Consumer Com- panies, Inc.), and Cutemol® (Summers Laboratories Inc.) as needed Mild Skin Toxicity Mild skin toxicity (papulopustular rash) is defined as generally Exfoliants (for scaly areas) localized, minimally symptomatic, with no sign of superinfection, • Ammonium lactate12% (Am-Lactin® ,Upsher-Smith and no impact on daily activities. Some attendees suggested that, Laboratories, Inc.) for body • Urea 20%–40% cream for palms, soles, and fissures in many instances, no intervention was necessary, whereas others felt that intervention of either topical hydrocortisone (1% or 2.5% Itching Topical agents cream) or clindamycin (1% gel) would be beneficial. Dose reduc- • Body: Sarna Ultra® (PharmaDerm) cream and Re- tion of the HER1/EGFR-targeted agent was not recommended. genecare® (MPM Medical, Inc.) gel as needed • Scalp: Fluocinonide 0.05% shampoo or clobetasol Moderate Skin Toxicity foam daily Moderate rash is defined as papulopustules with mild pruritus Sun exposure Oral agents or tenderness, with minimal impact on activities of daily living • Antihistamines (diphenhydramine 25–50 mg twice and no signs of superinfection. The suggested therapeutic inter- daily and/or cetirizine 10–20 mg per day) vention is hydrocortisone (2.5% cream), clindamycin (1% gel), or • Pregabalin (Lyrica®, Pfizer) 75–100 mg twice daily pimecrolimus (Elidel®, Novartis) (1% cream), with the addition of • Any broad-spectrum sunscreen containing zinc oxide or titanium dioxide doxycycline (100 mg PO BID) or minocycline (100 mg PO BID) (Micantonio et al., 2005; Molinari, De Quatrebarbes, Andre, & Aractingi, 2005; Sapadin & Fleischmajer, 2006). Dose reduction of the HER1/EGFR-targeted agent was not recommended. wear gloves when washing dishes or using chemical clean- ing agents. Hands and feet should be moisturized frequently; Severe Skin Toxicity petroleum jelly is particularly effective and should be applied to the skin around the nails periodically throughout the day. Severe skin toxicity is defined as a rash that may be generalized At night, applying a thick coat to hands and feet and covering and accompanied by severe pruritus or tenderness; this level of with white cotton gloves and socks may be helpful. toxicity has a significant impact on activities of daily living and • If a patient develops trichomegaly (i.e., excessive eyelash has the potential for superinfection. The dose of the HER1/EGFR growth) or eye complaints, the eyelashes should be trimmed inhibitor should be reduced (according to the principal investiga- and the patient should have an ophthalmologic consultation. tor). The skin toxicity should be treated the same as for moderate Most importantly, patients should be educated to call a health- rash but with the addition of a methylprednisolone dose pack. In care professional as soon as they develop any symptoms of the event that severe rash symptoms fail to respond to the above- cutaneous toxicity. Early intervention is critical in the clinical mentioned interventions, interruption of the HER1/EGFRI-tar- management of these events, so an early (< 14 days from EGFR- geted therapy is recommended. However, treatment may resume inhibitor therapy onset) follow-up is advisable. (most likely at a lower dose) once skin reactions have diminished in severity at a recommended follow-up of two weeks. Clinical Management The use of pimecrolimus or tacrolimus (Protopic®, Astellas Pharma, Inc.) for HER1/EGFR-associated skin reactions is being The treatment algorithm presented in Figure 3 represents the investigated at a number of institutions; however, it is an immu- key output from the forum. The effective treatment of skin rashes nosuppressant, which should be taken into account when con- associated with HER1/EGFR-targeted inhibitors depends largely sidering treatment options (Novartis, 2006). Although a causal on accurate grading of skin reactions to allow for appropriate relationship has not been established, rare cases of skin malig- intervention. The National Cancer Institute (2006) Common nancies and lymphoma have been observed in patients treated Toxicity Criteria (NCI-CTC) is used most commonly to grade with calcineurin inhibitors, such as pimecrolimus (Novartis). adverse events in clinical trials with HER1/EGFR-targeted agents Such incidences most likely are associated with long-term usage; (see Table 3); it is designed, primarily, as a surveillance tool and pimecrolimus is not recommended, however, in immunosup- is of limited use as an aid to selecting intervention. Although cer- presed patients (Novartis). As a result, great care should be tain categories are relevant to events associated with HER1/EGFR taken when considering its use in patients with cancer. inhibitors, including rash and desquamation, they often are not sufficiently specific. For example, within the NCI-CTC, rash sever- Conclusion ity is based on body surface area coverage; this can be misleading because rash associated with HER1/EGFR inhibitors generally The skin toxicities associated with HER1/EGFR-targeted are confined to the face and upper trunk. For the purposes of inhibitors can cause patients physical and psychological symp-

Clinical Journal of Oncology Nursing • Volume 12, Number 2 • Managing Skin Reactions 287 • Employ a proactive approach in managing skin reactions. • Suggest patients use a thick, alcohol-free emollient cream. • Suggest patients use a sunscreen of SPF 15 or higher, preferably containing zinc oxide or titanium dioxide. • If a patient presents with rash, verify appropriate administration and follow the proceeding algorithm in a step-wise manner.

Rash Severity Intervention

Mild Continue EGFR inhibitor at current dose and monitor for change in severity. • Generally localized • Minimally symptomatic No treatment Topical hydrocortisone 1% or 2.5% cream* and/or clindamycin 1% gel • No impact on ADL or • No sign of superinfection Reassess after 2 weeks (either by healthcare professional or patient self-reported); if reactions worsen or do not improve, proceed to next step.

Moderate • Generalized Continue EGFR inhibitor at current dose and monitor for change in severity; continue treatment of • Mild symptoms (e.g., skin reaction with the following: pruritus, tenderness) • Minimal impact on ADL • No sign of superinfection Hydrocortisone 2.5% cream* or Clindamycin 1% gel or pimecrolimus 1% cream PLUS doxycycline 100 mg BID or minocycline 100 mg BID

Reassess after 2 weeks (either by healthcare professional or patient self-reported); if reactions worsen or do not improve, proceed to next step.

Severe • Generalized • Severe symptoms (e.g., pruritus, tenderness) Reduce EGFR-inhibitor dose as per label and monitor for change in severity; continue treatment of • Significant impact on skin reaction with the following: ADL • Potential for superinfection Hydrocortisone 2.5% cream* or clindamycin 1% gel or pimecrolimus 1% cream PLUS doxycycline 100 mg BID or minocycline 100 mg BID PLUS medrol dose pack

Reassess after 2 weeks; if reactions worsen, dose interruption or discontinuation may be necessary.

* The use of topical steroids should be employed in a pulse manner based on your institution’s guidelines. ADL—activities of daily living; BID—twice daily; EGFR—epidermal growth factor receptor; SPF—sun protection factor Figure 3. Proposed Therapy Algorithm for the Management of Skin Reaction Associated With Human Epidermal Growth Factor Receptor Inhibitors 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. 618. Copyright 2007 by AlphaMed Press. Reprinted with permission.

toms, particularly given that rash characteristically occurs The algorithm suggested by the consensus group and pre- on exposed areas such as the face. Although the concerns of sented in this article represents current best practice for the patients (and caregivers) must be addressed sympathetically, treatment of rash associated with HER1/EGFR inhibitors. Con- in most cases, these adverse events can be managed without trolled studies remain necessary to fully evaluate the efficacy the need for dose modification or interruption to the HER1/ of the strategies presented in the algorithm, but this approach EGFR-inhibitor regimen. Moreover, in refractory cases, the hopefully will be a useful guide for nurses and other healthcare suspension of HER1/EGFR inhibitor therapy is temporary, professionals, ensuring that patients receive the maximum pos- allowing for appropriate intervention and diminution of skin- sible clinical benefits from the continued and uninterrupted use toxicity severity. of the HER1/EGFR inhibitors.

288 April 2008 • Volume 12, Number 2 • Clinical Journal of Oncology Nursing Table 3. Classification of Dermatologic Toxicities Associated With Human Epidermal Growth Factor Receptor Inhibitors

Grade

Adverse event 1 2 3 4 5

Dry skin Asymptomatic Symptomatic, not interfering with Interfering with ADL – – ADL

Nail changes Discoloration, ridging, Partial or complete loss of nails; Interfering with ADL – – pitting pain in nailbed(s)

Pruritus/itching Mild or localized Intense or widespread Intense or widespread and inter- – – fering with ADL

Rash/ Macular or papular Macular or papular eruption or Severe, generalized erythro- Generalized exfolia- Death desquamation eruption or erythema erythema with pruritus or other derma or macular, papular, or tive, ulcerative, or without associated associated symptoms; localized vesicular eruption; desquamation bullous dermatitis symptoms desquamation or other lesions covering > 50% BSA covering < 50% BSA

Rash: acne/ Intervention not Intervention indicated Associated with pain, disfigure- – Death acneform indicated ment, ulceration, or desquamation

Dermatology/ Mild Moderate Severe Life threatening; Death skin—other disabling

ADL—activities of daily living; BSA—body surface area Note. From Common Terminology Criteria for Adverse Events (CTCAE) [v.3.0], by National Cancer Institute, 2006. Retrieved February 20, 2008, from http://ctep.cancer.gov/forms/CTCAEv3.pdf. Adapted with permission.

The authors gratefully the participants of the October 2006 inter- Greatens, T.M., Niehans, G.A., Rubins, J.B., Jessurun, J., Kratzke, R.A., disciplinary forum: Jean Pierre DeLord, Jody Gary, Giuseppe Giaccone, Maddaus, M.A., et al. (1998). Do molecular markers predict survival Patricia LoRusso, Thomas J. Lynch, Barbara Melosky, Martin Reck, in non-small-cell lung cancer? American Journal of Respiratory Roman Perez-Soler, Jennifer Temel, and Dennis P. West. The authors and Critical Care Medicine, 157(4, Pt. 1), 1093–1097. also acknowledge third-party medical writing support from Gardiner Herbst, R., Fox, L.P., Viele, C.S., & Messner, M. (2006). Managing Caldwell US, funded by Genentech, Inc., OSI Pharmaceuticals, Inc., rash and other skin reactions to targeted treatment. Retrieved and F. Hoffmann-La Roche Ltd. February 20, 2008, from http://www.cancercare.org/pdf/book- lets/ccc_managing_rash.pdf Author Contact: Beth Eaby, MSN, CRNP, OCN®, can be reached at eabyb@ Hoang, T., & Schiller, J.H. (2002). Advanced NSCLC: From cytotoxic systemic chemotherapy to molecularly targeted therapy. Expert uphs.upenn.edu with copy to editor at [email protected]. Review of Anticancer Therapy, 2(4), 393–401. Jost, M., Kari, C., & Rodeck, U. (2000). The EGF receptor—An essen- References tial regulator of multiple epidermal functions. European Journal Arteaga, C.L. (2001). The epidermal growth factor receptor: From mu- of Dermatology, 10(7), 505–510. tant oncogene in nonhuman cancers to therapeutic target in human Kris, M.G., Natale, R.B., Herbst, R.S., Lynch, T.J., Jr., Prager, D., Be- neoplasia. Journal of Clinical Oncology, 19(18, Suppl.), 32S–40S. lani, C.P., et al. (2003). Efficacy of gefitinib, an inhibitor of the Bruno, R., Mass, R.D., Jones, C., Lu, J., & Winer, E. (2003). Preliminary epidermal growth factor receptor tyrosine kinase, in symptomatic population pharmacokinetics (PPK) and exposure-safety (E-S) rela- patients with non-small cell lung cancer: A randomized trial. JAMA, tionships of erlotinib HCI in patients with metastatic breast cancer 290(16), 2149–2158. (MBC) [Abstract 823]. Proceedings of the American Society of Lacouture, M.E. (2006). Mechanisms of cutaneous toxicities to EGFR Clinical Oncology, 22, 205. inhibitors. Nature Reviews Cancer, 6(10), 803–812. Clark, G.M., Perez-Soler, R., Siu, L., Gordon, A., & Santabarbara, P. Lacouture, M.E., Basti, S., Patel, J., & Benson, A., III. (2006). The (2003). Rash severity is predictive of increased survival with erlo- SERIES clinic: An interdisciplinary approach to the management tinib HCI [Abstract 786]. Proceedings of the American Society of of toxicities of EGFR inhibitors. Journal of Supportive Oncology, Clinical Oncology, 22, 196. 4(5), 236–238. Cooke, T., Reeves, J., Lannigan, A., & Stanton, P. (2001). The value of Micantonio, T., Fargnoli, M.C., Ricevuto, E., Ficorella, C., Marchetti, the human epidermal growth factor receptor-2 (HER2) as a prognos- P., & Peris, K. (2005). Efficacy of treatment with tetracyclines to tic marker. European Journal of Cancer, 37(Suppl. 1), S3–S10. prevent acneiform eruption secondary to cetuximab therapy. Fox, L.P. (2006). Pathology and management of dermatologic Archives of Dermatology, 141(9), 1173–1174. toxicities associated with anti-EGFR therapy. Oncology, 20(5, Molinari, E., De Quatrebarbes, J., Andre, T., & Aractingi, S. (2005). Suppl. 2), 26–34. Cetuximab-induced acne. Dermatology, 211(4), 330–333.

Clinical Journal of Oncology Nursing • Volume 12, Number 2 • Managing Skin Reactions 289 Nanney, L.B., Stoscheck, C.M., King, L.E., Jr., Underwood, R.A., & Salomon, D.S., Brandt, R., Ciardiello, F., & Normanno, N. (1995). Holbrook, K.A. (1990). Immunolocalization of epidermal growth Epidermal growth factor-related peptides and their receptors in factor receptors in normal developing human skin. Journal of human malignancies. Critical Reviews in Oncology/Hematology, Investigative Dermatology, 94(6), 742–748. 19 (3), 183–232. National Cancer Institute. (2006). Common terminology criteria Sapadin, A.N., & Fleischmajer, R. (2006). Tetracyclines: Nonantibiotic for adverse events (CTCAE) [v.3.0]. Retrieved February 20, 2008, properties and their clinical implications. Journal of the American from http://ctep.cancer.gov/forms/CTCAEv3.pdf Academy of Dermatology, 54(2), 258–265. Nicholson, R.I., Gee, J.M., & Harper, M.E. (2001). EGFR and cancer Segaert, S., & Van Cutsem, E. (2005). Clinical signs, pathophysiology prognosis. European Journal of Cancer, 37(Suppl. 4), S9–S15. and management of skin toxicity during therapy with epidermal Novartis. (2006). Elidel® (pimecrotimus) [Package insert]. Re- growth factor receptor inhibitors. Annals of Oncology, 16(9), trieved February 20, 2008, from http://www.pharma.us.novartis 1425–1433. .com/product/pi/pdf/elidel.pdf Sipples, R. (2006). Common side effects of anti-EGFR therapy: Acne- Ohsaki, Y., Tanno, S., Fujita, Y., Toyoshima, E., Fujiuchi, S., Nishigaki, form rash. Seminars in Oncology Nursing, 22(1, Suppl. 1), 28–34. Y., et al. (2000). Epidermal growth factor receptor expression cor- U.S. Food and Drug Administration. (2005). Patient information relates with poor prognosis in non-small cell lung cancer patients sheet gefitinib (marketed as Iressa). Retrieved February 20, with p53 overexpression. Oncology Reports, 7(3), 603–607. 2008, from http://www.fda.gov/cder/drug/InfoSheets/patient/ O’Keeffe, P., Parrilli, M., & Lacouture, M.E. (2006). Toxicity of targeted gefitinibPIS.htm therapy: Focus on rash and other dermatologic side effects. Oncol- Woodworth, C.D., Michael, E., Marker, D., Allen, S., Smith, L., & ogy Nurse Edition, 20(13), 1–6. Nees, M. (2005). Inhibition of the epidermal growth factor recep- People Living With Cancer. (2006). Skin reactions to targeted thera- tor increases expression of genes that stimulate inflammation, pies. Retrieved February 20, 2008, from http://www.plwc.org/ apoptosis, and cell attachment. Molecular Cancer Therapeutics, portal/site/PLWC/menuitem.169f5d85214941ccfd748f68ee37a01d 4(4), 650–658. /?vgnextoid=81dd2daf1034b010VgnVCM100000ed730ad1RCRD Yarden, Y., & Sliwkowski, M.X. (2001). Untangling the ErbB signalling Perez-Soler, R. (2006). Rash as a surrogate marker for efficacy of epi- network. Nature Reviews, Molecular Cell Biology, 2(2), 127–137. dermal growth factor receptor inhibitors in lung cancer. Clinical Lung Cancer, 8(Suppl. 1), S7–S14. Perez-Soler, R., Chachoua, A., Hammond, L.A., Rowinsky, E.K., Huber- Receive free continuing nursing education credit man, M., Karp, D., et al. (2004). Determinants of tumor response for reading this article and taking a brief quiz on- and survival with erlotinib in patients with non-small-cell lung line. To access the test for this and other articles, cancer. Journal of Clinical Oncology, 22(16), 3238–3247. visit www.cjon.org, select “CE from CJON,” and Rhee, J., Oishi, K., Garey, J., & Kim, E. (2005). Management of rash choose the test(s) you would like to take. You and other toxicities in patients treated with epidermal growth fac- will be prompted to enter your Oncology Nurs- tor receptor-targeted agents. Clinical Colorectal Cancer, 5(Suppl. ing Society profile username and password. 2), S101–S106.

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