Support Care Cancer (2011) 19:1079–1095 DOI 10.1007/s00520-011-1197-6 REVIEW ARTICLE Clinical practice guidelines for the prevention and treatment of EGFR inhibitor-associated dermatologic toxicities Mario E. Lacouture & Milan J. Anadkat & René-Jean Bensadoun & Jane Bryce & Alexandre Chan & Joel B. Epstein & Beth Eaby-Sandy & Barbara A. Murphy & MASCC Skin Toxicity Study Group Received: 14 February 2011 /Accepted: 17 May 2011 /Published online: 1 June 2011 # Springer-Verlag 2011 Abstract Results Prophylactic and reactive recommendations for pap- Background Epidermal growth factor receptor inhibitors ulopustular (acneiform) rash, hair changes, radiation derma- (EGFRI) produce various dermatologic side effects in the titis, pruritus, mucositis, xerosis/fissures, and paronychia are majority of patients, and guidelines are crucial for the presented, as well as general dermatologic recommendations prevention and treatment of these untoward events. The when possible. purpose of this panel was to develop evidence-based recom- Conclusion Prevention and management of EGFRI-related mendations for EGFRI-associated dermatologic toxicities. dermatologic toxicities is critical to maintain patients’ Methods A multinational, interdisciplinary panel of experts in health-related quality of life and dose intensity of antineo- supportive care in cancer reviewed pertinent studies using plastic regimens. More rigorous investigation of these established criteria in order to develop first-generation recom- toxicities is warranted to improve preventive and treatment mendations for EGFRI-associated dermatologic toxicities. strategies. The MASCC Skin Toxicity Study Group is composed of Andrei Barasch, Camilla Beder, Christine B. Boers-Doets, Tracey Doherty, Judith E. Raber-Durlacher, Dion Forstner, Seppo Langer, Judith Lees, and Dan Mellor. Electronic supplementary material The online version of this article (doi:10.1007/s00520-011-1197-6) contains supplementary material, which is available to authorized users. M. E. Lacouture (*) A. Chan Dermatology Service, Department of Medicine, National University of Singapore, Memorial Sloan–Kettering Cancer Center, Singapore, Singapore Rockefeller Outpatient Pavilion Suite 228, 160 East 53rd Street, New York, NY 10022, USA e-mail: [email protected] J. B. Epstein University of Illinois at Chicago, M. J. Anadkat Chicago, IL, USA Washington University School of Medicine, St. Louis, MO, USA B. Eaby-Sandy R.-J. Bensadoun University of Pennsylvania, Centre Hospitalier Universitaire de Poitiers, Philadelphia, PA, USA Poitiers Cedex, France J. Bryce B. A. Murphy Istituto Nazionale dei Tumori, Vanderbilt University Medical Center, Naples, Italy Nashville, TN, USA 1080 Support Care Cancer (2011) 19:1079–1095 Keywords Rash . Xerosis . Paronychia . Pruritus . Radiation ically similar dermatologic conditions were analyzed and dermatitis . Mucositis . EGFR inhibitors . Recommendations reported. Background Methods Overexpression of the epidermal growth factor receptor Participants (EGFR) is strongly associated with cancer development and progression of a number of malignancies. EGFR inhibitors The Multinational Association for Supportive Care in Cancer (EGFRI) are targeted agents used for treating lung (MASCC) Skin Toxicity Study Group assembled an interna- (erlotinib), pancreatic (erlotinib in combination with gem- tional, interdisciplinary group of experts in dermatology, citabine), breast (lapatinib in combination with capecitabine medical and supportive oncology, health-related quality of or anastrozole), head and neck (cetuximab in combination life (HQOL), and pharmacovigilance. Topic review commit- with radiotherapy), and colorectal cancers (cetuximab, tees were formed according to expertise to review the panitumumab) [1]. EGFRI may be used as first-line through literature and develop guidelines for the following dermato- third-line treatments, alone or in combination with other logic toxicities: papulopustular (acneiform) rash, hair changes, agents in the aforementioned cancers. radiation dermatitis, pruritus, mucositis, xerosis/fissures, and Commonly experienced dermatologic side effects in- paronychia. clude papulopustular (acneiform) rash, hair changes, radi- ation dermatitis enhancement, pruritus, mucositis, xerosis/ Recommendation development fissures, and paronychia. Incidences of these side effects are frequent and range from 36% for mucositis to 80% for Each review committee consisted of three members with a papulopustular (acneiform) rash. Clinical presentation, primary reviewer to present the findings of the committee incidence, impact on quality of life and cost, effect on to the Skin Toxicity Study Group. Literature reviews were EGFRI dosing, and risk factors for these toxicities have performed via databases such as Ovid MEDLINE (National been described elsewhere [1]. When severe, dermatologic Library of Medicine, Bethesda, MD, USA) and EMBASE toxicities may to lead to dose modification or discontinu- (Elsevier B.V. Amsterdam, The Netherlands). Published ation by 36% and 72% of health care providers, respec- literature as of November 2010 was included and each tively [2]. Although the side effect profile may be primarily committee reviewed between 17 and 35 papers to formulate dermatologic, toxicities result in significant physical and the recommended guidelines. Randomized clinical trials emotional discomfort, thus it is critical to maximize were considered the best source, and considerations for supportive measures. recommendations included Level of Evidence and Grade of Although most patients receiving EGFRIs experience Recommendation (Tables 1 and 2)[3]. In the absence of these toxicities, few controlled studies have been conducted experimental evidence, pertinent studies and case reports to determine the best practices for their management. were presented in conjunction with expert opinion derived Instead, much of the literature contains prevention and from clinical practice. Recommendations were developed treatment recommendations based on case reports or studies based on the presented findings and panel consensus. When with small samples sizes and nonrandomized patient available, data were extrapolated from other dermatologic allocation. In addition, available reports are beset with conditions with similar clinical or pathologic characteristics methodological issues including failure to adequately (xerosis, alopecia and hirsutism, pruritus, paronychia, and describe assessment tools or frequency, lack of validated radiation dermatitis). tools for the assessment of dermatologic toxicities, and passive data collection. Given that these agents are relatively devoid of systemic and hematopoietic toxicities and have shown benefit in a variety of solid tumors, further Table 1 Levels of evidence [3] large-scale studies to define best supportive care are necessary but are unlikely to become available in the Level I evidence is reserved for meta-analyses of randomized controlled trials or randomized trials with high power. foreseeable future. The purpose of this article is to provide Level II evidence includes randomized trials with lower power. comprehensive supportive care prevention and treatment Level III evidence includes nonrandomized trials, such as cohort or recommendations for EGFRI-induced dermatologic toxic- case-controlled series. ities based on the pertinent literature currently available. In Level IV evidence includes descriptive and case studies. cases where randomized clinical trials specific to EGFRI Level V evidence includes case reports and clinical examples. toxicities were not available, trials investigating phenotyp- Support Care Cancer (2011) 19:1079–1095 1081 Table 2 Recommendation grades [3] with moisturizer, sunscreen, and doxycycline 100 mg bid for Grade A is reserved for level I evidence or consistent findings from the first 6 weeks is recommended based on randomized data. multiple studies of levels II, III, or IV evidence. Another study revealed that prophylactic minocycline Grade B is for levels II, III, or IV evidence with generally consistent 100 mg daily is an effective agent in reducing the number findings. of lesions during the first 8 weeks. Doxycycline appears to Grade C is similar to grade B but with inconsistencies. have a more favorable safety profile, especially in patients Grade D implies little or no evidence. with renal dysfunction, whereas minocycline is less photo- sensitizing, thus preferable in geographic or seasonal locations with a high UV index. Results and recommendations Reactive use of medium- to high-potency topical cortico- steroids is recommended based on studies showing in vitro Papulopustular (acneiform) rash release of inflammatory chemokines after EGFRI therapy. Vitamin K3 (menadione) is currently being investigated, During the first weeks to months of EGFRI therapy, a but published reports on vitamin K1 are based on studies papulopustular (acneiform) rash is the most clinically without control groups [13, 14]. Similarly, studies investi- significant dermatologic toxicity. The rash usually develops gating isotretinoin for the treatment of EGFRI-induced rash in cosmetically sensitive areas, and it affects the majority of have not included control groups, but consistent reports of treated patients. Pruritic and tender erythematous papules isotretinoin at doses lower than those used for acne support and pustules develop in skin (Fig. 1a–c) with a high density the recommendation of their use when other measures have of sebaceous glands (scalp, face,