皮疹处理指南

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 Background Epidermal 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 recom- mendations for EGFRI-associated dermatologic toxicities. Methods A multinational, interdisciplinary panel of experts in supportive care in cancer reviewed pertinent studies using established criteria in order to develop first-generation recom- mendations for EGFRI-associated dermatologic toxicities. Results Prophylactic and reactive recommendations for pap- ulopustular (acneiform) rash, hair changes, radiation derma- titis, pruritus, mucositis, xerosis/fissures, and paronychia are presented, as well as general dermatologic recommendations when possible. Conclusion Prevention and management of EGFRI-related dermatologic toxicities is critical to maintain patients’ health-related quality of life and dose intensity of antineo- plastic regimens. More rigorous investigation of these toxicities is warranted to improve preventive and treatment 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 (*) Dermatology Service, Department of Medicine, Memorial Sloan–Kettering Cancer Center, Rockefeller Outpatient Pavilion Suite 228, 160 East 53rd Street, New York, NY 10022, USA e-mail: lacoutuM@mskcc.org M. J. Anadkat Washington University School of Medicine, St. Louis, MO, USA R.-J. Bensadoun Centre Hospitalier Universitaire de Poitiers, Poitiers Cedex, France J. Bryce Istituto Nazionale dei Tumori, Naples, Italy A. Chan National University of Singapore, Singapore, Singapore J. B. Epstein University of Illinois at Chicago, Chicago, IL, USA B. Eaby-Sandy University of Pennsylvania, Philadelphia, PA, USA B. A. Murphy Vanderbilt University Medical Center, Nashville, TN, USA Support Care Cancer (2011) 19:1079–1095 DOI 10.1007/s00520-011-1197-6 Keywords Rash . Xerosis . Paronychia . Pruritus . Radiation dermatitis . Mucositis . EGFR inhibitors . Recommendations Background Overexpression of the epidermal growth factor receptor (EGFR) is strongly associated with cancer development and progression of a number of malignancies. EGFR inhibitors (EGFRI) are targeted agents used for treating lung (erlotinib), pancreatic (erlotinib in combination with gem- citabine), breast (lapatinib in combination with capecitabine or anastrozole), head and neck (cetuximab in combination with radiotherapy), and colorectal cancers (cetuximab, panitumumab) [1]. EGFRI may be used as first-line through third-line treatments, alone or in combination with other agents in the aforementioned cancers. Commonly experienced dermatologic side effects in- clude papulopustular (acneiform) rash, hair changes, radi- ation dermatitis enhancement, pruritus, mucositis, xerosis/ fissures, and paronychia. Incidences of these side effects are frequent and range from 36% for mucositis to 80% for papulopustular (acneiform) rash. Clinical presentation, incidence, impact on quality of life and cost, effect on EGFRI dosing, and risk factors for these toxicities have been described elsewhere [1]. When severe, dermatologic toxicities may to lead to dose modification or discontinu- ation by 36% and 72% of health care providers, respec- tively [2]. Although the side effect profile may be primarily dermatologic, toxicities result in significant physical and emotional discomfort, thus it is critical to maximize supportive measures. Although most patients receiving EGFRIs experience these toxicities, few controlled studies have been conducted to determine the best practices for their management. Instead, much of the literature contains prevention and treatment recommendations based on case reports or studies with small samples sizes and nonrandomized patient allocation. In addition, available reports are beset with methodological issues including failure to adequately describe assessment tools or frequency, lack of validated 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 large-scale studies to define best supportive care are necessary but are unlikely to become available in the foreseeable future. The purpose of this article is to provide comprehensive supportive care prevention and treatment recommendations for EGFRI-induced dermatologic toxic- ities based on the pertinent literature currently available. In cases where randomized clinical trials specific to EGFRI toxicities were not available, trials investigating phenotyp- ically similar dermatologic conditions were analyzed and reported. Methods Participants The Multinational Association for Supportive Care in Cancer (MASCC) Skin Toxicity Study Group assembled an interna- tional, interdisciplinary group of experts in dermatology, medical and supportive oncology, health-related quality of life (HQOL), and pharmacovigilance. Topic review commit- tees were formed according to expertise to review the literature and develop guidelines for the following dermato- logic toxicities: papulopustular (acneiform) rash, hair changes, radiation dermatitis, pruritus, mucositis, xerosis/fissures, and paronychia. Recommendation development Each review committee consisted of three members with a primary reviewer to present the findings of the committee to the Skin Toxicity Study Group. Literature reviews were performed via databases such as Ovid MEDLINE (National Library of Medicine, Bethesda, MD, USA) and EMBASE (Elsevier B.V. Amsterdam, The Netherlands). Published literature as of November 2010 was included and each committee reviewed between 17 and 35 papers to formulate the recommended guidelines. Randomized clinical trials were considered the best source, and considerations for recommendations included Level of Evidence and Grade of Recommendation (Tables 1 and 2) [3]. In the absence of experimental evidence, pertinent studies and case reports were presented in conjunction with expert opinion derived from clinical practice. Recommendations were developed based on the presented findings and panel consensus. When available, data were extrapolated from other dermatologic conditions with similar clinical or pathologic characteristics (xerosis, alopecia and hirsutism, pruritus, paronychia, and radiation dermatitis). Table 1 Levels of evidence [3] Level I evidence is reserved for meta-analyses of randomized controlled trials or randomized trials with high power. Level II evidence includes randomized trials with lower power. Level III evidence includes nonrandomized trials, such as cohort or case-controlled series. Level IV evidence includes descriptive and case studies. Level V evidence includes case reports and clinical examples. 1080 Support Care Cancer (2011) 19:1079–1095 Lenovo 高亮 Results and recommendations Papulopustular (acneiform) rash During the first weeks to months of EGFRI therapy, a papulopustular (acneiform) rash is the most clinically significant dermatologic toxicity. The rash usually develops in cosmetically sensitive areas, and it affects the majority of treated patients. Pruritic and tender erythematous papules and pustules develop in skin (Fig. 1a–c) with a high density of sebaceous glands (scalp, face, upper chest, and back). Histological analyses reveal a superficial inflammatory cell infiltrate surrounding hyperkeratotic or ectatic follicular infundibula or a florid neutrophilic suppurative folliculitis with rupture of epithelial lining. The rash is noteworthy for its impact on psychosocial well-being, related costs, secondary infections, and effects on dose intensity. As measured using Skindex-16, an HQOL tool used in dermatology, greater severity of rash will result in a greater decrement in HQOL, with emotions being the most important aspect of people’s lives affected. Pain, burning, and irritation were common symptoms affecting the majority of patients [4]. Moreover, a survey of oncology practitioners demonstrated that 32% of providers discon- tinued therapy and 76% modified dose due to rash when severe [5]. Several factors have been associated with an increased risk of developing rash: for erlotinib, nonsmokers, people with fair skin, and older than 70; for cetuximab, male gender and those younger than 70. Moreover, severe rash is more frequent with monoclonal antibodies (10–17%) than with low-molecular- weight tyrosine kinase inhibitors (5–9%). As with other toxicities, management can be preventive/prophylactic or treatment/reactive. Randomized controlled trials for EGFRI rash have been conducted in the preventive/prophylactic setting, whereas uncontrolled reports reveal options for reactive treatment. Table 3 displays the recommendations for the prevention and treatment of papulopustular (acneiform) rash. Based on the high frequency of rash in EGFRI-treated patients and the consistent presentation within the first 2–4 weeks of therapy, preventive/prophylactic management is recommended unless there are contraindications based on patient and/or health care provider factors [6–12]. Hydrocortisone 1% combined with moisturizer, sunscreen, and doxycycline 100 mg bid for the first 6 weeks is recommended based on randomized data. Another study revealed that prophylactic minocycline 100 mg daily is an effective agent in reducing the number of lesions during the first 8 weeks. Doxycycline appears to have a more favorable safety profile, especially in patients with renal dysfunction, whereas minocycline is less photo- sensitizing, thus preferable in geographic or seasonal locations with a high UV index. Reactive use of medium- to high-potency topical cortico- steroids is recommended based on studies showing in vitro release of inflammatory chemokines after EGFRI therapy. Vitamin K3 (menadione) is currently being investigated, but published reports on vitamin K1 are based on studies without control groups [13, 14]. Similarly, studies investi- gating isotretinoin for the treatment of EGFRI-induced rash have not included control groups, but consistent reports of isotretinoin at doses lower than those used for acne support the recommendation of their use when other measures have failed. Additional support for isotretinoin is provided by patient reports of improved HQOL, and there is evidence of clinical response to the EGFRI [1, 15–17]. Although the rash peaks in weeks 4–6 after EGFRI initiation and decreases in severity after weeks 6–8, postinflammatory skin alterations (erythema and hyperpigmentation) are long- term sequelae that can last for months or years. Therefore, prophylactic strategies are important, and appropriate medication (Table 3) should be considered throughout EGFRI treatment and follow-up in order to minimize these late effects. Hair changes A variety of hair changes have been described in patients taking EGFRI and include trichomegaly (elongation and curling of the eyelashes), hypertrichosis often presenting as facial hirsutism, and scalp hair changes ranging from brittleness and slowed growth to alopecia. Nonscarring alopecia occurs after 2–3 months of therapy and may present as frontal or patchy patterns, with a tendency to progress to diffuse alopecia with prolonged EGFRI therapy, which may resolve spontaneously in some patients. Alopecia generally resolves after discontinuation of therapy, though hair regrowth may be of varying quality. No interventions to reduce or prevent nonscarring alopecia in these patients have been published in the literature, and recommended interventions are supportive (education, cosmetic approaches for patient comfort) and based on studies in androgenetic (male-pattern) and female alopecia (Table 4). Minoxidil has been found effective for treating non- scarring alopecia in the general patient population [18–20]. In two studies, males’ subjective reporting of increased hair growth was statistically significant for both the 2% and 5% Table 2 Recommendation grades [3] Grade A is reserved for level I evidence or consistent findings from multiple studies of levels II, III, or IV evidence. Grade B is for levels II, III, or IV evidence with generally consistent findings. Grade C is similar to grade B but with inconsistencies. Grade D implies little or no evidence. Support Care Cancer (2011) 19:1079–1095 1081 Lenovo 高亮 Lenovo 高亮 Lenovo 高亮 Lenovo 高亮 Lenovo 高亮 Lenovo 高亮 A B C D E F G H I Fig. 1 a Mild papulopustular (acneiform) rash, b and c pap- ulopustular (acneiform) rash, d and e radiation dermatitis, f and g mucositis, h fingertip fissure, and i paronychia 1082 Support Care Cancer (2011) 19:1079–1095 minoxidil groups versus placebo and objective hair counts also were significantly higher in the two treatment groups [18, 19]. Similar findings were reported in one study with females randomized to the same two treatment groups versus placebo group for hair count, although no difference was found between the groups for subjective reporting of increased hair changes [20]. Higher incidences of pruritus and hypertrichosis were reported in the minoxidil 5% group than in the 2% group [18, 19]. These should be monitored if minoxidil is prescribed for patients receiving EGFRIs as these also are possible skin toxicities associated with the EGFRI therapy. Scarring alopecia also has been reported in these patients and is consequent to scalp, facial, and chest lesions that can lead to permanent hair loss. Prevention and management strategies, based on expert opinion, aim to reduce inflamma- tion and scarring for patients receiving EGFRI therapy. Options include topical hydrocortisone 0.2%, steroid shampoos, and class 1 steroid lotions [21]. Use of bath oils or mild shampoo followed by antibiotic spray has been recently reported [22]. Preventive strategies for reducing papulopustular (acneiform) rash severity, as described above, also should be employed to minimize scarring alopecia. Facial hypertrichosis (hirsutism) and trichomegaly appear after the first 1–2 months of therapy, and these symptoms do not wane over time; instead, they tend to persist for the duration of therapy with EGFRIs. Unwanted or excess facial hair may be treated with temporary or permanent hair removal. Trichomegaly is associated with patient discomfort and the abnormal eyelash growth can lead to corneal abrasions and further ocular complications. Trichomegaly can be treated with lash clipping every 2–4 weeks, and referral to an ophthalmologist is indicated for patients with irritation or persistent discomfort. Topical eflornithine cream has been well tolerated and efficacious for the treatment of hirsutism in open-label trials with the general female population and has been found to significantly improve HQOL in a randomized clinical trial [23, 24]. Laser hair removal has been shown to reduce hair growth in a small sample [25], but eflornithine plus laser hair removal has been reported to be more effective than laser hair removal alone in randomized trials with the general population [26, 27]. Amelioration of symptoms, patient education, and support are recommended for patients with hair changes so that EGFRI therapy may continue. Radiation dermatitis The development of some degree of radiation dermatitis is considered inevitable for the majority of patients receiving Table 3 Papulopustular (acneiform) rash recommendations Recommend Not recommended Level of evidence Recommendation grades Comments Preventive (weeks 1–6 and 8 of EGFRI initiation) Topical Hydrocortisone 1% cream with moisturizer and sunscreen twice daily Pimecrolimus 1% cream IIa C Tazarotene 0.05% cream Sunscreen as single agent Systemic Minocycline 100 mg daily Tetracycline 500 mg bid IIa A Doxycycline is preferred in patients with renal impairment. Minocycline is less photosensitizing. Doxycycline 100 mg bid Treatment Topical Alclometasone 0.05% cream Vitamin K1 cream IVa C Fluocinonide 0.05% cream bid Clindamycin 1% Systemic Doxycycline 100 mg bid Acitretin IVa C Photosensitizing agents Minocycline 100 mg daily Isotretinoin at low doses (20–30 mg/day) a EGFRI study Support Care Cancer (2011) 19:1079–1095 1083 radiotherapy due to direct injury to epidermal basal cells and connective tissue changes that usually develop within the first few weeks of radiation initiation. Furthermore, higher incidence of high-grade radiation dermatitis results from the addition of EGFRIs to radiotherapy [28]. Radiation dermatitis ranges from erythema and dry or wet desquamation to skin necrosis or ulceration of full thickness dermis with spontaneous bleeding from the involved site (Fig. 1d, e). The establishment of a proper technique to minimize the dose delivered to the epidermis and a quality assurance program for radiotherapy planning and delivery is critical not only in therapeutic terms but also from the perspective of avoiding unnecessary skin toxicity. A primary step in the management of radiation dermatitis of any severity is to establish that the skin reactions are not a result of any concomitant medication, other than EGFRI. In the case of more severe skin reactions, correct radiation dose and distribution should be verified. Table 5 displays the recommendations for the prevention and treatment of radiation dermatitis. An important step in managing and treating radiation dermatitis is to keep the irradiated area clean and dry, even when ulcerated. Gentle washing and drying of the skin within the radiation portal have been shown to reduce the acute radiotherapy- associated skin reactions in patients receiving radiotherapy for breast cancer and is now routinely recommended for all patients receiving radiotherapy [29, 30]. A number of topical agents can be considered, all of which are considered high-potency topical corticosteroids (mometa- sone, methylprednisolone, beclomethasone, and betametha- sone creams [31, 32]. The recently reported results of Radiation Therapy Oncology Group trials (99-13) in patients with squamous cell carcinoma of the head and neck failed to show any benefit of the systematic use of interventional or prophy- lactic trolamine emulsion in reducing skin toxicity [33]. Another study showed no significant benefit of pentoxifyl- line prophylaxis on the development of acute skin reactions [34]. The potential benefit of oral zinc supplementation in postponing the development of severe mucositis and dermatitis and in alleviating the degree of mucositis and dermatitis in patients receiving radiotherapy for cancers of the head and neck [35] warrants additional confirmatory studies. Where infection is suspected, the treating physician should use best clinical judgment for management, includ- ing considering swabbing the affected area for identifica- tion of the infectious agent. In patients for whom skin infection is suspected or documented, the neutrophil count Table 4 Hair changes recommendations Recommend Not recommended Level of evidence Recommendation grades Comments Preventive hair loss Topical For scarring alopecia, follow