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表皮生长因子受体抑制剂西妥昔单抗的不良反应

Adverse Reaction to Cetuximab, an Epidermal Growth Factor Receptor Inhibitor.

作者信息

Štulhofer Buzina Daška, Martinac Ivana, Ledić Drvar Daniela, Čeović Romana, Bilić Ivan, Marinović Branka

机构信息

Daška Štulhofer Buzina, MD, PhD, University Hospital Center Zagreb, Department of Dermatology and Venereology, School of Medicine University of Zagreb, Šalata 4, 10000 Zagreb, Croatia;

出版信息

Acta Dermatovenerol Croat. 2016 Apr;24(1):70-2.

Abstract

Dear Editor, Inhibition of the epidermal growth factor receptor (EGFR) is a new strategy in treatment of a variety of solid tumors, such as colorectal carcinoma, non-small cell lung cancer, squamous cell carcinoma of the head and neck, and pancreatic cancer (1). Cetuximab is a chimeric human-murine monoclonal antibody against EGFR. Cutaneous side effects are the most common adverse reactions occurring during epidermal growth factor receptor inhibitors (EGFRI) therapy. Papulopustular rash (acne like rash) develop with 80-86% patients receiving cetuximab, while xerosis, eczema, fissures, teleangiectasiae, hyperpigmentations, and nail and hair changes occur less frequently (2). The mechanism underlying these skin changes has not been established and understood. It seems EGFRI alter cell growth and differentiation, leading to impaired stratum corneum and cell apoptosis (3-5). An abdominoperineal resection of the rectal adenocarcinoma (Dukes C) was performed on a 43-year-old female patient. Following surgery, adjuvant chemo-radiotherapy was applied. After two years, the patient suffered a metastatic relapse. Abdominal lymphadenopathy was detected on multi-slice computer tomography (MSCT) images, with an increased value of the carcinoembryonic antigen (CEA) tumor marker (maximal value 57 ng/mL). Hematological and biochemical tests were within normal limits, so first-line chemotherapy with oxaliplatin and a 5-fluorouracil (FOLFOX4) protocol was introduced. A wild type of the KRAS gene was confirmed in tumor tissue (diagnostic prerequisite for the introduction of EGFRI) and cetuximab (250 mg per m2 of body surface) was added to the treatment protocol. The patient responded well to the treatment with confirmed partial regression of the tumor formations. Three months after the patient started using cetuximab, an anti-EGFR monoclonal antibody, the patient presented with a papulopustular eruption in the seborrhoeic areas (Figure 1) and eczematoid reactions on the extremities with dry, scaly, itchy skin (Figure 2). Furthermore, hair and nail changes gradually developed, culminating with trichomegaly (Figure 3) and paronychia (Figure 4). The patient was treated with oral antibiotics (tetracycline) and a combination of topical steroids with moisturizing emollients due to xerosis, without reduction of EGFRI therapy and with a very good response. Trichomegaly was regularly sniped with scissors. Nail fungal infection was ruled out by native examination and cultivation, so antiseptics and corticosteroid ointments were introduced for paronychia treatment. During the above-mentioned therapy, apart from skin manifestations, iatrogenic neutropenia grade IV occurred, with one febrile episode, and because of this, the dose of cytostatic drugs was reduced. After 10 months of therapy, progression of the disease occurred with lung metastases, so EGFRI therapy was discontinued and the patient was given second-line chemotherapy for metastatic colorectal carcinoma. This led to gradual resolution of all aforementioned cutaneous manifestations. Since the pathogenesis of skin side-effects due to EGFRI is not yet fully understood, there are no strict therapy protocols. Therapy is mainly based on clinical experience and follows the standard treatments for acne, rosacea, xerosis, paronychia, and effluvium. The therapeutic approach for papulopustular exanthema includes topical and systemic antibiotics for their antimicrobial as well as anti-inflammatory effect, sometimes in combination with topical steroids. Topical application of urea cream with K1 vitamin yielded positive results in skin-changes prevention during EGFRI therapy, especially with xerosis, eczema, and pruritus (6). Hair alterations in the form of effluvium are usually tolerable, and if needed a 2% minoxidil solution may be applied. Trichomegaly or abnormal eyelash growth can lead to serious complications, so ophthalmologic examination is needed. At the beginning of the growth, regular lash clipping may reduce possibility of corneal abrasion (7,8). Nail changes can just be a cosmetic problem (pigmentary changes, brittle nails), and in the occurrence of paronychia or onycholysis (of several or all nails) they result in high morbidity and impair daily activities. Nail management should be started as soon as possible because of slow nail growth and the relatively long half-life of EGFRI. Combination of topical iodide, corticosteroids, antibiotics, and antifungals with avoidance of nail traumatization will yield the best results (9). EGFRI are potentially life prolonging therapies, and our goal as dermatovenereologists is to provide optimal patient care and improve their quality of life in a multidisciplinary collaboration with oncologists, radiotherapists, and ophthalmologists.

摘要

尊敬的编辑,抑制表皮生长因子受体(EGFR)是治疗多种实体瘤的新策略,如结直肠癌、非小细胞肺癌、头颈部鳞状细胞癌和胰腺癌(1)。西妥昔单抗是一种针对EGFR的嵌合型人鼠单克隆抗体。皮肤副作用是表皮生长因子受体抑制剂(EGFRI)治疗期间最常见的不良反应。80-86%接受西妥昔单抗治疗的患者会出现丘疹脓疱性皮疹(痤疮样皮疹),而皮肤干燥、湿疹、皲裂、毛细血管扩张、色素沉着以及指甲和头发变化则较少见(2)。这些皮肤变化的潜在机制尚未明确。EGFRI似乎会改变细胞生长和分化,导致角质层受损和细胞凋亡(3-5)。

对一名43岁女性患者进行了直肠腺癌(Dukes C期)腹会阴联合切除术。术后进行了辅助放化疗。两年后,患者出现转移性复发。多层螺旋计算机断层扫描(MSCT)图像显示腹部淋巴结肿大,癌胚抗原(CEA)肿瘤标志物值升高(最大值57 ng/mL)。血液学和生化检查均在正常范围内,因此采用奥沙利铂和5-氟尿嘧啶(FOLFOX4)方案进行一线化疗。肿瘤组织中证实为KRAS基因野生型(引入EGFRI的诊断前提),并在治疗方案中加入西妥昔单抗(每平方米体表面积250 mg)。患者对治疗反应良好,肿瘤灶证实部分消退。

患者开始使用抗EGFR单克隆抗体西妥昔单抗三个月后,在脂溢性区域出现丘疹脓疱性皮疹(图1),四肢出现湿疹样反应,皮肤干燥、脱屑、瘙痒(图2)。此外,头发和指甲逐渐出现变化,最终出现毛发过长(图3)和甲沟炎(图4)。由于皮肤干燥,患者接受口服抗生素(四环素)治疗,并外用类固醇与保湿润肤剂联合使用,未减少EGFRI治疗,且反应良好。毛发过长定期用剪刀修剪。通过直接检查和培养排除了指甲真菌感染,因此采用防腐剂和皮质类固醇软膏治疗甲沟炎。

在上述治疗期间,除了皮肤表现外,还出现了IV级医源性中性粒细胞减少,并伴有一次发热发作,因此降低了细胞毒性药物的剂量。治疗10个月后,疾病进展并出现肺转移,因此停止EGFRI治疗,患者接受转移性结直肠癌二线化疗。这导致上述所有皮肤表现逐渐消退。

由于EGFRI引起皮肤副作用的发病机制尚未完全明确,因此没有严格的治疗方案。治疗主要基于临床经验,遵循痤疮、酒渣鼻、皮肤干燥、甲沟炎和脱发的标准治疗方法。丘疹脓疱性皮疹的治疗方法包括外用和口服抗生素,利用其抗菌和抗炎作用,有时联合外用类固醇。在EGFRI治疗期间,外用含维生素K1的尿素霜对预防皮肤变化,尤其是皮肤干燥、湿疹和瘙痒产生了积极效果(6)。脱发形式的毛发改变通常可以耐受,如有需要可外用2%米诺地尔溶液。毛发过长或睫毛异常生长可导致严重并发症,因此需要进行眼科检查。在毛发开始生长时,定期修剪睫毛可降低角膜擦伤的可能性(7,8)。指甲变化可能只是一个美容问题(色素沉着、指甲变脆),但出现甲沟炎或甲床分离(几个或所有指甲)时,会导致高发病率并影响日常活动。由于指甲生长缓慢且EGFRI半衰期相对较长,应尽早进行指甲处理。外用碘化物、皮质类固醇、抗生素和抗真菌药联合使用,避免指甲外伤,将产生最佳效果(9)。

EGFRI是具有潜在延长生命作用的疗法,作为皮肤性病科医生,我们的目标是在与肿瘤学家、放疗科医生和眼科医生的多学科合作中,为患者提供最佳护理并改善其生活质量。

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