Rash from EGFR Inhibitors: Characterization & Palliation of a Symptom Cluster

描述(由申请人提供)：皮疹是表皮生长因子受体(EGFR)抑制剂最常见的副作用，70%服用这些药物的癌症患者会出现皮疹。这种皮疹发生在面部、躯干和四肢上，严重时可能导致癌症治疗的中断。EGFR抑制剂的处方频率越来越高，在各种恶性肿瘤患者中具有良好的抗肿瘤作用。然而，人们对它们引起的皮疹知之甚少。我们小组已经完成了两项临床试验(n=177)，试图预防和缓解这种皮疹，我们小组和其他人的初步观察引发了一系列悬而未决的问题。EGFR抑制剂引起的皮疹是否通常与其他令人痛苦的症状有关，如皮肤灼热和瘙痒？它是否与心理痛苦有关？如果是的话，程度如何？外用甲奈二酮的有希望的临床前数据能否导致癌症患者皮疹的预防和缓解？皮疹的病理生理学基础是什么？一氧化氮介导的炎症可能是关键成分吗？鉴于这些悬而未决的问题，这项建议有以下目标：目标1：利用先前患有EGFR抑制剂引起皮疹的癌症患者的焦点小组，首次确定与皮疹相关的整个体征和症状的特征。目的#2：通过一项随机、安慰剂对照试验，探讨外用甲奈二酮是否能预防和缓解皮疹以及皮疹相关症状群的其他方面。目的#3：通过一系列的皮肤活检，探讨局部应用甲奈酮是否逆转了皮肤一氧化氮合酶信号通路的改变，从而减少角质形成细胞的凋亡。公共卫生相关性：表皮生长因子受体(EGFR)抑制剂在癌症治疗中的使用频率越来越高。这些药物会引起面部、躯干和手臂上的皮疹，并与不良的 以一系列症状为特征，似乎包括瘙痒、疼痛和心理痛苦。这个 这项建议的目的是从临床和基础科学的角度更好地描述这一皮肤相关症状群的特征，并测试药剂甲奈二酮以共同预防它。

DESCRIPTION (provided by applicant): Rash is the most common side effect of epidermal growth factor receptor (EGFR) inhibitors, occurring in > 70% of cancer patients who take these drugs. This rash occurs on the face, trunk, and extremities and, when severe, can lead to discontinuation of cancer therapy. EGFR inhibitors are being prescribed with increasing frequency and have well established antineoplastic effects among patients with a variety of malignancies. Yet relatively little is known about the rash they cause. Our group has completed two clinical trials (n=177) in an effort to try to prevent and palliate this rash, and preliminary observations from our group and from others prompt a series of unanswered questions. Is the EGFR inhibitor-induced rash typically associated with other distressing symptoms such as cutaneous burning and itching? Is it associated with psychological distress, and, if so, to what extent? Can the promising preclinical data with topical menadione lead to the prevention and palliation of this rash in cancer patients? What is the pathophysiology underlying this rash, and might nitric oxide-mediated inflammation be a key component? In view of these unanswered questions, this proposal has the following aims: AIM #1: To utilize focus groups among cancer patients who had previously suffered from an EGFR inhibitor induced rash in an effort to characterize, for the first time, the entire cluster of signs and symptoms associated with this rash. AIM #2: To explore by means of a randomized, placebo-controlled trial, whether topical menadione prevents and palliates this rash and the other aspects of this rash-related symptom cluster. AIM#3: To explore, by means of serial skin biopsies, whether topically applied menadione, which in other settings has been shown to inhibit endothelial nitric oxide synthase, reverses cutaneous alterations of the nitricoxide signaling pathway, thereby leading to decreased keratinocyte apoptosis. PUBLIC HEALTH RELEVANCE: Epidermal growth factor receptor (EGFR) inhibitors are being used with increasing frequency in cancer therapy. These agents cause a rash which occurs on the face, trunk, and arms and is associated with a poorly characterized cluster of symptoms that appears to include itching, pain, and psychological distress. The purpose of this proposal is to better characterize this skin-related symptom cluster from a clinical and basic science standpoint and to test the agent menadione to prevent it all together.