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，发生在> 70%服用这些药物的癌症患者中。这种皮疹发生在面部、躯干和四肢，严重时可导致癌症治疗中断。EGFR抑制剂的处方频率越来越高，并且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），试图预防和减轻这种皮疹，我们小组和其他人的初步观察提示了一系列未回答的问题。表皮生长因子受体诱导的皮疹是否通常与其他令人痛苦的症状（如皮肤灼热和瘙痒）相关？它是否与心理困扰有关，如果是，程度如何？有希望的临床前数据与局部甲萘醌导致预防和减轻这种皮疹在癌症患者？这种皮疹的病理生理机制是什么？一氧化氮介导的炎症可能是一个关键因素吗？鉴于这些未回答的问题，该提案具有以下目的：目的#1：利用先前患有EGFR抑制剂诱导的皮疹的癌症患者中的焦点组，首次描述与该皮疹相关的整个体征和症状群。目标2：通过一项随机、安慰剂对照试验，探讨外用甲萘醌是否能预防和缓解皮疹以及皮疹相关症状群的其他方面。目标3：通过一系列皮肤活检，探索局部应用甲萘醌（在其他情况下已被证明可抑制内皮型一氧化氮合酶）是否逆转一氧化氮信号通路的皮肤改变，从而导致角质形成细胞凋亡减少。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。这些药物引起皮疹，发生在面部、躯干和手臂上，并与不良的免疫反应有关。 以瘙痒、疼痛和心理痛苦为特征的一系列症状。的 该建议的目的是从临床和基础科学的角度更好地表征这种与皮肤相关的症状群，并测试甲萘醌试剂以一起预防它。

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.