Prevention and Treatment of Oxaliplatin-Induced Peripheral Neuropathy

项目总结/摘要 奥沙利铂与标准5-氟尿嘧啶化疗方案联合治疗结直肠癌的获益 许多随机对照试验表明，癌症患者的病情得到了改善， 自由和总体生存。然而，这种治疗的主要剂量限制性副作用是奥沙利铂诱导的 周围神经病变（OIPN），其影响大部分治疗患者。OIPN可以是急性的， 在奥沙利铂输注期间或输注后立即发生，或慢性，也可在输注之间发生 在完成治疗后。急性症状通常是轻微的，而慢性OIPN更使人虚弱， 通常表现为双侧远端神经病变，症状包括神经性疼痛、麻木/ 刺痛和感觉性共济失调这些症状干扰日常生活活动，并与 伤害/发病率，包括福尔斯、精神障碍和睡眠障碍-所有这些 严重损害结直肠癌幸存者的生活质量。一些由国家癌症研究所赞助的试验已经启动， 在试图找到可以预防和/或治疗化疗诱导的周围神经病变的疗法中 （CIPN）。作为这些试验的结果，目前仅推荐一种药物度洛西汀治疗CIPN; 没有推荐的预防性治疗。然而，其他药物/疗法在小型研究中显示出希望 但由于缺乏科学严谨性而未被推荐。观察比较有效性 利用监测、流行病学和最终结果数据库与医疗保险索赔相结合的研究 （SEER-医疗保险）能够利用大量的患者社会人口统计、治疗和临床数据 长期随访。这些研究克服了小样本量和有限的随访限制， 临床试验，并可以提供新的信息，治疗效果的几个不足，潜在的 有效的治疗。在这项研究中，我们将使用SEER医疗保险数据库提供新的证据， II-IV期结直肠癌患者OIPN预防和治疗方案的有效性，并确定 增加/降低OIPN诊断可能性的患者社会人口统计学/临床特征 随着时间我们将评估文拉法辛、度洛沙汀和氧卡马西平预防OIPN的能力。为 治疗OIPN，我们将评估文拉法辛，去甲替林， 加巴喷丁/普瑞巴林、经皮电神经刺激、脊髓刺激和阿片类药物 与度洛西汀相比。还将评估其他治疗。将评估治疗的有效性 预防/解决OIPN并减少OIPN相关结果的能力。最后，为了提供新的见解， 关于OIPN的病因，我们将评估患者的社会人口统计学和临床特征， 增加/减少早期和长期OIPN的可能性。这项研究的结果是迫切需要的， 为大量结直肠癌幸存者提供预防和治疗OIPN的新治疗选择 患有奥沙利铂化疗的这种使人衰弱的后果。

PROJECT SUMMARY/ABSTRACT The benefit of adding oxaliplatin to the standard 5-fluorouracil-based chemotherapeutic regimen for colorectal cancer patients was demonstrated by a number of randomized controlled trials that reported improved disease- free and overall survival. However, the major dose-limiting side effect of this therapy is oxaliplatin-induced peripheral neuropathy (OIPN), which affects a large proportion of treated patients. OIPN can be acute, occurring during or immediately after oxaliplatin infusion, or chronic, which can occur between infusions as well as after completing treatment. Acute symptoms are typically mild whereas chronic OIPN is more debilitating, usually presenting as bilateral, distal neuropathy with symptoms that include neuropathic pain, numbness/ tingling, and sensory ataxia. These symptoms interfere with activities of daily living and are associated with a number of injuries/morbidities including falls, psychiatric disturbances, and sleep disorders—all of which significantly impair colorectal cancer survivors’ quality of life. A number of NCI-sponsored trials were launched in an attempt to find therapies that could prevent and/or treat chemotherapy-induced peripheral neuropathy (CIPN). As a result of these trials, only one drug, duloxetine, is currently recommended to treat CIPN; there are no recommended preventive therapies. However, other drugs/therapies have shown promise in small studies but have not been recommended due to a lack of scientific rigor. Observational comparative effectiveness research utilizing the Surveillance, Epidemiology, and End Results database combined with Medicare claims (SEER-Medicare) is able to leverage large amounts of patient sociodemographic, treatment, and clinical data with long-term follow-up. These studies overcome the small sample size and limited follow-up limitations of clinical trials and can provide new information on treatment effectiveness for several understudied, potentially effective therapies. In this study, we will use the SEER-Medicare database to provide new evidence on the effectiveness of preventive and treatment options for OIPN in stage II-IV colorectal cancer patients and identify sociodemographic/clinical characteristics of patients that increase/decrease the likelihood of OIPN diagnosis over time. We will evaluate the ability of venlafaxine, duloxetine, and oxcarbamazepine to prevent OIPN. For treatment of OIPN, we will evaluate the potential superiority of venlafaxine, nortriptyline, gabapentin/pregabalin, transcutaneous electrical nerve stimulation, spinal cord stimulation, and opioids compared to duloxetine. Additional therapies will also be evaluated. Effectiveness of therapy will be assessed by the ability to prevent/resolve OIPN and reduce OIPN-related outcomes. Lastly, to provide new insight concerning the etiology of OIPN, we will evaluate sociodemographic and clinical characteristics of patients that increase/decrease the likelihood of early and long-term OIPN. The results of this study are critically needed to provide new therapeutic options to prevent and treat OIPN for the large number of colorectal cancer survivors suffering from this debilitating consequence of oxaliplatin chemotherapy.