Lau Darryl, Rutledge Caleb, Aghi Manish K
Department of Neurological Surgery, University of California, San Francisco, California.
Neurosurg Focus. 2015 Feb;38(2):E11. doi: 10.3171/2014.10.FOCUS14700.
OBJECT Cushing's disease (CD) can lead to significant morbidity secondary to hormonal sequelae or mass effect from the pituitary tumor. A transsphenoidal approach to resection of the adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma is the first-line treatment. However, in the setting in which patients are unable to undergo surgery, have acute hypercortisolism, or have recurrent disease, medical therapy can play an important role. The authors performed a systematic review to highlight the efficacy of medical treatment of CD and discuss novel molecular insights that could guide the development of future medical treatments of CD. METHODS A search on current medical therapies for CD was performed. After individual medical therapeutic agents for CD were identified, each agent underwent a formal systematic search. The phrase "(name of agent) and Cushing's" was used as a search term in PubMed for all years up to 2014. The abstract of each article was reviewed for studies that evaluated the efficacy of medical treatment of CD. Only studies that enrolled at least 20 patients were included in the review. RESULTS A total of 11 articles on 6 individual agents were included in this review. Specific medical therapies were categorized based on the level of action: pituitary directed (cabergoline and pasireotide), adrenal/steroidogenesis directed (ketoconazole, metyrapone, and mitotane), and end-tissue directed/cortisol receptors (mifepristone). The studies identified consisted of a mix of retrospective reviews and small clinical trials. Only pasireotide and mifepristone have undergone Phase III clinical trials, from which they garnered FDA approval for the treatment of patients with CD. Overall, agents targeting ACTH secretion and steroidogenesis were found to be quite effective in reducing urine free cortisol (UFC) to levels near normal. A significant reduction in UFC was observed in 45%-100% of patients and a majority of patients gained clinical improvement. Similarly, inhibition at the end-tissue level led to clinical improvement in 87% of patients. However, side-effect rates associated with these drugs are high (up to 88%). Ketoconazole has been shown to enhance tumor appearance on MRI to facilitate pituitary resection. Promising molecular targets have been identified, including epidermal growth factor receptor, retinoic acid receptors, and cyclin dependent kinases. These pathways have been linked to the regulation of pro-opiomelanocortin expression, ACTH secretion, and tumor growth. CONCLUSIONS Despite encouraging Phase III clinical trials leading to FDA approval of 2 agents for treatment of patients with CD, no agent has yet produced results comparable to resection. As a result, the molecular insights gained into CD pathogenesis will need to continue to be expanded until they can lead to the development of medical therapies for CD with a favorable side-effect profile and efficacy comparable to resection. Ideally these agents should also reduce tumor size, which could potentially permit their eventual discontinuation.
目的 库欣病（CD）可因激素后遗症或垂体肿瘤的占位效应导致严重的发病情况。经蝶窦入路切除分泌促肾上腺皮质激素（ACTH）的垂体腺瘤是一线治疗方法。然而，在患者无法接受手术、患有急性皮质醇增多症或疾病复发的情况下，药物治疗可发挥重要作用。作者进行了一项系统评价，以突出CD药物治疗的疗效，并讨论可指导未来CD药物治疗发展的新分子见解。方法 对目前治疗CD的医学疗法进行检索。确定治疗CD的各个药物后，对每种药物进行正式的系统检索。在PubMed中，使用“（药物名称）和库欣病”这一短语作为检索词，检索截至2014年的所有年份的文献。对每篇文章的摘要进行审查，以查找评估CD药物治疗疗效的研究。本评价仅纳入至少纳入20例患者的研究。结果 本评价共纳入了关于6种个体药物的11篇文章。特定的药物治疗根据作用水平进行分类：针对垂体的（卡麦角林和帕瑞肽）、针对肾上腺/类固醇生成的（酮康唑、美替拉酮和米托坦）以及针对终末组织/皮质醇受体的（米非司酮）。所确定的研究包括回顾性综述和小型临床试验的混合。只有帕瑞肽和米非司酮进行了III期临床试验，并因此获得了美国食品药品监督管理局（FDA）批准用于治疗CD患者。总体而言，发现针对ACTH分泌和类固醇生成的药物在将尿游离皮质醇（UFC）降低至接近正常水平方面相当有效。在45% - 100%的患者中观察到UFC显著降低，且大多数患者有临床改善。同样，在终末组织水平的抑制使87%的患者有临床改善。然而，与这些药物相关的副作用发生率很高（高达88%）。酮康唑已被证明可增强MRI上肿瘤的显影，以利于垂体切除。已确定了有前景的分子靶点，包括表皮生长因子受体、视黄酸受体和细胞周期蛋白依赖性激酶。这些途径与阿片促黑皮质素原表达的调节、ACTH分泌和肿瘤生长有关。结论 尽管令人鼓舞的III期临床试验使2种药物获得FDA批准用于治疗CD患者，但尚无药物产生与手术相当的效果。因此，对CD发病机制的分子见解需要继续扩展，直到能开发出副作用良好且疗效与手术相当的CD药物治疗方法。理想情况下，这些药物还应缩小肿瘤大小，这可能最终允许停药。
