wjcr World Journal of Cancer Research 2164-9049 2164-9057 beplay体育官网网页版等您来挑战! 10.12677/wjcr.2025.151002 wjcr-104811 Articles 医药卫生 化疗相关认知障碍的治疗研究进展
Advances in Therapeutic Research on Chemotherapy-Related Cognitive Impairment
刘立石 1 2 黑龙江中医药大学研究生院,黑龙江 哈尔滨 黑龙江中医药大学附属第一医院肿瘤二科,黑龙江 哈尔滨 03 01 2025 15 01 9 15 7 12 :2024 3 12 :2024 3 1 :2025 Copyright © 2024 beplay安卓登录 All rights reserved. 2024 This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/ 化疗相关认知障碍(CRCI)是肿瘤患者化疗所引起的常见不良反应,在肿瘤幸存者中,它的发生率非常高,对患者的治疗依从性和生活治疗带来极大影响。目前,CRCI并无明确有效的治疗方法,主要的治疗方法有药物干预和非药物干预。近些年,治疗CRCI的方法层出不穷,也有大量与之相关的随机对照试验和系统综述发表。因此,本文对这些化疗相关认知障碍的治疗方法进展进行综述,以期为临床治疗CRCI提供参考。
Chemotherapy-related cognitive impairment (CRCI) is a common adverse effect of chemotherapy in cancer patients, with a particularly high incidence among cancer survivors. This condition signi- ficantly impacts patients’ treatment adherence and quality of life. Currently, there is no definitive and effective treatment for CRCI; the main therapeutic approaches include pharmacologic and non-pharmacologic interventions. In recent years, there has been a proliferation of treatments for CRCI, and numerous randomized controlled trials and systematic reviews related to these interventions have been published. Therefore, this article reviews the progress of various therapeutic approaches for chemotherapy-related cognitive impairment, aiming to provide a reference for clinical treatment.
化疗,化疗相关认知障碍,CRCI,多奈哌齐,认知行为治疗,针灸
Chemotherapy
Chemotherapy-Related Cognitive Impairment CRCI Donepezil Cognitive Behavioral Therapy Acupuncture
1. 引言

全世界的癌症幸存者人数巨大。临床医生总是关注癌症特异性临床终点,例如总生存期、无进展生存期和客观缓解率。随着各种治疗技术的进步和应用,癌症患者的生存率提高了,死亡率也有所下降。因此,患者的生活质量问题突显出来。作为生活质量的重要组成部分,癌症患者的认知功能下降已在许多研究中被提出 [1] - [4] 。这些癌症幸存患者出现认知功能减低,通常被认为是化疗所引起的 [5] ,所以也称为化疗相关认知障碍(chemotherapy-related cognitive impairment, CRCI),但并非所有癌症患者在化疗后都会发生CRCI。CRCI的发病率约为17%~70%,在乳腺癌中甚至达到75% [6] ,35%的乳腺癌患者即便在化疗后3~4年其认知功能仍未完全恢复 [7] [8] 。CRCI的主要表现为认知领域的缺陷,包括化疗后的记忆减退、注意力难以集中、执行功能下降、和反应时间延长 [9] 。相比于中枢神经系统疾病所造成的认知障碍,CRCI通常为轻度至中度 [6] ,但CRCI仍然会破坏治疗依从性,增加疾病负担,并对乳腺癌患者的生活质量产生深远影响,给她们在经济、情感和人际关系方面带来巨大代价 [10] - [12]

CRCI的发病机制并不是非常明确,大致可分为化疗药物的直接神经毒性作用和间接作用 [13] 。化疗可通过对神经细胞的直接毒性损伤来损害大脑代谢和细胞功能,铂类化合物可少量穿透血脑屏障,诱导线粒体DNA损伤,增加海马神经元凋亡,使认知功能受损 [14] 。抗肿瘤药物5-Fu可分解髓鞘完整性,使海马神经退化 [15] 。也可能通过间接机制引起,例如治疗引起的细胞因子紊乱 [16] 、氧化应激、遗传多态性和荷尔蒙水平。

目前CRCI的治疗方法较为局限,主要分为药物干预和非药物干预 [17] [18] 。药物干预包括抗痴呆药物(如多奈哌齐、美金刚和银杏叶)、中枢神经系统兴奋剂(如哌醋甲酯和莫达非尼)和促红细胞生成素等。然而,这些药物的疗效尚不明确 [19] - [21] ,甚至可能引发其他不良反应,所以还需要大规模的研究来证明这些疗法的治疗效果和机制。目前更推荐使用非药物干预,如认知训练、心理干预和运动疗法等,仅当其他干预措施无效时才考虑使用药物治疗 [18]

2. 药物治疗

目前,并没有治疗CRCI的指南,临床所使用的药物都是基于临床经验所使用,很少有药物被证明可有效减少CRCI患者的认知障碍,因此需要有更大样本量的临床试验来评估这些药物的疗效。

2.1. 抗痴呆药物

中枢乙酰胆碱酶抑制剂多奈哌齐与兴奋性氨基酸受体拮抗剂美金刚,常用于改善阿尔兹海默病患者的认知功能,具有抗痴呆作用。Winocur等 [22] 在一项动物实验中使用多奈哌齐治疗经甲氨蝶呤和5-Fu联合使用诱导产生认知障碍的小鼠模型,结果证实化疗可对认知功能产生不利影响,并表明多哌奈齐可改善这种认知障碍。Lim [23] 等使用正电子放射断层扫描判断多哌奈齐对于化疗后认知障碍大鼠模型的影响,结果表明多奈哌齐增加了双侧额叶、顶叶和海马体的葡萄糖代谢,强化了化疗后认知障碍大鼠模型的记忆功能。在一些临床随机对照试验中,多哌奈齐被证明对CRCI是有效的,Lawrence [20] 等使用多哌奈齐治疗辅助化疗后1至5年有CRCI的女性乳腺癌患者,多哌奈齐在两个记忆参数明显优于对照组,而在其他认知功能、生活质量无明显差异。而在另一些设计更严谨的试验中,多哌奈齐并不是那么有效,Rapp [21] 等的研究表明,乳腺癌患者完成化疗后1~5年有记录的记忆问题,随机分配到24周每天一次5~10 mg多奈哌齐,在治疗结束时在记忆、其他认知功能或主观功能测试中的表现与随机分配到安慰剂组的表现没有不同。Sung [24] 等的研究表明美金刚通过调节小鼠的神经受损和验证来防止紫杉醇诱导的认知障碍。Nakamura [25] 等开展的Ⅱ期单臂试验的初步结果表明大多数接受乳腺癌化疗的患者服用美金刚,都表现出稳定或改善的认知能力。

2.2. 中枢神经系统兴奋剂

哌醋甲酯,可以阻断突出前神经对去甲肾上腺素和多巴胺的再摄取,据报道哌醋甲酯可改善认知障碍。Mar Fan [26] 等在一项纳入57名接受乳腺癌辅助化疗女性的随机对照研究中,使用哌醋甲酯进行防治认知功能减低,结果表明,在任何评估量表中,治疗组和对照组并无差异,没有证据表明哌醋甲酯可以改善认知障碍。莫达非尼,被认为是一种认知增强剂,一项随机对照研究表明其可以通过增强记忆和注意力来改善乳腺癌幸存这的认知能力,但这种改善仍需要进一步证实 [27]

2.3. 其他神经保护作用药

促红细胞生成素是一种有效的神经保护剂,可防止神经元凋亡,O’Shaughnessy等在一项随机对照试验中研究了其对于乳腺癌患者CRCI的影响,结果表明,促红细胞治疗组的EXIT25评分高于安慰剂,表明促红细胞生成素可能减轻乳腺癌辅助化疗期间大神的认知障碍。

Attia [28] 等人评估了银杏叶治疗后接受放疗的脑肿瘤患者的认知功能,发现在速度、执行功能和记忆力测试方面有显着改善。但是,该试验没有设计随机对照组。相应地,Barton等人进行的一项随机对照试验没有发现银杏叶能够改善CRCI [29]

褪黑素是一种有松果体分泌的生理性睡眠调节剂,一项随机对照试验证明了褪黑激素对神经可塑性过程的神经保护作用。它可以减少乳腺癌患者在辅助化疗期间的认知功能下降、睡眠质量受损和抑郁症状 [30]

2.4. 中医草药

在中医学中,并无认知障碍这一病名,根据其症状,可以将其当做癫病、脏躁和百合病来论治。李佩文教授治疗CRCI必先调养脾肾,以归脾汤合左归丸为基本方加减,后再加以温阳行气、开窍醒脑的中药,如淫羊藿、巴戟天、川芎、石菖蒲等,取得了很好的效果 [31] 。陈佳静等使用三阴方干预三阴性乳腺癌化疗脑,结果表明其可通过缓解化疗不适症状改善三阴性如新啊唉患者自我感知的认知障碍相关症状,对三阴性乳腺癌化疗相关认知障碍有预防作用 [32]

3. 非药物治疗

一项系统评价纳入了13项研究,涉及1138名受试者,评估了多项药物干预(中枢神经系统兴奋剂、促红细胞生成素α和银杏叶)和非药物干预(认知训练和身体活动)对于接受化疗的乳腺癌患者认知障碍的影响。此研究结果表明,非药物干预相比于药物干预,可更有效改善患者的认知障碍,提高患者的认知功能、记忆和语言能力 [33]

3.1. 认知行为治疗

认知行为治疗分为认知治疗和行为治疗,认知治疗主要通过教育、认知重建、角色转换等方式,有效矫正认知扭曲,帮助消除负面情绪和不合适的行为,改善睡眠质量和心理压力等症状。行为治疗类似于认知训练。主要鼓励患者进行放松训练、角色扮演、团体活动和行为阻断,使患者通过学习来学习适应行为,以减少认知障碍对生活质量的影响。Dos Santo [34] 等人组织的一项来探讨计算机辅助认知康复对CRCI影响的随机对照试验中显示,认知行为疗法改善了癌症患者的认知功能和生活质量。多项系统评价评估了多种非药物干预对于CRCI的治疗效果,他们最终发现,冥想、认知训练、认知康复和运动干预对CRCI的影响具有统计学意义,其中认知康复的提升最明显 [35] [36]

3.2. 运动锻炼

运动锻炼包括瑜伽、太极拳、八段锦、体育锻炼等,这些运动被证明可以增加脑血流量、增加神经可塑性,以改善CRCI。Reid-Arndt [37] 等人对23名女性癌症患者进行了为期10周的太极拳训练,发现她们的神经心理功能(包括注意力、记忆力、执行功能和处理速度)得到了显着改善。多项关于体育锻炼对乳腺癌女性CRCI影响的随机对照试验正在进行中 [38] [39] 。Koevoets [40] 等人在一项随机对照研究中发现,运动干预改善了乳腺癌化疗患者的认知障碍。魏小林 [41] 在她的研究中证明八段锦可改善化疗期乳腺癌患者认知功能及其生活治疗。

3.3. 正念疗法

正念疗法,是一种从坐禅、冥想、参悟等发展而来的一种精神训练方法,在这种精神训练中,强调需要有意识地觉察、将注意力集中于当下,但对当下的一切观念都不作分析、不作批判。通过正念的自我调节,可以减轻疲劳、疼痛和睡眠障碍。多项随机对照试验表明,正念疗法可以改善乳腺癌患者的焦虑、抑郁和疲劳,也能减轻化疗引起的认知功能的降低 [42] [43]

3.4. 针灸

针灸是中医疗法中的一种非常重要的治疗手段,通过将针插入人体特定部位(穴位),并施加振动、电流或其他形式的刺激,以达到治疗的目的 [44] 。在一篇关于非药物干预治疗CRCI的网络meta分析中,针灸在所有非药物干预中排在前列 [36] 。Zhang [45] 等使用电针三叉神经刺激加体针治疗乳腺癌患者CRCI,这种治疗可以减少化疗引起的工作记忆障碍、焦虑和食欲不振。Zeng [46] 等所开展的一项队列研究表明,针灸可通过降低脱髓鞘的减少和增强海马体神经元活力来改善妇科肿瘤患者的CRCI。

4. 讨论

乳腺癌患者经化疗治疗后有很大概率发生CRCI,虽然这种认知障碍是轻中度的,但其仍然困扰着乳腺癌患者,使乳腺癌患者的治疗进程和生活质量受到很大影响。而使用药物来治疗CRCI的疗效并不是非常明确,与非药物干预相比并无优势,且有副作用。因此,非药物干预被首选治疗CRCI,其中认知行为疗法应该广泛应用,其可明显改善CRCI。中医功法(如太极拳和八段锦)和针灸在治疗CRCI方面也有不错的效果。并且,应大量开展设计严谨的、大样本的随机对照试验以研究药物干预的有效性和安全性。

NOTES

*通讯作者。

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