维生素D缺乏与乳腺癌化疗致周围神经病变的相关性研究进展

Research advances on the association of vitamin D deficiency with chemotherapy-induced peripheral neuropathy in breast cancer

摘要

化疗是乳腺癌综合治疗中的重要组成部分，足量、按时完成化疗对改善患者预后具有关键意义。然而，化疗相关不良反应，尤其是化疗致周围神经病变（CIPN），可严重损害患者生活质量，甚至影响治疗依从性，目前尚缺乏公认有效的防治手段。近年来研究发现，维生素D缺乏可能是乳腺癌患者发生CIPN的重要危险因素。多项基础及临床研究提示，维生素D通过参与神经髓鞘形成、轴突修复、炎症调控及抗氧化应激等过程，在CIPN的发生发展中发挥潜在保护作用，补充维生素D有望降低CIPN发生风险并缓解症状。本文对乳腺癌CIPN的发病机制及维生素D缺乏与CIPN之间的相关性研究进展进行综述，并对维生素D补充的潜在临床价值与未来研究方向进行展望，以期为乳腺癌CIPN的预防与干预提供新的思路。

Abstract

Chemotherapy is a cornerstone of comprehensive treatment for breast cancer, and the administration of adequate doses on schedule is crucial for improving patient outcomes. However, chemotherapy-related adverse effects, particularly chemotherapy-induced peripheral neuropathy (CIPN), can substantially impair quality of life and compromise treatment adherence, while effective preventive or therapeutic strategies remain limited. Growing evidence indicates that vitamin D deficiency may represent an important risk factor for the development of CIPN in breast cancer patients. Experimental and clinical studies suggest that vitamin D may exert neuroprotective effects by promoting myelination, facilitating axonal regeneration, modulating inflammatory responses, and alleviating oxidative stress, thereby potentially reducing the incidence and severity of CIPN. This review summarizes current advances in the pathophysiological mechanisms of CIPN and the association between vitamin D deficiency and CIPN in breast cancer, and discusses the potential clinical implications of vitamin D supplementation, aiming to provide new insights into the prevention and management of CIPN.

关键词

乳腺肿瘤 / 维生素D缺乏 / 周围神经系统疾病 / 化疗反应 / 综述

Key words

Breast Neoplasms / Vitamin D Deficiency / Peripheral Nervous System Diseases / Chemotherapy Side Effects / Review

乳腺癌是女性最常见的恶性肿瘤之一，发病率占全球11.6% ^[1]。乳腺癌的临床治疗方案的制定遵循个体化原则^[2]，即根据不同的病理分期及分子亚型制定不同的手术、化疗、内分泌治疗、靶向治疗及放疗等方案^[3-4]。其中，化疗发挥重要作用，可以减少患者乳腺癌复发、转移和死亡的发生率，但是化疗带来的不良反应也不容忽视。化疗引起的周围神经病变（chemotherapy-induced peripheral neuropathy，CIPN）是主要的不良反应之一，以麻木、疼痛、灼烧感、四肢“袜套”感等感觉异常为表现。这些症状通常可在化疗结束后很长时间仍存在^[5]。化疗还可以通过影响感觉编码而引起共济失调^[6]，使患者的基本劳动能力减弱或丧失，甚至无法行走，严重影响患者的生活质量，还可能会降低其对治疗的依从性^[7]。目前有关乳腺癌CIPN的影响因素及作用机制尚未清楚，但有研究表明其可能与维生素D缺乏相关，补充维生素D对缓解CIPN有一定作用^[7]。

1 乳腺癌CIPN概述

化疗作为乳腺癌的不可或缺的治疗方法已获得全球认可。乳腺癌患者通常使用包含铂类化合物、长春花生物碱、紫杉烷类、蛋白酶体抑制剂和免疫调节剂等药物的化疗方案^[8-10]，在治疗过程中可能会面临CIPN^[11]。CIPN是一种剂量限制性副作用，通常与各种类型的化疗药物相关。其中铂类药物和紫杉烷类药物是神经毒性最强的类别^[8]。不同药物导致的CIPN发生率各异：奥沙利铂约50%~75%，顺铂17%~100%，长春新碱约35%~45%，紫杉醇约57%~83%^[12-14]。乳腺癌化疗患者CIPN发生率较高，这类化疗不良反应已引起国内外研究者的关注。李若琳等^[15]在401例乳腺癌化疗患者的研究中，得出CIPN发生率约为77.6%，且70.1%的患者出现感觉异常，11.8%的患者出现运动异常。在赵芳等^[16]收集的305例乳腺癌化疗患者中，发生CIPN共211例，占69.18%。丹麦一项前瞻性研究^[17]表明，44.8%接受多西他赛辅助治疗的乳腺癌患者在开始化疗1年后仍存在CIPN症状。此外，乳腺癌患者发生CIPN可能与年龄、高血压史、化疗药物累积剂量、肝功能异常、化疗前贫血、输注时间>30 min、体质量指数（BMI）≥24 kg/m²、焦虑、抑郁、睡眠时相、疲劳、缺乏陪护、运动量低、社交能力低、糖尿病史、营养风险筛查2002（nutritional risk screening 2002，NRS 2002）、甘油三酯升高等因素相关^[18-20]。相关研究发现，维生素D缺乏也是乳腺癌化疗患者发生CIPN的高危因素^[7,21-22]，但目前确切有效的治疗手段仍需进一步探索。

由此可见，乳腺癌患者CIPN对患者的生活质量造成严重影响，寻找CIPN的影响因素对临床防治策略有着重要意义。

2 维生素D对周围神经系统的作用

维生素D是人体正常代谢所必需的维生素之一，在维持钙磷平衡、调节免疫反应以及促进细胞分化和抑制细胞增殖等众多过程中发挥着关键作用。维生素D与多种疾病相关，包括骨骼疾病、糖尿病、心血管疾病和多种癌症等^[23]。维生素D缺乏与乳腺癌CIPN的发生风险增加相关。乳腺癌化疗方案大部分包含铂类或紫杉烷类，Jennaro等^[21]的研究报道，维生素D缺乏的乳腺癌患者使用紫杉醇后发生CIPN的风险更高。Chen等^[7]通过小鼠实验表明，维生素D缺乏直接导致神经毒性，并增加对紫杉醇神经毒性的敏感性。Chakraborty等^[22]发现维生素D缺乏及维生素D受体（vitamin D receptor，VDR）基因的FokI多态性增加了北印度女性患乳腺癌的风险。关于维生素D在周围神经系统中的作用机制已有较多研究，这些发现为理解维生素D在乳腺癌CIPN发生中的作用提供了启示，其主要包括：促进髓鞘形成、神经元分化、少突胶质细胞增殖^[24]，减少脱髓鞘，诱导轴突再生^[25-26]。维生素D可改善轴突生长和感觉反应，促进电生理恢复；通过上调VDR和下调I型钙通道提供神经保护^[27]；并与疼痛相关通路[神经生长因子、胶质源性神经营养因子、表皮生长因子受体和阿片受体]存在潜在相互作用^[28]。VDR缺失导致髓鞘形成减少；而维生素D能增加施万细胞中髓鞘碱性蛋白的表达，从而减少脱髓鞘^[29]。VDR激活在脱髓鞘模型中可增加髓鞘蛋白、减少脱髓鞘、促进轴突生长、神经干细胞分化迁移及髓鞘再生^[30]，并通过减少小胶质细胞活化和巨噬细胞浸润促进此过程^[31]。除神经修复作用外，维生素D还能降低血浆炎症和疼痛相关细胞因子水平，从而缓解慢性肌肉疼痛^[32]。补充维生素D可增加神经细胞中神经生长因子表达并降低炎症因子^[33]。此外，它还能激活抗氧化途径，提高谷胱甘肽水平，保护少突胶质细胞和神经传导通路完整性^[34]。

综上，维生素D在神经系统稳态的维护及缓解神经损伤相关性疼痛具有积极作用^[26]，对进一步研究维生素D治疗乳腺癌CIPN有一定指导意义。

3 维生素D与乳腺癌CIPN相关

乳腺癌患者化疗后发生CIPN的概率较高。CIPN的出现及加重使约25%的患者需要中断、延迟甚至停止化疗，而乳腺癌化疗疗效的保证，建立在给药足量按时的基础之上^[21]。Chen等^[7]回顾性分析发现，在1 191例乳腺癌患者中，化疗前有维生素D缺乏者为33.3%，其中17.1%出现3级及以上的感觉神经病变或运动神经病变。Grim等^[35]对70例接受紫杉醇化疗的患者进行危险因素分析，发现CIPN组患者的血清维生素D水平显著低于无CIPN组。一项采用秩相关分析的研究^[34]表明，较高的维生素D水平与紫杉醇诱导的神经性疼痛发生概率降低相关。病例报告^[7]显示，维生素D缺乏患者在使用硼替佐米后出现CIPN，经每天补充3 000 IU维生素D及物理治疗后，神经痛症状得到改善。Zirpoli等^[36]调查了1 225例接受紫杉醇治疗的乳腺癌患者，关注其诊断及治疗前和治疗6个月后的维生素及其他补充剂使用情况，发现补充多种维生素合剂可降低CIPN发生风险。

此外，研究人员^[37]通过回顾性分析186例接受含85 mg/m²或130 mg/m²的奥沙利铂化疗方案治疗的结直肠、胃癌或胰腺癌患者，发现维生素D水平与2~3级的CIPN相关。Wang等^[38]对111例接受硼替佐米和/或沙利度胺治疗至少12周的多发性骨髓瘤患者进行分析，结果显示CIPN的严重程度与较低的维生素D水平相关。

以上研究证实，维生素D缺乏患者发生CIPN的概率更高，补充维生素D可降低CIPN发生风险。但以上研究仍存在一定的设计缺陷，如病例数量少、未设置无补充剂的对照组，未设置不同维生素D补充剂剂量等。二者相关性的研究尚处于探索阶段，仍缺乏大数据支持。

4 讨论与展望

4.1 CIPN的发病机制

乳腺癌CIPN作为一种常见且严重的治疗相关并发症，鉴于其不仅显著影响患者的生活质量，更因其缺乏特效治疗方案而成为临床工作的痛点^[39]，深入研究CIPN的发病机制对于开发新的预防和治疗策略十分重要。乳腺癌CIPN有急性和慢性之分。急性CIPN症状往往在给药后短时间出现，但可在几天内快速消失；慢性CIPN则是在化疗药物积累后出现，需要长时间缓解，甚至可能伴随终生。急性CIPN和慢性CIPN的发病机制有所不同。

急性CIPN的机制主要涉及离子通道功能改变、神经胶质细胞活化和转运蛋白作用。其中离子通道改变是核心：化疗药可减慢轴突Na⁺通道失活、降低Na⁺电流幅度^[40-41]、激活Kv7通道可减少感觉神经元放电 ^[42-43]、增强T型Ca²⁺通道电流致神经元兴奋^[44]、增加Cav3.2蛋白^[45]、升高脊髓后根神经节（dorsal root ganglion，DRG）中瞬时受体电位V1、瞬时受体电位A1和瞬时受体电位阳离子通道M8的敏感度及mRNA水平从而导致周围神经痛^[46]。胶质细胞活化：化疗药物激活外周胶质细胞，释放促炎因子致神经元敏化，如紫杉醇通过Toll样受体4活化小胶质/星形胶质细胞，释放促炎因子^[47-48]。转运蛋白：有机阳离子转运蛋白调节铂类在DRG积累，诱导急性CIPN^[40]。综上，急性CIPN机制涉及离子通道、胶质细胞活化及转运蛋白。

慢性CIPN机制更复杂，主要涉及核DNA损伤、线粒体损伤、氧化应激、信号通路和神经炎症。核DNA损伤：铂类易在缺乏血－神经屏障的DRG中积累（受铜转运蛋白和有机阳离子转运蛋白、多药和毒素排除蛋白1等转运蛋白调节），形成DNA加合物诱导损伤^[49-50]。DRG神经元过表达miR-15b等微小RNA亦可致痛^[51-52]。线粒体损伤与氧化应激：化疗药结合线粒体DNA，抑制转录复制，导致形态功能异常、ATP生成减少及过量活性氧（reactive oxygen species，ROS）产生^[53]。ROS介导氧化应激，通过调控如瞬时受体电位A1等通道致痛和促进神经炎症^[54-55]。神经炎症：化疗药增加外周免疫细胞（如CD4⁺/CD8⁺ T细胞）及炎症因子（如白介素4），升高神经炎症标志物活化转录因子3水平^[56]。神经损伤后，小胶质细胞释放肿瘤坏死因子和白介素1，刺激星形胶质细胞激活释放趋化因子C-C基序趋化因子配体2和C-C基序趋化因子配体3^[5]通过促进突触传递来增强慢性疼痛。信号通路：caspase、MAP kinases、ERK1/2早期激活促进DRG神经元凋亡^[41]。紫杉醇还可激活C5aR1进而激活NF-κB/P38通路致痛^[5]。中枢变化如奥沙利铂诱导丘脑/中脑导水管周围灰质PKC-γ上调和γ/ε亚型磷酸化增加来增强痛觉过敏^[57]。

急、慢性CIPN机制虽不同，但均反映化疗药作用于神经系统后引起细胞因子/炎症介质改变导致感觉异常。因此，探究维生素D是否与上述关键因子或通路存在相互作用，可能为阐明其缓解乳腺癌CIPN的机制提供重要线索，并为CIPN的预防和治疗策略开发新思路。

4.2 维生素D补充推荐剂量

维生素D作为维持高等动物生命所必需的营养素^[58]，其缺乏状态（25-羟基维生素D<20 ng/mL）已被证实与乳腺癌CIPN风险增加相关^[21]。因此，明确有效的维生素D补充方案，尤其是具体的推荐剂量，成为临床实践中亟待解决的问题。目前，针对乳腺癌化疗患者CIPN防治的维生素D补充剂量尚无统一标准。欧洲临床营养与代谢协会指南推荐维生素D缺乏患者每天补充4 000~5 000 IU（100~125 μg），持续2个月，以使血清25-羟基维生素D水平达到40~60 ng/mL^[59]。Pludowski等^[60]通过大规模随机对照试验证实，每天2 000 IU（50 μg）的剂量既能有效预防又能治疗成年人的维生素D缺乏，同时建议根据个体情况在800~2 000 IU（20~50 μg）范围内调整剂量，并定期监测血清水平以避免不足或过量。对于需要快速纠正缺乏状态的患者，可在治疗初期4~12周采用6 000 IU/d的高剂量方案，后续转为800~2 000 IU/d的维持剂量。而高风险人群如吸收不良综合征患者应在治疗6~12周后复查评估疗效^[61]。在预防方面，Na等^[62]建议普通成人补充600 IU/d（上限4 000 IU），70岁以上老年人800 IU/d，而美国内分泌学会则推荐更高的1 500~2 000 IU/d剂量（成人上限10 000 IU/d）。最新研究探索了维生素D在多发性骨髓瘤患者中的应用，采用20 000 IU负荷剂量联合800~3 200 IU/d维持剂量的方案可显著提升维生素D水平并改善神经性疼痛症状，且维生素D₃效果优于维生素D₂^[63]。但这些发现是否能运用在乳腺癌患者化疗前后以防治CIPN，仍需更大规模的验证性临床研究支持。赵芳、Sánchez-Barroso等^[16,64]通过单因素及多因素分析发现年龄≥65岁是乳腺癌CIPN的危险因素。随着患者年龄的增加神经系统会退化，且免疫功能下降，更易被化疗药物的损害^[16]。乳腺癌患者年龄每增加1岁，发生3级神经病变的风险增加5%^[64]。值得探讨的是，不同年龄分层的乳腺癌患者对维生素D补充剂量的需求是否存在差异。此外，目前尚无研究比较补充维生素D对急性与慢性CIPN的疗效差异。这些均是未来潜在的研究方向。

综上所述，乳腺癌CIPN关系到患者给药的足量性和治疗的依从性以及治疗结束后患者长期的生活质量。发现和验证一种预测性强且易于纠正的生物标志物可以减少患者继发于CIPN的痛苦，最大限度地提高治疗获益^[20]。维生素D缺乏与CIPN发生有相关性，化疗前补充维生素D可能成为预防和治疗CIPN发生的最经济有效的措施。目前包括欧洲内科肿瘤学会等重要的肿瘤治疗指南都把患者生活质量的评估列入肿瘤整体临床获益评估体系，因此希望更多医务工作者能够重视治疗相关性CIPN的发生并通过本文为大家探索CIPN的防治提供参考。

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基金资助

广西壮族自治区医疗卫生适宜技术开发与推广应用基金资助项目(S2020068)

广西壮族自治区医疗卫生重点培育学科建设基金资助项目(桂卫医发〔2022〕17号)

广西壮族自治区卫生健康委自筹经费科研基金资助项目(Z-C20240195)