Scan for full text
Cite this article
Objective: To observe the clinical effect of Yiqi Wenyang Tongmai Formula on the patients with chemotherapy induced peripheral neuropathy (CIPN).
The randomized controlled trial was carried out. A total of 135 patients with CIPN were selected and randomly divided into the observation group (69 cases) and the control group (66 cases). The patients in the observation group were orally reated with Yiqi Wenyang Tongmai Formula and the patients in the control group were orally treated with mecobalamin tablets, with a course of 2 months. Before and after treatment, the Chinese medical symptom scores of the two groups were compared. The curative effects on Chinese medical syndrome and the improvement of peripheral neuropathy classification in the two groups were evaluated. Before and after treatment, the sensory nerve conduction velocity (SNCV) and motor nerve conduction velocity (MNCV) of median nerve and sural nerve of patients in the two groups were measured and compared. The total neuropathy score (TNS) scale was used to evaluate the peripheral nerve injury. The life quality of the patients was evaluated by FACT/GOG-Ntx scale.
During the study, 2 cases in the observation group and 5 cases in the control group were excluded, finally 67 cases in the observation group and 61 cases in the control group were included in the statistical analysis. ①After treatment, the symptom scores of hand and foot numbness, pain, fear of cold and fatigue in the observation group were significantly decreased compared with those before treatment (P<0.05), the symptom scores of hand and foot numbness and pain in the control group were also decreased compared with those before treatment (P<0.05), and the symptom scores of hand and foot numbness, pain, fear of cold and fatigue in the observation group were lower than those in the control group (P<0.05). ②After treatment, the total effective rate on Chinese medical syndrome was 46.27% in the observation group and 19.67% in the control group, and the effect of the observation group was better than that of the control group (P<0.05). ③After treatment, the total effective rate on the improvement of peripheral neuropathy classification was 85.07% in the observation group and 80.33% in the control group, and the curative effect of the observation group was better than that of the control group (P<0.05). ④After treatment, the SNCV and MNCV of median nerve and sural nerve in the two groups were significantly faster than those before treatment (P<0.05), and the SNCV and MNCV of median nerve and sural nerve in the observation group were also significantly faster than those in the control group (P<0.05). ⑤After treatment, the scores of TNS scale in the two groups were decreased compared with those before treatment (P<0.05), and the score of the observation group was lower than that of the control group (P<0.05). ⑥After treatment, the scores of FACT/GOG-Ntx scale in the two groups were decreased compared with those before treatment (P<0.05), and the score of the observation group was lower than that of the control group (P<0.05).
Compared with mecobalamin, Yiqi Wenyang Tongmai Formula can better improve the clinical symptoms and the peripheral neuropathy of the patients with CIPN, increase the peripheral nerve conduction velocity, thus improve the quality of life and enhance the confidence and compliance of the patients in the treatment of cancer.
化学药物治疗是恶性肿瘤治疗的主要手段,很多患者可得到治愈。然而,化疗药物作为一把双刃剑,其副反应往往制约着临床应用。化疗致周围神经病变(chemotherapy induced peripheral neuropathy,CIPN)是化疗药物常见的毒副反应之一,临床症状包括手足的感觉障碍、麻木、疼痛、刺痛或冷过敏及自主神经系统的运动减弱或障碍。CIPN的发病机制、严重程度、发病概率等因化疗药物的种类及蓄积剂量不同而具有差异[
1.1.1 西医诊断标准
参照美国国立癌症研究所通用毒性判定标准(NCI-CTCAE v3.0)中关于化疗药物致周围神经损伤的分级[
1.1.2 中医辨证标准
根据《实用中医内科学》[
1.2.1 纳入标准
①化疗后产生周围神经损伤症状的患者,符合上述周围神经损伤Ⅰ~Ⅳ级诊断;②结束化疗的患者;③年龄>18岁且<80岁;④Karnofsky功能状态(Karnofsky’s performance status,KPS)评分在50分以上;⑤预计生存期≥6个月;⑥各项生化指标达标,无严重器质性损害及凝血、造血功能障碍;⑦患者依从性佳,了解治疗过程,接受并签署知情同意书。
1.2.2 排除标准
①心、脑、肝、肾等重要脏器合并损伤或造血、凝血系统功能障碍的患者;②有多种药物过敏史或过敏体质患者;③伴有其他神经系统疾病,可能影响疗效判定者;④精神病患者。
1.2.3 剔除、脱落标准
①误纳入者;②入组后治疗中接受了其他相关治疗措施者;③依从性差,未按既定治疗方案治疗者;④缺乏完整资料,无法判定疗效者;⑤观察期间出现严重病情变化者;⑥脱落或失访者。
纳入病例为2018年10月至2021年2月在上海中医药大学附属龙华医院肿瘤二科住院或在特需门诊就诊的CIPN患者,共计135例,采用随机数字表将纳入患者随机分为观察组69例和对照组66例。本课题已通过上海中医药大学附属龙华医院伦理委员会批准,批准号:2018-063。
对照组患者给予甲钴胺[卫材(中国)药业有限公司,规格:0.5 mg/片,批号:1806062]口服,每次1片,每日3次,连续服用2个月。观察组患者给予中药复方益气温阳通脉方口服。益气温阳通脉方组成:黄芪30 g,桂枝9 g,全蝎3 g,川芎15 g(中药饮片由上海中医药大学附属龙华医院中药房提供)。煎煮及服用方法:中药由龙华医院中药房代煎,药材按配伍比例加入煎药机,冷水浸泡1 h后,煎煮30 min,滤出药液;加水再煎,将2次的药液合并、分装。每袋150 ml,患者每次服用1袋,每日2次,于早餐及晚餐后30 min温服,连续服用2个月。嘱所有患者注意保暖,避免接触寒冷物品或进食生冷食物。
1.5.1 中医证候疗效评价
参照《中药新药临床研究指导原则(试行)》[
1.5.2 周围神经病变分级改善疗效评价
参照NCI-CTCAE v3.0[
1.5.3 周围神经传导速度测定
治疗前后,采用NDI-092神经肌电图仪(上海海神医疗电子仪器有限公司)测定正中神经和腓肠神经的感觉神经传导速度(sensory nerve conduction velocity,SNCV)、运动神经传导速度(motor nerve conduction velocity,MNCV),传导速度越快提示周围神经功能损伤程度越轻。
1.5.4 周围神经损伤情况评价
采用总神经病变评分(total neuropathy score,TNS)[
1.5.5 生活质量评估
采用美国癌症治疗功能评价系统(FACT)针对肿瘤患者神经毒性拟定的生活质量评价量表FACT/GOG-Ntx量表[
所有数据均采用SPSS 25.0软件进行统计分析。计量资料以ˉx±s表示,符合正态分布者采用t检验,不符合正态分布者采用秩合检验;计数资料用例数和百分比表示,非等级资料采用χ2检验,等级资料采用CMH χ2检验。以P<0.05为差异有统计学意义。
研究中,观察组和对照组因疾病进展分别剔除2例、5例患者,最终纳入统计分析者观察组67例、对照组61例。两组患者的年龄、性别构成、肿瘤类型、肿瘤分期、使用化疗药物及治疗前的周围神经毒性分级等资料比较,差异均无统计学意义(P>0.05),具有可比性。见
项目 | 观察组(n=67) | 对照组(n=61) |
---|---|---|
年龄(ˉx±s,岁) | 60.76±9.49 | 61.20±9.97 |
性别(男/女,例) | 34/33 | 29/32 |
肿瘤类型(例) | ||
肺癌 | 31 | 27 |
食管及胃癌 | 7 | 4 |
结直肠癌 | 11 | 8 |
乳腺及妇科肿瘤 | 12 | 16 |
其他 | 6 | 6 |
使用化疗药物(例) | ||
铂类 | 58 | 51 |
紫杉醇 | 15 | 17 |
嘧啶类 | 30 | 20 |
长春新碱 | 5 | 5 |
肿瘤TNM分期(例) | ||
Ⅰ~Ⅲ期 | 60 | 56 |
Ⅳ期 | 7 | 5 |
周围神经毒性分级(例) | ||
0级 | 0 | 0 |
Ⅰ级 | 25 | 20 |
Ⅱ级 | 31 | 33 |
Ⅲ级 | 9 | 7 |
Ⅳ级 | 2 | 1 |
2.2.1 中医症状积分
治疗前,两组患者的各项症状积分比较,差异均无统计学意义(P>0.05)。治疗后,观察组患者的手足麻木、疼痛、怕冷、神疲乏力症状积分较治疗前均明显降低(P<0.05),对照组患者的手足麻木、疼痛症状积分较治疗前亦降低(P<0.05),且观察组患者的手足麻木、疼痛、怕冷、神疲乏力症状积分均低于对照组(P<0.05)。见
组 别 | 观察 时点 | 手足麻木 | 疼痛 | 怕冷 | 神疲乏力 |
---|---|---|---|---|---|
观察组 (n=67) | 治疗前 | 4.10±1.07 | 2.66±1.01 | 2.30±0.65 | 2.15±0.61 |
治疗后 | 2.39±1.56*# | 1.64±1.18*# | 1.84±0.67*# | 1.70±0.60*# | |
对照组 (n=61) | 治疗前 | 4.39±1.14 | 2.98±1.01 | 2.33±0.63 | 2.18±0.70 |
治疗后 | 3.51±1.19* | 2.59±0.92* | 2.26±0.66 | 2.13±0.62 |
注: 与本组治疗前比较,*P<0.05;与对照组治疗后比较,#P<0.05
2.2.2 中医证候疗效
治疗后,观察组患者的中医证候疗效总有效率为46.27%,对照组为19.67%,观察组的疗效优于对照组(P<0.05)。见
组 别 | n | 临床治愈 | 显效 | 有效 | 无效 | 总有效率(%) |
---|---|---|---|---|---|---|
观察组 | 67 | 0(0) | 12(17.91) | 19(28.36) | 36(53.73) | 46.27 |
对照组 | 61 | 0(0) | 0(0) | 12(19.67) | 49(80.33) | 19.67 |
治疗后,观察组患者的周围神经病变分级改善疗效总有效率为85.07%,对照组为80.33%,观察组的疗效优于对照组(P<0.05)。见
组 别 | n | 临床治愈 | 显效 | 有效 | 无效 | 总有效率(%) |
---|---|---|---|---|---|---|
观察组 | 67 | 18(26.87) | 21(31.34) | 18(26.87) | 10(14.93) | 85.07 |
对照组 | 61 | 1(1.64) | 15(24.59) | 33(54.10) | 12(19.67) | 80.33 |
治疗前,两组患者的正中神经、腓肠神经的SNCV、MNCV比较,差异无统计学意义(P>0.05)。治疗后,两组患者的正中神经、腓肠神经的SNCV、MNCV较治疗前均明显增快(P<0.05),且观察组患者的正中神经、腓肠神经的SNCV、MNCV较对照组亦明显增快(P<0.05)。见
组 别 | 观察时点 | SNCV(正中) | SNCV(腓肠) | MNCV(正中) | MNCV(腓肠) |
---|---|---|---|---|---|
观察组 (n=67) | 治疗前 | 41.09±4.04 | 39.09±4.42 | 43.92±6.02 | 37.06±3.53 |
治疗后 | 46.39±4.49**# | 44.20±6.28**## | 50.50±4.44**## | 42.07±6.82**## | |
对照组 (n=61) | 治疗前 | 41.80±4.04 | 38.27±1.99 | 45.45±5.34 | 36.51±2.11 |
治疗后 | 44.00±7.31* | 40.57±5.72** | 47.86±5.94** | 39.12±5.49** |
注: 与本组治疗前比较,*P<0.05,**P<0.01;与对照组治疗后比较,#P<0.05,##P<0.01
治疗前,两组患者的TNS量表评分比较,差异无统计学意义(P>0.05)。治疗后,两组患者的TNS量表评分较治疗前均降低(P<0.05),且观察组患者的评分低于对照组(P<0.05)。见表6。
组 别 | n | 治疗前 | 治疗后 |
---|---|---|---|
观察组 | 67 | 13.61±3.17 | 8.54±3.64*# |
对照组 | 61 | 13.95±3.61 | 12.03±3.27* |
注: 与本组治疗前比较,*P<0.05;与对照组治疗后比较,#P<0.05
治疗前,两组患者的FACT/GOG-Ntx量表评分比较,差异无统计学意义(P>0.05)。治疗后,两组患者的FACT/GOG-Ntx量表评分较治疗前均降低(P<0.05),且观察组患者的评分低于对照组(P<0.05)。见
组 别 | n | 治疗前 | 治疗后 |
---|---|---|---|
观察组 | 67 | 21.90±2.49 | 19.73±2.61*# |
对照组 | 61 | 22.13±2.80 | 21.08±2.66* |
注: 与本组治疗前比较,*P<0.05;与对照组治疗后比较,#P<0.05
恶性肿瘤患者往往需坚持长期治疗,而CIPN是化疗药物引起的常见不良反应之一,具有潜在的致残可能性,导致患者生活质量下降,给患者长期治疗带来严重困扰。临床上,CIPN多在患者接受铂类、紫杉醇类、长春碱类及蛋白酶抑制剂硼替佐米、沙利度胺等化疗方案后发生,以铂类药物最常见,有时CIPN甚至成为化疗失败的主要原因[
在中医学中,根据CIPN的临床表现,可将其归属于“痹证”范畴。徐振晔教授认为,化疗药物属大毒大寒之品,久用耗伤人体气血,气虚一则使化生精血不足,难以濡养四肢末梢,二则不能帅血以行周身,以致气虚血瘀,血虚则不能温养四末,加之余毒滞留肢体关节四末,五脏功能失调,阳气不达末梢,寒凝血脉,从而出现手足不仁或麻木、疼痛、畏寒怕冷等“痹证”表现。恶性肿瘤患者精气亏虚,癌毒稽留,再遇化疗之大毒,致气血重伤,而犯虚虚之弊。化疗药物之余毒沉积四末,阻碍气血运行,精气亏虚,无力帅血运行,而致血瘀,四末皮肉筋脉失荣,以致肢端麻木、疼痛及怕冷畏寒、神疲乏力等症。徐教授通过长期临证,结合该病病理、生理特点,从精气亏虚、血瘀寒凝立论组方,拟定益气温阳通脉方。该方以黄芪、桂枝益气温阳为君药;臣以全蝎温经通络止痛、攻毒散结;川芎为佐使药,行气活血,既助黄芪帅气行血,又辅全蝎活血止痛。全方贵在短小精悍,君、臣、佐、使共4味药,在药物的选择上,体现了徐教授深厚的理论基础与临床经验。《中华人民共和国药典(2015年版:一部)》记载,黄芪“味甘,性微温;归肺、脾经。具有补气升阳,固表止汗,利水消肿,生津养血,行滞通痹,托毒排脓,敛疮生肌之功效。用于气虚乏力……血虚萎黄,半身不遂,痹痛麻木,痈疽难溃,久溃不敛”[
本研究结果显示,中药复方益气温阳通脉方可有效改善CIPN患者的临床症状和周围神经损伤状况,提高患者的生活质量,从而增加了患者抗癌治疗的信心和依从性。CIPN是目前临床关注的热点之一,本研究所采用的中药自拟方短小精悍,在临床中应用多年,疗效较佳,其优势体现在药味的精简及虫类药的使用等方面。针对CIPN的治疗,西医目前尚无确切有效的药物,临床使用甲钴胺治疗较为普遍[
LICHT T, KEILANI M, CRENENNA R. Chemotherapy-induced peripheral neuropathy (CIPN)[J]. Memo, 2021, 14(2):34-38. [Baidu Scholar]
LU Y T, ZHANG P, ZHANG Q Y, et al. Duloxetine Attenuates Paclitaxel-Induced Peripheral Nerve Injury by Inhibiting p53-Related Pathways[J]. J Pharmacol Exp Ther, 2020, 373(3):453-462. [Baidu Scholar]
YANG Y, HU L, WANG C Y, et al. p38/TF/HIF-α Signaling Pathway Participates in the Progression of CIPN in Mice[J]. Biomed Res Int, 2019(397):1-11. [Baidu Scholar]
KAWASHIRI T, MINE K, KOBAYASHI D, et al. Therapeutic Agents for Oxaliplatin-Induced Peripheral Neuropathy; Experimental and Clinical Evidence[J]. Int J Mol Sci, 2021, 22(3):1393-1417. [Baidu Scholar]
饶志璟, 邓海滨, 祝利民, 等. 化疗药物所致周围神经毒性中西医研究进展[J]. 世界科学技术-中医药现代化, 2020, 22(4): 1307-1314. [Baidu Scholar]
苏婉, 徐振晔. 活血温阳通痹法治疗化疗致周围神经毒性临床观察[J]. 上海中医药大学学报, 2019, 33(4): 39-42. [Baidu Scholar]
师悦. 通络蠲痹汤外洗防治化疗药物致周围神经毒性的临床研究[D]. 合肥:安徽中医药大学, 2017. [Baidu Scholar]
XIONG Z F, WANG T, GAN L, et al. Clinical efficacy of acupoint injection for chemotherapy-induced peripheral neuropathy of patients with breast cancer[J]. World J Acupunct Moxibustion, 2016, 26(2): 20-24. [Baidu Scholar]
乔雪蕾. 当归四逆汤合身痛逐瘀汤联合中药外洗治疗化疗后周围神经病变临床研究[D]. 保定: 河北大学,2019. [Baidu Scholar]
易嘉雯, 林丽珠, 董家辉. 外用和血通脉方治疗抗肿瘤化疗药所致周围神经毒性的临床疗效观察[J]. 中医临床研究, 2017, 9(3): 49-51. [Baidu Scholar]
戴黎颖. 针灸治疗化疗所致周围神经病变临床研究的Meta分析[D]. 广州:广州中医药大学, 2019. [Baidu Scholar]
National Cancer Institute, National Institutes of Health, US Department of Health and Human Services. Common terminology criteria for adverse events v3.0 (CTCAE)[S/OL]. (2006-08-09)[2021-03-03]. http://ctep.cancer.gov/protocol development/electronic applications/docs/ctcaev3.pdf. [Baidu Scholar]
王永炎, 严世芸. 实用中医内科学[M]. 2版. 上海:上海科学技术出版社, 2009: 1926-1933. [Baidu Scholar]
郑筱萸. 中药新药临床研究指导原则(试行)[M]. 北京:中国医药科技出版社, 2002: 81-85. [Baidu Scholar]
上海市卫生局. 上海市中医病证诊疗常规[M]. 2版. 上海:上海中医药大学出版社, 2003. [Baidu Scholar]
CAVALETTI G, FRIGENI B, LANZANI F, et al. The Total Neuropathy Score as an assessment tool for grading the course of chemotherapy-induced peripheral neurotoxicity: comparison with the National Cancer Institute-Common Toxicity Scale[J]. J Peripher Nerv Syst, 2007, 12(3): 210-215. [Baidu Scholar]
CASTELINO S M, RODDAY A M, PEI Q, et al. Performance of FACT-GOG-Ntx to assess chemotherapy-induced peripheral neuropathy (CIPN) in pediatric Hodgkin lymphoma (HL) patients[J]. J Clin Oncol, 2019, 37(15suppl): 10064. [Baidu Scholar]
HOU S, HUH B, KIM H K, et al. Treatment of Chemotherapy-Induced Peripheral Neuropathy: Systematic Review and Recommendations[J]. Pain Physician, 2018, 21(6): 571-592. [Baidu Scholar]
GREENWALD M K, RUTERBUSCH J J, BEEBE-DIMMER J L, et al. Risk of incident claims for chemotherapy-induced peripheral neuropathy among women with breast cancer in a Medicare population[J]. Cancer, 2019, 125(2): 269-277. [Baidu Scholar]
李世东, 石建华, 李学记. 甲钴胺联合谷胱甘肽防治消化系统肿瘤患者FOLFOX4方案化疗所致的神经毒性反应[J]. 中华肿瘤杂志, 2016, 38(8): 632-635. [Baidu Scholar]
SMITH E M, PANG H, CIRRINCIONE C, et al. Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: a randomized clinical trial[J]. JAMA, 2013, 309(13): 1359-1367. [Baidu Scholar]
魏晓晨, 朱立勤, 王春革, 等. 维生素类药物预防化疗致周围神经毒性的疗效及安全性的Meta分析[J]. 中国现代应用药学, 2016, 33(4): 476-484. [Baidu Scholar]
国家药典委员会. 中华人民共和国药典(2015年版):一部[M]. 北京:中国医药科技出版社,2015:152-153, 302-303. [Baidu Scholar]
白海英, 张凯雪, 包芳, 等. 黄芪和红芪对比研究进展[J]. 西北药学杂志, 2020, 35(3): 460-466. [Baidu Scholar]
俞春林, 杜正彩, 郝二伟, 等. 四类不同功效桂枝药对化学成分与药理作用的研究进展[J]. 中国实验方剂学杂志, 2020, 26(1): 226-234. [Baidu Scholar]
杨志欣, 汲丽丽, 刘慧, 等. 全蝎化学成分和药理作用的研究进展[J]. 中南药学, 2020, 18(9): 1523-1529. [Baidu Scholar]
张晓娟, 张燕丽, 左冬冬. 川芎的化学成分和药理作用研究进展[J]. 中医药信息, 2020, 37(6): 128-133. [Baidu Scholar]
赵孟煜. 自拟益气祛瘀通络方治疗奥沙利铂导致周围神经毒性(气虚血瘀型)的临床研究[D]. 福州: 福建中医药大学, 2019. [Baidu Scholar]
王世昌, 陈朝. 活血通痹方联合甲钴胺注射液治疗胃肠肿瘤化疗致周围神经病变的疗效观察[J]. 中国实用神经疾病杂志, 2014, 17(7): 96-97. [Baidu Scholar]
李海金, 陈亚男, 董良, 等. 中药熏洗联合甲钴胺治疗化疗致周围神经病变临床观察[J]. 浙江中西医结合杂志, 2019, 29(4): 298-301. [Baidu Scholar]
120
Views
624
Downloads
0
CSCD
15
CNKI Cited
Related Articles
Related Author
Related Institution