●临床研究●
多西紫杉醇联合表柔比星序贯化疗对局部进展期
乳腺癌的临床疗效观察
邵 华1,姜 磊2*,张 华3,李白艳1,王媛媛1
(医科大学第一附属医院 1影像中心,2神经外科,3肿瘤科, 乌鲁木齐,8300)
摘要:目的 探讨多西紫杉醇联合表柔比星序贯化疗对局部进展期乳腺癌的临床疗效。方法 选取2014年1月-2018年1月我院收治的120例局部进展期乳腺癌患者,按照随机数字表法平均分为两组。对照组采用TEC方案化疗;观察组采用EC-T序贯化疗,均连续治疗8个周期。治疗结束后比较两组患者的临床疗效、不良反应发生情况及MRI诊断效能。结果 治疗后,观察组患者临床总有效率显著高于对照组,差异具有统计学意义(41.7% vs. 66.7%,。观察组患者红P<0.05)细胞减少、肝功能损伤的发生率明显低于对照组,而中性粒细胞减少发生率显著高于对照组,差异具有统计学意义(P<0.05);两组患者白细胞减少、血小板减少、肾功能损伤、便秘的发生率比较,差异无统计学意义(P>0.05);两组患者恶心、呕吐的发生率均达100%。观察组患者MRI诊断效能明显高于对照组,差异具有统计学意义(P<0.05)。结论 多西紫杉醇联合表柔比星序贯化疗对局部进展期乳腺癌具有较好的临床疗效,且并未增加药物不良反应的发生,具有较好的安全性和耐受性。
关键词:局部进展期;乳腺癌;多西紫杉醇;表柔比星;序贯化疗
中图分类号:R737.9 文献标识码:A 文章编号:2095-12(2019)03-0431-05doi:10.3969/j.issn.2095-12.2019.03.17
★
Clinical Efficacy of Sequential Chemotherapy of Docetaxel Combined with
Epirubicin for Locally Advanced Breast Cancer ★
SHAO Hua 1, JIANG Lei 2*, ZHANG Hua 3, LI Baiyan 1, WANG Yuanyuan 1
(1 Imaging Center, 2 Neurosurgery Department, 3Oncology Department, the First Affiliated Hospital of Xinjiang Medical Univer-sity, Urumqi, Xinjiang, 8300, China)
Abstract: Objective To compare the clinical efficacy, adverse reactions and MRI evaluation of neoadjuvant chemotherapy regimen do-cetaxel combined with epirubicin in sequential chemotherapy for locally advanced breast cancer. Methods A total of 120 patients with locally advanced breast cancer admitted to our hospital from January 2014 to January 2018 were selected and divided into two groups according to the random number table method. Each group included 60 cases. The control group was treated with epirubicin+ docetaxel +cyclophosphamide chemotherapy for four treatment cycles. The observation group was treated with epirubicin + cyclophosphamide as the control group during the first four cycles, but got docetaxel sequential therapy from the fifth treatment cycle. All patients were treated for 8 consecutive cycles. After treatment, evaluate and compare the clinical efficacy, adverse reactions and MRI evaluation. Results Compared with the control group, the total clinical effective rate of the observation group was significantly higher than that of the control group, and there was a significant difference be-tween the two groups (41.7% vs.66.7%, P<0.05). After treatment, the incidence of erythrocytopenia, liver function injury and constipation in the observation group were significantly lower than in the control group, while the incidence of neutropenia of observation group were significantly higher than that of the control group (P<0.05). There were no significant differences between the two groups in the incidences of leukopenia, thrombocytopenia, renal function injury and constipation (P>0.05). Nausea and vomiting occurred in both groups, and the incidence was 100% in each group. MRI evaluation results showed that the diagnostic efficiency of the observation group was significantly higher than that of the con-trol group (P<0.05). Conclusion For locally advanced breast cancer, sequential chemotherapy with docetaxel and epirubicin not only has better clinical efficacy, but also does not increase the incidence of adverse drug reactions. It has a good safety and tolerance.
Key words: Local progression; Breast cancer; Docetaxel; Epirubicin; Sequential chemotherapy
★
基金项目:维吾尔自治区自然科学基金项目(2015211C097)。作者简介:邵华,女,硕士,副主任医师,研究方向:乳腺疾病及影像诊断,E-mail:383283715@qq.com。*
通讯作者:姜磊,男,硕士,主任医师,研究方向:肿瘤相关疾病的诊疗,E-mail:jiangleidr@126.com。
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前言
乳腺癌是中年女性常见的恶性肿瘤,近年来其发病率呈低龄化上升趋势,因其较高的复发率和转移率对女性健康构成了极大的威胁
[1]
。局部进展
期乳腺癌是指乳腺原发病灶较大,手术切除困难,但未发生远处转移的乳腺癌,患者区域淋巴结转移程度较高,预后较差[2]
。随着现代医学技术的深入发展,乳腺癌的临床治疗已从单纯的手术切除发展至全身性综合治疗。其中新辅助化疗是目前乳腺癌综合治疗手段的重要组成部分,具有降低肿瘤分期、提高可手术率、降低细胞耐药性等优势,并已逐渐成为局部进展期乳腺癌的常规治疗手段。紫杉类药物与蒽环类药物联合化疗是目前转移性乳腺癌的首选化疗方案[3-4]。本研究采用多西紫杉醇联合表柔比星对局部进展期乳腺癌患者进行序贯化疗,调整了联合应用方案,以期为局部进展期乳腺癌患者临床治疗方案的选择提供参考依据。
1 资料与方法
1.1 一般资料 选取2014年1月-2018年1月在我院接受治疗的120例局部进展期乳腺癌患者。纳入标准:符合《中国抗癌协会乳腺癌诊治指南与规范》中关于乳腺癌诊断标准,并经临床病理活检确诊为乳腺癌,临床分期为ⅡB-ⅢC期,且分子分型为Luminal型;预计生存时间>12个月;无其它并发恶性肿瘤;经常规检查无化疗禁忌。排除标准[5]:拒绝参与本次研究或临床数据不完善的患者;血常规和心电图异常、严重肝、肾功能不全,或对相关治疗药物过敏的患者。按照随机数字表法将120例患者随机分为两组,各60例。观察组患者年龄25~50岁,平均年龄(31.2±6.4)岁,浸润性导管癌45例、乳头状癌6例、浸润性小叶癌8例、髓样癌1例;对照组患者年龄27~52岁,平均年龄(29.5±4.7)岁,浸润性导管癌42例、乳头状癌7例、浸润性小叶癌9统计学意义例、髓样癌(2P例。两组患者基线资料比较,>0.05),具有可比性。所有患者或其差异无家属均自愿签署知情同意书,并获得医院伦理委员会批准。
1.2 方法 对照组采用TEC方案化疗,给予
表柔比星(辉瑞制药(无锡)有限公司,国药准字H20000497)100 mg·m-2+多西紫杉醇(齐鲁制药有限公司,国药准字H20041128)75 mg·m-2+环磷酰胺500 mg·m-2,3周为1个治疗周期,连续治疗4个周期[6]。观察组采用EC-T方案序贯化疗,给予表柔比星100 mg1·m-2+环磷酰胺500 mg·m-2,3周为周期开始序贯使用多西紫杉醇个治疗周期,连续治疗4个周期;100 mg从第1疗个治疗周期,8个周期。治疗结束后比较两组间相关指标连续治疗4个周期。两组患者均治·m-52,个治疗3周为[7]。
化疗期间,每周对治疗效果及化疗不良反应进行评估,并给予对症治疗[8]。
治疗期间对两组患者进行MRI扫描,常规扫描横断面双回波T1WI、T2WI。对患者的轴位乳腺容积进行动态增强扫描,层厚约为2.3 mm;使用高压注射器进行增强扫描,注射钆喷酸葡胺(Gd-DTP),注射流率3.0 mL·s-1,剂量为0.1 mmol·kg-1;共扫描8个时相,每个时相的扫描时间为56 s。扫描结束后采用Functool软件对数据进行处理,以确定病灶情况。1.3 观察指标 依据国际抗癌联盟实体瘤通用评价标准评价两组患者的临床疗效[9]。完全缓解CR):肿瘤病灶完全消失;部分缓解(PR):肿瘤体积缩小>50%,未出现新病灶;疾病稳定(SD):病情无显著好转,肿瘤体积缩小25%~50%,未出现新病灶;进展(PD):肿瘤体积增大>25%或出现新病灶。以CR+PR为治疗有效。
依据WHO实体瘤评价标准对两组患者的不良反应进行评价[10],包括血液系统毒性、肝、肾功能损伤、胃肠道反应等。
评价两组患者的MRI诊断效能,主要包括特异度、灵敏度、阴性预测值和阳性预测值。
1.4 统计学方法 采用SPSS 19.0数据处理软件对研究数据进行统计分析。计数资料采用非参数检验。计量资料用均值±标准差(x±s)表示,进行正态分布检验,服从正态分布且方差齐的数据采用t检验;不服从正态分布的数据采用非参数检验。以P<0.05为差异具有统计学意义。
2 结果
2.1 临床疗效 观察组患者治疗总有效率
(肿瘤药学2019年6月第9卷第3期 Anti-tumor Pharmacy, June 2019, Vol. 9, No. 3- 433 -
(66.7%)显著高于对照组(41.7%),差异具有统计学意义(P<0.05)(表1)。
表1 两组患者近期疗效比较[例(%)]
Tab. 1 Comparison of short-term efficacy between the two
groups [n(%)]组别例数
CR
PR
SD
PD
总有效率
对照组6010(16.7)15(25.0)21(30.0)14(23.3)25(41.7)观察组6016(26.7)24(40.0)15(25.0)5(8.3)40(66.7)χ2P
011.00.6
2.2 不良反应发生情况 两组患者化疗期间均有不同程度的不良反应发生。血液系统毒性方面,观察组红细胞减少的发生率明显低于对照组,中性粒细胞减少的发生率显著高于对照组,差异具有统计学意义(P<0.05);观察组白细胞减少和血小板减少的发生率低于对照组,但组间差异无统计学意义(P>0.05)(表2)。
表2 两组患者血液系统毒性发生率比较[例(%)]
Tab. 2 Comparison of hematologic toxicity incidence between
the two groups [n(%)]组别例数白细胞 红细胞 中性粒 血小板
减少减少细胞减少减少对照组6051(85.0)33(55.0)9(15.0)3(5.0)观察组6036(60.0)12(20.0)17(28.3)2(3.3)χ2
P
01..6778
012.00.9
09.00.6
20..2361
观察组肝功能损伤发生率明显低于对照组,差异具有统计学意义(P<0.05);肾功能损伤发生率低于对照组,但组间差异无统计学意义(P>0.05)(表3)。
表3 两组患者肝、肾功能损伤发生率比较[例(%)]
Tab. 3 Comparison of liver and kidney impairment incidence
between the two groups [n(%)]组别例数ALT升高AST 升高Scr 升高BUN升高对照组6021(35.0)10(16.7)2(3.3)2(3.3)观察组60
10(16.7)3(5.0)1(1.7)0χ2P
010.00.5
09..0096
10..0753
——
胃肠道反应方面,两组患者恶心、呕吐发生率均达100%;两组患者均出现便秘,组间差异无统计学意义(P>0.05);观察组患者腹泻和口腔溃疡的发生率明显低于对照组,差异具有统计学意义
(P<0.05)(表4)。
表4 两组患者胃肠道反应发生率比较[例(%)]
Tab. 4 Comparison of gastrointestinal reactions incidence
between the two groups [n(%)]组别例数恶心、呕吐腹泻
便秘
口腔溃疡对照组6060(100)11(18.3)2(3.3)17(28.3)观察组60
60(100)4(6.7)1(1.7)9(15.0)χ2—10.71.148.86P
—
0.00
0.26
0.01
2.3 MRI评价 观察组患者MRI特异性、灵敏度、阳性预测值均明显高于对照组,差异具有统计学意义(P<0.05)(表5)。
表5 两组患者MRI诊断效能比较
Tab. 5 Comparison of diagnostic efficacy between the two
groups组别例数特异性灵敏度阴性预测值阳性预测值对照组6065.0%46.7%58.3%70.0%观察组60
88.3%65.0%71.7%88.3%χ2P
014.00.1
012.00.7
01..0987
08..00
3 讨论
乳腺癌是全身性病变疾病,虽然Ⅱb-Ⅲb期的早期患者在临床上表现为局部病变,但大多数已有周身微小转移灶,因此,在治疗方案的制定上必须考虑“局部控制、兼顾全身”的治疗原则[11]。新辅助化疗在乳腺癌、大肠癌、胃癌等多种恶性肿瘤的临床治疗中取得了较好的疗效,其对乳腺癌的临床疗效已在国内外多中心对照研究中获得肯定。新辅助化疗的主要技术优势有以下几个方面:首先,新辅助化疗可以最大程度地缩小原发病灶,提高保乳手术成功率;其次,新辅助化疗能最大程度地减少微小转移灶的扩散,减少化疗耐药的发生,增加化疗药物对肿瘤细胞的敏感性,延长患者的生存期[12-13]。蒽环类药物联合紫杉类药物化疗虽然是乳腺癌的推荐治疗方案,但均需要通过剂量密集给药才能发挥最大的协同作用。而密集给药治疗可能增加药物不良反应的发生,导致患者因不能耐受而调整治疗方案。为避免联合用药引起的毒副作用叠加,本研究采用序贯化疗方案,其与常规联合化疗方案的主要差异是化疗周期的长短与多西紫杉醇的用药差异,
- 434 -肿瘤药学2019年6月第9卷第3期 Anti-tumor Pharmacy, June 2019, Vol. 9, No. 3
即在不减少化疗药物总剂量的前提下延长化疗周期,降低不良反应发生率。本研究结果显示,多西紫杉醇序贯化疗方案具有较好的安全性。
多西紫杉醇是新型的人工半合成紫杉醇衍生物,为细胞周期特异性抗肿瘤药物,其作用机制为通过作用于微管蛋白系统,对微管蛋白的解聚产生紫杉醇联合表柔比星序贯化疗,不仅可获得较好的临床疗效,且并未增加药物不良反应的发生,具有较好的安全性和耐受性。
参考文献(References)
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抑制作用并阻止其多聚化,保持微管蛋白的相对稳定;对肿瘤细胞的有丝产生干扰作用,并使细胞停留在G2、M期,抑制肿瘤细胞的增殖和生长,从而发挥抗肿瘤作用[14]。与普通紫杉类药物相比,多西紫杉醇的水溶性更强,在肿瘤细胞内停留的时间更长,浓度更为集中,因此,其抗肿瘤活性更强[15]。表柔比星是细胞周期非特异性蒽环类药物,其作用机制为直接嵌入细胞DNA核酸碱基对之间,干扰核酸的转录过程,阻止mRNA的形成,从而抑制肿瘤细胞的增殖;此外,表柔比星还可抑制拓扑异构酶Ⅱ的活性,发挥抗肿瘤作用。虽然表柔比星具有较好的抗肿瘤活性,但其主要不良反应为心脏毒性,主要表现为心律失常、心功能紊乱、充血性心力衰竭,甚至导致死亡,临床使用时应密切监测患者的心脏功能。本研究结果显示,观察组治疗总有效率显著高于对照组,提示序贯化疗可明显改善患者的临床症状,延缓病情进展。联合化疗方案的不良反应是值得临床关注的,白细胞减少是蒽环类药物及紫杉类药物的常见毒副作用,但本研究中观察组患者除中性粒细胞减少的发生率明显高于对照组之外,红细胞减少、肝功能损伤以及腹泻、口腔溃疡的发生率均显著低于对照组,其它不良反应发生率亦低于对照组,提示序贯化疗方案可显著降低不良反应发生率,且未增加其他药物不良反应。 MRI技术已广泛应用于乳腺癌的临床诊断,具有良好的多参数成像方式、组织对比度和可重复性,在评估乳腺癌患者的化疗效果方面具有重要作用。动态增强MRI扫描是目前临床较常用的诊断方法,不仅能够较好地显示肿瘤的通透性、血管密度、增殖信息和代谢等,还能够较好地反映患者对治疗药物的一系列反应。本研究结果显示,观察组患者MRI诊断效能明显高于对照组,提示联合序贯化疗方案的治疗效果更具有优势,与临床疗效结果相互印证。 综上所述,对局部进展期乳腺癌患者采用多西
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