蒌慈散结方预防三阴性乳腺癌复发转移的临床观察及生存预后模型的构建

【作者】 张英；

【导师】 万冬桂；

【作者基本信息】 北京中医药大学 ， 中西医结合临床（专业学位）， 2022， 硕士

【摘要】 本文包括文献综述和临床研究各2篇。综述一:主要总结了近年来早期三阴性乳腺癌(triple negative breast cancer,TNBC)新/辅助化疗后的强化治疗进展,为TNBC放化疗后的继续治疗提供思路和方法。TNBC是乳腺癌的一种分子亚型,具有恶性程度高、侵袭性强、复发转移快、生存时间短等特点,在标准的手术、新/辅助化疗、放疗后仍有较高的复发风险。为强化新/辅助化疗作用,改善早期TNBC患者预后,新辅助治疗后未达pCR者术后可予6-8周期卡培他滨强化治疗,新辅助治疗中应用过帕博丽珠单抗的高复发风险TNBC患者可继续予帕博丽珠单抗强化治疗,在完成标准的辅助治疗后可予低剂量卡培他滨强化治疗,对BRCA胚系突变的TNBC患者可予奥拉帕利强化治疗。此外,环磷酰胺、甲氨蝶呤、多西他赛、阿司匹林等药在抗早期TNBC复发转移方面也有一定的强化治疗作用。综述二:主要对近年来中医预防TNBC空窗期复发转移的研究进行总结,为TNBC空窗期的中医诊治提供思路和参考。卡培他滨、奥拉帕利等西药预防TNBC空窗期复发转移疗效显著,但不良反应较多,具有一定的局限性。中医认为TNBC空窗期忧郁悲恐,情志内伤,经手术、放化疗后正气已伤,余毒未清,邪毒旁窜,易发转移,病机以“虚、痰、毒、郁、瘀”为特点,体质类型以“阳虚质、气郁质、痰湿质”为主,中医证型表现多样,中医通过“治未病”和“辨病-辨证-辨体”的治疗理念,采用黄芪等药补气、山慈菇等药化痰散结、白花蛇舌草等药清热解毒、柴胡等药疏肝解郁和当归等药活血化瘀,临床研究发现二至丸合桂枝汤等经典方剂、蒌慈散结方、化毒三阴方、乳癌术后方等自拟方剂、槐耳颗粒、西黄丸、六味地黄丸、八宝丹等中成药均具有良好的抗TNBC复发转移作用。临床研究一:蒌慈散结方预防三阴性乳腺癌复发转移的388例疗效观察目的:观察蒌慈散结(LCSJ)方预防TNBC复发转移的临床疗效。方法:根据纳排标准收集2016年1月1日至2018年12月31日就诊于中日友好医院医院中西医结合肿瘤内科,且服用LCSJ方的TNBC患者资料。将本研究入组患者的临床病理信息、西医治疗信息、LCSJ方每年服用疗程、持续时间、不良反应等中医信息记录于Excel表格,建立数据库。通过门诊、电话等方式回顾性随访入组患者的复发转移时间、部位、死亡时间等信息,观察LCSJ方对早期TNBC患者无病生存时间(DFS)和总生存时间(OS)的影响。结果:本研究共纳入了 388例服用LCSJ方的早期TNBC患者,中位随访50个月,其 3 年、5 年 DFS 分别为 91.01%和 88.30%,3 年、5 年 OS 分别为 97.42%和 95.55%。TNBC患者年平均服用LCSJ方1疗程、2疗程、3疗程及以上者的5年DFS分别为84.33%、89.39%、94.16%(p=0.03),5 年 OS 分别为 92.22%、95.57%、98.49%(p=0.04)。LCSJ方持续服用1年、1-2年、2-3年、3年及以上者的5年DFS分别为80.01%、88.25%、94.82%、100.00%(p<0.01),5 年 OS 分别为90.46%、98.67%、100.00%、100.00%(p<0.01)。不同发病年龄、肿瘤大小、淋巴结转移数目、TNM分期、Ki-67表达TNBC患者的5年DFS和OS具有统计学差异(p<0.05),不同发病位置、病理类型、组织学分级、手术方式、是否放疗TNBC患者的5年DFS和OS无明显统计学差异(p>0.05)。388例TNBC患者无明显不良反应。结论:LCSJ方能够有效提高TNBC患者的3年、5年DFS,且具有较好的安全性。LCSJ方年平均服用疗程越多,持续服用时间越长,TNBC患者5年DFS和OS越高。发病年龄、肿瘤大小、淋巴结转移数目、TNM分期、Ki-67表达水平可能是影响服用LCSJ方TNBC患者预后的因素。临床研究二:蒌慈散结方干预早期三阴性乳腺癌患者生存预后模型的构建目的:探讨影响LCSJ方干预早期TNBC患者生存预后的危险因素,并构建针对LCSJ方干预早期TNBC患者个体的生存预测模型。方法:根据纳排标准收集2016年1月1日至2018年12月31日就诊于中日友好医院医院中西医结合肿瘤内科,且服用LCSJ方的TNBC患者资料,建立Excel数据库。通过R语言软件以7:3的比例将入组患者随机分为训练组和验证组。对训练组进行单因素和多因素分析,筛选出影响LCSJ方干预早期TNBC患者生存预后的危险因素,利用R软件构建训练组TNBC 3年、5年DFS预测模型列线图。最后通过C指数和校准曲线验证模型的稳定性和准确性。结果:本研究共入组388例TNBC患者,训练组272人,验证组116人,两组基线资料无统计学差异(p>0.05)。将单因素、多因素筛选出的发病年龄、TNM分期、Ki-67表达状态、术后LCSJ方年平均服用疗程及持续服用时间等5个因素纳入生存预测模型,构建了 TNBC 3年、5年DFS列线图。训练组和验证组的C指数分别为0.89(95%CI:0.83-0.95)和0.84(95%CI:0.76-0.92),且两组校准曲线均靠近45°参考线。结论:本研究构建的LCSJ方干预早期TNBC患者生存预后模型具有良好的稳定性和准确性,可用于临床对服用LCSJ方的TNBC患者进行个体化的指导。更多还原

【Abstract】 This article includes two literature reviews and two clinical researches.The first review mainly summarizes the progress of intensive treatment after neo/adjuvant chemotherapy for early triple negative breast cancer(TNBC)in recent years,and provides ideas and methods for the continued treatment of TNBC after radiotherapy and chemotherapy.TNBC is a molecular subtype of breast cancer with the characteristics of high malignancy,strong invasiveness,rapid recurrence and metastasis,and short survival time.In order to strengthen the effect of neo/adjuvant chemotherapy and improve the prognosis of early TNBC patients,those who do not achieve pCR after neoadjuvant therapy can be given 6-8 cycles of capecitabine intensive therapy.TNBC patients with high recurrence risk who have used pembrolizumab in neoadjuvant therapy can continue to receive intensive pembrolizumab therapy.Low-dose capecitabine maintenance therapy can be given after completion of standard adjuvant therapy.Intensive treatment with olaparib can be given to TNBC patients with BRCA germline mutations.In addition,cyclophosphamide,methotrexate,docetaxel,aspirin and other drugs also have a certain intensified therapeutic effect in anti-early TNBC recurrence and metastasis.The second review mainly summarizes the research on the prevention of TNBC recurrence and metastasis by traditional Chinese medicine in recent years,and provides ideas and references for the diagnosis and treatment of TNBC by traditional Chinese medicine.Western medicines such as capecitabine and olaparib are effective in preventing TNBC recurrence and metastasis,but they have many adverse reactions and have certain limitations.Traditional Chinese medicine believes that TNBC patients in the blank period after standard treatment are sad,depressed,and fearful.After surgery,radiotherapy and chemotherapy,TNBC patients suffer from deficiency of righteousness,residual toxins,and evil toxins,which are prone to metastasis.The pathogenesis of TCM is characterized by "deficiency,phlegm,poison,depression and blood stasis".The main types of constitution are "yang-deficiency constitution,qi stagnation constitution,phlegm-dampness constitution",and the TCM syndrome types are diverse.Traditional Chinese medicine adopts the treatment concepts of "preventive disease treatment" and "disease differentiation-syndrome differentiation-body differentiation".Traditional Chinese medicine uses huangqi and other medicines to invigorate qi,Shancigu and other medicines to resolve phlegm and dissipate stagnation,baihuasheshecao and other medicines to clear heat and detoxify,chaihu and other medicines to soothe the liver and relieve depression,and danggui and other medicines to activate blood and remove blood stasis.Clinical studies have found classic prescriptions such as Erzhi Pill and Guizhi Decoction,self-made prescriptions such as Louci Sanjie Fang,Huadu Sanyin Recipe,and Breast Cancer Postoperative Recipe,Chinese patent medicines such as Huaier Granules,Xihuang Pills,Liuwei Dihuang Pills,and Babaodan have good anti-TNBC recurrence and metastasis effects.The first clinical research:Observation of curative effect of Louci Sanjie recipe in preventing recurrence and metastasis of early triple-negative breast cancerObjective:To observe the clinical efficacy of Louci Sanjie(LCSJ)recipe in preventing the recurrence and metastasis of TNBC.Methods:The data of TNBC patients who visited the Department of Integrated Traditional Chinese and Western Medicine in the China-Japan Friendship Hospital from January 1,2016 to December 31,2018 and took LCSJ prescription were collected according to the inclusion and exclusion criteria.The clinical pathological information,western medicine treatment information,LCSJ prescription’s annual course of treatment,duration,adverse reactions and other traditional Chinese medicine information of the patients enrolled in this study were recorded in an Excel table to establish a database.The recurrence and metastasis time,location,and death time of the enrolled patients were retrospectively followed up through outpatient clinics and telephone calls,to observe the effects of LCSJ prescription on disease-free survival(DFS)and overall survival(OS)of early TNBC patients.Results:A total of 388 patients with early TNBC taking LCSJ prescription were included in this study.The median follow-up was 50 months.The 3-year and 5-year DFS were 91.01%and 88.30%,respectively,and the 3-year and 5-year OS were 97.42%and 95.55%,respectively.The 5-year DFS of TNBC patients taking 1 course,2 courses,3 courses or more of LCSJ prescription on average were 84.33%,89.39%,94.16%(p=0.03),and the 5-year OS was 92.22%,95.57%,98.49,respectively%(p=0.04).The 5-year DFS of those who continued to take LCSJ for 1 year,1-2 years,2-3 years,3 years or more were 80.01%,88.25%,94.82%,100.00%,respectively(p<0.01),and the 5-year OS was 90.46%,98.67%,100.00%,100.00%(p<0.01).The 5-year DFS and OS of TNBC patients with different onset age,tumor size,number of lymph node metastasis,TNM stage,and Ki-67 expression were statistically different(p<0.05).There were no significant differences in 5-year DFS and OS among TNBC patients with different onset locations,pathological types,histological grades,surgical methods,and whether they received radiotherapy(p>0.05).There were no obvious adverse reactions in 388 TNBC patients.Conclusion:LCSJ prescription can effectively improve the 3-year and 5-year DFS of TNBC patients with good safety.The more treatment courses and the longer the continuous use of LCSJ,the higher 5-year DFS and OS of TNBC patients.Age of onset,tumor size,number of lymph node metastases,TNM stage,and Ki-67 expression level may be factors that affect the prognosis of TNBC patients taking LCSJ prescription.The second clinical research:Construction of a survival and prognostic model for patients with early triple-negative breast cancer treated with Louci Sanjie RecipeObjective:To investigate the risk factors affecting the survival and prognosis of patients with early TNBC after intervention with LCSJ prescription,and to construct a survival prediction model for individual patients with early TNBC treated with LCSJ prescription.Methods:According to the inclusion and exclusion criteria,the data of TNBC patients who visited the Department of Integrated Traditional Chinese and Western Medicine in the ChinaJapan Friendship Hospital from January 1,2016 to December 31,2018 and took LCSJ prescription were collected,and an Excel database was established.The enrolled patients were randomly divided into training group and validation group in a ratio of 7:3 by R language software.Univariate and multivariate analyses were performed on the training group to screen out the risk factors affecting the survival and prognosis of TNBC patients treated with LCSJ recipe.R software was used to construct the nomogram for the 3-year and 5-year DFS prediction model of the training group.Finally,the stability and accuracy of the model were verified by C index and calibration curve.Results:A total of 388 TNBC patients were enrolled in this study,including 272 in the training group and 116 in the validation group.There was no significant difference in baseline data between the two groups(p>0.05).Through univariate and multivariate analysis,we screened out five factors including age of onset,TNM stage,Ki-67 expression status,average annual course of treatment and duration of LCSJ prescription after operation.These five factors were incorporated into the survival prediction model,and the 3-year and 5-year DFS nomograms of TNBC patients were constructed.The C-index of the training group and the validation group were 0.89(95%CI:0.83-0.95)and 0.84(95%CI:0.76-0.92),respectively,and the calibration curves of both groups were close to the 45° reference line.Conclusion:The survival and prognosis model of LCSJ prescription intervention in early TNBC patients constructed in this study has good stability and accuracy,and can be used for individualized guidance of TNBC patients taking LCSJ prescription.更多还原