温通消肿外敷方治疗乳腺癌术后上肢水肿的随机、双盲、安慰剂平行对照、多中心临床研究

发布时间：2018-02-27 19:56

本文关键词： 安慰剂临床试验乳腺癌术后上肢水肿温通消肿外敷方中药　出处：《北京中医药大学》2015年博士论文　论文类型：学位论文

【摘要】：[研究背景]乳腺癌术后上肢水肿(Breast cancer related lymphedema, BCRL)是乳腺癌病人手术后常见的并发症之一,常伴许多不适症状,目前仍无法治愈,且具有终身发病的风险,BCRL患者因此在身体、精神上承受巨大的痛苦而显著降低了患者的生活质量。随着近年来乳腺癌发病率的增高、5年生存率的改善,BCRL已经成为乳腺癌术后患者一个棘手的问题。现代医学治疗BCRL的有效手段非常有限,目前多主张采用物理治疗为主,最佳治疗的有效率也不甚理想。传统中医药治疗BCRL的国内报道较多,不管中药内治还是外治,其治疗有效率普遍在80-100%,中西医治疗差异显著。对比Pubmed和CNKI文献库后发现,尽管中药治疗BCRL的中文报道较多,但缺点是这些研究结论缺乏高级别循证医学证据支持,仅为病例回顾分析或简单的病例对照研究；而Pubmed上目前仍没有中药治疗BCRL的任何研究报道。因此,设计一个具有较高级别循证医学证据的临床试验来验证中药治疗BCRL的临床疗效,将有助于改善BCRL的治疗现状,更好的发挥中医的优势。课题组前期对乳腺癌术后患者的中医证型规律进行研究,发现温阳为主的治疗是乳腺癌术后的主要治疗大法,在此基础上,以“温阳益气,利水消肿”为大法自拟“温通消肿外敷方”,采用随机、双盲、安慰剂平行对照、多中心的临床课题设计治疗BCRL,以期待通过高级别临床试验将中药治疗BCRL推向世界。[研究目的]1.探讨“温通消肿外敷方”治疗BCRL的临床疗效；2.评价“温通消肿外敷方”治疗BCRL的安全性。[研究方法]本课题采用前瞻性的随机、双盲、安慰剂平行对照、多中心的临床研究设计,同时接受课题资助方北京市科委指派的北京岐黄药品临床研究中心全程监察。在多次方案论证后确定最终研究方案,完成患者招募前的准备工作,包括通过四个研究中心的伦理审查,完成国际临床试验注册,培训四个中心的研究者,协调药品采购,制剂室依据循证医学中心预先设定的盲底准备药品浓煎剂(试验药和安慰剂药)。随后根据入组标准招募BCRL患者,完成入组检查,包括上肢动静脉B超、腋窝淋巴结B超、血常规、尿常规、便常规、肝肾功能和电解质检查。患者根据入组顺序领取每个中心已经预先设盲的药物,记录患者治疗第0、3、5、7、14日的臂围、并填写上肢功能评价表(DASH),记录不良反应。患者治疗结束后完成出组检查(与入组时检查项目相同)后出组,并可根据意愿免费领取14天“温通消肿外敷方”真药继续治疗。所有病例数据录入后由循证医学中心锁定数据,在循证医学、岐黄监察人员和课题负责人三方在场下揭盲,完成数据统计分析。最后明确“温通消肿外敷方”治疗BCRL的临床疗效,并进行安全性评价。[研究结果]1.课题从启动、实施到最后揭盲,在严格的质量控制下完成,基本符合课题预期的质量控制标准。整个课题完成的质控内容包括：伦理审核、循证医学中心编盲设盲、药品统一采购和质量把关、制剂室设计药品制备流程、国际临床试验注册、研究者培训、患者招募、第三方每月质量监察、循证医学数据管理、标准化揭盲。以上质控的完成保证了课题数据的准确性和真实性。2.本课题按要求招募96例BCRL患者入组,历时18个月,其中4例患者因不良反应中途退出研究,8例患者脱落失访,共计84例患者完成本次研究,疗程为14天。基线分析示试验药组和安慰剂组在患者年龄、乳腺癌手术方式、腋窝淋巴结转移情况、药物过敏史、中西医治疗史、临床分期、水肿分级等方面无明显差(P0.05),入组时两组的臂围测定值和DASH评分值无明显差别(P0.05),入组检查提示两组病人在血常规、尿常规、便常规、肝肾功能、电解质水平和心电图等方面无明显差异(P0.05)。总之,两组BCRL患者在入组基线上具有可比性,符合随机设计。3.根据课题设定的临床有效标准,39例试验组患者中20例为临床有效,有效率为51.3%；45例安慰剂组患者中31例临床有效,有效率为68.9%,两组有效率之间差异无显著性(P=0.12)。分层分析示四个中心有效率分别为55.6%、50.0%、72.7%和27.3%,中心之间无显著性差异(P0.05)。扣除中心效应后,试验药组和安慰剂组有效率仍无显著差异。符合方案数据分析集分析后结论仍不变。4.次要结局指标分析发现,随着治疗时间的延长,观察指标(臂围和上肢功能DASH评分)不断改善,但臂围变化不如DASH评分变化明显。治疗前后观察指标的变化在试验药组和安慰剂组之间无明显差异(Z=-0.94,P=0.35 and Z=-1.81,P=0.07);上肢功能改善的生存分析发现安慰剂组达到临床有效标准约在第6.23天,试验药组患者达到上肢功能DASH有效标准平均需要7.26天,两组有效病人达到临床有效时间之间无明显差异(P=0.37)。5.试验药组发现3例皮肤Ⅱ度过敏反应患者,不良反应发生率为7%,此外试验药组发现1例感冒发烧患者；安慰剂组未发现不良反应中止治疗的患者。试验药组皮肤不良反应发生率,与安慰剂组比较未发现显著性差异(P=0.11)。治疗后发现的血常规、尿常规、便常规、肝肾功能、钾钠氯离子水平和心电图等指标异常情况在两组中无明显差别(P0.05)。[研究结论]1.在充分论证的基础上,完成本次随机、双盲、安慰剂平行对照、多中心的临床课题设计,课题设计严谨、实施过程监管严格,为循证医学高级别证据,结论真实。2.主要结局指标分析发现,寒热理论指导下的温热外敷能够提高乳腺癌术后上肢水肿的临床有效率,而温通消肿外敷方和安慰剂治疗BCRL的临床有效率无显著差别,温通消肿外敷方不具有治疗优势。3.次要结局指标分析发现,温通消肿外敷方和安慰剂均可改善患肢臂围和上肢功能,但臂围变化不如DASH评分变化明显,两种指标的改善程度在试验药组和安慰剂组之间无明显差异。两组病人上肢功能改善达有效标准所需时间无明显差异。4.中药外敷治疗方式可以引起皮肤的过敏反应,不注意保暖时还有发生感冒发烧的风险,使用“温通消肿外敷方”治疗BCRL患者时皮肤过敏反应(Ⅱ)发生率为7%,与安慰剂组比较未发现显著性差异。与安慰剂相比,未发现“温通消肿外敷方”治疗BCRL患者时增加患者血常规、尿常规、便常规、肝肾功能、钾钠氯离子水平和心电图等指标的恶化风险。5.本研究未发现采用“温通消肿外敷方”治疗BCRL的临床有效率高于安慰剂,但不能以此简单的否定“温通消肿外敷方”的临床功效,因为本研究的结果只能限于本次研究设计而言,如患者的入组方式、疗程、课题资金支持力度、患者样本量、患者依从性等方面,不能推广到所有的患者,本研究结论还需要在今后升级版的高级别临床试验中进一步证实。
[Abstract]:[background] breast cancer postoperative upper limb edema (Breast cancer related lymphedema, BCRL) is one of the common complications after operation of breast cancer patient, often accompanied by many symptoms, there is still no cure, and the risk with lifelong disease, patients with BCRL in the body, the spirit bear great pain and decreased the quality of life of patients with breast cancer incidence increased in recent years, the 5 year survival rate improvement, BCRL has become after breast cancer patients a thorny problem. Effective means of modern medicine in the treatment of BCRL is very limited, the advocate the use of physical therapy, the effective rate of treatment is not ideal the traditional Chinese medicine. The treatment of BCRL reported more, whether oral or external treatment, the effective rate of treatment in 80-100% generally, traditional Chinese medicine and Western medicine treatment were significantly different. Compared with Pubmed and CNKI library after the discovery, though Chinese medicine treatment of BCRL Chinese reported more, but the drawback is that these conclusions lack of high-level evidence-based support, only for the review of cases analysis or simple cases; while on Pubmed, there are still no reports on Chinese medicine for the treatment of BCRL. Therefore, the design of a clinical trial of a higher level of evidence based medicine to verify the clinical curative effect of traditional Chinese medicine in the treatment of BCRL, will help to improve the current treatment of BCRL, better play the advantages of Chinese medicine. Previous research on TCM syndrome in patients after breast cancer surgery, we found that warming yang as the main treatment is the main treatment for breast cancer after operation method, on the basis of this, "Wen Yang Qi, and water swelling" method by "Wen Tong swelling external application", a randomized, double-blind, placebo-controlled, multi center clinical study design for BCRL, to look through the senior Don't be clinical trials of Chinese medicine treatment of BCRL to the world. The purpose of the study is to investigate the]1. warming detumescence clinical curative effect of the treatment of external application of "BCRL"; safety. Methods 2. evaluation "Wen Tong swelling external application of" treating BCRL this topic using prospective randomized, double-blind, placebo parallel control, clinical study design multi center, supported by the party and accept the Beijing Municipal Science and Technology Commission appointed Beijing Qihuang clinical research center of medicine of process monitoring. To determine the final research program in a number of demonstration program, complete the preparatory work before the patients were recruited, including through the ethical review of four research centers, international clinical trial registration, training centers and four researchers coordination, drug procurement, preparation room based on evidence-based medical center preset blind end of the preparation of the medicine concentrated decoction (test drug and placebo drugs). Then according to the standard set of recruited patients with BCRL. Check into the group, including upper extremity arteriovenous ultrasound, axillary lymph node B, blood routine, urine routine, stool routine, liver and kidney function and electrolytes examination. Patients according to the group order for each center has been previously blinded, the treatment of patients with 0,3,5,7,14, arm circumference records, and fill in the upper limb function evaluation scale (DASH) and the adverse reactions were recorded. Patients completed a check after the end of treatment group (with the same examination group) after the group, and according to the willingness to receive a free 14 day "Wen Tong swelling external party" really medicine to treatment. All cases of data entry by evidence-based medicine center lock the data in evidence-based medicine. Qihuang inspectors and responsible for the issue of three party presence unblinded, analysis of statistical data. Finally, the clear "Wen Tong swelling external application of clinical efficacy in the treatment of BCRL, and the safety evaluation was carried out. The results of the]1. study topic from start to implement the After Unblinding, completed under strict quality control, accord with the standard of quality control. The quality control content of the whole project is expected to complete the project include: ethical review, evidence based medicine center for the blind blind drug, unified procurement and quality control, design of drug preparation room preparation process, international clinical trial registration, researchers training the patients were recruited, third party, monthly quality supervision, evidence-based medicine data management, standardized quality control to complete the above unblinded. To ensure the accuracy and authenticity of the data subject.2. this topic according to the requirements of the recruitment of 96 patients with BCRL were enrolled, which lasted 18 months, among which 4 patients withdrew from the study due to adverse reactions, 8 patients lost off, a total of 84 patients completed the study, 14 days for a course. The baseline analysis shows the test drug and placebo groups in the age of patients, surgical breast cancer and axillary lymph node metastasis situation, in the history of drug allergy The history of Western medicine treatment, clinical stage, edema grading of no significant difference (P0.05), group of two groups of arm circumference measured value and DASH score showed no significant difference (P0.05), the group of two groups of patients in blood routine examination, urine routine, stool routine, liver and kidney function, no significant difference between the electrolyte level the electrocardiogram (P0.05) and other aspects. In conclusion, BCRL in the two groups were comparable in the baseline group, consistent with the random design of.3. according to the standard set by the topic of clinical effective, 39 cases of patients in the trial group of 20 cases for clinical effective rate was 51.3%; 45 cases of patients in the placebo group in 31 cases effective. Efficiency is 68.9%, the efficiency of the two groups no significant difference (P=0.12). Four stratified analysis center efficiency were 55.6%, 50%, 72.7% and 27.3%, there was no significant difference between the center (P0.05). After deducting the center effect, drug test group and placebo group effective rate are not significant According to the design data set. The difference analysis results are still invariant.4. secondary outcomes analysis found that with the prolongation of treatment time, observation index (arm circumference and upper extremity DASH score) continue to improve, but the change of DASH score as arm circumference changes. No obvious difference was observed before and after treatment the changes in the test group and the placebo group (Z=-0.94 P=0.35, and Z=-1.81, P=0.07); the upper limb function improved survival analysis found that the placebo group reached the clinical effective standard about in the 6.23 days, the test drug group reached the upper limb function DASH standard requires an average of 7.26 days, two groups of patients achieved no significant difference between the clinical effective time (P=0.37).5. test the medicine group found 3 cases of patients with skin allergic reactions, the incidence of adverse reaction was 7%, in addition to the test drug group found 1 cases of patients with cold have a fever; the placebo group found no adverse reactions to suspend Treatment of the patients. The incidence of adverse drug reaction test group skin, compared with placebo group found no significant difference (P=0.11). After the treatment of blood routine, urine routine, stool routine, liver and kidney function, abnormal potassium sodium chloride levels and electrocardiogram showed no significant difference in the two groups (P0.05) based. Conclusion]1. in the full argument on the completion of the randomized, double-blind, placebo-controlled, multi center clinical research design, project implementation process is rigorous, strict supervision, high levels of evidence for evidence-based medicine, the primary outcome of real.2. conclusion analysis, guidance and theory under the warm external application can improve the breast after the operation of carcinoma of upper limb edema clinical efficiency, temperature and external application of clinical swelling and placebo treatment had no significant difference between the BCRL efficiency, Wen Tong has no external application of swelling treatment of.3. secondary outcomes Found that temperature through external application of swelling and placebo can improve limb function and upper arm circumference, arm circumference as DASH score change but changes significantly, no significant difference between the improvement degree of two indexes between the experimental drug and placebo groups. Two groups of patients with upper extremity allergic reaction function to improve the time needed to reach the effective standard no difference.4. traditional Chinese medicine treatment mode can cause the skin, do not pay attention to keep warm when there is risk of a cold have a fever, "Wen Tong swelling external party" in the treatment of BCRL patients with skin allergic reaction (II) the incidence rate was 7%, compared with placebo group found no significant differences. Compared with placebo, found no warming swelling external application of "treating BCRL patients is increased in patients with blood routine, urine routine, stool routine, liver and kidney function, the risk of deterioration of.5. potassium sodium chloride levels and electrocardiogram index has not found in this study by" Wen Tong Xiao Swollen external party "in the treatment of BCRL clinical efficiency is higher than that of placebo, clinical efficacy but denied" not as a simple external application of swelling of Wen Tong ", because the results of this study can only be limited to the study design, such as into the group of patients, treatment, subject to financial support, with the sample size, patient compliance so, can not be extended to all of the patients, the conclusions of this study are needed in the future upgrade of the high level in clinical trials is further confirmed.

【学位授予单位】：北京中医药大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R737.9

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