The time-acupoints-space acupuncture spirit turtle eight method(ATAS) in patients with postoperative chemotherapy of breast cancer fatigue randomized controlled clinical trials(RCT)

Zheng Zuo, Mian-sheng Zhu, Wen-hui li, Li-ya Ju, Jean-Pierre Armand, Yun-feng Li, Liang-xian Liu, Chun-xin Chen, Mathieu Noel,Ran Song, Xiong-ying Bao, Ling-ling Wang, Ying-hao Wang, Yuan Kai

(1.yunnan university of Chinese medicine , kunming, yunnan, 650500;2.Paris Public Hospital Group,Paris 75013;3.Yunnan cancer hospital, Kunming 650106;4. European platform for precision medicine,Paris 75013;5.Kunming TCM Hospital, Kunming 650051;6.Kunming st John's rehabilitation hospital kunming 650033)

 

Résumé

Utilisation d’ ATAS Linggui Baga chez des patients traité par chimiothérapie post-pératoire d’un cancer du sein, dans un essai clinique randomisé évaluant la fatigue.

Le plan comprend la modalité du projet de recherche, les résultats de l’étude, les conclusions, l’innovation et le biais et interprétations.

Ce projet de recherche a été conçu à la fois par une équipe Francaise de haut niveau d’experts en oncologie aunsi que par des experts chinois du cancer du sein de l’hopital de cancerologie du Yunnan et l’institut ARIATAS. L’ensemble a été controlé par des experts Français pour répondre au standards internationaux des essais clinique de phase 3.

 

Conclusion

Un essai clinique rigoureux, randomisé, en simple aveugle, a été mené pour étudier les effets d’un traitement par la méthode d’acupuncture Linggui Bafa-ATAS sur la fatigue induite post chirurgie cancéreuse du cancer du sein. Il a été montré la faisabilité de cet essai clinique, la bonne compliance des patientes, la sureté de la méthode et son efficacité réelle. 

La méthode Linggui Bafa-ATAS améliore significativement la fatigue post-chirurgie des cancers du sein ainsi qu’elle réduit le niveau d’anxiété, de dépression, l’insomnie et améliore la qualité de vie des patients.

La méthode Linggui Bafa-ATAS améliore significativement le niveau de cortisol des patients ayant un grand niveau de fatigue post chirurgie du cancer, réduit leur taux de cytokine inflammatoire permettant d’améliorer leur statut inflammatoire chronique et endocrinien. De plus Linggui bafa-ATAS améliore le ratio de cellules CD3+T et CD4+T  chez les patients avec CRF, maintient l’équilibre du ratio des lymphocytes CD4/CD8 et régule les fonctions de l’immunité cellulaire des patients CRF après une chirurgie du cancer du sein.

 

1. Research scheme design

This research protocol was jointly designed by the French high-level team of clinical oncology research experts, breast cancer experts of Yunnan Cancer Hospital and spatio-temporal Acupuncture Research Institute. It was evaluated by French experts and met the standards of the international clinical trial Phase III protocol.

The main experts participating in the scheme design are:

Gustav Huth Institute of Clinical Research, France(Institut Gustave Roussy)Breast cancer specialist:Mahasti Saghatchian;

President of the European Federation of Oncologists and President of the European Agency for the Approval of Clinical Research on Anticancer drugs(EORTC):JeanPierre Armand;

Ju Liya, CHIEF executive officer and senior immunologist of European Precision Medicine Platform;

Director of Statistics, Curie Cancer Hospital, France:Bernard ASSELAIN、Director of the Centre for Clinical Research in A variety of medicine, Ministry of Health, France(Unité INSERM U1178):Bruno FalissardAnd the special Commissioner:Caroline Barry;

Li Wenhui, vice President, Chen Dedian, Liu Dequan, Nie Jianyun, director of mammary gland Department, The Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital);

Director of Spatio-temporal Acupuncture Research Institute: Professor Zhu Miansheng.

 

2. Clinical research

Study design :Single - blind, randomized, controlled clinical trial

research object :reast cancer patients with postoperative chemotherapy fatigue

Recruitment methods: Hospital patients ,Recruitment notice, Telephone registration

Sample size

 

Based on the relevant literature and the tutor's experience in the treatment of cancer induced fatigue (CRF), the average improvement amplitude of the time-space acupuncture group was 1.45 points higher than that of the blank control group and the sham acupuncture group, namely =1.45. Three sets of standard deviation is 2.0, namely s = 2.0 take alpha = 0.025 (unilateral), beta = 0.2, 1-0.025 = 1.96 is mu, mu 1-0.2 = 0.84.

By substituting the above parameters into the formula, n=2x[(1.96+0.84)x2.0÷1.45]2 = 29.7992≈30

In other words, 30 effective cases should be completed in each group, and the three groups should be designed in a 1:1:1 parallel design. A total of 90 effective cases should be completed in the three groups for treatment and follow-up.

A total of 108 subjects were required for inclusion at a loss rate of not more than 20%. At present, 104 patients have been included in this study, and 90 effective cases have been treated and followed up.

Randomized:ATAS group; Sham group; Blank control group

Random method: Random hiding: Random number table was used to generate random number and grouping results according to the order of medical treatment.Group hiding: opaque envelope sealed, sealed by special person for safekeeping.

Blinded

Due to the particularity of acupuncture intervention, acupuncturists are not blind,Blind patients and oncologists; Blind the data statistics and outcome evaluators,Operation, evaluation and statistical analysis should be separated to ensure the objectivity of the results.

 

Treatment options    

A:ATAS  group

 

Preparation before acupuncture:

(1) Placement of the patients and the four diagnostic methods

(2) Three tones: body, breath and spirit

(3) Holes

 

Acupuncture operation:

(1) Point selection and body position: temporal and spatial points

(2) Acupuncture sequence: acupuncture time points and then acupuncture space points

(3) Insertion and alignment techniques

(4) Retention and release of needles

 

Time acupoints

(1) The time points of Linggui Eight methods are eight meridional intersection points: Gongsun, Neiguan, Zhaohai, Liemu, Shenmai, Houxi, Foot-Linweiwei, and Waiguan

(2) The pairing combinations of eight Mai Intersection points: Gongsun with Neiguan, Neiguan with Gongsun, Zhaohai with Lieyue, Lieyue with Haihai, Shenmai with Houxi, Houxi with Shenmai, Foot-lin with Waiguan, and Foot-lin with Foot-lin. In each pair of acupoints, the first acupoint is the main acupoint, and the second acupoint is the matching acupoint, which must be used simultaneously.

(3) The time-acupoints-space acupuncture spirit turtle eight method was different from those of memory points, and the memory points of this experiment were divided into five categories. A. Acupuncture point of chemotherapy time; B. Time acupoints of aggravation of fatigue; C. The original psychological point of breast cancer; D. Time acupoints of breast cancer surgery; E. Birth hour points of breast cancer patients with genetic factors. Note: This experiment mainly USES acupoints at the time of seeking medical treatment. When obtaining sufficient evidence related to specific events of patients' onset or change of their condition, relevant time acupoints can also be selected in memory acupoints.

 

Space acupoints

The spatial acupoints for preventing postoperative chemotherapy fatigue caused by breast cancer through time-space acupuncture and Lingturtle eight methods are composed of three groups of nine points: the nine points of the neck and back, the nine points of the head and hands, and the nine points of the chest, abdomen and lower limbs.

 

B:Sham group

Preparation before acupuncture: The placement of the patients was combined with the four diagnostic methods

Acupuncture operation:

(1) Acupoint selection: 16 stimulus points

(2) Acupuncture sequence and position

(3) Insertion and alignment techniques

(4) Retention and release of needles

 

Sham acupuncture

(1 No or little specific therapeutic effect: The meridians with no definite effect on the treatment of CRF of breast cancer were selected for side-opening acupuncture (reference).

(2Acupuncture on areas that have no specific therapeutic effect: Breast cancer CRF is a complex disease, but it is currently believed to be mainly related to the endocrine system, so we avoid acupoints that have regulatory effects

(3)Subjects can hardly detect the difference between comfort acupuncture and therapeutic acupuncture: The points selected by spatiotemporal acupuncture involve the whole body, Sham   acupuncture .The selected acupoints also involve the whole body, and the operation is carried out in a single room, so as to avoid patients' private communication.

 

C :Blank control group

Adjuvant chemotherapy only, not any acupuncture treatment.

Adjuvant chemotherapy regimen: Epirubicin 90mg/m2+ cyclophosphamide 600mg/m2, q3wX4.

In the course of chemotherapy involved in the scale assessment and peripheral blood detection.

 

Clinical observation index

Scale evaluation; Peripheral blood test; Safety/compliance evaluation

PiPer fatigue Multidimensional scale

Compiled by Piel in 1991 and later translated into Chinese by Sokw

There are 27 entries in total, graded by the number 0 ~ 10, 0 means no, 10 means heaviest

Four subjective dimensions: behavioral dimension, emotional dimension, perceptual dimension and cognitive dimension

Total score = total entries ÷ entries; Dimension = Dimension entry score ÷ entry number

Simple one- dimensional fatigue scale

By the Man - doza research and development

There are 9 entries in total, graded by the number 0 ~ 10, 0 means no, 10 means heaviest

Severity of insomniaISI

There are 7 items in total, and each item is rated from 0 to 4

Quality of life (SF-36)

Developed by the New England Medical Center Health Research Institute in Boston, United States

General physical health assessment: physiological function, physiological function, physical pain, overall sense of health

General assessment of mental health: vitality, social function, emotional function, mental health

Hospital anxiety, depressionHADS

Zigmond AS and Snaith RP

There were 14 items in total, 7 were anxiety (single number) and 7 were depression (double number). Each item was rated on a 4 scale, of which 8 were rated in reverse

To evaluate the changes of anxiety and depression before and after treatment

Peripheral blood test

Cortisol: Venous blood test was performed under fasting state at 8:00am     Radioimmunoassay (RIdioim-Munoassay (RIA) was used for assay

Inflammatory Cells factor:Fasting venous blood was tested for IL-2, IL-6 and TNF-A Chemiluminescent immunoassay (CLIA)

Immunology Relevant indicators: Fasting venous blood test for T lymphocyte cell line ratio (CD3+, CD4+, CD8+, CD4+/CD8+) and natural killer cells (NK)Use Flow Cytometry Detection (FCM)

Safety/compliance evaluation

Safety:Side reaction scale;Adverse event record sheet;Blood routine, liver and kidney function, ecg and other tests

Compliance:Needling chart Compliance record sheet Study completion Summary table follow-up record sheet Satisfaction evaluation

Data management

Database: EPI Data database software

Data entry: double entry, real-time proofreading, data verificationPersonnel management

Statistical analysis:SPSS(IBM. Version 20.0)

Descriptive statistics: Mean plus or minus standard deviation (Mean±SD), 95% confidence interval. Measurement data were compared among groups. All groups were normally distributed with homogeneous variances. One-way ANOVA was used for one-way ANOVA, and nonparametric test was used for non-normal distribution. In group comparison, paired sample T-test was used for normal distribution, and two samples non-parametric test was used for non-normal distribution. Counting data: chi-square test was used.

Safety evaluation

SERS scale: None of the three groups had serious side effects.

Adverse events: All the adverse events occurred during treatment in the three groups were mild.

Routine hematuria and stool examination and liver and kidney function examination were performed before and after treatment in the three groups. During the study, no clinically significant changes were found, and a small number of patients showed mild liver dysfunction. Drug-induced liver injury caused by chemotherapy drugs was considered in combination with medical history, clinical symptoms and other factors.

 

3. Conclusions

(1) A rigorous single-blind, randomized controlled clinical trial was conducted to verify that the time-acupoints-space acupuncture spirit turtle eight method for the treatment of postoperative cancer-induced fatigue (CRF) of breast cancer has strong operability, good patient compliance, safe clinical operation and accurate efficacy.

(2) The time-acupoints-space acupuncture spirit turtle eight method can effectively improve the fatigue symptoms of patients with cancer-related fatigue after breast cancer surgery, reduce the degree of anxiety, depression and insomnia caused by breast cancer-related fatigue, and improve the quality of life of the patients.

(3) The time-acupoints-space acupuncture spirit turtle eight method can effectively improve the cortisol content of patients with high CRF; Reducing inflammatory cytokine levels to improve endocrine and chronic inflammatory status in breast cancer PATIENTS with CRF; In addition, the time-acupoints-space acupuncture spirit turtle eight method  can improve the RATIO of CD3+T and CD4+T cells in breast cancer PATIENTS with CRF, maintain the balance of THE ratio of CD4+/CD8+T lymphocytes, and regulate the cellular immune function of patients with CRF after breast cancer surgery .

 

4.Innovative

(1)For the first time, a single-blind, well-designed randomized controlled clinical trial was used to explore the difference in efficacy and mechanism of different intervention measures on various levels of breast cancer CRF in combination with relevant scales and peripheral blood tests.

(2)It is the first time to evaluate the clinical efficacy, safety and patient compliance of the time-acupoints-space acupuncture spirit turtle eight method in the intervention of breast cancer CRF, and to discuss the mechanism of its treatment.

(3)The whole process of the implementation of this program runs through the diagnostic method of "observation, listening, asking and cutting" and the concept of "treatment based on syndrome differentiation" in TCM. In addition, this experiment adopts the eight methods of the time-acupoints-space acupuncture spirit turtle eight method, and combines the opening of time acupoints with the application of space acupoints (three nine palaces), which fully reflects the thought connotation of "heaven and man correspond" and the treatment principle of "time, place and person correspond" and "treating the disease to seek the root" in Traditional Chinese medicine. On the whole, this experiment has realized the close combination of TCM individualized treatment and clinical trial standardization, and embodies the essence of acupuncture and moxibustion.

 

5 . Limitations and Prospects

(1) The clinical trial was a single center with a small sample size, and the extrapolation of the conclusions was relatively limited. Not all data are normally distributed, so the selection of statistical analysis method is limited.

(2) Due to the circadian rhythm of some of the indicators measured in this study, this study was designed to measure only once before and after treatment, considering the compliance of the clinical trial. If the indicators can be measured at multiple time points in the same day and combined with different time points in the treatment cycle, the secretion rhythm and change trend of different indicators under different intervention measures can be deeply discussed.

(3)This research experts academician workstation team for the yunnan Zhu Mian students 2018 key international  project fund part of the research content of yunnan province (space-time acupuncture to improve breast cancer postoperative chemotherapy side effects in clinical studies) : on the premise of clinical curative effect is confirmed, will the blood of molecular biology index and inventory synchronization study, will get more valuable research results.

 

Zheng ZUO

Docteur en médecine, professeur de l'Université de Yunnan de MTC, maître tuteur. Ses recherches sont principalement basées sur la prévention et le traitement des rhumatismes et des maladies rénales par l'acupuncture spatio-temporelle et la MTC combinée à l'acupuncture.