In this study, we focus on survivors of postoperative chemotherapy for breast cancer, specifically reporting on the impact of ATAS on fatigue in these patients. The aim is to assist and guide breast cancer survivors suffering from fatigue and to explore whether ATAS is more effective in reducing CRF with fewer side effects.

In September 2017, a project discussion meeting involving breast cancer experts from China and France was organized in Kunming, Yunnan Province, China. Subsequently, leveraging the resources of Yunnan Cancer Hospital and with French precision medicine platform experts as contributors, a methodological design was developed based on the clinical characteristics of ATAS. The clinical trial protocol was completed, covering statistical foundations, efficacy evaluation methods, and implementation processes. The complete date of the first trial registration for this experiment was 11/12/2017. The research was approved by the Ethics Committee of Yunnan Cancer Hospital, approval number YJZ201705; Chinese Clinical Trial Registration number ChiCTR-IPR-17013652.All eligible participants signed informed consent forms before enrollment, and the trial was reported according to the Consolidated Standards of Reporting Trials (CONSORT) guidelines ( Supplementary Material 1 ).

All diagnoses were confirmed through pathological histology, mammography, and other examinations, following the diagnostic criteria for breast cancer outlined in the Guidelines and Norms for the Diagnosis and Treatment of Breast Cancer (2015 Edition) by the Chinese Anti-Cancer Association. Inclusion criteria: 1. Meeting the diagnostic criteria for breast cancer, having undergone breast cancer surgery, and with no evidence of distant metastasis; 2. Meeting the criteria for adjuvant chemotherapy; 3. Patients aged between 18 and 60 years; 4. KPS score of ≥60. Exclusion criteria: 1. Known severe inflammation or metabolic disease; 2. Having received acupuncture treatment within the past 4 months; 3. Treated for cancer within five years prior to recruitment; 4. Mental disorders; 5. Patients with a fear of needles; 6. Skin disease at the acupuncture sites.

The sample size was estimated using a superiority trial design with a 1:1:1 group ratio, and the sample size estimation formula is as follows: n = 2 [ ( μ 1 − α + μ 1 − β ) s ϵ ] 2 .

In the above formula: n represents the sample size required for each group, α represents Type I error, β represents Type II error, 1-β represents power, s is the standard deviation, μ is the population mean, μ₁ -α and μ₁ -_β represent the one-sided critical values corresponding to 1-α and 1-β, and ϵ is the effect size difference between the experimental group and the control group. Based on relevant literature and Professor Zhu Miansheng’s previous experience in treating CRF, the improvement in the Space-time Acupuncture Linggui Bafa group was 1.45 points higher than that in the control and sham acupuncture groups, i.e., ϵ = 1.45; the standard deviation for the three groups was assumed to be 2.0, i.e., s = 2.0. α = 0.025 (one-sided) and β = 0.2 were used. Substituting these parameters into the formula, 30 valid cases are required for each group. With a 1:1:1 parallel design for the three groups, a total of 90 valid cases need to be treated and followed up. Considering a dropout rate of no more than 20%, a total of 108 participants are required to be included.

After participants provided consent and signed the informed consent form, we used stratified block randomization for group assignment. The 108 enrolled patients were stratified into three groups based on age (18-30 years, 31-60 years). In the first step of grouping, the patients were divided into 12 groups, each consisting of 9 participants, for a total of 108 subjects. Next, randomization was performed. Participants were sequentially numbered based on their order of visits. Starting from a specific position on the random number table, consecutive random numbers were selected and assigned to the corresponding groups: numbers 1-3 for group A (ATAS group), numbers 4-6 for group B (sham acupuncture group), and numbers 7-9 for group C (waitlist control group). Each group consisted of 36 participants, maintaining a 1:1:1 ratio. Due to the specific nature of acupuncture procedures, our study employed a single-blind design. Only the acupuncturists and the research coordinators who had no contact with the patients were aware of the random group assignments.

This study recruited participants from the breast cancer ward at Yunnan Cancer Hospital between March 2018 and December 2019. Recruitment was primarily conducted by the doctors and nurses in the ward. We contacted interested participants by phone to screen for eligibility based on the inclusion criteria. Eligible participants were provided with detailed information about the study. They voluntarily chose to participate or decline and were informed that they had the right to withdraw at any time without any impact on their treatment ( Figure 1 ).

Data analysis was conducted using SPSS 28.0 software. The data in this study are presented as “ x ¯ ± s”, and normality and homogeneity of variance tests were conducted. For comparisons between three groups that met the assumption of normal distribution, one-way ANOVA was used. If homogeneity of variance was assumed, the LSD method was applied; if homogeneity was not assumed, the Tamhane’s T2 method was used. Non-normally distributed data were analyzed using the rank-sum test. Categorical data were analyzed using the chi-square test. A P-value of < 0.05 was considered statistically significant.

A total of 108 postoperative chemotherapy patients with breast cancer were screened for eligibility, and 102 qualified participants (94.4%) were randomly assigned. Figure 1 shows the screening process and the reasons for exclusion. Thirty participants were assigned to receive ATAS, thirty to receive sham acupuncture, and another thirty to the waitlist control group. A total of 90 participants (100%) completed the intervention, and 86 participants (95.6%) completed the follow-up assessment.

Twelve participants (11.8%) withdrew from the study for various reasons: 4 from the ATAS group, 4 from the sham acupuncture group, and 4 from the waitlist group. The participants’ ages ranged from 18 to 60 years, and all were female. The average age in the ATAS group was 48.85 years [95% CI, 40.82 to 56.78], 49.6 years in the sham acupuncture group [95% CI, 40.16 to 59.04], and 48.03 years in the waitlist group [95% CI, 39.64 to 56.42]. Table 1 shows the baseline characteristics of the three groups.

In the ATAS group, the total PFS score after the intervention was 4.98 [95% CI, 3.96 to 6.00], showing a decrease of 0.8 points from the baseline (decreasing from 5.78 to 4.98, P < 0.05). The scores for each dimension after the intervention were as follows: Behavior Dimension, 5.10 [95% CI, 3.80 to 6.40], Affection Dimension, 5.57 [95% CI, 4.53 to 6.61], Perception Dimension, 5.07 [95% CI, 3.45 to 6.69] and Cognition Dimension, 4.30 [95% CI, 2.93 to 5.67]. All of these changes were statistically significant (P < 0.05). In the sham acupuncture group, the total PFS score after the intervention was 5.67 [95% CI, 4.90 to 6.44], showing an increase of 0.1 points from the baseline (P > 0.05). Additionally, the scores for the four dimensions before and after the intervention showed no statistically significant differences (P > 0.05). The Behavior Dimension is 5.87 [95% CI, 4.65 to 7.09], the Affection Dimension is 6.17 [95% CI, 5.15 to 7.19], the Perception Dimension is 5.73 [95% CI, 4.82 to 6.64], and the Cognition Dimension is 4.90 [95% CI, 3.71 to 6.09]. In the waitlist control group, the total PFS score increased from 5.68 [95% CI, 5.09 to 6.77] to 6.47 [95% CI, 5.93 to 7.01]. The scores for all four dimensions increased, with the magnitude of the increase greater than that in the sham acupuncture group. The Behavior Dimension is 6.60 [95% CI, 5.71 to 7.49], the Affection Dimension is 6.97 [95% CI, 5.87 to 8.07], the Perception Dimension is 6.37 [95% CI, 5.48 to 7.26], and the Cognition Dimension is 5.93 [95% CI, 4.73 to 7.13]. After completing the treatment, statistical analysis was conducted for the three groups. The ATAS group showed significantly better results in total PFS scores, as well as in the Behavior Dimension, Affection Dimension, Perception Dimension, and Cognition Dimension, with all differences statistically significant (P < 0.05) ( Table 2 ).

In the ATAS group, the ISI score after the intervention was 15.17 [95% CI, 12.28 to 18.06], showing a decrease of 2.5 points from the baseline (from 17.67 to 15.17, P < 0.05). In the sham acupuncture group, the ISI score after the intervention was 16.70 [95% CI, 13.17 to 20.23], showing a decrease of 0.47 points from the baseline (from 17.17 to 16.70, P > 0.05). In the waitlist control group, the ISI score after the intervention was 18.30 [95% CI, 15.30 to 21.30], showing an increase of 1.07 points from the baseline (from 17.23 to 18.30, P > 0.05). After treatment, the difference in ISI scores between the ATAS group and the other two groups was statistically significant (P < 0.05).

In terms of HADS, the ATAS group showed a decrease in HADS-A scores from 11.97 [95% CI, 6.87 to 17.07] to 8.63 [95% CI, 5.18 to 12.08] (P < 0.05) and a decrease in HADS-D scores from 11.11 [95% CI, 6.78 to 15.56] to 7.80 [95% CI, 4.73 to 10.87] (P < 0.05). In the sham acupuncture group, the HADS-A score decreased from 10.77 [95% CI, 6.69 to 14.85] to 10.43 [95% CI, 6.85 to 14.01], with a decrease of 0.34 (P > 0.05). The HADS-D score decreased from 10 [95% CI, 6.49 to 13.51] to 8.97 [95% CI, 6.20 to 11.74] (P < 0.05). In the waitlist control group, the scores increased: HADS-A rose from 9.7 [95% CI, 5.79 to 13.61] to 12.37 [95% CI, 8.94 to 15.80], and HADS-D increased from 9.20 [95% CI, 5.72 to 12.68] to 10.93 [95% CI, 7.49 to 14.37]. After treatment, the ATAS group showed significant advantages in HADS scores compared to the other two groups, with statistically significant differences (P < 0.05).

In the ATAS group, after the intervention, IL-2 and IL-6 scores decreased by 3.02 points (a decrease from 23.20 to 20.18, P < 0.05) and 3.87 points (a decrease from 28.43 to 24.56, P < 0.05), respectively. At the same time, CD3⁺T and CD4⁺T levels increased. CD3⁺T increased from 68.63 [95% CI, 58.83 to 78.43] to 79.03 [95% CI, 68.56 to 89.50], and CD4⁺T increased from 36.84 [95% CI, 28.25 to 45.43] to 42.89 [95% CI, 35.14 to 50.64]. In the sham acupuncture group, after the intervention, IL-2 and IL-6 levels decreased by only 0.91 points (a decrease from 24.43 to 23.52, P > 0.05) and 0.09 points (a decrease from 27.81 to 27.72, P > 0.05), respectively. CD3⁺T and CD4⁺T levels decreased compared to before the intervention. In the waitlist control group, IL-2 and IL-6 levels showed an increasing trend compared to before the intervention. IL-2 increased from 22.43 [95% CI, 11.44 to 33.42] to 27.55 [95% CI, 14.92 to 40.18], and IL-6 increased from 28.00 [95% CI, 8.94 to 47.06] to 36.08 [95% CI, 16.21 to 55.95]. CD3⁺T increased from 70.32 [95% CI, 59.11 to 81.53] to 72.47 [95% CI, 61.79 to 83.15], while CD4⁺T decreased by 3.26 points. After treatment, the differences in IL-2, IL-6, CD3⁺T, and CD4⁺T between the ATAS group and the other two groups were statistically significant (P < 0.05).

Seven participants in the ATAS group and the sham acupuncture group reported a total of nine adverse events. These adverse events included hematoma, bleeding, or pain around the acupuncture sites. No adverse events were reported in the waitlist control group ( Table 3 ).

Our randomized controlled trial indicates that, compared to sham acupuncture and waitlist control, ATAS intervention significantly alleviated fatigue in postoperative breast cancer patients. It also resulted in greater reductions in secondary outcome measures such as insomnia, anxiety, and depression compared to the sham acupuncture group. Additionally, ATAS lowered levels of inflammatory cytokines, improved the inflammatory status of patients, and had a positive effect on their quality of life. In the ATAS group and the sham acupuncture group, a total of nine adverse events occurred, with an incidence rate of 11.7%. All adverse reactions were mild and transient, requiring no medical intervention. The occurrence of adverse events might have been due to a failure to apply pressure immediately after needle removal. This should be addressed in future clinical practice.

In terms of outcome measures, our study focused on patients’ subjective experiences, such as fatigue, insomnia, anxiety, and depression. Emphasizing patients’ subjective perceptions, symptom improvement, satisfaction with disease diagnosis and treatment, and quality of life plays an irreplaceable role in evaluating clinical efficacy outcomes (23) Adjuvant treatments for breast cancer patients primarily include radiotherapy, chemotherapy, and endocrine therapy. Clinical studies on patients receiving chemotherapy have shown that 25% to 50% of these patients may develop peripheral neuropathy (24). Patients with stage I-III breast cancer experience poorer sleep, increased fatigue, and more severe depressive symptoms during chemotherapy (25, 26). Reports from breast cancer survivors indicate that most patients worry about disease recurrence, struggle to return to work, experience strained family relationships, and face psychological distress related to their social roles. As a result, after completing treatment, patients may experience varying degrees of pain, fatigue, sleep disturbances, and depression (27). These symptom clusters are persistent (28, 29) and significantly associated with multiple dimensions of quality of life (30).

Professor Zhu Miansheng is the founder of ATAS and a recipient of the French Knight of the Legion of Honor, First Class. Linggui Bafa is known as the “Qi Jing Na Gua” method in ancient China. A special structure is formed based on the Eight Trigrams and Luo Shu. Professor Zhu’s previous clinical studies revealed that Space-time acupuncture Linggui Bafa not only improves the symptoms of perimenopausal syndrome but also lowers serum FSH levels and raises E2 levels (31). It can further reduce the frequency of nighttime urination in elderly individuals, extend sleep duration, and enhance the overall quality of life for patients (32). The space acupoints of Space-time acupuncture Linggui Bafa consist of three groups of acupoints. In each group, the first acupuncture point corresponds to the acupoint associated with the time, and then, after combining with the Eight Trigrams, the other space acupoints are needled in sequence. Among the three groups of acupoints, the middle acupoints belong to the GV and CV. Taoism in China believes that this is a channel where energy converges. Therefore, we selected the acupoints of GV and CV, which reflect the characteristic of spatial acupoints gathering energy. SI11, CV17, ST25, BL18, BL20, and ST36 are commonly used and important acupoints for treating breast diseases. The space acupoints, as a whole, represent the three groups of acupoints as carriers and channels for the communication of the energy of heaven and earth.

ATAS is an innovation based on traditional acupuncture that combines time acupoints and space acupoints into a new acupuncture method (33). With the development of society and changes in people’s lifestyles, the spectrum of modern diseases has also undergone significant changes. Human diseases have shifted from primarily external invasive diseases to predominantly chronic and psychosomatic diseases. This phenomenon has become a major challenge for doctors. In clinical treatment, it is necessary to address the causes of fatigue in patients, tailoring the treatment according to the time, location, and individual characteristics. When selecting time acupoints in ATAS, five main methods are used: based on the time of psychological trauma, the time of accidents or natural disasters, the onset time of treatment-induced adverse reactions, diseases with specific onset times, and the patient’s birth time (34). The etiology and pathogenesis of CRF in breast cancer are complex, involving factors such as the cancer itself, surgery, and psychological trauma. In the treatment using the ATAS method, all these factors are taken into consideration. For example, if fatigue is significantly worsened after surgery, the time of the surgery would be selected as the time acupoint. Space acupoints are always used after time acupoints, following a specific sequence, and integrating the time points and space points into a cohesive system (35). This approach can address the disease itself while also having a positive effect on symptoms induced by the treatment. Additionally, in the ATAS method, the combination of time acupoints and space acupoints fully embodies a personalized treatment plan that considers the specific timing and individual needs of each patient. This trial achieved a close integration of traditional Chinese medicine’s individualized treatment approach with the standardized requirements of clinical trials, embodying the essence of acupuncture’s original principles. We hope that this clinical trial research will provide a reference design for traditional Chinese medicine clinical trials, offer clinicians better treatment options for breast cancer CRF, and enable breast cancer CRF patients to have more choices in their treatment.

Our study found that the total PFS score in the ATAS group decreased by 0.8 points after the intervention. The etiology of cancer-related fatigue may be related to immune-inflammatory responses (36). Di Meglio (37) found that high levels of IL-6 and IL-2 are associated with CRF. Cohen (38) found that IL-6 and IL-8 play a modulatory role in the relationship between physical activity and fatigue. Inflammatory cytokines from the peripheral system can transmit signals to the brain via the vagus nerve or endocrine system (39), triggering the further release of inflammatory mediators, leading to fatigue, cognitive dysfunction, or sleep disturbances, among other behavioral changes, in an attempt to restore homeostasis (40). At the same time, tissue damage caused by tumor treatments such as surgery, radiotherapy, and chemotherapy also triggers systemic inflammation, and psychological stress related to cancer diagnosis or treatment is one of the factors contributing to the imbalance of inflammatory factors (41). Sleep disorders are often observed before cancer treatment, and it has been confirmed that they coexist with other conditions such as anxiety and depression. Different breast cancer treatment methods increase the risk of sleep disorders, which, in turn, adversely affect the efficacy of cancer treatment (42). Cellular immunity is an essential component of the immune system, with T cells playing a central role in defending against pathogen invasion, eliminating cancer cells, preventing autoimmune diseases induced by pathogens and the environment, and limiting chronic inflammation, thereby maintaining immune homeostasis (43, 44). Research has shown that in breast cancer survivors with persistent fatigue, T lymphocyte levels are elevated, particularly CD4⁺ T cells (45). CD4⁺ T cells and CD8⁺ T cells interact and exert both positive and negative regulatory effects on immune responses, thereby jointly regulating immune homeostasis. Acupuncture also has a bidirectional regulatory effect, which may be related to the mechanism through which acupuncture modulates immune function.

Considering the relationship between inflammation and immune suppression, anti-inflammatory treatments and the restoration of host immunity may be effective strategies for cancer treatment (46). In recent years, numerous studies have investigated the mechanism of acupuncture’s anti-inflammatory effects (47, 48), which can be both local and systemic. The anti-inflammatory effect of acupuncture is primarily achieved in two ways: one through sensory stimulation from acupuncture to the central nervous system, stimulating the HPA axis, sympathetic, or vagal nerve pathways to regulate immune function. The other is through acupuncture as a minimally invasive stimulus to the body surface, inducing or enhancing the body’s own inflammatory reflex (49). Previous studies have shown that electroacupuncture is effective in treating various diseases involving excessive inflammatory responses (50, 51). A meta-analysis showed (52) that the acupuncture treatment group exhibited improved immune function, with increases in CD3 cells, CD4 cells, and the CD4/CD8 ratio, while IL-1, IL-4, IL-6, and CRP levels of inflammatory markers decreased. Acupuncture may improve immune outcomes and reduce inflammation during cancer treatment. A clinical cancer study found that, in the acupuncture group, CD3⁺ T and CD4⁺ T cell levels increased, while IL-6 and CRP levels decreased (53). A systematic review of 28 clinical studies showed that acupuncture can significantly reduce clinical scores of depression and anxiety in cancer patients (54), and the American Society of Integrative Oncology also recommends acupuncture for treating breast cancer-related negative emotions in its clinical guidelines (12). Regarding immune system regulation under emotional disturbances, studies suggest that electroacupuncture can reduce the elevation of inflammatory factors in the serum of animals subjected to postoperative stress or chronic adolescent restraint stress models (55, 56). Therefore, acupuncture may regulate immune responses by alleviating emotional disturbances in stressful conditions, and this immune modulation could be one of the potential mechanisms by which acupuncture contributes to cancer prevention and treatment in the future. Thus, selecting acupuncture for patients after breast cancer surgery can regulate immune function while also positively affecting accompanying symptoms. This study found that, in the ATAS group, the levels of CD3⁺ T lymphocytes and CD4⁺ T lymphocytes increased throughout the study, while IL-2 and IL-6 levels decreased. This indicates that ATAS positively affects the chronic inflammatory state in breast cancer patients after chemotherapy and enhances immune function in breast cancer CRF patients.

The limitations of this study include a small sample size and a short observation period, with effects observed only after one chemotherapy cycle post-surgery. The results related to quality of life, survival time, and mortality of breast cancer patients after treatment could not be immediately presented. In the next stage of the study, we plan to increase the sample size, conduct follow-up tracking, and perform further analysis. In the later stages of the study, due to the specificity of acupuncture procedures, the acupuncturist could not be blinded, which limits the single-blind design. Therefore, we blinded the outcome assessors and data analysts, who were not involved in the treatment procedures. The study reported only mild adverse events and lacked long-term safety assessments. In future studies, regular monitoring of patient fatigue, sleep disorders, anxiety, and depression should be conducted to assess whether they worsen. Additionally, imaging tests and estrogen levels should be monitored for abnormalities, and attention should be paid to the occurrence of cardiovascular diseases, fractures, and peripheral neuropathy.

Currently, the application of acupuncture in oncology treatment is still in its early stages, primarily used to manage adverse reactions induced by comprehensive treatments like radiotherapy and chemotherapy. Therefore, future research should not be limited to treating symptoms caused by tumors. More convincing research is needed to demonstrate the inhibitory effects of acupuncture on tumors, thereby fully leveraging the potential advantages of acupuncture in cancer treatment research.