Acupuncture for Climacteric-Like Symptoms in Breast Cancer Improves Sleep, Mental and Emotional Health: A Randomized Trial

Abstract

Objective: Breast cancer is the most prevalent malignant neoplasm in women. Optimal treatment frequently includes a hormonal-blockage phase maintained for 5–10 years. Pharmacologic agents used for this blockage induce many climacteric-like symptoms, which often exact a heavy toll on patients' quality of life. Acupuncture has had promising results for treating climacteric-like symptoms induced by hormonal blockage, but there is no evidence of efficacy for controlling hot flashes.

Materials and Methods: This trial used acupuncture to treat the climacteric-like symptoms of patients with breast cancer, focusing on the mental, physical, and genitourinary symptoms and sleep disturbances, to determine the influence of acupuncture treatment. The randomized placebo-controlled trial, at a university-based cancer center, with blinded data collectors, compared an Acupuncture group (A), a Sham-Acupuncture group (S), and a Wait-List Control group (C). The patients were receiving tamoxifen. Group A had 10 weekly sessions of manual Acupuncture; Group S had 10 weekly sessions of Sham Acupuncture; and Group C spent 10 weeks on a Wait-List. The main outcome measures were the Beck Depression Inventory–II (BDI-II), the Pittsburgh Sleep Quality Index (PSQI), and the Menopause Rating Scale (MRS).

Results: Primary analysis revealed differences among the groups' improvements in scores for the 3 questionnaires (P < 0.001), The A group had significant improvements on the BDI-II (P < 0.001), PSQI (P < 0.002), and MRS (P < 0.004) compared to the S group in a post hoc analysis.

Conclusions: Acupuncture improved sleep, and mental and emotional distress symptoms induced by hormonal blockage in patients with breast cancer.

Clinical Trial: This trial was registered at CAAE as trial #: 37758414.8.0000.0065.

Introduction

Breast cancer is the most prevalent malignant neoplasm in women, with an estimated 2.3 million new cases worldwide in 2020.¹ Optimal treatment involves a hormonal-blockage phase in addition surgical removal of the cancer and chemotherapy, depending on the tumor-cell's biology. The hormonal-blockage phase is meant to inhibit the growth and development of tumor cells that may have escaped these previous 2 phases of treatment and should be maintained for a few years, usually 5–10, in order to induce a natural death of those occasional remaining tumor cells.²

Pharmacologic agents used for hormonal blockage induce a myriad of climacteric-like symptoms, which exact a heavy toll on patients' quality of life (QoL) and well-being, compromising compliance with the treatment plan, leading to an increased risk of suboptimal treatment.³

The most-common therapy for climacteric-like symptoms would be hormonal replacement therapy but this is exactly the opposite case in this scenario. Other pharmacologic options, such as antidepressants and anticonvulsants, seem to reduce symptoms but also induce toxicity profiles that may compromise compliance.⁴ Psychotherapy, exercise (particularly regular exercise), and herbal and natural products produce some relief,⁵ but fail to have sustained and meaningful clinical effects.⁶

Acupuncture has shown mixed results in trials as a treatment for climacteric symptoms,^7,8 with some evidence of its efficacy for controlling menopausal symptoms induced by hormonal blockage but failing to produce statistically significant responses with respect to hot flashes' frequency and severity,^9,10 compared to placebo interventions.

To determine the benefits that acupuncture may provide to women battling breast cancer better, acupuncture was tested as treatment for their climacteric-like symptoms' cluster, focusing on sleep and mental disturbances, as well as the physical and genitourinary symptoms. A standard selection of classical acupoints was used based on Traditional Chinese Medicine (TCM).¹¹

Materials and Methods

This study was conducted to outline the benefits of acupuncture for symptom control in women who are undergoing the hormonal-blockage phase of breast-cancer treatment.

Eligibility criteria included female gender, diagnosed with breast cancer, receiving tamoxifen treatment for at least 6 months, and experiencing climacteric-like symptoms. Exclusion criteria were modification of the tamoxifen regimen, active chemotherapy, previous experience with acupuncture, or failure to comply with weekly visits to the clinic during the interventional phase of the study.

This was a single-blinded, randomized, placebo-controlled trial with blinded data collectors. Standards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA) guidelines were used for this trial. Box 1 shows the STRICTA checklist that was used. Boxes 2 and 3 show the STRICTA methodology and results reporting for this trial.

Box 1.

Standards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA)—Checklist

Acupuncture rationale	(1a) Traditional Chinese Acupuncture
	(1b) Reasoning: Tonify Kidney-essence
	(1c) Fixed points; no variations
Details of needling	(2a) Number of needle insertions: 6
	(2b) Points used: GV 16, GV 20, BL 23 & CV 6
	(2c) Insertion for 1.5 cun deep (0.2 cun at GV 20 - scalp)
	(2d) Response sought: De Qi
	(2e) Needle stimulation: Manual
	(2f) Needle retention time: 20 minutes
	(2g) Needle type: 0.25 × 40 mm, stainless steel
Treatment regimen	(3a) Number of treatment sessions: 10
	(3b) Frequency & duration of treatment sessions: once a week, 20 minutes
Other components of treatment	(4a) No other intervention associated
	(4b) Hospital setting
Practitioner background	(5) Medical-doctor, licensed acupuncturist, hospital employee, with 10 years of acupuncture practice
Control intervention	(6) Wait-List Control group & Sham Acupuncture group with Streitberger device14

Box 2.

Standards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA)—Methodology

Trial design (3ab)	Randomized controlled trial
Participants (4ab)	Women with breast cancer
Interventions (5)	Acupuncture & Sham Acupuncture
Outcomes (6ab)	Beck Depression Inventory-II, Pittsburgh Sleep Quality Index & Menopause Rating Scale
Sample size (7ab)	60 subjects; 1:1:1
Sequence generation (8ab)	Simple randomization done with www.randomization.com
Allocation concealment (9)	Opaque envelope
Implementation (10)	Consecutive sampling
Blinding (11ab)	Streitberger needles; blinded data collectors
Statistical methods (12ab)	Analysis of variance for baseline characteristics Kruskal–Wallis for outcomes

Box 3.

Standards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA)—Results

Participant flow (13ab)	Allocation; baseline assessment; intervention for 10 weeks; outcome assessment
Implementation	September 2015 to July 2018
Recruitment (14ab)	Targeted health care provider–based
Baseline data (15)	Table 1
Numbers analyzed (16)	Tables 1–3
Outcomes and Estimations (17ab)	Figures 1–3
Ancillary Analyses (18)	Table 3
Harms (19)	Minor local bruises from needling

The true-Acupuncture intervention (manual acupuncture) followed the TCM rationale that the climacteric syndrome results from a lack of balance between the inherited life energy stored in the lower portion of the abdomen and roughly translated as “Kidney-essence” and the “brain,” a plausible correlation with Western medical knowledge of the hypothalamic–pituitary–gonadal axis.¹² Therefore, according to TCM, the treatment should tonify Kidney-essence and regulate brain activity.

Point selections for the true-Acupuncture group (A), designed by Xi Xuemin, MD, and his colleagues at the First Affiliated Hospital of Tianjin University of TCM,¹³ consisted of Fengfu (GV 16), Baihui (GV 20), Shenshu (BL 23), and Qihai (CV 6).

The needling technique varied according to the acupoints: for GV 16, the needle was inserted 1 cun deep, with the needle tip directed toward the mandibula; for GV 20, the needle was inserted transversely backward 0.5 cun deep; and for CV 6, the needle was inserted perpendicularly 1.5 cun deep. These were all manipulated with the even method. For BL 23, the needle was inserted obliquely toward the spinal column 1.5 cun deep and manipulated with the twirling reinforcing method. De Qi was always desired at all acupoints and was consistently obtained with the twirling reinforcing manipulation of the needles at BL 23.

Needles were kept in place for 20 minutes with 2 repeated manipulations during this timeperiod. The treatment was given once weekly for 10 consecutive weeks.

The Sham-Acupuncture group (S) received simulated needling with Streitberger needles,¹⁴ at the same acupoints except for the one located at the head (GV 20) due to practical difficulties. The Streitberger device requires placement of adhesive tape to keep the needles from falling out, preventing its use on the scalp due to the abundant presence of hair in most patients. Again, subjects were kept lying down on their sides and seen twice for 20 minutes for mock needle manipulations. These patients received the Sham-Acupuncture intervention once weekly for 10 weeks and, after a follow-up timeperiod, were readmitted for true-Acupuncture treatment.

Wait-List Control (C) group subjects completed the initial questionnaires on enrollment day; waited 10 weeks for treatment; after 10 weeks, completed the same questionnaires again; and finally received the conventional Acupuncture treatments.

The measurement tools focused on sleep disturbances, depression, and “menopause syndrome” symptoms in Emotional, Physical, and Genitourinary domains. Three measurement tools were chosen: (1) the Beck Depression Inventory–II (Beck),^15,16 a well-validated and copyrighted tool; (2) the Pittsburgh Sleep Quality Index (PSQI),¹⁷ a very sensitive indicator; and (3) the Menopause Rating Scale (MRS),¹⁸ the only specific menopause-syndrome scale translated and validated in the Brazilian Portuguese language when the current study was designed.

After the subjects signed informed consent forms, these 3 questionnaires were administered, and the subjects were instructed to choose the options that identified the burdens of the symptoms experienced. If any subjects had difficulty with completing the forms, a nurse helped the patients understand the questions and the options for answers. This nurse was completely blinded to which group each patient was assigned (the nurse was a blinded data collector). The same procedure was performed just before the last acupuncture session was performed to prevent the immediate actions of the acupuncture procedure to influence the answers.

As a pilot study, sample-size definition was based on assumptions that the outcome data would be qualitative, ordinal, and nonparametric with no need for high precision and no subgroup analysis. Thus, 60 subjects were randomized via an electronic randomization tool in the 3 groups (simple randomization): 20 in the intervention group (true Acupuncture, A), 20 in the placebo group (Sham Acupuncture, S); and 20 in the Wait-List Control group (C).

After institutional review board approval, the study protocol was presented to the medical staff of the Instituto do Câncer do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, in São Paulo, Brazil. The subjects were then referred to the acupuncture clinic by their attending physicians and placed on a list of 66 positions according to the initial reference dates (consecutive sampling).

Randomization was performed with an electronic tool^* that generated a list for simple randomization in which the 66 positions were randomly assigned to the 3 groups (assuming an estimated 10% dropout rate). This list remained inside an opaque envelope at the clinic's reception desk to maintain allocation concealment, so each allocation was unavailable to the investigator prior to its use. Blinding effectiveness was assessed after the tenth session by asking the participants of the Sham-Acupuncture group which group they guessed they were in. Possible answers were “active,” “placebo,” and “do not know.”

Statistical analysis was performed using Stata 11 software to run a Kruskal–Wallis test; this is a nonparametric test used to analyze 3 or more independent groups with more than 6 subjects and capable of determining if there are differences between at least 2 of the groups. The 3 questionnaires provided ordinal values. These values were compared in the search for differences between the initial assessment and the follow-up one. Statistical difference was established assuming an error of 5% at most (P < 0.05).

Results

From September 2015 to July 2018, 62 patients were enrolled through referrals from their attending physicians. These subjects were randomly assigned to groups A (n = 21), S (n = 20), or C (n = 21). Among the randomized participants, 2 (3.2%) dropped out during the study: 1 (4.76%) in group A and 1 (4.76%) in group C. Baseline characteristics of the participants were similar among groups (Table 1).

Table 1.

Baseline Characteristics

Group assignment	Age (mean)	Weight (mean)	Mos on tamoxifen treatment (mean)
Wait-List (C)	50.8 yrs	75.4 kg	16.8
True Acupuncture (A)	48.6 yrs	70.9 kg	21.23
Sham Acupuncture (S)	51.6 yrs	66.4 kg	19.8
P-value (ANOVA)	P = 0.625	P = 0.49	P = 0.187

Mos, months; yrs; years; ANIVA, analysis of variance.

Participants received 10 sessions of treatment in the A and S groups while patients who were randomized to the C group were scheduled to begin true-Acupuncture sessions after a 10-week waiting period.

For testing the blinding effectiveness, participants in the Sham-Acupuncture group were asked which group they thought they were in after the tenth session; 20% guessed correctly, 50% answered “do not know,” and 30% guessed incorrectly that they were in the “active” group. Blinding of the data collector was not accessed.

The A group had greater median improvements in the questionnaire scores as shown in Figures 1–3.

FIG. 1.

Pittsburgh sleep quality index (PSQI). Treatment groups: A = True Acupuncture; C = Wait-List Control; and S = Sham Acupuncture.

FIG. 2.

Menopause Rating Scale (MRS). Treatment groups: A = True Acupuncture; C = Wait-List Control; and S = Sham Acupuncture.

FIG. 3.

Beck Depression Inventory–II (Beck). Treatment groups: A = True Acupuncture; C = Wait-List Control; and S = Sham Acupuncture.

On the Beck, subjects in group A had a median decrease of 7 points; subjects in group S had a median change of 2 points; and subjects in group C. had no change. PSQI scores also decreased in the A group with a median change of 6 points; the S group had a median 1.5 change; and the C group had no change. On the MRS, the global score decreased 9.5 points for the A group; the S group had a 3-point decrease; and the C group remained stable.

The initial Kruskal–Wallis test (Table 2) included the 3 groups and identified differences among them in responses to every questionnaire, even when the MRS scale was broken down into the Physical, Emotional, and Genitourinary domains.

Table 2.

Kruskal–Wallis Test Results of Comparisons among the Groups

PSQI	MRS	MRS Physical	MRS Emotional	MRS G-U	Beck
P < 0.001	P < 0.001	P < 0.001	P < 0.005	P < 0.04	P < 0.001

PSQI, Pittsburg Sleep Quality Index; MRS, Menopause Rating Scale; MRS Physical, Menopause Rating Scale physical component; MRS Emotional, Menopause Rating Scale emotional component; MRS G-U, Menopause Rating Scale Genitourinary component; Beck, Beck Depression Inventory–II.

Further analysis performed one-on-one comparing A × S, A × C, and S × C showed that group A's response was statistically different from that of group C on every questionnaire and in most of the questionnaires compared to the S group's response with exception of the physical and genitourinary symptoms domains on the MRS scale (Table 3).

Table 3.

Post-Hoc Analysis

Comparison	PSQI	MRS	MRS Physical	MRS Emotional	MRS G-U	Beck
A × S	P < 0.002	P < 0.004	P = 0.385*	P < 0.001	P = 0.123*	P < 0.001
A × C	P < 0.001	P < 0.001	P < 0.001	P = 0.024	P = 0.008	P < 0.001
C × S	P < 0.016	P = 0.115*	P < 0.001	P = 0.307*	P = 0.49*	P = 0.091*

^* Non-significant P-values.

PSQI, Pittsburg Sleep Quality Index; MRS, Menopause Rating Scale; MRS Physical, Menopause Rating Scale Physical component; MRS Emotional, Menopause Rating Scale Emotional component; MRS G-U, Menopause Rating Scale Genitourinary component; Beck, Beck Depression Inventory–II.

Discussion

This article described an experimental, parallel-design acupuncture trial, with 3 arms. It was single-blinded, randomized, and sham-controlled, and had a blinded data collector. The trial indicated a possible improvement in QoL for women treated with tamoxifen for breast cancer. There were different responses among the 3 groups, with true Acupuncture resulting in the best questionnaire scores, except in the Physical and Genitourinary symptoms' domains of the MRS scale.

The TCM rationale offers an understanding that the brain can activate and control all bodily functions and, in turn, depends on the appropriate functioning of the body organs to maintain its own activities.¹² In normal physiologic conditions, the brain dominates the Kidney, and the Kidney nourishes the brain; a failure in this relationship leads to symptoms.

According to TCM, Deficiency of Kidney-essence is the foremost causative factor of the climacteric syndrome, inducing a systemic lack of balance that involves all the other organs and generating symptoms such as hot flashes, palpitations, sleep disturbances, gastrointestinal disorders, and mental illnesses.¹¹

The Acupuncture treatment protocol chosen was based on this TCM understanding and focused on current Western-medicine knowledge of acupuncture's mechanisms of action, specifically Langevin and Yandow's findings on the needling sensation (De Qi) and the connective-tissue “needle grasp” that seems to play a key role in the specific actions of acupuncture stimuli.¹⁹ In addition the Sham-Acupuncture procedure chosen in this trial was the Streitberger device, which is a false needle that retracts when pressed against an obstacle, producing minimal stimuli, compared to the twirling technique applied to a real needle.²⁰ This seems to be an effective way to blind subjects. In this trial, only 20% of the participants in the Sham-Acupuncture group guessed their actual group placements correctly after the tenth session.

However, the best way to check blinding status should include a pretest during the study-design stage, an early test during the run of the protocol and a last test toward the end of the interventions. These tests should include the whole study population and enable a formal statistical test. This was especially important in this trial because the outcomes derived from subjective scales measuring symptoms and signs, and these domains could be influenced by detection bias. To address this need, a blinded data collector was included to enhance the blinding protocol further and decrease the chance of bias, although this was not formally tested.

One of the assessment instruments used were the Brazilian version of the PSQI, a well-validated questionnaire developed by Buysse.¹⁷ It relies on self-reporting to differentiate “good sleepers” from “poor sleepers,” assessing a time frame of 1 month. This was a natural choice for measuring sleep quality in this trial, given that the main objective was to evaluate the influence of acupuncture over an intermediate timeperiod, rather than other questionnaires focused on “last night's sleep” and those used to evaluate longer timeperiods that would surpass the time frame of the intervention. In addition, sleep quality may be hindered both by mental and physical distress; thus could serve as a general marker of the proposed benefits from acupuncture.

Other questionnaires utilized were the validated Brazilian version of the Beck (the 1996 updated version of the original instrument proposed by Beck in 1960),¹⁵ that helped identify psychologic and somatic manifestations of 2-week-long major depressive episodes, and the also-validated Brazilian version of the MRS. The MRS is one of the most frequently used instruments to evaluate severity of menopausal symptoms. It is comprised of 11 items divided into 3 components (Physical, Emotional and Genitourinary) and useful for identifying severe overall climacteric symptomatology.

These instruments were chosen to encompass the most common symptoms experienced by tamoxifen users.³ The 3 questionnaires, theoretically, could be used to measure different aspects related to overall QoL. Repeated use of these instruments could reveal changes in overall well-being.

The Beck has 21 questions with 4 alternative answers, scored at 0–3 points each with a range of 63 points. On the Beck, higher scores indicate greater suffering. When scoring the PSQI, 7 component scores are derived, with each scored from 0 (no difficulty) to 3 (severe difficulty). The component scores are added together to produce a global score (range: 0–21). Higher scores indicate worse sleep quality. The MRS scale presents 11 symptoms scored at 0–4 added up as a global score (range: 0–44) that can be broken down into the 3 components: Physical (0–16), Emotional (0–16), and Genitourinary (0–12). Higher scores indicate greater discomfort.

As mentioned in the Results session, this study revealed statistically different responses among the groups. When the analysis focused on the MRS' different symptoms' aspects, only the Emotional component had a statistically significant difference when A was compared with S, while the Physical and Genitourinary components presented a possibility of error that surpassed the 5% cutoff that was established. This is compatible with prior studies that failed to show statistically significant differences between acupuncture and placebo interventions regarding the number and severity of hot-flash episodes,⁸ but consistently revealed QoL improvement when acupuncture was used to treat menopausal symptoms of breast cancer patients.⁹

The 3 instruments covered many signs, symptoms, and feelings that comprise the menopausal experience, especially in a cancer scenario in which the nature of suffering is multidimensional. These choices may have helped to delineate the actual benefits better that can be expected from acupuncture for such patients. The results showed improvements in sleep quality and mental and emotional health, although genitourinary and other physical disturbances remained stable.

The limitations of this study included its small sample size, unique acupuncture provider, single-center setting, ordinal-self-reported outcome data, absence of a follow-up, and uncertainty about the blinding protocol success. The strong points were the TCM rationale behind the point selections, the apparent adequate blinding of patients and data collectors, the technical aspects of needling with De Qi sensation consistency, the elevated retaining of subjects (low dropout rate), and firm study-protocol adherence and comprehensive outcome measures. The recruitment was targeted and health care-provider-based, which proved to be slow but reliable and may have contributed to retention of subjects during the interventional phase, increasing internal validity.

Conclusions

This trial showed that acupuncture improved management of climacteric-like symptoms induced by hormonal blockage in patients with breast cancer through relief of sleep, and mental and emotional distress. To understand the external validity of this apparent benefit better from this acupuncture treatment protocol for women treating breast cancer, a larger, multicenter trial should be carried out.

Author Disclosure Statement

No financial conflicts of interest exist.

Funding Information

No funding was obtained for this research.