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Abstract

Background:

Chinese herbal medicine (CHM), a commonly used alternative therapy, has been reported to reduce the side effects of cancer treatments and improve the quality of life (QOL) in breast cancer (BC) patients. However, there is limited research on the effects of CHM in BC patients experiencing hot flushes (HFs) during adjuvant chemotherapy. We conducted a non-randomized controlled trial to evaluate the effectiveness of CHM on side effects, QOL, and changes in meridian electrodermal activity.

Methods:

Forty-eight patients with stage I-III BC undergoing adjuvant chemotherapy were non-randomly assigned to either a 24-week CHM treatment group or a 24-week non-CHM control group. The CHM intervention involved a combination of Jia Wei Xiao Yao San and Er Zhi Wan in a 3:1 ratio, with a total daily dose of 4 g taken 3 times a day. The primary outcome was the occurrence of 10 or more HFs per week and the severity of symptoms, rated using a visual analog scale (1-10). Secondary outcomes included the Functional Assessment of Cancer Therapy-Breast Cancer questionnaire to assess health-related QOL, and meridian energy analysis to measure skin electrical conductance and sympathetic activity. The difference between the CHM and non-CHM groups in individual changes from baseline to week 24 was evaluated using an independent t-test.

Results:

A total of 43 participants completed the study, with 25 in the CHM group and 18 in the control group. The CHM group showed a statistically significant reduction in HF frequency at 12 and 24 weeks and a decrease in HF severity at 12 weeks compared to the control group (P < .05). Physical well-being and specific concerns scores also improved significantly over time in the CHM group compared to the control group (P < .05). While CHM treatment did not lead to significant changes in overall electrical conductance at acupoints (P = .251), it did significantly affect specific meridians, including the heart, liver, and kidney (P = .032, P = .035, and P = .035, respectively). Additionally, sympathetic activity was reduced in the CHM group after completing chemotherapy (P = .045).

Conclusions:

CHM therapy appears to have a preventive effect on chemotherapy-related HFs in BC patients and is safe, with no severe adverse effects observed.

Keywords

Chinese herbal medicine hot flushes meridian energy breast cancer non-randomized controlled trial

Introduction

Breast cancer (BC) is one of the most frequent cancers worldwide and its treatment can produce distressing symptoms including hot flushes (HFs), the sudden and transient episodes of heat and sweating with possible co-occurring palpitations and anxiety.¹ HFs affect up to 51% to 82% of BC patients during the oncology treatment,^1,2 significantly impacting their quality of life (QOL) with sleep disruption, depressive mood, avoidance of social situations and intimate relationships, decreased performance and ability to work, and even interfere with drug adherence.^3,4 BC survivors also experience more frequent, severe, and distressing HFs for longer periods compared to healthy women.⁵

The timing and severity of HFs during cancer treatment can vary significantly from person to person. The most cited risk factor and hypothesized causal link for HFs is related to the rapidity of endogenous estrogen withdrawal.⁶ Therefore, BC therapy-induced HFs can vary by age and by dose and type of treatment. Certain chemotherapeutic agents can disrupt ovarian function, potentially leading to permanent changes in neurochemicals like noradrenaline, serotonin, and estrogen.^7,8 Recent studies suggest a potential link between HFs and autonomic dysfunction following chemotherapy,^9,10 as well as disturbances in thermoregulation within the hypothalamus, leading to increased body temperature.¹¹ Younger women are less likely than midlife women to undergo chemotherapy-induced menopause at higher dosages, although younger postmenopausal women tend to report more frequent HFs during endocrine therapy. In contrast, older patients or those whose ovaries are within the radiation field during treatment experience the most severe ovarian damage and face a higher risk of HFs.¹²

Although estrogen-containing hormone therapy (HT) is the most effective treatment for HFs, it is not recommended for BC patients due to the heightened risk of relapse and cardiovascular events.^13,14 Clonidine has shown promise as an alternative to HT, with studies indicating a reduction in HFs by 35% to 40%,^15,16 compared to a 20% to 25% reduction with placebo.¹⁷ Newer antidepressants like venlafaxine have also demonstrated effectiveness, as seen in early studies from 2000.¹⁸ Gabapentin, in a 2005 trial by Pandya et al, was found to reduce HFs to a similar degree when taken at a dose of 900 mg/day.¹⁹ However, despite these promising alternatives, their efficacy remains lower than that of HT, and each treatment is associated with its own toxicities, limiting their use.²⁰

Chinese herbal medicine (CHM) is one of the most widely practiced treatments in East Asia and has been extensively used to manage menopausal symptoms for many years.²¹ In Taiwan, CHM is commonly adopted by cancer patients to address endocrine, nutritional, mood, and immune imbalances.²² Among BC patients experiencing symptoms such as insomnia, HFs, fatigue, or depression, CHM is more frequently used compared to other cancer groups. Classical CHM herbal formulas mentioned in ancient Chinese medical texts have long been aimed at alleviating menopausal symptoms. Research has highlighted potential benefits from CHM recipes such as Jia Wei Xiao Yao San, Suan Zao Ren Tang, Zhi Bai Di Huang Wan, and Er Zhi Wan in treating menopausal symptoms.^23,24 These prescriptions are also consistent with traditional Chinese medicine (TCM) viewpoint regarding any menopause-like syndrome, which address these imbalances by tonifying Kidney energy, regulating the Liver, and strengthening the Spleen.²⁵

Jia Wei Xiao Yao San (JWXYS), a traditional formula consisting of herbs like Radi. Angelicae Sinensis (Dang Gui), Radix. Paeoniae Alba (Bai Shao), Poria (Fu Ling), Rhizoma. Atractylodis Macrocephalae (Bai Zhu), Radix. Bupleuri (Chai Hu), Cortex. Moutan (Mu Dan Pi), Fructus. Gardeniae (Zhi Zi), Radix. Glycyrrhizae Preparata (Zhi Gan Cao), Herba. Menthae Haplocalycis (Bo He) and Rhizoma. Zingiberis Recens (Sheng Jiang), was first recorded during the Song Dynasty. Clinically, JWXYS has been widely used to treat mental illness, gynecological diseases and digestive system diseases, which involves Liver stagnation and blood deficiency with heat syndrome.²⁶ Research, including randomized controlled trials (RCTs), has shown that JWXYS is well-tolerated, safe, has less estrogenic effects and causes fewer metabolic changes compared to HT.²⁷ Additionally, population-based studies report high prescription rates of JWXYS due to the prevalence of psychosomatic disorders in BC patients.²⁸

Er Zhi Wan (EZW), a combination of Fructus. Ligustri Lucidi (Nu Zhen Zi) and Herba. Ecliptae (Han Lian Cao), was first described in the Ming Dynasty by Wu Min Ji in “Fu Shou Jing Fang.” In TCM theory, EZW is used to nourish and tonify the Liver and Kidney Yin, helping to relieve muscle weakness and counter aging. It is commonly used as an adjunct treatment for metrorrhagia, non-cyclic uterine bleeding, dermatitis and neurasthenia.²³ A RCT by Fu et al found that EZW effectively reduced HFs in women during the perimenopausal period.²⁹

The effectiveness of JWXYS and EZW in managing chemotherapy-induced HFs still requires further study. We hypothesize that these combined formulas may provide better outcomes in alleviating chemotherapy-associated HFs in BC patients compared to standard treatments. In addition, we used a meridian energy analysis device (MEAD) to assess skin conductance at specific points on the body to assess the flow of vital energy and potentially identify imbalances after treatment. To evaluate this hypothesis, we designed a non-randomized controlled pilot study to compare the effectiveness of these 2 regimens in BC patients experiencing chemotherapy-related HFs.

Methods

Study Design and Participants

This prospective, non-randomized, pilot study was conducted from November 2018 to October 2020 at Kaohsiung Chang Gung Memorial Hospital (KCGMH) in southern Taiwan. Forty-three female BC patients were enrolled. Inclusion criteria were age over 20 years, a confirmed diagnosis of stage I-III breast cancer, surgical treatment within the past month, and planned adjuvant chemotherapy consisting of 6 to 8 cycles of standard regimens containing anthracyclines and taxanes. The National Comprehensive Cancer Network (NCCN) guidelines recommend several regimens, with sequential anthracycline-cyclophosphamide followed by taxane (AC-T) being a commonly accepted standard.³⁰ Additionally, non-anthracycline-based regimens like docetaxel and cyclophosphamide (TC) may also be effective, and their use is increasing. The choice of regimen depends on various factors, including tumor biology (HER2 status, hormone receptor status), stage, and patient characteristics. Exclusion criteria included untreated or unstable psychiatric illness, liver or renal disorders, neoadjuvant chemotherapy, and the use of unknown complementary and alternative medicine interventions. To minimize selection bias and priming effects, participants were informed that the study aimed to monitor general well-being and health-related symptoms.

Procedure

The study included a 4-week screening period, a 24-week treatment period, and a 4-week follow-up period. At baseline, eligible patients were consulted regarding their willingness to receive CHM. After the confirmation with the TCM physician, the trial medication using extract granules was packaged in a sealed foil sachet under the supervision of the Chinese Medicine Pharmacy. The herbal formulas were supplied by Sheng Chang GMP Pharmaceutical Co., Ltd., a certified CHM extract granules manufacturer in Taiwan. Quality control and quality assurance, such as identification of products and quality and safety testing, were conducted by the manufacturer. The herbal license, manufacturing batch number and expiration date can be checked on the official website of the Ministry of Health and Welfare (https://service.mohw.gov.tw/DOCMAP/CusSite/TCMLQueryResult.aspx).

JWXYS and EZW are based on the principle of treatment in strengthening the Liver and Kidney and eliminating the inner fire in TCM theory, and most BC patients with HFs manifested with Yin-deficiency-heat syndrome.³¹ The formulae following a modified TCM protocol for breast cancer has been used in our Integrative Cancer Center for many years.³² For those in the CHM group, JWXYS and EZW were combined in a 3:1 ratio, with a total dose of 4 g taken 3 times daily after meals. CHM treatment began on the third day the patient received her first chemotherapy injection. To promote adherence to the treatment plan, participants received a diary to record any days they did not take their CHM and the reasons for non-adherence. They were also instructed to bring all used CHM packaging to each monthly visit, allowing calculation of their compliance rate. The study was approved by the Institutional Review Board of Chang Gung Memorial Hospital (No. 201801559A3) and was registered with the ClinicalTrials.gov (ID: NCT03797248). All patients provided written informed consent and received oral instructions on use of trial medications.

Study Objectives

The study had 2 primary objectives: (1) to evaluate the preventive effect of the CHM formulation on HFs, and (2) to assess the impact of the CHM formulation on health-related quality of life. Secondary endpoints included evaluating the effects of the CHM formulation on changes in skin electrical energy and on an index of sympathovagal balance.

Study Assessments

Patients were asked to record the number and severity of their HFs in a diary every 2 weeks at baseline and during weeks 12 and 24 of adjuvant chemotherapy, in both the CHM group and the control group. The number and percentage of patients experiencing at least 10 problematic HFs per week were summarized, along with the maximum reported visual analog scale score, using a 10 cm line over a 7-day period for each group.

To assess health-related QOL, patients completed the Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire.^33,34 This validated tool consists of a 37-item general functional status scale (FACT-G), which includes 4 subscales: physical, social/family, emotional, and functional well-being. Additionally, the 10-item Breast Cancer Subscale (BCS) evaluates symptoms such as breathing difficulties, pain, lymphedema, stress, and appearance concerns. The FACT-B was completed at baseline and after the 24-week treatment period, with higher scores indicating better health-related QOL.

MEAD detects changes in micro-electrical currents to reflect physiological status, sympathetic activity, and pathological phenomena within the corresponding meridians.³⁵ Variations in skin conductance can indicate characteristics like deficiency/excess or Yin/Yang imbalances according to TCM concepts. Previous studies have demonstrated that meridian electrical conductance can provide insights into disease prognosis, treatment response, and autonomic nervous system balance.^36,37

MEAD measurements begin with a very low current that is gradually increased to a maximum of 200 μA. The electrical conductivity of the meridians is recorded and entered into a computerized system, with conductivity values calculated based on the voltage supplied by the device (ME100; Med-Pex Enterprises, Taichung, Taiwan). The current measured in the meridians is expressed on a scale of 0 to 100. Additionally, the sympathovagal balance index, which is the ratio of the highest to the lowest average electroconductivity values on the dorsal or ventral side, is automatically calculated by the device. A normal index range is between 1.0 and 1.5; values outside this range may indicate autonomic imbalance.

The procedure was conducted by a trained technician in a quiet room with a temperature of 26°C to 28°C and constant humidity. Prior to the procedure, participants rested in a supine position for 15 minutes. The 24 modified Yuan points were measured one by one, starting on the left side in the following order: Lung (LU9), Pericardium (PC7), Heart (HT7), Small Intestine (SI4), Triple Heater (TH4), Large Intestine (LI5), Spleen-Pancreas (SP3), Liver (LR3), Kidney (KI3), Urinary Bladder (BL65), Gallbladder (GB40), and Stomach (ST42).

Statistical Analysis

The continuous variables were summarized using means and standard deviations, whereas the categorical variables were summarized using counts and percentages. Baseline characteristics for continuous variables between CHM users and nonusers were analyzed using an independent t-test; categorical variables were analyzed using a chi-square test or Fisher’s exact test. Pre- and post-treatment continuous variables were compared using a paired t-test. Changes in skin electrical conductance, sympathovagal index, FACT-B, and blood parameters between the CHM user and nonuser groups were evaluated using independent t-tests. Statistical significance was defined as P < .05. Data analyses were conducted using SPSS version 17.0 (SPSS, Inc., Chicago, IL).

Results

A total of 48 female patients were screened, with 43 included and assigned to non-randomized groups. Of these, 25 patients were placed in the CHM group, and 18 in the control group. During the study, no participant withdrew due to intolerance, lack of efficacy, or other concerns or had missing follow-up data. The characteristics of patients are presented in Table 1. Among the total population, 23 patients (53.5%) had stage II BC, and 65.1% were Her2 positive. The median age was 50.5 years, and the median body weight was 59.1 kg. The majority of patients were married (83.7%), employed (90.7%), entering menopause (58.1%), and had a college education or higher (34.9%). Baseline demographic and clinical characteristics were similar between the 2 groups, including hormone therapy, menopausal status, and chemotherapy regimens, except for lymph node invasion (P = .03).

Table 1.

Patient Characteristics.

Characteristics	Total (n = 43)	CHM group (n = 25)	Non-CHM group (n = 18)	P value
Mean age (SD)	50.51 ±8.23	52.04 ±7.69	48.39 ± 8.7	.154
Married	36 (83.7)	21 (84)	15 (83.3)	1
Incumbency	39 (90.7)	21 (84)	18 (100)	.127
Menopause	25 (58.1)	17 (68)	8 (44.4)	.122
College degree or above	15 (34.9)	8 (32)	7 (38.9)	.64
BW	59.14 ± 9.81	56.85 ± 8.56	62.32 ± 10.76	.071
Comorbid
Diabetes mellitus	4 (9.3)	2 (8)	2 (11.1)	1
HTN	5 (11.6)	2 (8)	3 (16.7)	.634
Cancer stage				.661
I	10 (23.3)	7 (28)	3 (16.7)
II	23 (53.5)	12 (48)	11 (61.1)
III	10 (23.3)	6 (24)	4 (22.2)
Tumor subtypes				.114
HER2+	28 (65.1)	15 (60)	13 (72.2)
HR+/HER2−	11 (25.6)	9 (36)	2 (11.1)
TNBC	4 (9.3)	1 (4)	3 (16.7)
NA	0 (0)	0 (0)	0 (0)
Lymph node invasion	25 (58.1)	18 (72)	7 (38.9)	.03
Chemotherapeutic regimen
CMF	41 (95.3)	25 (100)	16 (88.9)	.169
Adriamycin-based	14 (32.6)	9 (36)	5 (27.8)	.57
Taxanes-based	4 (9.3)	3 (12)	1 (5.6)	.628
Concurrent hormone therapy	32 (74.4)	18 (72)	14 (77.8)	.736

Abbreviation: CMF, cyclophosphamide, methotrexate, and fluorouracil.

As shown in Table 2, the number of patients experiencing frequent problematic HFs was lower in the CHM group compared to the non-CHM group at both 12 weeks (P = .037) and 24 weeks (P = .014). There was no significant difference in HF severity between the groups at baseline. However, at 12 weeks, the HF severity rating in the CHM group was 4.52 (SD 1.98) compared to 6.33 (SD 2.17) in the non-CHM group, showing a significant reduction (P = .007). By 24 weeks, the difference in HF severity between the CHM and control groups was not statistically significant (P = .053).

Table 2.

Evaluation of Percentage and Severity of Hot Flushes for Both Groups at Baseline and After 3, and 6 Months of Treatment.

Clinical outcomes	CHM group (n = 25)	Non-CHM group (n = 18)	P value
Hot flush frequency (≥10/week)
Baseline	2 (8%)	1 (5.6%)	1.000
12 wk	10 (40%)	13 (72.2%)	.037*
24 wk	10 (40%)	14 (77.8%)	.014*
Hot flush severity (VAS 0-10)
Baseline	1.12 (0.78)	1.44 (0.78)	.187
12 wk	4.52 (1.98)	6.33 (2.17)	.007*
24 wk	3.88 (2.24)	5.39 (2.73)	.053

Statistically significant difference between CHM and non-CHM groups (P < .05).

Regarding health-related QOL, as seen in Table 3, there were no differences in the total FACT-B scores between the groups at 6 months. However, among the 5 functional subscales of the FACT-B, the CHM group showed significant improvements in physical well-being (PWB; P = .03) and breast cancer-specific concerns (BCS; P = .04).

Table 3.

Change in Functional Assessment of Cancer Therapy-Breast Cancer (FACT-B) in Physical Well-Being (PWB), Social Well-Being (SWB), Emotional Well-Being (EWB), Functional Well-Being (FWB), Breast Cancer Specific Concerns (BCS) and Total Score at Baseline and at the 6 Months Between the 2 Groups.

Variable		CHM group (n = 25)		Non-CHM group (n = 18)		P value^a
Variable		Pre-Tx,Mean (SD)	Post-Tx,Mean (SD)	Pre-Tx,Mean (SD)	Post-Tx,Mean (SD)	P value^a
FACT-B	PWB	22.52 (4.72)	24.08 (4.19)	24.67 (2.89)	24.9 (2.08)	.03*
	SWB	22.36 (5.69)	20.54 (4.52)	23.31 (5.38)	23.1 (3.24)	.882
	EWB	16.8 (4.74)	18.15 (4.02)	17.33 (4.13)	19.3 (3.47)	.08
	FWB	17.24 (6.07)	15.92 (5.96)	19.06 (6.07)	21.1 (3.38)	.068
	BCS	22.12 (5.96)	25.2 (5.04)	21.56 (4.9)	22 (5.91)	.04*
	Total	101.04 (21.84)	98.92 (17.01)	106.03 (17.59)	112.4 (13.22)	.075

Between 2 groups.

Statistically significant difference between CHM and non-CHM groups (P < .05).

Figure 1 illustrates changes in electrical conductance for both groups during the 6-month chemotherapy period. The average electrical conductance value for whole body in the CHM group did not differ significantly from the control group (P = .251). However, the index of sympathetic activity was significantly lower in the CHM group compared to the control group after treatment (P = .045). Figure 2 provides an analysis of individual electrical conductance values throughout the treatment period, showing significant changes in 3 meridians in the CHM group: a decrease in the HT meridian (26.73 ± 27.96 vs 30.01 ± 23.97) and LI meridian (33 ± 25.42 vs 29.45 ± 22.52), and an increase in the KI meridian (39.35 ± 25.12 vs 13.08 ± 17.15), with significant differences (P = .032, P = .035, and P = .035, respectively).

Figure 1.

The variation of (A) Mean skin electrical conductance (current; mA), and (B) index of sympathovagal balance at baseline and that after therapy in the 2 groups. P < .05.

Figure 2.

Comparison of the 12 electrical conductivities before and after therapy in the 2 groups. P < .05.

The effect of JWXYS and EZW on the biological indicators of the experimental and control group is presented in Table 4. The results indicated that all laboratory parameters measured remained within the physiological range throughout the 24-week experimental period. Despite significant changes being observed in hemoglobin (P = .048), the other parameters (white blood cells, platelets, liver function, and creatinine) remained non-significant between the control and treated groups. No serious adverse events were reported in either group. Four patients in the CHM group experienced mild abdominal discomfort at the start of treatment, but this resolved within 1 week without any specific intervention.

Table 4.

Laboratory Values Before and After 4-Month Treatment.

Variable	CHM group (n = 25)		Non-CHM group (n = 18)		P value^a
Variable	Pre-Tx,Mean (SD)	Post-Tx,Mean (SD)	Pre-Tx,Mean (SD)	Post-Tx,Mean (SD)	P value^a
White blood cells (1000/µL)	6.33 (2.29)	5.45 (1.56)	7.84 (3.61)	3.75 (1.49)	.125
Hemoglobin (g/dL)	12.26 (1.5)	11.4 (1.26)	12.68 (1.09)	10.88 (1.11)	.048*
Platelet (1000/μL)	247.17 (84.41)	254.47 (72.28)	274.83 (82.94)	247.33 (71.34)	.318
Aspartate aminotransferase (µ/L)	20.52 (4.86)	30.36 (12.04)	18.65 ± 4.3	30.17 (16.29)	.977
Alanine aminotransferase(µ/L)	27.41(25.48)	37.36 (32.53)	21.5 (6.72)	44.4 (30.75)	.2
Creatinine (mg/dL)	0.71 (0.18)	0.68 (0.1)	0.64 (0.06)	0.6 (0.06)	.873

Between 2 groups.

Statistically significant difference between CHM and non-CHM groups (P < .05).

Discussion

This study was a prospective non-randomized controlled trial conducted to evaluate the effectiveness of JWXYS and EZW combination in alleviating HFs symptoms among BC patients undergoing chemotherapy. Baseline comparisons revealed no significant differences in HFs symptoms between the 2 groups. Following intervention, both groups experienced reductions in symptom severity, but the CHM group demonstrated a more rapid decrease in both frequency and severity at weeks 12 and 24 compared to the non-CHM group. Additionally, QOL improved, particularly in the physical and BCS domains, after TCM treatment. MEAD analysis was used to explore related TCM theories, showing that the control group exhibited significant Yin deficiency and excessive internal heat, aligning with common TCM menopausal syndromes. In contrast, CHM therapy reduced excessive Yang energy, especially in the Heart and Liver meridians. These findings suggest that JWXYS and EZW therapy outperformed control treatment.

HFs in natural menopause typically last 1 to 2 years, although 15% of women may experience symptoms for up to 30 years, with episodes lasting 3 to 10 minutes and varying in severity.³⁸ Chemotherapy-induced HFs result from estrogen deprivation caused by cytotoxic agents, leading to earlier onset, higher intensity, and longer duration compared to natural menopause.^39,40 Age differences were ruled out in this study, as baseline characteristics were comparable between the 2 groups. Previous research indicates that regimens containing cyclophosphamide and anthracyclines, with or without taxanes, are strongly linked to ovarian suppression and the occurrence of HFs, particularly among younger or premenopausal women.^7
-9 Endocrine therapies, such as tamoxifen and aromatase inhibitors, are also well known to exacerbate vasomotor symptoms. In our study, however, the distribution of chemotherapy regimens was relatively balanced between the CHM and control groups, minimizing the likelihood that the observed benefits of CHM were solely attributable to differences in chemotherapy type. Nonetheless, given the potential influence of specific chemotherapy regimens on menopausal symptoms and QOL, future investigations should stratify patients by chemotherapy type and explicitly assess its interaction with CHM efficacy.⁴¹ Moreover, although a greater proportion of patients in the CHM group presented with lymph node invasion—a factor that may temporarily impair physical, emotional, and social well-being after surgery—long-term QOL is generally more affected by chemotherapy and its associated symptoms than by lymph node status alone.⁴² Importantly, our findings indicate that CHM treatment was associated with a faster recovery in QOL, suggesting potential benefits in alleviating symptom-related burdens.

A 2016 study by Chang et al involving 253 BC survivors found that nearly half experienced HFs, with an average frequency of 1.8 episodes per week.⁴³ In our study, TCM use significantly reduced the frequency of HFs at weeks 12 and 24, but severity differences between groups were not significant at 24 weeks. This may be attributed to the natural progression of HFs, as severity often decreases over time, and patients develop tolerance. These findings align with Chang’s research, which showed that HFs severity in BC survivors is often mild or asymptomatic over time.⁴³

Our study also showed that CHM treatment significantly improved QOL, particularly in physical and BCS subscales, which include emotional and symptom-specific items. Beyond physiological outcomes, addressing vasomotor symptoms such as HFs plays a crucial role in improving the overall QOL for BC patients. According to Jing et al,⁴⁴ symptom clusters including HFs, fatigue, and emotional distress significantly impair QOL among women receiving endocrine therapy in China. Stein et al also highlighted that HFs are among the most disruptive symptoms experienced by postmenopausal BC survivors, impacting sleep, mood, and daily functioning.⁴⁵ Therefore, even modest improvements in hot flash severity and frequency may translate into meaningful gains in emotional well-being, social functioning, and adherence to cancer treatment. In addition, Chen et al demonstrated in a randomized placebo-controlled trial that managing HFs—whether through melatonin or other interventions, could positively influence mood and sleep quality in BC survivors.⁴⁶ These findings suggest that symptom relief strategies, including CHM, should not be viewed merely as supportive or secondary, but as integral to comprehensive cancer care. However, future studies should clarify the extent to which reduction in vasomotor symptoms contributes to measurable improvements in patient-reported outcomes and whether these changes hold clinical significance in terms of long-term survivorship and treatment compliance.

Pharmacological treatments for HFs in BC patients, including megestrol, medroxyprogesterone, certain antidepressants, anticonvulsants, and clonidine, are limited by side effects and inferior efficacy compared to estrogen replacement therapy.⁴⁷ Sleep medications are often used to address symptoms associated with chemotherapy-induced menopause, but the multifaceted pathophysiology of HFs and insomnia remains a clinical challenge.⁴⁸ Non-pharmacological approaches, such as TCM or plant-based hormones, are viable alternatives. For example, phytoestrogens derived from plant sources, such as soy isoflavones, have been evaluated for their potential to alleviate vasomotor symptoms; however, their use remains controversial in hormone-sensitive cancer populations due to possible estrogenic activity.⁴⁹ Acupuncture is another non-pharmacological intervention that has gained attention. A pilot study conducted in Korean BC patients receiving antiestrogen therapy demonstrated that acupuncture significantly reduced the severity and frequency of HFs, suggesting it may serve as a viable supportive therapy.⁵⁰ Furthermore, a systematic review and meta-analysis by Li et al analyzed the efficacy of various herbal medicines for HFs management in women undergoing endocrine therapy and found that several herbal interventions—including CHM formulations—may offer symptom relief with favorable safety data.⁴⁹ Earlier research considered that CHM for HF may alleviate symptoms through both hormonal modulation and neurovascular regulation,^51
-53 though the exact mechanisms are complex and not fully understood. Some CHMs may influence hormone levels, particularly estrogen, which is known to fluctuate during menopause and affect thermoregulation^52,53 . Additionally, CHMs may impact on the nervous system, particularly the hypothalamus, which plays a crucial role in regulating body temperature.⁵⁴

In our study, no immediate side effects were observed in patients receiving CHM treatment, but we acknowledge that hidden estrogenic effects cannot be ruled out. Pharmacological studies have suggested that JWXYS may act as a mild selective estrogen receptor modulator, potentially offering symptom relief without promoting estrogen-dependent tumor growth.^27,55 Although JWXYS contains compounds with phytoestrogenic properties, current in vitro and clinical studies have not demonstrated a clear adverse interaction with endocrine therapy in BC patients.⁵⁶ Likewise, 2 major ingredients of Er Zhi Wan—Fructus Ligustri Lucidi and Herba Ecliptae—contain flavonoids and phenolic compounds that may have lipid-lowering, hepatoprotective, and antioxidative effects.^57
-60 These herbs have been used traditionally to tonify the body’s essence and blood, and some studies suggest they may support overall metabolic health in cancer patients. Nevertheless, long-term safety data specific to hormone-sensitive cancer populations are limited, and potential interactions with chemotherapy or endocrine therapy require further evaluation through rigorous pharmacokinetic and pharmacodynamic studies.

Herb-drug interactions are another concern in modern healthcare, with almost 13% of cancer patients in Taiwan using herbal medicine alongside conventional pharmaceuticals.²² Current evidence, however, does not support a negative impact of CHM on chemotherapy efficacy such as interfering with cytotoxic effects or contributing to drug resistance. On the contrary, several systematic reviews and clinical studies suggest that CHM may help reduce chemotherapy-associated side effects without compromising — and in some cases potentially enhancing — anti-cancer outcomes. Li et al conducted a meta-analysis indicating that CHM adjunct therapy significantly alleviated chemotherapy-induced toxicity (eg, nausea, myelosuppression, fatigue) while maintaining therapeutic efficacy in BC patients.⁶¹ Similarly, Zhang and Shi demonstrated that combining CHM with postoperative chemotherapy was associated with improved QOL and reduced recurrence rates.⁶² In a Taiwanese cohort study, Lee et al reported that BC patients who received integrated treatment with CHM and Western medicine had better overall prognosis compared to those receiving conventional treatment alone.⁶³ Furthermore, Li et al analyzed national cohort data and found no evidence suggesting that CHM use led to inferior survival outcomes or reduced chemotherapy effectiveness.⁶⁴ Mechanistically, recent insights by Li et al highlighted the potential of CHM in modulating tumor microenvironments, enhancing chemosensitivity, and mitigating resistance pathways when tailored.⁶⁵

The MEAD has become a valuable diagnostic tool in TCM, assessing energy flow along meridians to detect imbalances affecting health. MEAD has demonstrated reliability in studies involving cancer, cardiovascular diseases, and temporomandibular dysfunction.^66
-69 In the context of HFs and the autonomic nervous system, the sympathetic activity, which is associated with “fight or flight” responses, is considered Yang, while the parasympathetic activity, which promotes relaxation and rest, is considered Yin. TCM sees menopause as a natural decline in Kidney essence and Yin, leading to a relative excess of Yang, which manifests as heat, sweating, constipation, and other symptoms.²⁴ This result was supported in our study to treat HFs, where the combination of JWXYS and EZW, particularly when tailored to TCM syndrome, alleviated HFs severity, and reduced sympathetic activity. In addition, our MEAD findings showed a significant increase in electrical conductivity in Yin meridians post-chemotherapy, consistent with this syndrome. Conductivity increases were observed in 6 Yin meridians (LU, PC, HT, SI, TH, and KI) and 1 Yang meridian (LI). These findings align symptoms such as HFs, anxiety, and dryness, reflecting Yin-deficiency-heat syndrome. Although HFs symptoms improved after 24 weeks, the underlying TCM syndrome persisted, supporting the hypothesis that symptoms may become tolerable over time. Notably, conductivity at the HT, LI, and KI meridians significantly decreased in the CHM group compared to the control. Kidney-heat, prevalent in menopause, was alleviated by EZW, which supports Yin and clears Kidney heat. JWXYS improved hyperactivity of Heart fire, addressing anxiety, depression, and insomnia, and improving mood-related QOL. Large intestine-heat, often linked to constipation, also improved due to the high oil content in EZW’s plant-based ingredients, providing intestinal lubrication.

This study has limitations. First, while chemotherapy-induced menopause includes symptoms such as insomnia and mood changes, this study focused primarily on hot flashes, and further research is needed to explore symptom interconnections. Second, as chemotherapy-induced menopause may persist beyond 1 year, future studies should assess the longevity of treatment effects. Third, the prospective CHM therapy was not randomized, which may introduce selection bias between the groups, although the patients’ baseline was similar among the 2 groups. Also, the relatively small sample size, may limit statistical power and affect applicability and reliability of findings. Fourth, multiple outcomes were tested without applying statistical correction for multiple comparisons, increasing the risk of type I errors (false positives), especially for results with p-values near the significance threshold. However, the results from our study do provide rationale for developing a RCT with large sample size. Finally, although the study uses fixed herbal formulas, TCM treatments are typically adjusted based on individual patient conditions in clinical practice. Perhaps TCM syndrome-based treatment can be considered a further stratification of patients when it is integrated with biomedical diagnoses in clinical practice to achieve higher efficacy.

Conclusion

The JWXYS and EZW combination have been shown to significantly alleviate HFs in patients with BC undergoing adjuvant chemotherapy. This effect was observed both during the treatment period and for at least 24 weeks after the treatment concluded. These findings suggest that CHM formulation can serve as an alternative therapy for managing HF discomfort and enhancing QOL. The study’s results align with TCM principles, clinical observations, and MEAD value assessments in managing HFs in BC patients. Further research with longer follow-up periods would be beneficial to confirm the long-term extended effect of this treatment.

Footnotes

Acknowledgements

We thank all our colleagues from the Integrative Breast Cancer Center of Kaohsiung Chang Gung Memorial Hospital for their enthusiastic help in this work.

ORCID iD

Ming-Yen Tsai

Ethical Considerations

This trial was conducted in accordance with the Declaration of Helsinki and has been approved by the Institutional Review Board of Chang Gung Memorial Hospital (Approval No. 201801559A3). Written informed consent was obtained from all participants prior to enrollment. The data collected in this study will not be used for any other purpose, and all personal information will be kept strictly confidential.

Author Contributions

Study conception and design: MYT. Data analysis planning: YCH, MYT. Data acquisition: CYC, SCW, HYW. Drafting of the manuscript: MYT, CYC. Critical revisions: CTL, MYT. Final approval of the article: all authors. Obtaining funding: MYT, who is responsible for the integrity of the work as a whole.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded by Chang Gung Memorial Hospital under grant number CMRPG8N1141-1142 & CMRPG8I0382. The funders have had no role in study design or trial design, manuscript writing, or decision making on publication.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

The datasets generated and/or analyzed during the current study will be available from the corresponding author upon reasonable request after the study’s completion.

Trial Registration

ClinicalTrials.gov ID: NCT03797248.

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Efficacy of Chinese Herbal Medicine in Managing Hot Flushes in Breast Cancer Patients on Adjuvant Chemotherapy: A Clinical Investigation

Abstract

Background:

Methods:

Results:

Conclusions:

Keywords

Introduction

Methods

Study Design and Participants

Procedure

Study Objectives

Study Assessments

Statistical Analysis

Results

Discussion

Conclusion

Footnotes

Acknowledgements

ORCID iD

Ethical Considerations

Author Contributions

Funding

Declaration of Conflicting Interests

Data Availability Statement

Trial Registration

References