Effectiveness of Combined Treatment with Traditional Chinese Medicine and Western Medicine on the Prognosis of Patients with Breast Cancer

Abstract

Objective:

Traditional Chinese Medicine (TCM) can be used to balance the body's immunity and tumor development during different stages of cancer treatment. Recently, TCM has been an important part of the health care system for breast cancer in Taiwan. This study was conducted as a prospective observation of the prognosis of Western medicine and combined treatment of TCM and Western medicine.

Methods:

Between April 2014 and March 2015, eligible participants were treated with Western medicine (n = 16) or TCM plus Western medicine (n = 29). The TCM treatment for patients followed the principles of a breast cancer protocol that had been developed in the Integrative Cancer Center. The outcome measures included quality of life, frequency of symptom distress, and clinical safety, and were measured with the Functional Assessment of Cancer Therapy-General (FACT-G), the Common Terminology Criteria for Adverse Events (CTCAE) Scale, and laboratory examinations, respectively. Data on these measures were collected at baseline and at 3 months after treatment initiation. Survival was estimated by Kaplan–Meier curves.

Results:

The two treatment groups did not differ significantly at baseline in terms of demographic information, FACT-G score, or frequency of symptom distress, except for fatigue, sleep disturbance, and mucositis. Most laboratory examinations did not differ significantly between the two groups, but higher red blood cell counts and lower liver function were found with the combined treatment than with Western medicine alone (p < 0.05). The mean overall survival rates were 25.5 months for the combined group and 22.7 months for the Western medicine group (p = 0.037).

Conclusion:

The results of this study suggest that combining Western and TCM therapy may have a favorable effect on the prognosis of breast cancer patients. Chinese herbal medicine is worth studying in a future larger cohort with a control group. It also warrants verification as a preventive intervention.

Introduction

Breast cancer is the most common cancer in women in Taiwan, and its incidence is increasing at an annual rate of 3.89%. Currently, breast cancer is the second leading cause of cancer-related deaths worldwide.¹ Cancer itself releases inflammatory substances that can cause symptoms such as fatigue, pain, insomnia, and depression.² In addition, anticancer therapies are commonly associated with the side effects of nausea, vomiting, mucositis, general weakness, and so on, which may adversely affect patients' quality of life (QOL).^3,4 Accumulated evidence shows that the use of complementary treatments has become increasingly common to improve breast cancer patient care.^5
–7 In most Asian countries, Traditional Chinese Medicine (TCM) is the most common complementary and integrative treatment. Indeed, TCM is an important part of the health care system for breast cancer in Taiwan,⁸ especially in treating weak and elderly patients with advanced-stage breast cancer.⁹

TCM treatments are not quantified, as they are in Western medicine, but rather are individualized according to patients' syndrome differentiation.^10,11 TCM also bases four diagnoses and treatment on patients' pattern types, which are identified into zang-fu (臟腑) and eight principals (八綱), and accounts for the pathogenesis of the disease.¹² In past decades, TCM has become well known in cancer treatment for adjusting the body balance between immunity and evil-qi (i.e., pollution, viruses, or cancer cells) in different stages.¹³ Recent studies have suggested that TCM is effective in enhancing the efficacy and safety of cancer treatment⁹ and in improving QOL,¹⁴ and that it has a partial effect in controlling cancer.¹⁵

Therefore, this study assessed the short-term effectiveness of combining TCM and Western medicine on the prognosis of patients with breast cancer by measuring survival time, symptom distress, physical function, and clinical safety.

Materials and Methods

Study design

This prospective observational study was conducted in patients with histologically proven invasive female breast cancer at Chang Gung Memorial Hospital (CGMH), Kaohsiung Branch, from April 2014 to March 2015. Patients were included according to these criteria: (1) adults aging >20 years, (2) completion of one cycle of standard chemotherapy treatment, the regimen of which contained anthracycline- or taxane-based medications, (3) cancer-related symptoms or side effects of cancer treatment greater than grade 1, (4) Eastern Cooperative Oncology Group (ECOG) score between 0 and 2, and (5) understanding of the research objectives and agreement to participate. Patients were excluded if they were pregnant, had inadequate biochemical and organ functions, or had an expected lifetime of <3 months. This study was approved by the institutional review board of Chang Gung Memorial Hospital (No. 104-8593A3).

Procedure

Once patients exhibited cancer-related symptoms or treatment side effects, attending physicians at oncology outpatient clinics consulted the patients regarding whether they would be willing to receive adjuvant Chinese herbal medicine (CHM) at the same time or Western medicine alone. In the Western medicine group, patients received radiotherapy, chemotherapy, hormone therapy, and optimal supportive therapy according to the National Comprehensive Cancer Network (NCCN) guidelines. After patients signed informed consent forms, they were assigned to groups according to their preference.

The combined-treatment group received CHM according to the modified TCM treatment for breast cancer protocol that was developed in the Integrative Cancer Center in 2014.¹⁶ The consensus assessment was based on expert judgments, clinical experience, and literature review of TCM patterns, and it was supported by a project of the Taiwanese Ministry of Health and Welfare. Therapy was administered by qualified TCM physicians, who considered patients' common symptoms associated with chemotherapy and the treatment guidelines (Table 1). For instance, the principle for selecting CHM for chemotherapy-induced abdominal pain, nausea, cramping, and flatulence, which belong to stomach heat syndrome, could be the application of Huang Lian Wen Dan Tang (黃連溫膽湯). Additional herbal medicine was also allowed, depending on the patient's clinical condition. Since CHM is an adjuvant therapy, patients received at least three monthly CHM treatments during the chemotherapy course. Patients usually visited the CHM outpatient clinic every 1 or 2 weeks, and all the herbal formulas used were prescribed by qualified TCM physicians. All CHMs were delivered by qualified pharmacists.

Table 1.

Common Pattern Types, Symptoms, Treatment Principles, and Prescriptions of Chinese Herbal Medicines for Breast Cancer Patients in Combined Treatment Group (n = 26)

Chemotherapeutic regimens	Common symptoms or side effects	Treatment principle	Prescriptions/dosage	Composition
Anthracycline based (adriamycin, epirubicin, or liposomal doxorubicin)	Nausea/vomiting, mucositis, abdominal flatulence, mood alteration (depression, anxiety, agitation), insomnia	Harmonizing the Stomach-qi, cleaning heat and removing the sludge, tranquilizing and sedating the mind	Huang Lian Wen Dan Tang 黃連溫膽湯: 6 g/day	Caulis Bambusae in Taeniam, Fr. Aurantii Immaturus, Rz. Pinelliae Preparatum, Per. Citri Reticulatae, Poria, Rx. Glycyrrhizae, Fr. Jujube, Rz. Zingiberis Recens, Rz. Coptidis
	Dizziness, fatigue (asthenia, lethargy, malaise)	Invigorating qi and enriching the blood	Ren Shen Yang Rong Tang 人參養榮湯: 12 g/day	Rx. Ginseng, Rx. Astragali, Rz. Atractylodis Macrocephalae, Poria, Rx. Angelicae Sinensis, Rx. Rehmanniae Preparata, Rx. Paeoniae Alba, Per. Citri Reticulatae, Rx. Polygalae, Fr. Schisandrae, Fr. Jujube, Cx. Cinnamomi, Rz. Zingiberis Recens, Rx. Glycyrrhizae
Taxane based (docetaxel or paclitaxel)	Diarrhea, edema, flush, anorexia	Relieving qi stagnancy in liver, strengthening the spleen	Jia Wei Xiao Yao San 加味逍遙散: 10.5–14 g/day	Fr. Gardeniae, Cx. Moutan, Rx. Bupleuri, Rx. Angelicae Sinensis, Rx. Paeoniae Alba, Rz. Atractylodis Macrocephalae, Poria, Rx. Glycyrrhizae Preparata, Hb. Menthae Haplocalycis, Rz. Zingiberis Recens Radix Codonopsis, Rhizoma Dioscoreae and Semen Coicis
	Hand–foot skin reaction (dry, furrowed skin that develops changes in pigmentation)	Nourishing the yin and blood	Er Zhi Wan 二至丸: 0.9–2.6 g/day	Fr. Ligustri Lucidi, Hb. Ecliptae
	Myalgia/arthralgia, peripheral neuropathy	Invigorating the circulation of qi and blood, alleviating pain	Shen Tong Zhu Yu Tang 身痛逐瘀湯: 4–6 g/day	Rx. Gentianae, Rx. Chuanxiong, Sm. Persicae, Flos Carthami, Rx. Glycyrrhizae, Rz. and Rx. Notopterygii, Myrrh, Rx. Angelicae Sinensis, Faeces Trogopterori, Rz. Cyperi, Rx. Cyathulae, Pheretima

Outcome assessment

Clinical data, including age, comorbidity, clinical stage, molecular type, treatment modality, and overall survival (OS), were recorded. Outcome measures included the Functional Assessment of Cancer Therapy-General (FACT-G) and the frequency of cancer-related symptoms, completed by the patients at the first visit and at 3 months. General QOL was measured with the fourth version of the FACT-G. This instrument has 27 items loaded in four domains (physical, social/family, emotional, and functional), and all items are scored on a scale of 0 (not at all), 1 (a little bit), 2 (somewhat), 3 (quite a bit), or 4 (very much).¹⁷ The FACT-G total score is computed as the sum of the four subscale scores. For each domain and the total score, a higher score indicates better QOL. The FACT-G is widely used to measure health-related QOL in adult cancer patients, including in clinical trials and in other medical assessment studies. The FACT-G has good internal consistency,¹⁸ and it distinguishes the differences in QOL between different levels.¹⁹ It is not affected by different diagnoses, stages of disease, or cultural differences.

Cancer-related symptoms or side effects of cancer treatment such as pain, flushes, anorexia, fatigue, sleep disturbance, negative mood, lymphedema, neuropathy, mouth sores, constipation or diarrhea, nausea, and vomiting were graded using the Common Terminology Criteria for Adverse Events (CTCAE) Scale, a commonly used measure.²⁰ A clinical description of severity of more than grade 1 indicates that the patient is symptomatic, that intervention is indicated, and that instrumental activities of daily living are affected. In addition, body weight and laboratory data were assessed before and after CHM treatment. OS is defined as the period from the beginning of chemotherapy to the date of death. OS was censored when the patients were still alive at the time of the last follow-up. The last follow-up time for survival data analysis was the end of August 2018.

Statistical analysis

The continuous variables were summarized using means and standard deviations, whereas the categorical variables were summarized using counts and percentages. The continuous variables of the baseline characteristics of TCM users and nonusers were analyzed with a Student's t test; categorical variables were analyzed with a chi square or Fisher's exact test. The continuous variables of before and after treatment were compared by paired t-test. The cumulative probability of survival for TCM users and nonusers was estimated using a Kaplan–Meier estimator with a log-rank test used to compare the survival curves between the groups. Statistical significance was determined as p < 0.05. Data analyses were performed in SPSS version 17.0 (SPSS, Inc., Chicago, IL).

Results

After assessment for eligibility, 45 patients were included in the study. Of these, 29 patients received a treatment course combining TCM and Western medicine, and 16 patients received a treatment course of Western medicine alone. No patients were lost to follow-up during the disease course. There were no significant differences in age, duration of disease, staging, pathologic classification, or type of Western therapy between the two groups. The clinical characteristics of both groups of patients are shown in Table 2.

Table 2.

Comparison of General Information Between the Two Groups

Variable	Western medicine (n = 16)	Combined treatment (n = 29)	p-Value
Mean age—SD (years)	53.75 ± 10.08	49.52 ± 8.81	0.150^a
Duration of disease (months)	2.94 ± 0.25	2.93 ± 0.26	0.936^a
Comorbidity
Diabetes	1 (6.3)	3 (10.3)	1.000^b
HTN	1 (6.3)	4 (13.8)	0.641^b
Liver disease	2 (12.5)	2 (6.9)	0.608^b
TNM stage			0.127^c
I–II	4 (25.0)	14 (48.3)
III–IV	12 (75.0)	15 (52.7)
Molecular classification			0.957^b
Luminal A	3 (18.8)	8 (27.6)
Luminal B	9 (56.3)	14 (48.2)
HER2/ERBB2-enriched	3 (18.8)	5 (17.2)
Triple negative	1 (6.3)	2 (6.9)
Surgery method			0.701^b
Breast-conserving surgery	1 (6.3)	5 (17.2)
Mastectomy	12 (75.0)	20 (69.0)
None	3 (18.8)	4 (13.8)
Hormonal or targeted biologic therapy	10 (62.5)	19 (65.5)	0.840^c
Radiotherapy	8 (50.0)	8 (27.6)	0.133^c
Number of chemotherapy	5.13 ± 2.60	4.66 ± 4.40	0.699^a
Chemotherapy intent			0.888^b
Adjuvant	10 (62.5)	20 (69.0)
Neoadjuvant	2 (12.5)	2 (6.9)
Recurrence	4 (25)	7 (24)
Chemotherapy regimen			1.000^b
Anthracycline based	2	5
Taxane based	4	7
ECx4- > Tx4	10	17

Unless otherwise noted, values are number (percentage).

Student's t test.

Fisher exact test.

Pearson's chi square.

ECx4- > Tx4: (Epirubicin + Cyclophosphamide) × 4 + Docetaxel × 4.

HTN, hypertension.

Table 3 shows the improvement on the QOL measure and cancer-related symptoms of cancer treatment in the combined treatment and Western medicine groups. After 3 months of combined treatment, there were no significant changes in the FACT-G total score or its subscales in the combined treatment group as compared with the Western medicine group (p > 0.05). The frequency of symptoms exceeding CTCAE grade 1 showed no significant improvement. However, some symptoms, such as fatigue (p = 0.037), sleep disturbance (p = 0.021), and mucositis (p = 0.039) were significantly lower in the combined treatment group than in the Western medicine group.

Table 3.

Change in Quality of Life and Comparison of Functional Assessment of Cancer Therapy-General Questionnaire in Physical Well-Being, Social Well-Being, Emotional Well-Being, Functional Well-Being, and Total Score as Well as Number of More Than Common Terminology Criteria for Adverse Events Grade 1 Cancer-Related Symptoms or Side Effects of Cancer Treatment at Baseline and at the Third Months Between the Two Groups

Variable	Western medicine (n = 16)		p-Value^a	Combined treatment (n = 29)		p-Value^a	p-Value^b
Variable	Pre-test	Post-test	p-Value^a	Pre-test	Post-test	p-Value^a	p-Value^b
FACT-G total score, Mean (SD)	75.14 ± 15.20	80.57 ± 14.23	0.006^c, ^*	70.87 ± 19.44	78.30 ± 15.50	0.055^c	0.557^c
Physical	21.88 ± 4.92	23.50 ± 3.50	0.085^c	17.76 ± 7.17	21.79 ± 4.72	0.003^c, ^*	0.899^c
Social	20.08 ± 7.22	20.19 ± 7.15	0.793^c	21.37 ± 5.99	21.27 ± 6.38	0.940^c	0.246^c
Emotional	17.50 ± 3.35	18.06 ± 3.42	0.499^c	15.55 ± 5.69	18.45 ± 3.87	0.004^c, ^*	0.441^c
Functional	15.69 ± 6.95	18.81 ± 5.75	0.002^c, ^*	16.21 ± 6.24	17.03 ± 6.34	0.576^c	0.736^c
Cancer-related symptoms or side effects of cancer treatment, n (%)
Pain	6 (37.5)	5 (31.3)	1.000^d	12 (41.4)	9 (31.0)	0.375^d	1.000^e
Flushes	3 (18.8)	3 (18.8)	1.000^d	9 (31.0)	4 (13.8)	0.063^d	0.686^e
Anorexia	7 (43.8)	6 (37.5)	1.000^d	15 (51.7)	4 (13.8)	0.001^d, ^*	0.131^e
Fatigue	8 (50.0)	8 (50.0)	1.000^d	10 (34.5)	5 (17.2)	0.125^d	0.037^e, ^*
Sleep disturbance	8 (50.0)	7 (43.8)	1.000^d	12 (41.4)	3 (10.3)	0.004^d, ^*	0.021^e, ^*
Negative mood	3 (18.8)	3 (18.8)	1.000^d	5 (17.2)	2 (6.9)	0.250^d	0.330^e
Lymphedema	3 (18.8)	3 (18.8)	1.000^d	7 (24.1)	7 (24.1)	1.000^d	1.000^e
Neuropathy	3 (18.8)	3 (18.8)	1.000^d	5 (17.2)	3 (10.3)	0.500^d	0.650^e
Constipation or diarrhea	4 (25.0)	1 (6.3)	0.250^d	4 (13.8)	0 (0.0)	0.000^d	0.356^e
Mucositis	3 (18.8)	3 (18.8)	1.000^d	5 (17.2)	0 (0.0)	0.000^d	0.039^e, ^*
Nausea and vomiting	6 (37.5)	4 (25.0)	0.500^d	7 (24.1)	2 (6.9)	0.063^d	0.166^e

Within group.

Between two groups.

Student's t test.

McNemar test.

Fisher exact test.

p-Value <0.05.

FACT-G, Functional Assessment of Cancer Therapy-General.

The results of routine blood tests, tumor markers, and hepatic and renal functions before and after treatment in both groups are shown in Table 4. Significant differences in red blood cell count (RBC) and alanine transaminase were found between the combined group and the Western medicine group (p = 0.25 and 0.09, respectively). In addition, no significant changes in body weight were reported in either treatment group.

Table 4.

Change in Body Weight, Laboratory Data, and Tumor Markers at Baseline and at the Third Months Between the Two Groups

Variable Mean (SD)	Western medicine (n = 16)		p-Value^a	Combined treatment (n = 29)		p-Value^a	p-Value^b
Variable Mean (SD)	Pre-test	Post-test	p-Value^a	Pre-test	Post-test	p-Value^a	p-Value^b
Body weight (kg)	56.46 ± 9.43	56.18 ± 8.75	0.650	61.56 ± 12.91	60.68 ± 12.11	0.364	0.054
Laboratory data
WBC (1,000/μL)	6.09 ± 2.44	5.21 ± 2.74	0.026^*	5.43 ± 1.79	5.76 ± 2.68	0.561	0.834
RBC (million/μL)	11.45 ± 1.49	11.89 ± 1.08	0.058	12.09 ± 1.36	12.26 ± 1.26	0.227	0.025^*
Platelet (1,000/μL)	262.94 ± 101.18	238.50 ± 87.16	0.121	217.28 ± 71.83	225.86 ± 102.32	0.490	0.893
Creatinine (mg/dL)	0.67 ± 0.15	0.66 ± 0.15	0.799	0.69 ± 0.42	0.67 ± 0.13	0.815	0.592
AST (μ/L)	27.25 ± 16.01	24.25 ± 5.89	0.370	27.31 ± 13.31	30.26 ± 12.22	0.127	0.145
ALT (μ/L)	27.96 ± 15.73	34.90 ± 22.99	0.074	24.44 ± 19.78	19.25 ± 9.18	0.198	0.009^*
Tumor marker
CEA (ng/mL)	4.05 ± 6.42	3.43 ± 4.52	0.244	2.29 ± 1.52	2.57 ± 2.74	0.437	0.850
CA-15-3 (μ/mL)	55.18 ± 106.48	46.10 ± 119.35	0.734	44.82 ± 114.64	23.00 ± 31.88	0.471	0.524

Within group.

Between two groups.

p-Value <0.05.

ALT, alanine transaminase; AST, aspartate transaminase; CEA, carcinoembryonic antigen; RBC, red blood cell count; WBC, white blood cell count.

Figure 1 shows the OS curves of patients who did and did not receive CHM. The mean survival time of patients in the combined group was 25.5 months, and that in the Western medicine group was 22.7 months (p = 0.037).

FIG. 1.

Survival analysis for combined treatment (black line) and Western medicine treatment (gray line) groups.

Discussion

Many studies have shown that it is beneficial to cancer patients' treatment response, disease control, and QOL to provide adjuvant TCM treatment.^21

–24 However, TCM and Western medicine treatments are often operated independently, and opportunities for integration are rare. Given the current growth of TCM-based evidence, integrative medicine may gradually be widely espoused. After all, the advantages of combining TCM and Western medicine in the same medical system through detailed medical records include understanding of patient information, progress in treatment, monitoring of clinical safety, and evaluation of adverse reactions. For example, Kang Ai Pian (抗癌片), a TCM formulation used to treat multiple cancers, was found to have potential herb–drug interactions when used concomitantly with chemotherapy.²⁵ The different CHM prescriptions and single herbs employed in TCM practice depend on the physical strength, syndrome type, and chief complaints of the patients. However, the goal of an integrative team should be to confirm whether treatment guidelines are necessary based on clinical experience, literature review, and evidence. Certainly, it is necessary to verify the efficacy and safety of these treatment principles of TCM through the scientific method.¹⁴

This study was the first to use the FACT-G to assess improvements in QOL in breast cancer patients receiving CHM during a treatment course of Western medicine. Although the physiology and emotion domains of QOL improved after treatment in the combined group, the differences did not translate into significant improvements in the total score and its subscales relative to the results of the Western medicine group. In recent years, the FACT-G scale has frequently been chosen as an adjuvant measure for TCM in cancer research.^26
–28 However, past research on breast cancer has focused exclusively on the application of acupuncture,²⁹ and it usually focused on specific symptoms, such as cancer-induced fatigue or joint pain caused by aromatase inhibitors.³⁰ Perhaps the FACT-G does not provide a sufficiently detailed analysis of the specific symptoms or side effects for specific cancers. It is suggested that custom-made measures, such as the Functional Assessment of Cancer Therapy-Breast (FACT-B) for breast cancer, or other QOL questionnaires (EORTC QLQ-C30 and QLQ-BR23) and the CTCAE could be employed.

Indeed, the results showed significant improvements in cancer-related symptoms or side effects of cancer treatment such as fatigue, insomnia, and mucositis after intervention in the combined group relative to the Western medicine group. The efficacy of TCM on breast cancer fatigue has been confirmed in previous studies.^9,31,32 Ren Shen Yang Rong Tang (人參養榮湯) was used to improve the severity of cancer-related fatigue within 2 weeks by nourishing qi and blood, and it also helped to ameliorate disturbed sleep, dry mouth, drowsiness, and poor appetite.³¹ 5-fu/epirubicin/cyclophosphamide is a common chemotherapy regimen for treating invasive breast cancer, which may cause oral ulcers. Rhodiola algida (紅景天) has the potential to alleviate mucositis by removing residual heat, preventing tissue damage and accelerating wound healing.³² As for the sleep disturbance of breast cancer patients, this symptom may be caused by anxiety about the cancer itself, the discomfort of Western medicine treatment, and changes in the patient's appearance. Wen Dan Tang (溫膽湯), a formula that is often used clinically to alleviate digestive symptoms such as nausea, belching, and poor appetite, has also been found to regulate ghrelin levels in the brain–gut axis and significantly reduce anxiety.³³ A retrospective cohort study found that Jia Wei Xiao Yao San (加味逍遙散) was the recommended prescription for insomnia and was significantly associated with reduced mortality.⁹ In addition, many studies have indicated that it can decrease the incidence of hepatitis and subsequent endometrial cancer in breast cancer patients receiving chemotherapy and Tamoxifen, respectively.^34,35

In this study, it is found that adjuvant TCM therapy during the 3-month Western medicine treatment was safe, and it even prevented the reduction of RBC and the elevation of liver function. A review article by Zhu et al. showed that CHMs can effectively reduce declines in the white blood cell count and platelets in patients with breast cancer but yielded no significant differences in RBC.³⁶ The improvement of anemia in patients with cancer can lead to better QOL, facilitate the tolerability and efficacy of anticancer treatment, and have a possible impact on prognosis.³⁷ The study provides further evidence supporting the effect of CHM in preventing decreased RBC.

Liver damage due to cancer treatment is common. It may be caused by certain chemotherapy drugs (i.e., carboplatin, etoposide, cisplatin, and docetaxel), an active hepatitis virus infection, or combinations of painkillers, antibiotics, antiemetics, or herbal and folk medicines.³⁸ A study by Ahn et al. in Korea found that of 178 breast cancer patients receiving chemotherapy during hospitalization, 37 of the 65 patients (56.9%) who used herbal remedies developed mild-to-moderate liver dysfunction.³⁹ The previous literature has also indicated that herbal medicine-related hepatotoxicity is a common consequence of treatment with Fructus xanthii (蒼耳子), Polygonum multiflorum (何首烏), aconite (烏頭), and Fructus toosendan (川楝子).⁴⁰ However, according to analysis by the Taiwanese National Health Insurance Research Database, these drugs are not often found in CHM prescriptions for the treatment of breast cancer.³⁵ Some articles present a positive view of the combined use of TCM during chemotherapy, claiming that it can protect liver function.⁴¹ In any case, it is necessary to provide proper CHM prescriptions and monitor liver function after precise TCM syndrome differentiation.

The findings of the study indicated that the median 2-year survival time was better in the combined group than in the Western medicine group. Because of the small number of cases, the authors did not subdivide the tumor stages and pathology types. Although they found no statistically significant differences in the TNM stage, the larger percentage of patients who were stage I–II in the combined treatment group might have affected the survival outcomes. Another question is whether the 2 years of observation time was sufficient. In 1996, Thomas Saphner et al. analyzed 3,585 breast cancer patients from 1978 to 1982 who underwent surgery and tracking for an average of 8 years. In that study, 45% of the patients had risk of recurrence after surgery.⁴² In addition to that at 5 years after the breast cancer tracking period, the peak risk of recurrence was 13.3% in the first 1–2 years after diagnosis.⁴² The characteristics in the high recurrence group were metastatic lymph node metastasis, large tumors, highly malignant tumors, human epidermal growth factor receptor 2 (HER2 gene) positive, hormone receptor (estrogen receptor and progesterone receptor) negative, or previous treatment with chemotherapy. Therefore, the 2-year prognosis of this study was reasonable, and the need for further follow-up must be noted.

According to TCM theory, inner inflammation caused by cancer itself and chemotoxicity upset the equilibrium between yin and yang, cause blockage of the meridians and viscera, and lead to deficiency of qi, as well as cause stasis of the blood, phlegm, and toxins.⁴³ Therefore, the patients in this study were mainly treated according to the therapeutic principles of invigorating qi and enriching the blood, cleaning heat and reducing toxicity, nourishing the yin and blood, tonifying the spleen and relieving qi stagnancy, and regulating qi to dissipate blood stasis. Table 1 lists the CHMs that were commonly applied in accordance with the aforementioned principles of breast cancer treatment in this study. To date, no standardization of syndrome differentiation for breast cancer treated with TCM has been conducted. Exploring the standardization of TCM pattern types using a randomized control study is difficult because such patterns are dynamic during the treatment course. The biggest problem is the large amount of heterogeneity in TCM diagnoses; consequently, the herbal treatments prescribed vary. Thus, it would be difficult to determine differences in these treatments and to identify whether one may be more useful than another. However, CHM therapy is practical when based on correct judgments of the syndrome classification according to the TCM system. Similarly, different CHM prescriptions, rather than a fixed formula for determining proper treatment based on patients' patterns, are gradually being emphasized. This approach seems to lack rigor from a scientific perspective, but it is closest to real-world TCM practice. Most research that has attempted to develop this complementary and integrative program for cancer care has reported improvements in the clinical outcomes.^44
–46 Given the development of evidence-based medicine and the importance of comprehensive treatment of breast cancer,⁴⁷ a cancer treatment model, including TCM, surgery, radiotherapy, chemotherapy, hormone therapy, immunotherapy, and other standardized treatments with individualized comprehensive treatment, has become the current global trend, especially for breast cancer.

The authors are aware of several limitations of the study. First, the study employed a small sample and was conducted at a single cancer center. Therefore, the relatively small selective sample limits the generalizability of the results to the general population. Second, the different types of CHMs and their possible implications in the breast cancer prognosis need to be assessed in the future as well. In addition, the combination of treatments prescribed by TCM physicians varied among patients, which only allowed estimation of general effects of TCM treatments. Finally, this was an observational study with inevitable selection bias. Without proper randomization, the beneficial effects of CHM could have been overestimated in this study due to participants being assigned to the groups according to preference. In addition, there was no adjustment for confounders such as stage or age. Another limitation is that 29 of the 45 patients received CHM, and this ratio between the two groups may also have led to a significant statistical imbalance. To resolve the problem, the authors analyzed the data between the two groups and determined that their baseline conditions were homogenous. Case-matching study is another way to evaluate the efficacy of CHM during Western medicine treatment in breast cancer patients.

Conclusion

In the patients with breast cancer in the combined treatment group, some symptoms and distress were alleviated during cancer treatment, with good safety, and the combination of CHM and Western medicine appeared to be effective in prolonging survival as compared with patients in the Western medicine group. The results of this study provide additional practice guidelines and justification for the administration of TCM as complementary therapy in breast cancer patients. Future studies should include a larger cohort study with controls to validate the results and examine the protocol for use as a preventive therapy.

Footnotes

Acknowledgments

The authors thank all the colleagues from the Cancer Center and TCM ward of Chang Gung Memorial Hospital, Kaohsiung Branch, for their enthusiastic help in this study.

Author Contributions

M.-Y.T. and Y.-H.C. designed the study. M.-Y.T. acquired the data. M.-Y.T., Y.-F.L., and Y.-C.H. analyzed the data and drafted the figures. M.-Y.T. and Y.-C.L. wrote the article. Y.-H.C. and Y.-F.L. provided clinical insights and references for oncology. M.-Y.T. revised the article. All authors read and approved the final article.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This study was supported by the Taiwan Ministry of Health and Welfare (MOHW107-CMAP-M-114-122111) and funded by Chang Gung Memorial Hospital (CMRPG-8I0381 and 8I0382).

References

Siegel

, Miller

, Jemal

. Cancer statistics, 2017. CA Cancer J Clin, 2017; 67:7–30.

Bower

, Ganz

, Irwin

, et al. Inflammation and behavioral symptoms after breast cancer treatment: Do fatigue, depression, and sleep disturbance share a common underlying mechanism?. J Clin Oncol, 2011; 29:3517.

Rashid

, Koh

, Baca

, et al. Clinical impact of chemotherapy-related adverse events in patients with metastatic breast cancer in an integrated health care system. J Manag Care Spec Pharm, 2015; 21:863–871.

Reinisch

, von Minckwitz

, Harbeck

, et al. Side effects of standard adjuvant and neoadjuvant chemotherapy regimens according to age groups in primary breast cancer. Breast Care, 2013; 8:60–66.

Boon

, Olatunde

, Zick

. Trends in complementary/alternative medicine use by breast cancer survivors: Comparing survey data from 1998 and 2005. BMC Womens Health, 2007; 7:4.

Wanchai

, Armer

, Stewart

. Complementary and alternative medicine use among women with breast cancer: A systematic review. Clin J Oncol Nurs, 2010; 14:E45–E55.

Garland

, Valentine

, Desai

, et al. Complementary and alternative medicine use and benefit finding among cancer patients. J Altern Complement Med, 2013; 19:876–881.

Lin

Y-H

, Chiu

J-H

. Use of Chinese medicine by women with breast cancer: A nationwide cross-sectional study in Taiwan. Complement Ther Med, 2011; 19:137–143.

Lee

, Chen

, Shih

YRV

, et al. Adjunctive traditional Chinese medicine therapy improves survival in patients with advanced breast cancer: A population-based study. Cancer, 2014; 120:1338–1344.

10.

Cohen

, Tagliaferri

, Tripathy

. Traditional Chinese medicine in the treatment of breast cancer. Semin Oncol, 2002; 29:563–574.

11.

Lin

S-CA

, Chu

P-Y

, Chen

L-L

, et al. The prevalence rate of deviations in body constitutions and related factors in follow-up stage breast cancer patients—A nationwide study. Complement Ther Med, 2017; 32:49–55.

12.

Yeh

Y-C

, Chen

H-Y

, Yang

S-H

, et al. Hedyotis diffusa combined with Scutellaria barbata are the core treatment of Chinese herbal medicine used for breast cancer patients: A population-based study. Evid Based Complement Alternat Med, 2014; 2014:202378.

13.

Liu

, Wang

, Zhang

, et al. Traditional Chinese medicine and cancer: History, present situation, and development. Thorac Cancer, 2015; 6:561–569.

14.

Lin

Y-H

, Shiu

J-H

, Chen

F-P

, Chiu

J-H

. Building an integrative outpatient care program for breast cancer patients in Taiwan. Integr Cancer Ther, 2016; 15:343–348.

15.

, Yang

, Li

, et al. Traditional Chinese medicine in cancer care: A review of controlled clinical studies published in Chinese. PLoS One, 2013; 8:e60338.

16.

Liu

C-T

, Chen

Y-H

, Huang

Y-C

, et al. Chemotherapy in conjunction with traditional Chinese medicine for survival of patients with early female breast cancer: Protocol for a non-randomized, single center prospective cohort study. Trials, 2019; 20:741.

17.

Cella

. Manual of the Functional Assessment of Chronic Illness Therapy (FACIT) Scales: version 4. Evanston, IL: Center on Outcomes Research and Education, Evanston Northwestern Healthcare and Northwestern University, 1997.

18.

Victorson

, Barocas

, Song

, Cella

. Reliability across studies from the functional assessment of cancer therapy-general (FACT-G) and its subscales: A reliability generalization. Qual Life Res, 2008; 17:1137–1146.

19.

Overcash

, Extermann

, Parr

, et al. Validity and reliability of the FACT-G scale for use in the older person with cancer. Am J Clin Oncol, 2001; 24:591–596.

20.

U.S. Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. 2010. Online document at: https://www.eortc.be/services/doc/ctc/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf, accessed February 27, 2019 .

21.

Chen

, Flower

, Ritchie

, et al. Oral Chinese herbal medicine (CHM) as an adjuvant treatment during chemotherapy for non-small cell lung cancer: A systematic review. Lung Cancer, 2010; 68:137–145.

22.

Chung

, Wu

, Lu

, et al. Chinese herbal medicine for symptom management in cancer palliative care: Systematic review and meta-analysis. Medicine, 2016; 95:e2793.

23.

Molassiotis

, Potrata

, Cheng

. A systematic review of the effectiveness of Chinese herbal medication in symptom management and improvement of quality of life in adult cancer patients. Complement Ther Med, 2009; 17:92–120.

24.

Tao

, Luo

, Cui

, et al. Practice of traditional Chinese medicine for psycho-behavioral intervention improves quality of life in cancer patients: A systematic review and meta-analysis. Oncotarget, 2015; 6:39725.

25.

Chan

, Tan

, Xin

, et al. Interactions between traditional Chinese medicines and Western. Curr Opin Drug Discov Devel, 2010; 13:50–65.

26.

Kuo

Y-h

, Tsay

S-L

, Chang

C-C

, et al. Cancer impact, complementary/alternative medicine beliefs, and quality of life in cancer patients. J Altern Complement Med, 2018; 24:276–281.

27.

Cheng

K-F

, Leung

P-C

. Use of Chinese herbal medicine as an adjuvant for cancer treatment: A randomized controlled dose-finding clinical trial on lung cancer patients. J Cancer Ther, 2011; 2:91.

28.

Jeong

, Ryu

, Kim

, et al. Bojungikki-tang for cancer-related fatigue: A pilot randomized clinical trial. Integr Cancer Ther, 2010; 9:331–338.

29.

Molassiotis

, Bardy

, Finnegan-John

, et al. Acupuncture for cancer-related fatigue in patients with breast cancer: A pragmatic randomized controlled trial. J Clin Oncol, 2012; 30:4470–4476.

30.

, Kimble

, Costa

, et al. Acupuncture for treatment of arthralgia secondary to aromatase inhibitor therapy in women with early breast cancer: Pilot study. Acupunct Med, 2013; 31:264–271.

31.

, Chen

, Li

, Wang

. Ren Shen Yangrong Tang for fatigue in cancer survivors: A phase I/II open-label study. J Altern Complement Med, 2015; 21:281–287.

32.

Loo

, Jin

, Chow

, et al. Rhodiola algida improves chemotherapy-induced oral mucositis in breast cancer patients. Expert Opin Investig Drugs, 2010; 19(sup1):S91–S100.

33.

Wang

, Song

, Li

, et al. Effects of Wen Dan Tang on insomnia-related anxiety and levels of the brain-gut peptide Ghrelin. Neural Regen Res, 2014; 9:205–212.

34.

Huang

, Yen

, Chiang

, et al. Chinese herbal medicine as an adjunctive therapy ameliorated the incidence of chronic hepatitis in patients with breast cancer: A nationwide population-based cohort study. Evid Based Complement Alternat Med, 2017; 2017:1052976.

35.

Tsai

Y-T

, Lai

J-N

, Wu

C-T

. The use of Chinese herbal products and its influence on tamoxifen induced endometrial cancer risk among female breast cancer patients: A population-based study. J Ethnopharmacol, 2014; 155:1256–1262.

36.

Zhu

, Li

, et al. Chinese herbal medicine as an adjunctive therapy for breast cancer: A systematic review and meta-analysis. Evid Based Complement Alternat Med, 2016; 2016:9469276.

37.

Busti

, Marchi

, Ugolini

, et al. Anemia and iron deficiency in cancer patients: Role of iron replacement therapy. Pharmaceuticals (Basel), 2018; 11:pii: E94.

38.

King

, Perry

. Hepatotoxicity of chemotherapy. Oncologist, 2001; 6:162–176.

39.

Ahn

J-H

, Kim

S-B

, Yun

, et al. Alternative therapy and abnormal liver function during adjuvant chemotherapy in breast cancer patients. J Korean Med Sci, 2004; 19:397–400.

40.

, Peng

J-H

, Hu

Y-Y

. Chinese herbal medicine-induced liver injury. J Clin Transl Hepatol, 2014; 2:170.

41.

Liu

M-L

, Chien

L-Y

, Tai

C-J

, et al. Effectiveness of traditional Chinese medicine for liver protection and chemotherapy completion among cancer patients. Evid Based Complement Alternat Med, 2011; 2011:291843.

42.

Saphner

, Tormey

, Gray

. Annual hazard rates of recurrence for breast cancer after primary therapy. J Clin Oncol, 1996; 14:2738–2746.

43.

Zhang

, Liang

, He

. Anticancer activities and mechanisms of heat-clearing and detoxicating traditional Chinese herbal medicine. Chin Med, 2017; 12:20.

44.

Guo

, Chen

. Standardization of syndrome differentiation defined by traditional Chinese medicine in operative breast cancer: A modified delphi study. ScientificWorldJournal, 2015; 2015:820436.

45.

Tang

W-R

, Yang

S-H

, Yu

C-T

, et al. Long-term effectiveness of combined treatment with traditional Chinese medicine and Western medicine on the prognosis of patients with lung cancer. J Altern Complement Med, 2016; 22:212–222.

46.

McPherson

, Cochrane

, Zhu

. Current usage of traditional Chinese medicine in the management of breast cancer: A practitioner's perspective. Integr Cancer Ther, 2016; 15:335–342.

47.

Tsunoda-Shimizu

, Nakamura

. Diagnostic assessment of nonpalpable breast cancer-the difference in diagnostic approach for the clinical treatment of breast cancer between the Japanese guidelines and the national comprehensive cancer network (USA) guidelines. Breast Cancer, 2005; 12:250.