We conducted a National Health Insurance Research Database-based Taiwanese nationwide population-based cohort study to evaluate whether Chinese herbal medicine (CHM) treatment decreased the incidence of chronic hepatitis in breast cancer patients receiving chemotherapy and/or radiotherapy. A total of 81171 patients were diagnosed with breast cancer within the defined study period. After randomly equal matching, data from 13856 patients were analyzed. Hazard ratios of incidence rate of chronic hepatitis were used to determine the influence and therapeutic potential of CHM in patients with breast cancer. The patients with breast cancer receiving CHM treatment exhibited a significantly decreased incidence rate of chronic hepatitis even across the stratification of age, CCI score, and treatments. The cumulative incidence of chronic hepatitis for a period of seven years after initial breast cancer diagnosis was also reduced in the patients receiving CHM treatment. The ten most commonly used single herbs and formulas were effective in protecting liver function in patients with breast cancer, where
Breast cancer is the most common and the second most life-threatening cancer in women. Conventional breast cancer treatments include surgery, radiation, and medication. Medical therapies (chemotherapy, hormone therapy, and target therapy) are adopted to improve the disease-free ratio, overall survival ratio, and patients’ quality of life. However, several adverse effects induced by medical treatments in patients with breast cancer include fatigue, phlebitis, alopecia, nausea, vomiting, mucositis, myelosuppression, cardiac toxicity, renal toxicity, and hepatotoxicity. Those adverse effects may affect up to 60% of patients and limit the application and efficacy of medical therapy [
Complementary and alternative medicines (CAM) are widely applied to healthcare approaches throughout the world. A recent study showed that up to 87% of women with breast cancer reported CAM use [
Hepatotoxicity is also a major side effect that may interrupt medical therapy of breast cancer. Patients with viral hepatitis frequently receive TCM for the drug resistance and dose-dependent side effects of antiviral agents. Recently, several studies have shown the efficacy of TCM to improve viral hepatitis [
This study used reimbursement claim data from the Taiwan National Health Insurance Program. An NHI program was implemented in March 1995, in which 22.6 million individuals from a total population of 23.0 million in Taiwan were enrolled. Currently, 99.6% of Taiwanese residents are covered by NHI. The National Health Insurance Research Database (NHIRD) is composed of every medical record reimbursed by the NHI. The datasets of the study consist of registry for beneficiaries, ambulatory, and inpatient care claims and Registry for Catastrophic Illness from NHIRD. We used ambulatory and inpatient care records for cancer care linking with the Registry for Catastrophic Illness patients in the period of 2000 to 2010 to identify study subjects for follow-up until the end of 2011. Ambulatory care claims contain individual’s gender and birthday, visit date, and codes for the International Classification of Disease, Ninth Revision, and Clinical Modification (ICD-9-CM) for three primary diagnoses. Inpatient claims contain ICD-9-CM codes for principal diagnosis up to four secondary diagnoses. Registry for Catastrophic Illness database contains data from those insured who suffer from major diseases and are granted exemption from copayment. The ICD-9-CM codes were used for diagnosis by Chinese medicine physicians. Because the NHIRD contains identified secondary data for research, the present study was waived from informed consent. This study was approved by the Institutional Review Board of China Medical University Hospital (CMUH104-REC2-115).
A retrospective study was conducted using the Catastrophic Illness database from 1997 to 2011 years. Breast cancer patients (aged ≧18 years) who were diagnosed with ICD-9-CM code 174 were identified from the Catastrophic Illness database covering 1997 to 2010 and were followed up until December 31, 2011. In this study, we excluded patients receiving acupuncture or moxibustion and a diagnosis date of chronic hepatitis before breast cancer (Figure
Study population flowchart diagram. Of the total amount of breast cancer patients registered in the NHIRD (
The primary outcome was chronic hepatitis (ICD-9-CM: 571.4) during the 14 years of follow-up. All eligible patients were followed up from the index date to December 31, 2011.
Patients using CHM for more than 30 days due to a diagnosis of breast cancer were defined as CHM users, whereas those without CHM outpatient records were defined as non-CHM users.
The Charlson Comorbidity Index (CCI) score was used to determine patients’ overall systematic health. The patients with treatments of radiotherapy and/or chemotherapy performed after the half year before diagnosis date of breast cancer were included.
Continuous variables were reported as mean and standard deviation, whereas categorical variables were reported as number and percentage. Differences in proportions and means were evaluated by chi-square test or
Of the 8918 CHM users and 12152 non-CHM users diagnosed with breast cancer from 1997 to 2010, after frequency matching both groups for age (per 5 years), CCI score, treatments, and initial diagnosis year of breast cancer, each group contained 6,928 patients. Cohort group and compared cohort group demonstrated similar characteristics without statistically significant differences (
Characteristics of breast cancer patients according to use and nonuse of Chinese herb.
Variable | Breast cancer patients |
|
|||
---|---|---|---|---|---|
Chinese herb used | |||||
No ( |
Yes ( |
||||
|
% |
|
% | ||
|
0.99 | ||||
18–39 | 1056 | 15.24 | 1056 | 15.24 | |
40–59 | 5377 | 77.61 | 5377 | 77.61 | |
≥60 | 495 | 7.14 | 495 | 7.14 | |
Mean ± SD (years) |
49.59 (9.73) | 49.56 (9.73) | 0.8371 | ||
|
0.99 | ||||
0 | 6491 | 93.69 | 6491 | 93.69 | |
1 | 227 | 3.28 | 227 | 3.28 | |
≥2 | 210 | 3.03 | 210 | 3.03 | |
|
|||||
Radiotherapy | 0.99 | ||||
No | 3137 | 45.28 | 3137 | 45.28 | |
Yes | 3791 | 54.72 | 3791 | 54.72 | |
Chemotherapy | 0.99 | ||||
No | 1291 | 18.63 | 1291 | 18.63 | |
Yes | 5637 | 81.37 | 5637 | 81.37 | |
|
|||||
Fluorouracil | 1275 | 18.4 | 2166 | 31.26 | <0.0001 |
Gemcitabine | 353 | 5.1 | 562 | 8.11 | <0.0001 |
Capecitabine | 601 | 8.67 | 804 | 11.61 | <0.0001 |
Cyclophosphamide | 1336 | 19.28 | 2466 | 35.59 | <0.0001 |
Tamoxifen | 3105 | 44.82 | 3842 | 55.46 | <0.0001 |
Letrozole | 855 | 12.34 | 1155 | 16.67 | <0.0001 |
Trastuzumab | 483 | 6.97 | 594 | 8.57 | 0.0004 |
|
2.73 (1.94) | 4.32 (3.55) |
Chi-square test;
The difference in cumulative incidence of chronic hepatitis between the two groups was illustrated through a Kaplan–Meier analysis (Figure
Incidence rates, hazard ratio, and confidence intervals of chronic hepatitis for breast cancer patients with and without Chinses herb used in the stratification of sex, age, CCI score, and treatment.
Variables | Chinese herb used | Crude HR | Adjusted HR | |||||
---|---|---|---|---|---|---|---|---|
No | Yes | |||||||
( |
( |
|||||||
Event | Person-years | IR† | Event | Person-years | IR† | (95% CI) | (95% CI) | |
|
442 | 18931 | 23.35 | 441 | 29910 | 14.74 | 0.74 (0.64–0.84) |
0.63 (0.54–0.72) |
|
||||||||
18–39 | 66 | 3149 | 20.96 | 65 | 4955 | 13.12 | 0.69 (0.49–0.98) |
0.65 (0.45–0.93) |
40–59 | 351 | 14662 | 23.94 | 352 | 23198 | 15.17 | 0.75 (0.64–0.87) |
0.63 (0.53–0.73) |
≥60 | 25 | 1119 | 22.34 | 24 | 1757 | 13.66 | 0.71 (0.4–1.25) | 0.64 (0.36–1.15) |
|
||||||||
0 | 424 | 17983 | 23.58 | 424 | 28321 | 14.97 | 0.74 (0.65–0.85) |
0.62 (0.54–0.72) |
1 | 11 | 486 | 22.64 | 13 | 858 | 15.15 | 0.68 (0.3–1.57) | 0.66 (0.28–1.54) |
≥2 | 7 | 462 | 15.16 | 4 | 731 | 5.47 | 0.44 (0.13–1.5) | 0.47 (0.13–1.69) |
|
||||||||
Radiotherapy | ||||||||
No | 263 | 9275 | 28.35 | 253 | 14587 | 17.34 | 0.72 (0.61–0.86) |
0.58 (0.48–0.69) |
Yes | 179 | 9655 | 18.54 | 188 | 15323 | 12.27 | 0.75 (0.61–0.92) |
0.7 (0.56–0.87) |
Chemotherapy | ||||||||
No | 89 | 3842 | 23.17 | 85 | 5780 | 14.71 | 0.74 (0.55–0.99) |
0.68 (0.5–0.93) |
Yes | 353 | 15089 | 23.39 | 356 | 24130 | 14.75 | 0.73 (0.63–0.85) |
0.61 (0.52–0.72) |
Crude
The estimated cumulative incidence of chronic hepatitis of those treated with CHM or none in the patients with breast cancer cohort by Kaplan–Meier analysis.
Stratified by age group, the incidence rates of chronic hepatitis in the 18–39-year group and 40–59-year group which used CHM were 13.12 and 15.17 per 1,000 person-years, respectively, which was lower than those in the comparison cohort (20.96 and 23.94 per 1,000 person-years). In addition, the 18–39-year group showed 0.65-fold (95% CI: 0.45–0.93) and the 40–59-year group showed 0.63-fold (95% CI: 0.53–0.73) lower risk of development of chronic hepatitis than the non-CHM cohort. As for the CCI score stratification, our results demonstrated that patients in the CHM-used cohort had lower risk and incidence rate of chronic hepatitis in comparison with the nonused CHM cohort group. There was statistical significance between the CHM users and non-CHM users in the subgroup of CCI score 0. We found that the CHM users also had the lower tendency to develop chronic hepatitis than those of non-CHM users; however, this lacks statistical significance as a result of small sample size of the other two subgroups (CCI scores 1 and ≥2) (Table
In Table
Ten most common herbs and formulas prescribed.
Herbal formula | Frequency | Number of person-days | Average daily dose | Average duration for prescription |
---|---|---|---|---|
(g) | (Days) | |||
|
||||
|
28428 | 368769 | 1.5 | 13 |
|
20713 | 260518 | 1.7 | 12.6 |
|
19329 | 249317 | 2 | 12.9 |
|
12432 | 163265 | 1.7 | 13.1 |
|
11319 | 137929 | 1.6 | 12.2 |
Zizyphi Spinosi Semen | 9981 | 124473 | 1.9 | 12.5 |
|
10585 | 122984 | 1.7 | 11.6 |
Rhei Rhizoma | 9590 | 111498 | 0.6 | 11.6 |
Polygonum multiflorum Thunb. | 8338 | 110657 | 1.4 | 13.3 |
|
8459 | 98822 | 1.5 | 11.7 |
|
||||
Jia-Wei-Xiao-Yao-San | 23987 | 302757 | 5.3 | 12.6 |
Xiang-Sha-Liu-Jun-Zi-Tang | 9450 | 123266 | 4.2 | 13 |
San-Zhong-Kui-Jian-Tang | 9672 | 113868 | 4.6 | 11.8 |
Suan-Zao-Ren-Tang | 6901 | 98059 | 4.1 | 14.2 |
Gui-Pi-Tang | 7367 | 92932 | 5 | 12.6 |
Zhen-Ren-Huo-Ming-Yin | 6797 | 88308 | 4.4 | 13 |
Bu-Zhong-Yi-Qi-Tang | 7445 | 87686 | 4.6 | 11.8 |
Zhi-Bai-Di-Huang-Wan | 6081 | 81750 | 4.5 | 13.4 |
Xue-Fu-Zhu-Yu-Tang | 6022 | 78473 | 6.6 | 13 |
Sheng-Mai-Yin | 6602 | 78261 | 4.3 | 11.9 |
Hazard ratios and 95% confidence intervals of chronic hepatitis risk associated with Chinese herbal formulas used among breast cancer patients.
CHM prescription | Chronic hepatitis | Hazard ratio (95% CI) | ||
---|---|---|---|---|
|
Number of events | Crude |
Adjusted† | |
|
6928 | 442 | 1 (reference) | 1 (reference) |
|
||||
|
1809 | 104 | 0.68 (0.55–0.84) |
0.51 (0.41–0.63) |
|
2161 | 117 | 0.64 (0.52–0.78) |
0.46 (0.37–0.57) |
|
1416 | 81 | 0.64 (0.50–0.81) |
0.47 (0.37–0.60) |
|
1640 | 91 | 0.66 (0.53–0.83) |
0.48 (0.38–0.61) |
|
1706 | 110 | 0.71 (0.58–0.88) |
0.53 (0.43–0.65) |
Zizyphi Spinosi Semen | 1578 | 84 | 0.60 (0.47–0.76) |
0.45 (0.35–0.57) |
|
1716 | 111 | 0.74 (0.60–0.91) |
0.54 (0.44–0.67) |
Rhei Rhizoma | 957 | 36 | 0.44 (0.32–0.62) |
0.33 (0.23–0.46) |
Polygonum multiflorum Thunb. | 1383 | 81 | 0.68 (0.54–0.86) |
0.53 (0.41–0.67) |
|
1467 | 67 | 0.52 (0.40–0.68) |
0.40 (0.31–0.52) |
|
||||
Jia-Wei-Xiao-Yao-San | 2814 | 180 | 0.69 (0.58–0.83) |
0.55 (0.46–0.65) |
Xiang-Sha-Liu-Jun-Zi-Tang | 1549 | 98 | 0.73 (0.58–0.91) |
0.54 (0.43–0.68) |
San-Zhong-Kui-Jian-Tang | 879 | 47 | 0.66 (0.49–0.90) |
0.50 (0.37–0.67) |
Suan-Zao-Ren-Tang | 1253 | 69 | 0.62 (0.48–0.80) |
0.48 (0.37–0.62) |
Gui-Pi-Tang | 1369 | 76 | 0.65 (0.51–0.83) |
0.49 (0.38–0.63) |
Zhen-Ren-Huo-Ming-Yin | 935 | 36 | 0.45 (0.32–0.63) |
0.34 (0.24–0.47) |
Bu-Zhong-Yi-Qi-Tang | 1356 | 84 | 0.69 (0.55–0.88) |
0.53 (0.42–0.67) |
Zhi-Bai-Di-Huang-Wan | 1142 | 69 | 0.69 (0.53–0.88) |
0.52 (0.40–0.67) |
Xue-Fu-Zhu-Yu-Tang | 1101 | 56 | 0.58 (0.44–0.76) |
0.45 (0.34–0.59) |
Sheng-Mai-Yin | 1147 | 61 | 0.63 (0.48–0.82) |
0.47 (0.36–0.62) |
Crude
The occurrence of liver injuries is often an impediment in clinical practice. Patients suffering from abnormal liver function during chemotherapy and/or radiotherapy may need to change the medication, modify the original dose, and even delay or terminate the treatment. Thus, the side effects induced by chemotherapy and/or radiotherapy may diminish the efficacy of treatment and lead to a drop in remission rate associated with failure to shrink tumor size, earlier relapse, and metastasis. Our study found that CHM treatment significantly decreased the incidence of chronic hepatitis after adjustment for age, CCI score, treatment modality, and medication used in patients with breast cancer. The cumulative incidence rates of chronic hepatitis in patients with breast cancer were also lower in CMH users in comparison with those of non-CMH users, up to the 7-year period. These findings indicate that CMH may be effective in protecting patients with breast cancer from liver injury.
As we know, the liver needs to confront the impact of drug toxicity and control major metabolism of xenobiotics taken from the gastrointestinal tract and portal circulation. There are several kinds of pathological injuries induced by drug-related hepatotoxicity, such as tissue necrosis, fibrosis, steatosis, steatohepatitis, cholestasis, and hepatic sinusoidal injury. The different modalities of treatment, including chemotherapy, hormone therapy, and targeted therapy frequently adopted in patients with breast cancer may have the possibility of inducing the side effect of hepatotoxicity. Medications such as fluorouracil, gemcitabine, capecitabine, cyclophosphamide, tamoxifen, letrozole, and trastuzumab might contribute to abnormal liver function independently or when combined and applied in clinical practice. In addition, liver injuries may also be exacerbated by other agents, including prophylactic antibiotics, antiemetics, and analgesic agents. Moreover, patients’ previous medical illness, nutritional status, or chronic infections could also influence liver function. For example, Taiwan has a high prevalence of, viral B and C hepatitis [
CMH prescription is based on the holism of TCM pattern differentiation. According to the theory of TCM, the major cause of breast cancer is qi stagnation and blood stasis and the major associated meridians involved include the liver, kidneys, stomach, spleen, pericardium meridian, and gallbladder. Several herbs and herbal formulas adopted for moving qi perform functions such as promoting blood, clearing heat, resolving phlegm, and dissipating binds. Our study found Jia-Wei-Xiao-Yao-San (JWXYS), a popular herbal formula for liver stagnation and spleen deficiency, is the most frequently prescribed herbal formula for patients with breast cancer associated with hormone therapy [
Some other formulas are adopted for resolving the side effects or complications resulting from western treatments of breast cancer. Sheng-Mai-Yin (SMY) is widely used to prevent excessive sweating and fatigue.
In our study, the top 10 frequently prescribed herbal formulas and single herbs presented significant benefits in ameliorating incidence of chronic hepatitis. Several herbal formulas and single herbs adopted in breast cancer treatment were also frequently used in hepatitis treatment and provided protection from liver injury. JWXYS was the second most prescribed herbal formula for patients with chronic hepatitis in Taiwan [
This study obtained the data from the NHIRD, a government-run, single-payer NHI program that covers over 99% of the Taiwanese population and 93% of healthcare institutes [
This population-based, retrospective cohort study showed that CHM combination therapy might decrease the risk of chronic hepatitis in breast cancer patients with chemotherapy and/or radiotherapy treatment. Our study results suggested CHM as an adjunctive therapy in breast cancer patients receiving chemotherapy and/or radiotherapy to prevent subsequent chronic hepatitis. Future clinical study is needed to substantiate the relationship of CHM to reduced hepatotoxicity in patients with breast cancer receiving chemotherapy and/or radiotherapy.
Bu-Zhong-Yi-Qi-Tang
Complementary and alternative medicines
Charlson Comorbidity Index
Chinese herb medicine
Confidence interval
Good Manufacturing Practice
Gui-Pi-Tang
Hazard ratios
International Classification of Disease, Ninth Revision, and Clinical Modification
Jia-Wei-Xiao-Yao-San
National Health Insurance
National Health Insurance Research Database
Sheng-Mai-Yin
San-Zhong-Kui-Jian-Tang
Suan-Zao-Ren-Tang
Traditional Chinese medicine
Xue-Fu-Zhu-Yu-Tang
Xiang-Sha-Liu-Jun-Zi-Tang
Zhen-Ren-Huo-Ming-Yin.
This study was approved by the Institutional Review Board of China Medical University Hospital (CMUH104-REC2-115) on 5 July 2015.
The present study was waived from informed consent because the NHIRD contains identified secondary data for research.
The authors declare that they have no conflicts of interest.
This study is supported in part by Taiwan Ministry of Health and Welfare Clinical Trial Center (MOHW106-TDU-B-212-113004), China Medical University Hospital, Academia Sinica Taiwan Biobank Stroke Biosignature Project (BM10601010036), Taiwan Clinical Trial Consortium for Stroke (MOST 106-2321-B-039-005), Tseng-Lien Lin Foundation, Taichung, Taiwan, Taiwan Brain Disease Foundation, Taipei, Taiwan, and Katsuzo and Kiyo Aoshima Memorial Funds, Japan. This work was also supported and funded by Ministry of Science and Technology with MOST 105-2320-B-039-035 and China Medical University Hospital with DMR-106-003. The authors would like to thank James Waddell, who is a Canadian, for the critical reading and correction of their manuscript.