Original Article
Adjunctive Traditional Chinese Medicine Therapy Improves Survival in Patients With Advanced Breast Cancer A Population-Based Study Yuan-Wen Lee, MD1,2,3; Ta-Liang Chen, MD, PhD2,3; Yu-Ru Vernon Shih, PhD4; Chu-Lin Tsai, MD, ScD5; Chuen-Chau Chang, MD, PhD2,3; Hung-Hua Liang, MD6,7; Sung-Hui Tseng, MD, PhD8; Shu-Chen Chien, PharmD1; and Ching-Chiung Wang, PhD1
BACKGROUND: Traditional Chinese medicine (TCM) is one of the most common complementary and alternative medicines used in the treatment of patients with breast cancer. However, the clinical effect of TCM on survival, which is a major concern in these individuals, lacks evidence from large-scale clinical studies. METHODS: The authors used the Taiwan National Health Insurance Research Database to conduct a retrospective population-based cohort study of patients with advanced breast cancer between 2001 and 2010. The patients were separated into TCM users and nonusers, and Cox regression models were applied to determine the association between the use of TCM and patient survival. RESULTS: A total of 729 patients with advanced breast cancer receiving taxanes were included in the current study. Of this cohort, the mean age was 52.0 years; 115 patients were TCM users (15.8%) and 614 patients were TCM nonusers. The mean follow-up was 2.8 years, with 277 deaths reported to occur during the 10-year period. Multivariate analysis demonstrated that, compared with nonusers, the use of TCM was associated with a significantly decreased risk of all-cause mortality (adjusted hazards ratio [HR], 0.55 [95% confidence interval, 0.33-0.90] for TCM use of 30-180 days; adjusted HR, 0.46 [95% confidence interval, 0.27-0.78] for TCM use of > 180 days). Among the frequently used TCMs, those found to be most effective (lowest HRs) in reducing mortality were Bai Hua She She Cao, Ban Zhi Lian, and Huang Qi. CONCLUSIONS: The results of the current observational study suggest that adjunctive TCM therapy may lower the risk of death in patients with advanced breast cancer. Future C 2014 American Cancer Society. randomized controlled trials are required to validate these findings. Cancer 2014;120:1338–44. V KEYWORDS: breast cancer, traditional Chinese medicine, complementary and alternative medicine, National Health Insurance Research Database, taxane.
INTRODUCTION Breast cancer is the most prevalent malignant tumor in female patients worldwide and the leading cause of death in women with cancer, accounting for approximately 1.38 million new diagnoses and 458,400 deaths every year.1 Although patient incidence and mortality are decreasing in some countries, the mortality rate of advanced breast cancer remains high.2 The current treatment for patients with advanced breast cancer includes surgery, radiotherapy, chemotherapy, and hormonal and targeted biological therapies.3 Recent studies have documented that at least 46% of patients with breast cancer receive complementary and alternative medicine treatments4,5 to boost immune system activity, decrease disease symptoms, minimize side effects resulting from conventional treatments, increase quality of life, and even as a treatment of cancer per se.6 Traditional Chinese medicine (TCM) is one of the most widely used complementary and alternative medicine therapies used by patients with breast cancer worldwide.7,8 Although studies have indicated that TCM facilitates the treatment
Corresponding author: Ching-Chiung Wang, PhD, School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing St, Taipei 11031, Taiwan; Fax: (011) 886-2-27329368; [email protected] 1 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; 2Department of Anesthesiology, Taipei Medical University Hospital, Taipei, Taiwan; 3Department of Anesthesiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; 4Department of Bioengineering, University of California at San Diego, La Jolla, California; 5Division of Epidemiology, Human Genetics and Environmental Sciences, University of Texas School of Public Health, Houston, Texas; 6Division of General Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei, Taiwan; 7Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; 8Department of Physical Medicine and Rehabilitation, Taipei Medical University Hospital, Taipei, Taiwan
This study was based in part on data from the National Health Insurance Research Database provided by the Bureau of National Health Insurance, Department of Health and managed by National Health Research Institutes. The interpretations and conclusions contained herein do not represent the opinions of the Bureau of National Health Insurance, Department of Health, or the National Health Research Institutes. DOI: 10.1002/cncr.28579, Received: September 15, 2013; Revised: December 16, 2013; Accepted: January 2, 2014, Published online February 3, 2014 in Wiley Online Library (wileyonlinelibrary.com)
1338
Cancer
May 1,2014
TCM and Survival of Patients With Breast Ca/Lee et al
of breast cancer, to the best of our knowledge, the majority of the reports on the alleviation of side effects by chemotherapy and hormonal therapy originate from laboratory findings.9-11 Patients are mostly concerned about disease mortality arising from the progression of cancer; however, to our knowledge large-scale clinical analysis of TCM on disease mortality in patients with breast cancer remains absent. In Taiwan, TCM is covered by National Health Insurance (NHI) and is a widely accepted form of medical treatment. According to the study by Lai et al, in addition to receiving conventional therapy, approximately 81.5% of patients with breast cancer in Taiwan had ever received any treatment with TCM during the 10-year study period.12 Using the population-based National Health Insurance Research Database (NHIRD), we investigated whether the combination of TCM and conventional cancer treatment affected the survival of patients with advanced breast cancer. MATERIALS AND METHODS Research Database
The NHI system in Taiwan is a compulsory, single-payer program that provides health coverage to nearly every individual in Taiwan. Currently, 99.6% of residents are covered by NHI.13 The Bureau of National Health Insurance allowed a random selection of 1 million representative patient records from the NHIRD (23 million insured individuals) to be distributed for research. The age, sex distribution, and premiums paid were not found to be statistically significantly different between the 1 million insured individuals and the general population.14 In the current retrospective population-based cohort study, we analyzed 1 million patients randomly selected from 23 million beneficiaries in the NHIRD between January 1, 1999 and December 31, 2010. The NHIRD contains comprehensive outpatient and inpatient information including age, sex, date of visit, International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9CM) codes, and complete prescription records. The detailed diagnoses and treatments provided by Chinese medicine physicians were also included. This study was approved by the Joint Institutional Review Board of Taipei Medical University.
cancer must be confirmed by specialists and pathological reports as was the case in the current study. Once patients fulfill the above-mentioned conditions, physicians and medical institutions must provide assistance to the patient to apply for the catastrophic illness certificate. The status of catastrophic illness is then registered into the NHI card. The current study comprised women aged > 18 years who were diagnosed with primary breast cancer (ICD-9-CM code 174) between 2001 and 2010. Although the stage of disease of patients with breast cancer cannot be obtained from the ICD-9-CM codes, we identified those patients with advanced breast cancer through taxane prescriptions. We used this approach because the Bureau of National Health Insurance reimburses taxane use only for those patients with locally advanced or metastatic breast cancer. Patients with advanced breast cancer who received taxane (docetaxel or paclitaxel) treatments between January 1, 2001 and December 31, 2010 were included in the current study. The initiation of taxane treatment was defined as the index date. We obtained detailed hospitalization, outpatient, and prescription information from 2 years before the index date to the end of the follow-up period for analysis. Patients who received taxane treatment before January 1, 2001 and those with a follow-up period of < 3 months were excluded. The baseline demographic variables of the patients were obtained from the registry for beneficiary files, and patient age was determined according to the index date. The baseline comorbidities were determined using the modified version of the Elixhauser comorbidity index15 according to the patient medical records 2 years before the index date. These comorbidities include hypertension, diabetes mellitus, congestive heart failure, stroke, chronic pulmonary disease, and liver disease. Distant metastases were defined as metastases to the lungs, liver, brain, bones, and other organs (ICD-9-CM codes 197.x, 198.0, 198.1, and 198.3-198.7). The type of treatment was considered as the treatment that a patient with breast cancer received 2 years before the index date until the end of the followup period. A patient undergoing both mastectomy and breast-conserving surgery was classified under mastectomy. Combination chemotherapy was defined as when patients received other chemotherapy medications in addition to taxanes.
Study Population
Insured individuals of the NHI diagnosed with severe and chronic diseases that require extended treatment, such as breast cancer, may apply for a catastrophic illness certificate to be exempted from copayments. To receive a catastrophic illness certificate, the diagnosis of a patient with Cancer
May 1, 2014
Exposure to TCM
The NHIRD records detailed prescription information for both TCM and Western medicine including drug name, dose, start date, frequency, duration, and method of administration. All TCMs covered by the NHI were 1339
Original Article TABLE 1. Characteristics of Breast Cancer Patients According to Use of TCM
Characteristics Age, y Urbanization Low Moderate High Comorbidity Hypertension Diabetes mellitus Congestive heart failure Stroke Chronic pulmonary disease Liver disease Distant metastases Type of treatment Surgery None Breast-conserving surgery Mastectomy Combination of chemotherapy Hormonal or targeted biologic therapy Radiotherapy
TCM Users(N 5 115)
TCM Nonusers(N 5 614)
Mean (SD) or No. (%)
Mean (SD) or No. (%)
P
50.5
(8.9)
52.3
(10.0)
.08
8 24 83
(7.0) (20.9) (72.2)
37 153 424
(6.0) (24.9) (69.1)
.63
10 1 3 1 15 16 41
(8.7) (0.9) (2.6) (0.9) (13.0) (13.9) (35.7)
83 25 15 24 92 100 228
(13.5) (4.1) (2.4) (3.9) (15.0) (16.3) (37.1)
.16 .10 >.99 .16 .59 .52 .76
28 19 68 110 81 66
(24.4) (16.5) (59.1) (95.7) (70.4) (57.4)
191 105 318 586 409 367
(31.1) (17.1) (51.8) (95.4) (66.6) (59.8)
.29
.92 .42 .63
Abbreviations: SD, standard deviation;TCM, traditional Chinese medicine.
prescribed by board-certified Chinese medicine physicians who received rigorous training in both Chinese and Western medicine in medical schools and through residency programs in hospitals. These physicians must also pass the national licensing examinations. TCMs are prescribed by Chinese medicine physicians according to TCM symptom patterns.10 Patients using TCM for 30 days due to a diagnosis of breast cancer were defined as TCM users, whereas those treated for < 30 days were considered as TCM nonusers. Moreover, to observe a doseresponse relationship, we further grouped TCM users into 2 groups: 1 group used TCM for 30 to 180 days whereas the other group used TCM for > 180 days. Study Outcome
The study outcome was all-cause mortality during the 10year follow-up. The patient’s date of death was determined according to the Registry of Catastrophic Illness Database of the NHIRD. The analysis period began from the index date and ended at the death of patient, withdrawal from NHI, or the end of 2010, whichever occurred first. 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 1340
users and nonusers were analyzed using a Student t test, and the categorical variables were analyzed using a chisquare or Fisher exact test. The cumulative probability of survival for TCM users and nonusers was estimated using a Kaplan-Meier estimator16 with a log-rank test17 used to compare the survival curves between the groups. The association between the baseline characteristics and mortality was estimated using a univariate Cox regression analysis18 and reported according to hazards ratios (HRs) with 95% confidence intervals (95% CIs). The variables with P values < .2 in the univariate analysis were included in the multivariable Cox proportional hazards model to identify the independent predictors of mortality. Log(-log[survival]) versus log of survival time plot was inspected to verify the proportional hazards assumption. The study endpoint was all-cause mortality. Patients who were alive at the time of last follow-up were censored at the date of withdrawal from NHI or the end of study period, whichever came first. To verify the dose-response relationship between TCM use and mortality, we treated TCM use category as a continuous variable to calculate the P value of the linear trend. Because stage of cancer is a major predictor of mortality, we conducted a sensitivity analysis limiting to patients with distant metastases to evaluate the robustness of our findings. Statistical significance was determined as P < .05. All analyses were performed using SAS statistical software (version 9.3; SAS Institute Inc, Cary, NC). Cancer
May 1, 2014
TCM and Survival of Patients With Breast Ca/Lee et al
RESULTS Of the 1 million people randomly selected from the NHIRD between 2001 and 2010, 786 female patients were aged > 18 years and received taxane treatment because of primary breast cancer. We further excluded 5 patients who received taxane treatment before January 1, 2001 and 52 patients with a follow-up period of < 3 months. Of the remaining 729 eligible patients, 614 were TCM nonusers, whereas the remaining 115 patients were TCM users, including 58 users who took TCM for 30 to 180 days and 57 users who used it for > 180 days. Characteristics such as age, urbanization, baseline comorbidity, and treatment did not appear to differ significantly between the groups (Table 1).
Figure 1. Kaplan-Meier curves of overall survival in patients with advanced breast cancer according to traditional Chinese medicine (TCM) use during the follow-up period.
The mean follow-up period for the patients was 2.8 years 6 1.9 years; 277 deaths occurred and the overall mortality rate was 38.0% during the analysis period. TCM users had 32 deaths (27.8%) and TCM nonusers had 245 deaths (39.9%). The Kaplan-Meier survival curve and log-rank test revealed a statistically significant difference between the survival curves of the groups (P < .001) (Fig. 1). The unadjusted Cox regression analysis demonstrated a strong association between the use of TCM and a decrease in mortality (Table 2). Compared with TCM nonusers, TCM users had reduced mortality by 47% (unadjusted HR, 0.53; 95% CI, 0.37-0.77 [P < .001]). On the multivariate Cox model controlling for 6 potential confounders (age, history of congestive heart failure, distant metastases, surgery, hormonal or targeted biologic therapy, and radiotherapy), the use of TCM remained highly associated with decreased mortality (the adjusted HR of TCM users was 0.50 [95% CI, 0.35-0.73]; P < .001) (Table 2). Further analysis demonstrated a dose-response relationship between TCM use and mortality. The adjusted HRs were 0.55 (95% CI, 0.33-0.90) and 0.46 (95% CI, 0.27-0.78) for patients with TCM use of 30 to 180 days and > 180 days, respectively. The longer the duration of TCM use, the lower the mortality rate (P for trend < .001). The other independent predictors of increased mortality included distant metastases, inoperable surgical status, and radiotherapy. Similar results were obtained when analyses were restricted to patients with distant metastases. Of the 269
TABLE 2. Unadjusted and Adjusted Cox Proportional Hazards Model Analysis of the Mortality of Patients With Breast Cancer Univariate Analysis Variable TCM use Nonusers (180 d Age (per 1 y) Congestive heart failure Distant metastases Surgery None Breast-conserving surgery Mastectomy Hormonal or targeted biologic therapy Radiotherapy
Multivariate Analysis a
HR
95% CI
P
aHR
95% CI
P
1 0.53 0.58 0.48 1.01 1.91 3.10
0.37-0.77 0.36-0.95 0.29-0.81 1.00-1.02 0.98-3.72 2.44-3.94
Adjunctive Traditional Chinese Medicine Therapy Improves Survival in Patients With Advanced Breast Cancer A Population-Based Study Yuan-Wen Lee, MD1,2,3; Ta-Liang Chen, MD, PhD2,3; Yu-Ru Vernon Shih, PhD4; Chu-Lin Tsai, MD, ScD5; Chuen-Chau Chang, MD, PhD2,3; Hung-Hua Liang, MD6,7; Sung-Hui Tseng, MD, PhD8; Shu-Chen Chien, PharmD1; and Ching-Chiung Wang, PhD1
BACKGROUND: Traditional Chinese medicine (TCM) is one of the most common complementary and alternative medicines used in the treatment of patients with breast cancer. However, the clinical effect of TCM on survival, which is a major concern in these individuals, lacks evidence from large-scale clinical studies. METHODS: The authors used the Taiwan National Health Insurance Research Database to conduct a retrospective population-based cohort study of patients with advanced breast cancer between 2001 and 2010. The patients were separated into TCM users and nonusers, and Cox regression models were applied to determine the association between the use of TCM and patient survival. RESULTS: A total of 729 patients with advanced breast cancer receiving taxanes were included in the current study. Of this cohort, the mean age was 52.0 years; 115 patients were TCM users (15.8%) and 614 patients were TCM nonusers. The mean follow-up was 2.8 years, with 277 deaths reported to occur during the 10-year period. Multivariate analysis demonstrated that, compared with nonusers, the use of TCM was associated with a significantly decreased risk of all-cause mortality (adjusted hazards ratio [HR], 0.55 [95% confidence interval, 0.33-0.90] for TCM use of 30-180 days; adjusted HR, 0.46 [95% confidence interval, 0.27-0.78] for TCM use of > 180 days). Among the frequently used TCMs, those found to be most effective (lowest HRs) in reducing mortality were Bai Hua She She Cao, Ban Zhi Lian, and Huang Qi. CONCLUSIONS: The results of the current observational study suggest that adjunctive TCM therapy may lower the risk of death in patients with advanced breast cancer. Future C 2014 American Cancer Society. randomized controlled trials are required to validate these findings. Cancer 2014;120:1338–44. V KEYWORDS: breast cancer, traditional Chinese medicine, complementary and alternative medicine, National Health Insurance Research Database, taxane.
INTRODUCTION Breast cancer is the most prevalent malignant tumor in female patients worldwide and the leading cause of death in women with cancer, accounting for approximately 1.38 million new diagnoses and 458,400 deaths every year.1 Although patient incidence and mortality are decreasing in some countries, the mortality rate of advanced breast cancer remains high.2 The current treatment for patients with advanced breast cancer includes surgery, radiotherapy, chemotherapy, and hormonal and targeted biological therapies.3 Recent studies have documented that at least 46% of patients with breast cancer receive complementary and alternative medicine treatments4,5 to boost immune system activity, decrease disease symptoms, minimize side effects resulting from conventional treatments, increase quality of life, and even as a treatment of cancer per se.6 Traditional Chinese medicine (TCM) is one of the most widely used complementary and alternative medicine therapies used by patients with breast cancer worldwide.7,8 Although studies have indicated that TCM facilitates the treatment
Corresponding author: Ching-Chiung Wang, PhD, School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing St, Taipei 11031, Taiwan; Fax: (011) 886-2-27329368; [email protected] 1 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; 2Department of Anesthesiology, Taipei Medical University Hospital, Taipei, Taiwan; 3Department of Anesthesiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; 4Department of Bioengineering, University of California at San Diego, La Jolla, California; 5Division of Epidemiology, Human Genetics and Environmental Sciences, University of Texas School of Public Health, Houston, Texas; 6Division of General Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei, Taiwan; 7Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; 8Department of Physical Medicine and Rehabilitation, Taipei Medical University Hospital, Taipei, Taiwan
This study was based in part on data from the National Health Insurance Research Database provided by the Bureau of National Health Insurance, Department of Health and managed by National Health Research Institutes. The interpretations and conclusions contained herein do not represent the opinions of the Bureau of National Health Insurance, Department of Health, or the National Health Research Institutes. DOI: 10.1002/cncr.28579, Received: September 15, 2013; Revised: December 16, 2013; Accepted: January 2, 2014, Published online February 3, 2014 in Wiley Online Library (wileyonlinelibrary.com)
1338
Cancer
May 1,2014
TCM and Survival of Patients With Breast Ca/Lee et al
of breast cancer, to the best of our knowledge, the majority of the reports on the alleviation of side effects by chemotherapy and hormonal therapy originate from laboratory findings.9-11 Patients are mostly concerned about disease mortality arising from the progression of cancer; however, to our knowledge large-scale clinical analysis of TCM on disease mortality in patients with breast cancer remains absent. In Taiwan, TCM is covered by National Health Insurance (NHI) and is a widely accepted form of medical treatment. According to the study by Lai et al, in addition to receiving conventional therapy, approximately 81.5% of patients with breast cancer in Taiwan had ever received any treatment with TCM during the 10-year study period.12 Using the population-based National Health Insurance Research Database (NHIRD), we investigated whether the combination of TCM and conventional cancer treatment affected the survival of patients with advanced breast cancer. MATERIALS AND METHODS Research Database
The NHI system in Taiwan is a compulsory, single-payer program that provides health coverage to nearly every individual in Taiwan. Currently, 99.6% of residents are covered by NHI.13 The Bureau of National Health Insurance allowed a random selection of 1 million representative patient records from the NHIRD (23 million insured individuals) to be distributed for research. The age, sex distribution, and premiums paid were not found to be statistically significantly different between the 1 million insured individuals and the general population.14 In the current retrospective population-based cohort study, we analyzed 1 million patients randomly selected from 23 million beneficiaries in the NHIRD between January 1, 1999 and December 31, 2010. The NHIRD contains comprehensive outpatient and inpatient information including age, sex, date of visit, International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9CM) codes, and complete prescription records. The detailed diagnoses and treatments provided by Chinese medicine physicians were also included. This study was approved by the Joint Institutional Review Board of Taipei Medical University.
cancer must be confirmed by specialists and pathological reports as was the case in the current study. Once patients fulfill the above-mentioned conditions, physicians and medical institutions must provide assistance to the patient to apply for the catastrophic illness certificate. The status of catastrophic illness is then registered into the NHI card. The current study comprised women aged > 18 years who were diagnosed with primary breast cancer (ICD-9-CM code 174) between 2001 and 2010. Although the stage of disease of patients with breast cancer cannot be obtained from the ICD-9-CM codes, we identified those patients with advanced breast cancer through taxane prescriptions. We used this approach because the Bureau of National Health Insurance reimburses taxane use only for those patients with locally advanced or metastatic breast cancer. Patients with advanced breast cancer who received taxane (docetaxel or paclitaxel) treatments between January 1, 2001 and December 31, 2010 were included in the current study. The initiation of taxane treatment was defined as the index date. We obtained detailed hospitalization, outpatient, and prescription information from 2 years before the index date to the end of the follow-up period for analysis. Patients who received taxane treatment before January 1, 2001 and those with a follow-up period of < 3 months were excluded. The baseline demographic variables of the patients were obtained from the registry for beneficiary files, and patient age was determined according to the index date. The baseline comorbidities were determined using the modified version of the Elixhauser comorbidity index15 according to the patient medical records 2 years before the index date. These comorbidities include hypertension, diabetes mellitus, congestive heart failure, stroke, chronic pulmonary disease, and liver disease. Distant metastases were defined as metastases to the lungs, liver, brain, bones, and other organs (ICD-9-CM codes 197.x, 198.0, 198.1, and 198.3-198.7). The type of treatment was considered as the treatment that a patient with breast cancer received 2 years before the index date until the end of the followup period. A patient undergoing both mastectomy and breast-conserving surgery was classified under mastectomy. Combination chemotherapy was defined as when patients received other chemotherapy medications in addition to taxanes.
Study Population
Insured individuals of the NHI diagnosed with severe and chronic diseases that require extended treatment, such as breast cancer, may apply for a catastrophic illness certificate to be exempted from copayments. To receive a catastrophic illness certificate, the diagnosis of a patient with Cancer
May 1, 2014
Exposure to TCM
The NHIRD records detailed prescription information for both TCM and Western medicine including drug name, dose, start date, frequency, duration, and method of administration. All TCMs covered by the NHI were 1339
Original Article TABLE 1. Characteristics of Breast Cancer Patients According to Use of TCM
Characteristics Age, y Urbanization Low Moderate High Comorbidity Hypertension Diabetes mellitus Congestive heart failure Stroke Chronic pulmonary disease Liver disease Distant metastases Type of treatment Surgery None Breast-conserving surgery Mastectomy Combination of chemotherapy Hormonal or targeted biologic therapy Radiotherapy
TCM Users(N 5 115)
TCM Nonusers(N 5 614)
Mean (SD) or No. (%)
Mean (SD) or No. (%)
P
50.5
(8.9)
52.3
(10.0)
.08
8 24 83
(7.0) (20.9) (72.2)
37 153 424
(6.0) (24.9) (69.1)
.63
10 1 3 1 15 16 41
(8.7) (0.9) (2.6) (0.9) (13.0) (13.9) (35.7)
83 25 15 24 92 100 228
(13.5) (4.1) (2.4) (3.9) (15.0) (16.3) (37.1)
.16 .10 >.99 .16 .59 .52 .76
28 19 68 110 81 66
(24.4) (16.5) (59.1) (95.7) (70.4) (57.4)
191 105 318 586 409 367
(31.1) (17.1) (51.8) (95.4) (66.6) (59.8)
.29
.92 .42 .63
Abbreviations: SD, standard deviation;TCM, traditional Chinese medicine.
prescribed by board-certified Chinese medicine physicians who received rigorous training in both Chinese and Western medicine in medical schools and through residency programs in hospitals. These physicians must also pass the national licensing examinations. TCMs are prescribed by Chinese medicine physicians according to TCM symptom patterns.10 Patients using TCM for 30 days due to a diagnosis of breast cancer were defined as TCM users, whereas those treated for < 30 days were considered as TCM nonusers. Moreover, to observe a doseresponse relationship, we further grouped TCM users into 2 groups: 1 group used TCM for 30 to 180 days whereas the other group used TCM for > 180 days. Study Outcome
The study outcome was all-cause mortality during the 10year follow-up. The patient’s date of death was determined according to the Registry of Catastrophic Illness Database of the NHIRD. The analysis period began from the index date and ended at the death of patient, withdrawal from NHI, or the end of 2010, whichever occurred first. 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 1340
users and nonusers were analyzed using a Student t test, and the categorical variables were analyzed using a chisquare or Fisher exact test. The cumulative probability of survival for TCM users and nonusers was estimated using a Kaplan-Meier estimator16 with a log-rank test17 used to compare the survival curves between the groups. The association between the baseline characteristics and mortality was estimated using a univariate Cox regression analysis18 and reported according to hazards ratios (HRs) with 95% confidence intervals (95% CIs). The variables with P values < .2 in the univariate analysis were included in the multivariable Cox proportional hazards model to identify the independent predictors of mortality. Log(-log[survival]) versus log of survival time plot was inspected to verify the proportional hazards assumption. The study endpoint was all-cause mortality. Patients who were alive at the time of last follow-up were censored at the date of withdrawal from NHI or the end of study period, whichever came first. To verify the dose-response relationship between TCM use and mortality, we treated TCM use category as a continuous variable to calculate the P value of the linear trend. Because stage of cancer is a major predictor of mortality, we conducted a sensitivity analysis limiting to patients with distant metastases to evaluate the robustness of our findings. Statistical significance was determined as P < .05. All analyses were performed using SAS statistical software (version 9.3; SAS Institute Inc, Cary, NC). Cancer
May 1, 2014
TCM and Survival of Patients With Breast Ca/Lee et al
RESULTS Of the 1 million people randomly selected from the NHIRD between 2001 and 2010, 786 female patients were aged > 18 years and received taxane treatment because of primary breast cancer. We further excluded 5 patients who received taxane treatment before January 1, 2001 and 52 patients with a follow-up period of < 3 months. Of the remaining 729 eligible patients, 614 were TCM nonusers, whereas the remaining 115 patients were TCM users, including 58 users who took TCM for 30 to 180 days and 57 users who used it for > 180 days. Characteristics such as age, urbanization, baseline comorbidity, and treatment did not appear to differ significantly between the groups (Table 1).
Figure 1. Kaplan-Meier curves of overall survival in patients with advanced breast cancer according to traditional Chinese medicine (TCM) use during the follow-up period.
The mean follow-up period for the patients was 2.8 years 6 1.9 years; 277 deaths occurred and the overall mortality rate was 38.0% during the analysis period. TCM users had 32 deaths (27.8%) and TCM nonusers had 245 deaths (39.9%). The Kaplan-Meier survival curve and log-rank test revealed a statistically significant difference between the survival curves of the groups (P < .001) (Fig. 1). The unadjusted Cox regression analysis demonstrated a strong association between the use of TCM and a decrease in mortality (Table 2). Compared with TCM nonusers, TCM users had reduced mortality by 47% (unadjusted HR, 0.53; 95% CI, 0.37-0.77 [P < .001]). On the multivariate Cox model controlling for 6 potential confounders (age, history of congestive heart failure, distant metastases, surgery, hormonal or targeted biologic therapy, and radiotherapy), the use of TCM remained highly associated with decreased mortality (the adjusted HR of TCM users was 0.50 [95% CI, 0.35-0.73]; P < .001) (Table 2). Further analysis demonstrated a dose-response relationship between TCM use and mortality. The adjusted HRs were 0.55 (95% CI, 0.33-0.90) and 0.46 (95% CI, 0.27-0.78) for patients with TCM use of 30 to 180 days and > 180 days, respectively. The longer the duration of TCM use, the lower the mortality rate (P for trend < .001). The other independent predictors of increased mortality included distant metastases, inoperable surgical status, and radiotherapy. Similar results were obtained when analyses were restricted to patients with distant metastases. Of the 269
TABLE 2. Unadjusted and Adjusted Cox Proportional Hazards Model Analysis of the Mortality of Patients With Breast Cancer Univariate Analysis Variable TCM use Nonusers (180 d Age (per 1 y) Congestive heart failure Distant metastases Surgery None Breast-conserving surgery Mastectomy Hormonal or targeted biologic therapy Radiotherapy
Multivariate Analysis a
HR
95% CI
P
aHR
95% CI
P
1 0.53 0.58 0.48 1.01 1.91 3.10
0.37-0.77 0.36-0.95 0.29-0.81 1.00-1.02 0.98-3.72 2.44-3.94
