Medicine

®

Observational Study

OPEN

Complementary traditional Chinese medicine therapy improves survival in patients with metastatic prostate cancer Jui-Ming Liu, MDa, Po-Hung Lin, MDb,c, Ren-Jun Hsu, PhDd,e,f, Ying-Hsu Chang, MDb, Kuan-Chen Cheng, PhDg,h,i, See-Tong Pang, MDb, Shun-Ku Lin, MDj Abstract

More than 50% of prostate cancer patients have used traditional Chinese medicine (TCM) in Taiwan. However, the long-term clinical efficacy of TCM in prostate cancer patients remains unclear. Here, we investigated the relationship between TCM use and the survival of prostate cancer patients. A retrospective nationwide cohort study of prostate cancer patients was conducted between 1998 and 2003 using the Taiwan National Health Insurance Research Database. Patients were classified as TCM users or nonusers, and monitored from the day of prostate cancer diagnosis to death or end of 2012. The association between death risk and TCM use was determined using Cox proportional-hazards models and Kaplan–Meier curves. Of the 1132 selected prostate cancer patients, 730 (64.5%) and 402 (35.5%) were TCM users and nonusers, respectively. The mean follow-up period was 8.38 years, and 292 (25.8%) deaths were reported. TCM users had a decreased mortality rate (21.9%) compared with nonusers (32.8%). A lower death risk was observed with longer TCM use, especially in patients who used TCM for ≧200 days (adjusted hazard ratio [aHR] 0.61, 95% confidence interval [CI] 0.44–0.84). TCM users with metastatic prostate cancer had a significant lower HR than nonusers (aHR 0.70, 95% CI 0.51–0.95). Chai-Hu-Jia-Long-Gu-MuLi-Tang was the most significant TCM formulae for improving survival in metastatic prostate cancer (aHR 0.18, 95% CI 0.04–0.94). The result suggested that complementary TCM therapy might be associated with a reduced risk of death in metastatic prostate cancer patients. Abbreviations: ADT = androgen deprivation therapy, aHRs = adjusted hazard ratios, CIs = confidence intervals, ICD-9-CM = The

International Classification of Diseases, Ninth Revision, Clinical Modification, LHID2005 = Longitudinal Health Insurance Database 2005, NF-kB = nuclear factor kappa-light-chain-enhancer of activated B cells, NHI = National Health Insurance, NHIRD = National Health Insurance Research Database, NT$ = New Taiwan Dollars, PSA = prostate-specific antigen, STAT3 = signal transducer and activator of transcription 3, TCM = traditional Chinese medicine.

Keywords: androgen deprivation therapy, complementary therapies, National Health Insurance Research Database, prostate cancer, traditional Chinese medicine

Editor: Ming-Hui Wu. Funding: The authors would like to express sincere gratitude for the partial support provided for this project in the form of grants from the Department of Health, Taipei City Government (10301-62-071),the Department of Chinese Medicine and Pharmacy (CCMP-102-CMB-7), the Chang Gung Medical Research Program (G3C1141), and the Ministry of Health and Welfare (10402). The authors have no conflicts of interest to disclose. Supplemental Digital Content is available for this article. a Division of Urology, Department of Surgery, Taoyuan General Hospital, Ministry of Health and Welfare, b Division of Urology, Department of Surgery, Chang Gung Memorial Hospital, c Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, d Biobank Management Center of the Tri-Service General Hospital, National Defense Medical Center, e Department of Pathology and Graduate Institute of Pathology and Parasitology, the Tri-Service General Hospital, National Defense Medical Center, f Graduate Institute of Life Sciences, National Defense Medical Center, g Graduate Institute of Food Science and Technology, National Taiwan University, h Institute of Biotechnology, National Taiwan University, i Department of Medical Research, China Medical University Hospital, China Medical University, j Department of Chinese Medicine, Taipei City Hospital, Renai Branch, Taipei City, Taiwan.

Correspondence: Shun-Ku Lin, Department of Chinese Medicine, Taipei City Hospital, Renai Branch, Taipei City, No.10, Sec. 4, Renai Rd., Daan Dist., Taipei City 106, Taiwan (e-mail: [email protected]). Jui-Ming Liu and Po-Hung Lin contributed equally to this work. Copyright © 2016 the Author(s). Published by Wolters Kluwer Health, Inc. All rights reserved. This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Medicine (2016) 95:31(e4475) Received: 12 January 2016 / Received in final form: 11 June 2016 / Accepted: 7 July 2016 http://dx.doi.org/10.1097/MD.0000000000004475

1

Liu et al. Medicine (2016) 95:31

Medicine

1. Introduction Prostate cancer is the most common cancer in men, and has increased in modern society, especially in people aged >65 years.[1] The incidence of prostate cancer rapidly increased in the recent few years in Taiwan (from 16.57 per 100,000 in 2000 to 40.56 in 2012).[2] The different types of treatment for distinct prostate cancer stages include radical prostatectomy, radiation therapy, hormone therapy, and chemotherapy,[3] but prostate cancer remains as one of the leading causes of cancer-related deaths in Taiwan. The incidence of prostate cancer-related death has also increased recently (5.59 per 100,000 in 2000 to 10.17 in 2012).[4] Therefore, patients and caregivers often consider complementary and alternative medicine as another treatment choice.[5] In Taiwan, traditional Chinese medicine (TCM) is the main form of complementary and alternative medicine. Lin et al demonstrated that an overall 52.6% of prostate cancer patients had used TCM in their 6-year cohort study. They also found a trend of increased TCM use among prostate cancer patients under the National Health Insurance (NHI), especially in cancer-specific TCM visits.[6] According to in vitro and in vivo studies, TCM might be beneficial for prostate cancer patients by inhibiting the invasion of cancer cells, inducing apoptosis, suppressing prostate cancerdependent angiogenesis, and down-regulating human androgen receptors.[7] However, there is a lack of large-scale studies to verify the long-term outcomes of TCM. Here, we used nationwide data to estimate the survival benefit after TCM treatment for patients with prostate cancer. To the best of our knowledge, this was the first study to date involving the largest cohort and longest follow-up period to investigate such an issue.

Figure 1. Flowchart of the patient enrollment procedure from one million longitudinal health insurance database. We identified patients with diagnosis of prostate malignant neoplasm by ICD-9 code (185) in Taiwan between 1998 and 2003, and patients were divided in to TCM use (n = 730) and TCM nonuse (n = 402). ICT-9 = The International Classification of Diseases, Ninth Revision; TCM = traditional Chinese medicine.

2. Materials and methods 2.1. Longitudinal health insurance database We designed a retrospective cohort study using 15 years data (from January 1, 1998 to December 31, 2012) of the Longitudinal Health Insurance Database 2005 (LHID2005), a subdataset of the National Health Insurance Research Database (NHIRD). The NHIRD is a national-scale research library with recorded medical and demographic information from >99% of the Taiwan population for >20 years, and >2000 studies have been currently published using the NHIRD.[8] The LHID2005 randomly selected 1 million people from the entire 23 million insurers of the NHIRD in 2005, and the demographic factors were similar between people in the LHID2005 and origin NHIRD.[9] The NHIRD included detailed outpatient and inpatient medical records, such as visiting or admission date, clinical diagnosis according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes, surgical procedure, and drug information (i.e., prescription date, duration, and dosage). Moreover, LHID2005 provides uninterrupted longitudinal tracking for every patient. Therefore, LHID2005 is suitable for long-term research about cancer and chronic diseases.[10] The study was reviewed and approved by the institutional review board of the Chang Gung Memorial Hospital, Linkou, Taiwan (CGMH IRB 103-3238B).

reviewed and issued by the Ministry of Health and Welfare; the audit process included diagnosis by a urology specialist and chart revision by senior physicians. Furthermore, the pathology and imaging report would also be censored. Therefore, patients who had catastrophic certification of prostate cancer could be definitely confirmed to have prostate cancer. A total of 1278 patients who were diagnosed with prostate cancer and issued catastrophic illness certificates were selected between 1998 and 2003. We excluded 138 patients who were diagnosed with prostate cancer in 1997 and 8 patients with uncompleted demographic data. Finally, 1132 patients with prostate cancer were enrolled in this study. We use the following steps to divided prostate cancer patients into TCM user and TCM nonuser groups. First, we obtained all outpatient medical data of prostate cancer patients from the NHIRD file “Ambulatory care expenditures by visits,” which contained detailed outpatient medical information including medical divisions, specialist of physician, date, and hospital or clinic. Second, we excluded all outpatient records before prostate cancer diagnosis and isolated the medical information of “traditional Chinese medicine divisions” as TCM groups. Patients who did not have Chinese medicine outpatient records were classified as “non-TCM” groups. Third, we link outpatient data with files “Details of ambulatory care orders,” which contain the information of every outpatient treatment, including drug name and dosage regimens. Fourth, we calculated each patient’s Chinese medical treatment time and dose of herbal formulae. The patients were divided into

2.2. Study participants The flowchart of patient enrollment is shown in Fig. 1. Patients who were diagnosed with prostate cancer (ICD-9-CM code 185) and who obtained catastrophic certification were selected from the LHID2005 database.[11] Catastrophic certification was 2

Liu et al. Medicine (2016) 95:31

www.md-journal.com

2 groups: TCM users (730, 64.5%) and TCM nonusers (402, 35.5%). All medical diagnoses, surgical procedures, and medications were completely recorded during the follow-up period.

Furthermore, Kaplan–Meier curves were used to show the difference in survival between the TCM users and nonusers. The statistical software package SAS (version 9.4, SAS Institute, Cary, NC) was used for data analysis.

2.3. Adjustment of covariates

3. Results

We classified patients into the following 4 age groups: 80 years. We classified the area of Taiwan into 4 groups: low urbanization, moderate urbanization, high urbanization, and very high urbanization. We also classified insurance payments, in New Taiwan Dollars (NT$), into the following 4 groups: dependent (no constant income), NT$ 1 to 19,999; NT$ 20,000–39,999, and >NT$ 40,000. The Charlson comorbidity index scores were categorized into the following 4 groups and were used to measure comorbidity from the NHIRD: ≦2, 2 to 4, 4 to 6, and >6. To assess the dose–response relationship between TCM use and the reduction of the risk of death, we divided TCM users into 3 groups according to the TCM treatment duration:

Complementary traditional Chinese medicine therapy improves survival in patients with metastatic prostate cancer.

More than 50% of prostate cancer patients have used traditional Chinese medicine (TCM) in Taiwan. However, the long-term clinical efficacy of TCM in p...
303KB Sizes 2 Downloads 26 Views