Journal of Ethnopharmacology 155 (2014) 702–708
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Research Paper
Prescription patterns of Chinese herbal products for post-surgery colon cancer patients in Taiwan Te-Hsin Chao a,b, Pin-Kuei Fu c,d, Chiung-Hung Chang e,f, Shih-Ni Chang g, Frank Chiahung Mao b, Ching-Heng Lin g,n, Evidence-based Chinese Medicine Research Groupg a
Department of Surgery, Taichung Veterans General Hospital, Taichung 40705, Taiwan, ROC Department of Veterinary Medicine, National Chung Hsing University, Taichung, Taiwan, ROC c Division of Critical Care & Respiratory Therapy, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan, ROC d Institute of Health Policy and Management, National Taiwan University, Taipei, Taiwan, ROC e School of Chinese Medicine, China Medical University, Taichung 404, Taiwan, ROC f Department of Traditional Chinese Medicine, Taichung Veterans General Hospital, Taichung 407, Taiwan, ROC g Department of Medical Research, Taichung Veterans General Hospital, #160, Section 3, Chung-Kang Rd., Taichung, Taichung 407, Taiwan, ROC b
art ic l e i nf o
a b s t r a c t
Article history: Received 22 January 2014 Received in revised form 3 June 2014 Accepted 4 June 2014 Available online 16 June 2014
Ethno-pharmacological relevance: Traditional Chinese medicine (TCM) is commonly provided to cancer patients, however, the patterns of prescriptions for this type of medicine in Taiwan are unclear. This study aimed to evaluate the use of traditional Chinese medicine products in colon cancer patients postsurgery in Taiwan and to research patterns of TCM. Material and Methods: This was a cross-sectional study of newly diagnosed colon cancer patients who received surgery between 2004 and 2008 identified from the National Health Insurance Research Database of Taiwan. The prescription patterns and reasons for the use of TCM for colon cancer were analyzed. Results: The results showed that “symptoms, signs and ill-defined conditions” (23.3%) and diseases of the digestive system (16.9%) were the most common reasons for using Chinese herbal medicine. Xiang-shaliu-jun-zi-tang (7.1%), Bu-zhong-yi-qi-tang (4.3%), Jia-wei-xiao-yao-san (4.1%), Shen-Ling-Bai-Zhu-San (3.7%), Ban-Xia-Xie-Xin-Tang (3.4%), Gui-pi-tang (2.4%), Ping-Wei-San (2.4%), Gan-Lu-Yin (2.0%), Bao-HeWan (1.9%), and Zhen-Ren-Huo-Ming-Yin (1.8%) were the most commonly prescribed single Chinese herbal formulae (CHF) for colon cancer patients post-surgery. Hedyotis diffusa Willd (Bai Hua She She Cao) (5.1%) and Scutellaria barbata (Ban Zhi Lian )(4.8%) were the most commonly prescribed single Chinese herbs. Conclusions: This study identified patterns of TCM use in colon cancer patients post-surgery in Taiwan. The herbal ingredients were most commonly used for stimulate ghrelin secretion to increase food intake and had potential anti-tumor effect. However, further research is required to evaluate any beneficial effects which could identify leads for the development of new treatment strategies using TCM. & 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Colon cancer Traditional Chinese medicine (TCM) Chinese herbal formula (CHF) Prescription patterns
1. Introduction Colorectal cancer is the third most common cancer and the fourth most frequent cause of cancer deaths worldwide (Jemal et al., 2011). In Taiwan, colon cancer is now the most common cancer and has increased markedly with overall incidence increasing from 34.0 cases per 100,000 population in 2002 to 41.4 cases per 100,000 population in 2009 (Taiwan Cancer Registry). Surgical
n
Corresponding author. Tel.: þ 886 4 2359 2525x4089; fax: þ 886 4 2359 2705. E-mail address: [email protected] (C.-H. Lin).
http://dx.doi.org/10.1016/j.jep.2014.06.012 0378-8741/& 2014 Elsevier Ireland Ltd. All rights reserved.
resection is considered to be the gold standard treatment for localized colon cancer, and post-operative chemotherapy is used to eradicate and decrease the recurrence of micrometastases. Patients with metastatic colorectal cancer cannot be cured, however, chemotherapy may offer palliation and some prolongation of life (Weeks et al., 2012). New therapies are clearly needed to improve survival and to also reduce side effects. To this end, some researchers have turned to complementary/alternative medicine such as TCM, which is now one of the most popular complementary/alternative medicines provided to patients in many countries (Baak et al., 2011). However, it is still unclear whether TCM combined with Western medicine (Baak et al., 2011;
T.-H. Chao et al. / Journal of Ethnopharmacology 155 (2014) 702–708
Shen et al., 2012; Xu et al., 2012b) has the potential to improve outcomes and prolong the ability to receive chemotherapy, and few studies have reported the use of TCM among colon cancer patients. In Taiwan, TCM is commonly offered to cancer patients, however, the patterns of prescriptions given for this type of medicine in Taiwan are unclear. The National Health Insurance (NHI) system was established in 1995, and it consists of all medical information from the National Health Insurance Research Database for more than 99% of the population in Taiwan. The NHIRD database provides researchers with a platform to examine and study the utilization of TCM prescription patterns by TCM doctors. This study aimed to evaluate the use of TCM in newly diagnosed colon cancer patients post-surgery in Taiwan, and to research patterns of TCM.
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Catastrophic Illness Certificate (malignancies are included in the category of catastrophic illness). Any patients who have been issued a Catastrophic Illness Certificate can receive co-payment exemption under the NHI program. If hospital administrators do not complete the medical care records of cancer patients, they will not be able to be reimbursed by the NHI system. Such cancer patients often consume a significant amount of financial resources for medical care and as a result, we can safely assume that very little data will be missing from the database. A date two months post-colon cancer surgery was defined as the index date. We divided the study subjects into two groups: the TCM group, patients who received TCM treatment within one year after the index date, and the non-TCM group, patients without any TCM treatment within one year after the index date (Fig. 1). 2.3. Key variables of interest
2. Materials and methods
The present cross-sectional study utilized data obtained from the National Health Insurance Research Database (NHIRD) which is the database released annually by the NHI Bureau for research purposes. The NHIRD consists of all medical information from the NHI program including complete data on outpatient visits, hospital admissions, prescriptions, disease status, and demographic data for more than 99% of the population living in Taiwan (Bureau of National Health Insurance, 2014). According to the NHI program guidelines, TCMs are only provided for outpatient care including CHF, acupuncture, and traumatology manipulative therapy. The CHF commonly used are combinations of two or more individual Chinese herbs (Wang et al., 2012), and each of them was covered by the NHI program. The diagnostic codes in the NHIRD are based on the International Classification of Disease, 9th Revision, Clinical Modification (ICD-9-CM).
The demographic variables of interest were compared between the TCM and non-TCM groups. Age was categorized into six groups: o30, 30–39, 40–49, 50–59, 60–69, 70–79 and ≧ 80 years. Urbanization was classified into four levels, with 1 indicating the highest level of urbanization and 4 the lowest. Family income was also grouped into five levels (in New Taiwan Dollars, NTD): 0, 1– 15840, 15841-28800, 28801-45800, and ≧ 45801. Geographic area was classified into North, Middle, South, and East. Occupation was classified into public and military, industrial, business, low income, others and retired. In Taiwan, TCM physicians (those who received series training in Chinese or both Chinese and Western medicine, all must pass the national licensing examinations and to go through residency training programs in hospitals) are requested to make diagnoses based on ICD-9-CM coding (no more than three diagnostic codes for each visit). Each prescription was connected to its diagnosis. Accordingly, we analyzed the number of the corresponding diagnostic codes for subjects with TCM prescriptions.
2.2. Study subjects
2.4. Statistical analysis
Patients were selected with newly diagnosed colon cancer who had undergone surgery for colon cancer between 1 January 2004 and 31 December 2008 (n ¼24303). Due to the fact that the SARS infection in 2003 and economic crisis in 2009 might influence patient willingness to go to hospital for medical care we attempted to establish a period of time that was not biased by these known factors. Therefore, we selected data from the year 2004 to 2008 for the purposes of this review. A diagnosis of colon cancer in this study was considered to be reliable because specialists must supply ICD-9-CM codes with pathological and histological results for Registry for Catastrophic Illness Patient Database verification. Patients who died within two months after operation were excluded from analysis (n ¼982). In the NHI system, the insured who suffer from certain major diseases can apply for a
Distributions of the demographic variables were compared between the TCM and non-TCM groups using the chi-square test. The top ten prescription rates of CHF for treating colon cancer were presented in descriptive statistics. The most frequent diagnoses for the prescriptions of CHF were also displayed by frequency and percentage. All statistical analyses were performed with SAS (version 9.3; SAS Institute, Cary, NC).
2.1. Data sources
3. Results Twenty-three thousand and three hundred twenty-one patients were identified from the NHIRD who had surgery for colon cancer from 1 January 2004 to 31 December 2008. The
Newly identified colon cancer patient between 2004 and 2008 from NHIR Database of Taiwan (N=29890)
Newly identified colon cancer patient post operation (n=24303)
TCM user Prescription of Chinese herbal medicine within one year after the index date (n=4620)
Exclude patients without operation (n=5587)
Exclude patients who died within two month post operation (n=982)
Non-TCM user Without prescription of Chinese herbal medicine within one year after the index date (n=18701)
Fig. 1. Flow diagram of study subjects selection from the National Health Insurance Research Database during 2004–2008.
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baseline characteristics of the patients are summarized in Table 1. Of the 23,321patients, 4620 (19.8%) received TCM treatment, with
the highest prevalence being in those aged 60–69 years. More women than men received TCM treatment (51.4% vs. 48.6%). 3.1. Frequency distribution of TCM visits in the colon cancer patients
Table 1 Baseline characteristics of the newly identified colon cancer patients from 2004– 2008. Variables
Age, years Mean 7 SD 0–29 30–39 40–49 50–59 60–69 70–79 ≧80 Sex Women Men Urbanizationa 1 2 3 4 Family income (NTD) Dependent 1-15840 15841-28800 28801-45800 ≧45801 Area North Midland South East Occupation Public and military Industry Business Low income Others and retired
P-value
TCM use No (n¼ 18701)
Yes (n¼ 4620)
n
n
(%)
(%) o 0.001
66.2 7 13.6 136 (0.7) 536 (2.9) 1389 (7.4) 3061 (16.4) 3879 (20.7) 5110 (27.3) 4590 (24.5)
62.3 7 13.2 43 (0.9) 174 (3.8) 485 (10.5) 1038 (22.5) 1097 (23.7) 1015 (22.0) 768 (16.6)
3.2. Prescriptions of CHF for colon cancer patients
o 0.001 8233 10468
(44.0) (56.0)
2373 2247
(51.4) (48.6)
5408 5269 2860 4797
(29.5) (28.7) (15.6) (26.2)
1309 1339 714 1139
(29.1) (29.8) (15.9) (25.3)
5954 3840 6821 1272 814
(31.8) (20.5) (36.5) (6.8) (4.4)
1397 830 1705 430 258
(30.2) (18.0) (36.9) (9.3) (5.6)
9427 2827 5995 402
(50.5) (15.2) (32.1) (2.2)
1940 1019 1532 112
(42.2) (22.1) (33.3) (2.4)
Analysis of the TCM visits and related complaints among the colon cancer patients (according to systematic categories of ICD-9CM codes) for the 4620 TCM users showed that “symptoms, signs and ill-defined conditions” was the most common reason for using CHF (23.3%, n ¼2443), followed by diseases of the digestive system (16.9%, n ¼1770), and malignant neoplasms (16.6%, n ¼1736) (Table 2). Frequency distribution of the main complaint for colon cancer patients post-surgery are shown in Table 3. The greatest frequency distributions were general symptoms, acute nasopharyngitis, and disorders of stomach function.
Xiang-sha-liu-jun-zi-tang (7.1%) was the most commonly prescribed CHF for colon cancer patients post-surgery, followed by Bu-zhong-yi-qi-tang (4.3%), Jia-wei-xiao-yao-san (4.1%), and Shen Ling Bai Zhu San (3.7%) (Table 4).
0.445
3.3. Prescription of single Chinese herbs for colon cancer patients o 0.001
Hedyotis diffusa Willd (Bai Hua She She Cao, 5.1%) was the most commonly prescribed single Chinese herb, followed by Scutellaria barbata (Ban Zhi Lian, 4.8%), Caulis patholobi (Jixueteng, 1.8%), Salvia Miltiorrhiza Radix (Dan Shen, 1.7%) and Radix astragali (Huangqi, 1.7%) (Table 5).
o 0.001
4. Discussion o 0.001
1328 6658 3879 164 3905
(8.3) (41.8) (24.3) (1.0) (24.5)
406 1609 1096 28 827
(10.2) (40.6) (27.6) (0.7) (20.9)
NTD: New Taiwan Dollars. a Urbanization level: 1 indicates the highest level of urbanization and 4 the lowest.
To the best of our knowledge, this is the first study to use the NHIRD to evaluate the prescription patterns of CHF for colon cancer patients. A major strength of this research was that it is a nationwide population-based study, which includes all colon cancer patients from 2004 to 2008. Therefore the size of our study was larger than many clinic-based studies. TCM physicians prescribed a variety of herbal formulae for colon cancer patients postsurgery in Taiwan, however, the prescription patterns and reasons for the use of TCM have not been reported previously.
Table 2 Frequency distribution of ICD-9-CM codes with TCM visits among the colon cancer patients. Disease
ICD-9-CM
Frequency
(%)
Symptoms, signs and ill-defined conditions Diseases of the digestive system Malignant neoplasm Disease of the respiratory system Diseases of the musculoskeletal system and connective tissue Injury and poisoning Diseases of the circulatory system Diseases of the genitourinary system Diseases of skin and subcutaneous tissue Endocrine, nutritional and metabolic diseases and immunity disorders
780–799 520–579 140–208 460–466, 470–478, 480–519 710–739 800–999, E800–E999 390–459 580–629 680–709 240–289
2443 1770 1736 1302 1177 426 302 297 233 217
(23.3) (16.9) (16.6) (12.4) (11.2) (4.1) (2.9) (2.8) (2.2) (2.1)
Diseases of the sense organs Diseases of the nervous system (except meningitis) Mental disorders Infectious and parasitic diseases and late effects of infectious and parasitic diseases Other neoplasms Congenital anomalies Complications of pregnancy, childbirth and the puerperium Other reasons for contact with health services
360–389 323–359 290–319 001–139, 7713, 320–322 210–239 740–759 630–676 V00–V82
175 157 84 69 27 26 25 13
(1.7) (1.5) (0.8) (0.7) (0.3) (0.2) (0.2) (0.1)
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Table 3 Frequency distribution of the main complaint for colon cancer patients post-surgery (Top 15). Disease
ICD-9-CM
Freq.
(%)
List
ICD-9
Freq.
(%)
General symptoms
780
774
(7.4)
Acute nasopharyngitis Disorders of stomach function
460 536
591 572
(5.6) (5.5)
Other sleep disturbances Sleep disturbances, unspecified Dizziness and giddiness Others Acute nasopharyngitis Dyspepsia and other specified disorders of stomach function Unspecified functional disorder of stomach Disorders of function of stomach Achlorhydria
780.59 780.50 780.4x – 460.xx 536.8x
226 215 108 225 591 278
(29.2) (27.8) (14.0) (29.1) (100.0) (48.6)
536.9x 536.xx 536.0x
269 23 2
(47.0) (4.0) (0.3)
Symptoms involving respiratory system and other chest symptoms Functional digestive disorders, not elsewhere classified Other and unspecified disorders of back Symptoms involving head and neck Other disorders of soft tissues Symptoms involving digestive system Other and unspecified disorder of joint Malignant neoplasm of rectum, rectosigmoid junction, and anus Gastritis and duodenitis Symptoms involving cardiovascular system Diseases of the oral soft tissues, excluding lesions specific for gingiva and tongue
786 564 724 784 729 787 719 154 535 785 528
4.1. Most common reasons for use of CHF for colon cancer patients post-surgery “Symptoms, signs and ill-defined conditions” and diseases of the digestive system were the two most common reasons for using TCM in colon cancer patients post-surgery. This indicates that, besides colon cancer care, post-surgery, attention should be paid to the general post-operative condition of the patient including sleep disturbance, respiratory and dyspeptic symptoms.
545 427 346 331 308 301 262 230 212 133 130
(5.2) (4.1) (3.3) (3.2) (2.9) (2.9) (2.5) (2.2) (2.0) (1.3) (1.2)
Zhu San, the fourth most commonly prescribed formula has been reported to have an antacid effect (Wu et al., 2010). Recent studies have reported that the anorexia–cachexia syndrome is one of the most common and devastating symptoms in patients with advanced cancer (Lasheen and Walsh, 2010; Yavuzsen et al., 2009). In the current study, most of the herbs were used to harmonize gastrointestinal function. Some herbal ingredients such as Ginseng Radix, Astragali Radix have been reported to enhance immunomodulatory activities (Jang and Shin, 2010; Shin et al., 2002).
4.2. Commonly used CHF for colon cancer patients post-surgery
4.3. Commonly used single Chinese herbs for colon cancer patients
Xiang-sha-liu-jun-zi-tang was the most frequently prescribed formula for colon cancer patients post-surgery. TCM is widely used to relieve the dyspeptic symptoms of gastrointestinal disorders (Sadakane et al., 2011; Tominaga et al., 2012) and to improve spleen Qi deficiency which involves decreased digestion, absorption and immune system function issues (Zheng et al., 2014). An ancient Chinese book (Pi Wei Lun) explains that for spleen Qi deficiency was defined as abdominal distension, loss of appetite, diarrhea and other signs of poor digestion. Recently, some studies have reported that liu-jun-zi-tang can stimulate endogenous ghrelin secretion to increase food intake in rats with cancer, and that it may play an important role in cancer cachexia treatment (Fujitsuka et al., 2012; Takeda et al., 2012). Bu-zhong-yi-qi-tang is the second most commonly prescribed CHF for colon cancer patients. In the classical literature (Pi Wei Lun), Bu-zhong-yi-qi-tang is said to enhance spleen Qi deficiency, and improve fatigue and appetite. Several studies have shown that Bu-zhong-yi-qi-tang can prevent surgical stress-induced immunosuppression by maintaining natural killer cell activity (Kimura et al., 2008), restoring impaired immune function, and enhancing natural killer cell activity with a concomitant anti-tumor effect (Harada et al., 1995; Hirokawa and Utsuyama, 2002; Utsuyama et al., 2001). Jia-wei-xiao-yao-san, the third most commonly prescribed formula for colon cancer patients, has been used for the treatment of psychological (depression, anxiety) symptoms in post-menopausal women, (Chen et al., 2003; Park et al., 2007) and to alleviate sleep disturbances. (Terauchi et al., 2011) Shen Ling Bai
Hedyotis diffusa Willd (Bai Hua She She Cao) and Scutellaria barbata (Ban Zhi Lian) were the two most frequently prescribed single herbs for colon cancer patients. According to the classical TCM literature, Hedyotis diffusa Willd (Bai Hua She She Cao) and Scutellaria barbata (Ban Zhi Lian) are used to clear heat and remove toxicity (Based on TCM theory, tumors are usually caused by heatinduced toxicity and stagnation of Qi and blood). Recent studies have reported that Hedyotis diffusa Willd (Bai Hua She She Cao) (Meng et al., 2013; Tang et al., 2009) can inhibit tumor angiogenesis, (Lin et al., 2011) induce apoptosis, (Lin et al., 2010) and suppress cancer cell proliferation (Lin et al., 2012). Scutellaria barbata (Ban Zhi Lian) has been reported to inhibit cell apoptosis and cytotoxic effects, (Yin et al., 2004) and inhibit tumor angiogenesis (Wei et al., 2012). Another commonly prescribed single herb, Caulis patholobi (Jixueteng), has been reported to have antimetastatic activities (Kang et al., 2003) and to be able to induce tumor cell apoptosis. (Ha et al., 2004) Salvia Miltiorrhiza Radix (Dan Shen) has been reported to induce apoptosis,(Jung et al., 2013) inhibit angiogenesis, (Tsai et al., 2011) and modulate inflammatory and immune responses (Kang et al., 2000; Qin et al., 2010). The other commonly prescribed herbs were used for reducing general symptoms (such as psychological, sleep disturbance). 4.4. Limitations The present study has three limitations that should be highlighted. First, an accurate diagnosis of colon cancer could be
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Table 4 The top 10 CHF prescribed for colon cancer patients post-surgery. CHM (in Chinese)
Ingredients
Function
Xiang-sha-liu-jun-zi-tang
Vladimiria Radix (Mu Xiang), Villous Amomum (Sha Ren) , Pericarpium citrireticulatae (Chen Pi), Pinellia ternate (BanXia), Ginseng Radix (Ren Shen), Atractylodes macrocephala (Bai Zhu), Poria cocos (Fu Ling), Glycyrrhiza Radix (Gan Cao), Zingiberis Rhizoma (Gan Jiang), Zizyphus Fructus (Da Zao) Astragali Radixa (Huang Qi), Glycyrrhiza Radix (Gan Cao), Bu-zhong-yi-qi-tang (Harada et al., 1995; Hirokawa and Utsuyama, Ginseng Radix (Ren Shen) , Angelica sinensis Radix (Dong 2002; Kimura et al., 2008; Utsuyama Quai), Pericarpium citrireticulatae (Chen Pi), Cimicifuge et al., 2001) Rhizoma (Sheng Ma), Bupleurum Radix (Chai Hu), Atractylodes macrocephala (Bai Zhu) Zizyphus Fructus (Da Zao), Rhizoma zingiberis officinalis (Sheng Jiang) Jia-wei-xiao-yao-san (Chen et al., Cortex Moutan Radicis (Mu Dan Pi), Gardenia Fructus 2003) (Shan Zhi Zi), Bupleurum Radix (Chai Hu), Angelica sinensis Radix (Dong Quai), Paeonia lactiflora (Bai Shao), Atractylodes macrocephala (Bai Zhu), Poria cocos, (Fu Ling), Zingiberis Rhizoma (Gan Jiang), Glycyrrhiza Radix (Gan Cao), Menthae Herba ( Bo He)
Shen Ling Bai Zhu San
Ban Xia Xie Xin Tang
Gui-pi-tang
Ping Wei San
Gan Lu Yin
Bao He Wan
Zhen Ren Huo Ming Yin
Doiichos iabiab L (Bai bian dou), Ginseng Radixa (Ren Shen), Atractylodes macrocephala (Bai Zhu), Poria cocos (Fu Ling), Glycyrrhizae Radix (Gan Cao), Batatatis Rhizoma (Shan Yao), Loti Semen, Coicis Semen ( Lian Zi), Platycod Radix ( Jie Geng), Villous Amomum (Sha Ren), Zizyphus Fructus (Da Zao) Pinellia ternate (Ban xia), Radix Scutellariae Baicalensis (Huang Qin), Zingiberis Rhizoma (Gan Jiang), Ginseng Radix a (Ren Shen ), Glycyrrhiza Radix (Gan Cao), Coptidis Rhizoma (Huang Lian), Zizyphus Fructus (Da Zao) Angelica sinensis Radix (Dong Quai), Astragali Radixa (Huang Qi), Atractylodes macrocephala (Bai Zhu), Ginseng Radixa (Ren Shen) . Poria cocos, (Fu Ling), Glycyrrhizae Radix (Gan Cao), Longan Arillus (Long Yan Rou), Polygalae Radix (Yuan Zhi) , Vladimiria Radix (Mu Xiang ) , Zingiberis Rhizoma (Gan Jiang ) , Zizyphi Spinosi Semen (Suan Zao Ren), Zizyphus Fructus (Da Zao) Pericarpium citrireticulatae (Chen Pi), Magnoliae Cortex (Hou Po), Atractylodes Rhizoma (Cang Zhu), Glycyrrhiza Radix (Gan Cao), Zingiberis Rhizoma (Gan Jiang) , Zizyphus Fructus (Da Zao) Eriobotya japonica (Pi Pa ), Rehmannia Radix (fresh and boiled) (Sheng Di Huang /Shu Di Huang), Ophiopogon Radix (Mai Men Dong), Asparagus cochinchinensis (Tian Men Dong), Dendrobium Caulis (Shi Hu), Radix Scutellariae Baicalensis (Huang Qin), Artemisia capillaries (Yin Chen Hao) , Citri Immaturus Fructus (Zhi Ke), Glycyrrhiza Radix (Gan Cao) Fermentata Massa Medicata (Shen Qu), Crataegi Fructus (Shan Zha), Poria cocos (Fu Ling), Pinellia ternate (Ban Xia), Pericarpium citrireticulatae (Chen Pi), Forsythia Fructus (Lian Qiao), Raphani Semen (Lai Fu Zi) Lonicerae Flos (Jin Yin Hua), Pericarpium citrireticulatae (Chen Pi),, Angelica sinensis Radix (Dong Quai) , Ledebouriellae Radix (Fang Feng), Angelicae Dahuricae Radix (Bai Zhi), Glycyrrhiza Radix (Gan Cao), Liliaceae Roylei Bulbus (Triet Boi Mau), Trichosanthir Radix (Tian Hua Fen), Frankincense (Ru Xiang), Myrrha (Mo Yao), Gleditsia Sinensis Lam (Zao Jiao Ci), Manidis Squama (Chuan Shan Chia)
Frequency (%)
GIR stimulate ghrelin secretion to increase food 1379 intake. (Fujitsuka et al., 2012; Sadakane et al., 2011; Takeda et al., 2012; Tominaga et al., 2012)
(7.1)
GIR anti-tumor effect (Harada et al., 1995; Hirokawa and Utsuyama, 2002; Kimura et al., 2008; Utsuyama et al., 2001
823
(4.3)
Reductions of psychological symptoms in postmenopausal women
785
(4.1)
alleviated sleep disturbances (Chen et al., 2003; Park et al., 2007) Antacid effects (Wu et al., 2010)
713
(3.7)
GIR
653
(3.4)
Memory recovery responsible for the autonomic 470 imbalances (Yamada et al., 1994)
(2.4)
GIR (Riedlinger et al., 2001)
463
(2.4)
GIR Oral ulcer Gingivitis
395
(2.0)
GIR
361
(1.9)
Sore, welling abscess ,boil .clove sore
353
(1.8)
GIR: relieve dyspeptic symptoms of gastrointestinal disorders ; ICD-9-CM 153: Colon Cancer a
Immunomodulatory activities.
obtained from the NHIRD because the patients underwent surgery, however, we were unable to obtain any histopathological reports to verify the TNM stage of each patient (the Tumor Node Metastases staging system of the American Joint Committee on Cancer/Union for International Cancer Control). Therefore, we were unable to draw any firm conclusions about the relationship between the cancer survival rate and TCM use. Second, this study did not include Chinese herbal remedies or decoctions purchased
directly from herbal pharmacies, which may have led to an underestimation of the frequency of CHF use in colon cancer. However, because the NHI program covers most TCM prescriptions, the cost is generally less than the CHF sold in Taiwan markets, so this underestimation may be relatively small. Third, it is not possible to evaluate if the TCM treatments had specific beneficial effects as most published data are based on in vivo and in vitro measurements rather than clinical studies. Further studies
T.-H. Chao et al. / Journal of Ethnopharmacology 155 (2014) 702–708
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Table 5 The top 10 single Chinese herbs prescribed for colon cancer patients post-surgery. Scientific name
CHM (in Chinese)
Reported activity
Frequency
(%)
Hedyotis diffusa willd Scutellaria barbata Caulis patholobi Salvia Miltiorrhiza Radix
Bai Hua She She Cao Ban Zhi Lian Jixueteng Dan Shen
1788 1672 634 604
(5.1) (4.8) (1.8) (1.7)
Radix astragali
Huangqi
602
(1.7)
Magnolia officinalis Herba taraxaci Poria Fermentata Massa Medicata Radix codonopisis
Houpo Pugongying Fuling Shen Qu Dangshen
Anti-angiogenesis , Anti-cancer activity (Lin et al., 2010; Lin et al., 2011; Lin et al., 2012) Anti-cancer activity anti- angiogenesis effects (Wei et al., 2012) Anti-metastatic activities (Kang et al., 2003) Anti cancer activity Anti-angiogenesis Modulation of Inflammatory and Immune Responses (Jung et al., 2013) Anti cancer activity Antioxidant effects Decrease chemotherapy side effects (Li et al., 2012; Liu et al., 2012) Antimicrobial and antioxidant activities (Chan et al., 2008)
591 564 561 550 505
(1.7) (1.6) (1.6) (1.6) (1.5)
Anti- tumor cell proliferation (Chen et al., 2010) Controlling the fermentation process. (Xu et al., 2013) Antitumor activity (Xu et al., 2012a)
ICD-9-CM 153: Colon Cancer.
are needed to evaluate any beneficial effects to patients which could identify leads for the development of new treatment strategies using TCM.
5. Conclusion This study identified the patterns of Chinese herbal medicine use for the treatment of colon cancer patients post-surgery in Taiwan. Chinese herbal products were most commonly used for immunological restoration, harmonizing gastrointestinal function. Some of the commonly used herb ingredients even have reported anti-tumor effects. However, further research is needed to investigate any beneficial effects which could help focus development of new treatment strategies based on TCM.
Contributions Te-Hsin Chao designed research/study, wrote the paper. Pin-Kuei Fu performed research/study. Chiung-Hung Chang performed research/study. Shih-Ni Chang performed research/study, analyzed the data Frank Chiahung Mao performed research/study. Ching-Heng Lin designed research/study, collated the data and reviewed/edited the manuscript.
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Research Paper
Prescription patterns of Chinese herbal products for post-surgery colon cancer patients in Taiwan Te-Hsin Chao a,b, Pin-Kuei Fu c,d, Chiung-Hung Chang e,f, Shih-Ni Chang g, Frank Chiahung Mao b, Ching-Heng Lin g,n, Evidence-based Chinese Medicine Research Groupg a
Department of Surgery, Taichung Veterans General Hospital, Taichung 40705, Taiwan, ROC Department of Veterinary Medicine, National Chung Hsing University, Taichung, Taiwan, ROC c Division of Critical Care & Respiratory Therapy, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan, ROC d Institute of Health Policy and Management, National Taiwan University, Taipei, Taiwan, ROC e School of Chinese Medicine, China Medical University, Taichung 404, Taiwan, ROC f Department of Traditional Chinese Medicine, Taichung Veterans General Hospital, Taichung 407, Taiwan, ROC g Department of Medical Research, Taichung Veterans General Hospital, #160, Section 3, Chung-Kang Rd., Taichung, Taichung 407, Taiwan, ROC b
art ic l e i nf o
a b s t r a c t
Article history: Received 22 January 2014 Received in revised form 3 June 2014 Accepted 4 June 2014 Available online 16 June 2014
Ethno-pharmacological relevance: Traditional Chinese medicine (TCM) is commonly provided to cancer patients, however, the patterns of prescriptions for this type of medicine in Taiwan are unclear. This study aimed to evaluate the use of traditional Chinese medicine products in colon cancer patients postsurgery in Taiwan and to research patterns of TCM. Material and Methods: This was a cross-sectional study of newly diagnosed colon cancer patients who received surgery between 2004 and 2008 identified from the National Health Insurance Research Database of Taiwan. The prescription patterns and reasons for the use of TCM for colon cancer were analyzed. Results: The results showed that “symptoms, signs and ill-defined conditions” (23.3%) and diseases of the digestive system (16.9%) were the most common reasons for using Chinese herbal medicine. Xiang-shaliu-jun-zi-tang (7.1%), Bu-zhong-yi-qi-tang (4.3%), Jia-wei-xiao-yao-san (4.1%), Shen-Ling-Bai-Zhu-San (3.7%), Ban-Xia-Xie-Xin-Tang (3.4%), Gui-pi-tang (2.4%), Ping-Wei-San (2.4%), Gan-Lu-Yin (2.0%), Bao-HeWan (1.9%), and Zhen-Ren-Huo-Ming-Yin (1.8%) were the most commonly prescribed single Chinese herbal formulae (CHF) for colon cancer patients post-surgery. Hedyotis diffusa Willd (Bai Hua She She Cao) (5.1%) and Scutellaria barbata (Ban Zhi Lian )(4.8%) were the most commonly prescribed single Chinese herbs. Conclusions: This study identified patterns of TCM use in colon cancer patients post-surgery in Taiwan. The herbal ingredients were most commonly used for stimulate ghrelin secretion to increase food intake and had potential anti-tumor effect. However, further research is required to evaluate any beneficial effects which could identify leads for the development of new treatment strategies using TCM. & 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Colon cancer Traditional Chinese medicine (TCM) Chinese herbal formula (CHF) Prescription patterns
1. Introduction Colorectal cancer is the third most common cancer and the fourth most frequent cause of cancer deaths worldwide (Jemal et al., 2011). In Taiwan, colon cancer is now the most common cancer and has increased markedly with overall incidence increasing from 34.0 cases per 100,000 population in 2002 to 41.4 cases per 100,000 population in 2009 (Taiwan Cancer Registry). Surgical
n
Corresponding author. Tel.: þ 886 4 2359 2525x4089; fax: þ 886 4 2359 2705. E-mail address: [email protected] (C.-H. Lin).
http://dx.doi.org/10.1016/j.jep.2014.06.012 0378-8741/& 2014 Elsevier Ireland Ltd. All rights reserved.
resection is considered to be the gold standard treatment for localized colon cancer, and post-operative chemotherapy is used to eradicate and decrease the recurrence of micrometastases. Patients with metastatic colorectal cancer cannot be cured, however, chemotherapy may offer palliation and some prolongation of life (Weeks et al., 2012). New therapies are clearly needed to improve survival and to also reduce side effects. To this end, some researchers have turned to complementary/alternative medicine such as TCM, which is now one of the most popular complementary/alternative medicines provided to patients in many countries (Baak et al., 2011). However, it is still unclear whether TCM combined with Western medicine (Baak et al., 2011;
T.-H. Chao et al. / Journal of Ethnopharmacology 155 (2014) 702–708
Shen et al., 2012; Xu et al., 2012b) has the potential to improve outcomes and prolong the ability to receive chemotherapy, and few studies have reported the use of TCM among colon cancer patients. In Taiwan, TCM is commonly offered to cancer patients, however, the patterns of prescriptions given for this type of medicine in Taiwan are unclear. The National Health Insurance (NHI) system was established in 1995, and it consists of all medical information from the National Health Insurance Research Database for more than 99% of the population in Taiwan. The NHIRD database provides researchers with a platform to examine and study the utilization of TCM prescription patterns by TCM doctors. This study aimed to evaluate the use of TCM in newly diagnosed colon cancer patients post-surgery in Taiwan, and to research patterns of TCM.
703
Catastrophic Illness Certificate (malignancies are included in the category of catastrophic illness). Any patients who have been issued a Catastrophic Illness Certificate can receive co-payment exemption under the NHI program. If hospital administrators do not complete the medical care records of cancer patients, they will not be able to be reimbursed by the NHI system. Such cancer patients often consume a significant amount of financial resources for medical care and as a result, we can safely assume that very little data will be missing from the database. A date two months post-colon cancer surgery was defined as the index date. We divided the study subjects into two groups: the TCM group, patients who received TCM treatment within one year after the index date, and the non-TCM group, patients without any TCM treatment within one year after the index date (Fig. 1). 2.3. Key variables of interest
2. Materials and methods
The present cross-sectional study utilized data obtained from the National Health Insurance Research Database (NHIRD) which is the database released annually by the NHI Bureau for research purposes. The NHIRD consists of all medical information from the NHI program including complete data on outpatient visits, hospital admissions, prescriptions, disease status, and demographic data for more than 99% of the population living in Taiwan (Bureau of National Health Insurance, 2014). According to the NHI program guidelines, TCMs are only provided for outpatient care including CHF, acupuncture, and traumatology manipulative therapy. The CHF commonly used are combinations of two or more individual Chinese herbs (Wang et al., 2012), and each of them was covered by the NHI program. The diagnostic codes in the NHIRD are based on the International Classification of Disease, 9th Revision, Clinical Modification (ICD-9-CM).
The demographic variables of interest were compared between the TCM and non-TCM groups. Age was categorized into six groups: o30, 30–39, 40–49, 50–59, 60–69, 70–79 and ≧ 80 years. Urbanization was classified into four levels, with 1 indicating the highest level of urbanization and 4 the lowest. Family income was also grouped into five levels (in New Taiwan Dollars, NTD): 0, 1– 15840, 15841-28800, 28801-45800, and ≧ 45801. Geographic area was classified into North, Middle, South, and East. Occupation was classified into public and military, industrial, business, low income, others and retired. In Taiwan, TCM physicians (those who received series training in Chinese or both Chinese and Western medicine, all must pass the national licensing examinations and to go through residency training programs in hospitals) are requested to make diagnoses based on ICD-9-CM coding (no more than three diagnostic codes for each visit). Each prescription was connected to its diagnosis. Accordingly, we analyzed the number of the corresponding diagnostic codes for subjects with TCM prescriptions.
2.2. Study subjects
2.4. Statistical analysis
Patients were selected with newly diagnosed colon cancer who had undergone surgery for colon cancer between 1 January 2004 and 31 December 2008 (n ¼24303). Due to the fact that the SARS infection in 2003 and economic crisis in 2009 might influence patient willingness to go to hospital for medical care we attempted to establish a period of time that was not biased by these known factors. Therefore, we selected data from the year 2004 to 2008 for the purposes of this review. A diagnosis of colon cancer in this study was considered to be reliable because specialists must supply ICD-9-CM codes with pathological and histological results for Registry for Catastrophic Illness Patient Database verification. Patients who died within two months after operation were excluded from analysis (n ¼982). In the NHI system, the insured who suffer from certain major diseases can apply for a
Distributions of the demographic variables were compared between the TCM and non-TCM groups using the chi-square test. The top ten prescription rates of CHF for treating colon cancer were presented in descriptive statistics. The most frequent diagnoses for the prescriptions of CHF were also displayed by frequency and percentage. All statistical analyses were performed with SAS (version 9.3; SAS Institute, Cary, NC).
2.1. Data sources
3. Results Twenty-three thousand and three hundred twenty-one patients were identified from the NHIRD who had surgery for colon cancer from 1 January 2004 to 31 December 2008. The
Newly identified colon cancer patient between 2004 and 2008 from NHIR Database of Taiwan (N=29890)
Newly identified colon cancer patient post operation (n=24303)
TCM user Prescription of Chinese herbal medicine within one year after the index date (n=4620)
Exclude patients without operation (n=5587)
Exclude patients who died within two month post operation (n=982)
Non-TCM user Without prescription of Chinese herbal medicine within one year after the index date (n=18701)
Fig. 1. Flow diagram of study subjects selection from the National Health Insurance Research Database during 2004–2008.
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baseline characteristics of the patients are summarized in Table 1. Of the 23,321patients, 4620 (19.8%) received TCM treatment, with
the highest prevalence being in those aged 60–69 years. More women than men received TCM treatment (51.4% vs. 48.6%). 3.1. Frequency distribution of TCM visits in the colon cancer patients
Table 1 Baseline characteristics of the newly identified colon cancer patients from 2004– 2008. Variables
Age, years Mean 7 SD 0–29 30–39 40–49 50–59 60–69 70–79 ≧80 Sex Women Men Urbanizationa 1 2 3 4 Family income (NTD) Dependent 1-15840 15841-28800 28801-45800 ≧45801 Area North Midland South East Occupation Public and military Industry Business Low income Others and retired
P-value
TCM use No (n¼ 18701)
Yes (n¼ 4620)
n
n
(%)
(%) o 0.001
66.2 7 13.6 136 (0.7) 536 (2.9) 1389 (7.4) 3061 (16.4) 3879 (20.7) 5110 (27.3) 4590 (24.5)
62.3 7 13.2 43 (0.9) 174 (3.8) 485 (10.5) 1038 (22.5) 1097 (23.7) 1015 (22.0) 768 (16.6)
3.2. Prescriptions of CHF for colon cancer patients
o 0.001 8233 10468
(44.0) (56.0)
2373 2247
(51.4) (48.6)
5408 5269 2860 4797
(29.5) (28.7) (15.6) (26.2)
1309 1339 714 1139
(29.1) (29.8) (15.9) (25.3)
5954 3840 6821 1272 814
(31.8) (20.5) (36.5) (6.8) (4.4)
1397 830 1705 430 258
(30.2) (18.0) (36.9) (9.3) (5.6)
9427 2827 5995 402
(50.5) (15.2) (32.1) (2.2)
1940 1019 1532 112
(42.2) (22.1) (33.3) (2.4)
Analysis of the TCM visits and related complaints among the colon cancer patients (according to systematic categories of ICD-9CM codes) for the 4620 TCM users showed that “symptoms, signs and ill-defined conditions” was the most common reason for using CHF (23.3%, n ¼2443), followed by diseases of the digestive system (16.9%, n ¼1770), and malignant neoplasms (16.6%, n ¼1736) (Table 2). Frequency distribution of the main complaint for colon cancer patients post-surgery are shown in Table 3. The greatest frequency distributions were general symptoms, acute nasopharyngitis, and disorders of stomach function.
Xiang-sha-liu-jun-zi-tang (7.1%) was the most commonly prescribed CHF for colon cancer patients post-surgery, followed by Bu-zhong-yi-qi-tang (4.3%), Jia-wei-xiao-yao-san (4.1%), and Shen Ling Bai Zhu San (3.7%) (Table 4).
0.445
3.3. Prescription of single Chinese herbs for colon cancer patients o 0.001
Hedyotis diffusa Willd (Bai Hua She She Cao, 5.1%) was the most commonly prescribed single Chinese herb, followed by Scutellaria barbata (Ban Zhi Lian, 4.8%), Caulis patholobi (Jixueteng, 1.8%), Salvia Miltiorrhiza Radix (Dan Shen, 1.7%) and Radix astragali (Huangqi, 1.7%) (Table 5).
o 0.001
4. Discussion o 0.001
1328 6658 3879 164 3905
(8.3) (41.8) (24.3) (1.0) (24.5)
406 1609 1096 28 827
(10.2) (40.6) (27.6) (0.7) (20.9)
NTD: New Taiwan Dollars. a Urbanization level: 1 indicates the highest level of urbanization and 4 the lowest.
To the best of our knowledge, this is the first study to use the NHIRD to evaluate the prescription patterns of CHF for colon cancer patients. A major strength of this research was that it is a nationwide population-based study, which includes all colon cancer patients from 2004 to 2008. Therefore the size of our study was larger than many clinic-based studies. TCM physicians prescribed a variety of herbal formulae for colon cancer patients postsurgery in Taiwan, however, the prescription patterns and reasons for the use of TCM have not been reported previously.
Table 2 Frequency distribution of ICD-9-CM codes with TCM visits among the colon cancer patients. Disease
ICD-9-CM
Frequency
(%)
Symptoms, signs and ill-defined conditions Diseases of the digestive system Malignant neoplasm Disease of the respiratory system Diseases of the musculoskeletal system and connective tissue Injury and poisoning Diseases of the circulatory system Diseases of the genitourinary system Diseases of skin and subcutaneous tissue Endocrine, nutritional and metabolic diseases and immunity disorders
780–799 520–579 140–208 460–466, 470–478, 480–519 710–739 800–999, E800–E999 390–459 580–629 680–709 240–289
2443 1770 1736 1302 1177 426 302 297 233 217
(23.3) (16.9) (16.6) (12.4) (11.2) (4.1) (2.9) (2.8) (2.2) (2.1)
Diseases of the sense organs Diseases of the nervous system (except meningitis) Mental disorders Infectious and parasitic diseases and late effects of infectious and parasitic diseases Other neoplasms Congenital anomalies Complications of pregnancy, childbirth and the puerperium Other reasons for contact with health services
360–389 323–359 290–319 001–139, 7713, 320–322 210–239 740–759 630–676 V00–V82
175 157 84 69 27 26 25 13
(1.7) (1.5) (0.8) (0.7) (0.3) (0.2) (0.2) (0.1)
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705
Table 3 Frequency distribution of the main complaint for colon cancer patients post-surgery (Top 15). Disease
ICD-9-CM
Freq.
(%)
List
ICD-9
Freq.
(%)
General symptoms
780
774
(7.4)
Acute nasopharyngitis Disorders of stomach function
460 536
591 572
(5.6) (5.5)
Other sleep disturbances Sleep disturbances, unspecified Dizziness and giddiness Others Acute nasopharyngitis Dyspepsia and other specified disorders of stomach function Unspecified functional disorder of stomach Disorders of function of stomach Achlorhydria
780.59 780.50 780.4x – 460.xx 536.8x
226 215 108 225 591 278
(29.2) (27.8) (14.0) (29.1) (100.0) (48.6)
536.9x 536.xx 536.0x
269 23 2
(47.0) (4.0) (0.3)
Symptoms involving respiratory system and other chest symptoms Functional digestive disorders, not elsewhere classified Other and unspecified disorders of back Symptoms involving head and neck Other disorders of soft tissues Symptoms involving digestive system Other and unspecified disorder of joint Malignant neoplasm of rectum, rectosigmoid junction, and anus Gastritis and duodenitis Symptoms involving cardiovascular system Diseases of the oral soft tissues, excluding lesions specific for gingiva and tongue
786 564 724 784 729 787 719 154 535 785 528
4.1. Most common reasons for use of CHF for colon cancer patients post-surgery “Symptoms, signs and ill-defined conditions” and diseases of the digestive system were the two most common reasons for using TCM in colon cancer patients post-surgery. This indicates that, besides colon cancer care, post-surgery, attention should be paid to the general post-operative condition of the patient including sleep disturbance, respiratory and dyspeptic symptoms.
545 427 346 331 308 301 262 230 212 133 130
(5.2) (4.1) (3.3) (3.2) (2.9) (2.9) (2.5) (2.2) (2.0) (1.3) (1.2)
Zhu San, the fourth most commonly prescribed formula has been reported to have an antacid effect (Wu et al., 2010). Recent studies have reported that the anorexia–cachexia syndrome is one of the most common and devastating symptoms in patients with advanced cancer (Lasheen and Walsh, 2010; Yavuzsen et al., 2009). In the current study, most of the herbs were used to harmonize gastrointestinal function. Some herbal ingredients such as Ginseng Radix, Astragali Radix have been reported to enhance immunomodulatory activities (Jang and Shin, 2010; Shin et al., 2002).
4.2. Commonly used CHF for colon cancer patients post-surgery
4.3. Commonly used single Chinese herbs for colon cancer patients
Xiang-sha-liu-jun-zi-tang was the most frequently prescribed formula for colon cancer patients post-surgery. TCM is widely used to relieve the dyspeptic symptoms of gastrointestinal disorders (Sadakane et al., 2011; Tominaga et al., 2012) and to improve spleen Qi deficiency which involves decreased digestion, absorption and immune system function issues (Zheng et al., 2014). An ancient Chinese book (Pi Wei Lun) explains that for spleen Qi deficiency was defined as abdominal distension, loss of appetite, diarrhea and other signs of poor digestion. Recently, some studies have reported that liu-jun-zi-tang can stimulate endogenous ghrelin secretion to increase food intake in rats with cancer, and that it may play an important role in cancer cachexia treatment (Fujitsuka et al., 2012; Takeda et al., 2012). Bu-zhong-yi-qi-tang is the second most commonly prescribed CHF for colon cancer patients. In the classical literature (Pi Wei Lun), Bu-zhong-yi-qi-tang is said to enhance spleen Qi deficiency, and improve fatigue and appetite. Several studies have shown that Bu-zhong-yi-qi-tang can prevent surgical stress-induced immunosuppression by maintaining natural killer cell activity (Kimura et al., 2008), restoring impaired immune function, and enhancing natural killer cell activity with a concomitant anti-tumor effect (Harada et al., 1995; Hirokawa and Utsuyama, 2002; Utsuyama et al., 2001). Jia-wei-xiao-yao-san, the third most commonly prescribed formula for colon cancer patients, has been used for the treatment of psychological (depression, anxiety) symptoms in post-menopausal women, (Chen et al., 2003; Park et al., 2007) and to alleviate sleep disturbances. (Terauchi et al., 2011) Shen Ling Bai
Hedyotis diffusa Willd (Bai Hua She She Cao) and Scutellaria barbata (Ban Zhi Lian) were the two most frequently prescribed single herbs for colon cancer patients. According to the classical TCM literature, Hedyotis diffusa Willd (Bai Hua She She Cao) and Scutellaria barbata (Ban Zhi Lian) are used to clear heat and remove toxicity (Based on TCM theory, tumors are usually caused by heatinduced toxicity and stagnation of Qi and blood). Recent studies have reported that Hedyotis diffusa Willd (Bai Hua She She Cao) (Meng et al., 2013; Tang et al., 2009) can inhibit tumor angiogenesis, (Lin et al., 2011) induce apoptosis, (Lin et al., 2010) and suppress cancer cell proliferation (Lin et al., 2012). Scutellaria barbata (Ban Zhi Lian) has been reported to inhibit cell apoptosis and cytotoxic effects, (Yin et al., 2004) and inhibit tumor angiogenesis (Wei et al., 2012). Another commonly prescribed single herb, Caulis patholobi (Jixueteng), has been reported to have antimetastatic activities (Kang et al., 2003) and to be able to induce tumor cell apoptosis. (Ha et al., 2004) Salvia Miltiorrhiza Radix (Dan Shen) has been reported to induce apoptosis,(Jung et al., 2013) inhibit angiogenesis, (Tsai et al., 2011) and modulate inflammatory and immune responses (Kang et al., 2000; Qin et al., 2010). The other commonly prescribed herbs were used for reducing general symptoms (such as psychological, sleep disturbance). 4.4. Limitations The present study has three limitations that should be highlighted. First, an accurate diagnosis of colon cancer could be
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Table 4 The top 10 CHF prescribed for colon cancer patients post-surgery. CHM (in Chinese)
Ingredients
Function
Xiang-sha-liu-jun-zi-tang
Vladimiria Radix (Mu Xiang), Villous Amomum (Sha Ren) , Pericarpium citrireticulatae (Chen Pi), Pinellia ternate (BanXia), Ginseng Radix (Ren Shen), Atractylodes macrocephala (Bai Zhu), Poria cocos (Fu Ling), Glycyrrhiza Radix (Gan Cao), Zingiberis Rhizoma (Gan Jiang), Zizyphus Fructus (Da Zao) Astragali Radixa (Huang Qi), Glycyrrhiza Radix (Gan Cao), Bu-zhong-yi-qi-tang (Harada et al., 1995; Hirokawa and Utsuyama, Ginseng Radix (Ren Shen) , Angelica sinensis Radix (Dong 2002; Kimura et al., 2008; Utsuyama Quai), Pericarpium citrireticulatae (Chen Pi), Cimicifuge et al., 2001) Rhizoma (Sheng Ma), Bupleurum Radix (Chai Hu), Atractylodes macrocephala (Bai Zhu) Zizyphus Fructus (Da Zao), Rhizoma zingiberis officinalis (Sheng Jiang) Jia-wei-xiao-yao-san (Chen et al., Cortex Moutan Radicis (Mu Dan Pi), Gardenia Fructus 2003) (Shan Zhi Zi), Bupleurum Radix (Chai Hu), Angelica sinensis Radix (Dong Quai), Paeonia lactiflora (Bai Shao), Atractylodes macrocephala (Bai Zhu), Poria cocos, (Fu Ling), Zingiberis Rhizoma (Gan Jiang), Glycyrrhiza Radix (Gan Cao), Menthae Herba ( Bo He)
Shen Ling Bai Zhu San
Ban Xia Xie Xin Tang
Gui-pi-tang
Ping Wei San
Gan Lu Yin
Bao He Wan
Zhen Ren Huo Ming Yin
Doiichos iabiab L (Bai bian dou), Ginseng Radixa (Ren Shen), Atractylodes macrocephala (Bai Zhu), Poria cocos (Fu Ling), Glycyrrhizae Radix (Gan Cao), Batatatis Rhizoma (Shan Yao), Loti Semen, Coicis Semen ( Lian Zi), Platycod Radix ( Jie Geng), Villous Amomum (Sha Ren), Zizyphus Fructus (Da Zao) Pinellia ternate (Ban xia), Radix Scutellariae Baicalensis (Huang Qin), Zingiberis Rhizoma (Gan Jiang), Ginseng Radix a (Ren Shen ), Glycyrrhiza Radix (Gan Cao), Coptidis Rhizoma (Huang Lian), Zizyphus Fructus (Da Zao) Angelica sinensis Radix (Dong Quai), Astragali Radixa (Huang Qi), Atractylodes macrocephala (Bai Zhu), Ginseng Radixa (Ren Shen) . Poria cocos, (Fu Ling), Glycyrrhizae Radix (Gan Cao), Longan Arillus (Long Yan Rou), Polygalae Radix (Yuan Zhi) , Vladimiria Radix (Mu Xiang ) , Zingiberis Rhizoma (Gan Jiang ) , Zizyphi Spinosi Semen (Suan Zao Ren), Zizyphus Fructus (Da Zao) Pericarpium citrireticulatae (Chen Pi), Magnoliae Cortex (Hou Po), Atractylodes Rhizoma (Cang Zhu), Glycyrrhiza Radix (Gan Cao), Zingiberis Rhizoma (Gan Jiang) , Zizyphus Fructus (Da Zao) Eriobotya japonica (Pi Pa ), Rehmannia Radix (fresh and boiled) (Sheng Di Huang /Shu Di Huang), Ophiopogon Radix (Mai Men Dong), Asparagus cochinchinensis (Tian Men Dong), Dendrobium Caulis (Shi Hu), Radix Scutellariae Baicalensis (Huang Qin), Artemisia capillaries (Yin Chen Hao) , Citri Immaturus Fructus (Zhi Ke), Glycyrrhiza Radix (Gan Cao) Fermentata Massa Medicata (Shen Qu), Crataegi Fructus (Shan Zha), Poria cocos (Fu Ling), Pinellia ternate (Ban Xia), Pericarpium citrireticulatae (Chen Pi), Forsythia Fructus (Lian Qiao), Raphani Semen (Lai Fu Zi) Lonicerae Flos (Jin Yin Hua), Pericarpium citrireticulatae (Chen Pi),, Angelica sinensis Radix (Dong Quai) , Ledebouriellae Radix (Fang Feng), Angelicae Dahuricae Radix (Bai Zhi), Glycyrrhiza Radix (Gan Cao), Liliaceae Roylei Bulbus (Triet Boi Mau), Trichosanthir Radix (Tian Hua Fen), Frankincense (Ru Xiang), Myrrha (Mo Yao), Gleditsia Sinensis Lam (Zao Jiao Ci), Manidis Squama (Chuan Shan Chia)
Frequency (%)
GIR stimulate ghrelin secretion to increase food 1379 intake. (Fujitsuka et al., 2012; Sadakane et al., 2011; Takeda et al., 2012; Tominaga et al., 2012)
(7.1)
GIR anti-tumor effect (Harada et al., 1995; Hirokawa and Utsuyama, 2002; Kimura et al., 2008; Utsuyama et al., 2001
823
(4.3)
Reductions of psychological symptoms in postmenopausal women
785
(4.1)
alleviated sleep disturbances (Chen et al., 2003; Park et al., 2007) Antacid effects (Wu et al., 2010)
713
(3.7)
GIR
653
(3.4)
Memory recovery responsible for the autonomic 470 imbalances (Yamada et al., 1994)
(2.4)
GIR (Riedlinger et al., 2001)
463
(2.4)
GIR Oral ulcer Gingivitis
395
(2.0)
GIR
361
(1.9)
Sore, welling abscess ,boil .clove sore
353
(1.8)
GIR: relieve dyspeptic symptoms of gastrointestinal disorders ; ICD-9-CM 153: Colon Cancer a
Immunomodulatory activities.
obtained from the NHIRD because the patients underwent surgery, however, we were unable to obtain any histopathological reports to verify the TNM stage of each patient (the Tumor Node Metastases staging system of the American Joint Committee on Cancer/Union for International Cancer Control). Therefore, we were unable to draw any firm conclusions about the relationship between the cancer survival rate and TCM use. Second, this study did not include Chinese herbal remedies or decoctions purchased
directly from herbal pharmacies, which may have led to an underestimation of the frequency of CHF use in colon cancer. However, because the NHI program covers most TCM prescriptions, the cost is generally less than the CHF sold in Taiwan markets, so this underestimation may be relatively small. Third, it is not possible to evaluate if the TCM treatments had specific beneficial effects as most published data are based on in vivo and in vitro measurements rather than clinical studies. Further studies
T.-H. Chao et al. / Journal of Ethnopharmacology 155 (2014) 702–708
707
Table 5 The top 10 single Chinese herbs prescribed for colon cancer patients post-surgery. Scientific name
CHM (in Chinese)
Reported activity
Frequency
(%)
Hedyotis diffusa willd Scutellaria barbata Caulis patholobi Salvia Miltiorrhiza Radix
Bai Hua She She Cao Ban Zhi Lian Jixueteng Dan Shen
1788 1672 634 604
(5.1) (4.8) (1.8) (1.7)
Radix astragali
Huangqi
602
(1.7)
Magnolia officinalis Herba taraxaci Poria Fermentata Massa Medicata Radix codonopisis
Houpo Pugongying Fuling Shen Qu Dangshen
Anti-angiogenesis , Anti-cancer activity (Lin et al., 2010; Lin et al., 2011; Lin et al., 2012) Anti-cancer activity anti- angiogenesis effects (Wei et al., 2012) Anti-metastatic activities (Kang et al., 2003) Anti cancer activity Anti-angiogenesis Modulation of Inflammatory and Immune Responses (Jung et al., 2013) Anti cancer activity Antioxidant effects Decrease chemotherapy side effects (Li et al., 2012; Liu et al., 2012) Antimicrobial and antioxidant activities (Chan et al., 2008)
591 564 561 550 505
(1.7) (1.6) (1.6) (1.6) (1.5)
Anti- tumor cell proliferation (Chen et al., 2010) Controlling the fermentation process. (Xu et al., 2013) Antitumor activity (Xu et al., 2012a)
ICD-9-CM 153: Colon Cancer.
are needed to evaluate any beneficial effects to patients which could identify leads for the development of new treatment strategies using TCM.
5. Conclusion This study identified the patterns of Chinese herbal medicine use for the treatment of colon cancer patients post-surgery in Taiwan. Chinese herbal products were most commonly used for immunological restoration, harmonizing gastrointestinal function. Some of the commonly used herb ingredients even have reported anti-tumor effects. However, further research is needed to investigate any beneficial effects which could help focus development of new treatment strategies based on TCM.
Contributions Te-Hsin Chao designed research/study, wrote the paper. Pin-Kuei Fu performed research/study. Chiung-Hung Chang performed research/study. Shih-Ni Chang performed research/study, analyzed the data Frank Chiahung Mao performed research/study. Ching-Heng Lin designed research/study, collated the data and reviewed/edited the manuscript.
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