Abstract
Background
Ginseng has been commonly used in Asian countries to promote longevity and health for >2000 years. Recent in vitro and in vivo studies, coupled with limited epidemiologic studies, have suggested that regular ginseng consumption may be related to lower cancer risk.
Objectives
We evaluated the association of ginseng consumption with risk of total and 15 site-specific cancers in a large cohort study conducted among Chinese women. Given the previous literature on ginseng consumption and cancer risk, we hypothesized that ginseng consumption might be associated with varying risks of cancer.
Methods
This study included 65,732 female participants (mean age: 52.2 years) of the Shanghai Women’s Health Study, an ongoing prospective cohort study. Baseline enrollment occurred between 1997 and 2000, and follow-up concluded on 31 December 2016. Ginseng use and covariates were assessed via an in-person interview conducted at the baseline recruitment. The cohort was followed for cancer incidence. Cox proportional hazard models were used to estimate HRs and 95% CIs for ginseng-cancer associations after adjusting for confounders.
Results
During a mean 14.7 years of follow-up, 5067 incident cancer cases were identified. Overall, regular ginseng use was mostly not associated with risk of any site-specific cancer, or all cancers combined. Short-term (<3 years) ginseng use was found to be significantly associated with increased risk of liver cancer (HR = 1.71; 95% CI: 1.04, 2.79; P = 0.035), whereas long-term (≥3 years) ginseng use was found to be associated with increased risk of thyroid cancer (HR = 1.40; 95% CI: 1.02, 1.91; P = 0.036). Long-term ginseng use was found to be significantly associated with decreased risk of lymphatic and hematopoietic tissue malignancy (HR = 0.67; 95% CI: 0.46, 0.98; P = 0.039) and non-Hodgkin’s lymphoma (HR = 0.57; 95% CI: 0.34, 0.97; P = 0.039).
Conclusions
This study provides suggestive evidence that ginseng consumption may be associated with risk of certain cancers.
Keywords: Asian, cancer, complementary medicine, ginseng, incidence, risk
Introduction
Ginseng is a herbal commonly used in east Asian countries for >2000 years to promote longevity and health of individuals [1]. Panax ginseng C.A. Meyer (Asian ginseng), known as white ginseng, and Panax quinquefolius L. (American ginseng) are the 2 most commonly used types of ginseng herbal remedies [1]. Treatment with ginseng, both in vivo and in vitro, has shown to improve biological activities and health benefits. Specifically, it may help enhance metabolism, improve nervous system activity and cognitive function, and also possess anti-inflammatory, antioxidative, and antidiabetic properties [2,3]. These studies suggested that ginseng consumption may reduce cancer risk.
There have been in vivo and in vitro findings of modulation of estrogen receptors by ginseng on human breast cancer cells, suggesting that ginseng could help reduce the risk of estrogen-dependent cancers [4]. Studies have shown that ginsenosides (specifically Rb1, Rg1, and Rh1), ginseng metabolites, could mediate steroid hormonal receptors, therefore affecting estrogen activities and estrogen receptors [[5], [6], [7], [8]]. There are a few in vitro studies that indicate ginseng in the form of ginseng seed oil treatment, although not as commonly used, could instead lead to apoptosis and inhibition of cancer cells, particularly breast cancer cells [9,10]. These studies suggested that potential estrogenic activity of ginseng could influence estrogen-dependent cancer and potentially increase cancer risk [11,12].
However, there are limited epidemiologic studies that have investigated the overall association between ginseng consumption and cancer risk. Yun et al. [13] found that ginseng consumption could have nonorgan-specific preventive associations with cancer. Another study by the same group found similar inverse associations for specific cancer, specifically, cancers of the oral cavity, pharynx, esophagus, stomach, colorectum, liver, pancreas, larynx, lung, and ovary [14]. Furthermore, a meta-analysis conducted in different populations; found a 16% significant lower risk of developing any cancer, suggesting that ginseng consumption may be associated with decreased cancer risk and that the effect may not be organ-specific (lung, gastric, colorectal, breast, and prostate) [15]. To our knowledge, there are only 9 studies analyzing the association between ginseng consumption and cancer risk, but these studies are limited by small sample size, including only a few cancer types, and typically have short follow-up periods. Therefore, the association between ginseng and cancer risk requires further investigation.
Given the previous literature on ginseng consumption and cancer risk, we hypothesized that ginseng consumption might be associated with varying risks of cancer. Using data collected in the Shanghai Women’s Health Study (SWHS), we analyzed the association between ginseng use (primarily American and white ginseng) and overall cancer and site-specific cancer risk.
Methods
Study population
SWHS is a population-based prospective cohort study. The details of this study have been published elsewhere [16]. In brief, the SWHS recruited 74,940 women between the ages of 40–70 y old, living in urban communities in Shanghai [16]. In-person baseline interviews with structured questionnaire were performed by trained interviewers between 1997 and 2000 to obtain information on demographic characteristics, lifestyle habits, personal and familial disease history, and physical activity level, with an overall response rate of 92.7% [16,17]. Anthropometric measurements were taken at the baseline interview. Information on the use of ginseng (ginseng root) or ginseng products was obtained with the questionnaire, based on self-report data [1,16]. Information collected included the type of ginseng used (white or red Asian ginseng, American ginseng, and ginseng products [extract, powder, tablet, capsule, etc.]), the duration (years) of use, the frequency (times/month) of use, and the reason for use [1,16]. Specifically, the question used to obtain this data is: during the past year, what is the amount you have taken (in liang (50 g) units for white, red, American, other, and liquid bottle ginseng)? Only a very small number of study participants consumed liquid (1.21%) and other types of ginseng (0.33%), and they were included in the exposed group for ever ginseng consumption. These individuals were excluded from the analysis by the amount and duration of ginseng use. Regular ginseng users were those who consumed ginseng products at least 5 times a year over the past 3 years, at time of survey. Written informed consent was obtained from all study participants. The study was approved by the institutional review boards of all participating institutions (Vanderbilt Institutional Review Board and Shanghai Cancer Institute Institutional Review Board).
Cancer ascertainment
Cancer information was obtained through the follow-up surveys and by linkage to the database of the Shanghai Cancer Registry and the Shanghai Vital Statistic Registry. The end date of the observation in this analysis was set as the diagnosis date of cancer cases, date of death for deceased cohort members, date of the last follow-up or 31 December 2016 for those who were still alive, half a year ahead of the last annual linkage with the Shanghai Death Registry, whichever came first. To classify the type of cancer, ICD 9th Revision code was used. The ICD-9 codes are the following: digestive cancer (150–159), stomach cancer (151), colorectum cancer (153–154), liver and intrahepatic bile duct cancer (155), gall bladder cancer (156), pancreatic cancer (157), lung cancer (162), breast cancer (174), corpus uteri cancer (182), ovarian cancer (183), urinary and bladder cancer (188), renal cancer (189), thyroid cancer (193), lymphatic and hematopoietic cancer (200–206), and non-Hodgkin’s lymphoma (202).
Statistical analysis
We excluded participants who had a prior history of cancer (n = 1598); stroke at baseline (n = 883, or were diagnosed with cancer or deceased within the first 3 years after study enrollment (n = 1714), along with person-years for the first 3 years of follow-up, to minimize potential influence of reverse causality on our study results. Specifically, we excluded individuals with stroke because it is a severe medical condition, and it is likely that patients with a prior diagnosis of stroke may take ginseng to help them recover. Therefore, including individuals who survived stroke attacks may result in potential bias because of reverse causation. Furthermore, only a small number of participants had a missing BMI value (n = 27); had a BMI of <18.5 kg/m2 (n = 2571); or ever smokers (n = 2113); or regular alcohol drinkers (n = 1678), and thus we also excluded these subjects to minimize potential confounding effects of these variables. Regular drinkers were defined as those who consumed alcohol (beer, wine, rice wine, and liquor) continuously at least 3 times per week, for >6 months. This refers to at least a 6-month period any time before the baseline survey. After excluding those participants, 65,732 women remained for the current analysis. We compared selected baseline characteristics of study participants by ginseng consumption status with the t-test for continuous variables and the chi-square test for categorical variables. The HRs and 95% CIs for the association of ginseng consumption with cancer risk were analyzed using Cox proportional hazards models using follow-up years as the underlying time scale. Total amount of ginseng consumption for both white and American ginseng combined was categorized as low use (<500 g of use over a year) and high use (≥500 g of use over a year). The duration of ginseng usage was categorized as short (<3 years) and long-term (≥3 years) use.
The Cox models were used to adjust for potential confounders, which included age at baseline survey, WHR, BMI (categorized as BMI <20, 20–24.99, 25–29.99, and ≥30 kg/m2), education (elementary school or less, middle school, high school graduate, and some college or higher); household income (<4000 yuan/(person × year); 4000–7999 yuan/(person × year); ≥8000 yuan/(person × year), exercise (continuous metabolic equivalent); diet quality (categorical quartiles and healthy dietary score); and history of CHD (yes or no); chronic liver disease (yes or no); chronic bronchitis (yes or no); gastritis (yes or no); cholelithiasis (yes or no); hypertension (yes or no); diabetes (yes or no); and lung tuberculosis (yes or no). The healthy dietary score was calculated based on 8 food groups—fruit, vegetables (excluding potatoes), dairy, fish and seafood, nuts and legumes, refined grains, red meat, and processed meat [18,19]. Although the methods are described elsewhere, in brief, the score was based on energy adjusted and sex-specific quintiles [18,19]. The first 5 food groups were given ascending values (1–5) and the last 3 groups were given descending values (5–1) [18,19]. The healthy dietary score was the sum of those values (ranging from 1–40), where a higher score indicated a better diet [18,19]. All statistical tests were 2-sided, and a P value of <0.05 was considered statistically significant [20]. We also used a P value of 0.003 (0.05/15) as the significance level to adjust for multiple testing as we evaluated the associations for 15 cancer types in this study.
Results
Demographic, lifestyle, and medical characteristics of the participants at baseline are presented in Table 1. The mean age for this cohort of 65,732 women was 52.2 years, with a mean follow-up time of 14.7 years. At baseline, 17,952 (27.3%) women reported using ginseng regularly and 47,780 (72.7%) women reported never using ginseng. Compared with never users, regular ginseng users were on average older, more educated, had a higher income, and exercised more regularly. However, regular ginseng users had a higher percentage of comorbidities, including hypertension and diabetes. American ginseng and white ginseng were the 2 types of most commonly used ginseng, accounting for ∼97.1% of total ginseng use.
TABLE 1.
Selected baseline characteristics of study participants by ginseng consumption status and cancer status, Shanghai Women's Health Study, 1996–2016
| Characteristics | Regular ginseng use |
Cancer |
||
|---|---|---|---|---|
| No | Yes | No | Yes | |
| Cohorts, n | 47,780 | 17,952 | 60,665 | 5067 |
| Age1, y | 51.1 (8.5) | 55.1 (9.1) | 51.9 (8.8) | 55.1 (9.2) |
| WHR1 | 0.810 (0.1) | 0.813 (0.1) | 0.811 (0.1) | 0.818 (0.1) |
| BMI1 (kg/m2) | 24.2 (3.2) | 24.2 (3.2) | 24.2 (3.2) | 24.7 (3.4) |
| Education2 | ||||
| No formal education | 8.3 | 12.6 | 9.2 | 13.3 |
| Elementary school or less | 8.8 | 14.1 | 10.0 | 13.3 |
| Middle school | 40.9 | 30.0 | 38.3 | 33.3 |
| High school graduate | 29.0 | 27.0 | 28.7 | 26.0 |
| Some college and higher | 13.0 | 16.3 | 13.9 | 14.1 |
| Household income2 | ||||
| Low | 15.7 | 14.8 | 15.3 | 16.8 |
| Middle | 75.1 | 73.8 | 74.7 | 74.9 |
| High | 9.2 | 11.4 | 9.9 | 8.3 |
| Currently married2 | 90.3 | 86.8 | 89.5 | 88.0 |
| Ever diagnosed with comorbidity2,3 | 49.6 | 62.1 | 52.5 | 59.3 |
| Ever diagnosed with hypertension2 | 21.3 | 28.4 | 22.8 | 29.3 |
| Ever diagnosed with diabetes2 | 3.4 | 5.9 | 4.0 | 5.6 |
| Regularly consumed vitamin supplements2 | 5.6 | 11.0 | 7.1 | 6.7 |
| Regularly consumed calcium supplements2 | 16.3 | 26.5 | 19.0 | 19.9 |
| Leisure-time physical activity (LTPA)2 | 30.5 | 45.9 | 34.3 | 39.5 |
Leisure-time physical activity (LTPA): physical activities that are performed at the discretion of the individual and are not essential daily activities.
Values are mean ± SD
Values are a percentage value.
Comorbidity includes a diagnosis of any of the following: bronchitis, hepatitis, heart, asthma, gastritis, pancreatitis, cholelithiasis, hypertension, diabetes, and lung tuberculosis.
Table 2 presented the associations between regular ginseng use and site-specific cancer risk in all participants and by type and duration of ginseng use. With a few exceptions, most of the HRs of cancer associated with regular ginseng use were not statistically significant. Short-term use of ginseng was found to be significantly associated with increased risk of liver cancer (HR = 1.71; 95% CI: 1.04, 2.79; P = 0.035), whereas long-term use of ginseng was found to be significantly associated with increased risk of thyroid cancer (HR = 1.40; 95% CI: 1.02, 1.91; P = 0.036), after adjustment for covariates. Additionally, long-term use of ginseng was also found to be significantly associated with decreased risk of lymphatic cancer (HR = 0.67; 95% CI: 0.46, 0.98; P = 0.039) and non-Hodgkin’s lymphoma (HR = 0.57; 95% CI: 0.34, 0.97; P = 0.039), after adjustment for covariates. We further excluded those with >5 years of follow-up and adjusted for baseline liver disease, to assess for residual confounding and found no association for liver cancer; however, the association remained for thyroid cancer. Similar associations were found when analyses were restricted to individuals who consumed ginseng for enhanced well-being (Supplemental Table 1). Bonferroni-adjusted P values were also calculated and presented for the nominally significant (<0.05) associations between ginseng use and cancer risk. However, none of these associations remain statistically significant according to the Bonferroni-adjusted P values (footnotes of Table 2).
TABLE 2.
Association of cancer incidence with duration of ginseng consumption, Shanghai Women's Health Study, 1996–2016
| Ginseng consumption2 (ICD-9 code) | Adjusted HR (95% CI)1 among all subjects |
|||
|---|---|---|---|---|
| Cases, n | Total users | Short-term users (< 3 years) | Long-term users (≥3 years) | |
| All cancer | 5067 | |||
| Never | 3497 | 1.00 | 1.00 | 1.00 |
| Ever | 1570 | 0.99 (0.93, 1.05) | 1.00 (0.91, 1.11) | 0.99 (0.92, 1.06) |
| American/white ginseng | 1476 | 0.99 (0.93, 1.06) | 1.00 (0.90, 1.14) | 0.99 (0.92, 1.06) |
| Digestive (150-159) | 1789 | |||
| Never | 1191 | 1.00 | 1.00 | 1.00 |
| Ever | 598 | 0.99 (0.89, 1.09) | 1.09 (0.92, 1.29) | 0.96 (0.85, 1.07) |
| American/white ginseng | 566 | 1.00 (0.90, 1.11) | 1.10 (0.93, 1.30) | 0.96 (0.86, 1.08) |
| Stomach (151) | 350 | |||
| Never | 238 | 1.00 | 1.00 | 1.00 |
| Ever | 112 | 0.94 (0.74, 1.18) | 0.92 (0.62, 1.37) | 0.94 (0.73, 1.21) |
| American/white ginseng | 104 | 0.92 (0.73, 1.16) | 0.94 (0.63, 1.41) | 0.92 (0.71, 1.20) |
| Colorectum (153-154) | 875 | |||
| Never | 588 | 1.00 | 1.00 | 1.00 |
| Ever | 287 | 0.99 (0.86, 1.15) | 1.11 (0.88, 1.41) | 0.95 (0.80, 1.11) |
| American/white ginseng | 272 | 1.01 (0.87, 1.17) | 1.14 (0.89, 1.45) | 0.95 (0.80, 1.12) |
| Liver and intrahepatic bile duct (155) | 159 | |||
| Never | 93 | 1.00 | 1.00 | 1.00 |
| Ever | 66 | 1.34 (0.97, 1.86) | 1.76 (1.10, 2.82) | 1.21 (0.84, 1.74) |
| American/white ginseng | 62 | 1.33 (0.95, 1.85) | 1.71 (1.04, 2.79)3 | 1.25 (0.86, 1.81) |
| Gallbladder (156) | 138 | |||
| Never | 94 | 1.00 | 1.00 | 1.00 |
| Ever | 44 | 0.86 (0.60, 1.22) | 0.75 (0.38, 1.48) | 0.92 (0.62, 1.36) |
| American/white ginseng | 41 | 0.85 (0.59, 1.22) | 0.62 (0.29, 1.32) | 0.96 (0.64, 1.43) |
| Pancreatic (157) | 194 | |||
| Never | 129 | 1.00 | 1.00 | 1.00 |
| Ever | 65 | 0.90 (0.67, 1.22) | 1.23 (0.77, 1.97) | 0.82 (0.58, 1.16) |
| American/white ginseng | 63 | 0.95 (0.70, 1.28) | 1.30 (0.81, 2.08) | 0.83 (0.59, 1.18) |
| Lung (162) | 661 | |||
| Never | 434 | 1.00 | 1.00 | 1.00 |
| Ever | 227 | 1.04 (0.88, 1.23) | 1.08 (0.81, 1.42) | 1.02 (0.85, 1.22) |
| American/white ginseng | 210 | 1.01 (0.85, 1.20) | 1.08 (0.81, 1.44) | 0.99 (0.82, 1.20) |
| Breasts (174) | 1137 | |||
| Never | 830 | 1.00 | 1.00 | 1.00 |
| Ever | 307 | 0.95 (0.83, 1.09) | 0.91 (0.72, 1.15) | 0.97 (0.83, 1.13) |
| American/white ginseng | 292 | 0.97 (0.85, 1.11) | 0.91 (0.71, 1.16) | 0.99 (0.85, 1.16) |
| Corpus uteri (182) | 224 | |||
| Never | 167 | 1.00 | 1.00 | 1.00 |
| Ever | 57 | 0.99 (0.72, 1.35) | 0.67 (0.36, 1.25) | 1.13 (0.80, 1.58) |
| American/white ginseng | 55 | 1.03 (0.75, 1.41) | 0.65 (0.34, 1.24) | 1.17 (0.83, 1.66) |
| Ovarian (183) | 165 | |||
| Never | 126 | 1.00 | 1.00 | 1.00 |
| Ever | 39 | 0.81 (0.56, 1.16) | 0.83 (0.45, 1.53) | 0.81 (0.54, 1.23) |
| American/white ginseng | 37 | 0.82 (0.57, 1.19) | 0.87 (0.47, 1.61) | 0.81 (0.53, 1.23) |
| Urinary and bladders (188) | 65 | |||
| Never | 44 | 1.00 | 1.00 | 1.00 |
| Ever | 21 | 0.94 (0.56, 1.59) | 0.74 (0.27, 2.08) | 1.02 (0.57, 1.81) |
| American/white ginseng | 21 | 1.04 (0.62, 1.76) | 0.79 (0.28, 2.20) | 1.09 (0.61, 1.93) |
| Renal (189) | 127 | |||
| Never | 80 | 1.00 | 1.00 | 1.00 |
| Ever | 47 | 1.13 (0.78, 1.62) | 0.93 (0.46, 1.87) | 1.21 (0.81, 1.79) |
| American/white ginseng | 42 | 1.03 (0.71, 1.50) | 0.77 (0.35, 1.67) | 1.19 (0.79, 1.79) |
| Thyroid (193) | 264 | |||
| Never | 188 | 1.00 | 1.00 | 1.00 |
| Ever | 76 | 1.20 (0.91, 1.59) | 0.76 (0.44, 1.30) | 1.41 (1.04, 1.91) |
| American/white ginseng | 70 | 1.17 (0.88, 1.55) | 0.75 (0.42, 1.31) | 1.40 (1.02, 1.91)3 |
| Lymphatic and hematopoietic tissue (200-206) | 201 | |||
| Never | 145 | 1.00 | 1.00 | 1.00 |
| Ever | 56 | 0.78 (0.56, 1.08) | 1.15 (0.71, 1.84) | 0.64 (0.44, 0.94) |
| American/white ginseng | 54 | 0.81 (0.59, 1.13) | 1.15 (0.71, 1.87) | 0.67 (0.46, 0.98)3 |
| Non-Hodgkin's lymphoma (202) | 110 | |||
| Never | 81 | 1.00 | 1.00 | 1.00 |
| Ever | 29 | 0.67 (0.43, 1.04) | 1.00 (0.52, 1.94) | 0.57 (0.34, 0.95) |
| American/white ginseng | 28 | 0.70 (0.45, 1.10) | 1.06 (0.55, 2.06) | 0.57 (0.34, 0.97)3 |
| Other | 1419 | |||
| Never | 956 | 1.00 | 1.00 | 1.00 |
| Ever | 463 | 1.01 (0.90, 1.13) | 1.12 (0.93, 1.35) | 0.96 (0.84, 1.09) |
| American/white ginseng | 434 | 1.00 (0.89, 1.13) | 1.11 (0.92, 1.35) | 0.96 (0.84, 1.09) |
PAMET, physical activity metabolic equivalent.
Adjusted for age, income, education, exercise, PAMET, BMI, WHR, diet, CHD, chronic liver disease, chronic bronchitis, gastritis, cholelithiasis, hypertension, diabetes, and lung tuberculosis.
Ever ginseng users are individuals who consumed any type of ginseng regularly (regular ginseng users).
P = 0.04, Bonferroni-adjusted P value = 0.60.
We further analyzed the association of the amount of ginseng use for either American or White ginseng, the 2 major types of ginsengs (Table 3 and Supplemental Table 2). However, no significant results were found for any site-specific cancer.
TABLE 3.
Association of cancer incidence with the amount of white/American ginseng consumption, Shanghai Women's Health Study, 1996–2016
| Ginseng consumption | Adjusted HR (95% CI)1 among all subjects |
||
|---|---|---|---|
| Cases, n2 | <500g | ≥500g | |
| All cancer | |||
| Cases | 3497 | 521 | 955 |
| American/white ginseng | 1476 | 1.02 (0.93, 1.12) | 0.98 (0.91, 1.05) |
| Digestive | |||
| Cases | 1191 | 217 | 349 |
| American/white ginseng | 566 | 1.09 (0.94, 1.26) | 0.94 (0.83, 1.07) |
| Stomach | |||
| Cases | 238 | 38 | 66 |
| American/white ginseng | 104 | 0.96 (0.68, 1.36) | 0.90 (0.68, 1.19) |
| Colorectum | |||
| Cases | 588 | 110 | 162 |
| American/white ginseng | 272 | 1.18 (0.95, 1.44) | 0.91 (0.76, 1.09) |
| Liver and intrahepatic bile duct | |||
| Cases | 93 | 20 | 42 |
| American/white ginseng | 62 | 1.22 (0.75, 1.99) | 1.43 (0.98, 2.09) |
| Gallbladder | |||
| Cases | 94 | 20 | 21 |
| American/white ginseng | 41 | 1.15 (0.71, 1.86) | 0.68 (0.43, 1.10) |
| Pancreatic | |||
| Cases | 129 | 23 | 40 |
| American/white ginseng | 63 | 0.98 (0.63, 1.53) | 0.90 (0.63, 1.30) |
| Lung | 661 | ||
| Cases | 434 | 71 | 139 |
| American/white ginseng | 210 | 1.03 (0.80, 1.33) | 1.02 (0.84, 1.25) |
| Breast | |||
| Cases | 830 | 95 | 197 |
| American/white ginseng | 292 | 0.95 (0.77, 1.17) | 0.97 (0.83, 1.14) |
| Corpus uteri | |||
| Cases | 167 | 20 | 35 |
| American/white ginseng | 55 | 1.05 (0.65, 1.68) | 1.00 (0.69, 1.45) |
| Ovarian | |||
| Cases | 126 | 14 | 23 |
| American/white ginseng | 37 | 0.89 (0.51, 1.56) | 0.77 (0.49, 1.20) |
| Urinary and bladder | |||
| Cases | 44 | 7 | 14 |
| American/white ginseng | 21 | 0.99 (0.45, 2.22) | 1.01 (0.55, 1.85) |
| Renal | |||
| Cases | 80 | 16 | 26 |
| American/white ginseng | 42 | 1.19 (0.69, 2.04) | 1.02 (0.65, 1.60) |
| Thyroid | |||
| Cases | 188 | 29 | 41 |
| American/white ginseng | 70 | 1.45 (0.97, 2.17) | 1.05 (0.75, 1.49) |
| Lymphatic and hematopoietic tissue | |||
| Cases | 145 | 15 | 39 |
| American/white ginseng | 54 | 0.65 (0.38, 1.11) | 0.88 (0.60, 1.27) |
| Non-Hodgkin’s lymphoma | |||
| Never | 81 | 8 | 20 |
| American/white ginseng | 28 | 0.61 (0.30, 1.26) | 0.73 (0.44, 1.22) |
| Other | |||
| Cases | 956 | 155 | 279 |
| American/white ginseng | 434 | 1.03 (0.87, 1.23) | 0.99 (0.86, 1.13) |
PAMET, physical activity metabolic equivalent.
Adjusted for age, income, education, exercise PAMET, BMI, WHR, diet, CHD, chronic liver disease, chronic bronchitis, gastritis, cholelithiasis, hypertension, diabetes, and lung tuberculosis.
Reference group is never any ginseng consumption.
Discussion
In this large prospective cohort study with a long-term follow-up, we found that regular ginseng use was in general not associated with site-specific cancer or all cancers combined. We found nominal significantly increased risks of liver and thyroid cancer associated with ginseng intake. We also found a nominal significantly decreased risks of lymphatic and hematopoietic tissue cancer and non-Hodgkin’s lymphoma associated with ginseng intake. However, none of these associations were statistically significant after adjusting for multiple testing.
There have been 5 previously conducted cohort studies using either Korean, Chinese, or American populations to assess ginseng consumption in a similar method [13,15,[21], [22], [23], [24]]. The results from these studies, particularly those in the Korean populations, suggest use of Panax ginseng could have nonorgan-specific preventive effects against cancer [13,15]. Additionally, 3 case-control studies have also shown similar results, but there could be bias because of selection [15,[25], [26], [27]]. Lastly, 1 randomized, double-blinded, placebo-controlled trial has also been performed in 4 hospitals in China, which administered red ginseng extract powder orally to each patient per week for a span of 3 years and included 8 years of follow-up [15,28]. The results from this study suggest administration of red ginseng extract powder could help prevent the incidence of nonorgan-specific human cancer, particularly in male patients, highlighting that gender associations could differ [15,28]. However, it remains unclear why our results differ from those reported in these other cohort, case-control, and randomized control trial studies, particularly considering the types of ginsengs used were similar between cohorts [15]. One possible explanation could be that the previous studies used control groups, which were selected among individuals who were seeking medical care in hospital, which could lead to lower risk ratios because the prevalence of ginseng use could be higher among these participants than controls drawn from general population [[13], [14], [15],21]. Recently, we showed that regular ginseng consumption was associated with a reduced all-cause and major cause-specific mortality in the SWHS [29]. This inverse association was primarily limited to those who used ginseng for enhanced well-being. It is possible that ginseng consumption could help to reduce mortality but has no major protective effects on cancer.
Furthermore, although we adjusted for chronic liver disease, another possible explanation for the association between ginseng consumption and increased liver cancer risk could be that liver cancer is often preceded by a long course of chronic liver disease [30]. There could be potential reverse causation between ginseng consumption and liver cancer because some individuals may use ginseng to help with chronic liver disease, which could confound the effect of ginseng on liver cancer risk. Additionally, the increased risk of thyroid cancer could be because of detection bias because the distribution of socioeconomic indicators suggests that individuals with thyroid cancer often tend to reside in areas of higher socioeconomic status [31,32]. These individuals may have increased access to health care facilities and insurance coverage, enhancing the detection of thyroid cancer cases [31,32]. To address these concerns, we conducted a sensitivity analysis further excluding cases diagnosed within 5 years of follow-up and found that the significant results from only excluding those with <3 years of follow-up could perhaps have been because of reverse causation. We performed an additional sensitivity analysis without excluding individuals who were underweight, smokers, or drinkers, and found similar results and trends. However only liver cancer and thyroid cancer had significant results for short-term ever ginseng consumption and long-term American/White ginseng consumption, respectively, suggesting that there may be some residual selection bias.
Our findings for associations between ginseng consumption and decreased risk of lymphatic and hematopoietic tissue cancer as well as non-Hodgkin’s lymphoma are interesting, particularly given the immune regulating effect reported for ginseng [33]. Previous studies have suggested that ginseng could help maintain homeostasis and enhance the resistance of the immune system by modulating the function of macrophages, NK cells, dendritic cells, T cells, and B cells [[33], [34], [35]]. These properties of ginseng could help reduce the risk of lymphatic and hematopoietic tissue cancer and non-Hodgkin’s lymphoma. However, more future research is needed to further assess these findings and determine association of ginseng consumption and cancer risk.
The strengths of this study include a prospective cohort design with a large sample size and a high participation rate and detailed assessments of ginseng use history. The prospective design and high response rates of our study decreased the information bias of ginseng use and other covariates. The detailed information collected in this study allowed us to perform a thorough analyses of the association of various levels of ginseng consumption with cancer risk with adequate control for potential confounding. However, a major limitation of this study is that ginseng consumption was self-reported, which could introduce potential misclassification, resulting in errors in the true amount and duration of ginseng consumption. These errors should be mostly nondifferential because of the prospective design, leading to attenuation of the true association between the factors. We asked participants to report the amount and the duration of ginseng consumption so that we could evaluate potential dose-response relation. Ginseng is considered to be a supplement and not a primary food, hence similar to other dietary validation studies, it was not included in the dietary validation study [29,36]. For these reasons, we cannot provide any specific data regarding the accuracy of ginseng consumption [29]. Comparable to tea drinking, although, it should be simpler, thus, more accurate to measure ginseng consumptions than dietary intakes [29]. We also obtained ginseng intake from a cohort study of breast cancer survivors to demonstrate how ginseng consumption was associated with an improved quality of life and survival [1]. Results from these studies support the validity of ginseng intake data obtained in our study. Furthermore, we also found that ginseng users were more likely to have a high income, a better education, more existing comorbidity conditions, and exercised more regularly than nonginseng users. It is possible that high socioeconomic status, healthy lifestyles, and poor health among ginseng users may have confounded the association. Although we have carefully adjusted for socioeconomic status and a wide range of lifestyle risk factors in our analysis, residual confounding may still exist. Lastly, we did not exclude women (n = 5531) who reported a diagnosis or a suspected diagnosis of coronary heart disease given that the large majority of these self-reported cases were likely to have a suspected angina. We did not have detailed information to distinguish between suspected angina and MI in this study. In our analysis, we adjust for a prior history of self-reported CHD. To further reduce bias resulting from these errors, we excluded participants who had prior major chronic diseases and were diagnosed with cancer within first 3 years of follow-up. In addition, we analyzed the associations of cancer risk with not only total ginseng but also with individual ginseng type, the amount, and the duration of ginseng use. Using various methods to assess ginseng consumption would improve the reproducibility and validity of our analysis.
In conclusion, we found no evidence to support an association of regular ginseng consumption with risk of all cancers combined. However, regular ginseng use might be associated with an elevated risk of liver and thyroid cancers but reduced risk of lymphatic and hematopoietic tissue malignancy and non-Hodgkin’s lymphoma cancers. These findings warrant further investigation.
Acknowledgments
We thank all study participants and SWHS research team members for their contribution to the study. Also, we would like to thank Rachel Mullen in the Division of Epidemiology, Vanderbilt University Medical Center, for assistance with preparation and editing of the manuscript.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.tjnut.2023.02.032.
Author contribution
The authors’ responsibilities were as follows – PP, WZ: designed research; WZ, XS, YG: conducted research; PP, WW: analyzed data and performed statistical analysis; PP, WW, WZ: wrote paper; PP, WZ: primary responsibility for the final content; XS, YG: assisted with critical review of the manuscript for important intellectual content; and all authors: contributed to the preparation and revision of the manuscript and approved the manuscript submission. All authors of this paper fulfill authorship criteria and have read and approved the final version of the manuscript.
Data Availability
Data described in the manuscript, code book, and analytic code will be made available upon request pending (application and approval).
Funding
This research leading to these results has received funding from the National Institutes of Health (UM1 CA182910) and Anne Potter Wilson Chair endowment funds to Vanderbilt University.
Author disclosures
PP, WW, HC, Y-TG, X-OS, and WZ, no conflicts of interest.
Appendix A. Supplementary data
The following is the Supplementary data to this article:
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Supplementary Materials
Data Availability Statement
Data described in the manuscript, code book, and analytic code will be made available upon request pending (application and approval).