Introduction

It is proved that most colorectal cancers were developed from colorectal adenoma and people of colorectal adenoma history were verified to be and recognized as a high-risk population of colorectal cancer [1-5].

However, there are no effective drugs to prevent adenoma progressing to cancer in colorectum. Colonoscopy can remove adenoma completely but it can’t prevent recurrence of adenoma and new appearance in colorectum that may progress to be malignant at later.

In the last century, a promising agent, Panax ginseng was confirmed of anti-carcinogenic properties in animal models [6-9]. Ginsenoside Rg3 (Rg3), a trace tetracyclic triterpenoid saponin, is extracted from ginseng and shown to have anticancer activity against severa types of cancers [10], later a significant anti-carcinogenic effect was exerted by 6-year-old red ginseng powder or extract [11]. In human epidemiology research by casecontrol study, reducing the risk of development of all cancers was reported and a dose-dependent effect was also observed in smoking-related cancers [12]. The red ginseng was confirmed again having a non-organ- specific preventive effect against cancer in two cohort studies [11-13,14]. and the red ginseng was found to have positive inhibition on colorectal cancer cells and patients [15-16]. Based on these finding, we conducted a random control trial to observe whether or not the red ginseng having the preventive effect of cancer occurrence on those of colorectal adenoma history

methods

Study design and data collection

A randomized, double-blind, placebo-controlled study was carried out in Haining city, Zhejiang province, China., in July 1997. A total of 577 permanent residents (aged 40-70 years old) of colorectal adenoma history (colorectal adenoma was diagnosed by colonoscopy and confirmed by pathology in the past 10 years) was selected as subjects and randomly divided into ginseng and placebo groups by table of random numbers. Those of family history of cancer and colorectal adenoma, and with personal cancer history were excluded. In the total 576 participants, four participants refused to take any capsules in two weeks later, therefore, 572 participants joined this study and participated in the research and were voluntarily signed an informed consent form. Capsules containing the red ginseng extract powder and placebo prepared by Korea Ginseng Corp, Seoul were purchased and information about the capsules content was not known by the field study team and research designer until all of the result data were collected in 2012. All of the participants were numbered firstly, then the capsules were distributed to them by randomization of using a table of randomly assorted digits. The study consisted of 3 years of intervention (1997 - 2000) and 12 years of follow-up (2001-2012). Each participant was administered with four capsules of ginseng extract powder or placebo(1g) every week from July 1997 to June 2000 with the delivery of one-month capsules. Participants were asked to complete questionnaires by face-to-face interview about these contents: demographic characteristics, occupation, smoking and alcohol drinking patterns, history of diseases, and history of ginseng intake at the beginning of the study, and were also asked to take any kinds of ginseng during the periods of 1997-2000. The participants were followed up for cancer occurrences and deaths for 12 years (from January ,2001 to December 30, 2012) after 3 years of intervention by telephone every year, and all new cancer cases were verified again through the local cancer registration system. At the end of this study, 12 years from the beginning of this trial, the identities of individual subjects were opened and confirmed. and 285 subjects were randomized to the placebo group whereas 287 to red ginseng group.

Statistical Analysis

The Relative Risks (RRs) were estimated by logistic regression models. Age distribution and duration of red ginseng intake were using t-test. The rate in both groups was analyzed by x².

Results

Sample characteristics

Of the 572 participants, 287 subjects took red ginseng whereas 285 subjects took a placebo. The sex, age, BMI (Body Mass Index), history of smoking, alcohol drinking and ginseng intake distribution were similar between the two groups, and the duration of capsule intake was also of no statistical difference in both groups (Table1).

Overall cancer occurrence observed in two groups

There were 40 cancer cases observed in both two groups in the following-up years, and 5 verse 2 colorectal cancer cases in placebo and red ginseng groups respectively whereas 15 and 18 non-colorectal cancer cases in each group (Table 2).

In the 40 cancers, there were 11 lung cancer cases(27.5%), 7 colorectal cancer cases(17.5%), 5 liver cancer cases(12.5%) and stomach cancer cases(12.5%), 3 esophageal cancer cases(7.5%), 2 pancreatic cancer cases(5.0%) and mouth cancer cases(5.0%), and 1 each case for gallbladder cancer case (2.5%), urinary bladder cancer(2.5%), peritoneal interstitial tumor case (2.5%), ovarian cancer case (2.5%) and bone marrow cancer case (2.5%) (Table 3).

Comparison of the cancer occurrence in two groups

There are 5 stomach cancer cases observed in the red ginseng group and the stomach cancer incidence rate is higher than which in the placebo group (p=0.047, Table 3).

The red ginseng decreased the risk for development of cancer only in women (RR=0.36, 95%CI, 0.07-1.85) and in the duration red ginseng intake of 53-104 weeks (RR=0.25, 95%CI, 0.44-1.43) compared to placebo group, whereas the RR is little higher in red ginseng group in man and in the longest duration of red ginseng intake (105-156 weeks), but all of these difference is of no statistical significance (Table 4 ).

*The p values of Fisher exact x² are calculated between colorectal cancer and Non-colorectal cancer groups by sex.

*The p values of Fisher exact x² are calculated between the placebo and red ginseng groups (**p values of Pearson x²).

The colorectal cancer prevalence in the red ginseng group (2/287) is 2.5 times lower than that in the placebo group (5/285), however, the difference of distribution of cancer type in two groups was of no statistical significance. The cumulative morbidity risk was a little higher in the placebo group than which in the red ginseng group from 2002 to 2011 and became almost the same level in 2012 in both two groups (Table 4 and Figure 1).

Discussion

Colorectal cancer is increasing quickly in China and will be a great burden to China government and patients. Except for screening, there are of no effective methods to reduce colorectal cancer mortality.

From previous studies, patients perceived to be at increased risk of colorectal neoplasm after adenoma removal are recommended surveillance colonoscopy [2-4]. Cottet V., reported that the 10-year cumulative probabilities of colorectal cancer were 2.05% (95% CI 1.14% to 3.64%) and 6.22% (95% CI 4.26% to 9.02%) in those of non-advanced adenoma and advanced adenoma history respectively [17]. CRC mortality of individuals who had adenoma removed was 237/10,000 in Sweden and Norwegian and 208/10,000 in UK [18,19], which is much higher than the general population.

From 2019, the China government issue “health China action” which including preventing cancer effectively at an early stage. Colorectal adenoma especially advanced adenoma is of high probability to develop to cancer; therefore, colorectal adenoma is the target disease of the prevention of colorectal cancer, and we defined individuals who had adenoma removed as the highrisk population of colorectal cancer and the target prevention population.

Up till now, there are no effective methods and drugs to prevent the colorectal adenoma except colonoscopy of the adenoma. Colonoscopy can remove most colorectal adenoma but it cannot prevent its recurrence and appearance. If there is a drug that can inhibit the occurrence and recurrence of colorectal adenoma, the colorectal cancer incidence will decrease rapidly and the burden from colorectal cancer will also decline. The Panix ginseng is expected to have the preventive effect of colorectal adenoma to cancer for the animal experiments and some epidemiological studies [20-22].

However, there is no obvious cancer-preventive effects observed in this study. The sex and age distribution were of no difference between red ginseng and placebo groups. There are 20 new cancer cases in the red ginseng group (287 participants, who taking ginseng) and 20 new cancer cases in the placebo group (285 participants, who took placebo) respectively in the next 14 following-up years, and the accumulated cancer incidence is almost the same in two groups (Table1). There were 5 verse 2 colorectal cancer cases in placebo and red ginseng groups respectively whereas 15 and 18 non-colorectal cancer cases in each group (Table 2).

There are 5 stomach cancer cases observed in the red ginseng group and the stomach cancer incidence rate in the red ginseng group is little higher than which in the placebo group with a boundary level of significance (p=0.047) (Table 3).

Other types of cancer cases distribution between the two groups were of no significance. This result implies that the longterm taking of red ginseng having the probability of increased risk of suffering stomach cancer in Chinese of colorectal adenoma history. However, in our previous RCT results, there was no difference of stomach cancer prevalence in Chinese of chronic atrophic gastritis patients in the red ginseng and placebo group [11]. The accumulative morbidity curves of all cancers in the red ginseng group was observed a little lower than which in the placebo group after taking ginseng for two or three years from 2002 through 2011 and became almost the same level in 2012 in both two groups (Table 4 and figure 1), which means that the red ginseng taking may decrease the risk of suffering cancer and the preventive effects will vanish in 10 years. For this study sample is not large enough, the decease of the risk of suffering cancer needs more evidence such as more larger sample random trial results to support it in the future.

Conclusion

In this study, the accumulative morbidity curves of all cancers in the red ginseng group was observed a little lower than which in the placebo group from 2002 through 2012, and the stomach cancer incidence rate in the red ginseng group is little higher than which in the placebo group with a boundary level of significance. the results hint that the red ginseng extract powder may have some preventive effects on the incidence of cancers in Chinese of colorectal adenoma history except stomach cancer, however, this result is not enough to confirm the preventive effects and more sufficient proofs from more large samples results are needed in the future.

Conflicts of Interest

This study was also approved by the ethics committee of the Second Affiliated Hospital, College of Medicine, Zhejiang University in 1998. The authors declare that they have no competing interests.

Acknowledgments

This study was supported by the Research on Prevention and Control of Major Chronic Noncommunicable Diseases under National Key R&D Program (2016YFC1302803), and the Zhejiang Medical and Health Science and Technology Project (2013KYA091). These funding bodies were independent of the study design, data collection, interpretation and manuscript writing. The authors thank Taik-Koo Yun ( M.D., Ph.D., Korea Institute of Cancer Chemoprevention, 566-30 Yeunnam Dong, Mapo Ku, Seoul 121-869, Republic of Korea, E-mail: tkyun@nuri. net) and his colleagues for his support and design for this study, and Dr. Xi-yong Liu for his work in the beginning of this study, we also thank the doctors( Wei-dong ,Li, Chun-fu, Yang, Gao-fei, Shen) and nurses of the local hospitals in the study population, in Haining county.

References

1. Gupta S, Jacobs ET, Baron JA, Lieberman DA, Murphy G, Ladabaum U, et al. Risk stratification of individuals with low-risk colorectal adenoma using clinical characteristics: a pooled analysis. Gut. 2017; 66(3): 446-453.
2. Lieberman DA, Rex DK, Winawer SJ, Giardiello FM, Johnson DA, Levin TR. Guidelines for colonoscopy surveillance after screening and polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology. 2012; 143: 844-857.
3. Hassan C, Quintero E, Dumonceau JM. Post-polypectomy colonoscopy surveillance: European Society of Gastrointestinal Endoscopy (ESGE) guideline. Endoscopy.2013; 45: 842-864.
4. Chung SJ, Kim YS, Yang SY. Five-year risk for advanced colorectal neoplasia after initial colonoscopy according to the baseline risk stratification: a prospective study in 2452 asymptomatic Koreans. Gut. 2011; 60: 1537-1543.
5. He X, Wu K, Ogino S, Giovannucci EL, Chan AT, Song M. Association Between Risk Factors for Colorectal Cancer and Risk of Serrated Polyps and Conventional Adenoma. Gastroenterology. 2018; 155(2): 355-373.
6. Yun TK, YunYS, Han IH. Anticarcinogenic effect of long-term oral administration of red ginseng on newborn mice exposed to various chemical carcinogens. Cancer Detection Prev. 1983; 6: 515-525.
7. Panwar M, Samarth R, Kumar M, Yoon WJ, Kumar A. Inhibition of benzo(a)pyrene induced lung adenoma by Panax ginseng extract, EFLA400, in Swiss albino mice. Biol Pharm Bull 2005; 28: 2063-2067.
8. Yan Y, Wang Y, Tan Q, Hara Y, Yun TK, Lubet RA, et al. Efficacy of polyphenon E, red ginseng, and rapamycin on benzo(a)pyrene-induced lung tumorigenesis in A/J mice. Neoplasia 2006; 8: 52-58.
9. Yun TK, Choi SY. A case-control study of ginseng intake and cancer. Int J Epidemiol. 1990; 19: 871-876.
10. Guo JQ, Zheng QH, Chen H, Chen L, Xu JB, Chen MY, et al. Ginsenoside Rg3 inhibition of vasculogenic mimicry in pancreatic cancer through downregulation of VE cadherin/ EphA2/MMP9/MMP2 expression. Int J Oncol. 2014; 45(3): 1065-1072.
11. Yun TK, Zheng S, Choi SY, Cai SR, Lee YS, Liu XY, et al. Non-Organ-Specific Preventive Effect of Long-Term Administration of Korean Red Ginseng Extract on Incidence of Human Cancers, J Med Food. 2010; 13(3): 489-494.
12. Yun TK. Experimental and epidemiological evidence of the cancer-preventive effect of Panax ginseng C.A. Meyer. Nutr Rev. 1996; 54: S71-S81.
13. Yun TK, Choi SY. Non-organ specific cancer prevention of ginseng: prospective study in Korea. Int J Epidemiol. 1998; 27: 359-364.
14. Jin X, Che DB, Zhang ZH, Yan HM, Jia ZY, Jia XB. Ginseng consumption and risk of cancer: A meta-analysis. J Ginseng Res. 2016; 40(3): 269-277.
15. Wong AS, Che CM, Leung KW. Recent advances in ginseng as cancer therapeutics: a functional and mechanistic overview. Nat Prod Rep. 2015; 32(2): 256-272.
16. Lee MS, Kim MS, Yoo JK, Lee JY, Ju JE, Jeong YK. Enhanced anticancer effects of a mixture of low-dose mushrooms and Panax ginseng root extracts in human colorectal cancer cells. Oncol Rep. 2017; 38(3): 1597-1604.
17. Cottet V, Jooste V, Fournel I, Bouvier AM, Faivre J, Bonithon-Kopp C. Long-term risk of colorectal cancer after adenoma removal: a population-based cohort study. Gut. 2012; 61: 1180-1186.
18. Emilsson L, Løberg M, Bretthauer M, Holme Ø, Fall K, Jodal HC, et al. Colorectal cancer death after adenoma removal in Scandinavia. Scand J Gastroenterol. 2017; 52(12): 1377-1384.
19. Atkin W, Wooldrage K, Brenner A, Martin J, Shah U, Perera S, et al. Adenoma surveillance and colorectal cancer incidence: a retrospective, multi-center, cohort study. Lancet Oncol. 2017; 18(6): 823-834.
20. Vayghan HJ, Ghadimi SS, Nourazarian AR. Preventive and therapeutic roles of ginseng- focus on colon cancer. Asian Pac J Cancer Prev. 2014; 15(2): 585-588.
21. Sreekanth TVM, Nagajyothi PC, Muthuraman P, Enkhtaivan G, Vattikuti SVP, Tettey CO, et al. Ultra-sonication-assisted silver nanoparticles using Panax ginseng root extract and their anti-cancer and antiviral activities.J Photochem Photobiol B. 2018; 188: 6-11.
22. Kee JY, Han YH, Mun JG, Park SH, Jeon HD, Hong SH. Effect of Korean Red Ginseng extract on colorectal lung metastasis through inhibiting the epithelial-mesenchymal transition via transforming growth factor-β1/Smad-signaling-mediated Snail/E-cadherin expression. J Ginseng Res. 2019; 43(1): 68-76.