Shi-Yun Shao, Qi Li,*

Research progress in the treatment of colorectal cancer in classical prescriptions

Shi-Yun Shao1, 2, Qi Li1, 2,*

1Department of Oncology, Shuguang Hospital Affiliated to Shanghai University of TCM, Shanghai 201203, China.2Cancer Institute, Shuguang Hospital Affiliated to Shanghai University of TCM，Shanghai 201203, China.

, an acient book of Chinese medicine that published in Han dynasty (219 C.E.), is the first monograph in China that has the principles of prescription and treatment. Modern physicians flexibly applied many classical prescriptions recorded on this acientd book, such as Banxia Xiexin decoction, Da Chengqi decoction, Yiyi Fuzi Bijiang decoction and Wumei pill for the treatment of colorectal cancer and its complications, and made some progress in clinical and experimental research. Studies have shown that classical prescriptions alone or in combination with other therapies can improve immunity, prevent cancer from recurrence and metastasis, reduce the side effects of anticancer drugs, improve quality of life, and prolong the survival of cancer patients. However, the current clinical and mechanistic studies on the treatment of classical prescriptions still need to explore in depth. This study aims to summarize the clinical and research progress in the treatment of colorectal cancer with classical prescriptions in recent years.

Classical prescription, Colorectal cancer, Traditional Chinese medicine

Traditional Chinese medicine is an important tumor-assisted treatment.

Classical formula has a good effect in colorectal treatment, but the mechanism is not clear.

Introduction

The incidence of colorectal cancer ranks third in the world [1]. In China, the incidence and mortality of colorectal cancer are increasing year by year [2-3]. Although the survival rate of patients with colorectal cancer has improved with the rapid progress of surgery, chemotherapy and biological therapy, patients with advanced colorectal cancer still have a high probability of recurrence, metastasis or drug resistance. Currently, the average survival rate of patients with advanced colorectal cancer is only about 30 months [4-5].

Traditiona Chinese medicine (TCM) is one of the effective methods for comprehensive treatment of colorectal cancer and is supported by clinical evidence. The application of TCM adjuvant therapy can synergistically inhibit tumor growth, significantly reduce complications and side effects caused by surgery, radiotherapy, and chemotherapy, improve chemotherapy tolerance, enhance human immunity, improve patient prognosis, and prevent recurrence and metastasis [6].

The Han dynasty doctor Zhang Zhongjing's( an acient book of China, 219 C.E.) is the first monograph in China that has the principles of prescription and treatment. The book contains a total of 280 prescriptions, and the prescriptions have the characteristics of refining and strict prescription. The symptoms of colorectal cancer and its complications are complicated, and modern medical doctors have applied chemistries to treat colorectal cancer and its complications, often achieving good results. This article will discuss the research progress of the treatment of colorectal cancer and its related complications from the clinical application and mechanism research.

TCM understanding of colorectal cancer

Ancient Chinese medicine did not directly record the name of colorectal cancer. Combined with its clinical symptoms, colorectal cancer can be attributed to the category of Jiju recorded in TCM theory, both have the same symptoms of abdominal pain and blood in stool. Ancient books of TCM have a long history to discuss this disease. "" (an acient book of China, unknown time) and “” (an acient book of China, unknown time) contain the description of colorectal cancer. The clinical practice of the past doctors believes that the etiology and pathogenesis of colorectal cancer mostly rely on positive Qi (a vital force that form part of living entity in traditional Chinese culture) deficiency as an internal cause and the invasion of external evils is an external cause. The poisonous toxicosis is in the intestinal tract, and the sputum is not scattered for a long time, and thus the tumor is formed. The pathological changes are mainly Yu, Du, Tan, and Xu (some pathological products resulted from disease in TCM theory). During the Ming and Qing Dynasties of China (1368-1644,, and 1636-1912,), the theory and practice of TCM in the treatment of colorectal cancer became more mature [7]. Such as "(an acient book of China, 1624)" described that patient with low immunity have an increased incidence of cancer. Early colorectal cancer has no obvious symptoms. In the late stage, there is mainly increased the frequency of bowel movements, diarrhea or constipation, bloody or mucus in the stool, abdominal pain, abdominal distension, abdominal mass, and other gastrointestinal symptoms.

Research progress in the treatment of colorectal cancer with classical prescriptions

Banxia Xiexin decoction

"Shanghan Zabing Lun "( an acient book of China, 219) described that patient with colorectal cancer generally have bloating, but no symptoms of abdominal pain. Changes in vomiting and bowel sounds can also accompany it. The causes of colorectal cancer are complex, and most of them are cold and hot, and they are mixed. Banxia Xiexin decoction reflects the combination of cold and heat and Yin and Yang (a concept of dualism that describing opposite forces that may be interdependent and give rise to each other in TCM culture) characteristics. It is mainly used in the syndrome of cold and heat, and to regulate the gastrointestinal dysfunction [8]. Clinically, it is often used to reduce adverse reactions after surgery and radiotherapy and chemotherapy. Li Yingjie. [9] treated 140 patients with colorectal cancer accompanied by postoperative gastrointestinal dysfuction with Banxia Xiexin decoction, the control group used conventional medical symptomatic supportive treatment. The results showed that the serum CEA level in the treatment group was lower than that in the control group, and the difference was statistically significant. The clinical effect was better than the control group. Common toxic and side effects after chemotherapy for colorectal cancer include systemic fatigue, limb weakness, gastrointestinal dysfunction, oral mucositis, neurotoxicity, leukopenia, thrombocytopenia, and other myelosuppressive symptoms. The symptoms of gastrointestinal dysfunction caused by it are similar to the Tan syndrome (a type of pathological products resulted from disease) of Chinese medicine theory. Besides, Banxia Xiexin decoction combined with chemotherapy can prevent and reduce the gastrointestinal toxicity caused by chemotherapy, and also has a certain effect on chemotherapy-related oral mucositis. Wang Jian. [10] used Banxia Xiexin decoction to treat the digestive tract reaction caused by chemotherapy in rectal cancer. The control group received routine vomiting treatment. The treatment group received oral Banxia Xiexin decoction 3 days before chemotherapy based on the control group. The effective rate of the treatment group for nausea and vomiting was 90.3%, which was much higher than that of the control group. Matsuda. [11-12] used Banxia Xiexin decoction to prevent chemotherapy-related oral mucositis. The incidence of ≥ grade 2 oral mucositis in the treatment group was 48.8%, and the median duration was 5.5 days. While the incidence was 57.4%, and the median duration was 10.5 days in the control group. This study shows that Banxia Xiexin decoction may shorten the healing time of the oral mucosa. Besides, studies [13] have shown that Banxia Xiexin decoction can resist inflammation and anti-oxidation, and has a good protective and regulating effect on the digestive system. These results indicate that colorectal cancer plays an important role in reducing the toxic and side effects after chemotherapy.

Da Chengqi decoction

Intestinal obstruction is a common complication of postoperative colorectal cancer with main symptoms of abdominal distension, abdominal pain, nausea and vomiting, and constipation. Zhu Huanhuan. [14] used preoperative Da Chengqi decoction and 5% dextrose sodium chloride injection plus potassium chloride to prevent postoperative intestinal obstruction in patients with colorectal cancer. The control group received traditional bowel preparation before surgery. The results showed that the treatment group had an effective rate of 90.2%, and the average anal exhaust (stomach tube removal) time was significantly shortened. After 72 hours, the peripheral blood CRP treatment group was lower. Wei Nan [15] used the addition and subtraction treatment of 41 patients with acute intestinal obstruction after colon cancer surgery. Compared with Western medicine routine symptomatic treatment of intestinal cancer with acute intestinal obstruction, the results showed that the treatment group gastrointestinal decompression the flow rate was significantly less than the control group. Yu Hailong. [16] treated 115 patients with colon cancer who received surgery were randomly divided into Da Chengqi decoction group and control group, and the control group received routine treatment. After one week, the incidence of abdominal distension in Da Chengqi decoction group was 7.94%, which was significantly lower than that of the control group (30.56%). Moreover, the Da Chengqi decoction group recovered faster and had a lower incidence of postoperative complications. Li Zhiju. [17] used Da Chengqi decoction in the treatment of colorectal cancer with intestinal obstruction, Da Chengqi decoction group in the improvement of clinical symptoms such as abdominal distension, bloating and defecation were significantly better than the conventional control group. The curative effect was exact, and the total effective rate was 93.94%, which was significantly better than the control group (70.97%). Clinical practice has proved that Da Chengqi decoction may improve the function of intestinal fistula, improve intestinal microenvironment, significantly increase gastrointestinal blood flow, reduce intestinal capillary permeability, and inhibit inflammation. Also, Da Chengqi decoction may have the function of reducing adhesion, and relieve postoperative intestinal obstruction in patients with colorectal cancer.

Yiyi Fuzi Baijiang decoction

Yiyi Fuzi Baijiang decoction has the function of reducing the volume of the mass. Du Yanlin. [18] treated 33 patients with colorectal cancer using Yiyi Fuzi Baijiang decoction combined with FOLFOX4 chemotherapy. Compared with the chemotherapy group, the results showed that the toxic side effects after chemotherapy were significantly reduced combined with Yiyi Fuzi Baijiang decoction. Professor Liu Shangyi and Tong Xiaolin [19-20] used this method in clinical practice to treat patients with an abnormal stool after bowel cancer surgery. Chen Lingling [21] and others also found that Yiyi Fuzi Baijiang decoction might regulate the number of intestinal flora and reduce the levels of inflammatory factors IL-6, thus reducing the inflammation reaction.

Wumei pill

Wumei pill now is used by clinicians to treat diarrhea, constipation, and bloating in patients with colorectal cancer. Li Zhiming. [22] used Wumei pill for the treatment of colorectal cancer during the rehabilitation of gastrointestinal tract dysfunction. Professor Jiang Shiqing. [23] summarized that Wumei pill may significantly reduce the occurrence of postoperative complications. Zhang Ran. [24] also observed that in the mouse model of colon cancer, a modified Wumei pill might inhibit the progression of the tumor through Wnt/JNK pathway, and significantly reduce the expression levels of Wnt, JNK protein and mRNA in colon cancer model mice. The Wnt/JNK pathway regulates cytoskeletal rearrangement during embryonic development and participates in gastrulation. Studies have shown that Wnt and JNK proteins are highly expressed in colonic atypical hyperplasia tissues and colon cancer tissues, and can be targeted for tumor therapy.

Huangqin decoction

Huangqin decoction is widely used in the treatment of nausea and vomiting caused by digestive tract diseases, abdominal pain, and diarrhea. Chemotherapy-associated diarrhea is a common side-effect of the digestive tract after chemotherapy in patients with colorectal cancer. Yu Yang. [25] treat 72 patients with colorectal cancer who received FOLFIRI chemotherapy. The results showed that the incidence of delayed diarrhea in the Huangqin decoction group was 29.41%, which was significantly lower than that of the chemotherapy alone group (57.89%). Moreover, the adverse reactions in the control group also decreased significantly. Liu Dongyan. [26] use Huangqin decoction combined with Mengtuoshi (montmorillonite) powder to prevent the treatment of delayed diarrhea caused by irinotecan, 100 patients with colorectal cancer receiving irinotecan chemotherapy were randomly divided into combination group and chemotherapy group. It was observed that the incidence of diarrhea and the duration of diarrhea in the combination group were lower than those in the chemotherapy group. Chen. [27] found that Huangqi decoction might resist oxidation, inhibit the production of inflammatory factors, repair the intestinal mucosal damage of the blind colon, thereby playing a role in the treatment and prevention of diarrhea in the animal models. The research team at Yale University developed the phytopharmaceutical PHY906 based on Huangqi decoction and conducted long-term experimental research. Professor Zheng Yongqi's team [28] studied the mouse model of allograft colon cancer and studied the effect of PHY906 on chemotherapeutic drugs. The mice in the experimental group were intragastrically administered with PHY906 and compared with the mice that were not treated with gavage. The results suggest that PHY906 may enhance the anti-tumor activity of chemotherapy and reduce the side effects of irinotecan. PHY906 works well in Phase I/II clinical trials. Compared with placebo plus chemotherapy, patients with PHY906 combined with chemotherapy had fewer life-threatening (grade 4) adverse events and a lower overall incidence of grade 3 or 4 diarrhea [29-32]. The research of PHY906 provides a good example for Chinese medicine to treat colorectal cancer, which brings new opportunities for Chinese medicine to fight cancer.

Xiao Chaihu decoction

Xiao Chaihu decoction plays an important role in the treatment of cancer fever. Dai Chunshan [33]. used Xiao Chaihu decoction alone to treat 48 cases of cancerous fever in the elderly, including 12 cases of liver cancer, 19 cases of lung cancer, 5 cases of pancreatic cancer, 4 cases of gallbladder cancer, 5 cases of colon cancer, 3 cases of gastric cancer, and the efficient rate was 81.25% and no obvious side effects were observed. Also, Professor Li Qi. [34] used Xiao Chaihu decoction and Sini decoction to treat postoperative oral ulcers in rectal cancer. Xu Bin. [35] demonstrated that Xiao Chai Hu detoction might increase intestinal alkaline phosphatase activity, promote lipid transport and lipid absorption, and inhibit fat accumulation, thereby inhibiting the proliferation of HCT-116 cancer cells. The mechanisms of Xiao Chaihu decoction immunomodulation and direct tumor suppression are also further clarified.

Sini decoction

Sini decoction may play an essential role in thrombocytopenia after radiotherapy and chemotherapy of patients with colorectal cancer. Wu Zhanxi. [36] demonstrated that the effect of Sini decoction on thrombocytopenia after chemotherapy, 78 patients with colorectal cancer who had thrombocytopenia after chemotherapy were randomly divided into control group and treatment group. The control group was given recombinant human interleukin-11 treatment, the treatment group was treated with Sini decoction, and the course of treatment was 2 weeks. Results showed that the platelet rise, the platelet count and hemoglobin, white blood cell index in the treatment group was significantly higher than the control group. It is confirmed that Sini decoction can increase IL-6 secretion, regulate immunity by promoting the production of antibodies by spleen cells, promote the proliferation of hematopoietic stem cells, and increase the production of platelets in patients.

Conclusion

Colorectal cancer is a chronic disease that the pathogenic mechanism is not yet clear. It has different manifestations at different stages of disease development. The prescription plays a role in the prevention and treatment of tumors from multiple targets. It is often used alone or in combination with other modern conventional therapies. It has the following advantages: (1) improve immunity and prevent cancer from recurrence and metastasis; (2) to alleviate the toxic side effects of anticancer drugs; (3) to alleviate the symptoms of patients, improve the quality of life, and prolong the survival of patients with cancer. In recent years, the application of prescription for the treatment of colorectal cancer and its related diseases has been extensive and clinically effective. However, the following problems still exist: (1) syndrome differentiation, treatment, and efficacy evaluation of colorectal cancer in TCM are not the same; (2) at present, there are many medical treatments for colorectal cancer, but there is a lack of large-scale randomized, double-blind TCM clinical trials to evaluate and confirm the efficacy of single and combined treatments for colorectal cancer, and lack of more reliable medical evidence; (3) lack of safety assessment and efficacy evaluation system for treatment; (4) the study of the mechanism, pharmacology, and compatibility of colorectal cancer is still in the preliminary exploration stage and needs further study. It is believed that with the continuous deepening of research in the field of anti-tumor, the prescription can fully exert its advantages and overcome its drawbacks. The field of Chinese medicine prevention and treatment of cancer will also open up a broader road.

1. Siegel RL, Miller KD, Jemal A. Cancer statistics 2017. CA Cancer J Clin 2017, 67: 7-30.

2. Msph LAT, Bray F, Siegel RL,. Global cancer statistics 2012. CA Cancer J Clin 2015, 65: 87-108.

3. Marley AR, Nan H. Epidemiology of colorectal cancer. International J Mol Epidemiol & Gen 2016, 7: 105.

4. Arnold M, Mónica SS, Laversanne M,. Global patterns and trends in colorectal cancer incidence and mortality. Gut 2017, 66: 683-691.

5. Wan Desen. Epidemiology and prevention of colorectal cancer. Chin J Integr Traditi Western Med 2011, 17: 3-7.

6. Chen D, Zhao J, Cong W. Chinese herbal medicines facilitates the control of chemotherapy-induced side effects in colorectal cancer: progress and perspective. Front Pharmacol 2018, 9: 1442.

7. Chen Y, Liu JT, Zhu Y,. TCM syndrome differentiation and treatment of colorectal cancer. Chin J Tumor 2015, 24.

8. Kong J, Lin XN, Lin B. Clinical treatment of Banxia Xiexin decoction. J Tradit Chin Med 2013, 41: 160-161.

9. Li YJ, Qiu SG, Liang J. Clinical study of Banxia Xiexin decoction in the treatment of liver and spleen syndrome after colorectal cancer operation. World Tradit Chin Med 2017, 12: 1523-1526.

10. Wang J, An C, Yan CX. Analysis of the effect of Banxia Xiexin decoction on gastrointestinal reactions in patients with colorectal cancer chemotherapy. J Comm Med 2014, 12: 29-30.

11. Matsuda C, Munemoto Y, Mishima H,. Double-blind, placebo-controlled, randomized phase II study of TJ-14 (Hangeshashinto) for infusional fluorinated-pyrimidine-based colorectal cancer chemotherapy-induced oral mucositis. Chemother Pharmacol 2015, 76:97-103.

12. Nishikawa K, Aoyama T, Oba MS,. The clinical impact of Hangeshashinto (TJ-14) in the treatment of chemotherapy-induced oral mucositis in gastric cancer and colorectal cancer: analyses of pooled data from phase II randomized clinical trials. J Cancer 2018, 9: 1725-1730.

13. Chen G, Yang Y, Liu M,. Banxia Xiexin decoction protects against dextran sulfate sodium-induced chronic ulcerative colitis in mice. J Ethnopharmacol 2015, 166:149-156.

14. Zhu HH, Lu GQ. Clinical observation on prevention and treatment of postoperative intestinal obstruction in colorectal cancer with integrated traditional Chinese and western medicine. J Shandong Univer Tradit Chin Med 2012, 3: 207-208.

15. Wei N. Therapeutic effect of Fufang Da Chengqi decoction on bowel cancer complicated with acute intestinal obstruction. Chin J Chin 2013, 22: 652-653.

16. Yu HL, Yu ZG, Bai XF. Clinical observation of Da Chengqi decoction in the treatment of 125 cases of postoperative bloating in colon cancer patients. Tradit Chin Med 2012, 29: 75-77.

17. Li ZJ. Treatment of 33 cases of colorectal cancer with intestinal obstruction with Da Chengqi decoction and nursing enema. Chin Pharmac 2015, 24:120-121.

18. Du YL, Wang ZM, Lu DR,. Treatment of 33 cases of colorectal cancer with Qifuzi Sauce powder combined with chemotherapy. Tradit Chin Med 2015, 22: 213-214.

19. Li J, Yang Z, Long FQ,. Professor Liu Shangyi uses Fuzi Yiyi Baijiang decoction to treat tumors. J Chengdu Univer Tradit Chin Med 2017, 40: 66-68.

20. Zhou Q, Yan B, Zhao XY,. Professor Tong Xiaolin uses Fuzi Yiyi Baijiang decoction to treat tumors. Chin J Clin 2013, 41: 70-71.

21. Chen LL, Zhang SW, Li DP,. Effects of Fuzi Yiyi Baijiang decoction on inflammatory factors and intestinal flora in diabetic mice. Shanxi J Tradit Chin Med 2018, 4: 415-418.

22. Li ZM. Treatment of 40 cases of gastrointestinal dysfunction in colorectal cancer during rehabilitation with Xiaoyao Sanhe Wumei pill. Massage Rehabilitation Med 2018, 4:112-117.

23. Wang S, Xu X, Zhang MZ,. Professor Jiang Shiqing's experience in treating colorectal cancer from Jueyin of Liujing. J Tradit Chin Med 2016, 31: 467-469.

24. Zhang R, Li SJ, Chen ZY,. Inhibition mechanism of colon cancer by Wnt pathway plus flavored Wumei pill. World Chin Med 2018,13: 1972-1975.

25. Yu Y, Li XS, Wu B,. Therapeutic effect of Jiawei Huangqi decoction on prevention of delayed diarrhea caused by irinotecan chemotherapy in patients with advanced intestinal cancer. Beijing Chin Med 2015: 427-430.

26. Liu DY, Yin PP, Bai ZC,. Therapeutic effect of Jiawei Huangqi recipe on prevention of delayed diarrhea caused by irinotecan chemotherapy in patients with advanced intestinal cancer. Guide to Health Care 2016: 321-321.

27. Chen G, Yang Y, Hu C,. Protective effects of Huangqin decoction against ulcerative colitis and associated cancer in mice. Oncotargets 2016, 7: 61643-61655.

28. Lam W, Bussom S, Guan F,. The Four-Herb Chinese medicine PHY906 reduces chemotherapy-induced gastrointestinal toxicity. Sci Transl Med 2010, 2:45ra 59.

29. Kummar S, Copur MS, Rose M,. A phase I study of the Chinese herbal medicine PHY906 as a modulator of irinotecan-based chemotherapy in patients with advanced colorectal cancer. Clin Colorec Cancer 2011, 10: 1-96.

30. Liu SH , Cheng YC . Old formula, new Rx: The journey of PHY906 as cancer adjuvant therapy. J Ethnopharmacol 2012, 140: 1-623.

31. Lam W, Jiang Z, Guan F,. The number of intestinal bacteria is not critical for the enhancement of antitumor activity and reduction of intestinal toxicity of irinotecan by the Chinese herbal medicine PHY906 (KD018). BMC Compl Alternat Med 2014, 14: 490.

32. Rockwell S, Grove TA, Liu Y,. Preclinical studies of the Chinese herbal medicine formulation PHY906 (KD018) as a potential adjunct to radiation therapy. Internal J Radiat Biol Related Studies in Physics, Chem Med 2013, 89: 16-25.

33. Dai CS, Wang XH, Chen B,. Treatment of 48 cases of cancerous fever in the elderly with Jiawei Xiao Chaihu decoction. Fujian J Tradit Chinese Med 2013, 44: 35-41.

34. Yang YQ, Zhang ZZ, Li Q. Professor Li Qi used Xiao Chaihu decoction to treat tumors. Jilin Tradit Chin Med 2018, 33: 132-137.

35. Xu B, Liang XF, Lu J,. Effects of Xiao Chaihu decoction and its cold-heat reduction on colon cancer cell proliferation, fat and alkaline phosphatase. Chin J Exper Tradit Med Formul 2018, 14: 132-139.

36. Wu Z Q. Observation on the effect of Jiawei Sini decoction on thrombocytopenia after chemotherapy in patients with colorectal cancer.Heilongjiang Med 2018, 31: 1072-1073.

12 February 2019,

03 April 2019,

18 June 2019.

Authors declare that they have no competing interests.

?2019 TMR Publishing Group Limited. This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License.

Classical Chinese medicine prescriptions are widely used in cancer treatment. Although obvious therapeutic effects have been observed in clinical practice, laboratory evidence is still lacking. Clinically effective prescriptions may become the research direction for the development of cancer therapeutic drugs.

Qi Li, Department of Oncology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, NO. 189 Pu'an Road, Huangpu District, Shanghai 201203, China, E-mail: Lzwf@hotmail.com.