Dong-Xu Zhang,Xin-Hua Zhao,Song-Jiang Liu

1Heilongjiang University of Chinese Medicine,Harbin 150040,China;2Department of Oncology,the First Affiliated Hospital of Heilongjiang University of Chinese Medicine,Harbin 150040,China.

Abstract

Key words:Esophageal cancer,Traditional Chinese medicine,Clinical research,Adjuvant treatment

Background

Esophageal cancer is one of the common malignant tumors of the digestive system in the world.According to statistics,in 2018,the incidence and mortality of esophageal cancer ranked seventh and sixth respectively [1].The incidence rate of newly diagnosed and dying patients in China accounts for about 55% of the world’s population.The incidence and mortality rate of esophageal cancer ranks fifth in the world.The number of esophageal cancer patients is increasing year by year,which has seriously threatened the health of our people [2–3].The present manuscript reviews the research progress of esophageal cancer in terms of traditional Chinese medicine understanding and treatment,may providing valuable information for the adjuvant treatment of esophageal cancer.

Chinese and Western medicine understanding of esophageal cancer

Esophageal cancer is mainly divided into two types,including squamous cell carcinoma (SCC) and adenocarcinoma.The two types have distinct epidemiological differences,of which the incidence of SCC in Southeast Asia and Central Asia is high,and the rate of adenocarcinoma in North America and Oceania is high [4].The etiology of esophageal cancer is not yet clear,and studies have shown that its occurrence may be related to dietary factors,smoking and drinking,human papillomavirus,genetic factors,et al.[5].For esophageal cancer,surgery is the preferred treatment without contraindications to surgery [6].However,the onset of esophageal cancer is hidden,there are no specific tumor markers,and there are often no apparent symptoms in the early stage,which cannot attract people’s attention.When the disease progresses to the middle and late stages,and symptoms such as progressive swallowing and short-term weight loss appear,the patient has missed the best time to visit [7].Patients with advanced esophageal cancer have lost the chance of surgery due to tumor invasion or extensive metastasis.Still,the effect of simple radiotherapy and chemotherapy is not right,the toxic and side effects are apparent,and the prognosis is poor.The overall 5-year survival rate (SR) is less than 20% [8].At present,treatment methods of Western medicine for esophageal cancer mainly include surgical treatment,radiotherapy and chemotherapy,targeted therapy and immunotherapy.There is no name for esophageal cancer in the ancient literature of traditional Chinese medicine (TCM).According to the symptoms,it belongs to the category of “Yege” (dysphagia) [9].Many Chinese medical doctors have different opinions on etiology and pathogenesis.Professor Zhu Liangchun [10] believes that the body conditions of patients in the early and middle stages of the disease can temporarily withstand the consumption of the disease.In the late stage of the disease,the disease often coupled with the difficulty of eating caused by this disease,frequent vomiting,resulting in a significantly weakened body and the appearance of cachexia.Professor Hua Baojin [11] believes that the core pathogenesis of esophageal cancer is the destruction of the body’s immune system,and the ability of immune surveillance and immune clearance is impaired,which leads to the occurrence of diseases.Professor Lin Lizhu [12] believes that esophageal cancer is caused by a decline in the body’s immunity and dysfunction of the body.In short,most Chinese medicine practitioners believe that the occurrence of esophageal cancer is related to the patient’s immune system damage,dysfunction of the body,plus external factors,high-risk carcinogenic factors and other reasons.As TCM enters the public’s field of vision,more and more Chinese herbal drugs and proprietary Chinese herbs are used in clinical practice.TCM has shown certain clinical advantages.It can reduce the occurrence of adverse reactions,improve patients’ related discomfort symptoms,and there are distinct advantages in improving the quality of life of patients [13].The current status of the research on TCM treatment of esophageal cancer is summarized as follows.

Application of TCM in treatment of esophageal cancer

Chinese medicine extract treatment

The active ingredients form TCM have a specific effect on inhibiting tumor cell viability,promoting tumor cell apoptosis,reducing tumor cell migration and invasion.

Li et al.[14] found that gallic acid can inhibit the expression of MMP2 and MMP9 in esophageal cancer cells KYSE150 and EC9706 cells,and induce G0/G1 cell cycle arrest in KYSE150 cells,EC9706 the cell cycle of S phase in cells is stagnant,thereby achieving the effect of inhibiting the viability,migration and invasion of esophageal cancer cells.Zhao Wenyu et al.[15] found that the water extracts and alcohol extracts of melon stalk inhibited the proliferation and migration of esophageal cancer TE-1 and EC-1 cells,and reduced the cloning ability stagnates the cell cycle and induces apoptosis.Guo Fangming et al.[16] found that grape seed extract proanthocyanidin can inhibit the expression of NF-κB,regulate PGE2 and CRP,and then activate Bax protein and inhibit Bcl-2,thereby activating Caspase-3,which promotes the apoptosis of esophageal cancer cell ECA109.Wang Tao et al.[17] found that Tengligen (Radix actinidiae) extractive may up-regulate the miR-451 expression level of esophageal squamous carcinoma cell in a certain concentration range,thereby achieving the effect of inhibiting the proliferation of esophageal cancer cell EC9706.In recent years,researchers on the anti-cancer effect of TCM monomers has gradually increased,and the research mechanism has slowly deepened.This provides a laboratory basis for the role of TCM monomers in the treatment of esophageal cancer.However,TCM may often have multiple effective active ingredients.Further analysis of the active ingredients of TCM and the role played by the active ingredients will be the research direction of TCM against tumors.Besides,many Chinese herbs have the effect of improving immunity,but there are few studies on the impact of immune cells in the tumor microenvironment.Whether Chinese medicine may promote the activation of effector cells,thereby killing tumor cells,further research is needed.

Chinese herbal compound treatment

TCM compounds may play a multi-target and multilink comprehensive regulation role in the treatment of tumors.It has certain advantages in inhibiting tumor growth,reducing toxic and side effects,improving quality of life and prolonging survival.

Wei Shimin [18] randomly divided 100 patients with advanced esophageal SCC into 2 groups.Fifty patients in the control group received chemotherapy TP regimen (paclitaxel 135mg/m2,once every 2 weeks,cisplatin 50mg/m2,weekly).Fifty patients in the treatment group were supplemented with the experienced prescription Qige powder treatment based on the treatment in the control group (see detailed prescription composition in Appendix figure 1).The treatment period is 30 days.The results showed that the TCM syndrome score in the treatment group was significantly better than the control group after treatment (P<0.05);the carcinoembryonic antigen and SCC antigen in the treatment group were also lower than the control group (P<0.05).Li Lulu et al.[19] randomly divided 53 esophageal cancer patients into 2 groups.Twenty-six patients in the comparison group were given intensity modulated radiation therapy (IMRT) and TP chemotherapy regimen and 27 patients in the treatment group added the experienced prescription Sijunzi decoction and Shashen Maidong decoction based on the treatment in the comparison group (see detailed prescription composition in Appendix figure 2).The results showed that the total effective rate (RR) and disease control rate of the treatment group were significantly higher than that of the comparison group (P<0.05).The 1,2,and 3-year SRs of the treatment group and the comparison group were 85.2%,63.0%,44.4% and 73.1%,53.8%,34.6%,respectively.The SR in the treatment group was significantly higher than that of the comparison group.The incidence of white blood cell,platelet,and hemoglobin reduction in the treatment group was lower than that in the comparison group (P<0.05).Feng Xianming et al.[20] randomly divided 90 patients with advanced esophageal cancer patients into two groups.Forty-five patients in the control group were treated with cisplatin combined with 5-fluorouracil (PPF) chemotherapy and 45 patients in the observation group were supplemented with the experienced prescription Shenqitongyou decoction based on the treatment in the control group (see detailed prescription composition in Appendix figure 3).Three weeks is a cycle and both groups are treated for 3 cycles.The results showed that the RR of solid tumors in the control group after treatment was 40.0%,and the RR of solid tumors in the observation group was 62.2%,the effective rate of the control group was obviously lower than that of the observation group (P<0.05).The level of carcinoembryonic antigen in the observation group after treatment was lower than that in the control group (P<0.05).The incidence of adverse reactions (leukocytes,thrombocytopenia,neurosensory disturbance,bone marrow suppression,gastrointestinal reactions,et al.) in the observation group was also lower than that in the control group (P<0.05).Xu Chao et al.[21] randomly divided 76 advanced esophageal cancer patients into 2 groups,and 38 patients in the control group received IMRT;38 patients in the treatment group were added the experienced prescription Fuzheng Kangai recipe based on the treatment in the control group (see detailed prescription composition in Appendix figure 4).The two groups were compared after 6 weeks of treatment.After treatment,the imbalance of Th1 and Th2 cytokines,IL-2,IL-4,IL-10 and IFN-γ in the treatment group was better than that of the control group after treatment (P<0.05).It demonstrated that the experienced prescription Fuzheng Kangai Fang combined with IMRT may effectively correct the immune imbalance of Th1/Th2 cytokines.It can be seen that the adjuvant treatment of esophageal cancer with TCM has a certain role in improving the symptoms of patients,improving the SR of patients,and reducing the adverse reactions of radiotherapy and chemotherapy.Also,cancer patients are generally accompanied by immune function disorders.Adjuvant therapy with TCM may improve the function of immune system to inhibit tumor growth.Compared with TCM monomer,the mechanism of TCM compound may play a more complicated role.In recent years,with the rise of network pharmacology and bioinformatics methods,the study of Chinese herbal compound has entered a new stage.Analyzing compound ingredients through network pharmacology and predicting possible targets can provide research directions for future experiments.TCM compound currently lacks the verification of experimental research,although the clinical efficacy is significant,laboratory data support is also an important part.

Chinese patent medicine treatment

Chinese patent medicine is guided by the theory of Chinese medicine,extract single or multiple active ingredients of Chinese medicine,process it into traditional Chinese medicine products of different dosage forms as needed,it has the advantages of convenient taking and good patient compliance.

Chinese medicine oral agent treatment.Li Hanjie et al.[22] randomly divided 110 patients with esophageal cancer into 2 groups,and 55 patients in the comparison group were given IMRT and chemotherapy drug oxaliplatin (130 mg/m2,once every 3 weeks);55 patients in the observation group were given the Chinese patent medicine Pingxiao capsules (the serial approved number of China’s National Medical Products Administration:Z61021330) based on treatment in the comparison group.Three weeks is a course of treatment,and both groups are treated for 2 courses.As a result,the CD3+,CD4+,CD4+/CD8+levels in the observation group were higher than those in the comparison group (P<0.05);the KPS score of the observation group was significantly higher than that of the comparison group (P<0.05).Han Lichun et al.[23] randomly divided 88 patients with mid-advanced tube carcinoma into 2 groups,and 44 patients in the comparison group were given paclitaxel combined with carboplatin chemotherapy regimen;44 patients in the treatment group took the Chinese patent medicine Yunzhi Tangtai capsules (the serial approved number of China’s National Medical Products Administration:Z10980124) based on treatment in the comparison group.Four weeks is a period of treatment,and both groups are treated for 4 periods.The results showed that the levels of serum invasive cytokines (CD44v,VEGF,MMP-9,OPN) in the treatment group after treatment were obviously lower than those in the comparison group (P<0.05),and the QLQ-C30 and SF-36 scale scores of the treatment group were higher than those of the comparison group after treatment (P<0.05).Yue Yunxia [24] randomly divided 76 esophageal cancer patients into 2 groups,38 patients in the comparison group were given conventional radiotherapy;38 patients in the treatment group were given the Chinese patent medicine Huachansu capsules (the serial approved number of China’s National Medical Products Administration:Z20050846) based on the treatment in the comparison group.After 30 days of treatment,the 2 groups were compared.As a result,the RR of solid tumors in the treatment group was significantly higher than that in the comparison group (P<0.05),and the incidence of adverse reactions was considerably lower than that in the comparison group (P<0.05).Xue Xiaochao [25] randomly divided 72 patients with locally advanced esophageal SCC into 2 groups,38 patients in the control group were given neoadjuvant radiochemotherapy;34 patients in the treatment group were given neoadjuvant radiotherapy and chemotherapy plus the Chinese patent medicine Xihuang capsules (the serial approved number of China’s National Medical Products Administration:Z20153041).Twenty-one days is a cycle,and both groups are treated for 2 cycles.Results showed that the incidence of acute radiation esophagitis in the treatment group was significantly lower than that in the control group (P<0.05).And the occurrence time of acute radiation esophagitis was delayed than the control group (P<0.05);the KPS score of the treatment group was also higher than that of the control group (P<0.05).

Chinese medicine injection treatment.Wu Yanhui [26] randomly divided 279 patients with advanced esophageal cancer into 2 groups,and 139 patients in the comparison group were given conventional chemotherapy;140 patients in the observation group were given the Chinese patent medicine Xiaoaiping injection (the serial approved number of China’s National Medical Products Administration:Z20025868) based on treatment in the comparison group.After 6 weeks of continuous treatment,evaluate the efficacy of the two groups.The results showed that the control rate of solid tumors after treatment in the observation group was higher than that in the comparison group (P<0.05).It is proved that the Chinese patent medicine Xiaoaiping injection combined with chemotherapy can effectively control tumor growth.Wu Shaobing et al.[27] randomly divided 60 patients with esophageal cancer into 2 groups,and 30 patients in the control group underwent IMRT.In the treatment group,the Chinese patent medicine Kushen injection (the serial approved number of China’s National Medical Products Administration ：Z14021231) was added based on the treatment in the control group,and the medication was continued until the end of radiotherapy.The results showed that the RR of solid tumors in the treatment group after treatment was 83.33%.The effective rate of solid tumors in the control group was 70.00%,compared with the control group,the effective rate of the treatment group was significantly improved,and the incidence of adverse reactions was significantly reduced (P<0.05).Wang Shuai et al.[28] randomly divided 60 patients with radical esophageal cancer into 2 groups,and 30 patients in the control group were given oxaliplatin combined with capecitabine chemotherapy;30 patients in the treatment group were added with the Chinese patent medicine Aidi injection (the serial approved number of China’s National Medical Products Administration:Z52020236) on the basis of the treatment in the control group.Three weeks is a cycle,and both groups are treated for 2 cycles.The results showed that although both bone marrow suppression occurred in the control group and the treatment group after treatment,but compared with the control group,the inhibition of the treatment group was significantly lighter (P<0.05);the levels of serum T cell subsets CD3+CD4+(TH) and TH/Ts in the treatment group were better than those in the control group (P<0.05).Niu Guangyu et al.[29] randomly divided 78 patients with advanced esophageal cancer into 2 groups,39 patients in the control group were given IMRT;39 patients in the observation group were given elemene injection (the serial approved number of China’s National Medical Products Administration:H20110114) on the basis of treatment in the control group.Both groups had 21 days as one cycle,and the efficacy of the two groups was compared after two cycles.The results showed that after treatment,the incidence and severity of adverse reactions in the observation group were significantly lower than those in the control group (P<0.05),and KPS score was significantly increased (P<0.05).

TCM external treatment

TCM external treatment is a commonly used treatment method of TCM,including acupoint application,acupoint injection,acupoint massage,et al.It is mainly based on the theoretical basis of TCM meridian and acupoints.By directly applying Chinese medicine to acupoints,the body’s immunity is improved,thereby preventing disease play a therapeutic role.

Rao Haiying et al.[30] randomly divided 105 patients with hiccups after esophageal cancer operation into 2 groups.Fifty-two patients in the control group were treated with oral domperidone tablets,and 53 patients in the observation group were given Chinese herb hot compress of middle and upper abdomen (see detailed prescription composition in Appendix figure 5) and acupoint massage (select acupoints:Neiguan (PC 6),Cuanzhu (BL 2),Zhongwan (RN 12),Geshu (BL 17),Yongquan (KI 1)).Both groups were treated for 7 days.The results showed that the hiccup score,mental state,sleep quality and other symptoms scores of the observation group were lower than those of the control group after treatment (P<0.01).Liang Jing et al.[31] randomly divided 76 patients with esophageal cancer into 2 groups.Thirty-eight patients in the control group were given conventional chemotherapy,and metoclopramide was intramuscularly injected 30 minutes before chemotherapy,and 38 patients in the observation group were given the same chemotherapy regimen as the control group,and metoclopramide was injected at Zusanli (ST 36) acupoint 30 minutes before chemotherapy.The two groups were treated for the same course of treatment,and the efficacy of the two groups was compared.As a result,the RR of nausea and vomiting control in the observation group was significantly higher than that in the control group (P<0.05).It is proved that metoclopramide have a well effect for the injection of acupoints in Zusanli (ST 36) than intramuscular injection for nausea and vomiting.Liu Jingtao et al.[32] randomly divided 62 patients with radical esophageal cancer into 2 groups,and 31 patients in the control group took symptomatic supportive treatment after surgery;31 patients in the treatment group were treated with Shenque (RN 8) acupoint application based on the therapy in the control group (see detailed prescription composition in Appendix figure 6).Observe the recovery time of bowel sounds,the first time of anal exhaust and the first time of defecation in the 2 groups.The results showed that the recovery time of bowel sounds,the time of first anal exhaust and the time of the first defecation of the patients in the treatment group after treatment were better than the control group (P<0.05).This shows that the external treatment of TCM has a certain effect on preventing adverse reactions after radiotherapy and chemotherapy and shortening the postoperative recovery time.

Conclusion

According to statistics,the incidence of esophageal cancer patients in China has increased year by year in recent years,Western medicine treats esophageal cancer with radiotherapy and chemotherapy as the primary treatment method,the symptoms of shortterm treatment may be controlled.Still,the toxic and side effects of long-term therapy of radiotherapy and chemotherapy,the patient’s body consumption,et al.,make the patient unbearable and interrupt the treatment,the overall effect is not satisfactory.In recent years,with the gradual maturity of TCM’s cognition of esophageal cancer,the application of Chinese herbal extracts,Chinese herbal compound,Chinese patent medicine,external treatment of TCM and other methods in clinical practice,Chinese medicine has made great progress and obvious effect in the treatment of this disease,especially in reducing the toxicity of radiotherapy and chemotherapy,enhancing patients’ immunity,reducing metastasis and recurrence,et al.,it has a significant role.However,there is no unified standard for syndrome differentiation in the treatment of esophageal cancer by TCM,the specific mechanism of the role of TCM is not yet precise and needs further study.

Looking forward to scientific researchers using bioinformatics,network pharmacology,molecular docking,related experiments and other technical research,further study the pathogenesis of esophageal cancer and the specific mechanism of TCM treatment of esophageal cancer.To better guide the clinical,so that the clinical efficacy of TCM can be further improved.