The incidence and mortality of esophageal cancer in mainland China rank sixth and fourth among malignant tumors, respectively, with about 320,000 new cases and 300,000 deaths per year, accounting for 55.3% of this type of cancer in the world [1-2]. At present, the treatment of esophageal cancer mostly adopts the method of combining traditional Chinese medicine and Western medicine, that is, traditional Chinese medicine combined with surgery, radiotherapy, chemotherapy, ion stent implantation, photodynamic therapy and other methods, which can significantly improve the quality of life and prolong the survival time of patients [3]. For patients with advanced esophageal cancer who cannot undergo surgery, radiotherapy, chemotherapy or disease progression after chemotherapy, traditional Chinese medicine has become an important choice. Traditional Chinese medicine has the characteristics of overall concept, dialectical treatment, and individualized conditions, and is cost-effective and convenient for treatment. In order to seek appropriate treatment options and improve the survival rate and quality of life of patients with advanced esophageal cancer, Zheng Yuling's research group, based on long-term clinical experience and combined with the basic theory of traditional Chinese medicine, believes that patients with advanced esophageal cancer have more evidence of spleen and kidney yang deficiency, stubborn sputum and blood, and developed a drug to treat and alleviate the clinical symptoms of advanced esophageal cancer Clove tube esophageal pills [4]. The research group conducted preliminary clinical observation in the early stage and found that the combination of clove tube esophagus granules combined with clove tube esophagus pills or clove tube esophagus pills alone can improve the clinical symptoms of patients and improve their quality of life. Based on this, randomized, controlled and prospective research methods were used to evaluate the clinical efficacy and safety of clove tube esophageal capsules alone or in combination with Gui Gui Esophagus granules in the treatment of advanced esophageal cancer, in order to improve the quality of life of patients with advanced esophageal cancer and provide a definite efficacy plan for the TCM treatment of esophageal cancer.
1 Objects and methods
1.1 Research Subjects From January 2020 to April 2021, 120 patients with advanced esophageal cancer admitted to the First Affiliated Hospital of Henan University of Chinese Medicine, Linzhou Hospital of Traditional Chinese Medicine and Haoxian Hospital of Traditional Chinese Medicine were selected as the research subjects. The block randomization method was used to divide patients with advanced esophageal cancer into three groups: control group, trial group 1, and trial group 2, with 40 cases each. This research plan was approved by the Ethics Committee of Henan Provincial Hospital of Traditional Chinese Medicine (Approval No.: 2019 Hospital Ethics Review No. (36)].
1.1.1 Inclusion Criteria (1) Meet the diagnostic criteria of traditional Chinese and Western medicine for esophageal cancer; (2) Patients who cannot undergo surgery, radiotherapy, chemotherapy or disease progression after chemotherapy; (3) Gender is not limited, age is not limited; (4) Estimated survival time > 20 days; (5) Physical Strength Status (KPS) score≥ 40 points; (6) Those who can still take oral Chinese medicine before treatment; (7) Those with normal blood routine and heart, liver and kidney function; (8) Patients who voluntarily sign the informed consent form with informed consent.
1.1.2 Exclusion Criteria (1) pregnant and lactating women; (2) Those with mental illness who are difficult to cooperate with treatment; (3) Those who are allergic to drugs; (4) Those with severe liver, kidney, heart and hematopoietic system diseases; (5) Those without a clear pathological diagnosis; (6) Those who have participated in other clinical studies; (7) According to the judgment of the researcher, there are other lesions or conditions that reduce the possibility of enrollment or complicate enrollment, such as frequent changes in the working environment, unstable living environment and other conditions that are likely to cause loss to follow-up.
1.1.3 Exclusion criteria (1) Cases without any evaluable records after taking the drug; (2) Subjects who met the inclusion criteria but did not complete the trial for various reasons, including subjects withdrawing spontaneously and subjects passively withdrawing. Excluded cases should state the cause, and their case report form (CRF) should be kept for future reference.
1.2 Diagnostic criteria
1.2.1 Western Medicine Diagnostic Criteria (1) All patients were diagnosed with esophageal cancer after a clear pathological diagnosis. Reference is made to the International Union for Cancer Control (UICC) and American Cancer Federation (AJCC) standards for TNM staging (8th edition) of esophageal cancer issued in 2017 [5]. (2) The histologic type is squamous cell carcinoma. (3) Pathological grade (G): Gx grade cannot be determined according to G1 stage; G1 differentiation is good; differentiation in G2; poor G3 differentiation; G4 undifferentiated is staged by G3 squamous cell carcinoma.
1.2.2 Diagnostic Criteria of Traditional Chinese Medicine The differentiation standards of traditional Chinese medicine refer to the national planning textbook "Oncology of Traditional Chinese Medicine" [6] of general higher education, and the team of Professor Zheng Yuling jointly formulated the clinical diagnosis of esophageal cancer, spleen, kidney yang deficiency, sputum and blood. Main symptoms: inability to eat; There is a choking sensation; Spit saliva foam; The tongue is light and fat, less mossy, and the pulse is fine or weak. Concomitant: pale; lack of energy; Cold and cold; edema of the face or both lower extremities; Irregular stool. Diagnosis basis: (1) inability to eat; (2) There is a feeling of choking; (3) Spitting water or salivation or thin phlegm or foam; (4) pale or weak energy; (5) Cold and cold; (6) edema of the face or both lower limbs; (7) irregular stool; (8) The tongue is light and fat, less moss, and the pulse is fine or weak. Diagnosis can be made by having 2 of the first 3 items and adding 2 of the last 5 items. Only after the judgment of 2 physicians at the level of deputy chief physician or above can they be enrolled.
1.3 Treatment
1.3.1 Control group The control group was given the Chinese Association of Chinese Medicine "Guidelines for the diagnosis and treatment of traditional Chinese medicine in tumors: ZYYXH/T136~156-2008" [7] The main prescription recommended for esophageal cancer was angelica tonic blood soup and guizhi ginseng soup granules (Sichuan New Green Co., Ltd.; Composition: Astragalus 15 g, angelica 30 g, dried ginger 6 g, codonopsis 15 g, baiju 15 g, cooked ground 15 g, white peony 12 g, guizhi 9 g, acute seed 5 g, banxia 9 g), 1 dose/d, 3 times/d, for 6 weeks.
1.3.2 Experiment Group 1 Test Group 1 was given clove tube esophagus containing chemical pills combined with Gui Guan esophagus granules: (1) Clove tube esophagus containing pills (Sichuan New Green Co., Ltd., Henan Provincial Hospital of Traditional Chinese Medicine pharmacy made pills; Production batch number: 20200801) is the experience side, the original name: tube esophagus containing chemical pills, composition: ginseng 15 g, cooked rehmannia 30 g, cinnamon 6 g, seaweed 30 g, etc., including chemical use, 1 pill / time, 3 times / d, for 6 weeks. (2) Attached Gui Guan Shitong Granules (Sichuan New Green Co., Ltd.), formerly known as: Fuzheng Guben Tong Granules, composition: 9 g of aconite, 5 g of cinnamon, 15 g of Codonopsis, 15 g of cooked land, 15 g of Huaiyam, 1 dose/d, 3 times/d, for 6 weeks.
1.3.3 Test Group 2 Test Group 2 was given clove tube esophagus containing pills, and the usage and dosage were the same as above.
The drugs were distributed and recorded by the pharmacy of Henan Provincial Hospital of Traditional Chinese Medicine in the order in which each subject was treated. Each follow-up visit recorded the number of medicines taken and returned by the subject during the cycle. Considering that patients with advanced esophageal cancer have poor physical condition and relatively short survival time, under the knowledge of the investigators of this trial, basic treatment, such as appropriate nutritional support and symptomatic treatment, can be given at the same time during the period of taking traditional Chinese medicine.
1.4 Observation indicators
1.4.1 General information Collect general information of patients, including gender, age, course of esophageal cancer, allergy history, smoking history (smoking cessation: those who quit smoking for at least 2 years before enrollment; Smoking: ≥1 stick/d, lasting more than 6 months, smoking and smoking cessation are smoking history), drinking history (alcohol abstinence: those who abstained from alcohol for at least 2 years before enrollment; Alcohol consumption: ≥1 time/week, lasting more than 6 months, drinking and abstinence are both alcohol history), history of surgical resection, history of chemotherapy, history of radiotherapy, history of targeted therapy, history of immunotherapy, history of coronary artery, history of hypertension, history of diabetes.
1.4.2 Main indicators Survival rate, quality of life (QOL) score after 6 weeks of treatment [8] (full score of 60 points, extreme difference of <20 points, difference of 21~30 points, generally 31~40 points, better 41~50 points, good 51~60 points, the higher the score, the higher the quality of life), KPS score [8] (full score of 100 points, the higher the score, the higher the quality of life), TCM syndrome points [9] (loss of appetite, vomiting mucus, dysphagia, retrosternal pain, Mental fatigue is scored, with 3 points for grade III, 2 points for grade II, 1 point for grade I, 0 for a total of 15 points, and the lower the score, the higher the quality of life).
1.4.3 Safety evaluation Vital signs include heart rate, breathing, blood pressure, and body temperature; Laboratory tests include CBC, urinalysis, liver function, renal function, ECG, and adverse event recordings.
1.4.4 Toxic side effects The toxic side effects of the treatment of patients are recorded, including digestive tract reactions, bone marrow suppression, liver and kidney function damage, and neurotoxicity.
1.5 Follow-up Through the patient's regular follow-up or electronic communication, the drug began to be followed up once a week, 2 weeks for 1 node, follow-up to 6 weeks, and the changes of observation indicators at each node (baseline, treatment 2 weeks, 4 weeks, 6 weeks) were recorded.
1.6 Statistical Methods SPSS 25.0 software was used for statistical analysis. The measurement data of normal distribution were expressed as (x±s), and univariate ANOVA ANOVA was used for comparison between the three groups. The non-normal distribution of the measurement data is represented by M (P25, P75), and the Kruskal-Wallis H-rank sum test was used for comparison between the three groups. Count data are expressed as relative numbers, using the χ2 test or Fisher's exact probability method. The QOL score, KPS score and TCM syndrome score of the three groups at different time points were compared using a generalized estimation equation. The difference in P<0.05 was statistically significant.
2 Results
2.1 Comparison of general data of the three groups of patients In this study, 109 patients with advanced esophageal cancer were finally included: 36 patients in the control group, 35 patients in the 1st group of the trial, and 38 patients in the 2nd group of the trial. There were no significant differences in gender, age, esophageal cancer course, allergy history, smoking history, alcohol history, surgical resection history, chemotherapy history, radiotherapy history, targeted therapy history, immunotherapy history, coronary heart disease history, hypertension history, and diabetes mellitus history (P>0.05), as shown in Table 1.
2.2 Comparison of survival rate of patients after 6 weeks of treatment After 6 weeks of treatment, the survival rate of the control group was 72.7% (26/36), the survival rate of trial group 1 was 88.6% (31/35), and the survival rate of trial group 2 was 86.8% (33/38), and the survival rate of patients in the three groups after 42 days of treatment was not statistically significant (χ2=4.026, P=0.133).
2.3 Comparison of QOL scores before and after treatment in the three groups There was no interaction between groups and time on QOL scores (P interaction>0.05), the main effect of the groups was not significant on QOL scores (>0.05 between P groups), and the main effect of time on QOL scores was significant (P time<0.05). The QOL scores of the three groups were higher than those at 4 weeks and 6 weeks of treatment were higher than those at baseline and 2 weeks of treatment, and the QOL scores at 6 weeks of treatment were higher than those at 4 weeks of treatment, and the differences were statistically significant (P<0.05), as shown in Table 2.
2.4 Comparison of KPS scores before and after treatment between the three groups There was no interaction between groups and time on KPS score (P interaction>0.05), the main effect of the group was not significant on KPS score (>0.05 between P groups), and the main effect of time on KPS score was significant (P time < 0.05). The KPS score of the three groups was higher than that of 4 weeks of treatment, and the difference was statistically significant (P<0.05), as shown in Table 3.
2.5 Comparison of TCM syndrome points before and after treatment of three groups There was no interaction between groups and time on TCM syndrome points (P interaction>0.05), the main effect of the groups on TCM syndrome points was significant (P group <0.05), and the main effect of time on TCM syndrome points was significant (P time<0.05). The TCM syndrome scores of the three groups were lower than baseline at 2 weeks, 4 weeks and 6 weeks of treatment, lower than 2 weeks of treatment at 4 weeks and 6 weeks of treatment, and lower than 4 weeks of treatment at 6 weeks, with statistically significant differences (P<0.05), as shown in Table 4.
There was interaction between group and time on vomiting mucus score (P interaction<0.05), and group and time did not interact on appetite loss, dysphagia, retrosternal pain, and fatigue score (P interaction>0.05). The main effect was significant in the scores of loss of appetite and vomiting mucus (0.05 between group P<), and the main effect on the scores of loss of appetite, vomiting mucus, dysphagia, and retrosternal pain (P time < 0.05). After 6 weeks of treatment, the scores of appetite loss and vomiting mucus in the two groups of the trial were lower than those in the trial group 1, and the difference was statistically significant (P<0.05).
At 2 weeks of treatment, the scores of loss of appetite, vomiting mucus, and retrosternal pain in the three groups were lower than baseline, and the differences were statistically significant (P<0.05). At 4 weeks of treatment, the scores of loss of appetite, vomiting mucus, dysphagia, and retrosternal pain were lower than the baseline, and the scores of loss of appetite and vomiting mucus were lower than those of 2 weeks of treatment, and the differences were statistically significant (P<0.05). At 6 weeks of treatment, the scores of appetite loss, vomiting mucus, dysphagia, retrosternal pain, and fatigue were lower than the baseline, and the scores of loss of appetite, vomiting mucus, and dysphagia were lower than those of 2 weeks of treatment, and the differences were statistically significant (P<0.05), as shown in Table 5.
2.6 Safety evaluation The adverse events of the three groups of patients included diarrhea, fever, dry mouth, sore throat, inability to eat, lung infection, etc., and most of the above adverse reactions were considered to be unrelated to drugs, and there were no serious related complications. The adverse event rates of patients in the three groups were 19.4% (7/36) in the control group, 17.1% (6/35) in the 1st group of the trial, and 18.4% (7/38) in the 2nd group. There was no significant difference in the incidence of adverse events between the three groups (χ2=0.063, P=0.969).
3 Discussion
In this study, for ethical reasons, the placebo control group was not set up, and the esophageal cancer treatment drugs recommended in the "Guidelines for the diagnosis and treatment of traditional Chinese oncology medicine: ZYYXH/T136~156-2008" [7] were selected as the control. Through the accumulation of long-term treatment experience and clinical treatment needs of successive generations of doctors, TCM formulas have gradually formed different internal and external dosage forms such as soup, wine, pills, powder, and ointment, among which pills are mostly used for chronic or debilitating diseases. The research drug clove tube esophagus pill is a pill, tumor patients generally have a long course of disease, without surgery, radiotherapy, chemotherapy and other treatment options, the pathogenesis is relatively stable, the pill can be taken for a long time. At the same time, the drug can be directly reached to the lesion and increase the drug concentration. In addition, pills are easy to take[10] and affordable. Therefore, this study uses clove tube esophageal pills for the treatment of advanced esophageal cancer, innovatively combines the concept of traditional Chinese medicine with clinical research, and provides a new idea for the study of the mechanism of traditional Chinese medicine in the treatment of esophageal cancer disease.
This study found that there was no statistically significant difference between the three treatment options in survival for advanced oesophageal cancer (P>0.05). The main effect was significant in the QOL score, KPS score and TCM syndrome score of the three groups (P<0.05). The QOL score and KPS score changed with time after treatment, and it was found that the QOL score improved after treatment with all three regimens. TCM syndrome points vary with time, and all three treatment options reduce TCM symptom points, especially in loss of appetite, dysphagia, retrosternal pain, vomiting mucus and mental fatigue. Compared between the three groups, the two groups were better than the control group in improving the symptoms of loss of appetite and vomiting mucus. In terms of safety, although the incidence of adverse reactions in trial group 1 and trial group 2 was lower than that in control group, the difference was not statistically significant (P>0.05), and no serious related complications occurred. The results showed that all three treatment regimens could effectively improve patients' clinical symptoms and improve their quality of life, and the two groups of trials were more obvious in improving patients' clinical symptoms. Considering that continuous administration of the drug may increase the patient's discomfort in taking the drug, there was no significant difference between the trial 1 group and the control group.
Clove tube esophagus pill is summarized by Professor Zheng Yuling's long-term clinical practice combined with rich theoretical knowledge, and has been awarded a national invention patent [4]. Clove tube food tong containing chemical pills is composed of cloves, agarwood, ginseng, cooked rehmania, cinnamon, fine spices and so on. Cloves in the prescription are essential medicines for the treatment of qi reversal and spleen and stomach; Agarwood into the kidney, the two meridians of life, the introduction of medicine into the kidney meridian, replenish the five internal organs, strong yuan yang, is yang and Shen, not only warm in the qi, reduce the reverse and stop vomiting, but also warm the kidney and absorb qi; The combination of the two, playing the function of reducing the temperature and regulating qi and choking, is a monarch medicine. Ginseng is the first medicine for qi replenishment, sweet taste and blood, the main supplement of the five internal organs, the essence of the kidney, the essence of the essence, the essence of the trick; Cooked ground yellow is warm but not hot, replenishing but not greasy, good at tonifying kidney yin blood, can also benefit the essence and fill the essence, and seek yang in the yin; When the two are used together, the body is harmonized with qi and blood, and the power of nourishing qi and blood is jointly displayed. Cinnamon warms the kidneys to help the fire, and the fire can give birth to the soil, so in the warmth, there is the function of replenishing the fire and helping the yang, warming the meridians, specializing in treating the deficiency of kidney yang, the evidence of the death gate fire decay, and also curing the "internal organs and knots"; Fine and good warmth through the chest, phlegm and tricks; The two work together, together to warm the kidney and yang, with ginseng that nourishes blood and nourishes yin, cooked ground yellow, can make yin get yang help and biochemical infinity, showing the effect of "seeking yang in yin", the combination of the four is a medicine. Turmeric bitterness can break blood, and the Lord breaks blood stasis; Three and seven lines of blood stasis and new blood, through the veins and blood, the two together activate the blood and eliminate the effect, blood line is qi travel, increase the monarch medicine qi ventilation effect, and can prevent the four flavors of the medicine from being too warm, the same as adjuvant. Seaweed salty into the kidney meridian, in order to dissolve phlegm soft and firm dispersion of medicine, lead the power of medicine in soft and firm dispersion, for medicine. The above nine flavor drugs complement each other, and together play the function of invigorating qi and nourishing blood, eliminating phlegm and removing stasis.
Modern pharmacological studies have shown that cloves induce apoptosis of tumor cells by upregulating the expression of apoptotic cells and downregulating the expression of anti-apoptotic cells [11]. Clove extract can enhance apoptosis of cancer cells mediated by fluorescent magnetic nanoparticles, and inhibition of cancer cell growth is one of the more effective methods for controlling tumors, and studies have shown that cell proliferation is significantly reduced after 24 h and further reduced in a dose-dependent manner after 48 h [12]. Agarwood was first recorded in the "Famous Doctors", and agarwood has antitumor, analgesic, antioxidant [14] and other activities. Ginsenosides may inhibit the production of tumor vascular networks by reducing vascular endothelial growth factor[15]; Antitumor effects are achieved by inhibiting angiogenesis, promoting apoptosis of tumor cells, inducing tumor cell cycle arrest, and reversing tumor cell drug resistance [16]. Rehmannia has anti-aging, anti-tumor, regulating blood lipids and blood sugar, bacteriostatic, antigastric ulcer, antidepressant, and hepatoprotective pharmacological activities [17]. Cinnamon is anti-tumor and improves human immunity, radiation resistance, and mutagenesis [18]. At present, a variety of pharmacological activities of Xanthine have been reported, among which α-octane ether components can inhibit the proliferation of human esophageal cancer cells by regulating the expression of genes related to mitochondrial apoptosis pathway, and can also control the proliferation of human lung cancer cells by regulating genes, which has certain anti-cancer effects [19]. In vitro it has the effect of regulating immunosuppression, in vivo and in vitro has anti-inflammatory effects, and volatile oil has antipyretic and analgesic effects [20]. Curcumin has anti-tumor effects, induces apoptosis and autophagy of tumor cells, inhibits the growth, invasion and metastasis of tumor cells, and then inhibits the early spread and recurrence of tumors, improving the prognosis of patients [21]. Panax notoginseng and its total saponin extract exert anti-tumor effects by inhibiting the malignant transformation of precancerous cells, inhibiting the proliferation of cancer cells, inhibiting cell metastasis, etc., and also have anti-myocardial ischemia, anti-cerebral ischemia or ischemia-reperfusion injury to protect brain tissue, improve memory, promote the proliferation of neural stem cells after cerebral ischemia to protect the nervous system, and have anti-inflammatory, antibacterial, anti-aging effects, etc. [22]. Seaweed has certain anti-tumor effects, and its mechanism is mainly to inhibit tumor cell proliferation, induce tumor cell apoptosis, and it is known to have anti-metastasis and anti-angiogenic activities in vivo [23-24].
It can be seen that the main components of clove tube esophagus pills have different degrees of anti-tumor, anti-inflammatory, antioxidant, immune regulation and other effects, which confirms its effectiveness in the treatment of esophageal cancer from a pharmacological point of view. The data in this study are repeated measurement data, which meets the application requirements of linear mixed model and generalized estimation equation, and for small sample data, the application of generalized estimation equation can obtain more stable results. Due to the impact of the epidemic, some patients have missing data, coupled with a relatively small sample size, the data does not conform to the normal distribution, and there are many missing values, so it is more reasonable to use a generalized estimation equation analysis in this study.
In summary, the simple application of clove tube esophageal containing pills, clove tube esophagus containing chemical pills combined with Gui Guan esophagus granules, angelica tonic blood soup combined with guizhi ginseng soup plus minus granules for the treatment of advanced esophageal cancer can alleviate the symptoms of patients and improve the quality of life of patients, and clove tube esophageal containing pills is more obvious in improving the clinical symptoms of patients. To a certain extent, the single or combined application of clove tube esophageal cancer pills can improve the survival rate of esophageal cancer patients, which is suitable for patients with advanced esophageal cancer, safe and effective, and worthy of clinical promotion. However, this study also has the limitations of small sample size and short observation time of some sub-centers, and multi-center and large-sample randomized controlled trials are still needed to verify the research conclusions in the future. The specific mechanism of action of clove tube esophageal pills in the treatment of advanced esophageal cancer is not clear, and will be further explored through animal experiments in the future.
Acknowledgements: Thank you for the strong support of the First Affiliated Hospital of Henan University of Chinese Medicine, the Third Affiliated Hospital of Henan University of Chinese Medicine, Henan Provincial Cancer Hospital, Haoxian Hospital of Traditional Chinese Medicine, Songxian Hospital of Traditional Chinese Medicine, Luoyang Hospital of Traditional Chinese Medicine, Jiyuan Hospital of Traditional Chinese Medicine, Linzhou Hospital of Traditional Chinese Medicine, and Nanyang Zhangzhongjing Hospital for their strong support (in no particular order).
There is no conflict of interest in this article.
Bibliography
Source: ZHENG Yuling, ZHANG Yaling, LIU Huaimin, et al. Clinical study of clove tube esophageal pills alone and combined with guigui tube esophageal granules in the treatment of advanced esophageal cancer[J]. Chinese Journal of General Practice, 2023, 26(30): 3765-3771. DOI: 10.12114/j.issn.1007-9572.2023.0177.