Study On The Dominant Population And Mechanism Of Qu-xie Capsule In Different Treatment Stages Of Metastatic Colorectal Cancer

Background:Metastatic Colorectal Cancer(mCRC)is almost incurable.For mCRC that cannot be cured,palliative treatment is recommended according to the guidelines.According to the specific situation of the patient’s treatment,it can be divided into first-line treatment,second-line treatment,3rd-line and above treatment.However,some mCRC patients are unable to tolerate or refuse standard chemotherapy and targeted treatment due to poor physical condition,old age,economic difficulties,and other reasons,turning to traditional Chinese medicine or a combination of traditional Chinese and Western medicine treatment,and still achieving good clinical efficacy.Traditional Chinese medicine has a long history of treating colon cancer,with the characteristics of simplicity,convenience,cost-effectiveness,and efficacy.It is an important component of mCRC treatment in China,and the combination of traditional Chinese and Western medicine is the advantage of malignant tumor treatment in China.A lot of studies have shown that traditional Chinese medicine treatment can bring clinical benefits to mCRC patients and has unique clinical efficacy.At the same time,traditional Chinese medicine has accumulated a lot of clinical experience in the long-term clinical practice of treating mCRC.Many clinical research results have shown that traditional Chinese medicine has the effects of prolonging the survival time of mCRC patients,improving their quality of life,reducing standard treatment side effects,and alleviating clinical symptoms.Qu-xie Capsule is a commonly used hospital prescription by Professor Yang-Yufei for the treatment of mCRC.Qu-xie Capsule is a modified version of the "Yin Yang Gong Ji Wan" written by Li-Zhongzi,physician of Ming Dynasty,in his book "Yi Zong Bi Du",which has the effects of "Fu Zheng Qu Xie" and "Wen Yang Tong Xia".Qu-xie capsule has been used in Xiyuan Hospital of the China Academy of Chinese Medical Sciences for nearly 30 years.A number of randomized controlled clinical trials(registration number of China Clinical Trial Center:ChiCTR-IOR-16009733,ChiCTR-IOR-1608924)found that Qu-xie capsule can improve the quality of life of mCRC patients,reduce the mortality rate,and prolong the total survival period of patients.However,there is no in-depth study or subgroup analysis to provide clinical evidence on the clinical efficacy of Qu-xie capsule at different treatment stages of mCRC.At the same time,the prescription of Qu-xie capsule is complex,with many components,and the mechanism of action is not single,and there is still a large part of the mechanism of action that has not been explored.Therefore,it is of great clinical significance to further clarify the benefits of Qu-xie capsule in different treatment stages of mCRC and the characteristics of the dominant population,and explore the mechanism of Qu-xie capsule in the treatment of colorectal cancer.Objective:To analyze the characteristics of the beneficiaries of Qu-xie capsule in different treatment stages of metastatic colorectal cancer,and explore the mechanism of Qu-xie capsule in the treatment of colorectal cancer.To provide reliable basis for the clinical application of Qu-xie capsule in metastatic colorectal cancer.Methods:The clinical study included 60 patients with mCRC(no less than 15 at the first-line,second-line,third-line and above)who visited the tumor clinic of Xiyuan Hospital from 2021.11.15 to 2023.1.5.They took Qu-xie capsule twice a day,5 capsules a time,and the course of treatment was 30 days(taking 20 days and rest for 10 days).According to the best median progression-free survival of the current western medicine treatment,the patients were divided into the Dominant patients who benefited from Qu-xie capsule and the non-Dominant patients who did not benefit from Qu-xie capsule.Compare the differences in baseline data,peripheral blood ctDNA abundance,immune cell distribution,tumor markers between the Dominant patients and the non-Dominant patients,summarize the characteristics of the Dominant population of Qu-xie capsule,and provide suggestions for the clinical application of Qu-xie capsule in mCRC.In vitro study,cancer SW480,HT-29 and Caco-2 cells were selected,and each type of cancer cell was divided into CTRL group(blank control),negative control group(normal saline intestinal absorption solution),Qu-Xie group(Qu-xie capsule intestinal absorption solution),and positive control group(5-Fu).CTRL group was given no intervention,negative control group was given normal saline intestinal absorption solution,Qu-Xie group was given Qu-xie capsule intestinal absorption solution with the best action concentration,and positive control group was given 20μg/mL of 5-Fu,the intervention time is the best action time when Qu-xie capsule intestinal absorption solution is screened.After the intervention,the proliferation and migration ability of three types of cancer cells,the damage of genetic material,cell cycle and apoptosis,and the expression of oncogene protein were detected respectively.Result:1.Qu-xie capsule can prolong the progression-free survival period of mCRC patients,and its clinical medication is safe.The common adverse reaction is diarrhea,which isⅠ-Ⅱ grade(CTCAE v4.03 grade).There were 18 patients with reduced medication usage due to Ⅰ-Ⅱ degree diarrhea.2.The Dominant population of Qu-xie capsule may have the following baseline characteristics:①lower proportion of rectal cancer,higher proportion of colon cancer,②lower proportion of ulcerative adenocarcinoma,③lower proportion of low differentiation,higher proportion of medium-high differentiation,④lower mutation rate of genotypic BRAF,⑤lower proportion of liver metastasis,higher proportion of distant lymph node metastasis,⑥lower tumor burden,⑦The proportion of "Liver depression and Spleen deficiency" and "Spleen and kidney deficiency" is higher,⑧The proportion of first-line treatment stage is higher,⑨the proportion of targeted drugs used in the past is lower,and the proportion of chemotherapy drugs used in the past is higher.3.The following reactions may occur after treatment in the Dominant population of Qu-xie capsule:①the abundance of ctDNA mutation in peripheral blood decreases,②lymphocytes,total T cells,CD8+T cells,NK cells,TNF-α raise,③γδ T cells,CEA,CA199,ALP,γ-GT reduction.4.Qu-xie capsule has inhibitory effect on the proliferation and migration of cancer SW480,HT-29 and Caco-2 cells.The inhibitory effect of Caco-2 cells is the best,followed by SW480 and HT-29 cells.5.Qu-xie capsule can damage the genetic material of cancer SW480,HT-29 and Caco-2 cells.The damage effect of HT-29 cells is the most obvious,and SW480 and Caco-2 cells are relatively light.6.Qu-xie capsule can induce cell cycle arrest and apoptosis of cancer SW480,HT-29 and Caco-2 cells.The effect of cell cycle arrest is more obvious in HT-29 and Caco-2 cells than in SW480 cells;The apoptosis rate of HT-29 cells was the highest,followed by SW480 and Caco-2 cells.7.Qu-xie capsule can regulate the expression of APC,TP53,MAPK and KRAS proteins in SW480,HT-29 and Caco-2 cells.The expression of cancer-related proteins in HT-29 cells is the most obvious,followed by SW480 cells,and Caco-2 cells showed the worst changes.Conclusion:Qu-xie capsule can prolong the progression-free survival period of mCRC patients.The dominant population of Qu-xie capsule may have the following baseline characteristics:the proportion of colon cancer is higher,the proportion of medium-high differentiation is higher,the BRAF mutation rate is lower,the tumor burden is lower,"Liver depression and Spleen deficiency" and "Spleen and kidney deficiency" is higher.The following reactions may occur after treatment of Qu-xie capsule in the dominant population:①the mutation abundance of ctDNA in peripheral blood decreased,②lymphocytes,total T cells,CD8+T cells,NK cells,TNF-α Raise,③γδ T cells,CEA,CA199,ALP γ-GT reduction.One of the mechanisms of Qu-xie Capsule in the treatment of colorectal cancer is to trigger the damage of cytogenetics substances,and then induce the cell cycle arrest or apoptosis of colon cancer cells,thus inhibiting the proliferation and migration of colon cancer cells.However,due to the numerous components and complex mechanisms of action of Qu-xie Capsules,their anti-tumor effects are not singular.Further research on Qu-xie Capsules or screening of the main anti-tumor components in the formulas can be carried out for anti-tumor research,in order to clarify the specific pharmacological components and comprehensive mechanism of action of Qu-xie Capsules against tumors.