| Objective:To observe the efficacy and safety of heavy-dosage heat-clearing and detoxifying traditional Chinese medicine in reducing lung cancer patients’ tumor markers,in order to provide preliminary evidence-based evidence for clinical application of heavy-dosage heat-clearing and detoxifying traditional Chinese medicine.Methods:The literature review summarized the research progress of common tumor markers and new tumor markers in lung cancer,as well as the history of lung cancer "toxin pathogenic" theory and the mechanism of heat-clearing and detoxifying treatment for lung cancer.The study adopted a single-center,prospective and single-arm clinical trial design.Subjects were selected from primary lung cancer patients with elevated tumor markers(CEA,CYFRA21-1,SCC-Ag,NSE,Pro-GRP)and diagnosis of cancer toxicity internal resistance syndrome who visited Beijing Traditional Chinese Medicine Hospital from October 1,2021 to November 30,2022.The intervention was the use of traditional Chinese medicine decoction containing heavy-dosage heat-clearing and detoxifying traditional Chinese medicine(the dosage of following drugs was greater than the upper limit of commonly used dosage:Scutellariae barbatae herba≥ 60g,Hedyotis diffusae herba≥60g,Solani nigri herba≥30g,Solani lyrati herba≥30g,Duchesneae indicae herba≥30g)for 4 months.We followed up with subjects to observe the tumor marker levels of subjects before and after treatment,evaluated their time to progression,follow-up time,response of tumors and tumor markers’maximum change rate,response and complete response.We assessed subjects’ changes in the quantitative TCM symptom score of cancer toxicity internal resistance syndrome and ECOG functional condition.We also observed whether heavy-dosage heat-clearing and detoxifying traditional Chinese medicine can lead to treatment-related adverse reactions in various systems,abnormal blood routine,liver and kidney function indicators.Results:46 patients were included in the study,44 patients completed the study,and 2 patients fell out.1.Compared the levels of lung cancer patients’ tumor markers before and after the treatment,it was found that there were significant differences in CEA(χ2=53.56,P<0.01),CYFRA21-1(χ2=56.66,P<0.01),NSE(χ2=82.27,P<0.01),and Pro-GRP(χ2=18.67,P<0.01).CEA,CYFRA21-1,NSE,and Pro-GRP remained stable and showed a downward trend after treatment.SCC-Ag after treatment were not significantly different from pretreatment level(χ2=4.13,P=0.39>0.05).There was no significant difference in tumor marker levels after treatment among subjects taking different types of heavy-dosage heatclearing and detoxifying herbs(P>0.05).2.The median TTP of 46 subjectts did not reach.Preliminary analysis showed that there was no significant relationship between subjects’ TTP and cumulative doses or types of heavy-dosage heat-clearing and detoxifying traditional Chinese medicine(P>0.05).46 subjects were followed for 2.07-18.03 months,with a median follow-up time of 9.07 months(95%CI:8.70-9.44 months).The median follow-up time of tumor-free subjects with elevated CEA was 6.23 months(95%Cl:6.18-6.28 months),the median follow-up time of tumor-bearing subjects with elevated CEA was 9.17 months(95%CI:8.86-9.48 months).The median follow-up time of tumor-free subjects with elevated CYFRA21-1 was 6.23 months(95%CI:3.61-8.86 months)and the median follow-up time of tumor-bearing subjects with elevated CYFRA21-1 was 8.83 months(95%CI:5.63-12.03 months).The median follow-up time of tumor-free subjects with elevated SCC-Ag was 9.20 months(95%CI:5.67-12.72 months)and the median follow-up time of tumor-bearing subjects with elevated SCC-Ag was 8.53 months(95%CI:4.97-12.09 months).The median follow-up time of tumor-free subjects with elevated NSE was 9.07 months(95%CI:3.6314.51 months)and the median follow-up time of tumor-bearing subjects with elevated NSE was 9.17 months(95%CI:5.61-12.73 months).The median follow-up time of tumor-free subjects with elevated Pro-GRP was 6.20 months(95%CI:6.00-6.40 months)and the median follow-up time of tumor-bearing subjects with elevated Pro-GRP was 9.23 months(95%CI:8.21-10.26 months).The median follow-up time of tumor-free and tumor-bearing subjects with elevated tumor markers was respectively compared with the median DFS of tumor-free lung cancer patients and median PFS of tumor-bearing lung cancer patients reported in the literature,it was found that the median follow-up time of CEA,CYFRA21-1,SCC-Ag,NSE and Pro-GRP elevated tumor-bearing subjects in this study was longer than the median PFS of tumor-bearing lung cancer patients with elevated tumor markers reported in the literature.3.Among the 21 patients with tumors,there were 16 SD patients,accounting for 76.19%of them,and 5 PD patients,accounting for 23.81%.There was no patient with CR or PR after treatment.There was no significant relationship between response of tumors and cumulative herbal dose or types of herbs in subjects(P>0.05).SD subjects had stable levels of CEA,CYFRA21-1,NSE and Pro-GRP with declining trend after treatment and PD subjects had persistent increases in at least 1 tumor marker after treatment.4.The number of negative subjects’ CEA maximum change rate(corresponding to the decrease of tumor markers from baseline)was 17 cases and positive(corresponding to the increase of tumor markers from baseline)was 1 case,ranging from-76.67%to 17.65%.The number of subjects’ CYFRA21-1 maximum change rate was 22 cases with negative values and 1 case with positive values,ranging from-79.30%to 50.85%.The number of subjects’ SCC-Ag maximum change rate was 8 cases with negative values and 11 cases with positive values,ranging from-54.38%to 92.05%.The number of subjects’ NSE maximum change rate was 23 cases with negative values and 1 case with positive values,ranging from-80.44%to 8.38%.The number of subjects’ Pro-GRP maximum change rate was 11 cases with negative values and 1 case with positive values,ranging from-33.39%to 21.84%.There was no correlation between the maximum change rate of CEA,CYFRA21-1,SCC-Ag,NSE and the corresponding cumulative herbal dose(P>0.05).There was a high degree of positive correlation between the Pro-GRP’s maximum change rate and cumulative dose(r=0.70,P=0.01<0.05),ProGRP’s maximum change rate=-55.871+0.002 ×cumulative dose(g).There was no difference in the maximum change rate of each tumor marker among subjects taking different herbs(P>0.05).5.In subjects with elevated CEA,there were 4 cases of CEA response(22.22%)and 1 case of CEA complete response(5.56%)after treatment.In subjects with elevated CYFRA21-1,there were 5 cases of CYFRA21-1 response(21.74%),and 1 case of CYFRA21-1 complete response(4.35%).In subjects with elevated SCC-Ag,there were 2 cases of SCC-Ag response(10.53%)and 1 case of SCC-Ag complete response(5.26%).Among subjects with elevated NSE,there were 6 cases of NSE response(25.00%)and 3 cases of NSE complete response(12.50%);No Pro-GRP response or complete response were observed.6.There was a statistically significant difference in the subjects’ total score of TCM symptom quantification before and after treatment(χ2=169.74,P<0.01).The average total score decreased month by month from baseline to the fourth month of treatment.After the treatment,the scores of symptoms such as cough,expectoration,chest pain,chest tightness,wheezing,dry mouth,bitter mouth,and constipation as well as the scores of tongue and pulse,decreased month by month with statistical significance(P<0.01).However,there was no significant difference in the scores of hoarseness before and after treatment(P=0.11>0.05).One subject had hemoptysis,and the symptom didn’t change significantly after treatment.7.There was no significant change in the ECOG functional condition(χ2=8.000,P=0.092>0.05)after treatment.8.There were 14 cases of treatment related adverse reactions among 46 subjects,the incidence of TRAEs was 30.43%,including 9 cases with diarrhea(19.57%),3 cases with abdominal distension(6.52%),3 cases with gastrointestinal distension(6.52%),2 cases with abdominal pain(4.35%),2 cases with dizziness(4.35%),1 case with nausea(2.17%),1 case with heartburn(2.17%),and 1 case with rash(2.17%).All TRAEs were gradeⅠ-Ⅱ,only one case of grade Ⅱ TRAEs was diarrhea(2.17%).Heavy-dosage heat-clearing and detoxifying herbs had no adverse effects on blood routine,liver and kidney function.There was no significant relationship between the incidence of TRAEs and cumulative herbal dose or typse of herbs(P>0.05).Conclusion:Heavy-dosage heat-clearing and detoxifying traditional Chinese medicine can maintain tumor markers stable with declining trend in lung cancer patients,including significant control of CEA,CYFRA21-1,NSE and Pro-GRP.Heavy-dosage heat-clearing and detoxifying traditional Chinese medicine may delay disease progression in patients with tumor-bearing lung cancer with elevated CEA,CYFRA21-1,SCC-Ag,NSE,or Pro-GRP.Persistent rise of tumor markers in lung cancer patients under heavy-dosage heat-clearing and detoxifying herbal treatment may indicate disease progression.The maximum change rate of CEA,CYFRA21-1,NSE and Pro-GRP in subjects corresponded to decreased tumor markers compared to baseline were more than that of increased tumor markers.Among subjects with elevated tumor markers,a higher proportion of NSE,CEA and CYFRA21-1 response occurred after treatment,and the proportion of complete response NSE occurred was the highest.Heavy-dosage heat-clearing and detoxifying traditional Chinese medicine had a relieving effect on symptoms of cancer toxin internal resistance syndrome in lung cancer patients.It had a significant effect in alleviating cough,expectoration,chest pain,chest tightness,wheezing,dry mouth,bitter mouth and constipation and reducing tongue and pulse scores.Heavy-dosage clearing-heat and detoxifying traditional Chinese medicine may lead to adverse reactions in lung cancer patients.Gastrointestinal adverse reactions were the most common TRAEs.All of TRAEs ranged from grade Ⅰ-Ⅱ,and the incidence of grade Ⅱ TRAEs was very low.It didn’t have adverse effects on subjects’ physical condition,blood routine,liver and kidney function of patients.In summary,heavy-dosage heat-clearing and detoxifying traditional Chinese medicine is worth promoting in clinical practice. |
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