Synergistic Effect Of Elemene Combined With First-generation EGFR-TKIs In The Treatment Of Advanced Lung Adenocarcinoma

Objective: In recent years,the morbility and mortality of lung cancer have increased significantly.EGFR-TKIs have a good effect on non-small cell lung cancer with EGFR-sensitive mutations.However,the lung cancer treatment was failed due to resistance to EGFR-TKIs eventually.This study intends to analyze the synergistic effect of traditional Chinese medicine extract elemene during first-generation EGFR-TKIs treatment of patients with advanced lung adenocarcinoma through real-world research methods,and provide more treatment methods for patients with advanced lung adenocarcinoma.Methods: This study included 113 patients with advanced lung adenocarcinoma(stage IIIB-IV)from January 2016 to December 2019 according to inclusion criteria.All patients were given the appropriate anti-tumor treatment according to the principles or guidelines of cancer theraoy in the real world.All patients were divided into three groups: elemene combined with EGFR-TKIs group,EGFR-TKIs group and the routine chemotherapy with/without radiotherapy group.Patients may be treated as first-line,second-line,or more according to clinical guidelines.The data of patients' demographics,short-term efficacy evaluation,subsistence analysis,quality of life score,and adverse reactions during treatment were collected.The Kaplan–Meier survival curves according to progression-free survival(PFS)of the three groups were analysed.Chi-square test or Fisher's exact test was used to compare the efficacy and adverse reactions between groups.Univariate and multivariate survival analyses were used to compare the correlation between clinical characteristics and survival time.Results: There were 34 cases divided in the elemene+EGFR-TKIs group,47 cases in the EGFR-TKIs group,and 32 cases in the chemotherapy with/without radiotherapy group.The ORR of the elemene + EGFR-TKIs group was 41.2%,which was higher than 29.8%(P=0.288)of the EGFR-TKIs group and 28.1%(P=0.266)of the chemotherapy with/without radiotherapy group,and the difference was not statistically significant.The DCR of the elemene + EGFR-TKIs group was 94.1%,which was higher than 78.7% of the EGFR-TKIs group,and the difference was not statistically significant(P=0.054).DCR in the elemene+EGFR-TKIs group was higher than 59.4% in the chemotherapy with/without radiotherapy group,and the difference was significant(P=0.0008).The m PFS in the elemene+EGFR-TKIs group,the EGFR-TKIs group,and the chemotherapy with/without radiotherapy group were 14.0 months,10.0 months(P=0.037),and 7.5 months(P=0.002).In the elemene+EGFR-TKIs subgroup,the differences in age(P=0.279),gender(P=0.432),and stage of patients(P=0.197)had no significant effect on PFS,the differences in KPS scores had significant effects on PFS(P=0.027),and the patients of KPS scores?80 points have a better prognosis.Univariate and multivariate analysis suggested that KPS score and smoking history were related to PFS in patients with advanced lung adenocarcinoma.Patients with a KPS score of ?80 and no history of smoking had a better prognosis.Among smoking patients,PFS in the elemene + EGFR-TKIs group was significantly longer than that in the EGFR-TKIs group(P = 0.029)and the chemotherapy with/without radiotherapy group(P = 0.027).Compared with the EGFR-TKIs group,the quality of life was significantly improved in the elemene+EGFR-TKIs group(P=0.047);the quality of life was significantly improved in the elemene+EGFR-TKIs group compared with the chemotherapy with/without radiotherapy group(P=0.008).None of the three groups of patients had grade IV adverse reactions.The rash incidence was significantly higher in the EGFR-TKIs group than in the elemene+EGFR-TKIs group(55.3% vs 23.5%,P=0.034).The incidence of nausea and vomiting in the chemotherapy with/without radiotherapy group was significantly higher than that in the elemene+EGFR-TKIs group(56.3% vs 8.8%,P=0.0005)and the EGFR-TKIs group(56.3% vs 12.8%,P=0.004).The incidence of myelosuppression was significantly higher in the chemotherapy with/without radiotherapy group than that in the elemene+ EGFR-TKIs group(53.1% vs 14.7%,P=0.008)and the EGFR-TKIs group(53.1% vs 14.9%,P=0.002).Conclusion: 1.Elemene combined with EGFR-TKIs in patients with advanced lung adenocarcinoma has significantly improved progression-free survival.2.Elemene combined with EGFR-TKIs can achieve higher disease control rate in the treatment of advanced lung adenocarcinoma.3.In patients with advanced lung adenocarcinoma,KPS score and smoking history were independent prognostic factors.4.The incidence of rash in elemene treatment is significantly reduced than EGFR-TKIs,which can improve the quality of life in lung cancer patients.5.The above results suggest that elemene combined with EGFR-TKIs has a potential synergistic effect in patients with advanced lung adenocarcinoma with EGFR mutations.The mechanism need to be investigated and the clinical effect need to be confirmed by further large-scale clinical randomized controlled studies.