Effects Of Irinotecan Versus Etoposide First-line Chemotherapy On Brain Metastasis In Small Cell Lung Cancer

Research background and purposeSmall cell lung cancer(SCLC)is the type of lung cancer most prone to brain metastasis,and its median survival time after brain metastasis does not exceed 6 months.Evaluating the risk of brain metastasis in SCLC patients and taking measures in advance to prevent brain metastasis can help improve the prognosis of SCLC patients.Irinotecan is a camptothecin analog,which can inhibit topoisomerase I,thereby interfering with the synthesis of tumor cell DNA and affecting tumor cell mitosis.The average cerebrospinal fluid concentration of irinotecan is 13.4%(4.8%-22%)of plasma,and the median ratio of cerebrospinal fluid and plasma concentration of etoposide is 0.3%(0.09%-3.12%),which makes irinotecan easier to penetrate Blood-brain barrier.At the same time,some studies have found that compared with etoposide,the use of irinotecan can significantly improve the objective response rate of central nervous system tumors(65%vs.37%).Therefore,we speculate that irinotecan may have a positive effect on the prevention and treatment of SCLC brain metastasis than etoposide.This study intends to retrospectively analyze the effect of irinotecan versus etoposide first-line chemotherapy on SCLC brain metastasis and short-term efficacy,so as to provide a reference for the prevention and treatment of clinical small cell lung cancer brain metastasis.Research methodA total of 225 SCLC patients with baseline brain-free metastasis that met the criteria for admission and discharge were collected from November 2011 to July 2018 in the First Affiliated Hospital of Army Military Medical University.Among them,183 patients received irinotecan plus platinum(IP)chemotherapy in the first line,and 42 patients received etoposide plus platinum(EP)chemotherapy in the first line.Through the use of EmpowerStats software,according to 2:1 for pairing,84 cases in the IP group and 42 cases in the EP group were included for further analysis.There were no statistically significant differences in gender,age,smoking history,VALG stage,distant metastasis,and chemotherapy cycle between the two groups.Irinotecan combined with platinum group(IP group):Irinotecan injection(brand name Aili,Jiangsu Hengrui Pharmaceutical Co.,Ltd.,100mg/branch)175 mg/m~2,intravenous drip,D1.Etoposide combined with platinum group(EP group):Etoposide injection(trade name Etoposide,Qilu Pharmaceutical Co.,Ltd.,0.1 g/branch)100 mg/m~2,intravenous drip,D1-D3.Each group has a period of 21-28 days.Research result1.The ORR of the IP group and the EP group were 79.8%and 76.2%,respectively,with no significant difference(P=0.645).And the DCR was 89.3%and 92.9%,respectively,with no significant difference(P=0.748).Subgroup analysis showed that the ORR and DCR of the two groups of patients with limited stage and extensive SCLC were similar,with no significant difference(P>0.05).2.During the follow-up period,a total of 121 patients with SCLC showed progress.The first progress of the two groups of patients was mainly the primary lesion(69 cases)and brain metastasis(32 cases).The median PFS of patients in the IP group was 7.5±0.779 months(5.974-9.026),and the median PFS of the patients in the EP group was 5.5±0.648 months(4.230-6.770).The difference between the two groups was statistically significant(P=0.015).Further subgroup analysis shows that the median PFS of the two groups of patients in the extensive stage were 6.9 months and 4.6 months,respectively,with no significant difference(P=0.222),while the median PFS of the patients in the limited stage was 8.6 months and 5.9 Months,the statistical difference was significant(P=0.024).At the same time,the median PFS of the first-line chemotherapy combined with primary radiotherapy group and the chemotherapy-only group in the two groups of limited-stage SCLC patients was 9.5±0.863 months and 5.5±0.758 months,respectively.The statistical difference between the two was very significant(P=0.008).3.During the follow-up period,a total of 32 SCLC patients(32/126,25.4%)developed brain metastasis,including 19 in the IP group and 13 in the EP group.During the follow-up period,the median CNS TTP in the IP group did not appear,and the median CNS TTP in the EP group was 9.5±1.638 months(6.290-12.710),the statistical difference was significant(P=0.035).Further subgroup analysis shows that the median CNS TTP of the IP group in the extensive and limited stage did not appear,while the median CNS TTP of the extensive and limited stage in the EP group were 8.6 months and 9.5 months,respectively.There was no statistically significant difference between the two groups in the extensive stage(P=0.490),but the statistical difference was significant in the limited stage(P=0.017).At the same time,there was no statistically significant difference in the median CNS TTP between the first-line chemotherapy combined with primary radiotherapy and the chemotherapy alone in the two groups of patients with limited-stage SCLC(P=0.994).COX regression analysis was performed on the sex,age,smoking history,TNM stage,radiotherapy history,and treatment methods of SCLC patients with limited stage.The results showed that chemotherapy was an independent influencing factor for brain metastasis(P=0.023).4.The CIR of brain metastasis in all patients at half a year and 1 year were 10.3%and21.4%,respectively.In the IP group and EP group,the 3-month brain metastasis CIR was2.4%,the half-year brain metastasis CIR was 9.5%and 11.9%,and the 1-year brain metastasis CIR was 17.9%and 28.6%,respectively.Further subgroup analysis shows that the brain metastasis CIR of limited stage SCLC in the IP group was lower than that in the EP group from the third month onwards,and the 3-month brain metastasis CIR of the IP group and the EP group were 2.4%and 4.6%,rspectively.The half-year brain metastasis CIR were7.1%and 13.6%,and the 1-year brain metastasis CIR was 14.3%and 31.8%,respectively.There was no significant difference in CIR in half-year and one-year brain metastasis in patients with extensive SCLC,and there was no significant difference in CIR in other progress(including primary tumor,liver metastasis,bone metastasis,etc.)of all patients in the two groups.5.In terms of toxic side effects,the two groups were mainly myelosuppressive,of which52 cases(52/84,61.9%)in the IP group,22 cases(22/42,52.4%)in the EP group,and 11cases in the IP group with bone marrow suppression above 3 degrees and 6 cases in the EP group,with no significant difference between the two groups(P=0.306).Nausea,vomiting,diarrhea,liver damage and other side effects were also not significantly different(P>0.05).Analysis conclusionThe results of this study show that compared with etoposide and platinum,first-line chemotherapy with irinotecan and platinum delays the brain metastasis of patients with limited stage small cell lung cancer,and may have a positive effect on the prevention and treatment of brain metastasis in patients with limited stage small cell lung cancer.