Intercalated Combination Of Chemotherapy And Tyrosine Kinase Inhibitors As First-line Treatment For Patients With Non-Small-Cell Lung Cancer

Objective:This study aim to investigate the efficacy and safety of epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs)combined with chemotherapy in the first-line treatment of non-small cell lung cancer(NSCLC)patients with EGFR gene mutations compared with EGFR-TKIs alone.Methods:1.In this longitudinal study,first treated patients diagnosed with EGFR positive NSCLC as confirmed by pathological diagnosis were consecutively recruited at first class tertiary hospitals in Shandong from January,2014 to December,2016 and were followed up until March,2017.General information,smoking status,EGFR mutation site positive ratios of patients were analyzed to reduce the choice of migration.2.94 untreated EGFR positive patients with NSCLC were randomly assigned to 1)Intercalated combination group:four cycles(21 days/cycle)chemotherapy(lung adenocarcinoma:carboplatin+ pemetrexed;lung squamous carcinoma:carboplatin+docetaxel).inserting TKIs(gefitinib,erlotinib or Icotinib)treatment except for two days before and after chemotherapy and chemotherapy day.After four cycles chemotherapy all patients accept TKIs until disease progression or not tolerance toxicity or death;2)TKIs monotherapy group:patients only received TKIs(gefitinib,erlotinib or icotinib)daily until disease progression or not tolerance toxicity or death.3.Tumor imaging,blood carcino-embryonic antigen(CEA),CYFRA21-1 protein(CYFRA21-1),squamous cell carcinoma(SCC),CA-125 antigen(CA-125),neuron specific enolase(NSE)changes,major adverse reactions and the survival time were estimated during follow-ups.The primary observation index was progression free survival(PFS);other observation indexes were objective response rate(ORR),disease control rate(DCR),overall survival(OS)and adverse reactions.4.The curative effect evaluation:according to RECIST curative effect evaluation standard:complete remission(CR),partial response(PR),stable disease(SD),disease progression(PD),CR + PR as objective response rate(ORR).CR + PR + SD as disease control rate(DCR);adverse evcents were evaluated according to the NCI-CTCAE 4.0 standard for drug toxicity developed by the National Cancer Institute,followed by an assessment of 2 months/time.Results:1.94 patients with newly diagnosed EGFR positive mutations were enrolled in this study.In intercalated combination group and TKIs monotherapy group,there were 49 cases and 45 cases respectively.There were 57 cases of female patients(intercalated combination group 29 cases,TKIs monotherapy group 28 cases),and 37 cases of male patients(intercalated combination group 20 cases.TKIs monotherapy group 17 cases).The total smoking rate was 30.9%in the two groups(32.7%in the intercalated combination group and 28.9%in the TKIs monotherapy group).The mutation rates of exon-18,exon-19 and exon-21 genes in the intercalated combination group were 2.0%(1/49),44.9%(22/49),53.1%(26/49)and the mutation rate of exon-18,exon-19 and exon-21 genes in the TKIs monotherapy group were 0.0%(0/45),46.7%(21/22)and 53.1%(26/49).The percentage of gefitinib,erlotinib,icotinib in the intercalated combination group were 22.4%(11/49),20.4%(10/49),57.1%(28/49);the percentage of gefitinib,erlotinib,icotinib in the TKI monotherapy group were 22.2%(10/45),17.8%(8/45)and 60.0%(27/45).2.The mean PFS in the intercalated combination group was 16.63 months(95%Cl 13.901-19.351)and 10.69 months for the TKIs monotherapy group(95%Cl 8.457-12.926),P<0.01;due to the end of the study for the PD,and some patients follow-up is not completely completed,OS could not be analyzed.3.The objective response rates(ORR)in the intercalated combination group and TKIs monotherapy group were 77.%(37/48),65.1%(28/43),respectively,P<0.01.The disease control rate(DCR)in the intercalated combination group and TKIs monotherapy group were 93.8%(45/48),83.7%(36/43),respectively,P<0.001.4.The incidence of leukopenia of patients in the intercalated combination group was 31.3%(?3 grade 2.1%)which was higher than that of the patients in the TKIs monotherapy group 9.3%(?3 grade 0%).The incidence of anemia in the intercalated combination group was 22.9%(?3 grade 0%)was significantly higher than that of the TKIs monotherapy group 7.0%(3 grade 0%),P<0.05;the incidence of thrombocytopenia was not statistically different between the two groups.The overall incidence of gastrointestinal adverse reactions(nausea and vomiting),fatigue and hair loss was significantly higher in the intercalated combination group than that of TKIs monotherapy group.The overall incidence of diarrhea,oral mucositis,rash and increased transaminase had no significant difference between the two groups.The difference of the incidence of adverse events between the two groups was mainly manifested in the difference between the adverse events of grade 1?2,and the incidence of severe adverse events(SAEs)was not statistically different between the two groups.10 patients in the intercalated combination group were treated with drug reduction due to toxic side effects,and 3 patients in the TKIs monotherapy group underwent drug reduction due to toxic side effects.The toxic side effects of all patients could be improved after the corresponding treatment,no treatment interruption cases.No drug-related deaths occurred,and no cases of interstitial pneumonia and renal dysfunction were recorded.Conclusion:This study found that the combination therapy based on platinum inserted with EGFR-TKIs as first-line treatment significantly prolong PFS for patients with NSCLC compared with TKIs alone therapy,improved ORR and DCR of NSCLC patients without obviously increased incidence of adverse reactions.