| Backgrounds Leptomeningeal metastasis(LM)is defined as the spread of malignant cells within the leptomeninges and subarachnoid space,resulting in a devastating prognosis with limited treatment options.LM is often associated with extremely poor prognosis,with a median OS(mOS)of 3-10 months after diagnosis.Non-small-cell lung cancer(NSCLC)is the most common primary tumor of LM,and epidermal growth factor receptor(EGFR)is the most important driver gene in NSCLC.The detection rate of LM in patients with NSCLC has been estimated to be 3-4% but increases to 9-16% in patients with lung adenocarcinoma harboring EGFR mutations.EGFR mutation status is a critical prognostic factor in the treatment of NSCLC with LM.A secondary EGFR test is often required to determine the status of T790 M drug-resistant mutation;however,it is difficult to obtain a second tumor tissue from most patients.Circulating cell-free DNAs(cfDNAs)are extracellular nucleic acids released by tumor cells that can be useful biomarkers for early diagnosis and prognosis.However,because of the blood-brain barrier,the role of plasma cfDNA in the diagnosis of metastatic brain cancer is very limited.Nevertheless,the enrichment of cerebrospinal fluid(CSF)with intracranial tumor cfDNA has become increasingly emphasized in intracranial tumor fluid biopsies.Currently,the options for systemic therapy for LM are limited,the efficacy of first-(erlotinib,gefitinib)and second-generation(afatinib)EGFR-TKIs remains dismal.Osimertinib is an irreversible third-generation EGFR TKI that selectively inhibits EGFR and EGFR T790 M mutations.Due to the existence of the blood-brain barrier,the therapeutic effect of systemic chemotherapy and targeted drug therapy is limited.Intrathecal chemotherapy can bypass the restriction of the blood-brain barrier and directly enter the subarachnoid space.Currently,intrathecal administration of anti-tumor drugs is considered to be a reliable method for the treatment of LM.Methotrexate,one of the most commonly used intrathecal chemotherapeutic drugs,is a folate antimetabolic drug,which mainly blocks the synthesis of tumor cells through the inhibition of dihydrofolate reductase.Pemetrexet is a multi-target antifolic acid agent that inhifies tumor growth by disrupting normal folate-dependent metabolic processes in cells and inhibiting cell replication.It is a first-line chemotherapy agent for NSCLC,but has poor penetration of the blood-brain barrier(<5%).Intrathecal injection of pemetrexed may be a method to overcome CSF penetration,and two small prospective cohort studies have also demonstrated the feasibility of intrathecal injection of pemetrexed.However,no studies have been conducted to compare the efficacy of intrathecal pemetrexed with methotrexate.Currently,there is a lack of large-sample clinical observation studies in China,and the first part of this study was to clarify the clinical and imaging characteristics,cerebrospinal fluid cytology and prognosis of patients with LM in our single-center.In the second part,the value of CfDNA detection in CSF in the early diagnosis of NSCLC and LM will be discussed,the therapeutic effect between the 3rd EGFR-TKI and the 1st / 2nd EGFR-TKIs in the treatment of NSCLC and LM will be compared,with the influencing factors of prognosis analyzed.In the third part of the study,we will compare the efficacy and safety of intrathecal injection of pemetrexed and methotrexate.Random survival forests method is usually used to select the most important variables that are linked with the time-to-event outcome(i.e.,OS).To the best of our knowledge,no studies have been conducted to predict the survival of pulmonary adenocarcinoma with LM using targeted therapy,and the use of machine learning methods such as random forests also lacks.In the fourth part,the prognostic model of lung adenocarcinoma will be studied,and TKI therapy will be introduced into molGPA model.Objective1.To describe the clinical manifestations,neuroimaging,cerebrospinal fluid(CSF)cytology and prognosis of Leptomeningeal metastases(LM).2.To develop a droplet digital PCR(ddPCR)method to detect plasma and CSF cfDNA and to compare the clinical efficacy of osimertinib with first or second-generation EGFR-TKIs,and to evaluate the efficacy influencing factors.3.To investigate the efficacy,safety and prognosis of intrathecal injection of pemetrexed and methotrexate in the treatment of LM.4.To explore predictive indicators related to pulmonary adenocarcinoma with leptomeningeal metastases(LM)and update the graded prognostic assessment model integrated with molecular alterations(molGPA).Methods1.The clinical manifestations,imaging features and CSF cytology of LM patients admitted to Zhengzhou University People’s Hospital from Jan 1,2014 to Dec 31,2020 was retrospectively analyzed.The overall survival(OS)was were evaluated by the time from the diagnosis of LM to death.2.The EGFR mutation status of circulating cell-free DNA(cfDNA)from paired CSF and the plasma of 23 patients with LM was detected by Droplet digital PCR(ddPCR).The overall survival(OS)and progression free survival(PFS)of patients with EGFR mutant NSCLC and LM treated with osimertinib and 1st / 2nd generation EGFR TKIs were compared.3.According to the open-label phase II clinical study of pemetrexed intrathecal injection(ChiCTR1800016615),patients enrolled in NSCLC complicated with LM were divided into pemetrexed group and methotrexate group.Intrathecal injection was performed according to the standard regimen of induction,consolidation and maintenance period,and the clinical efficacy and adverse reactions of the two groups were observed.4.We collected data from 202 lung adenocarcinoma patients with LM diagnosed in the menstrual neuropathology laboratory and pathology department,enrolled between April 2017 and January 2022.The included patients were randomly divided into training set and validation set.The Cox proportional hazard regression analysis was performed to identify statistically significant predictors and the random survival forest method was utilized to verify the results of Cox model.We constructed a predictive model and further analyzed the survival of three groups of molGPA model,and finally compared the C-index between 2021 molGPA model and previous research prediction model.Results1.A total of 141 patients with LM were enrolled in the retrospective study,and the median age was 59 years(range:28～78 years).According to the pathological classification,it was lung cancer in 99 cases(70.2%),gastric cancer in 20 cases(14.2%),breast cancer in 8 cases(5.7%).The median Karnofsky Performance Scale(KPS)score was 50.LM was the initial manifestation of cancer in 52 patients(36.9%).Tumor cells or atypical cells were found in 93.8% of patients for the first time,and activated monocytes in 72 cases(67.3%).By Jun 30,2021,111 patients(75.0%)died,17 patients(12.1%)survived and 13 patients(9.2%)were lost to follow-up.The median overall survival(mOS)time was 2.08(95% CI :1.29-2.87)months,and the1-year survival rate was 14.5%.The mOS of LM patients with lung cancer was 3.00(95% CI: 1.37-4.63)months,which was better than that of other tumor(p=0.000).The patients with KPS>60 had a median overall survival of 6.00(95% CI: 3.92-8.08)months,longer than those with KPS ≤ 60.The 65 patients treated with tyrosine kinase inhibitor(TKIs)(median OS 6.92 [95% CI: 4.54-9.30] months)were better than those treated without TKIs(p=0.000).The mOS was 7.00(95% CI: 4.60-9.40)months in18 patients treated with whole-brain radiotherapy(WBRT),and the difference was statistically significant(p=0.010)compared with the group without radiotherapy.Univariate analysis showed that lung cancer,KPS > 60,TKIs treatment,and WBRT were favorable prognostic factors(p<0.005).Multivariate regression analysis showed that KPS score,TKIs treatment,and WBRT were independent prognostic factors for patients with LM.2.In the second part of the study,a total of 78 patients with NSCLC complicated with LM were enrolled,with a median age of 61(28-78)years and a median OS of6(95%CI: 2.36-9.14)months.Rates of EGFR mutation in plasma and CSF were 56.5%and 60.9%,respectively,with no statistical difference(p = 0.765).Detection rate for T790 M in plasma and cerebrospinal fluid was 30.4%.Forty-four osimertinib-treated patients had an improved mOS of 13.15(95% CI: 5.74-20.57)and a median progression-free survival(PFS)of 9.50 months(95% CI: 6.77-12.23)when compared with patients treated with first or second-generation EGFR TKI(mOS=3.00 [95% CI:1.32-4.68] and median PFS=1.50 months [95% CI: 0.00-3.14]).In the osimertinib group,mOS values for CSF with and without T790 M mutation were 22.15(95% CI:9.44-34.87)and 13.39 months(95% CI: 7.01-19.76),respectively,with no statistical difference.3.In the study of intrathecal treatment for LM of NSCLC,a total of 29 subjects were included from June 2019 to January 2021,including 17 cases of intrathecal methotrexate(MTX)and 12 cases of intrathecal pemetrexed.In the MTX group,seven cases received ≥8 intrathecal chemotherapy,and 3 cases received maintenance treatment at present.In the pemetrexed group,6 cases completed consolidation phase treatment,and 4 cases were currently receiving maintenance phase treatment.The intrathecal pemetrexed group received 78 intrathecal injections,with a median OS10.0(95% CI:3.75-16.31)months,the median PFS 4.0(0.00-12.53)months,and the overall clinical assessment response rate reached 66.7%(8/12).The intrathecal MTX group received 128 intrathecal injections,the median OS was 5.70(1.67-9.73)months,and the median PFS was 3.0(0.476-5.52)months.The overall assessed clinical response rate was 58.8%(10/17).There was no significant difference in efficacy and survival between the two groups.The total incidence of adverse reactions(AE)in the pemetrexed group was 75.0%,including 6 cases of grade 1-2 adverse reactions(50.0%),1 case of grade 3 adverse reactions,2 cases of grade 4 myelosuppression.The total AE in MTX group was 58.8%,including 6 cases of grade 1-2 ADR(35.3%) and 4 cases of grade 3 ADR(23.5%).Patients with KPS score ≥ 60 had better prognosis than those with KPS score < 60(HR 0.271,95% CI: 0.102-0.720).The times of intrathecal injections ≥ 8 was a good prognostic factor(hr0.160,95% CI:0.056-0.455,P = 0.001).4.The fourth part of this study was a predictive model for lung adenocarcinoma.Data were collected from 202 patients with LM lung adenocarcinoma from April 2010 to March 2021.Patients with incomplete clinical data(n= 29)and lost follow-up(n=11)were excluded,and 162 patients were included in the study cohort and randomly divided into a training set(80%,N =130)and validation set(20%,n=32).The Cox regression and random forest models both identified four variables,including Karnofsky performance status(KPS),LANO neurological assessment,tyrosine kinase inhibitor(TKI)therapy line,and controlled primary tumor as statistically significant predictors.A novel target-therapy assisted molGPA model(2021)using the above four prognostic factors was developed for predicting LM of lung adenocarcinoma cancer.The C-indices of this predictive model on the training set(80% of the cohort)is 0.710(95% CI [0.685,0.729])and 0.714(95% CI[0.629,0.800])for the validation set(20% of the cohort).These values were about 7.0%and 5.5% higher than the lung-molGPA(2017)and molGPA(2019)models.Conclusions1.The overall prognosis of LM is poor.The median overall survival of LM was2.08 months,and the 1-year survival rate was 14.5%.Univariate and multivariate COX regression analysis showed that KPS score ≥60,TKIs drug therapy,and whole brain radiotherapy were favorable factors for the prognosis of patients.2.Plasma and CSF cfDNA detection is a minimally invasive method that enables continuous monitoring of EGFR status in NSCLC patients with LM.Osimertinib was demonstrated to have a significant efficacy against NSCLC with LM.3.Intraocular pemetrexed in the treatment of NSCLC and LM achieved a 66.7%response rate,the total adverse reaction rate was 75.0%,of which 50.0% were grade 1to 2 adverse reactions,2 cases of grade 4 myelosuppression.There were no statistically significant differences in efficacy or survival compared with MTX.The number of intraocular injection ≥8 times was a good factor for prognosis.4.We develop a novel target-therapy assisted 2021 molGPA model for predicting LM of lung adenocarcinoma cancer by incorporating TKI therapy line in addition to controlled primary tumor,KPS,and LANO neurological assessment.The 2021 molGPA model is a substantial update of the previous molGPA models and has better prediction performance. |
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