| Backgrounds and Object:Non-small cell lung cancer(NSCLC)is a type of malignancy with high morbidity and mortality in the worldwide.it gains a poor treatment duiring the late-stage.In recent years,the increasing in the number of smokers,the increasing environmental pollution,and chronic respiratory diseases have caused the incidence of lung cancer to increase significantly,compared with 10 years ago.Most malignant tumors have reached the middle and advanced stages at the time of initial diagnosis and are accompanied by other organ metastases.The prognosis of distant metastases of NSCLC is relatively poor,especially with brain metastases.If no intervention treatment is performed in time,the average survival time is only 2-3 months.For patients without driver gene mutations and after at least two lines chemotherapy and brain radiotherapy,when the disease recured again,the targeted therapy is less effective,while the conventional chemotherapeutic drugs have a lower concentration in the central system and can not achieve the corresponding anti-tumor effect.The majority of older,weaker patients can not tolerate the adverse reactions caused by multiple brain radiotherapy.Therefore,these patients often have limited clinical treatment options.Most patients are in poor disease control,leading to rapid disease progression and survive for a short period time.Docetaxel(DOC)is a second-generation paclitaxel antitumor drug,and has been approved by the FDA for salvage treatment of advanced NSCLC.The adverse reactions were mainly mild.Both fotemustine(FTM)and temozolomide(TMZ)could enter the central nervous system through the blood-brain barrier.Among them,formolimus is a nitrosoureas and has good lipid solubility.It can make the DNA of tumor cells alkylate,and the degradation process and synthesis are limited.At the same time,it will affect the synthesis and function of proteins.Temozolomide is a novel oral alkylating agent that can efficiently penetrate the blood-brain barrier(BBB).The drug concentration in the central nervous system can reach 30%to 40%of peripheral blood drug concentration.At the same time,the adverse reactions of temozolomide are small,and a number of clinical trials suggest that it has a good tolerance.Therefore,both formolimus and temozolomide can exert good effects in the treatment of glioma and melanoma brain metastases through the blood brain barrier.The effect has been recommended as a first-line treatment drug.At the same time a number of clinical trials have also confirmed its clear effect in the brain tumor metastasis.Based on this,docetaxel was combined with these two drugs,to compare the efficacy and safety of patients who had recurrent brain lesions after multiple treatments,in order to provide more clinical treatment basis.MethodsTo determine the comparison of these two regimens,a retrospective analysis was undertaken at our hospital network among patients treated between March 2016 and February 2017.Fifty five cases of non-small cell lung cancer patients who were treated with radiotherapy and multi-line chemotherapy after brain lesions in the First Affiliated Hospital of Zhengzhou University.Inclusion criteria:(1)Non-small cell lung cancer patients with brain metastases diagnosed by senior pathologists in our department of pathology;(2)Without EGFR,ALK,Braf,Kras et al.drive gene mutations;(3)measurable metastases in the brain;(4)at least two or more chemotherapy regimens;brain lesions undergoing radiotherapy(whole-brain radiotherapy or stereotactic radiotherapy);(5)eastern tumor cooperation The score of Eastern Cooperative Research Group(ECOG)was?2 points and the estimated survival time was?3 months.(6)The peripheral blood neutrophil count was?1.5×109/L and the white blood cell count was?4.0×109/L.Platelet count?100×109/L;(7)Blood biochemical requirements:electrolyte,renal function,normal liver function(serum creatinine?1.5 mg/dL,normal creatinine clearance,total bilirubin?1.5 mg/dL,aspartate aminotransferase And alanine aminotransferase?2.5times the normal value),normal heart function and clotting time is normal.Exclusion criteria:(1)Patients with acute coronary syndrome(ACS)or acute myocardial infarction in the past 3 months;(2)severe infection or inflammatory disease;(3)patients with severe liver and renal insufficiency;(4)Recently suffered severe trauma and surgery.34 patients in the arm fotemustine received intravenous docetaxel(75mg/m~2)on day 1,fotemustine(100mg/m~2)on days 1 and 8,and dexamethasone(10mg)for three days continuously since one day before using docetaxel.21 patients in group temozolomide received intravenous docetaxel(75mg/m~2)on day 1,as the same as the arm fotemustine,and temozolomide 150(mg/m~2),oral 1h before every meal,from days 2 to days 6.Clinical symptoms,treatment effects,and adverse reactions were collected.An imaging examination was performed every 2 cycles to evaluate intracranial lesions and extracranial lesions.Adverse events were recorded and the immediate and long-term effects were observed.The quality of life was assessed.Response distributions and toxicity rates were compared among the two arms using the chi-square test.After the treatment was completed,the progression-free survival and overall survival were recorded.OS and PFS were estimated with standard errors and their 95%confidence intervals(CI)were estimated using Kaplan-Meier to account for censoring.The x~2 test was used to compare the count data.The log-rank method was used for the difference test(P<0.05 was considered statistically significant).ResultsThirty-four patients received formostine and 21 patients receivedtemozolomide.Baseline comparisons between the two groups were not statistically different.There were 43 cases of adenocarcinoma,4 patients were large cell carcinoma,and 8 adenosquamous carcinoma cases.Thirty-four patients had neurological symptoms and 35 patients had significantly elevated tumor markers.After treatment,patients were evaluated for intracerebral lesions,extracranial lesions,and systemic curative effects.The effective rates of the patients in the formostine group were 5.88%,5.88%,and 2.94%,respectively;the disease control rates were38.24%,55.88%,and 47.06%,respectively;The effective rates of the temozolomide group were 9.52%,14.28%,and 14.28%,respectively;the disease control rates were47.62%,71.43%,and 52.38%.The difference in efficacy between the two groups was not statistically significant and the efficacy was equally between two groups.The long-term follow-up evaluation showed that the median progression-free survival time of brain lesions in the formostin group and temozolomide group were(5.2+1.726),(8.6+1.394)months,and the median overall survival was:(7.2+1.19),(9.7+1.463)months,the difference was statistically significant(P=0.048<0.05).The median progression-free survival rates of the systemic effects of formostin and temozolomide were(5.4+1.038)and(8.5+0.731)months,respectively.There was also a statistically significant difference between two groups.The adverse reaction of hematological toxicity was nearly in grades III-IV in the fotemustine group;however,mild myelosuppression and gastrointestinal reactions were found in the temozolomide group.After symptomatic and supportive treatment,the symptoms of bone marrow hematopoietic,antiemetic,hepatoprotective,gastrointestinal protective,myocardium protective and neuroprotective have improved or controlled.Also,the difference between those two groups was statistically significant.Among the quality of life assessments,the scores of two treatments were statistically significant.The scores of the majority of patients in the temozolomide group was improved evidently,compared with the other group.ConclusionTemozolomide combined with docetaxel has better long-term efficacy,significantly less adverse reactions,and improved quality of life for the NSCLC patients with brain metastases without gene mutation and after multiline therapies. |
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