Clinical Observation On The Treatment Of Advanced Non Small Cell Lung Cancer With Crizotinib And Clinical And Pathological Features Of ALK Positive Lung Cancer

Part One Clinical observation on the treatment of advanced non small cell lung cancer with CrizotinibObjective:The Lung cancer is one of the most common malignant tumors in the world.The incidence and mortality of lung cancer are increasing year by year in China.More than 80% of patients with non-small cell lung cancer,most of the patients due to the early onset of hidden,in the presence of symptoms can not be surgery,so radiotherapy,chemotherapy and molecular targeted therapy has become the main means of treatment.At present,the standard first-line treatment program is a platinum based combination of drugs,although the survival of patients has improved,but the efficiency is low,large side effects.With the booming development of tumor related pathway and related gene detection methods,many NSCLC driven gene at the molecular level is confirmed,China has been able to choose different type according to the pathology and gene targets for individualized treatment of lung cancer.ALK is a transmembrane protein of 1620 amino acids,which is composed of extracellular ligand binding region,transmembrane region and intracellular tyrosine kinase domain.In recent years,as a new type of drug,targeted drugs have stronger pertinence,can enhance the lethality of tumor cells and reduce the toxic and side effects to normal cells,and become a hot spot of NSCLC drug therapy.Crizotinib is one of them,for the ALK positive NSCLC patients,showed crizotinib significantly increased in patients with lung cancer objective remission rate,well tolerated,and significantly improved the quality of life of patients with advanced lung cancer.Clinical trials have shown that both first-line and second-line treatment with crizotinib is better than chemotherapy.Based on the results of the study,in 2011 by the U.S.Food and Drug Administration(FDA)approved for the treatment of patients with locally advanced or metastatic NSCLC,in China in 2013 approved by the FDA.Because of the late listing in China,lack of large-scale real world research.In this study,we took part in the actual work of patients who took part in the oral administration of the drug.Methods:47 patients with advanced or locally advanced non-small cell lung cancer were treated with oral administration of crizotinib during October 2012 to January 2017.All the patients in the study group were confirmed by histopathology and cytology,and were detected as positive ALK rearrangement gene or ROS1 gene rearrangement.In order to treatment within1 months before the imaging data as a baseline for the first time,to assess efficacy after 1 months of treatment,after every 2 months for an imaging detection,using standard RECIST1.1 solid tumor evaluation of lesions,and adverse events were recorded before and after the treatment period.Until the disease progression or adverse reactions can not be tolerated.Results:The objective response rate was 61.7%,the disease control rate was93.6%,and the mPFS was 19 months.The number of metastatic sites were analyzed,number of metastatic sites more than 3 patients with ORR,DCR and mPFS were 45.5%,91%,11months;3 of the number of metastatic sites "in patients with ORR,DCR and mPFS were 63.9%,94.5% and 19 months,there were significant differences between the mPFS,P=0.040.On the age of 60 years of age or older patients in ORR and DCR were40%,100%;age less than 60 years in patients with ORR and DCR were71.9%,90.6%,two ORR with significant difference,P=0.036;there was no significant difference between DCR and P=0.225.The timing of treatment were analyzed,the first application of crizotinib ORR and DCR were 78.2%,100%;the second and above application of crizotinib in patients with ORR and DCR were 45.8%,87.5%,two ORR with significant difference,P=0.022;there was no significant difference between DCR and P= 0.083.Age,gender,smoking history,stage,duration of treatment,baseline brain metastasis,pathological type,test specimen acquisition,detection methods and TTF-1 were not associated with PFS.The patient’s gender,smoking history,stage,baseline brain metastasis,the number of organ metastases,pathological type,test specimen acquisition methods,detection methods,and whether the TTF-1 positive and ORR unrelated.This group was the main adverse reaction for gram oral imatinib patients for visual abnormalities,nausea and vomiting,diarrhea and elevated transaminases,limb edema,neutrophil count,reduce anemia,albumin decreased,the majority of 1-2 grade,grade 3 adverse reactions include nausea and vomiting in 1 cases(2.1%),2 cases of transaminase increased(4.3%),neutrophil count decreased in 1 cases(2.1%),1 cases of limb edema(2.1%).No adverse events occurred in 4 patients,no severe adverse reactions were terminated and no new adverse events occurred.Adverse reactions were similar between the two age groups,but there was no statistically significant difference.In this study,25.5%(12/47)patients had baseline brain metastases.The occurrence of disease progression in crizotinib during the treatment of patients with 9 cases of new onset cerebral metastases or original lesions increased,most of them take the treatment strategies for continued crizotinib or replacement of the second and three generation of ALK-TKI treatment combined with local radiotherapy for brain metastases.This study included 3 cases(6.4%)of ROS-1 positive patients,1 cases(2.1%)crizotinib efficacy evaluation of SD PFS for 7 months;1 cases(2.1%)had disease progression after treatment in January;1 cases of crizotinib efficacy evaluation of SD PFS for 5 months.This study included 2 cases(4.3%)patients with ALK positive lung squamous cell carcinoma,1 cases(2.1%)crizotinib efficacy evaluation of PR has been used for 19 months,the other 1 cases were stable;(2.1%)crizotinib efficacy evaluation for SD,PFS for 7 months.The study included 1 patient(2.1%)in ALK positive patients with sarcomatoid carcinoma of young,combined with immunohistochemical C-MET(3+),but not further FISH testing confirmed that the application of crizotinib therapy for PR has the best curative effect,orally for 9 months,is currently in a stable condition.Conclusions:1 For patients with ALK/ROS-1 positive advanced NSCLC,the disease control rate,objective remission rate and median progression free survival of patients with positive were 93.6% and 9 months,respectively.2 The efficacy of the treatment of patients with advanced NSCLC with regard to the number of transferred organs but sex,smoking history,staging,pathological type,detection method,acquisition method,the existence of brain metastases,TTF-1 positive and is independent.3 Crizotinib for lung cancer have the curative effect of ROS-1 positive and ALK positive special pathological type.4 The development of intracranial is easy to develop with the use of crizotinib,and the progression of brain metastasis is not the indication of stopping the use of crizotinib.5 The common adverse reactions in the treatment of nausea,vomiting,elevated transaminase,abnormal vision.Part Two Clinical and pathological features of ALK positive lung cancerObjectives:In recent years,with the development of molecular medicine and the emergence of targeted drugs,the treatment of advanced non-small cell lung cancer has entered the era of individualized treatment and has made remarkable progress.At present,the concept of precision medical has been deeply rooted among the people,targeted therapy in the treatment of lung cancer in the status of individual treatment is particularly prominent.In this study,we collected the clinicopathological characteristics of 87 patients with NSCLC,and further defined the clinical and pathological features of ALK positive patients.Methods:87 patients with non-small cell lung cancer(ALK)were examined by pathology or cytology during April 2008 to January 2017 and collected the clinicopathological characteristics.Results:Of the 87 patients,there were male(n = 42.2%)and female(n = 51)with a mean age of 53.6±11.4 years.Non smoking accounted for 75.6%,of which I accounted for 7.3%,II accounted for 6.1%,III accounted for 26.8%,,IV accounted for 59.8%.The pathological diagnosis was adenocarcinoma,73 cases(83.9%),squamous cell carcinoma in 4 cases(4.3%),adenosquamous carcinoma in 6cases(6.9%),sarcomatoid carcinoma in 1 cases(1.2%),the pathological type of unknown in 3 cases(3.4%).61 cases(70.1%)were obtained from the primary lesion,and the pathological changes were obtained from the metastatic lesions in 26 cases(29.9%).Histopathology accounted for 95.4%,cytology and pathology accounted for 4.6%.49 cases(56.3%)Ventana IHC detection of ALK positive,32 cases(36.8%)of FISH ALK was detected in 5 cases(5.7%),RT-PCR detection of ALK positive,1 cases(1.2%)NGS detection of ALK positive,including 13 cases of ALK Ventana IHC were detected with immunohistochemical C-MET(+);1 cases of ALK Ventana IHC detection positive with immunohistochemical C-MET(3+)FISH,but without further verification.The positive of TTF-1 was 58.6%,and the negative was accounted for 3.5%,unknown accounting for about 37.9%.3 cases with immunohistochemical ALK(D5F3,3+)by FISH was further confirmed as positive;2 cases of ALK Ventana IHC and FISH detection were all positive;1 cases of ALK Ventana IHC,Rt-PCR detection was positive.Conclusions:1 The dominant population of ALK gene fusion was young,non-smoking adenocarcinoma patients2 The ALK gene fusion is also present in the lung of the special pathological type3 The common detection methods of ALK gene are FISH,Ventana IHC and Rt-PCR,the advantages and disadvantages of the three techniques are different,and there is a certain complementarity between them.