The Study Of Curative Effect Prediction And Monitoring Factors In Treatment On Advanced Non-Small Cell Lung Cancer Using Egfr-tki

ObjectiveLung cancer has become one of serious threat to human health today. Although the medical profession has made great progress on the lung cancer clinical features and pathogenesis, but the cure rate is still low, long-term survival of non-small cell lung cancer (NSCLC) is still in a low level. For patients of advanced non-small cell lung cancer, the efficacy of conventional chemotherapy is in the platform term, Increase of dose and duration can not increase the efficacy and survival, but increased adverse reactions in patients. In recent years, the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) has brought hope to patients with NSCLC, Among that, Erlotinib is the first one been shown to be significantly extend the OS of patients with advanced NSCLC EGFR-TKI, it provides new ways and ideas for the treatment of patients with advanced NSCLC.2011U.S. National Comprehensive Cancer Network (NCCN) non-small cell lung cancer treatment guidelines referred that epidermal growth factor receptor tyrosine kinase inhibitors can be chosen as first-line treatment of advanced non-small cell lung cancer when the known existing EGFR gene mutations. For patients failed in first-line chemotherapy previously can choose EGFR-TKI as second-line treatment. As a new treatment large-scale clinical studies is lacked for Erlotinib EGFR-TKI drugs, and we still need to further explore the relationship between the efficacy and clinicopathological factors. Although the medical profession have known EGFR mutations is an effective predictors for drug efficacy in EGFR-TKI, but drugs is invalid for some patients, even they are EGFR mutation patients. Because these drugs are expensive, and clinical work should try to avoid ineffective treatment, so how to further improve the predictive ability of the therapeutic efficacy of EGFR-TKI have become the urgent problems in the international community. And in clinical work, often due to various reasons can not do the detection of EGFR mutations, in such cases, how to predict the efficacy of the epidermal growth factor tyrosine kinase inhibitors is a clinical difficult problem. Particularly in the development of advanced non-small cell lung cancer first-line treatment plans, how to get Erlotinib Nepalese efficacy predictors is particularly important. In addition, in the process of treatment for non-small cell lung cancer application using EGFR-TKI therapy, clinicians need to judge the efficacy of the drug as soon as possible, so to determine whether to continue treatment as before or change the treatment. Conventional means is to use of CT, MRI and other imaging studies, however, these checks can not reflect changes in tumor metabolism and in other such biochemical aspects, and they are expensive, it is not conducive for often regular inspection. Whether there is an accurate, convenient, economical, better repeatability way to early judge the efficacy, so that to guide clinicians to amend on the treatment program? We collected the data of56advanced NSCLC cases who were treated by Erlotinib, analyzed on clinical pathological characteristics, efficacy and survival results. At the same time using PET-CT, serum tumor markers and other means to predict and monitor the efficacy of Erlotinib, in an attempt to solve the above problem by these means.Method:1. Clinical datainclusion criteria:1> age between18-85years who are not accompanied by any serious systemic disease (such as heart failure, severe liver, kidney disease, etc.);2> Patients who were confirmed as non-small lung cancer in pathology and have no indication for surgery in ⅢB-Ⅳ stage;3> East collaboration tumor group (Eastern Cooperation Oncology, group, ECOG) performance status of0-3;4> Patients must be newly diagnosed for the first-line treatment, and before Erlotinib there were no surgery, radiotherapy and chemotherapy treatment; for the second and third line treatment of patients, before Erlotinib, they received at least one chemotherapy regimen;5> The patient's blood, biochemical tests are normal;6> Signed informed consent, patient compliance with follow-up;7> Life expectancy was at least8weeks;2. experiment equipment and reagent PET-CT imaging reagent is18F-FDG, imaging devices:the Discovery LS of United States GE. All serum were collected5mL vena blood with fasting in morning, batch determination serum was separated after centrifugation, using automatic electrochemiluminescence method, the kit are the production of Roche Diagnostics Germany, operated in strict accordance with the instructions step. Detecting EGFR mutations by PCR, test sequence by sequence test method.Result1. Efficacy and impact factors Among the whole group of56patients, the case sof CR is1, the PR is25, Sd is17, PD is13, the overall OR R was46.4%, DCR is76.8%. x2tests showed in objective remission rate, women are higher than men (63.3%vs.26.9%, P=0.006),adenocarcinoma higher than the non-adenocarcinoma (56.4to%vs.23.5%P=0.023), non-smokers higher than smokers (64.5%vs.24.0%, P=0.003), rash patients higher than patients without rash (59.5%vs.21.1%, P=0.006). For the SUV values <5patients, objective remission rate is higher than the patients with SUV of≥5(65.5%vs.25.9%, P=0.003). For the disease control rate, women is higher than men (90.0%vs.61.5%, P=0.012), adenocarcinoma is higher than the non-adenocarcinoma (89.7to%vs.47.1%P=0.002), non-smoker is higher than smoker (93.5%vs.56.0%, P=0.001), patients with rash is higher than patients without rash (91.9%vs.47.4%. P=0.001). Mutiple logistic regression show that GEFR gene mutation is an independent predictor of disease objective remission, P=0.028. The rash is an independent predictor of disease control, P=0.024.2. The improvement of symptoms In the56cases of the whole group,27case were improved symptoms (48.2%), mainly showed as the improvement of cough, shortness of breath, the releasing of chest tightness, chest pain and bone pain,fatigue reduced, physical state was improved, median time of symptoms improvement is25days.1CR case was improved in symptoms (100%),18cases in25PR cases were improved (72%),5cases of17SD patients was improved (29.4%),1case of13PD cases was improved (7.7%).3. Survival period and influencing factors The median PFS of all patients was7.6months, OS was16.0months, one year survival rate was66.1%. patients with PS score0-1had longer PFS than patients with PS score2-3(5.4months vs.9.7months, P=0.001), patients with adenocarcinoma had longer PFS compared with non-adenocarcinoma patients (8.8months vs.3.8, P=0.000), non-smoking patients had longer PFS compared with smoking patients (9.2months vs.4.9months, P=0.001),patients with rash had a longer PFS than patients without rash (8.4months the vs..5.1months, P=0.015), all patients who were rated as objective remission (CR+PR) had a longer PFS compared with non-objective remission patients (9.6months the vs..5.2months, P=0.001), all patients who were rated as effective treatment (CR+PR+SD) had a longer PFS compared with patients as treatment inefficacy (9.0months vs..1.5months, P=0.000). Line Ⅰ treated patients had a longer PFS compared with the patients with Ⅱ/Ⅲ line treated (11.5months vs.5.8months, P=0.003). PFS of patients with SUV values <5are higher than the ones whose SUV≥5(8.5vs6.0, P=0.047). In aspect of overall survival, patients with PS score0-1had a longer OS compared with patients of PS score2-3(17.5months vs.13.1months. P=0.022). patients with adenocarcinoma had a longer OS compared with non-adenocarcinoma patients (17.4months vs9.5months P=0.000), non-smoking patients had a longer OS compared with smokers (17.9months vs.11.3months, P=0.000), patients with rash had a longer OS than patients without rash (16.7months vs.11.6months, P=0.008), all patients who were rated as objective remission (CR+PR) had a longer OS compared with non-objective remission (18.4months vs.12.0months, P=0.000), all patients who were rated as objective and effective treatment (CR+PR+SD) had a longer OS compared with those treatment inefficacy (17.9months vs.5.3months, P=0.000). Line Ⅰ treated patients had a longer OS compared with the Ⅱ/Ⅲ line treated patients (22.0months vs.12.6month, P=0.000). patients of SUV values<5had a higher OS than SUV≥5(17.1vs12.7, P=0.018). Cox regression analysis showed that risk factors for disease progression of patients include the treatment period, PS score, and treatment efficacy, the risk factors of death of patients include the treatment period, pathological type and treatment efficacy.4. Adverse Effects Most are Ⅰ, Ⅱ, Ⅲ grade adverse reactions, there was patients no withdraw treatment because of intolerable adverse effect, no case happen interstitial pneumonia and had no drug-related death case. The most common adverse events were rash (37/56), diarrhea (25/56), dry skin (11/56), anorexia (14/56), fatigue (13/56), elevated aminotransferases (13/56).5. The results related to PET-CT The median PET-CT SUV value of all patients was4.9. Among them, the SUV value of non-adenocarcinoma patients is higher than adenocarcinoma (8.9vs5.3, P=0.006), SUV in patients without rash is higher than rash (8.2vs5.3, P=0.009).5. The results related to tumor markers Average NSE values in patients of age≥60years was higher than patients the age <60(12.0vs6.0. P=0.002). CEA level of adenocarcinoma was higher than the non-adenocarcinoma (32.0vs11.5P=0.000), CYFRA21-1level of non-adenocarcinoma was higher than that of adenocarcinoma (23.0vs4.3P=0.000), CEA levels of smoking patients was less than non-smoking patients (16.8vs33.0, P=0.003), CEA levels of Ⅰ-line treatment patients was higher than patients with Ⅱ,Ⅲ, line treatment(36.4vs22.2, P=0.034), CEA levels in patients of PET-CT SUV value<5was higher than the patients with≥5(34.4vs16.5, P=0.001), CEA levels of EGFR gene mutation-positive patients was higher than the mutation-negative patients (30.2vs15.5, P=0.018). CYFRA21-1levels of EGFR gene mutation-positive patients was lower than the negative patients (4.3vs34.0P=0.000), CEA levels of patients with rash after treatment was higher than patients without rash (32.3vsl2.9, P=0.000), CEA levels of patients with objective remission performance (CR+PR) was higher than patients without remission (37.3vs15.7, P=0.000), CEA level of patients with objective valid performance after treatment (CR+PR+SD) was higher than patients invalid (30.5vs10.1. P=0.000). No significant correlation between the rest of the clinicopathological factors and the three tumor markers.Review the three tumor markers after1month treatment with Erlotinib, took the marker levels decreasing20%as the cutoff value grouping, results show that objective remission rate (ORR) in patients whose CEA levels decreased≥20%is superior to CEA levels decline <20%(70.4%vs20.7%, P=0.000), objective remission rate (DCR) in patients with CEA levels≥20%is superior to those CEA levels <20%(100%vs55.2%, P=0.000), objective remission rate (DCR) in patients with NSE level decline≥20%of patients was superior to patients with NSE levels decreased <20%(100%vs62.9%, P=0.004), while there was no significant statistics difference for the CYFRA21-1in efficacy evaluation. In the aspect of evaluation on PFS and OS, took average before treatment CEA values of all patients be-25.8as the sector grouping, evaluated the difference of PFS and OS. the results showed that the PFS in patients with CEA level of≥25.8was superior to patients with CEA level <25.8(10.2the months vs.5.6, P=0.001); OS in patients with CEA level25.8was superior to CEA levels <25.8(19.3vs.12.6months, P=0.000); reviewed after 1month treatment, PFS in patients with CEA level decreased≥20%was superior to CEA levels <20%(9.8vs.4.8, P=0.000), OS in patients with CEA levels declined≥20%was superior to CEA levels <20%(19.0vs11.3, P0.000); reviewed after1month treatment, PFS levels in patients with NSE decreased≥20%was better than NSE levels decreased <20%of (9.8vs5.7, P=0.001), OS in patients with NSE levels decreased≥20%is better than NSE levels decreased <20%(18.7vs12.8, P=0.001).7. The EGFR gene test EGFR gene mutation incidence rate of Adenocarcinoma and adenocarcinoma respectively was82.1%(32/39) and41.2%(7/17), their difference was statistically significant (P=0.003). the rest of the clinical factors, such as the history of smoking, age, gender, pathological stage (ⅢB and Ⅳ), the physical status, PET-CT SUV value, rashes, all have not statistical difference. Patients of EGFR gene mutation-positive have higher objective response rate (ORR)(59.0%vs17.6%. P=0.004), and a better objective response rate (DCR)(87.2%vs52.9%, P=0.014). EGFR gene mutation-positive patients had longer PFS (8.5months vs4.5months, P=0.004), and better OS (16.9months vs10.8, P=0.003).8. Detection results of Cancer stem cell markers ALDH1A1. CD133and CD34Positive expression rate of ALDH1A1was42.9%(24/56), objective response rate (ORR) in patients of positive ALDH1A1expression and negative ALDH1A1expression were (20.8%vs.65.6%respectively, P=0.001), disease control rate (DCR) were (the58.3%vs.90.6%, P=0.005), median progression-free survival (PFS) were (5.3months vs.8.7months, P=0.009). overall survival (OS) were (12.7months vs.16.6months, P=0.041). CD133-positive expression rate was37.5%. ORR of patients with positive CD133expression and negative CD133expression are (4.8%vs.71.4%, P=0.000). DCR were (57.1%vs.88.6%, P=0.018), PFS were (6.5months vs.8.0months, P=0.269), OS were (14.8month vs.15.1, P=0.880). CD34positive expression rate was42.9%, ORR of patients with CD34expression positive and negative were (16.7%vs.68.8%,P=0.000), DCR were (58.3%vs.90.6%, P=0.005), PFS were (5.2months vs.8.8months, P=0.005), OS were (12.0months vs.17.2months, P=0.006). Patients with all positive expression of ALDH1A1, CD133and CD34were23.2%, ORR of patients with three indicators were all positive expression was worse than patients with negative expression (0%vs.78.3%, P=0.000), DCR were respectively (42.9%vs.91.3%, P=0.005), PFS were (4.8months vs.9.6, P=0.007) and OS were(10.9months vs.17.3months, P=0.007).Conclusion:1. As a representative drugs of inhibitor for epidermal growth factor tyrosine kinase, Erlotinib have a better clinical efficacy, patients can get a better objective response rate and objective response rate, and patients can get a better progression-free survival and totallifetime, and the clinical side effects is light. Gender, histological type and smoking history are clinical pathology predictors of Erlotinib efficacy.2. joint detection on SUV value of PET-CT and EGFR mutations can get more accurately predict on the efficacy of Erlotinib compare to single detection of EGFR gene. in this study, the joint detection improved forecast level of objective response rate (ORR) by14.9%, improved forecast level of disease control rate (DCR) by4.1%, which helps guide more accurately on making first-line treatment plan for advanced non-small cell lung cancer in the clinical work. Expression of ALDH1A1, CD133and CD34is associated with the efficacy of EGFR-TKI drugs on NCSLC. which can reflect the prognosis to some extent. of EGFR gene mutation and expression of ALDH1A1, CD133and CD34. to a certain extent, can improve the forecast level of EGFR-TKI drug efficacy. In this stud, Joint detection improved the prediction level on drug objective response rate (ORR) by26.0%. 3. The SUV value of PET-CT in non-small cell lung cancer patients is relative to EGFR-TKI efficacy, patients with pre-treatment SUV values <5patients get better efficacy compare to patients with pre-treatment SUV values≥5. SUV value of PET-CT can be a judge method on the efficacy of Erlotinib, in the case of can not doing EGFR gene detection, can be used as a reference of EGFR-TKI therapy.4. This study found that during treatment CEA, NSE level decreased by≥20%can be used as one of the criteria of effective treatment. Joint detection of serum CEA and dynamic changes of NSE based on the imaging test can more accurately monitor Erlotinib efficacy than the detection based on imaging studies singly. Patients of serum CEA and NSE level decreased≥20%get better prognosis compared with patients whose decrease <20%.