Prognostic Factors And Comprehensive Treatment Of Small Cell Lung Cancer

Part Ⅰ:The prognostic value of AJCC 7th TNM staging, clinical outcomes and prognostic factors of sequential chemoradiotherapy in Limited-stage Small cell lung cancerObjective:To examined the impact of AJCC 7th TNM staging on survival outcome in limited-stage small cell lung cancer, to evaluated the effect of sequential chemoradioterapy and the impact of clinical factors on of limited stage small cell lung cancer.Material and methods:Between January 1996 and December 2006,437 patients with completed diagnosis and treatment data were reclassified according to AJCC 7th TNM staging. The log-rank test was used to identify prognostic value.Three hundreds and thirty-five of 437 patients were treated with sequential chemoradiotherapy. The Kaplan-Meirer and log-rank test, Cox regression were used for survival analysis and to identify prognostic factors.Results:The median follow-up time was 54 months.1-year.2-year and 5-year overall survival were 86.0%,52.7%,29.7%, respectively. The median survival time was 26.2 months and median progression free survival time was 13.7 months. By log-rank test, TNM stage was statistically significant prognostic factor for OS in LS-SCLC (P<0.001). TNM staging system generally allowed a good separation in pairwise comparisons for OS between successive stage except there is no statistically significant difference between stage Ⅰ and stage Ⅱ (P=0.061).N stage also confirmed significant influence on OS with marginal but not significant differences between successive stage except N1 and N2(P=0.01). T stage show lower discriminatory power in pairwise comparisons. TNM stage was statistically significant prognostic factor for PFS but with no significant difference between successive stage. The cumulative brain metastasis rate of stage I stage Ⅱ, stage ⅢA, stage ⅢB were 17.3%,28.6%,33.3%,35.8%, respectively, and were 12.8%,30.8% for pathological stage Ⅰ and clinical stage Ⅰ. The median survival time was 23.8months for patients received sequential chemoradiotherapy. Overall survival rate of 2y,3y, 5y were 47.3%,32.9%,22.9%, respectively. The acute toxicity were relatively mild, the incidence of >Grade 3 hematological toxicity, >Grade 3 gastrointestinal toxicity,>Grade 2 radiation pneumonitis and >Grade 2 acute esophagitis were 37%,14.9%,11.2%,38.8%, respectively.By univariate analysis, Karnofsky perform status(p=0.005), smoking status(p=0.02) and high LDH level (p=0.043)were statistically significant prognostic factor for OS in LS-SCLC.KPS (p=0.011) and weight loss (p=0.048) show statistically significant difference in multivariate analysis.Conclusions:AJCC 7th TNM staging criteria for limited-stage small cell lung cancer patients have a higher prognostic impact and are therefore preferable in clinical practice and future therapeutic trials. Sequential chemoradiotherapy can be safely and effectively performed in limited-stage small cell lung cancer. Krnofsky perform status and weight loss were independent risk factors for overall survival of limited-stage small cell lung cancer.Part Ⅱ:Thoracic radiation and prophylactic cranial irradiation in extensive small cell lung cancer:a phase Ⅱ trailObjective:To evaluate the effectiveness and safety of thoracic radiation and prophylactic cranial irradiation (PCI) in patients with small-cell lung cancer (SCLC) in extensive stage.Material and methods:Between April 2010 and December 2011,30 patients who response to 4-6 cycles initial chemotherapy were assigned to this trail. The median age was 57 years (range from 40-71years). All the patients received thoracic radiation and PCI. Thoracic radiation was delivered in conventional fractions, the median dose was 54Gy(50-60Gy).The fractionation schedules of PCI used in this trail was 25Gy in 10 fractions. The primary end point was 1-year survival, failure patterns and the time to brain metastases. RECIST 1.1, CTC 3.0AE and RTOG/EORTC criteria were used to evaluated response and toxicity.Results:Twenty-nine of 30 patients complete treatment plan, none of them got disease progression in radiation. The rates of CR, PR, SD over the treatment were 13%,27%, 60%, respectively. Disease control rate was 100%.Sixteen patients get disease progression during follow-up period. Local-regional failure, distant failure, simultaneous local-regional and distant failure were occurred in 1,9,6 patients, respectively.The 1-year brain metastases rate was 10%..The 1-year survival rates were 71% for overall survival and 37% for disease-free survival. The acute toxicity were relatively mild,>grade 2 hematological toxicity and >Grade 2 acute esophagitis were occurred in 34% and 14% of the patients.Conclusions:Regardless of high selectivity of the patients and limited sample volume, Thoracic radiation and prophylactic cranial irradiation can be safely performed and may notably prolong survival and reduce brain metastases in extensive small cell lung cancer.Part Ⅲ:Clinical Outcomes of Extensive Stage Small Cell Lung Cancer Patients Treated With Intensive Modified RadiotherapyPurpose:To determine the effect and the patterns of failure in extensive small cell lung cancer patients treated with thoracic Intensive Modified Radiotherapy(IMRT.)Methods:A retrospective review was conducted on extensive Stage Small Cell Lung Cancer (ES-SCLC) patients treated from January 2007 to December 2012.130 Patients with ES-SCLC who received thoracic IMRT were identified, and 35 of them received PCI. The median thoracic radiation dose was 56Gy (32Gy-67Gy) with 1.8-2.3Gy per fractions. The schedules for cranial irradiation including 25 Gy in 10 fractions and 30 Gy in 10 fractions. The cumulative local-regional failure rate, distant failure rates and brain metastases rate were calculated. Survival was assessed using the Kaplan-Meier method.Results:The median age of the study patients at diagnosis was 60 years (range,31-81). The median follow-up duration was 37 months (range,4-66) in all patients and 18months (range,4-84) in the survivors. The 1-year and 2-year actuarial overall survival rate were 72.3% and 38.3%, respectively. Of the 92 patients with recurrence,78 had metastatic disease and 31 had locoregional failure. Overall,128 of 130 patients completed treatment plan. The rates of CR, PR, SD and PD over thoracic radiation were 4.6%,72.3%,6.2% and 13.1% respectively. The acute toxicity was relatively mild. Hematological toxicity of ≥grade 2 occurred in 22.3% and acute esophagitis of ≥Grade 2 occurred in 12.2% of the patients. Ten patients developed ≥Grade 2 radiation pneumonitis after radiation. Cumulative brain metastases rates were 18.4% and 37.2% (p=0.038) respectively for patients received thoracic radiation only and thoracic radiation plus PCI. Patients received thoracic radiation EQD2< 54Gy had poor overall survival HR=1.615,95%CI 1.016-2.567; p=0.043) compared to those with EQD2≥54Gy.Conclusions:Definitive thoracic radiation by IMRT in ED-SCLC responsive to chemotherapy may improve local-regional control and overall survival. Relatively high BED radiation seems to be favorable. Prophylactic cranial irradiation can notably prolong survival and reduce brain metastases.Part Ⅳ:Effect of MicroRNA-150 on human small cell lung cancer cell line biological phenotypeBackground and Purpose:we have identified that patients with high-expression level of miR-150 have better overall survivals and progressive-free survivals compared to the low-expresion level patients in small cell lung cancer(SCLC) patients,and this miRNA is an independent predictor of prognosis for SCLC patients. This work was aimed to investigate the effect of overexpressed miR-150 on the phenotype of lung cancer cell lines in vitro.Methods:SCLC cell line NCI-H446 and NCI-H1688 were transient transfected with chemically synthesized mature miR-150 mimicoligonucleotides by lipofecatamine 2000. At 48h after transfection, we carried out the validation of expression level for each miRNA in cell lines by real-time RT-PCR. At 24h after transfection, the proliferation assay was carried out by MTS assay; the untreated transwell model and pre-coated matrigel transwell model was used for the migration and invasion assay, respectively;flow cytometry was usedto analyze the distribution of cell cycle with PI staining.At 24h after tarnsfection, these cells were treated with cisplatin for 24h,and then flow cytometry with Annexin-FITC/PI staining was employed to analyze cell apoptosis. Cell line NCI-H446 and NCI-H1688 stable overexpression miR-150 were established and repeat the assays above.Results:at 48h after transfection,the expression level of miR-150 in NCI-H446 and NCI-H1688 cell lines were all significantly upregulated. In in vitro migration assay, invaded cell number from NCI-H446 stable overexpressed miR-150 and control cells was respectively 104±3 and 170±4, from NCI-H1688 stable overexpressed miR-150 and control cells was respectively 71±2 and 120±3; In in vitro invasion assay, invaded cell number from NCI-H446 stable overexpressed miR-150 and control cells was respectively 44±3 and 84±2, from NCI-H1688 stable overexpressed miR-150 and control cells was respectively 35±2 and 60±3; However, miR-150 had no significant effect on cell proliferation,cell circle and apoptosis induced by cisplatin in NCI-H446 and NCI-H1688 cell lines.Conclusions:These findings indicate cancer-protective effect of miR-150 in SCLC may come from suppression of migration and invasive ability of small cell lung cancer cells.