MicroRNA-related Polymorphisms In Apoptotic Pathway Genes And Clinical Outcomes In Limited-Stage Small Cell Lung Cancer Patients & Comparison Of Lung Toxicity In The Treatment Of Locally Advanced Non-small Cell Lung Cancer Treated With Intensity Modulate

Part Ⅰ:MicroRNA-related Polymorphisms in Apoptotic Pathway Genes and Clinical Outcomes in Limited-Stage Small Cell Lung Cancer PatientsBackground and Purpose:The apoptotic pathway plays an important role in tumor development and treatment including small cell lung cancer. Given the regulatory to gene expression of microRNA (miRNA), this study was to investigate the impact of single nucleotide polymorphisms (SNPs) located at miRNA-binding sites of the 3’-UTR of the genes in apoptotic pathway on limited disease-small cell lung cancer (LD-SCLC) patients’prognosis.Methods:12 tagSNPs of miRNA-binding sites in 7 genes of apoptotic pathway were genotyped on Sequenom MassARRAY Platform by using DNA from blood samples of 146 LD-SCLC patients with chemoradiotherapy from January 2007 to June 2014. The primary endpoint was the association of genotype and survival. Cox proportional hazard regression model and recursive partitioning analysis for combined SNP analyses were performed to identify significant SNPs correlated with overall survival.Results:Three SNPs, rs1045494(C>T) of CASP8, rs3756668(A>G) of PIK3R1 and rs4353229(T>C) of CASP7 gene, were associated with longer overall survival in LD-SCLC patients after chemoradiotherapy, with the adjusted hazard ratio [HR](95% confidence interval [CI]) of 0.480(0.258-0.894),0.405(0.173-0.947) and 0.446(0.247-0.802), respectively. They remained significant after multiple comparison correction. These SNPs retained its prognostic impact on overall survival in stage III patients in subset analysis. Recursive partitioning analysis was conducted to classify patients into three risk subgroups based on unfavorable genotypes combinations of SNPs of rs1045494 and rs4353229, and the adjusted HR of intermediate and high risk groups compared with low risk group were 2.150(1.081-4.275) and 3.760(1.680-8.415).Conclusions:Our findings suggest miRNA-related polymorphysims in the apoptoitc pathway may be potential biomarkers for selection of LD-SCLC patients benefited from chemorad iot her ap y.Part II:Comparison of Lung Toxicity in the treatment of Locally Advanced non-small cell lung cancer treated with Intensity modulated radiotherapy(IMRT) or three-dimensional conformal radiotherapy (3D CRT)Purpose:Intensity-modulated radiotherapy (IMRT) has a distinctive dosimetric feature in thoracic radiotherapy and its role in radiation induced lung toxicity is uncertain in patients with locally advanced non-small-cell lung cancer (LA-NSCLC). This study is to compare lung toxicity in a large cohort of patients treated with IMRT or 3-dimensional conformal radiotherapy (3-DCRT).Methods:480 patients with LA-NSCLC treated with definitive radiation at our institution between 2002 and 2011 were retrospectively reviewed. Symptomatic radiation induced lung toxicity(SRILT), namely the grade 2 or higher RILT, was assessed and compared between two techniques using chi-square tests and logistic-regression. Dosimetric parameters were also compared and evaluated for the association with toxicity.Results:SRILT was observed in 104 patients(21.7%). The rates of SRILT in patients with all MLD≥17.5Gy,V5≥62.5% and V20≥29.2% were significantly higher than those with MLD<17.5Gy, V5<62.5% and V20<29.2%(42.1%vs.17.5%,28.5%vs.19.0%, 36.9%vs.18.4%, respectively), as it is in other dosimetric index(5Gy to 60Gy in all whole and ipsilateral, and 5Gy to 15Gy in contralateral lung). Compared to 3DCRT, IMRT decreased the risk of SRILT significantly(27.8% vs.18.0%, p=0.026). In dosimetric comparison, IMRT produced a higher V5 in whole lung, similar V20-V60 in ipsilateral lung, while reduced V15-V60 in contralateral lung. IMRT led to more SRILT reduction(29.5%) compared to 3DCRT(53.7%) in patients with whole MLD≥ 17.5Gy(P=0.024), as it is in other dosimetric index. In patients with PTV≥506.4ml, SRILT were observed 18.5% in IMRT group. significantly lower than 36.1% in 3DCRT groupConclusions:IMRT could reduce SRILT in patients with locally advanced NSCLC compared with 3DCRT independent of improving dose distribution.Part Ⅲ:Hypofractionated radiotherapy for medically Inoperable stage I non-small cell lung cancerObjective:To investigate the clinical outcomes and toxicity of hypofractionated radiotherapy for medically inoperable stage I non-small cell lung cancer(NSCLC).Material and methods:Patients treated with radiotherapy with a dose of 4-6Gy per fraction using fixed-field intensity modulated radiotherapy (IMRT) or volumetric-modulated arc therapy (VMAT) at our hospital from June 2005 to December 2013 were analyzed. The cone beam CT was employed to ensure high-precision delivery. The total prescription doses ranged from 50 to 78 Gy with four to six Gy per fraction The most common schedule was six Gyxl2 fractions. The median follow-up period was 24 months. The survival was estimated by the Kaplan-Meier method.Results:A total of 65 patients with stage I NSCLC were analyzed, including 43 primary NSCLC patients and 22 patients with recurrent or secondary primary NSCLC. And 72% patients were histologically confirmed as NSCLC. An objective response (complete response or partial response) was achieved at six months in 84.6% of patients. The three-year local control rate was 90.8%. The Kaplan-Meier estimates of local failure-free, progress ion-free, overall survival and cancer-specific survival rates at three years were 90.3%,64.3%,68.9% and 88.8%, respectively. The overall survival rate at three years was 66.7% in 46 patients confirmed by pathology or cytology, receiving radiotherapy for recurrent NSCLC had a significantly poorer PFS than those with primary NSCLC (P=0.047). Post-treatment failure occurred in 23 patients (35.4%) during follow-up, including local failure in seven (10.8%), regional failure in eight (12.3%), and distant metastases in 11 (16.9%) patients. BED≥100 Gy led to a trend of better local control but was not different sigificantly (P=0.240). The rate of symptomatic radiation pneumonitis was 16.9%, and no grade 4-5 toxicity was observed.Conclusions:Favorable local control and outcome was achieved with hypofractionated radiotherapy in patients with inoperable stage I NSCLC with acceptable toxicity. The most common schedule of six Gy×12 fractions may be a promising regimen, and a prospective study is in process.