| Background and Purpose:Compared with conventional fractionated radiotherapy,stereotactic body radiation therapy(SBRT)shares the advantages of high dose to targets while sparing surrounding normal structures and short course of treatment.SBRT has been recommended as the standard treatment for medically inoperable early stage peripheral non-small cell lung cancer(NSCLC)patients.However,for patients with central NSCLC whose tumor abuts or invades the trachea and bronchus,SBRT may lead to a high incidence of toxicity.Currently,it is still controversial whether SBRT is suitable for patients with central NSCLC.How to balance the efficacy and adverse effect of SBRT is a hot issue of academic concern in recent years.This study will discuss the safety and efficacy of SBRT for patients with central NSCLC from the following four aspects.Firstly,we retrospectively reviewed the outcomes and toxicity of SBRT for patients with stage III/IV central NSCLC.Secondly,we conducted a prospective controlled study to compare the outcomes and toxicity of SBRT versus intensity modulated radiation therapy(IMRT)for patients with central NSCLC.Thirdly,we evaluated the outcomes,toxicity,and dosimetric parameters of SBRT for patients with advanced stage ultra-central NSCLC.Fourthly,we compared the outcomes and toxicity of SBRT versus IMRT for patients with stage III ultra-central squamous NSCLC.Materials and Methods:Part?:We retrospectively reviewed the clinical data of stage III/IV patients with central NSCLC treated with SBRT in our hospital between January 2013 and December2014.Central tumors were defined as tumors located within 2cm of the proximal bronchial tree.Patients who previously received both SBRT and IMRT were excluded.SBRT using CyberKnife and GammaKnife with a regimen of 25.5-48 Gy in 4-6fractions and 36.3-52.5Gy in 10-12 fractions,respectively.Patients' clinicopathological information including age,gender,date of lung cancer diagnosis,pathological type,clinical stage,tumor diameter,salvage treatment regimen,radiotherapy effect evaluation,local or distant failure patterns,treatment-related adverse events,and survival data was collected and recorded.Radiotherapy in-field effect was evaluated using RECIST v1.1.Adverse events were assessed using the CTCAE v4.0.Overall survival(OS)was defined as the time from the date of the radiotherapy to the date of death or at the end of follow-up.Data were analyzed using SPSS version 20.0(v20.0).Local control time(LC)and OS were estimated using the Kaplan–Meier method.The last follow-up time was January 30,2016.Part?:We prospectively enrolled the clinical data of central NSCLC patients treated with SBRT or IMRT in our hospital from March 2015 to March 2017.Central tumors were defined as tumors located within 0.5cm of the trachea or main bronchus.SBRT using CyberKnife with a regimen of 30-40 Gy in 5-6 fractions.IMRT using linear accelerator with a regimen of 60-66 Gy in 30-33 fractions.Radiotherapy in-field effect was evaluated using RECIST v1.1.Toxicity was assessed using CTCAE v4.0.Possibly treatment-related deaths were scored as grade 5 toxicity in this study.OS was defined as the time from the date of the radiotherapy to the date of death or at the end of follow-up.Data analysis was performed using SPSS v20.0.Kaplan-Meier method was used to estimate the LC,progression free survival(PFS),and OS for each group,and comparison between the two groups was performed with log-rank test.Univariate analysis was performed to identify the predictive factors for all patients using Kaplan-Meier method,and variables with p < 0.10 were selected for multivariate analysis using Cox proportional hazard regression model.Significant predictors were identified as p<0.05.The last follow-up time was April,2018.Part?:Fifty-one consecutive patients with advanced stage ultra-central NSCLC treated with SBRT in our hospital between December 2014 and August 2017 were reviewed.Clinical outcomes,dosimetric parameters and SBRT toxicity were analyzed.“Ultra-central” was defined as tumors abutting or invading the trachea or the proximal bronchial tree.We included locally advanced patients who were unfit or unwilling to receive conventional chemoradiotherapy and patients with metastatic or postoperative recurrent disease.Patients previously receiving thoracic irradiation were excluded.SBRT using CyberKnife with a regimen of 30-37.5Gy in 4-6 fractions.Radiotherapy in-field effect was evaluated using RECIST v1.1.The critical structures including the trachea and proximal bronchial tree,esophagus,heart,spinal cord,and the normal lung were contoured using the Accuray MultiPlan treatment system,and the dosimetric parameters were calculated.SBRT-related toxicity was recorded using CTCAE v4.0.Possibly treatment-related deaths were scored as grade 5 toxicity in this study.For each patient,only the highest grade of toxicity was recorded.OS was defined as the time from the date of the radiotherapy to the date of death or at the end of follow-up.All statistical analyses were performed using SPSS v20.0.Survival curves for LC,PFS,and OS for stage III and stage IV or recurrent patients were generated with the Kaplan-Meier method and between-group differences assessed by log-rank test.Statistical graphs were generated using GraphPad Prism v7.A univariate analysis for LC,PFS,OS,and grade?3 toxicity was performed with Kaplan–Meier method,respectively,including the potential predictive patient factors and dosimetry factors.Variables that were associated with a p<0.10 in the univariate analysis were included in the Cox proportional hazard regression model for multivariate analysis and significant predictors were identified as p<0.05.The last follow-up time was September 2018.Part? : The outcomes and toxicity of forty-four stage III patients with ultra-central squamous NSCLC treated with IMRT or SBRT in our hospital between January 2014 and April 2017 were retrospectively reviewed.“Ultra-central” was defined as tumors abutting or invading the trachea and proximal bronchial tree.Patients previously receiving thoracic radiotherapy or surgery were excluded.IMRT was delivered using linear accelerator with 60-66 Gy in 30-33 fractions while SBRT using CyberKnife with 31-36 Gy in 5-6 fractions.Radiotherapy in-field effect was evaluated using RECIST v1.1.Toxicity was assessed using CTCAE v4.0.Possibly treatment-related deaths were scored as grade 5 toxicity in this study.OS was defined as the time from the date of the radiotherapy to the date of death or at the end of follow-up.All statistical analyses were performed using SPSS v20.0.Demographic data was compared between the IMRT and SBRT group using Mann-Whitney U test and Fisher exact tests.Curves for LC,PFS,and OS between IMRT group and SBRT group were generated using log-rank tests.Statistical graphs were generated using GraphPad Prism v7.A univariate cox proportional hazard model was used to identify significant predictive factors(p<0.05)associated with LC,PFS,OS and grade 3 or higher toxicity.A multivariate cox proportional hazard model was performed with all variables with p<0.10 in the univariate analysis,and p<0.05 was statistically significant.The last follow-up time was September 2018.Results:Part?:Fifty-three patients with stage III/IV NSCLC were enrolled,including 34 with adenocarcinoma,14 with squamous carcinoma,and 5 with other pathology types.The median age at SBRT was 63 years(range: 40-79).The median tumor diameter was4cm(range: 1-11cm).The median follow-up time was 20 months(range,3-43 months).The response rate(CR+PR)was 66.0%.The median local control time was 37 months(95% CI:22.3-51.7 months).The 1-year and 2-year local control rate was 81.4% and59%,respectively.The median OS was 29 months(95% CI:21.3-36.7 months).The1-year,2-year,and 3-year OS rate was 83.0%,64.1%,and 42.1%,respectively.At the end of follow-up,distant failure rate was 86.8%(46/53).Grade 1 or 2 toxicity was observed in 37.8% patients.One patient(1.89%)experienced grade 3 radiation pneumonia.Grade 3 or higher toxicity was observed in 1.89% patients.No grade 4 or 5toxicity was observed.Part?:Eighty-seven eligible central NSCLC patients were prospectively enrolled,including 56 treated with SBRT and 31 treated with IMRT.The median age at radiotherapy was 65 years(range: 35-84).The median sum of tumor diameters was5.3cm(range: 1.4-16.4).The median follow-up time was 18 months(range: 3-36)for all patients and 29 months(range: 12-36)for the alive patients.The tumor response rate for SBRT group and IMRT group was 83.9% and 58.1%,respectively.The 1-year local control rate for SBRT group and IMRT group was 71.2% and 76.8%,respectively(p=0.762).The 1-,2-year PFS rate for SBRT group and IMRT group was 41.1% and28.7%,35.5% and 29.0%,respectively(p=0.571).The 1-,2-year OS rate for SBRT group and IMRT group was 67.9% and 49.4%,45.2% and 32.3%,respectively(p=0.083).Multivariate analysis showed sum of tumor diameters was significantly associated with OS(p=0.026).The grade 3 or higher toxicity rate for SBRT group and IMRT group was 8.9% and 6.5%,respectively.Part?:Fifty-one advanced stage ultra-central NSCLC patients were enrolled,including 20 with stage III and 31 with stage IV or postoperative recurrent disease.The median age was 63 years(range: 35–82),and the median tumor diameter was 6.8 cm(range: 2.1–12.4).The median follow-up time was 17 months(range: 3–39)for all patients and 25.5 months(range: 13–39)for the alive patients.The tumor response rate was 80.4%.For stage III and stage IV or recurrent patients,the median local control time was 17 months and 11 months,respectively(p=0.59);the 1-year local control ratewas 61.2% and 49.1%,respectively;the median PFS was 8 months and 7 months,respectively(p=0.48);the 1-,2-,3-year PFS rates were 35.0%,15.0%,0 and 22.6%,12.9%,6.5%,respectively;the median OS was 17 months and 21 months,respectively(p=0.38);the 1-,2-,3-year OS rates were 70%,36.6%,0 and 61.3%,46.0%,36.6%,respectively.Grade 3 or higher toxicity was observed in 9.8% patients.Part?:Forty-four stage III ultra-central NSCLC patients were enrolled,including15 treated with SBRT and 29 treated with IMRT.All patients treated with SBRT were unfit or unwilling to receive conventional chemoradiotherapy.The median age at radiotherapy was 63 years(range: 39-78).The median tumor diameter was 5.8cm(range:1.2-10.7).The median follow-up time was 16.5 months(range: 3-50)for all patients.The tumor response rate for SBRT group and IMRT group was 86.7% and 37.5%,respectively.The 1-year local control rate for SBRT group and IMRT group was 60.8%and 37.5%,respectively(p=0.230).The 1-,2-year PFS rate for SBRT group and IMRT group was 33.3% and 20.7%,6.7% and 8.6%,respectively(p=0.905).The 1-,2-year OS rate for SBRT group and IMRT group was 66.7% and 61.7%,27.0% and 38.1%,respectively(p=0.481).The grade 3 or higher toxicity rate for SBRT group and IMRT group was 20.0% and 24.1%,respectively.Conclusion:This study preliminarily shows SBRT for central NSCLC has the advantages of high dose per fraction,precision irradiation,short course of treatment,and it also achieves similar therapeutic benefit ratio for ultra-central NSCLC,compared with IMRT.As a palliative treatment option,SBRT with a moderate dose regimen of 30-40 Gy in 4-6fractions for patients with advanced central NSCLC with stage III/IV or postoperative recurrence is effective with tolerable adverse effect,which is a good choice for palliative radiotherapy. |
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