Simultaneous Integrated Boost-intensity Modulated Radiotherapy For Non-small Cell Lung Cancer

PART Ⅰ The comparative analysis of simultaneous integrated boost-intensity modulated radiotherapy,intensity modulated radiotherapy and three-dimensional conformal radiotherapy plansPurposes To compare the differences of target conformity index（CI）,target dose levels,dose homogeneity Index（HI）and irradiation doses to normal tissues for simultaneous integrated boost-intensity modulated radiotherapy（SIB-IMRT）plans,intensity modulated radiotherapy（IMRT）plans and three-dimensional conformal radiotherapy（3D-CRT）plans,in order to analysis the feasibility and advantages of SIB-IMRT plans.Methods 18 patients with NSCLC were respectively designed for hypo-SIB-IMRT,IMRT and 3D-CRT plans.GTVs were defined as the imaging visible lesions;i GTV were attained by different positioning methods containing tumor motion information;PTV1 were targets 5mm margins extended from GTV or i GTV;and PTV2 were targets 5mm expansion on the basis of PTV1.Prescription doses of IMRT and 3D-CRT plans were given to their PTV1 respectively.PTV2 was usd for dose assessments.Field numbers,angles,weights and the optimization index of IMRT plans are the same as those in hypo-SIB-IMRT plans.3D-CRT plans were made to achieve clinical executable standards,and the doses of normal organs were not exceed the limitations.Patients with early stage NSCLC were given 5Gy/fraction to PTV1 of total 15 frations,and patients with locally advanced NSCLC were given2.5-2.8Gy/fraction to PTV1 of total 25 frations.Then we respectively compared the differences of CI,target dose levels,dose HI and irradiation doses to normal tissues for hypo-SIB-IMRT plans,IMRT plans and 3D-CRT plans.Results The i GTV CIs of SIB-IMRTplans for early stage P-NSCLC（group A）,C-NSCLC（group B）and locally advanced stage NSCLC（group C）were0.83,0.88,0.85,respectively,and all higher than those of IMRT and 3D-CRT plans with statistically significant differences,which were 0.65 and 0.62,0.72and 0.69,0.66 and 0.58,respectively.However,there were no significant differences between IMRT and 3D-CRT plans.The i GTV HIs of SIB-IMRT in three groups were1.08,1.07 and 1.06,and all obviously superior to PTV1 in IMRT and 3D-CRT plans with significant differences.There were statistically differences of the i GTV HIs between SIB-IMRT and IMRT plans in all three groups,between IMRT and 3D-CRT plans in group B,and between SIB-IMRT and 3D-CRT plans in group C.The target volumes of PTV2 received 75Gy or 70Gy in IMRT and 3D-CRT plans were 17.7±1.4cm³ and 39.6±3.1cm³（group A）,5.54±1.56cm³ and 12.8±3.7cm³（group B）,59.8±7.47 cm³ and 89.2±6.8cm³（group C）with significantly differences,respectively.SIB-IMRT technology in this study for normal tissues protection had certain advantages.All normal tissues in group A,evaluated tissues except D_max of spinal cord in group B,and evaluated tissues except D_max of spinal cord,V5 and V10of lung in group C,were all lower than those in IMRT and 3D-CRT plans.There were no significant differences among three different plans of three groups.Compared with3D-CRT plans,IMRT technology could reduce irradiation doses of some normal tissues,while SIB-IMRTtechnology could reduce irradiation doses of more normal tissues,and thereby protect the normal tissues better.The V5 and V10 of bilateral lungs in group A and B did not increase obviously,while V5,V10 of bilateral lungs and D_max of spinal cord were higher than those in IMRT and 3D-CRT plans.Conclusions SIB-IMRT technology further played the advantages of IMRT.Compared with IMRT and 3D-CRT plans,SIB-IMRT increased target CIs and dose HIs.Simple application of IMRT did not improve the target CIs and dose HIs obviously,while combined with SIB and IMRT technologies did not have complete dose HIs,the surrounding normal tissues received higher irradiation doses than those in IMRT plans.SIB-IMRT technology had certain advantages in protecting more normal tissues.However,for irregular tumor targets with large volumes of locally advanced stage NSCLC,the bilateral lung and spinal cord were exposed to more irradiations than those in IMRT and 3D-CRT plans,which need stricter dose controls of the formulation and implementation of SIB-IMRT plans.PART Ⅱ The influence of periodic motions on absolute dose error of hypofractionated-simultaneous integrated boost-intensity modulated radiotherapyPurpose To verify the influence of periodic motions on absolute dose error of hypofractionated-simultaneous integrated boost-intensity modulated radiotherapy（hypo-SIB-IMRT）.Methods The chest phantom was placed on a two-dimensional periodic motion platform,marking the relative position of chest phantom and platform.The motion ranges of the platform were adjusted to±2cm in head-foot direction,±0.2cm（group A）,±0.5cm（group B）,±0.7cm（group C）and±1.0cm（group D）in left-right direction,respectively.Transmit the reconstructed 4DCT images of chest phantom on4 different motion amplitudes to three dimensional inverse planning system（Varian Medical Systems,Palo Alto,CA,USA;Version 8.5）.The gross tumor volume（GTV）consisted of a circular area with a diameter of 3cm,while the internal GTV（i GTV）was fusions of 12-layer GTVs on 10 phases of 4D CT.Clinical target volume（CTV）was defined by expanding the i GTV with 5 mm,while CTV expanded by 5 mm set-up margin as planning target volume（PTV）.The time dose fractionations were i GTV 75Gy,CTV 60Gy,and PTV 45Gy in 15 fractions.The hypo-SIB-IMRT plans were formulated by the same physical technician and then produced validation plans.The absorbed dose in ionization chamber on the plans were the planning doses,while irradiation doses measured by ionization chamber according to verification plans were actual measured doses.To calculate the average relative errors of planning doses and accrual measured doses at three different times in group A-D.The relative error=（plan dose-measured dose）/measured dose.If the relative errors were more than±5%,the planned doses in the execution were with large errors,which need to be revised.Results The average relative errors of planning doses and accrual measured doses at three different times in group A-D were+0.2%,-0.4%,-0.5%and+0.7%without significant differences.Conclusion In the movement ranges of±2cm in head-foot direction,and±0.2cm to±1.0cm in left-right direction,the absolute measured point doses by ionization chamber were with high accuracy,and the periodic motions did not have obvious impact on the implementation of hypo-SIB-IMRT plans localized by 4D CT.PART Ⅲ Prospective Study of Peripheral Early Stage Non-Small-Cell Lung Cancer Treated with Hypofractionated-simultaneous Integrated Boost-Intensity Modulated Radiation TherapyPurposes To analyze the effects of hypofractionated-simultaneous integrated boost-intensity modulated radiation therapy（Hypo-SIB-IMRT）on medically inoperable patients with early stage peripheral non-small-cell lung cancer（P-NSCLC）.Patients and Methods 67 qualified patients with early stage P-NSCLC were included.Hypo-SIB-IMRT was delivered in 15 fractions with internal gross tumor volume（i GTV）75Gy,clinical target volume（CTV）60Gy,and planning target volume（PTV）45Gy on weekdays in 3 weeks.The conventional planning CT scan with active breath control（ABC）,¹⁸fluorodeoxyglucose-position emission tomography(¹⁸FDG-PET)scan,or four dimensional CT scan（4D CT）were employed to do simulation.All IMRT plans were optimized with heterogeneity correction using Pinnacle or Eclipse systems.During the treatment,cone beam CT（CBCT）were performed 2-3 times per week to verify the reproducibility of the target.Results The 1-,2-and 3-year overall survivals（OS）were 100%,75%and 51%,respectively,with a median survival of 61 months.The 1-,2-and 3-year progression free survivals（PFS）were 98%,80%and 63%,while distant metastasis-free survivals（DMFS）were 98%,83%and 71%,respectively.The cancer-specific survivals（CSS）were 100%,88%and 65%,and local control（LC）were 100%,94%,and 87%,respectively.There were not significant differences in OS,PFS,CSS,LC between the subgroups of tumor volumes（>30 cm³ vs.≤30 cm³）,stages and age classes.14.9%（10/67）were with Grade 1or 2 radiation pneumonitis（RP）,6.0%（4/67）with Grade 1esophagitis and 4.5%（3/67）of patients occurred local pain.Of the 10 patients with RP,9.0%（6/67）developed Grade 1 radiation pulmonary fibrosis（RPF）.Conclusions Due to the favorable long-term OS,PFS,DMFS,CSS,LC and minimal toxicities for patients with early stage(T_1-3N₀M₀)P-NSCLC who were medically inoperable,Hypo-SIB-IMRT presented in this prospective study may be considered an option to these patients.PART ⅣProspective Study of Central Early Stage Non-Small-Cell Lung Cancer Treated with Hypofractionated-simultaneous Integrated Boost-Intensity Modulated Radiation TherapyPurposes To analyze the effects of hypofractionated-simultaneous integrated boost-intensity modulated radiation therapy（Hypo-SIB-IMRT）on medically inoperable patients with central early stage central non-small-cell lung cancer（C-NSCLC）.Patients and Methods 26 qualified early stage（T1-3N0M0）C-NSCLC patients without lymph nodes metastasis were included.Hypo-SIB-IMRT was delivered in 15fractions with internal gross target volume（i GTV）75Gy,clinical target volume（CTV）60Gy,and planning target volume（PTV）45Gy in 3 weeks.All IMRT plans were optimized with Pinnacle or Eclipse systems using heterogeneity correction.Results The 1-,3-and 5-year overall survivals（OS）rates were 91%,80%and 34%,respectively,with a median survival of 42 months.The 1-,3-and 5-year progression free survivals（PFS）were 92%,64%and 49%,while distant metastasis-free survivals（DMFS）were 92%,81%and 81%,respectively.The cancer-specific survivals（CSS）were 91%,80%and 56%,meanwhile local control（LC）were 92%,73%,and 59%,respectively.Patients with stage I tumors had better survivals and LC than those with stage II ones,and local relapses were more frequent for larger i GTVs.42.3%（11/26）of patients had grade 1or 2 radiation pneumonitis（RP）,and only 7.7%（2/26）grade 2esophagitis.Of 11 patients with RP,23.1%（6/26）developed grade 1 radiation pulmonary fibrosis（RPF）.Conclusions Hypo-SIB-IMRT presented in this prospective study could achieve relative good outcomes without high-grade toxicities,and may be considered an option to medically inoperable early stage C-NSCLC patients.PARTⅤProspective Study of Locally Advanced Non-Small-Cell Lung Cancer Treated with Simultaneous Integrated Boost-Intensity Modulated Radiotherapy Combined with Concurrent ChemotherapyPurposes To investigate the feasibility,efficacy and toxicities of locally advanced NSCLC treated with simultaneous integrated boost-intensity modulated radiotherapy combined with chemotherapy.Patients and Methods From April 2013 to February 2014,10 patients with locally advanced NSCLC from Radiation Oncology VI,Shandong Cancer Hospital were enrolled in this study.¹⁸Fluorodeoxyglucose-position emission tomography(¹⁸FDG-PET)scan,or four dimensional CT scan（4D CT）were employed to do localization according to the tumors’locations and sizes,in order to reduce the influence of respiratory movement on radiotherapy target.Prescription doses were given to the clinical target volume（CTV）2.2Gy per fraction,planning target volume 2.0Gy per fraction.To the normal tissues’dose limit,when the exposure doses of any normal tissues reached a critical value,the internal gross tumor volume（i GTV）dose was considered to reaching the maximum.That is,the prescription dose of i GTV were determined according to the optimization of radiotherapy planning and maximum tolerated doses of normal tissues.All IMRT plans were optimized with heterogeneity correction using Pinnacle or Eclipse systems.During the treatment,cone beam CT（CBCT）were performed everytime at the first two weeks,while 2-3times per week according to the results of the validation to verify the reproducibility of the target.Hypo-SIB-IMRT was delivered in 25 fractions on weekdays in 5 weeks,5 times per week,once daily.All patients accept two cycles concurrent chemotherapy.The chemotherapy were the PP regimen as pemetrexed cisplatin（PEM）500mg/m²day1 and DDP25mg/m² day1-3,Q21/cycle.After the end of concurrent radiochemotherapy,another two cycles chemotherapy would be delivered to the patients who were well responsed to the therapy.Patients with squamous cell carcinoma were recommended Gemcitabine and cisplatin,while nonsquamous cell carcinoma were still recommended PP regimen.Results All the patients completed the treatment of SIB-IMRT combined with concurrent chemotherapy.The mean conformal index（CI）of i GTV,CTV and PTVwere 0.84±0.08,0.758±0.09 and 0.762±0.069 respectively,and the homogeneity index（HI）of i GTV was 1.16±0.05.The irradiation doses of all organs were in the limited ranges.The therapeutic effect of 8 patients achieved partial remission,while 2 patients with stable disease with localcontrol rateof 100%.Up to the end of follow-up,all patients had not occurren regional recurrence and metastasis.8 patients developed grade 1-2 acute radioactive pneumonia,while 5of them developed grade 1 radiation pulmonary fibrosis.8 patients occurred grade 1-2acute radiation esophagitis,6 patients were with radiation-induced skin reactions,and one patients had local pain.There were not grade 3-5 moderate and severe toxicities,rib fracture,nerve injury,andcardiac function injury and so on.During the treatment of chemotherapy,6 patients appeared grade 1-2gastrointestinal reactions,9 cases were with grade 1-2 bone marrow suppression,and1 patients had grade 3 bone marrow suppression.There were not grade 4 bone marrow suppression,erythra,liver or renal function damages and so on.All patients tolerated the regimen well after corresponding treatments of adverse reactions.Conclusions Due to the favorable LC and minimal toxicities for locally advanced NSCLC patients treated with SIB-IMRT combined with chemotherapy,this regimen was considered feasible and safety.