Simultaneous Integrated Boost of intensity modulated radiation therapy to Stage II-III Non-Small Cell Lung Cancer with metastatic lymph nodes

Simultaneous Integrated Boost of intensity modulated radiation therapy to Stage II-III Non-Small Cell Lung Cancer with metastatic lymph nodes | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research article Simultaneous Integrated Boost of intensity modulated radiation therapy to Stage II-III Non-Small Cell Lung Cancer with metastatic lymph nodes qingsong li, Na Liang, Wei-Wei Ouyang, Sheng-Fa Su, Zhu Ma, Yi-Chao Geng, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-15993/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 09 Sep, 2020 Read the published version in Cancer Medicine → Version 1 posted You are reading this latest preprint version Abstract Background: Local tumor failure remains a major problem after radiation-based nonsurgical treatment for unresectable locally advanced Non-Small Cell Lung Cancer （NSCLC）and inoperable stage II NSCLC .The aim of this study was to evaluate the feasibility of Simultaneous Integrated Boos of intensity modulated radiation therapy (SIB-IMRT) to Stage II-III NSCLC with metastatic lymph nodes. Methods: Patients were diagnosed by pathology or PET-CT. PTV was divide into two parts as follow, the PTV of primary tumor (PTVp) and the PTV of metastatic lymph nodes (PTVn) .The radiation doses were simultaneously prescripted 78Gy (BED = 101.48Gy) for PTVp and 60-65Gy (BED = 73.6-81.25Gy) for PTVn, 26f/ 5.2 weeks .Response was scored according to WHO criteria. Radiotherapy toxicity was scored according to RTOG criteria .Hematology and gastrointestinal toxicity were scored according to CTCAE1.0 criteria. Results: A total of 20 patients were enrolled. 17 patients were diagnosed by pathology and 3 patients were diagnosed by PET-CT . All patients were treated with SIB-IMRT. The objective response rate (ORR) was 90%, with CR 25%, PR 65%, NC 10% and PD 0%. Although Radiation toxicitiy was common, there were no grade≥3，with Radiation pneumonitis (10 cases), esophagitis (17 cases) and dermatitis (12 cases). The local control rates at 1, 3 and 5 years were 85%, 75% and 70%, respectively. The overall survival（OS）and local progression-free survival(LPFS) rates at 1, 3 and 5 years were 90%, 42.6%, 35.5% and 84.4%, 35.5% , 28.4%, respectively. The MST was 24 months. Conclusions: SIB-IMRT can significantly improve ORR and suivival for stage II-III NSCLC with metastatic lymph nodes , with high safety and satisfactory efficacy . Keywords: cancer/non-small-cell lung cancer; radiation therapy /SIB-IMRT; efficacy; safety Retrospective Trial Registration： (ChiCTR 2000029304) Oncology Cancer Biology cancer/non-small-cell lung cancer radiation therapy /SIB-IMRT efficacy safety Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Concurrent thoracic chemoradiotherapy (CCRT) is the standard of care in patients with good performance status and inoperable stage II-III non-small-cell lung cancer(NSCLC) who have metastatic lymph nodes, especially for locally advanced NSCLC [ 1 ] . The radiation dose is one of the controversial focuses. At present, the uniform dose of radiation therapy was 60 Gy, but treatment outcomes remain poor. RTOG trials led to the conclusion that local tumor control was significantly correlated with improved survival [ 2 ] . 60 Gy may be not a reasonable dose [ 3 – 5 ] .In this study, it is conceived that using the biological effective dose (BED) ≥ 100 Gy of large fractionated radiotherapy for stage Ⅰ-Ⅱ NSCLC can obtain more than 90% local control rate [ 6 ] and recurrence rate of mediastinal metastatic lymph nodes for locally advanced NSCLC with concurrent chemoradiotherapy (median dose 60 Gy/30f) was only 20% [ 7 ] . Different doses of radiotherapy were simultaneously prescribed for primary tumor and metastatic lymph nodes through SIB-IMRT. The aim of this study was to evaluate the safety and efficacy of (SIB-IMRT) for Stage II-III Non-Small Cell Lung Cancer(NSCLC) with metastatic lymph nodes. Methods Patient selection Inclusion criteria were as follows: (1) histologically or cytologically or PET-CT confirmed NSCLC; (2) newly diagnosed stage II-III disease (staged according to the 2009 system of the American Joint Committee on Cancer); (3) KPS ≥ 70; (4) no contraindications to radiation therapy or chemotherapy; (5) Normal range of blood routine and biochemical indexes (7)good compliance with treatment and follow-up. Pretreatment evaluations All patients underwent fiberoptic bronchoscopy and contrast-enhanced computed tomography (CT) of the chest to evaluate the extent of the primary tumor and regional lymph node status. All patients also underwent bone scintigraphy, contrast-enhanced CT of the abdominal region, and magnetic resonance imaging (MRI) of the brain to detect distant metastases. Positive findings on positron emission tomography (PET) /CT or bone scintigraphy required other additional radiologic confirmation (e.g., MRI or CT of bone). Pretreatment evaluations were to be completed within 2 weeks before treatment was begun. Treatment methods Thoracic radiation therapy Using 6 MV X-ray, intensity-modulated radiotherapy(IMRT). The patient was positioned in the supine position with thermoplastic film fixation and 5-mm-thickness enhanced CT. The target Volume of primary tumor and metastatic lymph nodes were delineated respectively. The gross tumor volume of primary tumor (GTVp) included the thoracic primary tumor in lung windows and was outlined on the treatment planning CT scan ,the clinical target volume of primary tumor (CTVp) was defined as the GTVp plus a 0.6-cm margin with anatomical correction༌the planning target volume of primary tumor (PTVp) was defined as the CTVp plus another margin of 0.5 to 1.0 cm. The gross tumor volume of metastatic lymph (GTVn) included any enlarged(> 1 cm on short axis) metastatic lymph nodes and was outlined on the treatment planning CT scan༌the clinical target volume of metastatic lymph (CTVn) was modified by the GTVn and expanded outward by 0.6 cm combined with anatomical correction༌the planning target volume of metastatic lymph (PTVn) was defined as the CTVn plus another margin of 0.5 cm. Different doses of radiation therapy were simultaneously prescribed for PTVp and PTVn through SIB-IMRT. The radiation doses were 78 Gy (BED = 101.48 Gy) for PTVp and 60-65Gy (BED = 73.6-81.25 Gy) for PTVn, 26f/ 5.2 weeks,, respectively. The radiotherapy plan was evaluated as 95% of the prescription dose line including 95% of PTV. The percentage of total lung volume receiving ≥ 20 Gy(V20),whole lung dose (MLD) and mean heart dose(MHD) was to be kept at ≤ 32%, ≤ 20 Gy and ≤ 30 Gy ༌respectively (Fig. 1–2). Chemotherapy Platinum-based doublet chemotherapy (cisplatin in combination with docetaxel, paclitaxel, or pemetrexed) or Single drug given every 21 to 28. The chemotherapy regimens of all patients were as follows: 1 case of docetaxel, 1 case of pemetrexed, 1 case of cetuximab + docetaxel, 1 case of pemetrexed + cisplatin, 1 case of paclitaxel liposome + carboplatin, 1 case of pemetrexed + cisplatin, 1 case of paclitaxel liposome + carboplatin, 9 cases of docetaxel + cisplatin( 2 cases of docetaxel + cisplatin + Endostar. Chemotherapy Cycles were from 2 to 4. 4 patients refused chemotherapy. Evaluation of treatment-related toxicity and response Response was scored according to WHO criteria as follows: complete response(CR), partial response (PR), and no change (NC), progressive response(PD). Radiotherapy toxicity was scored according to RTOG criteria .Hematology and gastrointestinal toxicity were scored according to CTCAE1.0 criteria. Follow-up evaluations and Statistical analyses At 1 month after completion of treatment, patients underwent CT scanning of the chest and abdominal region and MRI of the head to assess tumor response. These tests were then repeated every 3 months for 2 years and every 6 months thereafter. Primary endpoints were OS,LPFS and acute toxicity. Kaplan-Meier analyses were used for statistical analysis. Results Patient characteristics From December 2009 to March 2019,20 patients were enrolled in this study. There were 3 patients with stage Ⅱ A ,1 patient with stage Ⅱ B ,12 patients with stage Ⅲ A and 4 patients with stage ⅢB .The patients with stage II refused operation Because of old-aged patients (3 cases) and pulmonary dysfunction (1 case).There were 17 males and 3 females. Median age of patients was 75 years (range, 44–82 years). 50% of patients (10/20) were older than 70 years. Age of 8 patients were ≥ 77 years (range,77–82 years). There were 4 adenocarcinomas, 10 squamous cell carcinomas, 3 non-small cell lung carcinoma and 3 clinically diagnosed lung cancers. Median long axis of primary tumor was 4.55 cm(range ༌1.2 -11cm). Median number of metastatic lymph nodes was 1(range ༌1–5). Median volume of GTVp was 69.99 cm3 (range ༌8.74-530.07 cm3). Median volume of PTVp was 189.22 cm3 (range༌83.85-886.71 cm3); Median volume of GTVn was 35.96 cm3(range ༌4.37 -139.05 cm3). Median volume of PTVn was 148.37 cm3 (range ༌35.79-405.68 cm3). The number of patients with V 20 ≤ 20%, 21%-25%, 25%-30% and > 30% were 4, 7, 7 and 2 (range༌12.1%-32%, median 24.6%),respectively. The number of with MLD ≤ 20 Gy and > 20 Gy were 17 and 3 (range 8.57–21.23 Gy, median MLD16.67 Gy), respectively. The number of patients mean heart dose༈MHD)≤ 26 Gy and > 26 Gy were 16 and 4 (range 1.83–32.41 Gy, median 7.65 Gy), respectively༈Table 1 ༉. Table 1 Clinical characteristics, treatment data and survival of 20 patients of stage II-III NSCLC No Sex A B C D stage metastatic lymph node GTV P (cm 3 ) PTV P (cm 3 ) GTV N (cm 3 ) PTV N (cm 3 ) V20 (%) MLD(Gy) MHD(Gy) PD Death Cause of death OS(month) LPFS(month) Drainage area Number 1 Male + - - - T2aN2M0 4R + 10R 2 79.13 290.08 46.93 169.93 24.9 18.32 11.91 L + M yes L + M 64 62 2 Male + - - - T3N2M0 4L + 7 2 465.91 886.71 37.28 137.57 31.3 20.43 32.41 L yes L + Hemoptysis 23 23 3 Male - - - - T1aN2M0 5 + 7 5 94.85 360.35 72.14 281.72 24.3 13.73 6.3 no yes Pulmonary infection 12 12 4 Male + - - - T2aN1M0 10L 1 26.13 123.83 61.65 239.53 32 21.19 30.86 no no 82 82 5 Male - - + + T2bN1M0 10R 1 49.2 163.01 16.03 63.07 19.9 14.96 2.35 no yes miocardial infarction 43 43 6 Male - + + - T3N1M0 10L 1 93.83 234.75 71.32 201.32 25.5 17.92 22.79 L yes Sudden cardiac death 14 12 7 Male - - + - T2aN1M0 10L 1 27.53 83.85 22.37 84.38 16.1 10.96 9.04 no yes Sudden cardiac death 24 24 8 Female - + - - T3N2M0 4R 1 398.47 711.64 32.44 123.93 26.5 16.96 19.39 M yes Pulmonary infection 18 9 9 Male + - - - T3N2M0 4R 1 76.35 204.29 62.72 159.16 23.9 21.23 7.58 no no 48 48 10 Male + - - - T3N2M0 2R 1 70.11 211.57 10.1 72.11 22.5 14.32 4.1 no no 43 43 11 Male + - - - T3N1M0 10L( fusion) Fusion 530.07 868.64 107.51 261.05 22.8 17.7 26.92 no yes Respiratory failure 15 15 12 Male + + - - T3N3M0 4L 1 69.87 174.15 21.56 74.76 27.3 16.49 7.7 no no Pulmonary infection 16 16 13 Male - - - - T2N2M0 4R 1 26.22 111.72 4.37 44.54 12.11 8.57 6.84 no no 24 22 14 Female - + - - TN1N1M0 10L 1 8.74 84.70 58.20 227.79 28.00 14.17 30.9 L + M no 66 30 15 Male - + - - T3N2M0 4R 2 46.28 133.98 7.68 35.79 17.9 18.32 1.83 no yes Pulmonary infection 32 32 16 Male - - - - T4N3M0 4R/L/7/10R 5 231.13 475.15 34.01 188.11 25.28 16.96 8.48 no no 16 16 17 Female - + - + T2N3M0 4R/L/5/6 6 52.12 96.08 12.15 76.36 20.49 12.78 1.98 no no 14 14 18 Male + - - - T4N2M0 6/7 5 261.14 472.17 34.63 132.15 21.92 13.82 4.74 L yes L 15 13 19 Male - - - - T3N2M0 2R/3A/4R/5/10R 5 35.24 118.53 80.61 245.22 27.43 16.85 5.94 no no 13 8 20 Male - - - - T2N2M0 2R/3A/4R(fusion),7 3 23.9 87.08 139.05 405.68 25.80 15.34 7.60 no yes Pulmonary infection 6 6 A: chronic obstructive pulmonary disease,B: hypertension,C: coronary heart disease,D: diabetes mellitus,L = local recurrence, M = distant metastasis Response The CR, PR and SD rate was 25%(5cases), 65% ༈13cases༉and 10%༈2cases༉,respectively. The CR, PR and SD rate of primary tumor was 30%༈6 cases༉、55%༈11 cases༉、15%༈3 cases༉respectively. The CR, PR and SD rate of metastatic lymph nodes was 25%༈5cases༉、60%༈12cases༉、15%༈3cases༉. The clinical benefit rate was 100%. Progress, cause of death and survival During follow-up, there were local recurrence and / or metastasis progressed in 7 patients (2 patients with local recurrence and bone metastasis, 1 patient with local recurrence and pulmonary metastasis, 1 patient with local recurrence ,1 patient with local recurrence and hemoptysis ༌1 patient with alone lung metastasis, 1 patient with malignant pleural effusion). By the last follow-up, 12 patients died .The cause of death in 9 patients was not related to tumor (3 died of cardiogenic death, 5 died of pulmonary infection and 1 died of respiratory failure). The cause of death in 3 patients was related to tumor(1 died of local recurrence with metastasis, 1 died of local recurrent hemoptysis and 1 died of local recurrence). The local control rates at 1, 3 and 5 years were 85%, 75% and 70%, respectively. The OS and LPFS rates at 1, 3 and 5 years were 90%, 42.6%, 35.5% and 84.4%, 35.5%, 28.4%, respectively. The MST was 24 months( Fig. 3 –4). Toxicity No patient experienced grade 3 + acute radiation toxicity. Grade Ⅰ radiation pneumonitis was observed in 9 patients (7 in concurrent chemoradiotherapy, 2 in radiotherapy alone) and grade Ⅱ in 1 patient (concurrent chemoradiotherapy). Grade Ⅰ radiation dermatitis was observed in 9 patients (8 in concurrent chemoradiotherapy, 1 in radiotherapy alone) and grade Ⅱ in 3 patients (all in concurrent chemoradiotherapy). Grade Ⅰ radiation esophagitis was observed in 7 patients (3 in concurrent chemoradiotherapy, 4 in radiotherapy alone) and grade Ⅱ in 10 patients (all in concurrent chemoradiotherapy). Chronic radiation-induced lung injury was observed in 1 patients, which occurred 3 months after radiotherapy (the serial number 12, lung V20 was 27%, MLD was 16.49 Gy). Grade Ⅰ, Ⅱ, Ⅲ and Ⅳ of gastrointestinal and hematological toxicity were 6, 8, 1, 0 and 1, 6, 5, 4 cases, respectively, all of which occurred in concurrent chemoradiotherapy. There was no radiomyelitis or heart injury observed in all patients. Discussion At present,,the radiation dose ≥ 60 Gy/30f is needed for concurrent chemoradio- therapy to locally advanced NSCLC [ 8 ] ༌but the local control rates at 1, 3 and 5 years were about 70%, 50%, 40% [ 9 ] ༌and the OS rate at 5 years was about 15% [ 8 , 10 ] .The local recurrence rates of stage Ⅱ-Ⅲ NSCLC with concurrent chemoradiotherapy at 1, 2, 3 and 5 years were 23% [ 11 ] 、30.8% -37.1% [ 12 ] 、28.1%、28.9 [ 10 ] .Uncontrolled local tumors may be a potential source of distant metastasis [ 13 ] .Although the RTOG0617 study showed that 60 Gy may be more reasonable than other radiation dose [ 3 ] , further analysis of the study showed that the result was affected by many other factors [ 12 ] .There is still debate about that increasing the dose of radiation therapy can reduce recurrence and prolong survival. A phase II clinical study by KongFM et al showed that the local control rate was 82% at 2 years and 30% at 5 years because of the high radiation therapy (86Gy/30day) with adaptive radiotherapy guided by PET/CT [ 4 ] .Many studies still supported the idea that high dose of radiation therapy was necessary [ 14 – 17 ] .After the report of RTOG0617 study in 2012, MachtayM et al conducted a meta-analysis, which included 7 prospective randomized concurrent chemoradiotherapy studies about locally advanced NSCLC. The study [ 18 ] showed that BED ≥ 74.67 Gy (conventional fractionated dose 62-64Gy) was more beneficial to improve the local control and survival, increasing the tBED of 1 Gy can increase the local control by 3%, and the BED of 1 Gy can increase OS by 4%.After conventional fractionated radiotherapy, dose escalation for local tumor may improve local control and survival [ 19 ] . Through changing the fractionated radiotherapy dose of 2.5-6Gy with concurrent chemoradiotherapy for locally advanced NSCLC ,the CR ,PR,1, 2, 3 years OS rates and mean suivival time(MST) were 26.5%, 42.9%,63.3%, 40.8%, 20.4% and 22 months, respectively [ 20 ] . A fraction dose of 3 Gy and total dose of 65-68Gy were given after initially 50 Gy/20 fractions ༌the 3-years OS and PFS rates were 32.1% and 29.8% respectively ༌and the 1 -, 2-and 3-years LRPFS rates were 69.6%, 60.9% and 60.9%, respectively [ 21 ] . Based on the characteristics of IMRT, the dose of the PTV was kept at 60 Gy and the dose of GTV was 72–78 Gy synchronously༌the result showed that MST was 25.3 months [ 13 ] . 63-103Gy was the recommended radiation therapy dose to improve the local control rate [ 22 ] . The commonness of these studies was that the primary tumor and drainage lymph nodes were defined as the same target. The ways to increase dose of physical or BED were as follows: dose escalation after conventional fractionated radiotherapy༌different doses were simultaneously prescribed to GTV and PTV. The aim was to improve the tumor local control and survival. The way of increasing the dose of radiotherapy in our study was different from the above studies. The primary tumor and drainage lymph nodes were defined as different targets༈GTVp and GTVn༉. Different doses of radiation therapy were simultaneously prescribed for primary tumor and metastatic lymph nodes through SIB-IMRT. One principle is that the BED ≥ 100 Gy for stage I NSCLC can obtain a local control rate of > 90% [ 23 ] , significantly reduce the local recurrence rate and improve the survival rate at 3-years [ 24 ] . Another principle is that the long-term local control rate is more than 50% through conventional fractionated radiotherapy dose ༈60-66Gy༉ for mediastinal metastatic lymph nodes [ 25 ] . Through SIB-IMRT, the radiation doses were simultaneously prescripted 78 Gy (BED = 101.48 Gy) for primary tumor and 60-65Gy / 26f (BED = 73.6-81.25 Gy) for metastatic lymph nodes .The result showed that the ORR was 90% (18 / 20), and the SD was only observed in 2 patients (primary tumor reduced by 14%, 30%, metastatic lymph node reduced by 44%, 32%).The ORR of primary tumor and metastatic lymph node was both 85% and there was no PD. The local control rates at 1, 3 and 5 years were 85%, 75% and 70%, respectively. Only 4 patients were diagnosed as local recurrence confirmed by imaging and / or pathology and 3 of them died from the following causes: myelosuppression grade IV, sudden cardiac death, hemoptysis. The result showed that the ORR was kept at 90% by SIB-IMRT ༌which was superior to the result of chemotherapy and conventional fractionated radiotherapy for local advanced NSCLC [ 26 ] . It may be due to the increase of ORR, the proportion of tumor shrinkage and regression increased ,which was beneficial to reduce the recurrence and mortality rate and positively correlated with the prolongation of survival rate [ 4 ] 。The OS and LPFS rates at 1, 3 and 5 years were 90%, 42.6%, 35.5% and 84.4%, 35.5%, 28.4%, respectively. The MST was 24 months. The injury control index used in the evaluation of radiotherapy plan was based on the standard of conventional fractionated radiotherapy of locally advanced NSCLC Acute radiation pneumonitis, radiation esophagitis and radiation dermatitis were all grade 1–2. Further analysis showed that grade 2 toxicity mainly occurred in concurrent chemoradiotherapy, which increased acute radiotoxicity [ 10 ] . Compared with the conventional radiotherapy, there was no increase in radiotoxicity despite the increase in fractionated dose(3Gy/f) and BED [ 27 ] .The main systemic toxicity was gastrointestinal toxicity (grade 1 in 6 patients, grade 2 in 8 patients, grade 3 in 1 patient) and hematological toxicity (grade 2 in 6 patients, grade 3 in 5 patients, grade 4 in 4 patients ). All of them occurred in concurrent chemoradiotherapy. Radiotherapy alone had no obvious systemic toxicity. It showed that systemic toxicity was mainly related to cytotoxic drugs. A total of 12 patients died. 5 patients died of pulmonary infection (ages: 55, 71, 78, 79, 85 years;V20: 26. 5%, 25.8%, 24.3%, 27.3%, 17.9%༛ RP grade:2, 0, 0, 2, 0༛ MLD < 20Gy ). 3 patients died of cardiogenic diseases (age 79, 78, 80 years༛ accompanied by hypertension and diabetes, coronary heart disease with coronary stent implantation, paroxysmal atrial fibrillation༛ MHD: 2.35 Gy, 22.79 Gy, 9.04 Gy).4 patients died of local recurrence,local recurrence along with metastasis, local recurrence with massive hemoptysis and respiratory failure༌respectively. Conclusions SIB-IMRT can significantly improve ORR and survival for stage II-III NSCLC with metastatic lymph nodes. This treatment approach has high safety and satisfactory efficacy . Abbreviations SIB-IMRT：Simultaneous Integrated Boos of intensity modulated radiation therapy; PTV： planning target volume ； PTVp： PTV of primary tumor；PTVn ：PTV of metastatic lymph ORR：objective response rate；CR: Complete response; PR: Partial response; NC：no change；PD: Progressive disease; MST：mean survival time； KPS: Karnofsky Performance Status; NSCLC: Non-small cell lung cancer; LPFS：local progression free survival; BED：biological effective dose. Declarations None of the authors have any financial disclosures or conflicts of interest to declare. No actual or potential conflicts of interest exist. Ethics approval and consent to participate This study was reviewed by the ethical review boards in China (Ethics Committee of Guizhou Cancer Hospital, GuiYang, China). Informed consent for treatment was obtained from patients. Consent for publication Not applicable Availability of data and material The datasets during and/or analysed during the current study available from the corresponding author on reasonable request. All authors have read and approved the final manuscript Funding This work was supported by grants from Major research project of innovation group of education department of Guizhou province (No.KY [2016]032). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Authors’ contributions BL designed the study. QSL，NL，WWO，SFS,ZM,YCG，WGY，YXH,HQL collected the data. BL and QSL undertook the data analysis and interpretation, and wrote the report. BL and QSL carried out the statistical analysis. All authors read and approved the final manuscript. Acknowledgements We would like to thank HuiQin Li from Guizhou cancer Hospital, China, for her work to follow up all patients. Author details 1 Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China. 2 Guizhou Cancer Hospital, Guiyang 550004, China. References [1] Ramnath N, Dilling TJ, Harris LJ, et al. Treatment of stage III non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013. 143(5 Suppl): e314S-e340S. [2] Perez CA, Pajak TF, Rubin P, et al. Long-term observations of the patterns of failure in patients with unresectable non-oat cell carcinoma of the lung treated with definitive radiotherapy. Report by the Radiation Therapy Oncology Group. Cancer. 1987. 59(11): 1874-81. [3] Bradley JD, Paulus R, Komaki R, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol. 2015. 16(2): 187-99. [4] Kong FM, Ten HRK, Schipper M, et al. Effect of Midtreatment PET/CT-Adapted Radiation Therapy With Concurrent Chemotherapy in Patients With Locally Advanced Non-Small-Cell Lung Cancer: A Phase 2 Clinical Trial. JAMA Oncol. 2017. 3(10): 1358-1365. [5] Zeng J, Rengan R. Dose Escalation Optimization in Patients With Locally Advanced Non-Small-Cell Lung Cancer: The Right Dose, in the Right Location, to the Right Patient, at the Right Time. JAMA Oncol. 2017. 3(10): 1365-1367. [6] Onishi H, Araki T. Stereotactic body radiation therapy for stage I non-small-cell lung cancer: a historical overview of clinical studies. Jpn J Clin Oncol. 2013. 43(4): 345-50. [7] Garg S, Gielda BT, Kiel K, et al. Patterns of locoregional failure in stage III non-small cell lung cancer treated with definitive chemoradiation therapy. Pract Radiat Oncol. 2014. 4(5): 342-8. [8] Bezjak A, Temin S, Franklin G, et al. Definitive and Adjuvant Radiotherapy in Locally Advanced Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Endorsement of the American Society for Radiation Oncology Evidence-Based Clinical Practice Guideline. J Clin Oncol. 2015. 33(18): 2100-5. [9] Ohri N, Duan F, Machtay M, et al. Pretreatment FDG-PET metrics in stage III non-small cell lung cancer: ACRIN 6668/RTOG 0235. J Natl Cancer Inst. 2015. 107(4). [10] Aupérin A, Le PC, Rolland E, et al. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. J Clin Oncol. 2010. 28(13): 2181-90. [11] Jouglar E, Isnardi V, Goulon D, et al. Patterns of locoregional failure in locally advanced non-small cell lung cancer treated with definitive conformal radiotherapy: Results from the Gating 2006 trial. Radiother Oncol. 2018. 126(2): 291-299. [12] Chun SG, Hu C, Choy H, et al. Impact of Intensity-Modulated Radiation Therapy Technique for Locally Advanced Non-Small-Cell Lung Cancer: A Secondary Analysis of the NRG Oncology RTOG 0617 Randomized Clinical Trial. J Clin Oncol. 2017. 35(1): 56-62. [13] Jeter MD, Gomez D, Nguyen QN, et al. Simultaneous Integrated Boost for Radiation Dose Escalation to the Gross Tumor Volume With Intensity Modulated (Photon) Radiation Therapy or Intensity Modulated Proton Therapy and Concurrent Chemotherapy for Stage II to III Non-Small Cell Lung Cancer: A Phase 1 Study. Int J Radiat Oncol Biol Phys. 2018. 100(3): 730-737. [14] Liu M, Wang Z, Zhou T, et al. Individual isotoxic radiation dose escalation based on V20 and advanced technologies benefits unresectable stage III non-small cell lung cancer patients treated with concurrent chemoradiotherapy: long term follow-up. Oncotarget. 2017. 8(31): 51848-51858. [15] Weiss E, Fatyga M, Wu Y, et al. Dose escalation for locally advanced lung cancer using adaptive radiation therapy with simultaneous integrated volume-adapted boost. Int J Radiat Oncol Biol Phys. 2013. 86(3): 414-9. [16] Wanet M, Delor A, Hanin FX, et al. An individualized radiation dose escalation trial in non-small cell lung cancer based on FDG-PET imaging. Strahlenther Onkol. 2017. 193(10): 812-822. [17] Lischalk JW, Woo SM, Kataria S, et al. Long-term outcomes of stereotactic body radiation therapy (SBRT) with fiducial tracking for inoperable stage I non-small cell lung cancer (NSCLC). J Radiat Oncol. 2016. 5(4): 379-387. [18] Machtay M, Bae K, Movsas B, et al. Higher biologically effective dose of radiotherapy is associated with improved outcomes for locally advanced non-small cell lung carcinoma treated with chemoradiation: an analysis of the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys. 2012. 82(1): 425-34. [19] Feddock J, Arnold SM, Shelton BJ, et al. Stereotactic body radiation therapy can be used safely to boost residual disease in locally advanced non-small cell lung cancer: a prospective study. Int J Radiat Oncol Biol Phys. 2013. 85(5): 1325-31. [20] Wang Y, Lan F, Kang X, et al. Outcome Study of Cobalt Based Stereotactic Body Radiation Therapy for Patients with Inoperable Stage III Non-small Cell Lung Cancer. Technol Cancer Res Treat. 2015. 14(5): 539-45. [21] Zhu ZF, Fan M, Wu KL, et al. A phase II trial of accelerated hypofractionated three-dimensional conformal radiation therapy in locally advanced non-small cell lung cancer. Radiother Oncol. 2011. 98(3): 304-8. [22] Kong FM, Ten HRK, Schipper MJ, et al. High-dose radiation improved local tumor control and overall survival in patients with inoperable/unresectable non-small-cell lung cancer: long-term results of a radiation dose escalation study. Int J Radiat Oncol Biol Phys. 2005. 63(2): 324-33. [23] Onimaru R, Fujino M, Yamazaki K, et al. Steep dose-response relationship for stage I non-small-cell lung cancer using hypofractionated high-dose irradiation by real-time tumor-tracking radiotherapy. Int J Radiat Oncol Biol Phys. 2008. 70(2): 374-81. [24] Onishi H, Araki T, Shirato H, et al. Stereotactic hypofractionated high-dose irradiation for stage I nonsmall cell lung carcinoma: clinical outcomes in 245 subjects in a Japanese multiinstitutional study. Cancer. 2004. 101(7): 1623-31. [25] Bao Y, Peng F, Zhou QC, et al. Phase II trial of recombinant human endostatin in combination with concurrent chemoradiotherapy in patients with stage III non-small-cell lung cancer. Radiother Oncol. 2015. 114(2): 161-6. [26] Steuer CE, Behera M, Ernani V, et al. Comparison of Concurrent Use of Thoracic Radiation With Either Carboplatin-Paclitaxel or Cisplatin-Etoposide for Patients With Stage III Non-Small-Cell Lung Cancer: A Systematic Review. JAMA Oncol. 2017. 3(8): 1120-1129. [27] Liang J, Bi N, Wu S, et al. Etoposide and cisplatin versus paclitaxel and carboplatin with concurrent thoracic radiotherapy in unresectable stage III non-small cell lung cancer: a multicenter randomized phase Supplementary Files CONSORTextension.doc Cite Share Download PDF Status: Published Journal Publication published 09 Sep, 2020 Read the published version in Cancer Medicine → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-15993","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research article","associatedPublications":[],"authors":[{"id":383681,"identity":"cd9bcbce-6d29-4376-ae55-aaaeec5c15fb","order_by":1,"name":"qingsong li","email":"","orcid":"https://orcid.org/0000-0002-6895-3495","institution":"Affiliated Hospital of Guizhou Medical University，and Guizhou Cancer Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"qingsong","middleName":"","lastName":"li","suffix":""},{"id":383682,"identity":"02c41b65-53e3-408c-a703-47d6e09e8d8a","order_by":2,"name":"Na Liang","email":"","orcid":"","institution":"Affiliated Hospital of Guizhou Medical University，and Guizhou Cancer Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Na","middleName":"","lastName":"Liang","suffix":""},{"id":383683,"identity":"081b64eb-8435-40e1-b7fd-dd2db4c4fd5d","order_by":3,"name":"Wei-Wei Ouyang","email":"","orcid":"","institution":"Affiliated Hospital of Guizhou Medical University，andGuizhou Cancer Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Wei-Wei","middleName":"","lastName":"Ouyang","suffix":""},{"id":383684,"identity":"eb1377bf-6e0f-4832-be69-faa2708fbb6d","order_by":4,"name":"Sheng-Fa Su","email":"","orcid":"","institution":"Affiliated Hospital of Guizhou Medical University，andGuizhou Cancer 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Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Wen-Gang","middleName":"","lastName":"Yang","suffix":""},{"id":383688,"identity":"21358648-670c-46f5-b76c-f1e571985557","order_by":8,"name":"Yin-Xiang Hu","email":"","orcid":"","institution":"Affiliated Hospital of Guizhou Medical University，and Guizhou Cancer Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yin-Xiang","middleName":"","lastName":"Hu","suffix":""},{"id":383689,"identity":"19d58a62-9205-4268-a125-57c82a96567d","order_by":9,"name":"Hui-Qin Li","email":"","orcid":"","institution":"Guizhou Cancer Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hui-Qin","middleName":"","lastName":"Li","suffix":""},{"id":383690,"identity":"21a24e77-b02e-4c80-afdf-91e38820f584","order_by":10,"name":"Bing Lu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxklEQVRIiWNgGAWjYBACPgkYi72x8eEHYrSwwbXwHG42lsCnFFOLRHqbAA9RWqTbr0ndqLGT55/5sI1BgsFOTreBkBaZM2XSOceSDWfcTmx7UMCQbGx2gKDDctKkc9iYGRtuJ7YbSDAcSNxGnJZ/9fbzbx5sk+AhTkv6MenctsOJG24wEqtF5gyzdW7f8eSNZxKBgWxAhF/4pdsf3s75Vm077/jxhw8/VNjJEdQCjEITpAg0IKgcBNgfE5VMRsEoGAWjYAQDAKjlQdDuhi6NAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-8655-1342","institution":"","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Bing","middleName":"","lastName":"Lu","suffix":""}],"badges":[],"createdAt":"2020-02-29 11:25:29","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-15993/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-15993/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1002/cam4.3446","type":"published","date":"2020-09-09T19:19:36+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":593881,"identity":"24e497ba-f428-482d-8586-61608f27f8ef","added_by":"auto","created_at":"2020-03-04 16:16:30","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":304206,"visible":true,"origin":"","legend":"PTVp and PTVn were given different prescription","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-15993/v1/Figure 1.png"},{"id":593883,"identity":"82d9292c-5633-4e20-9e7e-bee677d0f18d","added_by":"auto","created_at":"2020-03-04 16:16:30","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":27913,"visible":true,"origin":"","legend":"dose volume histogram","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-15993/v1/Figure 2.png"},{"id":593884,"identity":"73c36e47-60d7-4176-aab5-f124ad398acb","added_by":"auto","created_at":"2020-03-04 16:16:31","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":12937,"visible":true,"origin":"","legend":"overall survival for all patients","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-15993/v1/Figure 3.png"},{"id":593885,"identity":"b01b4d25-eb36-45c6-b046-af1626741cf5","added_by":"auto","created_at":"2020-03-04 16:16:31","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":16749,"visible":true,"origin":"","legend":"Local progression free survival for all patients","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-15993/v1/Figure 4.png"},{"id":13492535,"identity":"08b190b9-8c39-4228-bc03-db331640c0ac","added_by":"auto","created_at":"2021-09-16 22:31:57","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":733453,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-15993/v1/2cebb8fc-64f6-4a16-a690-e544ea2c8d7d.pdf"},{"id":593882,"identity":"e4187ac0-7100-4cb6-b6be-2a96a5e7ef90","added_by":"auto","created_at":"2020-03-04 16:16:30","extension":"doc","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":173568,"visible":true,"origin":"","legend":"","description":"","filename":"CONSORTextension.doc","url":"https://assets-eu.researchsquare.com/files/rs-15993/v1/CONSORT extension.doc"}],"financialInterests":"","formattedTitle":"Simultaneous Integrated Boost of intensity modulated radiation therapy to Stage II-III Non-Small Cell Lung Cancer with metastatic lymph nodes","fulltext":[{"header":"Background","content":" \u003cp\u003eConcurrent thoracic chemoradiotherapy (CCRT) is the standard of care in patients with good performance status and inoperable stage II-III non-small-cell lung cancer(NSCLC) who have metastatic lymph nodes, especially for locally advanced NSCLC\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. The radiation dose is one of the controversial focuses. At present, the uniform dose of radiation therapy was 60\u0026nbsp;Gy, but treatment outcomes remain poor. RTOG trials led to the conclusion that local tumor control was significantly correlated with improved survival\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. 60\u0026nbsp;Gy may be not a reasonable dose \u003csup\u003e[\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e.In this study, it is conceived that using the biological effective dose (BED)\u0026thinsp;\u0026ge;\u0026thinsp;100\u0026nbsp;Gy of large fractionated radiotherapy for stage Ⅰ-Ⅱ NSCLC can obtain more than 90% local control rate \u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003eand recurrence rate of mediastinal metastatic lymph nodes for locally advanced NSCLC with concurrent chemoradiotherapy (median dose 60\u0026nbsp;Gy/30f) was only 20% \u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. Different doses of radiotherapy were simultaneously prescribed for primary tumor and metastatic lymph nodes through SIB-IMRT. The aim of this study was to evaluate the safety and efficacy of (SIB-IMRT) for Stage II-III Non-Small Cell Lung Cancer(NSCLC) with metastatic lymph nodes.\u003c/p\u003e "},{"header":"Methods","content":" \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatient selection\u003c/h2\u003e \u003cp\u003eInclusion criteria were as follows: (1) histologically or cytologically or PET-CT confirmed NSCLC; (2) newly diagnosed stage II-III disease (staged according to the 2009 system of the American Joint Committee on Cancer); (3) KPS\u0026thinsp;\u0026ge;\u0026thinsp;70; (4) no contraindications to radiation therapy or chemotherapy; (5) Normal range of blood routine and biochemical indexes (7)good compliance with treatment and follow-up.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003ePretreatment evaluations\u003c/h2\u003e \u003cp\u003eAll patients underwent fiberoptic bronchoscopy and contrast-enhanced computed tomography (CT) of the chest to evaluate the extent of the primary tumor and regional lymph node status. All patients also underwent bone scintigraphy, contrast-enhanced CT of the abdominal region, and magnetic resonance imaging (MRI) of the brain to detect distant metastases. Positive findings on positron emission tomography (PET) /CT or bone scintigraphy required other additional radiologic confirmation (e.g., MRI or CT of bone). Pretreatment evaluations were to be completed within 2 weeks before treatment was begun.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eTreatment methods\u003c/h2\u003e \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e \u003ch2\u003eThoracic radiation therapy\u003c/h2\u003e \u003cp\u003eUsing 6 MV X-ray, intensity-modulated radiotherapy(IMRT). The patient was positioned in the supine position with thermoplastic film fixation and 5-mm-thickness enhanced CT.\u003c/p\u003e \u003cp\u003eThe target Volume of primary tumor and metastatic lymph nodes were delineated respectively. The gross tumor volume of primary tumor (GTVp) included the thoracic primary tumor in lung windows and was outlined on the treatment planning CT scan ,the clinical target volume of primary tumor (CTVp) was defined as the GTVp plus a 0.6-cm margin with anatomical correction༌the planning target volume of primary tumor (PTVp) was defined as the CTVp plus another margin of 0.5 to 1.0\u0026nbsp;cm. The gross tumor volume of metastatic lymph (GTVn) included any enlarged(\u0026gt;\u0026thinsp;1\u0026nbsp;cm on short axis) metastatic lymph nodes and was outlined on the treatment planning CT scan༌the clinical target volume of metastatic lymph (CTVn) was modified by the GTVn and expanded outward by 0.6\u0026nbsp;cm combined with anatomical correction༌the planning target volume of metastatic lymph (PTVn) was defined as the CTVn plus another margin of 0.5\u0026nbsp;cm.\u003c/p\u003e \u003cp\u003eDifferent doses of radiation therapy were simultaneously prescribed for PTVp and PTVn through SIB-IMRT. The radiation doses were 78\u0026nbsp;Gy (BED\u0026thinsp;=\u0026thinsp;101.48\u0026nbsp;Gy) for PTVp and 60-65Gy (BED\u0026thinsp;=\u0026thinsp;73.6-81.25\u0026nbsp;Gy) for PTVn, 26f/ 5.2 weeks,, respectively. The radiotherapy plan was evaluated as 95% of the prescription dose line including 95% of PTV. The percentage of total lung volume receiving\u0026thinsp;\u0026ge;\u0026thinsp;20 Gy(V20),whole lung dose (MLD) and mean heart dose(MHD) was to be kept at \u0026le;\u0026thinsp;32%, \u0026le; 20\u0026nbsp;Gy and \u0026le;\u0026thinsp;30\u0026nbsp;Gy ༌respectively (Fig.\u0026nbsp;1\u0026ndash;2).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eChemotherapy\u003c/h2\u003e \u003cp\u003ePlatinum-based doublet chemotherapy (cisplatin in combination with docetaxel, paclitaxel, or pemetrexed) or Single drug given every 21 to 28. The chemotherapy regimens of all patients were as follows: 1 case of docetaxel, 1 case of pemetrexed, 1 case of cetuximab\u0026thinsp;+\u0026thinsp;docetaxel, 1 case of pemetrexed\u0026thinsp;+\u0026thinsp;cisplatin, 1 case of paclitaxel liposome\u0026thinsp;+\u0026thinsp;carboplatin, 1 case of pemetrexed\u0026thinsp;+\u0026thinsp;cisplatin, 1 case of paclitaxel liposome\u0026thinsp;+\u0026thinsp;carboplatin, 9 cases of docetaxel\u0026thinsp;+\u0026thinsp;cisplatin( 2 cases of docetaxel\u0026thinsp;+\u0026thinsp;cisplatin\u0026thinsp;+\u0026thinsp;Endostar. Chemotherapy Cycles were from 2 to 4. 4 patients refused chemotherapy.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section3\"\u003e \u003ch2\u003eEvaluation of treatment-related toxicity and response\u003c/h2\u003e \u003cp\u003eResponse was scored according to WHO criteria as follows: complete response(CR), partial response (PR), and no change (NC), progressive response(PD). Radiotherapy toxicity was scored according to RTOG criteria .Hematology and gastrointestinal toxicity were scored according to CTCAE1.0 criteria.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eFollow-up evaluations and Statistical analyses\u003c/h2\u003e \u003cp\u003eAt 1\u0026nbsp;month after completion of treatment, patients underwent CT scanning of the chest and abdominal region and MRI of the head to assess tumor response. These tests were then repeated every 3\u0026nbsp;months for 2\u0026nbsp;years and every 6\u0026nbsp;months thereafter. Primary endpoints were OS,LPFS and acute toxicity. Kaplan-Meier analyses were used for statistical analysis.\u003c/p\u003e \u003c/div\u003e "},{"header":"Results","content":" \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics\u003c/h2\u003e \u003cp\u003eFrom December 2009 to March 2019,20 patients were enrolled in this study. There were 3 patients with stage Ⅱ A ,1 patient with stage Ⅱ B ,12 patients with stage Ⅲ A and 4 patients with stage ⅢB .The patients with stage II refused operation Because of old-aged patients (3 cases) and pulmonary dysfunction (1 case).There were 17 males and 3 females. Median age of patients was 75\u0026nbsp;years (range, 44\u0026ndash;82\u0026nbsp;years). 50% of patients (10/20) were older than 70\u0026nbsp;years. Age of 8 patients were \u0026ge;\u0026thinsp;77\u0026nbsp;years (range,77\u0026ndash;82\u0026nbsp;years). There were 4 adenocarcinomas, 10 squamous cell carcinomas, 3 non-small cell lung carcinoma and 3 clinically diagnosed lung cancers. Median long axis of primary tumor was 4.55 cm(range ༌1.2 -11cm). Median number of metastatic lymph nodes was 1(range ༌1\u0026ndash;5). Median volume of GTVp was 69.99\u0026nbsp;cm3 (range ༌8.74-530.07\u0026nbsp;cm3). Median volume of PTVp was 189.22\u0026nbsp;cm3 (range༌83.85-886.71\u0026nbsp;cm3); Median volume of GTVn was 35.96\u0026nbsp;cm3(range ༌4.37 -139.05\u0026nbsp;cm3). Median volume of PTVn was 148.37\u0026nbsp;cm3 (range ༌35.79-405.68\u0026nbsp;cm3). The number of patients with V 20\u0026thinsp;\u0026le;\u0026thinsp;20%, 21%-25%, 25%-30% and \u0026gt;\u0026thinsp;30% were 4, 7, 7 and 2 (range༌12.1%-32%, median 24.6%),respectively. The number of with MLD\u0026thinsp;\u0026le;\u0026thinsp;20\u0026nbsp;Gy and \u0026gt;\u0026thinsp;20\u0026nbsp;Gy were 17 and 3 (range 8.57\u0026ndash;21.23\u0026nbsp;Gy, median MLD16.67\u0026nbsp;Gy), respectively. The number of patients mean heart dose༈MHD)\u0026le; 26\u0026nbsp;Gy and \u0026gt;\u0026thinsp;26\u0026nbsp;Gy were 16 and 4 (range 1.83\u0026ndash;32.41\u0026nbsp;Gy, median 7.65\u0026nbsp;Gy), respectively༈Table\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e༉.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cdiv class=\"SimplePara\"\u003eClinical characteristics, treatment data and survival of 20 patients of stage II-III NSCLC\u003c/div\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"21\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cdiv class=\"SimplePara\"\u003eNo\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cdiv class=\"SimplePara\"\u003eSex\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cdiv class=\"SimplePara\"\u003eA\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cdiv class=\"SimplePara\"\u003eB\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cdiv class=\"SimplePara\"\u003eC\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cdiv class=\"SimplePara\"\u003eD\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cdiv class=\"SimplePara\"\u003estage\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cdiv class=\"SimplePara\"\u003emetastatic lymph node\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\" morerows=\"1\" rowspan=\"2\"\u003e \u003cdiv class=\"SimplePara\"\u003eGTV\u003csub\u003eP\u003c/sub\u003e\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e(cm\u003csup\u003e3\u003c/sup\u003e)\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\" morerows=\"1\" rowspan=\"2\"\u003e \u003cdiv class=\"SimplePara\"\u003ePTV\u003csub\u003eP\u003c/sub\u003e\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e(cm\u003csup\u003e3\u003c/sup\u003e)\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c12\" morerows=\"1\" rowspan=\"2\"\u003e \u003cdiv class=\"SimplePara\"\u003eGTV\u003csub\u003eN\u003c/sub\u003e\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e(cm\u003csup\u003e3\u003c/sup\u003e)\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c13\" morerows=\"1\" rowspan=\"2\"\u003e \u003cdiv class=\"SimplePara\"\u003ePTV\u003csub\u003eN\u003c/sub\u003e\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e(cm\u003csup\u003e3\u003c/sup\u003e)\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c14\" morerows=\"1\" rowspan=\"2\"\u003e \u003cdiv class=\"SimplePara\"\u003eV20\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e(%)\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c15\" morerows=\"1\" rowspan=\"2\"\u003e \u003cdiv class=\"SimplePara\"\u003eMLD(Gy)\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c16\" morerows=\"1\" rowspan=\"2\"\u003e \u003cdiv class=\"SimplePara\"\u003eMHD(Gy)\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c17\" morerows=\"1\" rowspan=\"2\"\u003e \u003cdiv class=\"SimplePara\"\u003ePD\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c18\" morerows=\"1\" rowspan=\"2\"\u003e \u003cdiv class=\"SimplePara\"\u003eDeath\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c19\" morerows=\"1\" rowspan=\"2\"\u003e \u003cdiv class=\"SimplePara\"\u003eCause of death\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c20\" morerows=\"1\" rowspan=\"2\"\u003e \u003cdiv class=\"SimplePara\"\u003eOS(month)\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c21\" morerows=\"1\" rowspan=\"2\"\u003e \u003cdiv class=\"SimplePara\"\u003eLPFS(month)\u003c/div\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cdiv class=\"SimplePara\"\u003eDrainage area\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cdiv class=\"SimplePara\"\u003eNumber\u003c/div\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e1\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003eMale\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e+\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cdiv class=\"SimplePara\"\u003eT2aN2M0\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cdiv class=\"SimplePara\"\u003e4R\u0026thinsp;+\u0026thinsp;10R\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cdiv class=\"SimplePara\"\u003e2\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cdiv class=\"SimplePara\"\u003e79.13\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cdiv class=\"SimplePara\"\u003e290.08\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cdiv class=\"SimplePara\"\u003e46.93\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e \u003cdiv class=\"SimplePara\"\u003e169.93\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cdiv class=\"SimplePara\"\u003e24.9\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c15\"\u003e \u003cdiv class=\"SimplePara\"\u003e18.32\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c16\"\u003e \u003cdiv class=\"SimplePara\"\u003e11.91\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c17\"\u003e \u003cdiv class=\"SimplePara\"\u003eL\u0026thinsp;+\u0026thinsp;M\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c18\"\u003e \u003cdiv class=\"SimplePara\"\u003eyes\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c19\"\u003e \u003cdiv class=\"SimplePara\"\u003eL\u0026thinsp;+\u0026thinsp;M\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c20\"\u003e \u003cdiv class=\"SimplePara\"\u003e64\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c21\"\u003e \u003cdiv class=\"SimplePara\"\u003e62\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e2\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003eMale\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e+\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cdiv class=\"SimplePara\"\u003eT3N2M0\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cdiv class=\"SimplePara\"\u003e4L\u0026thinsp;+\u0026thinsp;7\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cdiv class=\"SimplePara\"\u003e2\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cdiv class=\"SimplePara\"\u003e465.91\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cdiv class=\"SimplePara\"\u003e886.71\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cdiv class=\"SimplePara\"\u003e37.28\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e \u003cdiv class=\"SimplePara\"\u003e137.57\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cdiv class=\"SimplePara\"\u003e31.3\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c15\"\u003e \u003cdiv class=\"SimplePara\"\u003e20.43\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c16\"\u003e \u003cdiv class=\"SimplePara\"\u003e32.41\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c17\"\u003e \u003cdiv class=\"SimplePara\"\u003eL\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c18\"\u003e \u003cdiv class=\"SimplePara\"\u003eyes\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c19\"\u003e \u003cdiv class=\"SimplePara\"\u003eL\u0026thinsp;+\u0026thinsp;Hemoptysis\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c20\"\u003e \u003cdiv class=\"SimplePara\"\u003e23\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c21\"\u003e \u003cdiv class=\"SimplePara\"\u003e23\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e3\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003eMale\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cdiv class=\"SimplePara\"\u003eT1aN2M0\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cdiv class=\"SimplePara\"\u003e5\u0026thinsp;+\u0026thinsp;7\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cdiv class=\"SimplePara\"\u003e5\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cdiv class=\"SimplePara\"\u003e94.85\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cdiv class=\"SimplePara\"\u003e360.35\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cdiv class=\"SimplePara\"\u003e72.14\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e \u003cdiv class=\"SimplePara\"\u003e281.72\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cdiv class=\"SimplePara\"\u003e24.3\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c15\"\u003e \u003cdiv class=\"SimplePara\"\u003e13.73\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c16\"\u003e \u003cdiv class=\"SimplePara\"\u003e6.3\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c17\"\u003e \u003cdiv class=\"SimplePara\"\u003eno\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c18\"\u003e \u003cdiv class=\"SimplePara\"\u003eyes\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c19\"\u003e \u003cdiv class=\"SimplePara\"\u003ePulmonary infection\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c20\"\u003e \u003cdiv class=\"SimplePara\"\u003e12\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c21\"\u003e \u003cdiv class=\"SimplePara\"\u003e12\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e4\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003eMale\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e+\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cdiv class=\"SimplePara\"\u003eT2aN1M0\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cdiv class=\"SimplePara\"\u003e10L\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cdiv class=\"SimplePara\"\u003e1\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cdiv class=\"SimplePara\"\u003e26.13\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cdiv class=\"SimplePara\"\u003e123.83\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cdiv class=\"SimplePara\"\u003e61.65\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e \u003cdiv class=\"SimplePara\"\u003e239.53\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cdiv class=\"SimplePara\"\u003e32\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c15\"\u003e \u003cdiv class=\"SimplePara\"\u003e21.19\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c16\"\u003e \u003cdiv class=\"SimplePara\"\u003e30.86\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c17\"\u003e \u003cdiv class=\"SimplePara\"\u003eno\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c18\"\u003e \u003cdiv class=\"SimplePara\"\u003eno\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c19\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c20\"\u003e \u003cdiv class=\"SimplePara\"\u003e82\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c21\"\u003e \u003cdiv class=\"SimplePara\"\u003e82\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e5\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003eMale\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e+\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e+\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cdiv class=\"SimplePara\"\u003eT2bN1M0\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cdiv class=\"SimplePara\"\u003e10R\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cdiv class=\"SimplePara\"\u003e1\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cdiv class=\"SimplePara\"\u003e49.2\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cdiv class=\"SimplePara\"\u003e163.01\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cdiv class=\"SimplePara\"\u003e16.03\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e \u003cdiv class=\"SimplePara\"\u003e63.07\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cdiv class=\"SimplePara\"\u003e19.9\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c15\"\u003e \u003cdiv class=\"SimplePara\"\u003e14.96\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c16\"\u003e \u003cdiv class=\"SimplePara\"\u003e2.35\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c17\"\u003e \u003cdiv class=\"SimplePara\"\u003eno\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c18\"\u003e \u003cdiv class=\"SimplePara\"\u003eyes\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c19\"\u003e \u003cdiv class=\"SimplePara\"\u003emiocardial infarction\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c20\"\u003e \u003cdiv class=\"SimplePara\"\u003e43\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c21\"\u003e \u003cdiv class=\"SimplePara\"\u003e43\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e6\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003eMale\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e+\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e+\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cdiv class=\"SimplePara\"\u003eT3N1M0\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cdiv class=\"SimplePara\"\u003e10L\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cdiv class=\"SimplePara\"\u003e1\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cdiv class=\"SimplePara\"\u003e93.83\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cdiv class=\"SimplePara\"\u003e234.75\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cdiv class=\"SimplePara\"\u003e71.32\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e \u003cdiv class=\"SimplePara\"\u003e201.32\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cdiv class=\"SimplePara\"\u003e25.5\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c15\"\u003e \u003cdiv class=\"SimplePara\"\u003e17.92\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c16\"\u003e \u003cdiv class=\"SimplePara\"\u003e22.79\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c17\"\u003e \u003cdiv class=\"SimplePara\"\u003eL\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c18\"\u003e \u003cdiv class=\"SimplePara\"\u003eyes\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c19\"\u003e \u003cdiv class=\"SimplePara\"\u003eSudden cardiac death\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c20\"\u003e \u003cdiv class=\"SimplePara\"\u003e14\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c21\"\u003e \u003cdiv class=\"SimplePara\"\u003e12\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e7\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003eMale\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e+\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cdiv class=\"SimplePara\"\u003eT2aN1M0\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cdiv class=\"SimplePara\"\u003e10L\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cdiv class=\"SimplePara\"\u003e1\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cdiv class=\"SimplePara\"\u003e27.53\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cdiv class=\"SimplePara\"\u003e83.85\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cdiv class=\"SimplePara\"\u003e22.37\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e \u003cdiv class=\"SimplePara\"\u003e84.38\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cdiv class=\"SimplePara\"\u003e16.1\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c15\"\u003e \u003cdiv class=\"SimplePara\"\u003e10.96\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c16\"\u003e \u003cdiv class=\"SimplePara\"\u003e9.04\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c17\"\u003e \u003cdiv class=\"SimplePara\"\u003eno\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c18\"\u003e \u003cdiv class=\"SimplePara\"\u003eyes\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c19\"\u003e \u003cdiv class=\"SimplePara\"\u003eSudden cardiac death\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c20\"\u003e \u003cdiv class=\"SimplePara\"\u003e24\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c21\"\u003e \u003cdiv class=\"SimplePara\"\u003e24\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e8\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003eFemale\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e+\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cdiv class=\"SimplePara\"\u003eT3N2M0\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cdiv class=\"SimplePara\"\u003e4R\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cdiv class=\"SimplePara\"\u003e1\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cdiv class=\"SimplePara\"\u003e398.47\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cdiv class=\"SimplePara\"\u003e711.64\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cdiv class=\"SimplePara\"\u003e32.44\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e \u003cdiv class=\"SimplePara\"\u003e123.93\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cdiv class=\"SimplePara\"\u003e26.5\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c15\"\u003e \u003cdiv class=\"SimplePara\"\u003e16.96\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c16\"\u003e \u003cdiv class=\"SimplePara\"\u003e19.39\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c17\"\u003e \u003cdiv class=\"SimplePara\"\u003eM\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c18\"\u003e \u003cdiv class=\"SimplePara\"\u003eyes\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c19\"\u003e \u003cdiv class=\"SimplePara\"\u003ePulmonary infection\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c20\"\u003e \u003cdiv class=\"SimplePara\"\u003e18\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c21\"\u003e \u003cdiv class=\"SimplePara\"\u003e9\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e9\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003eMale\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e+\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cdiv class=\"SimplePara\"\u003eT3N2M0\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cdiv class=\"SimplePara\"\u003e4R\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cdiv class=\"SimplePara\"\u003e1\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cdiv class=\"SimplePara\"\u003e76.35\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cdiv class=\"SimplePara\"\u003e204.29\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cdiv class=\"SimplePara\"\u003e62.72\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e \u003cdiv class=\"SimplePara\"\u003e159.16\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cdiv class=\"SimplePara\"\u003e23.9\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c15\"\u003e \u003cdiv class=\"SimplePara\"\u003e21.23\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c16\"\u003e \u003cdiv class=\"SimplePara\"\u003e7.58\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c17\"\u003e \u003cdiv class=\"SimplePara\"\u003eno\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c18\"\u003e \u003cdiv class=\"SimplePara\"\u003eno\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c19\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c20\"\u003e \u003cdiv class=\"SimplePara\"\u003e48\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c21\"\u003e \u003cdiv class=\"SimplePara\"\u003e48\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e10\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003eMale\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e+\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cdiv class=\"SimplePara\"\u003eT3N2M0\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cdiv class=\"SimplePara\"\u003e2R\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cdiv class=\"SimplePara\"\u003e1\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cdiv class=\"SimplePara\"\u003e70.11\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cdiv class=\"SimplePara\"\u003e211.57\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cdiv class=\"SimplePara\"\u003e10.1\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e \u003cdiv class=\"SimplePara\"\u003e72.11\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cdiv class=\"SimplePara\"\u003e22.5\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c15\"\u003e \u003cdiv class=\"SimplePara\"\u003e14.32\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c16\"\u003e \u003cdiv class=\"SimplePara\"\u003e4.1\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c17\"\u003e \u003cdiv class=\"SimplePara\"\u003eno\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c18\"\u003e \u003cdiv class=\"SimplePara\"\u003eno\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c19\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c20\"\u003e \u003cdiv class=\"SimplePara\"\u003e43\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c21\"\u003e \u003cdiv class=\"SimplePara\"\u003e43\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e11\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003eMale\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e+\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cdiv class=\"SimplePara\"\u003eT3N1M0\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cdiv class=\"SimplePara\"\u003e10L( fusion)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cdiv class=\"SimplePara\"\u003eFusion\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cdiv class=\"SimplePara\"\u003e530.07\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cdiv class=\"SimplePara\"\u003e868.64\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cdiv class=\"SimplePara\"\u003e107.51\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e \u003cdiv class=\"SimplePara\"\u003e261.05\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cdiv class=\"SimplePara\"\u003e22.8\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c15\"\u003e \u003cdiv class=\"SimplePara\"\u003e17.7\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c16\"\u003e \u003cdiv class=\"SimplePara\"\u003e26.92\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c17\"\u003e \u003cdiv class=\"SimplePara\"\u003eno\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c18\"\u003e \u003cdiv class=\"SimplePara\"\u003eyes\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c19\"\u003e \u003cdiv class=\"SimplePara\"\u003eRespiratory failure\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c20\"\u003e \u003cdiv class=\"SimplePara\"\u003e15\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c21\"\u003e \u003cdiv class=\"SimplePara\"\u003e15\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e12\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003eMale\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e+\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e+\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cdiv class=\"SimplePara\"\u003eT3N3M0\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cdiv class=\"SimplePara\"\u003e4L\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cdiv class=\"SimplePara\"\u003e1\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cdiv class=\"SimplePara\"\u003e69.87\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cdiv class=\"SimplePara\"\u003e174.15\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cdiv class=\"SimplePara\"\u003e21.56\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e \u003cdiv class=\"SimplePara\"\u003e74.76\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cdiv class=\"SimplePara\"\u003e27.3\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c15\"\u003e \u003cdiv class=\"SimplePara\"\u003e16.49\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c16\"\u003e \u003cdiv class=\"SimplePara\"\u003e7.7\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c17\"\u003e \u003cdiv class=\"SimplePara\"\u003eno\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c18\"\u003e \u003cdiv class=\"SimplePara\"\u003eno\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c19\"\u003e \u003cdiv class=\"SimplePara\"\u003ePulmonary infection\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c20\"\u003e \u003cdiv class=\"SimplePara\"\u003e16\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c21\"\u003e \u003cdiv class=\"SimplePara\"\u003e16\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e13\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003eMale\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cdiv class=\"SimplePara\"\u003eT2N2M0\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cdiv class=\"SimplePara\"\u003e4R\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cdiv class=\"SimplePara\"\u003e1\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cdiv class=\"SimplePara\"\u003e26.22\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cdiv class=\"SimplePara\"\u003e111.72\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cdiv class=\"SimplePara\"\u003e4.37\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e \u003cdiv class=\"SimplePara\"\u003e44.54\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cdiv class=\"SimplePara\"\u003e12.11\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c15\"\u003e \u003cdiv class=\"SimplePara\"\u003e8.57\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c16\"\u003e \u003cdiv class=\"SimplePara\"\u003e6.84\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c17\"\u003e \u003cdiv class=\"SimplePara\"\u003eno\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c18\"\u003e \u003cdiv class=\"SimplePara\"\u003eno\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c19\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c20\"\u003e \u003cdiv class=\"SimplePara\"\u003e24\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c21\"\u003e \u003cdiv class=\"SimplePara\"\u003e22\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e14\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003eFemale\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e+\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cdiv class=\"SimplePara\"\u003eTN1N1M0\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cdiv class=\"SimplePara\"\u003e10L\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cdiv class=\"SimplePara\"\u003e1\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cdiv class=\"SimplePara\"\u003e8.74\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cdiv class=\"SimplePara\"\u003e84.70\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cdiv class=\"SimplePara\"\u003e58.20\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e \u003cdiv class=\"SimplePara\"\u003e227.79\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cdiv class=\"SimplePara\"\u003e28.00\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c15\"\u003e \u003cdiv class=\"SimplePara\"\u003e14.17\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c16\"\u003e \u003cdiv class=\"SimplePara\"\u003e30.9\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c17\"\u003e \u003cdiv class=\"SimplePara\"\u003eL\u0026thinsp;+\u0026thinsp;M\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c18\"\u003e \u003cdiv class=\"SimplePara\"\u003eno\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c19\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c20\"\u003e \u003cdiv class=\"SimplePara\"\u003e66\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c21\"\u003e \u003cdiv class=\"SimplePara\"\u003e30\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e15\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003eMale\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e+\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cdiv class=\"SimplePara\"\u003eT3N2M0\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cdiv class=\"SimplePara\"\u003e4R\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cdiv class=\"SimplePara\"\u003e2\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cdiv class=\"SimplePara\"\u003e46.28\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cdiv class=\"SimplePara\"\u003e133.98\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cdiv class=\"SimplePara\"\u003e7.68\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e \u003cdiv class=\"SimplePara\"\u003e35.79\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cdiv class=\"SimplePara\"\u003e17.9\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c15\"\u003e \u003cdiv class=\"SimplePara\"\u003e18.32\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c16\"\u003e \u003cdiv class=\"SimplePara\"\u003e1.83\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c17\"\u003e \u003cdiv class=\"SimplePara\"\u003eno\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c18\"\u003e \u003cdiv class=\"SimplePara\"\u003eyes\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c19\"\u003e \u003cdiv class=\"SimplePara\"\u003ePulmonary infection\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c20\"\u003e \u003cdiv class=\"SimplePara\"\u003e32\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c21\"\u003e \u003cdiv class=\"SimplePara\"\u003e32\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e16\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003eMale\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cdiv class=\"SimplePara\"\u003eT4N3M0\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cdiv class=\"SimplePara\"\u003e4R/L/7/10R\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cdiv class=\"SimplePara\"\u003e5\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cdiv class=\"SimplePara\"\u003e231.13\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cdiv class=\"SimplePara\"\u003e475.15\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cdiv class=\"SimplePara\"\u003e34.01\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e \u003cdiv class=\"SimplePara\"\u003e188.11\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cdiv class=\"SimplePara\"\u003e25.28\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c15\"\u003e \u003cdiv class=\"SimplePara\"\u003e16.96\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c16\"\u003e \u003cdiv class=\"SimplePara\"\u003e8.48\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c17\"\u003e \u003cdiv class=\"SimplePara\"\u003eno\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c18\"\u003e \u003cdiv class=\"SimplePara\"\u003eno\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c19\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c20\"\u003e \u003cdiv class=\"SimplePara\"\u003e16\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c21\"\u003e \u003cdiv class=\"SimplePara\"\u003e16\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e17\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003eFemale\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e+\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e+\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cdiv class=\"SimplePara\"\u003eT2N3M0\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cdiv class=\"SimplePara\"\u003e4R/L/5/6\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cdiv class=\"SimplePara\"\u003e6\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cdiv class=\"SimplePara\"\u003e52.12\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cdiv class=\"SimplePara\"\u003e96.08\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cdiv class=\"SimplePara\"\u003e12.15\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e \u003cdiv class=\"SimplePara\"\u003e76.36\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cdiv class=\"SimplePara\"\u003e20.49\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c15\"\u003e \u003cdiv class=\"SimplePara\"\u003e12.78\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c16\"\u003e \u003cdiv class=\"SimplePara\"\u003e1.98\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c17\"\u003e \u003cdiv class=\"SimplePara\"\u003eno\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c18\"\u003e \u003cdiv class=\"SimplePara\"\u003eno\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c19\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c20\"\u003e \u003cdiv class=\"SimplePara\"\u003e14\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c21\"\u003e \u003cdiv class=\"SimplePara\"\u003e14\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e18\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003eMale\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e+\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cdiv class=\"SimplePara\"\u003eT4N2M0\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cdiv class=\"SimplePara\"\u003e6/7\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cdiv class=\"SimplePara\"\u003e5\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cdiv class=\"SimplePara\"\u003e261.14\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cdiv class=\"SimplePara\"\u003e472.17\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cdiv class=\"SimplePara\"\u003e34.63\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e \u003cdiv class=\"SimplePara\"\u003e132.15\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cdiv class=\"SimplePara\"\u003e21.92\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c15\"\u003e \u003cdiv class=\"SimplePara\"\u003e13.82\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c16\"\u003e \u003cdiv class=\"SimplePara\"\u003e4.74\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c17\"\u003e \u003cdiv class=\"SimplePara\"\u003eL\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c18\"\u003e \u003cdiv class=\"SimplePara\"\u003eyes\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c19\"\u003e \u003cdiv class=\"SimplePara\"\u003eL\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c20\"\u003e \u003cdiv class=\"SimplePara\"\u003e15\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c21\"\u003e \u003cdiv class=\"SimplePara\"\u003e13\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e19\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003eMale\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cdiv class=\"SimplePara\"\u003eT3N2M0\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cdiv class=\"SimplePara\"\u003e2R/3A/4R/5/10R\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cdiv class=\"SimplePara\"\u003e5\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cdiv class=\"SimplePara\"\u003e35.24\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cdiv class=\"SimplePara\"\u003e118.53\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cdiv class=\"SimplePara\"\u003e80.61\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e \u003cdiv class=\"SimplePara\"\u003e245.22\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cdiv class=\"SimplePara\"\u003e27.43\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c15\"\u003e \u003cdiv class=\"SimplePara\"\u003e16.85\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c16\"\u003e \u003cdiv class=\"SimplePara\"\u003e5.94\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c17\"\u003e \u003cdiv class=\"SimplePara\"\u003eno\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c18\"\u003e \u003cdiv class=\"SimplePara\"\u003eno\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c19\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c20\"\u003e \u003cdiv class=\"SimplePara\"\u003e13\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c21\"\u003e \u003cdiv class=\"SimplePara\"\u003e8\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e20\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003eMale\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cdiv class=\"SimplePara\"\u003eT2N2M0\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cdiv class=\"SimplePara\"\u003e2R/3A/4R(fusion),7\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cdiv class=\"SimplePara\"\u003e3\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cdiv class=\"SimplePara\"\u003e23.9\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cdiv class=\"SimplePara\"\u003e87.08\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cdiv class=\"SimplePara\"\u003e139.05\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e \u003cdiv class=\"SimplePara\"\u003e405.68\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cdiv class=\"SimplePara\"\u003e25.80\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c15\"\u003e \u003cdiv class=\"SimplePara\"\u003e15.34\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c16\"\u003e \u003cdiv class=\"SimplePara\"\u003e7.60\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c17\"\u003e \u003cdiv class=\"SimplePara\"\u003eno\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c18\"\u003e \u003cdiv class=\"SimplePara\"\u003eyes\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c19\"\u003e \u003cdiv class=\"SimplePara\"\u003ePulmonary infection\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c20\"\u003e \u003cdiv class=\"SimplePara\"\u003e6\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c21\"\u003e \u003cdiv class=\"SimplePara\"\u003e6\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"21\"\u003eA: chronic obstructive pulmonary disease,B: hypertension,C: coronary heart disease,D: diabetes mellitus,L\u0026thinsp;=\u0026thinsp;local recurrence, M\u0026thinsp;=\u0026thinsp;distant metastasis\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eResponse\u003c/h2\u003e \u003cp\u003eThe CR, PR and SD rate was 25%(5cases), 65% ༈13cases༉and 10%༈2cases༉,respectively. The CR, PR and SD rate of primary tumor was 30%༈6 cases༉、55%༈11 cases༉、15%༈3 cases༉respectively. The CR, PR and SD rate of metastatic lymph nodes was 25%༈5cases༉、60%༈12cases༉、15%༈3cases༉. The clinical benefit rate was 100%.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eProgress, cause of death and survival\u003c/h2\u003e \u003cp\u003eDuring follow-up, there were local recurrence and / or metastasis progressed in 7 patients (2 patients with local recurrence and bone metastasis, 1 patient with local recurrence and pulmonary metastasis, 1 patient with local recurrence ,1 patient with local recurrence and hemoptysis ༌1 patient with alone lung metastasis, 1 patient with malignant pleural effusion). By the last follow-up, 12 patients died .The cause of death in 9 patients was not related to tumor (3 died of cardiogenic death, 5 died of pulmonary infection and 1 died of respiratory failure). The cause of death in 3 patients was related to tumor(1 died of local recurrence with metastasis, 1 died of local recurrent hemoptysis and 1 died of local recurrence). The local control rates at 1, 3 and 5\u0026nbsp;years were 85%, 75% and 70%, respectively. The OS and LPFS rates at 1, 3 and 5\u0026nbsp;years were 90%, 42.6%, 35.5% and 84.4%, 35.5%, 28.4%, respectively. The MST was 24 months( Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u0026ndash;4).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eToxicity\u003c/h2\u003e \u003cp\u003eNo patient experienced grade 3\u0026thinsp;+\u0026thinsp;acute radiation toxicity. Grade Ⅰ radiation pneumonitis was observed in 9 patients (7 in concurrent chemoradiotherapy, 2 in radiotherapy alone) and grade Ⅱ in 1 patient (concurrent chemoradiotherapy). Grade Ⅰ radiation dermatitis was observed in 9 patients (8 in concurrent chemoradiotherapy, 1 in radiotherapy alone) and grade Ⅱ in 3 patients (all in concurrent chemoradiotherapy). Grade Ⅰ radiation esophagitis was observed in 7 patients (3 in concurrent chemoradiotherapy, 4 in radiotherapy alone) and grade Ⅱ in 10 patients (all in concurrent chemoradiotherapy). Chronic radiation-induced lung injury was observed in 1 patients, which occurred 3 months after radiotherapy (the serial number 12, lung V20 was 27%, MLD was 16.49\u0026nbsp;Gy). Grade Ⅰ, Ⅱ, Ⅲ and Ⅳ of gastrointestinal and hematological toxicity were 6, 8, 1, 0 and 1, 6, 5, 4 cases, respectively, all of which occurred in concurrent chemoradiotherapy. There was no radiomyelitis or heart injury observed in all patients.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e "},{"header":"Discussion","content":" \u003cp\u003eAt present,,the radiation dose\u0026thinsp;\u0026ge;\u0026thinsp;60\u0026nbsp;Gy/30f is needed for concurrent chemoradio- therapy to locally advanced NSCLC\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e༌but the local control rates at 1, 3 and 5\u0026nbsp;years were about 70%, 50%, 40% \u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e༌and the OS rate at 5\u0026nbsp;years was about 15% \u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e.The local recurrence rates of stage Ⅱ-Ⅲ NSCLC with concurrent chemoradiotherapy at 1, 2, 3 and 5\u0026nbsp;years were 23% \u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e、30.8% -37.1%\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e、28.1%、28.9\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e.Uncontrolled local tumors may be a potential source of distant metastasis \u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e.Although the RTOG0617 study showed that 60\u0026nbsp;Gy may be more reasonable than other radiation dose \u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e, further analysis of the study showed that the result was affected by many other factors \u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e.There is still debate about that increasing the dose of radiation therapy can reduce recurrence and prolong survival. A phase II clinical study by KongFM et al showed that the local control rate was 82% at 2\u0026nbsp;years and 30% at 5\u0026nbsp;years because of the high radiation therapy (86Gy/30day) with adaptive radiotherapy guided by PET/CT\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e.Many studies still supported the idea that high dose of radiation therapy was necessary \u003csup\u003e[\u003cspan additionalcitationids=\"CR15 CR16\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e.After the report of RTOG0617 study in 2012, MachtayM et al conducted a meta-analysis, which included 7 prospective randomized concurrent chemoradiotherapy studies about locally advanced NSCLC. The study\u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e showed that BED\u0026thinsp;\u0026ge;\u0026thinsp;74.67\u0026nbsp;Gy (conventional fractionated dose 62-64Gy) was more beneficial to improve the local control and survival, increasing the tBED of 1\u0026nbsp;Gy can increase the local control by 3%, and the BED of 1\u0026nbsp;Gy can increase OS by 4%.After conventional fractionated radiotherapy, dose escalation for local tumor may improve local control and survival \u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThrough changing the fractionated radiotherapy dose of 2.5-6Gy with concurrent chemoradiotherapy for locally advanced NSCLC ,the CR ,PR,1, 2, 3\u0026nbsp;years OS rates and mean suivival time(MST) were 26.5%, 42.9%,63.3%, 40.8%, 20.4% and 22 months, respectively \u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e. A fraction dose of 3\u0026nbsp;Gy and total dose of 65-68Gy were given after initially 50\u0026nbsp;Gy/20 fractions ༌the 3-years OS and PFS rates were 32.1% and 29.8% respectively ༌and the 1 -, 2-and 3-years LRPFS rates were 69.6%, 60.9% and 60.9%, respectively\u003csup\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e. Based on the characteristics of IMRT, the dose of the PTV was kept at 60\u0026nbsp;Gy and the dose of GTV was 72\u0026ndash;78\u0026nbsp;Gy synchronously༌the result showed that MST was 25.3\u0026nbsp;months \u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. 63-103Gy was the recommended radiation therapy dose to improve the local control rate \u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e. The commonness of these studies was that the primary tumor and drainage lymph nodes were defined as the same target. The ways to increase dose of physical or BED were as follows: dose escalation after conventional fractionated radiotherapy༌different doses were simultaneously prescribed to GTV and PTV. The aim was to improve the tumor local control and survival. The way of increasing the dose of radiotherapy in our study was different from the above studies. The primary tumor and drainage lymph nodes were defined as different targets༈GTVp and GTVn༉. Different doses of radiation therapy were simultaneously prescribed for primary tumor and metastatic lymph nodes through SIB-IMRT. One principle is that the BED\u0026thinsp;\u0026ge;\u0026thinsp;100\u0026nbsp;Gy for stage I NSCLC can obtain a local control rate of \u0026gt;\u0026thinsp;90% \u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e, significantly reduce the local recurrence rate and improve the survival rate at 3-years \u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e. Another principle is that the long-term local control rate is more than 50% through conventional fractionated radiotherapy dose ༈60-66Gy༉ for mediastinal metastatic lymph nodes \u003csup\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e. Through SIB-IMRT, the radiation doses were simultaneously prescripted 78\u0026nbsp;Gy (BED\u0026thinsp;=\u0026thinsp;101.48\u0026nbsp;Gy) for primary tumor and 60-65Gy / 26f (BED\u0026thinsp;=\u0026thinsp;73.6-81.25\u0026nbsp;Gy) for metastatic lymph nodes .The result showed that the ORR was 90% (18 / 20), and the SD was only observed in 2 patients (primary tumor reduced by 14%, 30%, metastatic lymph node reduced by 44%, 32%).The ORR of primary tumor and metastatic lymph node was both 85% and there was no PD. The local control rates at 1, 3 and 5\u0026nbsp;years were 85%, 75% and 70%, respectively. Only 4 patients were diagnosed as local recurrence confirmed by imaging and / or pathology and 3 of them died from the following causes: myelosuppression grade IV, sudden cardiac death, hemoptysis. The result showed that the ORR was kept at 90% by SIB-IMRT ༌which was superior to the result of chemotherapy and conventional fractionated radiotherapy for local advanced NSCLC\u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e. It may be due to the increase of ORR, the proportion of tumor shrinkage and regression increased ,which was beneficial to reduce the recurrence and mortality rate and positively correlated with the prolongation of survival rate \u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e。The OS and LPFS rates at 1, 3 and 5\u0026nbsp;years were 90%, 42.6%, 35.5% and 84.4%, 35.5%, 28.4%, respectively. The MST was 24\u0026nbsp;months.\u003c/p\u003e \u003cp\u003eThe injury control index used in the evaluation of radiotherapy plan was based on the standard of conventional fractionated radiotherapy of locally advanced NSCLC Acute radiation pneumonitis, radiation esophagitis and radiation dermatitis were all grade 1\u0026ndash;2. Further analysis showed that grade 2 toxicity mainly occurred in concurrent chemoradiotherapy, which increased acute radiotoxicity\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. Compared with the conventional radiotherapy, there was no increase in radiotoxicity despite the increase in fractionated dose(3Gy/f) and BED \u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/sup\u003e.The main systemic toxicity was gastrointestinal toxicity (grade 1 in 6 patients, grade 2 in 8 patients, grade 3 in 1 patient) and hematological toxicity (grade 2 in 6 patients, grade 3 in 5 patients, grade 4 in 4 patients ). All of them occurred in concurrent chemoradiotherapy. Radiotherapy alone had no obvious systemic toxicity. It showed that systemic toxicity was mainly related to cytotoxic drugs.\u003c/p\u003e \u003cp\u003eA total of 12 patients died. 5 patients died of pulmonary infection (ages: 55, 71, 78, 79, 85 years;V20: 26. 5%, 25.8%, 24.3%, 27.3%, 17.9%༛ RP grade:2, 0, 0, 2, 0༛ MLD\u0026thinsp;\u0026lt;\u0026thinsp;20Gy ). 3 patients died of cardiogenic diseases (age 79, 78, 80 years༛ accompanied by hypertension and diabetes, coronary heart disease with coronary stent implantation, paroxysmal atrial fibrillation༛ MHD: 2.35\u0026nbsp;Gy, 22.79\u0026nbsp;Gy, 9.04\u0026nbsp;Gy).4 patients died of local recurrence,local recurrence along with metastasis, local recurrence with massive hemoptysis and respiratory failure༌respectively.\u003c/p\u003e "},{"header":"Conclusions","content":" \u003cp\u003eSIB-IMRT can significantly improve ORR and survival for stage II-III NSCLC with metastatic lymph nodes. This treatment approach has high safety and satisfactory efficacy .\u003c/p\u003e "},{"header":"Abbreviations","content":"\u003cp\u003eSIB-IMRT：Simultaneous Integrated Boos of intensity modulated radiation therapy; PTV： planning target volume ； PTVp： PTV of primary tumor；PTVn ：PTV of metastatic lymph ORR：objective response rate；CR: Complete response; PR: Partial response; NC：no change；PD: Progressive disease; MST：mean survival time； KPS: Karnofsky Performance Status; NSCLC: Non-small cell lung cancer; LPFS：local progression free survival; BED：biological effective dose.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eNone of the authors have any financial disclosures or conflicts of interest to declare.\u003c/p\u003e\n\u003cp\u003eNo actual or potential conflicts of interest exist.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was reviewed by the ethical review boards in China (Ethics Committee of Guizhou Cancer Hospital, GuiYang, China). Informed consent for treatment was obtained from patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets during and/or analysed during the current study available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003eAll authors have read and approved the final manuscript\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by grants from Major research project of innovation group of education department of Guizhou province (No.KY [2016]032). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBL designed the study. QSL，NL，WWO，SFS,ZM,YCG，WGY，YXH,HQL collected the data. BL and QSL undertook the data analysis and interpretation, and wrote the report. BL and QSL carried out the statistical analysis. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank HuiQin Li from Guizhou cancer Hospital, China, for her work\u003c/p\u003e\n\u003cp\u003eto follow up all patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor details\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e1 Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China.\u003c/p\u003e\n\u003cp\u003e2 Guizhou Cancer Hospital, Guiyang 550004, China.\u003c/p\u003e"},{"header":"References","content":"\u003cp\u003e[1]\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;Ramnath N, Dilling TJ, Harris LJ, et al. Treatment of stage III non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013. 143(5 Suppl): e314S-e340S.\u003c/p\u003e\n\u003cp\u003e[2]\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Perez CA, Pajak TF, Rubin P, et al. Long-term observations of the patterns of failure in patients with unresectable non-oat cell carcinoma of the lung treated with definitive radiotherapy. Report by the Radiation Therapy Oncology Group. Cancer. 1987. 59(11): 1874-81.\u003c/p\u003e\n\u003cp\u003e[3]\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Bradley JD, Paulus R, Komaki R, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol. 2015. 16(2): 187-99.\u003c/p\u003e\n\u003cp\u003e[4]\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Kong FM, Ten HRK, Schipper M, et al. Effect of Midtreatment PET/CT-Adapted Radiation Therapy With Concurrent Chemotherapy in Patients With Locally Advanced Non-Small-Cell Lung Cancer: A Phase 2 Clinical Trial. JAMA Oncol. 2017. 3(10): 1358-1365.\u003c/p\u003e\n\u003cp\u003e[5]\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Zeng J, Rengan R. Dose Escalation Optimization in Patients With Locally Advanced Non-Small-Cell Lung Cancer: The Right Dose, in the Right Location, to the Right Patient, at the Right Time. JAMA Oncol. 2017. 3(10): 1365-1367.\u003c/p\u003e\n\u003cp\u003e[6]\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Onishi H, Araki T. Stereotactic body radiation therapy for stage I non-small-cell lung cancer: a historical overview of clinical studies. Jpn J Clin Oncol. 2013. 43(4): 345-50.\u003c/p\u003e\n\u003cp\u003e[7]\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Garg S, Gielda BT, Kiel K, et al. Patterns of locoregional failure in stage III non-small cell lung cancer treated with definitive chemoradiation therapy. Pract Radiat Oncol. 2014. 4(5): 342-8.\u003c/p\u003e\n\u003cp\u003e[8]\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Bezjak A, Temin S, Franklin G, et al. Definitive and Adjuvant Radiotherapy in Locally Advanced Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Endorsement of the American Society for Radiation Oncology Evidence-Based Clinical Practice Guideline. J Clin Oncol. 2015. 33(18): 2100-5.\u003c/p\u003e\n\u003cp\u003e[9]\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Ohri N, Duan F, Machtay M, et al. Pretreatment FDG-PET metrics in stage III non-small cell lung cancer: ACRIN 6668/RTOG 0235. J Natl Cancer Inst. 2015. 107(4).\u003c/p\u003e\n\u003cp\u003e[10]\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Aup\u0026eacute;rin A, Le PC, Rolland E, et al. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. J Clin Oncol. 2010. 28(13): 2181-90.\u003c/p\u003e\n\u003cp\u003e[11]\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Jouglar E, Isnardi V, Goulon D, et al. Patterns of locoregional failure in locally advanced non-small cell lung cancer treated with definitive conformal radiotherapy: Results from the Gating 2006 trial. Radiother Oncol. 2018. 126(2): 291-299.\u003c/p\u003e\n\u003cp\u003e[12]\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Chun SG, Hu C, Choy H, et al. Impact of Intensity-Modulated Radiation Therapy Technique for Locally Advanced Non-Small-Cell Lung Cancer: A Secondary Analysis of the NRG Oncology RTOG 0617 Randomized Clinical Trial. J Clin Oncol. 2017. 35(1): 56-62.\u003c/p\u003e\n\u003cp\u003e[13]\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Jeter MD, Gomez D, Nguyen QN, et al. Simultaneous Integrated Boost for Radiation Dose Escalation to the Gross Tumor Volume With Intensity Modulated (Photon) Radiation Therapy or Intensity Modulated Proton Therapy and Concurrent Chemotherapy for Stage II to III Non-Small Cell Lung Cancer: A Phase 1 Study. Int J Radiat Oncol Biol Phys. 2018. 100(3): 730-737.\u003c/p\u003e\n\u003cp\u003e[14]\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Liu M, Wang Z, Zhou T, et al. Individual isotoxic radiation dose escalation based on V20 and advanced technologies benefits unresectable stage III non-small cell lung cancer patients treated with concurrent chemoradiotherapy: long term follow-up. Oncotarget. 2017. 8(31): 51848-51858.\u003c/p\u003e\n\u003cp\u003e[15]\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Weiss E, Fatyga M, Wu Y, et al. Dose escalation for locally advanced lung cancer using adaptive radiation therapy with simultaneous integrated volume-adapted boost. Int J Radiat Oncol Biol Phys. 2013. 86(3): 414-9.\u003c/p\u003e\n\u003cp\u003e[16]\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Wanet M, Delor A, Hanin FX, et al. An individualized radiation dose escalation trial in non-small cell lung cancer based on FDG-PET imaging. Strahlenther Onkol. 2017. 193(10): 812-822.\u003c/p\u003e\n\u003cp\u003e[17]\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Lischalk JW, Woo SM, Kataria S, et al. Long-term outcomes of stereotactic body radiation therapy (SBRT) with fiducial tracking for inoperable stage I non-small cell lung cancer (NSCLC). J Radiat Oncol. 2016. 5(4): 379-387.\u003c/p\u003e\n\u003cp\u003e[18]\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Machtay M, Bae K, Movsas B, et al. Higher biologically effective dose of radiotherapy is associated with improved outcomes for locally advanced non-small cell lung carcinoma treated with chemoradiation: an analysis of the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys. 2012. 82(1): 425-34.\u003c/p\u003e\n\u003cp\u003e[19]\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Feddock J, Arnold SM, Shelton BJ, et al. Stereotactic body radiation therapy can be used safely to boost residual disease in locally advanced non-small cell lung cancer: a prospective study. Int J Radiat Oncol Biol Phys. 2013. 85(5): 1325-31.\u003c/p\u003e\n\u003cp\u003e[20]\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Wang Y, Lan F, Kang X, et al. Outcome Study of Cobalt Based Stereotactic Body Radiation Therapy for Patients with Inoperable Stage III Non-small Cell Lung Cancer. Technol Cancer Res Treat. 2015. 14(5): 539-45.\u003c/p\u003e\n\u003cp\u003e[21]\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Zhu ZF, Fan M, Wu KL, et al. A phase II trial of accelerated hypofractionated three-dimensional conformal radiation therapy in locally advanced non-small cell lung cancer. Radiother Oncol. 2011. 98(3): 304-8.\u003c/p\u003e\n\u003cp\u003e[22]\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Kong FM, Ten HRK, Schipper MJ, et al. High-dose radiation improved local tumor control and overall survival in patients with inoperable/unresectable non-small-cell lung cancer: long-term results of a radiation dose escalation study. Int J Radiat Oncol Biol Phys. 2005. 63(2): 324-33.\u003c/p\u003e\n\u003cp\u003e[23]\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Onimaru R, Fujino M, Yamazaki K, et al. Steep dose-response relationship for stage I non-small-cell lung cancer using hypofractionated high-dose irradiation by real-time tumor-tracking radiotherapy. Int J Radiat Oncol Biol Phys. 2008. 70(2): 374-81.\u003c/p\u003e\n\u003cp\u003e[24]\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Onishi H, Araki T, Shirato H, et al. Stereotactic hypofractionated high-dose irradiation for stage I nonsmall cell lung carcinoma: clinical outcomes in 245 subjects in a Japanese multiinstitutional study. Cancer. 2004. 101(7): 1623-31.\u003c/p\u003e\n\u003cp\u003e[25]\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Bao Y, Peng F, Zhou QC, et al. Phase II trial of recombinant human endostatin in combination with concurrent chemoradiotherapy in patients with stage III non-small-cell lung cancer. Radiother Oncol. 2015. 114(2): 161-6.\u003c/p\u003e\n\u003cp\u003e[26]\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Steuer CE, Behera M, Ernani V, et al. Comparison of Concurrent Use of Thoracic Radiation With Either Carboplatin-Paclitaxel or Cisplatin-Etoposide for Patients With Stage III Non-Small-Cell Lung Cancer: A Systematic Review. JAMA Oncol. 2017. 3(8): 1120-1129.\u003c/p\u003e\n\u003cp\u003e[27]\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Liang J, Bi N, Wu S, et al. Etoposide and cisplatin versus paclitaxel and carboplatin with concurrent thoracic radiotherapy in unresectable stage III non-small cell lung cancer: a multicenter randomized phase\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"cancer/non-small-cell lung cancer; radiation therapy /SIB-IMRT; efficacy; safety","lastPublishedDoi":"10.21203/rs.3.rs-15993/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-15993/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground: Local tumor failure remains a major problem after radiation-based nonsurgical treatment for unresectable locally advanced Non-Small Cell Lung Cancer （NSCLC）and inoperable stage II NSCLC .The aim of this study was to evaluate the feasibility of Simultaneous Integrated Boos of intensity modulated radiation therapy (SIB-IMRT) to Stage II-III NSCLC with metastatic lymph nodes. Methods: Patients were diagnosed by pathology or PET-CT. PTV was divide into two parts as follow, the PTV of primary tumor (PTVp) and the PTV of metastatic lymph nodes (PTVn) .The radiation doses were\u0026nbsp;simultaneously prescripted 78Gy (BED = 101.48Gy) for PTVp and 60-65Gy (BED = 73.6-81.25Gy) for PTVn, 26f/ 5.2 weeks .Response was scored according to WHO criteria. Radiotherapy toxicity was scored according to RTOG criteria .Hematology and gastrointestinal toxicity were scored according to CTCAE1.0 criteria.\u0026nbsp;Results: A total of 20 patients were enrolled. 17 patients were diagnosed by pathology and 3 patients were diagnosed by PET-CT . All patients were treated with SIB-IMRT. The objective response rate (ORR) was 90%, with CR 25%, PR 65%, NC 10% and PD\u0026nbsp;0%. Although Radiation toxicitiy was common, there were no grade≥3，with Radiation pneumonitis (10 cases), esophagitis (17 cases) and dermatitis (12 cases). The local control rates at 1, 3 and 5 years were 85%, 75% and 70%, respectively. The overall survival（OS）and local progression-free survival(LPFS) rates at 1, 3 and 5 years were 90%, 42.6%, 35.5% and 84.4%, 35.5% , 28.4%, respectively. The MST was 24 months. Conclusions: SIB-IMRT can significantly improve ORR and suivival for stage II-III NSCLC with metastatic lymph nodes , with high safety and satisfactory efficacy .\u0026nbsp;\u0026nbsp;Keywords: cancer/non-small-cell lung cancer; radiation therapy /SIB-IMRT; efficacy; safety Retrospective Trial Registration： (ChiCTR 2000029304)\u003c/p\u003e","manuscriptTitle":"Simultaneous Integrated Boost of intensity modulated radiation therapy to Stage II-III Non-Small Cell Lung Cancer with metastatic lymph nodes","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-03-04 16:16:30","doi":"10.21203/rs.3.rs-15993/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4598afbc-cf07-4f1c-a1b3-cc3f2e726431","owner":[],"postedDate":"March 4th, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":65871,"name":"Oncology"},{"id":65872,"name":"Cancer Biology"}],"tags":[],"updatedAt":"2021-07-22T19:19:36+00:00","versionOfRecord":{"articleIdentity":"rs-15993","link":"https://doi.org/10.1002/cam4.3446","journal":{"identity":"cancer-medicine","isVorOnly":true,"title":"Cancer Medicine"},"publishedOn":"2020-09-09 19:19:36","publishedOnDateReadable":"September 9th, 2020"},"versionCreatedAt":"2020-03-04 16:16:30","video":"","vorDoi":"10.1002/cam4.3446","vorDoiUrl":"https://doi.org/10.1002/cam4.3446","workflowStages":[]},"version":"v1","identity":"rs-15993","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-15993","identity":"rs-15993","version":["v1"]},"buildId":"cBFmMYwuxLRRLfASyISRj","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}