Research On Key Issues Of Precision Radiotherapy For Primary Tumors In Advanced Non-Small Cell Lung Cancer

Objective:In recent years research have shown that in advanced non-small cell lung cancer,combined with primary tumor radiation therapy on the basis of drug therapy prolongs survival than drug therapy alone.Controversy exists in the implementation of radiotherapy.Therefore,this paper will focus on（1）Changes of subclinical lesions of subcutaneously transplanted tumors in nude mice before and after EGFR-TKI treatment.（2）The feasibility of volumetric modulated arc therapy instead of intensity-modulated radiotherapy.（3）The clinical value of primary tumor radical dose radiation therapy on the prognosis of patients with oligometastases,three directions are studied.To provide a clinical basis for radiotherapy of primary tumors in advanced non-small cell lung cancer.Methods:1.Subclinical Lesion Research.Sixty nude mice were divided into control and treatment groups.Human lung adenocarcinoma cell lines were subcutaneously transplanted on the right hind legs of the nude mice in both groups.Three-dimensional pathological sections were taken respectively to observe the subclinical lesion area when the long diameter of the transplanted tumors in the control group grew to 5mm,10mm,15mm,and 20mm.In the treatment group,targeted therapy with gefitinib was applied to the nude mice when the long diameter of the transplanted tumors in them grew to 20 mm,and the long diameters of the transplanted tumors shrank to 15 mm,10 mm,5 mm,and 0 mm consequently.Three-dimensional pathological sections were taken to observe the subclinical lesions after tumor shrinkage.The observation results was compared between the two groups.Clinical EGFR-M（+）lung lobe specimens were pathologically sectioned in three-dimensional directions under the filled state to observe the subclinical lesion infiltration range.2.Research on the researchability of VMAT instead of IMRT.A retrospective analysis was performed on the primary tumors of stage III and IV non-small cell lung cancer（NSCLC）who received IMRT or VMAT radiotherapy from September 2008to March 2020.Propensity Score Matching（PSM）was used to evaluate the Response Rate（RR）,local control rate（LCR）,local progression-free survival（LPFS）,Overall Survival（OS）,toxicity and dose-volume parameters of the two radiotherapy techniques.3.Clinical efficacy study of primary tumor radical dose radiotherapy in patients with oligometastases.Inclusion criteria,pathologically confirmed na?ve non-small cell lung cancer,clinical stage IV（AJCC 7th edition）,metastatic organ≤3,age 18 to 80years,KPS score≥70 or ECOG 0-2,radiation the primary tumor can receive a prescribed dose of 63 Gy under the premise of controllable damage.Patients who met the inclusion criteria were randomly divided into a primary tumor radical dose group(63Gy of definitive radiotherapy,D₆₃)and a palliative dose group(45Gy of palliative radiotherapy,P₄₅).The primary endpoints were progression-free survival（PFS）,local progression-free survival（LPFS）,and overall survival（OS）.Secondary endpoints included objective response rate（ORR）,local control rate of primary（LCR_P）,safety,and failure factors.Results:1.Subclinical Lesion Research.The long diameters of transplanted tumors in group C were 5mm,10mm,15mm,20mm,the smallest infiltration range of subclinical lesions was 0.23mm,0.78mm,1.24mm,2.98mm,and the edge of transplanted tumor was placed 5.14mm,including 95%of subclinical lesions.The long diameter of the transplanted tumor in the T group shrank to 15mm,10mm,5mm,0mm,the smallest infiltration range was 5.74mm,2.13mm,2.13mm,0.11mm,and the edge of the transplanted tumor was placed 8.99mm,including 95%of subclinical lesions.The externally exposed T group range is significantly more extensive than group C（P=0.000）.The minimum range of subclinical lesions in 3 cases of lung lobe specimens in the filling state was 3.25mm,and the external 7.35mm included 95%of the subclinical lesions.2.Research on the researchability of VMAT instead of IMRT.According to the case screening criteria,a total of 637 patients were included,with 51,91,68 and 427cases of stage IIIA,IIIB,IIIC and IV,respectively.There were 102 cases of driver gene sensitive mutation（83 cases of EGFR mutation,19 cases of ALK mutation）,and10.20%received molecular targeted therapy（28 cases of Gefitinib,22 cases of Icotinib,2 cases of Osimertinib,13 cases of Crizotinib）,chemotherapy accounted for89.80%.The 483 patients were treated with IMRT and 154 patients were treated with VMAT.After propensity score matching,308 patients were matched.There was no significant difference in RR,DCR and LCR before PSM between the two groups（P>0.05）.Acute radiation esophagitis（RE）and pneumonia（RP）treated with VMAT were lower than those treated with IMRT（P<0.05）.However,there was no significant difference in grade 3-4 toxicity（χ2=2.77,P=0.096）.There was no significant difference in RR,DCR,LCR,LPFS,OS,RP and RE between the two groups after PSM（P>0.05）.The normal whole lung（V5,V20,MLD）and cardiac（V30,V40,MHD）dose-volume parameters of all patients and N2 staged patients after PSM were significantly lower than those of IMRT（P<0.05）.3.Clinical efficacy study of primary tumor radical dose radiotherapy in patients with oligometastases.From January 2014 to February 2021,344 cases met the case selection criteria,14 cases were lost to follow-up(8 cases in the D₆₃ group and 6 cases in the P₄₅ group),and the follow-up rate was 95.5%.The last randomised case was followed up for 13 months.There were 310 and 319 cases for comparative analysis of efficacy and safety,respectively.According to the study design,the dropout rate was less than 15%.The m PFS of the D₆₃ group and the P₄₅ group was 10 months and 9months,and the 1,2,and 3-year PFS were 39.9%and 29.5%,17.6%and 6.4%,and10.9%and 0%（χ2=12.49,P=0.000）.The m LPFS was 18 months and 13 months,and the 1,2,and 5-year LPFS were 62.9%and 50.4%,36.9%and 24%,20.5%and 5.5%（χ2=9.997,P=0.002）.The m OS was 21 months and 18 months,and the OS at 1,2,and 5 years was not statistically significant（χ2=3.014,P=0.083）.The response of D₆₃group and P₄₅ group were similar,with ORs of 54.30%and 53.45%,respectively（χ2=1.144,P=0.564）.The local control rate at 1,2 and 5 years in the D₆₃ group was better than that in the P₄₅ group（χ2=8.747,P=0.003）.Risk factor analysis showed that D₆₃ group prolonged PFS,LPFS,and OS had a tendency to prolong.Stratification showed that DCR_C was the common basis for prolonging OS,PFS,and LPFS after radical radiotherapy for primary tumors.The incidence of RE in D₆₃ was higher than that in P₄₅（82.7%vs 68.7%,P=0.004）,and there was no significant difference in grade III-IV RE（7.1%vs 4.9%,P=0.419）.There was no difference in the incidence of RP（45.5%vs 39.3%,P=0.259）,and the radical dose of grade III-IV RP was higher than the palliative dose（6.8%vs 1.2%,P=0.015）.There was no significant difference in gastrointestinal,hematology and liver related to chemotherapy（P>0.05）.The primary tumor radical dose radiation therapy can reduce the local failure rate（χ2=16.83 P=0.000）.The main failure after first-line treatment was distant metastasis（67.7%）,and there was no difference between D₆₃ and P₄₅ distant metastasis（χ2=0.005 P=0.944）.Brain metastasis failure was the main failure mode（39.1%）,followed by bone（22.8%）,lung（19.5%）,liver（16.2%）,pleura（10.5%）,distant lymph nodes（9.0%）,Adrenal gland（8%）,other（3.3%）.Conclusions:1.The subclinical lesion receded after gefitinib treatment,but was wider than that of tumor of same long diameter without treatment.Even if the complete imaging response was achieved,there were still small infiltrating lesions.Subclinical lesions in primary tumors of lung adenocarcinoma patients with EGFR-sensitizing mutations and no driver mutations may have similarities.2.Radiation therapy of A-NSCLC primary tumors using VMAT can achieve a similar efficacy to that of IMRT.The volume parameters of normal tissues and organs were significantly reduced,especially in patients with stage N2.Therefore VMAT may be more beneficial for reducing radiation damage of normal tissues and organs.3.Radical dose radiation therapy for the primary tumor of advanced NSCLC with metastases in less than or equal to 3 organs significantly prolonged PFS and LPFS.There is a tendency to prolong the OS.Significantly prolong survival based on the benefit of chemotherapy.For stage IV NSCLC whose primary tumor can receive radical dose radiotherapy,the efficacy of systemic therapy should be evaluated before the radiotherapy plan is decided.