Effect Analysis Of SRT Combined With Bevacizumab In The Treatment Of Brain Metastases In Non-small Cell Lung Cancer

BackgroundLung Cancer(LC)ranks second in incidence and first in mortality among malignancies worldwide.In2020,Chinese patients accounted for 24% of new diagnoses of malignant tumours worldwide and Chinese patients accounted for 30% of deaths from malignant tumours worldwide.At the same time,lung cancer is also a malignant tumour with a high incidence and mortality rate in China,seriously affecting the health of our population.More than 80% of lung cancer patients worldwide have non-small cell lung cancer(NSCLC),and at least one fifth of these patients develop brain metastases(BM)at the time of initial diagnosis and during cancer progression.Treatment modalities for BM include surgery,Stereotactic Radiosurgery or Stereotactic Radiotherapy(SRS/SRT),Whole Brain Radiotherapy(WBRT)and a combination of systemic chemotherapy,targeted therapy and immunotherapy.After the 1950 s,WBRT was considered as the standard of caring for patients with brain metastases from lung cancer,but was gradually replaced by SRT due to its side effects,high radiation neurotoxicity and impact on neurocognitive function and quality of life.The growth and development of brain metastases is dependent on the formation of new blood vessels,and angiogenesis occurs through various signalling pathways,with the Vascular Endothelial Growth Factor(VEGF)signalling pathway being one of the most important.VEGF not only promotes tumour metastasis and growth by inducing neovascularisation,but also increases vascular permeability,causing leakage of fluid and serum proteins and the formation of peritumoural oedema,which increases the volume occupied by the tumour,induces and worsens neurological dysfunction and leads to symptoms such as increasing intracranial pressure.In addition,the produced peri-tumoural oedema increases the risk of surgery and radiotherapy damage.In recent years,several clinical studies have shown that bevacizumab can be used in combination with chemotherapy and targeted therapy to treat patients with advanced NSCLC brain metastases with significant efficacy,safety and efficacy.It has been shown that radiation treatment causes damage to the cerebral microvasculature in brain tissue and symptoms of cerebral oedema,which is associated with the alteration of blood-brain barrier permeability and abnormal activation of the VEGF signalling pathway.Currently,the combination of bevacizumab and radiotherapy significantly improves refractory peri-tumoural oedema and radiotherapy response after radiotherapy.In contrast,studies on the efficacy of SRT in combination with bevacizumab in the treatment of brain metastases from NSCLC are still relatively scarce.The aim of this study was therefore to investigate the combined efficacy of SRT in combination with bevacizumab in the treatment of patients with brain metastases from NSCLC,as well as to analyse the factors affecting the survival of patients with brain metastases.ObjectiveBy retrospectively analyzing 138 patients admitted to Nanshi Hospital of Henan University with pathologically diagnosed NSCLC and brain metastases detected by cranial MRI or CT between January2017 and December 2021,we aimed to explore the efficacy and safety of SRT combined with bevacizumab in the treatment of patients with NSCLC brain metastases and the survival factors affecting them,and to provide a reference basis for the future treatment of patients with NSCLC brain metastases.MethodsPatients diagnosed with NSCLC brain metastases and treated with cranial SRT from January 2017 to December 2021 at Nan Shi Hospital,Henan University were collected,and 138 eligible patients were screened according to the inclusion and exclusion criteria of this study.The 138 patients were divided into two groups A and B.Group A was SRT-treated patients and Group B was SRT combined with bevacizumabtreated patients.All patients were followed up by inpatient review,telephone,We Chat,and outpatient review.The follow-up date is up to 31 December 2022.Microsoft Access software was used to archive,enter and verify patients’ clinical and follow-up personal data to create a database of patients with NSCLC brain metastases.SRT all use the GMX-B gyroscopic rotating 60 Co stereotactic radiotherapy system manufactured by Shanghai Gamma Star,fixed using a U-shaped mask,images scanned by GE 16-row CT localizer at a layer thickness of 3mm,images reconstructed by the 3D planning system,transmitted to the Gamma-STAR-TPS planning system to scientifically formulate treatment plans and precisely outline tumour target areas and endangered organs.Gross Tumor Volume(GTV)is defined as the contrast-enhanced tumor border with 3mm outward radiation to form the Planned Target Volume(PTV).The physiotherapist designs the target distribution,uses different types of collimators depending on the size of the lesion,has a multi-target design and strictly limits the dose to important structures.There are 5 to 18 treatment targets.Depending on the location of the tumour growth,the brain tissue is subjected to different radiation doses,and the PTV is covered by a dose curve of 50% to 75%,with a single dose of 280-350 c Gy and 8 to 16 treatments,with a peripheral dose of 2880 c Gy-5600 c Gy,from Monday to Friday,once a day.Patients with intracranial hypertension are also treated with mannitol,glycerol fructose and dexamethasone for symptomatic dehydration and lowering of cranial pressure during radiotherapy.Patients in group B were given bevacizumab 15mg/kg after radiation therapy at 21-day intervals for 6 cycles.All patients had their cranial MR reviewed within 1 month after the end of radiotherapy and every 3months thereafter,and the second review criteria was taken to compare with the pre-treatment cranial MR to evaluate the patient’s recent outcome,which was evaluated by using the 2009 RECIST version 1.1 criteria for evaluating the efficacy of solid tumours.Follow-up visits assess patients’ adverse effects,complications,long-term outcomes intracranial Progression-free Survial(PFS),Overall Survival(OS),and analysis of factors affecting patient survival.The data were analysed by using SPSS(IBM SPSS26.0,SPSS Inc.)software,with normally distributed indicators statistically described by means(standard deviations)and independent samples t-tests used to compare data between two groups.Indicators that were not normally distributed were statistically described by median(interquartile spacing)and comparisons between groups were made using rank sum tests.Count data are expressed as number of cases(%)and the chi-square test was used for comparison between groups.Patient survival was calculated by using the Kaplan-Meier method and survival curves were plotted;single factors affecting survival prediction were analysed using Log-rank tests and multiple factors affecting survival prediction were analysed by using Cox proportional hazards regression models.P<0.05 was considered a statistically significant difference.ResultsIn this study,138 patients were screened according to the inclusion and exclusion criteria.90 patients in Group A were treated with SRT and 48 patients in Group B were treated with SRT in combination with bevacizumab.(1)The two groups of patients in AB were compared in terms of gender,age,KPS score,number of lesions,presence of neurological symptoms prior to radiotherapy,extracranial organ metastases,presence or absence of chemotherapy,presence or absence of targeted therapy,previous surgery or radiotherapy for the primary lung lesion,and whether the intracranial lesion was re-radiated after recurrence,All were P > 0.05,and the clinical characteristics were largely balanced and comparable between the two groups of patients in AB.(2)The recent objective efficacy evaluation of the two groups of AB showed that there were 90 patients in group A,14(15.6%)cases of CR,63(70.0%)cases of PR,4(4.4%)cases of SD,9(10%)cases of PD,the objective response rate(CR+PR)was 85.6%,and the tumor control rate(CR+PR+SD)was 90%;Among the48 patients in group B,8(16.7%)had short-term efficacy of CR,35(72.9%)cases of PR,1(2.1%)of SD,and 4(8.3%)cases of PD,with an objective response rate(CR+PR)of 89.6% and a tumor control rate(CR+PR+SD)of 91.7%.The P values for recent efficacy,objective remission rate and tumour control rate in the two AB groups were 0.888,0.448 and 0.750,respectively,and these P values were >0.05 which had no statistical significance.(3)Long-term efficacy was assessed in both AB groups: median intracranial PFS was 10 and 12 months and median OS was 12 and 24 months in groups A and B,respectively.Survival rates at 6 months,12 months,18 months and 24 months were 66%/92%,48%/81%,37%/60% and 18%/46% for both groups A/B respectively.The P-values for the analysis of intracranial PFS and OS survival curves for the two groups of patients in AB were 0.005 and 0.000 respectively,both <0.05,indicating a significant difference in intracranial PFS and OS survival curves between the two groups.Patients in Group B had better intracranial PFS,OS and survival rates than Group A.(4)Adverse effects in the two AB groups: no significant difference in the presence of epilepsy,tumour stroke haemorrhage and cranial hypertension in the two AB groups(all P values > 0.05);Patients in Group B were more likely to have proteinuria,gastrointestinal reactions,bone marrow suppression and liver function impairment than in Group A(all P values <0.05),but all symptoms resolved after symptomatic treatment.(5)Univariate analysis of the whole group of patients showed that the number of lesions,type of pathology,lesion volume,presence of neurological symptoms prior to radiotherapy,KPS score,extracranial organ metastases,presence of targeted therapy,and presence of chemotherapy were factors influencing the patients’ intracranial PFS(all P values < 0.05).KPS score,type of pathology,number of lesions,lesion volume,extracranial organ metastases,presence of targeted therapy,presence of chemotherapy,and presence of re-radiation after recurrence of intracranial lesions were factors influencing patients’ OS(all P values <0.05).(6)Multifactorial analysis of the whole group of patients showed that the number of lesions,presence of neurological symptoms before radiotherapy,presence of targeted therapy,presence of chemotherapy,and KPS score were independent prognostic influences on the patients’ intracranial PFS(all P < 0.05).Among them,high KPS score,targeted therapy and chemotherapy were protective factors for intracranial PFS in patients.The number of lesions >4 and the presence of neurological symptoms prior to radiotherapy were risk factors for intracranial PFS in patients.KPS score,number of lesions,presence or absence of targeted therapy,presence or absence of chemotherapy,and presence or absence of anti-angiogenic therapy were independent prognostic influences on patients’ OS(all P < 0.05).Among these,high KPS score,targeted therapy,chemotherapy and anti-angiogenic therapy were protective factors for patients’ OS.The number of lesions >4 was a risk factor for OS in patients.Conclusions1.SRT combined with bevacizumab treatment did not significantly improve the immediate outcome of patients,but improved median PFS,median OS and survival,especially for patients with a more significant improvement in OS and survival.2.Patients treated with SRT in combination with bevacizumab have no significant bleeding symptoms.Although adverse effects such as proteinuria,gastrointestinal reactions,bone marrow suppression and liver damage may increase,they can all be resolved with symptomatic treatment,making SRT in combination with bevacizumab a viable treatment for brain metastases from NSCLC.3.Univariate analysis showed that KPS score,type of pathology,number of lesions,lesion volume,extracranial organ metastases,presence or absence of targeted therapy,and presence or absence of chemotherapy were independent prognostic influences on the patients’ PFS and OS.The presence or absence of neurological symptoms before radiotherapy was an independent prognostic influence on the patient’s PFS.The presence or absence of re-radiation after intracranial lesion progression was an independent prognostic influence on the patient’s OS.4.Multifactorial analysis showed that high KPS score,targeted therapy and chemotherapy were protective factors for PFS and the number of brain metastases >4 and neurological symptoms before radiotherapy were risk factors for PFS.High KPS score,targeted therapy,chemotherapy,and anti-angiogenic therapy were protective factors for patient OS,and the number of lesions >4 was a risk factor for patient OS.