For non-small cell lung cancer brain metastases, stereotactic radiotherapy is gradually replacing whole brain radiotherapy as the standard treatment. When patients have multiple brain metastases or larger tumors (diameter>2cm), single session stereotactic radiotherapy (SRS) may cause significant neurological damage, so fractionated stereotactic radiotherapy (FSRT) is often used. The recent objective remission rate of FSRT is about 50%, and the 1-year intracranial control rate is about 45%, but intracranial progression remains the main factor affecting long-term survival of patients.

Bevacizumab is a recombinant humanized monoclonal antibody against vascular endothelial growth factor, which can improve the efficacy of cranial radiotherapy by normalizing neovascularization and improving the hypoxic state of tumor cells. In addition, bevacizumab can improve the abnormal permeability of neovascularization, reduce exudation and extracellular brain edema, thereby further alleviating the toxic side effects associated with brain radiotherapy.

Based on this, this prospective, controlled phase III study will explore the efficacy and safety of the combined use of fractionated stereotactic radiotherapy and bevacizumab in multiple brain metastases of lung adenocarcinoma.

This prospective, controlled phase III study will explore the efficacy and safety of the combined use of fractionated stereotactic radiotherapy and bevacizumab in multiple brain metastases of lung adenocarcinoma.

Patients will be randomly assigned to three groups in a ratio of 1:1:1. The FSRT+beva group receives FSRT radiotherapy+bevacizumab treatment; FSRT targets visible intracranial lesions with a total dose of 30Gy, administered once a day for a total of 5 days, with a fraction dose of 6Gy. Bevacizumab starts on day 1 (one week before FSRT treatment), q3w， A total of 4 treatment courses, intravenous injection, with a dose of 7.5mg/kg. The FSRT group receives simple FSRT radiotherapy; FSRT is targeted at visible intracranial lesions, with a total dose of 30Gy, administered once a day for a total of 5 days, and a fraction dose of 6Gy for segmentation. The WBRT group receives whole-brain radiotherapy (WBRT) with a simultaneous integrated boost (SIB) to visible intracranial lesions. The prescribed doses are: 40 Gy total to gross lesions and 25 Gy total to the whole brain, delivered in 10 daily fractions.

Inclusion Criteria:

• Age ≥ 18 years old;
• Cellular or histopathological confirmation of lung adenocarcinoma;
• Prior to enrollment, brain enhanced magnetic resonance imaging shows (1) 1-2 brain metastases, with at least one measuring ≥3 cm in diameter; or (2) 3-10 brain metastases, with at least one measuring ≥2 cm in diameter; or (3) 11-20 brain metastases; and deemed unsuitable for single-session SRS by radiation oncologists;
• At the time of enrollment, the extracranial disease status is stable;
• Eastern Cooperative Oncology Group (ECOG) physical fitness status score 0-2 points
• Normal liver, kidney, and bone marrow function within 14 days prior to enrollment: peripheral blood white blood cell count ≥ 4 × 10^9/L; neutrophil count ≥ 1.5 × 10^9/L, platelet count ≥ 100 × 10^9/L, hemoglobin ≥ 100g/L, serum creatinine<1.5 times the upper limit of normal values; Bilirubin<1.5 times the upper limit of normal value; Transaminase<2 times the upper limit of normal value;
• The patient and their family agree and sign an informed consent form.

Exclusion Criteria:

• There are contraindications for bevacizumab, such as a history of cardiac and/or thromboembolic events, or uncontrolled hypertension;
• Meningeal metastasis or extensive intracranial metastasis are not suitable for FSRT;
• Bleeding tendency or coagulation dysfunction;
• Patients with hemoptysis (≥ 1/2 teaspoon of fresh blood per day) within the past month;
• Use full dose anticoagulant therapy within the past month;
• Has experienced severe vascular disease in the past 6 months;
• Have experienced gastrointestinal fistula, perforation, or abdominal abscess within the past 6 months;
• Has experienced hypertensive crisis, hypertensive encephalopathy, symptomatic heart failure (New York Class II or above), acute myocardial infarction, cerebral infarction, cerebral parenchymal hemorrhage, or other active cerebrovascular or cardiovascular diseases within the past 6 months;
• Patients with a history of arterial aneurysm or arteriovenous malformation;
• Having undergone major surgery within 28 days, or minor surgery or needle biopsy within 48 hours;
• Urinary protein 3-4+, or 24-hour urinary protein quantification>1g;
• Simultaneously accompanied by serious and uncontrolled other diseases.

This study is a clinical trial to ensure that patient privacy information is not disclosed.