This is a phase 3, randomized, controlled clinical trial comparing two brain-directed treatment strategies for adult patients with extensive brain metastases from lung adenocarcinoma. The trial compares fractionated stereotactic radiotherapy combined with bevacizumab (FSRT-Bev) versus hippocampus-avoidant whole-brain radiotherapy with simultaneous integrated boost (HA-WBRT-SIB). The main objectives are to evaluate intracranial tumor control and preservation of neurocognitive function .
Patients will be randomly assigned in a 1:1 ratio to receive either FSRT plus bevacizumab or HA-WBRT-SIB. In the experimental group, FSRT is delivered to visible brain tumors over 5 daily treatments (total 30 Gy, 6 Gy per fraction). Bevacizumab is given intravenously every 3 weeks for 4 cycles. In the control group, patients receive hippocampus-avoidant whole-brain radiation (25 Gy) with a simultaneous dose boost to metastatic lesions (40 Gy total) over 10 daily treatments.
Age ≥18 years
Pathologically confirmed non-squamous non-small cell lung cancer (adenocarcinoma)
Stable extracranial disease
ECOG performance status 0-2
Contraindications to bevacizumab (uncontrolled hypertension, history of bleeding/thromboembolism, recent surgery, etc.)
Leptomeningeal metastasis
Prior brain radiotherapy or surgical resection of brain metastases
Significant mass effect requiring urgent neurosurgical intervention
Parallel
FSRT
RadiationThe FSRT-bevacizumab group receives FSRT plus bevacizumab. FSRT targets visible intracranial lesions, with a total dose of 30 Gy administered once daily for 5 fractions (6 Gy per fraction).
HA-WBRT-SIB
RadiationThe HA-WBRT-SIB group receives whole-brain radiotherapy with hippocampal avoidance and a simultaneous integrated boost (SIB) to visible intracranial lesions. A total dose of 25 Gy is delivered to the whole brain, while visible lesions are simultaneously boosted to 40 Gy. Treatment is administered once daily for a total of 10 fractions.
Bevacizumab
DrugBevacizumab is initiated one week before the start of FSRT and administered every 3 weeks for a total of 4 cycles, via intravenous injection at a dose of 7.5 mg/kg.
Intracranial Progression-Free Survival (IPFS)
Defined as the time from randomization to the first documentation of intracranial progression, death, or last follow-up.
Neurocognitive Function failure
Neurocognitive failure is the first failure, defined as a neurocognitive decline using the reliable change index (RCI) on at least one of the following assessments: HVLT-R, TMT, or COWA
Progression-Free Survival (PFS)
Defined as the time of randomization to the first documentation of disease progression, death, or last follow-up.
Overall Survival (OS)
Defined as the time of randomization to death or last follow-up.
Quality of Life Assessment
Quality of life (QoL) is assessed at baseline and at 2, 6, and 12 months after radiotherapy using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), version 3.0.
Safety Assessment
Safety is assessed by monitoring adverse events (graded by CTCAE), laboratory tests, neurological toxicity, and radiation-induced brain necrosis. All treatment-related toxicities are documented and analyzed for severity and clinical significance.
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