Overview
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.
Description
Background
Brain metastases represent a severe complication of lung adenocarcinoma, significantly impairing both survival and quality of life. For patients with multiple or large brain metastases who are not candidates for stereotactic radiosurgery (SRS), hippocampus-avoidant whole-brain radiotherapy is considered a standard treatment option. However, this approach is limited by residual neurocognitive decline and suboptimal intracranial disease control.
Bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, has been shown to normalize tumor vasculature, enhance radiation sensitivity, reduce cerebral edema, and lower the risk of radiation-induced brain necrosis. Fractionated stereotactic radiotherapy (FSRT) offers effective local control with reduced toxicity compared to single-session SRS. A prior phase 2 study demonstrated promising efficacy and safety of FSRT combined with bevacizumab in this patient population. The present phase 3 trial aims to test the hypothesis that FSRT plus bevacizumab (FSRT-Bev) improves intracranial control and reduces neurocognitive toxicity compared to hippocampus-avoidant whole-brain radiotherapy with simultaneous integrated boost (HA-WBRT-SIB).
Study Design
This is a prospective, open-label, phase 3 randomized controlled trial being conducted at Sun Yat-sen University Cancer Center. Patients are randomized in a 1:1 ratio to one of two treatment arms:
Arm A (Experimental): FSRT combined with bevacizumab; Arm B (Control): HA-WBRT with SIB
Treatment Interventions
Arm A: FSRT is delivered to the gross tumor volume (GTV) at a total dose of 30 Gy in 5 daily fractions (6 Gy per fraction) using image-guided radiotherapy (IGRT). Bevacizumab is administered intravenously at a dose of 7.5 mg/kg every 3 weeks for 4 cycles, beginning one week prior to the start of FSRT.
Arm B: Hippocampus-avoidant whole-brain radiotherapy is delivered at a dose of 25 Gy in 10 daily fractions, with a simultaneous integrated boost (SIB) to gross metastatic lesions up to 40 Gy in 10 fractions.
Co-Primary Endpoints
- Intracranial Progression-Free Survival (IPFS): Defined as the time of randomization to the first intracranial progression or death.
- Neurocognitive failure Rate at 6 Months Post-Radiotherapy: Assessed using the reliable change index (RCI) based on validated neurocognitive tests, including the Hopkins Verbal Learning Test-Revised (HVLT-R), Controlled Oral Word Association Test (COWA), and Trail Making Test Parts A and B (TMT-A, TMT-B).
Eligibility
Inclusion Criteria:
- Age ≥18 years
- Pathologically confirmed non-squamous non-small cell lung cancer (adenocarcinoma)
- Extensive brain metastases meeting any of the following:
1-2 metastases with at least one ≥3 cm in diameter; or 3-10 metastases with at least one ≥2 cm; or 11-20 metastases
- Stable extracranial disease
- ECOG performance status 0-2
- Adequate bone marrow, hepatic, and renal function
- Written informed consent
Exclusion Criteria:
- 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
- Severe cardiovascular, vascular, or gastrointestinal disease within 6 months
- Proteinuria ≥3+ or 24-hour urine protein \>1 g
- Other active malignancies (except curable non-melanoma skin cancer or cervical carcinoma in situ)
- Inability to comply with neurocognitive testing
- Pregnancy or breastfeeding
