Bevacizumab Plus FSRT Versus Hippocampus-Avoidant WBRT in Lung Adenocarcinoma With Extensive Brain Metastases

April 3, 2026 updated by: Hui Liu, Sun Yat-sen University

Application of Bevacizumab Combined With Fractionated Stereotactic Radiotherapy (FSRT-Bev) Versus Hippocampus-Avoidant Whole-Brain Radiotherapy With Simultaneous Integrated Boost (HA-WBRT-SIB) in Patients With Extensive Brain Metastases From Lung Adenocarcinoma: A Phase III Randomized Controlled Trial Evaluating Intracranial Control Efficacy and Neurocognitive Function

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed 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

  1. Intracranial Progression-Free Survival (IPFS): Defined as the time of randomization to the first intracranial progression or death.
  2. 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).

Study Type

Interventional

Enrollment (Estimated)

220

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

  • Name: Bo Qiu
  • Phone Number: 02087343031

Study Locations

  • China
    • Chongqing Municipality
      • Chongqing, Chongqing Municipality, China, 400016
        • Recruiting
        • The First Affiliated Hospital of Chongqing Medical University
        • Contact:
    • Guangdong
      • Guangzhou, Guangdong, China, 510060
        • Recruiting
        • Sun Yat-sen University Cancer Center
        • Contact:
      • Guangzhou, Guangdong, China, 510405
        • Recruiting
        • The First Affiliated Hospital of Guangzhou University of Chinese Medicine
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: The FSRT-beva group
The 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). Bevacizumab 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.
Radiation: FSRT
The 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).
Drug: Bevacizumab
Bevacizumab 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.
Active Comparator: The HA-WBRT-SIB group
The 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.
Radiation: HA-WBRT-SIB
The 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Intracranial Progression-Free Survival (IPFS)
Time Frame: 18 months
Defined as the time from randomization to the first documentation of intracranial progression, death, or last follow-up.
18 months
Neurocognitive Function failure
Time Frame: 6 months
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
6 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Progression-Free Survival (PFS)
Time Frame: 18 months
Defined as the time of randomization to the first documentation of disease progression, death, or last follow-up.
18 months
Overall Survival (OS)
Time Frame: 18 months
Defined as the time of randomization to death or last follow-up.
18 months
Quality of Life Assessment
Time Frame: 18 months
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.
18 months
Safety Assessment
Time Frame: 18 months
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.
18 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sun Yat-sen University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 20, 2026

Primary Completion (Estimated)

September 15, 2029

Study Completion (Estimated)

September 15, 2029

Study Registration Dates

First Submitted

March 15, 2026

First Submitted That Met QC Criteria

March 15, 2026

First Posted (Actual)

March 19, 2026

Study Record Updates

Last Update Posted (Actual)

April 6, 2026

Last Update Submitted That Met QC Criteria

April 3, 2026

Last Verified

April 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2025-FXY-308

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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