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

Official title

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

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.

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).

Interventions

• 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).
• 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.
• 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.

Primary outcome measures

• Intracranial Progression-Free Survival (IPFS) [Time frame: 18 months]
• Neurocognitive Function failure [Time frame: 6 months]

Secondary outcome measures (4)

• Progression-Free Survival (PFS) [Time frame: 18 months]
• Overall Survival (OS) [Time frame: 18 months]
• Quality of Life Assessment [Time frame: 18 months]
• Safety Assessment [Time frame: 18 months]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 3 centers

• The First Affiliated Hospital of Chongqing Medical University — Chongqing
• Sun yat-sen University Cancer Center — Guangzhou
• The First Affiliated Hospital of Guangzhou University of Chinese Medicine — Guangzhou

Publications

• Boothe D, Young R, Yamada Y, Prager A, Chan T, Beal K. Bevacizumab as a treatment for radiation necrosis of brain metastases post stereotactic radiosurgery. Neuro Oncol. 2013 Sep;15(9):1257-63. doi: 10.1093/neuonc/not085. Epub 2013 Jun 27. PMID 23814264
• Xiangying M, Rugang Z, Lijuan D, Yaowei Z, Bing S, Junliang W, Dan L, Shikai W. Low-dose bevacizumab as an effective pre-treatment for peri-tumoral brain edema prior to CyberKnife radiosurgery: A case report. Cancer Biol Ther. 2018 Jun 3;19(6):461-464. doi: 10.1080/15384047.2018.1433499. Epub 2018 Mar 21. PMID 29420112
• Lehrer EJ, Peterson JL, Zaorsky NG, Brown PD, Sahgal A, Chiang VL, Chao ST, Sheehan JP, Trifiletti DM. Single versus Multifraction Stereotactic Radiosurgery for Large Brain Metastases: An International Meta-analysis of 24 Trials. Int J Radiat Oncol Biol Phys. 2019 Mar 1;103(3):618-630. doi: 10.1016/j.ijrobp.2018.10.038. Epub 2018 Nov 2. PMID 30395902
• Jiang T, Zhang Y, Li X, Zhao C, Chen X, Su C, Ren S, Yang N, Zhou C. EGFR-TKIs plus bevacizumab demonstrated survival benefit than EGFR-TKIs alone in patients with EGFR-mutant NSCLC and multiple brain metastases. Eur J Cancer. 2019 Nov;121:98-108. doi: 10.1016/j.ejca.2019.08.021. Epub 2019 Sep 27. PMID 31569068
• Westover KD, Mendel JT, Dan T, Kumar K, Gao A, Pulipparacharuv S, Iyengar P, Nedzi L, Hannan R, Anderson J, Choe KS, Jiang W, Abdulrahman R, Rahimi A, Folkert M, Laine A, Presley C, Cullum CM, Choy H, Ahn C, Timmerman R. Phase II trial of hippocampal-sparing whole brain irradiation with simultaneous integrated boost for metastatic cancer. Neuro Oncol. 2020 Dec 18;22(12):1831-1839. doi: 10.1093/neu PMID 32347302
• Brown PD, Gondi V, Pugh S, Tome WA, Wefel JS, Armstrong TS, Bovi JA, Robinson C, Konski A, Khuntia D, Grosshans D, Benzinger TLS, Bruner D, Gilbert MR, Roberge D, Kundapur V, Devisetty K, Shah S, Usuki K, Anderson BM, Stea B, Yoon H, Li J, Laack NN, Kruser TJ, Chmura SJ, Shi W, Deshmukh S, Mehta MP, Kachnic LA; for NRG Oncology. Hippocampal Avoidance During Whole-Brain Radiotherapy Plus Memantine PMID 32058845
• Gondi V, Pugh SL, Tome WA, Caine C, Corn B, Kanner A, Rowley H, Kundapur V, DeNittis A, Greenspoon JN, Konski AA, Bauman GS, Shah S, Shi W, Wendland M, Kachnic L, Mehta MP. Preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): a phase II multi-institutional trial. J Clin Oncol. 2014 Dec 1;32 PMID 25349290
• Aoyama H, Shirato H, Tago M, Nakagawa K, Toyoda T, Hatano K, Kenjyo M, Oya N, Hirota S, Shioura H, Kunieda E, Inomata T, Hayakawa K, Katoh N, Kobashi G. Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA. 2006 Jun 7;295(21):2483-91. doi: 10.1001/jama.295.21.2483. PMID 16757720

Identifiers

NCT: NCT07481786 · 2025-FXY-308

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗