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

Официальное название

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

Обзор

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.

Подробное описание

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).

Вмешательства

• Лучевая терапия 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).
• Лучевая терапия 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.
• Препарат 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.

Первичные конечные точки

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

Вторичные конечные точки (4)

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

Критерии участия

Критерии включения

• 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

Критерии исключения

• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 3 центра

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

Публикации

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• 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

Идентификаторы

NCT: NCT07481786 · 2025-FXY-308

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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