Neurocognitive Outcome of Conformal Whole Brain Radiotherapy With or Without Hippocampal Avoidance for Brain Metastases: A Phase II Single Blind Randomized Trial
试验速览
- 阶段
- 不适用
- 入组人数
- 70
- 试验地点
- 1
- 主要终点
- Hopkins Verbal Learning Test-Revised (HVTL-R) delayed recall score
研究概览
简要总结
Brain metastases are the most common brain tumors in adults. It is estimated that around 10-30% of cancer patients would develop brain metastases during the course of their illness.
Whole brain radiotherapy (WBRT) is the treatment of choice for the majority of patients with brain metastases. WBRT yields high radiologic response rate (27~56%) and is effective in rapid palliation of neurologic symptoms as well as prolongs time to neurocognitive function decline caused by intracranial lesions. By using conventional fractionation, 33% of patients developed late neurocognitive toxicity while memory impairment was the most common symptom. The incidence is even higher when a formal and sensitive neurocognitive assessment was prospectively evaluated. With more long-term survivors nowadays, it has become increasingly important to minimize neurocognitive function decline and maintain quality of life in patients with brain metastasis.
The function of hippocampus is cooperation in learning, consolidation and retrieval of information and essential for formation of new memories. Bilateral and unilateral radiation injury of the hippocampus is known to alter learning and memory formation. Several preclinical studies support the hypothesis of hippocampus-mediated cognitive dysfunction by ionizing radiation. Clinical studies show increase in radiation dose to hippocampus is associated with subsequent neurocognitive function impairment in adult and pediatric patients. Furthermore, the preliminary result of Radiation Therapy Oncology Group (RTOG) 0933 suggested hippocampal avoidance significant reduce the mean relative decline at 4 months from 30% in historical cohort with WBRT to 7% in experimental cohort.
Previous studies showed brain structures other than hippocampus are also associated with radiation-induced decline in neurocognitive function. There is presence of placebo effect for interventions seeking improvement in neurocognitive function. In present study, a single blind randomized phase II trial is designed to investigate the effectiveness of neurocognitive function preservation using conformal WBRT with or without hippocampal avoidance.
详细描述
This is a single institutional, randomized phase II study to assess the neurocognitive outcome of conformal WBRT with or without hippocampal avoidance in patients with multiple brain metastases.
Patients will be randomly assigned 1:1 to receive conformal WBRT with or without hippocampal avoidance using permuted blocks within strata that are defined by Graded Prognostic Assessment (GPA) score and baseline neurocognitive status. All patients and co-investigators except the principal investigator and attending radiation oncologists will be blinded for treatment groups.
The whole brain planning target volume (PTV) will receive 30 Gy in 10 fractions. Treatment will be delivered once daily, 5 fractions per week, over 2 to 2.5 weeks. Breaks in treatment should be minimized.
Hippocampal Avoidance WBRT:
The dose is prescribed such as 90% of cranial content PTV is covered by the prescription dose.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Participant)
入排标准
- 年龄范围
- 20 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •To be eligible for inclusion, patients must fulfill the following criteria:
- •Patients with a histologic diagnosis of non-hematopoietic malignancy and radiographic evidence of brain metastases
- •Patients with brain metastasis outside a 5-mm margin around either hippocampus on gadolinium contrast enhanced MRI obtained within 30 days prior to registration
- •Patients with brain metastasis who have not been or will not be treated with stereotactic radiosurgery (SRS) or have received SRS for≤ 5 intracranial metastatic lesions
- •No evidence of leptomeningeal metastasis on gadolinium-enhanced MRI within 30 days prior registration
- •Age ≥ 20 years
- •Karnofsky Performance Status ≥ 60%
- •Life expectancy of ≥ 4 months.
- •Women of childbearing potential and male participants must practice adequate contraception
- •Patients must be able to comply with the study protocol and follow-up schedules and provide study- specific informed consent
排除标准
- •Patients fulfill any of the following criteria will be excluded from this trial
- •Prior radiotherapy to brain or SRS to > 5 intracranial metastatic lesion(s) or the biological equivalent dose in 2-Gy fractions was greater than 7.3 Gy to 40% of the volume of bilateral hippocampus from prior SRS
- •Serum creatinine > 2.0 mg/dL within 30 days prior registration
- •Contraindication to MRI such as implanted metal devices or foreign bodies, severe claustrophobia
- •Patients with leptomeningeal metastases
- •Severe, active comorbidities which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and adverse events of the protocol, or limit compliance with study requirements, defined as follows:
- •Uncontrolled active infection requiring intravenous antibiotics at the time of registration
- •Transmural myocardial infarction ≤ 6 months prior to registration
- •Unstable angina or congestive heart failure requiring hospitalization ≤ 6 months prior to registration
- •Life-threatening uncontrolled clinically significant cardiac arrhythmias
- •Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects
- •Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration
- •Uncontrolled psychiatric disorder
- •Uncontrolled, clinically significant cardiac arrhythmias
- •Will receive any other investigational agent or chemotherapy and/or target therapies during WBRT
- •Women of childbearing potential and male participants who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the radiation treatment involved in this study may be significantly teratogenic
研究组 & 干预措施
Hippocampal avoidance WBRT
Conformal whole brain radiotherapy with hippocampal avoidance
干预措施: Hippocampal avoidance WBRT (Radiation)
Conformal WBRT
Conformal whole brain radiotherapy without hippocampal avoidance
干预措施: Conformal WBRT (Radiation)
结局指标
主要结局
Hopkins Verbal Learning Test-Revised (HVTL-R) delayed recall score
时间窗: At 4 months after radiotherapy
Decline in Hopkins Verbal Learning Test-Revised (HVTL-R) delayed recall score from baseline to 4 months after the start of conformal whole brain radiotherapy with or without hippocampal avoidance for brain metastases
次要结局
- Patient reported outcome (Quality of Life questionnaire)(at 1, 2, 4, 6, 9, 12 months after radiotherapy, and then every 3 months until date of death from any cause, assessed up to 24 months)
- Acute toxicity (Common Toxicity Criteria for Adverse Events version 4)(From date of radiotherapy until 90 days after radiotherapy starts)
- Intracranial progression (Number of participant with intracranial progression on MRI of brain)(From date of enrolment until the date of first documented intracranial progression or date of death from any cause, whichever came first, assessed up to 60 months)
- Overall survival(From date of enrollment until the date of death from any cause, assessed up to 60 months)
- Neurocognitive function by a standardized neurocognitive battery(at 1, 2, 4, 6, 9, 12 months after radiotherapy, and then every 3 months until date of death from any cause, assessed up to 24 months)
- Late toxicity (Common Toxicity Criteria for Adverse Events version 4)(From 90 days after radiotherapy starts until the date of death from any cause, up to 60 months)