Forschung

HIPPORAD

Whole-brain irradiation with hippocampal sparing and dose escalation on metastases: neurocognitive testing and biological imaging. A phase II prospective randomized multicentre study

Study design: Prospective, randomized two-arm phase II multi-centre trial; assessors of neurocognitive function (NCF) and magnetic resonance imaging (MRI) as well as patients are blinded to the treatment arm

Indication:
At least 4 brain metastases of solid tumours and not exceeding 10 metastases ≥5mm (i.e. eligible for dose escalation) 

Trial objectives:
The aim of this study is to investigate the benefits of whole brain radiotherapy (WBRT) with hippocampal avoidance (HA) and concomitant boost on the metastases compared to WBRT and concomitant boost without HA on Memory performance and morphological cerebral alterations in patients treated for multiple brain metastases. The study will serve as proof-of-concept. A conservative estimate of the effect size anticipated for a subsequent confirmative trial will be derived from the analyses by a combination of clinical and statistical judgement.

Primary endpoint: 
- Neurocognitive function, measured by the difference between verbal learning performance at three months after radiation therapy and at baseline

Secondary endpoint: 
- Intracranial progression (local tumour progression, progression in the WBRT area without dose escalation, within hippocampus, overall; number of new cerebral metastases)
- Extracranial Progression
- Overall survival
- Death due to brain metastases
- Locally progression-free survival
- Progression-free survival
- Changes in other cognitive performance measures
- Depression
- Health-related and individual quality of life
- Morphological alterations on MRI

Inclusion criteria:
- Patient's written informed consent has been obtained
- Age 18-80 years, male or female
- Legal capacity, patient is able to understand the nature, significance, and consequences of the Trial
- At least 4 brain metastases of solid tumors and not exceeding 10 metastases ≥5mm (i.e. eligible for dose escalation)
- RPA classification I or II
- No metastases within the hippocampus or in a distance of 7mm to the hippocampus (= hippocampal avoidance region, HAR)

Exclusion criteria:
- Simultaneous participation in other interventional trials which could interfere with this Trial
- Participation in a clinical trial within the last thirty days before the start of this trial, previous participation (randomisation) in this Trial
- Known or persistent abuse of medication, drugs or alcohol
- Persons who are in a relationship of dependence/employment with the sponsor or the investigator
- Pregnancy, nursing or patient not willing to prevent a pregnancy during Treatment
- Cerebral lymphomas, metastases of germ cell tumours, SCLC
- Acute neurological symptoms demanding an immediate start of RT
- CNS diseases or syndromes accompanied by cognitive deficits or radiological changes of the brain, e.g., dementia, depression, clinically manifest hypertensive encephalopathy, meningiosis carcinomatosa
- Previous brain irradiation or surgical resection of brain tumours (biopsy allowed) 
- Last application of chemotherapy/immunotherapy/targeted therapy <1 week before randomisation
- RT planning conforming to OAR constraints not feasible
- Benzodiazepines, barbiturates, topiramate, hydantoine as antiepileptic medication
- > 1 brainstem metastasis ≥5mm
- Brainstem metastasis >2cm
- Brain metastasis >3.5cm

Treatment:

Experimental intervention (Arm A): HA-WBRT with concomitant boost to the metastases, total dose to whole brain (PTVwhole brain A = (CTVwhole brain + 5mm) - HAR - PTVmetastases) 30Gy, 2.5Gy/fraction, 5x/week, dose to individual brain metastases 51Gy, 4.25Gy/fraction on 95% of volume, 5x/week (brain stem metastasis: 3.5Gy/fraction)

Control intervention (Arm B): WBRT with concomitant boost to the metastases but without HA, total dose to whole brain (PTVwhole brain B = (CTVwhole brain + 5mm) - PTVmetastases) 30Gy, 2.5Gy/fraction, 5x/week, dose to individual brain metastases 51Gy, 4.25Gy/fraction on 95% of volume, 5x/week (brain stem metastasis: 3.5Gy/fraction)

Status: geschlossen

Start: 19.04.2017

DRKS-Register Number: DRKS00004598