Whole brain radiotherapy versus stereotactic radiosurgery for 4-10 brain metastases: a phase III randomised multicentre trial

Abstract

Background: Maintenance of quality of life is the primary goal during treatment of brain metastases (BM). This is a protocol of an ongoing phase III randomised multicentre study. This study aims to determine the exact additional palliative value of stereotactic radiosurgery (SRS) over whole brain radiotherapy (WBRT) in patients with 4-10 BM.

Methods: The study will include patients with 4-10 BM from solid primary tumours diagnosed on a high-resolution contrast-enhanced MRI scan with a maximum lesional diameter of 2.5 cm in any direction and a maximum cumulative lesional volume of 30 cm3. Patients will be randomised between WBRT in five fractions of 4 Gy to a total dose of 20 Gy (standard arm) and single dose SRS to the BMs (study arm) in the range of 15-24 Gy. The largest BM or a localisation in the brainstem will determine the prescribed SRS dose. The primary endpoint is difference in quality of life (EQ5D EUROQOL score) at 3 months after radiotherapy with regard to baseline. Secondary endpoints are difference in quality of life (EQ5D EUROQOL questionnaire) at 6, 9 and 12 months after radiotherapy with regard to baseline. Other secondary endpoints are at 3, 6, 9 and 12 months after radiotherapy survival, Karnofsky ≥ 70, WHO performance status, steroid use (mg), toxicity according to CTCAE V4.0 including hair loss, fatigue, brain salvage during follow-up, type of salvage, time to salvage after randomisation and Barthel index. Facultative secondary endpoints are neurocognition with the Hopkins verbal learning test revised, quality of life EORTC QLQ-C30, quality of life EORTC BN20 brain module and fatigue scale EORTC QLQ-FA13.

Discussion: Worldwide, most patients with more than 4 BM will be treated with WBRT. Considering the potential advantages of SRS over WBRT, i.e. limiting radiation doses to uninvolved brain and a high rate of local tumour control by just a single treatment with fewer side effects, such as hair loss and fatigue, compared to WBRT, SRS might be a suitable alternative for patients with 4-10 BM.

Trial registration: Trial registration number: NCT02353000 , trial registration date 15th January 2015, open for accrual 1st July 2016, nine patients were enrolled in this trial on 14th April 2017.

Keywords: Brain metastases; Quality of life; Stereotactic radiosurgery; Whole brain radiotherapy.

Conflict of interest statement

Author information

JZ: radiation oncologist, MAASTRO clinic Maastricht, the Netherlands.

AB: radiation oncologist, VU university medical centre, the Netherlands.

DE: radiation oncologist, MAASTRO clinic Maastricht, the Netherlands.

CH: clinical physicist radiation oncology, Catharina Hospital, Eindhoven, the Netherlands.

AS: clinical physicist radiation oncology, MAASTRO clinic, Maastricht, the Netherlands.

PL: radiation oncologist and research professor, MAASTRO clinic, Maastricht, the Netherlands.

Ethics approval and consent to participate

This study was approved by the ethics committee of the following hospital: the Maastricht University medical center (Mumc), Maastricht, the Netherlands: reference number protocol NL53852.068.15/METC153053. The responsible investigator will ensure that this study is conducted in agreement with the Declaration of Helsinki (Brazil, October 2013) and in accordance with the Medical Research Involving Human Subjects Act (WMO). The protocol has been written, and the study will be conducted according to the ICH Harmonized Tripartite Guideline for Good Clinical Practice (ref: http://www.ifpma.org/pdfifpma/e6.pdf). All patients will be informed about the aims of the study, the possible adverse events, the procedures and possible hazards to which they will be exposed. They will be informed about the strict confidentiality of their data, and that their medical records may be reviewed for trial purposes by authorised individuals other than their treating physician. Information will be given in both spoken and written form as given in the Patient Information text. The Patient Informed consent statement and the Patient Information text are given as an appendix to this protocol. It will be emphasised that the participation is completely voluntary, and the patient does not need to give any further explanation for not participating. The patient is allowed to refuse further participation in the protocol whenever he wants. This will not prejudice the patient’s subsequent care. Documented informed consent must be obtained for all patients included in the study before they are registered in the study.

Consent for publication

All patients have provided written informed consent for participation in this trial, and publication of the results gathered in this trial. The publication does not contain recognisable individual patient data, but an analysis of the results of the whole study population (n = 230).

Competing interests

The department of radiotherapy of MAASTRO clinic has a research agreement with Varian Medical Systems, Palo Alto USA. Varian Medical Systems is not involved in the design of the study, and collection/storage/analysis of the data gathered in this study.

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Figures

Fig. 1

Dose distribution difference between WBRT (left) and SRS (right). A typical dose distribution on a planning-CT of WBRT on the left side and SRS on the right side. With WBRT, the healthy brain tissue receives the same low palliative radiation dose (non-ablative). With SRS, only the metastatic tissue receives a high ablative dose