Whole Brain Radiotherapy (WBRT) versus Stereotactic Radiosurgery (SRS) for 4 up to 10 brain metastases: a phase III randomized multicenter trial

In the Dutch guideline the advice is stereotactic radiosurgery (SRS) for
patients with 1 up to 3 brain metastases (BM) and whole brain radiotherapy
(WBRT) for patients with 4 or more BM. An interim analysis of the QUARTZ study
showed that WBRT did not provide benefit in quality of life (EQ5D EUROQOL
score) nor survival over best supportive care. WBRT has significant side
effects, such as hair loss, fatigue, and cognitive dysfunction which may result
in decreased quality of life (QOL). A recently published study showed that SRS
in patients with 5 up to 10 BM results in comparable survival as SRS in
patients with 2 up to 4 BM. Many systemic therapies do not have a satisfactory
intracranial response, because of the blood-brain barrier. There are potential
advantages of SRS over WBRT, i.e, limiting radiation doses to the uninvolved
brain and a high rate of local tumor control by just a one tot three
treatments. The next logic step would be to compare WBRT with SRS alone in
patients with 4-10 BM and evaluate whether SRS is superior to WBRT with regard
to QOL.

To determine if SRS is a better palliative treatment than WBRT for patients
with 4 up to 10 BM in terms of QOL at 3 months post-radiotherapy.

Prospective randomized multicenter phase III trial

Patients will be randomized between WBRT in 5 fractions of 4 Gy to a total dose
of 20 Gy. (standard arm) and one to three dosisse SRS to the BM (study arm).
The largest BM or a localization in the brainstem will determine the prescribed
dose for all BM. According to the volume criteria presented in the Dutch
National Platform Radiotherapy and Neuro-oncology (LPRNO) consensus (November
2014 Eekers, Hurkmans) SRS for BM, the prescribed dose will be determined in
the range of one tot three fractions of 15Gy up to 24Gy dependent on Planning
Target Volume (PTV).

For patients in a good physical shape with one to three BM, SRS is the
preferred treatment. For patients with 4 or more BM current Dutch guidelines
advise WBRT. This study is performed in patients with 4 up to 10 BM referred
for radiotherapy. The aim of this study is to compare the
standard of care, WBRT, with the experimental arm SRS, and determine which arm
provides best palliation treatment in terms of QOL. SRS requires an extra MRI,
but is delivered in less fractions than WBRT, and there is globally broad
experience with SRS. WBRT is a fast treatment,
which takes 5-10 minutes per visit. With recent technical advances, the beam-on
time during treatment with SRS for patients with multiple BM, is in the range
of several minutes to 45 minutes, a high rate of local tumor control by just
one to three treatments and the avoidance of complete hair
loss. For this study, no standard imaging during follow-up is performed
outside institutional standards, except when indicated on clinical grounds.
The baseline and follow-up scores of the EQ5D questionnaires will be collected
in patients treated with WBRT or SRS followed by telephone contact at several
time-points post-treatment and will take less than 10 minutes. In case a
patient refuses participation in the study, patient will be treated according
to the institutional standard, which most often will be WBRT, in agreement
with Dutch guidelines. For centres that have the logistic capacity extra
neurocognitive tests and more extensive QOL tests will be done before treatment
and only at 3 months after treatment.