Ultrasound Navigation Guided Improvement of High Grade Glioma Resection and Quality of Life: a phase III Randomized Controlled Trial.

Median survival of high grade glioma is only 15 months after surgery, radio-
and chemotherapy. Prognosis of patients with HGG is independently associated
with larger surgical resections of the tumour. However, larger resections also
have the risk of damaging normal brain and could therefore have detrimental
effect on quality of life of these patients. Achieving GTR without causing new
neurological deficits is therefore still a great challenge in glioma surgery.

The term gross total resection (GTR) is used in the literature to indicate no
residual tumour on post-operative MRI scans. GTR in newly diagnosed, untreated
HGG patients varies in the literature from 33% to 85% in retrospective studies.
GTR of HGG patients operated in Erasmus MC is around 30% and comparable to the
only known published randomized controlled study, investigating the use of
fluoro-guided resection16. The relatively low GTR*s are caused by the technical
difficulty to identify interface during resection between tumour and white
matter of the brain. The neurosurgeon is therefore not able to distinguish
tumour from white matter clearly. New intraoperative high resolution imaging is
needed to overcome this problem.

With the use of navigation equipment, pre-operative MRI scans are used to help
neurosurgeons navigate to the destination of the glioma in the brain during
surgery. However, due to brain and tumour shift during operation, these images
do not reflect the real-time situation in the brain during surgery.
Intraoperative acquired, real-time images are therefore needed to correct for
brain and tumour shift to optimize tumour resection. Nowadays, intraoperative
MRI (iMRI) is an increasingly used as a tool to acquire real-time images and to
improve extent of glioma resection during surgery. However, installing this
technique in the operating room is highly expensive (between 3*5 million
euros), has high maintenance costs, is extremely time consuming during
operations (1-2 hours), and will not be available for most of the neurosurgical
centres around the world. Intraoperative navigated high resolution ultrasound
(US) could be an alternative.

Recently, a new intraoperative navigated high resolution US (developed by
Brainlab and BK-medical) has been shown to be a promising cost-effective tool
to acquire real-time intraoperative images to localize and to resect gliomas.
Intraoperative US guidance costs a fraction of an MRI, has almost no
maintenance costs, is much less time consuming and can be used to acquire real
time images during surgery. With the use of (older) US, GTR percentages between
63% and 94% could be attained, but most of these published studies are biased
by selection, where superficial small tumours have better resections as
compared to more difficult to operate deeply seated larger tumours. The new
intraoperative navigated high resolution US (developed by Brainlab and
BK-medical) is a significant improvement as and has the potential to be
incorporated standardly during resection of HGG in contrast to older
(non-navigation fused) US devices.

The purpose of this study is to investigate the effectivity of the newly
acquired intraoperative navigated US in achieving GTR in patients with HGG and
to measure influence on quality of life. Our primary goal is to investigate
whether the use of IOUS additional to neuronavigation improves after the extent
of high grade glioma resection compared with the use of neuronavigation only.
Our secondary goal is to investigate whether ultrasound guided tumor resection
improves neurological outcome, quality of life and survival time, when compared
with non-ultrasound guided tumor resection

Primary Objective
To investigate whether ultrasound guided tumor resection succeeds gross total
resection significantly more frequently, when compared with the conventional
non-ultrasound guided tumor resection.

Secondary Objective(s)
To investigate whether ultrasound guided tumor resection improves the extent of
resection , quality of life and survival time, without causing new neurological
deficits more frequently, when compared with the conventional non-ultrasound
guided tumor resection.

Randomized Controlled Trial, Single Blinded
All newly diagnosed, untreated, contrast enhancing presumed high-grade glioma
patients (18-75 year) will be randomized in two groups. In one group glioma
surgery will be performed by using neuronavigation only (conventional
treatment). In the other group, glioma surgery will be performed with the use
of intraoperative ultrasound in addition to neuronavigation (ultrasound
guided).

The study consists of two treatment arms: non-ultrasound guided glioma
resection (conventional treatment) versus ultrasound guided glioma resection
(intervention) .

The standard treatment of glioblastoma patients consist of combined radiation
and chemotherapy for a period of 6 weeks after surgery, followed by monthly
cycles of chemotherapy alone, mostly during 6 months. Maximal and safe
resection is the main goal of glioblastoma surgery and is currently still a
great challenge. Finding an adjuvant neurosurgical tool to improve the extent
of glioblastoma resection is of high importance. Ultrasound guided resection is
a very low-risk alternative to a standard tumor resection procedure, which
possibly shortly extends the time of surgery. In this study, patients will be
randomised in two treatment arms: ultrasound guided or non-ultrasound guided
glioblastoma surgery. During a follow up time of 6 months, patients will be
called up 3 times to fill in 2 questionnaires to compare quality of life and
neurological functioning. Both treatment arms will follow the standard
treatment protocol for glioblastoma and no additional interventions will be
done.