The SAFE-trial: Safe Surgery for Glioblastoma Multiforme: Awake Craniotomy versus Surgery under General Anesthesia. A multicenter prospective randomised controlled study

Glioblastoma multiforme (GBM) or astrocytomas grade IV (WHO) are devastating
tumors with one of the worst prognosis in oncology. The median survival after
surgery and treatment with chemo and radiotherapy ranges from 12 to 15 months
and no curative therapy is currently available. The annual incidence is
approximately 5 per 100.000 with a prevalence of 800-1000 cases each year in
the Netherlands. Patients usually present with speech difficulties, unilateral
paresis in arms and/or legs, headache, cognitive problems or epilepsy. Multiple
studies show that extent of resection of the tumor improves survival in
patients with GM. Further analyses showed that patients who previously had
complete resection derived the most benefit from the temozolomide regimen
compared with those who had had incomplete resection. Thus, in addition to the
survival benefit associated with maximum cytoreductive surgery such surgery
seems essential for the efficacy of modern adjuvant treatment.
More than 50% of GM's are located near or in eloquent areas of the brain.
Eloquent areas are important areas within the brain were speech and/or motor
functions are locate. Damaging these areas during surgery has serious impact on
the quality of life and could even exclude patients from after treatment with
radio- and chemotherapy. The surgeon cannot identify these eloquent areas
during resections under general anesthesia (GA). Therefore, when resecting GMs
in these areas, they are usually not operated as aggressive as possible, due
the chance of seriously damaging the patient with a rather low life expectancy.
However, partial or subtotal resections will benefit less from radio and
chemotherapy as total resections. A surgical technique optimizing resection of
the tumor in eloquent areas but preventing neurological deficits is necessary
to improve survival and maintain quality of life in these patients.

The study will take place in 5 neurosurgical centers in the Netherlands
(Erasmus MC, UMC Utrecht, Elizabeth Ziekenhuis Tilburg, MC Haaglanden The
Hague, UMCG Groningen) and one center in Belgium (UZ Gent). All centers have
ample experience with the AC technique. When patients with a GBM fulfill the
inclusion criteria on MRI, they will be informed by a neurosurgeon regarding
participating in the trial. The randomisation will take place in Rotterdam by
the controlled trial center (CTC). After informed consent, the patient will be
informed about the procedure. Preoperatively, a full neurological exam will be
carried out as well as two questionnaires regarding quality of life and a
neurolinguistic test-battery. Standard preparation before the operation, the
operation itself (awake or general anaesthesia) and postoperative care will
take place in the referenced hospitals. A MRI scan 48 hours before- and after
the operation will be done. The patient will then be treated with radiotherapy
and chemotherapy. At 6 weeks, 3 months and 6 months after the operation, a full
neurological exam will be carried out again as well as two questionnaires.
After 3 months, the neurolinguistic test-battery will be carried out again. The
survival of the patients will be documented. After all the data have been
collected, the statistical analyses will take place. With this analysis,
significant differences between the groups for the primary and secondary
outcomes measures will be calculated.

The trial is set up as a multicenter randomized controlled study. Patients with
glioblastomas in eloquent areas on diagnostic MRI will be selected by the
neurosurgeons according the eligibility criteria. After written informed
consent the patient will be randomized for awake craniotomy (AC) or regular
craniotomy under general anesthesia (GA). After surgery, only patients with
histologically proven GBM will be included in the study. Thereafter, patients
will receive the standard treatment with concomitant temozolamide and radiation
therapy and standard follow up. Primary outcome is neurological morbidity on
the NIHSS scale at 6 weeks after surgery and percentage of patients with total
resection on post operative MRI. Secondary outcome is HRQoL at 6 weeks, 3
months and 6 months after surgery, progression free survival at 6 months and
overall survival after 2 years. Total duration of the study is 4 years. Patient
inclusion is 3,5 years. Follow-up is 1 year. Statistical analysis, cost benefit
analysis and article writing will taken 6 months.

An awake craniotomy

Assessments:
- Neurological examination: 15 minutes. Will take part 4 times. Before the
operation, and 6 weeks, 3 months and 6 months after the operation.
- Questionnaires: 10 minutes. Will take part 4 times. Before the operation, and
6 weeks, 3 months and 6 months after the operation.
- Neurolinguistic test-battery: 30 minutes. Will take part 2 times. Before the
operation and 3 months after the operation.
- MRI-scan: before the operation, 48 hours after the operation, and then after
3 months and 6 months. These MRI are part of the standard/usual care.

Possible complications:
- bleeding
- infection
- paresis/paralysis of extremities
- speech problems
- epilepsy
- death