Neoplasms

Nervous System Diseases

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Brain Neoplasms

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Intervention: iMRI-guided brain tumour biopsy. The PoleStar N20 iMRI system (Medtronic Navigation, Louisville, CO, USA) with a 0.15-T constant magnet imager will be used in all cases. After the patient's positioning, the preoperative reference examination is routinely carried out. The entry point, target and optimal biopsy trajectory are then defined by the operator on the basis of the obtained iMRI images. Serial tissue samples are collected. Following each operation, a control iMRI (T1-weighted, axial, 4 mm scan examination) is routinely performed to confirm and document the proper targeting and to exclude postoperative hyperacute intraparenchymal bleeding.

Intervention: Stereotactic frameless brain tumour biopsy. A frameless STx biopsy is performed for each patient from the control group with the use of a neuronavigation system. The entry point, target and optimal biopsy trajectory are defined by the operator before the operation on the basis of the preoperatively obtained high-field MR images with the use of a neuronavigation workstation (Cranial 5, StealthStation Application Software, Medtronic Navigation, Louisville, CO, USA).

The PoleStar N20 iMRI system (Medtronic Navigation, Louisville, CO, USA) with a 0.15-T constant magnet was used in all procedures.

iMRI-guided brain tumour biopsy

The entry point, target and optimal biopsy trajectory were defined by the operator before the operation on the basis of the preoperatively obtained high-field MR images with the use of a neuronavigation workstation (Cranial 5, StealthStation Application Software, Medtronic Navigation, Louisville, CO, USA).

Stereotactic frameless brain tumour biopsy

Wlodzimierz Jarmundowicz, Professor

Background: The aim of the study was to assess the safety and effectiveness of stereotactic brain tumour biopsy (STx biopsy) guided by low-field intraoperative MRI (iMRI) in comparison with its frameless classic analogue based on a prospective randomized trial.

Patients are prospectively randomized into a low-field iMRI group and a control group that undergo a frameless STx biopsy. The primary endpoints of the analysis are: postoperative complication rate and diagnostic yield, and the secondary endpoints: length of hospital stay and duration of operation.

INTRODUCTION Stereotactic brain biopsy (STx biopsy) offers a relatively straightforward, accurate and safe method of obtaining diagnostic tissue. Frameless computer-based neuronavigation is now widely used in brain tumor surgery. It has many advantages over frame-based techniques and provides similar accuracy to the rigid frame. One of the methods applied to improve diagnostic yield and safety is the usage of intraoperative magnetic resonance imaging (iMRI), proposed by Bernays et al. in 2002.

Besides the obvious indications given in previous papers, including STx biopsy of very small, deeply localized or cystic lesions, iMRI guidance is particularly useful in two cases. The first one is when a satisfactory 3D volume modality cannot be obtained during preoperative high-field diagnostic MR imaging. When using iMRI there is no need to perform preoperative 3D imaging of any kind and manually register the patient's head in a neuronavigation system before the operation, which helps to significantly improve the workflow. In our study the total amount of patients with insufficient neuroimaging - admitted from outside medical centers - is over 30%. The second case is for teaching purposes - frameless iMRI guided STx biopsy, is relatively uncomplicated and technically straightforward and can be introduced as the first procedure during training in neurosurgical intraoperative imaging.

Although the usefulness of ultra-low-field iMRI in STx biopsy was subsequently confirmed by other authors, according to our knowledge no previous published studies have compared iMRI to preoperative MRI for brain tumor biopsy according to evidence-based medicine guidelines (EBM). Though this method has been subject to slight criticism, it has been consequently applied in neurosurgical daily practice in recent years.

The aim of our study was to verify the safety and effectiveness of the STx biopsy guided by low-field iMRI in comparison with its frameless classic analogue basing on a prospective randomized parallel-group, controlled trial. In the current paper we present the study design and results of the interim analysis.

MATERIAL AND METHODS

Patients Patients who are - following contemporary recommendations - scheduled to undergo STx biopsy, are prospectively recruited for the study. Each patient sign a written consent to participate in the study.

Inclusion criteria The inclusion criteria were as follows: male and female patients ≥ 18 years with supratentorial brain tumor scheduled to undergo STx biopsy. The estimated number of patients needed to reveal the difference of over 5% between primary endpoints' - diagnostic yield and complications ratio - at the level of significance 0.05 and power 80% was 465 per each arm.

Exclusion criteria Patients unable to provide informed consent and those with metal implants which could prevent or influence the head MR study were excluded from the study.

Allocation Patients were prospectively allocated by minimization according to demographic (gender, age) and epidemiologic data (preoperative Eastern Cooperative Oncology Group Performance Status-ECOG- a scale providing information about neurological and social status of a patient with oncological disease, maximum tumor diameter, presence of contrast enhancement, independent risk factors of hemorrhage - basal and thalamic localization and preoperative diabetes) into the iMRI and the control group.

Intervention After being transferred to the operating room each patient was sedated with an intravenous infusion of Remifentanil with passive oxygen therapy and monitoring of vital functions. Additionally, the sites of head holder pins and skin incision were anaesthetized with 1% Lignocaine. All biopsies in both groups were performed via a 6 mm burr-hole with the use of the Vertec system (Medtronic Navigation, Louisville, CO, USA). A passively navigated side cut 2.2 mm biopsy needle was used. All operations were performed by one of the three first authors.

In the iMRI-guided group the head of each patient was immobilized with a 3-pin iMRI-compatible head holder. The PoleStar N20 iMRI system (Medtronic Navigation, Louisville, CO, USA) with a 0.15-T constant magnet was used in all procedures. Subsequently, after the patient's positioning, the preoperative reference examination was routinely carried out (T1+gadolinum, T2 or FLAIR weighted - depending on the pathology, axial 4 mm scans). Images were automatically transferred into the neuronavigation system (StealthStation, Medtronic Navigation, Louisville, CO, USA). The entry point, target and optimal biopsy trajectory were then defined by the operator on the basis of the obtained iMRI images. Serial tissue samples (4 from the central and another 4 from the marginal part of the tumor) were collected according to the modified protocol described by Shooman et al., which made use of intraoperative histopathological examination obsolete. Following each operation, a control iMRI (T1-weighted, axial, 4 mm scan examination) was routinely performed to confirm and document the proper targeting and - as proposed by Bernays et al. - to exclude postoperative hyperacute intraparenchymal bleeding.

A frameless STx biopsy was performed for each patient from the control group with the use of a neuronavigation system. The entry point, target and optimal biopsy trajectory were defined by the operator before the operation on the basis of the preoperatively obtained high-field MR images with the use of a neuronavigation workstation (Cranial 5, StealthStation Application Software, Medtronic Navigation, Louisville, CO, USA). Following surgery the specimens were sent for independent histopathological analysis.

Postoperative care Postoperative care was conducted according to standard protocols and clinical guidelines. A postoperative follow-up head CT was subsequently performed 4 to 6 hours after each procedure. All patients were followed up with a clinical examination 2 weeks postoperatively performed by an independent and blinded for the allocation investigator.

Data collection Demographic and epidemiological data were collected prospectively. The primary endpoints were: the ratio of acute postoperative complications and the diagnostic yield. The presence of acute postoperative complication was noted if any of following findings was noted: (wound site infection up to two weeks after the operation, a new neurological deficit developed up to 24 hours following the operation and present in a follow up clinical examination 2 weeks postoperatively), intraparenchymal hematoma with radiological or clinical signs of the intracranial expansion.) and the diagnostic yield. The diagnostic yield was expressed according to the literature as a percentage of patients in whom the histopathological diagnosis was possible on the basis of the biological material obtained during the operation. Secondary endpoints included: the preoperative (LOSpre), postoperative (LOSpost) and total length of hospital stay (LOS) as well as the preparation (Tprep), operation (Top) and total operating room (TOR) time. The LOS and T were routinely measured and recorded in the central hospital files by the independent staff.

Intraoperative MRI-guidance in Frameless Stereotactic Biopsies

The Safety and Effectiveness of Low Field Intraoperative MRI-guidance in Frameless Stereotactic Biopsies of Brain Tumours - a Prospective Randomized Trial

The presence of acute postoperative complication is noted if any of following findings is present: wound site infection up to two weeks after the operation, a new neurological deficit developed up to 24 hours following the operation and present in a follow up clinical examination 2 weeks postoperatively, intraparenchymal hematoma with radiological or clinical signs of the intracranial expansion.

The diagnostic yield is expressed as the number of patients in whom the histopathological diagnosis was made based of the biological material obtained during the operation.

The preoperative (LOSpre), postoperative (LOSpost) and total length of hospital stay (LOS)

the preparation (Tprep), operation (Top) and total operating room (TOR) time

Wroclaw Medical University

M.D., Ph.D.

The PoleStar N20 iMRI system (Medtronic Navigation, Louisville, CO, USA) with a 0.15-T constant magnet is used in all procedures. Subsequently, after the patient's positioning, the preoperative reference examination is routinely carried out (T1+gadolinum, T2 or FLAIR weighted - depending on the pathology, axial 4 mm scans). The entry point, target and optimal biopsy trajectory are then defined by the operator on the basis of the obtained iMRI images. Serial tissue samples (4 from the central and another 4 from the marginal part of the tumour) are collected. Following each operation, a control iMRI (T1-weighted, axial, 4 mm scan examination) is routinely performed to confirm and document the proper targeting and to exclude postoperative hyperacute intraparenchymal bleeding.

Stereotactic intraoperative magnetic resonance (iMRI)-guided frameless brain tumour biopsy: The PoleStar N20 iMRI system (Medtronic Navigation, Louisville, CO, USA) with a was used in all procedures.

iMRI

A frameless STx biopsy is performed for each patient from the control group with the use of a neuronavigation system. The entry point, target and optimal biopsy trajectory are defined by the operator before the operation on the basis of the preoperatively obtained high-field MR images with the use of a neuronavigation workstation (Cranial 5, StealthStation Application Software, Medtronic Navigation, Louisville, CO, USA).

Stereotactic frameless brain tumour biopsy: The entry point, target and optimal biopsy trajectory were defined by the operator before the operation on the basis of the preoperatively obtained high-field MR images with the use of a neuronavigation workstation (Cranial 5, StealthStation Application Software, Medtronic Navigation, Louisville, CO, USA).

Non-iMRI

The PoleStar N20 iMRI system (Medtronic Navigation, Louisville, CO, USA) with a 0.15-T constant magnet is used in all procedures. Subsequently, after the patient's positioning, the preoperative reference examination is routinely carried out (T1+gadolinum, T2 or FLAIR weighted - depending on the pathology, axial 4 mm scans). The entry point, target and optimal biopsy trajectory are then defined by the operator on the basis of the obtained iMRI images. Serial tissue samples (4 from the central and another 4 from the marginal part of the tumour) are collected. Following each operation, a control iMRI (T1-weighted, axial, 4 mm scan examination) is routinely performed to confirm and document the proper targeting and to exclude postoperative hyperacute intraparenchymal bleeding.

Stereotactic intraoperative magnetic resonance (iMRI)-guided frameless brain tumour biopsy: The PoleStar N20 iMRI system (Medtronic Navigation, Louisville, CO, USA) with was used in all procedures.

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Poland

Region of Enrollment

The ECOG Scale of Performance Status:

0 - Fully active, able to carry on all pre-disease performance without restriction

1. - Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work
2. - Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 50% of waking hours
3. - Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours
4. - Completely disabled; cannot carry on any selfcare; totally confined to bed or chair
5. - Dead

ECOG Performance Status

Maximum tumour diameter

Enhancement noted

No enhancement noted

Number of participants with contrast-enhancing tumors.

Tumour enhancement

basal localisation of the tumor

non-basal localisation of the tumor

Number of participants with basal localisation of the tumor.

Basal localization

thalamic localisation of the tumor

extra-thalamic localisation of the tumor

Number of participants with thalamic localisation of the tumor.

Thalamic localization

Diabetes recorded

Diabetes not recorded

Number of participants with preoperative diabetes.

Diabetes

Dr. Marcin Czyz

Complications assessed: Haematoma, Neurological deterioration, Infection

Number of Participants Presenting With Complications

Diagnostic Yield

Length of the postoperative hospital stay

Total length of hospital stay

The length of preoperative hospital stay

The length of postoperative hospital stay

Length of Hospital Stay

Total OR time

Time of preparation

Time of the operation

Time

The PoleStar N20 iMRI system (Medtronic Navigation, Louisville, CO, USA) with a 0.15-T constant magnet is used in all procedures. Subsequently, after the patient's positioning, the preoperative reference examination is routinely carried out (T1+gadolinum, T2 or FLAIR weighted - depending on the pathology, axial 4 mm scans). The entry point, target and optimal biopsy trajectory are then defined by the operator on the basis of the obtained iMRI images. Serial tissue samples (4 from the central and another 4 from the marginal part of the tumour) are collected. Following each operation, a control iMRI (T1-weighted, axial, 4 mm scan examination) is routinely performed to confirm and document the proper targeting and to exclude postoperative hyperacute intraparenchymal bleeding.

Stereotactic intraoperative magnetic resonance (iMRI)-guided frameless brain tumour biopsy: The PoleStar N20 iMRI system (Medtronic Navigation, Louisville, CO, USA) was used in all cases.

Overall Study

Behaviors and Mental Disorders

Cognitive Dysfunction

Each patient will undergo cognitive tests and questionnaires

Cognitive tests and Patient Reported Outcomes

Morten Høyer, MD

Lene Haldbo-Classen, MD

Aida Muhic

Morten Høyer

Lene Haldbo-Classen

Petra Witt

Slavka Lucakova

Charlotte Haslund

Rikke Dahlrot

Lene Haldbo-Classen, M.D

This study will assess cognitive function in patients with a primary brain tumour treated with radiation therapy (RT) to generate radio-sensitivity and volume effect parameters for the development of cognitive dysfunction. All types of brain tumours apart from glioblastoma will be included.

RT is fundamental in the treatment of primary brain tumours. RT contributes to improved local control and prolonged progression-free survival in patients with a broad range of tumour types. Irradiation to the normal brain may lead to cognitive impairments. Clarifying the nature and severity of impairment in adult RT-treated brain tumour patients, including region-specific effects, are important for optimal utilization of novel conformal RT technologies such as proton therapy.

The study is a prospective nationwide study including approximately 300 brain tumour patients from the Danish Center of Particle Therapy and the four Neuro Oncology Centers in Denmark.

The patients will be assessed with a comprehensive battery of standardized cognitive tests and complete a questionnaire (PRO's). They will do this prior to RT treatment and 1, 3, 5 and 10 years afterwards. The PRO's includes measures on quality of life, fatigue, sleep, depression, anxiety, and socio demographics. The standardized tests are: Trail making Test (TMT); Hopkins Verbal Learning Test (HVLT); Controlled Oral Word Association Test (COWAT) - Animals and S; Coding and Digit Span from WAIS-IV. The correlation between cognitive scores and RT dose-volume parameters to specific areas in the brain will be tested.

This study will elucidate the dose-response relationship in radiation-induced damage to substructures of the brain such as hippocampus, thalamus, temporal and frontal lobes that will allow the clinician to prioritize these structures in planning of proton radiotherapy.

Cognitive Function After Radiation Therapy for Primary Brain Tumours

Examined by the Hopkins Verbal Learning Test revised. It will be correlated to the mean radiation dose to the hippocampus. Outcome is number of correct words (0-24)

Examined by the Trail making Test part A (TMT_A). Outcome for TMT_A is time in seconds (0-120 seconds).

Examined by the Coding from Wechsler Adult Intelligence Scale (WAIS-IV). Outcome for Coding is number of correct (within 2 minutes) (0-100)

Examined by Wechsler Adult Intelligence Scale (WAIS_IV_digit_span). Outcome on WAIS digit span is number of correct (0-36)

Examine by the Hopkins Verbal Learning Test revised (HVLT-r) - total and delayed. Outcome is number of correct words (0-24)

Examined by the Controlled Oral Word Association Test (COWAT) - Animals and letter_S. Outcome is number of words produced in 1 minute (0-100)

Examined by Trail making Test part B (TMT_B). Outcome for TMT_B is time in seconds (0-300).

Examined by the STROOP colour and word test (STROOP). Outcome for STROOP is number of corrects (0-120)

Assessed by questionnaire; European organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) in order to examine the level of quality of life in brain tumour patients who has received radiation therapy. The total score is a number (0-100)

Assessed by EORTC Brain Neoplasm Questionnaire, BN20 (an addition to QLQ-C30 mentioned above) in order to measure side effects to radiation therapy for a brain tumour. the score is a number (0-100)

Assessed by questionnaire: Pittsburgh Sleep Quality INDEX, (PSQI) in order to explore the level of quality of sleep in brain tumour patients who has received radiation therapy. Outcome is a number (0-33)

Assessed by questionnaire: Functional Assessment of Chronic Illness Therapy (FACIT) - Fatigue scale (version 4) in order to explore the level of fatigue in brain tumour patients who has received radiation therapy. Outcome is a number (0-52)

Assessed by questionnaire: Hospital anxiety and depression Scale (HADS) in order to explore level of depression and anxiety in patients treated with radiation therapy for their brain tumour. Outcome is a number (0-56)

Assessed by questionnaire; Patient's Assessment of Own Functioning Inventory (PAOFI), in order to assess patients own perception of cognitive function. Outcome is a number (35-210)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Intraoperative MRI-guidance in Frameless Stereotactic Biopsies	NCT01779219	Primary Brain T...	iMRI-guided bra... Stereotactic fr...	18 Years -	Wroclaw Medical University
Cognitive Function After Radiation Therapy for Primary Brain Tumours	NCT04306432	Primary Brain T... Radiation Toxic... Cognitive Impai...	Cognitive tests...	18 Years - 100 Years	University of Aarhus

Spots Global Cancer Trial Database for primary brain tumour