Blood-Brain Barrier Opening in Primary Brain Tumors with Non-invasive MR-Guided Focused Ultrasound: A Clinical Safety and Feasibility Study methods
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Introduction
Various methods to overcome the BBB have been investigated though each with disadvantages that preclude successful translation to patients. Direct intracranial injection or convection-enhanced delivery can improve drug concentrations at the target, but also have safety concerns of open surgery. Modification of therapeutics to bypass the BBB via human insulin receptors has been shown to have low spatial specificity and off-target effects posing safety concerns in non-human primate studies. Minimally invasive surgery is attractive to patients for improved recovery time and certain surgical risks such as hemorrhage and infection. Stereotactic radiation and MR-guided focused ultrasound (MRgFUS) are two minimally invasive methods of disrupting the BBB with high spatial resolution. Although increased BBB permeability is achievable with a small dose of radiation, the time frame to maximal...
Introduction
A surgically implanted pulsed ultrasound system has recently been used for BBB disruption in conjunction with systemic microbubbles. Carboplatin delivery through this method was well tolerated in patients with recurrent GBM, and was not associated with clinical or radiographic adverse events. MRgFUS is different in that it does not require open surgery and provides fine spatial control over the treatment field and uniformity of the BBB opening. Our primary objective is to determine the safety and feasibility of opening the BBB in peritumor brain tissue using transcranial low-intensity MRgFUS during the administration of systemic chemotherapy, with a secondary aim to quantify drug levels in sonicated and unsonicated tissue. This is the first report of targeted chemotherapy delivery using MRgFUS and has significant implications for future neuro-oncology and surgical trials and practice.
Results
All patients underwent MRgFUS BBB disruption procedure with no clinically significant ultrasound related clinical or radiologic adverse events (e.g. intracerebral haemorrhage or edema). Specifically, the sonication procedure itself was well tolerated with no new or worsening symptoms in the 24 hours between MRgFUS procedure and tumor resection. One patient aborted prior to the final sonication target due to back pain on the MRI table. Minor headache at the helmet attachment sites was reported in two patients; this resolved in both prior to the surgical procedure the following day. Following resection of right temporal tumor, patient one suffered a post-operative left superior quadrant hemianopsia from the sacrifice of a temporal artery traversing the tumor. The neurological exam post FUS and preceding surgery were normal. The surgically induced deficit resolved, and visual field...
Results
Sample T1 weighted post-gadolinium MRI from patient five obtained 30 days prior to BBB opening procedure (left), immediately following BBB disruption (middle) and 20 hours post BBB disruption (right). Ill-defined contrast enhancement is seen in the peritumoral region on images acquired immediately after MRgFUS (white arrows). This contrast enhancement has resolved in the peritumor region on the day 1 follow-up image indicating closure of the BBB. T2* sequence acquired immediately following BBB disruption for this patient show no evidence of microhemorrhages.
MR-guided focused ultrasound procedure
Following a full head shave, the participant's head was fitted with a stereotactic frame. One hour prior to sonication, participants were systemically administered a sub-therapeutic dose of chemotherapy. The administration was timed so the concentration would be maximal concentration at the expected time of BBB opening. The participant was placed supine on the MRI table, kept awake and given an emergency switch to abort the procedure in case of discomfort or pain. Anaesthesia services were available on standby to provide mild sedation or pain medication as needed.
MR-guided focused ultrasound procedure
Pre-sonication T1, T2 (Fast Spin Echo) and T2* MR sequences were acquired for baseline and target planning. The sonication volumes were delineated by a cubic 3-by-3 grid with 3 mm spacing, totalling approximately 9 × 9 × 6 mm 3. Fig. depicts production of the grid. Sonication volumes were placed at tumor margins aligned with the surgical trajectory for tumor resection the following day. Once the target regions were identified, the participant received an intravenous injection of Definity® (4 µl/kg) immediately preceding sonication at each target location. The total dose of Definity® did not exceed 20 µl/kg. Optimal power for BBB opening was calculated as 50% of the power at which cavitation signals were first detected using acoustic feedback from an incremental sonication power protocol. Each sonication was deliv...
MR-guided focused ultrasound procedure
Following the completion of sonications, a gadolinium enhanced T1-weighted MRI was performed to confirm BBB opening. Contrast enhancement at the targeted regions signified the end of the procedure. Participants were admitted to a neurosurgical ward for observation and for subsequent tumor resection the next day. A follow-up MRI with gadolinium was performed the morning after MRgFUS procedure prior to open surgery to ensure BBB closure. All patients underwent the planned craniotomy for tumor resection in the standard fashion.
Outcomes
A preliminary assessment of drug delivery feasibility using this technique was assessed by measuring the concentration of chemotherapy in tissue samples taken during surgery. Surgical resection of the tumor and sonicated and unsonicated peritumor tissues took place approximately 24 hours after chemotherapy administration and FUS. Prior to tumor resection, needle biopsy of the sonicated and unsonicated regions was performed using a frameless stereotaxic system. The targets were defined on the post sonication T1 with contrast enhanced MRI. The patients then underwent standard craniotomies and maximal safe tumor resection. Samples were stored at -80 °C. It should be noted that following the first participant, the protocol for chemotherapy agent was amended to more closely align the research methods with the clinical care. Participant 1 received intravenous liposoma...
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Evidence quotes (8)
Various methods to overcome the BBB have been investigated though each with disadvantages that preclude successful translation to patients. Direct intracranial injection or convection-enhanced delivery can improve drug concentrations at the target, but also have safety concerns of open surgery. Modification of therapeutics to bypass the BBB via human insulin receptors has been shown to have low spatial specificity and off-target effects posing safety concerns in non-human primate studies. Minimally invasive surgery is attractive to patients for improved recovery time and certain surgical risks such as hemorrhage and infection. Stereotactic radiation and MR-guided focused ultrasound (MRgFUS) are two minimally invasive methods of disrupting the BBB with high spatial resolution. Although increased BBB permeability is achievable with a small dose of radiation, the time frame to maximal disruption is unknown and recovery may take as long as 90 days.
A surgically implanted pulsed ultrasound system has recently been used for BBB disruption in conjunction with systemic microbubbles. Carboplatin delivery through this method was well tolerated in patients with recurrent GBM, and was not associated with clinical or radiographic adverse events. MRgFUS is different in that it does not require open surgery and provides fine spatial control over the treatment field and uniformity of the BBB opening. Our primary objective is to determine the safety and feasibility of opening the BBB in peritumor brain tissue using transcranial low-intensity MRgFUS during the administration of systemic chemotherapy, with a secondary aim to quantify drug levels in sonicated and unsonicated tissue. This is the first report of targeted chemotherapy delivery using MRgFUS and has significant implications for future neuro-oncology and surgical trials and practice.
All patients underwent MRgFUS BBB disruption procedure with no clinically significant ultrasound related clinical or radiologic adverse events (e.g. intracerebral haemorrhage or edema). Specifically, the sonication procedure itself was well tolerated with no new or worsening symptoms in the 24 hours between MRgFUS procedure and tumor resection. One patient aborted prior to the final sonication target due to back pain on the MRI table. Minor headache at the helmet attachment sites was reported in two patients; this resolved in both prior to the surgical procedure the following day. Following resection of right temporal tumor, patient one suffered a post-operative left superior quadrant hemianopsia from the sacrifice of a temporal artery traversing the tumor. The neurological exam post FUS and preceding surgery were normal. The surgically induced deficit resolved, and visual fields were full to confrontation at post-operative day 14.
Sample T1 weighted post-gadolinium MRI from patient five obtained 30 days prior to BBB opening procedure (left), immediately following BBB disruption (middle) and 20 hours post BBB disruption (right). Ill-defined contrast enhancement is seen in the peritumoral region on images acquired immediately after MRgFUS (white arrows). This contrast enhancement has resolved in the peritumor region on the day 1 follow-up image indicating closure of the BBB. T2* sequence acquired immediately following BBB disruption for this patient show no evidence of microhemorrhages.
Following a full head shave, the participant's head was fitted with a stereotactic frame. One hour prior to sonication, participants were systemically administered a sub-therapeutic dose of chemotherapy. The administration was timed so the concentration would be maximal concentration at the expected time of BBB opening. The participant was placed supine on the MRI table, kept awake and given an emergency switch to abort the procedure in case of discomfort or pain. Anaesthesia services were available on standby to provide mild sedation or pain medication as needed.
Pre-sonication T1, T2 (Fast Spin Echo) and T2* MR sequences were acquired for baseline and target planning. The sonication volumes were delineated by a cubic 3-by-3 grid with 3 mm spacing, totalling approximately 9 × 9 × 6 mm 3. Fig. depicts production of the grid. Sonication volumes were placed at tumor margins aligned with the surgical trajectory for tumor resection the following day. Once the target regions were identified, the participant received an intravenous injection of Definity® (4 µl/kg) immediately preceding sonication at each target location. The total dose of Definity® did not exceed 20 µl/kg. Optimal power for BBB opening was calculated as 50% of the power at which cavitation signals were first detected using acoustic feedback from an incremental sonication power protocol. Each sonication was delivered at 0.74% duty cycle for 50 seconds, and further details are described by Huang et al..
Following the completion of sonications, a gadolinium enhanced T1-weighted MRI was performed to confirm BBB opening. Contrast enhancement at the targeted regions signified the end of the procedure. Participants were admitted to a neurosurgical ward for observation and for subsequent tumor resection the next day. A follow-up MRI with gadolinium was performed the morning after MRgFUS procedure prior to open surgery to ensure BBB closure. All patients underwent the planned craniotomy for tumor resection in the standard fashion.
A preliminary assessment of drug delivery feasibility using this technique was assessed by measuring the concentration of chemotherapy in tissue samples taken during surgery. Surgical resection of the tumor and sonicated and unsonicated peritumor tissues took place approximately 24 hours after chemotherapy administration and FUS. Prior to tumor resection, needle biopsy of the sonicated and unsonicated regions was performed using a frameless stereotaxic system. The targets were defined on the post sonication T1 with contrast enhanced MRI. The patients then underwent standard craniotomies and maximal safe tumor resection. Samples were stored at -80 °C. It should be noted that following the first participant, the protocol for chemotherapy agent was amended to more closely align the research methods with the clinical care. Participant 1 received intravenous liposomal doxorubicin, and the remaining received TMZ.
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