Glioblastoma multiforme constitutes the most common primary brain tumor and carries a grim prognosis for patients treated with conventional therapy including surgery, radiation therapy, and chemotherapy. There has been a recent revival of selective intra-arterial delivery of targeted agents for the treatment of glioblastoma multiforme. Because these agents are less toxic and their delivery leads to a higher tumor–drug concentration, this combination may provide a better outcome in patients with high-grade glioma. This article discusses early experiences in patients who received superselective intra-arterial cerebral infusion of bevacizumab, cetuximab, and temozolamide after blood–brain barrier disruption with mannitol.
Every year approximately 12,000 cases of glioblastoma multiforme (GBM) are newly diagnosed in the United States, constituting the most common primary brain tumor. GBM carries a grim prognosis with a 2-year survival rate after diagnosis of approximately 26.5%, even with a multidisciplinary treatment including surgical resection followed by radiation therapy and concomitant temozolomide. Once the tumor recurs, patients are treated with several chemotherapeutic agents, such as bevacizumab and irinotecan, which have been shown to improve progression-free survival and overall survival. Because treatment effects are modest and nothing to date has been shown to extend life satisfactorily, there is a great need for novel therapeutics. Several novel therapeutic modalities are under study and development, including immunotherapies involving tumor vaccines and selective intra-arterial (IA) delivery of chemotherapeutics.
Application of IA delivery of chemotherapeutics to treat malignant gliomas was introduced into clinical practice decades ago with the IA infusion of carmustine by an intracarotid approach. These early studies showed no survival difference between IA and intravenous administration and even revealed a high complication rate, such as white matter necrosis or blindness in patients treated with the IA approach, which most likely occurred as a result of unselective catheter use and direct infusion of toxic agents. Recently, however, modern specialized microcatheters are better able to selectively deliver drugs to distal tumor vessels to enhance local drug delivery. At our institution, we use specialized microcatheters for superselective infusion of bevacizumab, cetuximab, and temozolomide. Our phase I trial revealed that the use of IA bevacizumab after blood–brain barrier disruption (BBBD) for recurrent GBM is safe and well tolerated.
Here, we present a technical case series of patients who received IA delivery of bevacizumab, cetuximab, or temozolamide after BBBD with mannitol. We describe the technical aspects of the procedure and the hospital course and 1-month imaging. All patients were included in an Institutional Review Board–approved phase I clinical trial to determine safety and tolerability. These data support the rationale to export the results to larger studies to evaluate the efficacy of this modality.
Illustrative cases
Case One: BBBD/IA Bevacizumab
History and examination
The patient is a 52-year-old woman, who presented after subtotal resection of a right temporal lobe GBM in June 2009 at a community hospital followed by 2 months of radiation therapy and temozolamide chemotherapy. Chemotherapy was complicated by a hematologic toxicity including thrombocytopenia and neutropenia. In January 2010, there was evidence of tumor progression on magnetic resonance imaging (MRI). The subinsular enhancing component increased in size, whereas the right temporal lesion remained stable ( Fig. 1 A). Because of her history of neutropenia, additional temozolomide therapy was not recommended, and the patient entered our phase I trial for IA infusion of bevacizumab after BBBD with mannitol in February 2010.
IA treatment: technical description
After obtaining consent, the patient was placed in the supine position in the angiography suite under general anesthesia. The right common femoral artery was found by palpation, and a 19-gauge single-wall needle was inserted into this artery. We replaced the needle with a 6F catheter sheath connected to continuous heparin saline flush. Then, a 5F Torcon catheter was advanced into the right common carotid artery over a 0.035-in angled guidewire. A right common and internal carotid artery angiogram were performed to ensure anterograde flow. Intravenous heparin was then administered after measurement of a baseline activated clotting time (ACT). An Excelsior SL 10 microcatheter angled 45 degrees was then advanced into the right M1 segment over a Synchro 2 soft microwire. After removal of the microwire, 10 mL of 25% mannitol solution was infused for 2 minutes (see Fig. 1 B). Then, we infused 13 mg/kg of bevacizumab in 36 mL of saline for 36 minutes; postinfusion angiogram excluded arterial vessel damage.
Immediate postoperative course
Postoperative hospital course was unremarkable and immediate follow-up MRI demonstrated a decreased in size in the heterogenous enhancement of the right temporofrontal mass and decreased F-18 fluorodeoxyglucose (FDG) uptake on positron emission tomography scan in the same area (see Fig. 1 A).
Case Two: BBBD/IA Temozolamide
History and examination
A 40-year-old man who presented in the emergency room with a 2-week history of nausea, vomiting, lethargy, and lower-extremity weakness became bradycardic with loss of consciousness. MRI revealed a heterogenous enhancing mass in the parasagittal left frontal lobe. The patient underwent craniotomy and gross total resection of the left parasagittal frontal lesion and was started on 2 months of chemoradiation with temozolomide. In January 2011, the patient reported clinical progression with some blurry vision in the left eye. MRI revealed recurrent left frontal mass with increased involvement of the corpus callosum ( Fig. 2 A). At this point, the patient was enrolled in our Phase I IA temozolamide trial.
IA temozolamide treatment: technical description
In February 2011, the patient was consented for selective IA infusion of temozolamide after BBBD with mannitol. The right common femoral artery was palpated, and a 19-gauge needle was inserted and then exchanged for a 6F catheter sheath connected to a continuous heparin saline flush. A 6F Envoy catheter was then advanced into the left common carotid artery over a 0.035-in guidewire under fluoroscopic guidance. Diagnostic angiograms were performed for the left common and internal carotid arteries to ensure normal anterograde flow. Afterward, heparin was administered intravenously after measurement of a baseline ACT. Then, using roadmap guidance, an Excelsior SL 10 microcatheter angled to 45 degrees was advanced into the A1-A2 junction over a Synchro 2 soft microwire. After removal of this microwire, 10 mL of 25% mannitol was infused for 2 minutes (see Fig. 2 B). Then, 83 mL of temozolamide (199 mg) was infused for 60 minutes. Postinfusion angiography was performed to ensure no arterial injury had occurred. The catheter was then advanced into the right common carotid artery under fluoroscopic guidance. An angiogram was performed for the right common and internal carotid arteries to ensure normal anterograde flow followed by intravenous heparin. Just as for the left anterior cerebral artery, 10 mL of 25% mannitol and subsequent 22 mL of temozolamide (53 mg) was infused into the right A1 segment.
Immediate postoperative course
Postoperative hospital course was unremarkable and 1-month follow-up MRI is illustrated in Fig. 2 A, which demonstrated decrease in size of the cystic component of the left frontal mass and decreased FDG uptake in the left frontal parasagittal lesion.
Case Three: BBBD/IA Cetuximab
History and examination
This 61-year-old male patient presented with ataxia and memory difficulties and subsequently underwent resection of a posterior right parieto-occpital GBM in December 2008. Postoperatively, the patient underwent radiation therapy and temozolamide chemotherapy for only 6 weeks because of noncompliance. He was then continued on maintenance temozolamide for 6 months. In August 2009, the patient was started on bevacizumab in addition to temozolamide. While on this treatment regimen, the patient progressed on MRI, showing a 3.5-cm enhancement in the parietal lobe and new heterogeneous enhancement in the right posterior lobe. Irinotecan was added to his treatment. From March 2010 to July 2010, the patient also underwent gamma knife radiation. Bevacizumab was discontinued in August 2010. At that point, the patient reported visual deficit and decreased ambulation. He denied seizures or weakness. However, MRI revealed increased signal enhancement and mass effect within the right parietal, temporal, and occipital lobes ( Fig. 3 A). In September 2010, the patient underwent a right parietal craniotomy and subtotal resection of brain tumor by the senior author (J.B.). Postoperative MRI revealed persistent T2 hyperintensity in the left lateral thalamus and residual tumor. Pathology showed robust (70%) expression of epidermal growth factor receptor on immunohistochemistry.
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