Abstract
Background
Intra-arterial administration of chemotherapy with or without osmotic blood–brain barrier disruption enhances delivery of therapeutic agents to brain tumors. The aim of this study ...is to evaluate the safety of these procedures.
Methods
Retrospectively collected data from a prospective database of consecutive patients with primary and metastatic brain tumors who received intra-arterial chemotherapy without osmotic blood–brain barrier disruption (IA) or intra-arterial chemotherapy with osmotic blood–brain barrier disruption (IA/OBBBD) at Oregon Health and Science University (OHSU) between December 1997 and November 2018 is reported. Chemotherapy-related complications are detailed per Common Terminology Criteria for Adverse Events (CTCAE) guidelines. Procedure-related complications are grouped as major and minor.
Results
4939 procedures (1102 IA; 3837 IA/OBBBD) were performed on 436 patients with various pathologies (primary central nervous system lymphoma 26.4%, glioblastoma 18.1%, and oligodendroglioma 14.7%). Major procedure-related complications (IA: 12, 1%; IA/OBBBD: 27, 0.7%; P = .292) occurred in 39 procedures including 3 arterial dissections requiring intervention, 21 symptomatic strokes, 3 myocardial infarctions, 6 cervical cord injuries, and 6 deaths within 3 days. Minor procedure-related complications occurred in 330 procedures (IA: 41, 3.7%; IA/OBBBD: 289, 7.5%; P = .001). Chemotherapy-related complications with a CTCAE attribution and grade higher than 3 was seen in 359 (82.3%) patients.
Conclusions
We provide safety and tolerability data from the largest cohort of consecutive patients who received IA or IA/OBBBD. Our data demonstrate that IA or IA/OBBBD safely enhance drug delivery to brain tumors and brain around the tumor.
We used dynamic MRI to evaluate the effects of monoclonal antibodies targeting brain tumor vasculature. Female athymic rats with intracerebral human tumor xenografts were untreated or treated with ...intetumumab, targeting αV-integrins, or bevacizumab, targeting vascular endothelial growth factor (n = 4-6 per group). Prior to treatment and at 1, 3, and 7 days after treatment, we performed standard MRI to assess tumor volume, dynamic susceptibility-contrast MRI with the blood-pool iron oxide nanoparticle ferumoxytol to evaluate relative cerebral blood volume (rCBV), and dynamic contrast-enhanced MRI to assess tumor vascular permeability. Tumor rCBV increased by 27 ± 13% over 7 days in untreated rats; intetumumab increased tumor rCBV by 65 ± 10%, whereas bevacizumab reduced tumor rCBV by 31 ± 10% at 7 days (P < .001 for group and day). Similarly, intetumumab increased brain tumor vascular permeability compared with controls at 3 and 7 days after treatment, whereas bevacizumab decreased tumor permeability within 24 hours (P = .0004 for group, P = .0081 for day). All tumors grew over the 7-day assessment period, but bevacizumab slowed the increase in tumor volume on MRI. We conclude that the vascular targeting agents intetumumab and bevacizumab had diametrically opposite effects on dynamic MRI of tumor vasculature in rat brain tumor models. Targeting αV-integrins increased tumor vascular permeability and blood volume, whereas bevacizumab decreased both measures. These findings have implications for chemotherapy delivery and antitumor efficacy.
Brain metastases commonly occur in patients with breast, lung and melanoma systemic cancers. The anti- alpha sub(V) integrin monoclonal antibody intetumumab binds cell surface proteins important for ...adhesion, invasion and angiogenesis in the metastatic cascade. The objective of this study was to investigate the anti-metastatic effect of intetumumab in a hematogenous breast cancer brain metastasis model. Female nude rats received intra-carotid infusion of human brain-seeking metastatic breast cancer cells (231BR-HER2) and were randomly assigned into four groups: (1) control; (2) intetumumab mixed with cells in vitro 5 min before infusion without further treatment; (3) intetumumab intravenously 4 h before and weekly after cell infusion; (4) intetumumab intravenously weekly starting 7 days after cell infusion. Brain metastases were detected by magnetic resonance imaging (MRI) and immunohistochemistry. Comparisons were made using the Kruskal-Wallis test and Dunnett's test. Survival times were estimated using Kaplan-Meier analysis. All control rats with brain tissue available for histology (9 of 11 rats) developed multiple brain metastases (median = 14). Intetumumab treatment either in vitro prior to cell infusion or intravenous before or after cell infusion prevented metastasis formation on MRI and decreased the number of metastases on histology (median = 2, p = 0.0055), including 30 % of animals without detectable tumors at the end of the study. The overall survival was improved by intetumumab compared to controls (median 77+ vs. 52 days, p = 0.0277). Our results suggest that breast cancer patients at risk of metastases might benefit from early intetumumab treatment.
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e13001
Background: Radiation therapy with concomitant temozolomide (TMZ) followed by 6 months of adjuvant TMZ is standard of care in newly diagnosed glioblastoma multiforme (GBM). The ...6-month time frame for adjuvant TMZ was chosen arbitrarily and the optimal duration of TMZ chemotherapy remains undefined. In addition, the duration of TMZ chemotherapy and survival can be affected by uncertainty in differentiating pseudoprogression (Ps), indicating necrosis/inflammation, from true tumor progression. This IRB-approved retrospective study determined the survival of GBM patients treated with chemoradiotherapy (CRT) and adjuvant TMZ continued until tumor progression. Methods: Patients with biopsy-proven newly diagnosed GBM at Oregon Health and Science University from January 2006 to June 2012 were treated with upfront CRT followed by adjuvant TMZ without Pneumocystis jirovecii pneumonia prophylaxis until tumor progression. Diagnosis of Ps was made by relative cerebral blood volume (rCBV) estimation based on perfusion MRI with ferumoxytol or RANO criteria. Survival was determined using Kaplan-Meier product limit analysis. Results: A total of 67 patients were included. Overall median survival in the whole group was 21.3 months (95% CI 17.3, 26.3), significantly higher than the median survival in Stupp et al (2008) (14.6 months; 95% CI 13.2, 16.8). However 46 (69%) patients of our series received bevacizumab. Ps was diagnosed in 17 of 47 patients underwent ferumoxytol perfusion MRI based on rCBV measurement; 4 additional Ps cases were diagnosed based on RANO criteria. Median survival in the 21 patients with Ps was 49.1 months, though the estimate may be unstable due to the small sample size and 12 patients remain alive. Median TMZ cumulative dose for all patients was 5250 mg/m
2
(range 2250 to 64000). Conclusions: The increase in median survival compared to historical data supports the continuation of adjuvant TMZ treatment, especially in patients with Ps. Differentiation between true tumor progression and Ps is important for treatment (TMZ) decisions and may affect survival. Ferumoxytol perfusion MRI may help as diagnostic tool.
The accurate mapping of the tumor blood volume (TBV) fraction (
v
b) is a highly desired imaging biometric goal. It is commonly thought that achieving this is difficult, if not impossible, when small ...molecule contrast reagents (CRs) are used for the
T
1-weighted (Dynamic-Contrast-Enhanced) DCE-MRI technique. This is because angiogenic malignant tumor vessels allow facile CR extravasation. Here, a three-site equilibrium water exchange model is applied to DCE-MRI data from the cerebrally-implanted rat brain U87 glioma, a tumor exhibiting rapid CR extravasation. Analyses of segments of the (and the entire) DCE data time-course with this “shutter-speed” pharmacokinetic model, which admits finite water exchange kinetics, allow TBV estimation from the first-pass segment. Pairwise parameter determinances were tested with grid searches of 2D parametric error surfaces. Tumor blood volume (
v
b), as well as
v
e (the extracellular, extravascular space volume fraction), and
K
trans (a CR extravasation rate measure) parametric maps are presented. The role of the Patlak Plot in DCE-MRI is also considered.
This retrospective study determined the survival of glioblastoma patients with or without pseudoprogression.
A total of 68 patients were included. Overall survival was compared between patients ...showing pseudoprogression (in most cases diagnosed using perfusion MRI with ferumoxytol) and in patients without pseudoprogession. MGMT methylation status was also analyzed in the pseudoprogression cases.
Median survival in 24 (35.3%) patients with pseudoprogression was 34.7 months (95% CI: 20.3-54.1), and 13.4 months (95% CI: 11.1-19.5) in 44 (64.7%) patients without pseudoprogression (p < 0.0001). The longest survival was a median of 54.1 months in patients with combination of pseudoprogression and (MGMT) promoter methylation.
Pseudoprogression is associated with better outcome, especially if concurring with MGMT promoter methylation. Patients never diagnosed with pseudoprogression had poor survival. This study emphasizes the importance of differentiating tumor progression and pseudoprogression using perfusion MRI.
A CT scan demonstrated that 13.3 cm of the 23 cm metallic pipe extended through his right orbit though his anterior cranial fossa, into the middle cranial fossa (figure 2). Removal of metal pipe ...followed by head CT scan for making decision regarding decompressive craniectomy. Following the dural opening, contused hemorrhagic temporal lobe was found to be budging out under high pressure. ...a partial temporal lobectomy was performed, which allowed access to the tip of the metal pipe intracranially, with exposure of the frontal and temporal lobes, as well as anterior and middle fossa floors (figure 3).
Brain metastases commonly occur in patients with breast, lung and melanoma systemic cancers. The anti-α^sub V^ integrin monoclonal antibody intetumumab binds cell surface proteins important for ...adhesion, invasion and angiogenesis in the metastatic cascade. The objective of this study was to investigate the anti-metastatic effect of intetumumab in a hematogenous breast cancer brain metastasis model. Female nude rats received intra-carotid infusion of human brain-seeking metastatic breast cancer cells (231BR-HER2) and were randomly assigned into four groups: (1) control; (2) intetumumab mixed with cells in vitro 5 min before infusion without further treatment; (3) intetumumab intravenously 4 h before and weekly after cell infusion; (4) intetumumab intravenously weekly starting 7 days after cell infusion. Brain metastases were detected by magnetic resonance imaging (MRI) and immunohistochemistry. Comparisons were made using the Kruskal-Wallis test and Dunnett's test. Survival times were estimated using Kaplan-Meier analysis. All control rats with brain tissue available for histology (9 of 11 rats) developed multiple brain metastases (median = 14). Intetumumab treatment either in vitro prior to cell infusion or intravenous before or after cell infusion prevented metastasis formation on MRI and decreased the number of metastases on histology (median = 2, p = 0.0055), including 30 % of animals without detectable tumors at the end of the study. The overall survival was improved by intetumumab compared to controls (median 77+ vs. 52 days, p = 0.0277). Our results suggest that breast cancer patients at risk of metastases might benefit from early intetumumab treatment.PUBLICATION ABSTRACT
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2077
Background: Ferumoxytol, an ultrasmall superparamagnetic iron oxide nanoparticle (USPIO), is approved for intravenous treatment of iron deficiency in chronic renal failure. The ...package insert warns of potential alterations of magnetic resonance imaging (MRI). Our initial animal studies provided evidence of USPIO uptake by macrophages and lymphoreticular cells suggesting its potential in CNS lymphoma (CNSL), post transplant lymphoproliferative disease, or CNS inflammation (i.e. multiple sclerosis). The mechanism of USPIO enhancement differs from gadolinium-based contrast agents (GBCA), which optimally image areas of increased vascular permeability. Methods: USPIO was administered as an MRI contrast agent to 20 patients with presumptive or de facto diagnosis of CNSL or CNS inflammation. Seventeen of 20 patients underwent both USPIO- and gadolinium-based MRI. Three patients received only USPIO due to risk of nephrogenic systemic fibrosis (NSF) with GBCA exposure. In the pilot phase of the study, patients were given the USPIO ferumoxtran-10 and subsequent patients were given a successor USPIO (ferumoxytol) which has improved pharmaceutical properties. All patients were monitored for adverse reactions. MRI scans were subsequently reviewed by a neuroradiologist. Results: No significant toxicities were seen. Thirteen of 17 patients who received both contrast agents showed equal numbers of enhancing lesions on postcontrast images. USPIO-based contrast revealed additional areas of enhancement in three of 17 patients that were not visible when GBCA was administered. In three patients more lesions were seen with GBCA. Examples of ferumoxytol utility include 1) improved targeting for surgical biopsy; 2) avoidance of NSF; 3) demonstrating enhancement related to macrophages within lesions; 4) correlating cerebral blood volume and CNS inflammation; 5) demonstrating pitfalls such as prolonged imaging changes (3 months) in one case due to intensive inflammation, which can simulate hemorrhage. Conclusions: These studies provide data about the utility and value of USPIO-based contrast imaging in CNSL and inflammatory CNS lesions that support a dual role for these agents beyond iron replacement.
Abstract
Objective: Agents that target tumor vasculature are gaining use as therapeutics for brain tumors. We used dynamic magnetic resonance imaging (MRI) to evaluate the vascular effects of the ...monoclonal antibodies bevacizumab, targeting vascular endothelial growth factor (VEGF), and intetumumab (CNTO 95), targeting αV integrins, in a rat model of lung cancer brain metastasis.
Methods: Female nude rats received intracerebral implantation of human LX-1 small cell lung carcinoma cells. At 10 days after tumor implantation, rats were untreated or treated with intetumumab (30 mg/kg IV) or bevacizumab (45 mg/kg IV) (n = 4-5 per group). MRI at 12T was performed prior to treatment and at 1, 3, and 7 days after treatment, using dynamic contrast enhanced (DCE) MRI with gadolinium-based contrast agent (GBCA), and dynamic susceptibility contrast (DSC) MRI with the blood pool iron oxide nanoparticle ferumoxytol. Tumor relative cerebral blood volume (rCBV) and permeability markers were assessed.
Results: Intetumumab increased brain tumor vascular permeability at 3 and 7 days after treatment on DCE-MRI, as determined by the ratio of maximum GBCA signal intensity to normal brain, a measure of the interstitial space volume fraction (ve), and time to peak enhancement, a surrogate for Ktrans, the rate constant for passive leakage across the blood-brain barrier. Intetumumab also increased tumor rCBV on DSC-MRI as compared to untreated controls. Tumors uniformly grew during the week assessment period. In contrast, bevacizumab decreased tumor permeability and rCBV, and slowed the increase in the volume of enhancing tumor on both T1-weighted and T2-weighted images, compared with controls.
Conclusions: The vascular targeting agents intetumumab and bevacizumab had diametrically opposite effects on dynamic MRI of tumor vasculature in a rat brain metastasis model. The αV integrin inhibitory antibody intetumumab appeared to increase tumor vascular permeability and blood volume, suggesting it may enhance chemotherapy efficacy by improving chemotherapy delivery to intracerebral tumors. Conversely, the effects of bevacizumab on tumor vasculature suggest it would actually decrease chemotherapy delivery, thereby minimizing chemotherapy efficacy.
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 649.
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