Varallyay P, Nesbit G, Muldoon LL, et al. Comparison of Two Superparamagnetic Viral-Sized Iron Oxide Particles Ferumoxides and Ferumoxtran-10 with a Gadolinium Chelate in Imaging Intracranial Tumors. AJNR Am J Neuroradiol 2002;23:510–19

This early clinical paper compared 2 different iron oxide nanoparticle contrast agents with gadolinium-based contrast agents (GBCA) using standard MRI sequences to assess anatomic characteristics of intracerebral neoplasms including location, size, and extent.

Different central nervous system pathologies can appear to be similar anatomically on MRI. GBCA-contrast-enhanced T1-weighted MRI represents information regarding the integrity of the blood-brain barrier, rather than the physiology of the brain lesions. Therefore, noninvasive imaging tools to assess pathophysiologic characteristics of CNS lesions are desirable. I am particularly interested in tumor angiogenesis assessment due to my neurosurgery/neuro-oncology background. Angiogenesis is one of the key elements of tumor growth and the target of multiple newly developed medications, yet it cannot be assessed just by using anatomic MRI sequences. Cerebral blood volume (CBV) measurement by perfusion-weighted MRI allows noninvasive measurement of tumor angiogenesis. Accurate CBV measurement using a standard dynamic susceptibility contrast MRI modeling approach relies on intravascular localization of contrast agent in the tissue of interest. This condition is compromised by the leaky BBB present within malignant brain tumors, especially after radiation and chemotherapy. Rapid extravasation of standard GBCA from blood vessels into the extravascular/extracellular space can lead to underestimation of CBV.  To improve the diagnostic accuracy of DSC MRI with GBCA, several methods have been proposed for leakage correction, such as the use of small flip-angle gradient-echo or dual-echo perfusion acquisitions, contrast preload methods, or postprocessing with multiple mathematic correction algorithms, but these still have a lack of consistency and reproducibility, and depend on magnetic field strength differences and MR pulse sequence details. Ferumoxytol iron oxide nanoparticles are confined to the blood pool for several hours after IV administration. The absence of ferumoxytol extravasation during DSC acquisition greatly simplifies modeling and evaluation of tumor angiogenesis.

A preclinical rodent study showed that brain tumor CBV was underestimated when GBCA was used in a human high-grade glioma intracerebral xenograft.¹ The accuracy of the CBV measurement was improved by using the GBCA preload leakage correction method; however, CBV values depended on the dose of contrast agent preload. Using ferumoxytol for DSC MRI in the same animals, we obtained consistent CBV estimation regardless of the permeability of the tumor vasculature independent of contrast agent preload (Figure 1).¹

Accuracy, consistency, and simplicity of processing of perfusion MRI with ferumoxytol are clinically important. For instance, radiographic worsening in patients after radiation therapy with or without chemotherapy and with or without clinical deterioration can be caused by true tumor progression or pseudoprogression. Unlike true tumor progression, MRI signal changes in pseudoprogression reflect treatment-induced inflammatory change with increased permeability of the BBB. These changes recover or stabilize spontaneously, generally without altering patient treatment regimens, and are associated with a favorable prognosis. The inability to reliably differentiate tumor progression from pseudoprogression can lead to continuation of ineffective therapy or early discontinuation of chemotherapy; it can cause inclusion of patients with pseudoprogression in experimental protocols, with further false-positive response to experimental treatment. Two recent studies showed the clinical benefit of perfusion MRI with ferumoxytol for CBV assessment in the differential diagnosis of true tumor progression and pseudoprogression (Figure 2).^2,3  We introduced dual-contrast imaging during a single MRI session: GBCA for BBB integrity assessment, and ferumoxytol for CBV assessment. The dual-contrast imaging that we pioneered is just the beginning of a multicontrast imaging era when different contrast agents will be applied for specific purposes, such as to confirm or rule out certain tumor types, establish the presence and magnitude of inflammation, or evaluate angiogenesis.

References

1. Gahramanov S, Muldoon LL, Li X, et al. Improved perfusion MR imaging assessment of intracerebral tumor blood volume and antiangiogenic therapy efficacy in a rat model with ferumoxytol. Radiology 2011;261:796–804. doi: 10.1148/radiol.11103503
2. Gahramanov S, Raslan A, Muldoon LL, et al. Potential for differentiation of pseudoprogression from true tumor progression with dynamic susceptibility-weighted contrast-enhanced magnetic resonance imaging using ferumoxytol vs. gadoteridol: a pilot study. Int J Radiat Oncol Biol Phys 2011;79:514–23. doi: 10.1016/j.ijrobp.2009.10.072
3. Gahramanov S, Muldoon LL, Várallyay CG, et al. Pseudoprogression of glioblastoma after chemo- and radiation therapy: diagnosis by using dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging with ferumoxytol versus gadoteridol and correlation with survival. Radiology 2013;266:842–52. doi: 0.1148/radiol.12111472