By: Dan Sperling, MD

The majority of prostate cancer (PCa) cases that are diagnosed today are early stage, low-to-moderate risk lesions that are confined to the prostate gland. It is usually assumed at the time of treatment in such cases that the cancer has not begun to metastasize (spread). However, a minority of cell lines are highly aggressive; furthermore, not all PCa is diagnosed at an early stage. Rates of positive surgical margins following radical prostatectomy range from less than 20% for low-risk patients to nearly 40% for high-risk patients[i], suggesting a risk for future metastatic disease (though this does not always occur).

One pathway for PCa spread is the pelvic lymph system. During radical prostatectomy for moderate-to-high risk cases, the surgeon routinely removes a number of lymph nodes from the region closest to the gland in order to evaluate them for evidence of PCa. However, detecting early metastatic PCa in the lymph nodes apart from this surgery is difficult. When a patient is suspected of harboring lymphatic metastasis, surgical dissection to remove nodes is invasive and not without risk. On the other hand, imaging technology has not had a high degree of success in identifying PCa in the nodes. Although the size, shape and location of lymph nodes can be depicted by both CT and MRI scans, it is not uncommon for cancerous lymph nodes to appear as normal size, making it impossible to distinguish them from healthy nodes.

A promising imaging agent, ferumoxytol, is made up of nanoparticles (ultra small particles) of a particular iron oxide called magnetite. Iron oxides, which are molecules made up of iron and oxygen, occur throughout nature and are widely used in geological, biological and paint-related technologies.  Magnetite, from which ferumoxytol is derived, is a superparamagnetic iron oxide; when the nanoparticles are synthetically coated with polyglucose sorbitol carboxymethylether, the result looks like a fine black powder; for use in humans, the powder is blended with an injectable liquid. Currently, ferumoxytol under the trade name Feraheme is FDA approved for the intravenous treatment of iron deficiency anemia—diminished number of red blood cells due to too little iron in the body—in patients with chronic kidney disease.

Because of its iron component, ferumoxytol has metallic properties that allow its use as a contrast agent in magnetic resonance imaging (MRI). This is an “off-label use” because the FDA has not approved it for this purpose. Because it takes time to be taken up by the target tissues, ferumoxytol is injected into the patient about 15 hours before imaging.

Once in the body, it is taken up by normal lymph nodes and their immune system cells known as macrophages, but cancerous lymph node tissues do not take it up. On T2-weighted MRI, the healthy lymph nodes without cancer appear dark due to reduced signal intensity, but nodes with metastatic PCa remain bright, essentially a “negative space” enhancement effect. While ferumoxytol has not yet been approved for use as an imaging agent, in clinical studies has already demonstrated utility with MRI scans for neurological disorders such as brain tumors, stroke, epilepsy and multiple sclerosis.[ii]

A precursor of ferumoxytol, Ferumoxtram-10 (U.S. trade name Combidex), was studied in Europe with promising results when Combidex-enhanced MR images showing PCa-positive lymph nodes were compared with results from biopsy or surgery.[i]^{, [ii]} Despite the approval in several European countries for Combidex in the detection of lymph node metastasis, the FDA’s Oncology Drug Advisory Committee denied approval for the contrast agent in 2005.

[i] Harisinghani M, Barentsz J, Hahn P et al. Noninvasive detection of clinically occult lymph-node metastases in prostate cancer. N Engl J Med 2003 Jun;348:2491-2499.

[ii]Heesakkers R, Jager G, Hövels A et al. Prostate cancer: detection of lymph node metastases outside the routine surgical area with Ferumoxtran-10 – enhanced MR imaging. Radiol. 2009 May;251:408-414.

Today, notable research into the safety and utility of ferumoxytol is ongoing at the National Cancer Institute/National Institutes of Health.  There is existing data to support nanoparticle-enhanced MRI, including data showing high sensitivity (65-92%) and excellent specificity (93-98%).[i]  Most recently, at the 2015 Genitourinary Cancers Symposium (Feb. 26-28, Orlando, FL) a poster was presented by Anna M. Brown on behalf of her research team at NCI/NIH. It was titled “Ferumoxytol Enhanced MRI for Lymph Node Staging in Prostate Cancer.” She reported preliminary results on 11 patients from a continuing clinical trial (Number NCT02141490). Lymph nodes with metastatic prostate cancer were correctly identified in 8 of the 11 patients. Of 16 lymph nodes identified by imaging, “10 were true positives, one was false positive and one was false negative with 4 nodes pending validation…Ferumoxytol enhanced MRI shows promise in detecting malignant LNs [lymph nodes] with diameter >6mm in prostate cancer patients.”[ii]

The ability to noninvasively identify prostate cancer metastasis to the lymph nodes, or the absence of it, has profound implications for treatment planning. The use of iron oxide nanoparticles applies to the following situations:

• Pretreatment patients with localized Gleason 7 disease
• Pretreatment patients at risk for metastatic disease, based on PSA >20 and other clinical factors such as abnormal DRE or urinary symptoms
• Post-radical treatment patients with evidence of biochemical recurrence

Aside from patients with a known sensitivity/allergy to iron, ferumoxytol appears to be a safe and very accurate 3T mpMRI contrast agent for the detection of hidden prostate cancer spread to the pelvic lymph nodes.

[i] Evans SM, Millar JL, Feydenberg M et al. Positive surgical margins: rate, contributing factors and impact on further treatment: findings from the prostate cancer Registry. BJU Int. 2014 Nov;114(5):680-90.

[ii] Liu JV, Jobst BC (2013) Potential Uses of Ferumoxytol in the Magnetic Resonance Imaging of Epilepsy. J Radiol Radiat Ther 1: 1005.

[iii] Harisinghani M, Barentsz J, Hahn P et al. Noninvasive detection of clinically occult lymph-node metastases in prostate cancer. N Engl J Med 2003 Jun;348:2491-2499.

[iv]Heesakkers R, Jager G, Hövels A et al. Prostate cancer: detection of lymph node metastases outside the routine surgical area with Ferumoxtran-10 – enhanced MR imaging. Radiol. 2009 May;251:408-414.

[v] Fortuin AS, Smeenk RJ, Meijer HF, et al. Lymphotropic nanoparticle-enhanced MRI in prostate cancer: value and therapeutic potential. Curr Urol Rep. 2014 Mar;15(3):389.

[vi] Brown, Anna M et al. Ferumoxytol Enhanced MRI for Lymph Node Staging in Prostate Cancer. 2015 Genitourinary Cancers Symposium, Feb. 26-28, Orlando FL. Abstract 208. http://meetinglibrary.asco.org/content/141983-159