By: Dan Sperling, MD

Multiparametric magnetic resonance imaging (mpMRI) reveals cancer by detecting functional characteristics of tumor cells, such as the restricted movement of water molecules, that differentiate them from healthy cells. In certain MRI scan procedures, a contrast agent is injected into the body that is engineered to be taken up selectively by tumor cells or immune system component cells that are attacking cancer cells; such contrast agents “enhance” (show up) on the MRI scan in a way that reveals the cancer. This article describes one such agent called Combidex® that is able to identify very early prostate cancer (PCa) that has spread to the lymph nodes, and that is too small to be picked up by other types of imaging.

When patients are at higher risk for spread, or metastasis, one of the first places to which the cancer can travel is the lymph nodes in the pelvic bed and groin. A rising PSA after may be a warning of metastasis, but actually finding PCa in the lymph nodes is very difficult. When patients are suspected of lymph node metastasis, they are often recommended for an exploratory surgical procedure called pelvic lymph node dissection (PLND). This is an invasive, painful and costly procedure used for manual exploration of hard lymph nodes, which are then removed for lab analysis (histopathology). An alternative to PLND is CT scanning, but this can only visualize positive nodes that are greater than 8 mm. Thus, it remains a challenge is to identify lymph node tumors when a treatment like radiation has the greatest chance of success, with minimal side effects for the patient. This is where Combidex comes in.

Combidex is an injectable IV fluid containing nanoparticles of iron (ferumoxtran-10) combined with a sugar compound that is selectively taken up by macrophages within 24 hours of infusion. Macrophages are special cells that are part of the immune system and are largely located in lymph nodes where they exercise anti-tumor activity against any cancer cells that begin to grow there (this is true for most cancers that travel to lymph nodes, such as breast cancer or head and neck cancers). When Combidex is present in macrophages, these cells enhance on MRI scans, showing the location of tumor activity. Additionally, macrophages are found in inflammations, so Combidex can be used with brain MRIs to identify the kind of neurological inflammation that is indicative of multiple sclerosis, aiding in diagnosing that noncancerous degenerative disease.

Numerous animal and human clinical studies throughout the 2000s have demonstrated the superior performance of Combidex-MRI over CT and PET scans, and these have involved other cancers and conditions besides PCa. The arguable global authorities in the use of Combidex to detect early lymph node PCa metastasis are the experts at Radboud University Nijmegen Medical Center (RUNMC) in Nijmegen, The Netherlands. Research led by Jelle Barentsz, MD, Professor of Radiology and his colleagues leads the body of published results on Combidex for detecting PCa lymph node spread. Two studies illustrate the work of the Dutch researchers:

1. The team compared tested ferumoxtran-10-enhanced T2-weighted MRI imaging at two different magnet strengths, 1.5 Tesla vs. 3.0 Tesla (weaker vs. stronger). Their purpose was to compare lymph node image quality.[i] (Ferumoxtran-10 is the scientific name for Combidex.) The study involved 48 PCa patients whose pelvic imaging was done under both types of magnet 24 hours after the infusion with the contrast agent. Three different readers evaluated the images for “total image quality, lymph node border delineation, muscle-fat contrast, and vessel-fat contrast.” Not surprisingly, the imaging done on the 3T magnet produced better quality of lymph node differentiation. The authors concluded, “Ferumoxtran-10-enhanced MR imaging can be performed at high magnetic field strengths and results in improved image quality, which may lead to improved detection of small positive lymph nodes.”
2. The Radboud team designed a study to evaluate how well the same type of imaging, with the same contrast agent, could depict lymph node metastasis outside the routine pelvic lymph node dissection (PLND) area.[ii] Existing evidence pointed to the ability of Combidex to detect positive lymph nodes within the PLND but the team wanted to discover how well their imaging could pick up positive nodes beyond the surgical zone. This large study (296 patients at four hospitals) examined men at known risk for lymph node spread based on their clinical factors. Nodes that appeared positive for PCa were identified as being inside or outside the routine PLND area. Patients found to have image-suspected nodes had them removed or biopsied for lab analysis (histopathology). The authors report positive image-based findings in 58 patients; and 44 were subsequently confirmed for PCa metastasis based on histopathology (the remaining 14 turned out to be false positives on imaging, as their lab results were negative for PCa). Of the 44 confirmed patients, 18 (41%) had nodes outside of the routine PLND area; in another 18 patients, positive nodes were picked up both inside and outside the area. In the remaining 8, the MR scans showed only nodes within the PLND area. The authors concluded, “In 41% of patients with prostate cancer, nodal metastases outside the area of routine PLND were detected by using MR imaging with ferumoxtran-10.”

Despite these and many other promising clinical papers supporting the use of Combidex-MRI, the U.S. Food and Drug Administration has failed to approve it in this country. In 2008, the U.S. manufacturer, AMAG Pharmaceutical, discontinued production of the contrast agent. However, in 2013, AMAG sold the exclusive technology and development rights to the Radboud center. Dr. Jelle Barentsz contacted a European consortium called BioConnection which has been able “to build the perfect development and production chain in an economical and timewise efficient way…”[iii]

Dr. Barentsz is now organizing international prospective clinical trials with a goal toward broad  approval of Combidex in both in the U.S. and the European Union. Dr. Barentsz is confident that Combidex will revolutionize the detection of early lymph node metastasis.

NOTE TO READER: Combidex-MRI is available in Nijmegen, The Netherlands. If you or someone you know is interested, the Sperling Prostate Center can assist with contacting Dr. Barentsz and his team to arrange a scan.

[i] Heesakkers RA, Fütterer JJ, Hövels AM et al. Prostate cancer evaluated with ferumoxtran-10-enhanced T2*-weighted MR Imaging at 1.5 and 3.0 T: early experience. Radiology. 2006 May;239(2):481-7.

[ii] Heesakkers RA, Jager GJ, Hövels AM et al. Prostate cancer: detection of lymph node metastases outside the routine surgical area with ferumoxtran-10-enhanced MR imaging. Radiology. 2009 May;251(2):408-14.

[iii] http://www.bioconnection.eu/about-us/news/50-bioconnection-builds-and-leads-dutch-cooperation-for-new-radboud-university-compound-combidex