Accurate staging of lymph node metastases has long been one of the most formidable challenges in oncology. Once the disease escapes the primary tumour, the stakes change entirely; this spread profoundly dictates treatment decisions, the patient's prognosis, and the eventual quality of life.
Unfortunately, our conventional tools—current standards such as CT, standard MRI, and even (PSMA) PET/CT—have significant blind spots. Because they rely predominantly on lymph node size or offer only limited functional resolution, they frequently overlook very small yet clinically critical metastases.
Against this backdrop, the true story of ferumoxtran comes into focus. Formerly known as ferumoxtran-10 or Combidex/Sinerem, this contrast agent represents far more than a scientific innovation. It embodies a 36-year odyssey of perseverance, unwavering scientific conviction, and sustained international collaboration.
Back in 1989, I recognized the immense clinical potential of this agent. Yet, its journey was nearly cut short. The industry was about to throw ferumoxtran away by abandoning the project after negative results from their suboptimally designed trials. Experiencing its potential to save lives and reduce morbidity I had, at that time, only one purpose:
‘to find a way to ensure it was not discarded.’
The true brilliance of ferumoxtran lies in its ability to make the invisible visible.
Ferumoxtran is an iron-based MRI contrast agent consisting of ultra-small iron oxide particles (USPIO). Following a slow intravenous infusion, these particles circulate in the bloodstream for an extended period. Their microscopic size (approximately 30 nanometers) allows them to pass through vessel walls, where they are actively "eaten" (taken up) by macrophages—the immune system’s scavengers.
This mechanism creates a clear and highly specific contrast between healthy and malignant lymph nodes. By effectively rendering the background tissue black, normal nodes fade from the view, while pathological nodes stand out as distinct white spots—regardless of their size.
Both LNs are white
Abnormal LN
Green: normal LN
Large LN -> black, SmallLN -> white
The clinical impact is profound. Macrophage MRI (m-MRI) can detect lymph node micro-metastases as small as 2 mm, well below the detection limits of CT (>8 mm), standard MRI (>8 mm), or PSMA PET/CT (>5 mm). Its diagnostic performance is consistently strong, with sensitivities of 80–90% and specificities of 90–96% [1, 2].
This is critical because studies indicate that 40–60% of patients with prostate cancer have lymph node metastases located outside the extended surgical dissection field. Without m-MRI, these metastases would remain undetected and untreated, acting as silent time bombs that substantially increase the risk of disease recurrence [3, 4].
Ferumoxtran was originally developed in the United States in the late 1980s. Despite compelling scientific evidence—including the landmark publication by Harisinghani and Barentsz in The New England Journal of Medicine [5]—regulatory approval studies conducted up to 2007 failed to meet their endpoints.
It is crucial to understand that this failure was not due to the agent's lack of efficacy, but rather to the industry's suboptimal trial design.
Then everything collapsed. Escalating costs and the 2008 financial crisis drove major pharmaceutical companies to abandon the field.
Ferumoxtran was left orphaned, its future hanging by a thread—on the brink of vanishing entirely, taking with it a revolutionary way of seeing disease and a vital hope for patients.
What now.........?
At this critical moment, I refused to let the technology disappear.
Having worked with m-MRI since the 1990s, participated in multiple Phase III trials, and applied the agent to more than 1,000 patients worldwide, I recognised something truly transformative. m-MRI introduced a visionary new way of imaging: for the first time, a simple MRI-contrast agent allowed us to visualise cellular behaviour—specifically macrophage activity—rather than anatomy alone.
This shift from structural imaging to imaging of disease biology was not an academic advance, but a patient-centred breakthrough, enabling earlier and better detection of diseased tissue, enabling better risk stratification, and more precise, less invasive clinical decisions.
In an unprecedented act of conviction, I secured the global rights to ferumoxtran for Radboudumc and brought its production back to the Netherlands.
By placing this breakthrough agent under academic stewardship, I was able to save this unique form of imaging from extinction and protected patients from losing access to a transformative diagnostic tool.
This bold decision reignited clinical use, now rebuilt on state-of-the-art imaging protocols, uncompromising quality control, and a single guiding principle: better care through better vision.
To bring the agent to market, SPL Medical was founded in 2015 as a Radboudumc spin-off, with medical leadership provided by Dr Patrik Zamecnik and Dr Jürgen Feuerstein.
The definitive breakthrough arrived when the Bender Gruppe, through b.e.imaging GmbH, became the principal investor and strategic partner. They contributed the necessary funding, industrial expertise, and international distribution capabilities. This collaboration successfully united my academic vision with their industrial execution.
It is crucial to understand that this failure was not due to the agent lacking efficacy, but rather to the industry's suboptimal trial design. Consequently, because of expenses and the financial crisis in 2008, major pharmaceutical companies withdrew, and ferumoxtran came perilously close to disappearing altogether.
In 2020, the international PROSTAPROGRESS registration study was launched at leading academic centers across Europe. Unlike previous attempts, the study was specifically designed to overcome the methodological shortcomings of earlier trials.Key Results (March 2025):·
1. All primary and secondary endpoints were met.·
2. Ferumoxtran-MRI clearly outperformed conventional imaging, with significantly higher sensitivity and non-inferior specificity.·
3. High diagnostic accuracy was demonstrated even in lymph nodes as small as 2 mm.·
4. An excellent safety profile was confirmed.
Together, these results provided the definitive clinical evidence required for regulatory approval.
While we have finally brought this agent to the shores of clinical reality for prostate cancer, I believe we are merely scratching the surface of its true potential. My vision does not stop at what we have achieved today; it focuses on what we must achieve tomorrow.
To ensure this momentum continues, I intend to establish a specialized ferumoxtran “Macrophage-MRI Think Tank”. This group will guide this promising agent toward its full clinical capacity, exploring frontiers far beyond prostate lymph nodes:
The journey has been long, but the future is limitless.
If you are interested in participating in the 'Think Tank', please let me know (mri@jellebarentsz.com).
Ferumoxtran has transformed from an abandoned drug into a fully validated imaging technology. By recognizing its early potential back in 1990 and helping to guide its redevelopment when others had walked away, I have been fortunate to play a central role in this journey.
Today, thanks to the combined efforts of Radboudumc, SPL Medical, b.e. imaging, and Sanochemia, ferumoxtran is approaching market approval, expected by late 2026, or early 2027. This milestone promises more effective patient care, including a significant reduction in unnecessary surgeries.
After 36 years of perseverance, I am gratified that
my Odyssey is now nearing its conclusion.
Customer number: 9086342
