Metastasis is perhaps the word cancer patients dread the most—it indicates that their primary tumor has escaped its original boundaries, and that the cancer has now spread to remote parts of the body.
Back in September 2007, Life Extension reported on life-saving cancer therapies that had shown their effectiveness in clinical studies, but whose approval was blocked by the FDA. One of the therapies reviewed was a diagnostic procedure available in Europe called Combidex®. This technique uses magnetic resonance imaging together with a novel contrast agent and is more effective than more invasive surgical processes for revealing small and otherwise undetectable lymph node metastases in patients with cancer.
Combidex® has the power to revolutionize the diagnosis of metastatic cancer. Yet over a year since the original Life Extension article, this life-saving procedure still languishes in the FDA’s bureaucratic process.
In this article, we explore how this remarkable diagnostic breakthrough is helping physicians—and patients—in their quest for early identification and tracking of metastatic lesions…while there is still an opportunity to implement aggressive therapies to eradicate the disease.
Combidex®—Enhancing Images For Health
Dr. Jelle Barentsz is a world-renowned radiologist and expert in the diagnostic field of functional imaging, in which specialists use a variety of methods to actually see not only what internal structures look like, but also how they are functioning. Life Extension recently caught up with Dr. Barentsz on a busy afternoon in his office at the Radboud University Medical Center in Nijmegen, The Netherlands, where he is professor of radiology and chair for research in the Department of Radiology. Dr. Barentsz’s work has been instrumental in improving oncologists’ and surgeons’ ability to recognize early lymph node metastases in patients with prostate cancer—and much of his success is related to his use of a dramatic new way to use magnetic resonance imaging, or MRI.
“Worldwide, more than $40 billion is spent each year trying to track down cancer metastases, usually with studies that are unrevealing,” Barentsz says. “That often leaves patients with surgical exploration as their only option;” a costly, painful, and often ultimately unrewarding process. “Surgical exploration itself can miss up to 30-40% of metastases in prostate cancer patients,” Barentsz explains, “So there’s a compelling need for better ways to find these metastases.” His passion for improving patient care led Barentsz to his work with a revolutionary new contrast material called Combidex® (ferumoxtran-10), which is helping him and a few others locate metastases earlier and more reliably than by any other technique—including surgery. Radiologists use contrast materials routinely to help them see the differences between tissues and organs, and between healthy and diseased body parts; Barentsz and others have shown that Combidex® enhancement on MRI scanning “results in improved image quality, which may lead to improved detection of small positive lymph nodes.”1
“With Combidex®-enhanced MRI scans,” Barentsz observes, “We can pinpoint lymph nodes that have been infiltrated with cancer cells, and then direct our radiation oncology colleagues to the precise location of the diseased nodes. That gives them an unprecedented ability to deliver targeted radiation just to the cancerous tissue, reducing the total body dose of radiation and helping to minimize side effects.” This is a critical advantage, particularly in men who have already undergone treatment for prostate cancer and whose levels of the cancer marker PSA (prostate-specific antigen) have started to rise again, signaling a likely relapse. “If we can find nodes smaller than 8 mm [the size limit for other forms of imaging], we can actually improve on the performance of surgical exploration, and deliver life-saving treatment to these men at a much earlier stage in their relapse,” Barentsz says.
That ability could easily make surgical exploration unnecessary, as was dramatically demonstrated in one of Barentsz’s group’s most recent studies, published in September 2008.2 The study was conducted precisely to evaluate the performance of Combidex®-enhanced MRI against the most up-to-date CT scanners, in an effort to provide an alternative to a surgical procedure. The current “gold standard” for detection of lymph node metastases in prostate cancer patients is pelvic lymph-node dissection, an invasive procedure in which the surgeon literally explores the patient’s pelvic (lower abdominal) region by hand, feeling for the telltale hard lumps that represent cancer-ridden lymph nodes. It is obvious that even the finest surgeon in the world can miss a single affected node in this arduous procedure, which carries with it considerable expense, pain, and risk of complications.3,4 Barentsz’s group tested Combidex®-enhanced MRI lymphangiography (MRL, viewing of lymph nodes and vessels) against CT for the detection of those less-than-8 mm nodes that can so easily be missed on surgical exploration. They studied 375 patients in total, from 11 hospitals in the Netherlands, all of whom had prostate cancer with an intermediate or high risk of having lymph-node metastases based on standard risk-assessment techniques. All patients had MRL plus state-of-the-art CT scans looking for those small cancerous nodes, and all patients then underwent either pelvic lymph-node dissection or a needle biopsy to confirm the diagnosis.
The researchers then compared the results of the imaging studies (Combidex® MRL and CT) with the microscopic findings of tissue removed during surgery. Sixty-one patients (16% of the total) had lymph node metastases. CT scanning detected a miserable 34% of those nodes, while Combidex® MRL identified 82%—a remarkably significant difference. Even more importantly, from the patient’s and surgeon’s standpoint, Combidex®-enhanced MRL had a negative predictive value of 96% (CT was only 88%)—this means that with a negative MRL scan result, there is less than a 4% chance of actually having a lymph node metastasis. That number is much lower than the known 30-40% of nodes that can be missed by surgical exploration itself. The study group concluded, “after a negative MRL, the post-test probability of having lymph-node metastases is low enough to omit a pelvic lymph-node dissection.” In other words, Combidex® MRL can be used instead of invasive surgery to rule out malignant metastases in prostate cancer patients! That’s a huge benefit to patients and surgeons alike.
In fact, as Dr. Barentsz observes in a recently published review, the Combidex®-enhanced MRL technique “allows the detection of small and otherwise undetectable lymph node metastases in patients with prostate cancer. This has an important clinical impact, as the diagnosis will be more precise and less invasive to obtain. Subsequently, this will reduce morbidity and health care costs.”5
Combidex® MRL—Putting Magnetism to Work
We’ll review some of the other impressive body of literature on Combidex®-enhanced scans in a moment, but first we need to take a quick look at the technique itself—how does it work, what does it do, and how safe is it? These are important questions, and mirror the questions that government agencies such as the FDA are asking. Most scientists and radiologists are convinced—but according to Dr. Barentsz, because of some bureaucratic fumbling and an inadequately designed application, FDA approval has still not been granted to this important diagnostic modality.
Dr. Barentsz is among the few European physicians allowed to use Combidex® regularly while the EU’s regulatory agencies review the data. “I’m frustrated by the slow pace of bureaucracy, both in the US and the EU,” says Barentsz during our interview. “This is a damn good contrast agent that hasn’t been properly written up for review, and the regulatory agencies have conflicting and unrealistic expectations for how it should perform. So I’m one of a handful of people fighting this uphill battle to get MRL accepted in order for us to bring improved imaging to cancer patients. I want to see more educated physicians and patients so that we can expand the benefit of these studies to more people.”
We did a little exploring of our own, to better understand how Combidex® works to enhance MRI scans, and reviewed a substantial part of the rapidly growing literature on this promising and fascinating material. Let’s start with the “what is it” question. Combidex®, generically known as ferumoxtran-10, is a remarkable contrast material composed of a simple sugar compound, dextran, and an iron component named ultrasmall superparamagnetic iron oxide, abbreviated as USPIO.6 As the name might suggest, USPIO consists of extremely tiny crystals of iron (the order of 25-50 nanometers in diameter—that’s millionths of a millimeter and very close to the size of some individual molecules).6-9 At that tiny size, the iron crystals demonstrate their other vital characteristic: they become superparamagnetic, which means that individually they don’t act as magnets, but when exposed to an external magnetic field (as in an MRI scanner), they become powerfully magnetized, giving them the ability to influence the signal produced by tissue during a scan. And when USPIO crystals are injected into humans (and other animals), they are selectively taken up by scavenger cells called macrophages that are chiefly found in lymph nodes as well as other areas where inflammation is taking place.5,6
So the bottom line for Combidex® is that it goes more or less directly to where the macrophages are (lymph nodes and inflamed tissue), where it affects the appearance of just that tissue in an MRI scanner. That produces a powerful means of contrasting the macrophage-containing tissue with its surroundings—hence the term “contrast agent.”10 And since inflammation is such a vital part of so many chronic, age-related conditions, Combidex® holds the potential for dramatically improving our ability to see disease at a very high resolution in conditions as apparently diverse as cancer, atherosclerosis, multiple sclerosis, and stroke.6,11-15
What about safety? There have been a number of safety and efficacy trials of Combidex® to date, all with encouraging results. Researchers at the University of Washington School of Medicine reported one such trial in 2003, using Combidex® in 152 patients undergoing MRI imaging for diagnosis of metastases to lymph nodes.16 As with Barentsz’s own study, this group found a dramatic improvement in performance of the scans using Combidex®, and just 6% of patients reported each of the following side effects: headache, back pain, flushing, and itching. “These effects are exactly the same as one sees using standard contrast agents,” comments Dr. Barentsz, “And they all resolve rapidly when we stop the infusion.” This study’s authors also concluded that Combidex® was safe and effective.
A new safety concern about standard MRI contrast media has brought additional urgency to the study of Combidex®. Researchers in Oregon published their work on nephrogenic systemic fibrosis, a recently recognized severe complication associated with traditional MRI contrast media. It affects primarily patients with kidney disease, and can cause severe additional kidney damage. The Oregon group reported on safety studies with over 150 patients receiving Combidex®, finding that Combidex® has an excellent safety profile, even in patients with decreased kidney function.17 They concluded that USPIO agents like Combidex® are a viable option for patients at risk for nephrogenic systemic fibrosis—and that may open the door for a safer contrast medium for all patients.
Combidex®—Setting the Stage for Staging
Let’s turn now to the impressive clinical track record that Combidex®-enhanced scans are establishing for themselves. Because of the USPIO’s remarkable ability to be taken up by hungry macrophages, they wind up preferentially in lymph nodes, helping to “light up” these important structures and revealing both their size and their function at unprecedented resolution. Those features have made Combidex® especially useful in the vital process of staging, that is, in determining how advanced a cancer is as soon as the primary tumor has been detected.18-20 Most radiologists and oncologists agree that there is a need for more accurate staging techniques,21 because traditional imaging has relied primarily on size criteria to detect metastases, and since existing scans can’t even detect smaller, but still potentially malignant nodes, they are limited in their ability to identify early, potentially treatable, metastases.20
The use of superparamagnetic iron oxide as an MR contrast agent is actually nearly as old as MR scanning itself. In 1989, with MR scanners in use for less than a decade, radiologists at the Massachusetts General Hospital were already demonstrating their ability to identify metastases in lymph nodes of rats.22 They found a dramatic difference in the way healthy nodes appeared on scans compared with nodes containing cancerous metastases. They concluded that “MR lymphography may potentially increase the sensitivity of MR imaging the detection of lymphatic malignancy.”
The following year the same researchers expanded their work, demonstrating that they could detect node metastases based on the intensity of their appearance, rather than on the less useful size criteria then in widespread use.23 A year later, this productive research group showed that they could even see minute differences in structures within lymph nodes when using the new contrast material—particularly those regions of the nodes where macrophages are found.10 By 1994, French researchers had achieved the ability to determine whether an enlarged node was benign or malignant—a vital step towards accurate staging procedures.24
It took nearly a decade for this work to be translated into human use, but in 2003 the research group at the University of Washington had completed their study of 152 adults with cancer, demonstrating a clearly improved ability to identify patients who had no metastatic nodes.16 Their ability to detect patients with dangerous metastases was also improved, but by a somewhat smaller amount—clearly work remained to be done.
That work wasn’t long in appearing—in 2006, Portuguese radiologists reported a study of 20 patients with aggressive head and neck cancers, performing MR scans before and 24-36 hours after an infusion with Combidex®.25 Surgical exploration was carried out immediately following the second (enhanced) scans, to obtain actual tissue samples for comparison, with a total of 63 nodes being removed and examined. When the results were tabulated, the Combidex®-enhanced scans were shown to have identified 96% of the metastatic nodes, while the unenhanced scans only identified 64% of the metastatic nodes. Just as importantly, when a Combidex®-enhanced scan was negative, there was only a 3.2% likelihood of there actually being a malignant node, while the unenhanced scan missed 23.1%—a potentially deadly difference. The researchers strongly endorsed Combidex®-enhanced scans for nodal staging of head and neck cancers.
Radiologists back in Boston confirmed and extended this success rate in a study of 169 nodes removed from 77 patients with a total of nine different malignancies.19 They concluded that Combidex®-enhanced scans alone may be adequate (instead of surgery) for lymph node characterization in these patients—though they also pointed out the importance of having an experienced radiologist interpret the scans.
By early 2006, British surgical oncologists were able to publish a powerful meta-analysis (study of multiple studies) on the diagnostic precision of Combidex®-enhanced scanning for lymph node metastases.21 They evaluated a large number of high-quality published studies, and pooled the data on each study’s accuracy in identifying malignant nodes. The results are compelling and definitive: overall, the enhanced scans detected 88% of malignant nodes, and were falsely positive in only 4%; the overall accuracy (percent of times the scan “got it right”) was 96%. Compare those numbers with unenhanced MR scans, which detected only 63% of true malignancies, were falsely positive 7% of the time, and had an overall accuracy of just 84%. As we’ve seen, individual studies have now shown even better performance at correctly identifying malignant nodes—good enough performance that, in the right hands, surgeons are becoming comfortable relying on enhanced scans alone, rather than surgical exploration, to develop an accurate idea of the risk of metastatic cancer spread.
Of course, those patients who do turn out to have malignant nodes will require aggressive treatment to eliminate them—often targeted radiation and sometimes surgical intervention. In such cases, Combidex®-enhanced scans are of great value to surgeons in their pre-operative planning. In a remarkable study by Dr. Barentsz’s own research group in the Netherlands, urologists compared scans done without Combidex® to those done with the contrast material, and then compared those results to findings at surgery.26 They identified 122 benign and 50 malignant nodes in 58 patients with bladder cancer. As with the studies cited above, the researchers found that Combidex® produced a dramatic increase in their ability to detect metastatic nodes, from 76% to 96%. Even more stunning, however, was the finding that metastases as small as 4 mm (less than a quarter of an inch) were identified within normal-sized nodes—nodes that, based on size criteria alone, were completely missed on the standard scan. Shockingly, the Combidex®-enhanced scan revealed nodes that were actually missed during direct surgical exploration in two patients! “Combidex-enhanced scanning in this case actually increased our ability to detect malignant nodes over the existing ‘gold standard’ of surgery,” says Barentsz in a conversation with Life Extension. “We’ve extended this in our more recent work to outperform the standard risk assessment [the so-called Roach Formula27,28] by a factor of two,” he continues.
This dramatic increase in the conspicuousness of tumor-infested tissue has now been applied successfully to the evaluation of patients with cancers of the uterus,29 head and neck,25 kidney,30 breast,31 and liver;32 we can confidently expect to see its use further enhance our ability to understand the extent and severity of other cancers.