Combidex the Detective: Where has the Cancer Spread?

MARK SCHOLZ, MD

In our book, Invasion of the Prostate Snatchers, Ralph Blum and I devoted a chapter to the heartbreaking story of how Combidex, a revolutionary way to detect cancerous lymph nodes, was shot down by the FDA.  Detecting cancer in the lymph nodes is the Holy Grail of cancer scanning because the lymph nodes are the first place prostate cancer usually spreads if it leaves the prostate.  Standard CT scans fail to detect cancer until the tumorous nodes are bulging with cancer.

The early detection of lymph node metastases has become a much higher priority now that lymph nodes can be safely targeted with modern radiation.  In the past, with older radiation, side effects were excessive due to collateral damage to the intestines.

 

At Prostate Oncology Specialists we have had reasonably good results imaging lymph nodes with C¹¹ acetate PET scans performed by Dr. Fabio Almeida in Phoenix.  Also, Choline PET scans have been used with success at the Mayo Clinic. However, even with PET scans there needs to be minimum amount of tracer present in the lymph node before it reaches the threshold of detectability. Therefore, PET scans may be unable to detect metastatic nodes until the cancerous nodules are more than 6 mm in diameter.  Studies evaluating intravenous Combidex in conjunction with MRI scanning indicate that normal lymph nodes can be distinguished from metastatic nodes even when the metastases are as small as 3 mm. In one study comparing Combidex with Choline PET scans, Combidex was more accurate at detecting metastatic nodes.

 

I am raising the matter of Combidex in this blog because now, for the first time in years, Combidex has become commercially available again in Europe.  Dr. Jelle Barentsz from the University in Nijmegen has been able to purchase all rights to Combidex along with all the documents and files from the original manufacturer. Unfortunately, as yet there are no sites in the United States that offer Combidex.

 

More than 50,000 men annually develop a cancer relapse after surgery or radiation.  A relapse is indicated by the presence of a rising PSA level in the blood. The rising PSA signals that cancer is present, but offers no indication about the location of the cancer in the body. New scans such as C¹¹ PET and Combidex-enhanced MRI have opened up a whole new realm of treatment possibilities. After all, if the cancer can be located, it creates a possibly for cure by targeting it with radiation.

 

We welcome the renewed availability of Combidex, thanks to the concerted efforts of Dr. Barentsz.

READ MORE ON COMBIDEX

Past Blogs by Ralph Blum
http://prostatesnatchers.blogspot.com/2012/11/life-after-combidex-part-1.html
http://prostatesnatchers.blogspot.com/2012/11/life-after-combidex-part-2.html
http://prostatesnatchers.blogspot.com/2012/12/blog-post.html

Latest PCRI Insights written by Jelle Barentsz, MD
http://prostate-cancer.org/detecting-lymph-node-metastases-combidex/

 

Life After Combidex - Part 2

BY RALPH BLUM

If after my long association with prostate cancer, I could achieve one objective—strike one blow for all the thousands of men facing the uncertainty of lymphatic involvement—it would be to see the presently FDA scorned and excommunicated compound “Combidex,” restored to favor, in production and universally available for the Combidex MRI.

This contrast fluid consists of minute Fe nanoparticles (iron particles) that are injected into a vein in the arm. After 24 hours, metastases in lymph nodes (LN) that show less “uptake” of the iron oxide nanoparticles, are visible as a white structure in a dark background, whereas normal nodes display as black and are thus not distinguishable. The white metastatic lymph nodes light up like light bulbs in the darkness, and can hardly be missed by the radiologist.

I do my due diligence: regular PSAs. But lately, I have been anxious; concerned that my immune system is no longer doing its job as well as it did in the past. True, I have no compelling evidence that my cancer is “on the move,” changing color by Mark’s Blue Scale, edging from “Sky” to “Teal” to “Azure”, with each deepening “Shade” bringing heightened  “Risk.” And yet sometimes in the night I wonder: Is that a swelling I feel in certain lymph nodes?

What makes this a period of greater insecurity is the absence of my old ally “Combidex”.  It wouldn’t be that difficult to set my mind at ease about whether or not there is lymphatic involvement if, as I did five years ago, I could again take myself off to the clinic of Dr. Jelle Barentsz, Professor of Radiology at Radboud University in Nijmegen, The Netherlands, and undergo a Combidex MRI.

There are other tests available. But from what I’ve seen of the stats, either they don’t do the job the way Combidex did, or more research is required. Still, here are four you might want to check out. I confess that I am out of my depth here, reporting as a non-medical voice without pretension of authority or a guarantee of accuracy:

1. 11C Choline PET CT while effective to a point, is not good in detecting nodes <5 mm. In this regard, Combidex was clearly superior.

2. Feraheme (ferumoxytol) is not as effective going to normal nodes as Combidex, and thus has a significantly higher number of false positives! Anyone who uses this agent for nodal imaging should be aware of this, So again, this substance is not a good substitute for Combidex.

3. The new Prostascint Imaging (Indium-111: Labeled Capromab Pendetide) which shows promise (it is more specific PSMA) but is still in its early phases of testing. Indications are that  Prostascint may be useful to evaluate post-prostatectomy patients with rising PSA who have an otherwise negative or equivocal workup for metastases. Another potential role for Prostascint (controversial) is in the staging of newly diagnosed prostate cancer.

What is worth doing? My mind is preoccupied with thoughts of risk (doing nothing) versus trauma (the ghastly side effects). I have long thoughts about the “velocity of change.” I meditate about risk versus trauma. And I pine for Combidex.

Perhaps my Better Angels have been on the job. Because just as I finished this blog, I received a note from Dr. Barentsz in the Netherlands, informing me that maybe—just maybe—Combidex is about to stage a come back. And asking for my help. Did he ever come to the right man! I will lay out the strategy in my final “Life After Combidex” blog.

Hot dog! Combidex redux!

Life After Combidex (Part 1)

BY RALPH BLUM

A few days ago I got an email bemoaning the demise of Combidex, and asking for a review of the situation, including what replacements were on the horizon. So in this Blog and the next, I will attempt to shed some light on the matter.

The most common areas of prostate cancer metastasis are the pelvic or abdominal lymph nodes and the bones, but detecting whether the cancer has spread to the lymph nodes is a problem, because no truly reliable diagnostic test for lymphatic involvement is currently available.

In 2007, when my Gleason score had gone from 6 to 7 and the cancer had arrived in the left seminal vesicle, I traveled to the Netherlands for a Combidex MRI. According to the makers, Advanced Magnetics, Inc. (now AMAG Pharma), Combidex, the brand name for ferumoxtran-10, could “assist in the differentiation between metastatic and non-metastatic lymph nodes in patients with confirmed primary cancer who were at risk for lymph node metastasis.” How it worked was that metastatic lymph nodes showed less “uptake” of the iron oxide nanoparticles. Fortunately for me, all my lymph nodes were clear. However (and it’s a long story that I detailed in Invasion of the Prostate Snatchers) the Combidex infusion MRI, by far the most reliable (better than 90% accurate) diagnostic test for lymph node detection, didn’t make it past the FDA watchdogs, and AMAG Pharma discontinued the production of ferumoxtran-10. So the Combidex MRI is presently no longer available anywhere.

The primary FDA-approved diagnostic test for detecting lymphatic involvement is the ProstaScint scan. Given by an intravenous injection, ProstaScint circulates throughout the body and attaches to prostate cancer cells. The injection contains a small amount of low-level radioactive material that is absorbed by the cancer cells and shows up as “hot spots.” But the findings are subtle, with a high risk of false positives, and an absolute necessity with the ProstaScint scan is an extremely experienced interpreter.

Meanwhile in Holland, Dr Jelle Barentsz, Professor of Radiology, UMC  St. Radboud,  Nijmegen, has been working on a validation study of Feraheme (made of nano-particles of iron) as a lymph node diagnostic agent. Feraheme is the contrast agent with which AMAG Pharma replaced Combidex, and Dr. Barentsz’ study is to find out if Feraheme is as good a contrast agent as Combidex. Currently Feraheme is only approved for treating patients with iron deficiency anemia or chronic adult kidney disease.

We desperately need better tests. The ability of oncologists to accurately detect lymph node involvement could signify a huge step forward in staging and, therefore, in making optimal treatment decisions for men with newly diagnosed and advanced prostate cancer.