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!

Provenge Treatment for Prostate Cancer

BY MARK SCHOLZ, MD

In 2010, Provenge was approved by the FDA, the first approved prostate cancer treatment that functions by enhancing the immune system.  Over the last couple of years Provenge has been gaining popularity with oncologists and urologists as well as with patients. What has been surprising to me is how slowly doctors and patients have warmed up to the idea of using the immune system to fight prostate cancer. For years my patients have been taking handfuls of Graviola, Shitaki mushrooms, Pau de Arco and Esiac tea because of unsubstantiated claims of immune enhancement. Yet, when the FDA approved an effective immune treatment that prolongs life I was surprised that my patients needed to be convinced to use it. 

Why, you might ask, is there any hesitation in the first place?  Well, Provenge is certainly different from other anticancer therapies at least in one very distinctive way:  Whereas the effectiveness of most treatments is signaled by a drop in PSA, PSA levels usually don’t decline after Provenge.  Having supervised more than a hundred Provenge-treated men, I have certainly seen exceptional cases with dramatic PSA declines. However, this is not the general rule. Most of the time PSA continues rising after Provenge. So people start wondering, if PSA is not dropping, how can Provenge prolong survival?  People forget that even though Provenge is administered over a six-week period, once the immune system is activated, it keeps functioning indefinitely; it’s the gift that keeps giving for the rest of your life.  Therefore, even if Provenge only slows disease growth slightly, the inhibitory effect keeps accumulating over time. So over a period of years, even a mild effect can become substantial.

If the hypothesis that Provenge is inducing a mild, long-lasting anticancer effect is correct, men take Provenge at an earlier stage (who have a longer projected survival) should receive a bigger survival benefit than men treated at a later stage. To test this thought, Dendreon, the manufacturer of Provenge, analyzed data from the original studies that led to FDA approval. Please note:  the researchers did not compare the survival of men treated earlier versus the survival of men treated later.  Obviously, men treated at an earlier stage live longer.  No, what they did is compare survival of Provenge-treated men with earlier-stage disease with similar-stage placebo-treated men.  They did the same analysis (Provenge-treated men versus placebo-treated men) in men with later-stage prostate cancer and in men with disease “in between” early and late stage.  Early stage—low-intermediate stage, high-intermediate stage and late stage—was defined by PSA levels of less than 22, 22-50, 50-134, and greater than 134 respectively. The table below summarizes the results of their analysis.

	Patients Grouped by Baseline PSA
	≤22	22–    50	50–134	>134
Number patients	128	128	128	128
Survival  months:
Provenge	41.3	27.1	20.4	18.4
Placebo	28.3	20.1	15.0	15.6
Survival Difference:	13.0	7.1	5.4	2.8

 As can be seen from the table, all groups that were treated with Provenge showed a survival advantage compared to the same stage men treated with placebo.  However, when Provenge was given at an earlier stage, the survival advantages became larger. Men with the earliest stage (PSA < 22) lived 13 months longer than similar stage men who were placebo-treated. Men with advanced stage only lived a couple months longer than advanced-stage placebo-treated men. 

This pattern of improved survival with earlier stage disease seems to fit the hypothesis that the inhibitory effect of Provenge results in a progressively longer survival when its effects are allowed to accumulate over a longer lifespan.  Based on this data one would logically conclude that Provenge induces the biggest benefits when administered at the earliest possible stage.  In the real world, where Provenge is only covered by insurance for men who are hormone resistant and have metastases, men on Lupron who have a rising PSA should be vigilantly monitored with scans such as Prostascint, C11 acetate PET and Sodium Fluoride PET scans every 6 months to detect metastatic disease at the earliest possible stage. 

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.

A Breakthrough Study in Prostate Cancer

BY MARK SCHOLZ, MD

Ten years ago everyone agreed that surgery was the “Gold Standard” to which every other kind of treatment should be compared.  Now as we approach 2013, you rarely encounter the Gold Standard argument to bolster surgery as the preferred treatment approach.  What has led to the change in perspective and why has it taken so long for this change to come about?

Good Science Finally Leads to a Clear Answer

The primary cause for the changed perspective about surgery is the result of a well-performed scientific study published this year by Dr. Timothy Wilt in the New England Journal of Medicine.  The study has been a long time coming.  It was first conceived way back in the early 1990s when Dr. Wilt and others designed a definitive trial to test whether or not radical prostate surgery improves survival compared to observation. Even back then, researchers knew that prostate cancer can often behave benignly and were questioning the benefits of radical surgery.  Therefore, between 1994 and 2002 over five-thousand men were invited to participate in a study comparing immediate surgery with no treatment.  To make the comparison totally fair, individuals volunteering for the study had to be willing to have either surgery or observation based on the flip of a coin.  Most of the more than five thousand men who were invited to participate in the study refused. Ultimately, however, 731 men agreed to participate.

Modest Benefits for “Bad” Cancer, No Benefit for “Good” Cancer

At the start of the study the average age of the men participating was 67 and the median PSA was 7.8. After ten years the difference in prostate cancer mortality was essentially the same in both groups, i.e., within the expected range of statistical variation: 5.8% died in the surgery group and 8.4% died in the observation group.  However, subgroup analysis of the 251 men in the study who started off with PSA levels above 10 showed a modest improvement in survival for the men undergoing surgery: 5.5% died in the surgery group and 12.8% died in the observation group.

Validation of the Right Way to Look at Prostate Cancer

This picture of how different types of prostate cancer behave over long periods of time (having a high PSA for example versus having a low PSA) has been slowly forming in the minds of the prostate cancer experts over the years.  Dr. Anthony V. D’Amico, MD, PhD, Professor of Radiation Oncology at Harvard Medical School, is credited with developing the modern staging system that divides men into Low, Intermediate and High-Risk categories (At the PCRI we call them Shades of Blue, i.e., Sky, Teal and Azure).  Dr. Wilt’s study conclusively validates the fact that favorable prostate cancer—termed Low-Risk—can be safely monitored without immediate treatment, whereas men with High-Risk disease derive a modest benefit from immediate treatment.  His study also reported an intermediate outcome for the men with Intermediate-Risk disease: After 10 years, men in the Intermediate category showed no improvement in cancer survival with surgery.  However, there was a 10% lower incidence of metastases in the men with Intermediate-Risk who had surgery.   

Conclusion

Dr. Wilt’s study is an important breakthrough because it is the first modern, large, long-term, prospective, randomized study comparing treatment versus no treatment in men with relatively early-stage disease, i.e. diagnosed via PSA screening.  This study provides critically important scientific confirmation validating the policy of withholding radical treatment in men with Low-Risk disease.  The study also validates the predictive accuracy of the D’Amico staging system which functions by dividing men into Low, Intermediate and High-Risk categories.  Lastly, Dr. Wilt’s study provides a quantifiable measure of the degree of benefit associated with immediate surgery in men with Intermediate-Risk and High-Risk disease.  Using this information, individuals with High-Risk disease can better understand the rather modest survival advantages of surgery, and weigh them against the probable deleterious side effects, enabling them to determine for themselves whether or not they want to proceed with radical treatment.