The Amazing Gleason Score

BY MARK SCHOLZ, MD


Everyone is excited about the latest craze in medical technology—genetic analysis of tumor cells, which I’ll call GAT for short. The scientific progress that has been made with GAT in my opinion is the second most exciting area of advancement in medical technology today (see further below for more about the first most exciting area). GAT technology is already being commercialized for use in the medical marketplace in products like Prolaris and Oncotype. This technology is able to predict the aggressiveness of prostate cancers, enabling us to differentiate between the men who need immediate treatment and those who can postpone treatment safely.

The predictive power of GAT is certainly exciting, but there is already an effective form of genetic testing available that has been around for more than 40 years, the Gleason scoring system. The Gleason system relies on the visual appearance of cells under the microscope to draw conclusions about their inner genetic makeup. In the medical world, using the visual appearance of the cancer cells is called phenotypic analysis. GAT is genotypic analysis.  Drawing conclusions about underlying genetic makeup by simple visual assessment is a pervasive in human experience.  In courtship, we rely on phenotypic analysis of the underlying genetic make-up of potential spouses to form an opinion about their suitability as potential mates.  Perusal of the genetic pool of immediate family members provides further insight.

So how can Gleason score draw conclusions about the underlying genetic potential for tumor aggressiveness simply by looking at the appearance of cells under a microscope?  The answer is to do a comparison of the visual appearance of cancer cells with the appearance of normal prostate cells. Normal cells in the prostate perform varied functions but still work together as a team.  Specifically, healthy cells form into definable structures called glands.  In these glands some cells manufacture prostatic fluid, a complex liquid comprising the ejaculate for the sperm to swim in.  Other cells organize to form ducts, a piping system to drain the fluid from the outer periphery of the gland and channel it into the middle of the prostate so that a large quantity of fluid can be expelled through the urethra at just the right moment.  All of these different cells work as a team and coexist in the prostate functioning together in a structured glandular arrangement.   
 
When a trained pathologist looks at tumor cells under the microscope he grades them by the degree of cellular disorder.  He is asking himself the question, “How much do these cells retain the normal glandular characteristics of the prostate gland?”  If a cross section of the tumor looks like an unbroken sheet of uniform cells, the cancer is high-grade; the cells have lost their ability to cooperate with each other and form glands. The cancer cells have been honed down into little race cars with only one mission, to aggressively pursue its own replicative destiny. When tumors have this appearance they are graded as a Gleason 9 or 10.  On the other hand, if the appearance of the tumor shows residual glandular components, it is less aggressive, perhaps a Gleason 7.  Gleason 6 “cancer,” the type the one that never spreads, looks almost like normal prostate gland tissue.  
 
Predicting future tumor behavior is obviously very important. How fast will it grow?  Is it likely to spread? How well can it be expected to respond to treatment?  As a result of decades of experience, doctors have learned to use the Gleason scoring system to accurately predict the long-term outcome in individual patients. The new GAT tests represent an important additional refinement, further enhancing our ability to predict the future behavior of an individual cancer. GAT holds one even bigger promise.  In the future we believe GAT testing will be a powerful aid in the selection of targeted therapy, i.e., picking cancer treatments with anticancer activity tailored to individual tumor types.  This hope, however, will have to be postponed until our limited armamentarium of effective treatments is further expanded.    
 
Now, what is it that I consider to be the most exciting area of medical progress? Since I am an impatient type of guy, someone who is looking for quick results, I find immunotherapy more exciting than GAT. To fully exploit the potential of GAT we will need to invent new pills for each of the myriad of genetically different tumor types. Immunotherapy on the other hand comes with its own “built-in” GAT system that enables it to target the unique genetic signature of individual cancer cells. The immune system is so smart, all we have to do is “flip the switch on” and starts cranking out genetically targeted anticancer therapy. Recent developments in the field of immunology are truly mind-boggling and hold promise for a big revolution in cancer therapy within the next 5-10 years.  I’ll try to address some of these recent advances in an upcoming blog. 

The 2013 PCRI Conference, How to Handle So Much New Information

MARK SCHOLZ, MD

Every year, it seems, the enthusiasm and excitement at the conference grows. Why?  Certainly Dr. Mark Moyad who moderates the conference, and the PCRI staff and I, who organize it, have grown from our experiences over the years. We are fine tuning and improving the agenda over time. But this isn’t the primary reason.

The prostate cancer world is changing, and changing quickly.  In the early years of putting a conference agenda together, I used to spend a lot of time “scrounging around the basement” to find content with high enough quality for presentation.  Back then the main treatments for early and advanced prostate cancer were surgery and chemotherapy respectively. Now for these same stages we have active surveillance and immunotherapy.

So the problem now – it is insufficient to do justice to all the new information in a two day conference. Nathan Roundy, one of our helpline volunteers, who recently returned to the PCRI from sabbatical, came up to me after the conference and said, “I can’t believe how much things have changed in just the last six months!”

The introductory comments I wrote in the conference syllabus convey some of these same thoughts about how the PCRI handles the massive overload of new information:

“Knowledge is power. And what you don’t know can indeed hurt you.  However, in this modern information age, the deluge of unfiltered data can be completely overwhelming. How can patients without professional training sort through it all out and distil a sensible plan of action?” 

No one can offer an easy solution.  The prostate cancer world is complex, and there are too many behind-the-scenes conflicts of interest to simply trust the first smiling doctor you encounter.  Although you can’t escape from the responsibility of doing your homework, you can make sure that you are registered ‘in the right classroom.’ 

The field of prostate cancer is vast, so the PCRI breaks the disease down into different categories, which we have termed Shades of Blue.  Failing to recognize the different Shades of prostate cancer is like wandering randomly between classrooms teaching totally different subjects. Is it any wonder there is so much confusion? Patients don’t need more information. They need personalized information—unbiased resources that are tailored to their specific disease category.”

Even though cancer is a serious subject, we had a lot of fun as well.  Ryan O’Neal came and shared his personal experience of having undergone focal cryotherapy with Dr. Duke Bahn. Dr. Mark Moyad and Ryan had a hilarious exchange culminating with Ryan giving Mark a kiss on the cheek.  Jerry Peters, our Grammy Award winning board member, along with his twelve-piece band, hosted a rocking evening at our Gala dinner Saturday night. Dr. David Hung, the CEO of Medivation, the manufacturer of Xtandi, gave a strikingly inspirational presentation concerning the acceleration of new drug development in the pharmaceutical world.

What a wonderful problem to have - with so many brand new treatments it’s hard to do justice to them in a two day conference.  The key is to recognize your shade of prostate cancer, identify the treatment options available based on that shade, and follow up with more research about those options.  The PCRI website is presently going through a major upgrade and will go live in the next week or so.  Check out www.pcri.org when you get a chance.

Xofigo—A Wonderful New Treatment for Men with Advanced Prostate Cancer

BY MARK SCHOLZ, MD

It’s a special event when the FDA approves a new treatment.  Xofigo, otherwise known as Radium 223 or Alpharadin, is now commercially available.  The FDA approved Xofigo based on the results of a large, prospective, placebo-controlled trial that demonstrated significantly greater survival in Xofigo-treated men compared to placebo-treated men.  The trial also shows a very low incidence of side effects and good relief of bone pain. The treatment is easy to administer, consisting of monthly intravenous injections.

How Xofigo Works
Cancer treatment falls into four major categories. Chemotherapy selectively targets fast growing cells. Unfortunately, since chemotherapy works as a nonspecific cell poison, it frequently causes prominent side effects. Hormonal and targeted agents work by blocking the internal mechanisms of the cancer cell, thus forestalling growth. These treatments tend to have fewer side effects than chemotherapy.  However, by nature cancers are genetically variable, so resistant clones eventually appear. Immunotherapy stimulates the patient’s immune system. New forms of immunotherapy are promising and development is progressing very rapidly but this area of study is still in its infancy. Lastly, there is radiation consists of high energy particles that blast cellular DNA. A cancer cell with disabled DNA can’t reproduce.

Radiation needs to be given in a dosage sufficiently large enough to be effective. However, it also has to be targeted accurately to spare the surrounding healthy tissue. Xofigo addresses both of these demands elegantly. In terms of power, just one of the alpha particles emitted by radium 223 can cause irreversible cell damage because alpha particles are large enough to sever double-stranded DNA (typical beam radiation with photons requires multiple hits on DNA because it only damages one of the two DNA strands).

Xofigo Targets the Bone Metastasis
When cancer invades the calcium matrix of the bone it stimulates the bone to accelerate its rate of calcium uptake.  Radium 223 has structural similarities to calcium so Xofigo is “mistakenly” taken up by the bone cells adjacent to the cancer in lieu of calcium. So after Xofigo is injected, it travels through the blood stream and concentrates in the irritated areas of the bone where the cancer is most active.

Xofigo would be effective against almost any type of cancer since most cancers that spread to the bone increase calcium turnover in the bone cells adjacent to the cancer. However, the manufacturers and distributors, Algeta and Bayer Pharmaceuticals, were wise to seek FDA approval for prostate cancer before pursuing development in other types of cancer. Prostate cancer has an extremely fastidious pattern of spread. Metastases occur almost exclusively in bone. The major organs like lung, liver, kidney or brain are almost always spared. Since prostate cancer spreads almost exclusively to bone, Xofigo targets most if not all of the disease.

Alpha Particles Only Travel a Few Micrometers
To most everyone, the thought of radiation easily conjures up horrible visions of toxicity. The concept of radiation by injection is not new. Strontium and samarium are two radioactive elements that also concentrate in areas of increased bone activity. However, they emit a different type of radiation, beta radiation, which acts over a much longer distance and induces collateral damage to the surrounding cells in the bone marrow, the cells of the all-important immune system. Fortunately, bone marrow toxicity appears to be rare in men treated with Xofigo because alpha particles characteristically dissipate over the distance of a couple of micrometers, restricting the radiation effect to the active area of the cancer where it is invading on the surface of the bone.

Potent, Highly-Targeted Therapy—Just What the Doctor Ordered
Advanced prostate cancer in the bones eventually becomes resistant to other treatments. Historically, external beam radiation therapy has been a potent method for killing cancer cells, particularly to control pain, when the effectiveness of other options seems to be failing. However, beam radiation must be used very judiciously because it also causes irreversible damage to the surrounding bone marrow. Xofigo is likely to rapidly gain widespread acceptance with both doctors and patients because it simultaneously targets multiple metastases yet spares the closely adjacent bone marrow.