Technology to the Rescue

BY MARK SCHOLZ, MD

My dad always told me that good ideas are a dime a dozen. The trick is to put the good ideas into motion so that by perseverance and hard work they come to fruition.  This is true of the pharmaceutical industry. Massive investment in basic research has yielded a much better understanding of how cancer “works,” creating opportunities for biochemists to design specific pharmaceuticals that will inhibit cancer growth and spread. However, the fact remains that multi-million dollar clinical trials must be performed before a new medicine can be approved and released by the FDA.

One pharmaceutical company that is making fast progress is OncoGenex.  They have developed an elegant solution for blocking an overactive enzymatic pathway that cancer cells use to protect themselves from chemotherapy. For example, blocking the effectiveness of one popular type of chemotherapy commonly used to treat prostate cancer is called Taxotere. The specific overactive enzyme the scientists at OncoGenex have identified is called clusterin. Cancer cells over-produce clusterin to protect themselves from chemotherapy.

OncoGenex has designed a medicine that accurately targets clusterin.  This new medicine, called Custirsen, sharply reduces the amount of clusterin inside the cancer cells. A preliminary trial, using Custirsen was added to the regimen of 82 men with advanced metastatic prostate cancer being treated with Taxotere (a chemotherapy drug that is commonly used to treat prostate cancer), showed a 40% improvement in survival rate when Custirsen was added to Taxotere--compared to the survival in men receiving Taxotere alone.

Clinicaltrials.gov reports that 141 centers around the country are currently participating in a larger trial combining Custirsen and Taxotere.  This larger trial, involving hundreds of men with advanced prostate cancer, is aimed at proving the effectiveness of Custirsen and getting approval by the FDA for commercial availability. Custirsen is administered as a weekly intravenous infusion.      

Over the course of my 20 years as an oncologist many of the common cancer medicines have proven to be  major disappointments—not very effective and overly toxic.  These earlier agents were discovered and developed through a slow and cumbersome process of trial and error. In that era we had only a vague idea of how the new treatments actually worked.  Most of those agents were broad spectrum inhibitors of cellular growth that resulted in considerable collateral damage on the faster growing normal cells of our body like the hair follicles and the white blood cells.  

Research leading to the discovery and development of newer agents like Custirsen is completely different. These agents are rationally designed and targeted to attack and destroy a very specific part of the cancer cells. As a result, they are not only more effective, they also have fewer side effects.

At last, it appears to be technology to the rescue.

The Radiation Round-Up

BY RALPH BLUM

Despite the significant advances in treatment options, there is still considerable uncertainty—even among doctors—about how or even whether to treat prostate cancer. The treatment controversy is the prostate cancer equivalent of a Dempsey-Firpo fight: the proponents of surgery slugging it out with those who favor some form of radiation.

In recent years we’ve seen the arrival of the elegant robotic surgery. Instead of cutting half-blind in a field of blood, with the da Vinci robot a surgeon can observe the anatomy blown up 100 times on a big TV screen and, with the aid of the robot, perform the complex and intricate surgery more precisely.

There are, however, two problems with this sophisticated new surgical procedure. First, it’s hard to justify the significant additional cost of the robot because the results are not that much different from those obtained with traditional surgery.

The second problem is rather disquieting. I have observed the power of the robot as a selling tool—a blend of high visibility, big bucks, slick advertising—with the result that a considerable number of men who really do not (repeat, do not) need surgery in the first place are seduced, Pied Pipered into the O.R. by what one critic called the “bloodless glamor” guaranteed by the da Vinci robot. You might want to consider my earlier blog, “The Robots Have Landed.” 

My feeling —depending, of course, on your risk category—is that if you are going to opt for radical treatment you should be lining up for one of the state-of-the-art targeted radiation treatments: either radioactive seed implantation, or intensity modulated radiation therapy (IMRT).

So how do you determine which you should choose?

Not all men are candidates for radioactive seed implants, otherwise known as brachytherapy. It is not recommended for men with enlarged prostate glands, men with pre-existing urinary problems, or men with cancer outside the prostate. If, however, you are eligible, seeds have the advantage of a single hospital visit, whereas IMRT requires daily sessions at a specialized facility for two months. Also, with seeds, the radiation dose is minimally higher, giving you the possibility of slightly better cure rates.

Bottom line your decision to go for seeds versus IMRT is mainly influenced by your risk category. In my case, if, after all these years of “prostate cancer coexistence,” if I decided on treatment, I would choose IMRT because it can be administered to a slightly broader field, thus creating a wider margin around the gland and even, if necessary, radiating the surrounding lymph nodes.

You will undoubtedly hear conflicting opinions about which treatment is best for you, and your decision will inevitably be complicated by multiple factors. With any prostate cancer treatment there is the risk of side effects, but with targeted radiation therapies the risk is significantly reduced. Moreover, both of these therapies—seeds and IMRT—are at least as effective as surgery at curing the disease without the additional risks of a major operation.

Provenge in 2012

BY MARK SCHOLZ, MD

Doctors finally seem to be comfortable with starting Provenge, a recently FDA approved immune therapy for prostate cancer.  Dendreon, the manufacturer of Provenge, just reported a sharp uptick in their quarterly financials, indicating that the use of Provenge is increasing as doctors increase the amount of the drug they order.

Although, Provenge has been on the market for 18 months but the medical community was slower to embrace this new treatment than was expected.  It seems that it has taken time for doctors to make peace with the fact that Provenge extends life, even though there is no lowering of PSA and very few side effects.

At Prostate Oncology Specialists, we recently completed an in-house review of the first 50 men treated with Provenge, I’ll jump right to the simple and somewhat mundane conclusion or our analysis: Provenge is relatively easy to give and side effects are uncommon.

Historically, the effectiveness of cancer treatments—like chemotherapy for example—has been closely associated with notable side effects. Side effects were often equated with effectiveness.  Even some of the new immune treatments, like Ipilimumab for example, usually have side effects. It’s ironic that patients receiving Ipilimumab on investigational trials are actually comforted when they get side effects—it confirms that they are not getting a placebo.

It’s also ironic that while doctors look for PSA decline as a measure of success, PSA has been rejected by the FDA as a method for measuring the effectiveness of drugs. The FDA demands a survival endpoint rather than changes in PSA.  (Personally, I think the FDA is crazy. I think that both PSA and survival endpoints are valid.)

Nevertheless, doctors and patients alike are confused. Their seemingly logical question is, “How can someone’s life be extended without PSA dropping?”  My explanation is as follows: When Provenge strengthens the immune system, is slows the rate of cancer growth.  Using the rise in PSA as analogous for cancer growth, Provenge slows the rate of PSA rise.

I am very comfortable with the idea that effective immune therapy slows cancer growth rather than reversing it.  This phenomenon of slowing the rate of PSA rise is exactly what we reported to the American Society of Clinical Oncology in 2010 when we presented our results with three medicines with immune activity, Leukine, Low-dose cytoxan and Celebrex.  The combination of these three agents caused substantial slowing in the rate of PSA rise.

Since Provenge is so well tolerated, the next logical step is to evaluate Provenge in combination with other immunologically active treatments.  MD Anderson is ramping up to do a trial of Provenge with full-dose Ipilimumab.  At Prostate Oncology Specialists we look forward to working with treatment options such as Provenge and Ipilimumab for our patients. Hopefully the net result will be greater than the sum of the parts.

Did I Actually Hear You Say “Just-Cut-It-Out?”

BY RALPH BLUM

On New Year’s Day, I heard from Max, an old friend who, to my surprise, announced, “I’m scheduled for surgery. I just don’t want to have to think about prostate cancer ever again.” His PSA and Gleason score put him at a low-risk level, and the last time we had talked he was planning to monitor the cancer for a while before making any treatment decision. So what had changed his mind?

I’ve said it before and I’m saying it again, because it doesn’t seem to sink in. I have interviewed hundreds of men newly diagnosed with prostate cancer, and an astonishing number of them seem to have failed to make this vital connection: When your family doctor refers you to the urologist, he is sending you to a surgeon.

It’s a feverish sense of frustration that has driven me to revisit this subject.  With the advent of safe, modern methods to monitor prostate cancer over the past 36 months, it is disturbing to have to report that radical prostatectomies for the same period are up 50%.

There are three likely reasons for this distressing increase:

First, because a urologist is a surgeon, it is only natural, providing you are under age 75 and your overall health is sufficiently good, that his treatment of choice would be surgery. And while a urologist is legally obliged to acquaint you with other forms of treatment available, not only have urologists made a huge personal investment in learning how to perform a highly complex procedure, but also they genuinely believes that surgery provides your best chance for a cure.

Second, although prostate cancer is typically a non-life-threatening disease, many men (like my friend Max) are highly motivated to be rid of the damn disease, to “just cut it out,” despite the risk of becoming impotent. They find it hard to believe that any kind of cancer can remain dormant for years, even decades, and so they rush into surgery without taking into account that even the most talented surgeon cannot guarantee a permanent cure, let alone know for sure that he can save the nerve bundles that control erections.

Three, probably the main reason why surgery is up 50% is that many men today are lured into undergoing a prostatectomy by the high-tech glamour and all the marketing hype surrounding “the robot that can operate.” But as I pointed out in my blog “The Robots Have Landed,” it is the man behind the robot who is actually performing the procedure, and a good outcome depends on the experience and skill of that surgeon. The learning time is significant—a urologist needs to perform as many as 200 procedures to achieve full competence.

And then there’s this strange irony: If it isn’t necessary for you to undergo an invasive procedure—particularly one where you risk impotence and other surgery-related, irreversible side effects—the fact that the technology available is greatly improved is irrelevant.

So do your own homework. Talk with other men who have faced the choices you are facing. Get a second opinion. Interview a prostate oncologist. There’s one thing to take comfort from despite your diagnosis, and it’s this: For 28 out of 30 men prostate cancer is no more life threatening than chronic asthma.
If there’s a mantra, a battle cry for the great majority of us with non-aggressive prostate cancer, it is this: “Die with it, not from it!” I have those six words taped to my shaving mirror.

Prostate Size Matters

BY MARK SCHOLZ

Having a large prostate is generally considered to be a bad thing because it is associated with urinary malfunction -- slow urination, getting up frequently at night and,  in the worst case scenario, total urinary blockage—an emergency condition that requires insertion of a catheter.

Treating urinary problems such as these is a big business.  A variety of herbal extracts containing ingredients such as saw palmetto as well as medications such as Flomax and Proscar are commonly prescribed and used with varying success. When total blockage occurs the urologists swings into action with lasers, microwave treatments or a good old-fashioned TURP, Transurethral Resection of the Prostate, sometimes referred to by laymen as the “rotorooter job.”

It should be made clear that many large prostate glands cause no urinary symptoms whatsoever.  Also, urinary problems like those described above can occur in men with normal sized glands.  Therefore you need to be aware that the connection between prostate size and urinary symptoms is a loose one.

A normal, healthy prostate gland is a walnut-sized organ that weighs approximately 15 grams in young men and around 30 grams (about an ounce) in men age 50 or older. The prostate gland is the only organ in the body that keeps growing as you get older. Enlarged prostates can weigh as much as 100 grams or more (the size of an orange or small grapefruit), and are more likely to lead to urinary problems.

However, as it turns out, having a large prostate can actually be a good thing, at least as far as prostate cancer concerned. Several studies show that men with big prostate glands tend to have lower Gleason scores. When men with big prostates are treated with radical prostatectomy, studies also show that they are less likely to have cancers that have spread through the capsule or into the seminal vesicles.

No one knows for sure why big (where cancer is concerned) is often better. One theory is that men with bigger prostate glands get biopsied more frequently and at a younger age because their PSA levels run higher. Therefore the cancer is being caught at an earlier stage and monitored.

Another theory is that bigger prostate glands result from hormonal changes within the gland and that these hormonal changes somehow have an inhibitory effect on cancer growth. The particulars of these purported hormonal changes are never specifically elucidated.

Regardless of the cause, men with smaller glands—say with prostate volumes less than 40 grams should be aware that, all other things being equal, their risk of harboring a higher Gleason score or a type of cancer that invades through the capsule is somewhat greater than it is for the men who have larger glands.

Prostate size is an additional factor besides Gleason score, PSA and the percentage of core biopsies involved with cancer that needs to be considered when going through the treatment selection process.