Shades of Blue, Trying to Simplify a Complex Situation

MARK SCHOLZ, MD

How can one disease be so vast?  Actually, it really isn’t one disease; there are hundreds of variations: Prostate cancer can be slow or fast growing, responsive or unresponsive to treatment, metastasizing early or not metastasizing at all.  In fact, selecting treatment for prostate cancer would be simpler if these extreme “either-or” types of examples I just cited were common. In reality, most men’s cases are not so extreme, they lie somewhere in the middle.  Selecting the best treatment, one that matches each variety of prostate cancer, is a really big challenge. Therefore, the process begins by trying to understand the disease as well as we can.

Characterizing the Disease
People often assume that differences in the way cancer behaves—life threatening vs. benign—comes from observing the same illness at different time points.  What’s often misunderstood is that distinct varieties of prostate cancer also exist. It’s not all one disease. This doesn’t mean that the stage of disease is unimportant. It’s just not the whole picture.  Patients frequently ask, “Am I stage A, B, C, or D?” without realizing the lettering system is just a description of what the surgeon feels during his finger exam. PSA and the Gleason grade are just as important as the stage of the disease. What can be confusing is that no single element comprehensively defines the disease. For example, one man with a higher PSA may do well while another man whose PSA is low may do poorly.

A Widely-Accepted Classification System
Therefore, a classification system to help predict cancer aggressiveness requires a “grid” that incorporates multiple prognostic elements—the letter-stage, PSA, Gleason and scan results.  Dr. Anthony D’Amico from Harvard is credited with developing the modern system that uses PSA, Gleason and stage to divide newly-diagnosed prostate cancer into low, intermediate and high-risk categories.

Building on the D’Amico system, and to further highlight the differences between categories, the Prostate Cancer Research Institute (PCRI) has named the risk categories with different Shades of Blue* and expanded the grid to include two more categories: men with disease relapsed after treatment with a rising PSA and men with metastatic disease or disease that has become resistant to hormonal therapy.

The Five Shades of Blue:  

Sky for low-risk
Teal for intermediate-risk
Azure for high-risk
Indigo for PSA-relapsed disease after treatment
Royal for men with metastases or hormone resistance

Does the system separate men into distinct categories?  Yes. For example, in a study published by Dr. Timothy Wilt in the New England Journal of Medicine, 731 men volunteered between 1994 and 2002 either to have immediate surgery or observation alone.  The subsequent outcome showed higher cancer mortality with in men in a higher-risk (Azure) category compared to Sky or Teal. It also showed an 8% improvement in ten-year survival rates for men in the Azure category when they underwent surgery (rather than observation).  Surgically-treated, intermediate-risk men (Teal) showed a 10% reduction in the incidence of metastases compared to the men who did not have surgery. Men in the low-risk category (Sky) showed no difference in mortality or metastases with or without treatment. Dr. Wilt’s study, therefore, went beyond merely validating the predictive ability of the D’Amico staging system. The study also provided a measure of the degree of benefit associated with doing surgery.

General Treatment Recommendations

While there are no absolute rules for treatment, as a starting point, here are some general guidelines:

Sky (low-risk): observation or monitoring with active surveillance

Teal (intermediate-risk): monotherapy, limiting treatment to a single therapy such as IMRT or surgery or brachytherapy

Azure (high-risk) combination therapy with IMRT, brachytherapy and hormone blockade

Indigo (relapsed-disease): Treatment intensity tailored to the location in the body of the relapsed disease and to the PSA doubling time rate

Royal (advanced-disease): Multimodality immunotherapy, hormonal therapy, chemotherapy and radiation sequentially or in combination

The message is that before treatment can be selected what we are treating needs to be accurately defined.  The starting point, therefore, is to begin with dividing prostate cancer into five broad categories or Shades of Blue.  By doing this, the number of treatment options can be narrowed down and finding the right treatment becomes easier.   

Is Prostate Surgery Right for You?

RALPH BLUM

As I wrote in my last blog, once your family doctor has referred you to a local urologist and you have been diagnosed with prostate cancer, your first and most important decision is choosing a doctor with the necessary skill and experience to help you weigh all your options and determine your best course of action. This doctor may not be your community urologist.

Provided the cancer is still contained within the prostate gland, and provided there is no medical reason surgery is contraindicated, your urologist (who is a surgeon) will almost certainly recommend it. And in your emotionally vulnerable state, and with a natural desire to just get rid of the cancer, it is quite likely you will uncritically take his advice, without question or research.

After talking with your urologist you may come away with the impression that prostate cancer surgery is fairly straightforward. It is not. Anatomically, the prostate is in absolutely the wrong place for a simple surgical procedure. Located as it is within millimeters of the bladder and the rectum, there is zero tolerance for a slip of the scalpel. To make matters worse, there is prolific venous blood supply surrounding the gland, and on a bad day even the best surgeons can end up operating in a pool of blood, and with restricted ability to see clearly in order to spare the miniscule nerves (thinner than a human hair) that control erections. With such an intricate and complex procedure the high rates of impotence are hardly surprising.

So much skill is required to successfully perform a radical prostatectomy that being operated on by less than the very finest surgeons dramatically increases the chances for a poor outcome. Levels of ability vary widely from surgeon to surgeon even in prestigious university centers. In 2004, Dr. Peter Scardino, Chief of Urology at Memorial Sloan-Kettering, published a study documenting the differenced in “talent” in this unregulated field. The study evaluated the surgical skill of twenty-six urologists on staff at Sloan-Kettering and Baylor.  The indicator used to measure skill was the frequency of leaving cancer behind after the operation (the technical term is “positive surgical margin”). The study reported that the best doctor in the group left cancer behind in 10% of his cases. The positive margin rates of the other twenty-five urologists ranged from 11% to a shocking 48%.

 

Despite these disturbing statistics surgery is still the primary treatment of choice for those diagnosed with prostate cancer. Yet while a select few surgeons perform dozens, perhaps a hundred or more procedures, generally speaking, the average urologist performs fewer than half a dozen prostate operations a year. In the U.S. there are somewhere around 70,000 radical prostatectomies done annually, and there are 10,000 urologists. If you do the math it’s clear that your community urologist is probably not doing enough prostate surgeries to stay proficient.

 

So buyer beware. Before you consent to surgery be sure to ask your urologist how many nerve-sparing prostatectomies he has performed--it should be at least 50. Preferably upwards of 200. Did often he get positive surgical margins? What percentage of the men he operated on are sexually potent a year after the procedure? What percentage suffers from incontinence a year later? And if you are over 70 years old and your urologist is recommending surgery, find another urologist, or better still, a prostate oncologist.

 

I hope this short essay has helped convey the importance of not rushing into treatment.  It bears repeating: Go slowly. Do your homework. I have avoided surgery for almost 25 years. Consider the options, including—since surgery is only right for some of you—“Do nothing,” which for many men translates as “Die with prostate cancer, not from it."

Hormone Therapy: Earlier is Better than Later

BY MARK SCHOLZ, MD

Prostate cancer is by far the most hormonally sensitive cancer. Practically all other types of cancer, except breast cancer, are totally immune to testosterone blockade. Just as normal cells need oxygen, prostate cells, cancerous or otherwise, depend on testosterone. Cells originating in the prostate are by nature very sensitive to testosterone blockade. This sensitivity can be exploited as a treatment. When a cancer cell is deprived of testosterone it initiates a suicide sequence called apoptosis. Low testosterone is acting like a signal, sending a biochemical message to the cell, telling it to release destructive intracellular enzymes, causing it to die.

Within a few months of blocking testosterone, cancer regression is usually dramatic. For example, one study used Zytiga prior to surgery. The surgically removed prostate glands were fine-sliced and examined under a microscope.  Some men showed no residual cancer in their prostates.

The testosterone inactivating pharmaceuticals (TIP) that block testosterone are listed below in order of ascending potency:

 

1.    5-alpha reductase inhibitors: Avodart (dutesteride), Proscar (finasteride):

2.    Anti-Androgens: Casodex (Bicalutamide), Eulexin (flutamide), Nilandron (nilutamide)

3.    Orchiectomy: Surgical removal of the testicles

4.    LHRH agonists and antagonists: Lupron, Zoladex, Eilgard, Firmagon

5.    Estrogen: Works basically the same way as #3, by suppressing luteinizing hormone (LH). In addition, however, there also may be some direct anticancer effects from estrogen.

6.    Cyp17 Inhibitors: Zytiga (abiraterone), Nizoral (ketoconazole):

7.    Multimodality androgen receptor inhibition: Xtandi (enzalutamide)

While categories 6 and 7 are clearly the most potent, as yet there is no conclusive evidence that either of these two categories is more potent than the other. However, a variety of studies have demonstrated that a combination of agents is more potent that agents used by themselves.

 

Also, a number of studies have shown that men live longer when they are treated with TIP at an earlier stage—that is, at the time of diagnosis—rather than at the time of relapse when the disease has become more entrenched:  In August 1997, The New England Journal of Medicine published a study comparing two groups of 200 men each, all of whom were treated with radiation for high grade prostate cancer (Gleason 8, 9, or 10 or a large tumor felt on digital rectal exam). The five-year death rate from prostate cancer was reduced by 80% in the men who received radiation plus TIP compared to radiation alone.

 

A study published in the British Journal of Urology in February 1997 looked at immediate TIP vs. starting TIP after the cancer was causing symptoms.  Two groups of 400 men were evaluated and compared. Mortality was 25% lower in the group that had early treatment.  A third study was published in the Journal of Urology in June 1998 in which ninety-one men were randomized between radiation alone and radiation with TIP.  The mortality rate was 50% less in the men that were treated with TIP.

 

Another famous study in New England Journal of Medicine authored by Dr. Messing in 1999 looked at the value of starting TIP right after surgery in a 100 men, all of whom had cancer confirmed to have spread into their lymph nodes. Half were randomly allocated to start TIP right after the operation.  The other half started TIP when they had disease recurrence and evidence of progression.  Seven years later the men treated with immediate TIP were eight times less likely to have died of prostate cancer: Two men treated with immediate TIP died of prostate cancer whereas 17 men treated with delayed TIP died of prostate cancer.

 

In this last study TIP was continued for life. Since we know that TIP has more side effects when administered over a longer period, one can’t help but wonder if the same survival advantage could have been achieved with a shorter treatment period, say for two years?

 

The side effects of TIP can indeed be troublesome, especially the lowering of libido.  In our experience 70% of men under age 60 and 90% of men over age 65 lose sexual desire completely—particularly if they are treated with drugs in category three or higher. Category two and category one drugs cause loss of libido in about 50% and 25% of men respectively.

 

It is important to make one thing clear: Libido is not a euphemism for getting an erection. Viagra is powerful enough to restore erections in most men on TIP. Loss of libido means undergoing a loss of sexual interest. After TIP is stopped, younger men recover libido quite nicely though a minority describe their libido as persistently diminished. Some men, particularly the older ones, are more likely to have a persistent reduction in libido.

 

The list of potential side effects from TIP (besides libido problems) is long. Most of the side effects are manageable with expert supervision. Please inquire about a copy of Preventing the Side Effects of TIP for further details. Using a category two drug like Casodex is one way to reduce TIP’s side effects. However, using a less potent agent raises another concern: Some studies have shown reduced anticancer efficacy. Clearly treatment selection depends on weighing the intensity of potential side effects against the expected survival benefit. In some cases, slightly diminished anticancer efficacy may be an acceptable tradeoff if side effects can be substantially reduced.

 

Prostate cancer’s Achilles heel is that it can’t survive without testosterone. While anti-testosterone medications have remarkable anticancer efficacy they can also cause notable side effects. Treatment intensity and timing needs to be varied in accordance with each patient’s individual characteristics. 

Pay-Off Versus Collateral Damage

BY RALPH BLUM

Life is full of risks, but if you are one of the legion of men with prostate cancer whose urologist is recommending a radical prostatectomy, make sure you have considered the following risks of collateral damage:

Incontinence: 
Urinary leakage is usually a temporary problem after a prostatectomy, but even the best urologists report that about 7% of their patients are left with permanent and constant urinary drainage.  Less skilled surgeons have much higher rates. After surgery, most men experience some minor leakage when they cough, lift, bend over, or laugh.

Another problem is the formation of scar tissue in the urethra, the passage from the bladder to the penis. The suture site where the severed urethra is reconnected can become constricted by scar tissue that blocks the flow of urine. This may be correctable with urethral dilation, a process forcing oversized, stainless steel probes up the penis to stretch out the ring of rock-hard tissue. Unfortunately, scar tissue is notoriously uncooperative, often refusing to stretch at all. In some cases the stretching fractures the brittle ring of tissue, resulting in permanent incontinence. If that happens, another operation is required to implant an artificial sphincter.

Impotence:
Without nerve-sparing surgery permanent erectile dysfunction is virtually inevitable. With nerve-sparing surgery, the best surgeons hope to be able to save the nerve bundles (located very close to the back of the prostate on both sides) that control erections. If both sides of the nerve bundles can be saved, potency is around 40% to 75% in patients under 70 years old (depending on which expert you consult, and the patient characteristics). If only one side of the nerve bundles can be saved, potency drops to around 25% to 45%. However, until the doctor actually performs your surgery, he won’t know whether he can spare the nerve bundles.

Even men who recover their erections after surgery undergo a prolonged period of impotence, often lasting up to a year or more. During this time of enforced abstinence, as with any unused muscle, atrophy of the penis occurs. This means that of the men who end up recovering some degree of erectile function, only 5% report that their erections are as good as before surgery.  Additionally, despite claims from urologists who maintained for years that patients’ complaints of penis shrinkage were anatomically impossible, diligent researchers have finally collected the necessary measurements showing that shrinkage is common. The average amount is about one-half inch, although some men undergo considerably greater shrinkage.

Studies show that impotence can totally redefine a man’s self-esteem, his self-confidence and his relational satisfaction. In some cases Viagra can help with surgically induced impotence. However, penis vacuum devices, penis tourniquets, penis injections (yes, with needles) or the surgical implantation of a plastic rod into the penis is often required to restore function. In my case, lead me to the monastery!

Other Rare but Possible Risks from Surgery:

• Significant blood loss requiring transfusions
• Pain from surgery
• Blood clots in the legs
• Heart Attack
• Infection
• Temporary or permanent memory loss from anesthesia
• Miscellaneous surgery-related problems

 

So with these considerable risks, what is the pay-off for undergoing surgery? The major pay-off is, if you are lucky and have a successful nerve-sparing prostatectomy, it will cure the cancer and you will suffer minimal collateral damage. The only other advantage is you get a better idea of how serious your cancer is because the pathologist evaluates the prostate after its removal. If he finds that the cancer has spread even a little, you and your doctor can decide what to do next.

 

No one knows for sure which prostate cancer treatment gives a better chance for cure or a better quality of life. But if you decide to go with a prostatectomy, make sure that the surgeon you are considering is experienced and skilled in the procedure.