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. 

Hormone Blockade for Early-Stage Prostate Cancer

MARK SCHOLZ, MD

Being medical oncologists rather than surgeons—and being more impressed by the toxicity of surgery than by its effectiveness—my partners and I hypothesized back in the early 1990s that since testosterone inactivating pharmaceuticals (TIP) are powerful enough to reverse metastatic disease, they should be even more effective against early-stage disease.

Clinical Experience with TIP for Early Stage
In 2011, we published a scientific article in the Clinical Genitourinary Cancer detailing the twelve-year outcome for 73 men who embarked on TIP as primary therapy. In this group of men the average PSA was 9 and the average Gleason score was 7 (intermediate grade). Most of the men had tumors in their prostate large enough to be felt by digital rectal examination. Twenty-one of them maintained a low PSA indefinitely with a single course of TIP—they never needed a second cycle.

Another group of 24 men required periodic repeat cycles of TIP to keep their PSA less than five. In the remaining 28 men, after one or more cycles of TIP, the decision was made to undergo treatment with surgery, seeds or radiation.  However, the average time to treatment was 6.2 years after the first cycle of TIP. Only three of those 28 men ever relapsed after treatment. In summary, this study showed that initial remissions with TIP were universal and that even if the remission was not permanent, treatment with more radical therapy was delayed many years.

In 2012, we published another scientific study in The Prostate, in which we evaluated the effect of 12 months of TIP in 102 men. Twenty-two men were in the Low-Risk category, 30 were Intermediate-Risk and 50 were High-Risk. The median PSA was 7.8 and the median Gleason score was 3 + 4 = 7. The attainment of a clear biopsy after TIP followed by a sustained 7- year remission occurred in forty-five men. The likelihood of durable remission was dependent on the risk category: 82% of Low-Risk, 47% of Intermediate-Risk and 25% of men with High-Risk required no further treatment.

Monitoring TIP’s Effectiveness
One of the beauties of TIP is how easily its anti-cancer effects can be monitored with PSA. Although there is much debate about using PSA for cancer screening, PSA is an amazingly accurate tool for monitoring treatment response. In a study we published in Urology in 2007, we showed that more than 95% of men with newly-diagnosed disease drop their PSA to less than 0.05 within eight months of starting therapy. It’s a rare for cancers to continue producing PSAs above a threshold of 0.05 after six months of TIP therapy.  However, when these rare cancers occur, i.e. when an elevated PSA nadir occurs, it is a flashing sign that aggressive multi-modality therapy should be instituted.

What about Side Effects?
So what is the catch?  To this point TIP sounds like a very logical way to initiate treatment. Even if the disease is not arrested altogether, it delays progression for many years. And men who select TIP as initial therapy can always “jump ship” and undergo radiation or surgery. Delaying surgery or radiation with their potentially irreversible side effects makes sense considering the acclerating pace of medical progress. In this rapidly changing environment, postponing irreversible treatment for even five years is unquestionably an attractive proposition.

The catch is that while TIP side-effects are manageable, they are not trivial. Without attention to diet, notable weight gain occurs. Without regular resistance training and weight lifting, significant muscle weakness will ensue. While on treatment, the majority men lose their sex drive. A loss of sex drive is, however, different than impotence. With medications such as Viagra and Cialis most men on TIP can have erections sufficient for intercourse. Sex can be enjoyed, but it is not sought after with the usual male verve. There is also the potential for additional side effects such as breast enlargement, osteoporosis and hot flashes. As dire as these sound, they are preventable with common medications such as Femara, Prolia and progesterone. However, the side effects are cumulative and become more prominent the longer TIP treatment is continued.

Final Thoughts
Some men are concerned that their cancer will progress if “real treatment” like surgery or radiation is delayed. They forget that surgery and radiation only eradicate the “friendly types” of prostate cancer, the ones that remain contained in the gland. The real danger lies in the possibility of microscopic metastasis. Radiation and surgery have no effect whatsoever on cancer that has already spread. Only TIP circulates throughout the entire body attacking early-stage micro-metastasis in the lymph nodes or bones.

In my next blog, I will be discussing a new, more powerful type of TIP that has recently been approved by the FDA. The enhanced effectiveness of this new drug may enable a shorter course of treatment. And since testosterone levels in the blood remain normal throughout, the risk of lingering side effects should be eliminated.   

Revisiting TIP (Testosterone Inactivating Pharmaceuticals)

BY RALPH BLUM

Why Does TIP Work?
Testosterone is the hormone that causes boys to become men at puberty. Prior to puberty, the prostate gland is roughly the size of a small marble. Then, when the teenage surge of testosterone occurs, the gland expands to walnut size and begins producing semen. This transformation occurs because the cells of the prostate gland are uniquely sensitive to the presence, or absence, of testosterone. Lowering the level of testosterone in the blood causes the cancer cells to shrivel up a die because the cancer cells are derived from prostate gland cells and retain the same dependence on testosterone for survival.

Long Term Results
One downside to TIP is that while it shrinks the cancer, it does not, ultimately, kill every last cell. However, it has been my treatment of choice for the past ten years. Studies done at Prostate Oncology Specialists, Inc. show that after twelve months of TIP the amount of residual cancer is usually too small to be detected with a lesion-directed biopsy using color Doppler ultrasound. In most cases PSA drops to near undetectable levels (mine dropped to 0.125), and TIP has the added benefit of having anti-cancer effects throughout the body.

When TIP is stopped, testosterone levels gradually return to normal, and a number of men require no further treatment. Some men require periodic treatment with TIP to keep their PSA levels under 5.  And other men, rather than continuing with intermittent TIP, decide to go for surgery, seeds or IMRT. However, even this latter group has bought themselves on average of five plus years before risking the intimidating potential side effects of more radical treatments.

Side Effects of TIP
Although no prostate cancer treatment is free of undesirable side effects, most of the side effects of TIP (weight gain, muscle loss, loss of libido)   are preventable with proper management. And loss of libido, unlike impotence, is reversible when TIP is stopped. Meanwhile, although some of the magic may be gone while on TIP, most men find that they can still enjoy sex (and give pleasure to their partners) with a little help from Big Pharma. Viva Viagra!

Final Thoughts
I can think of only three reasons why this non-invasive alternative to surgery and radiation is not more often the treatment of choice for men with Intermediate-Risk prostate cancer:

1)  Patients never hear that it is an option: Urologists usually don’t suggest TIP to men with Intermediate-Risk cancer as a viable alternative to their preferred treatments—surgery and radiation.

2)  Doctors are unfamiliar with the TIP option.  Finding an oncologist with experience in state-of-the-art methods of administering TIP is still a challenge.

3)  Most men are shocked and fearful when they are first diagnosed with prostate cancer, and it’s hard to resist the emotional appeal of “Just cutting it out”—especially when the risks of more radical treatment are sometimes glossed over.

Thankfully, in 2002, when I learned that my PSA had bumped up to 18.3, my fear of being sliced open, or fried by radiation led me to Mark Scholz, and TIP. And although I would not describe my experience as “a day at the beach,” I am deeply grateful that I chose TIP, and, more importantly, ten years later, I am still here!

Is the Wizard of Wall Street Losing His Way?

BY MARK SCHOLZ, MD

According to a recent CNN News Release, Warren Buffett, American business magnate and philanthropist, addressed his prostate cancer diagnosis, dismissing it as a "non-event."

In a letter to shareholders last month, Buffett, 81, disclosed that he had been diagnosed with prostate cancer. The announcement sparked discussion about who'll take over from Buffett one day.

"I feel terrific," Buffett said in response to a question at the Berkshire Hathaway annual meeting. "I have four doctors; at least a few own Berkshire Hathaway (stock). They described various alternatives and the ones they recommended do not involve a day of hospitalization. They don't require me to take a day off work, the survival numbers are way up.”

This announcement reveals the lack of progress in general public understanding of the unique nature of prostate cancer. People still have not learned that when the condition is newly-diagnosed it almost always means that even in the worst case scenario, cancer mortality will be postponed for at least 10 years, if not indefinitely. 

Other news releases have indicated the Mr. Buffett is planning to undergo radiation, probably IMRT. IMRT cure rates range between 80 to 100% depending on specific individual factors such as Gleason score, PSA and how many biopsy cores contain cancer, details that have not, in Mr. Buffett’s case, been made available.

The real question is: Considering that Mr. Buffett is 81, does he require radiation? Getting cured sounds like a no brainer until you realize that his chance of dying is incredibly small even if he skips radiation altogether. And even with modern radiation there is a risk of permanent damage to sexual, urinary and rectal function.

Why is his risk of dying so small?  Prostate cancer has a unique Achilles heel. It needs a continuous supply of the male hormone testosterone to survive, without it prostate cancer shrivels and dies.

Pharmaceutical agents that block testosterone constitute an amazing safety net.  With this safety net in place, an 81-year-old man has the option of monitoring his status rather than feeling obligated to rush to immediate curative treatment, as would be the case with other types of cancer. 

If, while monitoring the situation, it appears that the disease is growing quickly, radiation can be administered at that juncture. After all, even if the very worst scenario ensues and the disease metastasizes—jumps to another part of the body—testosterone inactivating pharmaceuticals can suppress the disease for an average of more than ten years.

Mr. Buffett has become famous for his wise capacity to make successful long-term investment decisions.  Rather than relying on the expertise of others he should apply some of his energy and talent toward researching his medical situation further. He might conclude that the risk of spending his twilight years with radiation-induced urinary or rectal damage is far greater than the risk of early mortality from prostate cancer.

Hormone Blockade Effectively Controls Prostate Cancer

BY MARK SCHOLZ

Ralph Blum, my coauthor of Invasion of the Prostate Snatchers, monitored his prostate cancer for 14 years before starting treatment in 2004.  Prior to meeting me, Ralph had been living in Hawaii and managing his own case.  However, when his PSA rose above 10 he came to Marina del Rey for a consult. I advised him to start treatment with either IMRT or Testosterone Inactivating Pharmaceuticals (TIP).  Ralph, after considerable uncertainty and discussion, embarked on TIP for 12 months.  So far he has required no additional therapy.

At Prostate Oncology Specialists, back in the 1990s, when radiation was more prone to burn than cure, we commonly treated men with TIP followed by active surveillance. Our first published report on the feasibility of intermittent TIP was presented at the annual meeting of the American Society of Clinical Oncology in 1997¹ and later published in The Oncologist in 2000.² In 2006 we updated our experience with intermittent TIP in the Journal of Urology and reported that Proscar (finasteride) extends the time-off period” after TIP is stopped.³

This December Clinical Genitourinary Cancer will publish our long-term outcome of 73 men treated at Prostate Oncology Specialists with TIP and monitored for a median of 12 years after treatment. A preprint of the article is available on our "publication" webpage found at prostateoncology.com. Here are the take-home messages we reported in the article about using TIP as first line treatment:

1.     Almost a third, 21 men, have not required any further treatment.

2.     One third, 24 men, have kept their PSA less than 5 with further cycles of TIP. 

3.     After an average of 5.5 years, slightly more than a third, 28 men, underwent delayed local therapy (surgery, seeds, IMRT or cryotherapy). After an additional six years observation, three men have developed a rising PSA (PSA relapse).

4.     Local treatment was administered much more frequently to younger men (whose testosterone recovered more quickly when TIP was stopped)—and to men with D’Amico High-Risk category disease (PSA > 20 or Gleason 8,9,10)—compared to older men and to men who were in the D’Amico Low-Risk or Intermediate-Risk categories.

5.     Mortality from prostate cancer was low.  After twelve years only three men (4%) died of prostate cancer, and none of the remaining 70 men developed metastatic disease. This result compares favorably to a group of 350 men with similar-stage prostate cancer treated with immediate surgery whose ten-year outcome was reported in the New England Journal of Medicine in 2005.⁴ In this group fifteen percent developed metastases and an additional ten percent died of prostate cancer. 

Unfortunately TIP, like all forms of prostate cancer treatment, is associated with a number of undesirable side effects including weight gain, muscle weakness, absent sex drive and hot flashes. However, for most men these side effects are either treatable⁵ or reversible.  Even so, as we have reported in the summary above, many men treated with TIP will, at some point, require further treatment, either with additional TIP or some form of local therapy.

All this not withstanding, in my mind there is no doubt that Testosterone Inactivating Pharmaceuticals (TIP), when appropriate and applied in a timely manner, acts effectively to control prostate cancer.

References:  Copies of all the articles referenced in this blog are available at our webpage  http://prostateoncology.com/education/publications

_________________________