The ROYAL Shade of Blue

BY MARK SCHOLZ, MD

Men in the ROYAL shade have metastatic prostate cancer that has spread to bone, or, to lymph nodes outside the pelvis, or, they have a PSA over 100, or, they have a rising PSA with a low testosterone level. Metastases are typically detected by doing a body scan or a bone scan.

Men with advanced prostate cancer tend to live longer than men with other types of cancer. One major reason is because prostate cancer doesn’t usually spread to critical organs like the brain, the liver or lungs.  Another reason is the availability of so many effective treatments. Standard hormonal treatment with Lupron and Casodex, for example, can induce long remissions. And just recently, the FDA approved two new types of hormone therapy—Xtandi and Zytiga. These medications are so powerful they can induce remissions in men who have become resistant to Lupron and Casodex. In addition to Xtandi and Zytiga, two non-hormonal treatments—Provenge and Xofigo—have also been recently approved by the FDA.

Since so many effective treatments are available, wasting time on a treatment that has stopped working is a terrible crime. Therefore, after initiating a new treatment close monitoring of disease status is essential. Monthly blood tests and PET scans with sodium fluoride or carbon 11 acetate help to determine when a specific treatment stops working. Ineffective treatment should be stopped as soon as disease progression occurs so that a more effective therapy can be started in a timely fashion.

Treatment for ROYAL
Men in the ROYAL category who have never had hormone therapy should start testosterone inactivating pharmaceuticals (TIP).  The standard approach is to begin with Lupron and Casodex in combination.

Men who have become resistant to Lupron, but have fewer metastases and a slower PSA doubling time, should take Provenge to boost their immune system. Studies show that Provenge works better when treatment is started earlier. Preliminary research has also suggested that Provenge might be more potent if it is combined with spot radiation directed at a site of metastatic cancer. Studies to evaluate this possibility are ongoing.

With or without Provenge, radiation to cancer metastases has historically been reserved for controlling bone pain, a use for which it is quite effective. However, newer thinking suggests that radiation directed to all known sites of metastases—when the numbers of metastases is relatively small, say less than five—may occasionally lead to longer remissions.

Potent medications to strengthen the bones—Xgeva and Zometa—are routinely recommended when bone metastases are present. These medications have three potential benefits: They inhibit cancer growth in the bones; they reduce bone pain; and they help counteract calcium loss that hormonal therapies commonly cause.

If men in ROYAL have the type of prostate cancer that progress quickly while on Lupron and Casodex, the first step should be to stop Casodex and start one of the following three options:

1.    Second-line TIP such as Zytiga or Xtandi

2.    Chemotherapy with Taxotere or Jevtana

3.     Xofigo, a form of injectable radiation

Three additional treatment options can be considered if these first three options are no longer effective in controlling the disease:

1.       Combination chemotherapy using Carboplatin or Xeloda with a Taxane or the combination of both Revlimid and Avastin added to a Taxane. 

2.       The “off-label” use of Cabozantinib (XL-184), a medication being researched for prostate cancer but already FDA-approved to treat thyroid cancer

3.       Other investigational medications

Investigational trials represent an opportunity for patients to get medications prior to FDA approval.  A patient’s enthusiasm for embarking on a study that uses an investigational medication, however, needs to be tempered by what is actually known about the effectiveness of the specific medication.  Some medications are so new that even the investigators performing the trial don’t know if they are going to work or not.

While on treatment men need to have their blood monitored monthly by checking PSA, PAP, ALP and CTC levels. Medication side effects and cancer-related problems also need to be screened for with monthly blood tests such as CBC, a metabolic panel and a hepatic panel.  A periodic bone scan and body scan should be performed to track the disease status.  Two to three months after starting a new treatment, if the blood markers are not improving, a change in therapy needs to be considered.    

Reducing the Side Effects of Treatment
Fatigue is one of the biggest challenges faced by men in ROYAL. First, both chemotherapy and radiation can cause tiredness. Second, muscle loss is a frequent occurrence from TIP-induced, low testosterone.  Stimulants such as Provigil or Nuvigil may be helpful, but the most important priority is to counteract muscle loss with consistent, diligent exercise. Resistance training with weight lifting is only known effective method for restoring muscle mass.

Xgeva and Zometa cause gum recession and infections of the jaw bone, a condition called osteonecrosis.  This phenomenon is much more likely to occur after a tooth extraction so men on this therapy are advised to avoid extractions as much as possible.  Osteonecrosis, when it occurs, generally resolves, albeit slowly, after Xgeva or Zometa are stopped.

A variety of different medications can be useful for reducing side effects from hormone therapy. Low-dose estrogen skin patches can control hot flashes. Excessive mood swings can be stabilized with low doses of antidepressant pills. Breast enlargement can be prevented with Femara. 

Final Thoughts

In this blog I have outlined a traditional, sequential approach to treatment selection.  Strong consideration, however, should be given to using these active new agents in combination and at an early stage.  Men in ROYAL have a potentially life-threatening type of prostate cancer. An aggressive and imaginative treatment plan should be designed that has the specific goal of attaining and maintaining a complete remission, i.e. a PSA less than 0.1. In my opinion, the standard “one treatment at a time” approach that is so popular at academic centers, it is a grave disservice to the men fighting aggressive prostate cancer. 

Did You Know: Stress Comes in Three Shades

BY RALPH BLUM

Our central nervous system, endocrine and immune systems communicate constantly with each other to maintain homeostasis—a healthy balance that promotes health and healing. Then at moments of perceived threat, these systems respond almost instantaneously with a chain of physical responses commonly known as fight-or-flight.

Originally evolved to protect us from acute physical danger—like an attack from a wild animal—the fight-or-flight system is a brilliant mechanism for handling acute, concrete threats, and then returning to homeostasis when the threat has passed. However, this emergency response system was not designed to be continuously activated, and when it receives a threat message for which there is no swift resolution, the result is chronically elevated levels of stress hormones that repress the action of the immune system. In fact, according to Bruce Lipton, Ph.D. stress hormones are so effective at curtailing immune function that doctors provide them to recipients of transplants so that their immune systems wouldn’t reject the foreign tissues.

In today’s world, the challenges most of us face have shifted from immediate physical threats to unending or chronic emotional ones. The term “stress” has become a generic term that we commonly use instead of specifically describing feelings as varied as frustration, exhaustion, anxiety, worry, grief, fear and despair. Yet these emotions, generated by stress, can trigger the same flight-or-fight response system that our body deploys to survive a close encounter with a lion, without, however, the release of escaping from that encounter and restoring homeostasis.

There are three distinct categories of stress which, taking my cue from Dr. Scholz’s Blue Shades of prostate cancer, I have designated GREEN, BLINKING YELLOW and FLASHING RED to indicate the different stress levels.

It is important to point out that not all stress is harmful. Brief episodes of stress heighten our alertness, sharpen our senses and actually improve immune function. It is what the flight-or-fight response was designed for and I consider them as GREEN stress responses.

The second category—BLINKING YELLOW—is referred to by researchers as “tolerable stress.” This is stress that could become harmful, however we have the capacity to recover though relationships, and through practices like regular exercise, meditation, healthy eating and adequate sleep. Though we are still disturbed by episodes of BLINKING YELLOW stress, if we recognize and respond to them at their onset, we are able to regain and restore internal balance.

Prolonged or toxic stress is the FLASHING RED variety.  In the grip of toxic stress, we don’t fully regain our equilibrium because the healing relationships and practices that may have worked with tolerable stress are insufficient and thus no longer successful. If it accumulates in our bodies, toxic stress “dysregulates” the systems that protect health and healing.

Some wags have suggested that a few large margaritas or smoking dope might help! But the hard fact is: When the BLINKING YELLOW occurs you need to act, to use available remedies so you do not progress to the toxic, FLASHING RED degree of stress. Strange to say (And I found it a pleasant surprise) activities like meditation and yoga seem to do the most to reestablish homeostatic balance. 

The INDIGO Shade of Blue

BY MARK SCHOLZ, MD

Prostate cancer is a vast and complicated field. To make it more manageable, PCRI breaks it down into five separate Shades of Blue. Men with recurrent disease after surgery or radiation are in the INDIGO shade. The outlook for men with INDIGO is optimistic.  Some men can still be cured. For those who can’t, the vast majority will be able to keep their disease in check with treatment.

A rising PSA confirmed on sequential measurements is the most common sign of a relapse.

Less common signs of relapse are:

a.     A positive biopsy from the prostate fossa. The “fossa” is where the prostate gland used to be prior to surgery (also, a nodule may or may not be felt on digital rectal examination)

b.    Persistent prostate cancer detected in the gland after radiation by needle biopsy, or by scans or by digital rectal examination

c.     Prostate cancer that has been detected in the pelvic lymph nodes by a scan.

 

People need to be aware that a PSA elevation after surgery or radiation can occur for noncancerous reasons, including incomplete removal of the prostate gland after surgery, prostate tissue “left behind” in the fossa, results in low but persistent levels of detectable PSA.

After radiation, the prostate gland remains in place. Therefore, in men who have been recently treated with radiation combined with testosterone inactivating pharmaceuticals (TIP), discontinuing TIP will lead to testosterone recovery which causes PSA levels to rise. Also, radiation-induced inflammatory reactions can occur in residual prostate gland cause a PSA rise. This rather common phenomenon is called the “PSA Bump.”  It’s essential to be aware of the noncancerous causes of PSA elevation so that well-intentioned but unnecessary treatment can be avoided.  

INDIGO men will require imaging studies to determine the extent of the disease.

1.     Color Doppler or MRI is used to look for residual cancer located in the surgical fossa or in the prostate gland in men previously treated with radiation. 

2.     Pelvic MRI or CT scans are used to look for spread to pelvic lymph nodes. (Carbon 11 acetate PET scan is more accurate than CT or MRI but is still considered to be under investigation)

3.     CT or MRI of the abdomen and bone scans are used to detect the presence of more distant spread to lymph nodes outside the pelvis or to the bones. Scan-detected disease outside the pelvis or in the bones changes the shade to ROYAL. 

Treatment for INDIGO

Treatment options include observation, radiation, TIP, cryotherapy, or combinations of TIP with radiation or cryotherapy. Treatment selection is guided by four factors—the cancer location, the original Shade, the PSA doubling time and a patient’s age. By incorporating all four factors into the treatment selection process, the risk over-treating, i.e., incurring unnecessary side effects from treatment, is reduced.  Awareness of all four of the factors also helps to avoid another common mistake—under-treating—which reduces the likelihood of achieving durable remission.

An isolated “local” relapse is one that appears to be localized inside the prostate after radiation. Local relapse may be curable with cryosurgery alone.  An isolated “local” relapse in the prostate fossa after surgery may be curable with radiation alone.

When no local disease can be detected and when all the scans are clear—termed a “pure” PSA relapse—treatment selection will be influenced primarily by the rate of PSA rise. For example, if the PSA is doubling in less than six months, aggressive combination treatment with TIP plus radiation or TIP plus cryosurgery may be best.  If the PSA doubling rates is between six and twelve months, a less aggressive treatment approach with radiation alone, cryosurgery alone or intermittent TIP alone, is reasonable.  When the doubling time is greater than 12 months, observation without immediate treatment may be considered.

A patient’s age and the original shade at the time of diagnosis also need to be factored into the treatment decision-making process. Men who are more elderly can “step down” the intensity of their treatment plan by temporizing with mild forms of TIP, such as low-dose Casodex. Younger men, who prior to relapse, were in the High-Risk (AZURE) category may want to consider prophylactic pelvic lymph node radiation, a more intensive type of TIP with Zytiga or Xtandi or even chemotherapy with Taxotere.    

Side Effects of Treatment—INDIGO

The residual prostate gland after radiation is anatomically close to the rectum, urinary bladder, and the nerves that control erections. Therefore treatment with salvage radiation or cryotherapy increases the risk of additional long-term sexual, urinary or rectal dysfunction beyond what has already caused by the original surgery or radiation.

Men who are already struggling with incontinence problems from previous surgery may experience further decline in their urinary control when they undergo radiation directed at the fossa. Men who have cryosurgery for a relapse after radiation almost always become impotent. Incontinence can also occur. Surgery to remove a previously radiated prostate causes very high rates of impotence and incontinence.

Radiation to the pelvic lymph nodes can cause damage to the surrounding intestines with symptoms of cramping, diarrhea or loss of rectal control. Since the advent of intensity modulated radiation (IMRT), however, bowel damage from pelvic radiation is a much less common event.

TIP is a common component of the treatment plan for men in the INDIGO category. The severity of side effects from TIP increases when it is continued for a longer duration. As a result, intermittent TIP is very popular. The intermittent TIP protocol is to continue treatment for six to twelve month after which TIP is stopped and a treatment “holiday” is ensues—assuming the PSA drops below the 0.1/ng threshold. The next cycle of TIP is resumed when the PSA rises back to the original PSA baseline, or up to five, whichever is lower.

The most troublesome side effects from TIP are weight gain and fatigue. Maintaining a careful diet and doing regular exercise is very helpful in offsetting these problems. Low libido, however, only responds to a treatment holiday. Daily Cialis is necessary to reduce the risk of permanent erectile atrophy.

Other side effects of TIP typically respond well to the following medications:  Low-dose estrogen controls hot flashes. Osteoporosis can be prevented by Prolia, Boniva or Actonel. Mood swings stabilize with antidepressants. Breast growth is prevented with nipple radiation or Femara.  Erectile dysfunction can be counteracted with Viagra.

Finding the right type of treatment for men in INDIGO is achieved when the benefit of treatment is weighed carefully against the potential for treatment-related side effects. Fortunately, a wide variety of effective treatment is available for men with INDIGO and the majority will have their disease controlled on a long term basis.

So much for getting “the Blues” when you have prostate cancer!

Fighting Stress: The Amygdala as Super-Hero

BY RALPH BLUM

Writing about “Stress Management” has been a Pandora’s box for me. I am convinced that, along with taking charge of my own recovery, an understanding of stress—it’s nature, how it operates, how to manage it—has served me well in facing the dragon of prostate cancer. Whether you are newly diagnosed or coping with bone metastases, I hope my exploration of stress will serve you—and give you renewed hope.

 

Stress is a poisonous compound of worry, anxiety, exhaustion, regret, fear, despair, and all the other toxic tourniquets that bind us to the wheel of suffering. In most people’s lives, these negative feelings are registering in our bodies chemically and organically much of the time. So let’s take a close look at the factor of stress in our lives, and see how it weighs down and impedes the process of recovery.

 

Really ancient, the word “stress” is a form of the Middle English destresse, which is in turn derived, through Old French, from the Latin stringere, “to draw tight.” Used first in physics to refer to strain on a material body, by the 1920s stress was being applied in medical circles to refer to mental strain, or harmful environmental “agents” that cause illness.

 

In 1926, Harvard Physiologist Walter Cannon used the term “stress” for its clinical significance, describing external factors that disrupted what he called “homeostasis,” a steady state or  equilibrium ideal for our well-being and healing. Moreover, Cannon’s book, The Wisdom of the Body, was the breakthrough in understanding that we actually have a capacity to self-correct from stress, and restore homeostasis.

 

It goes without saying that a potentially life-threatening situation, like cancer creates the kind of stress that persists over time, taking a significant toll on the body and seriously disrupting homeostasis. So what can we do to alleviate chronic stress?

 

While I was looking for fresh ways to manage stress in my life, I came across an exotic “game” created by high school teacher and psychologist, Justin Galusha.  His game asks you to create 17 “Superheroes, Villains and Sidekicks” for "17 areas of the human brain.” In order to “play,” you need a name for the character, a description of that character’s super powers and/or weaknesses, the brain area where the character is found, and what it actually controls in the brain. Among the areas (and characters) he includes Cerebellum, Thalamus, Hippocampus, Temporal Lobe and the Amygdala. Since we’re not playing the game, we don’t have to look at all seventeen,  focusing on just one—the one that coordinates all the others—the amygdala.

 

I was already aware of the power of the amygdala to process emotions and manages stress, particularly when feelings of anxiety or fear are involved. Seated at the center of an exquisitely tuned and coordinated emergency response system, the amygdala is a small almond-shaped structure, buried deep within the temporal lobe, part of the brain’s limbic system.  For his game, Galusha describes the amygdala as “governing emotions related to self-preservation . . . in particular stimuli that are threatening to the organism.” And he means life threatening, So that’s what this is all about—self-preservation.

 

In Galusha’s brain game, here is how the role of the amygdala—dubbed “Amyg’DaMan”—is described:

Blessed with a heightened amygdala thanks to a freak accident in the Vidal Sassoon mouse testing facility, Amyg’DaMan knows when he can win a fight or when he needs to take flight . . . With only his superhuman ability to read facial features and govern emotions, Amyg’DaMan never gets in over his head. He sports a caveman like costume as a shout out to his ancestors. . .  Had it not been for their amygdalas they wouldn’t have known when to run from predatory trolls with extra arms or stay and slaughter innocent docile foes. This one’s for you Amygdala guy—and the quick judgment that saves your life.

The whole idea—including a hairy caricature of his club-wielding caveman hero—made me laugh. And while the conventional fight or flight options described here are not available to a man with newly diagnosed with prostate cancer, the primitive emotions are the same. Stress is the result. Laughter is one antidote. And self-preservation is the objective.

 

I’d say laughing at the vision of Amyg’DaMan whooping those four-armed predatory trolls is good anti-stress activity.

 

In my next blog I will consider stress as three-tiered, one toxic, one tolerable, and one (I was surprised to learn) both positive and useful, capable of improving the function of the immune function.