Sir Spheres for Liver Metastases from Prostate Cancer

BY MARK SCHOLZ, MD

Cancer that spreads outside the prostate gland is what makes prostate cancer dangerous. Metastatic prostate cancer cells cause malfunction by impeding normal function. Some organs, like lymph nodes for example, continue to function quite nicely, even if the degree of cancer spread is extensive.  Lymph node spread, therefore, is the least dangerous form of prostate cancer metastases.  At the other end of the spectrum is the liver, which is far less tolerant.  The seriousness of bone metastases, the most common site of prostate cancer spread, lies about half way between that of node metastases and liver metastases.


The earliest stages of metastases are microscopic and therefore invisible even with the best available technology. To be detected with the best available PET scan technology, small tumors must measure more than 1/8 of an inch across. For detection with standard CT scans and MRI scans, more than a half-inch sized tumor is necessary. Since the presence of metastases is such a defining issue when describing a cancer’s character, men who are newly-diagnosed are labeled as low, intermediate or high-risk depending on their estimated likelihood of micro-metastatic disease. Liver metastases are extremely rare at the time of initial diagnosis of prostate cancer. When they occur it is usually after many years of ongoing treatment for known metastatic disease in the bone.


Prophylactic treatment with hormone therapy, chemotherapy or radiation to treat the possibility of micro-metastases is common for high-risk prostate cancer and occurs maybe half the time in intermediate-risk prostate cancer. The goal is to cure the micro-metastases at an early stage when they are most susceptible to eradication, thus preventing the future development of detectable metastases which is what makes cancer life threatening.


When talking about prostate cancer, even though this is a blog about metastases, it should always be remembered that many common types of prostate cancer never spread. These low grade “cancers” are genetically distinct and represent a totally different category of disease.  However, when discussing the type of prostate cancer that is capable of metastasis, the following factors impact how dangerous it is:

1. The site of spread.
2. The extent of spread
3. The tumor cell growth rate
4. The efficacy of available treatment

As noted above, the liver is far less tolerant to metastatic invasion than bone or lymph nodes.  In addition, because liver metastases tend to occur in men with advanced disease, tumor growth rates tend to be brisk. Also, the most commonly administered treatments, hormone therapies and chemotherapy, have often already been tried before liver metastases first develop. The advent of liver metastases, therefore, usually represents a very serious and life threatening issue.


Liver metastases may first be suspected when standard blood tests such as ALT, AST or ALP which are components of a hepatic panel blood test, register outside the normal range. Investigation into their cause often leads to doing a CT scan or MRI scan of the abdomen and pelvis to confirm the presence of disease in the liver. Alternatively, a scan may detect abnormal spots in the liver during routine periodic scanning that is being performed as regular surveillance.


Hormone therapy with Lupron, Zytiga and Xtandi, or chemotherapy with Taxotere, Jevtana and Carboplatin, is the standard approach to treatment for liver metastasis.  However, these treatments may have already been tried or may no longer be effective.  Since liver failure is tantamount to death, prostate cancer growth in the liver needs to be stopped immediately, regardless of how the disease is faring in the bones or nodes.


Much that has been learned about the treatment of liver metastases comes from reviewing common methods for managing metastatic colon cancer. The liver is the cancer’s preferred site of metastatic spread for colon cancer.  Treatments that have been employed include surgery, radiation and blockage of the blood supply to the liver by embolization of the arteries, all with variable success.  More recently, radioactive microspheres injected directly into the tumor, called SIR-Spheres, have shown notable efficacy with very tolerable side effects.


Prostate cancer and colon cancer are similar in that they are both adenocarcinomas which means they are derived from glands. Therefore, they are likely to have similar susceptibility to radiation.  As such, we have been administering SIR-Spheres to a limited number of prostate cancer patients with liver metastases.  Results have been encouraging with a notable improvement of survival compared to our historical experience treatment patients with liver metastases without SIR-Spheres.  Our preliminary results using SIR-Spheres in six patients is being presented at the 2016 Genitourinary Cancers Symposium - San Francisco in January 2016.

When “No Action” Can Be “Right Action”

BY RALPH BLUM

Back in 1990, when a suspicious lump was discovered on my prostate, my ignorance of the prostate gland and the possibility of prostate cancer was monumental. No one in my family or even among my close friends had ever had prostate cancer, and it never occurred to me that I might one day have the disease.

Now, 25years later I am still alive, the average man over 50 is more aware of prostate cancer, and also many less toxic and more effective treatment options are available. And yet one thing has not changed: just hearing the doctor say, “I’m afraid it’s cancer,” can leave even the most pragmatic man planning the music for his funeral.

Truth is there is still a lot of misinformation and misunderstanding out there about this disease. So here are some facts that I hope will alleviate some of your fears, and also clarify why I still contend that if you have to have cancer, prostate cancer is the best deal in town.

Prostate cancer is unique among cancers because the mortality rate is so low. According to the American Cancer Society, more than 2 million men who have been diagnosed at some point are living with the disease in the U.S. It’s difficult to determine actual prostate cancer survival rates because most men are around 70 years old when diagnosed, and many of them will die from medical problems unrelated to the disease. But if you check out the “relative” 5-year survival rate of all stages of prostate cancer, you will find it is almost 100%. And that almost 100% of men with low-risk or  intermediate-risk disease live more than 10 years after diagnosis.

Why is it that the statistics for prostate cancer are so much less frightening than for other cancers?
 
1)    The PSA test is an early warning system that other cancers don’t have.
2)    It can easily be diagnosed at an early stage.
3)    In most cases it has an exceptionally slow growth rate.
4)    Extremely effective monitoring and treatment is now available.
5)    It has a pattern of spread that spares critical organs like the brain, lungs and liver.
6)    There is a safety net like no other called “hormone blockade” that induces remissions lasting more than 10 years in men with relapsed disease after surgery or radiation.

So instead of thinking about your funeral, what you really want to be focusing on is not rushing into some form of radical treatment that will virtually guarantee  some degree of impotence or incontinence.

It appears that patients and doctors alike struggle with the idea of “watching” anything called cancer. But unless you have the less common high-risk form of the disease, my advice to you is to consider “Active Surveillance” really carefully, especially if you are over 70. Because bottom line—and it bears repeating—out of over 200,000 men in the U.S. diagnosed annually with prostate cancer, the overwhelming majority will die with the disease, and not from it.

The AZURE Shade of Blue

BY MARK SCHOLZ, MD

Patients frequently ask their physicians, “Am I stage A, B, C or D,” without realizing that the original purpose of a lettering system was simply to guide urologists in the selection of candidates for surgery. While stage matters, a combination of PSA level and the Gleason grade is a better way to assess disease status. So rather than using stage, it’s best to incorporate all three factors together—PSA, Gleason and stage—to divide prostate cancer into five broad categories or Shades of Blue.

Using standard doctor terminology, the AZURE Shade of Blue is essentially the same thing as “High-Risk” prostate cancer. “Risk” refers to a higher probability of relapse after surgery or radiation compared to men in SKY or TEAL shades. Therefore, men in AZURE are usually treated with combination therapy consisting of IMRT, a seed implant and testosterone inactivating pharmaceuticals (TIP) for 18 months.

 

Here are the specific factors that define AZURE. 

1.     No previous treatment with surgery or radiation.

2.     Bone and body scans without metastasis.

3.     One or more of the following three factors:

a.     PSA above 20 and less than 100, or

b.    Gleason score above 7, or

c.     A prostate tumor felt by digital rectal exam extending across the midline of the gland or outside the capsule.

Men with two or three of these factors are still classified as AZURE. Men with spread to pelvic nodes are classified as INDIGO.  Men with metastasis that has spread to bones or to nodes outside the pelvis are ROYAL. Radiation—rather than surgery—is the preferred treatment for AZURE because of the risk for cancer infiltration outside the prostate. Safe surgical removal is next to impossible when the disease extends into surrounding organs.  Incomplete cancer removal means radiation will be required to “mop up” the residual cancer anyway. Therefore, most experts recommend radiation because the risk of needing both surgery and radiation is so much lower.

Within the AZURE category exist subcategories of men who have a relatively more advanced type of AZURE. For example, some men have larger tumors, higher PSA levels above 40 and Gleason grade 9 or 10.  Men in this situation might want to try to further enhance their cure rates by adding a more potent form of TIP such as Xtandi or Zytiga to their therapeutic plan.  Also, a short course of Taxotere chemotherapy can be considered.

My last blog (about TEAL) reviewed potential side effects from surgery and radiation.  The side effects of TIP become more severe when treatment duration is prolonged. The three most troublesome TIP-related problems are low libido, weight gain and fatigue. However, libido recovers after TIP is stopped.  Weight gain and fatigue can be reduced with diet and exercise. Yet as we all know, maintaining a consistently good diet and getting adequate exercise over long periods of time can be very challenging.  Obtaining professional support from a trainer or a physical therapist is one way to sustain a disciplined program on an ongoing basis. 

 

Other common TIP side effects can be controlled with medications.  Hot flashes regress with a low-dose estrogen patch. Calcium loss from the bones can be prevented with an injection of Prolia every six months, a Fosamax pill weekly or with an Actonel or Boniva pill monthly. Mood swings can be reduced with low-doses of an antidepressant called Effexor.  Effexor also has salutary effects on hot flashes. Breast growth can be prevented with an estrogen-blocking pill called Femara.  When libido is chronically low, men tend not to care about getting erections, so taking daily Cialis should be considered standard for men receiving TIP.

Unfortunately, many doctors have limited knowledge about how to prevent TIP side effects. Patients, therefore, need to protect themselves by getting as much education as possible. Certain side effects, such as breast growth, erectile atrophy and osteoporosis, are preventable with appropriate intervention.  However, once they are allowed to occur, these effects can be permanent.

While side effects are an important consideration, men in the AZURE group have a relatively more dangerous type of prostate cancer compared to men with SKY or TEAL.  The appropriate treatment stance, therefore, is to be aggressive—to get cured.

The good news is that the majority of men with the AZURE stage of prostate cancer will be cured with the treatment approach outlined above.  Studies have shown that the best results come from using IMRT, radioactive seed implantation and testosterone inactivating pharmaceuticals (TIP) in combination with each other. 

So if you do find yourself in the AZURE zone, don’t despair: There is good reason for hope.

Xtandi as Primary Therapy

MARK SCHOLZ, MD

The largest oncology market in the world is the early-stage prostate cancer market. Every year, 80,000 men undergo surgery. Even greater numbers are treated with IMRT, seed implants, cyberknife and proton therapy.

What about Hormones?
Hormone therapy is another popular treatment approach, especially for older men. For example, the Capsure database indicates that hormone blockade is used more commonly than radioactive seeds.  Randomized clinical trials also indicate that intermittent hormone therapy is feasible:  Men who stop hormone therapy and take “treatment holidays” have identical survival rates to men who stay on continuous treatment.

Standard Treatment is Deplorable
Since PSA screening started in the early 1990s, surgery and radiation have been all the rage.  Aggressive treatment has succeeded in reducing annual prostate cancer mortality by half a percent. Now “only” 2.5% of men die of prostate cancer. Previously, prior to the advent of PSA screening, 3% of men died from prostate cancer. The “cost” of achieving this mortality reduction, however, should be measured in terms of diminished quality-of-life. The frequency of serious side effects is typically under-appreciated. For example, at the highest quality treatment centers only 5% of men recover sexual function similar to what they enjoyed prior to treatment. 7% of men are grossly incontinent; 50% have stress incontinence and 20% chronically ejaculate urine.

The reason for such a minuscule impact of local treatment on survival is obvious: Surgery and radiation are only effective when implemented prior to metastases. Ironically, until metastases occur, local treatment is unnecessary. After metastases, local treatment is ineffective.  Logically, early therapy with an anticancer agent with both local and systemic effects will result in better cancer control.

Active Surveillance is Now Mainstream
It is now known that Low-Risk disease (Gleason 6, PSA < 10, Stage T1c or T2a) can safely be monitored with active surveillance. At worst, active surveillance has the positive effect of delaying treatment and postponing treatment-related side effects like impotence and incontinence. With delayed local treatment, men benefit from the fact that medical technology is continually improving.  The best case scenario of active surveillance is when cancer never progresses and men are able to avoid treatment indefinitely.

Widely-accepted active surveillance methodology relies on periodic random 12-core needle biopsies.  Now encouraging studies are reporting that 3T multiparametric MRI detects high-grade disease more accurately than biopsy.  Also, new computerized imaging technology enables doctors to record the exact location of the cancer within the prostate gland so that areas of known disease can accurately be resampled with targeted biopsies.

Hormone Therapy Causes Remission of Localized High-Risk Disease with Reversible Side-Effects
A study using a six-month induction course of abiraterone (Zytiga) shows complete pathologic remission or close to complete remission in a third of men with High-Risk disease. Logic predicts that complete response rates will be substantially better in men with Intermediate-Risk prostate cancer.

For the most part, side effects of hormone therapy are reversible or preventable—hot flashes, breast enlargement, osteoporosis, and erectile dysfunction respond to DepoProvera, Femara, Prolia and Viagra respectively. Muscle atrophy can be counteracted with strength training. Low libido dissipates after therapy is stopped. Careful diet averts weight gain.

However, the reversibility of hormone therapy depends on the resumption of normal testosterone production after treatment is stopped. Unfortunately, LHRH agonists, the traditional hormone medications employed, often induce lingering low testosterone levels. Some men, particularly those over 70, are saddled with permanently low testosterone.

Xtandi is Well-Suited to Intermittent Administration
Xtandi has several potential advantages over LHRH agonists.   First, it is more potent.  Studies show that Xtandi has notable activity even after cancer had developed resistance to LHRH agonists. Second, Xtandi blocks testosterone activity rather than suppressing testicular production. Therefore the risk of delayed testosterone recovery or long-term testicular atrophy is circumvented.  Third, though perhaps this is a relatively small issue, most men would rather take a pill than a shot.

An Observational Trial of Intermittent Xtandi Could Revolutionize Intermediate-Risk
Laurence Klotz, M.D. prospectively accrued men with Low-Risk (and some Intermediate-Risk) prostate cancer to a simple observational trial starting in the mid-1990s.  By simply reporting a very favorable ten-year mortality rate he brought about a total change in clinical practice patterns in the United States and throughout the world.

Intermittent hormone therapy as primary treatment is certainly feasible for localized prostate cancer.  Active surveillance methodology has been refined with improved imaging.  New genetic tests can estimate cancer aggressiveness with more accuracy. The animus to delay treatment, even for a few years, is increasing as the pace of technological innovation accelerates and the hope for the discovery of less toxic treatment increases. Now, with the recent FDA approval of this more potent, more convenient oral agent that is free of lingering effects, the impetus for men to embark on a six-month induction course of Xtandi followed by active surveillance will be even greater.

Selecting a Meaningful Endpoint for an Observational Clinical Trial
Published studies already document excellent survival with primary hormone therapy (see attached). Hence, the most meaningful clinical outcome measure of Xtandi efficacy would be its capacity to forestall or delay local treatment. The objective endpoint, therefore, should measure the number of months or years before local therapy is required, starting from the date of initiating Xtandi and ending when (and if) local therapy is ultimately implemented.

While complete avoidance of local treatment may be a frequent occurrence (in the men who show durable responses to a single cycle of Xtandi) it can be anticipated that men who have locally recurrent disease and whose initial experience with Xtandi was tolerable, may elect to use repeated cycles of Xtandi at the time of recurrence rather than risking the potentially irreversible side effects of local therapy. Conversely, the men most likely to select local therapy are those who experience a particularly short treatment holiday or suffer more severe hormone-related side effects.

A six-month course of Xtandi can also function as a “disease-related stress test.” Men in the subgroup manifesting either high PSA nadir or rapid disease recrudescence after treatment are those most likely to harbor an aggressive prostate cancer variant. Thus, this initial “test” using Xtandi will help ensure that men referred for radical local therapy are those who actually need it.

A Landmark Study: Surgery for Prostate Cancer

BY MARK SCHOLZ, MD

Between in 1994 and 2002, 731 men with an average PSA of 7.8 and age 67 volunteered to have either immediate surgery or observation based on a coin flip. The New England Journal of Medicine reported the 10-year survival statistics this week. What follows is a summary of the statistical outcome of the study.  I think the raw numbers speak for themselves.

Of the 364 who had surgery, 21 men died of prostate cancer.  Of the 367 assigned to observation 31 men died of prostate cancer.  So with observation, the risk of dying was less than 9%.  However, there was still a 6% chance of dying even with immediate surgery.  The net difference between observation and immediate surgery was 3%.

During the first 30 days after surgery there were a number of very serious side effects including one death.  Additionally, there were two men with blood clots in their legs, one stroke, 2 with blood clots in the lungs, 3 heart attacks, 1 man with renal failure requiring dialysis, 10 who required additional corrective surgery, 6 who required additional blood transfusions and 6 who still had urinary catheters more than 30 days after surgery.

Forty-nine men (17%) who had surgery compared to 18 men (6%) who underwent observation “have a lot of problems with urinary dribbling,” some losing larger amounts of urine than dribbling but not all day,” others who “have no control over urine,” and the remainder who “have an indwelling catheter.”

Two hundred thirty one men (81%) who had surgery compared to 124 men (44%) who underwent observation had erectile dysfunction defined as the inability to attain an erection sufficient for vaginal penetration.

Further statistical analysis of a subgroup of men with High-Risk prostate cancer indicated an 8% improved chance of not dying of prostate cancer compared to observation. Also, men who had surgery who were in the Intermediate-Risk or High-Risk category were 10% less likely to develop bone metastases within 10 years compared to the men on observation.

There was no difference in the incidence of mortality or metastases between surgery and observation in the men in the Low-Risk category.

This high-quality study, published in the most prestigious medical journal in the world evaluating the risks and benefits of surgery, required 18 years to perform.  It shows a barely discernible benefit resulting from immediate surgery for men with High-Risk prostate cancer. These findings are quite similar to another large randomized trial of surgery versus watchful waiting that reported 15-year results in the New England Journal of Medicine in May 2011.

The bottom line is very clear:  For men with Low-Risk disease, where surgery is concerned, the treatment is definitely worse than the disease.  Even more striking, is the relatively small survival benefit for surgery in men with High-Risk disease. One can’t help but wonder if the substantial risks of immediate treatment-related side effects outweigh the small benefit in survival.  

Why Choosing Treatment for Prostate Cancer is so Difficult

BY MARK SCHOLZ, MD

Selecting the right treatment for prostate cancer is unbelievably challenging. With other cancers, where survival is paramount, the choice is simple—do everything that can be done! But with prostate cancer, quality-of-life considerations play a much larger role, since the treatments available at this time can seriously impact the quality of your life. For some men, once their type of prostate cancer is determined, choices are somewhat easier. For example, Low-Risk prostate cancer is relatively harmless and can be safely monitored. Treatment is often deferred because the cure is worse than the disease. Decisions about treating High-Risk prostate cancer are also fairly straightforward. Most experts agree that treatment with combination therapy is appropriate. The men faced with the biggest dilemma, however, are the 60,000 to 80,000 men diagnosed every year with Intermediate-Risk prostate cancer. 

All too often, prostate cancer treatment causes some degree of impotence and incontinence.  Who wants to face sexual dysfunction unless it is absolutely required for survival? Men with Intermediate-Risk disease often feel like they are in limbo because withholding treatment for their cancer is slightly risky, but so is the treatment.  

The situation is even more confusing because if you talk to men who have already been through treatment, some seem to have weathered surgery or radiation just fine. Unfortunately, if you keep inquiring, you will come across men who feel their lives have been ruined. Men reflecting on these issues face a hard reality: choosing one of the existing treatment options can immediately destroy quality of life, while forgoing immediate treatment means having to live with the ongoing possibility that delaying treatment might someday translate into fewer years of life.

Even after careful analysis, lingering questions are inevitable, since the very best that medical science can offer is an estimate of risk. The ambiguity of these circumstances, however, leaves a lot of room for personal preference. Once a man is thoroughly educated about all his options, he, rather than the physician, is in the best position to select treatment.  After all, he is the one who will spend the rest of his life living with the consequences.

Still, there is good reason to expect things to change, hopefully in the near future. Effective ongoing research is progressing rapidly in the areas of imaging, genetics, immune therapy, and targeted pharmaceuticals. The fact that prostate cancer, in the majority of cases, is a slow-growing condition, also works to the patient’s advantage.  Every year that goes by we are one step closer to less toxic solutions. As Ralph and I always emphasize, “If waiting makes sense, time is on your side.”

*See the What’s Your Type brochure at PCRI.org for a full explanation of the difference between Low, Intermediate and High-Risk prostate cancer

Adjuvant Hormone Blockade (HB) after Surgery for Men with Aggressive Disease

BY MARK SCHOLZ

The term "adjuvant" means treatment “added to” the primary or initial treatment. When the primary treatment is surgery, even when all detectable disease is removed, there remains a statistical risk that the cancer will return due to microscopic cancer cells left behind. Men with high-risk features such as extra-prostatic extension or high Gleason score face a higher risk of recurrence.

We need to understand the rationale for considering hormone blockade (HB) in treating aggressive prostate cancer. However, the scientific studies supporting this approach are still preliminary. Patients who have aggressive prostate cancer now are forced to make the best treatment decision possible with the data currently available.

In May 2011 the Journal of Clinical Oncology, Dr. Tanya Dorff and others reported on 351 men, average age 60, who were treated with two years of Casodex & Zoladex initiated immediately following surgery. The average PSA prior to surgery for men in the study was 7.8. PSA had to be less than 0.2 after surgery to be eligible for participating in the study. After completing two-years of hormone blockade half the men recovered normal testosterone within a year. By 18 months, 89% had recovered. After five years, relapse free survival rates of over 90% are impressive for these high risk patients where “high risk” is determined by historical relapse rates that approach 50%.

Almost all previous studies evaluating the benefit of adding HB to surgery showed no benefit. The resultant lack of benefit was probably due to the very short duration of HB—usually for only three months. There is one study by Dr. Martin Gleave at Vancouver General Hospital, comparing three months with eight months of HB after surgery, and showing a slightly better outcome for men with aggressive disease when HB was continued eight months.

The most compelling previously published study of adjuvant HB, authored by Edward Messing was performed in 98 men with proven node metastasis, half of whom received immediate HB.  In the case of men who did not get adjuvant HB, the relapse rate was quadrupled.

Adding HB to radiation for men with bad prognostic factors is standard because several large randomized prospective trials show that HB reduces relapse rates and prolongs survival. Given these indisputable benefits, it is surprising that a similar study to evaluate the benefit of longer duration HB after surgery has never been undertaken.

Long-term HB after surgery results in a much lower incidence of PSA progression compared to historical PSA relapse rates that have been reported in multiple studies. However, actual proof that long-term hormone blockade after surgery will enable men to live longer will require a randomized prospective trial.  The table below lists the projected five year outcome in the study by Dorff et al. depending on the different stages of the men participating in the study.

CLICK TABLE FOR LARGER VIEW