Predicting Prostate Cancer’s Future Behavior

BY MARK SCHOLZ, MD


Developing an accurate prognosis, i.e., predicting how a man’s cancer is likely to behave in the future, is the first and most important step toward optimal care. Future predictions are often looked at with some suspicion. With prostate cancer, however, our power to anticipate future cancer behavior is quite accurate unless there is a lack of thoroughness in gathering information.

The Size of the Tumor
Tumor size is a universally important prognostic sign for almost all types of cancer including prostate cancer. The method for incorporating tumor size into the Anthony D’Amico’s staging system relies on the degree of PSA elevation, the tumor grade and on how the prostate "feels" with the finger of a trained practitioner. These indicators are useful but don’t incorporate information from modern imaging. Imaging provides accurate information about tumor size and the presence or absence of extracapsular extension. These are very powerful prognostic predictors and it would be foolish to disregard their importance. As things stand presently these indicators are often used to divide the low, intermediate and high risk categories into "favorable" and "unfavorable" subcategories, each with a different spectrum of recommended treatment options.


Knowing Past Treatments Tells Something about Future Prognosis
Historically, since the total number of available treatments is relatively limited, practitioners have used a sequential "trial and error" treatment methodology that administers the standard treatment options in a fairly predictable sequence. For example, it is not uncommon for men to start with surgery or radiation. When a relapse occurs, standard hormone therapy (Lupron) is often started and given intermittently or continuously. Hormone therapy usually controls the disease for an average of 10 years. When Lupron stops working, immunotherapy with Provenge is usually follows. After Provenge, more potent hormone therapy with Xtandi or Zytiga is started. If these two agents prove ineffective, chemotherapy with Taxotere or radiation with Xofigo would be considered next.

The whole point of presenting the treatment sequence described in the previous paragraph is to convey the idea that the number of previous treatments communicates important information about that patients’ future prognosis. Having "failed" Lupron, for example, bespeaks of a much more worrisome prognosis compared to the situation where Lupron continues to be effective.


Response to Lupron, The Mother of All Metrics
The quality of the "response" to Lupron is actually one of the most powerful prognostic metrics available. The degree of PSA decline after Lupron is incredibly important. How low the PSA drops after starting Lupron is called the "PSA nadir." The specific PSA threshold used to determine a "good response" is less than 0.1. Believe it or not, there is a huge difference in prognosis between a man on Lupron for six months who has a PSA of 0.1 versus a man whose PSA levels off at 1.0.

An Established History is also a Prognostic Indicator
Another somewhat obvious prognostic indicator that is often overlooked and almost never discussed in textbooks has to do with the prognosis of men who have been diagnosed years ago -- over time it is apparent that things are turning out much better than what might have been expected based on their initial indicators. For example, take the case of a man who started off with a panoply of bad indicators—tumor is in the lymph nodes and Gleason 10—but after aggressive treatment remains in remission for 5 years. The fact that things have gone well for five years counts bigtime in his favor going forward. Remember, the original prognostic predictors of a Gleason 10 were just that, predictors. No predictor is 100% accurate. Five years of established history is a stronger predictor than the original Gleason score. The fact that things have gone well for five years, strongly indicates that the future is for that individual is bright. Such individuals have "beaten the odds."

The Location of the Tumor in the Body
Another extremely important indicator of prognosis, something that even laypeople anticipate by simple common sense, is the location of the cancer in the body. Location says volumes about how things are likely to progress in the future. For example, consider the following sequence of progressively more serious cancer sites:

•Contained within the prostate
•Extended into the seminal vesicle
•Spread to the lymph nodes
•Bone metastases
•Liver metastasis

Each of these locations is very important for determining prognosis.

This short blog is just an introduction to some of the "profiling" methods utilized in generating an accurate prognosis. Space limitations preclude discussion here about other known prognostic factors such as the size of the prostate gland (discussed in a previous blog), genetic tests and PSA doubling time. The D’Amico risk categories constitute the backbone of useful prognostic information. However, the additional prognostic information beyond the D’Amico risk categories that are discussed in this blog, provide additional useful information necessary for determining an accurate prognosis. An accurate prognosis is the starting point for accurate selection of treatment.

High Cost of Pharmaceutical Agents

MARK SCHOLZ, MD

In the last five years the prostate cancer world has been blessed with some incredible pharmacetucal breakthroughs--Zytiga, Xofigo, Xtandi, Provenge and Jevtana, just to name a few.  All these new medications are proven to prolong life and improve quality of life.  In my day to day life practicing as a prostate oncologist, I have seen with my own eyes how these new medications have transformed "hopeless" situations into genuine cancer remissions.

The extremely high cost of these new pharmaceutical agents, however, is a hot topic that I have addressed in prevous blogs. A recent editorial  from the Wall Street Journal addresses this issue with uncommon wisdom and aptly points out how potentially dangerous seemingly well-intentioned efforts to control costs can end up snuffing out the new drug development process.

Please click on the link HERE to read this short and extremely well-written editorial: http://goo.gl/F7pG8w

 

A Xofigo Update

BY MARK SCHOLZ, MD

Since Xofigo was FDA approved two years ago, the doctors at Prostate Oncology—Dr. Richard Lam, Dr. Jeffrey Turner and I—have been avid users.  So this seems to be a good time to provide an informal update of our experience with Xofigo to the present time.

The clinical trial that led to Xofigo’s approval by the FDA was a prospective, placebo-controlled study demonstrating improved survival in Xofigo-treated men compared to men treated with placebo alone.  The trial showed a very low incidence of side effects and good relief for men who were suffering from bone pain.

Xofigo is made out of radium, a radioactive element. After it is injected into the blood stream it concentrates near the cancer and delivers a potent dose of radiation.  So after Xofigo is injected into the patient, it travels through the blood stream and concentrates in the irritated areas of the bone and emits radiation where the cancer is most active.  Since prostate cancer spreads almost exclusively to bone, an injection of Xofigo ends up targeting most if not all of the cancer. Radiation consists of high energy, subatomic particles that blast cellular DNA. Once the DNA of the cancer cell has been hit, the cell is rendered incapable of reproduction.  If you stop cancer reproduction you basically stop the cancer.

To almost everyone, radiation conjures up horrible visions of toxicity. Fortunately, bone marrow toxicity is rare in men because Xofigo emits a different type of radiation, “alpha particles,” rather than the standard “photon type” of external beam radiation. Alpha particles dissipate their energy over a very short distance, only a couple of millimeters. External beam radiation therapy, the type of radiation that has traditionally been relied on to kill cancer cells in the bone, needs to be used very judiciously because the radiation is “beamed” through the body to hit the target in the bone. Typically it causes irreversible damage to the surrounding bone marrow.

Over the last two years at Prostate Oncology, we have treated over 50 patients with Xofigo.  The treatment has been very well tolerated.  Occasionally, we have seen a few patients with mild diarrhea or nausea that has been easily managed with common medications. Men experiencing pain from cancer usually see either partial improvement or total resolution of their pain after one to three of the monthly treatments.

As reported from the original study that led to FDA approval, even though pain relief occurs and alkaline phosphatase (ALP) levels in the blood decline, PSA may continue to rise.  This “disconnect” between PSA and other clinical parameters such as pain and ALP can be disconcerting to doctors and patients alike.  The reason that it occurs is unclear. A similar phenomenon has been observed with another FDA-approved cancer therapy called Provenge.

Experts hypothesize that the survival advantage from Xofigo and Provenge is due to a slowing of cancer progression rather than an actual regression of the cancer. This “slowing” is powerful enough to extend patients’ lives but insufficiently powerful to consistently induce a decline in PSA.  However, in our practice at Prostate Oncology notable declines in PSA have been observed in a few patients treated with Xofigo.  One patient dropped his PSA from 50 down to zero and his PSA still remains at undetectable levels.  Another recent patient has dropped his PSA from 150 down to 8.

For the patients on Xofigo who have rising PSA levels, it is logical to consider adding another effective anticancer agent such as Xtandi, Zytiga or Taxotere.  It is encouraging to know that several studies now show that Xofigo can be safely combined with these other effective therapies.

Xofigo has been a very welcome addition to our anticancer armamentarium.  The standard FDA approved protocol consists of a course of monthly treatments continued for a total of six months.  Further trials are in progress to study the potential advantages of continuing Xofigo for longer than six months.  Our experience to date suggests that longer therapy would indeed be advantageous in some instances.

Xtandi and Zytiga, The Future is Now

MARK SCHOLZ, MD

There are two new kids on the block, Xtandi and Zytiga. Both medications are real game changers. They are special because they can induce cancer remissions in men whose prostate cancer has become resistant to Lupron.  These pills are so effective that protocols for managing hormone resistant prostate cancer have been completely revamped.  Previously, men with hormone resistance were first treated with Taxotere chemotherapy, typically with undesirable side effects and frequent doctor’s visits.  When men on Xtandi and Zytiga are responding well, since they no longer need an intravenous infusion of Taxotere every three weeks, they only have to come in for a doctor’s visit every three months.

While Xtandi and Zytiga are now FDA approved for hormone resistant prostate cancer, there is no reason to believe they won’t also show enhanced effectiveness against earlier-stage, hormone-sensitive disease as well.  This rationale is based on a long established fact about anticancer treatments in general: “Any treatment that is effective against advanced cancer generally proves to be more effective against earlier-stage cancer.”  This assumption is so logical one might wonder why the academic medical world insists on doing studies to prove it.  Honestly, the biggest barrier is probably cost.  Insurance companies that pay for these expensive medications demand ironclad proof of a beneficial effect before being willing to cover their expanded use.

Physicians, particularly urologists, who are unfamiliar with these potent new agents, are another barrier to the expanded use of Xtandi and Zytiga in earlier-stage prostate cancer.  Urologists, the surgeons who over the last 20 years have only slowly become familiar with how the standard medications Lupron and Casodex function, are often uncomfortable using new agents that can be associated with rare side effects such as high blood pressure, seizures, liver problems and potassium depletion.  To urologists, the doctors who are managing the men with early-stage prostate cancer, Xtandi and Zytiga are relative unknowns.

In spite of all these barriers, the logical place to consider using Xtandi and Zytiga is in earlier-stage, “high-risk” situations which have suboptimal cure rates with Lupron alone.  The situations where this might apply are listed below:

·         Newly-diagnosed men with a PSA over 20 and a Gleason score over 8

·         Newly-diagnosed men with seminal vesicle invasion or pelvic lymph node metastases

·         Relapsed men after surgery with a PSA doubling < 3 months having salvage radiation

·         Newly-diagnosed oligometastatic disease undergoing radiation to all sites of disease

In all these situations, Lupron is known to be beneficial.  In some cases, the addition of Casodex to Lupron further increases the anticancer effect over Lupron alone. This is an important observation because compared to Xtandi or Zytiga, Casodex is a very weak anticancer agent.  Substituting these far more potent agents for Casodex is very likely to result in substantial improvement of the anticancer benefit and is a logical consideration for men who want to optimize their cure rates.        

New Ways of Using “Old” Technology

BY MARK SCHOLZ, MD

My old professor from USC, Dr. John Daniels, once told me that most “new inventions” are usually the result of “old invention” being repurposed in a new way.  His own company was an example.  Dr. Daniels developed a process for extracting collagen from cow hides (before Botox came along, collagen was injected into wrinkles for cosmetic reasons). Collagen was FDA approved for injection into wrinkles, but Dr. Daniels readapted it for treating cancer.  He performed studies that injected collagen into the blood vessel feeding liver tumors to block the blood supply.

A couple weeks ago at the PCRI’s midyear update, Dr. Margolis spoke about the possibility of readapting multiparametric MRI (MP-MRI) for cancer screening in men with high PSA as an alternative to random biopsy. For those of you who don’t know, MP-MRI has already gained widespread acceptance as a backup plan for finding prostate cancers in men with high PSA levels when an initial 12-core random biopsy fails to detect cancer.

Any logical person would think that, “If the MRI is more accurate, less invasive and less expensive, why not simply do the MRI first, before the biopsy?”  Then, if the MRI is clear a biopsy can be avoided altogether. (And when the MRI does show a suspicious spot, only one or two cores are needed to biopsy it.)

However, the medical community, which has been doing random biopsy for the last 25 years, patiently awaits the results of studies to evaluate the accuracy of random biopsy and MP-MRI in head to head trials.  Unfortunately, these studies will take many years to complete.  And in the meantime, should we keep doing random biopsies in a million men every year?

We are all well aware of how quickly the development of new medical technology is accelerating.  So in this blog, my goal is to point out that as all these new treatments are becoming available, it creates new uncertainties about how to use them in the most optimal fashion.

Newly-approved, more powerful hormone treatments like Zytiga and Xtandi are a good case in point. Studies clearly validate their superiority over traditional hormone shots and pills in men with advanced disease.  But doctors are reluctant to prescribe such procedures for men with earlier-stage disease, even when the cancer is unequivocally high risk. Once again they cite, “The absence of clinical studies to support this new and expanded role.”  

One question always seems to arise when proposing to use a new treatment in an expanded role. The question is “Maybe we should reserve the new treatment in case the traditional treatment fails.  After all, don’t we need a backup plan?”  The problem, at least as far as treating relapsed cancer is concerned, is that most cancer “backup plans” can’t bring about a cure. The best chance for curing cancer is always with the first treatment.  And it’s not like this question hasn’t been already looked into.  Numerous studies have addressed the question of sequencing treatments versus using the same treatments simultaneously in combination.  Almost every time the cure rates are improved by using the treatments in a combination, “up-front” approach rather than trying one treatment and waiting to see if it fails before starting the second treatment.

So in summary, this is a new era of hope and discovery. I’m sure none of us are complaining about having a whole bunch of new and effective treatments available.  However, with this privilege come new responsibilities. But doctors and patients will need more flexibility in their thinking. In this era of rapid technological progress the standard preconceived notion that every treatment recommendation must be backed up by a scientific study will need to be reconsidered.   

Avodart & Proscar

BY MARK SCHOLZ, MD

Frequently I am asked about Proscar and Avodart, two medications that are FDA approved to reduce urinary side effects from prostate enlargement (BPH).  It turns out that these medications have a much wider spectrum of application than simply treating BPH. They function by blocking a type of testosterone called dihydrotestosterone (DHT) that occurs primarily inside the prostate. A short blog can’t summarize this vast field.  However, I think even a brief review might be helpful.  Here is a list of their potential applications:

• Lower the risk of being diagnosed with prostate cancer
• Improve the detection rate of high-grade prostate cancer
• Cause Gleason 6 cancer to regress or be suppressed
• Synergize with other hormone therapy medications (such as Casodex)
• Help maintain men on active surveillance to avoid surgery or radiation
• Prolong the “holiday period” in men on intermittent hormone therapy
• Reduce male pattern baldness
• Delay orgasm in men with premature ejaculation

The occasional side effects that can occur, such as reduced libido, impotence and breast enlargement, are manageable or preventable as long as the medication is stopped in a timely fashion when side effects occur.

In a randomized study comparing Proscar with placebo, 10,000 men underwent a prostate biopsy. The Proscar-treated men were diagnosed with cancer 25% less frequently compared to placebo. However, enthusiasm for the routine use of Proscar to prevent cancer was dampened when the same study reported a 1% increased incidence of diagnosing high-grade prostate cancer. Even though many experts hypothesized that Proscar was increasing the detection rate, not causing high-grade disease, Peter Scardino, a prominent urologist from Memorial Sloan Kettering published an opinion that Proscar could be causing high-risk cancer, raising all kinds of consternation and inciting the FDA to place a warning. Fortunately, subsequent follow up published in the August 15, 2013 issue of the New England Journal of Medicine showed that after 18 years of observation there was no increased prostate cancer mortality from Proscar.

Much of what is known about Proscar can also be said about Avodart. Both agents block 5- alpha reductase (5-AR), an enzyme that converts testosterone into DHT.  A possible advantage of Avodart is that it blocks two of the three forms of 5-AR whereas Proscar only blocks one.  No clinical trials, however, have been performed to compare clinical efficacy of the two agents.  In our in-house trials we have found that DHT blood levels are lower with Avodart than Proscar.

Since both Proscar and Avodart lower PSA by about 50%, the question arises, “Are they masking the capacity of PSA to signal cancer progression?”  Briefly, the answer is no. These medications do not stop a PSA rise in men with progressive cancer. However, after starting Proscar or Avodart the PSA baseline does reset 50% lower. On average, a man with a PSA of 6.0 before starting Proscar will drop to 3.0 within a few months. Subsequently, if the PSA rises consistently above 3.0, cancer progression should be entertained as a possible cause.

The rationale for concluding these agents are beneficial when added to other hormonal agents is based on the known fact that no pharmaceutical drug by itself can totally eradicate or block testosterone. So logically, the addition of a nontoxic 5-AR inhibitor to further lower DHT is likely to be helpful. Studies show that these agents suppress PSA in men with relapsed disease, delaying the rise in PSA, on average, for a couple of years.  It has also been shown that these agents can double the duration of the “holiday period” in men on intermittent hormone blockade.

Proscar and Avodart—mild agents with mostly reversible side effects—almost never interact with other medications.  They can be taken anytime of the day, with or without food. Proscar is available as a generic called finasteride and is very affordable. There is certainly an important role for these well-tolerated medications though in this era of new, high-powered hormonal agents such as Zytiga and Xtandi, Proscar and Avodart often get forgotten.  

Read another Prostate Snatchers blog written on Avodart & Proscar here:  http://prostatesnatchers.blogspot.com/2011/05/avodart-proscar-for-men-on-active.html
 

INDIGO: Relapsed Prostate Cancer

MARK SCHOLZ, MD

Those dreaded words, “relapsed cancer,” shake you to the core. They mean that surgery or radiation has failed to “get it all.”  However, while with most cancers “relapse” is a fatal pronouncement.  However, prostate cancer has its own distinct reality. Most men who relapse don’t die from the disease.  The outlook is good because relapses are usually detected by a rising PSA when the cancer is still microscopic. Visible, scan-detected metastases may not appear for ten or more years after the PSA relapse occurs.

Multiple Treatment Options for a Rising PSA
The list of potential treatment options for INDIGO is extensive: observation, radiation, hormone therapy with Lupron and Casodex, salvage seed implant, salvage cryotherapy, Zytiga, Xtandi and Taxotere. However, combinations of these treatments are most commonly employed. Some of these combinations are listed below in order of increasing treatment intensity:  

1.     Observation

2.     Mild hormone therapy consisting of continuous or intermittent Casodex

3.     Monotherapy with fossa radiation, seed implant or cryotherapy for persistent local disease

4.     Combination hormone therapy with Lupron and Casodex given intermittently

5.     Same as #4 but with the addition of pelvic radiation and 4 months of hormone therapy

6.     Same as #5 but with hormone therapy extended for 18 months

7.     Same as #6 but with the addition of Taxotere or Zytiga or Xtandi

Defining Different Types of Relapses
Just as PSA, cancer grade, scan findings and stage were instrumental for assigning a SHADE in newly-diagnosed men; SHADES are important for putting a relapsed in perspective. Ultimately, how to treat INDIGO is guided by a combination of four factors— the SHADE before treatment, the PSA doubling time, individual patient factors such as age, sexual functionality and urinary control, and last, but not least, the cancer location.

The Original Shade before Treatment
In general, treatment should be more aggressive (combined therapy with Lupron and pelvic lymph node radiation) if the original SHADE was unfavorable (AZURE for example).  Treatment should lean toward a less aggressive approach—cryotherapy alone, seed implant alone or Casodex alone—if the original SHADE was SKY.

The PSA Doubling Time
Treatment is heavily influenced by the rate of PSA rise. For example, if the PSA is doubling in less than six months, aggressive combination treatment with Lupron and Casodex plus radiation (or cryosurgery in men previously treated with radiation) is probably required.  If the PSA doubling rate is between six and twelve months, a less aggressive treatment approach with radiation alone, cryosurgery alone or intermittent Lupron and Casodex is reasonable.  When more than a year is required for the PSA to double, observation without immediate treatment may be considered.

Patient Factors that Affect Treatment Selection
A patient’s age needs to be factored into the treatment decision-making process. Men who are more elderly can “step down” the intensity of their treatment by temporizing with milder hormone therapy such as Casodex with Avodart. Younger men, who, prior to relapse, were in the High-Risk (AZURE) category may want to consider upgrading the intensity of treatment by using prophylactic pelvic lymph node radiation plus a more intensive hormone therapy such as Zytiga or Xtandi and/or chemotherapy with Taxotere.

Searching for the Location of the Cancer
Men with rising PSA should undergo standard imaging studies (listed below) in an attempt to determine the location of the cancer. Unfortunately, these scans are often unable detect recurrent cancer unless the PSA is over 20. However, improved PET scans that utilize C11 choline or acetate have the potential to detect recurrent disease with much lower PSA levels. Unfortunately, the PET scans are so new that insurance coverage is often limited.

Sometime even the best scans can’t detect where the cancer is. When this occurs after surgery, particularly when the PSA doubling time is slow, residual cancer in prostate fossa is often suspected and radiation to the prostate fosse is often administered. Cure rates are better when radiation is initiated at a lower level of PSA. 

Standard Imaging Studies for INDIGO

• Color Doppler Ultrasound or Multiparametric 3 Tesla MRI can be used to look for residual cancer in the surgical fossa or in the prostate gland in men previously treated with radiation. 
• Pelvic MRI or CT scans are used to check for spread to pelvic lymph nodes. (Carbon 11 acetate PET scan, however, is far more accurate than CT or MRI but some centers still consider them investigational/experimental)
• Technetium bone scans are standard. New F18 PET bone scans, however, are preferable because they can detect much smaller cancers than technetium bone scans.

Apparent Locally Recurrent Disease

Scans done in a man with a rising PSA after radiation that indicate a recurrence localized inside the prostate, may be curable with cryosurgery alone or possibly with a seed implant alone.  Similarly, an isolated local relapse in the prostate fossa after surgery may be curable with radiation alone. Even though scans show no metastases outside the prostate or the fossa, microscopic metastases in the pelvic nodes may be present, especially in men who have fast PSA doubling times or whose SHADE was originally AZURE.  In these higher risk situations, the addition of prophylactic pelvic lymph node radiation with intensity modulated radiation (IMRT) combined with hormone therapy may be advisable.

Regional Spread to Lymph Nodes

When cancerous nodes are detected in the pelvis, the idea of doing node-directed IMRT is even more compelling. Since overt cancer in the lymph nodes is an indication of potentially life threatening disease, an extended course of hormone therapy, possibly with the addition of second generation hormones such as Zytiga or Xtandi, can be contemplated. Taxotere chemotherapy is an additional consideration.

Hormone Therapy Alone

When the location of the relapse is unclear, or if the risks of side effects from radiation appear too high, relapsed disease can be effectively suppressed for many years with hormone therapy alone. The side effects of hormone therapy tend to increase with longer use so intermittent therapy is very popular. A typical intermittent protocol is to begin with an initial course of treatment for six to twelve month followed by treatment holiday. After hormone therapy is stopped, testosterone starts to recover and the PSA begins to rise. Treatment is restarted when the PSA rises back to the original PSA baseline, or up to five, whichever is lower.

Putting It All Together

Treatment selection for INDIGO can be complex. Constructing a cancer “profile” using the original SHADE, the PSA doubling time, and scan finding, is the first step. Unfortunately, the location of the recurrent cancer may remain uncertain, even after doing the best scans.  When this is the case the extent of disease may require a professional “guesstimate” based on the PSA doubling time and the original SHADE.  Despite all these difficulties and uncertainties, the good news is that a wide variety of treatment options are available and treatment is usually very effective. For the majority of men the disease can be controlled on a long-term basis, and some cases it can even cured. 

CALENDAR ALERT TO THOSE WHO LIVE AROUND LONG BEACH, CA Learn more about prostate cancer treatments as Mark Scholz, MD, discusses treating PSA relapsed disease at UsTOO Long Beach Prostate Cancer Support Group July 22, 2014 - 6:30 PM to 8:30 PM, at Long Beach Memorial Medical Center. For more information follow this link: http://goo.gl/HMojNV

 

Introduction to Hormone Therapy for Prostate Cancer

BY MARK SCHOLZ, MD

Testosterone is the primary male hormone. It comes mostly from the testicles and to a lesser degree, from the adrenal glands. Testosterone causes the common male characteristics such as bigger muscles, facial hair growth and increased sex drive. Testosterone is also essential for prostate cancer to grow.

 

Why Blocking Testosterone Kills Prostate Cancer

The prostate gland, located near the bladder, makes semen. Prior to puberty the gland is only the size of a peanut. However, when the testicles begin making testosterone, the prostate comes to life and grows to the size of a walnut. The cells of the prostate, therefore, require testosterone to proliferate. Since prostate cancer originates from the prostate gland, the cancer also depends on testosterone.

 

Hormonal therapy works by blocking testosterone. When prostate cancer cells are deprived of testosterone they commit suicide in a cell death process called apoptosis.  The amount of cell death in early-stage prostate cancer is usually dramatic.  Not uncommonly, when men are pretreated with potent forms of hormonal therapy, there is no residual cancer after surgery. More typically, there is a dramatic reduction in the number of cancer cells, but not total elimination of the cancer.

 

The mechanism for testosterone to stimulate cancer growth occurs through the activation of a multifaceted protein called the androgen receptor.  Before binding with testosterone the androgen receptor is inactive. Once the receptor comes into contact with testosterone, the activated androgen receptor is transported into the nucleus of the cell where it stimulates DNA.  As a result, a plethora of cell-growth-enhancing proteins are synthesized that stimulate cancer growth and progression.

Hormone Therapy Comes in Many Form
Prior to the advent of modern medications, hormone blockade was accomplished by surgical castration. These days, testosterone is blocked with shots or pills. Agents that block testosterone by inhibiting the pituitary gland are Lupron, Zoladex, Firmagon, Eligard and Trelstar.  Medications that work by interposing themselves between testosterone and the androgen receptor to block its activation are Casodex, Nilutamide or Flutamide.  A third milder type of hormonal agent, the 5-alpha-reductase inhibitors, such as Avodart and Proscar, work by inhibiting the chemical conversion of testosterone into its more potent form, dihydrotestosterone (DHT).

Recently the FDA approved two new, and more potent, hormonal agents, Zytiga and Xtandi. Their increased anticancer efficacy was demonstrated through prolonged survival in men whose cancer became resistant to Lupron. Zytiga and Xtandi work by different mechanisms. Zytiga inhibits cancer cells from making their own testosterone. Xtandi works by blocking the activity of the androgen receptor.

The Nitty Gritty of Treatment Selection
The most potent anticancer action is achieved through complete blockade with agents from different functional classes administered together for a prolonged period of time. Therefore, the variables that affect the intensity of hormone blockade treatment are:  1. the type of medicine; 2. how many medicines are used; and 3. how long the medications are continued.  Of course, medical skill and experience is required to fine-tune the selection and duration of therapy.  Nevertheless, here is a brief presentation of some rough guidelines.
 

1.    A short course, say three to four months, to shrink the prostate or to improve cure rates in men with intermediate-risk disease (Teal Shade of Blue) undergoing radiation

2.    A short course of four months to improve cure rates with radiation in men with intermediate-risk disease (Teal Shade of Blue)

3.    An intermediate course (6-12 months) for treatment for intermediate-risk disease (Teal Shade of Blue) as a sole form of therapy

4.    A long course (18-24 months) to improve cure rates in men with high-risk (Azure Shade of Blue) prostate cancer undergoing radiation

5.    An intermediate to long course in conjunction with radiation to improve cure rates in men with a rising PSA after surgery (Indigo Shade of Blue) who are undergoing salvage radiation

6.    Intermittent use to suppress a rising PSA after surgery or radiation (Indigo Shade of Blue)

7.    Intermittent or continuous use to treat men with metastatic disease (Royal Shade of Blue)

8.    Salvage treatment with Xtandi or Zytiga to control disease in men on Lupron who have progressive disease (Royal Shade of Blue) 

Over the last ten years the medical community has been roiled by the discovery that some forms of prostate cancer are truly harmless, raising a serious concern about men receiving surgery and radiation they don’t need. However, overtreatment with hormone therapy also occurs. The overriding goal is to use a hormone therapy approach that achieves a maximum anticancer benefit while minimizing side effects as much as possible. Treatment always has to be personalized so the intensity and duration of treatment is appropriate for each individual’s specific situation.

Selecting Prostate Cancer Treatment

BY MARK SCHOLZ, MD

"You mean you have never heard of diffusion-weighted imaging” Exclaimed a recently-diagnosed prostate cancer patient to his doctor.  How could his doctor be unacquainted with this important aspect of modern prostate imaging? It’s shocking when a patient realizes he possesses more medical information than the “expert.” 

No One Can Be an Expert in Everything
Actually, in this modern era, this situation is being encountered more and more frequently. It’s not so surprising when considering the explosive growth rate of new medical information. It’s humanly impossible for anyone to stay abreast of every new medical development.  For example, even though urologists “specialize” in diseases of the urinary system, their area of responsibility demands expertise in a wide variety of unrelated but important areas such as urinary infections, prostate enlargement, prostate infections, sexual dysfunction and kidney stones. They also have to be expert at the surgical treatment of such problems as congenital defects, bladder cancer, testicular cancer and kidney cancer… just to name a few.

Prostate Cancer by Itself is Quite Complex
Prostate cancer alone is intricate enough to keep a specialist occupied full time. For example, simply staging prostate cancer is complicated. Prostate cancer staging uses a multimodality profiling system that estimates the likelihood of microscopic metastases outside the prostate using PSA, Gleason grade, and a percentage of cancer-containing biopsy cores.  Now, new imaging techniques are providing further information about the size and location of the cancer within the prostate gland. And even more recently molecular profiling has become commercially available.  Staging prostate cancer properly has become a continually developing art form.

Seeking Advice—Delivered from a Level Playing Field
Equally important is the need to seek out unbiased treatment advice. Unfortunately, the process of rendering advice about treatment options is usually very slanted. Urologists (who are surgeons) usually recommend surgery.  Radiation therapists usually recommend radiation. This is not to imply that these physicians have less than the best intentions.  Over time they just become convinced that what they do is the best option for their patients who are consulting them.

What You Don’t Know Can Hurt You
The number of treatments available for men with newly-diagnosed disease is rapidly expanding.  For example, what was previously known simply as “radiation” now includes IMRT, Proton therapy, Cyberknife, two types of Brachytherapy as well as various combinations of these different radiation modalities.  Hormone therapy options have now expanded beyond traditional Casodex and Lupron to include Zytiga and Xtandi. The management of the potential side effects of hormone therapy requires special training in diet physical fitness, bone integrity and sexual health to limit the risk of lingering damage after treatment is completed. These days, relapsed or advanced prostate cancer requires physicians who are conversant in genetic typing, modern PET scans, immunotherapy and injectable radiation.

Every Journey Begins with a Single Step
So newly diagnosed prostate cancer patients are faced with daunting situation. Clearly there is no simple answer to this tangle of complicated issues. However, the newly diagnosed cancer patient is far from helpless. He has two overriding responsibilities. First, he must learn as many facts as possible by getting thoroughly educated about the different treatments for his specific type of prostate cancer. Second, he must use discernment in the selection of which physicians to consult.

There is Time to Learn
With prostate cancer there is rarely a need to rush into making a treatment decision because it is usually slow growing.  There is plenty of time for the shock of diagnosis to wear off, giving you enough time to get educated about the scientific facts.  Published studies comparing outcomes are available. The PCRI in particular publishes articles that translate scientific information into a patient-friendly format.  Ultimately, all claims about treatment should be supported by references published in the scientific literature.  Selecting treatment for prostate cancer is a high stakes proposition, potentially risking sexual function, urinary function, even life itself.  I want to encourage patients to take a leadership role in the treatment-selection process.

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.