Monday, July 30, 2012

Bone Health and Prostate Cancer: What Every Man on Androgen Deprivation Therapy Should Know

One of the most significant risks facing men on androgen deprivation therapy (ADT) for prostate cancer is osteoporosis.  Representing a critical decrease in the density of bones, osteoporosis is usually associated with menopause in women.  However, men with prostate cancer, particularly those on androgen deprivation therapy, are also at risk for this condition.  So why do we care about osteoporosis?  By making bones less dense, osteoporosis also makes them more prone to fracture.  These fractures can be devastating, decreasing the ability to move around and, even worse, substantially increasing the risk of death.  In fact one study demonstrated that people with osteoporosis related fractures had a risk of death two times that of similarly aged people without fractures.  In addition, another study showed that fractures decreased the life expectancy of men with prostate cancer by more than 3 years. As a result, men with prostate cancer who receive ADT should make bone health a top priority.  In this post, I will discuss the steps all men undergoing ADT need to take to prevent osteoporosis.  In addition, I will describe the treatment options for those men found to already have low bone density.

ADT and Osteoporosis:  What is the Connection?

When most people think about bones, they imagine sturdy, stable structures that really don’t change much from day to day.  In reality, however, this perception could not be further from the truth.  Every bone in the body represents a constant battle between two opposing classes of cells.  Osteoblasts, the bone builders, work frantically to strengthen bones by incorporating calcium into them.  Osteoclasts, in contrast, remove calcium from bones and, in so doing, weaken them.  While most of the time, these two cells are in a stalemate called “dynamic equilibrium”, occasionally one cell type wins.  For example, when there is not enough calcium circulating in the body, osteoclasts free calcium from bones into the bloodstream.  In this situation, bones are weakened.  When this situation continues for a prolonged period of time and bones are weakened beyond a critical point, osteoporosis occurs.

So what does ADT have to do with osteoporosis and the battle between osteoblasts and osteoclasts?  These competing cells are regulated by various hormones in the body.  Two of these very important hormones are estrogen and testosterone.  Estrogen works to deactivate osteoclasts .  As a result, the hormone works to increase the strength of bones.  During menopause, estrogen levels are decreased, allowing osteoclasts to function more effectively and to weaken bones.  This leads to osteoporosis associated with menopause in women.  Testosterone also functions to strengthen bones through its impact on the osteoclasts and osteoblasts.  This male hormone activates osteoblasts, stimulating them to strengthen bones by incorporating more calcium.  In addition, in men, some testosterone gets converted to estrogen, leading to deactivation of osteoclasts and secondary strengthening of bones as well.  For men with prostate cancer, the administration of ADT leads to the decrease of testosterone (and subsequently estrogen) in the body.  While this decrease in testosterone is great in battling prostate cancer, it can be devastating to bone health. 
Through its decrease of testosterone and estrogen, ADT secondarily shifts the balance of power to osteoclasts and leads to osteoporosis and its associated risks for many men undergoing this treatment for prostate cancer.  Studies have demonstrated that ADT decreases bone density in men by 1-5% per year.  As a result, one study demonstrated that 80% of men on ADT develop osteoporosis after 10 years of treatment.  As a result, men on ADT have been found to be 13-30% more likely to develop a fracture as compared to their counterparts with prostate cancer not treated with ADT. 

Starting ADT?  Get Your Bone Density Checked

Given this propensity for ADT to decrease the density of bones, it is important for men starting this hormonal therapy to evaluate their risk of osteoporosis at the outset of treatment.  This task is accomplished through a bone density scan. Also known as a DEXA scan, this simple x ray test can easily and non invasively determine the density of bones over the span of 10-30 minutes.  It is no more painful than a chest x ray and its only risk is the low level of ionizing radiation that you absorb during the test.

The bone density scan is reported as a series of scores.  The first score, called the T score, determines the overall bone density as compared to the maximal potential bone density.  A T score of greater (more positive) than -1 is considered normal.  Men with T scores ranging from -1 to -2.5 are considered to have low bone density or osteopenia.  T scores of less than -2.5 indicate osteoporosis.  The second score, called the Z score, compares the measured bone density to that of other people with the same age and gender.  This score helps to differentiate a pathologically low bone density from a low bone density that is “normal” for a particular age and gender.  Using these scores, a physician can determine whether a man about to start ADT has low bone density and who, in turn, is at higher risk for fractures.  As such, the scores help determine who needs pre-emptive treatment for osteoporosis or osteopenia and what kind of treatment would best suit them.

Treatments to Maximize Bone Density in Men Starting ADT

Once bone density and strength is determined via a DEXA scan, a man starting ADT can begin protecting his bones with various treatment options.  While some treatment options should be undertaken by all men starting ADT, others should be reserved for those with documented osteoporosis. All men undergoing ADT, for example, should undergo lifestyle modifications to maximize their bone health.  Simple steps such as exercising more, stopping smoking, and limiting caffeine and alcohol can significantly prevent the onset and progression of osteoporosis.  In addition, most men starting ADT should begin supplementation with Calcium and Vitamin D.  These supplements serve as the building blocks with which the osteoblast cells build up bones. The usual dosage is 1500 milligrams of calcium and 800 units of Vitamin D per day in divided doses.  Certain medical conditions (such as kidney stones) prevent men from taking these supplements at full or even decreased doses.  As a result, all men contemplating taking these supplements should first seek guidance from a physician. 

While such treatments are applicable to all men undergoing ADT, some therapies are reserved only for men with confirmed osteoporosis.  One such treatment involves a class of drugs called bisphosphonates.  Available in oral or intravenous forms, bisphosphonates improve bone density and fight against osteoporosis by blocking the bone destroying activity of osteoclast cells.  Numerous studies have evaluated this class of drugs in men with prostate cancer undergoing ADT.  These studies have demonstrated that while bisphosphonates do prevent loss of bone density over time (some studies demonstrate that these drugs can even increase bone density), they have yet to demonstrate that these drugs can prevent fractures in these men.  However, a decrease in fracture risk has been demonstrated in postmenopausal women taking bisphosphonates.  While this class of drugs can, indeed, be helpful in protecting the bones of men on ADT, they are not without risks.  Oral bisphosphonates, like Alendronate (Fosamax), often produce upset stomachs as well as other gastrointestinal side effects.  As a result, many patients often do not stick with the therapy.  In fact, one study of postmenopausal women demonstrated that less than 60% actually continued the once monthly oral therapy long term. 

Intravenous bisphosphonates, like Zolendronic Acid (Zometa) and Pamidronate (Aredia), are usually better tolerated.  Some patients do experience flu like symptoms during the first intravenous infusion but this reaction is usually mild.  A much more serious potential side effect is kidney toxicity, sometimes leading to kidney failure requiring dialysis.  As a result, men undergoing treatment with these drugs need to have their kidney function closely monitored with periodic blood tests.  Another very serious, although thankfully rare, side effect of these IV drugs is osteonecrosis or destruction of the jaw bone.  Because of this potential side effect, all men starting these drugs should have dental work completed prior to the start of therapy, maintain good oral hygiene, and get periodic dental checkups.

As I mentioned previously, the female hormone, estrogen, potently blocks the bone destroying activities of osteoclast cells, making bones stronger.  Not surprisingly then, estrogen has been tried in the treatment of osteoporosis.  While, indeed, successful in increasing bone density, estrogen unfortunately comes with the associated risks of heart attack as well as blood clots.  Because healthy bones are of no use to people dead from heart disease, estrogen is not routinely used to treat osteoporosis in men on ADT.  Instead, a related class of drugs called selective estrogen receptor modulators (SERM) have been successfully used to fight osteoporosis while avoiding the heart risks. Including drugs such as Raloxifene and Toremifine, SERMs have been demonstrated to significantly increase the bone density of men on ADT.  A  recent study of 1389 men on ADT also demonstrated that Toremifine reduced vertebral (spine) fractures by 53%.

Another new method of tackling osteoporosis in men on ADT for prostate cancer is the creation of antibodies against a compound called RANKL.  In the body, RANKL binds to osteoclast cells, activating them and prolonging their survival.  As you may remember from earlier in this post, osteoclasts resorb bone, making it less dense and promoting osteoporosis.  Drugs that serve as antibodies against RANKL, in turn de-activate it.  As a result, its ability to activate osteoclasts is diminished, preventing bone resorption and subsequent osteoporosis.  One such drug called Denosumab(Xgeva) was recently studies in 1468 men with nonmetastatic prostate cancer who were undergoing ADT.  The study reported that Denosumab, given as an injection once every 6 months, significantly improved bone density throughout the body and decreased the risk of fracture by 62% over a 3 year period.  This success was even more impressive given that the drug was extremely well tolerated with minimal adverse side effects.

Take Home Message

Osteoporosis is a serious problem facing men with prostate cancer treated with ADT.  All men starting ADT should undergo bone density testing to determine how strong and dense their bones are.  Depending on the results, men should undergo one of the various treatments to increase or maintain bone density.  At the very least, barring any contraindications, all men undergoing ADT should take Calcium and Vitamin D in addition to making some lifestyle modifications.  In addition, those men diagnosed with osteoporosis prior to or during ADT should begin one of the many excellent treatment options available. Of course, all men considering treatment for this and any other medical conditions should carefully discuss the options with their physician prior to embarking on any treatment plan.  Through such measures, men undergoing ADT for prostate cancer can enjoy good bone health and prevent the dreaded fractures associated with osteoporosis. 

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Sunday, April 8, 2012

Hot Flashes and Prostate Cancer: Treating One of the Most Dreaded Side Effects of Androgen Deprivation Therapy

One of the earliest and most bothersome side effects of androgen deprivation therapy for prostate cancer is the hot flash.  Very similar to those experienced by women during menopause, hot flashes can be debilitating for men receiving medications such as Lupron.  Many are too embarrassed by hot flashes to even mention them to their physician.  Others don’t discuss them because they feel that these hot flashes cannot be treated or prevented.  In reality, this could not be further from the truth.  In this post, I will describe hot flashes and discuss what causes them.  In addition, I will review the most common medications employed to prevent and treat hot flashes experienced by men undergoing androgen deprivation therapy for prostate cancer.

What Is a Hot Flash?

A hot flash is a sudden overwhelming sensation of warmth usually experienced in the face, neck, upper chest and back.  This feeling is often accompanied by redness or blotching of the skin as well as heavy sweating.  This constellation of symptoms can occur to varying degrees, with some being so severe that they require a change of clothing or a shower.  Other associated symptoms can include nausea, rapid heartbeat, anxiety, and even trouble breathing.  Hot flashes can last from less than 5 minutes to over 30 minutes.  They can also occur with varying frequency, from once in a few days to several times per hour.

Why Does Androgen Deprivation Therapy Cause Hot Flashes?

Men undergoing androgen deprivation therapy (ADT) with medicines such as Lupron to treat their prostate cancer often get hot flashes.  In fact, studies have demonstrated that 60-80% of men undergoing ADT experience hot flashes at some point during treatment.  For most men, this first occurs within the first few months of treatment .  Interestingly, nearly a third of men who experience hot flashes during ADT for prostate cancer state that these symptoms are the most debilitating side effects of the treatment.  Nearly half of men experiencing hot flashes report a significant decrease in their quality of life.

Recent research has helped determine why men undergoing ADT actually experience hot flashes.  As you may remember from my previous post,  ADT fights prostate cancer by removing its food, testosterone, from the blood stream.  It turns out that testosterone, like other sex hormones, is an important regulator of the “thermostat” of the human body.  This “thermostat” is actually located in a part of the brain called the hypothalamus.  By causing a rapid drop of testosterone in the bloodstream, ADT confuses the “thermostat.”  Without its usual input from testosterone, the “thermostat” believes that the body is too hot.  As a result, the “thermostat” tries to cool the body off by making the blood vessels near the skin dilate, which allows for the release of heat on the skin surface.  This, in turn, leads to the characteristic blotching of the skin, feeling of warmth, and perspiration. 

How Do You Treat Hot Flashes?

1.     Hormonal Treatments:  As you would imagine, if a lack of hormones is the cause of hot flashes, replacing these hormones can help to treat these bothersome symptoms.  Certainly, we cannot simply replace the testosterone removed by ADT as this would defeat the purpose of the treatment: starving the prostate cancer.  However, studies have shown that other hormones, aside from testosterone, can also be used to regulate the “thermostat” and, thus, prevent hot flashes.  The first of these hormones to be tested was the female hormone, estrogen.  While estrogen did, indeed, reduce the incidence of hot flashes, it also increased the incidence of life threatening blood clots and painful breast tenderness.  As a result, estrogen has not been used as a mainstream treatment for hot flashes.  Other hormones, however, have been demonstrated to improve hot flashes while avoiding the risks of estrogen.  Two of the most popular treatments for hot flashes are derived from just such a hormone: progesterone.

A.     Megestrol Acetate – A study of 66 men undergoing ADT for prostate cancer were given either Megestrol Acetate (20 milligrams twice a day) or a placebo(sugar pill) for 4 weeks.  The study found that 79% of men receiving Megestrol Acetate reported a 50% decrease in hot flashes as opposed to only 12% of men receiving placebo pills.  The time to achieve the maximal effect of the drug was 2-3 weeks and the most common side effects were weight gain, fluid retention, and headaches.

B.     Medroxyprogesterone Acetate – A study of over 100 men undergoing ADT for prostate cancer were given Medroxyprogesterone Acetate (20 milligrams daily) for 4 weeks.  The study reported that 84% of men demonstrated a greater than 50% improvement in hot flashes while 37% enjoyed a complete resolution of hot flash symptoms.  Side effects of the medication included intestinal upset, water retention, and increased blood pressure.
2.     Non-Hormonal Treatments:  As more research has been carried out about hot flashes, studies have found that hormones are not the only substances in the body that control the “thermostat.”  These discoveries have provided more treatment options for men with prostate cancer suffering from hot flashes from ADT.

A.     Venlafaxine – Also known as Effexor, this drug is part of a class of antidepressant drugs known as serotonin norepinephrine reuptake inhibitors (SNRI).  The utility of this drug for treating hot flashes was discovered when postmenopausal women taking Venlafaxine for depression were found to have fewer and less intense hot flashes.  Subsequent studies confirmed the benefit of this drug in treating hot flashes in men treated with ADT.  One small study of 16 men demonstrated that taking 25 milligrams of Venlafaxine daily for 4 weeks decreased hot flashes by 50% in 63% of men.  A larger study of 97 men taking 75 milligrams of Venlafaxine daily confirmed the benefit, demonstrating a 47% decrease in hot flashes.  Of note, however, this same study demonstrated that medroxyprogesterone was more effective, reducing hot flashes by 84%.  The most common side effects of the drug are gastrointestinal in nature, including dry mouth, nausea, and decreased appetite.

B.     Gabapentin – The mechanism by which Gabapentin, a drug used to alleviate nerve pain, relieves hot flashes is unknown.  Nonetheless, a study of 350 women with hot flashes demonstrated a 46% decrease in hot flashes for women taking 900 milligrams of the drug daily versus a 15% decrease for those women taking a placebo drug.  To my knowledge, no specific study has looked at the benefits of Gabapentin for treating hot flashes in men on ADT.

3.     Alternative Therapies:  Small studies have also demonstrated that hot flashes can also be treated without taking medications at all. 

A.      Acupuncture – A very small study of 7 men with prostate cancer evaluated the effects of acupuncture on hot flashes.  The men in the study underwent 30 minutes of acupuncture treatment twice a week for 2 weeks and then once a week for 10 weeks.  The study reported that the men enjoyed a 50% reduction in hot flashes at 3 months following the final treatment.
B.      Electroacupuncture – A study of 15 postmenopausal women undergoing electroacupuncture demonstrated at least a 50% decrease in hot flashes in 73% of women as late as 6 months following the final treatment.

Take Home Message

Hot flashes are very common side effects of androgen deprivation therapy for men fighting advanced prostate cancer.  While most men reluctantly accept these debilitating symptoms and their subsequent impact on quality of life, they should not.  Numerous medications and alternative therapies are available to significantly decrease hot flashes.  While these treatments have their own side effects, they are often worth trying for men with severe hot flashes.  Of course, the various medications and treatments I have discussed in this post may not be for everyone.  Certain people have medical conditions that preclude the use of some or all of these medications.  As always, never start any medicine without first discussing it with your doctor. 

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Friday, March 23, 2012

Positive Margins After Prostatectomy: They Are Not All The Same

One element of a pathology report that every urologist looks for after performing a prostatectomy is the status of the surgical margins.  The term “margins” refers to the cut surfaces of the prostate and, specifically, whether prostate cancer can be found at these cut surfaces.  When pathologists receive a prostate specimen after a prostatectomy they usually cover the surfaces of the prostate with ink.  They then look to see if prostate cancer cells can be found within these inked margins.  The presence of prostate cancer at one of these inked surfaces is termed a “positive margin”.  Found in approximately 30% of prostatectomy specimens, positive margins can impact the prognosis of men with prostate cancer as well as result in the need for adjuvant therapy after surgery.  However, as I will explain, not all positive margins are the same. In this post, I will describe the different types of positive margins as well as the significance of these findings.

Types of Positive Margins

You would imagine that a positive margin is a pretty straightforward thing.  After all, cancer cells are either present at the margins or not, right?  While this is true, prostate margins are, in reality, a little more complicated.  Different types of positive margins occur for different reasons and, in turn, have different consequences.

1)      Positive Margin in Organ Confined Disease (T2):   The prostate is covered by  a lining called the capsule.  Prostate cancer that is organ confined is located entirely within the limits of the prostate and, in turn, within the capsule.  During prostatectomy, the surgeon may accidentally cut into the prostate, stripping some of the prostate capsule away and possible exposing an area of prostate that contains prostate cancer.  In this situation, prostate cancer can be  seen extending to the margin while no capsule is seen in the area.  In this situation, the pathology report may state that the capsule in the area of the positive margin is “stripped” or “not seen.”  This type of positive margin is usually due to technical error during surgery rather than to aggressive disease.  Positive margins have been reported in 5-27% of men undergoing prostatectomy for organ confined disease.

2)      Positive Margin in Non Organ Confined Disease (T3-T4): Occasionally aggressive prostate cancer can extend through the capsule and out of the prostate.  This is called extracapsular extension (ECE) or extraprostatic extension(EPE).  Either way, it means that the cancer went outside of the prostate before the prostatectomy was performed.  Occasionally, the surgeon can cut around the prostate widely enough to still remove the cancer completely despite the ECE.  Sometimes, however, the cancer extends beyond where the surgeon can safely cut and, so, some cancer is left behind, creating a positive margin.  The pathology report in this situation usually reports that cancer cells are seen “extending through the capsule and are noted at the margin.”  This positive margin is caused by the aggressiveness of the cancer rather than by surgical technique. Positive margins have been reported in 17-65% of men undergoing prostatectomy for non organ confined disease.

3)      Artifactual Positive Margin: Sometimes what appears to be a positive margin is not one at all.  Occasionally, the way a prostate specimen is manipulated during surgery or during pathology processing creates an appearance of a positive margin.  This is, of course, often difficult to distinguish from the real thing.  Given the anatomy of the apex of the prostate (the tip of the prostate that connects to the urethra) what appears to be a positive margin at that location is often thought to be an artifact.

Risk Factors for Positive Margins

Many studies have determined specific preoperative factors that make positive margins more likely.  As you might imagine, the different types of positive margins have different risk factors.  Positive margins in non organ confined disease are usually more likely to be found in men with high risk prostate cancer at biopsy.  These men usually have higher PSA, higher Gleason score, and/or prostate nodules that can be felt on rectal exam.  In contrast, risk factors for positive margins in organ confined disease are more technical in nature.  A prostatectomy performed on an obese man or someone with a narrow pelvis is usually more challenging to perform, making an inadvertent cut into the prostate and subsequent positive margin more likely. Obese men, for example, have twice the likelihood of having a positive margin as compared to men of normal weight. Similarly, surgeons with less experience are less likely to be able to identify and preserve the important surgical landmarks of the prostate, also making positive margins more likely.

Impact of Positive Margins

So why do we care about positive margins? Aside from serving as a surgical benchmark for urologists, positive margins also have a significant impact on cancer outcomes after prostatectomy.  For example, studies have shown that men with a positive surgical margin have double the risk of a PSA recurrence (cancer recurrence) as compared to men with negative margins, even after taking into account other risk factors.  Of course, positive margins in men with non organ confined disease (positive ECE) have a worse prognosis than those with positive margins and organ confined disease.  For example, in one study, while 18% of men with positive margins and ECE developed metastases, no men with a positive margin and organ confined disease developed metastatic spread after 7 years of follow up.  Nonetheless, positive margins in organ confined disease also often yield a worse prognosis.  One study, for example, demonstrated that men with organ confined disease and a positive margin have as high a likelihood of having progression of their prostate cancer as men with ECE but negative margins (25%).  Hence, positive margins in organ confined disease have the effect of   “up staging” the prostate cancer from T2 to T3 when seen from the standpoint of prognosis.  While demonstrating such a significant impact on prostate cancer outcomes, however, positive margins do not always result in a prostate cancer recurrence.  In fact, studies have demonstrated that 40-50% of men with a positive margin never demonstrate a PSA recurrence.  This statistic is often attributed to the existence of the artifactual positive margins described above as well as to small positive margins in cases of non-aggressive prostate cancer.

Dissecting Positive Margins Further

As if positive margins and their consequences were not confusing enough, pathologists are now looking at margins in even more detail to create further risk categories.  Some elements of positive margins that have been studied include the length of the positive margin, its location within the prostate, and whether there is a single versus multiple positive margins.  Studies have demonstrated significant impacts of the margin sub-characteristics on the chance of PSA recurrence (and, in turn, prostate cancer recurrence) after surgery.  Multiple positive margins, for example, have been demonstrated to yield a 40% higher chance of PSA recurrence as compared to a single positive margin.  Also, an extensive or long positive margin (the critical length has ranged from less than 1 to over 3 millimeters) has been shown to result in a PSA recurrence 30% more often than small or “focal” positive margins.  The location of positive margins has, also, been demonstrated to predict the potential for recurrent prostate cancer.  Historically, for example, a positive margin at the apex (or tip) of the prostate has been considered to be much less worrisome than positive margins at other areas of the prostate, particularly those at the back of the prostate near its lateral edge.  Unfortunately, there is a great deal of contradictory data emerging about these sub-characteristics of positive margins.  In addition, a recent large study of over 5000 patients demonstrated that while these sub-characteristics do help to predict the risk of cancer recurrence, they do not appear to add any further predictive power above and beyond that derived from the simple presence or absence of positive margins.  As a result, while these sub-characteristics of positive margins are somewhat useful in helping to sort out the significance of a positive margin, they are not powerful enough to substantially change the approach to dealing with a given positive margin.

Managing Positive Margins

While understanding positive margins can be helpful in predicting the risk of cancer recurrence after prostatectomy, this knowledge also creates a dilemma of how to proceed.  As mentioned previously, while positive margins can double the risk of prostate cancer recurrence, nearly half of men with positive margins never have a recurrence of their prostate cancer.  As a result, immediately treating ALL men with positive margins to prevent a recurrence would mean that 50% of these men would be undergoing treatment unnecessarily.  Given the fact that the treatment of choice in this situation would be radiation the added, unnecessary, risks of this radiation to 50% of the men in question would be unacceptable.  As a result, a great deal of controversy exists as to who should get radiation treatment for a positive margin right away (adjuvant radiation) and who should wait for a PSA recurrence first (salvage radiation).  I have discussed this controversy in my previous post entitled, “High Risk Prostate Cancer After Prostatectomy: Radiate or Wait?”  : 


Thursday, March 22, 2012

Rising PSA After Negative Prostate Biopsy Part II: Can PCA3 Prevent Unnecessary Biopsies?

In my last post I discussed some PSA based tools that can be used to determine whether a rising PSA is due to prostate cancer or to other causes.  Such tools are very important because repeat biopsies for men with rising PSAs are positive for cancer in only 10-30% of cases, depending on how many biopsies are performed.  The yield (chance of cancer found) is less and less for every subsequent biopsy performed.  As a result, 70-90% of men may be undergoing these biopsies unnecessarily.  The problem with performing all of these repeat biopsies, aside from the pain and discomfort, is that they are not without risk (some more information about what to expect from prostate biopsies can be found in this previous post).  Unfortunately, the PSA tools I described, while helpful, are far from perfect.  The problem with these tests stems back to the basic problem with PSA: it is not only produced by prostate cancer but by normal prostate tissue.  As a result, PSA tests can be falsely elevated by other factors like infections, large prostates, and having sex.  Due to this limitation, PSA and PSA based tools can often overestimate the risk of prostate cancer in men with previously negative biopsies.  This, in turn, can lead to many unnecessary biopsies in men without prostate cancer.  Fortunately, a new test has recently been approved that may help determine which men really need to undergo a repeat biopsy in response to a rising PSA.  This test, called PCA3, may significantly decrease the need for repeat biopsies in select men with rising PSAs.  In this post, I will explain what PCA3 is, why it may be more informative than PSA, and how it may be used to prevent unnecessary biopsies.

What is PCA3?

Lets first discuss what PCA3 actually is.  PCA3 is a gene found within the DNA of human cells.  Like other genes, PCA3 serves as a code to produce a type of protein called mRNA.  It turns out that prostate cancer cells produce over 60 times more of the PCA3 mRNA than normal prostate cells.  In addition, no other tissue type in the human body produces this mRNA either.  Identifying this very prostate cancer specific protein, scientists then developed a test to identify and quantify it in men.  Unlike PSA, the PCA3 test is actually a urine, rather than blood, based test.  The test begins with a “prostate massage” by the physician.  Basically, this is a vigorous prostate exam that lasts for a few more seconds than a routine rectal exam.  After this exam, the patient then urinates and the urine is analyzed to look for and quantify the amount of PCA3.  The idea here is that the prostate exam causes the prostate to secrete the PCA3 protein into the urine, which can then be collected for quantification.

How is PCA3 better than PSA?

As I mentioned earlier, the major flaw of PSA is that it is not specific enough for prostate cancer.  In other words, way too many other things can cause PSA elevation aside from just prostate cancer.  PCA3, in contrast, is very specific for prostate cancer.  Neither infection nor sexual intercourse elevate PCA3.  In addition, unlike PSA, PCA3 is not proportional to the size of the prostate.  In other words, larger prostates do not produce more PCA3.  Finally, even urological procedures like prostate biopsies and cystoscopies, notorious for raising PSA, have no effect on PCA3.  I am sure that you are now starting to see the beauty of this new test.  Because it is so specific for prostate cancer, it may be able to prevent the unnecessary pain and risk of repeat biopsies in men with rising PSAs.  Lets see how this theoretical advantage pans out in practice.

PCA3 and the Prostate Biopsy Decision

Numerous studies have evaluated the utility of PCA3 in predicting prostate cancer.  One study evaluated the accuracy of PCA3 in predicting the extent and significance of prostate cancer.  The study obtained PCA3 tests from men with known prostate cancer about to undergo radical prostatectomy and then correlated the PCA3 level with the pathology findings from the surgery.  The study reported some very encouraging findings.  First, the study found that men with small amounts of cancer demonstrated significantly lower PCA3 values than those with large cancer volumes (PCA3 scores of 17 versus 47, respectively).  The study similarly found that men with insignificant or low risk prostate cancer also demonstrated substantially lower PCA3 scores than their counterparts with more substantial prostate cancer (PCA3 scores of 16 versus 45, respectively).

While PCA3 has, thus, been demonstrated to be a good predictor of significant prostate cancer, can this new test help predict the presence of prostate cancer and the need for prostate biopsy in men with a rising PSA after a previously negative biopsy?  Several studies have done just that.  A small study of 51 men, for example, performed a PCA3 test on men with a negative prostate biopsy who then underwent  a repeat biopsy for a further rising PSA.  The study reported that men with a positive repeat biopsy demonstrated substantially higher PCA3 values (median 50) as compared to those men with negative repeat biopsy (median 28).  A substantially larger study of over 1100 men undergoing repeat biopsies demonstrated a similar discrepancy of PCA3 values of 34 versus 17 for men with positive versus negative repeat biopsies, respectively.  This large study also reported that men with a PCA3 level greater than 35 had twice the risk of a positive biopsy as compared to those men with PCA3 less than 35.  Given this ability of PCA3 to differentiate prostate cancer from other causes of rising PSA, another study of 127 men reported that the PCA3 test can help avoid up to 73% of unnecessary repeat biopsies. 

Is there a downside to PCA3?

The main downside to PCA3 appears to be the lack of an accepted, definitive cutoff point above which the presence of prostate cancer is nearly certain.  While higher values of PCA3 are certainly more indicative of prostate cancer than lower values, there is no single magic number that can serve as a cutoff.  Numerous studies have used 35 as such a cutoff but with mixed results.  For example, one study evaluated using 35 as the PCA3 cutoff.  The study demonstrated that if only men with PCA3 over 35 were biopsied, 85% of previously undiagnosed prostate cancers would be detected while avoiding 50% of unnecessary, repeat negative biopsies in men without cancer present.  The study demonstrated that if a PCA3 cutoff of 44 is used to trigger a repeat biopsy, in contrast, only 75% of previously undiagnosed cancers would be detected while avoiding 73% of unnecessary, repeat negative biopsies. Still other studies have argued for lower cutoffs (such as 15 or 25), which identify larger percentages of previously undiagnosed cancers (95%) for the tradeoff of substantially more unnecessary biopsies.  So what is the magic number?  Is it more important to identify more cancers or prevent more unnecessary biopsies?  That is the million dollar question that is still being debated.  That is also a drawback of the test.

Take Home Message

For many years, urologists have been looking for a noninvasive test that can reliably predict the presence of prostate cancer in men with a rising PSA and a negative previous prostate biopsy. A rising PSA can often be misleading as its rise can be triggered by factors not related to prostate cancer such as an enlarging prostate, urinary tract infection, or even sexual intercourse.  A test was needed that can eliminate such extrinsic factors to determine if a man really does need a repeat biopsy or if he can safely avoid the risks and discomfort of this procedure. 

In many respects, PCA3 seems to be just such a test. It is only produced by prostate cancer and, so, is not affected by extrinsic factors.  It is fairly easy to obtain if you discount the discomfort of a “vigorous” rectal exam.  It appears to differentiate significant from relatively innocuous prostate cancer.  And it has been demonstrated through numerous studies to significantly reduce the number of unnecessary prostate biopsies while not substantially decreasing the ability to identify prostate cancer.  Is PCA3 the holy grail of prostate cancer diagnosis?  Of course not.  Is it without its limitations?  No.  However, it appears to be a valuable tool to be used in conjunction with the PSA tools I previously discussed to reliably determine which men really need a repeat prostate biopsy and which can avoid the risk and discomfort of a repeat procedure.

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Thursday, March 8, 2012

Rising PSA After A Negative Prostate Biopsy Part I: Crunching The Numbers

One of the most pleasant phone calls I can make is to tell one of my patients that their prostate biopsy was negative…no cancer.  I can often hear the sigh of relief on the other end of the line after several days of anticipation end in the best possible news.  After allowing the patient to rejoice for a while, however, I proceed to explain that a negative biopsy is not a guarantee of the absence of cancer.  I explain that while a prostate biopsy is undertaken through ultrasound guidance and in a systematic fashion, it is not 100% accurate. After all, a biopsy entails removing 12 tiny slivers of tissue from a gland that can vary in size from that of a walnut to that of a grapefruit.  You can imagine how possible it can be to miss some prostate cancer, particularly in men with very large prostates and small amounts of cancer.  As a result, I counsel these patients that, while the news is great, we still have to be cautious by checking the PSA every 6 months (some urologists advocate yearly tests) as well as performing a rectal exam at the same time intervals.  Most of my patients agree to this follow up protocol.

Unfortunately, at a later point in time, some of these men demonstrate a rise in their PSA.  This leads to a much less festive phone call.  Instead of a sigh of relief, I often hear anxiety and fear.  I also invariably hear the same question: “ Doc, what do we do now?”  This is actually a very important question with a complicated answer.  For some men, it means a repeat biopsy.  For others, in contrast, it means just repeating the PSA again in a few more months.  So how do you determine how to deal with a rising PSA after a negative prostate biopsy?  There are many tools that help urologists to figure out who needs a repeat biopsy in this setting.  In this post, I will cover how a more detailed look at the PSA can help determine whether a PSA rise after a negative biopsy is a sign of missed cancer or simply of benign growth of the prostate.

What Causes the PSA to Rise?

Before delving into the details of PSA rises, lets first explore why the PSA rises in men:

1) Artificial Rises: As I described in a previous post, at least 50% of elevated PSA tests are actually elevated in error.  PSA can be falsely elevated due to sexual intercourse within 2-3 days of the test, urinary tract infections, motorcycle riding, and even lab errors.  As a result, as with a single elevated PSA in new patients, I always recommend a repeat PSA test for those men who demonstrate a rise in PSA after a negative prostate biopsy.

2) Benign Prostatic Hypertrophy (BPH):  PSA is not only produced by prostate cancer cells.  It is also produced by normal prostate cells.  As a result, when benign prostate tissue grows in the form of BPH (the condition that gives you a slow stream and makes you urinate multiple times at night), the PSA naturally rises as a result.

3) Prostate Cancer:  Of course, in some men, a rising PSA is actually a sign of growing prostate cancer.  Most prostate cancer cells produce PSA and as the cells reproduce and grow, more and more PSA is produced.

Dissecting PSA Further

So how do we differentiate among these three potential causes of a rising PSA in a man after a prostate biopsy?  As I just mentioned, artificial rises in PSA can simply be differentiated from the other two through a repeat test after refraining from activities such as sexual intercourse while simultaneously checking a urine culture.  Determining whether a true rise in PSA is due to BPH versus prostate cancer is a much more complicated task after a negative prostate biopsy.  However, this determination can be made by taking a more detailed look at some specific aspects of PSA:

1) PSA Velocity:  Studies have demonstrated that a “normal” rise in PSA can be as high as about 0.7-1 per year.  This rise in PSA can safely be ascribed to BPH.  A yearly rise in PSA higher than this amount is a warning sign that cancer may be present and often triggers a repeat biopsy in men with a previously negative biopsy.

2) PSA Density:  Another aspect of PSA that can be valuable in distinguishing between BPH and prostate cancer is the PSA density.  During a biopsy, the urologist usually obtains an accurate measurement of the prostate volume by means of the ultrasound.  This size is usually described in grams or cubic centimeters (cc).  This measurement can be very helpful in evaluating future PSA elevations after the biopsy by allowing for the determination of the PSA density.  This calculation is carried out by dividing the PSA by the prostate volume.  For example, a man with a PSA of 5 and a prostate volume of 50 grams has a PSA density of 0.1.  Because BPH can also produce PSA, men with very large prostates should be expected to have higher PSA values than men with small prostates.  The PSA density allows you to compare apples to apples by determining the PSA in men per gram of prostate tissue.  Studies demonstrate that a PSA density of greater than 0.15 is suspicious for prostate cancer.

3) PSA Doubling Time: The PSA doubling time appears pretty self explanatory.  The term refers to the time it takes for the PSA to double in value.  To calculate this number you need a few PSA values spread at least 3 months apart.  You also need to use a fairly complex formula to get the exact value.  For our purposes, a rough, eyeball assessment will do just fine.  For example, by looking at a series of PSA values we can roughly estimate if the PSA is doubling every month, every 6 months, or every year, etc... Studies have demonstrated that PSA doubling time is one of the most important prognostic factors used to evaluate a rising PSA after a negative biopsy.  A PSA that doubles in 3-6 months is substantially more worrisome with regards to potential underlying prostate cancer as compared to a PSA that doubles in 1-2 years.

4) Free PSA:  Believe it or not, the PSA test actually represents a combination of two different types of PSA that are found in the blood stream: free and complexed.  While free PSA floats freely through the bloodstream, complexed PSA floats through the bloodstream attached to a specific protein. Why do we care about these two PSA subtypes?  Free and complexed PSA are sort of like good and bad cholesterol.  A higher free PSA is actually associated with a lower prostate cancer risk.  In contrast, a higher complexed PSA is associated with a higher prostate cancer risk.  While there is no great commercially available complexed PSA tests, a free PSA test is available.  The free PSA is reported as a percentage of the overall PSA test.  A I mentioned , the higher the free PSA, the less likely prostate cancer is present.  Studies have demonstrated that a free PSA of greater than 15-18% represents a low risk for prostate cancer as opposed to a free PSA less than 8% which represents a high risk for malignancy of the prostate.  Using such parameters, free PSA can help predict the likelihood of prostate cancer being present in men with a rising after a negative prostate biopsy.

Take Home Message

A rising PSA can be a stressful and worrisome finding in men following a negative prostate biopsy.  In this situation, the PSA needs to be further examined in terms of PSA velocity, doubling time, density as well as free PSA.  These various PSA based tests are used in combination to gauge the risk of prostate cancer in men with a rising PSA after a negative prostate biopsy.  Because prostate biopsies are not without risks, not every PSA rise in men necessitates a repeat biopsy.  Prudent use of these PSA tests can help determine which men with rising PSA after a negative prostate biopsy really need a repeat biopsy and which simply need to be followed with serial PSA tests and digital rectal exams.  In future posts, I will discuss other tests that can help to determine when a PSA rise after prostate biopsy truly indicates the presence of cancer.

Check out my new Book: 

  Prostate Doc’s Guide to Life After Prostatectomy


Wednesday, February 29, 2012

One Year Anniversary

It is hard to believe that a year has gone by since I started the Prostate Doc blog!  What a year it has been.  I am so honored and thankful for all of the enthusiasm and support.  With nearly 40,000 visits from over 50 countries, the interest in the blog has exceeded all of my expectations.  The interest in the blog has also reinforced my belief that men with prostate cancer need more information about their disease than is offered by their physicians.  I truly believe that writing this blog and, more importantly, getting your feedback, has made me a better urologist with a keener awareness of the needs of my prostate cancer patients.  At the same time, your continued positive feedback has made the experience all the more rewarding.

Many readers have noticed and commented that, recently, my posts have been few and far between.  This recent hiatus has been due to two reasons.  First, unfortunately, my own family has faced some pretty daunting health issues that have required a great deal of my time and attention.  The second reason is, fortunately, much more positive and exciting.  I have put together my first book!  I have noticed that the majority of the questions coming from readers have to do with radical prostatectomy and its consequences.  As I read and absorbed all of these questions and comments, I began to realize that men undergoing radical prostatectomy need a guide which can lead them through their often confusing journey.  As a result, I wrote:

I have made this book available at the Prostate Doc Library.  This sister site of the blog will feature this and future books.

I hope that you find the book useful.  I also am very excited and energized to write many new posts for the blog.  While I have many ideas about what I want to cover, I would also love to hear from you.  Please leave your comments about the prostate cancer topics that you most want covered in the blog and I will definitely try to discuss them.

Thanks again to you all for your continued support of the blog.  You have been a tremendous inspiration for me. 

Prostate Doc

Thursday, November 17, 2011

Androgen Deprivation Therapy For Prostate Cancer: Understanding How It Works

Approximately one third of men with prostate cancer will eventually need androgen deprivation therapy.  While this treatment was first used for advanced, metastatic prostate cancer, androgen deprivation therapy is increasingly used for other indications as well.  Many patients undergoing radiation therapy for aggressive prostate cancer are treated concurrently with androgen deprivation therapy to maximize treatment outcomes.  Men with PSA recurrence after prostatectomy are also placed on this therapy.  Despite the frequency with which androgen deprivation therapy is used, many men undergoing the treatment don’t know how it works. In this post, I will introduce androgen deprivation therapy.  Specifically, I will focus on the first line androgen deprivation therapy and how it works.

The Food of Prostate Cancer

One of the most important discoveries related to prostate cancer was that androgens serve as the fuel or food of prostate cells and prostate cancer cells.  Androgens are basically male hormones.  They are the compounds, circulating in the bloodstream, which give men their masculine features.  The most famous androgen, testosterone, is mainly produced in the testes.  Other, less potent androgens are also produced in the adrenal glands.  Once produced, testosterone and the adrenal androgens are secreted into the bloodstream and travel to the prostate.

Testosterone binds to a target on prostate cells called the androgen receptor.  By binding the androgen receptor, testosterone initiates a cascade of events that stimulates further growth and multiplication of the prostate cells.  The same occurs with prostate cancer cells which, fueled by testosterone, multiply and spread to distant sites in the body. 

Starving the Beast

The understanding that prostate cancer feeds on testosterone was perhaps the fundamental discovery in the battle against the disease.  With this understanding, the next obvious step was to try to prevent prostate cancer cells from obtaining their fuel.  The most direct way of ridding the body of testosterone is to get rid of the source: the testicles.  As a result, the first form of androgen deprivation therapy was simple surgical castration.  By surgically removing the testicles, doctors were able to dramatically and rapidly decrease the level of circulating testosterone and, in turn, significantly slow down the growth of advanced prostate cancer.  Of course, surgical castration has its downsides.  Most men are psychologically impacted by having their testicles removed and would rather avoid surgery.  As a result, the search began for a chemical means to decrease the amount of testosterone in the body.

Chemical Castration

A turning point in the treatment of prostate cancer came with the discovery that the  production of testosterone in the testicles is not constant or automatic  Rather, it is regulated.  Studies demonstrated that the presence of testosterone or estrogen (the female equivalent of testosterone) in the bloodstream have a negative effect on the production of testosterone by the testicles.  In other words, the body regulates the amount of sex hormones in the blood stream by a process of negative feedback: large amounts of circulating sex hormones actually inhibit the testicles from producing more testosterone.  Negative feedback is a useful regulatory tool that the body uses to make sure that too much of given compound is not produced or present at a given time.

The discovery of negative feedback led to the use of an estrogen-like compound called DES in treating advanced prostate cancer.  Scientists reasoned that the presence of this ingested estrogen analog in the bloodstream could provide the negative feedback to the testicles needed to stop testosterone production.  As a result, they reasoned, prostate cancer would be starved of its vital fuel.  Turns out, they were right.  The use of DES worked incredibly well in reducing the growth and extent of prostate cancer.  However, it was soon discovered that men treated with DES suffered from heart attacks and other blood clots.  As a result, DES was no longer offered for men with advanced prostate cancer.

The real breakthrough in androgen deprivation therapy came in the late 1970s when the actual mechanism behind the negative feedback regulation of  testosterone production was revealed.  At that time, it was demonstrated that the negative feedback which regulates testosterone production by the testicles is actually carried out by hormones produced in the brain.  A part of the brain called the hypothalamus produces a compound called gonadotropin releasing hormone(GNRH) which stimulates another part of the brain called the pituitary gland to produce a hormone called leutinizing hormone(LH).  LH travels from the brain through the blood stream and into the testicles to stimulate the production of testosterone. High levels of testosterone and/or estrogen circulate through the bloodstream to the brain to provide the negative feedback.  This negative feedback allowed DES (a compound very similar to estrogen) to successfully decrease testosterone production and limit the growth of prostate cancer.

Stemming from this discovery was the further understanding that the hypothalamus usually emits GNRH in spurts rather than in a continuous fashion.  As long as this hormone is released in this fashion, the pituitary gland will continue to produce LH.  In turn, the LH will then stimulate testosterone production by the testicles.  However, researchers found that if the GNRH is secreted continuously it would actually decrease LHRH by the pituitary which would then decrease the production of testosterone by the testicles.  With this discovery, modern androgen deprivation was born in the form of GNRH agonists like Leuprolide and Goserilin.  These monumental drugs, used in mainstream androgen deprivation protocols today, work by maintaining a steady, continuous flow of GNRH which serves to shut down production of LH by the pituitary and, subsequently, stops the production of testosterone by the testicles.

Several years later, this discovery of the pathway and regulation mechanisms of testosterone production led to the development of another class of drugs used in androgen deprivation.  Rather than relying on GNRH analogs that shut down the production of LHRH in the pituitary, researchers developed a compound that inactivates GNRH altogether.  These GNRH antagonists, like Abarelix and Degarelix, have some important advantages over GNRH agonist drugs.  However, due to cost issues and some important side effects, these drugs have not reached the same level of mainstream use as GNRH agonists except for certain specific indications.  I will further explore this issue in a future post.

Take Home Message

Modern androgen deprivation therapy has evolved greatly over time.  From surgical castration to GNRH agonists and antagonists, the treatment of advanced prostate cancer has become more and more refined as discoveries have shed greater light on how the food of prostate cancer is created and regulated.  Understanding this background can help men undergoing androgen deprivation therapy have a better grasp of the rationale behind the often complex twists and turns experienced during their battle against advanced prostate cancer.  In future posts, I will build upon this background to explain some limitations and pitfalls of androgen deprivation therapy as well as to describe what happens when such first-line therapy fails.
