Lymph Nodes And Prostate Cancer Part I: Who Needs A Lymph Node Dissection?

When I was undergoing my training in urology, the approach to managing lymph nodes for patients with prostate cancer was pretty simple.  First, everyone undergoing a prostatectomy would also undergo a lymph node dissection. Second, anyone with proven metastases to the lymph nodes would be given a horrible prognosis and be treated with hormonal therapy.  Since that time, however, the management of lymph nodes has become much more complicated and controversial for men with prostate cancer.  Far fewer men are undergoing lymph node dissection.  Also, the management of men found to have prostate cancer in their lymph nodes is not quite as clear-cut.  In my next two posts, I will attempt to shed a little light on the controversies surrounding the evaluation and management of lymph nodes in men with prostate cancer.  In this first post, I will explain what the lymph nodes are, why they deserve our attention, and who actually needs a lymph node dissection during a prostatectomy.  In the second post, I will elaborate on the prognosis and treatment for men found to have prostate cancer in their lymph nodes.

What are lymph nodes?

The lymphatic system is a transport network for our immune system. It is a way for immune cells to move throughout the body.  When an infection occurs in a part of the body, immune cells attack the infection and then travel to local hubs called lymph nodes where they can reproduce and further target the foreign invaders.  As more immune cells travel to and reproduce in these hubs, the lymph nodes enlarge.  This is why we can actually feel tender lymph nodes around an area of infection.  For example, the lymph nodes of the neck can get swollen during an infection of the throat.  

In cases of cancer, the lymph nodes are also involved.  Cancer that spreads from its location of origin can move through either the blood vessels or the lymphatic system.  For prostate cancer, spread through the blood vessels leads to metastatic deposits in the bones while lymphatic spread leads to cancer in the lymph nodes.  These nodes are located on either side of the prostate within the pelvic cavity. 

What is a lymph node dissection?

A lymph node dissection is a surgical procedure usually performed at the start of a radical prostatectomy, which involves removing all of the lymph nodes surrounding the prostate.  This can be performed through either an open or laparoscopic (robotic) approach with equivalent success.  After removal, the lymph nodes are sent for pathologic evaluation.  The number of lymph nodes removed is quantified and the contents of the lymph nodes are inspected under a microscopic to look for the presence of metastatic prostate cancer.

One would think that by removing lymph nodes that harbor metastatic prostate cancer, a lymph node dissection could improve outcomes in the treatment of prostate cancer.  To date, however, there has been no significant evidence demonstrating that the removal of pelvic lymph nodes changes the prognosis for men undergoing treatment for prostate cancer, whether or not prostate cancer is found in the nodes.  If lymph node dissection provides no therapeutic benefit, why go through the trouble of performing it?

Why is a lymph node dissection important?

When prostate cancer spreads to the lymph nodes, the entire approach to treatment changes.  First, the presence of prostate cancer in the lymph nodes means that the prostate cancer is no longer curable.  The prognosis is significantly worse for men with positive lymph nodes.  As a shall describe in the next post, the prognosis varies considerably depending on how many lymph nodes are involved as well as the density of positive lymph nodes.  This information is critical in counseling and in medical decision making.   In addition, as I shall also discuss in the next post, the presence of positive lymph nodes calls for the early administration of hormonal therapy.  If such treatment is not promptly initiated because the presence of prostate cancer within the lymph nodes is not revealed, the prognosis can be substantially worse.

At this point you are probably asking yourself a very logical question.  If the lymph node dissection is only valuable from a diagnostic perspective, aren’t there less invasive ways to find out if prostate cancer has spread to the lymph nodes?  The answer is not really.  Mainstream imaging modalities such as CT scans and MRIs are only able to detect prostate cancer in the lymph nodes in approximately 20-30% of cases.  The reason for this is the fact that the resolution of these techniques is around 1cm.  That means that unless a cancerous lymph node has reached 1 cm in size, a CT scan or MRI cannot detect it.  As a result, most lymph nodes, which are often less than 1cm in size, go undetected.  PET scans, as well, have not been very helpful in detecting occult prostate cancer in lymph nodes for this and other reasons.  New technology has been developed which can increase the ability to detect cancerous lymph nodes with an accuracy of 80-90%.  This technique uses a special contrast medium composed of nanoparticles that have an affinity for lymph nodes.  Called Combidex in the United States and Sinerem in Europe, this contrast medium has demonstrated amazing success in detecting prostate cancer within the pelvic lymph nodes when used in conjunction with standard imaging techniques.  For reasons that I have not yet unearthed, however, this new technique has not been approved for use in the United States and, I believe, the manufacturer may have even stopped producing it.  

Why aren’t lymph node dissections routinely performed as part of prostatectomies?

If non-invasive imaging techniques are not sensitive enough to detect most cancerous lymph nodes, shouldn’t every man undergoing a prostatectomy also undergo a lymph node dissection.  After all, if the surgeon is working in that area already and the dissection can provide important information that can change the treatment plan, it only makes sense to perform a lymph node dissection on everyone, right?  In medicine, like in all other aspects of life, there is no free lunch.  A lymph node dissection, like any other surgery, has potential serious complications that need to be weighed against the potential benefits of the dissection.  The reported complication rates for pelvic lymph node dissections have ranged from 2-20% depending on the extent of the dissection performed.  The most common complications include:

1. Lymphocele formation:  during a lymph node dissection, numerous little lymphatic channels are clipped off and cut.  Occasionally these channels are not appropriately sealed and can leak lymphatic fluid into the pelvis.  This fluid can accumulate and form a collection called a lymphocele.  These collections of lymphatic fluid can grow quite large, compressing nearby structures like blood vessels (which can cause swelling of the legs), the bladder (causing trouble with urination) and the intestines (causing bloating).  Lymphoceles are treated by placing a temporary drain which allows the fluid to leave the pelvis.  Occasionally, more invasive surgical intervention is required as well.

2. Nerve injury: one of the boundaries of a lymph node dissection is the Obturator nerve.  This nerve provides impulses to the leg, which causes it to move inward or towards the midline of the body.  During a lymph node dissection, this nerve can be inadvertently injured or cut.  Such damage can impair the movement of the leg on that side of the body, which can significantly affect the ability to walk or drive a car.  Some sensation is also affected by damage to this nerve.

3. Blood vessel injury:  another boundary of a pelvic lymph node dissection is the external iliac vein.  This is one of the main veins of the body, which drains blood from the legs and feet back to the heart.  Occasionally a tear in this vein can occur which can lead to significant loss of blood during surgery.  In addition, compression of the vein during the procedure can lead to a large blood clot called a deep vein thrombosis or DVT.  Such a clot can cause swelling of the leg and foot and severe pain.  Occasionally, the clot can even travel to the lungs and cause a life threatening condition called a pulmonary embolism.

Understanding these potential complications, one can see why lymph node dissections should not be taken lightly and should certainly be performed only when necessary.  The question, of course, becomes when is the dissection necessary?

Who needs a lymph node dissection?

To answer this question we must first determine who is at greatest risk of harboring occult, metastatic prostate cancer within their lymph nodes. Overall, only about 4-5% of men with prostate cancer have lymph node positive disease.  However, this rate greatly depends on other characteristics of a given prostate cancer.  Men with low risk prostate cancer, for example, have rarely been found to have lymph node disease.  As I described in a previous post, low risk disease is characterized by a Gleason score of 6 or less, a PSA less than 10 and no to minimal cancer felt on rectal exam.  Studies have shown that men with prostate cancer meeting these criteria  harbored occult lymph node disease in less than 1% of cases, on average.  Men with more extensive prostate cancer are much more likely to have positive lymph nodes.  For example, men with a PSA score greater than 10 have been found to have lymph node involvement in 7-29% of cases, depending on the Gleason score and rectal exam findings.  Similarly, a man with a PSA of 7 or greater has a significantly higher chance of lymph node involvement, even when the PSA is less than 10. One study of men with prostate cancer and a PSA <10, for example, reported lymph node involvement in 3% of men with a Gleason score of 6 as opposed to 25% for those men with a Gleason score of 7 or higher.  Several tools have been developed to help determine a particular man’s chance of harboring lymph node metastasis.  One such tool, called the Partin Tables, uses a patient’s PSA, Gleason score, and rectal exam findings to make this determination.  This tool is available to the public through the Johns Hopkins website at:

http://urology.jhu.edu/prostate/partintables.php

Using such tools, patients and urologists can understand the risk of lymph node metastases and, with this knowledge, make the determination of whether or not to proceed with lymph node dissection.  While no hard and fast rules exist as to when lymph node dissection should be performed, most urologists use similar criteria.  Low risk patients, for example, rarely if ever undergo the dissection.  In contrast, men with a Gleason score above 6 and/or a PSA above 10 almost always have their lymph nodes removed.  Some urologists also rely on a cutoff risk of 7% (as predicted by the tools described above) of lymph node metastasis, above which they routinely perform a lymph node dissection.  

Take Home Message

The lymph node dissection can provide important information that can lead to significant changes in the management of prostate cancer.  Removal of the pelvic lymph nodes, however, is not risk free and should not be routinely performed in all men treated for prostate cancer.  Rather, the decision of whether or not to perform a lymph node dissection should be determined based on the risk of lymph node metastasis as ascertained from a prediction tool.

Check out my new Book: 

   Prostate Doc’s Guide to Life After Prostatectomy

This blog is not a medical practice and cannot provide specific medical advice. This information should never be used to replace or discount the medical advice you receive from your physician

Bladder Neck Contractures After Prostatectomy

Men undergoing radical prostatectomy need to be aware of a potentially serious complication called a bladder neck contracture.  This narrowing at the connection between the bladder and urethra can cause significant symptoms including a slow stream and incontinence.  These symptoms are often ignored until full retention of urine occurs.  In this post I discuss bladder neck contractures, their etiology, and how to treat them.

What is a Bladder Neck Contracture?

The prostate is usually located between the bladder and the urethra.  I often describe the relationship to patients in the following manner: the bladder is like an upside down fishbowl which is connected to a donut (the prostate) which is subsequently connected to a straw (the urethra).  Urine leaving the bladder goes through the donut hole of the prostate and out the urethra.  During a prostatectomy, the prostate is removed, requiring this plumbing to be rerouted.  In order to do this, the “neck” of the bladder, which was previously attached to the prostate, is sewn directly to the urethra tube.  In 2-20% of cases, that connection gets scarred down to form a bladder neck contracture.  The extent of this contracture can be variable, ranging from a mild narrowing to a complete obliteration of the connection.  Either way, a bladder neck contraction can create significant difficulty with the passage of urine from the bladder to the urethra.

What Causes a Bladder Neck Contracture?

While the true causes of bladder neck contractures have not been definitively elucidated, numerous theories have been presented.  The two most popular explanations include:

1) Gaps in anastomosis:  When the anastomosis (the surgically created connection between the bladder neck and urethra) is made during a prostatectomy, several problems can occur.  First, the sutures placed in the bladder or urethra can tear.  Also, bleeding from the surgery can create a large clot called a hematoma which can insinuate itself between the stiches and stretch the anastomosis.  Either of these situations will create gaps in the anastomosis between the bladder neck and urethra.  The human body has a natural tendency to fill gaps with fibrotic tissues or scar.  As a result, gaps in the anastomosis allow scar tissue to form which, in turn, creates a bladder neck contracture.
2) Poor blood supply:  Many urologists have postulated that bladder neck contractures occur due to decreased blood supply to the anastomosis.  Generally, when a tube or connection in the body does not get an adequate supply of oxygen-rich blood, it gets obliterated by scar tissue.  This situation, the theory proposes, is exactly what creates a bladder neck contracture.  So what causes poor blood supply to the anastomosis?  Several factors have been implicated.  First, tying down the sutures connecting the bladder and urethra too tightly can strangulate the blood vessels to the area and decrease the flow of blood.  Others have argued that prostatectomies performed without nerve sparing can also decrease blood supply to the area.  Finally, some men are simply predisposed to problems with blood vessels.  Men with diabetes, high cholesterol, and heart disease, for example, demonstrate poor blood flow to all parts of the body, including the anastomosis.  Not surprisingly, older men (who are more prone to problems of blood flow) are more likely to experience bladder neck contractures than their younger peers.

What are the Signs of a Bladder Neck Contracture?

Men usually start to experience symptoms from a bladder neck contracture between 3-6 months after surgery.  The initial symptom in most men is a subtle slowing of the urinary stream.  This symptom is often ignored until it gets substantially more dramatic.  Often times, men actually complain of urinary incontinence after a period of dryness following radical prostatectomy.  This leakage is due to the overflow of urine from a bladder distended with urine that is barely able to escape into the urethra.  Eventually, if left unattended, bladder neck contractures lead to complete urinary retention.  Unable to urinate, men present to the emergency room where doctors and nurses are usually unable to negotiate a catheter into the bladder due to the narrowing from the contracture.  At this point, an urologist needs to be called to provide treatment.

How Are Bladder Neck Contractures Treated?

Men complaining of symptoms suggestive of a bladder neck contracture first need to be evaluated with a cystoscopy.  This procedure, done in the urologist’s office with local anesthesia, involves passing a flexible camera through the penis and towards the bladder.  With this camera, an urologist can tell if there is any scar tissue creating a blockage at the anastomosis between the bladder and urethra.  In addition, he can determine if there are any other problems in the bladder or urethra that could be mimicking these symptoms.

If a bladder neck contracture is confirmed during an office cystoscopy, a decision then needs to be made to determine how to proceed.  One option is to perform a gentle dilation at that time under local anesthesia.  A dilation is performed with the use of a variety of tubes of varying diameters.  The urologist starts by passing the smallest tube through the contracture and into the bladder.  He then stretches the contracture by passing larger and larger tubes through it until a catheter (like the one in place after prostatectomy) can be successfully placed in the bladder.  This catheter usually stays in place for a few days and is then removed.

 Although definitely tolerable, a dilation performed under local anesthesia can be uncomfortable.  As a result, some men choose to have their bladder neck contractures treated in the operating room under more extensive anesthesia.  In the operating room, more extensive procedures can be offered besides just dilation.  For example, a larger camera can be advanced to the location of the contracture and a knife (within the camera) can be used to cut the contracture.  This procedure also requires a catheter for a few days.

Regardless of which procedure is chosen, bladder neck contractures are successfully managed with a single treatment in 60-80% of cases.  Some men, however, have very tough contractions that recur soon after treatment.  For these men, more aggressive operative therapy is needed.  One such therapy involves aggressively and deeply cutting the contracture with a hot knife, also through an endoscopic approach using the camera.  If this does not work, some surgeons use a permanent, metallic stent (called Urolume) which can be deployed across the contracture.  These aggressive treatments usually lead to significant incontinence.  As a result, most men that are successfully treated with such aggressive options subsequently also need to undergo placement of an artificial urinary sphincter (AUS) to help them overcome the leakage of urine.  I describe the AUS in detail in my previous post on surgical options for urinary incontinence after prostatectomy: http://myprostatedoc.blogspot.com/2011/06/managing-urinary-incontinence-after_26.html

Take Home Message

Bladder neck contractures develop in a small proportion of men undergoing radical prostatectomy for prostate cancer.  Presenting 3-6 months after surgery, this scar tissue at the connection between the bladder and urethra often causes slow stream and occasionally retention of urine.  In some men, it can also cause urinary incontinence.  Men with these symptoms after prostatectomy should seek expedient evaluation and, if necessary, treatment for bladder neck contracture from their urologist.  Such proactive management can save a great deal of potential stress and discomfort during a late night visit to the emergency room .

Check out my new Book: 

   Prostate Doc’s Guide to Life After Prostatectomy

This blog is not a medical practice and cannot provide specific medical advice. This information should never be used to replace or discount the medical advice you receive from your physician

Understanding The Gleason Score And Its Implications

For men in the prostate cancer community, a Gleason Score is sort of like an identity badge.  This simple number, used to grade the severity of prostate cancer, is forever etched into the minds of men diagnosed with prostate cancer.  Knowing this number is crucial in determining how to approach the prostate cancer and whether the cancer even needs to be addressed.  The simple number obtained from a prostate biopsy can also speak volumes as to what kind of prognosis a man with prostate cancer can expect.  In this post, I will explain how a Gleason Score is determined, explain its significance, and provide a very important warning about the dangers of relying on this number too greatly.

What is a Gleason Score?

About 40 years ago a pathologist in Minnesota named Donald Gleason evaluated the pathology specimens of hundreds of veterans diagnosed with prostate cancer.  He attempted to correlate how prostate cancer looked under the microscope with how men faired clinically.  In essence, he tried to look for patterns of the prostate cancer cells that could be then linked to prognosis and outcomes.  In so doing, Doctor Gleason created the grading system currently used worldwide to microscopically evaluate prostate cancer.

The Gleason score is determined by first surveying prostate samples under the microscope.  When prostate cancer is identified, it is evaluated in terms of how aggressive it looks.  Specifically, the pathologist looks at the shape and size of the cells, how they stick together, and whether they take the form of glands or simply look like amorphous sheets.  This last characteristic is called differentiation.  Well differentiated tumors look more like normal glands while poorly differentiated tumors do not really look like anything more than random cells stuck together.  Depending on this microscopic appearance, pathologists score the cancer on a scale of 1-5, with 1 being very mild or well differentiated and 5 being extremely aggressive or poorly differentiated.  After grading all of the cancerous areas in this fashion, the pathologist next determines the two types of tumors he sees most frequently in the specimen.  He then adds these two numbers up to get the Gleason Score.  For example, if the pathologist finds that 60% of the cancer is Grade 3 and 40% is Grade 4, the Gleason Score would be 3+4=7.  In short, the cancer in this example would be labeled Gleason 7. The Gleason Score can range from a score of 2(1+1) through 10 (5+5).  In reality, however, individual Gleason Scores of 1 or 2 are no longer seen as most pathologists no longer consider these patterns as true cancer.  Instead, practically speaking, the lowest individual score is 3, making the lowest realistic Gleason Score 6.  Rarely, a total Gleason Score of 5 may still be encountered.

Why is the Gleason Score Significant?

Gleason scores, themselves, are also grouped into categories.  Gleason 6 disease is considered mild to moderate risk prostate cancer.  It is the run-of –the-mill prostate cancer that most men get.  Gleason 6 cancer is the type to think about when you hear that prostate cancer is slow growing and MAY not affect you.  In contrast Gleason 8-10 cancer is considered aggressive cancer that most likely will affect you, particularly if you do nothing about it.  Prostate cancer with a Gleason Score of 8-10 is much more likely to grow outside of the prostate, leave positive margins after prostatectomy, and metastasize to the bones or lymph nodes as compared with cancer of a lower Gleason grade.  In addition, a Gleason Score of 8-10 significantly impacts the survival of men with prostate cancer.  A classic study followed men with prostate cancer that were treated conservatively.  After 15 years, the study reported that men in their 50s diagnosed with a Gleason 8-10 prostate cancer had an 80% chance of dying from the cancer as opposed to 20% for men with Gleason 6 disease.  I should, again, stress that these statistics were for men NOT aggressively treating their cancer, which truly demonstrates that differing natural history of Gleason 6 versus Gleason 8-10 disease.

In between Gleason 6 and Gleason 8-10 disease, of course, lies Gleason 7.  This type of prostate cancer is moderately aggressive with a prognosis that logically falls between the two groups.  In the above mentioned study, for instance, about 60% of men in their 50s died of Gleason 7 prostate cancer after 15 years.  Gleason 7 disease, however, can be more of a wild card.  It is very hard to predict how aggressive such disease really is.  Some Gleason 7 cancers behave more like Gleason 6 disease while others act much more aggressively, like Gleason 8-10 tumors.  Some of this discrepancy may have to do with whether a Gleason 7 cancer is 4+3 or 3+4.  As you may recall, the Gleason score is a sum of the two most commonly found cancer patterns in a prostate specimen.  In a Gleason 4+3=7 tumor, the more aggressive type 4 pattern is found in greater abundance than the milder type 3 pattern.  The opposite is true for Gleason 3+4=7 disease.  Studies have demonstrated that Gleason 4+3=7 disease is much more aggressive than Gleason 3+4=7 tumors.  One study, for example, demonstrated that after 5 years of follow up, men treated for Gleason 4+3=7 prostate cancer demonstrated a 40% risk of cancer progression as opposed to a 15% risk for their counterparts treated for Gleason 3+4=7 disease.  Hence, this small distinction may make a significant difference in treatment planning and prognosis and may explain why not all Gleason 7 tumors are the same.

The Pitfalls of the Gleason Score

Because the Gleason Score has demonstrated such correlations with outcomes for men treated for prostate cancer, it is heavily relied upon in making treatment decisions.  For those men choosing active surveillance rather than treatment, for example, a Gleason Score less than 7 is really mandatory.  As such, the Gleason Score can have a monumental impact on future quality of life.  The problem with relying on the Gleason Score from a prostate biopsy, however, is that this score is not always accurate.  Because the score is subjectively determined by a pathologist, there can be a great deal of variability in scoring.  One study, for example, reported that when prostate biopsy specimens were sent for a second opinion, 7% of tumors initially graded Gleason 6 were upgraded to a Gleason 7 while 16% of tumors initially graded Gleason 7 were downgraded to Gleason 6.  As I described above, this one point disparity can have a significant impact on treatment decisions and outcomes.  This is particularly true for men who choose active surveillance for what they think is Gleason 6 disease but , really, have Gleason 7 prostate cancer. 

Another limitation of a Gleason Score determined from a prostate biopsy is that a biopsy may not provide a representative sample of the entire prostate.  Each biopsy sample is only a few centimeters long and a few millimeters wide as compared to the entire prostate, which can range in size from a walnut to a peach.  As a result, the Gleason Score on prostate biopsy is usually accurate only about 50% of the time as compared to the Gleason Score determined when the whole prostate is subsequently removed and examined after a prostatectomy.  One study, for example, evaluated 134 men with Gleason 6 prostate cancer on biopsy who subsequently underwent prostatectomy.  The study reported, that 50% of these men (who were thought to have Gleason 6 cancer) were actually determined to have Gleason 7 prostate cancer when the entire prostate was evaluated after prostatectomy.

Fortunately, studies have provided some guidance as to how to better determine if  a biopsy Gleason score may be underestimating the true aggressiveness of a given prostate cancer.  These studies have demonstrated that other aspects of the prostate cancer, gleaned from the biopsy and clinical information, may help predict more aggressive disease.  For example, men with a PSA greater than 5 and a prostate less than 60 grams in size may actually have more aggressive disease than the Gleason 6 prostate cancer found on biopsy.  In addition, prostate cancer that occupies more than 5% of the total biopsy tissue, is found on more than 1 biopsy core (sample), or takes up more than 10% of any core is likely to be more aggressive than the biopsy Gleason Score is reporting.  As a result, many active surveillance protocols exclude men with the criteria above despite the fact that they have only Gleason 6 disease.

Take Home Message

The Gleason Score is a very important characteristic of prostate cancer.  It is like a cancer ID card that allows urologists to determine prognosis and guide treatment decisions based on the appearance of prostate cancer cells under the microscope.  While a useful tool in evaluating prostate cancer, however, the Gleason Score can prove to be a double edged sword.  Gleason Scores reported on prostate biopsies are often inaccurate due to pathologist error or as a result of poor sampling.  As a result, the Gleason Score reported on a prostate biopsy can underestimate the true aggressiveness of prostate cancer.  While this inaccuracy may not be important for a man choosing to proceed with a prostatectomy or with radiation therapy, it can be critical for those men choosing to forego treatment and, instead, proceed with active surveillance.  For those men, it may be beneficial to get a second pathological opinion to make sure that their Gleason 6 prostate cancer is actually Gleason 6.  In such situations, looking at the Gleason score in the context of other risk factors such as PSA and tumor volume may also help determine the accuracy of the biopsy Gleason Score and provide some added reassurance that a more aggressive cancer is not lurking undetected in the prostate.  As always, talk to your urologist and make sure that you are getting all of the information necessary to make a knowledgeable decision about your prostate cancer.

Check out my new Book: 

   Prostate Doc’s Guide to Life After Prostatectomy

Intermittent Androgen Deprivation: The Future of Hormonal Therapy?

Hormonal therapy is a vital tool in fighting advanced prostate cancer.  Although it is not a cure, hormonal therapy can keep prostate cancer in a state of suspended animation, at least for a while.  By slowing the growth of the prostate cancer, hormonal therapy can provide men with locally advanced, metastatic, or recurrent disease many years of life that is free of the effects of prostate cancer. For some men, however, the side effects of the hormonal therapy can be almost as unbearable as the prostate cancer itself.  Symptoms like hot flashes, weakness, weight gain, and sexual dysfunction can ruin quality of life and make men yearn to stop the therapy.  Out of this dilemma has come a controversial, EXPERIMENTAL approach to hormonal therapy called intermittent androgen deprivation (IAD).  In this post, I will describe the theoretical basis for IAD, describe the ideal candidates for this therapy, and report the outcomes of studies that have evaluated it.

Intermittent Androgen Deprivation Revealed

Before we can dive into the details of IAD we first need to explain what IAD actually involves and how it is different from traditional hormonal therapy or continuous androgen deprivation (CAD).  Intermittent androgen deprivation involves giving the same class of drugs as traditional hormonal therapy.  In contrast to CAD, however, IAD gives these medicines in a more sporadic fashion.  For example, rather than receiving Depot Lupron continually every 3 months  (as with traditional hormonal therapy), men undergoing IAD may receive the medication every 3 months for 2-3 doses, but then do not receive it again for over a year.  In so doing, IAD allows for breaks in treatment, which provides time for the testosterone level (and PSA) to climb.  While this may seem counterproductive, allowing the PSA and testosterone to rise may provide IAD with advantages in terms of cancer survival and limitation of side effects.

Theories Behind Intermittent Androgen Deprivation

Intermittent androgen deprivation has been postulated to provide two very different, theoretical advantages over traditional hormonal therapy. 

    1) Cancer Control: numerous studies have demonstrated that when prostate cancer is exposed to long-term androgen deprivation, it eventually develops ways to outsmart the treatment and become castration resistant. As a result, the prostate cancer can live and thrive despite the absence or significant limitation of testosterone.  The theory behind this adaptation is that a few “androgen independent” cells within a prostate cancer cell population thrive and rapidly replicate once the remaining “androgen dependent” cells are suppressed in a low testosterone environment.  By intermittently re-introducing testosterone to the environment of prostate cancer cells, IAD was thought to theoretically delay the overgrowth of “androgen independent” cells by allowing some more docile,  “androgen dependent” cells to remain and compete for resources with their more aggressive counterparts. Thus, researchers have argued that IAD may successfully treat advanced prostate cancer for a longer period of time than traditional hormonal therapy by staving off the emergence of castration resistant prostate cancer.

    2) Limitation of Side Effects : The other theoretical advantage of IAD is the limitation of the most common side effects of traditional hormonal therapy.  By allowing testosterone to intermittently return to normal levels, IAD can provide a reprieve from the side effects commonly experienced with low testosterone such as hot flashes, fatigue, and sexual dysfunction, if only on a short term basis.

Outcomes of Intermittent Androgen Deprivation

Numerous studies have been performed to try to determine whether the theoretical advantages of IAD actually pan out in a clinical setting.  Although differing in study design and the details of the IAD regimen, these investigations have demonstrated similar results.  First, most studies have demonstrated that while IAD is not superior to continuous androgen deprivation, it is, at least, not inferior.  The previously largest study to date was carried out in Europe and randomized over 600 men to either undergo IAD or traditional hormonal therapy.  After 8 years of follow up, the study demonstrated equivalent overall mortality (54% vs 54%).  Interestingly, the study did report that men undergoing IAD were more likely to die from prostate cancer than those men undergoing CAD (34 vs 27%).  However, this difference was counteracted by the fact that men undergoing traditional hormonal therapy were more likely to die from heart disease than those men undergoing IAD (17% vs 13%).  

The results of this study were confirmed in June of 2011 when the preliminary results of Southwestern Oncology Group (SWOG) JPR7 study were released at the meeting of the American Society of Clinical Oncology.  This very large study randomized over 1400 men to undergo either continuous or intermittent androgen deprivation.  After following these men for an average of 6 years, the investigators found that IAD was at least equivalent to traditional hormonal therapy in terms of overall survival.  While those men on IAD did demonstrate a longer period of time until they progressed to hormone refractory disease, they demonstrated a higher rate of deaths from prostate cancer.  However, as in the European study, this higher risk of death from prostate cancer was mitigated by a lower rate of death from other causes as compared to those men undergoing CAD.

While IAD has not been demonstrated to be superior (but also not inferior) to traditional hormonal therapy in terms of survival, numerous studies have reported significant advantages of IAD in relation to side effects.  The European study previously discussed, for example, demonstrated significantly lower rates of hot flashes and breast tenderness in men undergoing IAD.  The SWOG study presented this year also reported fewer hot flashes.  Phase II studies have reported that men undergoing IAD also demonstrated significant improvement in sexual function during the off-treatment phase of the regimen (when their testosterone and PSA levels were allowed to rise).  These off treatment-phases can be lengthy.  In the large European study previously mentioned, for example, the average time off-therapy was approximately 1 year while 29% of men were able to stay off-therapy for more than 3 years.  Hence, IAD can potentially allow for up to 3 years of recovered sexual function without jeopardizing cancer control!  Unfortunately, the first off-treatment cycle is usually the longest with subsequent off-treatment cycles lasting for shorter periods of time.  Also, older men tended to regain their testosterone levels more slowly in off-treatment cycles and, thus, also reported lower sexual function and quality of life during these periods of time as compared to their younger peers.  Nonetheless, the ability of IAD to provide a respite from sexual dysfunction, hot flashes and other destroyers of quality of life while not impacting overall survival is compelling.

Guidelines for Intermittent Androgen Deprivation

Because IAD is still experimental, no hard and fast rules exist as to who are the optimal candidates for the therapy and how the treatment regimen should be carried out.  Nonetheless, using the data generated from the studies completed to date, numerous recommendations have been published.

Optimal Candidates for IAD: 

a. Initial PSA less than 50

b. Initial PSA doubling time of greater than 12 months

c. For those men with an initial PSA greater than 10, a decrease of PSA to less than 4 following the first cycle of hormonal therapy

d. For those men with an initial PSA of less than 10, a decrease of PSA to less than 0.2-0.5 following the first cycle of hormonal therapy

e. Men without bulky tumors, numerous positive lymph nodes, or extensive bone metastases.

The criteria about the PSA nadir after the first cycle of hormonal therapy are particularly important. Studies have demonstrated that men without significant declines in PSA in response to hormonal therapy were much more likely to progress to hormone resistant disease and eventual death as compared to men with the optimal PSA responses mentioned above.

Recommendations have also been made about treatment protocols for IAD.  Typically, men are initially treated with 6-9 months of continuous androgen deprivation.  If an appropriate PSA nadir is reached, hormonal therapy is then stopped and PSA levels are monitored.  Androgen deprivation is not reinstituted until a threshold PSA level is reached.  This level has been a PSA of 10 in many studies although this is an arbitrary number not really substantiated by any specific data.  Such a regimen is repeated until a hormone refractory state is reached during which PSA is found to rise despite androgen deprivation.  At that point, alternative therapies are employed.

Why is Androgen Deprivation Therapy Still Considered Experimental

As I mentioned previously, IAD is still considered an experimental therapy for prostate cancer.  The reason for this status is that not enough long-term data is available to recommend it as a mainstream strategy.  In addition, the numerous short-term studies conducted to date were all carried out using somewhat different inclusion criteria and treatment protocols, making comparisons difficult.  As a result, while we await more long term data from studies such as the Phase III SWOG trial previously mentioned, IAD has to be considered investigational and approached very carefully.  Nonetheless, for those men facing long-term androgen deprivation and worried about associated side effects, IAD should be at least considered and discussed with their urologist or oncologist.

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This blog is not a medical practice and cannot provide specific medical advice. This information should never be used to replace or discount the medical advice you receive from your physician