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.

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

Managing Urinary Incontinence After Prostatectomy Part II: When Conservative Measures Fail

In my last post, I stressed the point that most men will regain continence within 12-18 months after prostatectomy.  I emphasized that although men undergoing prostatectomy should be proactive about pelvic floor muscle exercises to regain their continence more quickly, they should also remain patient because the vast majority of men do reach almost complete if not total dryness after prostatectomy.  For some men, however, this relief from urinary incontinence never comes.  Ten to fifteen percent of men remain significantly wet even years after surgery.   For some of these men, this incontinence requires changing diapers several times per day which ruins their quality of life, destroys their self esteem, and limits their ability to take part in beloved pastimes and activities.  For these men, more aggressive options are available to limit the leakage of urine.  In this post I review the invasive, surgical treatments of urinary incontinence.  I, again, stress that these options should be reserved for intractable incontinence that persists 12-18 months post prostatectomy and beyond.

Urethral Bulking Agents

The least invasive surgical option for refractory incontinence after prostatectomy is the injection of urethral bulking agents.  Such a procedure is performed using a camera to visualize the inside of the urethra and, specifically, the area of the urinary sphincter.  Once this muscle is visualized, a bulking agent (gluteraldehyde crosslinked collagen) is injected endoscopically (through the camera) into the lining of the sphincter.  The idea behind this treatment is to “bulk up” the sphincter, increasing the resistance to urine travelling from the bladder.  Early studies on the use of urethral bulking agents after prostatectomy were encouraging.  One study reported that 58% of men with incontinence who underwent the procedure had either good or at least improved results at a follow up of 10.3 months.  More recent studies were not so positive, however, with reports of complete dryness of 8-17% and social dryness (no more than 1 pad per day) of 38% after multiple injections.  A recent study of over 300 men treated with injectable bulking agents reported that men undergoing the procedure still required an average of up to 3 pads per day.  The same study reported that the therapy was only effective for an average of 6 months, after which another injection was required.  Due to these suboptimal results, bulking agents are generally NOT recommended for men with incontinence after prostatectomy.

Male Slings

A more invasive surgical option for men with incontinence after prostatectomy is the male sling.  While numerous types of slings are commercially available, they all share a common mechanism of action: compression of the urethra.  As with the bulking agents, the idea is to compress the urethra so as to increase the resistance to urine leaking from the bladder.  Unlike the direct injection of agents into the sphincter, however, slings are secured underneath the urethra.  Created as an artificial polyester mesh, the sling is like a hammock which sits under the urethra to serve as a backstop and provide gentle pressure to restrict urinary leakage.

Various versions of male slings date back to the late 1990s.  The first male slings were fashioned after slings used for female incontinence during the same time period.  The hammock portion of the sling was connected to sutures (strings) that were pulled out above the muscles of the anterior wall of the abdomen (the muscles referred to as a “six pack” in those of us who work out).  The sutures would then be tied above these muscles(but below the skin) to secure the sling in place.  The whole procedure could be carried out through a small incision underneath the scrotum and another, even smaller, incision just over the bladder.  A study evaluating men undergoing this early version of male slings reported complete dryness in 56% and satisfaction in 90% of men undergoing the procedure.

This early version of the male sling was refined in 2001 with the development of the bone-anchored sling.  This new variant avoided passing sutures through the abdomen (and the associated risk of damaging the bladder and intestines) in order to secure the sling.   Instead, this new sling was secured in place under the urethra via sutures that were actually anchored into the pelvic bones adjacent to the urethra.  Success rates reported with the bone anchored sling have been variable, ranging from 37-87%, depending on the definition of complete continence. 

      

 Diagram of a Bone Anchored Sling

More recently, yet another version of the male sling has been developed.  This version is called the Transobturator (or AdVance) Sling.  The sling, also placed under the urethra for compression, is secured by passing it through a canal within the pelvic bones.  As such, the synthetic material is passed through an incision underneath the scrotum and out of another incision in the inner thigh (just underneath the groin crease).  The sling is then cut at the skin surface of the incision in the thigh so it is not visible after surgery.  The results of this technique mirror those of the bone anchored sling.  The transobturator sling and bone anchored sling

are currently the two most commonly used slings for incontinence after prostatectomy.

                                       Diagram of a Transobturator Sling

Like any other surgery, implantation of the male sling can result in complications.  Urinary retention can sometimes be experienced (3%) if the sling is made to tight, requiring a subsequent surgery to loosen or remove it.  Because the sling is a foreign object within the body it can become infected (6%) or can actually erode into the urethra (2%).  Either of these complications requires a repeat operation with complete removal of the sling.

Artificial Urinary Sphincter

Although more invasive then urethral bulking agents or male slings, the artificial

urinary sphincter (AUS) remains the gold standard for men with persistent incontinence after prostatectomy.  The AUS is composed of three interconnected parts.  The main part of the device is comprised of an inflatable cuff which is wrapped around the urethra (in the same location as where the male sling is usually placed).  The cuff is connected to a reservoir (containing fluid) that is implanted in the abdomen and a pump that is implanted in the scrotum.  At baseline, the cuff encircling the urethra is inflated with fluid.  As such, the cuff compresses the urethra, preventing leakage of urine from the bladder.  However, when the patient pushes on the pump within the scrotum (which can be manipulated through the skin), fluid from the cuff is transferred to the reservoir.  When all of the fluid is transferred from the cuff to the reservoir, the cuff is deflated and no longer compresses the urethra.  This allows urine to flow from the bladder and out of the penis. The fluid in the reservoir drains back into the cuff after a fixed period of time, inflating it and allowing it to compress the urethra again.  The whole process is carried out via hydraulics. 

Diagram of Artificial Urinary Sphincter

The advantage of the AUS is that it replicates normal continence.  Men with the AUS remain dry until they want to void at which time they activate the device, allowing the urine to drain for a set period of time.  Success rates with the AUS have been notable.  Initial studies reported complete dryness ranging from 79-100% with one study finding a decrease in pad usage from 2.7 to 1 per day.  More recent studies have demonstrated social continence (up to 1 pad per day) of 58-88%.  There are some drawbacks, however.  First, any man that wants an AUS needs some level of manual dexterity that will allow him to operate the pump in the scrotum.  In addition, as with all machines, the device can and does break down (6% rate over 5 years), requiring the parts to be removed or replaced through further surgery.  Other complications associated with an AUS include infection (5.5%) and erosion into the urethra (6%).  As with the male sling, either of these two complications requires removal of the device.  Another potential complication is  recurrent incontinence.  This complication usually occurs due to urethral atrophy, which prevents the cuff from successfully compressing the urethra.  In this situation, a repeat procedure is performed in which a second (tandem) cuff is added to provide additional compression of the urethra.

Take Home Message

While most men will eventually regain continence after prostatectomy, some will continue to have moderate to severe, debilitating leakage.  Fortunately, men with this complication still have hope in the form of surgical techniques.  While minimally invasive and creating the least risk, urethral bulking agents are not very effective and generally not recommended for the treatment of incontinence after prostatectomy.  Male slings, although somewhat more invasive have been demonstrated to have significant efficacy and are being used more and more commonly for mild to moderate incontinence.  The gold standard, however, remains the artificial urinary sphincter.  Although not a panacea and definitely plagued by its own risks and complications, the AUS has provided reliable dryness for men with moderate to severe incontinence after prostatectomy.  Regardless of the technique chosen, the decision to proceed with surgical management should be considered carefully after thoroughly weighing the risks and benefits with a qualified urologist.  This decision should not even be considered until at least a year after surgery.

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

Managing Urinary Incontinence After Prostatectomy Part I: Be Proactive But Patient

One of the more notorious complications of radical prostatectomy is urinary incontinence.  Ranging from a few drops to complete lack of control, leakage of urine after prostatectomy can be a debilitating side effect that has a dramatic impact on quality of life.  Reading numerous posts from men on various prostate cancer forums, I got the impression that many men feel that urinary leakage after prostatectomy is inevitable, permanent, and devastating.  In reality, the presence, extent, and timing of urinary incontinence is highly variable and, to a significant extent, can be successfully managed.  In this post I will explain who should expect to have urinary incontinence after prostatectomy, how long such leakage usually lasts, and how to prevent and treat it. 

Who Experiences Urinary Incontinence After Prostatectomy?

The reported rates of urinary incontinence after radical prostatectomy are variable at best.  Studies have reported rates of urinary incontinence between 3 and 74%.   One reason for this tremendous disparity is the definition of “dry.”   While some studies categorized men as dry if they did not use any pads after prostatectomy, others were more lenient, designating men that use 1-2 pads per day as dry as well.  Other studies did not even rely on pad usage and simply asked men whether they subjectively felt wet or dry. 

In truth, immediately after surgery, most men will leak urine.  When the catheter is removed, the majority of men will require pads or diapers, if even for a short period of time.  The reason for this initial leakage has to do with damage to the urinary sphincter, the main mechanism for controlling urination.  During prostatectomy, this muscle complex, which is located near the tip of the prostate, is damaged to varying degrees.  As a result, when the catheter is removed soon after surgery, the debilitated sphincter is often not strong enough to control the flow of urine from the bladder, particularly during times of increased abdominal pressure while coughing, straining, or lifting heavy objects. 

While most men will leak immediately after a prostatectomy, studies have demonstrated that some men are more prone to significant incontinence than others.  Older men, for example, are more likely to leak, presumably due to less muscle mass in their sphincters as compared to those of younger men.  In addition, overweight men are more likely to suffer from incontinence.   As I mentioned in my post about obesity and prostate cancer   (http://myprostatedoc.blogspot.com/2011/04/prostate-cancer-and-obesity-deadly.html), overweight men pose a technical challenge during surgery, making damage to the sphincter and subsequent leakage more likely.  Similarly, men with larger prostates and those with more aggressive cancers have been shown to develop urinary incontinence more frequently, also due to the fact that their more challenging anatomy can increase the risk of damaging the sphincter during surgery.  Of course, while such risk factors may increase the risk of incontinence after surgery, they by no means guarantee it.

Despite the tremendous variation as to the incidence of incontinence reported after prostatectomy, there appears to be a consensus about its resolution.  Fortunately, the majority of studies demonstrate that most men eventually regain control of urination after surgery.  These studies report a progressive return of continence over time with 51-71% of men regaining urinary control after 3 months, 70-87% enjoying continence after 6 months and 80-92% reporting dryness at 1 year.  While this data does not provide solace for the minority of men that don’t reach continence, it does provide evidence that incontinence after prostatectomy needs to be approached with patience.

Managing Incontinence After Prostatectomy

Although most men will regain continence after prostatectomy, a proactive approach can significantly decrease the time to reach this sought after dryness.  The best way to ensure a quicker path to continence is to strengthen the sphincter.  Like any muscle in the body, the sphincter becomes stronger and more efficient if it is exercised.  In a sense, men need to take their sphincters to the gym.  The main exercises developed to “work out” the sphincter are the Pelvic Floor Muscle Exercises (PFME).  These types of exercises are better known to women as “Kegels.”  These exercises are performed by trying to stop urinary flow once it has begun.  Once men identify the muscles needed to accomplish this task, they can then perform the exercises even when they are not urinating. 

Some men find it difficult to identify the exact muscles they need to exercise.  For these men, biofeedback therapy may be appropriate.  This therapy involves placing a probe in the rectum, which can measure the force with which the sphincter is contracted during PFME.  Through such a device, a therapist can provide feedback to the patient as to whether they are contracting the right muscles.   After such biofeedback, patients can be more confident that they are performing the PFME correctly.  However, studies have not demonstrated significant differences in continence between men undergoing biofeedback versus those treated with PFME alone.

The more PFME that can be performed on a daily basis, the better.  Urologists generally recommend a hundred or more a day.  Studies have demonstrated significant decreases in the time to continence in men performing such exercises after surgery.  In fact, randomized studies demonstrated that 74-88% of men regularly performing PFME were dry 3 months after prostatectomy as opposed to only 30-56% of men who did not perform the exercises.  Interestingly, these same studies did not demonstrate a significant difference in continence between the two groups at 1 year after surgery, signifying that while PFME can decrease the time to continence, most (although certainly not all) men will achieve dryness by 12-18 months after surgery, regardless.

Preventing Incontinence Before it Starts

While PFME performed after prostatectomy have been demonstrated to decrease the time to continence, this benefit is even more dramatic for those men that start to perform the exercises prior to surgery.  A randomized study of 118 men undergoing radical prostatectomy, for example, compared continence rates at 1 and 3 months after surgery for those men starting PFME 1 month prior to surgery versus those starting these exercises postoperatively.  The study demonstrated that men starting PFME prior to surgery were only 40% as likely to have incontinence at 1 and 3 months after surgery as compared to those men that did not start the PFME until after prostatectomy. 

Another way to prevent or at least limit incontinence after prostatectomy is through nerve sparing prostatectomy.  Investigators have suggested that the nerves around the prostate may not only provide nerve impulses to the penis (to stimulate erections) but also to the sphincter.  As a result, sparing these nerves during surgery may better preserve nerve signals to the sphincter and maintain its function after surgery.  Such a theory was supported by a study which demonstrated that men undergoing nerve sparing surgery recovered their urinary control twice as quickly (5.3 versus 10.9 months, respectively) as those men who did not have their nerves spared during the procedure.  Of course, the decision to perform nerve sparing is not simple in men with high risk disease for whom the benefits of nerve sparing must be weighed against the potential for positive margins and recurrent cancer.

Take Home Message

Urinary incontinence is a common side effect of radical prostatectomy.  While almost all men suffer from some degree of leakage of urine immediately after surgery, most regain their continence within 12-18 months.  Men with risk factors for incontinence such as advanced age, obesity, high risk disease, and large prostates, need to be aware before surgery that they may be challenged by more severe incontinence for longer periods of time.  All men planning to undergo prostatectomy should learn PFME and begin such exercises prior to surgery.  In addition, when safe and possible, nerve sparing surgery should be performed.  Through such precautions, most men will be able to regain the ability to control their urination more quickly and effectively.  Despite all of these efforts, however, some men have debilitating, persistent incontinence.  After failure of conservative management for 12-18 months (and sometimes longer), appropriately qualified men need to be offered more aggressive, surgical management of their incontinence.  I will cover these options in my next post.

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

Perineural Invasion On Prostate Biopsy: How It May Change The Game Plan

A reader recently asked me to share my thoughts on perineural invasion found on a prostate biopsy.  In formulating my response to this question, I was surprised that I did not cover this topic sooner.  After all, perineural invasion (PNI) is found in approximately 30% of biopsies.  The presence of PNI on a prostate biopsy can sometimes be a sign that the prostate cancer found on the biopsy may be just the tip of the iceberg in terms of the cancer within the prostate.  As such, PNI can change both the prognosis and treatment course for men with newly diagnosed prostate cancer.  In this post, I will describe PNI and explain its impact on treatment plans and prognosis.

Defining Perineural Invasion

Before I explain the importance of perineural invasion, we must first be on the same page as to what this finding on a prostate biopsy actually means.  The presence of PNI means that the pathologist has seen prostate cancer cells surrounding or tracking along a nerve fiber within the prostate.  The importance of this finding becomes apparent when you realize that nerves within the prostate travel outside of the gland through microscopic holes within the prostate capsule.  The capsule, as you may remember from my previous post about positive margins, is the outer covering of the prostate.  This covering serves as a barrier preventing the spread of cancer outside of the prostate, at least for a while.  Because nerves travel through holes in the capsule, prostate cancer growing around these nerves can follow them all the way out of the prostate without needing to overcome the resistance of the capsule.  As a result, the presence of PNI on a biopsy portends a higher likelihood of prostate cancer that has or will escape the prostate gland.  Studies have, indeed, validated this theory while also demonstrating other negative impacts of PNI.

The Impact of Perineural Invasion on Final Pathology

Numerous clinical studies have compared the final pathologic findings (after radical prostatectomy) of those patients with and without PNI on initial biopsy.  The results are very striking.  Large studies have demonstrated that men with PNI have a 2-3 times higher rate of extracapsular extension (prostate cancer outside of the gland) and nearly twice the likelihood of positive margins after prostatectomy when compared to men without PNI on their prostate biopsy.  That means that the presence of PNI at least doubles the chance of T3 disease in a man undergoing treatment for what is clinically localized, T2 disease.  In addition, numerous studies have demonstrated that PNI on biopsy is associated with higher grade disease (Gleason 8-10) on final pathology even when only low grade disease (Gleason <7) is found on biopsy. In fact, one study demonstrated that over 40% of men with PNI and low grade disease on biopsy are subsequently found to have high grade disease on final pathology after prostatectomy.  The reason for this disparity appears to be sampling error, with high grade disease not caught in the original biopsy specimens.  Hence when a prostate biopsy demonstrates Gleason 6 disease and PNI, there is a high likelihood that higher grade, more aggressive cancer is present in the prostate but was not detected.  Other studies have also demonstrated a higher risk of seminal vesicle invasion and lymph node metastases in men found to have PNI.

Perineural Invasion and Prognosis After Prostatectomy

Given the significant adverse impact of PNI on final pathology, it is not surprising that PNI has also been demonstrated to negatively affect prognosis after surgery.  One study out of Johns Hopkins followed 1256 men with prostate cancer for an average of 3 years after radical prostatectomy.  Out of this patient population, 188 men (15%) were found to have PNI on prostate biopsy.  Even over this relatively short follow up period, men with PNI on biopsy were found to have three times the likelihood of PSA recurrence as compared to those men without PNI. Similar findings were reported in 6 out of 10 studies of the impact of PNI on men undergoing radical prostatectomy for prostate cancer.  Not surprisingly, men with low risk prostate cancer (Gleason 6, T1-T2a, and PSA<1O) and PNI are three times more likely to require salvage radiation than their low risk counterparts without PNI.

Perineural Invasion and Prognosis After Radiation Therapy

The prognosis after radiation therapy, as well, appears to be negatively impacted by the presence of PNI on prostate biopsy.  One study followed 381 men undergoing radiation therapy for localized prostate cancer, 86(23%) of whom were found to have PNI on prostate biopsy.  After 5 years of follow up, 69% of men without PNI were free of cancer as compared to only 47% of men with PNI.  When dividing men into risk categories, the study demonstrated that only 50% of men with low risk prostate cancer (Gleason 6, T1a-T2a, PSA <10) and PNI were free of cancer at 5 years of follow up.  This rate of cancer free survival was lower than the 53% rate achieved by men with high risk prostate cancer (Gleason 8-10 or T2c-T4 or PSA >20) but without PNI.  Hence, the presence of PNI could instantly transform an otherwise low risk prostate cancer into a high risk disease.  Such findings were validated in 5 out of 10 large studies of men treated with radiation therapy.  Interestingly, one large study of men undergoing brachytherapy for prostate cancer did not demonstrate a difference in treatment outcomes of men with and without PNI.  Of note, however, is that men selected for brachytherapy generally have lower risk disease than those who undergo external beam radiation.

How Perineural Invasion Can Change the Treatment Plan

Given the significant impact of PNI on final pathology and prognosis, it seems obvious that the presence of PNI can influence the treatment course chosen by patients and their doctors. A study of surgical approaches in men with PNI demonstrated that removing the nerves on the side of the prostate with PNI on biopsy led to a positive margin rate of 11%.  In contrast, the positive margin rate was 100% when the nerves were spared on the side of PNI.  Of note, a recent study from Johns Hopkins reported that nerve sparing did not impact positive margin rates or prognosis in men with PNI.  This data needs to be taken with an enormous grain of salt however in that all men in the study were operated on by Dr Patrick Walsh, the urologist credited for the development of the modern day open radical prostatectomy.  It would see unlikely (at best) that such outcomes could be replicated by the typical urologist performing the surgery.  As a result, most urologists will sacrifice nerve sparing in order to assure negative margins in men with PNI.  In addition, given the high likelihood of positive margins and T3 disease, urologists often counsel patients with PNI on biopsy that they may likely need to undergo radiation therapy following radical prostatectomy.  Similarly, radiation oncologists treating men with PNI often approach them as high risk patients regardless of clinical stage, PSA, or Gleason score.  As a result, they often treat men with PNI with a combination of radiation and hormonal therapy rather than radiation therapy alone.  In addition, they may also use dose escalation as part of their radiation protocol.

Take Home Message

Perineural invasion is a very significant finding on a prostate biopsy.  It often indicates high risk prostate cancer, even in men with seemingly low risk disease.  PNI is also usually associated with a poorer prognosis, leading to a higher risk of recurrent disease.  As a result, men with prostate cancer that are found to have PNI on prostate biopsy are often provided with more aggressive therapy, whether it be in the form of surgery or radiation.  Understanding the significance of PNI on prostate biopsy is crucial to formulating a successful battle plan against prostate cancer.

Check out my new Book: 

   Prostate Doc’s Guide to Life After Prostatectomy

Shortening Of The Penis After Prostatectomy: Yes, It Really Happens

When counseling patients about the complications of radical prostatectomy, most urologists spend a great deal of time discussing impotence and incontinence.  Few urologists, in contrast, discuss another very common but not well known postoperative problem: shortening of the penis.  While not noticed by some men, shortening of the penis can lead to significant problems with self esteem, sexual satisfaction, and quality of life after radical prostatectomy for prostate cancer.  Despite these significant consequences, many urologists disregard it  while others are simply not familiar with it.  As a result, many patients agree to and proceed with a radical prostatectomy without being aware of this postoperative issue and do not take any steps to minimize it.  In this post, I will discuss shortening of the penis, how often it occurs and what, if anything, can be done to prevent or limit its occurrence.

It Happens More Often Than You Think

Despite its obscurity, shortening of the penis is actually a common complaint of men undergoing radical prostatectomy.  Studies have shown that nearly half of men undergoing prostatectomy demonstrate some decrease in penis size postoperatively.  The average decrease in flaccid penis length at 1 year after surgery has been reported to be about 1.3cm.  A larger decrease of 2.3cm (nearly an inch) has also been reported in the length of the erect penis after the same period of time.  One study reported that, after prostatectomy, almost 20% of men lose 15% of the length of their penises when measured in the erect state.  You can imagine that such a decrease is noticeable and disheartening for a large number of men.

What Causes Shortening of the Penis ?

Many theories have been advanced, speculating about the root cause of shortening of the penis.  One such theory that has been debunked (for the most part) is that of tension from the urethra.  It was thought that because the prostate is removed, tension is created in bringing together the bladder and urethra.  As a result, the urethra is pulled up towards the bladder, simultaneously pulling the penis into the body and shortening it.  This theory does not make much anatomic sense as the urethra is tethered to the part of the pelvic muscles called the urogenital diaphragm.  As a result, the urethra cannot really get pulled much in either direction, limiting its ability to shorten the penis.

Recently, a more comprehensive theory has emerged which divides the causes for shortening of the penis into short and long term.  Shortening of the penis can first be noticed from the time of catheter removal through the first month or so after surgery.  This initial shortening is thought to occur directly as a result of damage to the nerves traveling around the prostate that are responsible for erections.  Damage to these nerves at the time of surgery leads to stimulation and hyperfunctioning of nerves that are part of the sympathetic nervous system.  These nerves, responsible for the “fight or flight” response, release adrenaline which leads to contraction of  smooth muscle in the body.  These sympathetic nerves send impulses to the penis where the smooth muscle of the erectile bodies contract.  This contraction of the penis pulls it into the body and makes it appear shorter.  Fortunately, this is a short term response which is reversible.

Long term shortening, in contrast, is caused by progressive, irreversible changes to the structure of the penis.  These changes are brought about through two mechanisms:

1)     Permanent nerve damage experienced during surgery:  When nerve damage occurs anywhere in the body, the tissues to which the damaged nerves supply impulses usually experience atrophy or breakdown.  This can often be seen in paraplegic, wheelchair bound people in whom the loss of nerve signal  causes a significant decrease in the size and muscle mass of the legs.  The same can be said of the penis after nerve damage during prostatectomy.  If permanent nerve damage occurs, the lack of impulses to smooth muscle of the penis leads to an atrophy or breakdown of the tissues responsible for erections and causes the penis to shrink both in length and girth.

2)     Decreased transport of blood and oxygen through the erectile tissue of the penis: As is widely known, loss of erections is a common side effect of prostatectomy, particularly in the first few months after surgery.  Erections lead to the circulation of oxygen-rich blood through the penis which nurtures it and keeps it healthy.  If no erections occur for extended periods of time, the lack of circulation of this oxygen-rich blood leads to fibrosis or scarring of the erectile tissue of the penis, also leading it to shrink in terms of length and girth.  This phenomenon has been demonstrated both through experimental animal studies and human studies.

Preventing Shortening of the Penis

While causing problems like shortening of the penis, radical prostatectomy still remains a vital tool in the fight against prostate cancer.  Most men will proceed with surgery to cure their prostate cancer even with the knowledge that a prostatectomy may significantly decrease the length of the penis.  But what if we could prevent or, at least, limit shortening of the penis after prostatectomy?  Studies have demonstrated that this, indeed, is possible.  While short term, reversible, shortening of the penis cannot truly be avoided, long term, permanent, shortening can be prevented or limited. 

The most effective method of minimizing the chance of shortening the penis depends on avoiding the permanent damage to the penis that I described above.  This requires some work by both surgeon and patient.  First, damage to the nerves around the prostate needs to be avoided by the surgeon.  The way to accomplish this task is to perform a meticulous nerve sparing prostatectomy.  Of course, every prostatectomy is always a fine balance between cancer control and nerve sparing.  That is why a skilled, experienced surgeon is vital to performing a prostatectomy that cures cancer with a minimal sacrifice of the nerves. Studies have demonstrated that the most important, independent, predictor of shortening of the penis is nerve sparing during surgery.  In fact, one study demonstrated that successful nerve sparing prostatectomies performed on potent men who maintained good erections after surgery led to no change in the length of the penis whatsoever.

Once the surgery is performed, the rest of the responsibility to prevent long term shortening of the penis falls on the patient.  Studies have shown that various “rehabilitation” strategies can ensure the continued circulation of oxygen-rich blood through the penis and prevent the scarring of the penis that I mentioned above.  As  a result, men who undergo such “penile rehabilitation” after surgery have demonstrated less extensive shortening of the penis.  One study, for example, evaluated the benefit of using a vacuum erection device daily from the time the catheter is removed after nerve sparing radical prostatectomy.  Measurements of penis length prior to and 3 months after surgery demonstrated a decrease in the length of the penis by more than 1 cm in only 3% of men who used the vacuum erection device regularly as opposed to 67% of men who were not compliant with the protocol.  Another study of men undergoing nerve sparing robotic prostatectomy evaluated a rehabilitation regimen of daily Viagra for 9 months after surgery. The study found that at 1 month after surgery, men suffered from a decrease in penis length of about 0.6cm.  This decrease in length was thought to be due to the short term, reversible process described above.  By 9 months after surgery, however, this decrease in the length of the penis was no longer present as the measured penis length appeared to be equivalent to that noted preoperatively.  Hence the short term process was reversed and the long term, irreversible process of shortening was prevented through the regimen of rehabilitation.

Take Home Message

Shortening of the penis is a very real complication of radical prostatectomy.  Although not often talked about, this phenomenon can lead to significant impairment of self esteem and a decrease in the quality of life for men undergoing surgery for prostate cancer.  The occurrence of shortening of the penis is lamentable in that, for the most part, it is preventable.  With meticulous nerve sparing, permanent nerve damage and subsequent damage to the penis can be limited.  Similarly, through a regimen of penile rehabilitation (via pills, injections, or pumps), many men can prevent or decrease permanent scarring of the penis and the inevitable, irreversible shortening it causes.

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Prostate Cancer Invading The Seminal Vesicle: Prognosis and Treatment

I have recently heard from many new friends here and on some patient forums with concerns about seminal vesicle involvement by prostate cancer.  Often times, when giving a patient his pathology result after a prostatectomy, the urologist will mention the seminal vesicle but not explain its significance or, more importantly, the significance of involvement of the seminal vesicle by prostate cancer.  In this post, I want to shed some light on what the seminal vesicles are, why it is important to know if prostate cancer invades them, and what can be done once seminal vesicle involvement is determined after a prostatectomy.

 The Seminal Vesicle Exposed

A good place to start this discussion is to provide a little background about the seminal vesicle.  As its name implies, the seminal vesicle is basically a container for semen.  Two such seminal vesicles are located behind the prostate.  On diagrams, they look like bunny ears emerging behind the prostate and the bladder.  The seminal vesicles, along with the prostate, produce most (about 90%) of the semen released during ejaculation.  They are attached to the prostate and actually have ducts which empty into the center of the prostate.  This is the part of the prostate through which the urethra travels into the bladder (the “donut hole”).  These ducts connect to those of the tubes carrying sperm from the testes (the vasa differentia).  When ejaculation occurs, the sperm from the vasa differentia mix with the semen produced by the seminal vesicles and the prostate in the part of the urethra travelling through the prostate. The whole mixture is then propelled out through the urethra and penis by means of a forceful contraction of the muscles of the pelvis (this contraction is what provides the feeling of an orgasm).  As is probably clear from this description, the seminal vesicles are intimately associated with the prostate. As a result, prostate cancer that has escaped the prostate can proceed to directly invade the seminal vesicles.

Prostate Cancer and the Seminal Vesicle

Prostate cancer invades the seminal vesicles in about 3-7% of men with the disease.  Historically, invasion of the seminal vesicle by prostate cancer has been considered a sign of a very poor prognosis for men with prostate cancer.  In the past, studies reported that 50% of men with seminal vesicle invasion actually had metastatic disease at the time of surgery and, in fact, invasion of the seminal vesicle, itself, has been considered metastatic disease by many urologists.  This idea was supported by the fact that the majority of patients with seminal vesicle invasion demonstrated a rather quick biochemical recurrence after prostatectomy. This rapid recurrence of PSA after prostatectomy often led to subsequent documented metastatic disease.  As a result, the survival rate for men with seminal vesicle invasion was historically reported to be as low as only 32% at 7 years. 

With the era of PSA testing, outcomes for men with prostate cancer invading the seminal vesicles have been somewhat more encouraging.  The chance of a PSA recurrence within 10 years of prostatectomy remains very high (around 80%) for men found to have seminal vesicle invasion.  The rate of metastatic disease, as well, remains high at 44% for these men at 10 years after surgery.  However, these high rates of recurrence and metastasis do not appear to the lead to the dismal survival rates I previously mentioned.  In fact, recent studies demonstrated that at 10 years after surgery, men with invasion of the seminal vesicles demonstrated an overall survival rate of 61%.  In addition, a cancer specific survival rate of 84% has been described for these men.  That statistic is pretty astounding if you think about it: despite extremely high recurrence and metastasis rates, only about 16% of men with seminal vesicle invasion died of prostate cancer at 10 years after surgery!  This discrepancy is most likely a strong testament to the efficacy of hormonal therapy in managing metastatic disease.

Managing Seminal Vesicle Invasion

Because of the high rates of metastatic disease and poor prognosis associated with seminal vesicle invasion, patients with this finding have often been treated as if they had metastatic disease.  As a result, doctors have waited for early signs of a PSA recurrence after which they initiated hormonal therapy to manage impending metastatic disease.  Even with such a pessimistic, conservative approach, the impressive 10 year cancer specific survival of 84% mentioned above was attained for men with seminal vesicle invasion at 10 years after surgery.

Recently, however, a new, viable treatment option has become available for men with seminal vesicle invasion thanks to a randomized trial published in 2008.  The SWOG 8794 trial included 139 men that were found to have seminal vesicle invasion with or without positive margins or extracapsular extension (I cover both of these topics in prior posts).  These men were randomized into 1 of 2 treatment arms:

1)    Adjuvant Radiation Therapy

2)    Observation

Of note, men in the observation arm of the study could be treated at the digression of their physicians once a recurrence was documented.  This treatment could include either delayed radiation or hormonal therapy. 

The study demonstrated that men undergoing adjuvant radiation therapy enjoyed a significantly higher freedom from recurrent disease of 36% versus 12% for those in the observation arm.  In addition, men undergoing the radiation therapy appeared to be half as likely to need long term hormonal therapy as those in the observation arm.  The study also found that, after 10 years of follow up, men undergoing adjuvant radiation therapy enjoyed a higher rate of freedom from metastasis (66% versus 47%) and a higher overall survival rate (71% versus 51%) as compared to those men undergoing observation and possible delayed treatment.  The differences in freedom from metastasis and in overall survival, although impressive, were not statistically significant.  This lack of statistical significance is most likely due to the 10 year follow up of the study, the small overall number of patients, and the fact that men in the observation arm did receive hormonal therapy or salvage radiation therapy. Nonetheless, the results of the study are clinically significant and have really changed the approach to managing prostate cancer in men with seminal vesicle involvement. Rather than waiting for recurrent cancer and palliatively treating metastatic disease, many doctors are now aggressively treating men with seminal vesicle disease with adjuvant radiation therapy.  While the side effects of radiation need to be kept in mind, the potential benefit of this adjuvant radiation therapy appears to be substantial.  Another fact important to point out is that the dose of radiation administered to patients in this study was fairly modest as compared to that received by contemporary patients.  As such, one would imagine that the results of the study would be even more impressive if current radiation doses were used.

Take Home Message

Invasion of the seminal vesicle is usually a sign of an aggressive cancer, very different from the “run of the mill” Gleason 6, localized disease usually thought of when referring to prostate cancer.  Seminal vesicle involvement is a poor prognostic indicator associated with high rates of recurrence and metastatic spread.  In the PSA era, however, seminal vesicle involvement no longer appears to be the death sentence it was historically thought to be.  Aggressive management with adjuvant radiation can delay prostate cancer recurrence and spread.  In addition, the prudent use of hormonal therapy to manage metastatic disease can lead to many more years of life.  Overall, while certainly a serious condition to deal with, seminal vesicle invasion can still be successfully treated when encountered in men with prostate cancer.

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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 

Is This The End Of Prostatectomies?

The annual meeting of the American Urological Association was rocked this year by the release of  PIVOT (Prostate Cancer Intervention Versus Observation Trial).  Journalists at the event stated that the presentation of the data brought a “collective gloom” over the hall filled with urologic surgeons.  The reaction is not surprising as the study basically concluded that radical prostatectomy is not necessary for the management of anything other than aggressive prostate cancer.  So does this study mark the beginning of the end for the widespread use of radical prostatectomy for the management of prostate cancer?  I think that in order to answer this question we first need to take a closer look at the design and results of the study.

PIVOT Study

The PIVOT study was created in 1994 to determine whether the use of prostatectomy in treating prostate cancer added to overall survival and cancer specific survival.  The study was designed to recruit 5000 men (less than 75 years of age) with newly diagnosed, localized prostate cancer.  Men eligible to proceed were then randomized into one of two groups:

1)      Prostatectomy: Actually, only 78% of men in this group underwent prostatectomy   while the rest underwent other therapies

2)      Observation:  Patients in this group did not undergo any treatment aside from palliative therapy for symptomatic management of metastatic disease

The patients in the two groups were then followed for an average of 10 years .

Results of the PIVOT Study

Before I get into the results of the study, I want to stress that just the basic data has been provided and, until the actual paper is published, the nitty gritty of the data cannot be really assessed.  Nonetheless, even the basic data that is available definitely provides a starting point for discussion.

Out of the 5000 patients recruited for the study, only about 700 of the eligible patients actually agreed to proceed.  These 700 men were then divided into two groups with, on average, similar characteristics in terms of age and degree of prostate cancer.  After an average of about 10 years of follow up, the results reported by the study were definitely eye opening:

1)      While 48% of the men in this study died within the 10 years of follow up, only 7% died from prostate cancer

2)      Prostatectomy led to an insignificant, absolute 2.9% increase in overall survival. 

3)      Prostatectomy led to an insignificant, absolute 2.7% increase in prostate cancer specific survival.

4)      For high risk patients with PSA greater than 10, prostatectomy provided a significant, 7.2% increase in survival.

Initial Reaction to the Results

Upon first glance at these results, it is not unreasonable to come to the conclusion that radical prostatectomy is an unnecessary procedure for the majority of men diagnosed with prostate cancer.  After all, with PSA screening, most men are diagnosed with low or moderate risk disease and a PSA well below 10.  This trend towards early stage disease is also demonstrated by the study itself in that 70% of men participating in the study had a Gleason score of 6 or less and 72% were classified as either low or intermediate risk.  If we take the study population as a microcosm of the general population, we would argue that over 70% of men simply do not need to undergo prostatectomy (or any other treatment for that matter) to treat prostate cancer.  We would argue that men should not expose themselves to the significant risks and quality of life impacts of prostatectomy for only a minimally higher chance of surviving prostate cancer.  We would then conclude that treatment for prostate cancer should be reserved only for those men with high risk cancer and a PSA greater than 10.  With the general data provided, these conclusions may very well all be true.  Before hanging up the scalpel for good, however, I thought I would take a closer look at the data.

Digging a Little Deeper

After my initial shock from these results wore off, two big questions became prominent in my mind:

1)  How healthy were the men in the study?  As I noted above, approximately half of the men in the study died within the 10 years of follow up.  Only a small percentage of these men died of prostate cancer.  There are two possibilities to explain the small number of men dying from prostate cancer:

A)   The low risk prostate cancer that afflicted most of the men in the study was just not that lethal.

B)   The men in the study had other health problems that were more lethal than prostate cancer.

The answer is probably a mix of both.  Men with significant medical problems (heart disease, stroke, diabetes) often do not live long enough to be affected by or to die from prostate cancer.  At this point you are probably thinking that I am proving the point of the study: most low or intermediate prostate cancer does not need to be treated.  However, not all men have significant medical problems.  Healthy men, particularly healthy young men, may well live long enough to suffer from and even die from prostate cancer.  A famous, large European study recently demonstrated that, when looking at men as a whole, 50 men with prostate cancer would need to undergo prostatectomy to save one life from prostate cancer.  HOWEVER, a follow up study then went on to demonstrate that, when looking at HEALTHY men, only 4 men with prostate cancer would have to undergo prostatectomy to save one life from prostate cancer.  Quite a difference! Unfortunately, I believe that the PIVOT study is too small to demonstrate this type of distinction.  Nonetheless, I hope that when the final, more specific, data from the trial is published, information about the overall health of these men is included to help us determine whether their overall health precluded them from benefiting from prostate cancer treatment.

2) Why was the study only carried out for 10 years?  During my residency training I, like most other urologists-to-be, learned that men with a life expectancy less than 15 years probably should not undergo aggressive treatment for low risk prostate cancer.  Studies have demonstrated that prostate cancer typically takes around 15 years to create metastatic disease significant enough to be lethal.  As a result, men that did not expect to live that long would not derive any benefit from treatment.  This previous data makes it not very surprising that, at 10 years, only a minimal survival advantage was noted in PIVOT for men undergoing treatment versus those men that chose to observe their cancers.  At 10 years, metastatic prostate cancer starts to present itself but usually not to the extent that can kill.  I would imagine that, like in previous studies, metastatic disease was found more often in men in the observation arm of the PIVOT trial.  I am not sure, however, that this was an endpoint recorded for the trial.  I would bet that if the investigators running the PIVOT trial would continue to collect data up to the 15 and 20 year marks, the tiny difference demonstrated in the survival curves  of men in the treatment versus observation arms of the study would prove to be only the initial separation point of two very divergent curves.

Of course, the average age of the men in the study was 67.  Men in this age group have a life expectancy of about 15 years so, for them, a survival benefit achieved 15-20 years after surgery is pretty useless.  But what about a 50 year old man?  His life expectancy is over 30 years.  For him, a survival advantage 15 years after surgery can mean the possibility of 15 extra years of life.  I don’t think the value of this survival advantage is really debatable.  This concept was demonstrated in a recent study of Scandinavian men with prostate cancer which, after 15 years of follow up, demonstrated a 38% survival advantage for men younger than 65 years of age undergoing surgery as opposed to observation.  For this reason, I feel that while the 10 year survival data from this study may be helpful in guiding a treatment (or no treatment) decision for a man in his late 60s or 70s, the data is not relevant to a healthy man in his fifties. 

Take Home Message

The purpose of this post was not to criticize the PIVOT trial.  Any well run, randomized trial evaluating 700 men deserves significant attention and must be taken very seriously.  The study, indeed, reaffirms many important concepts in the management of prostate cancer.  First, men with low risk prostate cancer should definitely be advised of the option of active surveillance, particularly if they are in their 60s or older and/or if they have significant medical problems.  These men, as the study demonstrates, may not derive significant benefit from prostatectomy or other treatments.  In the same vein, men with aggressive prostate cancer should be offered treatment, even if they are older or may have some other medical problems.  These aggressive cancers, as demonstrated by PIVOT, can lead to premature death even within a 10 year time frame. 

What the PIVOT trial does NOT prove to me, however, is that prostatectomy is useless for YOUNG, HEALTHY men with low or intermediate risk prostate cancer. Of course, these young men need to be counseled on the risks and quality of life implications of treatments such as prostatectomy. They need to be told that any survival advantage from surgery or other treatments would not be enjoyed for more than a decade. They also need to be advised of the risks and benefits of active surveillance as well.  However, until large, randomized, long term studies prove otherwise, I believe that these young, healthy men should not be told that treating their prostate cancer is unnecessary.

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