Sunday, May 29, 2011

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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Sunday, May 22, 2011

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.


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.

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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

Friday, May 6, 2011

Combining Hormonal Therapy With Radiation To Treat Prostate Cancer: Who Needs It And For How Long?

A question that I have repeatedly heard from readers has been about the length of time hormonal therapy needs to be given in conjunction with radiation to treat prostate cancer.  As I replied to these readers, the answer, like most aspects of prostate cancer treatment, is not very straightforward and remains somewhat controversial.  In this post I will attempt to clarify which men actually need hormonal therapy in addition to radiation, the benefits of this additional hormonal therapy, and the ideal duration of the therapy.

Why Add Hormones to Radiation Therapy?

The benefits of adding hormones to radiation therapy for prostate cancer were first demonstrated through animal experiments.  These studies evaluated the added efficacy of androgen deprivation (hormonal therapy) when combined with radiation therapy in treating prostate tumors in mice.  The studies scientifically demonstrated that the hormonal therapy reduced the amount of radiation necessary to destroy and control the growth of the tumors.  These and other studies have proposed that radiation and hormonal therapy work synergistically to destroy prostate cancer cells and keep them from spreading locally and into the bloodstream. 

The added benefits of hormonal therapy were then tested in the clinical setting on real patients.  One of the seminal studies testing the theory was conducted in Europe over a decade ago. The study compared the outcomes of men with locally advanced prostate cancer who underwent either radiation therapy alone or radiation therapy combined with a 36 month course of hormonal therapy.  The study demonstrated that, 10 years after treatment,  men undergoing combination therapy enjoyed superior overall survival (58% vs 39%) and a much lower chance of dying specifically from prostate cancer ( 11% vs 31%) when compared with those men undergoing radiation alone.  Studies such as this ushered in the wave of hormonal therapy that has been becoming more and more popular in the treatment of localized prostate cancer.     

As more and more patients were placed on hormonal therapy, it soon became apparent that this additional treatment does not represent a free lunch.  As I described in my previous post, hormonal therapy comes with significant risks to your heart while increasing your chance of developing diabetes.  In addition, hot flashes and sexual dysfunction can have a dramatic impact on quality of life for men on the therapy.  As such, many began to wonder if 3 years of hormonal therapy is really worth the benefits.  Studies have been conducted comparing the combination of radiation plus short term hormonal therapy (4-6 months) with radiation alone.  One such study demonstrated a superior 8 year overall survival for men undergoing the combination therapy (74% vs 61%) as compared to men undergoing radiation therapy alone.  The presence of this new data subsequently begged the question of whether long term hormonal therapy yielded any benefits above and beyond those achieved with short term hormonal therapy.  Excellent, randomized studies were conducted to answer just this question. 

Optimal Duration of Hormonal Therapy

Two large, randomized trials have been carried out comparing short term with long term hormonal therapy in combination with radiation therapy.  These studies were carried out specifically in men with HIGH RISK prostate cancer.  Only men with either locally advanced prostate cancer (T2c-T4) or positive lymph nodes were evaluated.  I emphasize this point because, as I shall explain later, the results and conclusions can not and should not be applied to treatment decisions for ALL men with prostate cancer. 

The first trial, known as Radiation Therapy Oncology Group 92-02 studied over 1500 men with T2c-T4 prostate cancer (cancer which took over both lobes of the prostate and/or extended out of the prostate to varying extents) with or without positive lymph nodes.  Men in the study were randomly enrolled into one of two treatment protocols:
1)      Radiation plus 4 months of hormonal therapy (starting 2 months prior to radiation)
2)      Radiation plus 28 months of hormonal therapy(starting 2 months prior to radiation)

The study demonstrated that, after 10 years, men undergoing long term hormonal  therapy enjoyed better cancer specific survival (89% vs 84%), lower chance of metastatic disease (15% vs 29%), and a lower chance of further local spread ( 12% vs 22%) than those undergoing short term hormonal therapy .  What the study did not demonstrate, however, was a significantly improved overall survival rate for men undergoing the long term versus the short term hormonal therapy.  The study then analyzed a particularly high risk subset of men with Gleason 8-10 prostate cancer.  In this subset of patients, in contrast, a significantly superior overall survival rate (45% vs 32%) was seen in men undergoing long term hormonal therapy.

The second study was conducted by the European Organization for Research and Treatment of Cancer.  This trial evaluated 970 men with either locally advanced prostate cancer (T2c to T4) or men with positive lymph nodes and any local stage.  The study divided the patients randomly into two treatment groups:
1)      Radiation therapy plus 6 months of hormonal therapy (starting the first day of radiation).
2)      Radiation therapy plus 36 months of hormonal therapy (starting the first day of radiation).

After about 6 years of follow up, the study demonstrated a small but significant overall survival advantage for men on long term versus short term hormonal therapy (85% vs 81%).  The difference in death rates (19% vs 15%) represented a 42% higher chance of death for men undergoing short term versus long term hormonal therapy. 

While demonstrating slightly different impacts, both studies concluded that men with HIGH RISK prostate cancer should be considered for long term hormonal therapy.

Long Term Hormonal Therapy: Who Really Needs It?
While the above mentioned studies argue for adding long term hormonal therapy to radiation for treatment of HIGH RISK prostate cancer, they DO NOT conclude that all men undergoing radiation therapy for prostate cancer need hormonal therapy.  Before discussing the suggested regimens for men without high risk disease, we should review the accepted “risk” categories for prostate cancer:

1)      High Risk: Prostate cancer that is locally advanced (T2C-T4) and/or Gleason score 8-10 and/or associated with a PSA greater than 20
2)      Intermediate Risk: Prostate cancer with moderate local stage (T2b) and/or Gleason score 7 and/or PSA 10-20.
3)      Low Risk: Prostate cancer with low local stage (T1b-T2a) and Gleason score 2-6 and PSA less than 10.

These risk categories are very important to understand, particularly in context of prostate cancer studies.  In relation to adding hormonal therapy to radiation for prostate cancer, the utility of the additional hormonal therapy depends on what risk group you are looking at.  As I mentioned above, the added benefits of hormonal therapy, particularly long term hormonal therapy were demonstrated only in HIGH RISK prostate cancer patients.  In contrast, no study has ever demonstrated any benefit of adding hormonal therapy to radiation of LOW RISK prostate cancer.  The data for INTERMEDIATE RISK is more mixed.  While no studies have specifically evaluated the added benefit of combining hormonal therapy with radiation therapy for INTERMEDIATE RISK prostate cancer, numerous patients with INTERMEDIATE RISK disease were included in the studies evaluating HIGH RISK patients.  These studies did demonstrate a benefit of adding hormonal therapy to a radiation therapy regimen for patients with INTERMEDIATE RISK disease.  No study, however, has demonstrated any significant additional benefit of long term over short term hormonal therapy for INTERMEDIATE RISK disease.  As a result, many of the radiation oncologists performing these studies recommend a combination of short term hormonal therapy and radiation for men with INTERMEDIATE RISK prostate cancer.  This recommendation, of course, is only valid  if the risks of the additional hormonal therapy (heart risk, diabetes, osteoporosis) do not outweigh the benefits for a given patient.  In addition, because no randomized studies have been carried out looking to answer this question in men with INTERMEDIATE RISK disease, the data and recommendations I have just mentioned for INTERMEDIATE RISK disease can be considered fairly trustworthy but not definitive.

Take Home Message

The controversy over the optimal duration of hormonal therapy to give in combination with radiation for prostate cancer again demonstrates the recurrent theme we hear about repeatedly in relation to prostate cancer therapy: prostate cancer treatment cannot be carried out with a “one size fits all” approach.  While studies seem to demonstrate a modest although significant advantage to long term ( > 2 years) hormonal therapy in addition to radiation for HIGH RISK prostate cancer, there has been NO evidence demonstrating that hormonal therapy for LOW RISK prostate cancer is of any benefit at all.  INTERMEDIATE RISK prostate cancer, in turn, may be optimally managed with a combination of radiation and short term hormonal therapy although we still await definitive studies to confirm this.  In addition, even when keeping these risk groups in mind, the final decision of whether or not to add hormonal therapy to radiation (and, if so, for how long ) really rests on weighing the risks and benefits for each individual patient. In some men with HIGH RISK prostate cancer, cardiac and metabolic risk factors may make the risks of heart attack and diabetes posed by hormonal therapy far outweigh the benefits of the treatment.  In contrast, some otherwise healthy men with HIGH RISK prostate cancer may derive significant benefits from the additional hormone therapy with minimal additional risks.  The key to answering this question is to really understand your situation.  Make sure that you understand your particular prostate cancer risk group.  Also, make sure that you discuss your cardiac and metabolic risk factors with both your urologist/radiation oncologist and your primary doctor (who is more familiar with your overall health).  Finally, make sure that your doctor weighs these competing factors with you so that you can be assured that, no matter what your given situation, the treatment course you chose truly provides you with more benefits than risks.

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