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The findings of a pathology report after a radical prostatectomy can be critical in determining outcomes for men with prostate cancer.  In these reports, pathologists describe key aspects of the prostate cancer including how aggressive it looks under the microscope and if it has spread outside of the boundaries of the prostate.  The pathologist also comments on whether the cancer was removed in its entirety or whether the surgeon cut across the cancer at one or more sites.  This information is not only critical in determining prognosis but, also, in determining if and when the patient may need supplemental radiation therapy.  In this post I will describe the “high risk” pathologic features and explain the necessity and timing of radiation therapy for men who have one or more of these features on their pathology report.

Upon reviewing the pathology report after a prostatectomy for prostate cancer, four characteristics are critical to determine about the prostate specimen that was removed:

The presence of these adverse factors on a prostate biopsy portends a much higher chance of recurrent cancer.  Studies have demonstrated that 40-50% of men with combinations of these factors will have PSA relapse.  This statistic is important because up to a third of men with PSA recurrence will develop metastatic disease within 8 years and 17% of these men will die of prostate cancer within 15 years.  The increased risk posed by these adverse pathologic factors led to the question of whether men with such features would benefit from immediate radiation therapy after prostatectomy.

Numerous studies have been performed to determine whether patients with high risk pathologic factors would benefit from radiation therapy immediately after prostatectomy.  Called adjuvant radiation therapy, this type of treatment is usually instituted starting approximately 3-4 months following prostatectomy.  One of the biggest studies evaluating adjuvant radiation therapy after prostatectomy was conducted by the Southwest Oncology Group (SWOG) and published in 2009.  The study evaluated 425 men determined to have the adverse pathologic factors noted above after radical prostatectomy.  In this study, half of the men were randomly assigned to undergo adjuvant radiation therapy and half were assigned to observation.  For those men undergoing observation, initiation of treatment (with radiation, hormonal therapy, or both) was usually stimulated by a rising PSA and was done at the discretion of the treating doctor. 

The SWOG study yielded some very impressive results supporting adjuvant radiation therapy.  The study demonstrated that men treated with adjuvant radiation therapy were only half as likely to have a PSA recurrence as compared to those men simply followed with observation.  After over 12 years of follow up, this translated into a 38% decreased risk of metastatic disease.  In addition, the implementation of adjuvant radiation therapy resulted in an approximately 8% higher chance of survival (74% vs 66%) at 10 years after treatment.

While the SWOG study made a strong argument for starting radiation therapy after prostatectomy for those men with high risk pathologic features, it also created some doubt.  The study had several limitations, one of the most important of which was that not all men in the observation arm actually got radiation after a PSA recurrence.  In fact, only 33% of patients who had a PSA recurrence underwent such delayed or salvage radiation therapy at the time of recurrence. This problem begged the question of whether adjuvant radiation therapy is really necessary or if, in fact, radiation therapy could be delayed until PSA recurrence is noted.

While no notable  prospective studies have been completed which directly compare adjuvant to salvage radiation therapy in men with pathologically high risk prostate cancer, numerous studies have evaluated salvage therapy in isolation.  A very widely cited study performed in 2007 retrospectively evaluated the outcomes of salvage radiation therapy in 500 patients with adverse pathologic factors after prostatectomy for prostate cancer.  The study demonstrated that men undergoing radiation therapy shortly AFTER PSA RECURRENCE demonstrated some good outcomes.  For example, the study reported that men with positive margins and a Gleason score less than or equal to 7 had a 61% chance of no progression after a PSA recurrence if salvage radiation was instituted at a PSA level less than or equal to 2.  In addition, the study demonstrated that, if implemented at a recurrent PSA level less than or equal to 0.5, salvage therapy resulted in no signs of disease in 48% of all men treated.

While also not perfect, this study led many urologists to question the need for immediate or adjuvant radiation therapy for patients with adverse pathologic findings on prostatectomy specimens.  Given the fact that the SWOG study determined that adjuvant therapy yielded a survival benefit in only 1 in12 men treated, many urologists argued that it would be more prudent to wait until PSA recurrence to begin radiation therapy. This argument was strengthened by the fact that radiation therapy is, of course, not without its own risks and side effects.  Studies have demonstrated that radiation can lead to injury to the rectum and bladder, occasionally causing diarrhea, blood in the urine and/or stool, urinary frequency and urgency, and pain.  In addition, radiation may cause scar tissue in the urethra tube.  Some have argued that radiation therapy administered soon after prostatectomy can also lead to decreased urinary control although studies have not shown this to be true.  As a result, common practice today is to closely monitor men with high risk pathologic features after prostatectomy and to give salvage radiation therapy upon the first signs of PSA recurrence.

While the policy of administering salvage radiation therapy for men with high risk pathologic features has been relatively successful, it really leaves the question of whether SOME men are losing some survival benefit by not getting adjuvant radiation therapy.  A study published last year by a very respected radiation oncologist ( Anthony D’Amico, MD) and urologist( Judd Moul, MD) tried to answer this question through a retrospective evaluation of over 1600 men undergoing radical prostatectomy for high risk prostate cancer at Duke University.  The study classified men with adverse pathologic features into those with T3 disease( extracapsular extension{ECE} or positive seminal vesicles), Gleason score 8-10, and positive margins. The study then compared men that underwent immediate adjuvant radiation with those that underwent salvage radiation only after PSA recurrence.  The study found that for those men who had only one adverse feature (for example a positive margin but with no ECE or seminal vesicle involvement and Gleason score less than or equal to 7), only 18% of the 587 men observed after prostatectomy demonstrated a PSA recurrence after 8 years of follow up.  Of these men that had a PSA recurrence AND got salvage radiation therapy at the time of recurrence, NONE died from prostate cancer after 9 years of follow up.  The study concluded that while men with multiple adverse pathologic factors should be considered for adjuvant therapy, those with a single adverse factor can reserve radiation therapy for a PSA recurrence, avoiding unnecessary radiation in 80% of cases without any increased risk of death from prostate cancer in the long term.

As you can see, deciding what to do about high risk pathologic features after prostatectomy can be very controversial.  Reviewing the pathology report with your urologist after surgery is critical.  Identifying high risk features in the report can help you determine your overall risk for recurrence and help guide you toward appropriate supplemental therapy if and when it is indicated.

After I diagnose a patient with prostate cancer, we often have a lengthy discussion about treatment options and prognosis for the disease.  Many patients have a great mentality and express the desire to fight the cancer in any way possible.  Invariably, I hear a recurring question from these patients: “Doc, what can I do to increase my odds of beating this thing?”  If they are overweight or obese, I answer very emphatically, “Lose some weight.” 

Obesity is becoming an all too common phenomenon worldwide.  In the United States approximately 50% of men are considered overweight and 30% of men are considered obese.  Obesity is usually determined through a calculation of the Body Mass Index (BMI) which is weight in kilograms divided by height in meters squared.  Overweight men are classified as those with a BMI over 25 while obese men have a BMI greater than 30.  This excess weight exerts a tremendous toll on health by contributing to heart disease, diabetes, and hypertension.  Studies have demonstrated that men who are considered obese have a 50-100% higher chance of dying than men who are considered normal weight.  While we all know that obesity is a major risk factor for heart disease and some related illnesses, what does this have to do with prostate cancer?  Well, studies have also shown that men who are obese have a 40-80% higher risk of getting cancer (nonspecific) than those men that are considered to have a normal weight.  One of the cancers that has been greatly studied in the context of obesity is prostate cancer. 

While there has been no definitive proof of how obesity affects prostate cancer, numerous theories have been described.  First, studies have postulated that obesity affects prostate cancer through it impact on sex steroids within the body.  Fat in the body converts circulating testosterone to estrogen.  While testosterone is basically the “food” of prostate cancer, studies have shown that men undergoing surgery for prostate cancer have a higher risk of advanced stage cancer if there testosterone values are low. In addition, other studies have demonstrated that lower levels of blood testosterone actually correlate with a small but significant increase in the risk of prostate cancer.  All of this data seems to point to the fact that, by lowering testosterone levels in the bloodstream, excess body fat can actually predispose men to more aggressive prostate cancers.  Another theory of how fat and obesity impacts prostate cancer has to do with insulin like growth factor-1(IGF-1).  In obese men, high levels of IGF-1 are usually found in the bloodstream.  Laboratory studies have demonstrated that prostate cancer cells multiply more quickly in environments with higher levels of IGF-1.  In addition, clinical studies have shown significant correlations between IGF-1 and prostate cancer risk. 

While these theories are interesting, they do not really show us the true impact of obesity on prostate cancer.  Numerous clinical studies have evaluated the role of obesity in clinical prostate cancer.  The evidence linking obesity with the development of prostate cancer has been mixed.  While some studies have found a relationship between obesity and an increased risk of prostate cancer, others have shown no association.  Still other studies have actually demonstrated an inverse relationship, meaning that obesity was actually associated with a lower risk of developing prostate cancer.

Once prostate cancer has been diagnosed, however, there is no confusion as to the impact of obesity.  Multiple studies have demonstrated that obese men appear to have pathologically more aggressive cancer in terms of higher Gleason scores.  In addition, surgery to treat prostate cancer has been found to result in significantly higher rates of positive surgical margins in obese men.  Positive surgical margins are noted when the removed prostate gland is examined under the microscope by the pathologist after surgery.  A pathology report consistent with positive margins means that prostate cancer cells were seen at the cut edge of the removed prostate gland, meaning that the surgeon cut across some cancer when removing the prostate and that some cancer has been left behind.  Many studies have attributed this higher rate of positive margins to the fact that the body habitus of an obese man makes surgery more technically challenging.  As a result, more bleeding can occur, making visualization more difficult and positive margins more likely.  Given this theory, some have argued that robotic surgery, which enhances visualization and minimizes bleeding, should lead to better margins in obese men.  However, at least one large study, which divided patients into open versus laparoscopic surgery groups, still demonstrated a higher rate of positive margins in obese men, regardless of surgery type undertaken.

Obesity has been demonstrated to have perhaps its most significant impact on prostate cancer recurrence after surgery.  Most studies have been in agreement that obese men are substantially more likely to have a PSA recurrence (consistent with cancer recurrence) after prostatectomy as compared to those men that are of normal weight.  One large study actually demonstrated that moderately to severely obese men are 2.5- 3 times more likely to have a PSA recurrence as compared with their non-obese counterparts.  This finding is even more astounding in that it accounts for other factors that can affect cancer recurrence like preoperative PSA and Gleason score, stage, positive margins, and lymph node status.  An interesting study from Johns Hopkins published this year evaluated the effects of weight gain on men undergoing prostate cancer surgery.  The study found that men who gained approximately 5 pounds (2.2 kg to be exact) during the period of time starting 5 years prior to surgery and continuing to 1 year post surgery had twice the likelihood of  a PSA recurrence after surgery as compared to those men who maintained a steady weight.  Not surprisingly, with its impact on surgical outcomes and PSA recurrence, obesity has also been uniformly associated with an increased risk of prostate cancer mortality. 

I think the take home message of this post is fairly obvious.  If you have prostate cancer, probably the most important, proactive thing you can do (aside from getting treatment) is making sure to control your weight.  Find out what your BMI is from your doctor or calculate it online.  If you fall into the obese category, lose some weight.  Studies have shown that the very process of exercise can help men with prostate cancer.  A healthy, low fat diet has also demonstrated significant benefits.  Even if all of this data is wrong and you don’t benefit from escaping obesity from a prostate cancer standpoint, there is overwhelming evidence that you would benefit from the standpoint of your heart.  On that note, I want to share 1 more statistic.  The Prostate Cancer Prevention Trial followed 18,000 men for 7 years to study the impact of a drug called Finasteride on prostate cancer.  During the study, a total of 10 men died of prostate cancer.  During the same time period, 1123 men died of other causes, most of which were related to heart disease. Is that not enough of a reason to lose a little weight?

A major milestone in the prostate cancer journey is obtaining a PSA level after treatment.  If a man has surgery, a procedure in which the entire prostate gland is removed, the expected result is a permanently undetectable PSA.  Because a successful surgery should remove all remnants of the cancer as well as the benign elements of the prostate, there should be nothing left to produce the dreaded PSA.  Patients derive a tremendous amount of satisfaction and relief in hearing that there PSA is undetectable, an unambiguous sign that their prostate cancer is gone.  For some men, however, the news is not as great.  At some point after surgery, 15-40% of  men hear the dreaded news that their PSA is not undetectable and that, most likely, there cancer has returned.  What many patients do not know is that not all PSA recurrences are created equal.  Some types of recurrences are much more worrisome than others and require very different treatment approaches.  In this post I will try to define PSA recurrence and attempt to differentiate the different types of recurrences.

Defining a PSA recurrence seems pretty obvious at first glance.  After all, PSA after prostatectomy should be 0.  Any other number is considered a PSA recurrence. In reality, things are not that simple.  First, we have to differentiate PSA recurrence from PSA persistence.  A first PSA test obtained 1-3 months after prostatectomy should be 0.  However, any PSA value other than 0 is not considered a PSA recurrence at this time.  The reason for this is that the PSA has not recurred but, rather, has persisted. Although this difference in terminology may seem like nothing more than semantics, it makes a tremendous difference in terms of prognosis and understanding the status of the prostate cancer.  Patient who have a persistent PSA after prostatectomy almost always have metastatic disease.  While imaging tests like a bone scan or CT scan may be negative, a persistent PSA indicates that some cancer cells are lurking somewhere in the body that are simply too small to identify on imaging tests.  These cells are then labeled micrometastatic disease.  Unfortunately, patients in this situation can no longer be considered curable.  Instead, they often get palliative hormonal therapy which, fortunately, can often keep those few micrometastatic cancer cells from significantly growing for many years. These patients may also qualify for clinical trials.

Unlike PSA persistence, PSA recurrence occurs when a postoperative PSA at first goes to 0 and then begins to rise after some period of time.  However, at least technically speaking, not all rises in PSA have been considered recurrences.  Historically, a PSA rise to 0.4 after surgery has been considered a recurrence.  Rises in PSA lower than this have been considered insignificant, possible due to some left over benign prostate tissue.  More recently, the value of 0.2 has been chosen.  Although these definitions seem pretty arbitrary they actually have significance because they determine when the patient has recurrent cancer and, in turn, when they should start salvage therapy.  With the advent of ultrasensitive PSA, much lower PSA values have been recorded and some doctors have initiated salvage therapy at PSA levels significantly lower than 0.2.

As I mentioned earlier in this post, a PSA recurrence has different implications on the status of prostate cancer and subsequent prognosis depending on several factors:

1)      Time from Surgery: Many studies have demonstrated that the longer the time between surgery and PSA recurrence, the less chance that the recurrent cancer is aggressive and likely to spread.  The consensus seems to be that 3 years appears to be a critical cut off point.  One study demonstrated that for men with otherwise good risk factors, those that had a PSA recurrence more than 3 years after surgery had a 13% greater chance of surviving their prostate cancer 15 years later as compared to those men with a PSA recurrence within 3 years of surgery( 94% versus 81% survival at 15 years).

2)      Gleason Score of Prostate Cancer:  The Gleason score is a measure of how aggressive the cells of prostate cancer look under the microscope.  It generally ranges from 6-10, with higher scores being associated with more aggressive cancer.  Men with Gleason scores above 7 who have a PSA recurrence after prostatectomy are at higher risk for metastasis and death from prostate cancer.  For example, a study demonstrated that men with recurrence of a Gleason 8 or higher prostate cancer within 3 years of prostatectomy had a 19% higher chance of surviving their prostate cancer within 15 years than those men with a recurrence of Gleason 6 or 7 prostate cancer within 3 years of prostatectomy( 62% versus 81% survival at 15 years).

3)      PSA Doubling Time: The PSA doubling time appears pretty self explanatory.  The term refers to the time it takes for the PSA to double in value.  To calculate this number you need a few PSA values spread at least 3 months apart.  You also need to use a fairly complex formula to get the exact value.  For our purposes, a rough, eyeball assessment will do just fine.  For example, by looking at a series of PSA values we can roughly estimate if the PSA is doubling every month, every 6 months, or every year, etc... Studies have demonstrated that PSA doubling time is one of the most important prognostic factors used to evaluate a PSA recurrence after prostatectomy.  Let’s look at an example:  If a man has a PSA recurrence more than 3 years after prostatectomy for a Gleason 6 prostate cancer and his PSA doubling time is more than 15 months, his chance of surviving the prostate cancer at 15 years is 94%.  If that exact same man has a PSA doubling time of less than 3 months, however, his chance of surviving prostate cancer at 15 years is only 19%.  As you can see, the importance of the PSA doubling time cannot be overstated.

These 3 factors are vital in evaluating a man with a PSA recurrence after prostatectomy not only to determine prognosis but, also, to figure out what future treatment needs to be undertaken, if any.  A man with a PSA recurrence more than 3 years after prostatectomy for a Gleason 6-7 prostate cancer and a PSA doubling time of greater than 15 months has a 94% chance of surviving his prostate cancer at 15 years.  In contrast, a man with a PSA recurrence less than or equal to 3 years after prostatectomy for a Gleason 8-10 prostate cancer and a doubling time of less than 3 months have <1 % chance of surviving for that same period of time.  As you can imagine, most men find their situation somewhere in between these two extreme scenarios. 

Men with favorable factors most likely have a local recurrence of the cancer in the part of the pelvis where the prostate was located.  This type of recurrence tends to move more slowly and can be cured with radiation therapy with some success.  Some men, depending on their overall health and age, may not even need any treatment for this type of low risk recurrence.  Men with high risk factors, in contrast, most likely have metastatic disease.  This type of recurrence is usually more aggressive and not responsive to local therapy.  Instead, men with this type of PSA recurrence are usually treated with palliative hormonal therapy to try to control rather than cure the recurrent cancer.  Others may opt for clinical trials to try novel treatments to battle the more aggressive cancer.

The take home message of this post is to NOT treat all PSA recurrences the same.  While a PSA recurrence is obviously disappointing and frightening it is not always as bad as you might think.  Many recurrences are very manageable and still offer the possibility of cure. Some recurrences may not even need to be treated.   Men with PSA recurrence should discuss their specific risk factors with their urologist in determining an appropriate treatment course.