Post-Treatment Monitoring

Important Definitions


Biochemical recurrence (BCR) 
= PSA recurrence after treatment for prostate cancer. Definition depends on the type of treatment.

Cure: A clinical state in which the cancer has been eradicated completely with no chance of recurrence. Note the emphasis on 'no chance'.

Clinical recurrence = Patient has either (1) imaging confirmation or (2) symptoms of recurrent disease. e.g. bony pain, blood in the urine or urinary symptoms. Always preceded by biochemical recurrence for prostate cancer.

No Evidence of Disease (NED) = A clinical state in which there is no evidence of persistent and recurrent disease accompanied by the ongoing possibilty that cure has been achieved. This does not exclude the possibility of future recurrence.

 

Background on Persistent Prostate Cancer

 

Prediction and Weighing the Potential Benefits and Harms of Treatment

 

It is obvious to everyone that the future is inherently uncertain. Predicting the future with certainty is difficult to impossible - even more so when trying to predict events that may occur far in the future. However, many people forget this fundamental fact of life when thinking about the result of treatment for cancer.

 

Weather forecasts, for example, are never 100% accurate. This doesn't stop meteorologists from making educated predictions. Prediction is a necessity in decision making when the information on which decisions are made is imperfect - and this is always the case to varying extents. In much the same way, there is inherent uncertainty regarding the effect of any treatment, or conversely the effect of not undertaking treatment. Therefore, one must always be thinking in terms of predicting future events, how those predictions are made and if a change in management is warranted. 

 

Every course of action has inherent potential to benefit and potential to harm. Unfortunately, there is no such thing as a 'free lunch' in cancer treatments. Fortunately, most treatments have reasonably well defined benefits and harms which can inform a patient as to which course of action is most acceptable to them. Only you can decide if the trade-offs and compromises of the treatment are best for you. Keep these ideas in mind when contemplate how men with prostate cancer are followed and managed following surgery or radiation.

 

Monitoring of patients after treatment involves following patients for potential adverse effects of treatment and checking patients for cancer recurrence. Some background information on how outcomes in cancer surgery are described may be helpful and can be found here. The risk of disease recurrence is best described as a probability at a specific time point after treatment. Management of complications can be found here.

 

"All men who have undergone treatment with curative intent are at risk for persistent disease." 


Curative intent treatment, also known as definitive management, is utilized when the prostate cancer may be curable. Curative intent treatments are based on either surgery (radical prostatectomy), radiation (sometimes with the addition of androgen deprivation) or a combination of these treatment modalities.

 

The potential for persistent disease, either local, systemic or both, is a critical concept which must be appreciated in order to understand how men are monitored and treated after surgery or radiation. Let's break this statement down into its components.

 

Let's define treatment with curative intent (also known as 'definitive management'). The intent of definitive management is to achieve a cure (see the definition above). Definitive management options include:

 

  1. Surgical approaches: radical prostatectomy and lymph node removal.
  2. Radiation approaches: external beam radiation, brachytherapy or a combination of these 2 forms or radiation; sometimes androgen deprivation is added.
  3. Multimodality treatment: a combination of (1) and (2).

 

The reasons for failure to achieve a cure following definitive management include:

 

  1. Disease was inherently incurable by virtue of the presence of systemic (metastatic) spread of disease prior to the administration of definitive therapy and beyond the reach of additional treatment. Traditionally, metastases to bone or lymph nodes (systemic disease) have been thought to be incurable. While this remains true for the majority of men with systemic disease, the approach to advanced disease continues to evolve.
  2. Disease was curable (there was no systemic/metastatic disease at the time of definitive management) but the treatment failed because it was unable to eradicate the local disease. Disease persisted locally and retains the potential to grow and spread. This may be the result of an inherent limitation of the treatment or because of technical errors. Examples include tumor beyond the margins of surgical resection or radiation-resistent disease.

 

All men ... are at risk for disease persistence. 

 

Take a moment to think about the terminology here. When prostate cancer is treated with the intent to cure the cancer and then the cancer is identified as being present at some late date after treatment, there are multiple words that are used to describe this: relapse, remission, recurrence, persistence (or residual disease) and (specific to prostate cancer) biochemical recurrence. If one is being precise, if prostate cancer is identified in the body after an attempt at cure has been made then it is the result of persistent prostate cancer (residual cancer may be used interchangeably with persistent disease). There may be a length of time during which the persistent cancer could not be identified with currently available diagnostic tests but it is never because the cancer left the body completely and then came back. If prostate cancer is identified at some time after treatment with curative intent it is because the cancer was not completely eradicated from the body.

 

Consequently, 'recurrent' cancer doesn't really exist for prostate cancer - it is simply cancer which was thought to have been cured but in reality never was cured. Remission means that the cancer has regressed or has been diminished in some capacity. This may be a 'partial' remission in which the size of the tumor has decreased or the symptoms of the cancer has diminished even if it is not cured. Remission may be complete - to the point where there is no identifiable cancer. Therefore, the most accurate way to speak about prostate cancer that rears it's head at some point after an attempt was made to cure it is to say that it is persistent. Biochemical recurrence is a specific disease state in prostate cancer when the PSA measurement rises above a level at which disesae persistence is likely to be present. There is much more on this below.

 

Treatment with definitiive therapy is administered with the hope that the cancer will be permanently eradicated and never come back. A 100% guarantee of success can never be provided. This means that cure cannot be guaranteed. To be very clear, this does NOT mean that cure never happens, it simply means that the result cannot be guaranteed or promised. Why can't we make a 100% guarantee that the cancer will not come back (or more accurately, that it is persistent)? The primary reason is that currently available tests are unable to exclude the presence if incurable disease with 100% certainty. Even the ost sensitive tests are unable to detect small amounts of cancer that may continue to grow  and only become large enough to detectable and then potentially cause a problem. Why is this? There are multiple reasons:

 

  1. Cancer cells are very, very small - in the range of microns (thousandths of a millimeter). The average size of a prostate cancer cell is about 8 x 8 microns (micrometer) or about 1/100th of a millimeter. 8 microns is about the same width as a single strand of spider web silk or the thickness of cling wrap. A millimeter is  about twice the width as a grain of salt which in turn is about 50 times wider than a prostate cancer cell.
  2. Conventional imaging (CT scan, bone scan and MRI) has a resolution that is measured in millimeters. It is incapable of identifying anyting smaller. That is, conventional imaging is 'insensitive' to small amounts of cancer. High resolution CT has a limit of 1-2 mm but cannot differentiate normal from cancerous tissues at that resolution. 'Gross' or obvious tumors are required before relapse can be identified - usually 10 mm or more for lymph nodes.
  3. Novel imaging (various flavors of PET scanning) has a fundamental resolution limit of about 1 mm and a practical resolution limit of a few mm.
  4. Prostate specific antigen (PSA) has a lower limit of detection of approximately 0.002 mcg/L (though often not reported below levels of 0.008 mcg/L). PSA is secreted by normal an cancerous cells which raises a couple of issues if there is a detectable PSA following definitive management.
    1. Is the PSA coming from cancerous or non-cancerous cells?
    2. PSA does not tell you where it is coming from. That is, it does not localize the source of the PSA to the pelvis, lymph nodes or bone.
    3. There is always some 'normal' prostate remaining after radiation which will secrete some PSA. What level is 'acceptable'?

 

Time is the ultimate test and this is the rationale for ongoing post-treatment monitoring (surveillance). A cornerstone of post-treatment suveillance is measurement of the PSA level (see below). PSA is by far the most sensitive test for prostate cancer cells but even when the PSA is undetectable (less than 0.008 mcg/L) it is impossible to exclude the presence of small amounts of prostate cancer. On if the PSA is elevated would one even consider imaging studies since they are much less sensitive than PSA.

 

The fact that cure cannot be guaranteed by undertaking definitive management should not dissuade a man from taking appropriate action. In reality, the goals of treatment go beyond simply trying to cure the cancer (though cure is one of the primary goals). More broadly, the aims of definitive management are to obtain a better overall quality and quantity of life when compared to that possible with the alternative courses of action (active surveillance, watchful waiting or delayed palliation). Even if cure is not possible, definitive management can not only 'buy time' and delay death from cancer but it can provide an opportunity for a better quality of life by delaying and reducing the overall impact of the cancer itself and cumulative burden of treatment.

 

Surveillance and Management of Men Following Definitive Management for Prostate Cancer

 

Definitive management with surgery or radiation is not an end point. It is only one part, admittedly a large part, of the process of of trying to achieve a longer and better quality of life. Surveillance and ongoing risk management are integral to achieving those goals.

 

In a man who has taken the step of definitive management, the question to be asked after treatment is "What can be done to assess the risk of disease persistence. What specific actions are appropriate to meet those goals of a longer and better quality of life? There are 3 steps to this process:

 

  1. Identify the specific probability of relapse for an individual man who has undergone definitive management. Repeated assessment of the risk takes place over time since the risk of relapse changes based on past history.
  2. Determine the clinical implications of for any specific relapse. Not all relapses have the same ramifications.
  3. Adapt management as appropriate. This sometimes means taking action while a patient is categorized as having no evidence of disease or before meeting any specific definition of biochemical recurrence.

 

Biochemical Recurrence: Putting BCR in Context

 

This is about placing the risk assessment in context, not just about the PSA level. It is important to determine what specific question is being asked and what information is necessary to answer it. PSA is not the only tool to assess the risk of relapse but it is readily and easily obtainable. Furthermore, it is virtually always the first test to suggest that there is residual prostate cancer. Interpretation of PSA requires placing this desceptively simple blood test in a larger context. 

 

Question Necessary Information
What is the risk of biochemical relapse?
  1. Type and treatment details of the primary treatment: surgery, radiation (and if androgen deprivation used).
  2. Clinical characteristics: Grade, PSA, stage, tumor volume
  3. Pathological characteristics: Grade, stage, margin status
  4. Interval during which there was no evidence of biochemical failure.
What is the risk of biochemical relapse if it has occurred?
  1. Everything above PLUS:
  2. PSA kinetics (e.g. rate of rise/doubling time, level)
  3. Age
How should the biochemical relapse be managed?
  1. Everything above PLUS:
  2. Patient preference regarding the risks and benefits of treatment.
  3. Tests to determine if the relapse has any potential for cure.

 

Biochemical Recurrence: Post-Treatrment PSA as a Measure of Disease Status Following Definitive Management

 

The most simple clinical test to assess for persistent disease is by measurement of the PSA. Post-treatment PSA measurement, however, has significant limitations in assessing risk. Having said that, a rising PSA following treatment is a pre-requisite to being at risk for developing something more serious in the future. The counterpoint is that a risking PSA does not mean that something more serious is inevitable. A PSA which rises above a pre-specified level following definitive management is known as 'biochemical recurrence'.

 

Note that some men will have 'biochemical persistence' which is defined as a failure of the PSA to drop to less than 0.1 mcg/L at 6 weeks following surgery. As can be seen in the table earlier, this is a strong marker for risk of development of metastases and death because it usually indicates that there is a substantial amount of persistent disease and is often associated with other adverse features (higher grade tumor and higher stage tumor).

 

Biochemical recurrence is always the earliest sign that prostate cancer has returned. A rise in the PSA will usually be detected many years before a patient will have any signs or symptoms or recurrent cancer. Clinical recurrence is when a patient actually has symptoms such as bony pain, urinary symptoms, weight loss or imaging findings of recurrence (e.g. bone scan). Because it is so unusual for patients to develop clinical recurrences in the absence of a large rise in PSA after treatment, patients should be reassurred that in the presence of a low PSA that any symptoms (such as difficulty urinating or back pain) are very unlikely to be the result of recurrent cancer.

 

Post-treatment PSA levels must always be interpreted in context. For men who are not currently on androgen deprivation (or receiving other therapy that may mask persistent disease), the PSA divides men into 2 separate groups.

 

  1. No evidence of disease (NED). In this case, the possibility that cure has been achieved remains but it does not (nor can it ever) exclude the possibility of future disease recurrence. The  definition of biochemical recurrence depends on the type of treatment.
    1. Following surgery: PSA less than 0.2 mcg/L
    2. Following radiation: Lowest level of PSA achieved (nadir) with a rise of 2 mcg/L or higher confirmed on a second measurement
  2. Evidence of persistent disease is present. This identifies that the cancer is still present and that cure has not been achieved (though does not preclude 

 

A major reason why different definitions are used for radiation and surgery is that radical prostatectomy removes the entire prostate whereas radiation (external beam and brachytherapy) leave the prostate in place. The remaining prostate tissue will release small amounts of PSA even if cancer is not present. The use of hormonal therapy can also affect interpretation of the PSA levels post-treatment - and can mask residual cancer. As a result, it is virtually impossible to compare treatment outcomes using biochemical recurrence as the yardstick. It has been estimated that if the same definition which is used for biochemical recurrence following radiation therapy were applied to men having undergone prostate surgery, the time to biochemical recurrence would be delayed for 5 years when compared to the more stringent criteria used for biochemical recurrence following radical prostatectomy. That is, biochemical recurrence results for radical prostatectomy at 5 years should probably be compared to 10 year radiation results. The development of clinical recurrence and/or death related to prostate cancer are much better yardsticks for comparing treatments. Ideally, we would have well designed randomized controlled trials to sort out the best treatments for different kinds of patients.

 

Both definitions of biochemical have limitations based on how they have been defined as well as the inherent limitations of using PSA for risk assessment. There is a very large grey zone between an undetectable PSA (<0.008 mcg/L in most assays) and the level at which the definition of biochemical recurrence is met (> 0.2 mcg/L for surgery or nadir +2 mcg/L for radiation). 

 

While the post-treatment PSA can assess the current status and crudely separate men into these 2 important groups it has major limitations. 

 

  1. Men classified as having no evidence of disesae (NED). As noted earlier, some men will have prostate cancer following definitive management but the PSA has not yet risen to the threshold where the PSA test can measure it. While some men who are NED have been cured, some remain at high risk of relapse in the future. Other information to predict failure is required (see below).
  2. Men classified as having recurrent disease. Context becomes even more important and is reviewed at length below.

 

Biochemical Recurrence: Commonly Accepted Definitions

 

The definition of biochemical recurrence differs based on the type of treatment that was undertaken. PSA is a crude measure of disease risk and the primary error is to focus on the PSA level while ignoring other, potentially more important, indicators of risk. Do not look at the PSA only!

 

The definitions and implications of biochemical recurrence are different for surgery and radiation. As a consequence, the risk of biochemical failure should NOT be used to determine which treatment is 'better'. Patients should focus on end points of importance to them: overall treatment burden (of the primary treatment and of salvage), the harms of the treatment and the chances of survival. If biochemical recurrence does occur, the implications for any individual patient are likely to differ significantly for any given PSA level. Context is always important.

 

Biochemical Failure After Radical Prostatectomy

PSA > 0.2-0.4 mcg/L

  • The most commonly used definition is >0.2 mcg/L and is currently advocated by the American Urological Association. Much of this is historical since the lower limit of detection of the PSA assay was about 0.2 and therefore levels below this were called 'undetectable'. Nowadays, PSA levels as low as 0.002 mcg/L can be detected. Some studies have suggested that a level of 0.3 mcg/L is the 'best' level at which to define biochemical recurrence. In realilty, the level should be interpreted in the context of a number of features - see below.
  • A recent reivew suggests that a PSA cutoff of 0.4 mcg/L and keeps increasing is probably a good definition for BCR and a level at which initiation of salvage radition should be considered(Van den Broeck et al. European Urology 2019). Other studies suggest that the intiation of salvage radiation should be 'risk adapted' - that is, based on the entire clinical picture including the stage, grade, etc. This is a more intuitively logical approach to this problem.

 

Biochemical Failure After Radiation

Nadir PSA +2 mcg/L ('Increase in PSA of 2 mcg/L above the lowest PSA recorded")

  •  This is called the 'Phoenix definition'. There is an ASTRO definition but this is thought to 'underperform' the Phoenix definition. 

 

Biochemical Recurrence: Assessing Risk if BCR Occurs

 

PSA is considered a 'proxy' or 'surrogate' marker for clinically meaningful events. Proxy/surrogate means that it is an indirect or substitute indicator - PSA is not the actual thing that causes harm (in fact, PSA is virtually harmless in the blood stream). Rather, what we are interested in are the cancerous cells that are producing the PSA and what they are doing. PSA has many limitations as a proxy marker which is why meeting the definition of biochemical recurrence alone is not the strongest predictor of progression.

 

Biochemical recurrence (BCR) is a pre-requisite to developing clinical progression (such as metastases) as well as death from prostate cancer but BCR does NOT invariably lead to clinical progression or death. In fact, only about 30% of patients with BCR will develop clinical recurrence (Pound et al. JAMA 1999) and only about half of these (16% of men with BCR) will ultimately die from cancer (Boorjian Eur Urol 2011). The Pound study found that when distant metastases did ultimately develop, the average length of time from identification of BCR to identification of distant metastases was 5-8 years.

 

What factors, then, help predict which of the men with BCR will have problems in the future? Once a man has biochemical recurrence, there are multiple disease features that can be used to assess individual risk. It is worth emphasizing that the overall prognosis in men with BCR after definitive management is favorable and that the majority of men with BCR do NOT die of prostate cancer. In those who are unfortunate enough to progress, the process usually takes many years.

 

The European Association of Eurology undertook a major review of the literature on the implications of biochemical recurrence after definitive management (Van den Broeck et al. European Urology 2019). The results are summarized here.

 

"Biochemical recurrence has an impact on survival [and conversely, the risk of death], but this effect appears to be limited to a subgroup of patients with specific clinical risk factors:

  • Short PSA doubling time
  • High final (pathologic) Gleason score after radical prostatectomy
  • Short interval before biochemical failure after radiation therapy

 

 

For patients with Biochemical Recurrence (BCR) Following Definitive/Curative Intent Treatment: The Factors Associated with Adverse Outcomes

  After Surgery After Radiation
Distant metastatic recurrence

Positive surgical margin

High pGS

High pT category

Short PSA-DT

High pre-sRT PSA

Short IBF

High bGS

High cT category

 

Prostate cancer specific mortality

High pGS

Short IBF

Short PSA-DT

Short IBF

Overall mortality

High pGS

Short IBF

Short PSA-DT

Short IBF

High Age

High bGS

High iPSA

Notes: Excludes patients with Biochemical Persistence (PSA never drops below the definition of BCR for radiation or surgery).

 

Definitions:

  • Outcomes:
    • Distant metastatic recurrence:
    • Prostate cancer specific mortality: chance of dying as a direct result of prostate cancer.
    • Overall morality: overall chance of death including that attributable to prostate cancer but also all other causes.
  • Predictive factors:
    • Positive surgical margin: cancer at the inked specimen; denoted by R1 in the pathologic T stage.
    • High bGS: high biopsy gleason score as determined by needle biopsy.
    • High pGS: high pathologic Gleason score as determined by the radical prostatectomy specimen.
    • High cT/pT category: high stage based on finger exam/imaging of the prostate (cT) or based on stage as assessed by pathologic exam of the radical prostatectomy specimen.
    • Short PSA-DT: PSA doubling time
    • High pre-SRT PSA: high PSA prior to salvage radiation.
    • High iPSA: high initial PSA; PSA determined at the time of diagnosis.
    • Short IBF: short interval before (biochemical) failure.

 

Comments:

  • Biochemical Recurrence: 
    • General: the presence of BCR predicts the distant metastases and prostate cancer specific mortality but to a lesser extent overall mortality. This means that men are more likely to 
    • After surgery: BCR has a modest effect on a man's overall risk of dying; risk is between 1-2 times baseline risk (Hazard ratio 1-2).
    • After radiation: BCR has a significant impact on risk of death with a roughly 20% absolute increase is the risk of death at about 10 years after treatment 
  • Initial PSA (iPSA): interestingly, despite the emphasis on using PSA for risk stratification prior to intervention the initial (pre-treatment) PSA does not consistently predict outcome once BCR has occurred after treatment
  • Gleason Score:
    • Gleason score: this is one of the storngest predictors of clinically meaningful adverse events for surgery or radiation. The ability of grade to 'risk stratify' patients is large - in fact larger than the effect of BCR.
    • After surgery: the Gleason score at surgery is very improtant in determining risk of developing distant metasases and prostate cancer specific mortality. The magnitude of the risk increases with the grade with a hazard ratio (from lowest to highest grade) ranging from roughly 1-10 times baseline. This stands out as the strongest predictor when looking at the highest grades vs. the lowest grades.
    • After radiation: very stongly correlated but more difficult to intepret because of different definitions that were used to define BCR.
  • Stage:
    • After Surgery: interestingly, the stage was not found to correlate with any of the outcomes in this review which is in contrast to the study below (Preisser et al. Eur Urol 2019) which found a significant correlation with seminal vesical invasion and lymph node tumor with all meaningful outcomes. A close look at the data in this study suggests that the presence of seminal vesical invasion is important but that the methodology of this study failed to show a difference.
  • Positive Surgical Margin: this can only be assessed after surgery. This is widely recognized as a risk for biochemical recurrence in general but it would seem that once you have biochemical recurrence it does not predict an increased risk of distant metastases, cancer-specific death or overall risk of death.
    • A positive surgical margin is a risk for BCR and by extention for needing additional treatment (which is suboptinal because of the side-effects of salvage radiation and ADT) but not for length of life.
  • Interval to Biochemical Failure
    • After surgery: a longer duration during which the PSA is less than 0.2 mcg/L is associated with lower risk of all adverse outcomes. Quantifying the magnitude of the effect was difficult. 
    • After radiation: very stongly correlated but more difficult to intepret because of different definitions that were used to define BCR.
  • Utilization of salvage radiation after BCR with surgery: shows a significant protective effect by reducing the risk of overall mortality to 0.19-0.55 of that of baseline (no salvage treatment).
    • Patients with the most aggressive disease (PSA-DT <6 months) only showed benefit with started within 2 years of BCR.
    • Initiation of sRT with the PSA >0.5 mcg/L was associated with an increased risk of developing metastases and prostate cancer specific mortality. No difference was noted so long as the sRT was started with a PSA <0.5 mcg/L, hence the recommendation to initiate sRT for PSA 0.4 mcg/L and rising.

 

How does one use this information? At present, there are limited tools for predicting outcomes in individuals using this granularity of data. One needs to consider the treatment options that are available. For patients whom have undergone surgery, radiation is typically considered when BCR has occurred and there are other features that suggest benefit is likely. For patients whom have undergone radiation, salvage treatment usually means palliative treatment with androgen deprivation since the risks of salvage prostatectomy are so high that most patients will prefer just about any other option.

 

Biochemical Recurrence: Taking a Deep Dive Into Results After Surgery

 

The study above takes a very broad view of BCR after surgery and radiation. The following data is more specific to radical prostatectomy and is more informative because the relative weighting of the different clinical features can be appreciated. Stage and grade remain the primary predictors of outcome in patients who have a PSA which is <0.2 mcg/L immediately following surgery. Of greatest concern are those patients whose PSA levels never drops below 0.2 mcg/L - most of these patients will have other adverse features such as high grade and stage.

 

Overview of Factors Important in Predicting Outcomes After Radical Prostatectomy (Hazard Ratios compared to reference group without the adverse feature). Risk factors are presented in descending risk for Death by All Causes. Repeated reference to this chart will be made below.

  Metastases Death by All Causes Death by Prostate Cancer
Comorbidity Index >= 1 or 2 0.80/0.85 NS 1.62/2.38 1.35/0.47 NS
Persistent PSA Post-operatively 3.59 1.86 3.15
Pathologic Stage T3b 3.87 1.63 4.0
Pathologic Grade Group 3-5 3.60 1.56 3.36
Pathologic Stage N1 1.48 1.38 NS 1.38 NS
Pathologic Stage T3a 2.14 1.03 NS 1.16 NS
Postive Surgical Margin R1 1.05 NS 1.26 1.72

Preisser et al. Persistent Prostate-Specific Antigen After Radical Prstatectomy and Its Impact on Oncologic Outcomes. European Urology 76 (2019) 106-114.

 

Definitions and Comments

  • Comorbidity IndexCharlson Comorbidity Index. This is a tool that predicts the probability of death at 10 years. The fact that men who unwell are more likely to die is not surprising. It bears emphasizing that definitivel management offers virtually no survival advantage to men with shortened life expectancy based on non-prostate cancer related illness or age. Patient selection for definitive management remains the most important factor in outcomes.
  • Persistent PSA post-operatively. This specifically refers to a PSA that did not fall to <0.1 mcg/L at 6 weeks after radical prostatectomy as distince from a PSA that was undetectable or <0.1 and rose above that level at a later date.
  • Pathologic Stage. This is the stage of the tumor determed from the surgical specimen that was removed at the time of surgery as opposed to the clinical staging.
    • T3a = outside the capsule
    • T3b = invasion into seminal vesicle
    • N1 = tumor involving pelvic lymph nodes
  • Pathologic Grade. This is the grade of the tumor determined from the specimen that was removed at the time of the surgery. A specific limitation is the lumping of Grade Group 3-5 into a single group. Note the difference between Gleason Grade, Gleason Score and Grade Group.
  • Positive Surgical Margin. Identified as having cancer cells touching the inked margin of the prostate specimen.

 

The Utility of Additional Treatment Following Radical Prostatectomy

 

While it is desirable that no additional treatment is necessary following radical prostatectomy this is sometimes not the case. The preceding dicussion reviewed that all men are at risk of having persistent prostate cancer but that the risk is not uniform - there is a spectrum of risk from low to high.

 

It should be obvious by this point that the management of prostate cancer is individualized and that context is very important. There is a substantial amount of information available from the pathology report that can guide the need for additional therapy. Additional therapy in cancer treatment is called 'adjuvant' - this means 'to help' the primary treatment. In some cases, when additional therapy is administered more than a few months after surgery it is termed 'salvage' therapy. The distinction between 'adjuvant' and 'salvage' is somewhat arbitrary but may be important in specific contexts and when a specific definition is being applied.

 

In considering the merits of adjuvant therapy following radical prostatectomy, the basic questions to be answered are:

 

  1. What is the risk risk of persistent disease and biochemical recurrence?
  2. Is there any indication that the patient may benefit from additional therapy even in the absence of biochemical recurrence?
    1. If so, what are the features that define which men are more likely to benefit from therapy?
    2. If so, what is the optimal timing of therapy?
  3. If observation is the initial management strategy but biochemical recurrence is ultimately identified at some later time after surgery, what options are available?
    1. If so, what are the features that define which men are more likely to benefit from therapy?
    2. If so, what is the optimal timing of therapy?

 

It bears emphasizing that treatment is individualized and that there are benefits and harms to every course of action. Guideline recommendations are just that - they are not hard and fast rules.

 

Prostate Cancer Has Spread To The Pelvic Lymph Nodes (pN1 or LN+)

 

This is a specfic scenario that arises when assessment of the lymph nodes removed at the time of radical prostatectomy are shown to harbor cancer. Not everyone requires a lymph node dissection. Lymph node dissection is performed when it is felt that the risk of lymph node involvement is increased (when the risk exceeds 3-5%). Furthermore, for the purposes of this discussion it can be assumed that the pre-operative imaging with CT or MRI did not have any findings that suggested that the cancer had spread to the lymph nodes. 

 

When a lymph node dissection is necessary, we will always perform an 'extended' bilateral lymph node dissection. The dissection is templated - that is, all of the lymph nodes within pre-specified boundaries are removed. The number of lymph nodes that are removed entirely depends on the number that are present. Everyone is different such that the yield of lymph nodes can be as few as 5 or as high as 30. In some cases, the template may be extended even further. 

 

The presence of cancer in lymph nodes will be designated on a pathology report in a number of ways:

  • "Lymph nodes involved:" followed by some quantiation of the extent (e.g. number of lymph nodes inovled or amount of tumor in the lymph nodes"
  • "pN1" designation

 

Historically, the presence of cancer in lymph nodes was felt to be a sign of incurable disease and that the presence of cancer in the lymph nodes would always be associated with disseminated disease elsewhere. The management approach was palliative - how to prolong life and best maintain quality of life without an attempt to cure. This involved androgen deprivation (medical castration). In hindsight, this was an oversimplication since things are rarely absolute - always is a strong word and fortunately happens to be inaccurate when describing lymph node positive disease as incurable.

 

It is now recognized that prostate cancer that has spread to the lymph nodes is sometimes curable. In fact, some men, albeit a minority, who have disease in their lymph nodes are cured by surgery alone and will not require any additional therapy. Furthermore, the addition of radiation to androgen deprivation can be helpful in some men. The routine addition of post-operative radiation plus androgen deprivation is not currently considered a standard of care in 2019 because of the lack of randomized controlled studies to support its use. As always, there is a tradeoff between benefit and harms with any course of action and the admnistration of radiation plus ADT is no difference.

 

There are 3 primary options for the management of men with pN1 disease following radical prostatectomy.

 

  1. Observation
  2. Androgen deprivation therapy (ADT)
  3. Radiation plus androgen depravation therapy

 

Observation. This is reasonable option when the pathologic features do not favor benefit from radiation or ADT. Management can be modified in the future if there is a change in the disease status that makes ADT or radiation+ADT likely to be of benefit. Routine PSA monitoring is advised. Approximately 30% of this select group will not require additional therapy and can avoid the side-effect of treatment.

 

Androgen deprivation therapy. The landmark study by Messing demonstrated that there was a marginal survival advantage to the administration of immediate and continuous androgen deprivation (Messing et al NEJM 1999). However, in clinical practice the vast majority of patients did not opt to go on this type of therapy - possibly because the cumulative sid-effects from lifelong medical castration were unappealing in exchange for modest survival benefit with most men would live well over 10 years and could go for extended durations without having any symptoms from the disease.  This approach is still rational in some men and an intermittent androgen deprivation strategy can be considered in some men to minimize treatment related side-effects.

 

Radiation plus Androgen Deprivation. A majority of men with pN1 disease, however, are likely to benefit from the addition of radiation plus androgen deprivation therapy.

 

Characteristics of men who are likely to benefit from additional treatment and consequently may be observed as the initial strategy are men WITHOUT any of the following features:

  1. ≥pT3b: seminal vesical invasion of local invasion as defined by T4
  2. Gleason score ≥9/10 = Grade Group 5/5
  3. ≥3 positive lymph nodes
  4. Positive surgical margin = R1

 

The majority of men WITH these features will benefit from the addition of radiation to the prostatic bed (where the prostate was removed) and the surrounding pelvic tissues. With each additional feature, the risk of disease progression increases. Men WITH NONE of these features or who feel that the potential harms of radiation + ADT are unacceptable may reasonably select observation as the initial management strategy. It bears repeating that there are no randomized controlled trials for radiation + ADT in this setting but the available data show benefit when the above criteria are met.

 

The goal is eradicate (or mop up) any persisting small amounts of cancer. The treatment will be ineffective if the cancer has spread beyond the pelvis but there is no way to know this with certainty until the utility of adjuvant radiation and androgen deprivation is useless. Therefore, the goal is typically to try and treat as soon as is reasonably possible. In most cases, a delay to allow a man to regain some urinary control is reasonable and unlikely to diminish the efficacy of the radiation.

 

Benefit vs. harms (refer to the table below). The data show that at 10 years, there is a 6% increased probability of remaining alive if radiation + ADT are administered vs. no radiation. Stated another way, for every 17 men treated with radiation + ADT, there is 1 fewer death at 10 years (NNT = 17). The difference in survival at 5 years is 3%.

 

Benefits and Harms for Men Receiving Radiation and Androgen Deprivation Following Radical Prostatectomy with Lymph Node Positive Disease and Having At Least One Adverse Feature

Benefits Harms

Overall survival: 

5 years 91% vs. 88%

10 years 74% vs. 68%

 

Androgen deprivation: sexual dysfunction, osteoporosis, loss of muscle mass, hot flushes, breast enlargement or tenderness, other

Radiation*: Severe toxocity of any sort in 5% of patients (RTOG grade 3 = severe diarrhea, blood in urine with clots; may be permanent and recurrent); overall toxicity rate of any severity about 25% with urethral stricture in 18%, total urinary incontinence in 6.5% and rectal complictions in 3% (overall roughly twice that in the observation group with the caveat that observation is not associated with any 'rectal complications'). 

Survival data from Gupta et al. Results rounded to nearest full percentage point.* Very little published on radiation toxicity in this setting but typical doses of approximately 68 Gy are similar to radiation post-prostatectomy (SWOG 8794, EORTC 22911)

 

References:

Touijer et al. Survival Outcomes of Men with Lymph Node-positive Prosate Cancer After Radical Prostatectomy: A Comparative Analysis of Different Postoperative Management Strategies. European Urology 2018.

Gupta et al. Adjuvant radiation with androgen-deprivation therapy for men with lymph node metastases after radical prostatectomy: identifying men who benefit. British Journal of Urology International 2018.

 

A Word on PSA Kinetics

 

PSA levels tend to rise logarithmically with disease recurrence and consequently changes are often described as 'doubling times' (e.g. the time it takes to change from 1 to 2 to 4 to 8 to 16 and so on). The time that the PSA takes to double in value tends to be relatively consistent - that is, the time for a PSA to go from 1 to 2 is similar to what it takes to go from 8 to 16 or 32 to 64. It can, however, take 2-3 years of measurements to assess the doubling time and assessment of doubling times at very low levels of PSA (especially less than about 2 mcg/L) can be challenging because of background noise. Rapid doubling times are defined as anything faster than 6-12 months. This is associated with more rapid progression of disease.

 

On the Web

General Prostate Cancer Web-Resources

Prostate Cancer Canada Resources

Prostate Cancer Basics: Screening and Diagnosis

Prostate Cancer Treatment Options

Prostate Cancer Post-Treatment Recovery and Side Effects

Memorial Sloan-Kettering Cancer Center in New York is an excellent resource for information on prostate cancer. Balanced, unbiased discussions of the disease, including discussion regarding some of the controversies in prostate cancer.

General Information on Cancer

UNDERSTANDING CANCER - Metrovan Urology info on the principles of diagnosis, staging, prognosis and more.

American Cancer Society

BC Cancer Agency: Good general website from the British Columbia Cancer Agency. Has contact information on locations.

National Cancer Institute: Excellent source of understandable and mainly unbiased information. Several very good brochures on every stage of prostate cancer.

National Comprehensive Cancer Network: peer-reviewed expert content/prostate cancer guidance on evidence-based cancer diagnosis and management. Best for Prostate and Kidney Cancer. The most in-depth information is located in the physician section and requires registration.