Is anyone with intermediate-risk prostate cancer a “good” candidate for AS?


There is no longer any doubt that men initially diagnosed with low- and very low-risk forms of prostate cancer are, in most cases, either excellent or good candidates for first-line management on active surveillance (AS). They may, of course, choose not to be managed in this way, and that’s fine. Shared decision-making is at the heart of good medical practice in the management of localized prostate cancer today.

What is less clear is the degree to which men who are initially diagnosed with intermediate-risk prostate cancer may — at least in some cases — be “good” candidates for first-line management on AS. To date there has been a “reasonable” (but not scientifically well validated) presumption that men with a relatively small amount of “favorable” intermediate-risk prostate cancer could consider and elect initial management on AS.  They should, however, only be doing this if they fully appreciate that they are at significantly higher risk for disease progression than men with low- and very low-risk disease.

A fascinating new paper by Patel et al., just published in the Journal of Urology, has now provided us with a structured analysis (using pretty large data sets) of the relative risks associated with the role of active surveillance in men with differing types of intermediate-risk prostate cancer, based on initial diagnosis and the results of pathological outcomes after radical prostatectomy.

This is a complex paper, and we are not going to attempt to explain all the nuances. Interested readers should see if they can obtain a full copy of the text from their own urologist or from the nearest medical library. It should also be noted that the paper has a very fundamental limitation, which is that all the patients whose data were used did, indeed, elect or agree to having a radical prostatectomy, so it is not based on a “management neutral” cohort of patients. That wouldn’t have been possible.

Having said that, here are some of the important aspects of this paper:

  • It was based on data from 51,688 patients with low-risk disease and 63,930 patients with intermediate-risk disease, all  identifiable in the US National Cancer Data Base (NCDB) and for all of whom there were data from an initial biopsy and from subsequent surgical pathology collected between 2009 and 2013.
  • The patients were initially categorized into one or other of two groups
    • Men with clinically low-risk disease on diagnosis (Grade Group 1, and clinical stage ≤ T2a, and PSA < 10 ng/ml)
    • Men with clinically intermediate-risk disease (Grade Group 1 or 2, and clinical stage ≤ T2b, and PSA < 20 ng/ml) but excluding all patients who met the criteria for low-risk disease
  • Adverse pathology at the time of radical prostatectomy was defined by any finding of Grade Group ≥ 3, seminal vesicle invasion (pT3b), or lymph node metastasis (pN1).
  • The patients with intermediate-risk disease were also categorized into two subgroups based on the Memorial Sloan-Kettering Cancer Center (MSKCC) risk criteria, as follows:
    • Men with “favorable” intermediate-risk disease at diagnosis (only one of Grade Group 2, or clinical stage T2b, or a PSA level of 10 to 20 ng/ml)
    • Men with “unfavorable” intermediate-risk disease at diagnosis (men who could not meet the more stringent criteria for “favorable” intermediate risk)
  • The researchers also explored whether the addition of an additional criterion (having < 50 percent of biopsy cores positive for cancer) might help to delineate differences between "favorable" and "unfavorable" categories of intermediate-risk disease (as recommended by the National Comprehensive Cancer Network or NCCN guidelines).

And so here are some of the fundamental findings:

  • 6.8 percent of the men with low-risk disease were found to have adverse pathology at the time of radical prostatectomy.
  • Men with GG2 intermediate-risk disease were three times more likely (at 20.8 percent) than the men with low-risk disease to have adverse pathology at the time of radical prostatectomy.
  • Men with GG1 intermediate-risk disease were twice as likely (at 13.7 percent) as men with low-risk disease to have adverse pathology at the time of radical prostatectomy.
  • All other subcategories of intermediate-risk disease seemed to place patients at between two and three times greater risk for adverse pathology at the time of radical prostatectomy.

Now let us be very clear that these results are not exactly a surprise. Having any amount of Gleason pattern 4 identifiable on biopsy (or any other potentially adverse sign of risk) is going to increase the risk for cancer that can metastasize over time.

But one can look at these data the other way around too (and it may be important to do this). They show that:

  • 93.2 percent of the men with low-risk disease had no sign of adverse pathology at the time of radical prostatectomy.
  • 79.2 percent of the men with GG2 intermediate-risk disease had no sign of adverse pathology at the time of radical prostatectomy.
  • 86.3 percent of the men with GG1 intermediate-risk disease had no sign of adverse pathology at the time of radical prostatectomy.
  • Between 84.0 and 80.1 percent of men with all other subcategories of intermediate-risk disease had no sign of adverse pathology at the time of time radical prostatectomy.

Does this leave the glass half full. Or half empty?

In our very humble opinion, what this excellent piece of research has done is to start us down the road to improving data-based guidance for men with intermediate-risk disease as to whether they are or are not potentially promising candidates for initial management on AS. And these data come with two very specific provisos, as follows:

  • Patients who do not meet the primary criteria for intermediate-risk disease specified above (Grade Group 1 or 2, and clinical stage ≤ T2b, and PSA < 20 ng/ml, but excluding all patients who met the criteria for low-risk disease) are normally not going to be good candidates for AS (but there are exceptions to every such rule).
  • Any patient diagnosed with intermediate-risk prostate cancer who elects to be managed, initially, on AS needs to be closely monitored and also needs to appreciate that he may well only be deferring treatment for a period of time (as opposed to thinking that he may never need treatment).

We would also concur with Patel et al. that the terms “favorable” and “unfavorable” may not be the most appropriate terminology when used to subcategorize intermediate-risk types of disease. They could easily mislead. It may be better, in the future, for us to redefine the categories of intermediate in some way similar to the following:

  • Intermediate risk type 1 (meaning any patient whose intermediate-risk prostate cancer meet Grade Group 1 criteria)
  • Intermediate risk type 2 (meaning any patient whose intermediate-risk prostate cancer meets Grade Group 2 criteria)

We are not, however, suggesting that these are the only or even the “right” subcategories. That will need to be worked on over time.

Having said all of this, we would point out that there is a small, growing, but highly identifiable cohort of men who, having been initially diagnosed with some amount (usually relatively small) of Gleason pattern 4 prostate cancer, and having elected initial management on AS, have now been on AS for as long as 13 years or more. Clearly, there are men like this who will do very well on active surveillance for long periods of time.

Two key future goals should be:

  • To find ways to appropriately identify, prospectively, such men who will do very well on AS for 5+ or 10+ years and who can then be well treated with curative intent (should they elect to do this)
  • To find ways to proactively extend the time that all men who are good candidates for initial management on active surveillance can be managed (by lifestyle management or relatively simple forms of therapy with very low risk for adverse effects) so as to extend the time that they can be so managed, thus potentially defering or avoiding all the risks associated with surgery or other forms of radical treatment for localized prostate cancer

Editorial note: The “New” Prostate Cancer InfoLink thanks Hiten Patel, MD, of the Johns Hopkins University School of Medicine for promptly providing us with a copy of the full text of this paper for review.

7 Responses

  1. I am confused as to whether the researchers consider extraprostatic externsion to be adverse pathology. Your bullet defining adverse pathology refers to “seminal vesicle invasion (pT3a)”. Seminal vesicle invasion is of course pT3b.

  2. Dear Tom:

    There is no reference whatsoever to pathological extraprostatic extension or positive surgical margins as adverse risk factors in the paper by Patel et al.

    I would point out that if there was any clear indication of extracapsular extension at time of diagnosis or biopsy, then the patient would be classified as having either cT3a or cT4 disease and would not be a candidate for AS in the first place. The same would be true if there was evidence of seminal vesicle invasion at diagnosis or biopsy (cT3b disease).

    My suspicion is that one of the problems with attempting to use pathological data on any cancer left behind because of axtracapsular extension or positive surgical margins is that this is not necessarily a reflection on the risk level of the cancer in and of itself, but has more to do with the skill and competence of the surgeon. In other words, while it would reflect the outcome of a particular patient, it probably shouldn’t be used to make any decisions about whether a patient is or ins’t a good candidate of AS in the first place ina patient with cT1c or cT2 disease at time of diagnosis.

  3. As you know @SM, I am in the cohort that is taking all this into the MRI era. So I will find a way of tracking this down, and read carefully in the context of that innovation. Right in my wheelhouse. Thank you as always.

  4. In this paper adverse pathology was defined as radical prostatectomy with the finding of GG3 or greater, seminal vesicle invasion (pT3b) or lymph node metastasis (pN1).

  5. Valery:

    Thank you for catching that error. It is now corrected.

  6. I’m afraid, not fully corrected: seminal vesicle invasion (pT3b) – not (pT3a)

  7. Dear Valery:

    Thank you again. I have GOT to find a way of not needing to do three things at once!

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google+ photo

You are commenting using your Google+ account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

This site uses Akismet to reduce spam. Learn how your comment data is processed.

%d bloggers like this: