Another Sunnybrook update: risk for metastasis on active surveillance

The Sunnybrook Group from the University of Toronto in Canada have just provided us with yet another update on the outcomes of their cohort of 980 patients managed initially on active surveillance and dating back to 1996.

In this, most recent update, Yamamoto et al. have focused very specifically on the risk for metastasis in their cohort of patients, and when they say “metastasis” they mean not just men with evident metastasis on a bone scan but also those men found to have positive surgical lymph nodes at the time of surgical treatment. (See also this report on the ScienceDaily web site.)

We should point out carefully what Klotz and his colleagues also point out in this paper: active surveillance is not a technique that is designed to eliminate prostate cancer; it is a technique designed and intended to manage very low-, low-, and “favorable” intermediate-risk prostate cancer with the goals of minimizing risk for over-treatment and maximizing the patient’s quality of life until it becomes evident that treatment is advisable.

We should also be very clear that the Sunnybrook protocol has always been (and was designed to be) an active surveillance protocol that gave a high degree of opportunity for patients to be managed on active surveillance for as long as possible. It very deliberately, therefore, permitted the inclusion of men who might do less well on active surveillance because they had high Gleason scores and higher PSA levels than most other active surveillance protocols. It is therefore unsurprising that a percentage of the patients enrolled at Sunnybrook have gone on to have positive lymph nodes and evident metastasis.

According to this most recent analysis, 30/980 patients (3.1 percent) monitored on active surveillance at Sunnybrook have now gone on to have either positive surgical lymph nodes or evident metastasis on bone scan at an average (median) follow-up of 6.3 years. And there are learnings from this.

Here are additional data on those 980 patients:

  • 211/980 patients enrolled in the study (21.5 percent) had favorable intermediate-risk prostate cancer at study entry.
  • 14/980 patients who progressed to metastatic disease (1.4 percent) came from that favorable intermediate-risk group of patients.
  • Average (median) time to metastasis  for the 30 patients found to have metastases (in the lymph nodes or elsewhere) was 8.9 years.
  • Of the 30 men with metastasis
    • 17/30 (56.7 percent) had metastasis to bone only.
    • 12/30 (40 percent) had metastasis to lymph nodes only.
    • 1/30  (3.3 percent) had metastasis to lymph nodes and to bone.
  • Potentially strong and independent indicators of risk for metastasis were
    • A PSA doubling time of < 3 years (hazard ratio [HR] = 3.7; p = 0.0006)
    • A Gleason score of 7 at study entry (HR = 3.0; p = 0.0018)
    • A total of three or more positive biopsy cores at study entry (HR = 2.7; p = 0.0028)
  • Patients with Gleason scores of 6 and PSA levels > 10 ng/ml were not at increased risk for metastasis.
  • Metastasis developed in only 2/769 men patients with Gleason scores 6 (0.3 percent) and neither of these patients had surgical pathology grading.

Yamamoto and his colleagues conclude that:

Active surveillance appears safe in patients at low risk and in select patients at intermediate risk, particularly those with Gleason score 6 and [PSA levels] greater than 10 ng/ml. Patients with elements of Gleason pattern 4 on diagnostic biopsy are at increased risk for eventual metastasis when treated with an initial conservative approach.

The “New” Prostate Cancer InfoLink would actually go further than that.

Based on these data and data from other series, we now believe the following:

  • Long-term active surveillance appears to be extremely safe for men confirmed on a re-biopsy to have very low- and low-risk prostate cancer and a PSA of up to 15 ng/ml (as opposed to just 10 ng/ml)
  • Long-term active surveillance remains a significant potential opportunity to defer treatment for appropriate men with a small amount of favorable, intermediate-risk prostate cancer, but such men need to be monitored with great care and attention so that treatment can be offered at the earliest identifiable signal of increased risk.
  • Other factors that increase risk for men on active surveillance include
    • A Gleason score of 3 + 4 = 7 at initial diagnosis
    • Having three or more positive biopsy cores at initial diagnosis
    • Having a PSA doubling time of < 3 years while on active surveillance
  • Active surveillance comes with some degree of risk for every active surveillance patient, and some men will be more comfortable with that risk than others; the patient’s individual willingness to accept such risk is a key component of whether active surveillance is an appropriate form of management for such individual patients.
  • Improvements in our ability to identify men on active surveillance at elevated risk for disease progression and early metastasis is a critical element in the implementation of active surveillance, and may include 3-T multiparametric MRI scans and/or genetic and genomic testing for risk of certain subtypes of prostate cancer.

We would point out that at an average (median) 6.3 years of follow-up there are going to be more men in the Sunnybrook cohort who are found to have lymph node positive or evident metastatic prostate cancer. That is important, however, is going to be (a) how many of those men actually go on to die from prostate cancer; (b) how many of those men are actually pleased by their outcomes on active surveillance, even if they do go to have lymph node positive or evident metastatic disease; and (c) the changes that are currently being made by Klotz and his colleagues to the Sunnybrook protocol to minimize risk for progression of men on active surveillance to lymph node positive or metastatic disease.

In our opinion the remarks being made by Koch and by Nelson in editorial comments in the Journal of Urology (and replicated on the ScienceDaily web site) are misguided, and utterly fail to take account of the idea that quality of life, for many patients, may be at least as important (and may in some cases be more important) than quantity of life. There are quite certainly going to be men who are extremely comfortable being monitored on some form of expectant management after diagnosis with some forms of intermediate-risk prostate cancer (as opposed to having someone hurry them into an operating room or a radiotherapy suite). Those men need people like Drs. Klotz and Nelson to be explaining that active surveillance may be an option for them, as opposed to trying to just tuck that option under the carpet and out of sight.

11 Responses

  1. Is there an apples to apples comparison of similar risk patients that were treated compared to those that were not?

    Or do the details show dissimilar pools?

  2. Michael:

    I am not aware of any “apples to apples” comparison of similar risk patients. We are going to get those data in the not too distant future from the ProtecT study ongoing in the UK.

  3. I’m not an advocate of active surveillance; it’s like leaving a ticking time bomb in situ, and waiting for a sign that it’s going to go off.

    To me, the earlier a cancer is treated, aggressively, the better the chances of a good outcome. And this applies not just to prostate cancer. Growing cells can break away, which is what causes metastases (as far as I know,} and I wouldn’t want to risk it.

    But this is written from hindsight; my own prostate cancer was too advanced and metastasized to bone and innumerable lymph glands to preclude any surgical intervention or a cure. I wish that the cancer could have been cut out of me, but the involvement of the prostate tumor with bladder and rectum wall wouldn’t allow removal — it would have just about gutted me.

    Why wait? Get treated now and the outcome is almost guaranteed to be better. That’s my humble opinion.

  4. Klotz and his colleagues began this study at a time when many urologists urged immediate definitive treatment after a positive biopsy. They bravely carried out a (initially) high-risk/high-benefit research program which has had a major impact on health policy. Their frequent updates on the analysis and outcomes are also really commendable. Everyone at risk for prostate cancer (i.e., all men who are getting older) should be grateful to the researchers and patients who made this trial possible.

    It’s odd that the ProtecT study, in contrast, still has not provided any preliminary analyses. Recruitment began 15 years ago (in 2001) and ended in 2009. I realize that the plan is to announce results sometime this year, but we’re already well into 2016 without a murmur regarding outcomes (and why wait so long in any event?). I wonder if there is some sort of unexpected finding or disagreement regarding the interpretation among the study team which has delayed public presentation of data of great interest. I’ve interacted with a urologist, for example, who believes that patients receiving radiation rather than surgery are demonstrating the natural course of the disease, since he believes radiation treatments in general have negligible effects. Finally we’ll have a well-designed head-to-head trial of surgery vs. radiation therapy. However, given that about three-quarters of the ProtecT cohort had Gleason 6 cancer at entry, mortality differences between arms seem likely to be small in magnitude.

    Anyway, thanks as usual to the sitemaster for posting and discussing these important, emerging findings.

  5. Dear Brian:

    Thanks for your comments about the Sunnybrook study, with which I am in complete agreement.

    With respect to the ProtecT study, as I understand it this study is still right on track. We have all known that it would take years for data from this trial to reach maturity for exactly the reasons you outline (the high percentage of low-risk patien ts enrolled in the trial). In all honesty, a year or so here or there in how long it takes for the study to meet it’s predefined endpoints wouldn’t surprise me in the least — and there are no “preliminary” results that can or should be announced until the study does reach its predefined endpoints. That is the difference between a real clinical trial like this and the sort of long-term cohort analysis that Klotz and his colleagues were doing in Canada.

  6. Great post! the poster above talking about “Why wait?’ and “Ticking time bomb” needs to read up a little more. Less fear, more facts.

    I have low volume Gleason 6. Only way I’d treat it is if you put a gun to my head. For those of us with a robust sex life, it’s inconceivable.

  7. C.E.W.:

    My empathy with your experience.Tough to deal with.

    Your case advocates for responsible PSA testing, though we may not agree on the reaction to a PSA result, you are a case where earlier testing would have served you well.

  8. Hi C. Eric Winter,

    Like you, I had a case that needed treatment.

    However, accumulating data from at least seven major active surveillance programs around the world (at least the part of it near the Atlantic Ocean) have pretty much proven that low- and very low-risk prostate cancer is far from a ticking time bomb, i.e., it is very unlike your case and mine, and that favorable intermediate-risk cancer is also a good bet, though not quite as reassuring.

    The research from these centers virtually proves that “growing [prostate cancer] cells” for these low-risk patients are extremely unlikely to break away, and, in the rare cases where that happens, we have the technology to spot the issue and treat it. Consider that “growing” is a relative term. While for some of us our cancer was doubling every 3 to 4 months (me) or even faster, about 20% of the men in the Sunnybrook group have cancers that take a hundred years or more to double! You could say that you need a microscope and very long duration time lapse photography, plus a lot of patience, to see any growth. The medical world did not know that in the early 2000s, but now it does.

    It has also become crystal clear that unnecessary aggressive treatment causes a lot of harm with virtually no benefit, other than in very rare cases.

    I hope you have found treatments that are enabling you to cope well with this disease. As you may know, there is enormous progress in prostate cancer, even for patients with metastatic disease.

    Walt –- Go for it!

    Sitemaster — Thanks again! Great article!

  9. Hi Brian ODonnell,

    In your comment you wrote: “… I’ve interacted with a urologist, for example, who believes that patients receiving radiation rather than surgery are demonstrating the natural course of the disease, since he believes radiation treatments in general have negligible effects ….”

    I used to hear of such a view of radiation frequently from surgery patients talking about their urologists, but only infrequently these days as radiation has clearly become highly effective and safe. Was the urologist quite senior? I’m thinking he has not been keeping up with developments in radiation for prostate cancer.

  10. Another reason to doubt Dr. Koch’s statements

    Dr. Michael O. Koch, Chairman, Department of Urology, Indiana University School of Medicine, wrote in one of the accompanying notes to the paper:

    “… While the authors have highlighted the risk factors for developing metastases in patients treated with AS, they may be
    overly optimistic about the safety of this management strategy, particularly in patients with Gleason 7 disease. In this report we find that metastases developed in 13 of 133 patients (10%) with Gleason 7 disease, of whom most will go on to die of prostate cancer.”

    I was surprised by this comment, in one of the notes accompanying the paper, considering the author’s position as chair of a urology department. In addition to the quality of life question raised by Sitemaster, it seems really odd that Dr. Koch stated that “most” of the 13 Gleason 7 patients who developed metastases would go on to die of prostate cancer. One point in contradiction is that often metastases are within range of curative salvage radiation treatment. Another point is that, in view of the many effective medications now available, survival will be extended for these men so that other causes of death that are completely independent of prostate cancer will likely take some of these patients. A final and very important point is that treatments that will emerge in coming years will likely prevent death from cancer patients for some of these men.

    Also, his comment that the Sunnybrook group is “overly optimistic”, basically regarding the GS 7 patients, does not seem to have accommodated the small proportion of these GS 7 patients on AS who develop metastases.

  11. Hi Jim.

    I don’t think it’s just senior urologists who believe that surgery has superior outcomes than radiation therapy, at least for localized prostate cancer. For example, a recent meta-analysis by Wallis et al. (which integrates data across many sources) in European Urology concludes that, “We reviewed published observational data on overall and prostate-cancer specific mortality following radiotherapy or surgery in the treatment of clinically-localized prostate cancer. We demonstrated consistent evidence of increased mortality for patients treated with radiotherapy.”

Leave a Reply

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

You are commenting using your 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: