What’s next on the active surveillance front?


Here — for whatever they are worth — are some musings about what (in our opinion) seems to have come out of the NIH state of the science conference on active surveillance held earlier this week. As previously noted, the initial draft consensus statement from the panel discussants can be found on line if you click here.

  • Everything about active surveillance as a method for managing early stage, localized prostate cancer is affected by the way that diagnosing and treating clinicians present management options to potentially appropriate candidates for active surveillance.
  • There are no good incentives today that would tend to encourage the average clinician to present all of the management options in a neutral manner to appropriate candidates for active surveillance.
  • We are still not sufficiently focused on the important distinction between (younger) men who may well need curative treatment at some point in the future, but could defer that treatment for a considerable period of time (a median of 7 years according to data presented at the meeting) with minimal impact on their survival, as opposed to the deferral of treatment in (older) men who actually have a high probability of never needing to be treated at all.  (These are two very different clinical scenarios.)
  • The entire prostate cancer community needs to be much more rigorous in its definition and monitoring of the medium and long-term consequence of both active surveillance and of treatment.
  • We do need to be highly focused on ways to avoid the use of routine biopsies as a method of assessing men’s need for treatment after initiation of active surveillance. MRIs may well offer this opportunity now, and other tests may in the future.
  • We definitely still need much better tests as a means to assess those patients who are and are not appropriate candidates for active surveillance.
  • We do need to reach some agreement about the appropriate definition(s) of suitable candidates for active surveillance as opposed to those men who are definitively in need of early intervention.
  • We do need better data on the long-term follow-up of men being managed under active surveillance protocols (although some of this data will presumably come from the ongoing ProtecT and PASS trials, as well as from other studies that are ongoing).
  • It is worth considering a well-structured trial to explore the potential of active surveillance in the management of men with lower risk forms of intermediate-risk prostate cancer (e.g., Gleason 3 +4 = 7 disease, a PSA level < 10 ng/ml, and no more than three positive biopsy cores in which the amount of Gleason pattern 4 disease should be no higher than [say] 10 percent).
  • It is worth considering randomized clinical trials of different ways to manage patients over time under active surveillance — but such trials should not be conducted with any hope of showing a survival benefit of one method over another, they would be all about recruitment, adherence to the protocol, the actual management protocols being tested, and long-term side effects.

We could go on for a considerable period of time.

What was good about this conference was that — at some time during the meeting — everything got laid on the table. What was not so good was that there was, in our opinion, an over-emphasis on the historically available data and an under-emphasis on the things that need to be done better to move us forward. The consensus statement tends to reflect that.

We would note that a number of the presentations seemed to be irrelevant to this meeting. As an example, the discussion of clinical trials of men on androgen deprivation therapy offered no insight to the potential of active surveillance. It should also be noted that (while these were well conducted trials providing us with useful information) the men recruited into the PIVOT trial (about 10 years ago) and the Scandinavian trial (20 years ago) are hardly representative of most of the men being diagnosed with low- and very low-risk prostate cancer today.

Three final points:

  • Until we lose our cultural fear of “cancer” (which could take another hundred years or more) there are always going to be men who will respond to a diagnosis of low-risk, localize prostate cancer by saying they just want it “outta there.” This is a perfectly reasonable — if irrational — response based on data available today. And it will continue to be a perfectly reasonable — if irrational — response unless we can develop tests that can prove that some of these men are at no risk for clinically significant disease.
  • We are beginning to see a new mindset about the appropriate approaches to the management of low-risk, localized prostate cancer among some of the upcoming and younger members of the prostate cancer research community. We are optimistic that this will lead to more helpful data related to the role of active surveillance and other forms of observational management in the near future.
  • We need to kill off the term “watchful waiting.” For historical reasons it is associated in the minds of too many men with the idea that, “So you mean you’re just going to watch while I do the dying.” At the end of the day, watchful waiting is just a form of active surveillance with a different intervention strategy that can be used when intervention is necessary.

17 Responses

  1. I would argue that we should first focus on the cases where there are most likely to be the biggest gains from active surveillance.

    So let’s identify cases clearly where the man is at very low risk of dying from prostate cancer, and have very clear protocols so that the vast majority of researchers would agree the risk is low, either because of age or the biopsy results.

    And then let’s develop a clear protocol for active surveillance. Right now, to my knowledge there is not a clear and definite set of standards as to when it makes sense to at least strongly consider abandoning active surveillance in favor of definitive treatment. What are we looking for? If men don’t get a clear answer to that question, why should they choose active surveillance? Right now, “active surveillance” is simply too amorphous as it is presented to most men.

    Later on, we can do research to see if we can extend active surveillance into cases that might be at greater than very low risk. But why not try for the most obvious gains first?

  2. That’s certainly one approach.

  3. The problem is that they are trying to force this issue when all answers are not available. They claim that most GS 6 diagnosed today is indolent and will never progress. That issue has not been answered conclusively.

    Is prostate cancer a progressive disease with a variable growth rate? Does this growth rate remains stable or can it change with time? Is age at diagnosis a significant issue? Is advanced disease diagnosed with higher Gleason scores disease that progressed through different stages of de-differentiation? Although this growth rate is recognized as slow, it seems that beyond 15 years after diagnosis, it can change to more active disease if untreated or palliatively treated with androgen deprivation.

    All these issues have been ignored under the umbrella that very few men die of prostate cancer or that most men die with prostate cancer and not from prostate cancer. Active surveillance can very well be the way to slow down imminent treatment on those that are properly identified as having a slow-growing cancer. Those qualifying should be monitored to avoid occult progression with a well-established protocol that has a high degree of certainty/success and has widespread support from those involved in treating the disease. That is not the case today. Many questions remain unanswered.

    To contemplate calling low-risk prostate cancer by other names to avoid over treatment is very telling. This is incredibly naive. There has to be another way to do that with properly established procedures. Why would any man subject himself to a procedure that will diminish his quality of life if he is assured that doing active surveillance by an approved protocol avoids treatment while he avoids disease progression? I wouldn’t. No sane man would. The problem is that at this point in time that question has not been answered for men with a longer life expectancy who are diagnosed young … or for more mature men without other health issues and a long life expectancy.

  4. To contemplate calling low-risk prostate cancer by other names to avoid over treatment is very telling. This is incredibly naive.

    Surely this has already been done? The decision — in 2005 — to not label material containing Gleason grade 2 focus as adenacarcinoma but merely as atypical cells was doing just this surely? Was that naive?

    And was Logotheis being naive when he said, back in 1963, that:

    One of the problems with prostate cancer is definition. They label it as a cancer, and they force us all to behave in a way that introduces us to a cascade of events that sends us to very morbid therapy. It’s sort of like once that cancer label is put on there we are obligated to behave in a certain way, and its driven by physician beliefs and patient beliefs and frequently they don’t have anything to do with reality.

    And what about Jonathan Oppenheimer with his suggestion:

    It is time to reconcile the discrepancy of the term that pathologists assign to a microscopic finding to the historical and practical significance of that term. The most common significant finding made by contemporary pathologists on prostate biopsies cannot be adequately described by ‘tumor’ (Greek: swelling), ‘cancer’ (from the crab-like extension), or ‘malignant’ (threatening to life or tending to metastasize). I propose the terms ‘prostatic tubular neogenesis’ (creation of new epithelial tubes or acini) and ‘potentially malignant’ to better describe the microscopic findings that we have in the past labeled ‘adenocarcinoma,’ ‘cancer,’ ‘tumor,’ and ‘malignant.’

    Are these men naive? Do they have some unknown agenda? Or are they expressing a clear and logical view that is aimed at taking the panic out of decision making?

    I believe that it might be of some significance to review the outcomes of all men who were graded as Gleason 5 back in the days before that naive change. The old Albertsen study completed before the impact of PSA testing suggested that men with localized prostate cancer that had a Gleason score of 5, either not treated or treated with immediate or delayed hormonal therapy, faced a 6% to 11% chance of dying from prostate cancer within 15 years of diagnosis depending on their age at diagnosis. What would a similar study show today?

    It is often said that what we call things doesn’t matter, but I do not believe that is true — and there are many studies that demonstrate the power of words and phrases. That is one of the reasons I have always opposed the use of the words “watchful waiting.” I’ve said it before, but to me that brings up a picture of a goat staked out as leopard bait.

  5. Dear Ralph:

    Have you seen Snuffy Myers’ most recent video?

    He was at the meeting … and appears to be convinced (by the PIVOT data) that men with low-risk disease who are 65 and older should never be offered surgery again (because their risk of death from having surgery is higher than their risk of death from prostate cancer).

    Mike

  6. Terry,

    This is déjà vu. We have talked about this before. What you say is incorrect. Gleason grade 2 is cancer. It is not reported in needle biopsies for several reasons. The ISUP modification of the Gleason system never said that pattern 2 is not cancer. Read on:

    “It was the consensus of the group that, rather than stating categorically that a Gleason score 4 on needle biopsy should ‘‘never’’ be made, this diagnosis should be made ‘rarely, if ever.’ Whereas recommending that the diagnosis of Gleason score 4 on needle biopsy should be made ‘rarely, if ever’ is similar to ‘never,’ it does allow for the exceedingly rare case where low-grade cancer has been sampled on needle biopsy. The consensus conference cautioned that, although the potential exists for rendering a diagnosis of Gleason score 4 on needle biopsy, it is a diagnosis that general pathologists should almost never make without consultation. Even when the exceedingly rare Gleason score 4 cancer is diagnosed on needle biopsy by an expert, a note should be added that almost always a higher grade cancer will be seen in the corresponding prostate (if examined at radical prostatectomy). The major limitation of rendering a diagnosis
    of Gleason score 4 on needle biopsy is that one cannot see the entire edge of the lesion to determine if it is completely circumscribed. Consequently, most of the lesions that appear to be very low grade on needle biopsies are diagnosed by urologic pathologists as Gleason score 2 + 3 = 5 or 3 + 2 = 5 (Fig. 3). Some participants stated that if the location of the needle biopsy were from the transition zone or possibly at the apex, where many lower-grade cancers are found, that might factor into diagnosing the rare Gleason score 4 on needle biopsy.”

    As far as Dr. Logothetis and Dr. Jon O, those are their opinions.

    To say “I have Gleason score 5 or 6 and I will never experience progression since it is not cancer because I was told so by two well known prostate cancer experts is naive.” Wish it was true, but I know better …

    Source: The 2005 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma. Jonathan I. Epstein, MD, William C. Allsbrook, Jr, MD, Mahul B. Amin, MD, and Lars L. Egevad, MD, PhD, and the ISUP Grading Committee. Am J Surg Pathol  Volume 29, Number 9, September 2005

  7. Hi Mike,

    Yes I did and was surprised that he had not seen the PIVOT trial results when Dr. Wilt made the presentation at this year’s AUA. I wish I had the full paper because the PIVOT trial started in 1994 and it took them 16 years to recruit a little over 700 men.

    I remember back in 1994 that they would accept men with PSA up to 50 and men age 75 was top made me wonder … I am not sure how those parameters changed in time. It would be interesting to see the data. I wonder what is the statistical power of the study given the smaller population.

    In his video I thought that he avoided mentioning that after surgery a good percentage of cases are upstaged to higher Gleason scores. How to tell before surgery. Also, in RP series, recurrence is the lowest for the lowest Gleason scores in the series so that means to me that those men died of other things other than prostate cancer. I assume that Dr. Wilt was the one making the presentation …

  8. I believe the key to increasing the use of active surveillance is to adopt a patient-centered care approach. First determine what are the patient’s life goals. Provide all the necessary information for the patient to make a decision about treatment options to meet those goals. Have shared decision-making on how to attain those goals. The key is to put the patient in the center of the process.

  9. Ralph:

    I think Wilt’s presentation at the NIH meeting is archived on the web already. The PIVOT data have stiull not been published yet, although Wilt stated that they had been accepted for publication. BHis presentation at this meeting was a good deal more detailed than the presentation at the AUA.

  10. Ralph, when you say,

    This is déjà vu. We have talked about this before.

    I say “Of course it is, to you, to me and (yawn) to Mike. But since there are about a quarter of a million men diagnosed in the US alone each year, some of those men may not have been bored by the information I put forward. They may simply accept that the word naive should be applied to the opinions of leading medical people. So Yes, I do repeat information time and again, as I have for the past 12 years plus.

    You go on to say

    What you say is incorrect. Gleason grade 2 is cancer. It is not reported in needle biopsies for several reasons.

    Does this mean that although men are found to have cancer cells, if this are given Gleason Grade 2, the men are not told they have cancer but are told that there is no cancer detected or that there are atypical cells or ….?

    And isn’t that what I said:

    Surely this [calling cancer cells by some other nomenclature] has already been done? The decision — in 2005 — to not label material containing Gleason grade 2 focus as adenocarcinoma but merely as atypical cells was doing just this surely? Was that naive?

  11. One way to increase the use of AS is to produce a balanced video on the pros and cons of it and other options including quality of life factors. It would remove the bias inherent in doctor’s counseling and insure that all men are getting similar information. Doctors would only be paid if the patient signs a form indicating they had seen the video.

    On another note, a new study on breast cancer screening is likely to have similar parallels to prostate screening unless AS is more actively used. When quality of life is factored into the equation, more harm than good is occurring in the population.

  12. Terry,

    Did you read the portion of the ISUP article that I posted? That is not what the article said. Read again!

  13. It might not hurt if there was an actual billing code for active surveillance (here in the USA anyway)

  14. If AS is managed correctly, costs need to be covered. There should be a billing code if AS is to become a recognized treatment for for well-verified, low-risk prostate cancer.

  15. Doctors are paid for doing procedures. That is what the “P” in CPT ( the billing code) stands for. If a patient wants to get unbiased information, he’s got to seek it out. I think a series of videos, podcasts, etc., can provide this better than harried doctors who aren’t paid for the substantial time it takes to educate, and who might very well have a bias in doing a type of procedure in which they have invested much time and perhaps quite a deal of money. People naturally want to do what they are experts in. Human nature.

    No doctor wants to lose the chance to cure or to see any of his patients go metastatic, or to get sued from faulty communication that leads a man to allege that he was not offered a chance for cure. Active surveillance (AS) is a risk a man can decide that he wants to take, and only he should take the responsibility for such a decision. Given the right circumstances, the odds are definitely in his favor, but some men will have bad results and will have to live (and perhaps die) with the consequences. The great majority of men will be the better for taking the calculated risk.

    For those that do AS, finding a trusted doc to partner with during the surveillance period is essential. The good ones will be honored to be coach and counselor.

    You can’t live without taking risks. If you’re a man, prostate cancer is just one of the risks you have to manage. We must make the best choices we can with the information we have at the time we make a decision. Those with a diagnosis of prostate cancer are fortunate in that there is rarely a need to rush to a decision. And after a decision is made and treatment undergone, never look back. Shoulda, woulda, coulda is for losers; can, will, do is always the winning strategy.

  16. The recommendations of the NIH advisory group clearly move us towards a more patient-centric approach when choosing treatment for low-risk prostate cancer. The challenge now is to implement these recommendations across a vast healthcare system. The respondents to this posting have made some good suggestions as how to implement these recommendations. We must now all work to get these processes in place.

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