Moving targets and the interpretation of “new” medical “knowledge”

In this week’s New England Journal of Medicine (NEJM), there is an interesting article entitled, “Contingent knowledge and looping effects — a 66-year-old man with PSA-detected prostate cancer and regrets”.

The full text of this article by Aronowitz and Greene is not (unfortunately) available for most people, but what is available is an audiorecording of a conversation between Dr. Aronowitz and the executive managing editor of the NEJM. We believe that this conversation may be of great interest to many prostate cancer patients in particular because it discusses the sociological ways in which our own behaviors (as doctors and as patients) end up affecting how we think about particular types of disorder, and because Dr. Aronowitz uses the case of “Mr. B” — a 66-year-old man diagnosed with prostate cancer — as a very specific case in point.

Your sitemaster is going to be clear, immediately, that some people will not concur with at least some of the opinions that Dr. Aronowitz expresses in this interview. This is a complex subject, and there is plenty of room for differences of opinion. However, what is really important here is not just what happened to “Mr. B.” but rather the general failure of many doctors and patients to appreciate that the state of medicine — at any point in time — is a moving target, and that over the past 50 or so years, as our medical knowledge has been more rapidly expanding, it has become a rather rapidly moving target.

The consequent implication is that making decisions today on the basis of information that is as little as 5 years old (e.g., in the management of prostate cancer) can be very dangerous. In the case of prostate cancer in particular, it can take years to get the results of large studies because — in most cases — prostate cancer is a slowly progressing disease. So a study that was started even in (say) 2010, is already 9 years out of date in terms of what we might know today about the patients who enrolled in that trial 9 years previously. So when the results of that trial get reported in (say) 2020, they are unlikely to have been taking account of all sorts of information that we would know about an equivalent set of patients today.

This does not mean the new data are “bad”. However, it does mean that they have to be interpreted in the context of what we now know and what we didn’t know when the study was started.

This is hard for both patients and physicians to deal with. This type of knowledge and the ability to think about new information in a specific disease with such appropriate contextual understanding means that you can’t just read the latest papers and take what they say as being some sort of gospel truth. It should also place an additional onus on the authors of papers in medical journals — and the editors of those journals — to ensure that the appropriate contextual background is being provided to the reader.

To give just one recent example of all this that is highly specific to prostate cancer, several new drugs have been or soon will be approved for the treatment of “non-metastatic castration-resistant prostate cancer” (nmCRPC). When those trials were initiated, men were defined as having nmCRPC solely on the basis of bone scans and CT scans. Very, very few patients had ever been given a PET scan for prostate cancer. Today, numerous patients receive all sorts of different types of PET scan as part of their evaluation as high-risk or potentially micrometastatic patients. But if you are postitive on such a scan, this does not mean that you are necessarily a good candidate for immediate treatment with some of these drugs that are being approved for treatment of nmCRPC. Why? Because what we mean by nmCRPC is changing and because having nmCRPC on a bone scan is not the same as having nmCRPC on (say) a gallium-68 PSMA PET/CT scan (already commonplace in places like Europe and Australia).

7 Responses

  1. I agree wholeheartedly. It is hard to think of the slowness of early prostate cancer as a problem, and the earlier the stage of the cancer, the more problematic the research. By the time actionable results are available, the therapies they investigated are irrelevant (either because of technology improvements or because some other simultaneously given therapy has changed the standard of care in the interim). For localized prostate cancer, the study has to extend for at least 15 years, and even then, surrogate endpoints (other than overall survival) have to be used. The “problem” is compounded by the fact that prostate cancer is a disease of older men, who may die of something else before the effectiveness of the therapy can become apparent. We will always have to make decisions with incomplete information.

  2. Sitemaster:

    What you are talking about here, e.g., how to integrate new diagnostic technology into the treatment plan for better treatment results, is a very big issue these days because in one view one would think finding a disorder early would permit getting a head start on treating that disorder and would result in better long term results.

    What one is hearing these days is that “we have to do a new study to see the influence of this new technology because all our studies were done using classical imaging”. The only problem with this is that the new study could take 10 yrs to complete. So what is a person to do who needs the best treatment now and has had the new imaging? I think a patient in this position needs to find a specialist familiar with the new technology who is sufficiently knowledgeable to be able to make use of the new technology to come up with a better treatment plan than one just using the classical imaging date/studies. In my opinion, it is not satisfactory for the needy patient to simply be told “I don’t know what to do with this new information and we will have to wait til your picture fits with the classical imaging of a previous study”. That was a quote from one EAU 2019 session participant.

    As Dr. Chris Sweeney has been quoted saying, “Instead of thinking of the next study to do, we need to stop and look back on what we have done previously and figure out how to actually cure patients.”

  3. I was unfortunately diagnosed with End Stage 4 Metastatic Prostate Cancer by a young, inexperienced, fresh graduate of urology in Vancouver, Canada. I was 50 years old at the time. My first PSA screening test resulted in a level of 11.9. The … urologist … dictated that I had to undergo immediate treatment by radical prostatectomy, which rendered me incontinent, impotent, and I also lost my fertility. Right after the surgery, my wife and I were divorced due to my inability to performed sexually. To make things even worse, I have only discovered recently that I was lied to by the urologist about my prostate cancer which was based on misdiagnosis! Now I have to file a legal lawsuit against the urologist.

    My words of advice: Do not rush into making a treatment decision without fully investigating how the treating specialist arrived at your diagnosis, your choice of treatment, and the treatment’s side effects. Ask yourself if you would make the same treatment decision 5 years from now, and walk away from your so-called urologist/oncologist if he/she rushes you into make a life-changing treatment decision. Document (better yet, bring a voice recorder to) all office visits, you may need them at a later day.

    Editorial note: A few words have been deleted from this comment because they identified a specific individual about whom the author of the comment has expressed an unproven opinion. We would also note that diagnosis with “End Stage 4 Metastatic Prostate Cancer” as stated above would almost never be an indication for an immediate radical prostatectomy. The more general observation that patients should never let themselves be rushed into making life-changing treatment decisions is, of course, correct, and applies to many conditions other that prostate cancer too.

  4. Dear Walter:

    Much as I would like to agree with Dr. Sweeney, who I have spoken with on several occasions, we have spent nearly 60 years now trying to “cure” prostate cancer, and we still aren’t doing very well for the men with aggressive forms of the disease. At the other end of the scale, for much of the more recent 40 years (since the early 1980s) we have been over-treating many men who never needed immediate treatment at all (and it took us 30 years to work out that we were doing that).

    You also need to appreciate that many of the experts who are most familiar with the new forms of imaging are among the most ardent advocates for the use of this technology, and so their opinions are at least “colored” by their beliefs. (This was very evident at the recent APCCC 2019 meeting in Basel.)

    You are quite correct that telling patients that “I don’t know what to do with this new information and we will have to wait til your picture fits with the classical imaging of a previous study” is not an appropriate response to patient need. On the other hand, telling patients that, “I am going to put you on this new and expensive drug even though there is no evidence that it will benefit you at all” is also an inappropriate message.

    All that anyone is saying here is that none of this is simple. Medicine is still an “art” much of the time — despite the increase in scientific knowledge. Patients and their doctors need to understand that the latest new form of treatment is not always, necessarily, the most appropriate form of care for a specific patient … however much one might like that to be the case. Exactly what should be done to provide the highest quality of care for each individual patient is by no means easy to determine today.

  5. Sitemaster,
    Thank you for your excellent reflections on new technology and treatments. The message one hears is — new is not always better and must be carefully examined before jumping in.

    One thing patients in the US should be aware of is that prostate PSMA PET/CT is really new here. Only a few centers offer it to prostate cancer patients and some clinicians are getting familiar with it and others not.

    Finding a doctor who is familiar with new technology and treatments is a real challenge. One place one might consider looking is, as such centers involved with such trials would at least be working with a group of patients and gaining experience from them. It does not mean that one would have to join the clinical trial but at least you could contact them to see if they could see you as a private patient.

    Along the lines of what Sitemaster is trying to say here, there was a recent abstract on UroToday looking at the PREDICT prostate prognostic model (which you can look up on line and use) which found that clinicians over-estimate cancer mortality and radical treatment benefit for non-metastatic PCa.

    Buyer beware as they say. Good luck!

  6. To give another recent example, published in June 2019, EAU-EANM-ESTRO-ESUR-SIOG guidelines on BCR recommend using a novel BCR classification system that stratifies patients with BCR after RP into

    — Low-risk (PSA-DT > 1 year and pGS < 8 [ISUP grade <4] and
    — High-risk BCR (PSA-DT < 1 year or pGS 8-10 [ISUP grade 4-5].

    But this classification seems irrelevant to patients with BCR undergoing early (0.2 to 0.5 ng/ml) and very early (0.01 to 0.2 ng/ml) salvage RT, because according to Working Group guidelines on PSA doubling time:

    “All PSA values used in the calculation should be ≥ 0.20 ng/ml and follow a rising trend. Minimum requirements for the calculation are 3 PSA values obtained over 3 months with a minimum of 4 weeks between measurements”.

    Now, when early and very early SRT are becoming more and more widely accepted, what is the use of this classification?

  7. Dear Valery:

    The PSA Working Group guidelines that you refer to are 10 years old. As far as I am aware, there is no current, revised “standard” set of recommendations as to the appropriate timing of salvage radiation therapy among men who have progressive disease after radical prostatectomy. On the other hand, I think it is fair to say that most physicians would consider that the post-surgical PSA level, pathological Gleason score (or ISUP grade), pathological stage, and PSA doubling time are all factors that should be considered in making the decision as to when to initiate salvage radiation therapy in an individual patient.

    The June 2019, EAU-EANM-ESTRO-ESUR-SIOG guidelines that you refer to have not (as far as I am aware) been endorsed by the AUA or by ASTRO here in the USA. They do not sound unreasonable for men with a PSA level of 0.2 ng/ml or higher, but whether they are appropriate for men with a PSA level of 0.005 to 0.200 is much harder to determine.

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