Better defining appropriate candidates for active surveillance

A forthcoming paper from Tewari’s group at Weill Cornell Medical College in New York describes a new set of nomograms for assessment of risk for worsening prognosis in men with localized prostate cancer who might otherwise be considered appropriate candidates for management under active surveillance.

Sooriakumaran et al. based their study on data from a cohort of 2,476 patients, all treated by robot-assisted laparoscopic prostatectomy (RALP) between January 2005 and September 2010. Of these 2,476 patients, 750 met reasonably well-established (“standard”) criteria suggesting that they would be eligible for management under active surveillance (a PSA level ≤ 10 ng/ml; clinical stage of ≤ cT2a; a Gleason score of ≤ 6; not more than two positive cores on biopsy; and not more than 50 percent of any individual biopsy core being positive for cancer). However, these patients were not ever given the repeat biopsy that is considered advisable by several leading centers prior to entry into an active surveillance protocol. Although all biopsy specimens were centrally reviewed at Weill Cornell prior to RALP, not all of the original biopsies had been carried out at this institution, and many patients were in fact treated there after prior biopsy at community-based urology practices and other centers. Pathologic examination and centralized review of all the post-surgical prostate specimens was conducted at Weill Cornell.

What the authors did then was to compare the post-surgical pathology findings to the biopsy pathology findings to clarify just what proportion of the 750 patients really were good candidates for active surveillance at the time of surgery, and to use these data to develop predictive nomograms that could help to better identify these patients. So … here are the initial findings:

  • 297/750 patients (39.6 percent) in the eligible study cohort actually had a post-surgical Gleason score > 6.
  • 29/750 patients (3.9 percent) in the eligible study cohort actually had a pathologic stage of at least pT3a.
  • 303/750 patients (40.4 percent) in the eligible study cohort were either upgraded and/or upstaged and were therefore not actually eligible for active surveillance at the time of surgery.
  • Patients found to be upgraded at post-surgical pathology shared a number of pre-surgical characteristics compared to those who were not upgraded.
    • They had significantly higher body mass indices (BMIs) (p = 0.04).
    • They had significantly higher preoperative PSA levels (p < 0.001).
    • They had higher numbers of positive biopsy cores.
    • They had higher maximum amounts of cancer in their biopsy cores.
  • Within the total eligible study cohort, there were no significant differences between the 303 patients who were upgraded and/or upstaged and the 447 who were not with respect to
    • Patient age
    • Numbers of biopsy cores taken at biopsy
    • Presence of high-grade PIN on biopsy
    • Pre-surgical Gleason score
    • Pre-surgical clinical stage

The authors go on to describe the development of three nomograms that can be used to estimate:

  • The probability of a patient being upgraded at the time of surgery (based on the preoperative PSA level, whether one or two cores was positive for cancer, and on the patient’s prostate volume)
  • The probability of a patinet being upstaged at the time of surgery (based on the preoperative PSA level, whether one or two cores was positive for cancer, and on the patient’s prostate volume, and the pre-surgical clinical stage )
  • The probability of a patient having a worsening prognosis if managed by active surveillance (again based on the preoperative PSA level, whether one or two cores was positive for cancer, and on the patient’s prostate volume)

Many in the urology community are concerned that patients with clinical evidence of low-risk disease who are managed with active surveillance may actually be at significant risk for progressive disease and that active surveillance for even a brief time period may permit disease progress to an incurable state. (The advocates for active surveillance would likely state, however, that the data now available do not generally support this concern.) The ability to project, with a high degree of accuracy, which patients who appear to be suitable candidates for active surveillance are actually not good candidates for management by monitoring in this manner is certainly critically important. However, The “New” Prostate Cancer InfoLink is concerned that the nomograms proposed by Sooriakumaran et al. may have a number of significant and inbuilt flaws, as follows:

  • First, since leading centers currently propose that patients being considered for active surveillance should be rebiopsied prior to entry into a study protocol, it seems to us that any nomogram of this type should be built on the basis of patients who have in fact been rebiopsied (or at least biopsied) according to a reasonably standardized protocol.
  • Second, the average age of the patients in this study cohort seems low (at about 58 to 60 years), which means they have average life expectancies of 20 or so years. Are these really typical candidates for active surveillance or are these data affected by a high rate of referrals of younger men for RALP at a widely recognized center specializing in this type of surgery? (Unfortunately, the age range of the patients is not available in the actual article.)
  • Third, the rate of upstaging and upgrading reported in this study seems relatively high at 40.4 percent compared to that supposedly being achieved today at other major academic centers.

The authors have commented on some of these issues in the Discussion section of their paper. They have also carefully noted that their nomograms have yet to be validated through the use of data from independent centers to see if it accurately predicts which patients are at risk for upgrading and upstaging based on another data set.

What this study definitely does do is offer a sound preliminary model, based on a large data set, for the development of predictive nomograms that can help the practicing clinician and his or her patients to assess the long-term risks and benefits of active surveillance as a management strategy — most particularly for those patients with a reasonable life expectancy of up to about 15 years. However, we really wonder whether better nomograms could potentially be developed based on data from the 10-year follow-up of cohorts of patients who have actually been enrolled in long-term active surveillance studies.

There are three critical issues regarding the value of nomograms (or other predictive tools) in expanding appropriate use of active surveillance, in our minds:

  • We clearly need to be able to accurately identify those patients whose potential pathologic status is likely not conducive to active surveillance even though their clinical status suggests they are appropriate candidates. We believe that a repeat biopsy prior to initiation of active surveillance may well be an essential component of the evaluation of such patients.
  • We need to be able to accurately identify the real need for repeat biopsies in men actually on active surveillance protocols, since every biopsy comes with risks for complications, and an excessive number of biopsies over time could, in and of itself, induce real long-term side effects.
  • We need to be very careful to ensure that the reasonable, normal life expectancy of the patient is taken into account in making decisions about the application of active surveillance. The application of active surveillance to a man in his late 40s may be conducted for quite different reasons to those for application of the same management strategy in a man with the same clinical characteristics who is in his mid to late 70s.

We would like to thank Drs. Tewari and Sooriakumaran for providing us with the full text of their paper (to be published in International Urology and Nephrology) and for clarifying certain technical questions about the content of that paper.

9 Responses

  1. If only 30% of patients qualify as candidates for AS and of those 40% are upgraded after surgery, how can the over treatment number be as high as claimed? It seems to me that those experts must be using the same computer models used to define the cause of global warming …

  2. If 39.6 per cent of these men were upgraded, there must have been a signficant number of men downgraded. Based on previous studies one could expect about the same percentage as the percentage upgraded.

    Since entry point for a diagnosis of prostate cancer is now a Gleason score of 6 from a needle biopsy, the men downgraded from Gleason 6 would not have been included in any kind of therapy choice — or active surveillance — if the needle biopsy result had been the same as the subsequent post-operative pathology result.

    No argument about those men being over-treated!!

  3. You are missing my point. The uncertainty of needle biopsy to define the actual status of disease present is evident in this study. If only 750 of 2,476 patients qualify to some of the current AS protocols’ requirements, and of those 40% have more actual disease present, the idea that over-treatment is as high as predicted by computer models is in question.

    The argument is not about the uncertainty of needle biopsy. The argument is about what is the real rate of over-diagnosis and over-treatment. I say computer models are being manipulated to yield an unfavorable answer when the real problem worldwide is under-diagnosis and under-treatment resulting is a high mortality for untreated prostate cancer or cancer diagnosed too late.

    As far are your insistence that a Gleason score of 5 or less is not cancer and therefore those men are always over-treated is very debatable because although the disease tends to be slow growing, the rate of progression is not set in stone and in time (past 15 years) it can become aggressive and become metastatic.

  4. Dear Ralph and Terry:

    First, let’s distinguish between what is happening in the USA and what is happening elsewhere in the world. We cannot use Tewari’s data to make generalizations about the whole of the world. These are highly selective data from one particular center in New York that is most unlikely to be representative of even the East Coast of the USA.

    Second, Terry is not insisting that “a Gleason score of 5 or less is not cancer.” What he is saying is that if cancer is present on biopsy in the eyes of a pathologist today, the lowest Gleason score that can be assigned is 3 + 3 = 6, which is a very different statement.

    Third, my guess would actually be that since the introduction of Gleason 6 as the lowest possible grade for a diagnosis of cancer on biopsy, the rate of downgrading of cancer from biopsy to RP has actually fallen significantly. Downgrading has, in any case, always been significantly less common than upgrading precisely because of the “uncertainty” of needle biopsies (i.e., missed foci of high Gleason score).

    What Tewari’s study tells me is that we continue to make treatment decisions based on very poor diagnostic and prognostic data. Given that scenario, I have no idea how anyone can reach any conclusions about whether we are overtreating or undertreating specific individuals (let alone populations) because there is an inbuilt flaw in the way we categorize patients. A 90-year-old man, with a single focus of Gleason 6 disease today is almost certainly at no risk for metastatic disease or prostate cancer mortality and very high risk for side effects if treated. By contrast, a 43-year-old man with a single focus of Gleason 6 disease is at significant risk for progression over time, but we still don’t know whether we should treat him immediately or whether we should monitor him carefully until there is a clear signal that immediate intervention is needed. And that’s assuming that the diagnoses of these two men are both accurate, which has significant inbuilt uncertainty.

    We are never going to resolve the over-/under-treatment debate until we can accurately diagnose and classify patients as having clinically significant or clinically insignificant disease with a far higher degree of accuracy than anything that we can accomplish at present.

  5. Mike,

    That is why actual data based on treatment is infinitely better than any computer model based on a definition. The Tyrol study in which men were diagnosed AND treated with surgery did that and yielded a much lower number than the computer models. I do not deny that there is over-treatment caused by the uncertainty of the present diagnostic tools. I question what the rate is and why those incredibly high numbers continue to be published …

  6. Ralph,

    Can you share with me what YOU consider the rate of over-treatment to be. I guarantee that I will not dispute your figure or argue — I’m just interested to know, if only to see how big a gap there might be between what you believe and what I think may be the case.

    And while you are at it, would you care to comment on why the issue is not more clearly stated to men with an appropriate diagnosis in terms such as:

    “Studies indicate that x number of men in y will benefit from immediate invasive therapy. All such therapies carry a risk of reduction in quality of life. Other studies show there is very little risk for men with your diagnosis if they delay the start of any therapy until diagnostic data show that the chances of your gaining benefit from treatment have changed”?

    As ever I’ll be interested in your response.

  7. Terry,

    First let me say that even in the USA, where the use of PSA testing is higher than in most other countries, the current problem is under-diagnosis and therefore undertreatment and not over-diagnosis and over-treatment. In most other countries the problem is even more acute. That said, I have read most papers about the issue and of all, consider one by Etzioni et al. (published in 2002) as being the most representative.

    In that particular report the rate is 15% for whites and 37% for blacks. Those numbers represent an upper boundary based on all diagnosis of all future clinical disease made by PSA testing. This means that the actual numbers will be lower as not all men are diagnosed by PSA testing. Far from it.

    A true result about over-treatment came from the Tyrol using Epstein’s definition for clinical insignificance. The rate reported was 8.7%. Based on these numbers, I believe that the true number here in the US is between 10% and 20% and far from the reported numbers by other computer models.

    If and when another more specific marker than PSA is developed, the response to your other question would be more positive. Today there is too great a discrepancy between needle biopsy prognosis and actual disease present to be able to tell a man with a high degree of certainty that he is safe to adopt AS. Worse yet is the fact that AS has not been, as it should (understanding the risk), accepted across the board for various reasons — including ignorance by patients and physicians, diagnostic uncertainty, and (in a minority of cases) pure greed.

    After reading about the natural history of untreated prostate cancer as reported in the Scandinavian medical literature I came to the realization that, given enough time for the disease to progress untreated, it can have a high disease-specific mortality. I also learned that such progression is not without symptoms and loss of quality of life. None of this is explained to newly diagnosed men either. Age at diagnosis is an important data point in the treatment/no treatment decision process because of the generally slow-growing process of the disease and the increased risk that in time the disease can escape and invade tissues and organs.

    If we are to be able to explain that x number of men in y will benefit from immediate invasive therapy and such therapies carry a risk of reduction in quality of life, then we should also explain that untreated progression is not without symptoms that degrade the quality of life.

    Still, I believe that we all must proceed with decisions that fit our personal lives and that may not be appropriate for others.

  8. Ralph,

    I was somewhat disappointed in your response. The 2002 (almost 10-year-old) study to which you referred dealt with the perceived over-diagnosis, defined as: … the detection of prostate cancer through PSA testing that otherwise would not have been diagnosed within the patient’s lifetime which is a different subject altogether.

    I also understand your views concerning the potential for under-diagnosis, but again that was not the question that I asked. In the context of the study posted above and the brief discussion that has followed I was seeking your personal opinion on the current level of over-treatment, i.e. the ratio of men who, after diagnosis with current methods and with a “low risk” profile might not benefit from immediate invasive therapy and who might have a better quality of life if they adopted an Active Surveillance approach.

    I understand that there are risks in AS. I understand that there may be side effects. I am not saying that these issues should be hidden from anyone.

    What I am trying to establish is what a man with your experience and knowledge feels the degree of over-treatment might be. I’m not asking you to “prove” this; I will not argue with your view: I will not use it in any other Forum in a way that it can be identified as your view, but i would like to know what you think.

    I am asking this because although you have said things like …I do not deny that there is over-treatment caused by the uncertainty of the present diagnostic tools., it is my belief that you are more inclined to the view expressed by Dr. Catalona — that every man diagnosed with prostate cancer should have early treatment and that treatment should be surgery in the majority of cases.

  9. Terry,
    The opinion that you requested of me has to be based on something. I can’t pull a number out of the air. It has to be based preferably on actual results and not in computer models based on definitions. The reference cited deals with the issue of over-diagnosis and over-treatment. I told you that in my opinion the degree of current over-diagnosis and over-treatment is between 10% and 20% in the US. I meet a high number of men at the support group level and on line to support that estimate.

    I do believe like Dr. Catalona that PSA testing saves lives, but I have never advocated for any patient to have surgery. Never in my almost 20 years have I said to anyone asking what to do to have surgery or any other treatment for that matter. If a man decides for surgery with a high GS I might warn the man that there is a risk of the cancer having escaped, but I have never told them to do it or not do it. I always tell men to learn the side effects of treatment because all treatment can have side effects.

    BTW, I am an old timer. I do not believe for a second that “new and improved” or the latest is best. That particular citation by Etzioni is well written and logically expressed and I am surprised that you considered it a different topic when it deals with the very topic in question. Sorry to disappoint…

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