AUA report and update no. 11: Thursday, April 30, 2009

Klotz et al. (abstract no. 1682) presented data on Tuesday updating information about their 14-year-long series of patients managed with active surveillance. This series is the longest and largest series of active surveillance patients under management at a single institution using a prespecified protocol (even though there has been one major change in the protocol over time). This is the first complete update on this series of patients since 2002.

Klotz and his collegues have now been following a total of 453 men in a single-arm, prospective study since 1995. The initial group of patients included a subset of men > 70 years of age who would now be defined as having intermediate risk disease (Gleason score 3 + 4 = 7 or PSA 10-15 ng/ml). However, in 2000 the cohort was restricted to men with exclusively low risk disease, i.e., screen-diagnosed patients with no symptoms, Gleason score  ≤ 6, and PSA ≤ 10 ng/ml). Patients are all closely followed with serial PSA tests and periodic biopsies. Definitive intervention is offered to any patient with a PSA doubling time of < 3 years, Gleason score progression to ≥ 4 + 3 = 7, or unequivocal clinical progression.

The results presented by Klotz at this meeting are as follows:

  • Median age of patients is 70 years, with a range of 45 to 86.
  • Median follow-up is 7.2 years, with a range of 1 to 13 years.
  • Overall survival is 83 percent.
  • Prostate cancer-specific survival is 99 percent with only 5/453 patients having died of prostate cancer.
  • 35 percent of patients have been reclassified to a higher level of risk and offered definitive treatment
  • The two most common reasons for offering definitive treatment have been a PSA doubling time of < 3 years (14 percent) and Gleason upgrading (6 percent)
  • Of 137 patients offered and receiving definitive treatment, 71 (52 percent) have had subsequent PSA failure.
  • Patients with biochemical failure after definitive treatment represent 15 percent of the total study cohort.

Klotz and his colleagues  conclude that:

  • This form of expectant management, with selective, delayed intervention based on well-defined criteria of risk reclassification is associated with a low rate of prostate cancer-specific mortality.
  • Patients with favorable baseline risk parameters who subsequently progress (as indicated by a PSA doubling time of < 3 years or Gleason score upgrading to 4 + 3 = 7) are a high risk cohort and demonstrate a 52 percent probability for biochemical progression after definitive treatment.

They note that this form of management offers initially low risk patients an individualized approach to their care that may decrease the burden of therapy in men with indolent disease while still providing the opportunity for definitive therapy for men with more aggressive disease.

6 Responses

  1. You just have to wonder if there is a window of opportunity to successfully treat early stage disease that is missed.

  2. Of course there is! The problem is that one doesn’t know in whom until after the event! As I ‘ve said a thousand times, we need much better, very early stage discriminatory tests — and that will never be accomplished using saturation biopsies or imaging techniques because we need to be able to identify an early biological event.

  3. Mike,

    How early does it have to be? After reading your excellent posts for over a year, it seems like about one in three newly diagnosed men truly have very small Gleason 6 cancers.

    Until someone develops a way to sort out which ones will progress, isn’t treating them focally with cryo or HIFU a more reasonable approach than the “let’s wait and see” approach that you support?

    The last time my wife went to the dermatologist, he didn’t look at some bad areas of skin and say, “I don’t like the looks of this and I could safely freeze this off, but let’s wait and see what happens.”

    Sorry, but that’s the fly in the ointment in an “active surveillance for anything that really scares you (no Gleason 7 or worse)” approach.

  4. Respectfully Steve, that’s the fly in the ointment that apparently scares you. You can’t and shouldn’t make the judgment call that it scares everyone else. It does not scare me. And apparently it did not scare most of Dr. Klotz’s patients who had a definitive diagnosis, either.

    If one believes in the dictum of “first do no harm,” my view is this is an easy decision, and your analogy to a “bad area of skin” is hardly comparable because in that case, short of a truly appallingly bad execution of very simple dermal excision, there is no risk for adverse events whatsoever.

    The difference between you and me is that I am not arguing that men should not have treatment. Those who wish to do so, should do so. I am merely expressing my opinion that active surveillance appears to be a very reasonable option for men with low risk, early stage disease based on the increasingly strong data available. I would also note that the data is not exclusive to those with “very small Gleason 6 tumors.” Klotz’s data certainly includes men with larger but still relatively indolent tumors. My personal suspicion is that tumor size is far less important than tumor biology.

    I would also point out that we have no data whatsoever to let us determine whether or not the men who either needed or decided to have treatment in Dr. Klotz’s study and went on to have progressive disease wouldn’t have had progressive disease anyway, regardless of a period of active surveillance of 1 day or 1 year.

  5. Did this protocol involve annual biopsies? What kind of model is suggested by the timing of progression from Gleason 6 to Gleason 4 + 3 =7 in this set of patients? Was it suggestive of an exponential distribution, by any chance? And how can we relate the growth of tumor (as estimated by the percent of biopsy positive for tumor, I suppose, or by a combination of that and the PSA) to the progression in Gleason score? I am of course aware that such considerations were not the point of the study, and that there is the problem that so-called progression in Gleason score on biopsy may be due to sampling variation.

  6. Dear Mr. Berele:

    These are very complex questions and I certainly cannot answer most of them. I am not even sure that Dr. Klotz or his colleagues in Toronto could answer some of them!

    In the actual abstract of the presentation, it states only that biopsies were conducted “periodically.” My suspicion is therefore that biopsies were driven by changes in PSA levels rather than being carried out annually. Please be aware that Dr. Klotz and his colleagues are not reporting the results of a true “clinical trial.” They are reporting the results of their clinical experience in a cohort of patients, and there may have been minor or even major changes in their clinical thinking over a period of 14 years.

    You may be able to get additional information from the report published by Klotz and his colleagues in 2002 on the initial 231 patients, but you would need to be able to review the actual paper, not just the abstract. Beyond that I am sorry, but I am unable to help you. I do expect that Dr. Klotz and his colleagues will publish a detailed report on their current data in the near future, and you can be sure we will report on that paper just as soon as we are aware of it.

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