PSA-based triggers for treatment in active surveillance protocols

A new report from Laurence Klotz’s group in Toronto basically tells us that no currently identified PSA-based “trigger” can be used alone to determine when a man on active surveillance should be switched over to active treatment.

This new paper by Loblaw et al., due to appear in the November issue of the Journal of Urology, but already available on-line, provides data from a prospective, Phase II clinical trial including data from 450 patients on active surveillance. Of these patients, 315 had received no treatment for their prostate cancer at the time of the current analysis (April 2009), and 305 of these 315 patients were eligible for data analysis.

In this cohort of 305 patients, Loblaw et al. tested nine different PSA-based triggers in three groups for their potential to predict the value of treatment:

  • PSA threshold triggers
    • An absolute PSA > 10 ng/ml
    • An absolute PSA > 20 ng/ml
  • PSA doubling time triggers
    • Fluctuating PSA doubling time < 2 years
    • Fluctuating PSA doubling time < 3 years
    • Linear regression-based PSA doubling time < 2 years
    • Linear regression-based PSA doubling time < 3 years
  • PSA velocity triggers
    • Overall PSA velocity > 2 ng/ml/yr
    • Selected PSA velocity > 2 ng/ml/yr
    • 1-year PSA velocity > 2 ng/ml/yr

The precise means of calculating the various PSA doubling time and PSA velocity triggers are described in the full text of the paper.

Of the 305 patients whose data was analyzed, it is important to understand that at a median follow-up of 6.1 years (in addition to the fact that not one has ever received active treatment for their prostate cancer), none have had any indication of metastatic disease and none have died of prostate cancer. Despite this fact:

  • All the abovementioned triggers would have recommended treatment for at least a percentage of these patients.
  • The range recommended for treatment was between 13.5 and 84.3 percent.
  • The absolute PSA value of > 20 ng/ml recommended treatment in only 13.5 percent of patients.
  • The selected PSA velocity > 2 ng/ml/yr recommended treatment in 84.3 percent of patients

In the conclusion to this paper, Loblaw et al. write as follows:

A transient increase in PSA should be interpreted with caution in men on active surveillance. If active surveillance is to be an effective long-term [management] option for men with favorable risk prostate cancer, more work is needed to identify a trigger which better strikes the balance between recommending treatment for those at high risk for progression and minimizing treatment for those at low risk for progression.

It should also be noted that of the 450 patients originally entered into the active surveillance protocol by Klotz and his colleagues, 117 (26 percent) were reclassified as having higher risk after initial entry into this study and subsequently received treatment, as reported by Klotz et al. in a publication earlier this year.

The “classic” reason for switching a patient from active surveillance to active treatment is an increase in the patient’s Gleason score (usually from 6 to 7 or higher) on follow-up biopsy.

3 Responses

  1. So what is the conclusion? Does it mean that men on active surveillance should not have PSA tests and the decision to switch them to active therapy should be based on biopsy results only? Or perhaps a combination of biopsy and color Doppler?

  2. No. It means that decisions about treatment need to be individualized and made with caution and probably should include a combination of factors (of which biopsy data would certainly be one). Others might include color Doppler or perhaps more sophisticated types of imaging (e.g., 3.0 T MRI, if available).

    But what it also means is that the average community urologist doesn’t have an “easy” way to tell patients on AS that they need to consider treatment.

  3. Thanks once again for reviewing this thought provoking paper from arguably the leading, longest running AS program.

    These patients have averaged over 6 years in the program, and it is quite reasonable that for a portion of these men, some BPH but especially some infection/inflammation would drive PSA, eclipsing the amount of PSA stemming from the cancer. I can easily see this circumstance affecting most of the nine triggers, and it seems clearly wise not to end an otherwise successful AS experience based solely on these triggers; it would be very important to look at other circumstances.

    However, I’m trying to think through two of the triggers, neither of which would seem especially vulnerable to BPH or infection:

    — Linear regression-based PSA doubling time < 2 years, and
    — Linear regression-based PSA doubling time < 3 years.

    Perhaps I'm not viewing these criteria properly. I'm visualizing them as the tell-tale exponential increase in PSA that so often is due to prostate cancer. Maybe the researchers were just focusing on the resulting doubling time and not the exponential pattern of increase.

    It does seem wise not to kick someone out of active surveillance just because a sole threshold has been breached, despite an overall pattern of success. This research is showing that post-eligibility monitoring and decision-making are different from initial eligibility. In the latter, where there is no track record of success on AS, it seems wise not to go on active surveillance if the threshold for just one criterion is breached.

    Any thoughts on any of this?

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