PSA kinetics do not predict pathology in men on active surveillance

The role of PSA kinetics (i.e., PSA doubling time and PSA velocity) in the early diagnosis of prostate cancer and in the monitoring of patients on active surveillance protocols has been controversial. We now have some more definitive data.

Ross et al. wanted to know whether PSA velocity (PSAV) and/or PSA doubling time (PSADT) could be used to predict for biopsy progression and adverse pathology at prostatectomy among men with low-risk prostate cancer participating in the active surveillance program at Johns Hopkins Medical Center.

The criteria for entry into the active surveillance program at Johns Hopkins are stringent: a PSA density of 0.15 ng/ml/cm3; a biopsy Gleason score of 3 + 3 = 6 with absolutely no sign of Gleason pattern 4; a maximum of two positive biopsy cores; and no more than 50 percent involvement of cancer in any biopsy core.

Ross and colleagues assessed data from 290 patients who met these criteria and who had had two or more serial PSA measurements after diagnosis between 1994 and 2008. All patients were followed with twice-yearly DREs, twice-yearly PSA measurements, and a yearly surveillance biopsy. Treatment was recommended to those patients who demonstrated biopsy progression based on one or more of the following: a Gleason score of 7 or higher; 3 or more positive biopsy cores; 50+ percent core involvement in any biopsy core.

The results of their study showed the following:

  • 188/290 patients (65 percent) showed no signs of disease progression and remained on active surveillance.
  • 102/290 patients (35 percent) demonstrated biopsy progression at a median follow-up of 2.9 years.
  • There was no significant association between PSADT and adverse biopsy findings (P = 0.83).
  • There was a marginally significant association between PSAV and adverse biopsy findings (P = 0.06).
  • Neither PSAV nor PSADT had both high sensitivity and high specificity for biopsy progression at any cut point.
  • Among the patients who eventually elected treatment by radical prostatectomy, neither PSAV nor PSADT were associated with the presence of unfavorable surgical pathology.

The authors conclude that PSA kinetics following initial diagnosis do not reliably predict adverse pathology and should not be used to replace annual biopsies for monitoring of men on active surveillance.

In a separate report on this study on the HealthDay web site, Whitson is quoted as stating that the data from this study may not be definitive. Dr. Whitson also wrote an editorial comment making the same point about the original paper by Ross et al. in the Journal of Clinical Oncology.

We should be clear that these data hold no specific impact for the relevance of PSA kinetics in the initial diagnosis of prostate cancer. There has been an ongoing controversy about whether PSA kinetics predict risk for prostate cancer any better than a single PSA measurement. What these data do suggest, however, is that we need resolution of this second controversy as well. If PSA kinetics are not able to predict the onset of adverse pathology in men already diagnosed with very early stage, low-risk prostate cancer, it seems to The “New” Prostate Cancer InfoLink that this does cast further doubt on the relevance of PSA kinetics to initial risk and diagnosis.

We should also be clear that the one place where PSA kinetics very definitively do have value is in the monitoring of patients after first-line treatment. Patients with higher PSAVs and shorter PSADT values are at significantly higher risk for metastasis and prostate cancer-specific mortality than those with low PSAVs and longer PSADT values.

6 Responses

  1. Velocity and doubling time are not the true kinetics analysis. PSA data must be screened for logarithmic growth to be a meaningful kinetics analysis. I have curves taken from a Johns Hopkins paper to demonstrate. I will send these if requested.

  2. Dear Mr. Speiss:

    I am not aware that there is any “true” way to measure PSA kinetics. There are a variety of ways to do this, and each has its potential uses. The Johns Hopkins analysis (like others) illustrates the distinctions between these different kinetic analyses. However, from a clinical point of view, the consistency of a specific methodology and its clinical application is what is important under specific circumstances. The “true” problem is that different groups have used different methods to measure PSA kinetics over time, so it is almost impossible to compare data from paper to paper. It is certainly the case that many academic groups are now closer to using a logarithmic-based definition of PSA velocity, which is helpful for comparative assessment of data published by these groups, but this definition of PSA velocity actually makes life more difficult for the non-academic, practicing clinician.

    As an additional note, since the paper commented on above came from the group at Johns Hopkins that makes the distinction between types of PSA kinetics you refer to, I assume that their use of PSA velocity and PSA doubling time in this paper was very deliberate and meets their criteria for the use of these forms of PSA kinetics.

  3. A true kinetics study would analyze the growth nature not velocity or doubling time. The most fundamental growth law of physics states that all basic growth is exponential, cancer no exception. To the extent that PSA indicates cancer, PSA growth will also be exponential. Check numerous PSA growth histories and you’ll find this to be, in a large proportion, true. Checking PSA histories for exponential growth is simple. Simply plot growth expansions on a semi-log graph (two decade resolution). An exponential expansion is a straight line where the slope is the growth rate.

  4. Dear Mr. Speiss:

    In the world of theoretical biology you are correct (assuming that all other factors are equal). No one would argue with this. The world of practical medicine is rather more complicated, however. The problem is that not even close to all patients’ PSA levels meet one standard set of growth criteria.

  5. Analyze any selection of PSA growth histories. Enough confirmed cancer patients experience PSA exponential growth to make a case for using exponential growth as one means of predicting men with prostate cancer. The advantage of plotting PSA on a semi-log graph is that exponential PSA growth appears at a very low PSA level thus exponential growth may provide the earliest possible cancer alert. I challenge you in that a large majority of cancerous PSA growth will follow the basic exponential growth law of physics.

  6. Mr. Speiss:

    There is no point in “challenging” us about this. Please feel able to “challenge” the specialists in PSA kinetics and the prediction of prostate cancer risk like Prof. Michael Kattan at the Cleveland Clinic or Andrew Vickers at Memorial Sloan-Kettering Cancer Center. They have spent years studying these issues.

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