Johns Hopkins: ultrasensitive PSA after surgery predicts biochemical relapse

We’ve looked at several retrospective studies this year that found that early ultrasensitive PSA (uPSA) results following surgery can reliably predict eventual biochemical relapse. Johns Hopkins examined its own database and found the same thing.The study by Sokoll et al. looked at the records of 754 men treated with surgery at Johns Hopkins between 1993 and 2008 whose first post-surgery PSA, taken at about 3 months, was “undetectable” (< 0.1 ng/ml). They reanalyzed the stored serum samples using an ultrasensitive PSA assay that could detect values of 0.01 ng/ml or higher. Each man was tracked until biochemical recurrence (BCR) — defined as  a PSA level ≥ 0.2 ng/ml — or for at least 5 years if there was no biochemical recurrence (median of 11 years).

  • Among men whose first uPSA was ≥ 0.01 ng/ml, about half eventually had BCR.
    • 57 percent were BCR-free at 5 years; 49 percent at 11 years.
    • Mean BCR-free survival: 10 years
  • Among men whose first uPSA was < 0.01 ng/ml, 87 percent remained BCR-free.
    • 92 percent were BCR-free at 5 years; 86 percent at 11 years.
    • Mean BCR-free survival: 15 years
  • Among men whose first uPSA was ≥ 0.03 ng/ml, 77 percent eventually had BCR.
    • 27 percent were BCR-free at 5 years; 22 percent at 11 years.
    • Mean BCR-free survival: 5.5 years
  • Among men whose first uPSA was < 0.03 ng/ml, 85 percent remained BCR-free.
    • 91 percent were BCR-free at 5 years; 84 percent at 11 years.
    • Mean BCR-free survival: 15 years

Other predictors of recurrence were the usual suspects: initial PSA, pathological stage, Gleason scores, and the presence of positive margins.

They additionally tracked a cohort of 44 men who’d had a cystoprostatectomy for bladder cancer in order to determine whether extraprostatic sources of PSA might interfere with the uPSA test’s sensitivity to detect recurrent prostate cancer. All but two had uPSA levels < 0.01 ng/ml, and those two had low values (0.01 and 0.02 ng/ml).

So we see that a uPSA cutoff of 0.01 ng/ml on a first test is no better than a coin toss at predicting eventual BCR, and would lead to a great deal of over-treatment. On the other hand, a uPSA cutoff of 0.03 ng/ml correctly predicted eventual BCR 77 percent of the time. It missed about 15 percent of the men who would eventually recur, but was no worse than the lower cutoff in this regard. Clearly, a uPSA cutoff of 0.03 ng/ml is prognostic of BCR and a lower cutoff is not. The authors seem to miss this point in their conclusion.

Their analysis seems congruent with the other studies we’ve seen lately. Koulikov et al. found that the 0.03 ng/ml cutoff was prognostic, but only when uPSA was increasing steadily. Kang et al. found that a cutoff of 0.03 ng/ml at any time after surgery optimized BCR predictions with a median 18-month lead-time advantage among men diagnosed with adverse pathology (pT3 and/or positive margins). And in a separate analysis among men with more favorable pathology (pT2, irrespective of margin status), Kang et al. found that a cutoff of 0.03 ng/ml on a first uPSA was predictive of later BCR (at a median of 33 months).

While we await more definitive results from randomized clinical trials, there seems to be an emerging consensus that 0.03 ng/ml is the optimal uPSA cutoff. Using a lower cutoff for early salvage or adjuvant RT will lead to over-treatment, and there seems to be no risk attached to waiting for it. Provisionally, I believe it should be viewed as a surrogate for the traditional definition of BCR following surgery.

Editorial note: This commentary was written for The “”New” Prostate Cancer InfoLink by Allen Edel.

5 Responses

  1. Ultrasensitive PSA Testing for Recurrence

    Hi Allen, thanks for posting this new study. I especially like the fairly large size of the study.

    These results are also quite similar to the results presented by Dr. Steven Strum, MD at the National Conference on Prostate Cancer way back in 2000. The workbook handed out to attendees actually included 10 abstracts of published studies that documented an important role for ultrasensitive testing, including monitoring for recurrence. One that I recalled without even looking was by Witherspoon and Lapeyrolerie. That particular study also added time — number of months without exceeding certain values as well as the initial very low values. I’m mentioning these studies mainly to make the point that ultrasensitive testing has been available for a very long time now, yet so many surgery patients and their doctors ignore it! (Ultrasensitive testing has been a vital part of management of my own case when I was on intermittent triple androgen deprivation therapy, and that is typical for those of us on that therapy.)

    However, there is a critical second part to such information about recurrence: the seriousness of the recurrence, which ranges from many cases that are mild enough to just monitor, to cases that need early follow-up treatment of some kind. Johns Hopkins has been a leader in such recurrence research, with an early effort led by Dr. Freedland (then at Johns Hopkins, later at Duke) indicating that three factors were important: the PSA doubling time (can be based on ultrasensitive testing though that was not done in the Freedland study), whether the recurrence threshold of 0.2 was hit within or later than 3 years (which also can be predicted using ultrasensitive testing — also not done in the study), and whether the pathological Gleason score was less than 8 versus 8 to 10. Later research has indicated that the two velocity-related criteria are fairly redundant with only one being needed.

    I could not access the full study that you cite, and I’m very curious whether this critical second part of the recurrence information was addressed in the study.

  2. All of the studies linked herein only address the issue of the earliest uPSA that reliably predicts recurrence. How long it takes for a recurrence to cause detectable metastases and prostate cancer mortality, and whether it will do so in the natural lifetime of the patient has been addressed in several other studies. A recent one from UCSF that you can read about here found a significant survival advantage to treatment before conventional PSA reached 1.0 ng/ml. However, none of these were prospective randomized clinical trials.

    You have to be very careful in interpreting all such studies because of the very long natural history of prostate cancer progression, which may be lengthened by the cytoreductive effect of surgery. I would not leap to the unwarranted conclusion that any recurrence is “mild enough to just monitor.” An otherwise healthy 60-year-old man with 20 or more years of life expectancy may derive great benefit from earlier treatment, and should be discussing the possibility with his radiation oncologist.

  3. Allen,

    Thank you very much for this article! I can’t seem to find the original study anywhere. Your article seems to indicate that this study’s findings were that an initial upsa following radical prostatectomy of <.03 has almost the same prognostic value as an initial upsa of <.01. The other abstracts on this study that I've been able to find, however, indicate that the study shows that an upsa of <0.03 only applies to initial upsa following cystoprostatectomy. Since I cannot find the original study, could you let me know whether it shows that an initial upsa value of .01 after radical prostatectomy is essentially the same as <.01? I'm 38 yoa and had my prostatectomy this past December (3+4=7, 10% involvement all on right side, clear margins but within 1 mm of tumor, no roe etc…, and psa of 3.85). My initial upsa after the procedure was .01. I can't thank you enough for your work!

  4. What I wrote in the above is correct and is based on my review of the full text of the study. A PSA of 0.01 is not the same as <0.01, but 0.01 was not a good predictor of biochemical recurrence, whereas 0.03 was.

  5. Somewhat Misleading Grouping of All PSAs of 0.01 and Higher Obscures Encouragement From Some Low PSAs Likely After Surgery

    Hi Tooyoungforthis,

    From long personal experience with ultrasensitive PSA testing and attention to the technology, it’s clearly better to have a score of <0.01 after surgery, but it is very good to have a score below 0.03, as you do with your score of 0.01. I suggest you do a search for some of the early research on ultrasensitive PSA testing. I just tried that with the search string " ultrasensitive prostate specific antigen AND prostate cancer " and got 140 hits, including 132 after I filtered out (the PubMed filter choice) papers without abstracts.

    A problem with this Johns Hopkins research (an institution that was not at all an early adopter of ultrasensitive testing) is that it lumps all PSA values of 0.01 or greater into a single group and discusses over treatment if such a cut-off value is used. In other words, that group for 0.01 and higher includes values of 0.03, 0.04, 0.05, … 0.08, 1.0 etc. – you get the idea, and those higher values have much higher odds of recurrence that are averaged in, artificially making the odds at a value of 0.01 seem bad, when they are in fact excellent.

    What some other research indicates is that the prognosis of recurrence for men with early PSAs after surgery of 0.01 and 0.02 also have odds of recurrence that are quite low, well below the group figure for all values down to 0.01 that this research reports. Even 0.03 has pretty encouraging results in some studies. At 0.04, and more so at 0.05, the likelihood of recurrence is significantly higher, PROVIDED the PSA is rising significantly as contrasted with being stable or shortly stabilizing at a low level, especially below 0.1. If the PSA is not rising, there is a good likelihood that most or all of the PSA is from a little healthy tissue that was not removed at surgery. For example, a PSA of 0.08, or a PSA that rose to that level and stabilized, would probably not eventually result in a recurrence.

    A key consideration in addition to the level of the PSA is PSA velocity, which is another way of looking at the stability question.

    I hope this helps.

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