Follow-up PSA testing after surgery for low-risk prostate cancer

One of our regular readers has suggested we comment on a recent paper questioning the need for annual, lifelong PSA testing after radical prostatectomy for patients treated for low-risk prostate cancer.

The recent paper by Tollefson et al. offers a retrospective analysis of data on the long-term follow-up of > 2,000 patients treated surgically for low-risk, localized disease between 1994 and 2004 at the Mayo Clinic.

In this study, the authors defined low-risk disease as pathological stage pT2c or less, Gleason score 6 or less, negative lymph nodes, negative surgical margins, and a presurgical PSA level of < 10 ng/ml. Patients who received any form of neoadjuvant or adjuvant therapy were excluded from the analysis. Biochemical failure was defined as a PSA level > 0.4 ng/ml and PSA levels < 0.15 ng/ml were considered to be undetectable.

The results of this study showed the following:

  • According to the abstract, 2,219 patients met the criteria for low-risk disease, but the full text of the paper states that only 93 percent of these patients actually had a biopsy Gleason score of 6 or less, and 14/2,219 (0.6 percent) had a biopsy score of 8 to 10, implying that about 6.4 percent or about 150 had a Gleason score of 7, so why were these patients included in the data set?
  • Median age at surgery was 61 years (range 33 to 84).
  • Approximately half of the patients received their surgery before 2000.
  • Median follow-up was 75 months (range 3 to 161 months).
  • Only 142/2,219 patients (6.4 percent) met the specified criterion for biochemical failure during the course of follow-up.
  • 200/2,219 patients (9.0 percent) has a detectable PSA > 0.15 ng/ml but never had a PSA ≥ 0.4 ng/ml (and therefore never met the study criterion for biochemical failure).
  • 7/2,219 patients (0.3 percent) showed clear signs of clinically significant (systemic) disease progression.
  • 2/2,219 patients (0.1 percent) actually died of prostate cancer.
  • 84/2,193 patients (3.8 percent) with an undetectable PSA at 1 year post-surgery ultimately experienced bichemical failure./li>
  • 59/2,117 patients (2.8 percent) with an undetectable PSA at 2 years post-surgery ultimately experienced biochenical failure.
  • For patients with a PSA level < 0.4 ng/ml at 5 years after surgery, the biochemical failure rates over the next 1, 3, and 5 years were 0.0, 0.7, and 1.3 percent, respectively.
  • For patients who had an undetectable PSA for 1, 3, 5, and 10 years after surgery, biochemical failure rates within the following 12 months were 0.2, 0.4, 0.0, and 0.0 percent, respectively.
  • 2,157/2,219 patients (97.2 percent) never needed or received any form of follow-up treatment for prostate cancer after their initial surgery.

Tollefson et al. conclude that,  in low-risk patients, the risk of biochemical failure is inversely proportional to time for which the PSA is undetectable after radical prostatectomy. They go on to suggest that taking PSA levels every 2 years should be sufficient to identify the majority of low-risk patients who experience biochemical progression.

The “New” Prostate Cancer InfoLink would certainly agree that annual PSA testing is probably unnecessary in the majority of patients who are treated surgically for low-risk disease if their PSA is undetectable after surgery. However, the key question is how long should annual PSA testing be carried out before the patient can be switched to testing every 2 (or perhaps even every 3) years. Based on this paper, it would seem likely that even low-risk patients should all receive at least annual testing for 3 years after surgery.

We are puzzled by some other issues associated with this paper. Most particularly, the generally accepted definition of an undetectable PSA is < 0.1 ng/ml (not < 0.15 ng/ml) and the usually accepted criterion for biochemical failure after surgery is a PSA level > 0.2 ng/ml (not 0.4 ng/ml). One wonders why the authors felt the need to use different criteria, and what impact the use of the “normal” criteria would have had on their results. It should also be noted that biochemical recurrences are well known to occur as long as 25 years after radical prostatectomy as first-line treatment for prostate cancer, so the follow-up data for this analysis is relatively short.

Perhaps the item that stands out most in consideration of these data, however, is the apparently compelling suggestion that many of these patients may never have needed treatment at all. With less than 7 percent of these patients showing any sign of even biochemical progression, and only 0.3 percent demonstrating systemic disease after their first-line treatment, one is forced to wonder what would have happened if this group of patients had all been carefully monitored according to an active surveillance protocol which suggested that treatment would only be appropriate if the patients exhibited a PSA doubling time of less than (say) 18 months.

8 Responses

  1. It seems to me that this is a very extensive, expensive, and meaningless study.

    Sitemaster’s thorough analysis highlights many inconsistencies and apparent faults in the study, but I would like to add a question.

    What is exactly is the purpose of the study? To show that it is sufficient to test for PSA only once every two years instead of every year? Why would anybody spend the time, energy, and money to do carry out such a study?

    The cost of a PSA test is negligible. Since the analyzed subjects have already been diagnosed and treated for prostate cancer, there is no danger of over-diagnosis or over-treatment. So why would anybody want to be tested only once every two or three years?

    Worse, the study does not take into account the existence of ultrasensitive PSA testing that can alert doctors and patients of a potential biochemical failure. While there is no threshold yet for ultrasensitive PSA, one can identify a trend at a much lower PSA value. For example, a patient whose PSA grows from 0.01 (lowest detectable value) to 0.02, 0.06, 0.08 at subsequent 3-month tests may very well consider the possibility of biochemical failure. Such a biochemical failure, when it occurs in low-risk patients (negative margins, no extracapsular invasion) may indicate remote metastasis for which the recommended treatment is ADT and not RT.

  2. Dear Reuven:

    (1) This study most certainly did take account of data from ultrasensitive PSA testing. That is clearly stated in the full paper.

    (2) The total costs of PSA testing are far from negligible when you start to take account of people’s time (as opposed to just the cost of the test).

    (3) The authors offer several reasons for doing this study: there has never previously been a data-based analysis of the need for annual PSA testing post-surgery in low-risk patients; the stress on patients of annual life-long PSA testing is considerable; the cost of annual PSA testing for the several hundred thousand men who have been treated with RP for low-risk disease since the mid-1990s is actually very considerable.

    (4) The comments offered on this study in the text above are just comments. It is not appropriate to characterize these as “inconsistencies and faults.” There may have been good reasons for the authors decisions — even though they are not necessarily apparent.

    (5) No clinical value has ever been shown to result from initiating androgen deprivation in a patient with a PSA of (say) 0.08 ng/ml who is suspected of having micrometastatic disease as compared to waiting until his PSA has reached (say) 0.4 ng/ml. Indeed, there are good reasons to believe that initiating hormone therapy at such low PSA levels may actually accelerate early development of androgen-resistant prostate cancer cells.

  3. (1) Sorry, but I didn’t have the whole article.
    (2) What is the cost saving? In particular if one takes into account the increase in metastasis-free survival. Think about additional productive years.
    (3) What is the additional stress for doing the test yearly instead of every two years? Is there a psychological test showing that? I am no psychologist, but I assume that if the test is considered to be a regular, standard test it will not add much stress.
    (4) There may indeed be good reasons and they are indeed not apparent.
    (5) At least the doctors I talked to think differently. The counter argument is that — although nobody knows — early ADT may starve and kill the metastatic cancer cells. As you correctly say, these are all hypothesis and are not supported by any scientific evidence. However, when you read the full article, you will find that in most cases the authors add caveats that the studies are not statistically valid or that the study — while showing an increase in metastatic free period — does not show any meaningful increase in survivability.

  4. Dear Reuven:

    I think you may be misunderstanding at least a part of this study. Only 7 out of 2,219 patients (or 7 out of 342 patients whose PSA rose to > 0.15 ng/ml at any time after surgery) showed any sign of clinically significant progressive disease over a median follow-up of > 6 years. It’s not as though progressive disease was being “missed” in some way. Therefore, if we assume that — at a minimum — the cost of drawing blood, running the PSA test, and communicating the result to the patient was $50.00, then to do that for 2,000 men each year would be $100,000. We are actually doing that for several hundred thousand men every year, and $50.00 is a almost certainly a significant under-estimate of the real cost. The authors suggest it could easily be hundreds of dollars per test. It all depends exactly how one assesses all of the time of all of the individuals possibly involved (schedulers, nurses, doctors, laboratory personnel, billing staff, you name it).

    While this study is (as the authors note) a retrospective analysis, its results are highly statistically significant, and the survival data is also very clear. Only 2 men died of prostate cancer. So that is also not an issue.

    Finally, all I can tell you from years of helping men to understand their prostate cancer is that for at least a significant percentage of those men (no, I can’t give you a number), the stress of annual PSA testing is actually very high. It really shouldn’t be (on a “logical” basis), but it is. For these men, it appears to re-trigger their initial fear that they have just been diagnosed with a deadly disease — even though prostate cancer (on a statistical basis) is one of the least deadly forms of cancer. So each year, before testing and until they get a negative PSA result (i.e., for several weeks), they go through an extended period of stress. Part of the authors’ argument is that if you know you don’t need to be tested every year (because it really is just a “safety check”) then the stress would be decreased.

  5. I agree with you on the data set and the criteria used to determine undetectable PSA. I wonder how things would have turned out had they excluded the higher biopsy scores and used the accepted definition of undetectable PSA. Maybe we could contact them for some clarification.

  6. No matter what the studies say, or don’t say, it is our/your responsibility to take care of your own health, no matter what the cost is. Go with your own instinct. There are studies being done all the time, and something new will pop up over and over, so do what is best for you!!!

  7. I am a prostate cancer patient that had surgery 2 years ago — the first year my PSA was undetectable; now it is going up again. I can tell you the uncertaintity of whether cancer has somehow survived and is still present is a major concern and there definitely is stress related to getting PSA values done and waiting for the results to find out whethter additional follow-up testing is necessary such as bone scans, etc. But, if it is there, I want to be able to find out so it can be treated — so for me I prefer once a year for the peace of mind

    I have seen enough cancer in my life with others who have not been as lucky as myself and it is not pretty. It is an awful and insidious disease which has a point of no return — often without many symptoms. Stay on top of it if you can is my suggestion.

  8. On April 20, 2012 I had the da Vinci removal procedure. My Gleason score was 6. I am a low-risk candidate. What I don’t understand is what is the big deal is about checking for PSA each year? Have it done as part of your blood screening when you go for your yearly physical. If you then have a number other than 0 you have a chance to catch it early. Make your decision with your doctor, then … Enjoy Life!

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