Projecting risk for metastasis after radical prostatectomy

A new paper in Clinical Genitourinary Cancer has provided us with some more detailed information about risk for metastasis in men with recurrent prostate cancer after first-line surgery.

We have known for some time that, among men whose PSA rises back up to to > 0.2 ng/ml or higher (biochemically recurrent prostate cancer) after first-line surgery and who have not had either salvage radiation therapy or androgen deprivation therapy (ADT) or a combination of the two, a relatively rapid PSA doubling time of < 12 months presents a significant risk for metastatic disease.

The new paper just published by Markowski et al. has used data from just under 31,000 patients, all of whom had first-line surgery for apparently localized prostate cancer at either Johns Hopkins Medical Center in Baltimore or whose data was compiled from military personnel at the Center for Prostate Disease Research (CPDR) at the Uniformed Services University of the Health Sciences.

Among the 30,936 patients in these two databases, there were 656 men with biochemically recurrent disease (i.e., a PSA level of 0.2 ng/ml or higher) and a PSA doubling time of < 12 months, who received no adjuvant/salvage ADT and/or radiation therapy, and who were prospectively followed until radiologic evidence of metastasis became apparent.

Among these 656 men

  • Metastasis was observed in 250/656 patients (38.1 percent).
  • Average (median) follow-up for those 250 patients was 5 years.
  • Risk of metastasis increased for PSA doubling times of 6.01 to 7.50, 4.51 to 6.0, 3.01 to 4.50, and ≤ 3.0 months, after adjusting for Gleason score.
  • A PSA value ≥ 0.5 ng/ml significantly and independently increased risk of metastasis in patients with a PSA doubling time of < 12 months (hazard ratio, 2.79; P = 0.001).

The authors were able to conclude that, in this group of 656 men, three different factors were each independent predictors of risk for metastatic disease:

  • A PSA doubling time of ≤ 7.5 months
  • A PSA level of ≥ 0.5 ng/m
  • The patient’s pathological Gleason score at time of surgery

These data should not come as any great surprise to most urologists or well-informed patients, but it is helpful to have these types of general belief confirmed by analysis of data from such large databases.

14 Responses

  1. IMO this article is a continuing example of the US delaying acknowledgement that serious disease is being ignored and that the US is behind Europe in prostate cancer diagnosis. Gleason 4 and 5 spreads — some fast some slow — but spread it does. Post RP and RT to the prostate bed, with my usPSA back up to 0.1, I was so disillusioned with prostate cancer management in US I went to the Netherlands for combined nano-particle MRI with gallium-68 PSMA PET/CT. Suspicious sites were identified in my lymph nodes. That led to extended pelvic removal surgery in Belgium — cancer had reached my para-aortics. Following that surgery, 18 months, my PSA remains < 0.01. PSA above 0.1 post-RP is cancer. If either Gleason 4 or 5 were present it is going to spread. Imaging is the key — the US needs to catch up.

  2. Dear Keith:

    As I have mentioned previously on this web site, the problem is a regulatory/legal one.

    In the US, we have long required proof that the imaging agents used in tests like the gallium-68 PSMA PET/CT scan are actually safe as well as effective (just like any other drug being given to patients). In Europe and other countries, there is no requirement for such proof, and so new imaging techniques like this can come into widespread use much more quickly.

    One can see this is as a good thing or a bad thing. What would you be saying if next week it was discovered that 40% of all men given a gallium-68 PSMA PET/CT scan were found to have early onset Parkinson’s disease (just as an example)? On the other hand, as you point out, it does mean that tests like this take longer to come to the market in the USA. At present there is a legal requirement for this type of testing in the USA, and so the “problem” isn’t going to go away unless the law is changed. It is not that the USA is “behind”. It is a very straightforward legal issue.

  3. Keith and Sitemaster,

    Sitemaster, thank you for posting this article and for your comment. I see FDA review as a good thing, though the associated delay is often frustrating.

    The classic example where the FDA’s refusal to accept a drug already accepted in Europe, the UK, Canada, and other countries, prior to further testing to confirm testing, is thalidomide, the drug which led to an epidemic of severely deformed babies in countries where the drug was available, but not in the US. (It is now available in the US for certain uses under extremely strict controls. I have been on it myself for prostate cancer, which is an unusual use that I am not encouraging without careful and informed consideration.)

    A much less known example is an imaging agent known as ferraheme that was used in investigational USPIO (ultra-small superparamagnetic iron oxide) scanning for prostate cancer. While it did a fine job of imaging, in a very few patients it resulted in life-threatening or even fatal allergic reactions; for that reason, it is not approved in the US. (I had that scan as part of the investigation and did fine.)

    I hope the new scans prove safe and are approved for US use, but it is wise for the FDA to take care whether approval should be granted.

  4. Sitemaster and Jim Waldenfels it astounds me that you say this as a straight forward legal issue. It is far more complex than this. Politics, money, power, control. Post-RP a PSA above 0.01 is most likely cancer — yet this article and other sources suggest otherwise. How many men are dying because the US is behind? Had I followed the recommendations of the many US docs I consulted with, and we are talking top names, I would have been on chemo, a non-curative modality for prostate cancer. The thalidomide issue is an outdated, poor example.The reference to USPIO is also a false flag. This is the agent I went to Netherlands for — the very agent that found my cancer. The documentation on the allergic reactions is incomplete — I studied the data. I have lived in Europe, my partner is a retired UK cancer specialist, several friends are radiologists. What you say about Europe and “no requirement” for such proof is a false statement.

  5. Unfortunate my reply was deleted. Our own FDA has not do so well with opioids, has it?

  6. Dear Keith:

    You are fully entitled to your opinions … but they are based on factual inaccuracies. Apparently you don’t have a complete and sophisticated understanding of how the regulatory authorities in the USA and Europe work when it comes to approvals for the use of medical imaging agents. The existence of “clinical evidence” is NOT the same as regulatory approval and/or the need for such regulatory approval.

    You are also clearly sufficiently affluent to be able to do whatever you feel like doing when it comes to your own management and treatment. From some 30 years experience, I am extremely well aware that this can profoundly affect how patients think and behave. This does not, however, necessarily imply that they are always making good decisions.

    As I have noted numerous times before on this web site, requisite clinical trials are currently being carried out in the US that will near to certainly lead to the approval of imaging agents such as gallium-68 PSMA in combination with PET/CT scans by the US FDA. This does not (of course) mean that most insurance companies in the US will necessarily pay the costs associated with such scans (which will be much higher in the US than they are elsewhere around the world). THAT is a political, financial, power, and control issue that affects ACCESS. The only thing stopping these imaging agents being AVAILABLE in the US is a regulatory/legal one.

  7. Dear Keith:

    No one has “deleted” your comment. Each comment is individually approved.

  8. Keith,

    I stand confidently by my previous comment and with Sitemaster. Your rebuttal to my points completely missed the mark.

    You also stated something as fact that I understand to be untrue: “Politics, money, power, control. Post-RP a PSA above 0.01 is most likely cancer.” My understanding is that, while an even lower PSA is more desirable, 0.01 and stable is quite encouraging, with 0.02 also being fairly encouraging. The research I have looked at indicates that a rising ultrasensitive PSA is concerning, and a PSA of 0.03 post-prostatectomy is equivocal. A PSA of 0.04 is concerning, tipping toward recurrence, and 0.05 is a fairly strong indicator of pending recurrence.

    Therefore, on what evidence are you basing your general statement that “Post-RP a PSA above 0.01 is most likely cancer”? By evidence I mean published medical research. Please provide the citations so I can check PubMed.

    Part of your concern may rest on terminology. I’m thinking the authors of the study are not counting recurrence in the prostate bed or nearby lymph nodes as metastasis, though the latter could be defined as metastasis. As you can tell from my comment, I am absolutely convinced that ultrasenstive PSAs are critical to good management of men who have had treatment, and waiting until the PSA gets to the levels mentioned in this article, if that is being advocated, strikes me as unwise. I’m thinking the authors are not advocating that but are using the PSA levels mentioned as signs of metastasis. (By the way, my own PSA, which was in a foggy zone at < 0.05 for several years after radiation in 2013, has remained at < 0.01 for the past half-year — remarkably low after radiation and ADT for someone who still has an intact, but well-radiated prostate.)

  9. Was it not approved — or perhaps i erred?

  10. Keith:

    There is no sign of any other comment that you left that was deleted. Perchance you left a comment somewhere else, or you failed to post the comment appropriately.

  11. Jim and Sitemaster,

    We have many topics within this thread. I will strive to be concise in this response.

    First, addressing a few points stated above, the reference to thalidomide is very outdated. Our own FDAs opioid crisis is a present-day example. As to no testing in Europe, this is a false statement. For example, are you familiar with NICE in the UK?

    Taking this discussion back to the title of the article, Projecting risk for metastasis after RP, restating my experience, had I followed the guidelines in this article, or various papers within PebMed portal, today I would most likely be in an incurable metastatic stage.

    In my own experience, I had cancer removed from my paraaortic lymph nodes at usPSA of 0.1; which is below several currently accepted PSA recurrence thresholds, including ones that can be found in PubMed. So, Jim, there are no papers in PubMed regarding my statement post-RP a PSA above 0.01 is most likely cancer.

    Here is my question – if a PSA threshold value of X is the definitive definition of recurrence, what is happening before that value? Is cancer not present? Is something other than cancer producing the PSA results? Then suddenly when the threshold is reached cancer recurrence begins?

    Jim to your point, “a PSA of 0.03 post-prostatectomy is equivocal. A PSA of 0.04 is concerning, tipping toward recurrence, and 0.05 is a fairly strong indicator of pending recurrence”, (restating my question) is a PSA of 0.01 or 0.02 not cancer?

    I present this statement from the AUA 2019 Prostate Cancer Highlights for your consideration regarding PSARisings article and the current accepted PSA thresholds:

    “One of the other things that I think is going to really shake things up is the new (sic) PSMA-based PET scans, which is an expensive (too expensive to save men’s lives?) imaging modality. A number of studies at this meeting looked at this. Five years ago, we would just make assumptions about whether patients had locally recurrent disease. PSMA-based PET makes it possible to detect metastatic disease far more clearly. Probably a lot more people probably had metastatic disease than what we knew about with the previous imaging capabilities. That’s going to rewrite a lot of the studies, too.”

  12. This is a very interesting commentary on the subject of undetectable PSA levels.

  13. Dear Murray:

    I am sorry, but you have now confirmed that you don’t understand the difference between what regulatory authorities like the FDA and EMEA do and the availability of data generated by organizations like NICE in England (and IWIG in Germany). For example, NICE doesn’t make decisions about whether drugs or tests or treatments are available in England. They only make decisions about whether the National Health Service wil cover the costs. NICE conducts analyses to see if particular tests, drugs, and procedures meet highly defined cost-efficacy criteria, not whether they are safe and effective (although that may change if the UK crashes out of the European Union and its drug approval process is no longer conducted in conjunction with EMEA). Incidentally, I just checked, and there is no reference to coverage of gallium-68 PSMA PET/CT scans on the NICE web site as yet, so I don’t think you’d be able to get this test in the UK outside of a clinical trial or unless you paid for it yourself!

    Second, no one is suggesting that gallium-68 PET/CT scans don’t have great potential value. All that we are saying is that the process for approval of this technology is different in different parts of the world. That is a political issue, not a regulatory one.

    Third, the opioid crises in the USA had very little to do with the FDA (much as everyone would like to blame them for it) and actually had far more to do with the ways in which drug companies were promoting these products and unscrupulous physicians were over-prescribing them. The FDA has very limited responsibilities when it comes to the actual prescription of drugs at all once a drugs is approved for a specific indication.

    Fourth, you may think that the thalidomide example is outdated, but in the opinions of a lot of specialists in the field of medical regulatory science, this actually remains the seminal example of why it is important for commercial companies to have to prove that their products are both effective and safe before they are allowed onto the market for prescription by physicians.

  14. Dear Murray:

    This is all very well (and mostly well known for years). PSA doubling times (and/or PSA velocities) are far better at indicating risk for PSA progression than any single PSA levels. However, the accuracy of PSA doubling times in men with PSA levels lower than 0.1 ng/ml has been well understood to be very difficult to estimate with accuracy for the best part of 20 years … and yes, I am extremely familiar with the work of both the late Tom Stamey and the alive and well Alan Partin, but of whom I knew or know personally.

    We can now measure PSA levels in blood samples down to femtogram per milliliter levels in the laboratory, but that doesn’t mean that this information can (or should) necessarily change the way an individual patient is treated.

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