Early detection of evident prostate cancer metastasis: perhaps not early enough?

It has long been a tenet of prostate cancer therapy (whether correct or not) that the appearance of evident metastasis (M1 disease) in men with supposedly progressive, micrometastatic (M0) disease is a key event in the management of patients because of the association between evident metastasis and the potential for onset of symptomatic bone disease.

However, a paper by Yu et al. (just published in the Journal of Urology) has shown clearly that a high percentage of patients thought by their doctors to have clinical stage M0 disease are actually already stage M1, which raises the question of whether men with stage M0 disease are sufficiently frequently monitored for their risk of evident metastatic (stage M1) disease.

The paper by Yu et al. is based on an analysis of data from the ENTHUSE M0 trial, which was a large, randomized, Phase III clinical trial designed to compare treatment with the endothelin A receptor antagonist zibotentan to treatment with a placebo in patients with non-metastatic, castration-resistant prostate cancer (nmCRPC). Although this study showed that zibotentan was not effective in the treatment of nmCRPC, it has proven possible to use data from this trial to explore other issues.

In the current study, Yu et al. show how an unexpectedly high number of patients thought to have M0 disease actually did not when they were given bone scans to confirm their eligibility for enrollment into the trial, and also discuss whether this screening failure rate can be used to promote better classification of patients thought to have nonmetastatic castration resistant prostate cancer and inform the design of future clinical trials of men with nmCRPC.

In examining the relevant data, the authors assessed the number of patients enrolled in and subsequently excluded from study and then analyzed these data by geographic region and by the specialty of the investigating clinician (oncology or urology) who enrolled the study patients. Here are their core findings:

  • 2,577 patients thought to be M0 by the referring physicians were initially enrolled at 350 hospital-based centers in 39 countries.
  • 1,155/2,577 patients (45 percent) were not eligible  for the trial after screening.
  • The most common reason for screening failure was the detection of metastatic disease (M1 disease) by bone scan in 32 percent of all screened patients and in 71 percent of those in whom screening failed.
  • The leading reasons for failed screening did not differ between investigator specialties overall or by geographic region.

The authors conclude that, “The high frequency of asymptomatic metastasis in men thought to have [nmCRPC] highlights the importance of periodic staging assessments for the condition.”

They go on to point out that the optimal forms of treatmenet for men with metastatic and non-metastatic prostate cancer may differ, and that unless physicians carry out regular testing to assess the metastatic status of men with progressive disease while on hormonal therapy, they may miss a window of opportunity to modify treatment appropriately.

It should be noted that we have no definitive information about whether the visible presence or absence of metastasis is actually important. Some physicians would argue that is probably is not. On the other hand, one can also argue that by using new techniques such as PET/CT scanning one may be able to demonstrate the presence of clinically evident metastasis much earlier than is possible with bone scans (thereby expanding the number of men known to mave nmCRPC at a point in time). Whether this could or should lead to modifications in treatment for men previously being treated with standard forms of hormone therapy is not yet clear.

It could also be argued that men with a rising PSA while on hormonal therapy for progressive disease after first and/or second-line hormone therapy are inevitably metastatic, whether one can see the metastases or not, and that maybe we need to modify the subdivisions of metastatic disease stage into the following categories:

  • Mo: No evidence of metastasis by any currently available test
  • M1: Categorical evidence of metastasis to any site by tests other than a bone or a CT scan
  • M2a: Categorical evidence of metastasis to any site by CT scan
  • M2b: Categorical evidence of metastasis to any site by bone scan
  • M3: Categorical evidence of metastasis to multiple sites by bone scan and CT scan

There may, of course, be better ways to reconsider the staging of metastatic disease, but it does seem as though some type of modification may be necessary and appropriate.

8 Responses

  1. Mike, it seems that the link to the ENTHUSE M0 trial is not working.

  2. To your knowledge (and I ask you this because I know you have a tremendous amount of knowledge), are you referring to a PET/CT, fereheme MRI, or something else to determine M1 disease? If so, that would presume that those tests are more sensitive than CT and bone scans for first detecting evident disease. You also must have concluded that a CT is more sensitive than a bone scan (to distinguish M2 and M3 disease). Is it your opinion then, that bone and CT scans are inadequate to detect the initial onset of evident metastatic disease in a rising PSA only context (whether hormone refractory or otherwise), and other tests, such as the PET/CT, fereheme MRI (or something else?) should be utilized? Thanks.

  3. Forgive me my bluntness, but this seems to me a totally wrong-headed perpetuation of a poor idea. It seems self-evident that anything based on a current moment in technology is a very poor choice for a lasting classification scheme.

    Think ahead to the year 2025, and imagine researchers (or, worse yet, patients) trying to make sense of medical literature on prostate cancer stretching from 1992 to 2022. The meaning of the word “metastatic”, or the term “M0”, would change from decade to decade, depending on whichever technology could or couldn’t detect metastasis at the time of writing.

    A maddeningly similar situation exists today with regard to the phrase “undetectable PSA”. Tens of thousands of men now incorrectly believe that they have no detectable levels of PSA. Why? Because the term “undetectable” is used instead of the more accurate and descriptive “PSA < 0.1". A fair percentage of these men will at some point freak out when they get a PSA reading of "0.08", because they will reasonably (but incorrectly) believe that it represents a rise from "undetectable". The only reason for this ridiculous situation is that the term "undetectable" became fossilized to mean "undetectable using the best assays of 1995". Undetectable-in-1995 does not mean undetectable-in-2012, but the label "undetectable" continues to be applied as if no change had occurred.

    In place of the context-dependent "M0", "M1", etc., a far better approach would be quantitative and independent of technology extant in 2012 (or 2022, or 1992). For example:
    • "M<0.5": Areas of metastasis, if any, all <0.5 cm. (By 2012 technology, this is "undetectable", and might thus well mean nonmetastasis.)
    • "M<1.5": Areas of metastasis, if any, all <1.5 cm. (By 1995 techmology, this was "undetectable", and might thus well have meant nonmetastasis.)
    • "M=2.5": One proven metastasis of size ~2.5 cm.
    • "M++:3.5,2.5,…": Proven metastases, the largest of size ~3.5 cm.

    Naturally, any such label should be supplemented by the name of the test when reporting at length. For example:
    • "M=2.5 per CT scan on [date2]; M<4 per bone scan on [date1]".

    To see the short-sightedness of tying an entire classification schema to a particular imaging technology (such as the proposed M2x categories), one has only to realize how such schemes will inevitably be made obsolete or untenable within a few decades by the invention of Lepton Imaging in 2022, the Higgsatonium Scan in 2032, and the Quantum Disentanglement Resolver in 2042.

    No, I have no crystal ball, but that's my point: We can't possibly know now the details of future advances, and it is struthionine to behave as if current technology will never be surpassed.

  4. Richard:

    Please understand that I am not “concluding” anything. There is limited published data on the use of Ferraheme. There is more data on PET/CT scanning, and it is clear that under a number of circumstances PET/CT can detect mets that are not visible on bone and standard CT scans … but there can also be false positives and false negatives. (The choline-based PET/CT scans appear to have greater potential than other types.)

    The issue is fundamentally (a) whether newer scanning techniques can accurately and reliably detect mets earlier than a bone scan or a CT scan and (b) whether detection of such mets actually makes any change to patterms of treatment that is of benefit to patients.

  5. Paul:

    I have no problem with your “bluntness.” However, the staging and grading systems for all cancers change on a regular basis. It is an inevitability of expanding knowledge. This is why we now use the TNM staging system as opposed to the earlier ABCD staging system in prostate cancer. There are significant “shifts” and modifications in the staging systems about every 7 to 10 years. I know of no way to establish a clinically useful staging system that would be valid for 30 to 40 years at a time.

  6. Wolfram:

    The link is fixed (although I have no idea what the problem was).

  7. Richard,

    I have had an 18F PET/CT scan. It is more sensitive and it provides for much sharper images than traditional CT and bone scans.

  8. Jerry,

    What were the results of your PET/CT relative to what you think would have been shown if you only had a CT or bone scan (if that’s even possible to answer)? Thanks.


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