When is a metastasis really metastatic today?

There is an interesting editorial commentary by Dr. Daniel George that was published just over a week ago on the UroToday web site.

The recently reported data from the PROSPER trial addressed the effects of enzalutamide (Xtandi) as compared to a placebo in the treatment of men with “non-metastatic” castration-resistant prostate cancer (nmCRPC), i.e., men who had had a rising PSA after treatment with standard androgen deprivation therapy (ADT) — for whatever reason — and, in many cases, other earlier forms of treatment. In other words, these were men with a rising PSA while on standard ADT who had no sign of bone metastasis on a traditional bone scan or of soft-tissue metastasis on a traditional CT scan at the time they were enrolled into the trial.

In his editorial, Dr. George notes — with some surprise — that, among these patients in the PROSPER trial, clinical progression (i.e., the earliest signs of metastasis) occurred

  • In bone
    • Among 32 percent of patients treated with enzalutamide
    • Among 50 percent of patients treated with a placebo
  • In soft tissue
    • Among 35 percent of patients treated with enzalutamide
    • Among 58 percent of patients treated with a placebo

But should we really be surprised by these findings?

Standard CT scans and standard bone scans are not particularly sensitive methods for the identification of early metastasis. As Dr. George himself points out, his European colleagues have been telling him that (since the initiation of the PROSPER trial back in 2013)

they routinely perform more sensitive scans for staging (whole body MRI or 68Ga PSMA PET) and would expect positive findings in most patients with PSA levels above 8 ng/ml or doubling times < 5 months.

We aren’t doing this yet here in the US — because of the costs and because such types of imaging aren’t easily accessible for a lot of patients.

Our suspicion is that the very design of the PROSPER trial (and of the SPARTAN trial of apalutamide too) may actually have resulted in the enrollment of a high percentage of men with early but not evident soft tissue disease (as opposed to early but not evident bone disease) who were progressing on standard ADT.

Indeed, if one set out to conduct the SPARTAN or the PROSPER trials today, one would probably have to redefine what we mean by “non-metastatic” disease to mean no signs of non-localized prostate cancer on a 68Ga PSMA PET/CT scan or an Axumin PET/CT scan and a bone scan. And that is a much earlier form of “non-metastatic” CRPC than that of the men enrolled in the PROSPER and the SPARTAN trials.

On the other hand, Dr. George makes an excellent point about the use of the term “non-metastatic” to describe these patients in the first place. These men were certainly “non-metastatic” in the traditional sense: they showed no sign of TxNxM+ disease on a traditional bone scan or CT scan, but they could have had TxN+M0 disease. This raises the interesting question of

  • “What do we mean by ‘metastatic’ and/or ‘non-metastatic’ disease today?”

Perhaps more accurately we should be asking these two other questions:

  • “How much prostate cancer does one need to be able to identify that is not ‘localized’ to the prostate and the immediately surrounding tissues (i.e., the prostate bed, the seminal vesicles, and the pelvic lymph nodes) to define M+ as opposed to M0 disease”?
  • “When does N+ prostate cancer actually become M+ prostate cancer?”

The current TNM staging system is based on two potential sets of findings:

  • Pathological findings, i.e., what a pathologist could find if the prostate and other tissues were removed or sampled by a surgeon at the time of radical prostatectomy and/or what s/he could find in a man who died of some other cause and who had an autopsy carried out
  • Radiological findings, i.e., what a radiologist or nuclear medicine specialist could see  when a patient was given a traditional bone scan or CT scan.

It may be that we need to start questioning whether that is sufficient way to “stage” prostate cancer today. And that would have implications for definitions of things like “node-positive”, “non-metastatic”, and “metastatic”.

In the meantime, however, we agree with Dr. George when he says that the term “non-metastatic” — as used to characterize the types of patients who were enrolled in the SPARTAN and the PROSPER trials — is at least potentially misleading. As he has pointed out previously — and points out again in this editorial:

not all metastases are equal; we shouldn’t treat them the same, either.

And that has implications for how specific prostate cancer patients may need to be treated.

16 Responses

  1. My reading of the editorial is that he was surprised at the location of the metastases and your statement is that he was surprised about the appearance of metastases, rather than location. More information, please.

  2. It appears that, for over 26 years following surgical removal in 1992 followed shortly thereafter by salvage radiation then followed by known recurrence in November 1996, my elevating PSA has been the result of lingering “soft tissue” disease (metastasis?).

    Androgen deprivation since then has run the gamut of most all available ADT medications short of chemotherapy and has obviously held that “soft tissue” activity in check, since the available, usual CT and bone scan imaging has never been able to identify its location. More recently my PSA has been showing slow, low elevation despite even the advanced medications such as abiraterone/Zytiga and enzalutamide/Xtandi, and in discussing with my medical oncologist what his thoughts were as to where this cancer cell activity was still occurring, he felt it must be in bone “somewhere.”

    In my daily reading of medical and scientific data to which I subscribe and available on the internet I came upon the recent availability of the radiotracer/isotope [18F]fluciclovine (a.k.a. Axumin) used with PET/CT imaging at the University of Kansas Medical Center Nuclear Radiology Department. Since that center is only 177 miles north of my residence in Wichita, Kansas, my son drove me there for this imaging procedure. Low-and-behold, this much more sensitive than usual CT/bone imaging — even considered a bit more sensitive than the C-11 imaging procedures — identified that the only activity in my body from the top of my head to the bottom of my pelvis was 1 cm occurring in the area of the anastomosis from the 26-years-ago reattachment of the urethra to the bladder neck following surgical removal of my prostate gland. We will be addressing that issue with targeting using the EDGE radiosurgery procedure.

    It is somewhat disconcerting that for all these years available imaging was not sufficiently sensitive to identify this apparent “soft tissue” area of activity and I had to experience the side effects of continuing androgen deprivation medications. If there is one thing to consider good about all this, it is that I was able to maintain reasonable control and management of my prostate cancer through my personal research and deep study of our insidious disease until research (thank you scientists) finally developed these radiotracers/isotopes and thus provided the sensitivity to identify cancer cell activity in bone or soft tissue.

    We must now get involved in encouraging the availability of these advanced nuclear radiotracers/isotopes for radiotherapy imaging procedures throughout the country rather than only in a few locations.

  3. Dear Tarhoosier:

    You are misunderstanding what I wrote.

    I did not say (or intend to imply) that Dr. George (or I) was surprised by the appearance of the metastases.

    What I said was that there is a perfectly simple explanation for why the number of metastases to soft tissue were as high as they were in this particular trial that was enrolling a very specific subset of patients:

    “the very design of the PROSPER trial (and of the SPARTAN trial of apalutamide too) may actually have resulted in the enrollment of a high percentage of men with early but not evident soft tissue disease (as opposed to early but not evident bone disease) who were progressing on standard ADT.”

  4. Dear Chuck:

    I sincerely wish that, when I first met you however many years ago it has now been, I had been able to tell you that what you needed wasn’t ADT but an [18F]fluciclovine PET/CT scan!


  5. Advancing Technology Made the Difference for Me Too

    In the first half of 2000, while radiation had been offered (after refusal — thank God — to do the surgery I requested for my challenging case), I was confirming that the odds of cure with radiation back then were quite low for my situation, as the radiation oncologist had advised. As it appeared I was having good success with ADT, I decided to try ADT in the hopes that it would control the cancer long enough for technology to improve.

    Over the next decade, radiation became much more effective, especially due to better imaging for targeting and higher doses that could be safely delivered by IMRT. I was able to hold the cancer in check with three rounds of IADT3 while watching the evolving improvements in technology, but still thinking that a shot at a cure was not in the cards for me.

    However, by 2012 I had become optimistic and was ready to see whether I had the distant metastases that had long been suspected, or whether they did not or no longer existed, thereby enabling a curative attempt with radiation. I had a Na18F PET/CT scan done locally to check the bones plus an investigational feraheme USPIO scan (no longer available) done for soft tissue. Both were quite sensitive, and both results were negative, giving me the green light for a shot at a cure with IMRT TomoTherapy in 2013 — supported by 18 more months of ADT3. As of this date my PSA after the radiation has never exceeded the lower limit of the current ultrasensitive PSA test used in my oncologist’s practice, which is < 0.05.

    Of course we now have scans that look even better, and these improvements in imaging mean that far fewer men will need to follow the course that Chuck and I followed for many years. It also means that cure of oligometastatic cancer may be possible for some of us.

  6. Implications for Access to Approved Drugs

    As a patient I’m thinking that the new imaging techniques that can detect earlier and smaller metastases will enable more patients to access some of the new, high-powered drugs much sooner than they could have accessed them before. Most of these recently approved drugs require metastasis as a criterion for eligibility, but now, thanks to superior imagery, that criterion will be much easier to satisfy.

    From a purist standpoint, it is arguable that studies have not demonstrated that these drugs are beneficial in men with the smaller metastatic levels that are picked up by the superior scans, as the approval trials were based on more advanced metastases that could be picked up by the relatively insensitive scans. (Follow-up analysis of the CHAARTED trial has illustrated that such a nicety can make a difference, as men with a heavier metastatic burden benefited from early chemotherapy while those with a lesser metastatic burden did not.) From a patient standpoint, that objection doesn’t bother me at all!

  7. Current scan evidence using bone specific targeting is more valid than the techniques focusing on soft tissue. Thus results will skew based on this variance. I think I have it now.

  8. Ah, Dear Sitemaster, wouldn’t that have been nice back in 2009 when you interviewed me that this radiotracer/isotope would have been available that 9 years ago?

    For what it is worth, here is that interview for anyone interested: and scroll down to “Let’s Talk About Prostate Cancer … with Chuck Maack.”

    Please note that in that interview when I meant to be talking about antiandrogens I mistakenly used the word “Lupron.”

  9. [18F]fluciclovine PET/CT scans just became available in Wichita, KS.

  10. The patients in the PROSPER trial all had a PSA value of 2 ng/ml or greater.

    A 68Ga PSMA PET/CT study by Eiber et al. found metastases in 96.8% of patients with biochemically recurrent prostate cancer who had a PSA value of 2 ng/ml or greater.

    So one can safely assume that the patients in the PROSPER trial did have metastases; these just could not be detected with either a bone scan or a CT scan.


  11. Mark Fritze:

    Since I live in Wichita, and my oncologist apparently was not aware of fluciclovine available in Wichita, where is this imaging available in Wichita?

  12. Dear Maack1:

    Your case is highly illustrative of the potential benefit of the new ultrasensitive imaging techniques, including PSMA-based studies.

    I believe your anastomotic site of detection should not be viewed as a soft tissue recurrence but as an anastomotic recurrence most likely from tissue left behind at the apical urogenital diaphragm at the time of radical prostatectomy 26 years ago.

    Also … Just curious … What was your PSA reading at the time of the 1 cm pickup by Axumin PET scan?

  13. So if one is N0M0 using conventional scans, they don’t need treatment, whereas if they’re metastatic using the newer scans they get treated? Isn’t that kind of like ignorance is bliss?

    Is there evidence that delayed treatment due to “old style” imaging giving false negatives is resulting in reduced overall survival? How can we justify using inefficient technology?

  14. Dear Bob:

    Your first sentence is not what anyone is saying at all.

    The problem is the cost of the equipment and facilities required to do the type of PET/CT scanning that is now possible. Many towns and small cities in America (let alone small rural communities) simply can’t afford this type of technology. And most men with a diagnosis of prostate cancer can’t afford to fly themselves to New York or San Francisco or elsewhere to get such high-technology scans carried out.

    This is not a “medical” issue. It is a political and social issue. We do not provide equal access to care here in the US. If a patient can’t get one of the new scans (for whatever reason) it is utterly impossible for a doctor to treat what he can’t see. If a patient can and does get one of the new scans, then the doctor and his patient can work together to make a reasonable decision about what needs to be done and when.

    Your statement that “old style” images are giving “false negatives” is a misleading one. Tests of any type can only give results commensurate with the quality of the technology of the test itself. Within my own lifetime there were no CT scanners, no MRI scanners, and quite certainly no PET scanners. You got an X-ray or nothing. As technology gets better, we can see things we couldn’t see before. That doesn’t mean that older technology is giving a “false negative” result. It means that what was N0M0 in 1990 (let alone in 1970) may no longer be N0M0 today.

    I have a solution to this problem, but most Americans wouldn’t like it for one reason or another: it is socialized medicine using a “Medicare for all” approach. Do you have a better solution?

    I would also point out that under a “Medicare for all” solution we would almost all see our taxes go up to pay for it. And the very latest advances in care still wouldn’t be available for most people because our ability to develop astonishing, new, and useful technologies has now far outpaced our ability to make them available for everyone who might like to have them at a cost we can afford as soon as they become available at a couple of major research centers.

  15. Sitemaster:

    Fair comment. Money talks, no doubt. And as usual in this day and age, fast-moving technology always leaves some behind at least temporarily. But we desperately need these kind of breakthroughs so eventually all of humanity will eventually benefit.


  16. Due to hip pain and a fast-rising PSA, I recently had a whole body bone scan which was negative. Turns out I had high hamstring tendonitis. I have a 68Ga PSMA PET/CT scan scheduled for October 18 at UCSF. They required my PSA to be > 2.1 since I have had prior RT.


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