Accurate identification of positive lymph nodes in men with progressive prostate cancer

One of the hardest things to be able to do, currently, in a man with progressive prostate cancer after first- or second-line therapy, is to determine his risk for lymph node-positive prostate cancer or LNPPC (i.e., one of the earliest  and more common components of metastatic prostate cancer).

In men who have negative bone scans and negative CT scans, this can most accurately be done by carrying out a lymph node biopsy, but it would be a great deal easier if the need for such biopsies could eliminated entirely or if it could be limited to men who clearly and reasonably accurately showed signs of LNPCC on some form of imaging test. There is no imaging test today that has been shown to do this with really high accuracy, although a variety of imaging tests (using [18F]fluoroethylcholine-based PET/CT scans, [11C]choline-based PET scans, Feraheme-based MRIs, and other imaging methods) are able to identify this type of miocrometastasis in some men with early forms of disseminated disease.

The problem is well illustrated by the recent approval of the Mayo Clinic’s Choline-11 for Injection — which came with a clear instruction that confirmation of results of [11C]choline-based PET scans must always be carried out through the use of lymph node biopsy (because of the risk for false positive results) and from a recent article by Tilki et al. (which illustrates a similar risk for false positive results in the use of [18F]fluoroethylcholine-based PET/CT scans).

Tilki et al. set out to assess the accuracy of [18F]fluoroethylcholine-based PET/CT scans in detection of LNPPC in men with rising PSA levels after first-line radical prostatectomy. To do this they compiled data from 56 patients between June 2005 and November 2011. All 56 patients were given an [18F]fluoroethylcholine-based PET/CT scan, demonstrated a positive result on the basis of that scan, and then underwent a bilateral pelvic and/or retroperitoneal lymphadenectomy.

Here is a summary of their results:

  • The patients’ average (median) PSA value at the time of scan analysis was 6.0 ng/ml.
  • In 48/56 patients (85.7 percent) histologic examination confirmed the presence of LNPPC.
  • The average (mean) number of lymph nodes removed per patient was 21.0 ± 18.3.
  • Elements of the overall accuracy of [18F]fluoroethylcholine-based PET/CT scanning were:
    • Sensitivity, 39.7 percent
    • Specificity, 95.8 percent
    • Positive predictive value (PPV), 75.7 percent
    • Negative predictive value (NPV) 83.0 percent
  • Elements of a site-based analysis of accuracy showed:
    • Sensitivity, 68.4 percent
    • Specificity, 73.3 percent
    • PPV, 81.3 percent
    • NPV, 57.9 percent

Since men at their clinic who had negative results after [18F]fluoroethylcholine-based PET/CT scanning did not receive lymphadenectomies, we have no information about the sensitivity, specificity, and NPV of negative results of such scans.

Tilki et al. conclude that while positive results of [18F]fluoroethylcholine-based PET/CT scanning could correctly predict the presence of LNPPC in about 85 percent of their patients with biochemical progression after radical prostatectomy, the test missed a significant percentage of men with metastatic lymph nodes and was not sufficiently accurate for the precise assessment of nodal recurrence. Since we also don’t know what percentage of their patients might really have had LNPPC but negative results on [18F]fluoroethylcholine-based PET/CT scanning, we have no idea of the size of that possible problem.

Ideally, we need an imaging methodology that can either identify micrometastases with high, overall and site-specific sensitivity and a high specificity (e.g., both > 90 percent, which would also imply a high PPV and a low NPV) or with a high sensitivity (> 80 percent) and a very high level of specificity (> 95 percent) that can be carried out at low cost and be confirmed by lymph node biopsy or lymphadenectomy.

5 Responses

  1. Yes, we first need the more accurate test. Then we need to use that test before any treatment plan. Not just as a test done post-radical prostatectomy/treatment. Were the accurate test available, 48 of the 56 would not have been a candidate for the radical prostaectomy. Or at least the treatment plan during the original surgery would have been differrent.

    The second question; is catching micrometastases at the lymph nodes really significant? In other words are the lymph nodes the pathway required to metastasize or just the first location of visibilty? Intuitively it is logical that the lymph nodess, if not required, are at least critical to metastasis. Given that micrometastases are known to be frequently undetectable in the early stages logic may not be correct.

  2. Dear Mike:

    (1) Even if such a test were to become available, it would be entirely inappropriate to give this test to everyone who had a positive biopsy (just as it is inappropriate to give bone scans to every patient diagnosed with prostate cancer). We already know how to make sound and very accurate assessments of the real risk for positive lymph nodes among newly diagnosed men. We wouldn’t want or need to run such a test on everyone.

    (2) The lymph nodes are a common site of early metastasis, but (a) having positive lymph nodes is not an absolute guarantee of further metastasis and (b) having negative lymph nodes is not a guarantee that metastasis hasn’t or won’t occur through other biological pathways. Metastasis is a very complex process, and can occur in a multitude of ways.

  3. Further to Mike’s comment above, here is my personal experience for what it is worth:

    I had an “intermediate risk” initial diagnosis (Gleason 3 + 4, no evidence of extracapsular spread). On the basis of that only four lymph nodes were sampled (all negative), but post-surgical pathology revealed high-risk disease. I then had a Feraheme-type MRI in Holland which showed positive lymph nodes. This was not tested by biopsy, but I nevertheless then had aggressive radiation that included the pelvic nodes (with subsequent life-altering side effects, but cancer control so far 3 years out).

    The study I read that was carried out by the team in Holland, with the MRI confirmed with extensive biopsies, showed very good negative predictive value, but a lot of false positives. I often wonder if such an imaging before surgery would have given the surgeon a list of high-risk lymph nodes to remove during the operation, thus negating the need for such extensive salvage radiation later?

  4. Thank you Richard for your example. Good living to you.


    (1) We are talking about a test that does not exist so complete agreement is highly unlikely. Test for everyone; no. Test for everyone prior to active treatment; yes. That is making the big assumptions that less unnecessary treatment would occur and more targeted necessary treatment would also occur.

    You stated that: “We already know how to make sound and very accurate assessments of the real risk for positive lymph nodes among newly diagnosed men.”

    I am not sure to what methods you refer, but they are not happening in my locale. The method described to me by two different surgeons was: we begin the surgery, pause for a quick lymph nodes check (which you understand may not be accurate anyway), then we will either complete the surgery or close you back up.

    You can do a lot of testing for the cost of pre-op and a surgical suite. I am only talking about the $ cost.

    As you so often point out, it is the uncertainty of prognosis which drives fear and so much unnecessary treatment. To my cost estimator eye, the whole MRI/CT scan approach is simply misguided anyway.

    When do you hold the greatest potential wealth of knowledge, the key to prognosis, in your hand? Not down through the lens of some multi-million dollar machine and its support staff. No, it is the live cancer cells contained in the biopsy. Currently 99% of that potential knowledge is thrown away, the sample killed and the remaining outline of the dead cells used as the basis of all future treatment. Not logical.

    (2) Total agreement and my point exactly.

  5. Dear Mike:

    You have completely lost me. Large numbers of men every year undergo RP with no lymph node biopsy because is is unnecessary. Whether they needed the surgery is, of course, also open to question, but a man with a single, tiny prostate cancer specimen in 1/12 biopsy cores, Gleason 6 disease,and a PSA level < 10 ng/ml who insists on have it removed (which is extremely common), certainly doesn't need a lymph node biopsy or any other test to see if he has positive lymph nodes. The chance is tiny.

    Since I don't know what your clinical characteristics were pre-surgery, I cannot tell you whether what your surgeons told you individually was or was not appropriate, but if you had either intermediate- or high-risk disease, then a lymph node biopsy was appropriate, and if the type of test we are discussing became available, then it would probably be an appropriate test for all such men. However, that still wouldn't justify using such a test on every man with low-risk disease who wanted treatment (as opposed to "needed" treatment).

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