Are two PET radiotracers better than one?

There seem to be clinical trials of new PET radiotracers for the detection of prostate cancer all the time. In addition to the FDA-approved [11C]choline, Na18F, FDG, and fluciclovine PET scans, most of the new PET scans target the PSMA protein on prostate cancer cells. On the horizon, we have seen some encouraging reports on PET radiotracers that target the gastrin-releasing peptide receptor (GRPR) with a peptide called bombesin. GRPR, as the name implies, is ubiquitous in the stomach and intestines, but seems to show up in several different kinds of cancer cells as well.

Zhang et al. reported the results of a very small pilot study using a synthetic molecule that targets two different receptor proteins at the same time (also see this link). One part of the molecule (bombesin or BBN) targets the GRPR protein. The other part, called RGD, targets a protein called αvβ3. αvβ3 is a member of a family of proteins called integrins. These proteins are responsible for maintaining the structural integrity of cells. αvβ3 promotes cell adhesion, cell spreading, and blood supply — qualities vital to metastatic progression.

They used both the single 68Ga-BBN PET/CT and the dual 68Ga-BBN-RGD PET/CT to detect prostate cancer among 13 patients (4 newly diagnosed, 9 recurrent) with biopsy-proven prostate cancer. The dual PET radiotracer found cancer in:

  • The prostates of 3 of the 4 men with newly diagnosed prostate cancer vs. 2 of the 4 men using the BBN-only radiotracer.
  • 14 metastatic lymph nodes vs. 5 metastatic lymph nodes using the BBN-only radiotracer.
  • 20 bone metastases vs. 12 metastatic bone metastases using the BBN-only radiotracer.

There were no toxic reactions.

While encouraging, it is still very early to draw conclusions. There is no confirmation that the extra “metastases” discovered were indeed metastases — they may be false positives. And there are no clues as to which kinds of prostate cancer the dual PET radiotracer is sensitive to, and which kinds are undetectable.

If confirmed by larger studies, it may be possible to not just detect the cancer, but to kill the detectable cancer cells as well with beta-emitters like Lu-177 or alpha-emitters like Ac-225.

Editorial note: This commentary was written by Allen Edel for The “New” Prostate Cancer InfoLink.

4 Responses

  1. In Denmark two university hospitals analysed the possible improvement with PSMA-based PET/CT. I wrote a meta-analysis of this PET/CT last year in European Urology Focus. The real gain is that PSMA PET/CT can be followed by targeted radioligand therapy. Positive results are accumulating and some series have more than 1 year of follow-up.


    Finn von Eyben

  2. Note: The abstract of the article that Dr. von Eyben referred to above can be found if you click here. It will presumably be published some time this year.

  3. Impressions of the 68Ga-Labeled PSMA PET scan reported by Dr. von Eyben

    Imaging is proving such an important tool for patients with challenging cases, and the field is developing rapidly. Thanks Allen, Sitemaster, and Dr. von Eyben for this report and comments. I come to this having benefited greatly from an NaF18 PET/CT and a Feraheme USPIO (no longer available due to safety concerns) prior to radiation in 2013. I’ve been following C11 acetate and choline PET/CT developments fairly closely.

    Here are key points I think I’m seeing in Dr. von Eyben’s study:

    (1) Important advantage in PSA level needed for the scan to work well: The 68Ga-labeled PSMA PET scan works with a lower PSA level than the C11 choline PET/CT. A key sentence from the meta-study states that a “50% detection rate (74 of 147 patients) for restaging PSA of 0.2–0.49 ng/ml,” with the “Patient Summary” section noting in contrast that “choline PET/CT is rarely positive for patients with restaging PSA levels under 1 ng/ml.” Indeed, Dr. Eugene Kwon, a leading exponent of C11 choline PET/CT imaging stated last September that he prefers to have the PSA be between 1.5 and 2.0 before doing a C11 choline PET/CT scan; a subsequent paper reported an “optimal PSA of 1.7 ng/mL or higher” (Sobol 2016). That’s an important difference, as research in recent years has indicated that salvage radiation works better when done earlier, such as when the PSA is 0.1 or 0.2 Dr. Mark Moyad, MD, who moderated Dr. Kwon’s talk at the PCRI/Us Too Conference on Prostate Cancer in September, asked Dr. Kwon about that unfortunate gap between C11 choline capability and the need for early radiation. Dr. Kwon acknowledged that it was “unfortunate,” but felt that a delay to let the tumors grow into the detectable range would not be harmful. If I were again facing the decision when to have radiation, that would make me a bit uneasy.

    (2) Sensitivity and specificity: The meta-study reported: “Patient-based and lesion-based analysis of staging 68Ga-PSMA PET/CT had sensitivity of 61–70% and specificity of 84–97%. The studies did not report any adverse effects due to imaging.” The Sobol paper summarized reported sensitivity and specificity values for choline PET detection of 85% to 100% for sensitivity and 76% to 96% for specificity — considerably better sensitivity for choline PET, though at a higher likely range of PSA values, and comparable or somewhat inferior specificity for choline PET, though close. I’m not sure what to make of these differences, all things considered. I’m sure we would all like to see that sensitivity for 68Ga PSMA a bit higher.

    (3) Important advantage to 68Ga in isotope half-life and availability. The half-life of the isotope is 68 minutes, and it can be manufactured in a normal hospital setting, apparently, in contrast to the 20-minute half-life of C11 and necessity for an expensive cyclotron for manufacture in close proximity to the treatment facility. This means patients would not have to travel to distant sites for the scan — a really important advantage!

    (4) Adverse effects: the article asserts there are no complications from the scan.

    (5) Advantage in track record to C11: Obviously, we have a lot of experience, and a great deal more experience with C11 scanning at this point.

  4. Some follow-up questions for Dr. van Eyben

    Dear Dr von Eyben,

    If you are still tuned in, here are some questions:

    1. Is the sensitivity of 68Ga PSMA PET scanning a function of the PSA value in the important range from 0.49 to 1.5 ng/mL, which is not well covered by the C11 choline PET scan? Does it look like slightly higher PSA values would significantly boost sensitivity?

    2. Does 68Ga PSMA PET scanning show a metabolic signal such that a follow-up scan after treatment would indicate whether a lesion was now dead versus still active?

    3. I’m visualizing 68Ga PSMA PET scanning results in color where the agent is picked up. Is that the case?

    4. C11 choline PET/CT results give nice color displays of uptake of the agent as well as anatomical detail, which, to my layman’s eyes, makes for easy interpretation, at least compared to older scans. (I had the old ProstaScint scan with PSMA as the target back in 2000, and that technology was a challenge for radiologists, with results looking to me like static on a TV screen.)

    Thanks for your work on 68Ga PSMA PET scanning.

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