FDA approves specialized imaging agent for PET scans in recurrent prostate cancer

The  U.S. Food & Drug Administration (FDA), yesterday, approved an imaging agent known as Choline C11 Injection for “production and use” to detect recurrent prostate cancer in men receiving positron emission tomongraphy or PET scanning.

Although the use of [11C]choline has been carried out for some years at certain specialized centers in the USA and around the world, we believe that this is the first time that the agent has been formally approved by regulatory authorities for use as an imaging agent, and the current approval is limited to a single manufacturing site — at the Mayo Clinic in Rochester, Minnesota. According to the media release issued by the FDA,

Choline C 11 Injection must be produced in a specialized facility and administered to patients shortly after its production. While PET imaging with Choline C 11 Injection has been performed at a few facilities over the past several years, none of these facilities were approved by the FDA to manufacture the agent. The Food and Drug Administration Modernization Act directed the agency to establish appropriate approval procedures and current good manufacturing practice requirements for all PET products marketed and used in the United States. The Mayo Clinic’s PET Radiochemistry Facility is now the first FDA-approved facility to produce Choline C 11 Injection.

The approval is limited to the use of [11C]choline in men with a rising PSA after prior treatment for prostate cancer who are undergoing PET scans in an attempt to detect tumors that are not detectable by conventional scanning methods (e.g., bone scans and CT scans). The FDA is also very clear that [11C]choline-facilitated PET scanning is associated with a significant risk for false positive results, at that all patienst having a positive scan result should also have “confirmatory tissue sampling of abnormalities detected”.

This approval is based on data from four small, independent studies in just 98 patients with elevated blood PSA levels but no sign of recurrent prostate cancer on conventional imaging. All 98 patients underwent tissue sampling of the abnormalities detected on their PET scans. The studies showed that

  • At least half the patients who had abnormalities detected on PET scans also had recurrent prostate cancer confirmed by tissue sampling of the abnormal areas.
  • False positive PET scans results were observed in between 15 and 47 percent of the patients (depending on the study).
  • The only adverse effect reported in these studies was a mild and uncommon skin reaction at the injection site.

What is not yet clear is the effect that this approval may have on the use of [11C]choline-facilitated PET scanning at other centers in the USA. [11C]Choline must be used within a relatively brief time period after its manufacture, and so it is not evident that the Mayo Clinic will be able to provide product for use at other PET scanning centers. On the other hand, those other centers may now only need to receive approval of their manufacturing facilities since the FDA has approved the actual product for clinical use. As of 7:30 a.m. this morning, there has been no statement from the Mayo Clinic about whether they will be able to manufacture and ship [11C]choline for use at other PET scanning centers.

22 Responses

  1. With a half-life of about 20 minutes, I consider it quite doubtful that manufacturing and shipping is at all practical. Maybe for a hospital 2 blocks away. I wonder what the status of [18F]choline is. That’s more practical, because of the ~ 2 h half-life, i.e. the same as the usual PET agent, FDG. I don’t think it’s as good as [11C]choline though.

  2. Is it known whether it is reimbursible by Medicare or insurance? It would be interesting to know how the “flow” goes when FDA approves, i.e., what sort of trigger there is then for CMMS action. This question (from one of my colleagues) made me aware of my ignorance in this area.

  3. This is excellent news. Dr. Kwon at Mayo has been working for quite some time to get this approved. Since the half-life of [11C]choline is around 30 minutes, shipping is really out of the question. For Mayo, however, this could mean that insurers will now pick up the tab.

    I haven’t read the studies so I’m not sure under what conditions false positives are most likely, but Dr. Kwon prefers to see patients once their PSA rises past 1.5 ng/ml. He also states that it works best for those with quickly rising PSAs, which probably are the ones who need it most anyway. He has had great success using this scan to localize recurrences so that they can be individually treated. We can all hope that oligometastatic presentations of prostate cancer may now have a better chance for a cure.

  4. Herb:

    It may take CMS a few weeks to issue any sort of statement about coverage of this test under Medicare. However, my bet would be that if your colleague was to call CMS he would be advised that it was “usual” for CMS to cover all FDA-approved products that are used strictly according to the product labeling. Private insurance coverage customarily follows along with whatever CMS decides to do, but my bet would be that private insurers will require pre-approval for coverage of any form of PET scan for any patient with prostate cancer.

  5. Do you know whether there are any pending FDA applications for approval for Feraheme or Combidex MRIs?

    Thank you.


  6. Dear Richard:

    Combidex (ferumoxtran-10) is no longer in development, so there will certainly never be any further FDA applications for the use of this product.

    Feraheme (ferumoxytol) — as far as I am aware — is not in development for use as an MRI imaging agent for diagnosis or prognosis of any disorder. Its only approved clinical use is in the treatment of iron deficiency anemia in adult patients with chronic kidney disease.

  7. Feraheme is being advertised by a group in Florida as the “next” or “replacement” Combidex imaging agent in MRI for LN detection. Just curious how it is that this group has seemingly usurped the need for examination by the FDA for the use of feraheme in MRI scanning, and if it is any better than other options in imaging.

  8. Tony:

    Physicians can decide to use approved agents outside the approved labeling for any purpose they feel like. The FDA is not responsible for how specific physicians decide to use approved agents. However, that doesn’t imply for one second that they are “approved” by anyone for such off-label usage. It also does not mean that any insurance provider (or Medicare) will pay for it. Thirdly, it does not imply that there are any good data to support such an off-label use.

    You should appreciate that some disorders have no drugs at all approved for treatment of those conditions — and physicians commonly use drugs off-label to try to manage those conditions as well as they can. This is where the skill and judgment of physicians and the willingness of the patient to take risk is critically important to individual decisions.

    There are, however, a variety of major (and minor) risks for all concerned in the use of drugs (and imaging agents) outside their approved clinical indications. Those risks can be ethical, moral, legal, financial, clinical, and sociological. The “marketing” and “advertising” of Feraheme as an imaging agent for use in combination with MRI is (at least arguably) both illegal and unethical … The FDA is able to do something about that should they decide to do so. However, the clinical use of the agent in that manner is entirely ethical and legal … especially if the users are doing this in the context of some form of clinical trial to accumulate data on the effectiveness and safety of the process … a simple registry trial would be good enough to meet such criteria. I have no idea whether the group of physicians you refer to is actually developing such a registry.

  9. I have a rising PSA post-prostatectomy (performed at H. Lee Moffitt Cancer Center). I’m 52 and had an undetectable PSA at 3 and 6 months, then 0.1 ng/ml at 9 months, undetectable at 1 year, 0.09 ng/ml at 15 months, 0.23 ng/ml at 18 months (after beginning testosterone for anorgasmia at 15 months), 0.2 ng/ml at 21 months, and 0.25 ng/ml at 24 months (after beginning treatment with Arimidex at 18 months).

    I understand the most likely course will be salvage radiation which I oppose in light of the potential side effects. How can I get your test to determine if it is localized?

  10. Dear Louis:

    First, it is important to put the recurrence of your disease into context. You have a PSA doubling time of about a year. (I can’t calculate it with precision because I don’t know exactly what the dates were for your various PSA tests, but you can use the doubling time calculator on the Memorial Sloan-Kettering web site to calculate this exactly if you want to).

    Second, as far as I know, the only way that you can get the [11C]choline-enhanced PET scan test at the present time is to go to the Mayo Clinic in Rochester, Minnesota.

  11. I used the MSK calculator and came up with 9.53 months.

    I spoke with a radiation oncologist at H. Lee Moffitt yesterday and he told me until the tumor(s) would be close to approx. 10 mm in diameter, they still would not show up.

    He estimates that with a PSA of only 0.25 ng/ml, the likelihood is tumor size in 1 mm. Does this sound correct?

    When would it be available at Mayo, Jacksonville?

  12. Louis:

    I am not sufficiently expert to be able to tell you with any degree of accuracy what tumor diameter would be required to identify tumors using the choline C11 PET scan; nor can I tell you with any degree of certainty what size your tumors might be based on your current PSA level. My understanding is that there can be considerable personal variation.

    I also have no idea when (or even if) this type of scan can be made available by the Mayo Clinic in Jacksonville. That would depend on (a) whether they have the facilities to manufacture choline C11 on site and (b) gaining certification of the manufacturing facility. That could be years away.

  13. I’m 51 years old and had a retropubic prostatectomy in April. PSA was over 500 at surgery. Three months post-surgery it was still 14 ng/ml. Six weeks later it was 20 ng/ml. CT scans and nuclear bones scans were negative before surgery and negative 4 months post surgery.

    I’m currently on hormone therapy and was scheduled for full pelvic radiation to start this week. My surgeon just today informed me that the Mayo Clinic in Phoenix cannot do an [11C]choline PET scan. Now I know why.

    Should I fly to Mayo in Minneapolis?

  14. Dear Jim:

    With a PSA level of > 500 ng/ml at diagnosis, it would seem to me that there was a strong possibility that you had micrometastatic disease that was not confined to your prostate or your pelvic region at the time of your surgery, even though there is no sign of any cancer on a bone scan or on a CT scan. I am assuming that at surgery you were found to have at least some positive lymph nodes, and that your pathologic stage was something like pT3-4N1M0.

    You certainly could consider flying up to Rochester, MN to have an [11C]choline PET scan, but you may want to make sure that your insurance provider will cover the costs of such a test before you do this. You should also discuss other possible options with your doctor. For example, a bone marrow biopsy (which could be conducted at many centers close to wherever you live) may be able to show you already have prostate cancer cells in your bone marrow, which would make a trip to Rochester unnecessary. And a bone marrow biopsy in your case would almost certainly be covered by your insurance provider.

  15. Biopsy taken of prostate pre-surgery had Gleason scores of 8 in all samples. Bilateral lymphadenectomy was negative for cancer. Cancer was found throughout the seminal vesicles, which were removed. Pathology of tissues taken during surgery did rate pT3.

    A small border margin of cancer was present but thought to be insignificant. Doctors at the Arizona Cancer Center are stumped as to why my PSA was and is so high. I was asymptomatic before surgery and other than incontinence (which is improving) and impotence, I am asymptomatic now.

    I am experiencing hot flashes and minor lack of endurance since the hormone therapy began. Both are manageable.

    Mostly I am reticent to radiate a bunch of healthy tissue in a shotgun-like approach in hope of killing some cancer cells that may or may not be present. So I’m looking for alternatives.

  16. Jim:

    With negative lymph nodes and a PSA of 500 ng/ml prior to surgery and your PSA rising again post-surgery, I feel you would be really wise to consider whatever tests are available to see if you can confirm micrometastatic disease (e.g., the bone marrow biopsy or a trip up to the Mayo in Rochester or something) before making any decision about radiation therapy that may be of no value at all.

  17. So my radiation oncologist said I would need to stop my hormone therapy, and allow my PSA to rise again before the C11-choline PET scan would be valuable. Do you concur? She also said Mayo in Phoenix has a C11-acetate PET scan that is virtually same thing. What do you know about this? Is the PET sufficiently sensitive to show metastasis, in any organ? Pertaining to the bone marrow biopsy, will it determine cancer cells if the PSA level is under 1?

  18. Dear Jim:

    (1) I don’t think that the specialists at the Mayo in Rochester would agree that the C11-acetate-based PET scan is as accurate as the C11-choline-based test, but you really need to ask them.

    (2) Either the PET scan or the bone marrow biopsy will be most accurate if you do indeed come off the hormone therapy. However, none of these tests is “perfect”. They all come with some degree of risk for both false positive and false negative results. You are looking for very small foci of cancer, and so there are all sorts of inherent problems.

    (3) As I understand it the C11-choline PET scan can theoretically identify tiny amounts of metastasis in any organ. However, no one can guarantee that it will do this with 100% accuracy in any specific organ in any specific patient. That just ain’t how even sophisticated types of medical technology works.

  19. So am I to understand I would need to discontinue my hormone therapy for both the C-11 choline PET scan and a bone marrow biopsy in order to get detect cancer cells. My PSA is down to 0.5 ng/ml 2 months into hormone treatment.

  20. Dear Jim:

    That is a question you need to discuss with your doctors. You have a chicken and an egg problem. Do you stop what appears to be an effective therapy to see if in fact a better treatment might be possible … or do you simply stick with a therapy that appears to be working (although such a therapy has never been proven to be curative)?

    It is also a question you could address to the specialists at the Mayo Clinic who offer the C-11 choline test or to a specialist in the use of bone marrow biopsy and its application to the diagnosis of micrometastatic prostate cancer. There is no way that we can possibly tell you what “the right” thing is to do under such circumstances. It may be that one or other of the possible tests can show the presence of distant cancer regardless of the drop in your PSA … but I would be concerned about false negative results under such circumstances.

  21. This is the Louis from the above.

    I continued on Arimidex until November last year (2013) with enormous benefit from the TRT in several ways, not the least of which was a positive mental attitude. This was in spite of the fact I was the primary caregiver for my sister during the last 6 months of her life — as soft tissue sarcoma stole her body from her.

    My PSA remained in a range from 0.2 to 0.4 ng/ml that was acceptable to my doctors at the H. Lee Moffitt Cancer Center in Tampa.

    It was recommended that I switch to an injectable, weekly, form of TRT from daily transdermal TRT as a more even dispensing method.

    My PSA has now risen from 0.54 in December 2013, to 0.71 in February 2014, and to 1.12 in May 2014.

    I’m waiting to speak with my doctors at Moffitt, but cannot get an appointment until December, so I may need to find another physician. Do you know if Mayo Jacksonville is running this test yet?

  22. Louis:

    I do not believe that you can get a choline-C11 PET/CT scan at the Mayo Clinic in Jacksonville as yet. The half-life of carbon-11 is extremely short and so it has to be made at the same facility where the test is to be carried out. As far as I am aware, they do not have the ability to produce carbon-11 at the Mayo facility in Jacksonville yet.

    Also Louis, the choline-C11 tyest is only given to patients once their PSA rises about 2 ng/ml becuase at levels lower than that thbe risk for false positive and false negative results is too high.

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