Insights on Nuclear Imaging for Prostate Cancer- Stefano Fanti

Stefano Fanti reviews the consensus paper on nuclear imaging for prostate cancer which was recently published in Lancet Oncology in December 2018.  PSMA PET should be offered early in biochemical recurrence as it is the most sensitive and the EAU has incorporated PSMA PET into their guidelines as well, recommending PSMA PET for PSA >0.2. Stefano and Alicia discuss the various PSMA technologies and take a look towards the future with advancements in theranostics.   

Biographies:
Stefano Fanti, Professor Department of Experimental, Diagnostic and Specialty Medicine - DIMES at the University of Bologna. He is Director of Nuclear Medicine Division of the PET Unit at the Policlinico S. Orsola and Director of Speciality School of Nuclear Medicine at University of Bologna.

Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.



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Alicia Morgans: Hi, I'm delighted to have here with me today, Dr. Stefano Fanti, who's a Professor of Imaging at the University of Bologna. Thank you so much for coming to speak with me today.

Stefano Fanti: It's my pleasure to be here again with you. So again, honored.

Alicia Morgans: Oh well thank you. You know, I love to speak with you because you have such insights that we in the medical oncology community and maybe in urology community are not as aware of and I really appreciate that you can lend us some guidance on things like PSMA, nuclear medicine scans that we hope to soon have access and use these scans, but we don't have that yet. And to help guide us, you and a team, an international team actually recently published in Lancet Oncology a consensus guidelines statement to provide some framework from which we can try to apply some of these new tools and I'd love to hear about that process.

Stefano Fanti: Thank you very much. It's been really a fruitful process that we started under the promotion of EANM, which is European Association of Nuclear Medicine. So it was me and Wim Oyen that co-chaired at this event and it was a consensus conference that was recruiting the most experts from the clinical oncology, urology, radiation oncologists. So all the fields involved with prostate cancer management in order to have this, which are not formally guidelines, but again a consensus with a panel and they were essentially aimed at building a very robust scientifically based approach and a Delphi modified processes.

All the panelists were asked to answer multiple questions and then they were get aware of the response and there was a second round where they knew if their opinion was in line with the others. To build up a consensus you need to reach an agreement of 70 or even more percent. So it was really a long lasting challenging. But at the very end, very rewarding because as you mentioned, we've been published in the Lancet Oncology and many of the issue covered there were relevant including which is the most interesting tracer for PET scanning, which are the most appropriate indication for PET scanning in prostate cancer. So results that were relevant. And again, it's been available since December in Lancet Oncology.

Alicia Morgans: Yes. And you're first author. So you were the one to tie up all of the consensus.

Stefano Fanti: I'm just a lucky guy. I did it together with my colleagues, EANM and 25 panelists. They all gave great contribution. And again, the key points regarding the fact, for example, that PSMA-PET is very, very useful in biochemical recurrence. So when a patient has already been operated on or radically treated them. And then there is a rising PSA then probably is the most sensitive approach and you should do that very early and not waiting too late because otherwise, you will not have an impact on patient management. So if you want to have the best clinical benefit, you should scan the patients very, very early and right now some recommendation has been also implemented into the EAU Guidelines because I happen to be part of that board as well. And so the recommendation is now to scan a patient with PSMA-PET for PSA values higher than 0.2.

Well of course, now the matter it's about availability. Because in Europe there are several countries that are ... Or in Australia where PSMA is easily available. That's not the case in North America unfortunately.

So I guess there are many, many good aspects. The first is again to have a consensus among a group of outstanding panelists from different specialties that bring the multidisciplinarity, which is a prerequisite for a good consensus in prostate cancer. The other, to bring it to the worldwide reality, the fact that the PSMA-PET is probably the most accurate approach in some indication. Not necessarily in every indication. So for example, primary diagnosis PSMA-PET has nothing to do. It's all about MRI. Staging gets some matter of debate. Probably can have a role for patient staging. It can in the future eventually have a role. We discuss that last year for theranostic. That's to say if you replace the diagnostic isotope with a therapeutic isotope, just like lutetium, you can probably end right now, there are ongoing trials with promising results. Again, the data from Australia, are very good on that. So a really very exciting field.

Alicia Morgans: Yes. Well very much we'll, let me just emphasize one of the points that you said actually a couple. Just to make it really clear because these are some of the things that practitioners have the biggest challenges with. In the initial diagnostic stage when you're thinking about moving forward with surgery or with radiation PSMA-PET is not to be used at that time. We can use standard imaging at that time to really understand the extent of disease, but after say a radical prostatectomy, if we see a rising PSA, a PSA as low as 0.2 is a PSA that should trigger a PSMA-PET and then we can think about based on the results of that scan, potentially pelvic radiation to salvage the patient.

So that 0.2 is really strikingly low and it's not something we can do with Axumin for example, we would probably be using a higher fluciclovine. We'd been using a higher PSA to really ensure that our sensitivity was going to be reasonable to understand what we see. But for PSMA we can go as low as 0.2 and that I think is a game changer because as you've said, we try to intervene early with salvage radiation and we have a much better opportunity to cure patients if we do. So 0.2 was defined, was that in a trial or was that a consensus?

Stefano Fanti: I mean there are stratification on meta-analyses. I can mention at least a couple. One is just being published by a colleague of mine, Debbie Sherer in European Urology Oncology and they stratify the paper and you can demonstrate quite easily that it's the most accurate approach for patients of the PSA lower than 0.5, let's say 0.2 to 0.5. PSMA completely outperformed the other approaches. We still don't have data from below 0.2 which is a matter of debate because biochemical recurrence is no longer define it as a values over. So it's ... The Australian are scanning some patients with doubling time, but probably we don't have to put too much pressure. We need more data on that. The data are not coming from one single prospective multicentric well designed a trial but it's more pooling data from several small trials. It's a bit inerrant due to the fact that behind the gallium PSMA there's no big company pushing for that because it's a product that you cannot patent. I mean the gallium PSMA 11 is one molecule that has been developed at Heidelberg and is not covered so far by a patent and will never apparently, so it's difficult to design those expensive trial if you don't have a strong sponsor.

Alicia Morgans: Yeah, that's true. But I think clinically we really appreciate that you and the rest of the consensus panel tried to make a recommendation to pool the data that was available and to make that recommendation. I think another point that clinicians struggle with is the possibility of a false positive finding on PSMA. Particularly if you have such a low PSA. What is your experience or your thought about false positives and if you do see things that are lighting up, are there abnormalities that you might see on a PSMA scan that you would say, well because it is in that anatomic location, I would actually biopsy that because it's higher risk of a false positive?

Stefano Fanti: Exactly. It's a very good point. Thanks.

Well, first of all, PSMA despite the fact that it's prostate specific membrane antigen is not prostate specific, so it's been demonstrated that you can have over expression in different malignancy. So for example, we have seen, I don't know, primary lung cancer, which was avidly taken PSMA. Now it's questionable if it's a false positive or not. Because if you see a nodule in the lung and it's uptaking PSMA, you know that's a malignancy. So, it could be a met, it could be a secondary or a second primary tumor. So it's not exactly in my view a false positive finding. It's possible to see false positive findings. As you mentioned at the sites, what is not so frequent to see mets. So for example, the inguinal node are frequently a little bit avid, especially if there is any sort of inflammation, the drainage from the lower from the legs are coming there.

So we have learned it. So there is a learning curve on that that to not call ... At the very beginning, we did, like you said, suggesting to make biopsy in order to confirm before changing the treatment of the gentleman if there are cancer cells there. But after a while, given that we almost always find the inflammatory findings, we simply learned to not call that as a met. Apart the patients that may have let's say 50 lesion and that's one of the 50 and that's of course completely different scenario. But if the scan is completely negative and you've just have a little faint uptake in those nodes, just don't call that as a positive finding. And so it's faint uptake that will learn reporting and to understand the biology of the cancer because the spread will go in different the pathways, up to territories, iliac but not to the inguinal usually.

Alicia Morgans: So using our understanding of anatomy, certainly the urologists have this understanding and thinking about lymphatic drainage is really important. Yeah. Well the other thing that I've heard in clinic and it gets back I think to what you were mentioning regarding the gallium isotope and the lack of patent, there is some conversation among medical oncologists and urologists and it's not necessarily because we understand or we know, but we'd love to hear from you as a nuclear medicine physician. What is the difference between the different PSMA options with gallium or a fluoride, I think it is?

Stefano Fanti: Yeah. I mean PSMA is a basket term and we refer to that for many different radiopharmaceuticals because they share this affinity and this ligand toward this target. So to me, whatever target there is called the PSMA, but it's a very wide term. The current comprise different molecules. So, one of that is not patented and is widely used. It's called PSMA-11 but there are other patented molecules that can be labeled with gallium. So, gallium is the isotope there and you may replace that with fluoride.

It's not about the quality of the image itself because again, there is some very small details but really minimal details that will impact on the clinical quality of the image for really, really a very minor degree. So clinically I would be surprised if there is any difference between the gallium and the fluorinated compounds. But logistically it's very different. Apart from the proprietary issue, so someone made develop his own tracers and sell it. So, making some business on that, fluoride has a half-life of two hours. So, making distribution, especially in North America when it's all about center with your pharmacy and you have to distribute something which allow you to have two hours time to bring it from the factory, the production site to the place where they use it is feasible. It's done with FDG. So it's logistically feasible.

Gallium has a half-life of one hour. So it's much more complicated. By the way, gallium requires a generator. And as far as I remember in US, the use of generator of gallium is not allowed so far or it's a very recent ongoing process. This discussion, while fluoride has been used at since, let's say more than 10 years. So logistically it's clear that fluoride have many advantages and there are companies are trying to patent, I mean, trying to get the registration of their patented product that is already there.

Alicia Morgans: So as clinicians we may not see much of a difference between these different compounds, but in terms of having access, we have access to any of them. We should try to just use them in our institutions probably already nuclear medicine doctors will help us figure that out. Maybe with the fluorinated compound being a little bit easier to obtain because of the longer half-life.

Stefano Fanti: It's a matter of time. I mean if you shoot that right now in the western Europe gallium is there, there's no patents around. So it's very cheap and that's the same in Australia. I mean the literature is there, all the data. So I would go for that to more and that's what I'm doing since a couple of years in my institution. Because that the data and the logistics are there. But probably in the future, if I'm talking about the next two, three, five years, fluorinated compounds may have a clear advantage for several reasons.

Alicia Morgans: Well, I guess we'll see and you'll have to enlighten us. So as we wrap up, I'd love to hear your thoughts on these consensus statements and guidelines. You've actually been involved in a number of panels because you are so knowledgeable and experienced and also very easy to work with. I think people love to talk with you and you share so wonderfully your experiences and your knowledge. So can you comment at all on the process of these, the development of these guidelines? It's hard on the minimal data and some situations that we have to come up with real evidence to back things up and some of the guidelines in a consensus statements are a little bit different in what they ultimately recommend. So I'd love to hear your thoughts.

Stefano Fanti: Thanks indeed. I guess it's not only about the expertise but also the fact that there are not that many nuclear medicine physician. We are a little bit of a panda as compared to the oncologists, so there's not many alternatives. But it's been a long time based on opinion of experts and that's clearly creating a major bias because there is an influence of leadership, the influence of opinion, that may be conflict of interest because many of those are clinicians are involved within trials and so on. So it's a complex issue. NIH has been working a lot on that and I guess that the methodology is becoming more and more robust now. All the organization and panels that have been involved with, they start with a very good professionally made literature data review and analysis, meta-analysis of pooling the data. So all the panelists are now made very well aware of which is the status of the art of the available scientific literature.

And then there are other companies, because a clinician may wonder why using a robust reproducible methodology, the results are different. So for example, I mean board within the ASCO guidelines and apparently they're not happy to discuss the use of products which are not authorized or licensed in the US, which is correct. I mean if it's a North American perspective, you should talk about what's really available and not talk in theory. That's not been the case, for example, at the EAU because despite the fact that the legislation in the different European country is very different, EAU is taking all the compounds as it would have been possibly use it. And then we mention if available, that make difference for their individual countries. So, for example, the EAU guideline right now recommend to do PSMA-PET scanning in biochemical recurrency when PSA is higher than 0.2. That is not the case for example, for the SNM so North American Nuclear Medicine guidelines, it will not be the case for the ASCO guidelines. In our consensus conference, so we came to recommendation about that again because the perspective was a worldwide perspective. So but I guess it's very important to provide those statements, consensus or guidelines in order to make the life easier for you, for the clinicians, for the oncologist and provide the most updated and robust, scientifically sound information.

Alicia Morgans: Absolutely. And I'm sure that they all continue to update them as this data is so fluid and fast-paced at this point and we all are clamoring to understand what do we make of it and how do we come to some consensus and some guidance there. So, I have so appreciated hearing your perspectives. If you had one final message for the audience, what would that be?

Stefano Fanti: Well as I just probably told you last year is so nice and to be and so excited to be involved in this area at present because there are so many ongoing innovations for diagnosis. I mean different compounds, different type of PSMA coming out, there are other tracer which are now going to Phase 1 study and the theranostic application, it's really so promising and coming possibly rapidly into well design and robust trial to demonstrate if there is any role. So it's really great to be in the field of nuclear medicine and prostate imaging and therapy right now. Yeah, thanks.

Alicia Morgans: Absolutely. Well thank you and I look forward, hopefully by next year we'll have some little bit of data at least to talk more about theranostics. We are always waiting for that and thank you so much for your time today.

Stefano Fanti: I agree. My great pleasure. Thank you.
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