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Philip Koo: My name is Phillip Koo, the Editor for the Imaging Center of Excellence on UroToday.com. Today I'm very pleased to announce a new lecture series that is produced by the Prostate Cancer Outreach working group of The Society of Nuclear Medicine and Molecular Imaging. This new lecture series will take us through the complete spectrum of prostate cancer imaging tools, with various recognized speakers who will be presenting on these topics over the next few months. Today we're very pleased to have with us Dr. Robert Flavell, who's an Assistant Professor of Radiology in the Department of Radiology and Section Head Nuclear Medicine at the University of California, San Francisco. He is also the Co-Chair of the Prostate Cancer Outreach working group, and he will kick us off with a lecture on prostate cancer diagnosis and treatment.

Robert Flavell: Alright, thanks very much, Phil, for that introduction. Today I'm very excited to bring to you the kick-off lecture on this new series, and the first lecture that I'll be presenting today is a teaser on how you can use new imaging practices to increase the quality of your patient care. I think this is an area of a lot of emerging new technologies, it's not yet clear which one of these technologies is the best, but it is clear that they are transforming the care of prostate cancer, and the title of this first lecture is Incorporating New PET Imaging and Theranostic Approaches.

So, imaging plays an important role in prostate cancer, together with the standard clinical and laboratory parameters. The imaging and therapy is really changing rapidly, particularly in multiple areas, including, first of all, patients with new diagnosis, patients who have biochemical recurrence, and even later on in the stage of patients with castrate-resistant prostate cancer. And leading the charge in this area are new PET imaging and theranostic approaches, which are really changing the management of these patients. 

However, there's a lot of questions that remain about the best use of these new technologies. There's a lot of competing new technologies out there, it's not yet clear to what extent these technologies actually help the patients. So there's a lot of excitement, a lot of buzz in this field right now, I think there's a lot of potential here, and this is just to give you a little teaser, and in the subsequent lecture series we're going to go through in more detail each of these individual imaging approaches.

So just to quickly review what is the standard of care of imaging of patients with prostate cancer, the first time when we typically see patients in the radiology department would be at the time of initial diagnosis, and following the diagnosis of high-risk prostate cancer, a variety of different imaging approaches can be used. At this point, I think it's safe to say that multiparametric MRI plays an important role in this setting to detect findings such as extracapsular extensions, seminal vesicle invasion, and other adverse pathologic features prior to definitive therapy. And in addition, in this initial stage in the high-risk setting, CT scans to look for lymph nodes and bone scans to look for bone metastases can be important.

So, following definitive therapy, many patients will, unfortunately, progress to biochemical recurrence, with a rise in PSA without clear imaging evidence of a disease. At this stage, most of them will then be treated by salvage radiation or hormonal therapy, and in this stage currently for imaging, for the most part, the use is MRI for use detecting local recurrence, for example in a prostate bed, and CT or bone scan for looking for lymph node and bone metastases. Later on, as patients progress on antiandrogen therapy and develop castrate-resistant prostate cancer, the MRI usually falls off the map and at this point, we're mostly using CT and bone scan to follow a patients’ response. And in this space of course, in the castrate-resistant prostate cancer side, there's lots of new therapies, and some of these include new nuclear therapies, such as radium 223.

Now, there's been a lot of changes and a lot of new things coming out in the last few years, in terms of new imaging and therapy in prostate cancer, and if you've been following the literature, you may have seen slides like this where you see about a dozen new agents that might be out there, and which one of these scans should you be ordering and which one of these techniques is the best? The answer to this is not yet clear, but in this lecture series, we're going to delve in detail on a few of these different approaches. One of these is choline, this has been used at several centers, primarily Mayo Clinic here in the US, many centers in Europe. We're going to talk about FABC, which is also called fluciclovine, or Axumin. This is an FDA approved tracer for the use of imaging biochemical recurrence in prostate cancer, and then finally we're going to talk about PSMA, which is the newer entry into the field, a lot of excitement around this new imaging agent.

So, rather than go through this comprehensively in this first series, I'm just going to illustrate a case of how you can use the information generated from these types of scans to help change the management of your patients, and I'm sure this is the type of case that many of you will be familiar with in your practice.

So, Mr. C is a 68-year-old man, he has a history of prostate cancer, presenting with rising PSA after radical prostatectomy and salvage radiation. So, on his initial presentation in 2013 he had a PSA of 4.2, which subsequently rose to 7.4 in October of 2014. In November of 2014, he underwent a radical prostatectomy for a biopsy-proven prostate cancer. At that time the pathology showed a Gleason 3+4 clinical stage T2aNxMx. Of note, the left posterior margin was positive, zero of 17 lymph nodes were positive. 

So, in January of the following year, his PSA was at 0.34, so incomplete response to the surgery, the slightly elevated PSA suggesting the presence of residual disease. And this PSA remained elevated on two measurements, and he subsequently underwent salvage IMRT in 37 fractions to the prostate bed. Following this, he had a nice response, with the PSA dropping down to 0.06, and subsequently nadiring at 0.03. It stayed around that level for a subsequent measurement, but then, however, again started to creep up. So numbers still quite low here, 0.06 really a very low measurement, but seems to be trending upwards.

So, in terms of other medical history, he had various other medical conditions; asthma, Afib, hyperlipidemia, hypertension, hyperthyroidism, kidney stones, melanoma in situ. Radical prostatectomy for surgery, in addition, remote tonsillectomy and melanoma excision. On a few medications, including losartan, pravastatin, and verapamil. Had a family history of cancer, breast cancer, colon cancer. He's a single retired veteran. Review of systems was unremarkable, as was his physical exam, and his labs were unremarkable, other than his PSA. Patient underwent standard of care imaging in this situation, which would include CT scan of the abdomen and pelvis, and a sodium fluoride PET/CT, kind of a more sensitive of your typical MDP bone scan, also normal.

So the question is, how would you manage this patient? And I don't think there's really any universal consensus on what you would do with this patient. It would be very reasonable to continue surveillance and not rush to treat this patient with any further therapy, such as radiation or antiandrogen therapy. However, this patient was referred to our institution for gallium 68 PSMA 11 PET CT. 

So this is a next-generation imaging approach designed to detect locations of biochemically recurrent prostate cancer. He underwent the scan, and I'm not going to belabor the details of the scan in detail, but I will just point out to you on the screen here, a focus of uptake in the region of the right pelvis, demarcated here with the arrow. On the PET CT fusion images, you can see this corresponds with an intense focus of uptake in the right ilium, just adjacent to the sacroiliac joint, and that was really the only finding of note on the scan.

So the report impression was that there was a single focus of uptake in the right ilium without CT correlate, suspicious for metastasis. So now, what do you do with this information in light of this new finding? Various options available. You might treat with radiation, you could simply opt to surveil the patient, or you could go for antiandrogen therapy.

In this case, the treatment team decided to go ahead with salvage androgen deprivation therapy in conjunction with stereotactic body radiotherapy. So he underwent SBRT 24 Gy in a single fraction to the right ilium and received also a single dose of Lupron. So, here's what happened, so he had his PSMA dose on the 29th, the subsequent day was given a single dose of Lupron, PSA initially 0.046 and then after that dropped to undetectable. Subsequently, in November he underwent SBRT 24 Gy in a single fraction to the right ilium, and since that time for about a year and a half afterwards, the PSA remained undetectable.

So it's an interesting example of how you might use these new next-generation imaging agents to, for example, target radiation to a new finding on this scan. And just a note, these findings were not visible on conventional imaging, on the CT or the bone scan nothing was seen. It was only picked up on this next generation imaging technique.

So, the next logical question you may ask yourself is, well this sounds like a good technology, but what scan should I be ordering? And the answer to this, I'll just emphasize, is not yet clear. Although, we are actively working on this in the nuclear medicine field to try to sort this out.

Now, what we do know for sure, and this has been documented in numerous studies, is that all of these new PET-based agents, including choline, fluciclovine, and PSMA, are all superior to the prior standard of care, which is CT or bone scan. That has been documented in multiple prior studies. Now, after that, it gets a little more gray. Now, case series suggest that fluciclovine and PSMA are superior to choline, and there's a very small case series recently reported suggesting that PSMA is superior to fluciclovine, although to be fair the jury is still out on that one.

So, how might you incorporate these into your practice? Well, in the setting of an initial diagnosis you have a few options. You've got the standard of care imaging, in this case, there's actually nothing really FDA approved for the standard of care imaging or even the next generation imaging agents. For example, PSMA is under a study in this area. I'll note that fluciclovine can be used in this setting, but this would be considered an off label indication, as it is only FDA approved for biochemical recurrence. In the biochemical recurrence setting, in addition to your standard of care imaging, including MRI, CT, and bone scan, you may want to consider incorporating fluciclovine, choline, or PSMA into your clinical practice, and in this setting I'll just note that fluciclovine is actually FDA approved, your access to choline or PSMA based imaging may vary depending on your local practice patterns. 

In the setting of castrate-resistant prostate cancer, the role of these next-generation imaging agents is not really yet clear, and this is definitely an area of active investigation. Furthermore, I'll add that in this castrate resistant setting, some of these agents, such as PSMA that we're talking about are, quote unquote, theranostic agents, meaning they cannot just be labeled with imaging agents, they can also be labeled with therapeutic isotopes, such as lutetium 177, and that is an area of active investigation and will be a topic of a later lecture.

So with that, I'm going to conclude this short lecture. I hope I've peaked your interest, and you'll be able to pay attention and watch the subsequent lectures in the series, where we're going to go over in greater detail the pros and cons of these different types of scans and therapies. So, thanks very much for your attention.

Philip Koo: Thank you very much, Dr. Flavell, for that great introduction into this upcoming lecture series. Just a few questions, so number one, that was an interesting case that you presented, how would you address the concerns with regards to change of management and impact of outcomes, if by treating patients such as that with EBRT, that in the past wouldn't have been treated at all?

Robert Flavell: I think that's really a great question. So, what we do know so far, and the literature is bearing this out pretty clearly, is that these next-generation imaging techniques are very effective at identifying sites of disease, and then if you treat these patients you will, in general, effectively treat the PSA number. 

Now, of course, the PSA number is not the end all and be all, and at the end of the day, the goal of treatment in this setting would be, you could probably envision two overall goals here. The first might be increasing overall survival, which of course is always our goal in oncologic care, and the second might be delay of time to androgen deprivation therapy. For example, if you can treat oligometastatic disease, for example, with targeted radiation to these identified sites of metastatic disease, perhaps you might be able to delay the time to androgen deprivation therapy.

Now, the answer to these questions is very difficult to study, and unfortunately, it's going to require large clinical trials with long term follow-up, because of course these patients overall with biochemical recurrence actually still have pretty good outcomes overall. So, the answer in terms of the long term clinical outcomes is not yet there, but my feeling based on preliminarily what we've seen, and some very small studies is that in the long run that metastasis directed therapy in this early setting will probably prove beneficial for many of these patients.

Philip Koo: Great. So, what advice do you have for urologists or urologic oncologists who have not used next-generation imaging, and have been a little concerned with regards to using this in their practice?

Robert Flavell: I think that's a great question, and I think the question there comes in, well what do I do with this information? I hope we can convince you based on this lecture series that these techniques are effective, are highly sensitive and specific for detecting sites of prostate cancer. I think the question remains and ties in with the first question that you asked, in other words, I can identify these sites of disease, I can treat them, for example with repeat surgical resection or radiation, but do I really improve the patient's outcomes? 

And I think it's reasonable to have some degree of skepticism at this point, because there is not yet true gold standard evidence that those sorts of therapies will clearly provide a long term patient benefit, but my belief is that that evidence will be accumulated over the years to come and that we're going to be seeing that these next-generation imaging approaches, coupled with metastasis directed therapy will improve patient outcomes. So, I think it's reasonable to have some degree of skepticism, but I think the outlook for this approach is probably going to be that it improves patient care in the long run.

Philip Koo: Great. And finally, could you just tell us a little bit about the Prostate Cancer Outreach working group and what you're doing, and what your goals are from the SNMMI's perspective?

Robert Flavell: That's great. Thanks very much for that question. So, the Society of Nuclear Medicine Prostate Cancer outreach group includes the people you see on the slide right now, and this is a group of specialists in nuclear medicine, we are people who actively do research on the development of these new technologies and their implementation, and we are excited about getting the word out there, and I think there's a lot of excitement about these new technologies, and frankly, a lot of this excitement comes from urologists, radiation oncologists, and medical oncologists. 

But on the other hand, we can also help by providing detailed and appropriate information about the interpretation and the use of these technologies. So I think our goal is to get the information out there, get the word out about how these techniques can help clinical practice, things that are great about it, things that are important, and also maybe what are some limitations of these technologies. So I think that's information that those of us who are in the Society of Nuclear Medicine working group can help get out there as experts on the implementation and interpretation of these imaging and therapeutic technologies.

Philip Koo: Great. Well, thank you, Dr. Flavell, for your time and for your expertise and sharing all of that information with us today, and thank you to the listeners for tuning in, and we encourage you to tune in next time when we move on to the next lecture in this SNMMI lecture series. Thank you.