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Phillip Koo: Hello. My name is Phillip Koo, editor of the Imaging Center of Excellence for UroToday.com. We're very fortunate to have with us today Dr. Ephraim Parent, assistant professor at Mayo Clinic and also the co-chair of the Prostate Cancer Outreach Working Group for the Society of Nuclear Medicine and Molecular Imaging.

Today we're going to continue the lecture series on prostate cancer imaging and therapies on UroToday. We're very fortunate to have an expert on the topic of bone imaging with us to share with us the latest information with regards to imaging of the bone and patients with prostate cancer, which we know is a very critical aspect of the disease in these men with advanced disease. So thank you very much.

Ephraim Parent: Thank you very much for inviting me. Today we're going to be talking about bone scintigraphy. General outline of what we're going to be doing is going to talk about initially the radiopharmaceuticals that are used for this technique; planar imaging, which is pretty much used throughout the nation as a standard way to evaluate for osseous metastatic disease; and then we're going to talk a little bit about ways that we can do cross-sectional imaging to get quantitative information that can be helpful in identifying and actually predicting or determining how people are responding to therapy; and then kind of future areas that modality and this an evaluation of osseous disease may take.

Overall, there's two main goals of why everybody does skeletal imaging. One, we want to identify where the disease is and how much of it is within the skeleton, and then we want to know if the therapy that the patient is on is working or not if they need to change directions.

The rationale for using this is that these agents, in one case technetium-99m diphosphonate or sodium fluoride PET has uptake in areas of metastatic disease and it's actually just the pseudo marker for tumor progression. It gets into places where there's new bone formation responding to insults such as metastatic disease, but it's not actually binding to the tumor itself.

In patients with prostate and breast cancer, the bone is often the only site or the dominant site of metastatic disease. In fact, 80% of patients that will end up dying with either breast or prostate cancer will have osseous metastatic disease. So this is an important technique to be able to identify rapidly and easily and accurately how much diseases in fact within the skeleton. This has been done for decades and it's relatively low cost and it has a high sensitivity for detecting metastatic disease.

How this works is that the tracer itself follows the bisphosphonate type metabolism. So it's bound to a cold bisphosphonate and it creates oligomer. We don't actually know the actual structure of the agent, but we do know that it binds onto the hydroxyapatite within the bone, and the delivery to those areas depends on blood flow and how fast it's being extracted into the hydroxyapatite. Like I said, it follows the bisphosphonates physiology and eventually washes out pretty quickly within a few hours and by 24 hours most of it is cleared in the system.

The exact binding mechanism of how this works is not exactly understood, but we do know that it goes to areas of osteoblastic disease. So in prostate cancer cells, most of the time we refer to them as sclerotic type metastases, but the happening is there's this reactive bone formation that the osteoclasts are putting down or osteoblasts are putting down and that creates a fresh layer of hydroxyapatite that the MDP or the sodium fluoride binds to. So we're able to get a good idea of where there's reactive bone formation, which again is a pseudo marker for the actual prostate metastasis in that area.

Again, just talked about generally how this works is; I kind of alluded to this earlier, it depends on the rate of blood flow, the permeability to the capillary system, and the bone surface area. So in areas of metastatic disease, there's more inflammation and these tumors create angioplasty effects where there's more blood flow coming to them so there's a higher proportion of the ratios are to that area. The bony surface actually is not within the cancellous bone, which is, so this is a kind of a blow-up of an actual like a femur, a long bone, but this area here this cancellous bone actually that's where most of the mass is. That's actually not where the disease is. It's actually in the medullary type system and that's actually where we are seeing this disease and that's where most of the binding is going to in the actual normal person as well. So this kind of creates a nice situation where we're able to get a lot of tracer being delivered to the area of the disease has increased uptake with the kind of milia that the tumor creates in a local environment.

These are kind of the images of what we see typically in prostate cancers. So these are kind of classic kind of images that we'll see, and we... The normal skeleton you'll see here of the oligometastatic disease has uptake in the normal skeleton... You can see there's very bright foci of uptake in the ribs, in the clavicle. Those are the areas where we have the disease. You might look at the patient with extensive osseous metastatic disease and we don't see these really bright spots like we did on other patients. In fact, what's happening is pretty much everything you're seeing is this person is riddled with disease throughout the skeleton. So we don't see exact lesions per say, but all of everything that we see is actually due to the actual tumor because it's so extensive throughout the skeleton.

Going back again to why we are doing this, the first thing is we want to identify it and we want to quantify it. So in this patient here, we can identify areas of disease. For example, on the left 10th rib, we see this kind of linear uptake. Maybe there's some stuff in the pelvis, but it is a little bit hard to identify exactly where all the disease is and that's where you have these other cross-sectional imaging techniques such as sodium fluoride PET. It can be very useful in identifying disease.

You can see in this, this is the exact same patient how much more relevant or not relevant or readily evident the disease is throughout the skeleton. These kind of bright spots, we still can identify them on the planar imaging, but it's so much more easy to see these lesions on the bone, cross-sectional imaging with the fusion, with the CT. So for example in this left iliac bone, we have the sclerotic lesion that has increased uptake. It's very evident in this image. On the planar image, we can see it, but it's a little bit harder to identify. Nevertheless, when patients with the disease, planar imaging actually does a pretty good job of being able to track how the disease is going on.

This is a single patient with kind of showing different stages of his disease. On the first set of images versus a PSA of 8.6, we have some disease in the spine, the ribs. There is some linear uptake along the right ribs, which is actually due to fractures. Then when we see the middle inset of images with a PSA of 65.2, we see much more extensive disease throughout the skull, throughout the ribs, spine, pelvis. It's very evident that this is a correlation with the degree of the lab values when we are getting some PSA levels. Then as he has a new therapy and the PSA going on, now you see on the right side of the images that actually we can really evidently see that there's actually less uptake in these areas, so he's responding to therapy. So this is matching quite a bit with our lab values or imaging values. They don't always go like this and sometimes it's a little bit harder, but you can overall for most patients get a good sense of how the disease is progressing within the skeleton.

Sometimes, however, it's a little bit more tricky and a little bit more difficult. This is a patient, again, this a single patient, various time points starting from May 2016 to 2017. He's been on several rounds of therapy and he's now on abiraterone. I've kind of focused areas of lesions in the spine and pelvis with the arrows. You can see going from May to August 2017 overall, there's a general increase in uptake. Especially on the last set of images, the August 2017, it's clear that there is a more extensive disease in these areas. In the middle ground, it looks like, are some of these getting worse? Are some of these getting better? And it's not quite as evident. If there's new areas of uptake, it's really easy to identify; oh yes, this is progression. If there's just a slight change, it's very difficult for the radiologist or the nuclear medicine physician to really accurately identify how things are going. It's kind of a skill that develops but again, there's a little bit of guesswork that's involved in that.

Again, that's where these kind of cross-section of imaging techniques can take place. Another one besides the sodium fluoride PET that I'd mentioned earlier is this quantitative SPECT/CT. This is that same patient that I just showed you, and you can see these same areas that are highlighted on the planar images. Now on the SPECT/CT, you can very clearly see where the degree, where the uptake is and you can actually get numbers here. We get these SUV values, which is the semi-quantitative metric, to tell us how much activities in these areas, which can infer to how the patient is, how much activity or how much tumor activity is in that area. We can actually get numbers that correlate with that and so this can be very useful in determining how the disease is progressing, again, how they're responding to therapy.

Now I want to kind of take a little step back in time to kind of talk about, well, is this really useful? Are we really wanting to quantify things? I will talk about... There's an agent that's used extensively throughout for almost all cancers called FDG or fluorodeoxyglucose, and that's a PET agent. Early on, they thought, well, we don't really need to quantify this uptake because we just want to look for areas of where uptake takes place. Now we know 30 years later on that actually that's not the case, but actually what we need to know is actually not just where the disease is but how it's changing and there's so much useful prognostic information that we can get from that. It's very similar with our studies here.

Both sodium fluoride PET and technetium-99m quantitative SPECT/CT I think can provide similar results. The sodium fluoride PET is the same technology that's been used for quite a while. The quantitative SPECT/CT is kind of a newer technique, but overall they provide the same information. The SPECT/CT has a few drawbacks. It's about 10% accuracy. It's about comparable to the PET but with plus/minus 10%. However, it does have poor spatial resolution and the [inaudible 00:11:19] is a little bit less. So while the technical aspects are not as good overall for what we want to do with imaging of bony disease is quite good.

I'm just going to go share here and show kind of how we can use this. So this is a quantitative measurement. So this is the patient I'd shown earlier that had the uptake the ribs and it shows this kind of this sodium fluoride PET. Again, here I'm giving you a number here where we can go at 24 for SUV. Then that number in itself doesn't really mean anything, but it's just a metric that we can use to identify how much activity in this area. We can see that on the second time point, we can actually see visually that there's decreased uptake. We can also see between the upper right image where there's the 24.2 SUV and the lower one where it says 7.5 that he's actually responding to therapy. There's less uptake there. We still can identify the lesion and thus we can kind of tell the clinician very easily, "Hey, this is how therapy is progressing for the osseous disease in this patient."

Where are we currently at in the United States for sodium fluoride PET? So it's been around for a while the actual sodium fluoride one of the most simple radiopharmaceutical that can exist, but where are we with it kind of being widespread? Why are we not doing this more? Well, there was a large study that was done where they evaluated several thousand patients. They actually found that when the clinicians understood that there was, the sodium fluoride is not giving things, there was no change in management, keep on or it's getting worse or progressive disease, they actually responded favorably. So basically, we were able to show that this information was very useful for clinicians and know how to treat the disease.

However, when these results were presented, the CMS decided not, it doesn't really justify imaging for all patients with prostate cancer. So while it's FDA approved and we can't do it kind of on a case-by-case basis, whether or not insurance is going to be covered this right now is kind of, it's really a case-by-case basis. We are doing it widespread right now and then mainly due to the kind of those issues. The technique is very good, but it's just a matter of how it gets paid for.

Now that might seem a little disheartening, but actually, maybe it's not such a big deal. So there is some evidence that when people look at other studies, is this really necessary or can we actually get the same information with just our normal bone scintigraphy. So there's a study here where they looked at a series of patients that have both just planar bone SPECT or not bone SPECT just planar bone scintigraphy and PET/CT. They really found that there is really, we get to get the same information that would affect management for both cases. So while PET/CT is very useful in clearly identifying the disease and can be useful in predicting our response to therapy, overall probably we can get the same information from the simpler cleaner scintigraphy.

I just wanted to talk a little bit about SPECT/CT, clinically the SPECT/CT because that's a newer technique. It's been around for a few years now. Both GE and Siemens have techniques or products that can use that and to identify or not identify, to calculate the quantitative information that we need from those. We basically get the same information that we get from the PET/CT. We need to have the CT attenuation correction, scatter correction, and the calibration. The text then just puts in the same information in terms of dose, times, and patient wait.

They do also have some techniques where they can use the a priori type imaging reconstruction to get sharper images and this is just comparison. This one xSPECT is where we have kind of the typical SPECT data and we can calculate some SUVs from that. Then if we apply their filter where they use the a priori where they're kind of pushing the counts into the areas of high attenuation, which is bone to help elucidate where there might be areas of metastasis that becomes much clear image. The SUV values do change and it's important to make sure that if people are wanting to do this, they are sticking with the same technique and not kind of flipping back and forth between the two and then using those SUV values because that could be some error inter-, how that study would be interpreted.

Additionally, it's important to understand that what's happening with this xSPECT type or a priori type reconstruction is that it's not really known or the computer doesn't know what's a tumor and what isn't a tumor. Sometimes you can see things that are clearly wrong. So this is a case that we had imaged. The top series of slide shows a slice through the abdomen and pelvis with the green arrows drawn on the aorta. If you look at the not a priori images, you don't see any uptake in the aorta. So what happens is the computer then sees, oh, this person has some atherosclerotic plaque, and they then start making it look like this on the middle PET-only image that there is uptake in that plaque and that could create some spurious information. So there's things, there's artifacts that can create in there that I think a lot of clinicians in the companies don't necessarily appreciate. It's definitely something that we can read around, but we need to understand overall as interpreting physicians how best to use this information to provide accurate information for the ordering physicians and the patients.

I want to talk a few minutes about some spurious things that we can see with these bone SPECTs that we need to get around. Sometimes, and this is not necessarily about one SPECT, but sometimes with metabolic imaging same with MR, other things, we'll have findings that we don't really know exactly what to do with. So for example, in this patient, the recurrent prostate cancer, very low PSA, and then there was a presacral node that we determined as positive; I'm not showing that. Then we also found this uptake here in the left iliac crest and you can see it on the images to the left.

When we looked at it in the coronal imaging, it didn't have that characteristic shape that we want to see with an osseous metastatic disease. So with the fluciclovine PET implied, there may be something there. We decided to follow this up with the sodium fluoride PET to see if there's a correlate. As there wasn't, we determined that this is actually just a false positive. So these type of bone imaging techniques can be used to either confirm or kind of dispute findings that may or may not be real with other types of imaging techniques.

Something else that we've started doing at the Mayo Clinic with our prostate cancer patients, we have started doing our fluciclovine prostate cancer patients with PET/MRI. We've introduced a T1 series. This is not a T1 series here but to help identify areas of osseous metastatic disease. So this patient here, he had a rising PSA. There is really no evidence of disease except for in this right femur. It was eventually treated with cryotherapy and his PSA went down. So this is a technique that might be used going forward to help identify kind of both combining the osseous disease and soft tissue disease into one overall study.

Again, the last note I want to make is for patients. It's important to understand that not all of these numbers are the same. It can sometimes be confusing because, in reports from my reporting SUV, this is a breast cancer patient, but I think the information is very valid. The top series is FDG PET/CT. In the bottom series is the quant-SPECT/CT for MDP. They both show uptake in the sternum, as you can see on these from the center images, but the numbers have no correlations with each other. So the 6.49 for the FDG does not correspond to the 7.4. These are just numbers that within the same technique have some information but between different tracers and things like that, there's no correlation. It's important to be able to understand that I think as a radiologist, we make it clear for using this information that we're reporting these numbers, how the clinician should be able to interpret them between radiotracers as the number of radiotracers is expanding kind of every year.

So kind of inclusion, acknowledgements, the bone scintigraphy is extensively used to identify and manage osseous metastatic prostate cancer. Both quantitative SPECT/CT and PET/CT are available and they do improve the sensitivity and specificity. However, currently, these are not routinely done primarily due to cost and reimbursement issues, but it may not be completely necessary. As with PET/CT, it is likely the quantitative SPECT will find a use in responding, determining response to therapy but overall, we kind of need to wait to see how things will go forward within itself.

I would just like to thank the Prostate Cancer Outreach Working Group and everybody else at the top of this presentation. Thank you.

Phillip Koo: So thank you very much for that wonderful presentation. Just wanted to ask a couple of questions. So with bone scan imaging, as you had talked about, the imaging of the bone you respond to something that's created some issues and the biggest issue that we've seen clinically is with the phenomenon called flare. Can you talk a little bit about that and the use of quantitative imaging in that setting and how sure we can be that certain changes aren't related to a drug response rather than the disease worsening?

Ephraim Parent: So it's a very good question and it's a very difficult question to be really firm on. This area of flare for both prostate and breast cancer is a very real phenomenon. I think it's understood a little bit better with breast cancer because they kind of have these certain responses which are both kind of not just the energy deprivation like with prostate cancer, but they have this kind of, with their tamoxifen and things actually have a partial agonist effect. So overall when we start on these hormonal therapies what will happen, a lot of times there'll be an increase in uptake.

Again, what we're seeing with bone scintigraphy for both of these patients, it's not the tumor itself, it's the response of the surrounding bone to that tumor. So what happens is when that deprivation therapy is going on, sometimes we'll see an increase in uptake for these lesions. Sometimes it can be quite pronounced and that can be a flare phenomenon. Now it could be real and the only way to really know is to follow them serially to see how things change. It's usually like a six month or so window, sometimes a little bit more, sometimes a little bit longer of where we start. If it's truly just a flare phenomenon that it would start going down, then we can kind of get a good sense of that's what it is.

The quantitative information needs to be very useful in those type of instances because visually, we can kind of get a sense of it, but we only have so much discriminatory power with our eyeballs. We don't really have that good quantitation to really say, "Oh, this is 20% less or 20% more." So I think that's going to be very important. Unfortunately, like I said, this is not done routinely. The one thing that I think that is easy to do if we see this on something is if there's new lesions. If there's new lesions, we can be pretty certain that this is actually a real progressive disease, but otherwise, it becomes very difficult.

Phillip Koo: Great. So now that we have FDA approval of fluciclovine and eventually we'll have approval of PSMA agents, it seems like those agents are going to change how we approach bone imaging. I think there's data from multiple sites, including the group from Italy that talked about how fluciclovine outperformed sodium fluoride PET/CT even for bone lesions. Can you talk a little bit about how the landscape will change with the eventual approval of PSMA agent for bone imaging?

Ephraim Parent: So there's kind of two different things. Let me talk about fluciclovine and choline initially, so. I think these also apply to PSMA, but PSMA is a little bit of a different character. So for both choline and fluciclovine and overall what we see with prostate cancer, so the initial course if we're talking about CT finding in terms of these kind of lytic or sclerotic lesions, the initial thing that we see is if someone first gets a met in the bone, let's just say in the vertebral body, on CT we initially don't see anything. There's no evidence that there's any change to that marrow or anything else. It's totally opaque or not opaque but just occult.

Then what happens? As the disease progresses, they inevitably always become lytic for both breast cancer and prostate cancer. Before therapy, before there's a response if these diseases are just progressing, they'll become lytic. Then as the body starts fighting it and as the chemotherapy or the hormonal therapy comes and the body starts responding to this, that's when things become sclerotic, and over time they can become very densely sclerotic.

So the reason I'm talking about it is because that really correlates to how much cellular density there is and that is the key to understanding the uptake and the sensitivity and specificity for these agents. So both choline and fluclocivine, I'm just going for the clarity, rather than saying difference, fluciclovine right now is more widespread. If the lesion is occult on CT or lytic, they will have intense uptake on fluciclovine PET. You can be very confident that that is probably something real, depending on the shape and other things like that. I think going into all the subtleties is kind of beyond scope of this, but those lesions have very high uptake.

As the lesion becomes sclerotic, you have more osseous matrix, but you have a lower cellular density. So even if you have a metabolically active disease in these densly chronic lesions, they can be really occult on PET where we don't see it because just so much of that area is due to the osseous matrix. So in terms... So in response to that, it kind of depends on where they are on that spectrum. So early on if we're talking about early disease or something like that, I think fluciclovine and choline is great. So if we're trying to evaluate some who's been on many therapies and their bones are very sclerotic, it's really hard to tell what's disease and what's not.

So I don't think that overall these patients where we're trying to follow them long term, the fluciclovine PET, serial fluciclovine PET or choline PET is a key. It has not been as rigorously studied and just what we know going forward it kind of loses its sensitivity as these lesions have been treated.

Now PSMA is kind of interesting because it doesn't appear that even in this chronic lesion that you can still have fairly high and increased uptake. I think that needs to be born out to have large studies of where we're looking at just osseous disease. There is evidence that the PSMA can somehow avoid some of these same issues. Overall it's still as a matter of cellular density and so in a density sclerotic things we expect to see less uptake, but the contrast between the prostate met and the normal decent bones in many cases so much better for PSMA, but I think it can be useful.

Whether or not this does this can be used for determining therapy, I mean that's going to be a question. The question is these planar bone scans are relatively cheap to do, but if we're talking about doing serial PSMA PET/CTs are kind of more to determine osseous disease, I mean, I think that becomes a real expensive proposition. I just don't think overall that these are going to replace bone scintigraphy for a large number of cases.

Phillip Koo: So you feel confident though that even though bone scintigraphy looking, assessing the bony response of the bony matrix that that is a more reliable source compared to something like a PSMA?

Ephraim Parent: No, it depends on do we need a drive. I mean, this goes into the policy [inaudible 00:28:48]. I mean, I think it's a good... Is it perfect? Absolutely not. Or like the sodium fluoride PET or if we did serial PSMAs? Absolutely, that's the best way, right? I'm not arguing that. I am saying who's going to be paying for that, right? Right now for fluciclovine PET, we have approved for a study for biochemical evidence. It's a very narrow indication, right? Now we will do those things. I know like at Mayo, we have many patients that have serial studies, but those are kind of off label and that's going to be depending on insurance and other things like that.

So with the bone scans, what we're able to see it's a very cheap technique to get a whole-body evaluation. We'll be imaging patients sometimes every couple months and I just don't see doing that with a PET. I mean, if we did I'd be very happy and ecstatic. I just, however, don't see insurance companies really wanting to do that.

Phillip Koo: Okay, agreed. I think there's still a lot more we need to learn about how these imaging tools will perform in a lot of these settings. Overall, I think it goes back to this idea that we talked a lot about before is we really need outcomes data to really show how these tests are impacting some sort of outcome measure.

Ephraim Parent: Absolutely.

Phillip Koo: I think that might be what helps us get over the hump when it comes to quantifying some of the bone scans that you discussed.

Ephraim Parent: Agreed. I mean, more large studies, like the [inaudible 00:30:27] study had a couple thousand patients. Those are the types of studies that they're very expensive, but really what we need to know what's going to be best. If overall why do we do imaging, we're hopefully doing imaging not to just let the patients know where the disease is, but we can really affect outcomes. If we can show that having serial PETs with PSMA are going to change outcomes and maybe with teaching PET/PSMA or Xofigo, maybe these things will happen. I think we just don't have that data yet.

Phillip Koo: Sure. Well, great. Thank you very much for your time and we appreciate the knowledge that you shared with us and we look forward to having you back some time.

Ephraim Parent: Thank you very much.