Oliver Sartor: Hi, this is Dr. Oliver Sartor. I'm with UroToday, and I'm going to have a very special guest from Melbourne, Australia. This is Dr. Rod Hicks. Dr. Rod Hicks to me is an extraordinary professor, although he doesn't use that term. He's going to be the founder of MTIC, which is the Melbourne Theranostic Innovation Center, and he put it together in order to advance theranostics. Rod, welcome to the show.

Rodney Hicks: Thanks very much, Oliver. It was a great pleasure to have you visit us here in Melbourne and to share some of our experience with you when you were here.

Oliver Sartor: It was a great pleasure for me. Let me begin by talking a little bit about what Rod showed me when I was in Melbourne that I found so extraordinary, and then we'll turn it over to Rod for an explanation that'll be much more intelligent than mine.

So when I went to Melbourne and went to MTIC, Rod was able to show me sensitivity of the PSMA PET scan in a manner that I'd never seen before, with extraordinary kinetics of imaging that I'd never seen before. And it was so eye-opening, I didn't even know what to think. Rod, you impressed me with the work that you've done and the innovation, and I wonder if you can share some of that with our viewers.

Rodney Hicks: Yes, certainly I can. One of the great advantages of the scanner that we have, which is a Siemens Biograph Quadra, is that it's got an axial field of view of over one meter, compared to around 20 to 30 centimeters for a conventional PET scanner. And that means that you can simultaneously image from the head to the upper thighs in individuals, and that gives us a unique opportunity to look at the kinetics or the uptake of a tracer as it passes through the body and accumulates in areas of tumor, but also in normal tissues.

One of the things that we've known for a long time is that PSMA is a high-affinity target that has ready access to the bloodstream. And so, you get rather rapid uptake and many people have done early imaging of PSMA. The problem with that is that eventually the radiotracer appears in the bladder and obscures the visualization of sites of disease around the bladder, particularly in the post-prostatectomy setting, where the most likely sites of recurrence are right at the anastomosis or in the vascular pedicles on either side. To acquire enough statistical quality in an image on a conventional scanner takes about three to five minutes, whereas with the Quadra, we get about ten-fold higher sensitivity than even the best digital conventional field-of-view scanners, and about twenty-fold higher sensitivity. And so, an image of 30 seconds to a minute is very high quality.

And almost with the first patient we did, and I can show you a slide of that, we saw an anastomotic and pedicle recurrence in a patient before there's any arrival of urine in the bladder that gets obscured by the urine as it comes down on delayed imaging and it's often missed. And we're also seeing very small lesions, in terms of lymph nodes, and we analyzed our first 300 patients done here at MTIC and found that the sensitivity or the positivity rate that we were getting in patients with PSAs less than 0.2... And most guidelines currently recommend, don't do it, it's a waste of time, you're not going to get a positive scan. Our positivity rate in that population was 67% in that group, and goes up to over 80% once we get more than 0.5.

But importantly, we also looked at the distribution of disease, which was really worrying to us that once the PSA got above one, we were finding that almost 50% of patients had disease outside the pelvis and clearly not salvageable by local radiotherapy. And the percentage of both metastatic disease and retroperitoneal nodal disease, which clearly can't be controlled by salvage pelvic radiotherapy, was significantly increased as the PSA went up. Actually, even at the lowest PSA level, we were still finding retroperitoneal nodes or oligometastatic bone disease in about 10% of patients. And so, this makes a huge difference to our salvage protocols for patients with biochemical recurrence.

Oliver Sartor: Indeed, true. And I've done a lot of salvage radiotherapy studies and I'll simply say, despite our very best efforts, they're never as good as we might have hoped. But with this imaging, the truth is that maybe we could be better clinicians knowing where to radiate and potentially taking an oligometastatic patient, adding in a little SBRT for those errant metastatic lesions, and probably get a better outcome.

I wonder if you might have any photographs or slides where you can show our audience exactly what you're talking about. And when you showed it to me, you had a little video with the uptake that I found impressive. I don't know if that's feasible for you today.

Rodney Hicks: Yeah, I can certainly share some of our slides that demonstrate the experience we've had.

Yeah, so this was one of the very first cases that we acquired. So this is a one-minute acquisition, about five minutes into a 10-minute dynamic series. And you can see by that stage, we can see focal abnormality on the dynamic image right at the apex of the bladder, consistent with an anastomotic recurrence. But also, a second area on the right of that, on the left as you look at the whole-body image, but you can see that very clearly in the top frame before there's any urine in the bladder, how clearly you can see that pedicle recurrence.

The other thing you'll notice on this image is that there's a focus of activity in the lung, which is there very early on and actually gets a little bit brighter as time goes by. And here's the sagittal image showing again, the anastomotic recurrence, which you wouldn't pick up on the delayed image because of the intense urinary activity in the bladder. Background activity matters, and dynamic imaging is feasible, and you can do it on a conventional PET, but the statistics are much poorer. But what you wouldn't get are the dynamics of uptake in this lung lesion showing that this gets more intense with time.

And so, what we've also found is that with the Quadra having very high sensitivity, we can do whole-body scanning in very short time. The image on the right is the delayed whole-body scan, about an hour after injection acquired in four minutes. And a very tiny retroperitoneal lymph node here, which is very close to blood vessels, not very well seen on the initial dynamic image where there's a lot of blood pool activity, still activity in the blood. So we can see those small retroperitoneal nodes that clearly make a big difference to the likelihood of this patient being salvaged. And in fact, they had no disease that we can identify either in their prostate bed or in pelvic nodes, just solely retroperitoneal nodal disease. And so, this is a win for the sensitivity with delayed imaging. So combination of the high sensitivity for prostate bed recurrence with the dynamic imaging and the much higher sensitivity for small-volume nodal disease with late imaging becomes important.

And the second aspect of doing multi-time point imaging is that the kinetics of uptake in prostate cancer have been well demonstrated by particularly Marty Pomper's group that showed that over time you get progressive accumulation and increase in intensity in the primary prostate cancer in nodes and in bone lesions. There are false positives in bone that have become very problematic on a single time point, but what we've seen is that benign lesions, because the uptake is primarily in pericytes rather than in tumor, you get washout over time. This is a hemangioma of the thoracic spine where the early blood pool images show quite high uptake that clearly washes out over time. And we found this to be a very useful technique for differentiating those uncertain bone lesions that everyone worries about, and potentially denying patients curative treatment when they have truly localized disease because they're assumed to have potentially metastatic disease. So they end up on ADT or avoid RP or sometimes even get chemotherapy for presumed metastatic disease.

Oliver Sartor: Rod, I want to ask a question for clarification. When you're looking at these early changes before there is activity within the urinary bladder, are you imaging at one minute, two minutes, three minutes? You talked about the acquisition time, but I didn't quite understand the kinetics after the injection. And you talk about the dynamic, and then so you're actually watching a video and then choose the frames to show us? Tell us a little more about that super early imaging.

Rodney Hicks: So, this is actually our current acquisition protocol, where you can see we acquire a 10-minute dynamic series. It's actually acquired in something called list mode, which we can break down even into one-second images to look at the transit through the lungs or the heart, but we reconstruct that as 10 one-minute frames and we look at those to find the last frame before there's any radioactivity in the bladder, because that gives the most time for accumulation in sites of tumor without being obscured by activity.

We then wait around 60 minutes, we get the patient to void and give them diuretic. And the reason we delay the diuretic is that some people have given diuretic about the same time as they give the tracer. The problem is that you are then forcing radioactive urine through the kidneys into the bladder. By delaying it, you allow the radioactivity to clear the blood and you're putting non-radioactive urine into the bladder. We wait 30 minutes, get the patient to void, and wait another 10 minutes for the bladder to refill, and that gives us a beautiful outline of the bladder and the relationship of recurrence. And in this case, you can see a small pedicle recurrence very clearly against the dilute urine in the bladder at that time point.

The other advantage of this particular approach is that we get incredible definition, so that's another series. And the last frame that the urine gets there is around frame 6, and on the frame before that, frame 5, you can see this posterior bladder recurrence between the pedicles. And in fact, clearly can't see that on the 90-minute post-injection image, but with the post-diuretic image, you can see that focus very clearly. And we found that the dynamic imaging had a high impact in identifying disease in around 44% of patients that we wouldn't have appreciated on the delayed image alone.

The other thing for the surgeons on the call or listening to the podcast is that we get incredible vascular anatomy from the dynamic image. What you're seeing in the red arrows there is the external iliac artery on frame 1, and the internal iliac with both anterior and posterior branches. So the relationship of nodes to those major vessels can be identified from that initial dynamic frame. Ignoring the fact this patient also has an axillary vein thrombosis and chest wall collaterals that you see on the first frame. But also in the later frames we get the ureters, and so you don't need a contrast urogram to identify where the ureters are. We get them generally on the later frames of the dynamic imaging series. And so, I used to do a lot of CT urograms so that we could identify nodes close to the ureter or where there was urinary pooling in the ureter, particularly as it goes over the iliac vessels, which can cause some diagnostic dilemmas. We can really exclude that very accurately because we know where the ureters are on these scans.

So, all of it sort of adds up to giving us, I think, a much more accurate view of the extent of disease. We had our MDT this morning and one of the radiation oncologists was asked whether they do MRIs anymore for biochemical recurrence and looking at the anastomosis, he says, "No, I just trust the MTIC scans and just irradiate them." And it's really changed their practice.

So for example, when there's a localized pedicle recurrence, they'll do stereotactic just to that site rather than the whole prostate bed, and it's virtually asymptomatic for the patients. Instead of getting all of the issues around rectal tenesmus and incontinence and bladder irritability, when you have a very small focus like that and you can give highly targeted radiotherapy. And we've got enough follow-up now and we're collecting more follow-up that when they're doing this very highly targeted salvage radiotherapy rather than whole prostate bed or whole pelvis, one or two nodes, they're treating those. We are getting very excellent PSA responses, confirming that these are true positive findings. But also, significantly delaying the onset or the need for ADT and systemic therapy. And as you know from long experience, the earlier you put someone on ADT, the earlier they become resistant to it. And so, that has to have an effect notwithstanding the side effects that patients get from being on those therapies. So if we can delay it, we think that that's a good thing.

Oliver Sartor: Absolutely, Rod. Let me ask a little bit about the tracer. Is this like PSMA-11, gallium-68, or is it some special tracer?

Rodney Hicks: We use both PSMA-11 and DCFPYL. And as you know, we're a research and development company. MTIC was mainly established to do that, so we're also trialing a whole range of next-generation prostate imaging agents as well as for other cancers. And the Quadra is ideal for this because we can do imaging of gallium out to four hours after administration. We've done out to eight hours after a fluorinated tracer, with very high quality images and quite reasonable acquisition times that are bearable for patients. And that gives us unbelievably good pharmacokinetic curves for biodistribution and enables us to optimize the subsequent acquisition protocols: should we be imaging at 40 minutes, at one hour, at an hour and a half or two hours with a given tracer. And we can do that at very low radiation doses for the patients, which is exciting.

Oliver Sartor: Rod, there is a bit of discussion around copper-64. I think you know a bit about that, and I don't want to veer too off topic, but I wonder if you might give a succinct view of copper-64 as an isotope for imaging.

Rodney Hicks: Yeah. As you'd be aware, there's the copper-64 bis-PSMA that Clarity has been developing. It was actually developed through my lab in collaboration with a researcher at the University of Melbourne, Paul Donnelly, and we did the initial preclinical studies with that agent and it was pretty exciting. I had also done work with a somatostatin analog with copper, we did the first-in-human study when I was at Peter Mac. And the exciting aspect of that is that the long half-life of copper, around 12.7 hours, allows time for clearance of activity from the blood and from the urinary tract, so you can potentially get more sensitive imaging. What the advantage of that is in comparison to this... now, some of the challenges that copper overcame, I think we overcome with improved technology.

But nevertheless, the real advantage to me is that there is a therapeutic version of copper, copper-67. And with late imaging and the Quadra, we've done out to 30 hours of imaging with copper-64 that you can do comprehensive dosimetry, prospective dosimetry to calculate the doses that you would deliver to your salivary glands, your kidneys, your bone marrow, and your tumor. And that enables you to select a dose of copper-67 that is going to have a high therapeutic index. And that's probably the major advantage. But I think diagnostically, the advances that we are seeing in new radiopharmaceuticals for prostate cancer are perhaps a little less clear than I thought they might be in the earlier days of development.

Oliver Sartor: Fabulous. I'll simply say, it is an absolute pleasure to have you here on UroToday. I love your dynamic imaging, I love your sensitivity. I appreciate the creativity of your approach, and I'll simply say, thank you for being here this evening. I think our audience is really going to appreciate your wisdom.

Rodney Hicks: It's been my great pleasure. Always lovely to talk to you and wish you well in your fishing and other endeavors.

Oliver Sartor: Thank you, Rod.