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Carlos Uribe: OK, so what I'm going to talk about is post-treatment imaging, and how does this move into dosimetry. So the problem here-- we're having patients. We, typically, get a PET. And then, well, we just keep going blindly while we have some clinical markers and maybe do some conventional imaging. But I think those, basically, miss some of the lesion-by-lesion response, the early sign of progression, and absorbed doses are rarely quantified retrospectively.

Sometimes, we even get some SPECT images, but we have patients that are very different. And well, we're still injecting both of them exactly the same without accounting for those differences, as my previous speaker said. And we know from the literature, patients, when we inject the same, they get different values of absorbed doses to the organs. They get orders of magnitude differences to the tumors. We've seen many of them are even not reaching the 23 gray that Ana was mentioning a moment ago.

So yeah. So we have a current practice misalignment, in which, sometimes, we are treating these RPTs like chemotherapy that happens to have radiation. But we know it's different, because here, the radiobiology is the pharmacodynamics of RPTs is that radiation.

But it's not exactly external beam radiation therapy. Here, we have the pharmacokinetics. That is completely different. And you saw the differences that Ana and Doctor Spratt were highlighting. Even that 23 gray is probably not making too much sense. So why not harness the full potential of theranostics to image, quantify, and guide treatment throughout the entire therapeutic journey?

And that's where I bring post-treatment imaging. And similar to what Tom Hope was talking yesterday, we can just use post-treatment SPECT to just monitor tumor response. And just by looking at the images, you can see-- OK, some tumors are disappearing and some others might be appearing.

This can help adjust treatment strategies across cycles or we can see some of those lesions that are appearing. And even just by looking at the CT portion of the SPECT-CT-- which is that white arrow that is shown in that image-- you can see that there are lesions that are not PSMA avid. But thanks to that CT, they can be detected. So those things can prompt changes in treatment strategy.

Well, this is my consensus for the selection of patients. And well, it starts with the PET-CT. And they allow the PET-CT within three months of starting of treatment. But as discussed also yesterday, well, things can change between that acquisition of the PET-CT and the first SPECT-CT. So this first cycle SPECT-CT provides a baseline for ongoing response assessments.

And we've seen from Doctor Hope's group that there's been a change in management when there's post-treatment SPECT performed. These papers showed management changes in about 27% of patients with higher grade tumors showing a higher rate of change, and primarily in cycles 2 and 3. That was for neuroendocrine tumors. But something similar should probably apply for prostate cancer

Now, post-treatment SPECT-- and there has been some discussions that we had yesterday about doing PET in between cycles. But I think post-treatment SPECT may obviate the need for those separate PET scans, because we're getting very similar information. Now, advantage here, there's no additional radiopharmaceutical needed. We already injected the patient. We can get the images with that injection, and it's way cheaper.

There's been discussions, like what's being shown in this paper by Doctor Iravani and Doctor Hofman that post-treatment SPECT might be important in the context of emerging cytopenias. Is that progressive marrow because of metastases? Or is it a treatment-related adverse event or cytopenias that we're seeing?

If there's a decrease in burden of the disease on SPECT-CT, maybe that's a related cytopenia. So maybe you can add delays of subsequent cycles, and recovery of blood cells is allowed, which may mean, if the metastasis is growing more, maybe you should go to another course.

And Doctor Emmett, also from Australia, has been showing that quantitative metrics that can be measured from these post-treatment SPECT images, like total tumor volume and SUVs, can be used to assess treatment response. And early changes in those quantitative values are associated with progression-free survival.

So I hope I convinced you a little bit why obtaining SPECT-CT images is beneficial. But once you collect SPECT-CT images, then there's a natural progression to performing dosimetry. Basically, this is the dosimetry workflow. And if that post-treatment SPECT-CT imaging is done in a quantitative way, we can just have guidelines for the acquisition protocols for SPECT images that are quantitative. Then we'll already have that first box that I'm highlighting there taken. So we can easily go through the rest of the dosimetry workflow.

Of course, ideally, as a physicist, I would like you guys to do more than one SPECT-CT imaging in each cycle because that will allow us to model the pharmacokinetics of the compound a lot better. But I understand that there's clinical limitations to bring the patient maybe more than once. So there's methods of having an estimate that use single-time-point scans. But to make it ideal and closer to the truth, I would recommend to do that scan closer to 48 hours.

Now, we do still have questions. We haven't yet unlocked how to dial in the response in radiopharmaceutical therapies, but measuring the absorbed dose is key to getting there. And if we want to try to answer these questions of "What are the absorbed dose limits for RPTs?" like "How we move beyond the 23 gray, but how high can we go?" or "What are the absorbed dose for tumor control?" Again, differences with external beam.

There's some initial evidence coming from our field. These are from radiopharmaceutical therapies which show nice correlations between dose and tumor response. And there's another couple of papers here. And once we have that, we can easily do the calculations in the clinic, and we can get into scenarios that look like this.

These are two patients treated at our institution. We perform dosimetry for them. And we have the total tumor burden dosimetry for both of them. And we also follow the kidneys. And we calculate a biologically effective dose. And we see big differences in tumor doses for those two patients. Although the uptake on PET was high on both.

So what do you think happened to these patients? Well, the patient at the top had a high absorbed dose to the tumors. The one at the bottom, not much. When we went and looked, the patient at the top responded very well. The patient at the bottom, not too much. And we kept following the BED for the kidneys. Although they got really close to 23 gray BED, none of these two patients have presented any toxicity.

So it can help us understand, if for example, that second patient should have gone to treatment. We're starting to have some more initial experience through our trial that we're performing at our institution in which we're injecting, and we're adjusting the administrative activity for subsequent cycles based on dosimetry. We're trying to reach the 28 gray BED to the kidneys as the limit.

But we, as you see, we're changing the slope on that first graph as we go on, and we see changes over the cycles. We still have questions if we should go to 28, 240, 250 or to some other different value in there. And that's what we need to collect the data.

But what does all this mean? Well, I think both post-treatment imaging and dosimetry can help us answer questions like, "Should this patient go two more cycles?", "Should we delay some of the cycles?", or "Should we just completely interrupt treatment?"

Our field is moving in this direction, in which what we're starting, what we're doing lutetium therapies. But actinium is becoming more the next therapy of the future. So as we move to alpha therapies, and we're going to be bringing some of these patients for retreatment, are we really just going to blindly send them to the next course of therapy or do we need the information of how much absorbed dose we have given those patients in the past?

We saw the news yesterday. Things are moving earlier on the disease course. Maybe some of these patients are going to start living longer. It's good to have track of how much radiation dose are we giving to these patients.

And Doctor Spratt talked a moment ago, and there's discussions that we had yesterday. What if some tumors are not fully reaching that dose, but we can boost them with external beam radiation therapy? Well, if we're going to do these combination therapies, it's important to know exactly how much absorbed dose we are giving to those tumors and organs.

So should we do dosimetry for every patient? Well, I would like to say yes. And hopefully, one day, we get there. I think that's where we should be headed. But I understand that we currently have some limitations, and we need more infrastructure. And we need more stuff. But I think there's a good cohort of our population.

From my perspective and from the discussions that I have with different colleagues and group, maybe, I would say, as a start, patients with a single kidney with eGFR less than 50, or patients that are going through dialysis or retreatment, maybe patients over 80 years old is a good cohort to start collecting data for dosimetry and making some of those decisions.

Thank you very much.