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Daniel Spratt: Appreciate the invitation, once again, to speak to you guys. This is the topic given to me: What lessons from radiation oncology can you guys use to improve PSMA RLT?

So to start, I’m going to—well, that last talk was actually fantastic, and one of the best in terms of using this correctly—but I’m going to actually challenge you a little bit more.

And I intentionally—sometimes people say I’m a little abrasive—so I took out the photos from the other talks here that have misused the term dose and dosimetry, not to call people out, but because what has followed throughout this conference—amongst most—this is the experts. So when we talk about going outside of this conference—constantly, we’re seeing people don’t like dosimetry or dose-escalation studies, and we’re just talking about gigabecquerels.

You look at this nice little paper from The New England Journal of Medicine with experts, industry experts, expert reviewers—and this is where I’m at: a dose of 7.4 GBq. That’s not a dose. You can go look. The ICRU has a report on dosimetry-guided radiopharmaceutical therapy. They define all of these terms for you guys. This is not a subject of debate. These are the terms.

This is what dose is. This is what activity is. These are the units. I would encourage you to read this paper if you don’t know what a biologically effective dose is, LET, or RBE. This is very important. I do not have time to go into all of this. It is not really actually a debate that dosimetry matters for radiopharmaceuticals. It’s more so that—I’ve actually asked many experts here, “How confident are you that you can tell me the exact absorbed dose throughout a given tumor?”

Almost everyone says no one can do that in this room. Whether you want to tell me you can—please let me know. But there is a dose–response relationship. We know in prostate cancer, we have many, many trials with external beam. And again, this is approximating the equivalent dose in 2 Gy per fractions (EQD2). At about 60 Gy, you get about 50% control. When you get up to about 95 Gy, it’s about 95%. It starts to plateau.

But if dose is not dose—you look at this—right here: 160 Gy of LDR brachytherapy is about as effective as 40 Gy of SBRT. So you can’t just, in your paper, say “we gave 10 Gy.” I have no idea what that biologically effective dose is.

So we’ve learned—this is going back now 40–50 years—and the last talk gave some insights into this:

Split-course radiation therapy has shown inferior outcomes in trials. And this goes to the four R’s of radiobiology. This is from—you can see—1975, 50 years ago. All these principles were fully fleshed out. It’s time to start using that in radiopharmaceutical therapy.

You are going to have repopulation—you just saw that beautifully in a clinical case.


You will have repair, which is what you’re also seeing.

Reoxygenation, which probably is more relevant for betas, and reassortment.

We also know geographic miss. Now, we could talk about this when we switched to IMRT, when we went from doing these huge box fields to now trying to conformally treat. When you miss something, the patient recurs.

You can look at the ORIOLE trial. When you ignore the PET-positive lesions, you're going to recur. So don’t miss disease. The minimum dose within a tumor matters, right?

This is an example of spine SBRT. That’s a vertebral body. The center is the spinal cord. Part of that, if you can see—my cursor doesn’t show—right at the anterior part of where the spinal cord would be, it’s underdosed.

That is going to drive the recurrence in this patient. It does not matter that you blasted all the rest of it. Because you underdosed just a small part of it, it’s going to recur. And you can see that in the Kaplan–Meier curve from Sloan Kettering. The tumors where minimum dose was not enough—they’re going to recur.

So I’ll fly through this because of time.

But again, some fundamental differences that are important to note: external beam, of course, is directed to the tumor. It’s independent of PSMA expression. Of course, if we’re talking about lutetium-PSMA or PSMA-targeted agents, it is not targeting tumor per se—it’s targeting PSMA, which happens to predominantly be on tumor—but it’s dependent on that expression.

And as you’ve seen, that expression goes away for many different reasons.

The fractionation—we’re giving radiation in seconds to minutes with external beam. If you’re talking about lutetium, we’ll say it’s delivered over the course of about one week. Very low dose rate. If you give six cycles, it’s over—what—36 weeks. There’s going to be, obviously, very heterogeneous dose response.

And then again, what organs are going to be impacted? That’s going to be driven by different things.

What would be incredible is—how do we get—and you’ve heard a lot of talks inching closer—but how do we get to some semblance of patient-specific dosimetry? It is mandatory. You could never treat a patient with external beam without pre-treatment planning and dosimetry.

We have as many dosimetrists in our department as physicians. How many dosimetrists work in your nuclear medicine department? Zero? OK.

So I think this is something where an investment is going to need to be made.

So how can we improve it? To fly through this:

Please, do not assume more activity, more cycles equals more absorbed dose or biologically effective dose.

I could give 100 Gy in a single fraction—not to the tumor. The tumor is going to stay there. So if you can’t prove that you’re actually giving more dose to all of the tumors, you may just be simply treating a subset of them to higher dose and leaving the others to receive inadequate dose.

Don’t miss the target. Now it’s even more relevant.

I think it is insane that people—especially now that it’s in this pre-chemo space—if you’re not getting an FDG PET, or a really good anatomic imaging, you are going to miss tumors that you’re going to leave there.

This is a very expensive treatment. You can’t use endless cycles.

I will always get a PSMA PET before doing MDT. I’m not going to base it on a CT and bone scan. I would never treat a prostate without getting an MRI.

Do not underdose the tumor. You guys just saw the data. If you have low PSMA expression, there’s probably—there’s no survival benefit. So you need to think—if you can’t get enough dose in there, why are you just giving something knowing they’re going to have a poor response?

And this falls right in there.

And lastly, don’t just rely on one thing, and I’ll get back to this.

You can overcome many of these things—this is my question from yesterday—with external beam radiation therapy to complement radiopharmaceutical therapy.

So we talked about this. You have fewer than five metastases. Why are you going to go give radiopharmaceutical therapy, when you could anatomically target these areas?

If you have low SUVmean, you know you’re not going to have sufficient dose to the tumor, you could either augment or complement and treat that with external beam.

Or if you’ve got a whole bunch of disease that’s not PET-avid, there’s probably a better treatment—especially if this moves earlier and earlier.

What I hope we can get to is that if there are tumors that you know are going to receive less than 40, 50, 60 Gy, we know they have a 50% higher chance of recurring.

And if this goes into mHSPC, where they’re going to live for years, that’s absolutely unacceptable.

So to show this—what I verbally said yesterday—here are two randomized Phase II trials of five or fewer mets: the rPFS benefit of just using MDT to these mets.

This is what you guys see from PSMAfore. In this setting, it’s almost identical—the rPFS benefit.

This is, of course, in patients with generally a much higher burden of disease. But you should be preferentially using a therapy for the patients who are going to benefit most.

This is just a case example. And I’ll fly through it:

Given ADT plus ARPI. The patient progressed to CRPC, got chemo, had progression, ended up getting radiation to the primary because the mets didn’t recommend it earlier, and they were obstructed and bleeding—and that resolved.

They had disease throughout the retroperitoneum and bone, got lutetium-PSMA. And despite a great PSMA response, the CT response—there was actually growing disease. They had celiac plexopathy, a huge mass. Fortunately, we have some great med oncs. They sent it to us. We gave dose-painted SBRT, and they’re going to continue with the remainder of cycles because there was still some PET avidity.

So if Michael Hofman, I think you’re here—this is the question for you guys: What does dose mean?

I show you on the left our neoadjuvant SBRT trial before surgery. 0% of patients had positive margins, and this is a very high-risk cohort. We gave 70 Gy EQD2.

LuTectomy—a little less aggressive cohort—almost half still had positive margins.

So definitely not as effective at eradicating microscopic disease.

The absorbed dose written in that paper is listed here. The question for you is—what the heck is 50 Gy? Is this BED? Is this EQD2? What does that mean?

And in the patient that got 115 Gy, it said there was zero response, pathologic response. So that 115 Gy is not EQD2. That would ablate the entire gland.

Thank you.