PM: What happens during PSMA radioligand therapy?

MH: The PSMA-ligand therapy now takes advantage of the fact that — as I’ve already proven with the PET scan, or in some cases unfortunately not proven, since there can also be PSMA-negative or low PSMA-expressing metastases — that this target structure is, at least assumedly, present in the body.

Now what I do is swap out the radionuclide used in the PET scan — Gallium-68, Fluorine-18, or sometimes Copper — and replace it with a therapeutic radionuclide. This means using a type of radiation emitter that releases what we call corpuscular radiation, or particle radiation. In most cases, when I use Lutetium-177, it’s what we call a beta emitter, meaning it emits electrons. But I could also use other radionuclides — we might get to those in a moment.

The radiopharmaceutical, as we call it, then binds to and is internalized by the cancer cell — in this case, via the PSMA. But this time, the goal is not to visualize it in an image, but to unleash its therapeutic effect.

And here’s what happens — what radiation, whether external or internal, essentially does to a cell: ideally, it begins to destroy the DNA of the cancer cell. The goal is to damage it so extensively that the cell can no longer divide, allowing the body to gradually break down and eliminate the tumor.

PM: You use different radionuclides — when do you choose which one?

MH: Yes — in fact, we offer several different radionuclides. On one hand, there’s Lutetium, a beta emitter that’s already widely established — it’s been used for over a decade in prostate cancer and even longer in other types of tumors because it has excellent properties: the beta radiation itself, its half-life, and its tissue penetration range, which is about one to two millimetres.

But we’ve also found — and this is currently a rapidly growing field of research — that other radionuclides can be extremely effective, sometimes even more effective against cancer cells while being gentler on the surrounding healthy tissue.

One important example here is Actinium, an alpha emitter that’s also been in use for a long time, at least in university settings, and is now increasingly being tested in clinical trials. It’s particularly well-suited for patients with extensive bone marrow involvement. Actinium emits alpha radiation, which has a very short range — about one to two cell diameters in tissue — meaning there’s virtually no collateral damage in areas where it doesn’t accumulate.

The only issue we’ve observed with Actinium-PSMA is that if treatments are repeated often, the salivary glands — which unfortunately also express this enzyme — can suffer damage.

In the bone marrow itself, even in patients with heavy marrow involvement, we see very little collateral damage, possibly even less than with Lutetium, because the radiation range is so short. That’s why we primarily use Actinium in cases with extensive bone marrow metastases.

And just recently, we’ve started offering Terbium-161 as well. This one’s a little more complex. What kind of radiation does Terbium emit? It’s somewhat comparable to Lutetium, with a beta component, though not as strong. But it also emits what are called Auger electrons and conversion electrons — I won’t go too deeply into the details here because it gets quite technical — but these have an ultra-short range.

This means the complex, once internalized into the cell, needs to get very close to the cell nucleus. Once it’s there, these electrons can release extremely high energy, potentially offering an even better chance of destroying the cell nucleus than Actinium’s alpha radiation. And because we don’t need to inject as much radioactivity as we would with Lutetium, there’s likely to be even less collateral damage.

However, we’re still in the early stages here — the first prospective clinical studies are currently underway. In practice, we tend to use Terbium when patients have become refractory to Lutetium and even to Actinium, and when we want to try one more therapeutic option, an individualized treatment attempt, with Terbium — though the available data is still quite limited at this point.

PM: Many clinics offer this therapy as an inpatient procedure, while you treat patients on an outpatient basis. Why?

MH: Cancer has a lot to do with the psyche, and especially at different stages of the disease — and particularly in earlier stages, where radioligand therapy is increasingly being used for prostate cancer — patients don’t want to be reminded of what things might look like in the final stages. They also don’t want to feel like they’re being locked away or treated as seriously ill when, in fact, they don’t feel that way.

Most patients walk into the clinic saying they don’t feel a thing from their prostate cancer, even if the PSMA-PET scan might suggest otherwise by lighting up with black spots all over. That’s actually what inspired us — coming from a clinical background, where we’ve done this therapy for years at the AKH in Vienna (Vienna General Hospital) — to rethink the situation. Until now, the only reason for keeping patients in the hospital was radiation protection, which dictated, “Well, just to be safe, let’s keep them for at least 48 hours,” as is still commonly done in Germany.

But we said: okay, let’s sit down with the authorities, carry out extensive measurements, and show that these patients aren’t actually a radiation threat to their surroundings. That’s what eventually got us the official approval. And in Austria, the trend — especially after our recent annual conference — is clearly moving in this direction. People are saying: of course, outpatient therapy is entirely safe from a radiation standpoint.

Of course, patients are given clear instructions, particularly if they’re going to be in contact with pregnant women or small children — in those cases, they’re advised to keep a bit of distance for about a week. That might mean not visiting the grandchildren or holding off on seeing a pregnant daughter for a few days. These are safety precautions that are easy to follow.

The treatment itself is short — essentially just a brief infusion. And while patients do have to drink plenty of fluids afterwards to help flush the substance out through the kidneys, that’s something any adult can easily manage at home. So there’s really little to no reason to keep relatively healthy patients in a hospital setting for this. It’s a different story, of course, with seriously ill patients — there the situation is handled differently.

PM: How does your therapy differ from other cancer treatments?

MH: Well, sticking to prostate cancer, there are very clear guidelines that have long placed hormone therapy at the start of treatment for metastatic disease. Hormone therapy, in its various forms — whether blocking hormone production or acting as an androgen receptor blocker — absolutely has its place. In practice, patients often see quick results with hormone therapy, but unfortunately, they also start experiencing side effects fairly quickly.

Chemotherapy, of course, is always a topic when it comes to cancer, and in prostate cancer — particularly with drugs like Docetaxel and Cabazitaxel — it has shown rather modest results. The side effects tend to be quite significant, and because prostate cancer typically isn’t a very fast-growing tumor, chemotherapy somewhat lacks a clear target.

Our target, ultimately, is radiation. And while we talk about it as if we were administering a drug — as it’s treated this way by regulatory agencies like the EMA and FDA — in the end, what we’re actually doing is a form of radiotherapy. The pharmaceutical component, the ligand that attaches to the cancer cell, could be administered in concentrations ten thousand times higher and still wouldn’t trigger any reaction in the body. That’s something we confirm through tests beforehand. The only therapeutic effect comes from the radiation. And that radiation can be delivered in different qualities, depending on the type of radionuclide we use. Essentially, it’s like external radiotherapy — but much more precise, because it takes place directly at the cell surface and throughout the entire body. That’s what fundamentally sets our therapy apart from external beam radiation.

PM: How well is radioligand therapy tolerated?

MH: We can actually build on what we just discussed. Because our treatment is extremely precise at the level of the cell surface, we see relatively little collateral damage. And here again comes the theranostic principle into play: first, I look at the PET/CT scan. In the PET/CT, I need to see, first and foremost, that the metastases ideally express PSMA more strongly than the other organs that also have PSMA.

And because — as I mentioned before — it’s somewhat misleadingly named, since PSMA is actually Folate Hydrolase, an enzyme, we unfortunately also find it in the salivary glands. I’ve already pointed that out. The kidneys also receive a certain amount of radiation. The other organs are typically less affected. The bone marrow gets a small dose too, but this is usually reversible. Prospective studies haven’t shown any significant, higher-grade side effects to a meaningful extent.

That said, if we perform many, many therapy cycles — and we have already done quite a few repeat treatments — we can start to see the salivary gland function slowly decrease over time. That’s understandable, because they are also exposed to some radiation.

Kidney function is generally only at risk when combined with other kidney-stressing medications, or if the kidneys already have pre-existing damage — whether from surgery, external radiation, other therapies, chemotherapy, and so forth. So it’s important to consistently monitor kidney function. Proper hydration before, during, and after the therapy is absolutely essential. And with good hydration management, even with multiple treatment cycles, we haven’t seen kidney damage occur.

PM: How do you check whether the treatment was successful?

MH: And here again, our wonderful PSMA-PET/CT comes into play. Within the theranostic concept, I can use the same target — as we call it — to check: is it gone? Ideally, of course, it’s no longer detectable. But we have to remember, we’re dealing with cancer, and cancer is something that can always strike back. There are cells in certain phases of the cell cycle where they’re not susceptible to damage — a bit like fungal spores hiding somewhere, waiting for a weakened immune system to reactivate them. That’s how recurrences can happen.

Naturally, what we’re doing here isn’t the holy grail that cures everything — recurrences can still appear later on. And if we detect something with the PSMA-PET but can’t resolve it properly, that sometimes has to do with the scanner’s resolution. We can’t visualize individual cells — that’s beyond the capability of current imaging — but we can use it as a surrogate marker. If the PSMA-PET no longer shows any activity, and ideally the PSA level is also undetectable — assuming the patient no longer has a prostate, because otherwise normal prostate tissue would still produce some PSA — then we can talk about a complete remission.

We can actually quantify the regression of metastases. We always compare the pre-therapeutic PSMA-PET, measuring both the volume of the metastases and their PSMA expression, which can be measured in the scan. Then we compare that to the post-therapeutic PET. We’ve already published studies showing that this measurement can reliably serve as a surrogate for the patient’s disease progression.