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Bennett Chin: Hello. My name is Dr. Bennett Chin. I am a faculty physician at the University of Colorado in Denver, Colorado. My topic today is a presentation on Lutetium-177 PSMA. This is part of a series of presentations on prostate cancer, imaging, and therapy sponsored by the Society of Nuclear Medicine.

So what is Lutetium-177 PSMA? Lutetium-177 PSMA is in a class of agents that are investigational, but they are targeted, radionuclide agents. At the moment they are not FDA approved. This overview is provided to review the basic principles of Lutetium-177 PSMA, and also to provide a brief overview of the existing data.

PSMA is a Prostate-Specific Membrane Antigen. This is a target molecule that is highly expressed on prostate cancer cells. Overexpression or increased expression is seen in higher grades of prostate cancer cells. It is a relatively specific molecule for prostate cancers.

So there is very little expression of this molecule on other cells, very little off-target expression in normal organs. It is also the same molecule to which the PET imaging agents bind in prostate cancer. So a Gallium PSMA scan binds to this PSMA molecule on the surface of prostate cancers, as does the F18 version or F18DCFPyL more commonly abbreviated as PYL PET/CT imaging.

Lutetium-177 is a radioactive beta emitter, and that is the therapeutic radiation that gives the cytotoxic or cell-killing effect to this agent. It's bound to the PSMA and it delivers targeted radiation therapy to these prostate cancer cells. So very direct radiation.

Beta emission is a type of radiation that travels only a very short distance within the body, typically a range of about a millimeter. So it delivers that radiation right to the target.

Lutetium-177 is also an emitter that gives off a small amount of what we call a gamma emission. Gamma emission is a penetrating emission, but very little of that is given off. So there is very little off-target radiation given to the normal organs and very little radiation to the people around the patients being treated. Lutetium-177 itself has a physical decay half-life of 6.7 days. So it sticks around for quite a while.

How does it work? Well, it's administered intravenously, and then it binds to the PSMA on the prostate cancer cells. It is then incorporated into the prostate cancer cells where it's retained so that radiation is delivered directly to those cells with very little excretion. The amount of Lutetium-177 PSMA that is not bound is excreted primarily through the urine.

Right now it is given in research protocols. So it's typically given as four to six injections at six-week intervals. Before and after every therapy, we take blood to measure bone marrow, kidney, and liver function to monitor those as the therapy progresses.

So what are the precautions for Lutetium-177 PSMA? It's given as a research protocol and radiation that is delivered to others around the patient is relatively low, so it can be given as an outpatient. The infusion takes less than five minutes and the observation period is also very short, typically less than an hour.

The precautions are based primarily on its route of excretion through the urine. Because of its urinary excretion, emphasis is placed on good hand hygiene. Precautions are taken to avoid contamination from urine and there is very little or minimal excretion from the bowel and salivary glands.

So what are the potential side effects of this therapy? Adverse events are typically less than those of chemotherapy. Mild to moderate adverse effects include bone pain, dry mouth, nausea, diarrhea, vomiting, low blood counts, dry eyes, abnormal sensations, such as tingling, which can be neuropathy and abnormal taste sensations. Severe adverse events can include bone pain or low blood counts.

So how effective is this new research agent? Well, data collection is still ongoing but the data thus far is very encouraging. It is potentially more effective than chemotherapy. It potentially is also the most effective single therapy. It has potentially fewer side effects compared to chemotherapy, and the preliminary data reported thus far has shown an improvement in overall survival.

Here's an example of PSMA scans before and after therapy in several patients. In the upper left corner, you can see patients with a tumor indicated by the red dots prior to therapy and below that their PSA values. In this patient, there is abdominal disease and a PSA of 15.

After therapy, as you can see just to the right, the patient's disease has resolved, and the PSA value has decreased to less than 0.01. As you can see in many of the other examples here, PSA values that were very high in the hundreds can go down to the single digits as in the next slide where you see a lot of disease in the bones essentially being resolved after therapy. These slides show the systemic effects of the PSA going down as well as the systemic treatment of prostate cancer throughout the whole body.

So the take-home message is that Lutetium-177 PSMA is a research agent still under late-stage studies. It specifically targets prostate cancer cells with beta radiation and studies thus far are very encouraging, showing results of therapeutic efficacy with relatively modest toxicity.

And finally, I'd just like to acknowledge my colleagues who helped with this presentation and the content and comments that they provided.