Wolfgang Fendler: Hello everyone. My name is Wolfgang Fendler, and it's my pleasure to introduce to you our module three together with my colleague Stephan Himmen. We are both from the Department of Nuclear Medicine of the Essen University Hospital. And we'll be talking in this module about performing a PMSA PET/CT scan and the aspects of indication, preparation, and execution of the scan. It is important to note that these are expert recommendations summarized in these slides and these recommendations were made in accordance with the joint EANM/SNMMI procedure guideline whenever possible. But, of course, also local law and national regulations and guidelines are not affected by additional information and should be taken into consideration for how to perform a scan.

We have separated the information into six major sections, and we will start with the indication part and used case scenarios for the PSMA/PET imaging, then go over to patient invitation information to patient consent, and then subsequently to patient preparation and the application of the PSMA ligand and then how to perform the PSMA scan itself and finally how to report. And we will, of course, summarize our information. In the first part, I will talk about the indication. There are three major used case scenarios for PSMA/PET imaging, which are highlighted here. And these are the initial staging of high-risk prostate cancer, localization of recurrent or persistent prostate cancer. And then also staging of prostate cancer prior to a PMSA-directed radio radioligand therapy.

The first and most important indication would be the initial staging of prostate cancer in patients that present with high-risk features. And these are summarized here in line with the findings of the pro-PMSA study. These are ISUP grade groups three to five or a PMSA of 20 or higher or a clinical-stage of T3 or higher. And when applied in these patients with high-risk features, PMSA-PET/CT has revealed a 27% greater accuracy when compared to a CT and bone scan as shown in the pro-PMSA study cited below. The second important indication or used case scenario is the localization of prostate cancer of recurrent or persistent disease.

Biochemical recurrence after prostatectomy is defined as a PSMA rise of 0.2 or higher measured six to 13 weeks after prostatectomy, which is also confirmed by a second measurement, but it's also defined as PSMA rise of two or higher above nadir achieved after radiotherapy. And on the other hand, biochemical persistence is defined as a consistently elevated PSMA level of 0.2 or higher six weeks or more after prostatectomy. And these scenarios are important indications and used case scenarios for PSMA-PET imaging. And then, of course, PSMA imaging is important prior to indication of PSMA directed radioligand therapy. And it's important to used PSMA pet imaging to assess the level of PSMA expression of lesions prior to therapy. And of course, a low piece PMSA expression in measurable lesions would pose a contraindication for radioligand therapy.

And low PSMA expression is rated in reference to the liver in ligands with renal elimination, as you will see in a further slide, and it's measured in reference to spleen uptake for ligands with hepatic elimination, an additional FTG-PET scan is feasible and might support the evaluation to detect the differentiated tumor lesions or secondary malignancies prior to a PSMA-directed radioligand therapy. This is an example of how PSMA-PET is used prior to PSMA therapy. This patient shows extensive bone disease in month one at the start before the start of radioligand therapy, as a PSMA level of 10.4. These metastasis demonstrate an intense radioligand uptake above the liver and spleen, and subsequently, two cycles of PSMA therapy are being performed leading to a partial response at month four and a rapid decreasing PSMA level.

And after further two cycles of PSMA therapy, the patient demonstrates a near-complete response with very low piece PSMA levels at month seven, and a good treatment response due to high PSMA expression of this initial disseminated bone disease. On the other hand, here's an example of PSMA-PET imaging when compared to simultaneously or year FTG-PET imaging, and both images can reveal the differentiated disease when they are compared to each other. In this patient, we note two lesions of the liver, which demonstrate high uptake on the FTG scale and are not depicted on PSMA-PET. And these are shown here by the red arrows and on the axial slices, there are two liver lesions or liver metastasis who demonstrate a high FTG uptake in the upper roll images, but absent or very low PSMA expression. And this is consistent with the differentiated disease.

This is a relevant hepatic mismatch, and most of these lesions show an uptake below the spleen and liver, and therefore PSMA radioligand therapy would not be indicated and useful in this patient. Next, I will move on to information on the patient invitation and important to note for patient invitation is that the patient should be informed about bringing several important information's. And these are previous reports, including recent lab results, which should include PSMA kinetics. And these should also include Gleason score. And of course, if an iodine contrasts CT is planned, the kidney and thyroid results, these previous reports should also include previous studies, imaging studies for comparison, and a recent history of prostate cancer, specific medications and treatments. The invitation, which is sent out to the patient should include information about the duration of the procedure, which would be two to four hours, depending on the local specific protocol.

And it should indicate that the patient does not have to stay NPO. Fasting is not required, and most medications can be taken normally prior to the scan. Of course, the prior appointment confirmation from the patient side is recommended in order to reduce downtime on your scanner operation. Next, we move on to the patient consent before we can move on to the patient preparation. For patient consent, it's important to explain the procedure and duration of the scan to explain that there will be radiation exposure involved and to explain the level of radiation exposure, of course, all in accordance with the local and national laws that apply. It's important to note that both the tracer application, as well as the CT contrast application might come with extravasation of the injection site. And it's important to note that if a CT contrast-enhanced protocol is used, that there might be consequences of this protocol summarized here as allergic reactions, thyroid malfunction, or kidney malfunction due to the CT contrast agent.

There are further important information for the patient of consent, which is talking about the prostate cancer-specific history to understand the individual patient's indication, which would be for primary prostate cancer to talk about the initial PSMA level, the Gleason score, and the T stage if it is known. In biochemical recurrence, it's important to talk to gather information on PSMA level on previous treatments, which are outlined here, numerous local but also systemic treatment options are important for scan interpretation. And to talk about the current medications, and to list current medications, to talk about current symptoms that might be important for how to conduct the PET/CT. Of course, it's important to discuss previous studies and examinations that the patient might know of and to clarify relevant co-morbidities before starting into patient preparation. The next step is patient preparation. And for this, I'm happy to hand it over to my colleague, Stephan Himmen for the next three sections.

Stephan Himmen: Thank you very much Mr. Fendler. Now, that we have acquired a patient's content, we have to prepare him for the upcoming scan and for the upcoming PSMA ligand application. Prior to the preparation, we have already gathered up the relevant information to perform the patient education about the upcoming scan and the whole procedure. Now, you have to apply a venous catheter. The size of the catheter depends on the used case. So if you're performing a PSMA-PET/CT scan combined with a CT in low dose quality, you have to apply a venous catheter with a smaller diameter compared to a protocol where we are using a CT with a contrasting agent where you need high flow. Depending on the PSMA compound, which is going to be used, patients should be hydrated during the uptake time in this case, meaning the time between application of the PSMA ligand and the skin itself, and it could also be beneficial to implicate furosemide as an i.v bolus.

In this case, you should keep in mind that too early application of the furosemide can lead to a prior PSMA elimination because it doesn't have enough time to accumulate in the tumor lesion. So it's recommended to apply the furosemide 30 to 45 minutes after the PSMA, like an application. This is where you should also keep in mind that furosemide has contraindications. And it's very important to ask the patient whether there are any urinary obstructions or kidney stones, as well as non-allergies to furosemide. Regardless of the used protocol and the used PSMA ligand, patients should always be sent to the bathroom right before the scan to void the bladder. Just so there is no remaining urine activity. We'll monitor this later. The PSMA radiotracer activity should be injected in accordance with its specifications, and it should always be flushed after the injection of the radiotracer with at least the same volume of 0.9 percentage saline solution.

This small table gives a short overview of the most commonly used PSMA compounds. As you can see, the PSMA compound always consists of two parts. The first part, which is either the Gallium or the fluorine is the so-called isotope. The second part of the PSMA is the PSMA compound itself. It's most notably that the isotope itself doesn't give any function to the tracer. Most of the function comes from the PSMA compound. So the isotope is actually there to provide a detectability in the body. So it provides the irradiation so that we can follow the trace inside the body and look at where it's going and where it's accumulating. The function and behavior of the PSMA compound is defined by the PSMA itself. The Gallium PSMA traces have a shorter half lifetime, it's just a physical half-life of the isotope itself compared to the fluorine-18. You can see that most of the traces are eliminated via the kidney.

Only the PSMA-1007 is mostly eliminated through the liver, all the PSMA traces and all the PSMA compounds after the injection should be flushed with at least the same volume of 0.9 percentage saline solution, just as I mentioned before. For the Gallium tracers, the injected activity is between 111 and 259, which is roughly about 1.8 to 2.2 per body weight. For the F18 traces, the injected activity should be between 296 to 370, which is roughly three to four per kilogram on body weight. You can see the uptake time again, uptake time meaning between tracer injection and the scan should be for all traces, at least 60 minutes. You can see that the F18-1007 has a longer uptake time. Studies indicate that for almost all of the PSMA compounds, the ideal uptake time would be two to three hours, but that's very difficult to perform on a daily basis.

And you have a very good contrast for tumor lesions and soft tissue in times of 90 to 120 minutes. For the PSMA compounds, which are orally eliminated, it's advised to perform IV hydration prior to the scan with at least 500 million liters are fluid, and it could be beneficial to also inject the furosemide 30 to 45 minutes after tracer injection. Fluoride is not needed in an F18-1007 compound because it's not really eliminated prior. Hydration can be beneficial depending on the protocol you are using. For example, if you intend to use a CT contrasting agent, it can be beneficial to hydrate a patient prior to the scan. This is a small overview of the things we need, or we use when applying the PSMA radioligand compound, and on the left side, it's just things for us, for our protection to measure radiation exposure for our fingers and for our body. On the right side, we do always use a saline syringe and 0.9 saline solution. Next to it is the activity syringe, which always has to be shielded by the special syringe shielding.

We always use a three-way stop during the injection and flushing procedure. A big check valve is also recommended. So if you disconnect anything from the patient, nothing flushes backs so all of the radiation stays inside the patient and the peripherals' catheter just for completion. Of course, this one is on the patient's arm, and this is the setup we use that's just built together to just give you a small hint of what we do or how we do it. This would be the three-way stop into the patient. We, in this case, would inject the activity and afterwards, we would flush it back. So we would minimize residual activity inside the syringe. And again, with the catheter turned to the patient, we inject again, the flush activity, and I would always suggest to flushing it twice if you have a big enough syringe, flush it twice. So now we have applied the PSMA.

This slide gives an overview of why a furosemide injection can be beneficial for patients in which we use a PSMA compound, which is eliminated through the kidneys. On the left side, you can see a Gallium-68 PSMA-11 PET scan where no insufficient hybrid occurred as well as no application of furosemide. On the right side, you can see a patient who received a furosemide injection 15 minutes before the scan. So it was roughly about 30 to 45 minutes after the tracer injection of the Gallium-PSMA. If you direct your eyes on this part, you can see that on the left side, you have a lot of residual activity inside the bladder, and it's not distinguishable from the local recurrence, which occurred here. On the right side, you can see that the residual activity inside the bladder is much lower compared to the local recurrence. This is why we try with furosemide and dehydration to try to keep the residual activity inside the bladder lower.

So you can have a better evaluation of local recurrence, as well as maybe a bladder infiltration or infiltration of the soft tissue surrounding the prostate area or the bladder. And this study, you can see a PSMA-1007 compound, which was applied in the patient. And just to see the difference between the residual urine activity, you can see that there's almost no activity inside the bladder, and it's much easier in this case to evaluate a local recurrence. And this is why a PSMA-1007 compound or scale PET scan, you won't need any furosemide. Now, that we have prepared the patient for the scan, as well as applied the PSMA ligand and given the tracer enough time to circulate the body. It's time to perform the scan. A PET/CT scan always consists of at least two scans, a CT, and a PET scan.

We usually perform the CT scan at first and after this, the PET scan, just to mention that there are more than one protocol to perform a CT scan. Normally, we perform a CT scan from a mid-skull to a mid-thigh. The direction of the scan can differ per local protocol. At our hospital, we perform a scan from top to bottom. A CT scan can be performed alone so we just use it with the CT for an anatomical correlation, as well as end attenuation correction. A CT scan can be performed as a full dose CT scan without contrasting an agent, and can also be performed contrasting an agent because there are many regulations and we would like to refer to the ESUR guidelines. In this case, whether a contrast agent application would be indicated or not. For a patient when the CT scan is performed, the arms of the patient should be positioned above the head of the patient so we minimize artifacts of the bones of counts.

For the PET scan, it's very important to note that we start normally from mid-thigh to the skull base. So the coverage should be identical to the CT scan and the scan direction is from the pelvis to the head. This is important to note because during the pet CT scan or the CT scan and the PET scan, the body function is normal and urine is produced. And mostly in the PSMA ligands which are regally eliminated, the bladder can fill during the scan, and this is why we start from the button. So we have the least amount of urine activity and can minimize the possibility of urine artifacts which is also, called halo artifacts around the bladder. The PET scan should be performed in continuous motion or around two to four minutes per bed position, meaning the scan area of the patient and it should be reconstructed with and without any deterioration correction.

Right after the scan, the quality has to be confirmed. This is normally done by the medical technician. So whether the patient was lying correctly and the scan is infused correctly to the CT. This is just to give you a small overview of the scan procedure. The CT scan is performed from mid-skull to mid-thigh, which requires of course, the anatomical information, the CT information. After this, we perform the PET scan where we perform the scan from mid-thigh to skull base in the opposite direction from the bottom to the top, which requires the PET. And after this, the images get fused inside the computer. So we get fusion or hybrid imaging. Now, that we have performed the scan, it's time to report. For this, I would like to refer you to the great lecture, Wolfgang Fendler who gave already a reporting on a PSMA-PET scan.

Wolfgang Fendler: So to summarize important indications for the current use of PSMA-PET/CT are initial staging in patients with high-risk features, localization of recurrent and persistent prostate cancer and staging prior to PSMA directed radioligand therapy, it is important for patient invitation and preparation of the patient to note that fasting is not required and most medications can be taken prior to the scan. It's important that prostate cancer-specific history is noted as well as PSMA level and PSMA kinetics. And of course, for renal eliminated prior hydration and or prostate can be used to better evaluate the local tumor, but also be aware of contraindications. For all compounds, we recommend voiding the bladder immediately before the scan. For a PSMA ligand application, we know that the injection of the radiotracer activity should be done in accordance with specifications. After the application, there should be flushing of the syringe with the same volume and the imaging delay for most of the tracers.

Also, the tracers are 6,220 minutes, depending on the compound. These are specifications that you have seen before, this is again a summary of our tracer specifications, noting either 68 or 110 minute, half-life either a renal or a liver dominant excretion for all traces is that we of course support intravenous bolus application with flashing. You can see, here again, the ranges for activity applications separate for Gallium and F18 tracers. And you can see the uptake time and also our recommendation to perform hydration or application of furosemide which is not new needed in the FPSMA-1007 compound. And with this, I'm handing over for the next summary to my colleagues, Stephan Himmen.

Stephan Himmen: Mm-hmm (affirmative). With the scan protocol, keep in mind that there are different dosages that can be used so a low dose or a full dose scan, as well as without or with a contrasting agent. In this case, depending on the used case indication, and of course, in accordance with the ESUR guideline. When the CT scan is performed, the arms should be placed above the head to minimize the possibility of artifacts of bones of the arm. And the scan direction is usually from skull-based to mid-thigh, but you can also extend the scan. This is not set in stone. So if there is an indication for a scan of the legs, you can also extend it to the legs or to the head.

The PET scan should always be in the identical coverage of the CT scan and should be performed from the bottom to top, so from the pelvis to the head, to minimize the possibility of urine activity or artifacts around the bladder. Thank you very much for listening today. As part of the UroToday PSMA-PET Academy Program, we wanted to give you a small introduction on how to perform a PSMA PET scan beginning from the indication of the preparation of patients, as well as the execution. And if you have any questions, feel free to contact us in the future. Thank you very much for listening.