Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU medical oncologist at Dana-Farber Cancer Institute. I'm so excited to share with everyone a Dana-Farber Cancer Institute prostate cancer tumor board, where we're really evaluating and investigating the use of PSMA PET in the care of patients with prostate cancer. Let me introduce my colleagues. First, Heather Jacene.

Heather Jacene: Evening, everybody. I'm Heather Jacene, the clinical director of nuclear medicine and PET CT at Dana-Farber.

Alicia Morgans: Thank you. Next, Dr. Paul Nguyen.

Paul Nguyen: Hi everyone. I'm Paul Nguyan. I'm the head of the genitourinary radiation oncology group at Dana-Farber and professor of radiation oncology at Harvard Medical School.

Alicia Morgans: And last but not least, Adam Kibel.

Adam Kibel : I'm Adam Kibel., I'm the the chief of urology both at the Dana-Farber Cancer Institute and at the Brigham Women's Hospital. Excited to be here today.

Alicia Morgans: Wonderful. So our next patient is Mr. PH. He's a 57 year old man with a history of coronary artery disease and Barrett's esophagus. He works in construction. In June of 2021, his PSA was 10.5. By August, it was down to 7.9 and in December it was still elevated at 7.6. He decided to pursue a prostate biopsy that demonstrated Gleason 4+5=9, grade group five disease in five cores on the left and the cores on the right were benign.

In January of 2022, he had a CT abdomen and pelvis with no metastatic disease, but an enlarged prostate. And he had a bone scan that was negative for evidence of bone metastases. In February, he had a PSA of 13 and then he underwent an MRI prostate that demonstrated seminal vesicle invasion and post biopsy changes with no lymphadenopathy or O osseous lesions. He saw medical oncology and urology and his imaging was reviewed, and they decided to order a PSMA PET. So let's review that.

Heather Jacene: So this is the patient's PSMA PET CT scan. If we start with the prostate gland, we can see that there was focal intense uptake from the starting, there was some invasion here into the left seminal vesicle. And then you can see that there was diffuse disease posteriorly extending all the way down near to the apex. In addition to the disease within the prostate gland, there were numerous scattered lymph nodes in the pelvis, including these tiny three to four millimeter perirectal node in the far. There was a right internal iliac lymph node. If I come back to here, you can also see there were little modules right outside of the prostate gland on the left.

As you come further up, you'll see by all these blue arrows, there were multiple external iliac lymph nodes that were bilateral. This was probably one of the largest nodes, that was one centimeter. This one was a little bit larger here and more intense on the right hand side. But then as you continue up, there was a small para aortic lymph node and there were several lymph nodes that were tiny, but PSMA avid just behind the inferior vena cava. And these lymph nodes, if we look on the sagittal view, these were now above the... These were just L5, L4. So just at the border of L3 and above the aortic bifurcation. So there was no additional metastatic disease outside of these lymph nodes, but there was a number of lymph nodes that were not seen on the conventional imaging.

Alicia Morgans: Well, that was a bit surprising, Dr. Kibel, what do you think?

Adam Kibel: You see a 57 old gentleman, you really want to treat him as aggressively as possible. He's young, he's healthy, so many more years of life left, but you have to recognize, when the cancer is spread, that you're not going to be able to cure him with surgery alone. There's really no data out there that would say that a patient such as this will live a day longer because you operate on them. So I think the wisest thing to do is to send [inaudible 00:04:20] to medical oncology to discuss systemic therapy and send him to radiation oncology to see whether or not they can provide some local control with the hope that that actually contributes to his curing.

There are good ongoing randomized trials in this space. SWOG, I think, is doing a trial where they're looking at this and [inaudible 00:04:41] very interested in the data, but at least at the current time, there's no data that the patients benefit from an aggressive surgical intervention. I wish there was.

Alicia Morgans: Paul, what do you think about this patient? Is this a patient that you think radiation would benefit and how are you thinking about the PET scan in terms of how it affects the fields that you design?

Paul Nguyen: Yeah, so this is a patient that I would radiate. Certainly I think adding local therapy would be better than systemic therapy alone. Technically, we don't have the data for that because he's not an oligometastatic patient per conventional imaging. But we also know, even for, let's say, high risk prostate cancer, adding radiation, it does improve overall survival. So we could even think about him that way as a conventional imaging negative high risk prostate cancer, adding radiation does improve survival.

So in terms of the field, the field is definitely changed by the PSMA PET here. As Heather pointed out, these nodes go above L4, L5, above the aortic bifurcation. And so those are not nodes that I would normally cover. So I would be extending the field here to cover those nodes. This would cause additional side effects, additional... We usually don't get nausea with this treatment, but this would probably cause nausea. And down around the rectum again, he's got perirectal nodes. I would normally not cover that. That's going to cause more rectal toxicity, but at 57 years old, I think we need to do it.

Alicia Morgans: I would agree. And from a systemic treatment standpoint, I think saying that this patient has clinical lymph node positive disease, at least [inaudible 00:06:23] PSMA PET, I think gives us the opportunity to consider intensification with abiraterone per STAMP[inaudible 00:06:30], and that recently published data that suggests a survival benefit to intensified systemic therapy in the setting of this very high risk localized disease.

In this case, this is lymph node positive and even metastatic disease, if you really take into account the location of these lymph nodes, although they are PSMA PET identified. So this is a new era, but this is an area where I think we are trying to maximally treat locally, we are trying to maximally treat systemically, and I think this is the kind of patient that, in our clinics, we might even then stop all of our systemic therapy at two years, wait for testosterone recovery and see what happens.

We don't know what's going to happen. And we hope that some of these patients, with the combination of that local and systemic therapy, may have a durable remission there, and some may be cured, though this patient, I think it will be a long shot given the extent of nodal involvement. What do you think, Paul?

Paul Nguyen: Yeah, I agree. I think that we certainly try as best we can to treat as much as we can and give the patient as best chance as possible, but I have dealt with many patients in situation where you treat as high as you can, and then they recur just above the field, just a little bit higher, and it is disappointing. And I guess we have to recognize that when there's this much disease, there's often disease beyond what we can see.

Adam Kibel: So I think all of us are very focused on intensifying therapy in patients in this area. But Paul, with using larger and larger radiation fields, I'm very interested in clinical trial setting and treating patients like this with aggressive surgical intervention. What do you think is on the horizon for somebody like this for intensification from a systemic approach? Are we talking about... What do you think about intensifying with lutetium or even triplet therapy in a patient such as this?

Alicia Morgans: I think it's a great question, Adam. I have a friend and former colleague, Dr. Husain, who said, "It would be great if there came a day where we could do as well as we've done in testis cancer, where we're using multiple treatments, different mechanisms of action, and really just obliterating this thing, with systemic therapies and potentially with some other treatments as well, multimodal therapy."

I don't know, in this particular setting, which would be very low volume metastatic disease, if we want to call it that, whether triplet therapy is going to be the right way to go with chemotherapy, as we currently think of triplet therapy, as ADT plus an AR targeting agent plus chemotherapy, because right now, the triplet therapy seems to be most effective in patients with de novo metastatic disease, which arguably this gentleman has some degree of, but also with a high volume disease burden.

But there are other triplets that are coming down the pike, and whether a different form of triplet therapy with multiple mechanisms of action may be helpful, perhaps someday incorporating lutetium, that might be able to target these very small areas of metastatic disease. Or a PSMA targeted alpha particle, perhaps, which might deliver super high dose radiation in that very targeted way where beta electrons might shoot off in different directions and might miss the bulk of the tumor because the bulk is so small. Maybe an alpha particle will be more effective there.

I don't know, but I think that the combination over time, triplet therapies over time, are going to be a way to go. And particularly in settings where we can't use total body radiation. We're not trying to do a transplant here. We're just trying to eradicate disease and there's a limit to what we can do with external beam radiation. Maybe the future will come where we're using radioligand therapy or other approaches. So I think it's a great question, Adam.

Heather, I'd love to hear your thoughts on this. And we've touched on this in some other cases that there's the disease that we can see, and there's the disease that we know is probably out there, but we might not be able to see because it's below the limit of our detection. And would you imagine that there might be metastatic disease or cells in transit to other areas that we just can't see because they're not in groups that are large enough for us to really pick up here?

Heather Jacene: Yeah, I think that's definitely possible. I think that in general, the resolution of PET is at that six to seven millimeter resolution. I think this particular tracer is very specific and you can see here that we see things that are even smaller than that, three to four millimeters, but certainly you're not going to get single cells or cells that are in transit, you may not see, so it's very possible that there's disease that you're not seeing still, when you see this on a PSMA PET scan,

Alicia Morgans: I think we should find out what happened to this gentleman, what we ended up doing. So let's do that. So this patient decided to move forward with radiation and ADT plus abiraterone for two years. And I think he is in good hands with the medical oncology team and Dr. Kibel, I'm sure, following along. So thank you guys for talking this through.