Alicia Morgans: Hi, I'm so excited to be here from the Dana-Farber Brigham Cancer Center, where we have colleagues across a multidisciplinary specialty team to really talk about patients and think about how we can integrate PSMA PET scans into their care. Let's start with Dr. Kibel. Can you introduce yourself please?

Adam Kibel: Sure. Hi, I'm Adam Stewart Kibel, I'm the Chief of Urology at the Brigham and the Dana-Farber. It's a pleasure to be here today.

Alicia Morgans: Wonderful. Thank you. And Dr. Nguyen.

Paul Nguyen: Hi, I'm Paul Nguyen, head of genetic urinary radiation oncology at the Dana-Farber Brigham, and professor of radiation oncology at Harvard Medical School.

Alicia Morgans: Thank you. And Dr. Jacene.

Heather Jacene: Hi, I'm Heather Jacene. I'm the clinical director of nuclear medicine at Dana-Farber and the assistant chief of nuclear medicine at Brigham and Women's Hospital.

Alicia Morgans: Great. Thank you all. Let's get started. This is GR, a 63-year-old man with no significant past medical history. He's married, and a retired construction worker with three adult children. He has a family history of ovarian cancer in his sister. In September of 2021, he had a PSA of 6.5. In November, he went to a prostate biopsy, where they identified Gleason 3+3=6 GG 1 prostate adenocarcinoma in two cores on the right. And this was on review by our pathologist. He, on outside pathology, just had that Gleason 3+3=6 GG 1 in one core. So really, quite low-risk disease here. He was reviewed by the multi-D team at the time, and they decided on active surveillance for his low-risk localized disease. And genetic testing was performed because, of course, he had this family history, and was very interested in understanding what his risk might be.

In March of 2022, he came in for three-month follow-up visits. At that time, they really discussed that he had identified a PALB2 mutation. Which is, I think, interesting, if we think about him potentially, or patients with this mutation, if they have advanced metastatic CRPC PALB2 mutations, seem to be really quite targetable with olaparib, for example, as a PARP inhibitor. Maybe not quite as robust of a response as a BRCA2 mutation, but almost there. So this is really, I think, interesting and important in certain patients for his family.

Additionally, of course, this patient had an MRI of the prostate in his follow-up, that identified a PI-RADS 5 lesion on the right, and concern for multiple enlarged pelvic lymph nodes. Of course, this was unexpected, given his two cores of Gleason 3+3. So the team's here to review the case. We did review that case, and of course, PSMA PET was ordered, to really help us understand better what was going on.

Dr. Jacene, can you please review the imaging?

Heather Jacene: So we have here his PSMA PET CT scan. We can see, on the MIB image, a lot of normal biodistribution, salivary glands, kidneys, bowel, the bladder. We can see this focal intense PSMA uptake, which on the axials, is correlating to the location of the PI-RADS 5 lesion on the MRI.

As we start to scroll up, looking for things outside of the prostate gland, we start to see some small lymph nodes. But then as you keep, some with low levels of PSMA uptake, but then as you scroll up, there are many large pelvic lymph nodes, external iliac, that are on both sides. They're really going up the entire iliac chain. You have first common and then periaortic lymph nodes. Now, these lymph nodes have much less intense PSMA uptake, compared to the primary lesion in the prostate gland. But as you continue to scroll up, there's a small retroperitoneal node with low-level uptake.

As we keep going then, up into the chest, there were not a lot of mediastinal. There were some small, but not a large amount of mediastinal nodes, but then in the axle, you could again see enlarged lymph nodes, it's bilateral. Very low levels of PSMA uptake again. And as you continue to scroll up, there were also a lot of enlarged and many cervical lymph nodes, again with low levels of PSMA uptake.

So, what's a little bit striking on the imaging is one, the focal, the uptake in the PI-RADS 5 lesion is very intense. But once we start to see multiple enlarged lymph nodes throughout the body, it raises the question of whether the nodes in the pelvis are related to the prostate cancer, or if it could be some other malignancy? And certainly, whenever we see diffuse lymphadenopathy, above and below the diaphragm, the question of lymphoma or another lymphoproliferative disorder, certainly comes to mind. And then, here with the lower levels of PSMA uptake, it also suggests that this possibly could be two different processes on the imaging.

Alicia Morgans: Great. That's really very, very helpful imaging. Thank you for that. So, Adam, I know this patient is your patient. I'm wondering if you can talk us through what you and the team thought about, or thinking about, as you're caring for this individual?

Adam Kibel: Well, it was a lot to unpack here. I mean, the gentleman came in, and we told him he just needed to be on active surveillance. I'm a huge proponent of that. He wasn't going to need surgery. And mostly, we got the genetic testing, because of the family history. The MRI was being obtained at the same time because I generally get MRIs on patients that are on active surveillance unless there's a clear contraindication. And both came back around the same time, showing something that was alarming, particularly the lymph nodes. And so, it was very natural to then get a PSMA PET, to sort of understand if the lymph nodes were positive or not.

I think one of the fascinating things about this is, this is medicine that we would not have been practicing three years ago. Genetic testing, PSMA testing, it really just shows where we're going.

It was difficult to see the question around the PSMA testing. I think, one of the things that's important to recognize, we spend a lot of time talking about the sensitivity of the PSMA test not being perfect. By that I mean, it's about 40%, meaning patients with positive lymph nodes do have negative PSMA PETs, but the specificity in the OSPREY study was really outstanding. And so, that gave us the confidence to go ahead and proceed with surgery. Obviously, we discussed with him whether we need to get a biopsy of this. This was not a decision made in a vacuum. And we spent a lot of time deciding whether we need to biopsy the lymph nodes. And we did discuss radiation therapy with him. He's a relatively young individual, and he wanted to proceed with some more definitive therapy.

And I guess lastly, the MRI was incredibly useful in making us feel that we were doing the right thing because he clearly did not have a low-risk prostate cancer on the base of that MRI.

Alicia Morgans: Yeah. Let's comment on the MRI for just a second here. I think, this really suggests to me the importance of an MRI in the process of doing active surveillance. And I think, one of the uses there too, is to make sure that you've, as the urology team, you've really identified areas that might be higher risk, and you've biopsied those appropriately. So it sounds like this is something that you're routinely integrating into your active surveillance protocols.

Adam Kibel: Absolutely. I think that you need an MRI. I think that's well within the standard of care. And we don't just act on the MRI. There was a lot going on in this patient that pushed us towards just definitive surgical treatment. But usually, you biopsy to see what's going on.

There are a couple of reasons for it. The first is, you want to make sure the MRI's accurate, there is some false positives associated with an MRI. And it can be incredibly useful for our radiation oncology colleagues, in terms of deciding whether the patient just needs radiation, or whether they need additional therapy, if they progress. So it makes us feel comfortable there, we're on active surveillance, so we're doing the right thing. And if they need additional therapy, it gives us much more comfort and that we'll be able to tailor the therapy to exactly the aggressiveness of the disease that they have.

Alicia Morgans: Yeah. And thank you for taking us through also, how you decided to go towards surgery. I think, the nice thing about surgery is, you get the pathology. So you do get to have the understanding of what you're actually dealing with in the pelvis. Paul, I know you were not involved in the earlier stages with this patient, but is this a direction that you think makes sense, from the perspective of what you've heard and what you've seen, in terms of imaging so far?

Paul Nguyen: Yeah, sure. I definitely think that some kind of definitive therapy is very reasonable for this patient. I think, looking at the overall picture, somebody with Gleason six disease, a low PSA, only a couple of cores positive, I really could not envision those lymph nodes having anything to do with prostate cancer. And so, just dealing with the prostate alone, I think would be very reasonable, whether that's by surgical approaches or radiation, whether brachytherapy or external beam, SBRT, something like that. I think, all of these are very reasonable options for this patient.

Adam Kibel: Paul, before you gave definitive radiation though, you'd want us to biopsy that MRI abnormality to determine that it was indeed, still Gleason six, or would you just proceed with treatment?

Paul Nguyen: Well, if we felt something that hasn't been biopsied yet, and it looks like a dark ADC, that could make us worry that it's a higher-grade lesion, then yeah. I would definitely feel better with a biopsy of it. Because, if there is Gleason 7/8, or something higher, we want to add some hormone therapy to that. And so, the answer would be, yes.

Alicia Morgans: Yeah. To that point, Adam, I find myself sometimes getting the MRI of the prostate after we have completed the biopsy. And I always feel like I reach out to my urology colleague and say, "Hey, can you let me know if that area was adequately biopsied or not?" Because as a medical oncologist, I have difficulty, maybe it's my barriers to spatial relations, I can't always tell where these things are lining up. Are those silly questions for a medical oncologist to ask a urologist? And please be honest. Or is that okay to reach out and ask for those areas to potentially be biopsied if not adequately done before?

Adam Kibel: Well, I think it's never a bad idea to reach out. Right? The whole key to multidisciplinary care is to feel comfortable seeking out the expertise of the others within your group. That's what it rests on. That's why the patients do better because you have multiple different approaches coming to bear on the same disease, and coming to some sort of consensus. So I would never argue against it.

Usually, the lesions that we don't adequately biopsy, or lesions that are away from the rectum, or more interior, or are quite small. Anything that's large, that's on the right or the left, we generally have hit.

I think, in 2022, pretty much most patients will have had an MRI before the biopsy. The problem is, if you do a biopsy and the biopsy is negative, then you're sort of backed into the corner of getting the MRI, and then doing another biopsy. And if the biopsy's positive, then everybody wants to get an MRI before they give definitive treatment. So the field is just moved towards getting the MRIs before the biopsy, so we can be one and done, and sort of settle the issue. So it should be rare that we get an MRI after the biopsy.

Alicia Morgans: That, and luckily none of my colleagues have said, that's a silly question. So we're all still good team players. So let's review what happened to this patient.

So Mr. GR did go forward with surgery, as you said. And he had a pT2N0 Gleason 4+4 prostate adenocarcinoma, right apex margin was positive, at less than 0.1 centimeters. He had atypical lymphoid infiltrates present in the prostatic and per-prostatic tissue, consistent with involvement with CLL, chronic lymphocytic leukemia. So really interesting.

Dr. Jacene, we didn't hear from you a whole lot on the appearance of those lymph nodes, other than when you described them when you were showing the images. Is this surprising to you, as the nuclear medicine physician, that this was not prostate cancer?

Heather Jacene: No. I think it makes sense, because of the pattern of disease of the lymph nodes above and below the diaphragm, the lower levels of uptake compared to the primary, this kind of pattern of discordant uptake in different biologic processes. I think we're very used to seeing that with FDG. And so, we're kind of applying those same processes, or thought processes, to PSMA. There is this case, and some other ones that we've seen did make me check a little bit into the literature. And there are a lot, a number of case reports, of other tumors that do take up PSMA. Some are very avid, like a clear cell renal cancer for lymphoma.

There, if you think about FDG, there's a very wide range of FDG uptake in lymphoma, from low grade, like CLL, to really, intensely FDG avid, like diffuse large B-cell and Hodgkin lymphoma. It seems that the range, in general, that's reported for PSMA and lymphoma is lower levels of uptake, with a much smaller range within the numerous number of types of lymphoma that there are. So I think, this imaging picture goes along pretty well with what the pathology ultimately showed.

Alicia Morgans: So I wonder, to everyone here, I feel like we're seeing a fair amount of patients having lymphoma identified. And it's really interesting to hear how our nuclear medicine colleagues are describing those lymph nodes as they're seeing them, as being lower level of uptake. Is this something you're seeing in your practices, or maybe it's just in mine? We'll go around the room. Dr. Kibel, what do you think?

Adam Kibel: Yeah. We're definitely seeing it. We're also seeing a lot of thyroid nodules. I've seen, I now have the head and neck surgeons on my speed dial, which I never had previously. So I think, it's important to recognize, that other tumors do light up with PSMA, and we need to recognize it, and be prepared to deal with it.

Paul Nguyen: Yeah. I've had a couple of patients with either CLL, or another kind of lymphoma, at the same time as their prostate cancer. And in this patient's case, at least originally, when he had low-risk disease, we could think, okay, these nodes aren't involved. But it gets tricky when you've got somebody with really bad prostate cancer, Gleason nine T3b, and you expect them to have lymph nodes. And then, they've got a lot of lymph nodes, and now you have to differentiate, well, which of those are the lymphoma lymph nodes, and which of those are the prostate cancer lymph nodes? I think hopefully, it's easier now that we have PSMA PET, but that has definitely been an issue in the past.

Alicia Morgans: Yeah. And to that point, I've had some of those situations. Dr. Jacene, would you ever consider using a PSMA PET to help someone who sees multiple lymph nodes in the pelvis, and is trying to figure out which lymph node to biopsy? If they're trying to get an understanding of whether the patient has maybe a lymphoma, maybe has prostate cancer, maybe both, would a PSMA PET be useful in differentiating at all? Or is that something that's going to be challenging anyway?

Heather Jacene: I think, it's a hard question to answer, because I think that sometimes it can be helpful, and sometimes it's probably less helpful, and you don't necessarily know until you actually see the image. So in this case, for example, we have a baseline. So we know the lymphoma is low, and the prostate cancer is high. So for him, probably in the future, it would be useful to be able to differentiate and guide a biopsy. But if you're talking about a known tumor type, that you know has more intense levels of PSMA uptake, I think, that's where it could become more challenging. So you have to think about what the histology is that you're trying to differentiate, where the nodes are and are the patterns similar or dissimilar? So I think, when you have the differential, it becomes easier, but if you don't have the differential, then it's not as useful. But you don't know sometimes, till you try.

Alicia Morgans: So that's fair. Thank you for that, Dr. Kibel, do you have anything you wanted to add?

Adam Kibel: Yeah. I think we spend a lot of time thinking about how PSMA PET intensifies therapy. We start giving systemic therapy because we identify disease that was otherwise not known. But there's also opportunities to deintensify therapy. You could imagine this patient in particular, undergoing a fusion biopsy, being identified as having Gleason pattern eight, and then them saying, "Look, we can't treat this patient. They have widely metastatic disease. We're just going to treat him with hormones, or abiraterone, or docetaxel." And that would not be the best treatment for this patient. There are opportunities, not only to intensify therapy but also deintensify therapy.

Alicia Morgans: Yeah. Ultimately, the way I view it is, to your point, trying to get the right therapy to the patient. Really trying to match the intensity of the therapy to the intensity of the disease, and to differentiate things that may or may not actually be responsive to treatment for prostate cancer. Of course, this lymphoma is not going to be very responsive. So that makes a lot of sense.

Paul Nguyen: Yeah. The flip side of that is that we'll have some patients let's say, with high-risk disease, who now have a new lesion that shows up on PSMA PET. And I try to be careful with those patients, not to withhold definitive therapy from them, if they don't have metastases based on conventional imaging, since the original trials didn't include PSMA PET. So I really try to think about PSMA more commonly, as something to intensify therapy, rather than deintensify.

Alicia Morgans: And I agree with that too. We don't want to really, not offer the opportunity for curative intent treatment when we would have offered it before, until we actually have data to show that, that's wrong. And at this point in time, we do not have that data. And so, using a curative intent approach, and potentially using our knowledge to use SBRT, or metastasis-directed therapy, perhaps in addition, or intensify our systemic therapy is, I think, the right thing for the patient at this point in time, too. So thank you for that.

Well, I appreciate this discussion. Thank you everyone for your help.