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 Stewart-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 genitourinary 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 patient RT, a 62-year-old man with a history of hypertension. In November of 2021, the patient had a PSA test that was notable for being 57.58. In January, the patient came in for a biopsy Gleason four plus four equals eight, grade group four. Prostate adenocarcinoma was identified in 12 of 12 cores. In February of 2022, the patient underwent an MRI of the prostate that demonstrated a large left-sided mass from apex to base extending into the median lobe and bladder neck with capsular abutment and additional diffused prosthetic involvement. This was a PI-RADS 5 lesion. Tiny nonspecific lymph nodes possibly concerning for metastatic disease were also identified on that MRI. He was seen by urology and was noted to have very high risk localized disease versus locally advanced disease due to possible pelvic lymph node involvement and a PSMA PET scan was ordered. Let's take a look at that imaging.

Heather Jacene: Here we have his PSMA PET CT scan. If I start in the pelvis, you can see that there's very intense PSMA uptake on the left side of the gland that extends all the way from the base here down to the apex. There's a little bit of activity also on the right-hand side. As we scroll then through the pelvis, we did not see any lymph nodes that were enlarged or PSMA avid, and there were no other distant metastases that were found, so the disease was localized to the prostate gland, matching the primary findings on the MRI, but the nodes were negative.

Alicia Morgans: Great. Thank you for that, Dr. Jacene. Let's think this through. This patient, I think, was seen by your team, Dr. Kibel. What do you think when you see these findings? That's a pretty locally advanced prostate cancer.

Adam Stewart-Kibel: Initially, you see the positive lymph nodes, you see a PSA of 57, you see aggressive cancer like this, you think, this guy is not a surgical candidate. All of a sudden you get the negative PSMA testing. You starts to think, okay, maybe this guy is a surgical candidate. I always think PSA is the least important variable in terms of outcome because other things can Jack up a patient's PSA besides prostate cancer, and we see patients with very elevated PSA. I'm not saying that isn't cancer in this particular case, but I always discount that a lot. It's the higher grade disease that I find more concerning.

This is a very difficult case and a lot of it comes down to the patient's concerns about management of their disease. I think it's a mistake not to consider radiation therapy and it's probably the direction I would push the patient, but I would still operate on the patient if the patient was concerned and felt that he wanted to give it a shot with surgery and keep radiation available in case he had a failure or he actually had high-risk disease at the time of surgery.

Alicia Morgans: Great. What do you think about that, Dr. Nguyen?

Paul Nguyen: Yeah. I would say without the PSMA, I would certainly lean towards radiation for somebody with a PSA of 60 and this kind of locally advanced-looking disease. With the PSMA, I would agree with Adam that it makes sense that surgery could be certainly a reasonable option here. I think if I were to counsel him, I'd say, well, if you have surgery, it's a pretty high chance that we'll be doing radiation at some point, so [inaudible] radiation and hormones. I think the upside for surgery for him is that he's a young guy and he has some pretty significant obstructive symptoms. Typically, when I do radiation, I like to do for these high-risk patients if possible to breakthrough therapy boost, and that can certainly make the obstructive symptoms worse. I think that certainly, he'll have better urinary flow if he has the prostate out. That would be a factor in favor of surgery. I'd say in general though, probably still this kind of patient with a PSA of 60 and high-grade disease, I'd still lean towards radiation [inaudible].

Alicia Morgans: Yeah. I think all of that is fair. As a medical oncologist, my thought would be that he seems like the kind of guy who would benefit from hormonal treatment because this is quite locally advanced. I worry about micrometastatic disease. I worry that if we don't do something to really eradicate that disease in the pelvis, we might be missing out. I think the PSMA PET though was very reassuring. It was surprisingly so, and so I wouldn't have expected that particular result. That's why I think this is an important person to really consider and for us to talk about because this is not what I would've thought in a very good way. I wonder what your thoughts are on that, Dr. Jacene. Do you find that you are able to reassure some patients and some teams that this is not as bad as it necessarily appears?

Heather Jacene: I think so, yes. The sensitivity of the test is sometimes limited for small lymph nodes, so I think we at least know that we're not seeing gross macro... I think everything we kind of see on imaging is not microscopic. It's macroscopic, so you're not seeing distant disease that would necessarily exclude someone from a chance at having some definitive therapy.

Adam Stewart-Kibel: One thing to recognize is with surgery, you get closer to truth. I'm not saying you get truth, but you get closer to truth. It is better than imaging, and then you can tailor additional therapy as a result of what you find. We'd hate to under-treat this patient just as much as you'd hate to over-treat. Sometimes you get the PSMA PET, it reassures you, and you decide to go in the more aggressive direction with somewhere between hope and expectation that maybe they don't have as bad disease as it appears.

Alicia Morgans: Let's see what happened to this patient. All right. Mr. RT moved forward with surgery. He tolerated it well. He had pT3bN1 prostate adenocarcinoma. Gleason four plus three equals seven, grade group three on pathology evaluation. He did have some tertiary Gleason five and had a positive margin. He actually went through some shared decision-making with his urology team, with his radiation oncology team and his medical oncologist. They decided on adjuvant radiation after that shared decision-making conversation. I think, to everyone's point, we were able to help this patient who felt strongly about going through a surgical approach really know if that was the right thing to do, and then to have an opportunity to do something on the back end that could continue to consolidate that local control. Dr. Nguyen, any comments here?

Paul Nguyen: Yes. When we face this pathologic node-positive setting, we do wonder about whether we should be thinking about adjuvant therapy or whether it might be okay to watch the PSA closely and do salvage in some of these patients. I think we know, we have randomized data from three trials that if you have a node-negative patient, that it's probably safe to wait for the PSA to rise and do salvage therapy. For these node-positive patients, we really don't have any data. Really, the data we have is from the old Messing trial that says that adding lifelong hormones improves overall survival compared to nothing.

Arguably, that argues for adjuvant hormone therapy, and perhaps we should just do the radiation at that time. We don't really know. I think we do take it on a case-by-case basis. I think for some patients it may be reasonable to watch and wait a little bit, buy them some time and think about salvage in this setting. Then for some patients who are very motivated and recognize that they're probably going to get the therapy anyway and if they want to just get started sooner, adjuvant is very reasonable. That's the kind of discussion that we have with these patients.

Alicia Morgans: Dr. Kibel, I have a feeling that when you saw this patient, you talked about this being something that was very possible even before the surgery happened, which I'm sure helps that conversation in that shared decision-making in the post-op setting. Is that true?

Adam Stewart-Kibel: Yeah. I essentially tell a patient like this they should expect to get radiation afterwards, and if they don't need it, that's a huge victory, but they should not run on the assumption that radiation is not in their future. I think the thing is that we're still learning how to use PSMA PET and examples like this show us not only do we see patients who have positive PSMA PETs that don't always show cancer. We see the other side of the coin as well. No test is perfect and we just need to integrate all the data we have to try and come up with the best possible treatment for an individual patient situation.

Heather Jacene: I'll just add that I think the size of the N1 in this particular case was two millimeters, which really shows some of the limitations of PET scan from resolution. Although you sometimes can see the four millimeter nodes and we feel reassured that we see them when they're really small, it's not surprising that this is not positive on a PSMA PET scan. Within that OSRI study where they had this overall sensitivity of 40% for the nodes when they took out, there was a subgroup analysis when they took out the nodes that were smaller than five millimeters. The sensitivity of the scan did improve to around the 50 to 60% range. This is similar to what you see for sentinel lymph node biopsies with cervical cancer, melanomas, and also breast cancer.

Alicia Morgans: Great. Well, thank you for running through that data with us and thank you team for talking through this case.

Paul Nguyen: Pleasure.

Heather Jacene: Thank you.

Adam Stewart-Kibel: Thank you.