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Alicia Morgans: Hi, and welcome back to Clinical Case-Based Learning. We are still talking about a virtual tumor board in advanced prostate cancer. And this is case number four, Mr. Elijah Lewis, and he has a prostate cancer recurrence. Mr. Lewis is a 70-year-old man with no past medical history other than locally advanced prostate cancer that was pT3N1M0. He had a Gleason 4+5 prostate adenocarcinoma and underwent radical prostatectomy and pelvic lymph node dissection in January of this year.

He had a rising postoperative PSA. Initially, his pre-op PSA was 5.9 in January, but it was rising, after such that in August it was 7.79. His pre-op staging scans included a bone scan and CT abdomen, pelvis, and all of these were negative. He underwent a bone scan in August when he had that elevated PSA and this was also noncontributory. He underwent an 18F-DCFPyL PSMA PET in September for further evaluation. Before we get to that scan, I just want to add that he has no other medical problems and lives with his wife. He spends time with his friends and travels to visit his grandchildren and he retired two years ago. So Andrei, can you show us the scans?

Andrei Iagaru: It will be my pleasure. So on this bone scan, some degenerative changes in the shoulders and elsewhere, and post-surgical changes resulting in urinary contamination. This is just the urine containing the radiopharmaceutical and I'm assuming he's wearing diapers and that is what we see outside the body. So, negative for the presence of bony metastatic disease. Now let's look at the PYL. Again, we can start with a projection image to guide us, mostly normal by distribution here, there is something with low-grade uptake in the left inguinal region. So we'll pay closer attention there. And again, the urine containing the radiopharmaceutical contaminates the diapers. So as we scroll from the pelvic region going cranially, there is this area of focal uptake in, but it's low grade, moderate grade in the left inguinal region. The lymph node is not enlarged. It has a fatty hilum, so I will not call this suspicious.

As we advance and we see more superior, there are some tiny areas of more focal uptake along the left common iliac region, as well as in the retroperitoneum. And these may represent early recurrence of prostate cancer, early metastatic disease. My suggestion is for all those who are going to use PYL PET, renew your fleet of PET CT scanners.  Our confidence in finding small lesions like this increases significantly with the use of digital scanners. And in fact, in our own experience, the sensitivity for detecting recurrent disease at low PSA levels is higher than what is published in other studies.

And I think that part of it is because of all our patients being scanned on digital scanners. In this particular case, probably because of the small nature of the lymph nodes, an FDA-approved Axumin scan was done. And you can appreciate that here we can see the same tiny areas of lymph nodes. They do not have Axumin uptake, so this is one case that it is the opposite of the other, where for small amounts of disease, the PYL is positive, and the Axumin is negative. This is in line with what has been reported in the literature, particularly for certain PSA levels. And I would not exclude the possibility of this being metastatic prostate cancer. With that, back to you, Alicia.

Alicia Morgans: Great. And thank you. So let's just recap here. He's a 70-year-old man with no past medical history other than the locally advanced prostate cancer which was a high grade here. He underwent a prostatectomy and lymph node dissection in January of 2021.  He never had a nadir PSA, underwent a standard bone scan and CT, and all of these were negative, even with a PSA of 7.79. We just saw the DCFPyL PSMA PET that demonstrated some very subtle areas of potential uptake that were not identified on an Axumin PET. And so the way that I think about this and I'm going to toss it to Hilary to hear her thoughts is that usually in patients who do not have overt evidence of metastatic disease in this post-prostatectomy setting with biochemical recurrence, we could think about pelvic radiation. And I think it's a little unusual that his PSA is actually so high, but salvage radiation I think is potentially still on the table. What do you think Hilary?

Hilary Bagshaw: Yeah, I think it's interesting. I mean, he has multiple risk features from his surgery, T3N1 grade group five. And as you said, his PSA is curious and very high compared to what we see on the imaging. While we as radiation oncologists have data that the salvage radiation doesn't work as well the higher the PSA is, specifically with PSAs above two, so the seven makes me pretty nervous. Since we do not see definitive metastatic disease, I think it would be worthwhile to try pelvic radiation for him with hormonal therapy. And I think that it's maximally aggressive, but maybe there's just something we do not understand about the imaging versus his PSA level and that is really his best option. Otherwise, we are just waiting for him to develop metastasis, I think.

Alicia Morgans: Thank you, Hilary. And you know, really this does speak to the heterogeneity of prostate cancer. I think it's interesting, such a high PSA and not a very clear uptake, but some subtle findings. What do you think Geoff, in terms of trying to confirm whether or not these areas are metastatic disease or recurrent disease, potentially, with something like a biopsy, they seem pretty small to me.

Geoffrey Sonn: I agree. I don't think there's anything here that's biopsiable. This is somebody that I would echo, that the surprise that he does not have obvious metastatic disease on his PyL PET, this is someone who is very likely under staged on his initial preoperative imaging. He was treated, we do see this occasionally.  I've had a handful of patients whose postoperative initial PSA was actually higher than their preoperative PSA, usually in the setting of very high-grade prostate cancer. And most of the time we're going to find metastatic disease. In the trials looking at PyL PET, you would expect to find disease in someone whose PSA is greater than five, in the mid-nineties percent chance. So this is unusual. But in this setting, I don't think there is anything biopsiable. I would agree that I would be worried about failure with radiation therapy, but in this setting, really, if we're going to be maximally aggressive, that would be the only thing that we would offer, I think would be radiation plus hormones.

Alicia Morgans: Mm-hmm (affirmative). Well, thank you. And the final question is back to you Andrei. If we decide after a shared decision with the patient that the best thing might be to monitor him because he does have some clear effects from the prostatectomy where it appears that he is incontinent and is older and maybe he doesn't want to jump into radiation right now. What scan type would you recommend for monitoring and what would your interval recommendation be?

Andrei Iagaru: I don't know that we know how frequently to do these scans. However, I would say that to be able to rule out aggressive cancer, so this high PSA, usually once you get a PSA one to two, as Geoff said, you have more than a 90% positivity rate on PSMA PET and it is not subtle. So even an [inaudible 00:08:34] may be useful here just to make sure that there is not some type of phenotype that is aggressive that is missed with this other imaging modalities. And if that is negative, then I would just return to what we discussed in case one, just monitor how fast the PSA is increasing, and maybe start with routine CT and take it from there.

Alicia Morgans: Well, thank you for sharing that. I think that's a completely reasonable recommendation and this is an unusual phenotype that we see here. But important to discuss it and interesting that we did see subtle PSMA PET findings. Thank you all.