Steven Y. Cho: Yes, I started January.
Phillip Koo: Great. So let's just dive right into it. PSMA imaging has really changed how we diagnose, we look at disease, but in the context of using it to select patients to undergo RLT, how do you manage when to image these patients now that we anticipate approval of this type of treatment across multiple disease states?
Steven Y. Cho: It's an evolving area for PSMA PET and the sensitivity of detection and also how you read the studies makes a big difference. I think in the setting of RLT, currently how it's used, it's in really advanced metastatic setting. So really what we're really looking for in the current setting pre or post-docetaxel is really the degree of uptake. Many of these patients have multiple sites of metastatic disease often. And so you're really looking for the degree of uptake. As a general rule, it's above liver activity. And so if you have PSMA avidity, then you actually have validity to treat with RLT and with rising PSA and other markers of progression.
I think in the earlier setting with smaller numbers of disease, maybe in an oligometastatic setting, then it becomes much more of a difficult and you have to be much more rigorous about what you're treating is truly real. So it's not just the level of uptake, but to confirm that what you have is really metastatic disease. So I think you will have to scrutinize the imaging more and maybe have more confirmatory validation that what you have is real.
Phillip Koo: I like that you brought up those nuances using PSMA PET in those different disease states. And I like that idea of having to confirm a little bit more in that setting. And I also like the comment that you made about greater than liver, because oftentimes I hear people talk about SUV max and having this distinct cutoff, which that isn't always the most accurate or precise metric, I guess, or measurement tool. So using liver as that standard, I think makes a lot of sense because there is a little bit more standardization with liver activity. So another question I have is when it comes to discordance or heterogeneity, we know disease, especially in the advanced setting, is very heterogeneous. How do you manage that when you might have some lesions that may not express as much PSMA uptake or maybe doesn't have any PSMA uptake?
Steven Y. Cho: So in disease heterogeneity, I think the main driver has been really the degree of PSMA uptake. So if you have heterogeneity and you have concordant PSMA positive and FDG positive disease, I think generally it's a risk factor. And so you know these patients are the course of neuroendocrine dedifferentiation, probably more aggressive disease, but you actually have a signal to treat with the PSMA radioligand. However, so for those patients, we've been generally treating and those patients maybe with the caveat that we're more wary that these patients may not be doing as well or may not respond as well to RLT.
Now, if you're looking for discordant disease where it's PSMA negative or low or an FDG positive, those are the cases that we're looking for. And if you have an isolated lesion, sometimes depending on the patient's disease state, if this is the only option or they have limited options, we may proceed maybe following that lesion for focal ablative therapies or maybe some other treatment options. But if they have extensive or numerous sites that are discordant, then that would be a contraindication. That's FDG positive, but PSMA low or negative.
Phillip Koo: Is it safe to assume if a lesion is PSMA negative that it would be FDG positive or is that too much of a leap?
Steven Y. Cho: Usually that's the case and that's the textbook answer, although there's always variations, but I think generally that's the case. But I think the FDG is a way to validate that that's a true tumor and not scar or some other residual, especially in bone where you have scarring and where you have sclerotic changes. There are many sites of treated disease that may not be FDG positive and PSMA negative. Then those would be maybe treated disease. I think in soft tissue lesions that are viable, then it may be maybe a different type of biology that may require biopsy.
Phillip Koo: Yeah. I haven't been the biggest fan of using FDG in part because it's taken a lot of time to get it performed, also taken a lot of time to get them read. And we're hearing some pretty amazing stories about wait times of two weeks or three weeks to actually get an interpretation for a PET scan. So let's talk about sites of disease. So you can get metastatic disease, the bone, lymph nodes, visceral mets. How do you take that into consideration in the APMR CRPC setting versus the hormone-sensitive APMS setting?
Steven Y. Cho: So in those settings, I mean, I think liver involvement is an area that we realize for PSMA imaging that it's a little bit of a Achilles heel or area that we're vulnerable to because of the high liver background activity. So looking for visceral disease involvement, that would usually prompt, at least for me, to recommend an FDG PET so that we can maybe see how extensive sites of more advanced disease and maybe a neuroendocrine de-differentiation there is that may be vulnerable and may make the patient ineligible or less attractive of a candidate for PSMA therapy. The liver, you have to be careful because the liver may be occult. And so you're looking for lesions that are maybe morphologically present, but maybe very subtly present or absent on PSMA PET. So that's an area that we're looking for.
And anytime you have visceral disease, I think it does raise the issue and we really recommend FDG PET, if at all possible. Now in answer to your other question about when to do FDG, we usually don't want to always have FDG hold up the radioligand therapy. So sometimes in the interest of getting the treatment, sometimes we hold off on the FDG PET-CT study maybe after cycle one and between cycle one and two so that if there's enough PSMA PET activity to treat, we may start the first cycle in some of these patients, but really try to get the FDG information on route maybe before cycle two that may help inform how we proceed with cycle two and later.
Phillip Koo: I think that's an interesting novel approach. So if we go to the hormone-sensitive APMS setting, there's less heterogeneity, less visceral metastatic disease. What's your imaging strategy in that hormone-sensitive patient population?
Steven Y. Cho: Yeah. So in that population, you really want to make sure that the level of PSMA uptake, especially for radioligand therapy, that you have sufficient uptake and smaller lesion really accounting for partial volume. And to make sure in that setting, to really make sure you don't have any PSMA negative neuroendocrine small cell dedifferentiated disease. And again, just from what we've talked about earlier, just to make sure in that setting that you really have disease that's truly PSMA-avid disease. Because sometimes you may have low disease burden and some of those you may be at risk for false positivity in that setting.
The other thing that we may be a little bit more worried about in that setting is patients, if they develop salivary gland issues, sialadenitis, or some other toxicities that in conjunction with the oncologist, if this gets approved, just to make sure we're not burning bridges in terms of toxicities that may keep them from getting other therapies or having long-term chronic toxicity that maybe for patients in more advanced diseases, maybe less of an issue or concern.
Phillip Koo: So is it safe to say that in the hormone-sensitive setting, your threshold regarding PSMA avidity is higher than that in later disease?
Steven Y. Cho: Yeah. I think you really want to make sure that the patient has PSMA-avid disease, that it really is, as a general rule, above physiologic liver activity and that it's really truly validated disease. So in using one of the criteria that have been proposed, the PSMA-RADS, you really want to make sure their PSMA-RAD four or five, that it's not equivocal, that it's unequivocally positive.
Phillip Koo: So last question, in terms of follow-up, there's so many different ways in which patients are being followed up after they start their RLT therapies. What's your approach and what would you recommend? Let's start off with that CRPC setting and then go to the hormone-sensitive setting as well.
Steven Y. Cho: Yeah. So in terms of following these patients, there are a variety of different approaches. Currently, at MD Anderson, we do post-therapy scans on every patient. There have been different approaches previously at the University of Wisconsin. We were doing them maybe more judiciously, maybe every other cycle. I do think the post-therapy imaging can be helpful. I think the jury's still out in terms of how much benefit does it provide for the patients. But I do think if you're doing it correctly, I think if you get really high resolution images, so if you do SPECT CT imaging from vertex of skull to mid-thigh, and you're getting quantitative SPECT, you can really follow these lesions to figure out, is this consistent with your PSA change or rise? Or do you have isolated disease that you can then focally ablate and maybe intervene? So I do think the post-therapy scans are helpful to that regard.
And it could also help trigger maybe more judicious use of PSMA PET-CT, which is in many settings, difficult to get an approved and you can't routinely get it. And there's oftentimes a wait. So I think that's been our approach. Many places you're getting PSMA PET CT maybe mid-course. So maybe if there's some other clinical PSA or other issues that may prompt some disease assessment on PSMA PET-CT. So not routinely after every cycle, which doesn't happen, but maybe post-cycle three, mid-therapy or the mid-course of a pivot go, then it's maybe helpful to help make changes. I think the other thing that has been helpful is to try to get some of this information mid-course so that you're able to have enough time to be able to coordinate and schedule what the next course of action is. And instead of right before the next cycle in which sometimes you're compelled to either give the next cycle or you have very limited time in which to make a decision.
Phillip Koo: Yeah. I think you bring up a lot of great points and there are a lot of practices out there that may not have access to SPECT CT. And I don't think that's necessarily a reason not to do these therapies because as you mentioned, there are a lot of other tools out there. You could do contrast enhanced CT. And PSA, as you mentioned, is a great biomarker. Clinical assessment's a great biomarker. And I like the idea that PSMA PET being done routinely probably is not the most appropriate use today. Perhaps it changes in the future, but using PSMA PET CT when there's a specific reason or trigger to look into it further, I think makes a lot of sense. So any closing thoughts that you have regarding PSMA PET regarding RLT selection and where the future is headed?
Steven Y. Cho: In terms of disease assessment and treatment assessment for radioligand therapy, I think it's really the jury's out there in terms of how do you know if the patients are doing well? How do you select patients? I think some quantitative imaging may be helpful and tumor burden assessment to see if the patients are doing well. I think we're really looking for... Many of these patients have multiple sites of metastatic disease. They're very difficult to read. So oftentimes you have a baseline PSMA PET CT. If you have multi-time point SPECT CT, sometimes you had an FDG PET CT. So you have multi-modality imaging with multiple lesions.
I think having good tools that are allowing you to be an aid to the nuc med physician or radiologist to track how these patients are doing, I think is something that's very much needed in the field and also maybe more standardized reporting so that our people receiving this, our oncologists, our radiation oncologists, we're all speaking the same language. Right now I think we're speaking multiple different languages and sometimes the message is not always getting through. So I think that's definitely something that people are working on that we can work on in the field to make sure we're reading these scans adequately with aid of software tools or AI and communicating these properly.
Phillip Koo: I think those are great pearls. Communication is always key. So thank you very much for joining us.
Steven Y. Cho: Great. Thank you. It's a pleasure to be here.