NCCN Guidelines: A Framework for PET Imaging Integration in Prostate Cancer Care - Edward Schaeffer

February 1, 2023

In this collaborative discussion, Alicia Morgans and Edward (Ted) Schaeffer examine the evolving guidelines for integrating PET imaging into the diagnosis and treatment of prostate cancer. Dr. Schaeffer emphasizes that these NCCN guidelines, which frequently adapt to new medical developments, act as a flexible framework rather than a rigid rulebook. The conversation explores the application of PSMA PET scans in localized disease settings and recurrent disease, with Dr. Schaeffer articulating that disease states depend not just on imaging but also the actual disease location. The conversation concludes by delving into the use of PET imaging in metastatic CRPC space, notably the lutetium-177-PSMA-617 treatment for patients with PSMA positive metastasis. Both Drs. Morgans and Schaeffer agree on the significance of interpreting imaging results accurately and incorporating these new tools wisely in clinical practice, with Dr. Schaeffer underlining the NCCN's nimbleness to revise guidelines in response to emerging evidence, thereby ensuring patients have access to life-prolonging therapies.


Edward Schaeffer, MD, PhD, Chair, Department of Urology, Feinberg School of Medicine, Program Director of the Genitourinary Oncology Program, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL

Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts

Read the Full Video Transcript

Alicia Morgans: Hi, I'm so excited to talk to a good friend and colleague, Dr. Ted Schaeffer of Northwestern University. Thank you so much for being here to talk with me today, Ted.

Edward Schaeffer: Well, thanks for having me, Alicia. It's nice to see you not in person like we used to practice, but certainly virtually.

Alicia Morgans: Well, it's good to see you too, and I always love to hear your insights as we think through really important guidelines that I know you're involved in creating, the NCCN guidelines in this particular instance. I wanted to talk with you so that we can think about how urologists, medical oncologists, and others can really think about how the guidelines might affect the integration of PET imaging into their daily practice.

Let's walk through each disease state where the guidelines recommend consideration, and we'll go from there. Let's start in the localized disease setting. What are your thoughts and what are the guidelines really recommending, at least in terms of consideration of PSMA PET scans, of course not replacing our traditional imaging, but an option for consideration?

Edward Schaeffer: Yeah. Great question. Let me just, if I can, just take one step backwards and just, or the audience, provide an overview for, A, what are guidelines, and then B, what are the variety of guidelines available, and then how does the NCCN guidelines fit in? Guidelines are recommendations, and you know that, but I think it's important to stress that it's not a rule book. It's really a framework. It's sometimes, maybe, guardrails. It provides directionality for what somebody may want to do in managing or helping to manage a patient. That's the first thing I would say.

There are many guidelines out there. I view them all as complementary. I have bias about the National Comprehensive Cancer Network's guidelines, and I'll mention why that is in a second, but I think it's always important to be familiar with and really facile with one particular set of guidelines, because it helps you in the clinical setting to really rapidly navigate and find the answer you're looking for, or the guidance you're looking for. I think the NCCN guidelines are the best, but I want to just acknowledge that there are other very nice, very complementary guidelines that have been assembled and rigorously built by many of my colleagues and your colleagues as well.

So, what's special about the NCCN guidelines? A couple of things. Number one, it's 32 comprehensive cancer centers that have participants that really spend a lot of time actually focusing on and thinking about the guidelines. One of the big differences in NCCN versus other guidelines is the frequency with which we meet and the frequency with which the guidelines are altered and changed. It's not right or wrong, but we spend a lot of time annually going over this. And so right now, this is obviously 2022, we're on version four of the guidelines already. Why is that? Because, when something new happens, when the FDA approves a new compound, a new imaging agent, a new radio pharmaceutical, we kind of drop everything, we convene a panel, we invite all of our experts from all 32 of our cancer centers and our patient advocates, and we talk about what these new approvals look like and what they may mean for us and how we think about the disease state. That's why I like the NCCN guidelines. We try to be as much evidence driven. There's areas of medicine that are not, and they're really just expert opinions.

With that in mind for 2022, there are new additions to the guidelines. The original 2022 guideline had inclusion of new imaging agents, these are PET-based agents. These are not the first PET agents within the prostate cancer space. There are other ones. The OG PET imaging agent, I guess, would be C-11 choline. The other imaging agents would be fluciclovine, which is an F-18 based tracer. And there are two different types of ways to image the transmembrane molecule PSMA, or prostate-specific membrane antigen, and those are with a G-68 based compound or an F-18 based compound. The FDA originally approved a G-68 based gallium PSMA compound that was brought forward for FDA approval from sister institutions, UCLA and UCSF. Soon after, that received FDA approval. Then a more widely available compound, which is an F-18 based compound based on a very similar molecular structure to the G-68 compound, was approved by the FDA as well. So now there's really widespread access for almost all patients to have these compounds.

There's two indications for these PET-based agents. One is in the localized space, one is in the more advanced space. Within the newly diagnosed localized space, it's for individuals who are considered to be high risk for lymph node or in involvement of metastatic lesions, and then in individuals who had primary treatment and have recurrent disease. Those are the two indications that these compounds are approved for. They're not really recommended. They've not really been well studied in more your space, Alicia, which is really assessing disease progression. I think that's the next big opportunity to understand how these agents behave. And so that's where these different agents can be used.

I think you asked me a question about what do I think about these imaging agents in the localized disease space, and within the localized disease space, the original FDA approvals were for individuals who had what we would call at NCCN, and I believe that the FDA called it that, unfavorable intermediate-risk prostate cancer, high-risk, and very high-risk prostate cancer. Those would be the initial presenting scenarios where it could be indicated. And in NCCN, we provide a framework for people, and the framework is really that we encourage for individuals with unfavorable intermediate-risk prostate cancer, imaging of bone and soft tissue for advanced disease. We said it like that because we're in a privileged position, as are you, major metropolitan area where we do have access to advanced PET-based imaging agents. But in NCCN, we try to provide a framework and try to enable individuals to get image for those disease states with potentially different tools if the PET-based agents are not available.

Alicia Morgans: I really think that it's important to just emphasize what you just mentioned, which is that the NCCN is really emphasizing, or encouraging, imaging of bone and soft tissue. And they're laying out a pathway to several methods of doing that, and that's really the most important message. What I think is important is that what, whether you're able to use a PSMA PET scan, or whether you're using bone scans and CTS, or maybe MRIs to do this, is really at the discretion of the insurance and the doctor and lots of different factors that are coming into play. But what's nice is that the NCCN seems to recommend that, as long as you're getting bone and soft tissue, you don't necessarily need to repeat all of the tests in order to be complete, you don't need to do them in a stepwise fashion. Whatever works for your practice, as long as you're meeting those goals, seems to be reasonable, and that, from my perspective, is a very practical way to approach it.

Edward Schaeffer: Yeah. There is increased sensitivity and specificity of PSMA PET tracers for detecting micrometastatic disease compared to conventional imaging. And I believe you could say the same thing for the fluciclovine agent as well. So, they're more sensitive and they're more specific for micrometastatic disease. It's an interesting concept, because we've been treating localized prostate cancer very successfully for many years with conventional imaging, and so, as you probably think about, I think about a lot, well, what will these new more sensitive tests mean for the contemporary or future staging of prostate cancer? I suspect that there's going to be substantial stage migration. The stage migration is going to impact outcomes for a localized high-risk prostate cancer, it's going to impact outcomes for node positive disease and advanced disease. And so, it's going to improve the outcomes for all those more advances disease states, or may improve the outcomes, because we're going to be capturing a larger kind of contingent of individuals.

Now, it's difficult to model and try to understand, well, how will that really impact the outcome? I think it's also important to understand that, that's happening, but we're also learning about treatment and management of localized lesions, localized primary tumors in the setting of advanced disease predominantly through STAMPEDE-based data. And so I think that's the countercurrent to what we just discussed, which is that there will be stage migration, but the stage migration, does it, or should it, prevent management of localized disease? And I do believe that STAMPEDE will be investigating this further in their STAMPEDE 2.0 trial. It is an interesting disease space.

In America, yes, there is a much higher rate of utilization of these advanced imaging agents. They, theoretically, reduce total radiation exposure for patients, which is great, their added cost overall, still a bone scan and a CAT or MR scan are cheaper, if you bundle them, than a PET-based scan, and there is a lot of subtlety in terms of how you read and interpret these images. So, although the PYLARIFY agent does enable more widespread access to these agents for patients, I think, in addition to widespread access, you need to have really good nuclear medicine radiology expertise in interpreting these images. And I think, in my mind, what I'm most looking forward to and will be most useful for me to have more confidence with these agents personally as a clinician, will be a catalog of, okay, what do we think are false positives. What do we think are false negatives? And how do you place and interpret those and fit them into your practice?

Because there is this, I think, development of understanding the solitary rib lesion, the lymph node on the side of the infusion side and the axilla, it's classic, the ganglia along the spine. So these are kind of classics, and I'd love for a little bit more experience and a consensus statement, because I see a lot of patients now in the community who get these PET agents and PET-based staging agents and they come in with what they think is advanced disease, they've had multiple attempted biopsies of the solitary axial lymph node, which are our people say, "No, that's an embolic infusion site." Which is not a PET PSMA-based phenomenon. That is a PET-based phenomenon. You will get emboli of the PET tracer, potentially, in the draining lymph nodes where the injections site was.

That kind of stuff, I think, is going to require some time to catch up, and then I think it will require a lot of very careful annotations to really understand what we're doing and how we're managing the patients differently. I like to think about, like any study, I order just like any study you order, I try to think about how will it change my management of this patient? And again, the guidelines are a recommendation, and so it's really like, "Okay, well, if you have an individual and they present with unfavorable or high-risk disease, how will imaging that demonstrates locally aggressive disease affect your management?" I think MRI's still better for that. How will imaging that potentially demonstrates a node positive situation change your management strategy? And then, if they have a suggestion of advanced disease, where is the advanced disease? Is it real? Do we believe it? And so I think you can't just put all your eggs in that basket, but you have to put on your thinking cap and try to be a great clinician and fit all that together.

Alicia Morgans: I think those are such important points, because just doing the study, of course, doesn't answer the question of what you do after the study is done, and all of the questions that you mentioned, plus I'm sure more, come up in day-to-day clinical practice when we get these results. So, as you said, I think we not only have to evolve in terms of our understanding of the imaging, how to best use it, when to best use it, then how to interpret it, and then what do we do with that information? And like any test in medicine, to your point, we have to know what we're going to do with that outcome before we even order the test. That's part of really ensuring that we're ordering tests for a good purpose. So lots to do there, lots to evolve around, I think, as a field, but really exciting that we're in process, and as we and our nuclear medicine colleagues work together, I'm excited to see where that goes.

As we think about the biochemical recurrent space, this is a space, of course, that has had PET imaging in the past continues to have PET imaging. Certainly we have fluciclovine and now we have some additional options in terms of PSMA PET. Any updates or any recommendations there that you would mention?

Edward Schaeffer: Yeah. I think in many ways, for me, at least, I'm not sure about for you, I find this space to be a little bit easier to conceptualize or navigate, but that's based on maybe my practice pattern. So, obviously I take care of a lot of men, I do surgery on some of the men that I take care of, and individuals who've had surgical resection of their lesion, their primary tumor, if they do have a recurrence, in my own mind, I think I can fit that into a framework that works for me. Meaning, we know, from very good data, that if you have a recurrence of disease, or frankly, if you have a recurrence of disease after primary definitive treatment, then they really should be considered for salvage radiation. So, we do imaging at that particular disease space to determine if they have disease outside of their pelvis, so to speak.

And so that's how I think about PET-based imaging. I think about it like, "Well, okay, do they have disease in their pelvis? Yes or no. And if they have no evidence of disease on their PET imaging, that's another scenario." And I think our colleagues at the Peter Mac in Australia have done a lot of work looking at and thinking about and reporting on outcomes for those individuals. So for me, that's a much easier algorithm. You have a biochemical recurrence, you're PET negative. I'm going to offer you what would be standard of care, which is salvage radiation, probably plus ADT. If you are PET positive in the pelvis, I'm still going to offer you salvage radiation. And if you're a PET positive outside the pelvis, I'm going to do additional studies to really understand, are those true positives or false positives? And if so, then we would develop a different algorithm for you.

So, I personally don't think that there has to be this separate disease space that is conventional negative PET positive, but maybe I'm wrong on that and maybe time will tell in terms of whether or not that's reasonable. But for me, your disease space isn't based on your imaging, it's based on where your disease is. Now, obviously it's a little bit of a circular argument, but nevertheless, that's kind of how I personally think about it.

Alicia Morgans: I agree, and I think it's all in the eye of the beholder. But either way, regardless of how you're thinking about it, whether you're a lumper or a splitter, you're making a lot of the same treatment choices that I would make. And of course, perhaps that's because we practice together, but that's also, I think, hopefully consistent with the data and with best practices in terms of really trying to give our patients the benefit of curative intent salvage therapy in these cases.

Edward Schaeffer: That's right. Yeah.

Alicia Morgans: The final area that I wanted to talk with you about is an area that continues to be an evolution, and it's the metastatic CRPC space. At this point in time, we are not using PET imaging to monitor disease progression throughout this metastatic setting and I do not order tests in that setting that are PET-based, at least yet. Perhaps data will cause that to change. But, we do have an indication for PSMA PET based imaging in order to identify patients who might be eligible for lutetium PSMA treatment. So, would love to hear your thoughts on how the NCCN guidelines describe the use in this particular setting and how we as clinicians can use those guidelines best.

Edward Schaeffer: Yeah, I think this is obviously a tremendous addition to our compliment of many therapies that our patients can benefit from. So I think that's the first and most important thing to think about. Lutetium-177-PSMA-617 is a new agent that was approved by the FDA for PSMA positive metastasis in the setting of metastatic castrate-resistant prostate cancer. So again, localized hormone-sensitive and then castrate-resistant prostate cancer, and in individuals who have castrate-resistant prostate cancer, who have a PSMA scan that shows more one or more PSMA positive lesions and or metastatic disease that is predominantly PSMA positive. Those individuals are potentially candidates to receive lutetium-177 PSMA, and the study that supports that it was a very nicely done study.

Now, I think there's not a lot of debate that addition of lutetium-177 PSMA is a great addition in the M1 space. And we have a nice grid on our section called pro 15, that really breaks out, well, where do these different agents fit? How could they work in this castrate-resistant space? So anybody who's really wants to get nitty gritty, that would be where you would want to go.

Now, the more controversial component of the FDA's approval of this particular agent was that they had linked the utilization of this lutetium-177 PSMA with a very specific PSMA-11 imaging agent, and that was because that was how the trial was done. Now, again, the NCCN is a consensus panel and the consensus panel really consists of experts in the field who synthesize all the data. So, the actual label says that, in order to be eligible for lutetium-177 PSMA, that you have to have a G-68 PSMA-11 screening assay to identify candidates for that particular agent.

But the NCCN panel has really a tremendous array of experts, and we provide our thoughts on different disease states, and our panel, not my panel, but the panel, believe that the F-18 PYLARIFY, PyL PSMA, can also be used in this space due to multiple reports describing equivalency between the G-68 and the F-18 PSMA agents. In particular, their molecular recognition motifs are almost identical, the normal organ biodistribution is nearly identical, and the detection accuracy for prostate cancer lesions is effectively identical. So, for those three foundational reasons, almost identical motifs, I mean, if you put them side by side, which Ippolito is our imaging guru in our panel, he presented them to us, they basically look identical, their organ distribution is basically identical, and their detection accuracy is basically identical. And so with that in mind, our panel thought, well, for our patients, that allowing them to have access to this really tremendous new therapeutic, the lutetium-177, but allowing them to be eligible for that with the F-18 compound was going to be important for them. So that's kind of how we thought about and structured it.

As I mentioned at the beginning, the NCCN guidelines are always updated, and so if something new were to come around and we thought we needed to make a shift or adjustment, obviously we would do that. But those were the thoughts of my esteemed colleagues on the panel. I had the pleasure of listening in and really listening to their discussions, and that's how we thought about it, and that's how we stated it in our guidelines.

Alicia Morgans: Well, I appreciate you walking us through not only what the guidelines say, but the thought process there and how you compared these imaging agents, and really tried to come to an expert consensus around this. And ultimately, I'm actually just grateful that this allows for some flexibility in our clinical practice, because there could be barriers and limitations to patient access to life-prolonging therapies if we don't ensure that they have access to the tests that they need in order to be eligible for those therapies. So I think that this makes sense. And as you said, if something changes that perspective, if evidence develops that this is not the right approach, or perhaps that we can add additional imaging modalities or tracers to this approach, these guidelines will evolve. And luckily, the NCCN can be nimble and can review the data and update as needed.

I sincerely appreciate you taking the time to walk through all of the nuances here, and there are many, and your expertise is always appreciated. And thank you also for what you and the entire panel, including the patient advocate, do on the NCCM guidelines to keep us in the know, up to date, and allow us to have some degree of understanding of how to best proceed, how do the experts proceed when they face the same things that we see in our clinical practices. I appreciate your time.

Edward Schaeffer: Yeah. Thank you very much for having me, and I just want to acknowledge all the hard work of all 32 of our panelists. They really do the heavy lifting, and I try to just keep everybody on track when we actually get together.

Alicia Morgans: Well, wonderful job. Thank you.

Edward Schaeffer: Yep. Bye-bye, Alicia.