How PSMA-PET shapes staging and recurrence workup in prostate cancer

Prostate-specific membrane antigen (PSMA)-PET has become a standard staging tool for many urologists treating patients with high-risk prostate cancer or biochemical recurrence. It can reveal metastatic disease missed on CT or bone scan, which shifts decisions about surgery, radiation, and surveillance. It has also raised new questions about how to interpret equivocal uptake.

Chad R. Ritch, MD, MBA, FACS, chair of the Division of Urology for the Cleveland Clinic Florida Market, spoke with Urology Times® about PSMA-PET in practice. He discussed how the modality has changed the imaging landscape, its role in staging and treatment planning for high-risk disease, and the workup of suspected recurrence after definitive treatment. He also addressed how clinicians should approach equivocal findings.

Urology Times: How has PSMA-PET changed the imaging landscape in prostate cancer?

Ritch: PSMA-PET imaging has changed the landscape pretty significantly. Probably a decade or more ago, conventional imaging like CT scan, bone scan, or MRI and bone scan were the traditional ways of staging patients with prostate cancer. Then came along another PET imaging agent, which is fluciclovine, and then after that came PSMA-PET scanning.

Once that became widely available, I think many of us transitioned, at least in the urology world, towards trying to get that for our patients with high-risk disease, where we had a high suspicion of metastases that we wanted to rule out. That’s now become the de facto standard of care where it’s available. It’s been a game changer, if you will, for staging high-risk patients. And for patients with biochemical recurrence after surgery or radiation, we’ve been using it as a standard of care since it became available.

Urology Times: How does PSMA-PET influence staging and treatment planning in newly diagnosed high-risk or very high-risk prostate cancer?

Ritch: What we’re looking for with a PSMA-PET scan is metastatic disease. If a patient comes in with metastatic disease, one of the things you want to do is look at the burden of disease: how many sites are affected. If it’s high-burden or high-volume metastases, that would rule out surgery as an option. In certain oligometastatic or locoregional cases, where you have a few lymph nodes that are positive, it doesn’t necessarily mean that surgery is ruled out, but that’s a case-by-case basis. But certainly, in high-burden metastatic disease, which may not have been detected on a conventional CT or bone scan and [was] picked up on a PSMA-PET scan, that changes the decision for surgery for a lot of people.

Similarly, when it comes to radiation therapy, [it helps] when counseling patients, because now we know that radiation in low-volume metastatic disease is a good localized strategy, as well as systemic therapy. When patients are diagnosed as metastatic on a PSMA-PET scan, and you can assess the burden accurately, that helps you to decide whether or not they can get additional local therapy with radiation as well as systemic therapy.

Urology Times: Why does a baseline scan matter before surgery in very high-risk patients?

Ritch: If you have a very high-risk patient, it’s good to know that they have no metastatic disease when you operate on them, because you’re going to be following them closely afterward, and you want to see, if they develop a biochemical recurrence, [whether] there was something on the previous PSMA-PET scan [compared with] the new PSMA-PET scan. So it’s good to set a baseline if you’re going to operate on these very high-risk patients. [There are] a number of different areas where it has helped us with our treatment counseling and subsequent surveillance.

Urology Times: How has PSMA-PET changed your workup of suspected recurrence after definitive treatment?

Ritch: After definitive treatment, it’s a little bit tricky, particularly for a prostatectomy, at least I find in my practice. When you do a prostatectomy, your PSA [prostate-specific antigen] should go down to undetectable levels: ideally less than 0.1 [ng/mL], or if you have an ultrasensitive PSA, less than 0.04 [ng/mL] at most institutions. When you’re tracking them for biochemical recurrence, if you start to see that PSA creeping upwards towards 0.2 [ng/mL] or higher, which is the threshold for biochemical recurrence, that’s where you do a PSMA-PET scan, and you may find it helpful.

In the literature, the number may vary, but at a very low level of PSA, 0.2 [ng/mL], it’s still hard for the PSMA-PET scans to detect something. But again, it sets the baseline at that point when you are at biochemical recurrence, because you may not necessarily change anything you’re doing with that PSMA-PET scan at such a low threshold of biochemical recurrence. But as you monitor the patient and you get subsequent scans and you see something new, then that can help guide your decision-making process.

Urology Times: What about patients with a rising PSA after radiation therapy?

Ritch: In terms of radiation, similarly, there’s a criteria for recurrence, which is called the nadir plus 2, or Phoenix criteria, and in those patients it can be even more challenging to detect biochemical recurrence. When you’re monitoring them, their PSA may be going up [but] hasn’t quite hit the technical threshold for recurrence after radiation, but you can get a PSMA-PET scan early. In some of those patients, you may find early either local prostatic recurrence, or you can find distant recurrence outside of the prostate.

I think it’s a very helpful tool in that gray zone of a rising PSA after radiation that hasn’t quite met the threshold, although there’s data as to whether or not that’s beneficial in terms of long-term survival and treatment.

Urology Times: How should clinicians approach equivocal PSMA-PET findings?

Ritch: That’s a tricky area. I struggle with that in my practice. A classic example is the group of [patients with] unfavorable intermediate-risk prostate cancer. That’s somebody with a grade group 3, Gleason 7 prostate cancer. They do have a low risk of metastasis; it’s not 0, but it’s also not that high. If you look at most guidelines, it says you can get a PSMA-PET scan in those patients, and most of us do. And you may find one of those equivocal lymph nodes in the area.

[When] you counsel patients, you tell them, “Hey, there is some uptake in this area. It possibly could be a metastasis.” But when you look at a lot of the studies with PSMA-PET agents, most of them don’t focus on unfavorable intermediate-risk patients. And in fact, because of the low rate of actual pathologic node-positive disease, some of these PET findings are false positives.

That’s kind of the counseling you go through with the patients. You explain to them that yes, there’s uptake, [but it] doesn’t necessarily mean that there is 100% certainty that there’s cancer there. And you tailor it to the overall risk group and Gleason score, things like percentage pattern 4, and you make a decision based on that. Just because you have one of these borderline findings doesn’t mean that it’s always metastasis. [That’s] what I tell patients. [That’s] very different from a very high-risk group, where if you see something positive, then the likelihood that that’s [a] true positive is much greater.

So again, case by case, you look at the patient, you look at the clinical features, the pathology. There’s also genomic testing that you can roll in with it to help you with these equivocal findings.

Urology Times: When do you turn to conventional imaging for an equivocal finding?

Ritch: For some of those patients, we may actually use conventional imaging to compare to the PSMA-PET scan. I’ve had patients where the PSMA-PET scan shows something in a rib, which I find can happen not infrequently, and then I do a bone scan and a CT scan to see if there’s a correlate, and there’s nothing there. In those cases, I reassure the patient, again looking at their clinical picture, that that’s probably a false-positive finding.