Utility of PSMA-PET in Intermediate Risk Prostate Cancer: Part 1

Neil Desai, MD, MHS, Associate Professor of Radiation and Oncology specializing in the treatment of GU malignancies at UT Southwestern Medical Center in Dallas, Texas, is interviewed by Daniel Tennenbaum, MD, chief resident at the Maimonides Medical Center urology residency program in Brooklyn, New York.

This is the first of a two-part interview with Dr. Desai. Watch part two here.

Dr. Daniel Tennenbaum: And welcome. Today, we are speaking with Dr. Neil Desai from UT Southwestern Medical Center in Dallas, Texas. He’s an Associate Professor of Radiation and Oncology at UT Southwestern, specializing in the treatment of GU malignancies. Having completed his medical school training as well as a master’s in Health Science at Yale University, he proceeded to train in radiation oncology at the prestigious Memorial Sloan Kettering Cancer Center in New York City. Dr. Desai has authored numerous peer-reviewed journal articles and maintains a robust clinical practice with a focus on improving treatments for bladder cancer and prostate cancer. Today, Dr. Desai will help us gain a better understanding of PSMA PET-CT imaging, intermediate risk prostate cancer, and the role they may have with one another. Dr. Desai, thank you so much for joining us today.

Dr. Neil Desai: Thank you so much, Dr. Tennenbaum, it’s my pleasure.

Dr. Tennenbaum: So first and foremost, in order to establish some parameters for our listeners, can you please define intermediate risk prostate cancer?

Dr. Desai: Right. So I think this all goes back to D’Amico, and to D’Amico’s criteria in looking at clinical pathologic variables based upon PSA, Gleason grade, or now ISUP grade groups, the T stage established by primarily DRE, with some controversies regarding MRI use in this assessment, and as well as, very importantly for radiation oncologists, the percent of positive cores from a template biopsy that are involved is a surrogate for the bulk of disease. Putting these parameters together, the most conventional definition of intermediate risk is to have one of these parameters, meaning PSA 10 to 20, Gleason grade group two to three, and a palpable disease on both sides of the gland. They basically have any of these factors, if you have more than one risk factor, you can be unfavorable intermediate risk versus favorable, as well as if you have more than 50% of positive cores involved, and a template biopsy, again, distinguishing from targeted biopsies, or having primary grade group four, or ISUP grade group three, that would make you unfavorable intermediate risk.

So a heterogeneous group with lots of struggles as defined by the criteria. And I think this is an area that’s of interests to us all, I think we’re getting better at.

Dr. Tennenbaum: And you had mentioned about the Gleason grade groups and favorable versus unfavorable intermediate risk classification for prostate cancer. As radiation oncologist, how do you approach the difference between favorable versus unfavorable prostate cancer, intermediate risk prostate cancer?

Dr. Desai: Yeah, so for us, the most actionable highlight for many radiation oncologists, the feeling based upon post-hoc data, primarily that favorable intermediate risk patients is defined by a single risk factor, and also that risk factor not being grade group before plus three, or 50% cores are more positive, that these men apparently do not benefit from the addition of hormone therapy to radiotherapy as compared to unfavorable engineering risk. Now, this is a contentious divide because we don’t actually have a prospective randomized trial telling us this, but there’s several lines of data that are, I think, convincing that, for most men with favorable intermediate risk, the benefit of hormone therapy addition appears to be quite low. So a very meaningful difference for us from a treatment paradigm.

Dr. Tennenbaum: Will your treatment parameters in terms of the anatomical borders or the dosage of your radiation differ depending on an unfavorable or favorable intermediate risk prostate cancer?

Dr. Desai: That’s a great question. So as a broader principle, the question of whether radiation dose intensification improves outcomes in a clinically meaningful way, and what does that mean clinically meaningful? It’s a very highly contentious question. So we have lots of lines of data saying that some radiation is better than none for substantial survival improvements over hormone therapy alone in higher risk disease. But in men with higher risk disease, does intensifying radiation, such as with brachytherapy, boost the entire prostate, improve outcomes? Well, it clearly improves biochemical control, but does it reduce metastasis or death from disease? And that’s much more contentious.

There are three randomized trials in this question, including in intermediate risk patients, that did not show a survival benefits, certainly. There’s some lines of evidence suggesting it lowered some metastasis risk, but there’s also a good amount of data saying that majority of metastases really do occur after local therapy due to the first wave or occult metastases, that are not captured by conventional imaging. So broadly, I think the synopsis for many of us is to say, “Well, if you have higher bulk, higher risk disease in a younger man who may have a higher risk of local failure long term, yes, most of us do prefer intensifying therapy, but to what end?” And you have brachytherapists who are very adamant, that means brachytherapy boost. I think now it’s less clear that it is a boolean, black or white, is it external conventional or brachytherapy boost? There’s a whole smattering of conventionally fractionated, moderately hyperfractionated, SBRT lesion based boosting approach that I think are bridging that gap.

So the synopsis, yes, there’s evidence for brachytherapy boost, or whole-gland boost, higher dose being better for biochemical control at a higher side effect risk. But the question really is not that it’s going to be, how do you improve survival or select better hormone therapies you need to… and review and control failures without increasing side effects unduly. So selecting patients for brachytherapy boost who urinary symptom burden, using modern brachytherapy techniques like real-time planning that has reduced injury rates. I personally like high-dose rate brachytherapy, it has a feral profile for urinary side effects as well in this regard. I don’t think the older trials of brachytherapy boost reflect contemporary side effect risk in that regard.

And if you’re really worried about the patient having higher…and burden risk, then perhaps lesion based boosting based on MRI is now validated a phase three trial called FLAME, where if you just do partial gland boost to higher dose, you get much better biochemical control without increasing side effects.

So I think, in general, yes, with higher risk, higher bulk disease, we’d like to intensify. The big question is, what’s it going to cost the patient and what is your practice specifically? So I think I told you mine, which is brachytherapy boost for whole gland, focal boost for lower volumes of disease that are aggressive.

Dr. Tennenbaum: That’s the first time I’ve heard about focal boosting. That’s quite interesting. I want to get back to that in a little bit. You were mentioning earlier about biochemical control and conventional imaging and trying to avoid any potential recurrence. So obviously, in today’s day and age, we’re hearing more and more about PSMA PET-CT scanning… PET-C imaging, excuse me, as a means to identify theoretical control. How does PSMA PET technology impact your practice? How do you utilize it?

Dr. Desai: Yeah. So as you noted, PET PSMA is a certainly disruptive technology. It’s certainly more sensitive in these early disease states than we’re ever going to have for CT or bone scan. It’s still a question of how it’s going to improve outcomes because the first issue is there’s a Will Rogers phenomenon, wherein you’re going to migrate patients with higher risk disease out of the categories you thought were not metastatic. For instance, you’re going to find some metastatic patients. So both categories will do better, because you’re stage migrating. So that’s happening already. NCCN has supported the FDA labeling of PSMA PET for staging of unfavorable intermediate risk prostate cancer, alongside higher risk. So you’re definitely going to see more occult metastatic patients and occult nodal patients and stage migrate them for better or worse to different therapies, versus what you had done before.

So I think we’re going to have to prepare ourselves from a trial interpretation standpoint, that this will change how we interpret data long term. You can’t compare to trials in the 1990s that did not have PET PSMA staging. We’ve long known that. MRI’s been doing this to some degree as well over the years. But this will be more critical.

Secondly, we got to watch also our outcomes data in interpreting trials in that PET PSMA is going to find a lot more biochemical failures in terms of where that failure’s occurring. So we say things like we know local recurrence rates, or regional recurrence rates, or distant metastasis rates, based upon older trials, but if you look at things like the TROG 03.04 RADAR trial, which is really randomizing long over shorter hormone therapy in unfavorable intermediate risk and high risk, you find that actually, if you look at the data is reported 45% of those men who have biochemical failure never had their disease found as the where it is, but they went on hormone therapy before you found it. So what is that breakdown amongst men nowadays? And what’s going to happen, what are we actually going to uncover? Are there actually more local failures than we think? Are there more regional failures?

I think so that to synopsize, the stage migration effect is real, it affects my practice that if someone’s clearly metastatic on PET PSMA, I don’t say… we got to make sure that’s really conventionally reproduced, that you’re not just calling a false positive. I think that’s very important to our practice, and we can get to that later as is it more likely to be false positive, but you give them benefit of the doubt. You’re going to treat them for cure, but maybe intensify hormone therapy in those men on a case by case basis.

Secondly, I think PET PSMA is going to show you that risk of nodal failures are much higher than we thought originally, based on conventional imaging. And I think his supports probably some data, at least in the higher risk setting from India, in the POP-RT trial, where they actually found for the first time benefits to treating pelvic nodes in a randomized trial, in a PET PSMA negative population. So the pet piece may positive findings may not be as important as finding a negative result, which would at least reduce the chance of occult disease. Maybe this identifies those men who are more likely to have microscopic nodal disease that might merit therapy. So I think PET PSMA being positive is important, it does affect our practice, but even a negative result has impacted our practice quite a bit in terms of both postoperative and intact radiation decision-making and the assuredness that your staging is complete.