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Zachary Klaassen: Hi, my name is Zach Klaassen, urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. Delighted to be joined on UroToday, as always, by Dr. Alex Kutikov, who is professor and chair of the Department of Urology at Fox Chase Cancer Center in Philadelphia, Pennsylvania. Alex, thanks so much for joining us on UroToday.

Alexander Kutikov: Hey, Zach, thanks for having me. Zach and I go way back. This is my brush with greatness today. Thanks for having me, Zach.

Zachary Klaassen: Likewise, my friend. So today, we're going to be talking about a pretty hot topic in kidney cancer. The management and of indeterminate renal masses, particularly with a spin on molecular imaging and what's coming down the pipeline. So maybe just at a very high level to get our listeners on the right page, what's the challenges of imaging and diagnosis of these indeterminate renal masses?

Alexander Kutikov: Well, listen, I'll level set it. I think every renal mass is indeterminate.

Zachary Klaassen: Sure.

Alexander Kutikov: You have enhancing solid renal masses. 20% of those are benign. That's an indeterminate mass by definition. You have cystic masses. The Bosniak system exists because these masses are indeterminate. They could be cancer. They could not be cancer. So there's a huge opportunity in our field to better characterize and better risk stratify every renal mass that is potentially found in a surgical candidate.

Zachary Klaassen: Yeah, absolutely. And I think we see a lot of kidney cancer, both you and I-- small renal masses, 16, 20-centimeter renal masses. When you get that 3 to 7 centimeter, you're thinking about active surveillance or a biopsy. You're talking about partial radical nephrectomy. How are you counseling those patients to maybe take a 3-centimeter versus say, a 4-and-1/2 to 5-centimeter?

Alexander Kutikov: Yeah, 3 centimeter is really clinically the most significant cutoff. Past 3 centimeters, that's where metastatic potential rate really goes up. This is where active surveillance data break down a little bit. Once you're over 3 centimeters, you got to try to figure out a plan here because surveillance for masses that are less three centimeters is incredibly safe. You got the luxury of time. You got all the options.

Once you're over 3 centimeters, you got to figure out whether this patient needs surgery or at least ablation. Not that it's inappropriate to watch greater than 3-centimeter mass, it is absolutely appropriate. But however there, there's a different discussion, right?

Zachary Klaassen: Yeah, and I think-- let's talk about those like say 2-and-1/2 to 3-centimeter. What characteristics are you looking for either in the tumor or the patient to maybe lead you towards active surveillance? Who are you biopsying right now? Who are you taking straight to either ablation or partial nephrectomy?

Alexander Kutikov: Yeah, so let's look at the active surveillance patient. These are the comorbid patients, the elderly patient. A lot of them not good enough for a haircut, much less a partial nephrectomy. Those patients, I'm watching. It's regardless of what the biopsy shows. I'm not biopsying those patients because it's not actionable. It's not going to change my management.

Now, on the other side of the spectrum is the young, non-comorbid, healthy patient, that even if I biopsy and it shows an oncocytic mass and they're in their 40s, I'm not sure what I'm doing with that. I'm resecting that anyway. I don't biopsy those either. And there's a slew of patients, the majority of patients that are in the middle, that I'm on the fence whether they need a surgery or not.

I make sure that when I do deploy a biopsy, it is actionable. It is something we're going to act on. When you and the patient agree that if a biopsy shows oncocytic or oncocytoma, even chromophobe, that you're going to watch it. Otherwise, there's no reason to biopsy.

Zachary Klaassen: Yeah, no, I think it makes sense. Let's switch gears a little bit. Let's talk a little bit about some of the evolving molecular imaging and PET-based agents we have for small renal masses. There's been some data in the last couple of years. Maybe just bring our listeners up to speed on that.

Alexander Kutikov: Yeah, absolutely. So there's FDG-PET. It sort of hasn't been very useful in the kidney cancer space, except for some exceptions. Actually, New England Journal Paper this year from the NCI for systemic therapy in patients with HLRCC, these genomic patients with fumarate hydratase mutation, there actually an FDG-PET is incredibly useful. You can pick up subclinical lymph nodes. You can pick up the mass.

These high-grade papillary tumors, especially with the fumarate hydratase mutation, there are FDG-PET avid. But for the rest of the tumors, most clear cell renal cell carcinomas just don't take up the tracer, don't take up FDG. You only get false positives. And it's not a useful study.

Now, there was an effort in the mid-2000s to bring molecular imaging to the kidney cancer space by harnessing their carbonic anhydrase and the fact that it's concentrated in clear cell renal cell carcinoma. There was a company. They did a trial, did not get FDA approval, and the effort died. Now, this is its rebirth.

This is sort of a new study, the ZIRCON trial that was spearheaded by Brian Shuch at UCLA. Very promising results. FDA approval is really probably imminent in sometime-- what I hear is end of August. And so this is going to disrupt the space. The ZIRCON trial, just in a nutshell, really shows you that your positive predictive value for this CA9, this carbonic anhydrase 9 PET scan is over 90%.

What does that mean? That means if this PET scan shows a hot mass, you can be very sure that it is a cancer. So when you look under the hood in the results, it's like 91%, 93% positive predictive value for clear cell. But your positive predictive value for a cancer is actually-- I think it was almost perfect in that trial. There was like some sarcoma-- some odd tumors that lit up hot.

And so if you have a hot PET, you can comfortably operate on the patient. Now, your negative predictive value was lower. And if you have a cold mass there, there's still a clinical dilemma of this could be a cancer. Can you leave this patient alone? There, perhaps a biopsy can be deployed.

But this is going to, I think, disrupt the space, because all of a sudden, can get a easy answer whether you have a cancer or not. Now, the caveats here, just for the audience, is that this study takes several days-- from injection to scan, it takes several days. I believe on average five days-- where there is going to be some barriers to getting these tests, because the patient needs two trips. So I would argue that's better than a biopsy.

Zachary Klaassen: Sure, absolutely. Let's fast forward. Let's say FDA approval is imminent. They get it for the molecular imaging. What scenarios in your clinic are you going to be using this going forward, would you say?

Alexander Kutikov: Well, yeah, I think this is staging. This is beyond just replacing a biopsy for certain scenarios. This is if I want to not take that elderly patient who has a 4-centimeter mass, and I don't want to operate on an oncocytoma, so I want to make sure I get that level of comfort that I'm going in for the right thing. I get this PET scan. It's hot. I go forward.

And listen, I didn't have to take him off that Plavix, off that Coumadin, and extra time for the biopsy. That's a big deliverable here. But beyond that, it's staging. It's post-treatment surveillance. I mean, these are for more advanced, for higher risk tumors, obviously. For treatment monitoring, again, you know, you have that patient that comes in from a different institution, positive margin on a clear cell. Hey, this is something you can deploy.

And in theory, and I think this is where the field is going is a theranostic potential for all these molecular imaging. You can deliver your therapeutic agent to the cancer using the same antibody. And the other thing is-- I talked a little bit about cystic masses. This is-- biopsy data on cystic renal cell is all over the place.

We just had a cover of Journal of Urology from Fox Chase that almost 25% of cystic masses that were operated on at the Center were high grade. Now, this is not a carte blanche operated on every cystic mass. Not at all. We followed sort of the majority of these masses.

And it was very safe to monitor. Nobody met it out. But still, there is a subset of cystic renal masses that are not cystic, they're truly necrotic, that have high-grade components. Hey, this is a really good study to deploy on that cystic mass, because it's hard to biopsy them.

Zachary Klaassen: Yeah, great points. Let me hit you with one more question. Regarding active surveillance, what patients may you consider a molecular PET image for active surveillance patients?

Alexander Kutikov: Well, I think it's the same as a biopsy.

Zachary Klaassen: Yeah.

Alexander Kutikov: Only the ones that are growing, only the ones that I'm uncomfortable watching. That's when I deployed. I don't need to do this study on a patient that's going to stay on surveillance regardless of the result.

Zachary Klaassen: Sure, absolutely. Always fun chatting with you, Alex. Any take home messages, any zingers for our audience before we wrap up?

Alexander Kutikov: Yeah, I think everybody's got to remember it's very easy to overtreat this patient population. Not all small renal masses need to be resected. Biopsy, better risk stratification. Possibly with this TLX250 new scan, better characterizing these masses before moving forward. I think there's a lot to be gained there.

This molecular imaging is coming. It's exciting. And stay flexible. This should be really personalized. There's no default for surgery, no default for surveillance. The best care is really the individualized discussion for all these patients.

Zachary Klaassen: Yeah, absolutely. I think it's just another toolbox for shared decision making, which will be really helpful.

Alexander Kutikov: Absolutely.

Zachary Klaassen: Alex, thanks so much. Always good chatting with you.

Alexander Kutikov: Same here, Zach. Thanks.