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Phillip Koo: Hi, this is Phillip Koo and welcome to UroToday for our coverage of ASCO 2024. Today we have with us Dr. Shankar Siva, who's a professor of radiation oncology from the Peter MacCallum Cancer Center. Thank you very much for joining us.

Shankar Siva: Thank you very much for having me, Dr. Koo.

Phillip Koo: You gave a very exciting presentation giving an overview of functional renal imaging. Before we dive into some of those details, can you give us a brief overview of what standard of care imaging for kidneys looks like today?

Shankar Siva: It's a good question. In 2024, the guidelines suggest that there are certain imaging modalities that we use for the primary localized kidney. For example, a triple-phase CT or MRI with IV contrast is the standard of care for localized primary kidney cancer, and this is in the ESMO guidelines, the NCCN guidelines, as well as the EAU guidelines.

When patients have symptoms or a suspicion of metastatic disease, then it's recommended to have at least a bone scan or a CT of the brain or an MRI of the brain. There are issues with bone scans, however, because most of the metastasis for renal cell carcinoma tend to be lytic and may not have the osteoblastic activity that's required to be detectable on a bone scan. For patients with high-risk localized kidney cancer, then we also are expected in the guidelines to have a CT scan of the chest to exclude pulmonary metastatic disease. At the moment, in all of these guidelines, including the most recent up-to-date EAU guideline, we do not recommend that there should be functional imaging as a standard of care in the space for RCC, but it certainly is an exciting space.

Phillip Koo: Great. So if we move into the future and we talk about localized disease and functional imaging, what does that mean and what are your thoughts on how that can be implemented most appropriately?

Shankar Siva: From a localized disease perspective, the main challenges clinically are those to differentiate what could be benign disease and non-threatening to the patient and those patients who may have high-risk disease to be able to assess whether or not there are other sites of occult metastatic disease that may be present. In that kind of benign setting, there is an acceptable standard for functional imaging called sestamibi scanning, and this is technetium-99 sestamibi scanning. Sestamibi scanning is used in a variety of benign or non-oncological conditions, including cardiac functions, but sestamibi scans are very useful in the primary kidney setting because it's useful in oncocytoma and hybrid oncocytoma.

There was a recent meta-analysis that was just published last year that was looking at multiple series of sestamibi scanning between 2016 and 2022 that showed there was a high sensitivity and a high specificity in about the mid-80% ranges for sestamibi for defining this benign disease. In fact, the negative predictive value was 98%. So having a scan that does not show activity would indicate that it's unlikely to be an oncocytoma or a hybrid oncocytoma tumor.

The issue with the scan is it's not very good at differentiating between chromophobe RCC and oncocytoma. In fact, it was only about 41% in this meta-analysis looking at the ability to distinguish these two types of diseases. Some would argue that a chromophobe RCC is relatively indolent and therefore this may not be such a challenge, but it is still a malignant condition and therefore this is one of the weaknesses of sestamibi scanning.

If we look at other tracers for primary kidney cancer, more recently there was the ZIRCON study, which is zirconium-89-labeled girentuximab, which is a monoclonal antibody that's labeled to CA IX. CA IX is over-expressed in the majority of clear cell kidney cancer, so greater than 90% have over-expression of this particular molecular marker, meaning that's a very good marker for detecting localized clear cell RCC. The ZIRCON study was a multi-center study, 284 patients, and it had a very high sensitivity and specificity, again, in the high 80% ranges for detecting clear cell RCC.

There are some issues with this tracer. One is that the production and the delivery of the tracer are slightly disjointed because administration of the tracer is at day zero, but it takes some time to actually accumulate enough function to be able to image, and imaging is between day three and day seven of using this tracer. So the patient requires two visits. There's also a relatively low background-to-tumor ratio. In other words, the scan time for the abdomen for one area can be a little bit onerous. Therefore, trying to do a whole body scan with girentuximab with low activity may take longer than is desirable. But it's a good scan for looking at the primary setting and perhaps defining which patients need a biopsy.

Phillip Koo: That's great. I think there's a huge opportunity in this space to better characterize primary lesions, and it's nice to hear. We have some older tracers like sestamibi, which are good. They were used for breast cancer as well. Maybe we could see a little bit more of a revival of that, especially because the costs are low. And it's also exciting to hear about some progress with things like girentuximab, which I think has a really big opportunity to change how patients are managed.

If we move to the advanced setting in patients who might have metastatic disease, there's some interesting developments that you talked about with imaging for those patients. Can you tell us more?

Shankar Siva: Advanced disease is a very interesting setting. I potentially highlighted the weakness of zirconium girentuximab in that setting as being a longer scan. There are other tracers that are more widely available, things like fluorinated FDG-PET or even a PSMA PET, which can be a fluorinated compound or it can be a gallium-68 compound, have a small molecule.

With these two imagings, they have different advantages and disadvantages. FDG is not very specific for clear cell RCC, however, it is pretty avid in those more dedifferentiated types. The sarcomatoid or the more aggressive type of clear cell carcinomas, these are very FDG-avid. PSMA is an interesting tracer because it's a bit of a misnomer. We call it prostate-specific membrane antigen. It's not particularly prostate-specific. In fact, it lights up very well in clear cell RCC because this tracer is attracted to the neovasculature of clear cell kidney cancer. In fact, PSMA has very high avidity.

We did a study in our own institution looking at patients who had both concurrent PSMA PET and a concurrent FDG PET in the advanced metastatic clear cell setting. And the SUV maxes from PSMA are actually very high. It's about 15 compared to FDG-PET, which is, on average, about seven, and mostly the two tracers are concordant. We had a concordance rate of about 70%, 80% in that mark. But there are more sites of disease that are picked up by PSMA than there are with FDG. We had almost 1 in 5 patients, so 18% of patients, who had PSMA-avid disease that was not picked up on the FDG-PET.

It's an interesting tracer because, at least in Australia, PSMA PET is becoming ubiquitously available, and therefore many of the centers have access to using such a tracer, and particularly with desktop-generated gallium-68-type small molecules, it's easier to deliver on an institutional basis as well.

Phillip Koo: I think this is a really good learning point for all of us. PSMA is not prostate-specific. Patients with prostate cancer who get a PSMA PET, perhaps you'll diagnose a renal cell or other malignancy as well. So I think it's a good learning point for all of us. Well, thank you so much for joining us. I think this whole space is going to be really exciting. I think we're seeing a lot of changes in our approach to imaging, which will then obviously affect how we manage these patients as well. So thank you very much for sharing your time and thoughts with us today.

Shankar Siva: It's a pleasure, Dr. Koo. Thank you for having me.