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Zach Klaassen: Hello, my name is Dr. Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. And I'm pleased to be joined today for a discussion with Dr. Karsten Zieger, who is at the Lillebælt Hospital in Denmark. Welcome, Dr. Zieger.

Karsten Zieger: Thank you very much.

Zach Klaassen: So, we're going to talk about some data presented at AUA 2023 looking at the Nordic registry for blue light cystoscopy. To get our listeners up to date and up to speed on blue light cystoscopy, can you tell us how it works in terms of visualizing bladder cancer?

Karsten Zieger: Yes. Blue light cystoscopy uses a photosensitizing agent known as Hexvix in Europe, and in America, it's Cysview; the chemical substance is hexaminolevulinate. It is administered intravesically one to four hours prior to the procedure and can also be done with the oral drug, which is called 5-aminolevulinic, which is preferably used in Asia, not in Europe. This is getting to the bladder via renal excretion.

It is preferably absorbed in tumor cells and this has some tumor specificity. I always believe that is because the tumor cells are not terminally differentiated and this has another permeability for small molecules, but also there are some transport proteins maybe involved. And yes, actually I'm not sure why they accumulate, but the fact is that they are accumulated in tumor cells preferably. There is also always some normal fluorescence in the bladder also on normal urothelium, so it's not that specific, but the fluorescence has another quality in tumor cells usually than normal urothelium.

Zach Klaassen: The pictures are quite striking, especially for carcinoma in situ. This is where we get a real benefit of seeing these tumor cells that maybe we can't see with regular white light cystoscopy, correct?

Karsten Zieger: Sure. Some carcinoma in situ is visible in white light and some is not, or not clearly visible in white light and the other blue light has its effect, making it more clear. I have to admit, so that some carcinoma in situ actually show no fluorescence. I don't know why, but we see this and it's also quite striking that they show absolutely no fluorescence. So in these cases, while the normal urothelium has at least some fluorescence.

Zach Klaassen: So tell us about the objective of the study you presented at the AUA 2023.

Karsten Zieger: We wanted to evaluate the utility of flexible blue light cystoscopy at all, and we had several patient categories used for this in the registry. In the poster, we only published results from surveillance patients, patients scheduled for routine surveillance where the routine surveillance white light cystoscopy was replaced by a blue light flexible cystoscopy. And these were preferably high-risk patients under surveillance and some intermediate and very few low-risk patients.

Zach Klaassen: Can you tell us about the logistical workflow in the clinic in terms of would you bring these patients in early to administer the agent or how did you guys make that work in the clinic setting?

Karsten Zieger: We actually, while we call them in some day surgery clinics, they don't get any anesthesia or something like this, but we get them into the consultation room, give them the drug, and then they wait at the waiting room for this one hour, about one hour, and we get them into the examination. So this is quite okay. We work with two nurses, assisting nurses, one doctor. So the one nurse is dealing with all about the patients scheduling new appointments and seeing their needs and administering the drug, the other nurse is dealing with the hardware.

Zach Klaassen: Okay, perfect. Tell us about the Nordic registry and what the study design specifically was for this data.

Karsten Zieger: As I said to you, we had several patient categories besides those under control for under surveillance for high-risk NMIBC. We split them up on those under surveillance after BCG or chemotherapy, intravesical chemotherapy and those who are not directly under control after that. And we have also considered patients which are referred for treatment of small recurrences in the bladder, in local anesthesia. And then another subgroup of patients where we find positive urine cytology in connection with a surveillance cystoscopy where we did not see obvious changes in the bladder. So we find this method can yield with really good information here. Some patients we also took in for diagnosis of some ambiguous or equivocal lesions with a negative cytology. We didn't find that... Under this indication there is not that big advantage, I think because you can biopsy them without Cysview and get the same results. There are really, really rarely found significant changes there. But all these considerations, they're reviewed in a consensus statement published in Nature Review Urology in 2019.

Zach Klaassen: Excellent. And the Nordic registry has how many centers in it and how many countries are involved in the Nordic registry?

Karsten Zieger: It's two countries involved. It's Denmark and Sweden. In Denmark, it's our clinic. And in Sweden, there are four different clinics.

Zach Klaassen: Okay, excellent, excellent. So what were the key results from your guys' study that you talked about at AUA?

Karsten Zieger: We haven't looked at all the data yet for the time being. We analyzed preferably the scenario where BLFC replaced the routine white light cystoscopy, of course. In general, we found that that BLFC improves the hit rate of biopsies. So you come to the bladder, you see something reddish or something not very suspicious, it's after BCG or chemotherapy. The bladder is rarely frankly normal now. Always some lesions to see and in the end of the day, you have to make a decision, take the biopsy or don't take the biopsy. And in this case, the BLFC helps. So you avoid unnecessary biopsies and if there is something to see, you can target your biopsies on the lesions.

Zach Klaassen: So when you guys do the surveillance in the clinic, you're mapping out the bladder, you're then taking them to the OR suite at a different time to do the biopsies, is that correct?

Karsten Zieger: We take them in the outpatients.

Zach Klaassen: Yes. Okay, so you're able to map and then direct where you're going to do the biopsy?

Karsten Zieger: We take them directly at the outpatients. They don't go to the OR.

Zach Klaassen: Perfect. Okay.

Karsten Zieger: Normally, actually, they don't go to the OR. We handle 90% of the patients in the outpatient clinic.

Zach Klaassen: One of the results that I found fascinating was that physicians reported a benefit to blue light cystoscopy in 84% of cases, which I think is a great buy-in from the centers involved in this registry. So what do you think the implications of that are? And not just in your guys' study, but maybe from more of a global perspective?

Karsten Zieger: Yeah, everybody is focusing on the additional lesions seen by BLFC. I think in my point of view, quite as important is the refusal of suspicious lesions or somewhat suspicious, as I told you. You see something you don't know whether it is... And we always use this procedure in connection with urine cytology and this really works well. The urine cytology in case of high-grade lesions carcinoma in situ has about a sensitivity of 80%, but you missed this 20% and in connection with the blue light, you have a negative cytology, you have a negative blue light. We feel very comfortable that this is a recurrence-free bladder and I think this is the main advantage when you look at these 84%. Of course, it's a subjective impression and the acid test is of course the follow-up and the results are pending. We work on this.

Zach Klaassen: That's great. I think you summarized it very well. I think the physician confidence is important when we're adding in new diagnostics. If you can summarize, either from your data or just blue light cystoscopy in general, what are two or three take-home messages that our listeners could take to the clinic tomorrow?

Karsten Zieger: You can use the BLFC to improve your hit rate. You avoid unnecessary biopsies, you avoid discomfort of the patient, you avoid bleeding complications. I highly recommend the use of voided urine cytology in connection with these surveillance procedures. And of course, it's a nice thing to have it in advance of the BLFC and I think it's worthwhile taking into consideration the cost of the Cysview. So I recommend making an additional schedule ahead of the BLFC to get a freshly voided urine in combination with the BLFC. And BLFC identifies a substantial number of additional lesions, in particular CIS. But the real advantage is for us and probably also for the patient, which is looking at the screen, live, that they get an enhanced confidence of a recurrence-free bladder.

Zach Klaassen: That's great. That's well summarized. Well, I want to thank you for your time and your valuable information for our UroToday listeners and thank you very much Dr. Zieger.

Karsten Zieger: Thank you.