Alicia Morgans: Hi, my name is Alicia Morgans. GU Medical Oncologist and Associate Professor of Medicine at Northwestern University. I am so excited to have here with me today, a friend and colleague, Dr. Sam Chang, who is a professor in the Department of Urology, as well as being the Patricia and Rodes Hart, Professor of Urology and the Chief Surgical Officer of the Vanderbilt Ingram Cancer Center. Thank you so much for joining me today, Sam.

Sam Chang: It's a real pleasure and an honor. Thank you, Alicia.

Alicia Morgans: Thanks. Well, I wanted to talk with you as a member on the guidelines committee from the AUA/SUO non-muscle invasive bladder cancer guidelines, how you're thinking about these guidelines and what you're doing in terms of non-muscle invasive bladder cancer these days.

Sam Chang: I think the nice thing about those guidelines is the evidentiary rigor that we really place, that the AUA and SUO did as well. We're actually in the process of updating these guidelines. But it was an attempt to give an algorithm for all clinicians of how we evaluate patients and actually stratify their risk in terms of recurrence and progression, but also looked at diagnosing patients, how you actually then treat them and then how you actually follow them up in terms of surveillance.

Alicia Morgans: Great. So part of this, I think, especially in the diagnosis period, has been an interest in using urinary markers to aid in that diagnosis. How are you using those and how do you distinguish between markers that may be helpful and markers that aren't yet ready for prime time?

Sam Chang: Great question. There's a lot of evolution as there is in much of medicine, the different types of urinary markers that have been around for decades, with cytology being still the standard that we use. We know various cytology is very good for higher-grade tumors. Sensitivity is fairly good for that. And actually very specific for high-grade tumors. But you miss actually the majority of low-grade tumors if you just use cytology as a screening tool. And so we've been using that and we've been trying to get the kind of holy grail of a combination of very specific test, as one that's very sensitive.

Sam Chang: And so whenever we get a test that's very sensitive, it tends not to be specific, and vice versa. So there are recent studies looking at some of the newer urinary markers that show, hey, we're getting better with the combination of good specificity and good sensitivity. Unfortunately, we're not quite to the point where we can use a urinary marker to tell us, "Hey, if you've got microscopic blood, you've got cancer. Yes or no." Or, "Hey, you've got a cancer. It looks like you've got a recurrence." So at this point, they're getting better and better, but still, the gold standard is that office cystoscopy.

Alicia Morgans: Yeah. So office cystoscopy certainly is the gold standard. But as I think about what we're dealing with right now, especially in terms of COVID-19 and changes that that has made in individual practices. How are you thinking about office cystoscopy and how that's been affected maybe by the changes from COVID-19?

Sam Chang: Yeah. And I think clearly it depends upon your geographical area, your relationship to COVID hotspots, versus where there's very little, fortunately, some places where there's very little exposure to COVID. If you look at perhaps a New York, or Seattle during its height, and its continued height, any evaluation, in office cystoscopy, a prostate biopsy, a visit to the office, that was put off, justifiably and rightly so. If you look at many, many documentation or documents that come out regarding what should we do in terms of someone with hematuria, should they be evaluated or not? The vast majority of recommendations were for those patients with microscopic hematuria that any type of evaluation, specifically a visit to the office requiring a cystoscopy. Those were delayed. To the point where mainly for safety, not only for physicians, but for patients as they would have probably, and possibly not something that would be dangerous urgently.

Sam Chang: Those patients with gross hematuria or significant symptomatology, those were patients who were considered more urgent. And those were ones that we tended to evaluate. So I think for every place, how you adjust your practice would depend upon your certain exposure in terms of the COVID-19 prevalence. So for microscopic hematuria, we had deferred for the past actually eight weeks, any type of evaluation. We are now just ramping up our in office cystoscopy evaluation. And we are still using it, I think everybody's practice would still use cystoscopy as a way to rule in or rule out cancer. Even though with white light cystoscopy, we can miss a certain percentage of patients that may have a bladder cancer or some other malignancy.

Alicia Morgans: So that really gets to the next set of questions, which are kind of around optimizing the use, or the utility, I guess, of the cystoscopy is that you do. And this is so especially important if you're trying to minimize engagements of our patients with the healthcare system and minimize instrumentation. I think from what I've heard from other urologists, the Photocure Cysview system seems to be a way that some urologists can optimize those in-office cystoscopies.

Sam Chang: Yeah, that's a really good point. The Cysview, blue light system, was actually included in the guidelines in terms of enhanced cystoscopy, and treatment and evaluation when those were actually available for the urologist. So as a patient I'd want the best possible way to evaluate these tumors. More recently, actually, within the past couple of years, that system has been able to be adapted and modified to actually be used in the office with a flexible cystoscope. And there are studies that have been done that show that a blue light in office cystoscopy is actually better at detecting tumors and actually helping to find tumors at an earlier stage and to be able to be more sensitive in picking up tumors. It's a system that requires more effort and it requires installation of agent prior to the cystoscopy. It requires a different scope, a different light mechanism, and that type of thing.

Sam Chang: But it clearly is if you asked me what's the most sensitive way to find a bladder tumor, it by far is better than our conventional white light cystoscopy, but it does require more effort, it requires more resources. I think importantly in the guidelines regarding surveillance, which actually fits in quite well during this COVID crisis is the old dictum that everybody would need a followup surveillance cystoscopy every three months for the first two years, then every six months for two years after that, then every year. Has really actually first modified by these set of guidelines a few years ago, when for low risk tumors, you did in fact less cystoscopies. The guidelines recommended fewer evaluations of the bladder. Unfortunately, I still see patients today that are referred that are still getting these every few months cystoscopies. When in fact for low-risk tumors, we recommend an initial followup cystoscopy at about three to four months, but then not another one for six to nine months after that.

Sam Chang: And after that, yearly. Just for a shorter period of time decreases the obvious morbidity associated with cystoscopy for the patients. But, especially in this day and age, it protects not only the patients, but the healthcare provider, decrease resources that are used. And so I think that really makes a beneficial impact. If you look at high risk patients and you want the most effective way, perhaps minimize the number of cystoscopies they may need. And I think an important study would be to look at well, if we were able to use enhanced cystoscopies, maybe we could defer even more these cystoscopies and not have to do them as frequently. And again, to increase the safety and preserve actually resources for patients that may need them more urgently than just surveillance and follow up.

Alicia Morgans: That's such an interesting way to think about trying to minimize cystoscopies and engagements for patients with low risk disease and ensure that the high risk patients are getting the assessment that's really necessary to follow them appropriately. And it's so helpful to think about how those guidelines apply now in the COVID-19 era. So thank you for that. The final thing though, that I wanted to just pick your brain about in terms of non-muscle invasive disease, is the BCG shortage that continues to plague the field. How are you thinking about that now in terms of both the guidelines, but also the limitations that we may have had and may have in the future related to COVID?

Sam Chang: Yes. BCG ... it's walking a tight rope a bit in terms of again, we've got a situation where we have an inequitable distribution of BCG. Some places have a lot of BCG, some have no BCG. And so how you ration the BCG kind of supply and what you do with it is a question that, again, varies upon individual practices. Even within the same city, there are institutions that may have plenty of BCG and others that have none. So the AUA, along with support from Beacon and the SUO, come up with a white paper regarding kind of the allocation and recommended distribution of BCG. And clearly, for high-risk individuals, induction BCG is important and is recommended. And if you had a limited supply, then those are the patients that should be getting BCG. Further down on the list would be the maintenance patients. Further down on the list would be those patients with not T1 or CIS, perhaps CA disease.

Sam Chang: But I think importantly, we should really not be treating patients with BCG that shouldn't be getting BCG. So those would be the low-risk patients or those patients with intermediate-risk disease that may be... And are just as effectively treated with either surveillance for the low risk or with intravesical chemotherapy, for those with intermediate-risk. And so that actually dovetails in well when you look at trying to improve the safety of our patients during this era, those patients should not be brought into the office for their sixth cycle of maintenance BCG for a tumor that perhaps is only intermediate-risk or doesn't require BCG. And so in recommendations that we've seen and that we've also published, for those patients during this era, when there's concern with the active virus and contagion associated with that, we don't recommend maintenance BCG. We want to save the BCG, honestly, for those with higher risk needs. But also to improve safety in terms of exposure to possibly the COVID virus. For those patients with intermediate risk disease, we don't advocate initiating BCG.

Sam Chang: Instead, we talk about Intravesical chemotherapy. And for low-risk patients, we really strongly actually advocate not using BCG. And so, as with anything you stratify risk and you balance the supply that's out there. When you have no BCG, then you have other options. And you always need to consider cystectomy for those patients with high-risk disease that may have symptoms or you're definitely more concerned about muscle invasion. And for other patients, we have intravesical chemotherapy options. But clearly again, you're balancing the risk of disease, risk of exposure of virus during this time period, and the benefits of chemotherapy versus perhaps something more in terms of cystectomy. So it's a tough act. The last thing I want to say though is, when we try to limit BCG though, we have to be careful. A recent trial that was presented, the NIMBUS Trial, actually at GU ASCO just this past Spring, actually the last meeting we were able to see each other actually personally. Was actually a review looking at a shortened and abbreviated course of BCG versus the standard course.

Sam Chang: And unfortunately, the shortened abbreviated course with fewer doses had a decreased efficacy. And so, now we have to battle that with, well, we don't have a lot of BCG. I applaud the authors for trying to determine what we can do with a limited supply BCG. Can we be as effective? And at this point, it doesn't look to be as effective. And so we know induction BCG is effective and maintenance helps with that. And so I really advocate if we start BCG maintaining that six-week course, but beyond that, or altering that, or decreasing that we have to be careful about the possible repercussions in terms of decreased efficacy.

Alicia Morgans: Absolutely. And I appreciate you bringing up the NIMBUS Trial because I think that we certainly learned from that some important lessons when we're trying to think about how do we properly ration this scarce resource in the setting of patients who I think they've demonstrated clearly needed that BCG.

Sam Chang: That's exactly right.

Alicia Morgans: Yeah. So thank you so much for talking through these non-muscle invasive guidelines, how we think of them in terms of really complicated things like COVID-19, BCG shortages, and how we think about incorporating new strategies for surveillance and for diagnosis, urinary markers, and then certainly things like Photocure Cysview. So I really, really appreciate you taking the time.

Sam Chang: Well Alicia, you're the best. Thanks again for the opportunity to talk about it.

Alicia Morgans: Thank you.