Enhancing the negative predictive value of cystoscopy

An ongoing challenge that urologists face in the bladder cancer space is being able to accurately identify patients with bladders that no longer harbor cancer.

Alexander Kutikov, MD

At the 2021 Society of Urologic Oncology Annual Meeting, Alexander Kutikov, MD, FACS, gave a presentation on determining and helping improve the negative predictive value of cystoscopy in ruling out muscle invasive bladder cancer for this year’s bladder cancer course.¹ In a recent interview, he discusses the main points from his talk and highlights ongoing advancements in bladder cancer. Kutikov is the chief of the division of urology and urologic oncology, professor in the department of surgical oncology, and the Roberta R. Scheller Chair in urologic oncology at the Fox Chase Cancer Center at Temple University in Philadelphia, Pennsylvania.

Could you provide a brief overview of your presentation and discuss some of its highlights?

Bladder removal is still the gold standard for treatment of bladder cancer, and one of the biggest challenges and the biggest opportunities in the space is the fact that when we remove someone's bladder, up to 30% of the time there's not a single cancer cell left in that bladder. This is especially true if patients received chemotherapy before bladder removal. This is clearly a giant opportunity to afford our patients the ability to keep their bladders, or at least have them keep bladders for a longer time—delay cystectomy. The problem is that we're not very good at predicting who is not harboring any cancer in their bladder. In fact, until recently we largely didn’t have prospective data describing negative predictive value of cystoscopy. The best way to establish this is to look in someone's bladder after chemotherapy and see if there is any cancer left. There are varying reports in the literature about how accurate that is. Almost all those reports are what we call 'retrospective.' Basically, there's clinical practice, things are done. And then, there's a database and you look back at this database and try to get the answer. There was only 1 attempt in the past to try to answer this question prospectively. This was a very small trial, with just 10 patients undergoing cystectomy, that showed a big miss rate. This was back in the 2000s.

Our group at Fox Chase [Cancer Center] really feels this is a very important question. Again, it's just a giant opportunity to potentially offer bladder sparing strategies to our patients. What we wanted to know is what is the negative predictive value of a normal cystoscopic examination? We call this systematic endoscopic examination, or SEE. [Some] patients were SEE t0, but still harbored muscle-invasive cancer. We looked in their bladder, the bladders look completely clean, we biopsied and scraped the bladder deeply, found no cancer, and then took out their bladders and established whether these patients did or did not have muscle-invasive disease. We did that in the same setting. We're very grateful to our patients for agreeing to do this. This was a trial where our patients agreed to have us look in their bladders right before bladder removal to get these data. What we learned is [that] up to 26% of the time, when we think the bladder is completely clean, there is muscle-invasive disease under the mucosa, under the inner lining of the bladder, which was a very important finding and gives us [a] jumping off point on how to move the needle on this. There's lots of work ongoing, where we're trying to find biomarkers and genomic correlates to improve that negative predictive value, to help us tell who's the wolf in sheep's clothing, whose bladder looks good, but [who have] an aggressive tumor under the inner lining. That work is ongoing with further trials planned.

What are some challenges in the clinical staging of MIBC?

The staging challenge [is] the fact that imaging and cystoscopy, which are our main staging tools, are just inadequate at predicting residual disease in the bladder. For imaging, the miss rate is on both sides. Sometimes, it looks like there is thickening of the bladder, there's [a] tumor potentially in the bladder wall. That thickening is actually just scar, so it's a false positive. And then there's the problem of false negatives, where you're just not picking up the tumor that may exist. So, imaging is an ongoing challenge and there's a lot of ongoing work, especially with MRI, to try to better identify these submucosal tumors. But honestly, the field is not there yet. Right now, we're counseling our patients that even though their bladder may look completely clean, and even if imaging is reassuring, there's approximately a 25% chance that they're harboring muscle-invasive disease.

What have been some of the notable highlights in the bladder cancer space from 2021? What advances are you anticipating in 2022?

Clearly, there's so much progress in bladder cancer over the last few years. The field had been stagnant for 3 decades, and all of a sudden, there's this really disruptive change and a lot of it stemming from systemic agents that are really active immunotherapies. In the last year, there's a very promising signal for adjuvant immunotherapy after surgery [that] appears to potentially be able to change some patients’ destiny, where patients who were destined to recur after cystectomy may not recur. At least their recurrence will be delayed if they receive immunotherapies, like nivolumab [Opdivo], so that's a really exciting finding. There's a lot of ongoing trials, including trials that we're doing Fox Chase Cancer Center, where we're using genomic signatures of tumors to try to predict response to chemotherapy and allow patients to keep the bladder. We finished enrollment of a trial called RETAIN,² and now we have a trial called RETAIN II that's enrolling. So, there's a lot of enthusiasm in this space [and] in this course that Dr. Seth Lerner and Dr. Andrea Apolo organized [at] SUO. It really highlighted just the amount of activity and the amount of excitement there is in the bladder cancer space in 2021, [whereas at] a meeting like this 5 [or] 6 years ago there [would] not [be] much to discuss. Everything was rather stagnant. It's very exciting to see how far we've come along.

References

1. Kutikov A. Can systematic bladder sampling predict pT0? Lecture presented at: 2021 Society of Urologic Oncology Annual Meeting; December 1-3, 2021; Orlando, Florida

2. Risk enabled therapy after initiating neoadjuvant chemotherapy for bladder cancer (RETAIN). ClinicalTrials.gov. Updated December 2, 2021. Accessed December 7, 2021. https://clinicaltrials.gov/ct2/show/NCT02710734