Advances in Endoscopic Treatment of Bladder Cancer

Interview with Yair Lotan, MD, Professor of Urology, Chief of Urologic Oncology, UT Southwestern Medical Center

WHITE LIGHT CYSTOSCOPY (WLC) has long been the standard for bladder cancer diagnosis and surveillance, but due to limitations such as detection of carcinoma in situ (CIS), methods to augment and enhance the sensitivity of cystoscopy were developed. One such technology was blue light cystoscopy (BLC), a technique that utilizes intravesical instillation of hexaminolevulinate (Cysview®, Photocure), a tumor photosensitizer. The biological principle behind this approach is that this photoactive porphyrin preferentially accumulates within neoplastic tissue, allowing emission of pink or red fluorescence under blue light (wavelength 360-450 nm).1 Hexaminolevulinate was first approved by the US Food and Drug Administration (FDA) in 2010 for use in the cystoscopic detection of non-muscle invasive papillary bladder cancer in patients with negative WLC cystoscopy.2 BLC was approved for surveillance cystoscopy by the FDA in 2018,3 based on documented improvements in the detection of CIS and papillary bladder tumors.3,4

GU Oncology Now spoke with Yair Lotan, MD, about the utility of BLC in urologic practice. Dr. Lotan is Professor in the Department of Urology and holder of the Helen J. and Robert S. Strauss Professorship in Urology, and Chief of Urologic Oncology at UT Southwestern Medical Center in Dallas, TX. Dr. Lotan spoke about advances in endoscopic treatment of bladder tumors during a plenary session of the 2021 annual meeting of the American Urological Association (AUA2021).

GU Oncology Now: How does BLC work?

Dr. Yair Lotan: Hexaminolevuliante is a protoporphyrin optical imaging agent that is taken up by cancer cells and converted to porphyrins which, when blue light is used, appear red or pink against a blue background. This highlights the location of tumors and improves the detection of bladder cancer by about 20% overall and 30% in CIS. BLC is currently recommended in the non-muscle invasive bladder cancer guidelines for improving detection and reducing recurrence.5-7 It is of help specifically in scenarios where patients have a history of CIS or positive urine cytology with a negative white light cystoscopy.

In your presentation at AUA2021 you emphasized the importance of BLC with hexaminolevulinate in accurately detecting non-muscle-invasive bladder cancer, stratifying bladder tumors, and helping to perform a complete transurethral resection of bladder tumor (TURBT) in the operating room. How did you illustrate this?

I presented several cases; one is in the operating room and others with surveillance cystoscopy in the office setting. One patient had positive urine cytology and negative WLC. Another patient had a history of CIS. Another had a history of recurrent low-grade tumors where BLC was used in the office with biopsy and fulguration to help identify all the tumors. In another patient who was BCG-unresponsive, BLC was used to assess the extent of the disease. The final patient I described was a case where the tumor was identified overlying the ureteral orifice (UO) and demonstrates how BLC can help identify the UO, as the urine efflux appears green.

How do you coordinate BLC in the office setting?

Patients are instructed to arrive around one hour and fifteen minutes ahead of their BLC appointment. When they arrive, vital signs are taken, and they are logged in our electronic medical record system (Epic) as having arrived for BLC. The nurse inserts a urinary catheter and instills the hexaminolevulinate solution in to the bladder, and then removes the catheter.

What is your equipment setup? In the US, hexaminolevulinate is indicated for use with the KARL STORZ D-Light C Photodynamic Diagnostic (PDD) system. Is KARL STORZ the only company that produces BLC equipment?

Yes. Here in the US, for hexaminolevulinate fluorescence cystoscopy, a special light cord, camera, and KARL STORZ telescopes and PDD tower are required. If you are already using KARL STORZ equipment, the outlay is not as much, but typically there is about a $50,000 capital equipment cost.

In Europe, other companies are producing BLC equipment, but because the FDA approved hexaminolevulinate as a package with the KARL STORZ equipment, there is a requirement for additional clinical trials to demonstrate efficacy if another company wants to use their BLC equipment with hexaminolevulinate. It is a bit of a roadblock. Of course, we never really want to be tied to one type of cystoscope. Certainly, if other cystoscope companies were able to provide BLC, I think it would make it easier for the technology to be disseminated.

On this point, urologists do not receive higher reimbursement to perform BLC, in the same way that they do not receive higher reimbursement for narrow-band imaging. However, there is increased reimbursement for BLC TURBT in the hospital setting. This is close to an extra $1000, so if one performed 50 TURBTs annually, the hospital could cover their capital equipment cost within one year. Many busy urologists perform 100-200 TURBTs per year, so at least on the hospital side, they can make a profit. Unfortunately, if you perform TURBTs in an outpatient surgery center, there is no extra reimbursement. There is also no additional reimbursement for standard BLC performed in the office.

How does BLC assist with the management of tumors near the UO?

Under WLC, urine appears clear and is difficult to see, which is why we often administer methylene blue or other dyes to find the UO. Under BLC, the urine appears green, which allows for easier identification of the UO.

Do you have a specific technique for resection of these tumors? Do you place a ureteral stent?

For small, low-grade, superficial tumors I try not to resect the UO. If the tumor is overlying the UO, or if it’s a high-grade tumor, you just resect and hope you uncover it. I don’t routinely place ureteral stents. The truth is, if you can see the UO to place a stent, you can check for urine efflux. If you cannot identify the UO, I usually make one of two decisions. If the patient has pre-operative severe hydronephrosis or flank pain, they will be admitted for a percutaneous nephrostomy tube. If they don’t fit those criteria, I will get a renal ultrasound several weeks later to assess for hydronephrosis.

Do you have any thoughts on en bloc resection of bladder tumors?

I have reviewed papers on that. Most of the en bloc literature originates in Asia; not many studies have been reported from the US. The tumors they resect are usually 3 cm or less. There haven’t been any good randomized trials showing benefits, although it is theorized that you can get a greater amount of muscle in the specimen. For small low-grade tumors where lamina propria involvement isn’t a concern, this benefit isn’t very applicable. Additionally, the literature hasn’t suggested that these patients do not need re-TUR. Many of the technologies used aren’t necessarily available to us, although I do have access to lasers. In my experience, I do not find lasers to be particularly good at hemostasis, so I’m surprised to find in reports that they do not have difficulty with hemostasis when lasering muscle. The bottom line is that very few US urologists are performing en bloc resections at present.

Do you have any thoughts about how BLC use or bladder tumor management is currently being taken up in the US?

Having recognized that WLC is inadequate, it is disappointing that more urologists haven’t adopted enhanced cystoscopy. We are managing a potentially lethal disease and we have technologies that will improve detection and which, in randomized trials, have been shown to reduce recurrence and which are recommended in our guidelines. Unfortunately, very few people have adopted them yet. As urologists, we are supposed to be early adopters of technology. We have Level 1 evidence that we can reduce recurrence if we find more tumors initially. BLC has been approved for over a decade in the US2 and was FDA-approved for office use in bladder cancer surveillance with flexible cystoscopy since 2018.

Why has BLC adoption been slow? Is it due to financial considerations or to a lack of exposure during training?

It is a combination of factors. The financial part is an important consideration, but if people didn’t perform BLC in residency, then they are less likely to use it in practice. I am an academic urologist with high volume, but someone who may only do a few TURBTs may feel differently as it is only affecting a small number of patients. Despite this, TURBTs are a general urology procedure. Urologists do workups for hematuria and if they find a tumor it isn’t necessarily referred to me. After the initial resection, and if it’s muscle-invasive, high-grade T1, multifocal CIS, they may refer the patient to me. The bulk of bladder cancer care in this country is conducted in the community setting and it should be. This also means that community urologists should embrace new technologies, just like many of them have adopted robotic surgery for robotic prostatectomy. Both enhanced cystoscopy and robotic surgery were released after I finished training. As urologists, we constantly see new technologies being released and we learn them as they come along, whether we learned them in residency or not. I would just hope there is less hesitation in future.

Do you expect to see wider adoption of narrow-band imaging (NBI) in bladder cancer?

NBI has been available on Olympus cystoscopes for a long time, and it hasn’t been adopted. I use Olympus cystoscopes and NBI more often than BLC. I use BLC selectively in my high-risk patients. NBI is not biologic, it reveals vascularity and many things in the bladder are hypervascular. Even vascularity does not allow you to decide whether an area is cancerous or not. There are false positives for both, but at least with BLC, hexaminolevulinate is taken up selectively by cancer. NBI demonstrates the contrast between blood vessels and background, which may help identify hypervascularity where some tumors are, but it doesn’t specifically identify tumors. If you look at levels of evidence in the literature, NBI has lower levels of evidence. That being said, it is still better than WLC alone.

If you have a patient with positive urine cytology and a negative WLC, do you ever employ random bladder biopsies?

I never do random bladder biopsies anymore; I only do BLC in this setting, although it won’t help in the prostatic urethra, due to the bladder neck’s being closed.

Akhil Abraham Saji, MD is a urology resident at New York Medical College / Westchester Medical Center. His interests include urology education and machine learning applications in urologic care. He is a founding and current member of the EMPIRE Urology New York AUA section team.

References

  1. Daneshmand S, Schuckman AK, Bochner BH, et al. Hexaminolevulinate blue-light cystoscopy in non-muscle-invasive bladder cancer: review of the clinical evidence and consensus statement on appropriate use in the USA. Nat Rev Urol. 2014;11(10):589-596. DOI: 10.1038/nrurol.2014.245
  2. Photocure announces US approval of Cysview™ for detection of bladder cancer. News release. Photocure, May 29, 2010. https://photocure.com/news/us-approval-of-cysview-/ Accessed September 15, 2021.
  3. Photocure announces U.S. FDA approval of new indications for blue light cystoscopy with Cysview®. News release. Photocure, February 16, 2018. https://photocure.com/news/fda- approval-snda-cysview/ Accessed September 15, 2021.
  4. Lotan Y, Bivalacqua TJ, Downs T, et al. Blue light flexible cystoscopy with hexaminolevulinate in non-muscle-invasive bladder cancer: review of the clinical evidence and consensus statement on optimal use in the USA—update 2018. Nat Rev Urol. 2019;16(6):377-386. DOI: 10.1038/s41585-019-0184-4
  5. Chang SS, Boorjian SA, Chou R, et al. Diagnosis and treatment of non-muscle invasive bladder cancer: AUA/SUO guideline 2016, Amended 2020. https://www.auanet.org/ documents/education/clinical-guidance/Non-Muscle-Invasive-Bladder-Cancer.pdf Accessed September 15, 2021.
  6. Flaig TW, Spiess PE, Agarwal N, et al. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Bladder cancer. Version 4. 2021. July 27, 2021. Available at https:// www.nccn.org/guidelines/guidelines-detail?category=1&id=1417 Accessed September 15, 2021
  7. Babjuk M, Burger M, Compérat S, et al. EAU guidelines on non-muscle-invasive bladder cancer. 2021 https://uroweb.org/guideline/non-muscle-invasive-bladder-cancer/ Accessed September 15, 2021.