Daniel C. Parker, MD

Bladder cancer is the sixth most commonly diagnosed cancer in the United States and is responsible for nearly 18,000 deaths per year in this country.

 Of the estimated 81,000 new cases of bladder cancer in 2020, 75% will be diagnosed as non–muscle–invasive bladder cancer (NMIBC).

 These cancers, by definition, are confined to the mucosa or subepithelial layer of the bladder and spare the muscularis propria.

Accurate staging of carcinoma in situ, Ta, and T1 cancers is of the upmost importance because the treatment of NMIBC is drastically different from that of muscle-invasive disease. Emphasizing the challenges associated with precise diagnosis and surveillance of NMIBC, national guideline organizations such as the American Urological Association,

 and the National Comprehensive Cancer Network

 have incorporated blue light cystoscopy (BLC) with hexaminolevulinate (HAL) into the recommendations for endoscopic detection of bladder cancer and bladder cancer recurrence. This article reviews the mechanism of action of HAL, familiarizes the reader with the body of evidence supporting its use, and provides a real-world workflow for incorporation of BLC into clinical practice.

HAL mechanism of action, indications, and efficacy

Under the trade name Cysview, HAL is FDA approved for the detection of bladder cancer, including carcinoma in situ, in patients with a known history of bladder cancer and also in patients undergoing cystoscopic evaluation for the suspicion of bladder cancer.

 In the cytoplasm of bladder cancer cells, HAL becomes incorporated into the heme biosynthetic pathway and is converted into coporphyrinogen. Coporphyrinogen is transported into mitochondria where it is further metabolized into photoactive porphyrins.

Photoactive porphyrins accumulate in the mitochondria, and in sufficient concentrations, fluoresce when exposed to 360- to 450-nm wavelengths of light—hence the moniker 

 In practice, this manifests as well-defined focal areas of pink mucosa where bladder cancer is likely present surrounded by a field of blue-appearing tissue where unaffected bladder exists.

The efficacy of BLC to increase detection of bladder cancer and reduce recurrence was established in 2018 through a phase 3, multicenter, prospective, randomized clinical trial.

 A total of 304 patients were instilled with HAL prior to undergoing a routine white-light cystoscopy. To ensure proper diligence of the white-light component of the exam, the patients were then randomized to either continue with a subsequent blue light component or were discontinued from the study.

In total, 103 patients from the blue light cohort of the trial went on to undergo a transurethral resection of bladder tumor for a suspicion of bladder cancer recurrence. In total, 63 patients (20% of the entire trial population) were diagnosed with bladder cancer recurrence that was detected only on the blue light component of the exam (

 <.001). Twenty-six patients (8.5%) were found to have carcinoma in situ, and of these, 9 (34%) were detected only with BLC (

BLC has also been shown to be well tolerated in the surveillance setting. In the phase 3 trial, Patient-Reported Outcomes Measurement Information System questionnaires evaluating anxiety, pain, and whether the procedure was felt to be worthwhile were administered.

 According to those surveyed, patients who underwent BLC had reduced anxiety without any significant increase in reported pain levels. Ninety-four percent of patients who underwent BLC reported that the procedure was worthwhile and would do it again. More than 90% of surveyed patients responded that they would recommend BLC to others.

Citing these data, guideline panels from the American Urological Association and the Society of Urologic Oncology have strengthened their recommendations that BLC “should” be offered, if available, in patients with NMIBC “to increase detection and decrease recurrence.”

 The National Comprehensive Cancer Network includes the use of BLC as an option.

 An expert panel consensus statement for BLC in the United States is also available supporting its use.

How I incorporate BLC into clinical practice

Performing cystoscopy with the aid of BLC can be easily incorporated into existing clinical practice both in the academic and the community setting. However, there is no escaping that the procedure takes longer than a traditional white-light cystoscopy. Adherence to a few simple principles will ensure that the existing workflow of the urologist’s clinic continues uninterrupted and that the procedure quickly becomes time efficient 

First, patients must arrive early. In my practice, the patient’s “appointment time” is actually the “scope time.” In order for my clinic staff to adequately intake the patient, instill their bladder with HAL, and provide the necessary dwell time, the patient must arrive 1 to 1.5 hours before their scope time. All patients are notified during their routine appointment reminder of both their arrival time and the expected scope time so that they are aware of the difference.

Second, the clinic staff should perform all intake and preparation responsibilities before and after scope time with minimal involvement of the urologist. This step requires that at least 1 member of the care team understand how to constitute the HAL for instillation, be skilled with in-and-out catheterization, and be adept at scope cleaning/equipment turnover. In my practice, these duties are assigned to a single medical assistant, although many practices will utilize registered nurses or nonphysician providers for this responsibility.

A high-functioning assistant trained in this exercise is essential for ensuring that the urologist continues to see nonprocedural patients during the 1 to 1.5 hours that the patient with BLC is in preparation or turnover. 

 demonstrates our procedure suite ready for BLC.

Third, keep the clinic rooms open and continuing to turn over. My patients with BLC occupy a consultation room only during instillation, and they are excused back into the waiting room during the 40-minute dwell period. This strategy keeps the encounter areas open and allows my staff to room patients who are not undergoing BLC during the dwell time. A restroom is adjacent to the waiting area in the event that the patient cannot tolerate holding the solution for the entire dwell time. The assistant then brings the patient to the procedure suite after the appropriate dwell time and positions them on the table with all drapes applied before declaring the patient ready for BLC.

If the urologist has the ability to biopsy and fulgurate lesions in the office, then preparing every patient for a potential biopsy from the outset is my fourth principle. We instill 10 to 15 mL of 1% lidocaine solution at the same time as the HAL and ensure the proper grounding pad is applied during positioning. 

demonstrates the necessary instillation components we apply to every patient. Early anticipation of lesion detection in this manner ensures that the urologist is ready to biopsy immediately upon identifying a lesion, can treat the entire area once the tissue has been sampled, and avoids unnecessary delays or scope reinsertions.

As with any procedure, developing a routine for the cystoscopy that can be easily replicated will save time and increase efficiency. Perform a complete white-light cystoscopy first. Identify any suspicious areas and note them. Retroflex the scope to visualize the anterior bladder neck as the last step of the white-light component, and with the scope in retroflexion, switch to BLC and perform the BLC in reverse order.

This strategy allows for a single retroflexion of the scope and avoids repeating the more uncomfortable portions of the exam. Biopsy and fulguration, if necessary, are performed only after completing comprehensive white- and blue-light components.

When a biopsy is performed, I use flexible biopsy forceps and a monopolar current set at 20 watts for fulguration and hemostasis. I engage the blue light before the biopsy to delineate the entire area needed for treatment. The cautery device can be used to demarcate this area, if desired. The blue light is then engaged again after the biopsy and fulguration to ensure that all fluorescing tissue has been treated. The entire duration of scope time, including time allotted for biopsy and fulguration, rarely exceeds the time necessary for a routine return office visit.

Having adhered to these principles, the urologist and staff should be able to perform at least 4 BLCs in a half day, all of which can be seamlessly interwoven with other nonprocedure appointments. With a motivated care team and dedication to optimizing this process over time, BLC will become a rewarding procedure that is easily replicable and results in improved outcomes for your patients with NMIBC.

Daniel C. Parker, MD, is an assistant professor of urology at The University of Oklahoma College of Medicine, Oklahoma City, Oklahoma.

1. Howlader N, Noone A, Krapcho M, et al. SEER Cancer Statistics Review (CSR) 1975-2017. National Cancer Institute. https://seer.cancer.gov/csr/1975_2017/

2. Babjuk M, Burger M, Compérat EM, et al. European Association of Urology Guidelines on Non-muscle-invasive bladder cancer (TaT1 and carcinoma in situ) - 2019 update. 

3. Chang SS, Bochner BH, Chou R, et al. Treatment of non-metastatic muscle-invasive bladder cancer: AUA/ASCO/ASTRO/SUO guideline. 

4. Flaig TW, Spiess PE, Agarwal N, et al. Bladder Cancer, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology. 

5. Hexaminolevulinate. Prescribing information. FDA; 2010:1-11. https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022555s000lbl.pdf. Accessed May 21, 2020.

6. Witjes JA, Redorta JP, Jacqmin D, et al. Hexaminolevulinate-guided fluorescence cystoscopy in the diagnosis and follow-up of patients with non-muscle-invasive bladder cancer: review of the evidence and recommendations. 

7. Daneshmand S, Patel S, Lotan Y, et al. Efficacy and safety of blue light flexible cystoscopy with hexaminolevulinate in the surveillance of bladder cancer: a phase III, comparative, multicenter study. 

8. Smith AB, Daneshmand S, Patel S, et al. Patient-reported outcomes of blue-light flexible cystoscopy with hexaminolevulinate in the surveillance of bladder cancer: results from a prospective multicentre study. 

9. 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. Vol 16. Nature Publishing Group 2019;377-386.

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Daniel C. Parker, MD

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