Blue Light Cystoscopy for Bladder Cancer

Bladder cancer is the fourth leading cause of cancer death in males and the most common site of cancer in the urinary system. An estimated 74,000 new cases of bladder cancer are expected to be diagnosed in the USA in 2015 and 16,000 deaths are estimated[1]. Non-muscle-invasive bladder cancer (NMIBC) has a high rate of recurrence and also a risk of progression that requires patients to undergo regular monitoring with cystoscopy after transurethral resection of the bladder tumor (TURBT). Current standard of care uses white-light cystoscopy (WLC) to map and resect all visible tumors. This blog will give an overview of the use of fluorescent cystoscopy in the management of NMIBC and review the evidence for its use.

Product Overview

Blue-light cystoscopy (BLC), also referred to as fluorescent cystoscopy or photodynamic diagnosis (PDD), is a procedure in which a photosensitizer medication is instilled in the bladder prior to cystoscopy. This photosensitizer is part of the heme biosynthesis pathway (that makes red blood cells) and causes an accumulation of photoactive porphyrins in neoplastic cells. These porphyrins preferentially accumulate in neoplastic cells due to the increased metabolic activity in these cells. When excited with blue-light in the 360-450 nm wavelength, the porphyrins emit a red light that can easily be seen during cystoscopy (Figure 1). There are two main photosensitizers that have been used in studies looking at fluorescent cystoscopy: 5-aminolevulinic acid (5-ALA) and hexaminolevulinate (HAL). HAL is the only photosensitizer that has been approved for use in the USA and Europe. In the USA it is marketed under the brand name Cysview, and in Europe under the brand name Hexvix.

Figure 1. 63 year old female with prior TURBT+BCG now with recurrence. (a) WLC of a prior resection site near a ureteral orifice. (b) Same site using BLC. Tumor was found to be high grade T1. (c) WLC showing an area of CIS that was missed upon repeat resection. (d) Same site using BLC.
From: Daneshmand, et al.[2]

Increased Tumor Detection

Most studies are in agreement that more tumors are found when using BLC compared to WLC alone. Perhaps the best evidence for this is a meta-analysis published in 2013 which looked at the raw data from 6 prospective studies including a total of over 800 patients[3]. This meta-analysis found that a significant proportion of tumors were missed by WLC alone. In fact, an additional 14.7% of Ta tumors were detected with BLC, 10.8% of T1 tumors, and 40.8% of CIS (carcinoma in situ or flat tumors) (Figure 2). Another meta-analysis by Shen et al4. failed to show a statistically significant difference in tumor detection rates between BLC and WLC, however this study was limited by the inclusion of a large number of studies which used the photosensitizer 5-ALA, which is not FDA approved and has been shown to have less fluorescent properties than HAL.

Figure 2. Increased detection of tumors using BLC alone when compared to WLC alone.
From: Burger, et al.[3]

Recurrence Free Survival

While the data on increased detection are consistent, data on recurrence-free survival (RFS) are less clear-cut. Cysview gained FDA approval following a study by Stenzl et al5. published in 2010. This study was a prospective, randomized, multi-center study that looked at 551 patients with suspected Ta or T1 disease and were randomized to either WLC or WLC+BLC. During the 9-month surveillance period, 47% of patients in the BLC group and 56% of patients in the WLC group had tumor recurrences for a relative reduction of 16%. Interestingly, the following year Stenzl published another paper which randomized patients to either 5-ALA or placebo which failed to show a difference in recurrence-free survival 12 months after tumor resection6. However, as previously mentioned, this study used 5-ALA which is not the FDA approved photosensitizer.

The study with the longest follow-up data is actually an extension to the original Stenzl study used for FDA approval. This study was published in 2012 by Grossman et al7. and showed that with a median follow-up for 53.0 months (WLC group) and 55.1 months (BLC group), 38% of the patients in the BLC group remained tumor free vs. 31.8% in the WLC group. The median time to recurrence was 16.4 months in the BLC group and 9.4 months in the WLC group. This study also looked at progression-free survival and cystectomy rates but was unable to show a statistical difference between the two groups, possibly due to the original study not being powered to look at differences in these outcomes.

Figure 3 summarizes additional studies that have looked at recurrence-free survival for BLC vs. WLC.

Figure 3. Summary of studies that have looked at recurrence-free survival for BLC vs. WLC.

Cost

Bladder cancer is one of the mostly costly cancers to treat on a per capita basis. Lifetime per capita costs have been estimated between $96,000 and $187,000 (2001 US dollars)8. Multiple analyses have looked at whether using BLC could reduce cost for bladder cancer treatments using the assumption that if a patient has a longer recurrence-free survival, they may require fewer or perhaps less frequent TURBTs. Garfield et al9. used a probabilistic decision-tree model and estimated that over 5 years, approximately $4,600 could be saved per patient by using BLC during diagnostic cystoscopy (excluding the cost of the equipment).

Indications

The current AUA guidelines for bladder cancer were written in 2007, 3 years before Cysview was approved for use in the USA and therefore do not have an official recommendation for the use of fluorescent cystoscopy in the management of NMIBC. The NCCN guidelines acknowledge that BLC has been shown to decrease recurrence in NMIBC but has not been shown to reduce progression. They suggest that “BLC may have the greatest advantage in detecting difficult-to-visualize tumors (eg, CIS tumors)” and “the limitations of BLC require judicious application of this additional diagnostic tool”10.

In 2013, an expert focus group convened in San Diego to create a consensus statement for appropriate use of BLC in the USA2. Based on the evidence reviewed, they recommend that BLC should be considered:
- At initial TURBT on suspicion of NMIBC
- In patients with positive urine cytology but negative WLC findings
- In patients with intermediate-risk NMIBC
- For assessment of disease recurrence

These recommendations are similar to consensus statements and guidelines from Europe.

Summary

Blue-light cystoscopy has been shown to increase detection of NMIBC during TURBT. Whether this increased detection leads to a difference in recurrence or progression is less clear. Most studies to date, especially those with longer follow-up times, have shown a decrease in recurrence in patients who undergo TURBT with BLC. No study to date has shown a difference in progression. It is likely that to show a statistically significant difference in progression, larger studies with longer follow-up will need to be conducted.

This blog was written by Kevin Curtiss, a medical student at Johns Hopkins School of Medicine. Kevin recently finished a four-week sub-internship at the Brady Urological Institute and gave a presentation to the department on "Blue Light Cystoscopy" from which this blog is inspired. Kevin is looking forward to a career in urology.





REFERENCES
1. Cancer of the Urinary Bladder - SEER Stat Fact Sheets. http://seer.cancer.gov/statfacts/html/urinb.html. Accessed September 2, 2015.
2. 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.
3. Burger M, Grossman HB, Droller M, et al. Photodynamic diagnosis of non-muscle-invasive bladder cancer with hexaminolevulinate cystoscopy: a meta-analysis of detection and recurrence based on raw data. Eur Urol. 2013;64(5):846-854. doi:10.1016/j.eururo.2013.03.059.
4. Shen P, Yang J, Wei W, et al. Effects of fluorescent light-guided transurethral resection on non-muscle-invasive bladder cancer: a systematic review and meta-analysis. BJU Int. 2012;110(6 Pt B):E209-E215. doi:10.1111/j.1464-410X.2011.10892.x.
5. Stenzl A, Burger M, Fradet Y, et al. Hexaminolevulinate guided fluorescence cystoscopy reduces recurrence in patients with nonmuscle invasive bladder cancer. J Urol. 2010;184(5):1907-1913. doi:10.1016/j.juro.2010.06.148.
6. Stenzl A, Penkoff H, Dajc-Sommerer E, et al. Detection and clinical outcome of urinary bladder cancer with 5-aminolevulinic acid-induced fluorescence cystoscopy : A multicenter randomized, double-blind, placebo-controlled trial. Cancer. 2011;117(5):938-947. doi:10.1002/cncr.25523.
7. Grossman HB, Stenzl A, Fradet Y, et al. Long-term decrease in bladder cancer recurrence with hexaminolevulinate enabled fluorescence cystoscopy. J Urol. 2012;188(1):58-62. doi:10.1016/j.juro.2012.03.007.
8. Botteman MF, Pashos CL, Redaelli A, Laskin B, Hauser R. The health economics of bladder cancer: a comprehensive review of the published literature. Pharmacoeconomics. 2003;21(18):1315-1330. http://www.ncbi.nlm.nih.gov/pubmed/14750899. Accessed September 2, 2015.
9. Garfield SS, Gavaghan MB, Armstrong SO, Jones JS. The cost-effectiveness of blue light cystoscopy in bladder cancer detection: United States projections based on clinical data showing 4.5 years of follow up after a single hexaminolevulinate hydrochloride instillation. Can J Urol. 2013;20(2):6682-6689. http://www.ncbi.nlm.nih.gov/pubmed/23587507. Accessed September 2, 2015.
10. NCCN Clinical Practice Guidelines in Oncology: Bladder Cancer. 2015;http://www. http://www.nccn.org/professionals/physician_gls/PDF/bladder.pdf. Accessed September 2, 2015.

The Surgical Management of Large Prostatic Adenoma

Introduction

Benign prostatic hyperplasia (BPH) is a prevalent disease, affecting 22% of men < 60 years old, and 45% of men 70-80 years old [1]. When BPH symptoms are refractory to medical management, surgical intervention is recommended. Optimal surgical management for large prostatic adenoma, defined as prostate mass > 100 g or volume > 80 cc, is controversial. While open simple prostatectomy (OSP) remains the gold-standard surgical management for severe BPH, the procedure is associated with significant morbidity, encouraging the use of other surgical options. This blog will discuss the surgical management of large prostatic adenoma, with emphasis on several alternatives to OSP, including bipolar TURP, holmium laser therapy, photoselective vaporization of the prostate (PVP), and robot assisted laparoscopic simple prostatectomy (RASP).

Open Simple Prostatectomy (OSP)

OSP is the gold standard surgical management for high volume (> 80 cc) prostatic adenoma. Advantages of this approach include more complete removal of prostatic adenoma under direct visualization, lower re-treatment rates, and no risk of TUR syndrome. A randomized controlled trial comparing transvesical open simple prostatectomy (TVP) with TURP for prostates > 80 cc demonstrated significant reduction in IPSS scores at 12 months post-op for the TVP group. Unfortunately, the peri-operative blood transfusion rate was 11% and 14% for the TVP and TURP arms, respectively (Figure 1) [2]. This morbidity associated with OSP has encouraged urologists to seek other alternatives for the management of large prostatic adenoma.

Figure 1: Complications for both TURP (n= 35) and Transvesical Open
Simple Prostatectomy (TVP) (n = 34). Ou et al. Urology 2010.

TURP

Monopolar TURP has been the gold standard surgical management for prostates 30-80 mL, but concerns regarding TUR syndrome and excessive bleeding prevent its routine use in larger prostatic adenoma. For this reason, many studies have focused on Bipolar TURP, which enables the use of normal saline irrigation with no risk of TUR syndrome. In a recent prospective, randomized trial comparing Bipolar TURP vs. OSP for prostates > 80 cc, Bipolar TURP was found to resect significantly less prostatic adenoma mass despite having similar pre-operative prostate size to the OSP arm. However, a significantly less hemoglobin drop, blood transfusion rate, and hospital stay was found in the Bipolar TURP arm [3].

Holmium Laser Therapy

Holmium laser therapy emits light at 2100 nm in pulses. This causes tissue water vaporization with limited (0.4 mm) tissue penetration. Because the procedure uses normal saline for irrigation, there is no risk for TUR syndrome manifested by dilutional hyponatremia. Laser settings commonly cited in the literature include 2-2.5 J and 40-50 Hz [4]. Several retrospective studies have found significant 6 month post-op reduction in IPSS scores for prostates greater than 75, 125, and 175 g [4-6]. Furthermore, these studies reported low peri-operative blood transfusion rates of 1.9-3.5%, which is significantly less than the reported OSP average blood transfusion rate of 8.5% or greater. For this reason, holmium laser therapy is often cited in the literature as having prostate “size independent” effectiveness.

Photoselective Vaporization of the Prostate (PVP)

Photoselective Vaporization of the Prostate (PVP) is commonly referred to as the Greenlight laser, as it vaporizes tissue at a wavelength of 532 nm. Because the laser is selectively absorbed by hemoglobin, the relatively fibrous prostatic capsule is resistant to absorption, making this procedure an attractive alternative to OSP. The current generation of the Greenlight laser is the 180 W XPS laser. The power has been increased from previous generations in order to improve adenoma removal and lower re-treatment rates. A multi-institutional prospective trial that looked at nearly 1,200 patients (2/3 with > 80 cc prostates; 1/3 with < 80 cc prostates) who underwent 180 W XPS laser therapy found that the larger prostate cohort maintained a mean IPSS reduction of 19 points at 6, 12, and 24 months post-op [7]. However, significantly more of the > 80 cc prostate cases had to be converted to TURP, most commonly due to bleeding that obscured the visual field. Therefore, PVP appears to be an effective, but imperfect alternative to OSP for large prostatic adenoma.

Robot assisted laparoscopic Simple Prostatectomy (RASP)

Robot assisted simple prostatectomy (RASP) appears to be a very attractive alternative to OSP, with the hope that it would produce the functional results of OSP while reducing the associated morbidity, including hospital length of stay, perioperative hemorrhage, and blood transfusion rates. The transvesical approach provides excellent visualization of the extent of the prostatic adenoma, while preventing injury to the ureteral orifices during incision of the bladder mucosa (Figure 2).

Figure 2: Transvesical RASP: Incision in bladder mucosa distal to the ureteral orifices.
Screen shot credit: Misop Han, M.D. Brady Urological Institute at Johns Hopkins Hospital.

Data from the Brady Urological Institute comparing RASP to OSP found reductions in estimated blood loss, blood transfusions, and hospital length of stay for the RASP arm (Figure 3). Although there was no significant difference in pre-operative prostate volume by transrectal ultrasound measurements, RASP had similar adenoma resection weights as compared to OSP. A review that looked at 13 RASP studies found an overall blood transfusion rate of 3.5% [8].

Figure 3. RASP vs. OSP Peri-operative Outcomes.
Brady Urological Institute at Johns Hopkins Hospital.

An edited video of a robot assisted laparoscopic simple prostatectomy performed at Johns Hopkins Hospital can be found below.

Key Points

• Open simple prostatectomy is the gold standard surgical management for large prostatic adenoma
• Bipolar TURP may remove less adenoma than OSP
• HoLEP has prostate “size independent” effectiveness
• PVP is effective but bleeding my obscure visualization
• RASP is an excellent alternative for severe BPH for those well versed in robotic radical prostatectomy

This blog was written by Bijan W. Salari, a medical student at Wright State University Boonshoft School of Medicine. Bijan recently finished a four-week sub-internship at the Brady Urological Institute and gave a presentation to the department on "The Surgical Management of Large Prostatic Adenoma" from which this blog is inspired. Bijan  is looking forward to a career in urology.

REFERENCES
1. Speakman et al. Burden of male lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) - focus on the UK. BJU Int. 2015 Apr;115(4):508-19. doi: 10.1111/bju.12745. Epub 2014 Oct 16.
2. Ou et al. A randomized trial of transvesical prostatectomy versus transurethral resection of the prostate for prostate greater than 80 mL. Urology. 2010 Oct;76(4):958-61. doi: 10.1016/j.urology.2010.01.079. Epub 2010 Apr 15.
3. Geavlete et al. Bipolar vaporization, resection, and enucleation versus open prostatectomy: optimal treatment alternatives in large prostate cases? J Endourol. 2015 Mar;29(3):323-31. doi: 10.1089/end.2014.0493. Epub 2014 Sep 17.

4. Krambeck et al. Holmium laser enucleation of the prostate for prostates larger than 175 grams. J Endourol. 2010 Mar;24(3):433-7. doi: 10.1089/end.2009.0147.
5. Matlaga et al. Holmium laser enucleation of the prostate for prostates of >125 mL. BJU Int. 2006 Jan;97(1):81-4.
6. Kuo et al. Holmium laser enucleation of prostate (HoLEP): the Methodist Hospital experience with greater than 75 gram enucleations. J Urol. 2003 Jul;170(1):149-52.
7. Hueber et al. Photoselective Vaporization of the Prostate for Benign Prostatic Hyperplasia Using the 180 Watt System: Multicenter Study of the Impact of Prostate Size on Safety and Outcomes. J Urol. 2015 Aug;194(2):462-9. doi: 10.1016/j.juro.2015.03.113. Epub 2015 Apr 4.
8. Patel et al. Robotic-assisted Simple Prostatectomy: Is there Evidence to go Beyond the Experimental Stage? Curr Urol Rep (2014) 15:443.