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.

Historical Contribution: 1966: Gibbons, Transurethral Freezing of the Bladder

1966
Gibbons RP. Transurethral Freezing of the Bladder: An Experimental Study. J Urol. 1966. 95;33-44.

 
Presented at the Urological Research Forum at the annual American Urological Association in New Orleans, 1965, Dr. Robert Gibbons presented early experiments to treat non-invasive urothelial cancers of the bladder. The proposed hypothesis was that by circumferentially destroying the mucosa of the bladder, the risk of subsequent, recurrent non-invasive cancers could be eliminated. Therefore Gibbons set out to find an acceptable freezing material and device to deliver a treatment that could treat these non-invasive bladder cancers.

 
Using a specially designed transurethral cooling device, Gibbons was able to deliver coolant to the entire surface of the bladder – effectively destroying the urothelial layer. 

The experiments were carried out in 30 dogs, and anatomic and pathological evaluation was carried out of the bladders at varying time points following treatment. By carefully tuning the cooling apparatus, Gibbons was able to achieve greater than 75% mucosal slough in many of the experiments. Importantly, Gibbons was never able to achieve 100% mucosal destruction, nor could he create reproducible outcomes by standardizing the coolant and methods to cool the bladder. Anatomic examination demonstrated reduced bladder capacity, new onset hydronephrosis and abdominal adhesions in many animals. Pathological evaluation demonstrated involvement of the submucosa in most specimens and often noticed full-thickness necrosis of the bladder wall in a number of cases. Unfortunately, this corresponded to peritoneal infections and death in a number of the experiments.

 
While this experiment could be considered a failure, this was an outstanding attempt to treat non-invasive bladder cancers. In 1965, there was no BCG or other intravesical treatment for the management of non-invasive urothelial cancers. Thermal ablation, or "freezing" of cancers was en vogue and being attempted in gastric, esophageal, retinal, brain and kidney cancers.

 
Visit the Centennial Website or click here to see more about the first 100 years at the Brady.

 

HISTORICAL CONTRIBUTIONS highlight the greatest academic manuscripts from the Brady Urological Institute over the past 100 years.  As the Brady Urological Institute approaches its centennial, we will present a HISTORICAL CONTRIBUTION from each of the past 100 years.  In the most recent experience, the most highly cited article from each year is selected; older manuscripts were selected based on their perceived impact on the field.  We hope you enjoy! 

Historical Contribution: 1960, Jewett, Bladder Cancer Mechanisms of Invasion

1960
Jewett HJ, Eversole Jr. SL. Carcinoma of the Bladder: Characteristic Modes of Local Invasion. J Urol. 1960. 83;4:383-89.

 
This 1960 manuscript is the transcript of a talk given by Dr. Jewett at the 1960 Annual Meeting of the American Association of Genitourinary Surgeons. Drs. Jewett and Eversole review the pathology from 303 infiltrating bladder cancers and made the following observations.

Jewett and Eversole arrived at three "characteristic modes of local invasion" in bladder cancer:
"1) as a fairly compact mass (70%)
2) as finger-like projections represented frequently as isolated masses (27%)
3) as intramural lymphatic metastases traveling in a direction more or less perpendicular to the plane of the overlying bladder mucosa (3%)"

To reach these conclusions, Jewett and Eversole first characterized the 300 specimens (from autopsy, cystectomy and transurethral resections) using Jewett's staging system: A, submucosa only; B1, less than halfway through the muscle; B2, halfway or more through the muscle; C, perivesical fat or prostate. They immediately found that the majority of cases of lymphatic invasion were stage B2 or C. In addition, well-differentiated tumors (low-grade) remained low-stage; and poorly differentiated, squamous and anaplastic tumor types were much more likely to reach the lymphatics at earlier-stages.

Using these observations, Jewett and Eversole looked closely at pathologic specimens to determine modes on invasion. They determined that many of the "early-stage" tumors were actually missed invasive tumors that invaded deeply into the bladder lymphatics as finger-like projections or perpendicularly into the bladder wall – both difficult to assess with the constraints of serial sectioning and two-dimensional pathologic analysis. While these finger-like and perpendicular growth patterns were relatively uncommon, they were more common in deeply invasive tumors (Stage B2 and C).

 
To read the entire manuscript: follow the link above, visit the Centennial Website or click here.

 HISTORICAL CONTRIBUTIONS highlight the greatest academic manuscripts from the Brady Urological Institute over the past 100 years.  As the Brady Urological Institute approaches its centennial, we will present a HISTORICAL CONTRIBUTION from each of the past 100 years.  In the most recent experience, the most highly cited article from each year is selected; older manuscripts were selected based on their perceived impact on the field.  We hope you enjoy! 

 

 

New Urine Test Shows Promise for Bladder Cancer

The majority of the 300,000 bladder cancers detected in the US each year are non-invasive bladder cancers, and, in general, are not dangerous. However, most of these patients will have recurrences and some will develop muscle-invasive, potentially fatal bladder cancer. Predicting who will "progress" to invasive disease is almost impossible and surveillance involves invasive testing including cystoscopy and biopsies of the bladder. 

Trinity J. Bivalacqua. MD, PhD

Trinity J. Bivalacqua, MD, PhD, Director of Urologic Oncology at the Brady Urological Institute explains, "Because of the high rate of tumor recurrence, we have to perform frequent follow-up cystoscopy procedures, but this results in an unacceptable rate of invasive procedures and ballooning costs." A new urine test developed at Johns Hopkins may become part of the arsenal in detecting new and recurrent bladder cancer.

Mutations in the promoter of the telomerase reverse transcriptase (TERT) gene have been demonstrated in upwards of 66% of muscle-invasive urothelial cancers of the bladder and is the most frequently mutated gene in advanced bladder cancers.[1,2] George Netto, MD, a genitourinary pathologist at Johns Hopkins states, "These are the most common genetic alterations ever identified in early bladder cancer."

The TERT promoter gene.  From Kinde et al. [3].

George Netto, MD

Researchers from the Brady Urological Institute, including Drs. Bivalacqua and Netto with collaborators from the Ludwig Cancer Research team, investigated 76 patients with a variety of bladder cancers. The looked at TERT mutations in early tumors from these patients and in follow-up urine samples as they monitored these patients for progression. They found a high rate of TERT promoter mutations in most (approximately 75%) tumors, including both papillary and flat lesions; and tumors of low- and high-grade nature. More importantly, among patients whose tumors harbored TERT promoter mutations, the same mutations were present in follow-up urines in seven of eight patients that recurred but in none of the six patients that did not recur – indicating that TERT may be a strong indicator of patients likely to recur!

"These exciting results strongly support the potential future analysis of TERT promoter mutations as a urine test that can facilitate the early diagnosis of bladder cancer, before it spreads deep into the bladder wall, in patients at high risk for disease progression. The test will also give us a non-invasive alternative to the many follow-up procedures we currently need to monitor our patients for recurrence of bladder cancer. This test has great potential to save many lives."

This work was published in Cancer Research.[3]

The story was extracted from:

"Urine Test Detects New, Recurrent Bladder Cancer" in Johns Hopkins Urology: News for Physicians, Winter 2015 by Johns Hopkins Medicine.

"Can Urine Test Can Detect Bladder Cancer Early" in Discovery: Volume XI, Winter 2015 by the Patrick C. Walsh Prostate Cancer Research Fund.

 
[1] Horn S, Figl A, Rachakonda PS, Fischer C, Sucker A, Gast A, et al. TERT promoter mutations in familial and sporadic melanoma. Science 2013;339:959–61.
[2] Killela PJ, Reitman ZJ, Jiao Y, Bettegowda C, Agrawal N, Diaz LA Jr., et al. TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc Natl Acad Sci U S A 2013;110:6021–6.
[3] Kinde I, Munari E, Faraj SF, Hruban RH, Schoenberg M, Bivalacqua T, Allaf M, Springer S, Wang Y, Diaz LA Jr, Kinzler KW, Vogelstein B, Papadopoulos N, Netto GJ. TERT promoter mutations occur early in urothelial neoplasia and are biomarkers of early disease and disease recurrence in urine. Cancer Res. 2013 Dec 15;73(24):7162-7. doi: 10.1158/0008-5472.CAN-13-2498. Epub 2013 Oct 11.

Historical Contribution: 1958, Jewett, Surgical Treatment of Bladder Cancer

1958
Jewett HJ. The Surgical Treatment of Carcinoma of the Bladder. J Urol. 1958. 79; 1: 87-93.


 
In the follow-up to his 1946 manuscript on the staging of bladder cancer, Dr. Hugh Jewett reviews the surgical management of bladder cancer stratified into the staging system he proposed. The purpose of this 1958 manuscript was to determine who most benefits from radical cystectomy, or as Jewett puts it,

"to steer a course between what may prove excessively radical on the one hand and ineffectually conservative on the other."

Jewett provides a wonderful summation and timeline of the understanding of bladder cancer in the first half of the 20^th century. Investigators at that time realized that tumor grade provided valuable information and a mechanism for invasive disease, but stage (i.e. depth of invasion) was most correlated with the presence of metastases. In 1951, the first update of his 1946 manuscript, Jewett reviews 80 cystectomy cases and demonstrates an extremely poor survival rate for advanced, infiltrative disease.

Jewett was quick to point out, "that intramural or even extravesical metastasis cannot occur until infiltration is well along. Such a concept would be naive since it is well known that metastasis can occur at any stage of infiltration…" Recognizing that superficial tumors were potentially curable through local excision he came up with the following criteria:

SUPERFICIAL INVASION

• Absence of palpable induration

• Only a "sprinkling" of carcinoma cells only

• Cancer involving only the submucosa, or superficial muscle layer

DEEP INVASION

• Palpable induration after resection

• Massive, invasion of the muscle bundles

Jewett used these criteria to define his staging system (and related survival statistics):
O: Mucosa
A: Submucosa
B1: Superficial muscle
B2: Deep muscle
C: Perivesical fat

Note the similar survival rates for patients with superficial disease undergoing segmental resection and cystectomy. Conversely, observe the potential survival benefit for patients undergoing cystectomy with invasive disease.

Therefore Jewett urged,

"A conscientious attempt to use this classification will prove rewarding. It will enable one-to avoid radical and mutilating surgery when it is unnecessary, to employ more effective instead of less effective measures when the tumor is deeper, and to compare intelligently the results of different kinds of treatment for tumors having roughly the same degree of potential curability."

 

To read the entire manuscript: follow the link above, visit the Centennial Website or click here.

HISTORICAL CONTRIBUTIONS highlight the greatest academic manuscripts from the Brady Urological Institute over the past 100 years.  As the Brady Urological Institute approaches its centennial, we will present a HISTORICAL CONTRIBUTION from each of the past 100 years.  In the most recent experience, the most highly cited article from each year is selected; older manuscripts were selected based on their perceived impact on the field.  We hope you enjoy! 


 

 

Urologic Oncology in the Middle East

The Emirates Oncology Conference and Pan-Arab Cancer Congress 2014 was held in Abu Dhabi, UAE as a joint program of the SEHA Health System in conjunction with Johns Hopkins International and its affiliate Tawam Hospital. While the conference covered a wide range of malignancies, there was a palpable focus on cancer care in the Middle East. In urologic oncology, the prevalence of renal cell, prostate and bladder cancers is different depending on the country and region – therefore, the treatments and outcomes can vary dramatically.

This blog will discuss differences in Renal Cell Carcinoma, Prostate Cancer and Bladder Cancer in countries of the Middle East. 

The incidence and mortality of urologic malignancies in the Middle East (Western Asia) and the more developed regions of the world including the United States and Europe.

RENAL CELL CARCINOMA

According to the WHO GLOBOCAN program, the annual incidence of RCC (renal cell carcinoma) is 213,924 people, with 90,802 deaths per year leaving a 5-year prevalence of 580,700 people. RCC is age-related (i.e. more common in older patients) and is most common in the more developed countries of the world like the United States and countries of Europe. In the United States, the ASR (age-specific rate) of RCC is 12.0 per 100,000 people (see Table below). While Israel has an ASR for RCC of 10.0, most Arab countries of the Middle East have rates between 2.0 and 3.0. Turkey has the highest ASR of 5.6 for RCC. 

The 20 highest age-specific rates of kidney cancer (per 100,000) in the countries of Western Asia from WHO GLOBOCAN.

Most of the figures are likely inaccurate and underestimate the true incidence of RCC as data in not consistently shared among countries and institutions within countries.  To address the shortcomings of systematic data collection in these countries, the Africa Middle-East Collaborative RCC Epidemiology Project was started as a cancer registry, collecting data from a number of countries including Algeria, Egypt, Jordan, Lebanon, Libya, Morocco, and Saudi Arabia. For instance, GLOBOCAN estimates the incidence of RCC in Lebanon to be approximately 2 per 100,000, while the actual data from the collaborative registry indicates the incidence in Lebanon is closer to 4.3 per 100,000.

Similar to other countries around the world, most RCC are low-grade, early stage tumors, however the significant proportion of patients that present with high-stage or metastatic disease mirrors the 20-30% seen globally.

 

PROSTATE CANCER

The prostate cancer data mirrors the data for RCC. The US has an ASR of 98.2 per 100,000 men; Turkey has the highest ASR of 40.6 in the Middle East. 

The 20 highest age-specific rates of prostate cancer (per 100,000) in the countries of Western Asia from WHO GLOBOCAN.

Interestingly, Lebanon has seen a dramatic rise in the incidence of prostate cancer due to a national screening campaign using PSA several years ago.

The increasing trends in prostate cancer in Lebanon coincide with a national PSA screening campaign.
From Shamseddine etal. [1]

In the United Arab Emirates, prostate cancer is the 3^rd most common malignancy. Most patients (77%) present with advanced disease and only approximately 20% receive radical local treatment (16.6% radiation treatment, 5.5% radical prostatectomy).[2] However, over the past decade there has been a tremendous shift toward a multidisciplinary approach to prostate cancer including oncology, urologic oncologists, robotic surgery, radiation oncology and cancer nursing. There are now approximately 30 daVinci Robotic Surgery Systems in the Middle East, with 12 in Saudi Arabia.

 

BLADDER CANCER

The ASR trends in bladder cancer are similar to those observed in RCC and prostate cancer. 

The 20 highest age-specific rates of bladder cancer (per 100,000) in the countries of Western Asia from WHO GLOBOCAN.

One of the more interesting trends in bladder cancer are the decreasing rates of schisosomiasis related squamous cell carcinomas of the bladder in Egypt (read more about schistosomiasis-related cancer of the bladder in our previous blog or click here). Control of schistosomiasis through antibilharzial campaigns have led to dramatic decreases in infestation rates and subsequent bladder cancer incidence. For instance, in Egypt the overall prevalence of schistosomiasis infection decreased from 37-48% to 3%, with a subsequent decrease in the proportion of bladder cancers from 31% to 12% of total cancers in the country.[3,4]

The second interesting trend in bladder cancer is the increasing incidence of cancers related to increasing rates of tobacco smoke. For instance, in Lebanon, the incidence of bladder cancer (13.7%) approaches that of prostate cancer (16.4%) – unheard of in most other countries! Recent data indicate that differences in the prevalence of drug metabolizing enzymes (S-transferases, N-acetyltransferases, and cytochromes P-450) in a number of ethnic groups may explain the susceptibility to bladder cancer in this population.[5]

	Age-specific Rate (per 100,000 population)
	Renal Cancer	Prostate Cancer	Bladder Cancer	Testis Cancer
United States of America	12.0	98.2	11.6	5.0
State of Palestine	3.1	15.2	7.6	1.6
Iraq	2.9	8.7	11.4	1.1
Israel	10.0	84.3	12.6	4.9
Jordan	3.2	15.3	7.1	1.7
Kuwait	2.2	14.5	5.5	0.6
Lebanon	3.2	37.2	16.6	2.4
Oman	2.1	10.2	4.8	0.4
Qatar	3.5	13.2	5.3	0.5
Saudi Arabia	2.3	9.5	3.6	0.6
Syrian Arab Republic	3.1	11.9	9.6	1.4
Turkey	5.6	40.6	15.2	3.2
United Arab Emirates	2.3	10.0	4.3	0.4
Yemen	0.6	2.7	1.8	0.1

 

SUMMARY

• The most common urologic malignancies (RCC, prostate and bladder cancer) are disease of older populations and more common in the most developed countries of the world.
• The incidence of these cancers is lower in all countries of the Middle East, although the true incidence may be underestimated by difficulties in gathering and sharing cancer data.
• A number of interesting trends in the incidence of urologic malignancies make the Middle East a fascinating frontier for investigating cancers of the genitourinary system.

 
This blog was inspired by the lecture, "Overview of Genito Urinary Malignancies in The MENA Region," by Professor Marwan Ghosn of Lebanon.
 
[1] Shamseddine A, Saleh A, Charafeddine M, Seoud M, Mukherji D, Temraz S, Sibai AM. Cancer trends in Lebanon: a review of incidence rates for the period of 2003-2008 and projections until 2018. Popul Health Metr. 2014 Mar 4;12(1):4. doi: 10.1186/1478-7954-12-4.
[2] Ghafoor M, Schuyten R, Bener A. Epidemiology of prostate cancer in United Arab Emirates. Med J Malaysia. 2003 Dec;58(5):712-6.
[3] Ministry of Health and Population, Department of Endemic Diseases, Prevalence of schistosomiasis in Egypt over time, Egypt, 2004.
[4] I. Gouda, N. Mokhtar, D. Bilal, T. El-Bolkainy, N.M. El-Bolkainy. Bilharziasis and bladder cancer: a time trend analysis of 9843 patients. J Egypt Natl Canc Inst, 19 (2) (2007), pp. 158–162
[5] Dhaini HR, Kobeissi L. Toxicogenetic profile and cancer risk in Lebanese. J Toxicol Environ Health B Crit Rev. 2014;17(2):95-125. doi: 10.1080/10937404.2013.878679.

 

Historical Contribution: 1946, Jewett & Strong, Bladder Cancer Staging

1946
Hugh J. Jewett and George H. Strong. Infiltrating Carcinoma of the Bladder: Relation of Depth of Penetration of the Bladder Wall to Incidence of Local Extension and Metastases.  The Journal of Urology, 1946: 55, 366-372.


 

Hugh J. Jewett, MD

Hugh J. Jewett III (1903-1990) finished the Brady Residency at Johns Hopkins Hospital under Hugh Hampton Young in 1936, became a Professor in the School of Medicine, reaching emeritus in 1969.  His work on the prognostication and evaluation of urological malignancies earned him the Barringer Medal by the American Association of Genitourinary Surgeons and the Ramon Guiteras Award by the American Urological Association.  The theme of that body of work is epitomized in this 1946 manuscript.

---

In this paper, Dr. Jewett reviewed the autopsies of 127 patients with infiltrating bladder cancer from 1919-1944. The depth of penetration of tumor into the bladder wall was documented in 107 cases and related to the incidence of 1) metastases, 2) lymphatic capillary invasion and 3) perivesical fixation. From this data, Dr. Jewett was able to stratify patients into three groups: those with submucosal invasion, those with invasion into the detrusor muscle and those with invasion through the detrusor. These groups served as the basis for and correspond to today's modern staging categories of non-muscle invasive (pTa, pT1), muscle invasive (pT2) and locally invasive (pT3, pT4) urothelial cancer.
 

Importantly, Dr. Jewett demonstrated that the number of lymph node and distant metastases, as well as the likelihood of pelvic fixation increased as the tumor grew into and through the bladder wall. He therefore deduced that 100% of patients with submucosal invasion were potentially curable and only 26% of those with perivesical fixation were potentially curable.

In addition, this manuscript defined the lymphatic drainage of the bladder in relation to the peritoneum and abdominal wall and detailed the principle sites of invasion of urothelial metastases (regional lymph nodes, liver, lungs and vertebral column).

This manuscript was a landmark paper, in that it described the basis for our modern-day staging of bladder cancer and developed a prognostic model that could be easily shared among physicians and patients. It has been cited over 400 times since its original publication.
 

To read the entire manuscript: follow the link above, visit the Centennial Website or click here.

HISTORICAL CONTRIBUTIONS highlight the greatest academic manuscripts from the Brady Urological Institute over the past 100 years.  As the Brady Urological Institute approaches its centennial, we will present a HISTORICAL CONTRIBUTION from each of the past 100 years.  In the most recent experience, the most highly cited article from each year is selected; older manuscripts were selected based on their perceived impact on the field.  We hope you enjoy! 

Bladder Preservation Strategies in the Treatment of Muscle-Invasive Bladder Cancer

It is estimated that in 2014, there will be 74,690 new cases bladder cancer and 15,580 deaths secondary to bladder cancer.1 Approximately 20-30% of patients with bladder cancer present with muscle-invasive bladder cancer (MIBC). The standard of care for MIBC is a radical cystectomy with removal of the pelvic lymph nodes, with some patients undergoing chemotherapy prior to surgery (neoadjuvant chemotherapy). While radical cystectomy is the preferred treatment option, it has significant morbidity and implications on quality of life.2,3 Therefore, bladder preservation therapies for MIBC have been developed, and may be an option for a select group of patients.4

Bladder preservation strategies include combination therapies as well as single modality therapies. Trimodal therapy, consisting of an aggressive transurethral resection of bladder tumor followed by concurrent chemotherapy and radiation therapy, is the most strongly supported and accepted bladder preservation option. In a recent systematic review, the 5-year cancer specific survival in medically operable patients undergoing trimodal therapy was 50-82%.5 These numbers are comparable to large radical cystectomy series. While there are no randomized trials comparing trimodal therapy to radical cystectomy, there is a growing body of accumulated data suggesting that trimodal therapy is a reasonable treatment option in well-selected patients.

While trimodal therapy is the most accepted option for bladder preservation, for the remainder of this post, we will discuss the role of each individual modality (transurethral resection, chemotherapy, and radiotherapy) in trimodal therapy, and outline some non-traditional approaches to bladder preservation.

Transurethral resection of bladder tumor

Transurethral monotherapy involves excising all visible tumor with deep resection. In highly selected patients, Dr. Harry Herr presented a series of 151 patients with MIBC that underwent an aggressive transurethral resection of bladder tumor with 10 years of follow-up.6 Of these patients, 99 underwent transurethral resection alone and 52 underwent radical cystectomy. There was no significant difference in survival between these groups, and overall, 57% of patients in this study survived more than 10 years with a functioning bladder. While these results are noteworthy, limited data overall supporting radical transurethral resection as monotherapy. Furthermore, there is a lifelong risk of developing recurrent invasive tumor in retained bladder: 42% of patients in this study underwent salvage radical cystectomy. The general consensus is that transurethral resection alone provides inadequate cancer control with high rate of recurrence and progression.

Chemotherapy

While the primary role for chemotherapy in the treatment of MIBC is neoadjuvant chemotherapy, there are circumstances where a patient will have no evidence of tumor following chemotherapy, and will subsequently refuse a cystectomy. Small series have described this scenario with good outcomes. In a recent retrospective review of 32 patients with muscle-invasive bladder cancer that had a clinical complete response to neoadjuvant chemotherapy, 25 patients refused to undergo an immediate cystectomy.7 Of the 25 patients that refused immediate cystectomy, 7 patients underwent delayed cystectomy for relapse and 18 patients successfully maintained their bladders. There was no difference in the cancer specific survival between patients that underwent immediate cystectomy and patients that opted for a bladder preservation strategy. We see that in select patients that achieve a complete response to neoadjuvant chemotherapy, bladder preservation may be achieved. However, at this point, it is difficult to determine who will have a response to neoadjuvant chemotherapy, and of those, who will be able to durably maintain their bladders.

Radiation Therapy

A multicentered randomized phase 3 trial examined the role of radiation alone versus radiation with chemotherapy in the treatment of MIBC.8 The authors found that the locoregional and invasive disease free survival was significantly better in the patients that underwent chemoradiation therapy as opposed to radiation alone. Furthermore, there was no increased toxicity with the addition of chemotherapy. The authors did not compare these modalities to patients undergoing cystectomy. Overall, when examining bladder preservation options, there is no role for radiation therapy alone, as concurrent chemoradiation is more effective.

SUMMARY

In conclusion, there are multiple options for bladder preservation. There are large trials reporting outcomes for trimodal therapy and small series for single modality treatments. From these experiences, we see that bladder preservation strategies can lead to acceptable outcomes, and may be considered a reasonable treatment option in select patients. Bladder preservation is not an option for all patients with MIBC, and patient selection is of paramount importance. Furthermore, it is essential to recognize that in these studies, only select patients were included. Bladder preservation is a treatment approach under investigation, and prospective trials comparing trimodal therapy and single modality bladder preservation options to radical cystectomy are needed to better define their role in the treatment of MIBC.

This blog was written by Alexa Meyer, Medical Student at Columbia University College of Physicians & Surgeons in New York, New York.  Alexa recently finished a four-week sub-internship at the Brady Urological Institute and gave a presentation to the department on "Trimodal Therapy for Bladder Cancer" from which this blog is inspired. Alexa is looking forward to a career in urology.






1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin 2014;64:9-29.
2. Aghazadeh MA, Barocas DA, Salem S, et al. Determining factors for hospital discharge status after radical cystectomy in a large contemporary cohort. J Urol 2011;185:85-9.
3. Goodney PP, Stukel TA, Lucas FL, Finlayson EV, Birkmeyer JD. Hospital volume, length of stay, and readmission rates in high-risk surgery. Ann Surg 2003;238:161-7.
4. Smith ZL, Christodouleas JP, Keefe SM, Malkowicz SB, Guzzo TJ. Bladder preservation in the treatment of muscle-invasive bladder cancer (MIBC): a review of the literature and a practical approach to therapy. BJU Int 2013;112:13-25.
5. Ploussard G, Daneshmand S, Efstathiou JA, et al. Critical analysis of bladder sparing with trimodal therapy in muscle-invasive bladder cancer: a systematic review. Eur Urol 2014;66:120-37.
6. Herr HW. Transurethral resection of muscle-invasive bladder cancer: 10-year outcome. J Clin Oncol 2001;19:89-93.
7. Meyer A, Ghandour R, Bergman A, et al. The natural history of clinically complete responders to neoadjuvant chemotherapy for urothelial carcinoma of the bladder. J Urol 2014;192:696-701.
8. James ND, Hussain SA, Hall E, et al. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med 2012;366:1477-88.

Historical Contribution: 1942, Jewett, New Method of Ureteral Reimplantation

1942
Jewett. A new method of ureteral transplantation for cancer of the bladder. Journal of Urology, 1942: (48), 489-513.

 
In the early 1940's, the mortality for extirpative bladder cancer surgery and reconstruction hovered around 50%. The mainstay for urinary diversion was the ureterosigmoidostomy, which was fraught with complications related to obstruction of the freshly implanted ureter. In the discussion, Dr. Lawrence Wharton comments that, "in spite of 65 or so techniques now available, [ureteral anastomosis] is still a dangerous operation and should never be done…" However, it was recognized that there are several circumstances, including iatrogenic ureteral injuries in addition to bladder cancer, where no other option is left and foregoing urinary diversion condemned the patient to certain death.

 
In this manuscript, Dr. Hugh J. Jewett describes 15 cases of a two-stage ureterosigmoidostomy. Without a viable option for urinary divesion, Jewett knew that patients would succumb to renal failure or be so debilitated by chronic obstruction and infection that they would be unable to survive radical cystectomy. For this operation, Jewett expanded upon a two-stage surgical technique from the 1930's – and developed a special cutting electrode to facilitate the operation. Briefly, the operation included:

Stage 1: submucosal implantation of both ureters into the sigmoid colon without a lumen-to-lumen connection. This preserved ureteral blood supply and allowed the ureter to safely anastamose to the colon. Importantly, Jewett covered the ureterocolonic anastomoses in omentum and peritoneum to preserve/enhance blood supply and healing.

 
Stage 2: Maturation of the ureterosigmoidostomies. Three or four weeks later, Jewett would take the patient back to the operating room to complete the ureterosigmoidostomy. The distal ureter was divided, giving Jewett access to the anastomosis of the ureters to the colon. Using his cutting electrode, the lumen of the bowel could be joined to the ureter, completing the anastomosis in a safe, well-vascularized fashion.

 
Outcomes
All patients had invasive urothelial cancer of the bladder. Thirteen of the fifteen patients proceeded to cystectomy after urinary diversion. Nine of the 15 were alive 1.5 years after surgery. Three died during the recovery period and three died after discharge from the hospital. All of the patients, except one, died with adequate urinary drainage and good renal function. One patient, who Jewett attributed to a technical error, died of urinary obstruction as an early electrode caused significant damage to the anastomosis. Four patients required subsequent operations due to: bowel complications, urine leak and/or abdominal infection. No patient developed an ascending pyelonephritis.

 
While recognizing that his operation carried significant morbidity and mortality, Jewett noted in his conclusions,

"In the cases which I have reported, the condition of the majority of the patients was considered hopeless, and every form of therapy had been tried elsewhere before the patient was subjected to transplantation of the ureters. In a group of patients representing better surgical risks, I believe the mortality could be considerably reduced."

 
To read the entire manuscript: follow the link above, visit the Centennial Website or click here.


 
HISTORICAL CONTRIBUTIONS highlight the greatest academic manuscripts from the Brady Urological Institute over the past 100 years.  As the Brady Urological Institute approaches its centennial, we will present a HISTORICAL CONTRIBUTION from each of the past 100 years.  In the most recent experience, the most highly cited article from each year is selected; older manuscripts were selected based on their perceived impact on the field.  We hope you enjoy! 


 

Immunotherapy for the Treatment of Bladder Cancer

CASE PRESENTATION

A 57-year-old man presented with a 30-pack year smoking history and high grade non-invasive bladder cancer. He initially underwent resection followed by a course of BCG, but developed a low-grade recurrence. He required further resection and a subsequent course of BCG + Interferon. He was kept on surveillance, but is again found to have T1 high-grade bladder cancer. He is strongly opposed to radical cystectomy and seeks alternative "bladder-sparing" options. Molecular analysis of his tumor was performed and showed FGFR3 mutation.

DISCUSSION

One of the most challenging dilemmas in urologic oncology is the patient with BCG-refractory and recurrent high-grade, non-muscle invasive urothelial cancer of the bladder. These patients are at an extremely high risk of progression to muscle-invasive, dangerous or fatal disease; however, justifying a major extirpative surgery is difficult when no invasive disease is present. This blog will review immunotherapy as a cutting edge therapy for such patients.

At initial diagnosis of bladder cancer, 75% of disease is locally confined, while 25% has advanced to regional/metastatic disease.[1] Of localized disease, 70% is found to be non-muscle invasive.[2] Indeed, molecular analyses of numerous bladder tumors demonstrate that there are two alternative processes that occur in the development of bladder cancer (Figure 1). A hyperplastic process that is associated with mutations in HRAS and FGFR3 genes can occur, leading to a low-grade non-invasive papillary tumor phenotype. Alternatively, a dysplastic process that is associated with loss of tumor suppressors p53 and RB can also occur, leading to an invasive tumor phenotype.[3]

Figure 1. Diagram of alternative processes occurring in urothelial carcinoma. Xu WR. 2005.[3]

Studies looking specifically at FGFR3 mutation status in tumor tissue show that FGFR3 is commonly mutated in non-invasive bladder cancer and also associated with a high level of recurrence.[4] Indeed, mutation occurs more frequently in lower stage and lower grade tumors (Figure 2).

Figure 2. FGFR3 is mutated more frequently in lower stage and grade tumors. Knowles. 2007.[4]

FGFR3 belongs to the Fibroblast Growth Factor Receptor family and includes 18 different proteins (ligands) and 4 different FGF receptors that control functions such as cell differentiation, proliferation, angiogenesis, and invasion.[5] There is a wealth of pre-clinical and laboratory literature that suggests FGFR3 may be an effective therapeutic target in bladder cancer. For instance, a mouse model of bladder tumors demonstrated an 84% reduction in UM-UC1 (a tumor cell line that overexpresses FGFR3), shrinking tumor size and reduced cell proliferation on microscopic examination (Figure 3).[6]

Figure 3. R3Mab, a monoclonal antibody against FGFR3, resulted in smaller UM-UC1 (over-expresses wt FGFR3) tumor xenografts and decreased cell proliferation compared to control IgG in an orthotopic in vivo mouse model. The cell line was transfected with a luciferase plasmid for the bioluminescence scan. Gust et al. 2013.[6]

Dovitinib is an oral medication, classified as a multi-kinase inhibitor with activity against a number of target molecules including FGFR1-4, VEGFR, PDGFR, FLT3, and c-KIT.[7] Laboratory evidence presented by Milowsky et al. demonstrated that Dovitinib could reduce tumor markers and tumor size in a dose-dependent manner, and was superior to tyrosine kinase inhibitors, sorafenib and sunitinib, at inhibiting growth.[8]

There is also clinical data to support the use of Dovitinib. Andre et al. analyzed the effectiveness of Dovitinib in treating women with metastatic breast cancer with FGFR1 mutation. This trial was in a patient population with very advanced disease – 78% of women had liver metastases and had received prior treatment with up to 3 hormone and chemotherapeutic agents or up to 3 chemotherapeutic agents, depending on their hormone receptor status. Nevertheless, there were a greater proportion of the patients treated with Dovitinib that had a partial clinical response or stable disease at ≥ 24 weeks follow up. Furthermore, tumors with large amounts of FGFR1 (amplification greater than 6 copies) showed a 20.2% reduction in tumor burden from baseline compared to tumors with less than 6 copies that had a mean 8.3% increase from baseline. The authors also showed in a waterfall plot that patients with FGF pathway mutation trended toward reduction in tumor burden as compared to increase in tumor burden in those that did not have FGF amplification (Figure 4).[9] Because of its effects against multiple tyrosine kinases, toxicity is a concern for Dovitinib and safety data from the trial showed that nausea, vomiting, diarrhea, and asthenia were common complications. Less common, but more serious complications included: hypertriglyceridemia, pulmonary embolism, and myocardial infarction.

Figure 4. Dovitinib was more effective in reducing tumor burden in tumors with FGF pathway amplification.
From Andre et al 2013.[9]

A recent Dovitinib Trial has opened at Johns Hopkins for the treatment of non-muscle invasive, recurrent bladder cancer.  The trial was designed by Dr. Noah M. Hahn, MD, Associate Professor of Oncology and Urology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, and is open to patients with histologically confirmed low stage disease (Ta, T1, or Tis), FGFR3 mutation, and documented BCG-refractory disease (evidence of disease after two courses of BCG). Patients are not allowed into the study if they have muscle-invasive disease, non-resectable locally advanced disease, or concurrent upper urinary tract non-invasive urothelial carcinoma. Patients enrolled in the trial will receive Dovitinib 500 mg orally for 5 days on and 2 days off. Cystoscopy with tumor and bladder biopsy, and urine cytology will occur every 3 months. The primary end point of the study is the 6-month complete response rate (no evidence of disease). Other outcomes of interest include the 1-year relapse free survival rate, the rate of progression to invasive bladder cancer, and the 3 and 6-month partial response rates (evidence of disease but lower stage than initially diagnosed). Further information can be found on clinicaltrials.gov: GU12-157.[10]

In conclusion, FGFR3 is a potential therapeutic target in non-invasive urothelial carcinoma and Dovitinib is a multi-kinase inhibitor that may be effective for treatment in this setting. The Dovitinib trial at Hopkins is currently enrolling patients and offers bladder sparing treatment for patients with non-invasive BCG-refractory disease and FGFR3 mutation.



This blog was written by Matthew Lee, a medical student at Columbia University, College of Physicians & Surgeons in New York, New York. Matthew recently finished a four-week sub-internship at the Brady Urological Institute and gave a presentation to the department on "A Phase II Clinical Trial of Dovitinib in BCG Refractory Bladder Cancer" from which this blog is inspired. Matthew is looking forward to a career in urology.

[1] Konety BR, Carroll PR. Urothelial Carcinoma: Cancers of the Bladder, Ureter, & Renal Pelvis. Smith’s Urology. Ch 21. 18 ed. 2013

[2] Pandith AA, Shah ZA, Siddiqui MA. Oncogenic role of fibroblast growth factor receptor 3 in tumorigenesis of urinary bladder cancer. Urologic Oncology: Seminars and Original Investigations. 2013; 31: 398-406. 

[3] Wu XR. Urothelial tumorigenesis: a tale of divergent pathways. Nature Reviews Cancer. 2005; 5:713-25.

[4] Knowles MA. Role of FGFR3 in urothelial carcinoma: biomarker and potential therapeutic target. World J Urology. 2007; 25: 581-593.

[5] Katoh M, Nakagama H. FGF Receptors: Cancer Biology and Therapeutics. Medicinal Research Reviews. 2014; 34(2):280-300.

[6] Gust KM, McConkey DK, Awrey S. et al. Fibroblast growth factor receptor 3 is a rational therapeutic target in bladder cancer. Mol Cancer Ther. 2013; 12: 1245-1254.

[7] Chase A, Grand FH, Cross NCP. Activity of TKI258 against primary cells and cell lines with FGFR1 fusion genes associated with the 8p11 myeloproliferative syndrome. Blood. 2007; 110: 3729-3734.

[8] Milowsky MI. Carlson GL, Shi MM, Urbanowitz G.  Zhang Y.  Sternbeerg CN. A multicenter, open-label phase II trial of dovitinib (TKI258) in advanced urothelial carcinoma patients with either mutated or wild-type FGFR3. Poster presented at ASCO Annual Meeting 2011. J clin ONcol 29: 2011 (suppl; abstr TPS186).

[9] Andre F, Bachelot T, Campone M, et al. Targeting FGFR with Dovitinib (TKI258): Preclinical and Clinical data in Breast Cancer. Clin Cancer Res. 2013; 19: 3693-3702.

[10] Hahn N. Dovitinib in BCG Refractory Urothelial Carcinoma with FGFR3 mutation or overexpression. Clinicaltrials.gov: NCT01732107.