TESTING FOR BLADDER CANCER Cancer is a race against being diagnosed and the growth of the tumor.

Usually the earlier healthcare providers can diagnose the patient the more of a chance the patient has in fighting in the cancer before it spreads beyond treatment. Since its conception in 1807 the cystoscope has been the primary diagnostic method for bladder cancer. The procedure involves anesthesia, a cystoscope, a trained professional, a hospital setting and several possible complications. This invasive procedure lead to several point of care kits being created, among the most common are the BTA STAT and the NMP22 kits. Point of care kits are testing that can be performed at the patient bedside, which allows physicians to diagnose patients more rapidly than traditional testing. Rapid results can enable better patient management decisions, improved patient outcomes as well as providing a safe and effective way to diagnose the bladder cancer. The BTA STAT and NMP22 kits test for proteins only released by bladder cancer cells into urine. The research shows that in comparison to cystoscopy the BTA STAT test is reliable to be used as a screening method if paired with an occasional cystoscopy. However flaws in three current research papers lead to the lack of data to prove that BTA STAT can be a replacement test for cystoscopy. Researchers ___, ___, and ____ in their papers ____, ____, and ____, respectively do not have evidence of the point of care tests to be reliable enough to be stand alone from cystoscopy for diagnosing bladder cancer. The earliest cytoscope was first invented by Philipp Bozzini in 1807 and was used for finding bullets (Reiner 2007). With time more uses were found for this instrument, one of which was to explore the bladder for biopsies, tumors and other ailments. For the bladder, using the cystoscope involves numbing the urethra with anesthesia, pushing a 5 mm diameter cystscope slowly through a ___mm urethera and slowly filling the bladder with water to get the patients reaction. The entire procedure may take as long as 45 minutes after which the patient may develop an infection requiring antibiotics, and have painful urination for sometime (WebMD 2006). Considering the subjects chosen to be part of the study were mainly elderly this is not a procedure to be taken lightly. The interpretation of the cystscopy procedure relies on the training of the person performing it (Giannopoulos, 2001). Pode, Ramakumar, and Giannopoulos used different pathologists to perform the cystoscopy but the procedure was not performed twice on the same patient by two different pathologists to show standardization and reproducibility. If similar results were found by both pathologists on the same patient then it can be concluded there was no variation on part of technique. Though it would be useful, being an invasive procedure, this part of the experiment would not be in the best interest of the patient. Urine cytology is no less invasive. The samples are collected either during a cystoscopy or taken from a voided urine. Cytology involves the need for a trained professional and having the urine be properly treated with a stains (Weiner 1998). The integrity of the treatment of the urine is important to this procedure possibly making it more costly. Both the BTA STAT and the NMP22 are kits involving the use of voided urine. BTA STAT uses untreated urine while NMP22 samples need to be treated with a solution containing protein stabilizers, protease inhibitors and buffers, and frozen at 20C before testing (weiner 1998). There is nothing invasive about peeing in a cup. The BTA STAT involves adding drops of urine into the well of the test card and waiting 5 minutes for indicator line (Pode, 1999). The simple presence or absence of the line will indicate the presence of the H protein (Giannopoulos, 2001). This protein has been shown to be found elevated in the urine of individuals with bladder cancer. It is found to be produced only by the cells involved in bladder cancer which makes it a specific and reliable indicator of bladder cancer. BTA STAT is an immunoassay that ________. NMP22 is _______. Both are provided by

several companies and available to physicians and laboratories anywhere. While the cystoscopy and the urine cytology cannot be repeated immediately, the kits are both repeatable without stressing the patient. Procedure for the two tests is simple and is safe to assume reproducibility since several technicians were involved in all studies. In choosing their test subjects the researchers did not include a broad population. The studies did not consider the prevalence of bladder cancer to be in men from Europe and North America, with North Africa and Western Asia becoming high-risk areas. Individuals with a history of bladder cancer and those with undiagnosed hematuria were chosen. However hematuria lacks specificity for bladder cancer and could indicate several other conditions (Gray 2004). Pode (1999) relied on 250 patients drawn from three healthcare sites. This population lacked a range of ages and did not include controls. A specific population that was in suspect of having bladder cancer and those previously diagnosed with cancer was recruited in Podes study. There is no data in this study for healthy individuals to test for sensitivity or specificity. Giannopoulos (2001) used 213 individuals and did include 21 healthy volunteers for their control but did not subject the healthy individuals to cystoscopy. The healthy volunteers were watched for approximately two years after for bladder cancer symptoms which none were found to develop (Giannopoulos, 2001). The number of control subjects used is not an adequate expression of the population, a larger control population would have shown more relevance. Ramakumar (1999) drew data from 196 patients who were undergoing cystoscopy, showing that they were already under suspicion, and in their control group, used individuals who did not have bladder cancer but another bladder condition. This may help show specificity to bladder cancer by including individuals with conditions having similar symptoms to bladder cancer but the sensitivity is lost since the population is narrowed to diseased individuals, no one healthy was screened. In analyzing the data, all studies used regression and the McNemar test. The McNemar method compares two values before and after an event and regression statistics is used to correlate variables in the study. Due to different population criteria, each of the studies has different values for sensitivity and specificity. Giannopoulos (2001) found BTA STAT to be 72.9% sensitive and 64.6 % specific when the entire test pool was included, however when patients with non-bladder genitourinary cancers were excluded the specificity of BTA rose to 75% to 80.6%. Removing interfering diseases to increase the specificity rate for BTA makes the value undependable and shows BTA as not being reliable as a screening test for bladder cancer since the ill patients may simultaneously have more than one undiagnosed condition at the some time. The researchers of this study did not show the effect on sensitivity when chosen data was excluded. If the sensitivity had also increased significantly then BTA could have been used as a screening test for genitourinary cancers. Leaving this bit of information out weakens the researchers argument for using BTA. Ramakumar (1999) found similar values in their study, with BTA having a sensitivity rate of 74% and specificity rate of 73%. This study also found that false-positives increased if another genitourinary condition exists. Pode (1999) showed the highest sensitivity rate in affected individuals, with a rate of 82.8% and a specificity of 95% in unaffected patients. This is acceptable and though the population for the unaffected patients was small and not comprehensive, it does show BTA results if there were no interfering conditions. With a specificity rate that high for the unaffected population, BTA can be used for screening. However a larger population data is first needed. Giannopoulos and Ramakumar both suggest combining two screening methods, such as NMP22 and the BTA to achieve a higher sensitivity and specificity. However, their own data shows that neither statistic has any significant improvement in detecting bladder cancer over

cystoscopy or urine cytology. Also, combining screening tests defeats the purpose of finding a fast and less costly method to diagnosing a patient. Though a study involving a larger range of individuals and no exclusion criteria to show relevance for whole population is necessary, with the results of these three studies, BTA can be used to screen for bladder cancer for the first time or be used for prognosis. Unfortunately, at this time BTA does not have enough conclusive data to warrant replacing cystoscopy, especially when another genitourinary cancer or condition exists.

[First Authors Last Name] Page 4 REFERENCES Aris Giannopoulos, T. M., Antonia Gounari, Constantinos Constantinides, Helen Choremi-Papadopoulou and Constantinos Dimopoulos (2001). Comparative Evaluation of the Diagnostic Performance of the BTA STAT test, NMP22 and Urinary Bladder Cancer Antigen for Primary and Recurrent Bladder Tumors. The Journal of Urology 166(August): 470-475. Dov Pode, A. S., Moshe Wald, Ofer Nativ, Menachem Laufer And and I. Kaver (1999). Noninvasive Detection Of Bladder Cancer With The Bta Stat Test. The Journal Of Urology 161(February): 443-446. Sanjay Ramakumar, J. B., Jennifer A. Besse, Steven G. Roberts, Peter C. Wollan, Michael L. Blute And Dennis J. Okane (1999). Comparison Of Screening Methods In The Detection Of Bladder Cancer. The Journal Of Urology 161(February): 388-394. (2008). "NMP22 BladderChek Test." from http://www.matritech.com/bladderchek.php. (2006). Cystoscopy. Retrieved May 20, 2008, from WebMD.com database. http://www.webmd.com/a-to-z-guides/cystoscopy-16692 Rainer Engel, MD. (10/24/2007). Development of the Modern Cystoscope: An Illustrated History. Retrieved May 23, 2008, from http://www.medscape.com/viewarticle/561774 D. Maxwell Parkin,, Paola Pisani, Jacques Ferlay. 1999. Estimates of the worldwide incidence of 25 major cancers in 1990. International Journal of Cancer. Volume 80, Issue 6, Pages 827-841 http://www3.interscience.wiley.com/cgi-bin/fulltext/66500131/HTMLSTART Mikel Gray; Terran W. Sims Posted 07/30/2004. NMP-22 for Bladder Cancer Screening and Surveillance. Urol Nurs 24(3):171-172,177-179, 186, 2004. Retrieved from Medscape: May 21, 2008 from http://www.medscape.com/viewarticle/481628_1 H.G. WIENER, CH. MIANa, A. HAITELa, A. PYCHAa, G. SCHATZLa and M. MARBERGER. June 1998. CAN URINE BOUND DIAGNOSTIC TESTS REPLACE CYSTOSCOPY IN THE MANAGEMENT OF BLADDER CANCER? The Journal of Urology. Volume 159, Issue 6, Pages 1876-1880. http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B7XMT4HMVJBRY&_user=687471&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000

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