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lamina propia invasion between smokers and non smokers. However, we found association between active smoking and high tumor grade (Chi-x2, p=0.046), larger size (Chi-x2, p=0.001), multiplicity (Chi-x2, p=0.012) and presence of associated carcinoma in situ (Chi-x2, p=0.001). At a mean time of 22.3 months we did not find differences regarding recurrence rate (log rank, p=ns), but the risk of progression to muscle invasive disease was higher in active smokers (log rank, p=0.03). However, in a multivariate study including age, gender, lamina propia invasion, tumor grade, size, number of lesions and smoking habit, only grade (p=0.005) and multiplicity (p=0.00) predicted recurrence and none of these characteristics predictive progression to muscle-invasion CONCLUSIONS: We can not consider cigarette smoking an independent predictor of recurrence or progression in patients with superficial bladder cancer. However, active smokers present more often with lesions of higher grade, larger size and multiplicity than non-active smokers. Although we cannot definitely conclude, cigarette smoking might have a negative influence on the natural history of superficial bladder cancer. Therefore, public health efforts directed to avoid this habit might even reduce the malignant potential of superficial bladder cancer.

Source of Funding: None

1913DOES SHORT-TERM ADMINISTRATION OF PRULIFLOXACIN REPRESENT AN EFFECTIVE STRATEGY IN THE PREVENTION OF INTRAVESICAL BCG-INDUCED TOXICITY?

Riccardo Autorino*, Marco De Sio, Giuseppe Quarto, Carmelo Quattrone, Mariano Pizzuti, Raffaele Muscariello, Sisto Perdonà, Naples, Italy; Renato De Domenico, Italo M Palumbo, Giuseppina Azzarito, Rocco Damiano, Catanzaro, Italy

INTRODUCTION AND OBJECTIVES: We aimed to determine whether short-term administration of prulifloxacin might improve tolerance to BCG intravesical therapy in patients with intermediate/high risk urothelial bladder cancer.

METHODS: 72 patients with non muscle-invasive bladder cancer were enrolled in this prospective, randomized, controlled clinical trial. After complete TUR, patients were randomized to receive induction treatment with BCG (Connaught strain, 81 mg/50 ml) and 3 capsules of Prulifoxacin 600 mg (first dose given orally 6 hours after the first urination after BCG instillation, the second 24 hours after capsule 1, the third dose 24 hours after capsule two - group 1 - n=37) or no prophylactic treatment (controls - group 2 - n=35). Adverse events were self-recorded by the patients after each instillation and classified as systemic or local and class I (mild) up to class III (severe). Based on the severity of adverse events experienced by the patient, one of the investigator, who was blind to the given therapy, decided whether the next instillation was to be done, postponed, deleted or whether the patient should receive specific anti-tuberculosis therapy. 3-month cystoscopy findings were also assessed.

RESULTS: No significant difference was found in terms of tumor aggressiveness between patients in groups 1 and 2. No significant difference in terms of baseline symptoms was observed between the two groups. Overall, there was a significant decrease in the percent of patients with at least 1 adverse event between instillations in prulifloxacin treated group compared to controls. Prulifloxacin significantly decreased the proportion of patients with at least 1 class II adverse event after the 4th instillation. Patients with at least 1 class III adverse event also decreased in the prulifloxacin treated group. More patients in the control group stopped or delayed the induction course of BCG instillations, primarily for toxicity reasons, compared with patients who received prulifloxacin (group 1=34% versus group 2=19%, p=0.04). Recurrence rates at 3-month cystoscopy were not affected by prulifloxacin treatment (group 1=13.5% and group 2=17%, p 0.06). Follow-up is ongoing.

CONCLUSIONS: The new fluoroquinolone prulifloxacin reduces the incidence of moderate and severe adverse events due to BCG intravesical therapy in patients with non muscle-invasive bladder cancer. Compliance to the induction BCG course can be improved with this strategy. Larger studies with a longer follow-up are needed.

Source of Funding: None

1914OPTIMIZED URINARY PH IS NECESSARY FOR THE IMPROVEMENT OF ADJUVANT MMC INSTILLATION TREATMENT FOR TUMOR RECURRENCE OF NON-MUSCLE INVASIVE BLADDER TUMORS.

Takahiro Maeda*, Eiji Kikuchi, Kazuhiro Matsumoto, Hidaka Kono, Hirohiko Nagata, Akira Miyajima, Ken Nakagawa, Mototsugu Oya, Tokyo, Japan

INTRODUCTION AND OBJECTIVES: Adjuvant intravesical chemotherapy or BCG treatment is selected for preventing tumor recurrence in patients with an intermediate risk for tumor recurrence. BCG is thought to be superior to MMC treatment, however, severe side effects may occur and sometimes the scheduled instillation can not be performed. Recently, some reports have suggested that MMC instillation may be more effective when using urinary alkalization, even though significant evidence is lacking. In the present study, we determined the association between urinary pH and the efficiency of MMC instillation.

METHODS: We identified 120 patients treated with TUR-BT and adjuvant intravesical instillation of MMC between 1985 and 2008 at our institution. The urinary pH level could be examined in 115 of these 120 patients just before the administration of MMC. The median follow-up was 3.5 years. We determined the association between urinary pH and clinicopathological characteristics. Clinicopathological features that included age, tumor grade, multiplicity, pathological stage, MMC instillation times, presence of concomitant CIS, and categorical urinary pH were analyzed using Cox regression univariate and multivariate analyses.

RESULTS: The median urinary pH was 5.73 ±0.05 (range, 5.00-7.20) during the scheduled MMC instillation period. We divided the patients into two groups according to urinary pH at the cut-off level of 5.5 (34 patients had a pH less than 5.5 and 81 patients had a pH equal to or greater than 5.5). Age, gender, tumor grade, multiplicity, pathological stage, MMC instillation times, and presence of concomitant CIS were not significantly different between the two groups. Multivariate analyses demonstrated that categorical urinary pH is an independent risk factor for tumor recurrence (p=0.027, HR1.89). The 3 and 5-year recurrence-free rates were 63.4 % and 57.7 % in patients with a urinary pH equal to or greater than 5.5, and 38.9% and 34.0% in those with a urinary pH less than 5.5, respectively (p=0.021). Furthermore, multivariate analyses revealed that HR of the urinary pH for tumor recurrence was 2.17 and 2.37 at cut-off levels of 5.4 and 5.2, respectively.

CONCLUSIONS: Our results suggest that urine alkalization to a pH level of at least 5.5 has a marked impact on tumor recurrence in patients treated with intravesical MMC treatment for non-muscle invasive bladder cancer. Monitoring urinary pH during MMC adjuvant treatment is necessary in order to improve the therapeutic efficacy.

Source of Funding: None

1915WHAT IS THE LONG TERM PROGNOSTIC VALUE OF PRO-APOPTOTIC, ANTI-APOPTOTIC, PROLIFERATION AND INVASIVENESS MOLECULAR MARKERS IN PATIENTS TREATED WITH BCG FOR HIGH RISK NON-INVASIVE BLADDER CANCER?

Sultan S Alkhateeb*, Mischel G. Neill, Bas W Van Rhijn, David Kakiashvili, Neil E. Fleshner, Michael A s Jewett, Toronto, ONCanada; Sas Bar-Moshe, Michel Petein, Claude Schulman, Thierry Roumeguere, Sandrine Rorive, Brussels, Belgium; Alexandre R Zlotta, Toronto, ON, Canada

INTRODUCTION AND OBJECTIVES: To evaluate the long-term prognostic value of pro-apoptotic, anti-apoptotic, proliferation and invasiveness molecular markers in predicting the outcome of high risk non-muscle invasive bladder cancer treated with intravesical BCG therapy. Most previous series have analyzed the short-term prognostic value of these markers only.

METHODS: A prospective study included 42 patients presenting with high risk non-muscle invasive bladder cancer (high grade or T1

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tumors or multiple rapidly recurrent tumors refractory to intravesical chemotherapy) treated with transurethral resection and intravesical BCG. Transurethral tumor resection samples were analyzed for the molecular markers p53, p21 waf1/cip, Bcl-2, Cyclin D1 and metallothionein 9 (MMP9) using immunohistochemical techniques. Frequency of positivity measured as a percentage was then assessed for interaction with clinical tumor characteristics (stage, grade, multifocality, size) and the tumor outcome variables of recurrence and progression using univariate and multivariate analyses as well as Kaplan-Meier curves (SSPS statistical package).

RESULTS: There were 38 men and 4 women (mean age 68.3 years) and median follow-up was 88 months (mean 99, range 14-212 months). In this high risk population, the overall recurrence rate was 61.9% and progression rate was 21.4%. As expected, in multivariate analysis, grade was predictive of recurrence and stage predictive of progression (p<0.05). In multivariate analysis adjusting for tumor stage, grade, multifocality and size, the only predictor of recurrence-free survival was p21 (p 0.041), while progression-free survival was predicted by Cyclin D1 (p 0.024) and MMP9 (p 0.054). Interestingly, the statistically significant predictive value of these markers at 5 years was maintained at longer follow-up both for recurrence and progression, MMP 9 only becoming of borderline significance (0.054).

CONCLUSIONS: Long-term response to BCG therapy of high risk non-muscle invasive bladder cancer may be predicted by molecular markers. These represent different elements of the carcinogenic pathway and may offer improved prediction compared to grade and stage alone. Larger series are needed to confirm these findings including new pathways like the FGFR-3.

Source of Funding: None

1916A MUTATION DETECTED IN THE FIBROBLAST GROWTH FACTOR RECEPTOR-3 IN CELLS OBTAINED FROM VOIDED URINE IS A STRONG PREDICTOR OF RECURRENT BLADDER CANCER

Tahlita C.M. Zuiverloon*, Madelon N van der Aa, Ewout W. Steyerberg, Rotterdam, Netherlands; Theo H. van der Kwast, Toronto, ONCanada; Chris H Bangma, Ellen C. Zwarthoff, Rotterdam, Netherlands

INTRODUCTION AND OBJECTIVES: Mutations in the Fibroblast Growth Factor Receptor-3 (FGFR3) are found in 60% of non-muscle invasive bladder cancer (NMI-BC) tumors and are associated with a good prognosis. NMI-BC recurs in 70% of the patients within 5 years after diagnosis and this necessitates life-long frequent and costly cystoscopic monitoring. We designed a simple SNaPshot assay for detection of the most common mutations in FGFR3. Our objective was to determine the potential of FGFR3 mutation analysis of voided urine samples to detect recurrences during surveillance of patients with NMI-BC.

METHODS: From 198 NMI-BC patients FGFR3 mutation status of the study inclusion tumor was determined. Patients were followed by cystoscopy and urine samples were collected simultaneously. FGFR3 mutation analysis was optimised and sensitivity and predictive power of the assay were determined by cross-sectional and longitudinal analyses.

RESULTS: Patients with an FGFR3 mutant tumor (n=132) at study inclusion were selected for analysis. During a median follow-up of 3.5 years, 44 histologically proven recurrences were detected in 42 patients. In 462 follow-up urine samples FGFR3 mutation analysis was performed. The sensitivity and specificity of FGFR3 mutation analysis for detection of concomitant recurrences were 25/44 (57%) and 332/419 (79%) respectively. Because multiple positive urine samples preceded a recurrence, we performed a longitudinal analysis. Of the 112 positive urine samples 76 were associated with a concomitant or a future recurrence. In contrast, only 41 of the 351 FGFR3 negative urine samples were associated with a recurrence (Figure 1). One pT1G3 and one pT2G3 tumor were missed by FGFR3 urine analysis, on the other hand all upper tract recurrences, including one pT2G3, were detected.

CONCLUSIONS: FGFR3 mutation analysis of voided urine samples is a simple and sensitive non-invasive diagnostic method for early detection of recurrences during surveillance of patients presenting with an FGFR3 mutant NMI-BC tumor.

Source of Funding: KWF, Koningin Wilhelmina Fonds grant: 2006-3672

1917REGIONAL VARIATION IN EARLY STAGE BLADDER CANCER CARE

Ted A Skolarus*, Zaojun Ye, Rodney L Dunn, John M Hollingsworth, Brent K Hollenbeck, Ann Arbor, MI

INTRODUCTION AND OBJECTIVES: Bladder cancer is among the most expensive malignancies from diagnosis to death. Because of its protracted natural history, early stage (i.e., superficial) bladder cancer is the chief contributor to this phenomenon. Without high level evidence to guide many aspects of clinical practice, variation is rampant. However, the incremental advantages of added care are unclear.

METHODS: We used SEER-Medicare data from 1992 through 2005 to identify 27,979 patients with early stage bladder cancer. Hospital referral regions were ranked according to their treatment intensity (as measured by their average bladder cancer expenditures in the first 2 years after diagnosis) and grouped into quartiles. We assessed the relationships between treatment intensity and outcomes, including the use of any aggressive therapy, overall and cancer-specific survival.

RESULTS: The average regional Medicare payments for bladder cancer ranged from $2,069 to $7,154, with endoscopic surveillance accounting for nearly three-fourths of all expenditures. High intensity regions more commonly performed endoscopic surveillance, used more intravesical therapy, urinary and imaging studies. However, the intensity of initial treatment was not associated with a lower risk of mortality (low vs. high intensity adjusted HR 1.00, 95% CI 0.95-1.05). Further, initial intensive management did not obviate the need for later major interventions. In fact, patients treated in high intensity regions were potentially more likely to undergo a subsequent major intervention compared to those treated in low intensity regions (9.93% vs. 9.18% respectively, p=0.10).

CONCLUSIONS: Urologists vary widely in how aggressively they manage early stage bladder cancer. Patients treated in high intensity regions do not appear to benefit in terms of survival or in avoidance of subsequent major interventions.