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Background: It has been demonstrated that multivariate prediction models predict cancer outcomes more accurately than cancer stage; however, the effects of these models on clinical management are unclear. The objective of the current study was to determine whether a previously published multivariate prediction model for bladder cancer ("bladder nomogram") improved medical decision making when referral for adjuvant chemotherapy was used as a model., Methods: Data were analyzed from an international cohort study of 4462 patients who underwent cystectomy without chemotherapy from 1969 to 2004. The number of patients eligible for chemotherapy was determined using pathologic stage criteria (lymph node-positive disease or pathologic T3 [pT3] or pT4 tumor classification) and for 3 cutoff levels on the bladder nomogram (10%, 25%, and 70% risk of recurrence with surgery alone). The number of recurrences was calculated by applying a relative risk reduction to the baseline risk among eligible patients. Clinical net benefit was then calculated by combining recurrences and treatments and weighting the latter by a factor related to drug tolerability., Results: A nomogram cutoff outperformed pathologic stage for chemotherapy in every scenario of drug effectiveness and tolerability. For a drug with a relative risk of 0.80, with which clinicians would treat

Background: Despite definitive surgery, the survival of patients with high-risk urothelial carcinoma (UC) is poor. Adjuvant cisplatin-based chemotherapy may be beneficial, but it is restricted by the need for normal renal function (RF). Sequential administration of adjuvant chemotherapy facilitates drug delivery and improves survival in patients with breast cancer. The objective of this study was to evaluate the feasibility and survival impact of adjuvant, sequential chemotherapy in patients with high-risk UC., Methods: Fifty patients were treated on 2 simultaneous protocols between 1997 and 2004. The patients on Protocol A (normal RF) received doxorubicin and gemcitabine (AG) followed by paclitaxel and cisplatin. The patients on Protocol B (impaired RF) received AG followed by paclitaxel plus carboplatin. Overall survival (OS) and disease-specific survival (DSS) were compared with a group of 203 contemporary control patients who had similar pathology and RF and who underwent surgery alone., Results: The median follow-up of protocol patients was 6.5 years (range, 0.9-8.6 years), and 25 patients remained alive. The median follow-up of the control group was 4.7 years (0.0-9.2), and 68 patients remained alive. The median OS for patients on Protocol A was greater than that for controls who had good RF (4.6 years vs 2.5 years; P = .03). The median OS for patients on Protocol B was greater than that for controls who had impaired RF (3.4 years vs 2 years; P = .04). DSS for the protocol and matched control groups was similar (good RF: 4.6 years vs 3 years; P = .24; impaired RF: 3.4 years vs 3.3 years; P = .40)., Conclusions: In this nonrandomized study, adjuvant, sequential chemotherapy for patients with high-risk UC did not improve DSS over that observed with surgery alone.

Background: UroVysion is a US Food and Drug Administration-approved fluorescence in situ hybridization (FISH) probe set for use in the detection of recurrent urothelial carcinoma and in patients with hematuria. The objective of the current study was to evaluate the usefulness of UroVysion as a reflex test in patients with a suspicious urine cytology diagnosis. The rationale was that a more aggressive workup might be indicated in patients with a suspicious cytology diagnosis and positive UroVysion test., Methods: The study population included 161 urine specimens diagnosed as suspicious over a period of 12 months. The sensitivity, specificity, negative predictive value (NPV), and positive predictive value (NPV) were calculated based on the histologic and cystoscopic correlation., Results: The results using the reporting criteria suggested by the manufacturer demonstrated a sensitivity of 68.3%, a specificity of 39.7%, a PPV of 56.8%, and a NPV of 51.9%. The results using the presence of any cytogenetic abnormality as a positive FISH test demonstrated a sensitivity of 82.9%, a specificity of 21.7%, a PPV of 54.8%, and an NPV of 51.7%., Conclusions: A negative UroVysion test did not rule out the presence of low-grade or high-grade urothelial carcinoma in urine specimens diagnosed as suspicious. The use of less strict criteria dramatically increased the sensitivity of UroVysion FISH; however, there was a marked decrease in specificity noted. The results in this current study appear to indicate that a more aggressive workup of patients with a suspicious cytology, positive UroVysion result, and negative cystoscopic evaluation is not currently justified., ((c) 2009 American Cancer Society.)

Background: Neoadjuvant cisplatin-based chemotherapy improves survival in muscle-invasive urothelial cancer, with MVAC (methotrexate, vinblastine, doxorubicin and cisplatin) considered the standard regimen. Gemcitabine plus cisplatin (GC) has similar efficacy and less toxicity than MVAC in metastatic disease, but is untested as neoadjuvant treatment., Methods: The authors retrospectively evaluated patients with muscle-invasive urothelial carcinoma who received neoadjuvant GC before radical cystectomy between November 2000 and December 2006 at Memorial Sloan-Kettering Cancer Center. Post-therapy pathological downstaging to either residual disease at cystectomy (pT0) or no residual muscle-invasion (

Background: By using the age-adjusted Charlson comorbidity index (ACCI), the authors characterized the impact of age and comorbidity on disease progression and overall survival after radical cystectomy (RC) for transitional cell carcinoma of the bladder. Also evaluated was whether ACCI was associated with clinicopathologic and treatment characteristics., Methods: The authors evaluated 1121 patients treated by RC for transitional cell carcinoma of the bladder at a single institution (1990-2004). Logistic regression was used to determine the relation between ACCI and clinical features. They evaluated the association between ACCI and overall and progression-free survival by using multivariate survival-time models with pathologic stage and nodal status as covariates., Results: ACCI scores increased during the study period (P = .009). Extravesical disease was present in 43% of patients with ACCI 5 (P = .051). Despite their higher prevalence of extravesical disease, patients with higher ACCI were less likely to have lymph-node dissection (odds ratio, 0.55 and 0.35, respectively, for ACCI 3-5 and >5 vs 5 vs

Background: The number of lymph nodes (LNs) removed during radical cystectomy (RC) for transitional cell carcinoma (TCC) of the bladder affects overall and disease-specific survival, but no consensus exists regarding the minimum number of LNs that should be removed. The goal of the current study was to determine if a threshold number of nodes exists, above which taking additional LNs has no clinical benefit., Methods: A total of 1121 patients were identified who underwent RC for clinically localized TCC of the bladder between January 1990 and April 2004. To determine the relation of LNs removal and overall survival, a Cox proportional hazards model was used with pathologic stage, age, and comorbidity as covariates. A dose-response curve, adjusted for covariates, was modeled to assess the impact of an increasing number of LNs removed on overall survival., Results: A median of 9 LNs were removed (range, 0-53 LNs). In multivariable analysis, all covariates (number of LNs removed, age, stage of disease, and comorbidity) were found to be predictive of survival. The dose-response curve for number of LNs versus survival revealed that, when adjusted for covariates, the probability of survival did not plateau but instead continued to rise as the number of LNs removed increased., Conclusions: No evidence was found that a minimum number of LNs is sufficient for optimizing bladder cancer outcomes when a limited or extended pelvic LN dissection is performed during RC. Instead, the probability of survival continues to rise as the number of LNs removed increases. This study supports a more extended LN dissection at the time of RC, and highlights the challenges of interpreting retrospective LN dissection data.

Background: Patients undergoing radical cystectomy (RC) for urothelial cancer are at increased risk for upper tract recurrence and anastomotic recurrence. In an attempt to reduce this recurrence risk, urologists employ intraoperative frozen sections to achieve an uninvolved ureteral margin. The utility of this surgical approach was examined., Methods: A retrospective review identified 1330 bladder cancer patients from 1990 to 2004 with pathologic evaluation of their ureters. Using pathologic findings on permanent section as the reference standard, the accuracy of ureteral frozen sections was examined. Ureteral involvement and margin status were examined as risk factors for upper tract and anastomotic recurrence and overall survival., Results: Of 2579 ureteral margins evaluated in 1330 patients, ureteral involvement was noted in 9% of ureters (13% of patients). The sensitivity and specificity of frozen section analyses were approximately 75% and 99%, respectively. The 5-year probability of anastomotic and upper tract recurrences was low: 2% and 13%, respectively. Evidence of involvement of the ureter or at the ureteral anastomotic margin was associated with higher likelihood of upper tract recurrence but not anastomotic recurrence or overall survival. Furthermore, sequential resection of ureters to reach a negative anastomotic ureteral margin did not eliminate the risk of anastomotic or upper tract recurrence., Conclusions: Patients with involved ureters and/or ureteral anastomotic margins have a higher risk of upper tract recurrence. However, the overall risk of recurrence is low and is not clearly associated with overall survival. The data do not support routine intraoperative frozen sections to assess ureteral involvement., ((c) 2006 American Cancer Society.)

Background: Perioperative cisplatin-based chemotherapy has shown benefit in patients with high-risk localized urothelial bladder cancer, but it is not widely used. Renal impairment may be a major factor limiting its use. The current study was designed to determine the proportion of patients ineligible to receive adjuvant cisplatin-based chemotherapy based on inadequate renal function alone., Methods: Patients who underwent radical cystectomy for urothelial cancer of the bladder with evidence of extravesical disease (> or =pT3 or any N+) were identified. Patients who received neoadjuvant chemotherapy were excluded. Serum creatinine immediately before and nadir serum creatinine after cystectomy were used to calculate creatinine clearance (CrCl) or glomerular filtration rate (GFR) using the Cockroft-Gault (CG), Jelliffe, and Modification of Diet in Renal Disease (MDRD) study formulas. A cutoff of CrCl <60 mL/min or GFR <60 mL/min/1.73 m2 was used to determine ineligibility for cisplatin-based chemotherapy. The proportion of patients ineligible by each formula was compared by univariate logistic regression. Univariate linear regression was performed to determine the effect of age on CrCl or GFR., Results: : Most patients were pT3 or greater; 39% were lymph node-positive. The overall proportion of patients ineligible for cisplatin-based chemotherapy was 28% by the CG formula, 52% by Jelliffe, and 24% by MDRD. Concordance between formulas was low. With all formulas the probability of ineligibility increased with age: by the CG equation, >40% of patients age >70 years were ineligible., Conclusions: : The widespread use of cisplatin-based perioperative chemotherapy in patients with high-risk localized bladder cancer may be significantly limited by the high prevalence of baseline renal insufficiency in this population. This finding is most striking in the elderly. Better selection of patients who may safely receive cisplatin and more effective regimens devoid of cisplatin are required to optimize outcomes in this group of patients., (Copyright 2006 American Cancer Society.)

Background: Although cigarette smoking is considered a major risk factor for bladder carcinoma, little is known about the interaction between metabolic genes such as glutathione-S-transferase P1 and tobacco smoking in this process. GSTP1 may play a role in detoxification of tobacco-related carcinogens., Methods: In this case-control study of 145 cases with bladder carcinoma (male:female = 7.5:1) and 170 noncancer controls (male:female = 3.7:1), the relation between genetic polymorphisms of GSTP1 and susceptibility to bladder carcinoma was investigated and the gene-environment interaction between tobacco smoking and GSTP1 polymorphism was evaluated. Epidemiological data were collected for all cases and controls by a standard questionnaire. Polymorphisms of GSTP1 were measured by polymerase chain reaction-restriction fragment length polymorphism. The logistic regression model in SAS was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs)., Results: Cigarette smoking was confirmed as a risk factor of bladder carcinoma with an OR of 3.1 (95% CI: 1.7-5.9) after controlling for potential confounding factors. The OR for pack-years of smoking as a continuous variable was 2.4 (95% CI: 2.0-2.8). The ORs were 7.6 (95% CI: 1.18-49.51) for isoleucine/valine (Ile/Val) and 6.5 (95% CI: 1.01-41.56) for Ile/Ile when the homozygous Val/Val was considered as comparison group after adjusting for age, gender, race, and education. The adjusted OR for interaction between smoking and the GSTP1 (any Ile genotype) was 11.42 (95% CI: 0.53-248.15)., Conclusions: The results indicate that the Ile 105 allele is associated with an increased risk of bladder carcinoma and suggest that individuals who smoke and possess the Ile allele might be at increased risk for bladder carcinoma.

The Cancer and Leukemia Group B (CALGB) Genitourinary Committee has developed a broad range of clinical trials across most stages of bladder cancer. Recurrence rates of superficial bladder cancer after transurethral resection range from 50-70%. Although adjuvant bacillus Calmette-Guerin reduces the risk of disease recurrence or progression, only 30% of patients have long-term disease-free survival. Because the development of novel secondline agents is needed, the CALGB is evaluating the utility of intravesicle gemcitabine as well as an oral proapoptotic agent (CP-461). In patients with locally advanced disease with an increased risk of disease recurrence after cystectomy, a randomized trial of conventional chemotherapy versus sequential dose-dense therapy is under development. The gemcitabine/cisplatin combination has become a commonly used regimen for the treatment of advanced transitional cell carcinoma (TCC). The CALGB is undertaking a Phase II study that incorporates a fixed dose rate gemcitabine infusion in this regimen, together with a selective epidermal growth factor receptor tyrosine kinase inhibitor, Iressa (Astra Zeneca, Wilmington, DE). In patients with renal insufficiency, a regimen of carboplatin, gemcitabine, and Iressa is planned. Novel agents, including arsenic trioxide and trastuzumab (Herceptin; Genentech, Inc., South San Francisco, CA), are being evaluated as secondline therapy in patients with advanced TCC who have disease progression after frontline therapy., (Copyright 2003 American Cancer Society)