Repeated 5-aminolevulinic Acid Instillations During Follow-up in Non-muscle-invasive Bladder Cancer: A Randomized Study.

BACKGROUND/AIM: Non-muscle invasive bladder carcinoma (NMIBC) is highly recurrent. We studied if 5-aminolevulinic acid (5-ALA) instillations before transurethral resection of bladder tumours (TURBT) and cystoscopy extend the time to recurrence during follow-up with NMIBC patients. PATIENTS AND METHODS: A prospective multicenter study enrolled 328 NMIBC patients. All TURBTs and control cystoscopies during the one-year study period were done with or without 5-ALA instillations. The primary endpoint was time to recurrence. The secondary endpoints were time to recurrence after 7.5, 10.5, and 13.5 months and the number of patients with progressive disease. RESULTS: The overall median follow-up time was 80.4 and 87.0 months for the control and study groups, respectively. There was no statistical difference in time to first recurrence between the two groups. CONCLUSION: We could not obtain significant differences between the control and 5-ALA groups in tumour recurrence among patients with NMIBC.

Seventeen-year follow-up of the prospective randomized Nordic CIS study: BCG monotherapy versus alternating therapy with mitomycin C and BCG in patients with carcinoma in situ of the urinary bladder.

OBJECTIVE: The aim of this study was to compare the long-term efficacy of BCG monotherapy to alternating therapy of mitomycin C (MMC) and BCG in patients with carcinoma in situ (CIS). MATERIALS AND METHODS: Between 1992 and 1997, 321 patients with CIS were randomized from Finland, Norway and Sweden in a prospective multicenter trial into two treatment groups. The alternating therapy comprised six weekly instillations of MMC 40 mg followed by 10 instillations of BCG (Connaught 120 mg) or MMC alternating monthly for 1 year. BCG monotherapy followed the same 6 + 10 schedule. Stratification was done by nationality and CIS category. Primary endpoints were time to first recurrence and time to progression. Secondary endpoints were disease-specific mortality and overall survival. The main statistical methods were the proportional subdistribution hazards model and Cox proportional hazards model with the cumulative incidence and Kaplan-Meier analyses. RESULTS: The median follow-up time was 9.9 years (maximum 19.9 years) in the BCG group and 8.9 years (maximum 20.3 years) in the alternating group. The risk of recurrence was significantly lower in the BCG group than in the alternating group (49 vs 59% at 15 years, respectively; hazard ratio 0.74, 95% confidence interval 0.54-1.00, p = 0.048). There were no significant differences in the other endpoints. Patients who progressed after 2 years were particularly prone to dying from bladder carcinoma. Younger patients performed worse than older ones. CONCLUSIONS: BCG monotherapy including monthly maintenance was effective and better than the alternating therapy. The risk of dying from bladder carcinoma after progression was high.

Intravesical Bacillus Calmette-Guérin Versus Combination of Epirubicin and Interferon-α2a in Reducing Recurrence of Non-Muscle-invasive Bladder Carcinoma: FinnBladder-6 Study.

BACKGROUND: Patients with non-muscle-invasive bladder cancer (NMIBC) belonging to the intermediate-risk group should be treated with intravesical instillations to prevent recurrence and progression. OBJECTIVE: We compared the outcome of a monthly maintenance bacillus Calmette-Guérin (BCG) regimen with that of epirubicin (EPI) and interferon-α2a (IFN) in patients with NMIBC. DESIGN, SETTING, AND PARTICIPANTS: Our prospective randomized multicenter study comprised 229 eligible patients with frequently recurrent TaT1 grade 1-2 or low-grade NMIBC enrolled between 1997 and 2008. INTERVENTIONS: The four-arm study involved a single perioperative instillation of EPI plus five weekly instillations of BCG or EPI/IFN, followed by 11 monthly instillations in the 1-yr BCG or EPI/IFN maintenance arms, further followed by four additional quarterly instillations in the two 2-yr maintenance arms. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Time to recurrence, progression, disease-specific survival, and overall mortality were analyzed using the Kaplan-Meier and cumulative incidence analyses plus the Cox and proportional subdistribution hazards models. RESULTS AND LIMITATIONS: The median follow-up time was 7.5 and 7.4 yr in the BCG and EPI/IFN groups, respectively. The probability of recurrence was significantly lower in the BCG group than in the EPI/IFN group. The probability was 39% versus 72% at 7.4 yr, respectively (hazard ratio [HR]: 0.41; 95% confidence interval [CI], 0.28-0.60; p<0.001). There was no significant difference in the probability of progression or in overall survival. However, there was a significant difference in disease-specific mortality in favor of the BCG group (HR: 0.20; 95% CI, 0.04-0.91; p=0.04). CONCLUSIONS: The monthly maintenance BCG regimen showed excellent efficacy and was significantly better in preventing recurrence than a similar regimen of EPI/IFN-α2a. PATIENT SUMMARY: A monthly bacillus Calmette-Guérin (BCG) regimen showed excellent efficacy and was significantly better in preventing recurrence than a similar regimen of epirubicin and interferon-α2a. TRIAL REGISTRATION: Registration was not considered necessary at this stage of the follow-up because the study was initiated as early as in 1997, before the current requirements concerning study registrations were implemented.

Long-term outcome of patients with frequently recurrent non-muscle-invasive bladder carcinoma treated with one perioperative plus four weekly instillations of mitomycin C followed by monthly bacillus Calmette-Guérin (BCG) or alternating BCG and interferon-α2b instillations: prospective randomised FinnBladder-4 study.

BACKGROUND: Recurrent TaT1 non-muscle-invasive bladder cancer (NMIBC) patients should be treated with immediate instillation of chemotherapy after transurethral resection of bladder tumour followed by instillation therapy. OBJECTIVE: To present long-term results of a study exploring the effect of initial mitomycin C (MMC) instillations followed by two types of immunotherapy for patients with frequently recurring NMIBC. DESIGN, SETTING, AND PARTICIPANTS: Between 1992 and 1996, 236 patients with frequently recurring TaT1 grade 1-2 NMIBC were enrolled in the prospective randomised multicentre FinnBladder-4 study. INTERVENTION: One perioperative plus four weekly instillations of MMC followed by monthly bacillus Calmette-Guérin (BCG) or alternating BCG and interferon (IFN)-α2b instillations for up to 1 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary end points were time to first recurrence and time to progression. Secondary end points were disease-specific mortality and overall survival. The principal statistical methods were the proportional subdistribution hazards model and Cox proportional hazards model plus cumulative incidence and Kaplan-Meier analyses. RESULTS AND LIMITATIONS: The median follow-up was 10.3 yr (maximum: 19.8 yr) in the MMC-BCG group and 8.6 yr (maximum: 19.8 yr) in the MMC-BCG/IFN group. The probability of recurrence was significantly lower in the MMC-BCG group than in the MMC-BCG/IFN group (43% vs 78% at 10 yr and 45% vs 80% at 15 yr, respectively; hazard ratio: 2.86; 95% confidence interval, 1.98-4.13; p<0.001). There were no significant differences in the probability of progression, disease-free mortality, or overall survival. CONCLUSIONS: Perioperative plus four weekly MMC instillations followed by monthly BCG, instead of alternating BCG and IFN-α2b instillations, significantly reduce long-term recurrence. PATIENT SUMMARY: We demonstrated in non-muscle-invasive bladder cancer patients with exceptionally frequent recurrences that the risk of long-term recurrence was reduced from 78-80% to 43-45% if one perioperative plus four weekly mitomycin C instillations were followed by monthly bacillus Calmette-Guérin (BCG) instillations for 1 yr instead of alternating instillations of BCG and interferon-α2b. TRIAL REGISTRATION: The registration was not considered necessary at this stage of the follow-up because the study was initiated as early as in 1992 and the last randomisation took place in 1996, before the current requirements concerning study registrations were implemented.

Long-term results of maintenance treatment of mitomycin C or alternating mitomycin C and bacillus Calmette-Guérin instillation therapy of patients with carcinoma in situ of the bladder: a subgroup analysis of the prospective FinnBladder 2 study with a 17-year follow-up.

OBJECTIVE: Only a few studies with a long-term follow-up exist on patients with carcinoma in situ (CIS) treated with instillation therapy. The objective was to study the long-term outcome of patients with CIS after mitomycin C (MMC) monotherapy or alternating therapy with MMC and bacillus Calmette-Guérin (BCG). MATERIAL AND METHODS: The study population comprised 68 patients with CIS belonging to a larger material of 256 patients with non-muscle-invasive bladder carcinoma who were randomized between 1987 and 1992 in a prospective multicentre study. Patients received the same induction period with MMC and continued with maintenance treatment comprising either monthly instillations of MMC alone or alternating MMC and BCG instillations for up to 2 years. Primary endpoints were cancer-specific and overall mortality. Secondary endpoints were time to first recurrence and time to progression. The principal statistical methods were the Kaplan-Meier method and cumulative incidence analysis. RESULTS: The overall median follow-up time of the patients with CIS was 7.2 years and the median follow-up time of the patients still alive was 17.1 years. The non-stratified probability of dying from bladder carcinoma at 5, 10 and 15 years was 13%, 25% and 28%, respectively. No significant difference was found between the study groups with respect to time to first recurrence, progression, or disease-specific or overall mortality. CONCLUSIONS: The long-term bladder cancer-specific mortality was unexpectedly low despite the relatively ineffective instillation therapy and the poor outcome of the patients after progression.

Pathologic downstaging is a surrogate marker for efficacy and increased survival following neoadjuvant chemotherapy and radical cystectomy for muscle-invasive urothelial bladder cancer.

BACKGROUND: Characterising responders to neoadjuvant chemotherapy (NAC) is important to minimise overtreatment and the unnecessary delay of definitive treatment of urothelial urinary bladder cancer. OBJECTIVE: To assess the effect of NAC on tumour downstaging and overall survival. DESIGN, SETTING, AND PARTICIPANTS: A total of 449 patients from the randomised prospective Nordic Cystectomy Trials 1 and 2 were analysed retrospectively. Eligible patients were defined as T2-T4aNXM0 preoperatively and pT0-pT4aN0-N+M0 postoperatively. The median follow-up time was 5 yr. INTERVENTION: The experimental arm consisted of cisplatin-based NAC; the control arm consisted of cystectomy only. MEASUREMENTS: The primary outcome was tumour downstaging defined as pathologic TNM less than clinical TNM. Different downstaging thresholds were applied: complete downstaging (CD) (pT0N0), noninvasive downstaging (NID) (pT0/pTis/pTaN0), and organ confinement (OC) (≤ pT3aN0). Downstaging rates and nodal status were compared between the study arms using the chi-square test. Secondary outcome was overall survival (OS) stratified by treatment arm, downstaging categories, and clinical stages, analysed by the Kaplan-Meier method. The following covariates were tested as prognostic factors in univariate and multivariate analyses using the Cox regression method: age, sex, clinical stage, pN status, NAC, CD, NID, and OC. RESULTS AND LIMITATIONS: Downstaging rates increased significantly in the NAC arm independent of the downstaging threshold. The impact was more prominent in clinical T3 tumours, with a near threefold increase in CD tumours. The combination of CD and NAC showed an absolute risk reduction of 31.1% in OS at 5 yr compared with CD controls. The combination of NAC and CD revealed a hazard ratio of 0.32 compared with 1.0 for the combination of no NAC and no CD. Limitations were the retrospective approach and uncertain clinical TNM staging. CONCLUSIONS: Survival benefits of NAC are reflected in downstaging of the primary tumour. Chemo-induced downstaging might be a potential surrogate marker for OS.

An individual patient data meta-analysis of the long-term outcome of randomised studies comparing intravesical mitomycin C versus bacillus Calmette-Guérin for non-muscle-invasive bladder cancer.

BACKGROUND: Patients with non-muscle-invasive bladder cancer with an intermediate or high risk need adjuvant intravesical therapy after surgery. Based largely on meta-analyses of previously published results, guidelines recommend using either bacillus Calmette-Guérin (BCG) or mitomycin C (MMC) in these patients. Individual patient data (IPD) meta-analyses, however, are the gold standard. OBJECTIVE: To compare the efficacy of BCG and MMC based on an IPD meta-analysis of randomised trials. DESIGN, SETTING, AND PARTICIPANTS: Trials were searched through Medline and review articles. The relevant trial investigators were contacted to provide IPD. MEASUREMENTS: The drugs were compared with respect to time to recurrence, progression, and overall and cancer-specific death. RESULTS AND LIMITATIONS: Nine trials that included 2820 patients were identified, and IPD were obtained from all of them. Patient characteristics were 71% primary, 54% Ta, 43% T1, 25% G1, 58% G2, and 16% G3, and 7% had prior intravesical chemotherapy. Based on a median follow-up of 4.4 yr, 43% recurred. Overall, there was no difference in the time to first recurrence (p=0.09) between BCG and MMC. In the trials with BCG maintenance, a 32% reduction in risk of recurrence on BCG compared to MMC was found (p<0.0001), while there was a 28% risk increase (p=0.006) for BCG in the trials without maintenance. BCG with maintenance was more effective than MMC in both patients previously treated and those not previously treated with chemotherapy. In the subset of 1880 patients for whom data on progression, survival, and cause of death were available, 12% progressed and 24% died, and, of those, 30% of the deaths were due to bladder cancer. No statistically significant differences were found for these long-term end points. CONCLUSIONS: For prophylaxis of recurrence, maintenance BCG is required to demonstrate superiority to MMC. Prior intravesical chemotherapy was not a confounder. There were no statistically significant differences regarding progression, overall survival, and cancer-specific survival between the two treatments.

Long-term efficacy of maintenance bacillus Calmette-Guérin versus maintenance mitomycin C instillation therapy in frequently recurrent TaT1 tumours without carcinoma in situ: a subgroup analysis of the prospective, randomised FinnBladder I study with a 20-year follow-up.

BACKGROUND: The long-term prospective data on bacillus Calmette-Guérin (BCG) and mitomycin C (MMC) instillation therapy are limited. OBJECTIVE: To compare the long-term benefit of BCG and MMC maintenance therapy in patients with recurrent bladder carcinoma. DESIGN, SETTING, AND PARTICIPANTS: Eighty-nine patients with frequently recurrent TaT1 disease without carcinoma in situ (CIS) were eligible. Originally, the patients were enrolled in the prospective FinnBladder I study between 1984 and 1987 and randomised to receive BCG or MMC. Both regimens involved five weekly instillations, followed by monthly instillations for 2 yr. Because of alkalinising the urine and adjusting the dose to bladder capacity, the average concentration of MMC was low: 30-40 mg in 150-200 ml of phosphate buffer. Overall median follow-up time was 8.5 yr, whereas the median follow-up time of the patients who were still alive was 19.4 yr. MEASUREMENTS: Primary end points were time to first recurrence and overall mortality. Secondary end points were progression and disease-specific mortality. RESULTS AND LIMITATIONS: Thirty-six of 45 patients (80.0%) in the MMC group experienced recurrence in contrast to 26 of 44 patients (59.1%) in the BCG group. This finding was reflected in significantly lower cumulative incidence estimates in the BCG group (p=0.005). There was a weak trend for fewer progressions (p=0.1) and cancer-specific deaths (p=0.2) in the cumulative incidence analysis, as 4 patients versus 10 patients progressed and 4 patients versus 9 patients died from the disease in the BCG group versus the MMC group, respectively. No difference existed in the overall mortality. The study population, however, was too small for conclusive evidence about progression or survival. CONCLUSIONS: An intensive intravesical BCG immunotherapy results in a sustained and significant long-term reduction in recurrence in frequently recurrent bladder carcinoma. The relatively low progression rate during the long follow-up suggests that it may be difficult to show significant differences in overall mortality with a substantially larger but otherwise similar study population. TRIAL REGISTRATION: Registration was not considered to be necessary at this stage of the follow-up because the study was initiated as early as 1984 and the last randomisation took place in July 1987, that is, long before the current requirements concerning study registrations were implemented.

Treatment of prostate cancer with Ad5/3Delta24hCG allows non-invasive detection of the magnitude and persistence of virus replication in vivo.

Hormone refractory metastatic prostate cancer is a deadly disease that currently lacks curative treatments. Conditionally replicating adenoviruses (CRAds) are promising new agents against cancer due to their innate capability to cause oncolysis of tumor cells. Their antitumor effect is determined in part by their capacity for infecting cancer cells. However, the respective primary receptor, the coxsackie-adenovirus receptor (CAR), is variably expressed in many cancer types. We created Ad5/3Delta24hCG, a novel CRAd retargeted to the adenovirus serotype 3 receptor, which has been reported to be highly expressed in tumors. Furthermore, we added a transgene for the beta-chain of human chorionic gonadotropin (hCGbeta), whose expression was tightly coupled to virus replication. Ad5/3Delta24hCG was found effective in killing prostate cancer cells, and oncolysis was seen in concordance with hCGbeta production. In a s.c. in vivo model of hormone refractory prostate cancer, Ad5/3Delta24hCG treatment resulted in statistically significant tumor growth inhibition. Moreover, i.v. injection of Ad5/3Delta24hCG prolonged the survival of mice with hormone refractory prostate cancer metastatic to the lung. Detection of hCGbeta in serum samples confirmed viral replication in vivo. Infection of human clinical samples of cancerous and normal prostatic tissue resulted in effective hCGbeta production in cancer tissue, whereas it remained low in nonmalignant tissue, suggesting cancer-specific replication. These results suggest that Ad5/3Delta24hCG is a potent virus for the treatment of hormone refractory prostate cancer in vitro and in vivo. These preclinical data set the stage for translation into clinical studies.

Overexpression of human chorionic gonadotropin beta genes 3, 5 and 8 in tumor tissue and urinary cells of bladder cancer patients.

OBJECTIVE: Human chorionic gonadotropin (hCG) is a marker of trophoblastic tumors, and the serum concentration of the free beta-subunit (hCGbeta) is an independent prognostic marker in several nontrophoblastic cancers. hCGbeta is encoded by six genes, of which the type II genes (hCGbeta 3/9, 5 and 8) are thought to be upregulated in relation to type I genes (hCGbeta 6/7) in cancer. METHOD: We developed a novel quantitative RT-PCR method for the quantification of the relative expression levels of the two groups of hCGbeta genes and analyzed 28 bladder tumors and 15 urine samples. RESULTS: We found a higher relative expression level of type II genes in malignant compared with benign urothelia (p = 0.016) and in exfoliated urinary cells from cancer patients compared with those from benign controls (p = 0.026). The expression level was increasing with higher stage (p = 0.014) and grade (p = 0.001) and tended to be higher in relapsing tumors (p = 0.059). CONCLUSION: The increased hCGbeta concentrations in body fluids of patients with aggressive bladder cancer may be due to overexpression of type II genes. Quantification of the relative mRNA expression levels of the hCGbeta type I and II genes in urine cells should be further studied as a potential noninvasive tool for the diagnosis and follow-up of bladder cancer.

Results of second-look resection after primary resection of T1 tumour of the urinary bladder.

OBJECTIVE: To study residual tumours at second-look resection in patients resected 4-8 weeks earlier for T1 tumours of the urinary bladder. MATERIAL AND METHODS: All patients randomized in the ongoing Nordic T1G2-G3 Bladder Sparing Study with monitored data available were included in the study. Data on residual tumours at second-look resection were compared to basic patient and tumour characteristics. RESULTS: There were 72 patients (56%) without and 57 with residual exophytic tumours. In the former group, 20 patients (28%) had carcinoma in situ, compared to 19 (33%) in the latter group. Potentially dangerous tumours (either carcinoma in situ, T1 or Ta grade 3) were observed in 55 patients (43%). Multiple tumours at primary resection were more prone to residual tumour at second-look resection than single tumours. No other tumour or patient characteristics could predict the occurrence of a residual tumour. CONCLUSIONS: Residual tumours are frequently observed at second-look resection 4-8 weeks after primary resection of T1 tumours. The majority of residual tumours detected at this stage are potentially dangerous; therefore, early second-look resection followed by intravesical instillation therapy is mandatory in patients with T1 tumours of the urinary bladder.

EAU guidelines on the diagnosis and treatment of urothelial carcinoma in situ.

OBJECTIVES: On behalf of the European Association of Urology (EAU), guidelines for the diagnosis, therapy and follow-up of patients with urothelial carcinoma in situ (CIS) have been established. METHOD: The recommendations in these guidelines are based on a recent comprehensive overview and meta-analysis in which two panel members have been involved (RS and AVDM). A systematic literature search was conducted using Medline, the US Physicians' Data Query (PDQ), the Cochrane Central Register of Controlled Trials, and reference lists in trial publications and review articles. RESULTS: Recommendations are provided for the diagnosis, conservative and radical surgical treatment, and follow-up of patients with CIS. Levels of evidence are influenced by the lack of large randomized trials in the treatment of CIS.

Neoadjuvant cisplatinum based combination chemotherapy in patients with invasive bladder cancer: a combined analysis of two Nordic studies.

OBJECTIVES: A Nordic collaborative group assessed the effectiveness of cisplatinum based combination chemotherapy prior to cystectomy in two consecutive trials. We analyzed overall survival in all patients and in prespecified subgroups defined by preoperative T-stage, gender and age. METHODS: The studies included in 1985-1997 620 patients with clinically T1G3, T2-T4aNXM0 urothelial bladder cancer and WHO performance

Tumor-associated trypsin inhibitor as a prognostic factor during follow-up of bladder cancer.

OBJECTIVES: To evaluate the prognostic value of tumor-associated trypsin inhibitor (TATI) in the serum and urine of patients in follow-up for urinary bladder cancer. METHODS: Serum and urine samples were taken during follow-up of 157 patients with transitional cell carcinoma of the bladder who were monitored by cystoscopy and cytology in 1986 to 1987. Initially, 117 (75%) of the 157 tumors were superficial. At the time of sampling, 93 patients (59%) had no detectable tumor and 48 (31%) had a superficial, and 16 (10%) an invasive, tumor. Cancer-specific survival was evaluated in 1998. RESULTS: During follow-up, 35 patients (22%) died of bladder cancer. An elevated TATI concentration in the serum (21 microg/L or more) was associated with a significantly shorter survival (P <0.001) compared with a normal value. Multivariate analysis showed that serum TATI and detectable cancer at sampling were independent prognostic factors (P <0.001 and P = 0.002, respectively), and age, grade, urine cytology findings, and urine TATI were not. CONCLUSIONS: Serum TATI is an independent prognostic factor in transitional cell carcinoma and is potentially useful for the identification of patients with an adverse prognosis.

Alternating mitomycin C and BCG instillations versus BCG alone in treatment of carcinoma in situ of the urinary bladder: a nordic study.

OBJECTIVES: To evaluate whether, in patients with carcinoma in situ (CIS) of the urinary bladder, alternating instillation therapy with mitomycin C (MMC) and bacillus Calmette-Guerin (BCG) was more effective and less toxic than conventional BCG monotherapy. METHODS: Patients were stratified prospectively for primary, secondary, and concomitant CIS and randomized to one of two regimens. Patients in the alternating group received six weekly intravesical instillations of MMC 40 mg, followed by alternating monthly instillations of BCG 120 mg and MMC for one year. In the monotherapy group, only BCG was instilled on the same schedule. RESULTS: Of 323 enrolled patients, 304 were eligible for analysis. After an overall median follow-up of 56 months, the Kaplan-Meier disease-free estimate for BCG monotherapy was significantly better than that for alternating therapy (p=0.03; log rank test). Risk for progression appeared lower in the BCG monotherapy group (p=0.07), but no differences existed in survival. Besides the regimen, CIS category also predicted outcome to some extent. BCG monotherapy caused significantly more local side-effects and premature cessation of instillation treatment than did the alternating therapy. However, no differences were observed in the number of serious side-effects. CONCLUSION: One-year BCG monotherapy was more effective than the alternating therapy for reducing recurrence and compared well with the best regimens reported from substantially smaller series. The alternating therapy was better tolerated.

Factors explaining recurrence in patients undergoing chemoimmunotherapy regimens for frequently recurring superficial bladder carcinoma.

OBJECTIVES: To study the factors determining new recurrences in patients with frequently recurring superficial bladder tumors. METHODS: Of all 205 eligible patients, each received 5 weekly intravesical instillations of mitomycin C (MMC), with the first instillation given perioperatively. This was followed, according to randomization, by BCG instillations alone or by alternating instillations of interferon-alpha and BCG monthly for up to 1 year. Impact of 12 variables on time to first recurrence was retrospectively studied with the Cox multiple hazards regression and Kaplan-Meier analysis. RESULTS: Type of regimen was the most significant factor determining new recurrences, with preceding recurrence rate being the most important prognostic factor. Timing of the first MMC was the third significant predictor in the main multivariate analysis, with more than a two-fold relative risk for a new recurrence if the first MMC instillation was given later than on day 0. CONCLUSION: Preceding recurrence rate, most accurately reflects, in patients with frequently recurring tumors, the inherent risk for new recurrences. This risk can be considerably reduced by use of an effective chemoimmunotherapy regimen, and in addition, by inclusion of an early perioperative chemotherapy instillation in such a regimen.

Differences between local and review urinary cytology in diagnosis of bladder cancer. An interobserver multicenter analysis.

OBJECTIVES: The objective of the study is to evaluate the agreement of local and review urinary cytology in patients with newly diagnosed bladder cancer and in those being followed for their disease. In addition, the effect of the type of institution on agreement was determined. METHODS: A total of 652 consecutive patients with bladder cancer from 19 institutions were evaluated; 575 (88.2%) of the patients had cytopathological sample available for central review and were eligible for analysis. One hundred and twenty nine (22.4%) of the patients had newly diagnosed bladder cancer, whereas the remaining 446 (77.6%) patients were under follow-up. A voided urine sample was obtained prior to transurethral resection of the bladder (TURB) or routine follow-up cystoscopy and split for culture and cytology. The cytopathological samples were first analysed by a local pathologist, and then re-analysed by a central reviewer. The agreement of cytological readings was determined by Kappa coefficient. RESULTS: The sensitivities of local and review cytology in detection of primary bladder cancer were 38.8 and 31.0%, respectively. Recurrence was observed in 119 of the 446 (26.7%) patients under follow-up, of which both local and review cytology detected 21 (17.6%) cases. Specificities of local and review cytology were 97.6 and 96.6%, respectively. Overall agreement of urine cytology was good in patients with primary bladder cancer and moderate in those being followed for their disease as Kappa coefficients were 0.70 and 0.60, respectively. However, some disagreement was found when results were analysed according to type of institution, to type of primary tumour, and to result of follow-up cystoscopy. In patients with primary bladder cancer the Kappa coefficient was 0.86 (very good) in university hospitals and 0.36 (fair) in city hospitals. Accordingly, in patients under follow-up the Kappa coefficient was 0.65 (good) in university hospitals and 0.39 (fair) in district hospitals. Although the stage of primary tumour had no effect on agreement, agreement was moderate (Kappa coefficient 0.45) in those with low grade tumour and good (Kappa coefficient 0.67) in those with high grade tumour. In addition, Kappa coefficients were 0.65 (good) and 0.40 (fair) in those with and without recurrence at follow-up cystoscopy. CONCLUSIONS: Although overall agreement of routine cytology was from moderate to good in both diagnosis and monitoring of bladder cancer, there is some variation in agreement according to the type of institution. Accordingly, grade of primary tumour and the result of follow-up cystoscopy had effect on agreement reflecting subjectiveness and weak reproducibility of this test. This not only emphasises the need for continuing education and quality control for urine cytologic analysis, but also inspires the development of more objective tests.

Perioperative single dose instillation of epirubicin or interferon-alpha after transurethral resection for the prophylaxis of primary superficial bladder cancer recurrence: a prospective randomized multicenter study--FinnBladder III long-term results.

PURPOSE: We evaluated the long-term efficacy of a single dose of interferon or epirubicin administered immediately after transurethral resection compared with transurethral resection alone for primary superficial bladder cancer recurrence. MATERIAL AND METHODS: A total of 200 patients with primary superficial stages Ta to T1, grades 1 to 3 bladder cancer were randomized into 3 treatment groups, including transurethral resection alone, transurethral resection plus 50 milliunits interferon-alpha2b and transurethral resection plus 100 mg. epirubicin. The primary end point was time to first recurrence. RESULTS: At a median followup of 72 months we observed a sustained effect of a single epirubicin instillation compared with other treatments. To date only 46% of the patients in group 3 have experienced recurrence in contrast to 73% and 68% in groups 1 and 2, respectively (p = 0.002). At 72 months the Kaplan-Meier disease-free estimates were 24%, 31% and 51% in groups 1 to 3, respectively (p = 0.002). The Cox multivariate model revealed a more than 2-fold relative risk of recurrence in group 1 versus group 3 (p <0.001). Other significant variables predicting recurrence were grade and the number of tumors. CONCLUSIONS: A single perioperative instillation of 100 mg. epirubicin causes a significant and sustained decrease in primary superficial bladder cancer recurrence, whereas a single dose of 50 milliunits interferon-alpha2b is ineffective for prophylaxis.

Chorionic gonadotropin beta-subunit and core fragment in bladder cancer: mRNA and protein expression in urine, serum and tissue.

OBJECTIVES: Many transitional cell carcinomas (TCC) of the bladder express the beta-subunit (CGbeta) of chorionic gonadotropin (CG), and elevated serum levels occur especially in advanced disease. We have compared the diagnostic utility of various methods for detecting CG and CGbeta expression at the protein and mRNA level. METHODS: We used RT-PCR to detect CGbeta mRNA in urinary cells and highly sensitive immunoassays to determine CG and CGbeta in serum and the core fragment of CGbeta (CGbetacf) in urine from patients under follow-up for bladder cancer. Tissue expression was studied by immunohistochemistry. RESULTS: CGbeta mRNA was detected in urinary cells in 50% (n=84) of the cancer cases and in none of the healthy controls (n=15). Positive staining for CGbeta in tissue samples was observed not only in 30% (n=96) of the TCC cases, but also in 5 of 20 histologically benign samples from TCC patients, and in 10 of 21 samples from benign bladder diseases. Serum and urinary concentrations of CGbeta were elevated in 29% (n=66) and 8% (n=72), respectively, while serum CG was elevated in 18% of the TCC patients. Urinary CGbetacf concentrations were higher in invasive (T1-T4) than superficial (T in situ and Ta) tumors (p=0.037), in cases positive for CGbeta mRNA (p=0.03) and cases with suspicious or malignant urinary cytology (p=0.002). The ratio of urinary to serum concentration of CGbeta showed the strongest correlation with tumor stage (p<0.00001), grade (p<0.00001), and staining for CGbeta (p=0.019). CONCLUSIONS: Although CGbeta expression may occur in benign bladder epithelium, CGbeta mRNA in urinary cells is a potential marker of bladder cancer. Urinary and serum CGbeta have low sensitivity in early disease, but the urine/serum ratio appears to indicate local release of CGbeta into urine. Further studies are needed to evaluate the clinical usefulness of different forms of CGbeta expression.