Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials.

OBJECTIVES: To provide tables that allow urologists to easily calculate a superficial bladder cancer patient's short- and long-term risks of recurrence and progression after transurethral resection. METHODS: A combined analysis was carried out of individual patient data from 2596 superficial bladder cancer patients included in seven European Organization for Research and Treatment of Cancer trials. RESULTS: A simple scoring system was derived based on six clinical and pathological factors: number of tumors, tumor size, prior recurrence rate, T category, carcinoma in situ, and grade. The probabilities of recurrence and progression at one year ranged from 15% to 61% and from less than 1% to 17%, respectively. At five years, the probabilities of recurrence and progression ranged from 31% to 78% and from less than 1% to 45%. CONCLUSIONS: With these probabilities, the urologist can discuss the different options with the patient to determine the most appropriate treatment and frequency of follow-up.

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.

Bacillus calmette-guerin versus chemotherapy for the intravesical treatment of patients with carcinoma in situ of the bladder: a meta-analysis of the published results of randomized clinical trials.

PURPOSE: We determined the short-term and long-term efficacy of bacillus Calmette-Guerin (BCG) and chemotherapy in the treatment of patients with carcinoma in situ (CIS). MATERIALS AND METHODS: A meta-analysis was performed on published results of randomized clinical trials comparing intravesical BCG to intravesical chemotherapy. RESULTS: Nine randomized trials including 700 patients with CIS compared BCG to either mitomycin C (MMC), epirubicin, adriamycin, or sequential MMC/adriamycin. Of 298 patients on BCG 203 (68.1%) had a complete response compared with 158 of 307 patients on chemotherapy (51.5%), a reduction of 47% in the odds of nonresponse on BCG (OR 0.53, p =0.0002). Based on a median followup of 3.6 years, 161 of 345 patients on BCG (46.7%) had no evidence of disease compared with 93 of 355 patients on chemotherapy (26.2%), a reduction of 59% in the odds of treatment failure on BCG (OR 0.41, p <0.0001). Although the long-term benefit of BCG was smaller in trials with MMC, BCG was superior to MMC in trials with maintenance BCG (OR 0.57, p =0.04). The reduction of 26% in the risk of progression on BCG (p =0.20) is consistent with the reduction of 27% (p =0.001) previously reported in a larger superficial bladder cancer meta-analysis. CONCLUSIONS: Intravesical BCG significantly reduces the risk of short and long-term treatment failure compared with intravesical chemotherapy. Therefore, it is considered to be the intravesical agent of choice in the treatment of CIS.

High-grade Ta urothelial carcinoma and carcinoma in situ of the bladder.

We sought to review the definition, diagnosis, prognosis, and treatment of high-grade Ta urothelioma carcinoma and carcinomas in situ (CIS) in order to provide evidence-based guidelines for their diagnosis and treatment. The English-language literature on high-grade Ta urothelial carcinoma and CIS was identified and critically reviewed by a panel of 9 international experts. The panel then met at a consensus conference to present their conclusions. Levels of evidence and grades of recommendation were assessed. Findings from approximately 100 publications appearing prior to February 2005 were reviewed and summarized. High-grade Ta urothelial carcinoma and CIS are relatively rare tumors; thus results are often based on small nonrandomized studies. Their assessment is made more difficult owing to inaccuracies in staging and grading. Although there were similar numbers of level 1, level 2, and level 3 evidence citations, guidelines have been developed based only on levels of evidence supporting grade A and grade B recommendations. These evidence-based guidelines have been developed to aid clinicians in the diagnosis and treatment of patients with high-grade Ta urothelial carcinoma and CIS.

A single immediate postoperative instillation of chemotherapy decreases the risk of recurrence in patients with stage Ta T1 bladder cancer: a meta-analysis of published results of randomized clinical trials.

PURPOSE: We determined if 1 immediate instillation of chemotherapy after transurethral resection (TUR) decreases the risk of recurrence in patients with stage Ta T1 single and multiple bladder cancer overall and separately. MATERIALS AND METHODS: A meta-analysis was performed of the published results of randomized clinical trials comparing TUR alone to TUR plus 1 immediate instillation of chemotherapy. RESULTS: Our study included 7 randomized trials with recurrence information on 1476 patients. Based on a median followup of 3.4 years and a maximum of 14.5 years, 267 of 728 patients (36.7%) receiving 1 postoperative instillation of epirubicin, mitomycin C, thiotepa or (2'R)-4'-O-tetrahydropyranyl-doxorubicin (pirarubicin) had recurrence compared to 362 of 748 patients (48.4%) with TUR alone, a decrease of 39% in the odds of recurrence with chemotherapy (OR 0.61, p <0.0001). Patients with a single tumor (OR 0.61) and those with multiple tumors (OR 0.44) benefited. However, after 1 instillation 65.2% of patients with multiple tumors had recurrence compared to 35.8% of patients with single tumors, showing that 1 instillation alone is insufficient treatment for patients with multiple tumors. CONCLUSIONS: One immediate intravesical instillation of chemotherapy significantly decreases the risk of recurrence after TUR in patients with stage Ta T1 single and multiple bladder cancer. It is the treatment of choice in patients with a single, low risk papillary tumor and is recommended as the initial treatment after TUR in patients with higher risk tumors.

The side effects of Bacillus Calmette-Guerin in the treatment of Ta T1 bladder cancer do not predict its efficacy: results from a European Organisation for Research and Treatment of Cancer Genito-Urinary Group Phase III Trial.

OBJECTIVES: Previous publications have suggested that patients developing local and/or systemic side effects to Bacillus Calmette-Guerin (BCG) have a better clinical result, however it is necessary to determine if toxicity is responsible for improved efficacy. METHODS: After transurethral resection, intravesical instillations of BCG were given during a 6-week induction course followed by 3-weekly maintenance courses at 3, 6, 12, 18, 24, 30 and 36 months. The prognostic importance of delaying or stopping BCG due to local and/or systemic side effects was assessed in 487 patients. RESULTS: Patients with local BCG side effects had a significantly longer time to first recurrence, suggesting that side effects are related to efficacy. However patients with a better outcome remain on study for a longer period of time and receive more BCG, thus increasing their risk to develop side effects. To prove whether toxicity is responsible for improved efficacy, the prognostic importance of toxicity occurring prior to the 6 month instillations was assessed using the landmark method. Neither local nor systemic BCG toxicity prior to 6 months was related to subsequent recurrence. CONCLUSIONS: While a correlation between BCG toxicity and efficacy exists, this study does not confirm that BCG toxicity is actually responsible for an improved outcome.

Maintenance Bacillus Calmette-Guerin for Ta T1 bladder tumors is not associated with increased toxicity: results from a European Organisation for Research and Treatment of Cancer Genito-Urinary Group Phase III Trial.

OBJECTIVES: After transurethral resection, the local and systemic side effects of Bacillus Calmette-Guerin (BCG) instillations were assessed during a 6-week induction course followed by 3 weekly maintenance instillations at 3, 6, 12, 18, 24, 30 and 36 months to determine if BCG toxicity increases over time. METHODS: 487 patients who received BCG in a multicenter phase III trial were included. Side effects were divided into 5 different treatment periods: the first 6 weeks induction, months 3 and 6, month 12, the second year, and the third year. RESULTS: 99 (20.3%) patients stopped BCG due to side effects. 72 (14.8%) stopped due to local side effects, including 59 for BCG induced cystitis, 33 during the first 6 months. 46 (9.4%) stopped due to systemic side effects: 23 due to fever, 19 within 6 months, and 15 due to general malaise, 12 within 6 months. 68% who stopped due to side effects did so during the first 6 months. The percent stopping after 6 months due to local side effects does not increase and actually decreases for systemic side effects. CONCLUSIONS: The majority of local and systemic side effects are seen already during the induction and the first half-year of maintenance. During further maintenance BCG toxicity does not increase and instillations are generally well tolerated.

The use of the marker tumor concept in Ta, T1 bladder cancer: is it justified?

Adjuvant instillations with chemo- or immunotherapy agents after transurethral resection of Ta, T1 bladder tumors are administered on non-measurable non-visible disease. To know whether adjuvant therapies are efficacious the marker tumor concept has been developed. The use of marker lesions has been questioned by many as dangerous and/or unethical because a deliberately left-behind tumor might be invasive or become invasive if the adjuvant therapy is not effective. However, 4 EORTC, 2 British, and one Japanese study using different drugs have shown that it is safe and ethically justified to use the marker tumor concept in clinical phase II studies. Data from six trials indicate the the risk of leaving an invasive tumor behind or that a tumor might progress while being treated with instillations is 0.8% (3/383). Marker lesion studies should be limited to intermediate risk patients. Expensive and inefficient long term phase III trials may be avoided by marker tumor trials. Exposing patients to ineffective drugs in prophylactic trials also jeopardizes the patient with regard to recurrence and/or progression of their bladder tumors.

Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials.

PURPOSE: We determine if intravesical bacillus Calmette-Guerin (BCG) reduces the risk of progression after transurethral resection to stage T2 disease or higher in patients with superficial (stage Ta, T1 or carcinoma in situ) bladder cancer. MATERIALS AND METHODS: A meta-analysis was performed of the published results of randomized clinical trials comparing transurethral resection plus intravesical BCG to either resection alone or resection plus another treatment other than BCG. RESULTS: We identified 24 trials with progression information on 4,863 patients. Based on a median followup of 2.5 years and a maximum of 15 years, 260 of 2,658 patients on BCG (9.8%) had progression compared to 304 of 2,205 patients in the control groups (13.8%), a reduction of 27% in the odds of progression on BCG (OR 0.73, p = 0.001). The percent of patients with progression was low (6.4% of 2,880 patients with papillary tumors and 13.9% of 403 patients with carcinoma in situ, reflecting the short followup and relatively low risk patients entered in many of the trials. The size of the treatment effect was similar in patients with papillary tumors and in those with carcinoma in situ. However, only patients receiving maintenance BCG benefited. There was no statistically significant difference in treatment effect for either overall survival or death due to bladder cancer. CONCLUSIONS: Intravesical BCG significantly reduces the risk of progression after transurethral resection in patients with superficial bladder cancer who receive maintenance treatment. Thus, it is the agent of choice for patients with intermediate and high risk papillary tumors and those with carcinoma in situ.

Variability in the recurrence rate at first follow-up cystoscopy after TUR in stage Ta T1 transitional cell carcinoma of the bladder: a combined analysis of seven EORTC studies.

OBJECTIVES: To assess the variability between institutions in the recurrence rate at the first follow-up cystoscopy (RR-FFC) after transurethral resection (TUR) in patients with stage Ta T1 bladder cancer. METHODS: A total of 2410 patients from seven EORTC phase III trials conducted between 1979 and 1989 were included. Patients with single and with multiple tumors were analyzed separately according to whether or not they received adjuvant intravesical treatment. RESULTS: The RR-FFC varied greatly between institutions. For patients with a single tumor, it ranged from 3.4% to 20.6% for patients not receiving any intravesical adjuvant treatment and from 0% to 15.4% in those receiving it. In patients with multiple tumors who had adjuvant treatment, it varied between 7.4% and 45.8%. There was a slight decrease over time in the recurrence rate for patients with single tumors, particularly in those receiving adjuvant intravesical treatment. CONCLUSIONS: For both patients with single and with multiple tumors, the percentage of patients with a recurrence in the bladder at the first follow-up cystoscopy after TUR varies substantially between institutions and cannot be explained by the factors that were assessed. It is suggested that the quality of the TUR performed by the individual surgeons may be responsible.

Cytogenetic and molecular analysis of early stage renal cell carcinomas in a family with a translocation (2;3)(q35;q21).

Previously, we described a family with renal cell carcinoma (RCC) and a constitutional balanced t(2;3) (q35;q21). Based on loss of heterozygosity and von Hippel-Lindau (VHL) gene mutation analyses in five tumor biopsies from three patients in this family, we proposed a multistep model for RCC development in which the familial translocation may act as a primary oncogenic event leading to (nondisjunctional) loss of the translocation-derived chromosome 3, and somatic mutation of the VHL gene as a secondary event related to tumor progression. Here, we describe the cytogenetic and molecular analysis of three novel tumors at early stages of development in two members of this family. Again, loss of derivative chromosome 3 was found in two of these tumors and a VHL mutation in one of them. In the third tumor, however, none of these abnormalities could be detected. These results underline our previous notion that loss of derivative chromosome 3 and VHL gene mutation play critical roles in familial RCC. In addition, they show that both anomalies may occur at relatively early stages of tumor development.