Adjuvant Intravesical Therapy Research Articles

Intravesical adjuvant therapy using mitomycin C

Bladder cancer is mostly superficial at first diagnosis. High incidence of recurrence is the major problem after initial management with transurethral resection (TUR) of bladder tumor. Adjuvant chemotherapy has been advocated to reduce the incidence of recurrence. A study was carried out to observe the efficacy of intravesical adjuvant therapy with single immediate versus delayed multi-dose regimen of Mitomycin C (MMC) in preventing recurrence of superficial bladder cancer. One hundred Patients having intermediate risk superficial bladder cancer were randomized into two equal groups. All patients were followed carefully. Total duration of follow-up was minimum 12 months, maximum 36 months, mean 29 months. No recurrence was seen on 3(rd), 6(th) and 9(th) month of intravesical therapy. As much as 94% and 96% of recurrence free rate was observed in immediate single and delayed multi-dose group respectively on 12(th) month; 86% and 84% on 18(th) month; 74% and 72% on 24(th) month; 70% and 68% on 36(th) month of follow-up cystoscopy respectively. Efficacy of post transurethral resection of bladder tumour (TURBT) MMC single immediate dose was found similar to that of MMC delayed multi-dose regimen in preventing the recurrence of intermediate risk superficial bladder transitional cell carcinoma (TCC) in the study. The difference between the two groups insignificant (p>0.05).

1571: Adjuvant Intravesical Therapy and Improved Survival Among Elderly Patients with Superficial Bladder Cancer

1571: Adjuvant Intravesical Therapy and Improved Survival Among Elderly Patients with Superficial Bladder Cancer

Photodynamic Diagnostics and Noninvasive Bladder Cancer: Is It Cost-Effective in Long-Term Application? A Germany-Based Cost Analysis

ObjectivesNoninvasive urothelial carcinoma of the bladder (UCB) causes an enormous economic burden to public health systems due to its life-long character and frequent recurrences. While white light (WL) cystoscopy is considered to be the gold standard for transurethral resection of the bladder, photodynamic diagnostic (PDD) has been shown to improve final outcome. Escalating healthcare costs warrant increased effectiveness in treating noninvasive UCB. No data based on assessment of costs have been published to date. MethodsA series of 301 patients with noninvasive UCB were randomized prospectively to standard WL or PDD transurethral resections of the bladder. Intravesical adjuvant therapy was administered as reflected in the appropriate guidelines. Expenditures of subsequent procedures and PDD-associated costs were assessed. ResultsMedian follow-up was 7.1 yr. Disease recurrence was found in 42% and 18% of WL and PDD patients, respectively (p=0.0003). In the WL group 2.0 and in the PDD group 0.8 transurethral resections of the bladder were noted per patient. In the WL group 1.0 and in the PDD group 0.3 recurring UCB occurred per patient, resulting in costs of €1750 per WL patient versus €420 per PDD patient in the follow-up period, respectively. Because a single expenditure of €135 was assessed for PDD, overall costs were significantly lower (by €1195) in PDD patients. As the median follow-up was 7.1 yr, costs saved by PDD per patient per year were €168. ConclusionOur data suggest that PDD significantly cut costs related to recurring UCB. Further studies are needed from an economic point of view.

腎盂尿管腫瘍における膀胱粘膜多部位生検の意義

We reviewed significance of multiple biopsies obtained from bladder mucosa in 59 patients of renal pelvic and ureteral carcinoma treated at Osaka Police Hospital between 1990 and 2003. The patients consisted of 41 males and 18 females. The median age was 68 years, ranging from 42 to 91 years. Multiple biopsies were carried out in principle to examine the following 5 cystoscopically normal-appearing bladder mucosal sites: (1) trigone, (2) posterior wall, (3) left lateral wall, (4) right lateral wall and (5) dome. Positive case of multiple biopsies was defined as patients having abnormalities in at least one biopsy specimen such as bladder tumor (BT) or dysplasia. Median follow-up period was 54 months. Of the 59 patients, 6 had positive multiple biopsies. Among them 3 had carcinoma n situ (CIS), and others had dysplasia. 4 patients with positive multiple biopsies had past or concurrent history of BT and received adjuvant intravesical instillation therapy. Positive rate of multiple biopsies significantly differed between patients with and without past and/or concurrent BT (4/15: 27% vs 2/44: 5% p = 0.03), indicating that multiple biopsies were useful to detect abnormal lesion accompanied with past and/or concurrent BT. 3-year bladder recurrence free rate was 61%. Postoperative bladder recurrence rate did not significantly differ between positive (1/6 17%) and negative (20/53: 38%) cases of multiple biopsies. Univariate analysis indicated stage (p = 0.03) and venous involvement (p = 0.02) to be significant prognostic factors for bladder recurrence free rate, but not multiple biopsies, although multivariate analysis with Cox's proportional hazard model revealed no independent prognosticators. Low recurrence rate of patients with positive multiple biopsies was possibly due to adjuvant intravesical instillation therapy to prevent bladder recurrence.

Analysis of factors predicting intravesical recurrence of superficial transitional cell carcinoma of the bladder without concomitant carcinoma in situ

The objective of this study was to investigate risk factors for intravesical recurrence in patients with superficial bladder cancer without concomitant carcinoma in situ (CIS). In this series, we analyzed data from patients with newly diagnosed superficial Ta or T1 transitional cell carcinoma (TCC) of the bladder without concomitant CIS who underwent complete transurethral resection (TUR) without any adjuvant intravesical instillation therapies. Multivariate analysis was used to determine significant risk factors affecting intravesical recurrence after TUR. Differences in clinicopathological features between primary and recurrent tumors were also characterized. Among 341 patients undergoing TUR of Ta or T1 bladder cancer, 187 diagnosed as having concomitant CIS and/or treated with adjuvant intravesical therapy were excluded, and the remaining 154 were evaluated. Intravesical recurrence was detected in 64 of the 154 patients, showing a 5-year recurrence-free survival rate of 58.3%. Among several factors examined, only tumor size was significantly associated with intravesical recurrence. Multivariate analysis identified tumor size as an independent predictor for intravesical recurrence irrespective of other parameters including age, gender, multiplicity, growth pattern, grade and stage. Recurrent tumors were significantly smaller and of a lower grade and lower stage than primary tumors, despite the absence of differences in growth pattern and the multiplicity between them. These findings suggest that primary tumor size could be used as a potential risk factor for predicting intravesical recurrence following TUR of superficial TCC of the bladder without concomitant CIS, and that the pathological characteristics of recurrent tumors are more favorable than those of primary tumors.

MP-15.17: Comparison of efficacy of post-TURBT adjuvant intravesical mitomycin C therapy in preventing the recurrence of intermediate risk superficial TCC: peri-operative single dose versus delayed multi-dose regimen, short- versus long-term result

Superficial bladder TCC especially G.I-II could be effectively managed by initial TUR with adjuvant intravesical therapy using Mitomycin C. To date, there is no worldwide consensus regarding the universally accepted protocol of MMC. Different studies claim better result with conventional delayed multi-dose regimen while others claim superior results with single peri-operative instillation. In the background of controversy we have designed a prospective study in the department of Urology, BSMMU, Dhaka, to compare the efficacy of adjuvant intravesical therapy of MMC, single peri-operative dose versus delayed multi-dose regimen in preventing the recurrence of intermediate risk superficial TCC.

Adjuvant intravesical therapy based on an in vitro cytotoxicity assay in the management of superficial transitional cell cancer of the urinary bladder

To investigate the utility of an individualized chemo/immunotherapy regimen of intravesical therapy based on the results of an assessment of in vitro cytotoxicity. Intravesical adjuvant chemo/immunotherapy was given to 47 patients based on the results of in vitro cytotoxicity assay of the responses of cultured autologous tumour cells to various cytotoxic drugs (mitomycin-C, doxorubicin and cisplatin) and immunomodulating agents (bacillus Calmette-Guérin, BCG and interferon-alpha2b). Intravesical therapy was given as single- or double-drug regimens according to the assay results: 16 (34%) patients showed cytotoxicity to a single drug and 31 (66%) showed maximum cytotoxicity to a combination of immunomodulators and cytotoxic agents. The efficacy of treatment in terms of tumour-free survival and recurrence rate was compared with 40 patients receiving intravesical BCG according to International Protocol (control group). In the in vitro assay group, seven patients (15%) had tumour recurrence, compared to 15 (38%) in the control group (P = 0.02). In the in vitro group, one of 16 patients on a single drug and six on the double-drug regimen had a recurrence. The patients given BCG with cytotoxic drugs had no recurrences, but 29% of patients given interferon-alpha2b combinations had recurrences. Kaplan-Meier analysis showed a longer recurrence-free survival in the in vitro group (75%) than in the control group (49%) at 48 months of follow-up. Intravesical therapy based on an in vitro cytotoxicity assay is an attempt to give individualized therapy, and to increase tumour-free survival in these patients, with no side-effects. Recurrences in seven patients in the in vitro group might be due to a defective host immune response, or to expansion of a subclone of tumour cells resistant to all treatment.

Praxis der intravesikalen Instillationsprophylaxe beim oberflächlichen Harnblasenkarzinom - Ergebnisse einer Umfrage in Sachsen

For patients with superficial bladder cancer, adjuvant intravesical chemotherapy or immunotherapy with Bacillus Calmette-Guerin (BCG) is recommended in national and international guidelines. We analyzed whether the recommended therapeutic regimens are used in daily urological practice. Questionnaires concerning the adjuvant intravesical therapy were sent to 152 urologists in the German Federal State of Saxony. Of the surveyed physicians, 134 practiced in an outpatient medical facility and 18 in a hospital. Of the questionnaires, 73 (48.02 %) were returned and evaluated. An adjuvant intravesical therapy after transurethral bladder tumor resection was performed in every second patient (median value 50.07 %). The majority of the urologists (79.4 %) treated the bladder tumors with intravesical chemotherapy or BCG depending on tumor stage and grade of malignancy. Chemotherapeutic agents or BCG was exclusively used in 13.6 % and 4.1 % of treated patients, respectively. Chemotherapeutic agents were predominantly applied up to the primary tumor stage T1 and malignancy grade G2. In cases with recurrent T1 bladder tumors of G2 or higher grade of malignancy, BCG was the main agent for intravesical treatment. In patients with recurrent T1G3 tumors, the majority of urologist (57.1 %) preferred another therapeutic regimen than intravesical instillation. Only 23.2 % of the urologists believed that intravesical BCG is superior to chemotherapeutic agents. These data demonstrate that adjuvant intravesical instillation with chemotherapeutic agents and BCG is well established in urological practice. In contrast to the recommendations of national and international guidelines, chemotherapeutic agents are more frequently used in cases with a high risk of progression.

Combined modality treatment of high-risk T1 bladder cancer: More effective than intravesical therapy, less radical than cystectomy

Current treatment options for high-risk superficial T1-bladder cancer (grade 3, associated Tis, multifocality, tumor diameter > 5cm or multiple recurrences) include early cystectomy or the goal of organ-preservation by adjuvant intravesical therapy after transurethral resection (TURBT). We have evaluated the efficacy of adjuvant radiotherapy (RT) or radiochemotherapy (RCT) on local control, bladder-preservation, recurrence rate and long-term survival after TURBT of high-risk T1-bladder cancer.

Preliminary European results of local microwave hyperthermia and chemotherapy treatment in intermediate or high risk superficial transitional cell carcinoma of the bladder.

Superficial bladder cancer can be treated by transurethral resection (TUR) and adjuvant intravesical therapy. Intravesical bacillus Calmette-Guérin (BCG) has been proven to be more efficacious with respect to recurrence prevention than intravesical chemotherapy, although at the cost of more severe side effects. There is a need for a new treatment modality with higher efficacy and less toxicity. The subject of this study is the efficacy of local microwave hyperthermia and chemotherapy treatment in intermediate or high risk superficial transitional cell carcinoma (TCC) of the bladder. Ninety eligible patients received adjuvant treatment with a combination of mitomycin-C (MMC) and local microwave hyperthermia. All patients had multiple or recurrent Ta or T1 TCC of the bladder and were classified as intermediate or high risk according to EAU criteria. In total, 41 patients were BCG failures. The treatment regimen included 6 to 8 weekly sessions followed by 4 to 6 monthly sessions. Follow-up consisted of video-cystoscopy and urine cytology every 3 months. All patients were observed for 2 years. Kaplan-Meier analyses of the total group (N = 90) indicated that 1 year after treatment only 14.3% (SE 4.5%) of all patients experienced a recurrence. After 2 years of follow-up the risk of recurrence was 24.6% (SE 5.9%). No progression in stage and grade was observed. Microwave induced hyperthermia combined with MMC has promising value in intermediate or high risk superficial bladder cancer patients compared to literature data of BCG and/or intravesical chemotherapy, particularly where other treatments, i.e. BCG, have failed.

Risk factor analysis in 165 selected patients with T1G3 transitional cell carcinoma of the bladder treated by TUR plus adjuvant intravesical therapy

Risk factor analysis in 165 selected patients with T1G3 transitional cell carcinoma of the bladder treated by TUR plus adjuvant intravesical therapy

Molecular genetics of urothelial malignancies: Mismatch repair genes as markers for detection and prognosis?

Urothelial malignancies were diagnosed in over 50,000 men and women in the United States last year. The majority of these tumors are not muscle invasive and can be treated endoscopically with or without adjuvant intravesical therapy. Cystoscopy and cytology at regular and frequent intervals are essential since many patients experience tumor recurrence, progression or fail to respond to intravesical treatments. Cancer recurrence, progression and intravesical treatment failures can be associated with increased risk of developing metastatic disease if not promptly detected and aggressively treated. Markers that identify patients at increased risk for recurrence, progression and poor response to intravesical therapy would provide useful information in the management of patients with urothelial malignancies. Mismatch repair (MMR) genes are potential markers for detection and prognosis since their expression is linked to tumor predisposition, progression and resistance to chemotherapeutic agents. The molecular biology and biochemistry of MMR will be reviewed and the potential role of human MMR genes for detection, prognosis and treatment of urothelial malignancies will be discussed.

Diagnosis and management of superficial bladder cancer

Bladder cancer is the fourth leading cause of cancer in American men, accounting for more than 12,000 deaths annually. It was one of the first malignancies in which carcinogens were recognized as an important factor in its cause. Currently, cigarette smoking is by far the most common cause of bladder cancer, although occupational exposure to arylamines has been implicated in the past. Gross or microscopic hematuria is the most common sign at presentation. Initial radiologic evaluation usually includes the excretory urography (intravenous pyelography), although further evaluation of the renal parenchyma with ultrasound or computed tomography scanning has been advocated by some. These radiologic studies are unable to provide adequate bladder imaging, and thus cystoscopy is required for the diagnosis of bladder cancer. Most bladder cancers present as ″superficial” disease, confined to the bladder mucosa or submucosal layer, without muscle invasion. Superficial tumors consist of papillary tumors that are mucosally confined (Ta), papillary or sessile tumors extending into the lamina propria (T1), and carcinoma in situ, which occurs as ″flat” mucosal dysplasia, which can be focal, diffuse, or associated with a papillary or sessile tumor. The natural history of these pathologic subtypes differ significantly. Most superficial tumors (60% to 70%) have a propensity for recurrence after transurethral resection. Some (15% to 25%) are at high risk for progression to muscle invasion. Most superficial tumors can be stratified into high- or low-risk groups depending on tumor stage, grade, size, number, and recurrence pattern. It is important to identify those tumors at risk for recurrence or progression so that adjuvant intravesical therapies can be instituted. Many intravesical chemotherapeutic agents have been shown to reduce tumor recurrence when used in conjunction with transurethral tumor resection. Unfortunately, however, none of these agents have proved to be of benefit in preventing disease progression. Most are given intravesically on a weekly basis, although many studies suggest that a single instillation immediately after transurethral resection may be as good as a longer course of therapy. Although all of these drugs have toxicity, they usually are well tolerated. Intravesical bacille Calmette-Guérin (BCG) is an immunotherapeutic agent that when given intravesically is very effective in the treatment of superficial transitional cell carcinoma. Compared with controls, BCG has a 43% advantage in preventing tumor recurrence, a significantly better rate than the 16% to 21% advantage of intravesical chemotherapy. In addition, BCG is particularly effective in the treatment of carcinoma in situ, eradicating it in more than 80% of cases. In contrast to intravesical chemotherapy, BCG has also been shown to decrease the risk of tumor progression. The optimal course of BCG appears to be a 6-week course of weekly instillations, followed by a 3-week course at 3 months in those tumors that do not respond. In high-risk cancers, maintenance BCG administered for 3 weeks every 6 months may be optimal in limiting recurrence and preventing progression. Unfortunately, adverse effects associated with this prolonged therapy may limit its widespread applicability. In those patients at high risk in whom BCG therapy fails, intravesical interferon-α with or without BCG may be beneficial in some. Photodynamic therapy has also been used but is limited by its toxicity. In patients who progress or do not respond to intravesical therapies, cystectomy should be considered. With the development of orthotopic lower urinary tract reconstruction to the native urethra, the quality of life impact of radical cystectomy has been lessened. (Curr Probl Cancer 2001;25:217-80.)

The early clinical course of primary Ta and T1 bladder cancer: a proposed prognostic index.

To develop a simple prognostic index for anticipating more precisely the early clinical course of primary superficial bladder cancer. The prognostic value of patient and tumour characteristics was examined in 333 patients with primary Ta or T1 bladder cancer who participated in a multicentre prospective study already completed. Primary tumour multiplicity, a diameter of > 3 cm, stage T1, and grade 2 or 3 were independent predictors of earlier recurrence in a multivariate analysis. A simplified prognostic index consisted of the number of adverse tumour characteristics (ATCs) initially present. After a median follow-up of 35.3 months, the 60 patients free of ATCs (19%) had a recurrence-free probability at 12 and 24 months of 86% and 69%, respectively, and none experienced progression. Recurrence outcomes deteriorated consistently as the number of ATCs increased among the other three groups. In patients with 3-4 ATCs, the 12- and 24-month recurrence-free probability was as low as 30% and 19%, and recurrence and tumour rates were about 2.6 times higher than in patients free of ATCs; 7% of these patients experienced progression within 35 months of follow-up. A prognostic index based on the number of ATCs (primary tumour multiplicity, diameter > 3 cm, stage T1, and grade 2 or 3) is a strong indicator of the clinical course of superficial bladder cancer within 3 years of the first endoscopic resection. This proposal is suggested for discussion and for validation in future studies but if confirmed, this simple prognostic index may greatly help to identify indicators for adjuvant intravesical therapy and to determine the optimal periodicity of control cystoscopy regimens.

Diagnosis and treatment of primary ureteral carcinoma—A report of 15 cases

Fifteen cases with primary ureteral carcinomas are reported with a review of the literature. We concludeL Excretory urography is the main method of diagnosis; retrograde uretero-pyelography is more helpful in diagnosis; cystoscopy is also necessary before operation; CT is useful in diagnosing and staging; ureteroscopy could be performed if necessary; the traditional total nephroureterectomy with a cuff excision of the urinary bladder remains the basic treatment of choice; cystoscopy, excretory urography and adjuvant intravesical therapy should be carried out regularly after operation.

Recent studies in bladder cancer.

The progression of carcinoma in situ of the bladder to invasive bladder carcinoma has been shown to be essentially regulated by p53 overexpression. In another study, however, loss of heterozygosity of chromosome 9 has also been shown to be essential for progression to muscle invasive disease. Routine random biopsies for predicting prognosis and deciding on adjuvant intravesical therapy should be abandoned because of the results of a well-designed trial on 1745 patients. The aforementioned study showed that the recurrence and progression rates could be only slightly improved at a cost of more intravesical therapy if random biopsies were done routinely. The survival of patients undergoing radical cystectomy was shown to be strongly affected by the primary tumor stage even in those patients with positive nodes. Radical cystectomy and lymph node dissection alone could be beneficial in node-positive patients if the tumor was confined to the bladder. Neoadjuvant chemotherapy and bladder sparing could be recommended only on selected patients with significant reduction in tumor size after chemotherapy. The response to adjuvant chemotherapy could be prolonged if consolidation surgical intervention is performed on responders. With the help of new prognostic parameters obtained from molecular genetic analysis, the already increasing survival trends in bladder carcinomas will hopefully continue to improve in the near future.

Selection of patients for intravesical therapy for superficial bladder cancer.

In a nonrandomized retrospective study, 133 patients with superficial transitional cell carcinoma of the bladder were evaluated to identify any clinical prognostic features which indicate the necessity of intravesical therapy (IVT). The risk factors taken into account were stage, grade and multiplicity of the tumour. All patients were treated initially by complete transurethral resection (TUR); 27 patients received no further treatment after resection of the tumour, 106 patients received adjuvant IVT over a period of 6 weeks. The mean follow-up was 23 and 18.8 months in the TUR-only group and TUR+IVT group, respectively. In the TUR-only group 7 and in the TUR+IVT group 29 recurrences were encountered. Patient group with no risk factors (Ta, GI, solitary tumour) or with only one risk factor revealed no statistical difference in terms of the recurrence rate from the identical control group. So it does not seem worthwhile to give additional therapy in the low-risk group. Another notable outcome of this study was that the higher the potential risk factors, the higher the likelihood of recurrence. The results suggest that T1 tumours, multifocal tumours, and high-grade tumours have poor prognosis, making additional treatment necessary.

Intravesical mitoxantrone for superficial bladder tumors.

Thirty-five patients (33 males, median age 58) with stage T alpha (21 patients) or T1, grade 1 (17 patients) or grade 2 superficial bladder carcinoma, were treated with transurethral resection (TUR) followed by intravesical prophylactic therapy with 10 mg mitoxantrone administered weekly for 6 weeks and then monthly for 10 months. Twenty-five patients were newly diagnosed and 10 had relapsed after previous therapy. Diagnosis was confirmed with cytology and biopsy. The aim of the study was to evaluate the prophylactic effect (relapse rate, disease free interval) and toxicity of intravesical mitoxantrone in superficial bladder carcinoma. Relapses were established with biopsy. After a mean period of 12 months follow-up (median 8.3 months), 63% of patients in the whole group, 72% in the newly diagnosed group and 40% in the group of previously relapsed patients remained relapse free. These rates compare very favorably with the most effective prophylactic agents available. At the end of the follow-up period the median disease-free survival for the whole group was not reached. Therapy was well tolerated with no systemic toxicity and 14 patients reporting grade 1-2 local toxicity. In no patient was treatment discontinued due to toxicity. Mitoxantrone is an effective and safe agent for the post-TUR adjuvant intravesical therapy.

Adjuvant Intravesical Therapy for Superficial Bladder Cancer

To review the results of clinical trials and adverse drug effects of thiotepa, BCG vaccine, mitomycin, and doxorubicin, which are used as adjuvant intravesical therapy for superficial bladder cancer. Information was retrieved from a MEDLINE search, of the English-language literature. Indexing terms included adjuvant pharmaceutics, bladder neoplasms, thiotepa, mitomycin, BCG vaccine, and doxorubicin. Data from several human and in vitro studies were assessed and evaluated, according to the strength of comparative data and therapeutic response. Emphasis was placed on clinical trials that assessed and evaluated dosage, therapeutic regimens, and therapeutic response of adjuvant intravesical therapy for superficial bladder cancer. Adjuvant intravesical therapy and long-term prophylaxis are effective for superficial bladder cancer. Studies have shown that doxorubicin, thiotepa, BCG, and mitomycin, when used as adjuvant therapy, provide better protection than transurethral resection alone against tumor recurrence and prolong the time to when cystectomy is required. Several randomized clinical trials suggest that BCG is superior to thiotepa, doxorubicin, and mitomycin in preventing bladder tumor recurrence and tumor progression. Local cystitis is an adverse effect produced by all four agents; however, BCG vaccine has been reported to cause a higher incidence of adverse reactions (e.g., dysuria, hematuria). BCG may also cause an influenza-like syndrome, arthralgias, and fever, but most of these reactions have resulted in few severe adverse effects when the drug is given in the relatively modest recommended doses.

RECURRENT OR AGGRESSIVE BLADDER CANCER: Indications for Adjuvant Intravesical Therapy

Advances in understanding of the variables that adversely affect the prognosis of patients with superficial bladder cancer allow more accurate predictions of the aggressive biologic potential of tumors. Intravesical therapy appears to be an effective and essential adjuvant in those patients with high-risk tumor variables. Multiple risk factors related to the tumor, individual patient characteristics, and treatment modality must be evaluated. Assignment of the relative importance of these risk factors will differ from patient to patient. Factors useful for predicting tumor aggressiveness in order to decide the appropriateness of adjuvant intravesical therapy include tumor size, configuration, and grade; ploidy status; Tis and T1 categories; multifocality; postoperative cytologic analysis; the failure of prior intravesical therapy; and prostatic urethral involvement. The integration of this information with formulation of a treatment plan represents both the art and the science of urologic oncologic practice. Research efforts need to be directed at the development of better tumor markers for superficial bladder cancer.