Significance of random bladder biopsies in superficial bladder cancer

OBJECTIVES: We investigated to what extent biopsies of normal-appearing urothelium taken from patients with superficial bladder cancer (Ta, T1, Tis) showed malignant disease and whether those findings had impact on therapeutical decisions. PATIENTS AND METHODS: 1033 consecutive patients presenting with Ta, T1 or Tis (carcinoma in situ) superficial bladder tumors at increased risk for recurrence underwent multiple random biopsies from normal-appearing urothelium during transurethral resection (TUR). Patients with small, primary, singular tumors (smaller or equal to 1cm) were excluded from random biopsies. RESULTS: No tumor was found in the random biopsies of 905 patients (87.6%). 128 patients (12.4%) showed urothelial bladder cancer in their random biopsies (Tis: 74, Ta: 41, T1: 12, T2: 1). In 14 patients, where transurethral resection of the primary tumor revealed no signs of malignancy, urothelial bladder cancer was detected in the random biopsy material: Ta 8 patients, Tis 5 patients and T1 one patient. 21 patients with Ta tumors and 29 patients with T1 disease showed concomitant Tis. Upstaging of the primary, resected tumor by histological examination of the random biopsy material occurred in 75 patients (7%). Altogether, due to the random biopsy results therapy was altered in 70 patients (6.8%) of our series: It changed intravesical chemotherapy to BCG in 45, provoked a second TUR in 48 and cystectomy in 15 patients. CONCLUSIONS: While the clinical significance of random biopsies is still controversial, random biopsy results had strong impact on therapeutical decisions in our series. Regarding random bladder biopsies a simple tool for the urologist to identify high risk groups of patients, we recommend them as part of the routine management of superficial bladder cancer.     

The significance of random bladder biopsies in superficial bladder cancer

Introduction: Today, there is no consensus about taking random bladder biopsies during transurethral resection of superficial bladder tumors for staging and to determine the urothelial abnormalities like dysplasia and carcinoma in situ. The aim of our study was to evaluate the results and indications of random bladder biopsies for primary superficial bladder cancer.Patients and methods: Random bladder biopsies were taken from 84 patients with primary superficial bladder cancer after transurethral resection. 40 patients had Ta and 44 had T1 tumor. The random biopsies were taken from right and left bladder walls, anterior and posterior walls, dome, trigone and prostatic urethra. The incidence of urothelial abnormalities were evaluated according to the stage and grade of the tumor.Results: None of the patients had carcinoma in situ or dysplasia with Ta tumor. In T1 group, 4 patients (9.1%) had carcinoma in situ and 3 patients (6.8%) had dysplasia. There was a statistically significant difference with regard to urothelial abnormalities between groups Ta and T1. The same difference was also seen between low and high grade tumors.Conclusion: In our study, only 7/84 (8.3%) of patients with primary superficial bladder cancer had urothelial abnormalities like carcinoma in situ or dysplasia. All of these pathologies were seen in T1 tumors. According to our results, we believe that random biopsies are not useful in superficial bladder cancers to detect urothelial abnormalities and also do not help for the planning of further treatment.     

Bacillus Calmette-Guerin versus doxorubicin versus thiotepa: a randomized prospective study in 202 patients with superficial bladder cancer

We report the second interim analysis of data from a randomized prospective trial comparing the prophylactic effect of 15 courses of 50 mg. doxorubicin, 50 mg. thiotepa or 150 mg. bacillus Calmette-Guerin instilled intravesically against recurrences and progression of superficial transitional cell bladder cancer. Of 202 enrolled patients 176 currently are evaluable with a mean follow-up of 3 years (range 3 to 97 months). The number of patients with recurrences was significantly lower in the bacillus Calmette-Guerin arm (9 of 67) compared to the doxorubicin (23 of 53, p equals 0.002) and thiotepa (20 of 56, p equals 0.003) arms. The over-all recurrence index per 100 patient-months also was lower for the bacillus Calmette-Guerin versus the thiotepa and doxorubicin groups (0.53 versus 1.55 and 1.7, respectively). Bacillus Calmette-Guerin also was superior in preventing recurrences and progression of high risk tumors, that is stage T1, grade 3 or multiple growths, associated or not with carcinoma in situ. In the stage T1 category 19 of 32 (60%) tumors recurred under treatment with doxorubicin, 11 of 33 (33%) with thiotepa and 6 of 49 (12%) with bacillus Calmette-Guerin. Toxicity to intravesical bacillus Calmette-Guerin was higher compared to the other drugs but it was not limiting: bladder irritability and malaise occurred in 42% of the patients, granulomatous cystitis in 16.4% and bladder contraction in 1.4% (1 of 64). The latter complication occurred in a patient whose stage T1m grade 2 tumors had recurred 3 times, who underwent 3 transurethral bladder resections within 15 months and who had received thiotepa for 4 months after having been removed from the study 11 months after entry. Three patients in the doxorubicin group (5.6%) underwent radical cystectomy for local urothelial progression. One patient (1.8%) in the same group died of distant progression. Our preliminary results suggest that at the dose, periodicity and duration used in the study bacillus Calmette-Guerin is significantly superior to the chemotherapeutic agents doxorubicin and thiotepa for the prophylaxis of recurrence and retardation of progression in superficial transitional cell bladder tumors.     

Intravesical electromotive mitomycin C versus passive transport mitomycin C for high risk superficial bladder cancer: a prospective randomized study

PURPOSE: In laboratory studies electromotive mitomycin C (MMC) demonstrated markedly increased transport rates compared with passive transport. We performed a prospective study in patients with high risk superficial bladder cancer to assess the efficacy of intravesical electromotive vs passive MMC using bacillus Calmette-Guerin (BCG) as a comparative treatment. MATERIALS AND METHODS: Following transurethral resection and multiple biopsies 108 patients with multifocal Tis, including 98 with T1 tumors, were randomized into 3 equal groups of 36 each who underwent 40 mg electromotive MMC instillation with 20 mA electric current for 30 minutes, 40 mg passive MMC with a dwell time of 60 minutes or 81 mg BCG with a dwell time of 120 minutes. Patients were scheduled for an initial 6 weekly treatments, a further 6 weekly treatments for nonresponders and a followup 10 monthly treatments for responders. Primary end points were the complete response rate at 3 and 6 months. MMC pharmacokinetics were assessed. RESULTS: The complete response for electromotive vs passive MMC at 3 and 6 months was 53% versus 28% (p = 0.036) and 58% versus 31% (p = 0.012). For BCG the responses were 56% and 64%. Median time to recurrence was 35 vs 19.5 months (p = 0.013) and for BCG it was 26 months. Peak plasma MMC was significantly higher following electromotive MMC than after MMC (43 vs 8 ng/ml), consistent with bladder content absorption. CONCLUSIONS: Intravesical electromotive administration increases bladder uptake of MMC, resulting in an improved response rate in cases of high risk superficial bladder cancer.     

The significance of bladder quadrant biopsies in patients with primary superficial bladder carcinoma

The prognostic significance of dysplasia (D I-III, Tis) based on bladder quadrant biopsies was established in 216 patients with primary urothelial carcinoma of the bladder (stage pTaGI-pTGIII). Collectively within the study, 51 of the 216 patients biopsied (24%) were found with abnormal urothelium. Twelve (6%) have coexistent Tis, and 30 (18%) were found with dysplastic changes D I-III. Further concerns included the incidence of dysplastic changes associated with tumor invasion, tumor dedifferentiation, and the presence of primary multifocal disease. The collective recurrence rate was 43%. However, with inclusion of quadrant biopsies, the predictability of positive biopsy results increased to 63% and the negative rate decreased to 37%.     

Fluid intake and the risk of tumor recurrence in patients with superficial bladder cancer

PURPOSE: High fluid intake has been associated with a decreased risk of bladder cancer development in men. We evaluated whether higher fluid intake can impact tumor recurrence rates in patients with superficial bladder cancer. MATERIALS AND METHODS: We conducted a prospective single institution analysis of fluid intake in 267 consecutive patients with superficial bladder cancer undergoing routine bladder cancer surveillance between January 1998 and December 2001. Fluid intake questionnaires, urine cytology and physical examination were routinely performed at each surveillance cystoscopy. Cytological and histological recurrences were recorded. All patients had a minimum followup of 2 years. RESULTS: No relationship between fluid intake and tumor recurrence was demonstrated. Average daily fluid intake was 2,654 ml daily, which was well within the highest protective level (more than 2,531 ml) previously reported. However, multivariate analysis failed to show a protective effect against recurrence at any level of fluid intake. Increasing age correlated with decreased fluid intake (Pearson's correlation coefficient -0.19, p = 0.0015), but did not increase the risk of recurrence (p = 0.59). Single fluid intake data correlated with the average of additional fluid intakes (median 5 per patient) in the same patient (Pearson's correlation coefficient, 0.45, p < 0.0001). Of the study population 123 patients (46%) experienced 1 or more tumor recurrences (range 0 to 11) within a median followup of 2.6 years. CONCLUSIONS: Our prospective study of fluid intake in patients with superficial bladder cancer at risk for recurrence did not find any association between daily fluid intake levels and tumor recurrence.     

Value of random mucosal biopsies in the management of superficial bladder cancer.

115 newly diagnosed patients with Ta-T1, G1-G2 superficial transitional cell carcinoma of the bladder underwent four quadrant biopsies of normal-looking bladder mucosa, in addition to the endoscopic treatment of the primary tumour or tumours. In 88 (77%) patients all the biopsies were normal; in the other 27 (23%) at least one biopsy revealed dysplasia or carcinoma in situ or G1-G2 carcinoma. 88 patients presented with a single tumour, of which 14 (16%) had abnormal biopsies compared to 13 (48%) of the 27 presenting with multiple tumours. The difference between the 2 groups was statistically significant (p < 0.01). The incidence of freedom from new tumours at 5 years was 68% in patients with normal biopsies compared to 33% in patients with abnormal biopsies (p = 0.002). In patients presenting with multiple tumours and in those with single tumours and abnormal biopsies, the incidence of freedom from new tumours was significantly lower than in those presenting with single tumours and normal mucosal biopsies (p = 0.002). The study shows that the exercise of performing random mucosal biopsies is particularly useful in patients presenting with single tumours, in order to identify those who are more likely to develop new tumours over the longer term. Such patients could be offered early prophylactic intravesical chemotherapy. The study did not substantiate tumour implantation as a factor for new tumour development in superficial bladder cancer.     

Prognostic significance of ABH antigenicity of mucosal biopsies in superficial bladder cancer

ABH antigenicity of mucosal biopsies was studied in 36 patients with superficial bladder cancer. Those with mucosal biopsies positive for antigen had a recurrence rate of 0.33 recurrences per year, compared to 1.97 in those negative for antigen. This difference was highly significant on statistical analysis. ABH antigenicity of mucosal biopsies proved to be a better predictor of recurrent disease than other prognostic indexes, such as number, size, histological grade and ABH antigenicity of primary tumors, as well as histological status of the mucosal biopsies.     

Continuous intravesical instillation of epirubicin immediately after transurethral resection of superficial bladder cancer: a prospective controlled study

Between November 1994 and July 1996, 45 patients with superficial bladder tumor were assigned to two groups before transurethral resection of bladder tumor. Twenty-one of the 45 patients were instilled with 20 mg epirubicin before endoscopic resection then continuously irrigated with 40 micrograms/ml epirubicin solution for 20 hours immediately after surgery; 24 of the 45 patients received continuous irrigation with saline in the same manner. The patients were assessed by cystoscopy and urinary cytology every 3 months during the first 2 years and every 6 months thereafter. One year recurrence-free rates in the treated and control groups were 56% and 32%, respectively. The recurrence-free period tended to be longer in the treated group than in the control group, although the difference was not significant (p = 0.17). One year recurrence-free rates in the treated and control groups for the patients with solitary tumor were 88% and 48%, respectively, the difference being marginally significant (p = 0.06). These results suggested that continuous bladder irrigation with epirubicin was effective for patients with a single tumor. Therefore, the long-term prophylactic therapy for a single tumor was an overtreatment. Prophylactic intravesical chemotherapy for superficial bladder cancer was proposed to be stratified by the number of tumors, single or multiple.     

Prophylactic intravesical instillation therapy in patients with superficial bladder cancer--results of a randomized prospective study]

A randomized prospective study was conducted for the purpose of investigating the efficacy of intravesical chemoprophylaxis of superficial bladder cancers. Eligible patients were randomized into three groups: 1) adriamycin (ADM) group; intravesical instillation with 50 mg of ADM dissolved in 100 ml physiological saline, 2) mitomycin C (MMC) group; intravesical instillation with 30 mg of MMC dissolved in 100 ml of physiological saline, 3) control group; transurethral resection or transurethral coagulation only. The characteristic features of our protocol consisted of frequent (six times) instillations of the drugs within two weeks after transurethral resection, followed by instillations on two consecutive days at four-week intervals for two years. Furthermore, large quantities (100 ml) of instillation fluid containing relatively low concentrations of the drugs (500 micrograms/ml for ADM or 300 micrograms/ml for MMC) were employed. One hundred and forty-four patients have been submitted to the study; 110 patients were fully evaluable for recurrence and 34 patients were eliminated as non-evaluable patients. The cumulative five-year non-recurrence rates of the patients with multiple tumors were 32% in the MMC group, 25% in the ADM group and 7% in the control group. The cumulative non-recurrence rates of the ADM and MMC groups were significantly higher than that of the control group. It is considered that this instillation therapy with ADM and MMC is useful for preventing the recurrence of superficial bladder cancers.     

Adjuvant intravesical mitoxantrone versus recombinant interferon-alpha after transurethral resection of superficial bladder cancer: a randomized prospective study

OBJECTIVE: To determine the efficacy and safety of two different doses of intravesical mitoxantrone and of recombinant interferon-alpha (IFNalpha-2b), instilled after transurethral resection (TUR) of superficial transitional cell carcinoma (TCC) of the bladder. MATERIAL AND METHODS: 208 patients (mean age 62.05 years) with primary or recurrent superficial (TaG1, T1G1, T1G2) bladder cancer were randomly allocated into four groups, after TUR of all visible tumors. Group A (45 patients) received no further therapy; group B (56 patients) received 10 mg of mitoxantrone (6 weekly and 20 fortnightly instillations), group C (54 patients) 20 mg of mitoxantrone (3 fortnightly and 10 monthly instillations) and group D (53 patients) received 100 MU of IFNalpha-2b (8 weekly, 8 fortnightly and 6 monthly instillations). RESULTS: During the follow-up (mean 21.09 months), 29 (64.44%) patients in group A had recurrence, compared with 19 (33.92%) in group B, 17 (31.48%) in group C and 15 (28.3%) patients in group D (p < 0.005). Furthermore, the differences in simple recurrence rates were statistically more significant (p < 0.05), when group A was compared with the three other groups in the terms of T1G2, recurrent and multiple neoplasms. Twenty-nine patients (10, 7, 8, and 4 in groups A-D) experienced tumor progression, and the differences between the four groups were not statistically significant (p > 0.05). The mean recurrence time was 9.03 months in group A, 13.74 in group B, 14.24 in group C and 17.4 months in group D (p < 0.001), and the recurrence rate per 100 patient-months was 4.39, 1.57, 1.48 and 1.06, respectively (p < 0.05). Toxicity (grade 1-3) was recorded in 23.21% in group B, in 31.48% in group C and in 9.43% in group D (p < 0.01). CONCLUSION: The two doses of mitoxantrone resulted in similar efficacy for the prevention of superficial bladder cancer recurrences, with the dose of 10 mg of mitoxantrone being related to fewer side effects. In comparison with mitoxantrone, the adjuvant intravesical immunotherapy with 100 MU of IFNalpha-2b showed a better combination of efficacy and safety.     

Multiple biopsies of normal‐looking urothelium in patients with superficial bladder cancer: Are they necessary?

BACKGROUND: The objective of the study presented here was to assess the usefulness and indications of multiple biopsies of normal-appearing urothelium in patients with superficial bladder cancer. METHODS: Between December 1996 and December 2002, multiple biopsies of normal-appearing bladder mucosa were performed in 100 patients with superficial bladder transitional cell carcinoma. Biopsy specimens were taken from seven different sites in females and nine different sites in males. RESULTS: In eight of 100 patients, bladder cancers were detected in the biopsy specimens. Three cases were Ta and five were Tis. All of the five patients with carcinoma in situ (CIS) in their biopsy specimens had multiple papillary broad-base tumors and positive urinary cytology. The detection ratio of CIS in patients with these findings was 17.9% (5/28). No concomitant CIS was detected in the 72 patients who had a solitary tumor, pedunculated tumor(s), or negative urinary cytology. CONCLUSION: Multiple mucosal biopsies of normal-appearing urothelium are not necessary for all patients with superficial bladder cancer. They are, however, necessary for patients with multiple papillary broad-base tumors and positive urinary cytology.     

Intravesical instillation of epirubicin in the prophylactic treatment of recurrent superficial bladder cancer

A retrospective study was performed to determine the efficacy of intravesical instillation of epirubicin in the prophylactic treatment for recurrent superficial bladder cancer when compared with no treatment controls. Seventeen patients with recurrent superficial bladder cancer received epirubicin (30 mg/40 ml in normal saline) seventeen times after transurethral resection (TUR). Historical controls consist of sixteen patients with recurrent superficial bladder cancer who received no adjuvant treatment after TUR. In the epirubicin group, 1-, 2- and 3-year recurrence free rates were 64.7%, 41.2% and 5.9%, respectively. In controls all of them recurred and 1- and 2-year recurrence free rates were 17.6% and 0%, respectively. The recurrence-free rate was significantly higher in the epirubicin group than in the controls (p < 0.05). We investigated whether intravesical instillation of epirubicin prolonged recurrence-free intervals when compared with recurrence-free intervals without adjuvant treatment after TUR in each patient. The 1- and 2-year recurrence free rates after initial TUR were 25% and 12.5%, respectively, and those with epirubicin treatment after TUR were 62.5% and 37.5%, respectively. Recurrence-free intervals were significantly prolonged by intravesical instillation of epirubicin as compared with those without adjuvant treatment in each patient. This study demonstrated the efficacy of intravesical instillation of epirubicin in the prophylactic treatment for superficial recurrent bladder cancer.     

Population study of genetic polymorphisms and superficial bladder cancer risk in Han-Chinese smokers in Shanghai

Background  

We investigated the association between the polymorphisms of DNA repair genes, metabolic enzyme genes, and superficial bladder cancer to better understand the role of gene polymorphisms in bladder carcinogenesis for the Han-Chinese population in Shanghai.     

The role of photodynamic therapy in the treatment of recurrent superficial bladder cancer

Photodynamic therapy is an exciting area of research for the treatment of superficial bladder cancer. Significant responses have been seen in patients resistant to standard intravesical treatments. New areas of research are focused on the development of new sensitizers and light distribution methods with less dermal and bladder toxicity.     

浅表性膀胱肿瘤对化疗药物的敏感性研究

目的:探讨敏感化疗药物预防浅表性膀胱癌术后复发的作用。方法:对30例表浅性膀胱癌体外原代细胞培养,用表阿霉素、羟基喜树碱、吡柔比星、丝裂霉素和盐酸米托蒽醌进行MTT法药物敏感实验(敏感实验组),用最敏感药物行膀胱灌注;同期选择30例患者用吡柔比星灌注作为对照(对照组)。结果:敏感实验组17例对吡柔比星最敏感,6例对盐酸米托蒽醌最敏感,3例对丝裂霉素最敏感,1例对羟基喜树碱最敏感,1例对表阿霉素最敏感,2例对5种化疗药物都不敏感。28例患者分别选择最敏感药物灌注后随访2年,2例复发(7.1%)。对照组吡柔比星灌注后随访2年,有8例复发(26.7%)。两组比较差异有统计学意义(P<0.05)。结论:5种化疗药物对膀胱肿瘤的体外细胞毒作用不同,其中吡柔比星的抑制作用最强。根据药物敏感实验对浅表性膀胱肿瘤行灌注治疗,对预防肿瘤复发有较好效果。