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Keywords:

  • bladder;
  • carcinoma;
  • non-muscle invasive;
  • recurrence;
  • transitional cell

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Objective:  To characterize the clinical outcome in a large contemporary series of Japanese patients with newly diagnosed Ta, T1 non-muscle invasive bladder cancer who underwent transurethral bladder tumor resection with or without intravesical chemotherapy or Bacillus Calmette-Guérin (BCG) therapy.

Methods:  We developed a database incorporating newly diagnosed non-muscle invasive bladder cancer data and outcomes from a Japanese bladder cancer registry between 1999 and 2001 and identified a study population of 3237 consecutive patients who had complete data based on pathological features. Median patient age was 69.9 years.

Results:  The 1-year, 3-year, and 5-year overall recurrence-free survival rates were 77.0%, 61.3%, and 52.8%, respectively. In multivariate analyses, the multiplicity of bladder tumors, tumor size greater than 3 cm, pathological stage T1, tumor grade G3, and the absence of adjuvant intravesical instillation were independent risk factors for tumor recurrence. Overall, 1710 patients (52.8%) received intravesical instillation; chemotherapy in 1314 (76.8%) and BCG treatment in 396 (23.2%). In patients treated with intravesical chemotherapy in which an anthracycline chemo-agent was used in 90.5% of the cases, multivariate analyses demonstrated that male gender, multiple bladder tumors, a tumor size greater than 3 cm, and pathological stage T1 were associated with tumor recurrence.

Conclusions:  The accumulation and analysis of data from the Japanese National Bladder Cancer Registry made it possible to determine the clinical characteristics, management trends, and survival rates for the period studied. Further study with a dataset created from longer follow-up data would be warranted to analyze tumor progression and disease survival.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Transurethral bladder tumor resection (TUR-BT) with or without intravesical therapy is the primary treatment modality in individuals with non-muscle invasive Ta, T1 bladder cancer. Some patients with risk factors, such as a high grade, lamina propria infiltration, multiplicity, a large tumor, and concomitant carcinoma in situ (CIS) still have a lifelong frequency of multiple recurrences and a probability of stage progression.1–4 To date, several contemporary single center series of patients treated with intravesical chemo- or immunotherapy after TUR-BT for Ta, T1 non-muscle invasive bladder cancer have been published to evaluate the prognostic indicators for tumor recurrence in Japan.5–8 These studies had relatively small patient populations and single center bias. Data compiled from multiple institutions may offer the benefit of understanding and generalizing the diagnosis, patient selection, staging, pathological evaluation, treatment, and follow-up protocol. In addition, a contemporary series of a large number of patients with Ta, T1 non-muscle invasive bladder cancer has the potential benefit of identifying bladder cancer recurrence as an outcome measure.

We developed a database incorporating comprehensive non-muscle invasive bladder cancer data and outcomes from data collected by multiple centers in Japan in retrospective fashion under the program of the Japanese National Bladder Cancer Registry. The aim of the present study was to characterize the clinical outcome in a large contemporary series of Japanese patients with newly diagnosed Ta, T1 non-muscle invasive bladder cancer who underwent TUR-BT with or without intravesical chemotherapy or Bacillus Calmette-Guérin (BCG) therapy for preventing tumor recurrence. In addition, we determined the association of established clinical and pathological characteristics with tumor recurrence.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Patient population

Data sets from multiple centers in Japan were collected in retrospective fashion under the program of the Japanese National Bladder Cancer Registry. The Registry was sponsored by the Japanese Urological Association. The registration included the background of newly diagnosed bladder cancer patients, their clinical and pathological characteristics, and their 3-year clinical outcome after the initial diagnosis. After combining the data sets, reports were generated for each variable to identify data inconsistencies and other data integrity problems. Ultimately we developed a database incorporating newly diagnosed non-muscle invasive bladder cancer data and outcomes between 1999 and 2001.

A total of 4036 patients with newly diagnosed non-muscle invasive bladder cancer (Ta, T1) N0M0 who were treated with initial TUR-BT from the database were identified. Exclusion criteria included the main histological component of non-urothelial carcinoma (n = 37), a non-curative operation was carried out (n = 703), the presence of a concomitant CIS (n = 32), or incomplete data (n = 27). We identified a study population of 3237 consecutive patients for whom there were complete data sets based on pathological features. After complete tumor resection, intravesical chemotherapy or BCG treatment was carried out in 1314 (40.6%) or in 396 (12.2%) patients, respectively for the purpose of preventing bladder tumor recurrence.

Clinical outcomes

Pathological specimens were reviewed by the genitor-urinary pathologist at each institution. Pathological staging and grading were classified according to the 2nd and 3rd edition of the General Rule for Clinical and Pathological Studies on Bladder Cancer.9,10 In the study we combined the pT1a and pT1b according to the 2nd edition and treated them as pT1. Recurrence was defined as a new tumor appearing in the bladder after initial clearance. Tumor progression was not analyzed in the present study because of the shorter follow-up period of our study. The time until tumor recurrence was calculated as the time from TUR-BT to the date of the first documented bladder tumor recurrence. Patients who had not experienced bladder tumor recurrence were censored at the last follow-up. Patients who died before bladder cancer recurrence were censored at the time of death.

Statistical analysis

Bladder tumor recurrence-free survival curves were constructed using the Kaplan–Meier method, and were compared with the log-lank test. Cox proportional hazards regression analysis was used to assess the prognostic indicators for recurrence. A P-value less than 0.05 was considered to indicate statistical significance. These analyses were carried out with the STATA version 7.0 statistical software package (Stata Corporation, College Station, TX, USA).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Patient characteristics of overall patient population

Of the 3237 patients (Table 1), 80.3% were men with a median age of 69.9 years (mean; 68.3, range, 18–103). Multiple tumors were found in 1312 cases (40.5%) and a tumor size greater than 3 cm was observed in 374 (11.6%). Disease was grade 1 in 24.2%, 2 in 57.2%, and 3 in 18.7%. Pathological tumor stage was Ta in 51% and T1 in 49%. There were 608 TaG1, 919 TaG2, 124 TaG3, 174 T1G1, 931 T1G2, and 481 T1G3 cases, respectively. Tumor grade was significantly associated with pathological stage (P < 0.001). A total of 1710 patients (52.8%) received intravesical instillation, consisting of chemotherapy in 1314 and BCG treatment in 396.

Table 1.  Clinicopathological characteristic in all patients (n = 3237)
 No. patients (%)
  1. BCG, Bacillus Calmette-Guérin.

Age (years) 
 ≤701660 (51.3)
 >701577 (48.7)
Gender 
 Male2600 (80.3)
 Female637 (19.7)
Papillary type 
 Yes2938 (90.8)
 No212 (6.6)
 Unknown87 (2.7)
Tumor stalk 
 Yes2251 (69.5)
 No785 (24.3)
 Unknown201 (6.2)
Multiplicity 
 Yes1312 (40.5)
 No1810 (55.9)
 Undetected33 (1.0)
 Unknown82 (2.5)
Tumor size 
 <1 cm1013 (31.3)
 1–3 cm1681 (51.3)
 >3 cm374 (11.6)
 Uncountable45 (1.4)
 Unknown124 (3.8)
Pathological T category 
 pTa1651 (51.0)
 pT11586 (49.0)
Grade 
 G1782 (24.2)
 G21850 (57.2)
 G3605 (18.7)
Intravesical treatment 
 Chemotherapy1314 (40.6)
 BCG396 (12.2)
 No treatment1527 (47.2)

Tumor recurrence in overall patient population

The 1-year, 3-year, and 5-year overall recurrence-free survival rates were calculated to be 77.0%, 61.3%, and 52.8%, respectively. Kaplan–Meier analysis (Table 2) and univariate Cox proportional hazards regression analysis (Table 3) revealed the presence or absence of tumor stalk, tumor multiplicity, tumor size, pathological stage, tumor grade, and with or without adjuvant intravesical therapy to be significant predictors of tumor recurrence. According to the intravesical instillation, the 1- and 3-year recurrence-free survival rates were 73.1% and 56.2%, respectively, in patients without any adjuvant therapy, compared with 80.3% and 64.2% in patients with intravesical chemotherapy, and 81.0% and 70.3% in patients with intravesical BCG therapy (Fig. 1). In multivariate analysis (Table 3), multiple bladder tumors, a tumor size greater than 3 cm, pathological stage T1, tumor grade G3, and the absence of adjuvant intravesical instillation were independent risk factors for tumor recurrence. Recurrence risk was 1.7 times higher for multiple tumors, and 1.5 times higher for tumors greater than 3 cm compared with those equal to or smaller than 3 cm. Intravesical instillations were a protective factor of tumor recurrence since the risk was lower than 1. The risk of recurrence was 0.65 and 0.4 times lower for patients treated with intravesical chemotherapy and BCG instillation, respectively. Patients treated with BCG instillation had significantly less likelihood of papillary type, tumor stalk, solitary, and small size tumor, but greater likelihood of a higher stage and higher grade tumor than those with intravesical chemotherapy or without adjuvant instillation (Table 4). Patients treated with intravesical chemotherapy had significantly less likelihood of a solitary, small size tumor, but greater likelihood of a higher pathological stage and higher grade tumor than those without adjuvant instillation.

Table 2.  The 1-year and 3-year recurrence-free survival rates according to clinicopathological characteristics in all patients
  % 1-year (mean ± SE)% 3-year (mean ± SE)P-value
  1. BCG, Bacillus Calmette-Guérin.

Age   0.146
≤70 years76.4 ± 0.0162.8 ± 0.01 
>70 years77.7 ± 0.0159.4 ± 0.01 
Gender   0.747
Male77.3 ± 0.0161.0 ± 0.01 
Female76.0 ± 0.0262.3 ± 0.02 
Papillary type   0.639
Yes77.0 ± 0.0161.4 ± 0.01 
No77.6 ± 0.0360.3 ± 0.03 
Tumor stalk   0.009
Yes78.2 ± 0.0162.8 ± 0.01 
No74.3 ± 0.0157.8 ± 0.02 
Multiplicity   <0.001
No82.7 ± 0.0166.3 ± 0.01 
Yes68.8 ± 0.0154.0 ± 0.02 
Size   <0.001
≤3 cm78.7 ± 0.0162.8 ± 0.01 
>3 cm64.2 ± 0.0349.8 ± 0.03 
Pathological T category   <0.001
pTa81.4 ± 0.0165.6 ± 0.01 
pT172.5 ± 0.0156.8 ± 0.01 
Grade   <0.001
G1/278.8 ± 0.0162.7 ± 0.01 
G369.6 ± 0.0255.2 ± 0.02 
Intravesical instillation   <0.001
No Tx73.1 ± 0.0156.2 ± 0.01 
chemoTx80.3 ± 0.0164.2 ± 0.01 
BCG81.0 ± 0.0270.3 ± 0.02 
Table 3.  Univariate and multivariate Cox regression analysis for tumor recurrence in all patients
  UnivariateMultivariate
P-valueHazards ratio95% CIP-value
  1. BCG, Bacillus Calmette-Guérin.

Age 0.159   
≤70 years    
>70 years    
Gender 0.764   
Male    
Female    
Papillary type 0.706   
Yes    
No    
Tumor stalk 0.011   
Yes    
No    
Multiplicity <0.001  <0.001
No 1  
Yes 1.691.50–1.92 
Size <0.001  <0.001
≤3 cm 1  
>3 cm 1.521.28–1.80 
Pathological T category <0.001  <0.001
Ta 1  
T1 1.321.17–1.50 
Grade <0.001   
G1/2 1 0.002
G3 1.281.10–1.50 
Intravesical instillation <0.001  <0.001
no Tx 1  
chemoTx 0.650.57–0.74<0.001
BCG 0.410.33–0.51<0.001
image

Figure 1. Kaplan–Meier curves for tumor recurrence in the overall patient population (n = 3237) comparing no instillation (n = 1527), Bacillus Calmette-Guérin (BCG) instillation (n = 396), and chemotherapeutic instillation (n = 1314).

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Table 4.  Clinicopathological characteristics in patients treated with intravesical chemotherapy (IVI), Bacillus Calmette-Guérin (BCG) instillation, and no adjuvant therapy
PatientsIVI chemotherapy No. patients (%)BCG instillation No. patients (%)No IVI treatment No. patients (%)P-value
13143961527
Age   0.853
 ≤70671 (51.1)199 (50.3)790 (51.7) 
 >70 years643 (48.9)197 (49.8)737 (48.3) 
Gender   0.287
 Male1038 (79.0)323 (81.6)1239 (81.1) 
 Female276 (21.0)73 (18.4)288 (18.9) 
Papillary type   <0.001
 Yes1224 (93.2)325 (82.1)1389 (91.0) 
 No69 (5.3)57 (14.4)86 (5.6) 
 Unknown21 (1.6)14 (3.5)52 (3.4) 
Tumor stalk   <0.001
 Yes925 (70.4)225 (56.8)1101 (72.1) 
 No316 (24.1)143 (36.1)326 (21.4) 
 Unknown73 (5.6)28 (7.1)100 (6.55) 
Multiplicity   <0.001
 Yes588 (44.8)242 (61.1)482 (31.6) 
 No690 (52.5)132 (33.3)988 (64.7) 
 Undetected14 (1.1)10 (2.5)9 (0.6) 
 Unknown22 (1.7)12 (3.0)48 (3.1) 
Tumor size   <0.001
 <1 cm369 (28.1)101 (25.5)543 (35.6) 
 1–3 cm716 (54.5)197 (50.0)768 (50.3) 
 >3 cm180 (13.7)68 (17.2)126 (8.25) 
 Uncountable15 (1.1)13 (3.3)17 (1.1) 
 unknown34 (2.6)17 (4.3)73 (4.8) 
Pathological T category   <0.001
 pTa672 (51.1)120 (30.3)859 (56.3) 
 pT1642 (48.9)276 (69.7)668 (43.8) 
Grade   <0.001
 G1287 (21.8)37 (9.3)458 (30.0) 
 G2817 (62.2)178 (45.0)855 (56.0) 
 G3210 (16.0)181 (45.7)214 (14.0) 

In a subgroup of patients with pT1G3, 164, 154, and 163 patients were treated with intravesical chemotherapy, BCG instillation, and without any adjuvant instillation, respectively. The Kaplan–Meier curve indicated that the differences among the groups were significant (P = 0.039 for intravesical chemotherapy vs BCG instillation, P = 0.007 for intravesical chemotherapy vs no adjuvant therapy, and P < 0.001 for BCG instillation vs no adjuvant therapy) (Fig. 2).

image

Figure 2. Kaplan–Meier curve for tumor recurrence in patients with T1G3 (n = 481) comparing no instillation (n = 163), Bacillus Calmette-Guérin (BCG) instillation (n = 154), and intravesical chemotherapy (n = 164).

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Tumor recurrence in patients treated with intravesical chemotherapy and BCG instillation

We next evaluated the prognostic indicators for tumor recurrence, particularly in patients treated with intravesical chemotherapy, which accounted for 76.8% of the intravesical adjuvant therapy. Intravesical chemotherapy consisted of adriamycin (doxorubicin) in 41, epirubicin in 468, pirarubicin in 680, mitomycin C (MMC) in 120, peplomycin in seven, and tiotepa in one. Overall, an anthracycline chemo-agent was used in 90.5% of the cases of intravesical chemotherapy. When patients treated with an anthracycline chemo-agent were compared with those receiving MMC treatment, Kaplan–Meier curve analysis revealed that the differences among the groups were not significant (Fig. 3).

image

Figure 3. Kaplan–Meier curve for tumor recurrence in patients treated with adjuvant intravesical chemotherapy comparing an anthracycline chemo-agent and mitomycin C treatment.

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Kaplan–Meier analysis (Table 5) and univariate Cox proportional hazards regression analysis (Table 6) revealed gender, presence or absence of tumor stalk, tumor multiplicity, tumor size, pathological stage, and tumor grade were significant predictors for tumor recurrence. In multivariate analysis, male gender, multiple bladder tumors, a tumor size greater than 3 cm, and pathological stage T1 were independent risk factors for tumor recurrence. Female patients had a recurrence risk 0.7 times lower than male patients. Recurrence risk was 1.7 times higher for multiple tumors, and 1.3 times higher for tumors greater than 3 cm compared with those equal to or smaller than 3 cm. Patients with T1 tumor had a recurrence risk 1.3 times higher than those with Ta.

Table 5.  The 1-year and 3-year recurrence-free survival rates according to clinicopathological characteristics in patients treated with intravesical chemotherapy
  % 1-Year (mean ± SE)% 3-Year (mean ± SE)P-value
Age   0.695
≤70 years79.2 ± 0.0264.7 ± 0.02 
>70 years81.6 ± 0.0263.4 ± 0.02 
Gender   0.025
Male79.2 ± 0.0162.7 ± 0.02 
Female84.6 ± 0.0269.7 ± 0.03 
Papillary type   0.209
Yes80.7 ± 0.0164.7 ± 0.02 
No74.5 ± 0.0557.6 ± 0.06 
Tumor stalk   0.016
Yes82.0 ± 0.0166.4 ± 0.02 
No76.2 ± 0.0258.9 ± 0.03 
Multiplicity   <0.001
No85.6 ± 0.0169.6 ± 0.02 
Yes73.8 ± 0.0257.5 ± 0.02 
Size   0.004
≤3 cm81.8 ± 0.0165.6 ± 0.02 
>3 cm70.7 ± 0.0455.8 ± 0.04 
Pathological T category   0.002
pTa84.0 ± 0.0268.1 ± 0.02 
pT176.4 ± 0.0260.1 ± 0.02 
Grade   0.001
G1/282.1 ± 0.0166.1 ± 0.02 
G371.1 ± 0.0354.5 ± 0.04 
Table 6.  Univariate and multivariate Cox regression analysis for tumor recurrence in patients treated with intravesical chemotherapy
  UnivariateMultivariate
P-valueHazard ratio95% CIP-value
  1. CI, confidence interval.

Age 0.660   
≤70 years    
>70 years    
Gender 0.030  0.008
Male 1  
Female 0.710.55–0.91 
Papillary type 0.706   
Yes    
No    
Tumor stalk 0.023   
Yes    
No    
Multiplicity <0.001  <0.001
No 1  
Yes 1.671.37–2.03 
Size 0.005  0.028
≤3 cm 1  
>3 cm 1.341.03–1.73 
Pathological T category 0.003  0.004
Ta 1  
T1 1.331.09–1.62 
Grade 0.002   
G1/2    
G3    

In patients treated with BCG instillation, no clinicopathological factors were associated with tumor recurrence in uni- and multivariate analysis (data not shown).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

In the present study, we characterized the clinical outcome of newly diagnosed non-muscle invasive bladder cancer in a large contemporary series of patients from a Japanese bladder cancer registry and determined the predictors for tumor recurrence. Overall, bladder tumor multiplicity, a tumor size greater than 3 cm, pathological stage T1, tumor grade G3, and the absence of adjuvant intravesical instillation were found to independently increase the risk of tumor recurrence. Numerous publications have reported the same prognostic indicators as ours for tumor recurrence in non-muscle invasive bladder cancer.1–3 Recently, a combined analysis was carried out using data from 2596 non-muscle invasive bladder cancer patients collected from seven European Organization for Research and Treatment of Cancer (EORTC) trials.4 In the analysis, six clinicopathological risk factors, namely multiplicity, tumor size, prior recurrence rate, pathological stage, concomitant CIS, and tumor grade were determined. Four of the six predictors for tumor recurrence in the present study were shared with their indicators; however, the big difference between their study and ours is that their population has included both primary and recurrent cases. A more homogenous population of patients who initially diagnosed non-muscle invasive bladder tumor was evaluated in our current study.

Overall, 12.2% received BCG instillation in our study. In the subgroup of patients treated with BCG instillation, no clinicopathological factors were associated with tumor recurrence. Kaplan–Meier analysis demonstrated that the recurrence-free survival in the BCG instillation group was significantly higher than that in the intravesical chemotherapy group especially in pT1G3 patients (P = 0.039), which was confirmed by others.11 Furthermore, BCG instillation was significantly selected in patients with multiple, larger, and higher pathological stage tumors, compared with intravesical chemotherapy. These results suggested that BCG instillation was carried out for the prevention of recurrence in a relatively smaller percentage of high risk patients than would have been expected from the current clinical situation.12,13 One reason for the difference in the percentage of BCG instillations carried out between 1999–2001 and the present is that the current clinical management for non-muscle invasive bladder cancer is highly affected by the guidelines.14,15

In our subgroup consisting of the 1314 patients treated with adjuvant intravesical chemotherapy, multivariate analyses demonstrated that male gender, bladder tumor multiplicity, a tumor size greater than 3 cm, and pathological stage T1 were independent risk factors for tumor recurrence. Only about 10% of the patients were treated with MMC intravesical chemotherapy. Au et al. reported that intravesical chemotherapy using a modified 40 mg dose of MMC accompanied by a decrease in urine volume during the procedure and urine alkalinization significantly improved the therapeutic benefit of traditional MMC treatment for the prevention of tumor recurrence.16 Meanwhile, Huncharek et al. have showed that maintenance intravesical chemotherapy reduced tumor recurrence, when compared with a single course of induction chemotherapy.17 Further study is warranted to prove the therapeutic benefit with these modalities, especially in Japanese patients who have these risk factors for recurrence. In our multivariate analyses, gender is an independent predictor for tumor recurrence in patients treated with adjuvant intravesical chemotherapy but not in overall patients. There has been no study to evaluate the influence of gender for tumor recurrence in a large series of bladder cancer patients treated with intravesical chemotherapy. The exact reason why female patients have better outcome for tumor recurrence than male patients has to be elucidated in a future study.

Frydenberg et al. conducted a survey of a population cancer registry that included about 700 newly diagnosed non-muscle invasive bladder cancers between 1990 and 1995 in Victoria of Australia. Logistic regression analysis revealed that tumor grade and pathological T stage were independent factors affecting the risk of recurrence. Less than 10% of the patients received adjuvant intravesical chemotherapy or immunotherapy.18 Gårdmark et al. analyzed the clinical characteristics of about 10 000 newly diagnosed cases of bladder cancer obtained from the Swedish National Bladder Cancer Register between 1997 and 2001.19 A large number of the patients, even in the high risk group, were still undertreated and they concluded that the survival rate of bladder cancer in Sweden during this period seemed to remain at the levels previously reported for the 1980s. The accumulation of data provided by a large cancer registry is of great importance to understanding the trends in the clinical characteristics of the disease and its treatment management, and to providing an opportunity for analysis of the indicators predicting prognosis.20

The present study has several limitations. First, the results were obtained from a dataset created by data only from centers participating in the bladder cancer registry. Since all of the centers in Japan do not participate in the cancer registry, the dataset does not include data for all bladder cancers in Japan. However, approximately 180 institutions participate in the cancer registry in Japan and the dataset contained data for approximately 6000 patients so we believe that the results represent an accurate reflection of the characteristics of patients with newly diagnosed bladder cancer and its clinical outcome in the period from 1999 and 2001.21 Another limitation is that the follow-up period was short. Median follow-up was 24 months and this bias might affect the understanding of true risk factors and the natural course of non-muscle invasive bladder cancer and make us unable to analyze the prediction of tumor progression and survival. In fact recurrence-free survival in our study was somewhat better than that reported in another large series.3 Several papers pointed out the importance of the use of data from long-term follow-up of non-muscle invasive bladder cancer.22,23 Further study would be warranted to accumulate long-term follow-up data in the bladder cancer registry.

In conclusion, patients with multiple tumors, a tumor size greater than 3 cm, tumor grade G3, or pathological T1 tumors were at greater risk, whereas those treated with intravesical BCG instillations had a decreased risk of tumor recurrence in the overall patient population. In patients treated with intravesical chemotherapy, male gender, bladder tumor multiplicity, a tumor size greater than 3 cm, and pathological stage T1 were independent risk factors for tumor recurrence. Further study of datasets created from longer follow-up data is warranted in order to analyze tumor progression and disease survival.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References
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    Lee C, Park MS. Prophylactic treatment of superficial bladder tumor. Int. J. Urol. 1998; 5: 51120.
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    Hall MC, Chang SS, Dalbagni G et al. Guideline for the management of nonmuscle invasive bladder cancer (stages Ta, T1, and Tis): 2007 update. J. Urol. 2007; 178: 231430.
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    Oosterlinck W, Lobel B, Jakse G, Malmstrom PU, Stockle M, Sternberg C. Guidelines on bladder cancer. Eur. Urol. 2002; 41: 10512.
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    Au JL, Badalament RA, Wientjes MG et al. Methods to improve efficacy of intravesical mitomycin C: results of a randomized phase III trial. J. Natl. Cancer Inst. 2001; 93: 597604.
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    Huncharek M, Geschwind JF, Witherspoon B, McGarry R, Adcock D. Intravesical chemotherapy prophylaxis in primary superficial bladder cancer: a meta-analysis of 3703 patients from 11 randomized trials. J. Clin. Epidemiol. 2000; 53: 67680.
  • 18
    Frydenberg M, Millar JL, Toner G et al. Management of superficial bladder cancer in Victoria: 1990 and 1995. ANZ J. Surg. 2005; 75: 2704.
  • 19
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