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European Urology
Volume 53, issue 5, pages 869-1100, May 2008Bladder Cancer
Prognostic Factors in Patients with Non–Muscle-Invasive Bladder Cancer Treated with Bacillus Calmette-Guérin: Multivariate Analysis of Data from Four Randomized CUETO Trials
Jesus Fernandez-Gomez a 
, Eduardo Solsona b, Miguel Unda c, Luis Martinez-Piñeiro d, Marcelino Gonzalez e, Rafael Hernandez f, Rosario Madero g, Antonio Ojea h, Carlos Pertusa i, Jesus Rodriguez-Molina j, Jose Emilio Camacho k, Santiago Isorna l, Mariano Rabadan m, Ander Astobieta n, Manuel Montesinos o, Pedro Muntañola p, Anabel Gimeno q, Miguel Blas r, Jose Antonio Martinez-Piñeiro d, Club Urológico Español de Tratamiento Oncológico (CUETO).
Accepted 3 October 2007, Published online 15 October 2007, pages 992 - 1002
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Abstract
Objectives
To evaluate the prognostic factors of recurrence and progression after intravesical adjuvant bacillus Calmette-Guérin (BCG) immunotherapy in patients with non–muscle-invasive bladder tumors.
Methods
From February 1990 to May 1999, the Spanish Club Urológico Español de Tratamiento Oncológico (CUETO) group has performed four randomized phase 3 studies comparing different intravesical treatments in patients with noninvasive bladder cancer. Data from 1062 evaluable patients treated only with BCG were analyzed. Most patients received BCG once weekly for 6 consecutive weeks and a short-term BCG maintenance (once every 2 wk 6 times more). Associated tumor in situ (TIS) was found in 7.5% (n = 80) of cases. There were 22.1% (n = 235) patients with T1G3 tumors, 22.9% of whom (n = 54) were associated with TIS. Stepwise multivariate Cox regression models with stratification by study and dose were used to assess the independent effect of predictive factors and hazard ratios (HRs) were estimated from the Cox model.
Results
Multivariate analysis demonstrated that female gender (HR = 1.71) compared to male gender, recurrent tumors (HR = 1.9) compared to primary tumors, multiplicity, and presence of associated TIS (HR = 1.54) increased the risk of recurrence. Recurrent tumors (HR = 1.62) compared to primary tumors, high-grade tumors (HR = 5.64) compared to G1 tumors, T1 tumors (HR = 2.15) compared to Ta tumors, and recurrence at 3-mo cystoscopy (HR = 4.6) increased the risk of progression.
Conclusion
Significant independent predictors for recurrence were female gender, history of recurrence, multiplicity, and presence of associated TIS. Age, history of recurrence, high grade, T1 stage, and recurrence at first cystoscopy were independent predictors of progression by multivariate Cox analysis.
Keywords: Bacillus Calmette-Guérin, Bladder cancer, Disease progression, Recurrence.
Article Outline
1. Introduction
Bacille Calmette-Guérin (BCG) is currently the most effective intravesical therapy for noninvasive bladder cancer, especially in high- and intermediate-risk tumors [1], and [2]. The optimal scheme and dose of BCG have not yet been defined but a 6-wk BCG induction course alone is suboptimal. In a recent meta-analysis of patients with non–muscle-invasive bladder cancer of all grades, Bohle et al found that BCG was superior to mitomycin C in preventing recurrences. Both the intermediate- and high-risk subgroups that received maintenance BCG for at least 1 yr or 12 administrations showed reduced recurrence rates that reached statistical significance [3]. Additionally, a meta-analysis of 24 randomized trials demonstrated that only patients receiving maintenance BCG benefited with a reduction in risk of progression [4].
Although BCG immunotherapy has markedly improved the outcome of non–muscle-invasive bladder cancer, a subgroup of patients fail to respond and are at risk of disease progression [5]. A tool to predict the response to intravesical immunotherapy would be invaluable because early cystectomy may save some non-responders to BCG therapy [6]. Unfortunately, predictive markers for recurrence and progression are lacking.
Prognostic factors in patients with non–muscle-invasive bladder cancer have been the subject of numerous publications for many years [7]. In these reports, a variety of factors predictive of the outcome of transitional cell carcinoma after BCG treatment have been put forward [5], and [8]. However, the prognostic importance of various factors is not always the same from one publication to another [9]. This may be due to differences in the choice of variables analyzed, their coding, and, in multivariate analyses, the correlation between the factors or the end point assessed [7].
Since 1990, in an attempt to achieve maximal efficacy decreasing toxicity, the Club Urológico Español de Tratamiento Oncológico (CUETO) group has carried out several randomized phase 3 studies based on intravesical BCG, with a similar maintenance schedule in all the trials and large numbers of patients. The objective of the present study was to evaluate the prognostic factors of recurrence and progression after intravesical adjuvant BCG immunotherapy in patients with non–muscle-invasive transitional cell carcinoma included in four CUETO trials. To our knowledge this is the first study analyzing prognostic factors of non–muscle-invasive bladder cancer with such a large number of patients and with such a long follow-up period in patients treated with BCG.
2. Patients and methods
2.1. Trial protocol
From February 1990 to May 1999, the Spanish CUETO group has carried out four randomized phase 3 studies that compared different intravesical treatments after transurethral resection (TUR) in patients with noninvasive bladder cancer. A total of 1491 cases with high- and intermediate-risk tumors were recruited in the four CUETO prospective trials [10], [11], [12], and [13]:
•CUETO 90008 (n = 499). Compared standard dose of BCG (81 mg) to low-dose BCG (27 mg) in high- and intermediate-risk tumors.
•CUETO 93009 (n = 407). Compared a sequential combination of mitomycin and BCG to BCG in multiple or recurrent Ta tumors, primary or recurrent T1 tumors, and carcinoma in situ (CIS).
•CUETO 95011 (n = 430). Compared low-dose BCG (13.5 and 27 mg) to mitomycin in TaG2 and T1G1–2 bladder tumors.
•CUETO 95012 (n = 155). It was a prolongation of 90008 in high-risk tumors (TIS, T1G3, Ta-1 + TIS) with a completely different cohort of patients, comparing a standard dose of BCG to low-dose BCG (27 mg).
In all the studies, visible tumors underwent complete transurethral bladder resection and were staged according to the 1987 TNM classification and the World Health Organization 1973 grading system. Within 7–10 d of pathologic confirmation patients were randomly assigned to receive the treatments using the method of centralized randomization stratified by participating center (variable size blocks). Finally, data of 1062 evaluable patients (patients treated with at least one BCG instillation and enough information available) were analyzed. Patients treated with mitomycin (CUETO 95011) or a combination of mitomycin and BCG (CUETO 93009) were not included.
Instillation 1 was given 7–14 d after transurethral bladder resection with 81, 27, or 13.5 mg BCG, Connaught strain, according to randomization and trial, diluted in 50 ml saline, which was retained at least 1 h. The instillation was repeated once weekly for 6 consecutive weeks and thereafter once every 2 weeks, six times more. Every patient would receive a total of 12 instillations within 5–6 mo after surgical intervention.
Patients were evaluated every 3 mo during the first 2 yr and thereafter every 6 mo. The evaluation involved cytology, cystoscopy, and biopsies of suspicious lesions. Excretory urography was performed at bladder tumor diagnosis to rule out a synchronous upper urinary tract tumor and repeated every year during follow-up. If non–muscle-invasive recurrence or persistence of TIS was detected at the endoscopic and cytologic evaluation, which was done after the induction cycle of six instillations, the patient was not withdrawn from the study and received the second cycle of six fortnightly instillations to complete the schedule. However, patients were withdrawn from the study at the first relapse occurring after the completion of treatment or in those with TIS when positive cytology persisted or reappeared after 12 instillations. Subsequent treatment was at the discretion of the researcher, but patients were followed until the end of the study or death. Ethics approval was received from the Committee of Clinical Trials at each participating center.
2.2. Statistical analysis
Variables included in the study were age, primary versus recurrent tumor, number and size of the tumors, doses of BCG and number of instillations, T category, grade, presence of associated CIS, and recurrence at first cystoscopy (3 mo). Quantitative data are shown as the mean ± standard deviation or median and range with qualitative data shown as percentages. The end points were:
•Time to first recurrence (disease-free interval): time from randomization to the date of the first bladder recurrence. The date of diagnosis of the first relapse, even in patients who did not complete the full course of 12 instillations, was taken as the date of first recurrence.
•Time to progression to muscle-invasive disease: time from randomization to the date of first increase to stage T2 or higher disease in the bladder.
The distribution of disease-free survival and time to progression were estimated by the Kaplan-Meier method. Univariate and stepwise multivariate Cox regression models with stratification by study and dose were used to assess the independent effect of several variables and hazard ratios were estimated from the Cox model. Although in the future we will use adjusted hazard ratios (HRs) by factor to calculate recurrence and progression scores in patients treated with BCG, the final goal of the multivariate analysis in the present study was to simply identify potential prognostic factors. Categorical variables with k categories (k > 2) were turned into k − 1 indicator variables. The HRs for indicator variables expressed the magnitude of the increased risk in relation to the reference category. The p values were based on overall test with (k − 1) degrees of freedom. The 2-sided test considered p < 0.05 statistically significant. All statistical analyses were performed with SAS version 9.
3. Results
Among the 1062 patients were 951 (89.5%) men and 111 women (10.5%). The median age was of 66 yr (25th percentile: 58; 75th percentile: 72). Table 1 shows patient and tumor characteristics. From the 1062 patients, 706 (66.5%) had primary tumors, including 167 (15.7%) grade 1, 629 (59.2%) grade 2, and 266 (25%) grade 3 tumors. CIS associated with papillary tumors was found in 80 cases (7.5%).
Table 1 Patient and tumor characteristics
| No. (%) | |
|---|---|
| Age, yr | |
| ≤60 | 331 (31.2) |
| 61–70 | 394 (37.1) |
| >70 | 337 (31.7) |
| Recurrent tumor | |
| No | 706 (66.5) |
| Yes | 356 (33.5) |
| No. of tumors | |
| 1 | 535 (50.4) |
| 2–3 | 278 (26.2) |
| 4–7 | 160 (15.1) |
| ≥8 | 89 (8.4) |
| Tumor size | |
| ≤1 cm | 283 (26.6) |
| 1–3 cm | 298 (28.1) |
| ≥3 cm | 481 (45.3) |
| Grade | |
| G1 | 167 (15.7) |
| G2 | 629 (59.2) |
| G3 | 266 (25) |
| T category | |
| Ta | 214 (20.2) |
| T1 | 848 (79.8) |
| Associated tumor in situ | |
| No | 982 (92.5) |
| Yes | 80 (7.5) |
| No. of instillations | |
| <6 | 45 (4.2) |
| 6–9 | 239 (22.5) |
| ≥10 | 778 (73.3) |
| Doses | |
| 13.5 mg | 137 (12.9) |
| 27 mg | 434 (40.9) |
| 81 mg | 491 (46.2) |
There were 22.1% patients (n = 235) with T1G3 tumors, 22.9% of which (n = 54) were associated with TIS. Multiple tumors were found in 49.6% (n = 527) and in 45.3% tumor size was ≥ 3 cm. At the end, 45 patients (4.2%) received fewer than 6 instillations, 239 (22.5%) had 6–9 instillations, and 778 (73.3%) received ≥ 10 instillations. The mean number of instillations performed in the high-risk subgroup (T1G3, associated TIS) was 10.5 ± 2.29 (range: 2–12).
The overall median duration of follow-up was 69 mo (25th percentile: 41; 75th percentile: 85). From the 1062 patients treated with BCG, 346 (32.6%) had recurrence and 142 (13.4%) had progression into muscle-invasive disease. Unfortunately, we lack complete data about the number of patients who were found to have persistent non–muscle-invasive papillary tumors or TIS after the first weekly cycle. Nevertheless, in 92 patients (8.7%) recurrence was already detected at first cystoscopy (3 mo).
3.1. Recurrence
Univariate analysis revealed that the rate of recurrence was statistically associated with female gender, older age, recurrent tumors, multiplicity, and presence of associated TIS. However, no statistical differences were found for tumor stage, grade, and tumor size (Table 2).
Table 2 Cox univariate and multivariate analysis of recurrence, stratified by study and dose
| Univariate | Multivariate | |||||||
|---|---|---|---|---|---|---|---|---|
| CI95% HR | CI95% HR | |||||||
| p | HR | Lower | Upper | p | HR | Lower | Upper | |
| Gender | 0.0001 | 0.0006 | ||||||
| Male | 1 | 1 | ||||||
| Female | 1.801 | 1.331 | 2.436 | 1.711 | 1.258 | 2.329 | ||
| Age | 0.0151 | |||||||
| ≤60 | 1 | |||||||
| 61–70 | 1.296 | 0.989 | 1.697 | |||||
| >70 | 1.502 | 1.140 | 1.980 | |||||
| Recurrent tumor | <0.0001 | <0.0001 | ||||||
| No | 1 | 1 | ||||||
| Yes | 2.049 | 1.652 | 2.541 | 1.900 | 1.526 | 2.365 | ||
| No. of tumours | <0.0001 | 0.0110 | ||||||
| 1 | 1 | 1 | ||||||
| 2–3 | 1.278 | 0.981 | 1.664 | 1.107 | 0.846 | 1.448 | ||
| 4–7 | 1.741 | 1.293 | 2.343 | 1.433 | 1.057 | 1.944 | ||
| ≥8 | 2.146 | 1.528 | 3.013 | 1.673 | 1.180 | 2.373 | ||
| Size | 0.0502 | |||||||
| ≤1 cm | 1 | |||||||
| 1–3 cm | 0.697 | 0.522 | 0.931 | |||||
| ≥3 cm | 0.842 | 0.654 | 1.084 | |||||
| Grade | 0.4532 | |||||||
| G1 | 1 | |||||||
| G2 | 1.042 | 0.762 | 1.424 | |||||
| G3 | 1.272 | 0.839 | 1.928 | |||||
| T category | 0.7787 | |||||||
| Ta | 1 | |||||||
| T1 | 1.040 | 0.793 | 1.362 | |||||
| Associated TIS | 0.0105 | 0.0239 | ||||||
| No | 1 | 1 | ||||||
| Yes | 1.628 | 1.121 | 2.364 | 1.547 | 1.059 | 2.260 | ||
The p values were referred to an overall test.HR = hazard ratios adjusted for variables; CI95% = 95% confidence interval; TIS = tumor in situ.
Multivariate analysis demonstrated that female gender (HR = 1.71) compared to male gender, recurrent tumors (HR = 1.9) compared to primary tumors, multiplicity, and presence of associated TIS (HR = 1.54) were significant unfavorable independent factors of recurrence (Table 2). Fig. 1 shows Kaplan-Meier distributions of time to first recurrence for those variables that were significant in the multivariate analysis.
01256-0/assets/gr1/gr1_584x464.jpg)
Fig. 1 Kaplan-Meier distributions of time to first recurrence for the four variables that were significant in the Cox multivariate analysis. Statistical differences (p) were calculated by univariate regression model with stratification by CUETO trial and dose of bacillus Calmette-Guérin (BCG).
3.2. Progression
Univariate analysis demonstrated that the rate of progression was statistically significant for older patients, recurrent tumors, intermediate- and high-grade tumors, presence of T1 and associated CIS, as well as with recurrence at first cystoscopy. However, no statistical differences were found for gender, multiplicity, and tumor size (Table 3).
Table 3 Cox univariate and multivariate analysis of progression, stratified by study and dose
| Univariate | Multivariate | |||||||
|---|---|---|---|---|---|---|---|---|
| CI95% HR | CI95% HR | |||||||
| p | HR | Lower | Upper | p | HR | Lower | Upper | |
| Gender | 0.98 | |||||||
| Male | 1 | |||||||
| Female | 1.007 | 0.578 | 1.757 | |||||
| Age | 0.0174 | 0.0520* | ||||||
| ≤60 | 1 | 1 | ||||||
| 61–70 | 1.743 | 1.123 | 2.706 | 1.568 | 1.004 | 2.447 | ||
| >70 | 1.863 | 1.181 | 2.940 | 1.738 | 1.098 | 2.753 | ||
| Recurrent tumor | 0.0145 | 0.0068 | ||||||
| No | 1 | 1 | ||||||
| Yes | 1.524 | 1.087 | 2.137 | 1.627 | 1.144 | 2.315 | ||
| No. of tumors | 0.3625 | |||||||
| 1 | 1 | |||||||
| 2–3 | 1.128 | 0.748 | 1.702 | |||||
| 4–7 | 1.267 | 0.782 | 2.055 | |||||
| ≥8 | 1.587 | 0.931 | 2.704 | |||||
| Size | 0.4147 | |||||||
| ≤1 cm | 1 | |||||||
| 1–3 cm | 0.746 | 0.478 | 1.166 | |||||
| ≥3 cm | 0.825 | 0.555 | 1.224 | |||||
| Grade | <.0001 | <0.0001 | ||||||
| G1 | 1 | 1 | ||||||
| G2 | 1.482 | 0.777 | 2.829 | 1.451 | 0.753 | 2.798 | ||
| G3 | 5.833 | 2.855 | 11.918 | 5.647 | 2.712 | 11.760 | ||
| T category | 0.022 | 0.0076 | ||||||
| Ta | 1 | 1 | ||||||
| T1 | 2.342 | 1.357 | 4.041 | 2.149 | 1.226 | 3.767 | ||
| Associated TIS | 0.026 | |||||||
| No | ||||||||
| Yes | 1.864 | 1.091 | 3.185 | |||||
| Recurrence at first cystoscopy | <0.0001 | <0.0001 | ||||||
| No | 1 | 1 | ||||||
| Yes | 5.220 | 3.505 | 7.780 | 4.600 | 2.994 | 7.069 | ||
The p values were referred to an overall test.HR = hazard ratios adjusted for variables; CI95% = 95% confidence interval; TIS = tumor in situ.
*
Multivariate analysis showed that recurrent tumors (HR = 1.62) compared to primary tumors, high-grade tumors (HR = 5.64) compared to G1 tumors, T1 tumors (HR = 2.15) compared to Ta tumors, and recurrence at the 3-mo cystoscopy (HR = 4.6) were significant independent predictors of muscle-invasive disease. Furthermore, we included age because differences were almost significant (p = 0.052) and the 95% confidence interval for the HRs never contained 1 (Table 3). Fig. 2 shows Kaplan-Meier distributions of time to progression for those variables that were significant in the multivariate analysis.
01256-0/assets/gr2/gr2_584x694.jpg)
Fig. 2 Kaplan-Meier distributions of time to progression for the five variables that were significant in the Cox multivariate analysis. Statistical differences (p) were calculated by univariate regression model with stratification by CUETO trial and dose of bacillus Calmette-Guérin (BCG).
4. Discussion
The identification of prognostic factors that predict recurrence and progression for patients with non–muscle-invasive bladder cancer has been undertaken by a variety of groups. In these studies, variable numbers of patients, heterogeneous follow-up times, and a mixture of drugs and therapeutic schedules have been involved [7]. However, few specific studies on prognostic factors in patients treated only with BCG have been reported.
Recently, Friedrich et al found that long-term mitomycin C treatment significantly reduced the risk of tumor compared with both short-term BCG and mitomycin C in patients with intermediate- and high-risk non–muscle-invasive bladder carcinoma [10]. However, these results should be heeded carefully because their high-risk group was limited to the least high-risk subset by excluding those with CIS or T1G3 tumors > 2 cm in size [11]. In their meta-analysis, Bohle et al [4] concluded BCG was superior to mitomycin C in preventing recurrences. Both the intermediate- and high-risk subgroups that received maintenance BCG for at least 1 yr or 12 administrations showed reduced recurrence rates that reached statistical significance. A possible limitation of the present study is that the maintenance schedule was relatively short. Most of the patients received a 6-wk induction cycle and maintenance instillations for 5–6 mo. Consequently, we believe that our findings can be generalized to patients treated with BCG maintenance for 1 yr. Nevertheless, new studies should be performed in patients treated with longer-term BCG maintenance regimens.
The minimal effective dose of BCG is not known. Different prospective studies and review articles have suggested that low doses of BCG are as effective as the standard dose, whereas the number of local and systemic side effects is decreased [12], [13], [14], [15], [16], [17], [18], and [19]. In the present study we selected a large number of cases with high and intermediate non–muscle-invasive bladder tumors from four randomized phase 3 CUETO studies that compared different intravesical treatments with BCG with a long follow-up. Some results from these studies have been previously reported. Martinez-Piñeiro et al reported that a third of a dose of intravesical BCG (27 mg) is as effective as the standard dose against progression in patients with high-risk non–muscle-invasive bladder carcinoma [12], and [20]. Furthermore, Ojea et al have found that one third of the standard dose of BCG increased the time to recurrence in patients with intermediate-risk non–muscle-invasive bladder tumors in relation to mitomycin C and very low doses of BCG (13.5 mg) [18], and [19]. Solsona et al reported a significant reduction of the odds of recurrence using a sequential combination of mitomycin and BCG compared to BCG with higher toxicity. Nevertheless, the authors did not find a significant impact of this combination with respect to progression [21].
Multivariate analysis demonstrated that tumor size was not predictive of recurrence or progression. Various reports have suggested an earlier recurrence and progression in larger tumors treated with BCG [22], and [23]. Nonetheless, cancer-specific survival has not been related to tumor size [5], and [12]. Considering gender, Saint et al demonstrated that urinary immunologic response, which has been associated with a good response to BCG, was more frequent in men than in women [24]. We found an association between gender and BCG response in multivariate analysis, in such a way that male patients showed a significantly longer time to recurrence than female patients. However, multivariate analyses did not show any significant relationship between gender and progression in our series.
Although age has been the patient characteristic most frequently associated with BCG response [5], and [8], several studies with larger cohorts have not shown any influence of age [12], [13], [25], and [26]. Our analysis showed that age was an independent predictive factor of progression. Recently, Joudi et al reported that aging appears to be associated with a decreased response to intravesical immunotherapy [27].
In the present analysis, multifocality was found to be an independent factor of recurrence after BCG treatment but not predictive of progression. Although multifocality is a classical prognostic factor for recurrence of non–muscle-invasive bladder cancer [2], its predictive value for the BCG response is controversial [5]. In the same way, the prognostic importance of a history of recurrence has not been categorically established. Martinez-Piñeiro et al reported that prior bladder cancer resection was a significant factor affecting progression in multivariate analysis [12], whereas Takashi et al [8] and Losa et al [28] found a significant association with recurrence. Although several studies have failed to show a correlation between the prior bladder cancer history and the BCG response [5], our results certainly demonstrate a decreased effectiveness of BCG in recurrent tumors.
Several studies have failed to demonstrate that stage is associated with a poor BCG response [25], and [29]. Nevertheless, our results confirmed that T1 tumors were significantly associated with progression in univariate and multivariate analysis. Zlotta et al have shown that high tumor stage was associated with a poor BCG response in relation to recurrence [30]. Additionally, some reports have demonstrated that BCG is less effective in T1 tumors than in Ta tumors preventing tumour progression [12], [31], and [32]. In our study, histologic grade was predictive of progression. Although in most reports this factor did not correlate with the time to tumor recurrence or progression in either univariate or multivariate analysis [5], in one large recent study [12], high tumor grade correlated with shorter time to progression.
Traditionally, TIS has been associated with worse outcome after BCG [22], [28], [33], and [34]. However, recent reports [29], and [35] have failed to confirm a link between TIS and the BCG response. Our analysis identified associated TIS as an independent factor for recurrence but not for progression. In our series we included 80 patients with associated TIS, with 70 of them having high-grade papillary tumors. TIS was highly correlated with grade and this might decrease its importance in the multivariate analysis of progression. Some authors have found the poor prognosis of T1 tumors associated with TIS when patients are treated with BCG [29], [36], and [37]. However, other authors have reported that a number of T1G3 tumors associated with TIS have risk of recurrence without progression [38]. The Southwest Oncology Group has demonstrated that TIS generally responds favorably to BCG [39].
Early recurrence (recurrence at first control cystoscopy) after BCG therapy was an independent predictive factor for progression. Solsona et al reported that the 80% of patients who did not achieve a complete response by 3 mo had progression [40]. Herr et al had previously found that bladder cancer onset <1 yr before the beginning of the BCG therapy was associated with tumor progression [31]. A concern regarding this approach is the incidence of residual tumor after TUR and the potential under-staging of TUR [40], [41], and [42]. In our series, repeated TUR was performed based on surgeon recommendation and patients with treatment failure after the initial induction course of intravesical therapy received a repeated induction course. Although leaving the decision to the surgeon must be considered a bias that can explain the high number of potential early recurrences, we consider that our findings are in agreement with those of Solsona et al [40], who reported a slight influence of residual tumors or under-staging in their overall results.
In summary, considering that a significant reduction in survival occurs as result of progression to muscle-invasive after BCG failure, it is necessary to develop predictive models for detecting tumors with highly malignant potential. In our preliminary analysis we found that history of recurrence, T1, high grade, and early recurrence were the most important prognostic factors in patients receiving BCG immunotherapy. Most of these factors were associated with recurrence and progression in patients treated with intravesical chemotherapy [1], especially history of recurrence and recurrence at first cystoscopy, which also were predictive factors for recurrence and progression in our patients.
5. Conclusions
Significant independent predictors for recurrence were female gender, history of recurrence, multiplicity, and presence of associated TIS. Furthermore, history of recurrence, high grade, T1 stage, and recurrence at first cystoscopy were independent predictors of progression by multivariate analysis.
Conflicts of interest
In the present study there was no financial support which might be considered as constituting an apparent conflict of interest.
References
- [1] F. Millan-Rodriguez, G. Chechile-Toniolo, J. Salvador-Bayarri, F. Algaba, J. Vicente-Rodriquez. Primary superficial bladder cancer risk groups according to progression, mortality and recurrence. J Urol 163 (2000) (680 - 684) Crossref.
- [2] A.P. van der Meijden, R.J. Sylvester. BCG immunotherapy for superficial bladder cancer: an overview of the past, the present and the future. EAU Update Series 1 (2003) (80 - 86) Crossref.
- [3] A. Bohle, D. Jocham, P.R. Bock. Intravesical bacillus Calmette-Guérin versus mitomycin C for superficial bladder cancer: a formal metaanalysis of comparative studies on recurrence and toxicity. J Urol 169 (2003) (90 - 95) Crossref.
- [4] R.J. Sylvester, A.P.M. van der Meijden, D.L. Lamm. Intravesical bacillus Calmette-Guérin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials. J Urol 168 (2002) (1964 - 1970)
- [5] F. Saint, L. Salomon, R. Quintela, et al.. Do prognostic parameters of remission versus relapse after bacillus Calmette-Guérin (BCG) immunotherapy exist? Analysis of a quarter century of literature. Eur Urol 43 (2003) (351 - 361) Abstract, Full-text, PDF, Crossref.
- [6] H.W. Herr, P.C. Sogani. Does early cystectomy improve the survival of patients with high risk superficial bladder tumors?. J Urol 166 (2001) (1296 - 1299)
- [7] R.J. Sylvester, A.P.M. van der Meijden, W. Oosterlinck, et al.. 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. Eur Urol 49 (2006) (466 - 477) Abstract, Full-text, PDF, Crossref.
- [8] M. Takashi, K. Wakai, T. Hattori, et al.. Multivariate evaluation of factors affecting recurrence, progression, and survival in patients with superficial bladder cancer treated with intravesical bacillus Calmette-Guérin (Tokyo 172 strain) therapy: significance of concomitant carcinoma in situ. Int Urol Nephrol 33 (2002) (41 - 47) Crossref.
- [9] F. Millan-Rodriguez, G. Chechile-Toniolo, J. Salvador-Bayarri, J. Palou, J. Vicente-Rodriguez. Multivariate analysis of the prognostic factors of primary superficial bladder cancer. J Urol 163 (2000) (73 - 78) Crossref.
- [10] M.G. Friedrich, U. Pichlmeier, H. Schwaibold, S. Conrad, H. Huland. Long-term intravesical adjuvant chemotherapy further reduces recurrence rate compared with short-term intravesical chemotherapy and short-term therapy with bacillus Calmette-Guérin (BCG) in patients with non–muscle-invasive bladder carcinoma. Eur Urol 52 (2007) (1123 - 1130) Abstract, Full-text, PDF, Crossref.
- [11] C.P. Evans. Editorial comment on: Long-term intravesical adjuvant chemotherapy further reduces recurrence rate compared with short-term intravesical chemotherapy and short-term therapy with bacillus Calmette-Guérin (BCG) in patients with non–muscle-invasive bladder cancer. Eur Urol 52 (2007) (1129 - 1130) Abstract, Full-text, PDF, Crossref.
- [12] J.A. Martinez-Piñeiro, N. Flores, S. Isorna, et al., for CUETO (Club Urológico Español de Tratamiento Oncológico). Long-term follow-up of a randomized prospective trial comparing a standard 81 mg dose of intravesical bacille Calmette-Guérin with a reduced dose of 27 mg in superficial bladder cancer. BJU Int 89 (2002) (671 - 680)
- [13] T. Shinka, M. Matsumoto, H. Ogura, A. Hirano, T. Ohkawa. Recurrence of primary superficial bladder cancer treated with prophylactic intravesical Tokyo 172 bacillus Calmette-Guérin: a long-term follow-up. Int J Urol 4 (1997) (139 - 143) Crossref.
- [14] A. Morales, C. Nickel, J.W.L. Wilson. Dose-response of bacillus Calmette-Guérin in the treatment of superficial bladder cancer. J Urol 147 (1992) (1256 - 1258)
- [15] D. Mack, W. Holtl, P. Bassi, et al.. European Organisation Research and Treatment of Cancer Genitourinary. The ablative effect of quarter dose bacillus Guérin on a papillary marker lesion of the bladder. J Urol 165 (2001) (401 - 403) Crossref.
- [16] A. Kumar, D. Dubey, P. Bansal, A. Mandhani, S. Naik. Urinary interleukin-8 predicts the response of standard and low dose intravesical bacillus Calmette-Guérin (modified Danish 1331 strain) for superficial bladder cancer. J Urol 168 (2002) (2232 - 2235)
- [17] C.W. Cheng, M.T. Ng, S.Y. Chan, W.H. Sun. Low dose adjuvant therapy for superficial bladder cancer literature review. ANZ J Surg 74 (2004) (569 - 572) Crossref.
- [18] A. Ojea, J.L. Nogueira, E. Solsona, et al.. members of the CUETO Group (Club Urológico Español De Tratamiento Oncologico). A multicenter, randomised prospective trail comparing three intravesical adjuvant therapies for intermediate-risk superficial bladder cancer: low-dose bacillus Calmette-Guerin (27 mg) versus very low-dose bacillus Calmette-Guerin (13.5 mg) versus mitomycin C. Eur Urol 52 (2007) (1398 - 1406) Abstract, Full-text, PDF, Crossref.
- [19] J.A. Witjes. What is the optimal BCG dose in non–muscle-invasive bladder cancer?. Eur Urol 52 (2007) (1300 - 1302) Abstract, Full-text, PDF, Crossref.
- [20] J.A. Martinez-Piñeiro, L. Martinez-Piñeiro, E. Solsona, et al., Club Urologico Espanol de Tratamiento Oncologico (CUETO). Has a 3-fold decreased dose of bacillus Calmette-Guérin the same efficacy against recurrences and progression of T1G3 and Tis bladder tumors than the standard dose? Results of a prospective randomized trial. J Urol 174 (2005) (1242 - 1247)
- [21] Solsona E, Gonzalez M, Fernandez JM, Unda M, Bernuy C, Pertusa C, members of CUETO Group Random trial comparing intravesical chemo-induction with MMC to immunotherapy with BCG versus intravesical BCG, in patients with intermediate-high risk superficial bladder cancer. Preliminary results of the CUETO Trial no. 93009. Abstract. XIXth Congress of the European Association of Urology, Vienna, 2004.
- [22] R. Hurle, A. Losa, A. Ranieri, P. Graziotti, A. Lembo. Low dose Pasteur bacillus Calmette-Guérin regime in stage T1, grade 3 bladder cancer therapy. J Urol 156 (1996) (1602 - 1605)
- [23] T. Lebret, F. Gaudez, J.M. Hervé, P. Barré, P.M. Lugagne, H. Botto. Low dose BCG instillations in the treatment of stage T1 grade 3. Eur Urol 34 (1998) (67 - 72) Crossref.
- [24] F. Saint, J.J. Patard, P. Maille, et al.. Prognostic value of a T helper 1 urinary cytokine response after intravesical bacillus Calmette-Guérin treatment for superficial bladder cancer. J Urol 167 (2002) (364 - 367)
- [25] H. Akaza, S. Hinotsu, Y. Aso, T. Kakizoe, K. Koiso. Bacillus Calmette-Guérin treatment of existing papillary bladder cancer and carcinoma in situ of the bladder. Four-year results. The Bladder Cancer BCG Study Group. Cancer 75 (1995) (552 - 559) Crossref.
- [26] C. Lundholm, B.J. Norlen, P. Ekman, et al.. A randomized prospective study comparing long-term intravesical instillations of mitomycin C and bacillus Calmette-Guérin in patients with superficial bladder carcinoma. J Urol 56 (1996) (372 - 376) Crossref.
- [27] F.N. Joudi, B.J. Smith, M.A. O’Donnell, B.R. Konety. The impact of age on the response of patients with superficial bladder cancer to intravesical immunotherapy. J Urol 175 (2006) (1634 - 1639)
- [28] A. Losa, R. Hurle, A. Lembo. Low dose Bacillus Calmette-Guérin for carcinoma in situ of the bladder: long-term results. J Urol 163 (2000) (68 - 72)
- [29] J.W. Davis, S.I. Sheth, M.J. Doviak, P.F. Schellhammer. Superficial bladder carcinoma treated with bacillus Calmette-Guérin: progression-free and disease specific survival with 10-year minimum follow-up. J Urol 167 (2002) (494 - 501)
- [30] A.R. Zlotta, J.C. Noel, I. Fayt, et al.. Correlation and prognostic significance of p53, p21WAF1/CIP1 and Ki-67 expression in patients with superficial bladder tumors treated with bacillus Calmette-Guérin intravesical therapy. J Urol 161 (1999) (792 - 798)
- [31] H.W. Herr, R.A. Badalament, D.A. Amato, V.P. Laudone, W.R. Fair, W.F. Whitmore. Superficial bladder cancer treated with Bacillus Calmette-Guérin: a multivariate analysis of factors affecting tumor progression. J Urol 141 (1989) (22 - 29)
- [32] E.A. Klein, A. Rogatko, H.W. Herr. Management of local Bacillus Calmette-Guérin failures in superficial bladder cancer. J Urol 147 (1992) (601 - 605)
- [33] H. Ovesen, T. Horn, K. Steven. Long-term efficacy of intravesical bacillus Calmette-Guérin for carcinoma in situ: relationship of progression to histologic response and p53 nuclear accumulation. J Urol 157 (1997) (1655 - 1659)
- [34] R. Hurle, A. Losa, A. Manzetti, A. Lembo. Intravesical bacillus Calmette–Guérin in stage T1 grade 3 bladder cancer therapy: a 7-years follow-up. Urology 54 (1999) (258 - 263) Crossref.
- [35] V. Pansadoro, P. Emiliozzi, F. de Paula, P. Scarpone, A. Pansadoro, C.N. Sternberg. Long-term follow-up of G3T1 transitional cell carcinoma of the bladder treated with intravesical bacillus Calmette-Guérin: 18-year experience. Urology 59 (2002) (227 - 231) Crossref.
- [36] T.R.L. Griffiths, M. Charlton, D.E. Neal, P.H. Powell. Treatment of carcinoma in situ with intravesical bacillus Calmette-Guérin without maintenance. J Urol 167 (2002) (2408 - 2412)
- [37] B.P. Schrier, M.P. Hollander, B.W.G. van Rhijn, L.A.L.M. Kiemeney, J.A. Witjes. Prognosis of muscle-invasive bladder cancer: difference between primary and progressive tumors and implications for therapy. Eur Urol 45 (2004) (292 - 296) Abstract, Full-text, PDF, Crossref.
- [38] B. Gattegno. T1G3 Bladder cancer: conservative management or cystectomy?. Eur Urol 45 (2004) (399 - 400) Abstract, Full-text, PDF, Crossref.
- [39] D.L. Lamm, B.A. Blumenstein, J.D. Crissman, et al.. Maintenance bacillus Calmette-Guérin immunotherapy for recurrent TA T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group study. J Urol 163 (2000) (1124 - 1129) Crossref.
- [40] E. Solsona, I. Iborra, R. Dumont, J. Rubio-Briones, J. Casanova, S. Almenar. The 3-month clinical response to intravesical therapy as a predictive factor for progression in patients with high risk superficial bladder cancer. J Urol 164 (2000) (685 - 689)
- [41] M. Brausi, L. Collette, K. Kurth, et al., EORTC Genito-Urinary Tract Cancer Collaborative Group. 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. Eur Urol 41 (2002) (523 - 531) Abstract, Full-text, PDF, Crossref.
- [42] A.M. Nieder, M. Brausi, D. Lamm, et al.. Management of stage t1 tumors of the bladder: International Consensus Panel. Urology 66 (Suppl 6A) (2005) (108 - 125) Crossref.
Footnotes
a Department of Urology, Hospital Central of Asturias, University of Oviedo, Oviedo, Spain
b Department of Urology, IVO, Valencia, Spain
c Department of Urology, Hospital of Basurto, Bilbao, Spain
d Department of Urology, Hospital La Paz, Madrid, Spain
e Department of Urology, Hospital Juan Canalejo, A Coruña, Spain
f Department of Urology, Hospital Marques Valdecilla, Santander, Spain
g Department of Statistics, Hospital La Paz, Madrid, Spain
h Department of Urology, Hospital Xeral, Vigo, Spain
i Department of Urology, Hospital Cruces, Bilbao, Spain
j Department of Urology, Hospital Clinico San Carlos, Madrid, Spain
k Department of Urology, Hospital General, Jerez de la Frontera, Spain
l Department of Urology, Hospital Dr. Negrin, Las Palmas de Gran Canaria, Spain
m Department of Urology, Hospital La Princesa, Madrid, Spain
n Department of Urology, Hospital Galdakao, Galdakao, Spain
o Department of Urology, Hospital Virgen del Camino, Pamplona, Spain
p Department of Urology, Hospital Alvarez-Buylla, Mieres, Spain
q Department of Urology, Hospital La Mancha, Alcazar de San Juan, Spain
r Department of Urology, Hospital Miguel Servet, Zaragoza, Spain
Corresponding author. Department of Urology, Hospital Central of Asturias, University of Oviedo, C/Celestino Villamil s/n, 33006-Oviedo, Asturias, Spain.
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